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Shekelle P, Newberry S, Maglione M, et al. Assessment of the Need to Update Comparative Effectiveness Reviews: Report of an Initial Rapid Program Assessment (2005–2009) [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2009 Sep 10.

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Assessment of the Need to Update Comparative Effectiveness Reviews: Report of an Initial Rapid Program Assessment (2005–2009) [Internet].

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ATTACHMENT IIEvidence Tables

CER 1 - Comparative Effectiveness of Management Strategies for Gastroesophageal Reflux Disease

Conclusions From CER Executive SummaryIs this conclusion almost certainly still supported by the evidence?Has there been new evidence that may change this conclusion?References
Key Question 1: What is the evidence of the comparative effectiveness of medical, surgical, and endoscopic treatments for improving objective and subjective outcomes in patients with chronic GERD?
Medical therapy with PPIs and surgery (fundoplication) appeared to be similarly effective for improving symptoms and decreasing esophageal acid exposure. 10 percent to 65 percent of surgical patients still require medications.

The limited data available did not support a significant benefit of fundoplication compared with medical therapy for preventing Barrett’s esophagus or esophageal adenocarcinoma.
YesNew Evidence:
a) Multicenter RCT comparing laparoscopic antireflux surgery (LARS) vs esomeprazole were similarly effective and well-tolerated over 3 years.
b) Lundell, 2008 Gut
Of the three nonrandomized studies that compared an endoscopic procedure with laparoscopic fundoplication in patients with GERD documented by pH or endoscopy, the longest followup was 8 months, and all three studies had significant bias that may invalidate the results. Two studies reported that more patients treated with laparoscopic fundoplication were satisfied with their results compared with those who had EndoCinchTM. One of these studies and a study of StrettaÒ also found less need for PPIs in patients who had fundoplication.
Comparison of medical treatments with endoscopic procedures.
Yes New Evidence:
a) Comparison of endoscopic with laparoscopic fundoplication. Nonrandomized prospective study of 51 pts with persistent GERD comparing transesophageal endoscopic plication (TEP) with laparoscopic Nissen fundoplication (LNF) finds both techniques improved symptom score, acid regurgitation, quality of life, and reduced requirement for PPIs. Control of heartburn and acid reflux was better for LNF. TEP, like LNF, had comparable safety and efficacy.

b) RCT comparing endoluminal gastroplasty (EndoCinch) with polymer injection (Enteryx) over 6 months demonstrates equal effectiveness in reducing PPI dosages and improving symptoms of pts.
a) Mahmood, 2006 AJG
b) Domagk 2006 AJG
There was no head-to-head comparison of medical treatments with endoscopic treatments. Yes New Evidence: None
PPIs were superior to H2RAs in resolution of GERD symptoms at 4 weeks and healing of esophagitis at 8 weeks. There was no difference between omeprazole, lansoprazole, pantoprazole, and rabeprazole for relief of symptoms at 8 weeks.
No significant difference was found in the comparisons of esomeprazole 40 mg with lansoprazole 30 mg or pantoprazole 40 mg for relief of symptoms at 4 weeks. Similarly, there was no difference in the comparison of esomeprazole 20 mg with omeprazole 20 mg in relief of symptoms at 4 weeks.
No New Evidence:
a) Meta-analysis performed of 10 studies comparing rates of endoscopic healing, symptom relief, and adverse events of esomeprazole versus alternative PPIs in treatment of erosive esophagitis. Esomeprazole demonstrated a statistically significant improvement, but only modest clinical benefit in improved healing of erosive esophagitis at 8-weeks. Found no evidence of what is believed to be “clinically meaningful improvement in symptom relief” between PPIs

b) Systematic review of RCTs in pts with reflux esophagitis demonstrates esomeprazole consistently has higher healing rates when compared with standard dose PPIs at 4 and 8 weeks.

c) RCT of pts with erosive esophagitis comparing PPI maintenance therapy demonstrates esomeprazole 20 mg qday more effective than lansoprazole 15 mg qday in maintaining endoscopic/symptomatic mission in pts with healed erosive esophagitis

d) RCT of GERD pts demonstrates famotidine 20 mg BID and omeprazole 20 mg qday were both effective in improving GERD symptoms, particularly non-erosive GERD disease over a period of 8 weeks.

e) RCT of pts with erosive esophagitis demonstrates esomeprazole 40 mg super to pantoprazole 40 mg for healing of erosive esophagitis and providing resolution of associated heartburn at 4 and 8-weeks.

f) RCT of pts with healed erosive esophagitis demonstrates esomeprazole 20 mg superior to pantoprazole 20 mg for maintenance therapy following healed erosive esophagitis and relief of GERD sytmpoms at 6 months.

g) RCT of pts with NERD, found that in patients who are H pylori negative, omeprazole more effective than famotidine for control of GERD symptoms, but in H. pylori positive symptoms, similar efficacy was observed

h) RCT of pts with moderate or severe erosive esophagitis demonstrates esomeprazole 40 qday heals EE faster and in more pts than lansoprazole 30 mg qda at 8 weeks. At 4 weeks, esomeprazole resolved heartburn in more pts than lansoprazole.
a) Gralnek, 2006 CGH
b) Edwards 2006 APT
c) Devault 2006 CGH
d) Wada, 2006 APT
e) Labenz, 2005 APT
f) Labenz, 2005 APT
g) Fujiwara 2005, APT
h) Fennerty, 2005 APT
New topic: Timing of treatment -“On-demand” vs “intermittent” vs “continuous” therapy X a) Systematic review of 17 studies. On-demaind PPI effective in long- term management of pts with NERD or mild and uninvestigated forms of GERD, but not in pts with severe erosive esophagitis. These studies include on-demand PPI vs. placebo and continuous PPI.

b) Systematic review of the efficacy of intermittent and on-demand therapy with H2As and PPIs in pts with erosive esophagitis or symptomatic heartburn. Regarding intermittent therapy, neither PPIs or H2As were effective in maintaining control of esophagitis pts. In regards to on-demand therapy, PPIs may work in a proportion of non- erosive GERD pts.

c) RCT of pts with erosive reflux esophagitis found that once daily esomeprazole 20 mg was better than “on-demand” for maintaining healed erosive esophagitis at 6 months.

d) RCT of pts with NERD or low grade esophagitis demonstrates a slightly higher rate of symptom relief at 6 months with the continuous rabeprazole group versus the on-demand group. For overall quality of life, there was not difference between the groups. Daily consumption was lower for the on-demand treatment group.

e) RCT of GERD pts demonstrates that at 6 months, on-demand treatment with lansoprazole in symptomatic pts after short-term, continuous treatment treatment is more effect than placebo in improving symptoms
a) Pace, 2007 APT
b) Zacny, 2005 APT
c) Sjostedt, 2005 APT
d) Bour, 2005 APT
e) Bigard, 2005 APT
New topic: Laryngeal/pharyngeal symptoms attributed to GERD. Caveat: the cause and effect relationship of GERD and laryngophayngeal reflux remains unclear X a) Meta-analysis of 5 studies using high-dose PPIs for treatment of laryngeal or pharyngeal symptoms was no more effective than placebo in provident symptomatic improvement or resolution of laryngopharyngeal symptoms.

b) RCT for of 39 pts with laryngopharyngeal reflux treated with pantoprazole vs. placebo. No difference in symptom improvement was found between the two groups.

c) Systematic review and meta-analysis of RCTs of pts with chronic cough associated with GERD demonstrating use of PPI for treat has some effect in some adults, but is less universal than suggested in consensus guidelines on chronic cough.
a) Gatta, 2007 APT
b) Wo, 2006 AJG
c) Chang, 2006 BMJ
New topic: Acupuncture vs. doubling PPI dose X a) RCT of 30 patients with refractory heartburn. All pts on PPI once daily. If symptoms refractory to treatment, pts randomized to doubling PPI dose vs. acupuncture twice weekly. Adding acupuncture was more effective than doubling PPI dose in controlling GERD symptoms in this pt populationa) Dickman, 2007 APT
New topic: Double dose or change PPI X a) RCT of pts with persistent heartburn symptoms found switching pts to different PPI was as effective as increasing PPI dosage to twice daily for controlling heartburn symptoms.a) Fass, 2006 CGH
New topic: Long-term prevention of erosive or ulcerative GERD relapse X a) RCT of pts with healthed erosive/ulcerative GERD found 5-year maintenance therapy with rabeprazole effective in preventing replase of erosive/ulcerative GERD. 20 mg better than 10 mg. Both better than placebo.a) Caos, 2005 APT
New topic: New endoscopic techniques X a) Radiofrequency energy delivery allows reduction or discontinuation of PPI therapy in patients with PPI-dependent symptoms.a) Coron, 2008 APT
New topic: AZD0865, potassium- competitive acid blocker X a) RCT comparing a potassium-competitive acid blocker (AZD0865) did not provide clinical benefit over esomeprazole in pts with nonerosive reflux disease

b) RCT of three doses of potassium-competitive acid blocker (AZD0865) (25, 50, 75 mg) and esomeprazole 40 mg. At 4 weeks, healing rates of esophagitis similar to esomeprazole. No significant differences in heartburn control. AZD0865 at 75 mg demonstrated reversible increases in liver transaminases.
a) Dent, 2008 AJG b) Kahrilas, 2007 CGH
New topic: Nocturnal symptoms X a) RCT in GERD patients with nocturnal heartburn concludes single- dose rabeprzole 20mg increases intragastric pH more than pantoprazole 40mg qday.

b) RCT in GERD patients with nocturnal symptoms, comparing immediate-release omeprazole 40 mg oral suspension, delayed release lansoprazole 30 mg capsules, and delayed-release esomeprazole 30 mg capsules. Omeprazole superior to lansoprazole and comparable to esomeprazole.

c) RCT in erosive esophagitis patients on daily PPI with experience night-time heart burn. OTC ranitidine 75 mg demonstrated decrease in symptoms vs. placebo on day 3, but not on day 14.

d) RCT of pts with nocturnal GERD demonstrates immediate-release omeprazole reduced nocturned gastric acidity better than delayed- release pantoprazole.
a) Warrington, 2007 APT
b) Katz, 2007 APT
c) Vakil, 2006 APT
d) Castell, 2005 APT
For maintenance medical treatment of 6 months to 1 year, PPIs taken at a standard dose were more effective than those taken at a lower dose.No new evidence foundNew Evidence: None
Laparoscopic fundoplication was as effective as open fundoplication for relieving heartburn and regurgitation, improving quality of life, and decreasing use of antisecretory medications. Almost 90 percent of patients who were followed for 5 or more years in both surgical arms reported improvement in symptoms.No new evidence foundNew Evidence: None
Compared to sham, StrettaTM was more effective in improving symptoms of reflux and improving quality of life at 6 months and was associated with a decrease in the need for antisecretory medications. Improvement of esophageal pH exposure compared with sham could not be demonstrated for StrettaTM.No new evidence foundNew Evidence:

a) Compared to sham, endoscopic gastroplication using Endocinch device reduced acid-inhibitory drug use, improved GERD symptoms, and improved quality of life
a) Schwartz, 2007 Gut
Key Question 2: Is there evidence that effectiveness of medical, surgical, and endoscopic treatments varies for specific patient subgroups?
Patients on maintenance antireflux medications may have higher rates of esophagitis if they have any of the following factors: increased severity of esophagitis at baseline (pretreatment), younger age, and moderate to severe regurgitation.No new evidence foundNew Evidence: None
There is no substantial evidence to support a difference in surgical outcome based on age, preoperative presence or severity of esophagitis, lower esophageal sphincter incompetence, or esophageal body hypomotility.
Patients treated surgically who have a history of psychiatric disorders may have worse symptom and satisfaction outcomes than those without a significant psychiatric history.
No new evidence foundNew Evidence: None
New topic: Early response to therapy predicts complete resolutionXa) Pooled analysis from three multicenter, double-blind trials of patients receiving PPI. Heartburn resolution during 1st week of PPI therapy is the best predictor of treatment success at week 4.a) Talley, 2006 APT
Key Question 3: What are the short- and long-term adverse effects associated with specific medical, surgical, and endoscopic therapies for GERD?
Higher adverse event rates were described for PPIs than for H2RAs or placebo. The most commonly cited events for PPIs and H2RAs were headache, diarrhea, and abdominal pain.No new evidence foundNew Evidence: None
The most commonly reported complications occurring intraoperatively or within 30 days after open fundoplication were the need for splenectomy, dysphagia, inability to belch, and inability to vomit. The most commonly reported complications for laparoscopic procedures were gastric or esophageal injury or perforation, splenic injury or splenectomy, pneumothorax, bleeding, pneumonia, fever, wound infections, bloating, and dysphagia. Major complications were generally reported at very low rates.No new evidence foundNew Evidence: None
Frequently reported complications for endoscopic treatments(intraoperatively or within 30 days after the procedure included chest or retrosternal pain, gastrointestinal injury, bleeding, and short-term dysphagia. The frequency and types of complications varied with the different procedures. Serious complications, including fatalities, have also been described.No new evidence foundNew Evidence: None
New topic: Rebound acid hypersecretionXa) Systematic review of 8 studies demonstrates no strong evidence for clinically relevant increased acid production after cessation of PPI therapy. Only 1 study included patients with reflux esophagitis and the remaining 7 studies enrolled healthy volunteers.a) Gatta, 2007 APT
New topic: Risk of bacterial gastroenteritisXa) Case control study. Pts with acute bacterial gastroenteritis and compared with a control group without acute bacterial GE. Current PPI use was associated with increased risk of bacterial GE. H2A use not associated with increased risk. Caveat is that this is a heterogenous patient population, including some with GERD.a) Rodriguez, 2007 CGH
Are there new data that could inform the key questions that might not be addressed in the conclusions?

CER 3 - Comparative Effectiveness of Epoetin and Darbepoetin for Managing Anemia in Patients Undergoing Cancer Treatment

Author, year, agent, trial name, countryInclusions/Exclusion Criteria, Sample#Study design, interventionOutcomes AssessedFindingsQuality/Notes
COMPARATIVE EFFICACY AND SAFETY
Hematologic Response
(4) Pirker et al., 2008Patients w/extensive- stage small-cell lung cancer receiving first-line platinum-containing chemo (carboplatin or cisplatin + etoposide) (n=600)Phase III RCT DA 300 ug, 1x/wk for 4 weeks, then every 3 weeks for up to 6 cycles chemo; patients observed until death or until end-of- study visitChange in Hgb concn from baseline to end of chemo and overall survivalDA maintained Hgb levels sign higher than placebo (p≤0.001); Transfusion risk sign. ↓ (HR, 0.40, 95% CI, 0.29–0.55)
No difference in survival (HR, 0.93, 95% CI, 0.78–1.11, p=0.431); DA assoc w/↑ thromboembolic events (9% vs. 5%)
Study reinforces benefit of erythropoesis stimulating agents (ESAs) in reducing transfusions but not improving survival
(8) Han et al., 2008Patients w/limited disease small-cell lung cancer (LD-SCLC) receiving two 28-day cycles cisplatin (30mg/m(2)) days 1 and 8 and irinotecan at a dose of 60 mg/m(2) (Days 1, 8, and 15) followed by two 21-day cycles of cisplatin at a dose of 60 mg/m(2) (Day 1) and etoposide at a dose of 100 mg/m(2) (Days 1–3) with concurrent twice- daily thoracic radiotherapy for a total of 45 days (n=76, but 15 of 36 amifostine pts did not get treatment)Phase II RCT: amifostine (500mg) vs. epo-alpha (10,000IU sc 3x/wk)Anemia and adverse eventsAmifostine~↑febrile neutropenia (p=0.003); grade 2–3 nausea (p=0.03); grade 4 leukopenia (p=0.05); Grade 3 esophagitis in 30% of amifostine pts. vs. 9% of epo patients (P = .059).
Epo associated with less grade 2–3 anemia (P = .031) and lower decreases in Hgb during therapy (P = .016).
Median survival times for both treatment arms were comparable (22.6 months in the amifostine arm vs 25.6 months in the epoetin-alpha arm; P = .447)
Epo was more effective than amifostene in preventing severe anemia in LD-SCLC pts undergoing chemo- hyperfractionated radiotherapy
(15) Aapro et al., 2008b Breast Cancer-Anemia and the Value of Erythropoetin (BRAVE) studyPatients w/metastatic breast cancer treated w/anthracycline- and/or taxane-based chemo, Hb<12.9Open-label multi-center RCT comparing EB (30,000U sc, Q1W, 24 wks1°:Survival 2°: progression-free survival, transfusion- and severe anemia-free survival, Hb response, safety, and QoL 18 months followupAt follow-up Overall Survival: EB: 62/231 (27%) vs. Control: 63/232 (27%) No difference (hazard ratio [HR] = 1.07; 95% CI, 0.87 to 1.33, P = .522) Progression-free survival: no difference (HR = 1.07; 95% CI, 0.89 to 1.30, P = .448).
Transfusion- and severe anemia-free survival: significant ↑ compared with control (HR = 0.59; P = .0097).
Median Hb: EB↑ Hb (11.7 g/dL at baseline to 13.3 g/dL at 24 weeks) vs. no change with control (11.5 v 11.4 g/dL).
TEEs: EB->↑ TEEs cf. controls (13% v 6%; P = .012) with no difference in serious TEEs (4% v 3%).
QoL: EB-> no significant improvement QoL in this study (in patients with a high baseline Hb value)
EB increased Hb in patients with initial Hb less than 12.9 g/dL. No difference was detected in overall survival but design may have precluded detection.
(16) Wright et al., 2007Patients with non-small cell carcinoma of the lung not curable with therapy and baseline Hb<12.1g/dl. (n=70: 300 intended but study stopped early)Multicenter RCT:
EA, sc, q1w, 12 weeks vs. placebo
Change in Functional Assessment of Cancer Therapy Anemia scores from baseline to 12 weeks; QOL, survivalEA decreased median survival (63 vs. 129 days, HR, 1.84, p=0.04), but EA appeared to ↑ Hb. Numbers too small to assess effect on QOL. EA’s association with decreased survival led to early termination of study.
(54) Wilkinson et al., 2006 UKOvarian cancer patients w/ Hb ≤12 g/dl receiving platinum chemo (n=182)Multicenter, open-label CCT:
EA, 10,000–20,000 IU q3w plus best standard treatment (BST) vs. placebo+BST
Hb, transfusion rates, QOLHb:
EA group had 1.8g/dl increase by 4–6 weeks, significantly increased from baseline and significantly greater than BST alone through end of study (p<0.001).
Transfusion rate: Significantly fewer EA than BST patients required transfusion(s) after the first 4 weeks of treatment (7.9 vs 30.5%; P<0.001)
QOL: EA->significant (P≤0.04) differences for all three median CLAS scores (Energy Level, Ability to Do Daily Activities, Overall QOL) and the median average CLAS score during chemotherapy
EA increased Hb, reduced transfusion use, and improved QOL in anemic ovarian cancer patients
(62) Razzouk et al., 2006Children 5–18 yoa receiving myelosuppressive chemo for nonmyeloid malignancies (excluding brain tumors) who developed anemia (222)RCT EA 600–900 U/kg q1w vs. placebo, 16 wksPedsQL-GCS: Patient and parent QOL (generic score [GS] and cancer-specific [CS]), Hb, AEMean final values for GS total score (P = .763 among patients; P = .219 among parents) and CS domain scores (P≥0.238≥P 0.081, respectively) were not significantly different between treatment groups.
EPO-treated patients had greater increases in Hb overall (P = 0.002) and were more likely to be transfusion free after 4 weeks (38.7% v 22.5%; P =0 .010). Change in Hb correlated with change in PedsQL- GCS total score in the EPO group (r = 0.242; P = .018), but not in the placebo group (r = 0.086; P = .430).
AEs were comparable between treatment groups.
Study confirmed the tolerability and hematologic benefits of once-weekly EPO in children with cancer. No significant difference in HRQOL between treatment groups, but a significant positive correlation was observed between Hb changes and HRQOL changes in the EPO group.
(63) Norager et al., 2006Patients admitted to a hospital for planned surgery for colorectal cancer; anemia not an inclusion criterion (151)RCT of DA 300 or 150 ug q1w vs. placebo depending on Hb status[?]Post-op work capacity, QOL, fatigue, postural sway, change in Hb d.7 and 30DA assoc with sign greater work capacity on d. 7 and 30 (p-0.03 for each) cf placebo.
No diffs in fatigue, postural sway or QOL Decrease in Hb: DA significantly reduced the decrease in Hb on d.7 (p<0.01) and resulted in earlier return to pre-op Hb (p<0.01) cf. placebo.
Perioperative DA treatment improved postoperative work capacity and Hb concentrations, but had no effect on postoperative fatigue, postural sway, QoL and muscle strength
Transfusion Rate
(2) Smith et al., 2008Patients with active cancer and anemia (how defined?), not receiving or planning to receive cytotoxic chemotherapy or myelosuppressive radiotherapy (n not reported in abstract)Phase III multi-center RCT comparing Darbepo alpha (DA) to placebo:
6.75 ug/kg every 4 weeks (Q4W) for up to 16 weeks
Need for transfusion in wks 5–17; adverse events; survival (over 2- year followup)DA assoc with non-statistically significant ↓ in # transfusions; DA assoc. with stat. sign. ↑ in cardiovascular and thromboembolic events, deaths in first 16 wks. Sign.↓ long-term survival (p=0.22) Survival effect varied by sex, tumor type, geographic region and disappeared w/sensitivity analysis*Study does not support use of DA in this subset of cancer patients w/ anemia
(4) Pirker et al., 2008Patients w/extensive- stage small-cell lung cancer receiving first-line platinum-containing chemo (carboplatin or cisplatin + etoposide) (n=600)Phase III RCT DA 300 ug, 1×/wk for 4 weeks, then every 3 weeks for up to 6 cycles chemo; patients observed until death or until end-of- study visitChange in Hgb concn from baseline to end of chemo and overall survivalDA maintained Hgb levels sign higher than placebo (p ≤0.001); Transfusion risk sign. ↓ (HR, 0.40, 95% CI, 0.29–0.55) No difference in survival (HR, 0.93, 95% CI, 0.78–1.11, p=0.431); DA assoc w/↑ thromboembolic events (9% vs. 5%)Study reinforces benefit of erythropoesis stimulating agents (ESAs) in reducing transfusions but not improving survival
(54) Wilkinson et al., 2006 UKOvarian cancer patients w/ Hb≤12 g/dl receiving platinum chemo (n=182)Multicenter, open-label CCT:
EA, 10,000–20,000 IU q3w plus best standard treatment (BST) vs. placebo+BST
Hb, transfusion rates, QOLHb:
EA group had 1.8g/dl increase by 4–6 weeks, significantly increased from baseline and significantly greater than BST alone through end of study (p<0.001).
Transfusion rate: Significantly fewer EA than BST patients required transfusion(s) after the first 4 weeks of treatment (7.9 vs 30.5%; P<0.001)
QOL: EA->significant (P≤0.04) differences for all three median CLAS scores (Energy Level, Ability to Do Daily Activities, Overall QOL) and the median average CLAS score during chemotherapy
EA increased Hb, reduced transfusion use, and improved QOL in anemic ovarian cancer patients
(62) Razzouk et al., 2006Children 5–18 yoa receiving myelosuppressive chemo for nonmyeloid malignancies (excluding brain tumors) who developed anemia (222)RCT EA 600–900 U/kg q1w vs. placebo, 16 wksPedsQL-GCS: Patient and parent QOL (generic score [GS] and cancer-specific [CS]), Hb, AEMean final values for GS total score (P = .763 among patients; P = .219 among parents) and CS domain scores (P≥0.238; P≥0.081, respectively) were not significantly different between treatment groups.
EPO-treated patients had greater increases in Hb overall (P = 0.002) and were more likely to be transfusion free after 4 weeks (38.7% v 22.5%; P =0 .010). Change in Hb correlated with change in PedsQL-GCS total score in the EPO group (r = 0.242; P = .018), but not in the placebo group (r = 0.086; P = .430). AEs were comparable between treatment groups.
Study confirmed the tolerability and hematologic benefits of once-weekly EPO in children with cancer. No significant difference in HRQOL between treatment groups, but a significant positive correlation was observed between Hb changes and HRQOL changes in the EPO group.
(70) Glaspy et al., 2006 (also appears below for KQ2)Patients≥18yoa w/ a nonmyeloid malignancy (most commeon were lung, breast, GI) with ≥8wks planned chemotherapy, and anemia (Hb≤11g/dl) (1,220, 1209 of whom received ≥1 dose of a study drug)RCT cf. DA 200ug q2w vs. EA 40,000U q1w up to 16 wks, with identical dose adjustment rulesIncidence of RBC transfusion; Definition of non-inferiority was that upper 95% CI limit of observed difference in transfusions between groups was <11.5%, based on treatment effect observed in placebo controlled EA studiesTransfusion incidence from week 5 to the end of the treatment phase (the primary end point) was 21% in the DA group and 16% in the EA group; noninferiority was concluded because the upper 95% CI limit of the difference between groups (10.8%) was below the prespecified noninferiority margin. Sensitivity analyses using alternate statistical methods and analysis sets yielded similar results. HB, QOL, and AEs did not differ between therapies.Study shows comparable efficacy of DA Q2W and EA QW. Less frequent dosing offers potential benefits for patients, caregivers and health care providers.
(74) Aapro et al., 2006 UKCancer patients (56% hematological cancers and 44% solid tumors) (1,413)Meta-analysis of 9 RCTs EB: median initial dose 30,000IU/wkSurvival, disease progression, TEE and TEE-mortalitySurvival (0–6mos) for EB same as control (0.31 vs. 0.32 deaths/pt-year)
Mortality risk: no difference (RR 0.97, 95% CI: 0.69, 1.36; P = 0.87)
Risk of rapidly progressive disease significantly reduced for EB (RR 0.78, 95% CI: 0.62, 0.99; P = 0.042).
TEE: slightly increased risk for EB (5.9% vs 4.2% of patients)
TEE-related mortality: no difference
Epoetin beta provided a slight beneficial effect on tumour progression and did not impact on early survival or thromboembolic- related mortality
Thromboembolic events
(14) Aapro et al., 2008a UKPatients with cancer (65% solid tumors; 35% non-myeloid hematological malignancies) (n=2297) Subgroup analysis on patients w/ baseline Hb≤11g/dl (EORTC treatment guidelines)Meta-analysis of 12
RCTs
Epo-beta (EB)
Survival, tumor progression, thromboembolic events (TEEs)Mortality: no effect overall (HR=1.13; 95% CI: 0.87, 1.46; P=0.355)
No effect in patients with baseline Hb≤11g/dl (HR=1.09; 95% CI: 0.80, 1.47; P=0.579).
Tumor Progression:
A trend for a beneficial effect overall (HR=0.85; 95% CI: 0.72, 1.01; P=0.072) and in patients with an Hb≤11 (HR=0.80; 95% CI: 0.65, 0.99; P=0.041).
TEEs: EB->↑TEEs vs. controls (7% vs 4%); however, TEEs-related mortality was similar in both groups (1% each)
EB had no negative effect on survival, tumor progression, or TEEs-related mortality
(15) Aapro et al., 2008b Breast Cancer-Anemia and the Value of Erythropoetin (BRAVE) studyPatients w/ metastatic breast cancer treated w/ anthracycline- and/or taxane-based chemo, Hb<12.9Open-label multi-center RCT comparing EB (30,000U sc, Q1W, 24 wks1°:Survival
2°: progression-free survival, transfusion- and severe anemia-free survival, Hb response, safety, and QoL 18 months followup
At follow-up
Overall Survival: EB: 62/231 (27%) vs. Control: 63/232 (27%) No difference (hazard ratio [HR] = 1.07; 95% CI, 0.87 to 1.33, P = .522) Progression-free survival: no difference (HR = 1.07; 95% CI, 0.89 to 1.30, P = .448).
Transfusion- and severe anemia-free survival: significant ↑ compared with control (HR = 0.59; P = .0097).
Median Hb: EB↑ Hb (11.7 g/dL at baseline to 13.3 g/dL at 24 weeks) vs. no change with control (11.5 v 11.4 g/dL).
TEEs: EB->↑ TEEs cf. controls (13% v 6%; P = .012) with no difference in serious TEEs (4% v 3%).
QoL: EB-> no significant improvement QoL in this study (in patients with a high baseline Hb value)
EB increased Hb in patients with initial Hb less than 12.9 g/dL. No difference was detected in overall survival but design may have precluded detection.
(74) Aapro et al., 2006 UKCancer patients (56% hematological cancers and 44% solid tumors) (1,413)Meta-analysis of 9 RCTs EB: median initial dose 30,000IU/wkSurvival, disease progression, TEE and TEE-mortalitySurvival (0–6mos) for EB same as control (0.31 vs. 0.32 deaths/pt-year) Mortality risk: no difference (RR 0.97, 95% CI: 0.69, 1.36; P = 0.87)
Risk of rapidly progressive disease significantly reduced for EB (RR 0.78, 95% CI: 0.62, 0.99; P = 0.042).
TEE: slightly increased risk for EB (5.9% vs 4.2% of patients)
TEE-related mortality: no difference
Epoetin beta provided a slight beneficial effect on tumour progression and did not impact on early survival or thromboembolic- related mortality
QOL
(54) Wilkinson et al., 2006 UKOvarian cancer patients w/ Hb≤12 g/dl receiving platinum chemo (n=182)Multicenter, open-label CCT:
EA, 10,000–20,000 IU q3w plus best standard treatment (BST) vs. placebo+BST
Hb, transfusion rates, QOLHb:
EA group had 1.8g/dl increase by 4–6 weeks, significantly increased from baseline and significantly greater than BST alone through end of study (p<0.001).
Transfusion rate: Significantly fewer EA than BST patients required transfusion(s) after the first 4 weeks of treatment (7.9 vs 30.5%; P<0.001)
QOL: EA->significant (P≤0.04) differences for all three median CLAS scores (Energy Level, Ability to Do Daily Activities, Overall QOL) and the median average CLAS score during chemotherapy
EA increased Hb, reduced transfusion use, and improved QOL in anemic ovarian cancer patients
(62) Razzouk et al., 2006Children 5–18 yoa receiving myelosuppressive chemo for nonmyeloid malignancies (excluding brain tumors) who developed anemia (222)RCT EA 600–900 U/kg q1w vs. placebo, 16 wksPedsQL-GCS: Patient and parent QOL (generic score [GS] and cancer-specific [CS]), Hb, AEMean final values for GS total score (P = .763 among patients; P = .219 among parents) and CS domain scores (P≥0.238; ≥0.081, respectively) were not significantly different between treatment groups.
EPO-treated patients had greater increases in Hb overall (P = 0.002) and were more likely to be transfusion free after 4 weeks (38.7% v 22.5%; P =0 .010). Change in Hb correlated with change in PedsQL- GCS total score in the EPO group (r = 0.242; P = .018), but not in the placebo group (r = 0.086; P = .430).
AEs were comparable between treatment groups.
Study confirmed the tolerability and hematologic benefits of once-weekly EPO in children with cancer. No significant difference in HRQOL between treatment groups, but a significant positive correlation was observed between Hb changes and HRQOL changes in the EPO group.
(63) Norager et al., 2006Patients admitted to a hospital for planned surgery for colorectal cancer; anemia not an inclusion criterion (151)RCT of DA 300 or 150 ug q1w vs. placebo depending on Hb status[?]Post-op work capacity, QOL, fatigue, postural sway, change in Hb d.7 and 30DA assoc with sign greater work capacity on d. 7 and 30 (p-0.03 for each) cf placebo.
No diffs in fatigue, postural sway or QOL Decrease in Hb: DA significantly reduced the decrease in Hb on d.7 (p<0.01) and resulted in earlier return to pre-op Hb (p<0.01) cf. placebo.
Perioperative DA treatment improved postoperative work capacity and Hb concentrations, but had no effect on postoperative fatigue, postural sway, QoL and muscle strength
Tumor Response and/or Progression
(14) Aapro et al., 2008a UKPatients with cancer (65% solid tumors; 35% non-myeloid hematological malignancies) (n=2297) Subgroup analysis on patients w/ baseline Hb≤11g/dl (EORTC treatment guidelines)Meta-analysis of 12 RCTs Epo-beta (EB)Survival, tumor progression, thromboembolic events (TEEs)Mortality: no effect overall (HR=1.13; 95% CI: 0.87, 1.46; P=0.355)
No effect in patients with baseline
Hb≤11g/dl (HR=1.09; 95% CI: 0.80, 1.47; P=0.579).
Tumor Progression:
A trend for a beneficial effect overall (HR=0.85; 95% CI: 0.72, 1.01; P=0.072) and in patients with an Hb 11 (HR=0.80; 95% CI: 0.65, 0.99; P=0.041).
TEEs: EB->↑TEEs vs. controls (7% vs 4%); however, TEEs-related mortality was similar in both groups (1% each)
EB had no negative effect on survival, tumor progression, or TEEs-related mortality
(74) Aapro et al., 2006 UKCancer patients (56% hematological cancers and 44% solid tumors) (1,413)Meta-analysis of 9 RCTs EB: median initial dose 30,000IU/wkSurvival, disease progression, TEE and TEE-mortalitySurvival (0–6mos) for EB same as control (0.31 vs. 0.32 deaths/pt-year)
Mortality risk: no difference (RR 0.97, 95% CI: 0.69, 1.36; P = 0.87)
Risk of rapidly progressive disease significantly reduced for EB (RR 0.78, 95% CI: 0.62, 0.99; P = 0.042).
TEE: slightly increased risk for EB (5.9% vs 4.2% of patients)
TEE-related mortality: no difference
Epoetin beta provided a slight beneficial effect on tumour progression and did not impact on early survival or thromboembolic- related mortality
Survival
(8) Han et al., 2008Patients w/ limited disease small-cell lung cancer (LD-SCLC) receiving two 28-day cycles cisplatin (30mg/m(2)) days 1 and 8 and irinotecan at a dose of 60 mg/m(2) (Days 1, 8, and 15) followed by two 21-day cycles of cisplatin at a dose of 60 mg/m(2) (Day 1) and etoposide at a dose of 100 mg/m(2) (Days 1–3) with concurrent twice- daily thoracic radiotherapy for a total of 45 days (n=76, but 15 of 36 amifostine pts did not get treatment)Phase II RCT: amifostine (500mg) vs. epo-alpha (10,000IU sc 3x/wk)Anemia and adverse eventsAmifostine~↑febrile neutropenia (p=0.003); grade 2–3 nausea (p=0.03); grade 4 leukopenia (p=0.05); Grade 3 esophagitis in 30% of amifostine pts. vs. 9% of epo patients (P = .059).
Epo associated with less grade 2–3 anemia (P = .031) and lower decreases in Hgb during therapy (P = .016).
Median survival times for both treatment arms were comparable (22.6 months in the amifostine arm vs 25.6 months in the epoetin-alpha arm; P = .447)
Epo was more effective than amifostene in preventing severe anemia in LD-SCLC pts undergoing chemo- hyperfractionated radiotherapy
(14) Aapro et al., 2008a UKPatients with cancer (65% solid tumors; 35% non-myeloid hematological malignancies) (n=2297) Subgroup analysis on patients w/ baseline Hb 11g/dl (EORTC treatment guidelines)Meta-analysis of 12
RCTs
Epo-beta (EB)
Survival, tumor progression, thromboembolic events (TEEs)Mortality: no effect overall (HR=1.13; 95% CI: 0.87, 1.46; P=0.355)
No effect in patients with baseline Hb≤11g/dl (HR=1.09; 95% CI: 0.80, 1.47; P=0.579).
Tumor Progression:
A trend for a beneficial effect overall (HR=0.85; 95% CI: 0.72, 1.01; P=0.072) and in patients with an Hb≤11 (HR=0.80; 95% CI: 0.65, 0.99; P=0.041).
TEEs: EB->↑TEEs vs. controls (7% vs 4%); however, TEEs-related mortality was similar in both groups (1% each)
EB had no negative effect on survival, tumor progression, or TEEs-related mortality
(15) Aapro et al., 2008b Breast Cancer-Anemia and the Value of Erythropoetin (BRAVE) studyPatients w/ metastatic breast cancer treated w/ anthracycline- and/or taxane-based chemo, Hb<12.9Open-label multi-center RCT comparing EB (30,000U sc, Q1W, 24 wks1°:Survival
2°: progression-free survival, transfusion- and severe anemia-free survival, Hb response, safety, and QoL 18 months followup
At follow-up
Overall Survival: EB: 62/231 (27%) vs. Control: 63/232 (27%) No difference (hazard ratio [HR] = 1.07; 95% CI, 0.87 to 1.33, P = .522)
Progression-free survival:
no difference (HR = 1.07; 95% CI, 0.89 to 1.30, P = .448).
Transfusion- and severe anemia-free survival: significant ↑ compared with control (HR = 0.59; P = .0097).
Median Hb: EB↑ Hb (11.7 g/dL at baseline to 13.3 g/dL at 24 weeks) vs. no change with control (11.5 v 11.4 g/dL).
TEEs: EB->↑ TEEs cf. controls (13% v 6%; P = .012) with no difference in serious TEEs (4% v 3%).
QoL: EB-> no significant improvement QoL in this study (in patients with a high baseline Hb value)
EB increased Hb in patients with initial Hb less than 12.9 g/dL. No difference was detected in overall survival but design may have precluded detection.
(16) Wright et al., 2007Patients with non-small cell carcinoma of the lung not curable with therapy and baseline Hb<12.1g/dl. (n=70: 300 intended but study stopped early)Multicenter RCT: EA, sc, q1w, 12 weeks vs. placeboChange in Functional Assessment of Cancer Therapy Anemia scores from baseline to 12 weeks; QOL, survivalEA decreased median survival (63 vs. 129 days, HR, 1.84, p=0.04), but EA appeared to ↑ Hb. Numbers too small to assess effect on QOL.EA’s association with decreased survival led to early termination of study.
(74) Aapro et al., 2006 UKCancer patients (56% hematological cancers and 44% solid tumors) (1,413)Meta-analysis of 9 RCTs EB: median initial dose 30,000IU/wkSurvival, disease progression, TEE and TEE-mortalitySurvival (0–6mos) for EB same as control (0.31 vs. 0.32 deaths/pt-year)
Mortality risk: no difference (RR 0.97, 95% CI: 0.69, 1.36; P = 0.87)
Risk of rapidly progressive disease significantly reduced for EB (RR 0.78, 95% CI: 0.62, 0.99; P = 0.042).
TEE: slightly increased risk for EB (5.9% vs 4.2% of patients)
TEE-related mortality: no difference
Epoetin beta provided a slight beneficial effect on tumour progression and did not impact on early survival or thromboembolic- related mortality
Other AEs
(8) Han et al., 2008Patients w/ limited disease small-cell lung cancer (LD-SCLC) receiving two 28-day cycles cisplatin (30mg/m(2)) days 1 and 8 and irinotecan at a dose of 60 mg/m(2) (Days 1, 8, and 15) followed by two 21-day cycles of cisplatin at a dose of 60 mg/m(2) (Day 1) and etoposide at a dose of 100 mg/m(2) (Days 1–3) with concurrent twice- daily thoracic radiotherapy for a total of 45 days (n=76, but 15 of 36 amifostine pts did not get treatment)Phase II RCT: amifostine (500mg) vs. epo-alpha (10,000IU sc 3x/wk)Anemia and adverse eventsAmifostine~↑febrile neutropenia (p=0.003); grade 2–3 nausea (p=0.03); grade 4 leukopenia (p=0.05); Grade 3 esophagitis in 30% of amifostine pts. vs. 9% of epo patients (P = .059).
Epo associated with less grade 2–3 anemia (P = .031) and lower decreases in Hgb during therapy (P = .016).
Median survival times for both treatment arms were comparable (22.6 months in the amifostine arm vs 25.6 months in the epoetin-alpha arm; P = .447)
Epo was more effective than amifostene in preventing severe anemia in LD-SCLC pts undergoing chemo- hyperfractionated radiotherapy
(2) ALTERNATIVE DOSING STRATEGIES
(6)Pedrazzoli et al., 2008Patients with lung, gynecologic, breast, and colorectal cancers and ≥12 weeks planned chemotherapy (n=176 pts, 33 institutions); Hemoglobin ≤11 g/L and no absolute or functional iron deficiency.RCT (?) of sodium ferric gluconate 125 mg/wk for the first 6 weeks (n = 73) or no iron (n = 76) in patients taking DA (150 ug subcutaneously once weekly for 12 weeks)Percentage of patients achieving hematopoietic response (hemoglobin ≥12 g/dL or ≥2 g/dL increase), safetyIntention-to-treat analysis:
Hematopoetic response:
DA+Fe: 76.7% (95%CI, 65.4% to 85.8%)
DA-Fe: 61.8% (95%CI, 50.0% to 72.7%) (P = .0495).
Among patients fulfilling eligibility criteria and having received at least four DA administrations:
hematopoietic responses in the DA+Fe: 92.5% (95% CI, 81.8% to 97.9%) (n = 53)
DA-Fe: 70% (95% CI, 55.4% to ≥82.1%) (n = 50)(P = .0033). Hb ↑ during treatment showed a time profile favoring DA/Fe with statistically significant effect from week 5 on. No difference in safety profile.
Fe reduces treatment failure of DA and improves effectiveness of DA
(13) Bastit et al., 2008Patients with nonmyeloid malignancies and hemoglobin (Hb) less than 11 g/dL (n=396)Multicenter, open-label, phase III RCT DA 500 ug with (n = 200) or without (n = 196) IV Fe Q3W for 16 weeksHematopoietic response (proportion of patients achieving Hb ≥12 g/dL or Hb increase of ≥2 g/dL from baseline) and # transfusionsHematopoietic response rate:
IV iron group: 86%
Standard practice group 73% (difference of 13% [95% CI, 3% to 23%]; P = .011).
Transfusions (week 5 to the end of the treatment period):
IV iron group: 9%
Standard practice group: 20% (difference of −11% [95% CI, −18% to −3%]; P = .005).
Both treatments were well tolerated with no notable differences in adverse events. Serious adverse events related to iron occurred in 3% of patients in the IV iron group: mostly gastrointestinal
Addition of IV Fe to DA in patients with chemotherapy- induced anemia was well tolerated, improved hematopoietic response rate, and decreased transfusion rate compared with DA alone
(58) Steensma et al., 2006Patients with cancer and anemia (n=365)RCT comparing EA 40,000U sc q3w followed by 1) standard weekly EA (40K) or 2) 120,000U EA (120K) sc q3w for 18 add’l weeksRequirement for transfusion, Hb increment; AE (TEE or death)Requirement for transfusions during the study did not differ: 23% in 40K arm vs. 18% in 120K arm (P = 0.22) Req. for transfusion during the maintenance phase also did not differ: 13% in 40K arm v 15% in 120K arm (P = .58).
Hb: 40K grp more likely than 120K grp to have a ≥2 or ≥3 g/dL Hb increment, to have a drug dose held because of high Hb, and had higher mean end-of-study Hb levels.
AE, including TEE and overall survival, were similar.
Global QOL: 40K arm higher at baseline but 120K grp improved more so equal at end of study.
After three weekly doses of 40K U EA, a dose of 120K U can be administered safely once every 3 weeks without increasing transfusion needs or sacrificing QOL. The Hb increment is somewhat greater with continued weekly EA. Lack of blinding as a result of different treatment schedules may have confounded results.
(70) Glaspy et al., 2006Patients ≥18yoa w/ a nonmyeloid malignancy (most commeon were lung, breast, GI) with ≥8wks planned chemotherapy, and anemia (Hb≤11g/dl) (1,220, 1209 of whom received ≥1 dose of a study drug)RCT cf. DA 200ug q2w vs. EA 40,000U q1w up to 16 wks, with identical dose adjustment rulesIncidence of RBC transfusion; Definition of non-inferiority was that upper 95% CI limit of observed difference in transfusions between groups was <11.5%, based on treatment effect observed in placebo controlled EA studiesTransfusion incidence from week 5 to the end of the treatment phase (the primary end point) was 21% in the DA group and 16% in the EA group; noninferiority was concluded because the upper 95% CI limit of the difference between groups (10.8%) was below the prespecified noninferiority margin. Sensitivity analyses using alternate statistical methods and analysis sets yielded similar results. HB, QOL, and AEs did not differ between therapies.Study shows comparable efficacy of DA Q2W and EA QW. Less frequent dosing offers potential benefits for patients, caregivers and health care providers.
(3) ALTERNATIVE THRESHOLDS FOR INITIATING TREATMENT
(56) Straus et al., 2006Patients with non- Hodgkin lymphoma, Hodgkin lymphoma, chronic lymphocytic leukemia, or multiple myeloma and baseline hemoglobin of 10–12 g/dL who were scheduled for ≥ 4 months of myelosuppressive chemotherapy (n=269 randomized)RCT:
Patients randomized to receive ≤16 weeks of EA at a dose of 40,000 U q1w immediately (early) or to wait and only receive EA if hemoglobin decreased to ≤9 g/dL (late). (Any patients with a hemoglobin level ≥12 g/dL after 3 chemotherapy cycles were not randomized
1°: Mean change in Functional Assessment of Cancer Therapy- Anemia (FACT-An) total
2°: Hb, AEs
Mean total FACT-An increased 3.84 (95% CI, 0.21–7.46) in early patients and decreased 4.37 (95% CI, −7.99 to −0.74) in late patients (P = .003).
Early patients had significantly (P< .05) higher mean scores for total FACT-General; FACT-General physical and functional well-being subscales, total anemia scale, and fatigue subscale; and daily activity, energy, and important activity Linear Analog Scale Assessment scales, as well as reduced bedrest days and restricted activity days. The mean Hb increased 1.2 g/dL (95% CI, 0.98–1.46) in early patients but decreased 0.2 g/dL (95% CI, −0.32–0.12) in late patients (P<0.0001). AEs were similar between groups (with fatigue being the most prevalent); clinically relevant thromboembolic events were more common in early patients
Treating mild anemia immediately with EA during chemotherapy for hematologic malignancy significantly improved QOL, productivity, and Hb compared with delaying treatment until the hemoglobin level decreases to < 9.0 g/dL.
(66) Lyman et al., 2006Systematic review of 11 studies of patients with chemotherapy induced anemia (abstract indicated that only a subset of these studies compared early and late intervention and did not indicate n)11 RCTs purporting to assess clinical benefit of early erythropoetic interventionProportion of pts w/ Hb≥10 g/dl, transfusion incidence,Erythropoietic treatment decreased transfusion incidence cf. placebo (RRR 0.50, 95% CI 0.43, 0.59; 7 studies, P< 0.0001) and the proportion of patients with hemoglobin <10 g/dL(0.40, 95% CI, 0.19, 0.83; 4 studies, P = 0.147).
Findings from both prospective studies and planned subset analyses in which early and late intervention were compared also indicated a reduction in the RR of transfusions (0.55, 95% CI, 0.42, 0.73; 5 studies, P<0.0001] and Hb <10 g/dL (0.44, 95% CI, 0.33, 0.57; 2 studies, P<0.0001] after early intervention
these findings suggest that optimal clinical benefit from erythropoietic treatment of chemotherapy- induced anemia may be achieved through early intervention
PATIENT CHARACTERISTICS USEFUL FOR SELECTING PATIENTS OR PREDICTING RESPONSES
(2) Smith et al., 2008Patients with active cancer and anemia (how defined?), not receiving or planning to receive cytotoxic chemotherapy or myelosuppressive radiotherapy (n not reported in abstract)Phase III multi-center RCT comparing Darbepo alpha (DA) to placebo:
6.75 ug/kg every 4 weeks (Q4W) for up to 16 weeks
Need for transfusion in wks 5–17; adverse events; survival (over 2- year followup)DA assoc with non-statistically significant ↓ in # transfusions; DA assoc. with stat. sign. ↑ in cardiovascular and thromboembolic events, deaths in first 16 wks.
Sign.↓ long-term survival (p=0.22) Survival effect varied by sex, tumor type, geographic region and disappeared w/sensitivity analysis*
Study does not support use of DA in this subset of cancer patients w/ anemia
*

Include in response to question 4 regarding patient characteristics

Notes: Fe: iron; Hb hemoglobin; iv: intravenous; Q3W: every 3 weeks; sc: subcutaneous;

CER 6 - Efficacy and Comparative Effectiveness of Off-Label Use of Atypical Antipsychotics

Conclusions From CER Executive SummaryHas there been new evidence that may change this conclusion?References
Key Question 1: What are the leading off-label uses of atypical antipsychotics in the literature?
The most common off-label uses of atypical antipsychotics found in the literature were treatment of depression, obsessive- compulsive disorder, posttraumatic stress disorder, personality disorders, Tourette's syndrome, autism, and agitation in dementia. In October 2006, risperidone was approved for use in autism.There are several new RCTs of atypicals for anorexia nervousa and bulimia. Court (2008) published a systematic review in Eating Disorders which included four RCTs.RCTs: Mondraty, 2005, Australas Psychiatry; Bissada, 2008, Am J Psychiatry; Spettique, 2008, BMC Pediatrics
Key Question 2: What does the evidence show regarding the effectiveness of atypical antipsychotics for off-label indications, such as depression?
How do atypical antipsychotic medications compare with other drugs for treating off-label indications?
There is a small but statistically significant benefit for risperidone and aripiprazole on agitation and psychosis outcomes in dementia patients. The clinical benefits must be balanced against side effects and potential harms.a) CATIE-AD found that olanzapine and risperidone improved NPI total score and BPRS (Brief Psychiatric Rating Scale) hostile suspiciousness factor. There were no significant differences between antipsychotics and placebo on cognition, function, care needs, or quality of life, except for worsened functioning with olanzapine.
b) New RCT shows quetiapine 200 mg associated with significant improvements in PANNS-EC, CGI-C compared to placebo
c) New meta-analysis shows effect sizes of atypical antipsychotics for behavioral problems in dementia are medium, and there are no statistically or clinically significant differences between them and placebo.
d) Head to head RCT shows quetiapine and risperidone equally effective and well tolerated.
e) New systematic review on dementia symptoms show olanzapine and risperidone effective compared with placebo. Short-term AEs similar to placebo. Risperidone had advantage over haldol in EPS. Evidence for other atypicals too limited to assess.
f) New RCT found aripiprazole 10 mg/day was efficacious and safe for psychosis associated with AD, significantly improving psychotic symptoms, agitation, and clinical global impression.
g) In another RCT in nursing home residents with AD and psychosis, aripiprazole did not confer specific benefits for the treatment of psychotic symptoms; but psychological and behavioral symptoms, including agitation, anxiety, and depression, were improved with aripiprazole, with a low risk of AEs.
h) An RCT in elderly patients with organic brain disease (N= 15) showed no difference between risperidone and placebo, as measured by PANSS items.
a) Sultzer, 2008, Am J Psychiatry
b) Zhong, 2007, Curr Alzheimer Res
c) Yury, 2007, Psychother Psychosom
d) Rainer, 2007, Eur Psychiatry
e) Carson, 2006, JAGS
f) Mintzer, 2007, Am J Geri Psych
g) Stein, 2008, Am J Geri Psych
h) Naber, 2007, Psychopharmacology
For SRI-resistant patients with major depressive disorder, combination therapy with an atypical antipsychotic plus an SRI antidepressant is not more effective than an SRI alone at 8 weeks.a) Aripiprazole approved by FDA for adjunctive tx in unipolar, non-psychotic depression after two RCTs (Marcus, 2008, J Clinc Psychopharmacol; Berman, 2007, J Clin Psychiatry)
b) RCT of risperidone augmentation showed higher odds of remitting (OR = 3.33) than placebo at 4 weeks.
c) New RCT shows olanzapine/ fluoxetine combo effective at 8 weeks.
d) Meta-analysis of 10 clinical trials finds patients on adjunct atypicals significantly more likely to experience remission or clinical response than those on adjunct placebo. No studies on aripiprazole or ziprasidone were included.
e) RCT of risperidone augmentation show significant reduction in depression symptoms, substantial increase in remission and response, compared to augmentation with placebo at 6 weeks.
a) Philip, 2008, J Psychiatric Practice
b) Keitner, 2008, J Psychiatr Res
c) Thase, 2007, J Clin Psychiatry
d) Papakostas, 2007, J Clin Psychiatry
e) Gharabawi, 2007, Ann Intern Med
In patients with major depressive disorder with psychotic features, olanzapine and olanzapine plus fluoxetine were compared with placebo for 8 weeks in 2 trials. There was a benefit for olanzapine alone.New Evidence: None
For bipolar depression, olanzapine and quetiapine were superior to placebo in one study for each drug, but data are conflicting in two other studies that compared atypical antipsychotics to conventional treatment.a) Two new RCTs found aripriprazole not significantly more effective in bipolar depression than placebo at 8 weeks.a) Thase, 2008, J Clin Psychopharmacol
We identified 12 trials of risperidone, olanzapine, and quetiapine used as augmentation therapy in patients w/ OCD who were resistant to standard treatment (nine trials were sufficiently similar clinically to pool). Atypical antipsychotics have a clinically important benefit (measured by the Yale-Brown Obsessive- Compulsive Scale) when used as augmentation therapy for OCD patients who fail to adequately respond to SRI therapy. There were too few studies of olanzapine augmentation to permit separate pooling for this drug.a) A retrospective comparative study showed ziprasidone was less effective than quetiapine in refractory OCD.
b) Head-to-head RCT showed both risperidone and olanzapine effective, no significant differences between the two drugs.
a) Savas, 2008, Clin Drug Investig
b) Maina, 2008, Eur Neuropsychopharmacol
We found four trials of risperidone and two trials of olanzapine of at least 6 weeks duration in patients with PTSD. There were three trials enrolling men with combat- related PTSD; these showed a benefit in sleep quality, depression, anxiety, and overall symptoms when risperidone or olanzapine was used to augment therapy with antidepressants or other psychotropic medication. There were three trials of olanzapine or risperidone as monotherapy for women with PTSD; the evidence was inconclusive regarding efficacy.A new meta-analysis (Pae, 2008) analyzed data from seven RCTs involving a total of 192 PTSD patients (102 randomized to AAs and 90 randomized to placebo). The results show that AAs may have a beneficial effect in the treatment of PTSD, as indicated by the changes from baseline in Clinician Administered PTSD Scale total scores [standardized mean difference (SMD)=−0.45, 95% confidence interval (CI) (−0.75, −0.14), P=0.004]. In addition, the overall SMD of the mean changes in the three Clinician Administered PTSD Scale subscores was statistically significant (P=0.007) between AAs and placebo groups, favoring AAs over placebo (SMD=−0.27, 95% CI=−0.47, −0.07).
In particular, the symptom of 'intrusion' was mainly responsible for this significance. Clinical significance of the results, however, should be carefully interpreted and translated into clinical practice, given that the quality and availability of currently existing RCTs included in the analysis.
Pae, 2008, In Clin Psychopharm
We identified five trials of atypical antipsychotic medications as treatment for borderline personality disorder & one trial as treatment for schizotypal personality disorder. Three RCTs each w/ no more than 60 subjects provide evidence that olanzapine is more effective than placebo & may be more effective than fluoxetine in treating borderline personality disorder.
The benefit of adding olanzapine to dialectical therapy for borderline personality disorder was small.
An RCT of ziprasidone failed to show benefit in BPD.Pascual, 2008, J Clin Psychiatry
Risperidone was more effective than placebo for the treatment of schizotypal personality disorder in one small trial.New Evidence: None
Aripiprazole was more effective than placebo for the treatment of borderline personality in one small trial.18-month f/u of the original included aripiprazole trial shows significant improvement at 18 months.Nickel, 2007
We found four trials of risperidone and one of ziprasidone for treatment of Tourette's syndrome. Risperidone was more effective than placebo in one small trial, and it was at least as effective as pimozide or clonidine for 8 to 12 weeks of therapy in the three remaining trials. The one available study of ziprasidone showed variable effectiveness compared to placebo.New Evidence: None
Two trials support the superiority of risperidone over placebo in improving serious behavioral problems in children with autism.Another trial showed that (non-autistic) children who respond to initial treatment with risperidone would benefit from continuous long-term treatment.Reyes, 2006
Key Question 3: What subset of the population would potentially benefit from off-label uses?
Other than specific populations listed in the finding for Key Question 2, there was insufficient information to answer this question. Therefore, it is included as a topic for future research.New Evidence: None
Key Question 4: What are the potential adverse effects and/or complications involved with off-label prescribing of atypical antipsychotics?
Olanzapine patients are more likely to report weight gain than those taking placebo, other atypical antipsychotics, or conventional antipsychotics.New Evidence: None
In a recently published meta-analysis death occurred in 3.5 percent of dementia patients randomized to receive atypical antipsychotics vs. 2.3 percent of patients randomized to receive placebo. The difference in risk for death was small but statistically significant.
Sensitivity analyses did not show evidence for differential risks for individual atypical antipsychotics. In another recently published meta-analysis of six trials of olanzapine in dementia patients, differences in mortality between olanzapine and risperidone were not statistically significant, nor were differences between olanzapine and conventional antipsychotics.
a) A new meta-analysis of six RCTs of risperidone regarding mortality in elderly dementia patients showed 4.0% mortality with risperidone versus 3.1% with placebo (relative risk 1.21, 95% CI 0.71–2.06) during tx or within 30 days or tx discontinuation.

b) Study assessed short-term mortality in a population- based cohort of elderly people in British Columbia who were prescribed conventional or atypical antipsychotic medications. Within the first 180 days of use, 1822 patients (14.1%) in the conventional drug group died, compared with 2337 (9.6%) in the atypical drug group (mortality ratio 1.47, 95% CI 1.39–1.56). Multivariable adjustment resulted in a 180-day mortality ratio of 1.32 (1.23–1.42).
a) Haupt, 2006, J Clin Psychopharmacol
b) Schneeweiss, 2007, Cmaj
In our pooled analysis of three RCTs of elderly patients with dementia, risperidone was associated with increased odds of cerebrovascular accident compared to placebo. This risk was equivalent to 1 additional stroke for every 31 patients treated in this patient population (i.e., number needed to harm of 31). The manufacturers of risperidone pooled four RCTs and found that cerebrovascular adverse events were twice as common in dementia patients treated with risperidone as in the placebo patients.
In a separate industry-sponsored analysis of five RCTs of olanzapine in elderly dementia patients, the incidence of cerebrovascular adverse events was three times higher in olanzapine patients than in placebo patients.
a) Retrospective cohort study with N >40,000 used a logistic regression model to show that relative to those who received no antipsychotics, community dwelling elderly newly dispensed an atypical were 3.2 times more likely, and those who received a conventional antipsychotic were 3.8 more likely, to develop any serious event during the first 30 days.
b) Retrospective cohort study of VA data on patients age 65+ (N = 10,615) who began outpatient treatment with psyc meds following a dementia diagnosis showed that those taking antipsychotics had significantly higher mortality rates (22.6% to 29.1%) than patients taking non-antipsychotic meds (14.6%). Adjusted mortality risks for atypicals were similar to those for conventional antipsychotics. The proportions of patients taking antipsychotics who died from cerbrovascular, cardiovascular, or infectious causes were not higher than rates for those taking other psyc meds.
c) Death rates for incident (N=16,634) and prevalent (N=9,831) users of various antipsychotics, carbamazepine, and sodium valproate age 65+ were compared. Haloperidol was consistently associated with increased risk of death compared with olanzapine (RR for incident users 2.26, 95% CI 2.08 – 2.47).
Risperidone (RR 1.23, 95% CI: 1.07 – 1.40) was also associated with increased risk of death compared to olanzapine in incident users.
a) Rochon, 2008, Arch Intern Med; Gill, 2007, Ann Intern Med
b) Kales, 2007, Am J Psychiatry
c) Hollis, 2007, Am J Geriatric Psychiatry
We pooled three aripiprazole trials and four risperidone trials that reported extrapyramidal side effects (EPS) in elderly dementia patients. Both drugs were associated with an increase in EPS.New Evidence: None
Ziprasidone was associated with an increase in EPS when compared to placebo in a pooled analysis of adults with depression, PTSD, or personality disorders.New Evidence: None
Risperidone was associated with increased weight gain compared to placebo in our pooled analyses of three trials in children/adolescents. Odds were also higher for gastrointestinal problems, increased salivation, fatigue, EPS, and sedation among these young risperidone patients.New Evidence: None
Compared to placebo, all atypicals were associated with sedation in multiple pooled analyses for all psychiatric conditions studied.New Evidence: None
Key Question 5: What are the appropriate dose and time limit for off-label indications?
There was insufficient information to answer this question. Therefore, it is included as a topic for future researchNew Evidence: None
Are there new data that could inform the key questions that might not be addressed in the conclusions?
Glucose/Diabetes: Sacher (2008, Neuropsychopharmacology) reports a small RCT where olanzapine but not ziprasidone lead to a decrease in whole body insulin sensitivity in response to a hyperinsulinemic euglycemic challenge in healthy adults.
Bayesian data-mining of FDA adverse events reporting system (DuMouchel, 2008, Ann Clin Psychiatry) showed consistent and substantial differences between atypicals in reporting ratios re glycemic effects, especially life-threatening ones. Low association: ziprasidone, aripriprazole, and risperidone; medium association: quetiapine, and strong association: olanzapine.
A VA retrospective cohort analysis (Duncan, 2007) showed that in patients without a random plasma glucose of >=160 mg/dl before medication exposure (n=1394), treatment with olanzapine, risperidone, or a typical antipsychotic was associated with an incidence of new diabetes-level hyperglycemia of 78.7 cases per 1,000 individuals exposed per year. Olanzapine was associated with a greater rate of developing at least one fasting glucose measurement of >=200 than risperidone (OR = 2.14).
In a systematic review of 17 pharmacoepidemiologic studies (Ramaswamy, 2006, Ann Clin Psychiatry) olanzapine, but not risperidone, was associated with significantly increased risk of new-onset diabetes. Of nine studies comparing relative risk of diabetes with olanzapine and risperidone, six demonstrated significantly greater risk with olanzapine.
A retrospective study of schizophrenia patients at Mass General (Henderson, 2007, J Clin Psychiatry) showed that the incidence of diabetes presenting as diabetic ketoacidosis was higher than in the general hospital population and differed across drugs (olanzapine, 0.8%, risperidone, 0.2%, no incidence with ziprasidone or quetiapine).
A retrospective analysis of diabetes risk in elderly patients with dementia in seven olanzapine clinical trails (Micca, 2006, Am J Geriatr Psychiatry) showed that risk of diabetes was not significantly associated with antipsyc treatment.
Pituitary tumors: Sarfman (2006) analyzed the FDA AERS and found that risperidone had the highest adjusted reporting rations for hyperprolactinemia, galactorrhea, and pituitary tumor among the antipsychotics, and one of the highest scores for all drugs in the database.
Cholesterol: Using MediCal data, Olfson (2006) estimated the relative risk of developing hyperlipidemia after treatment with antipsychotics compared to no antipsychotic treatment. 12,133 incident cases of hyperlipidemia were matched to 72,140 control subjects. Compared with no antipsyc meds, tx with risperidone (OR 1.56, 95% CI 1.43 – 1.64), quetiapine (OR 1.52, 95% CI 1.40 – 1.65), olanzapine (OR 1.56, 95%CI 1.47 – 1.67) and ziprasidone (OR 1.40, CI 1.19 – 1.65) were associated with increased risk of hyperlipidemia, as were conventional antipsychotics (OR 1.26, 95% CI 1.14 – 1.39).
Muscle toxicity: Waring (2006) reviewed case notes from 64 consecutive patients admitted after olanzapine overdose. Serum creatine kinase was > 5 times the upper limit of normal in 17% of patients, and there was a dose-dependent relationship. No patients developed renal failure.
New drug: Paliperidone-ER, first atypical with extended release formulation approved by FDA for schizophrenia (Lautneschlager, 2008; Yang, 2007; Owen, 2007; Howland, 2007).

CER 7 - Comparative Effectiveness of Second-Generation Antidepressants in the Pharmacologic Treatment of Adult Depression

Treatment of Major Depressive Disorder (KQ 1): For adults with MDD, dysthymia, or subsyndromal depressive disorders, do commonly used medications for depression differ in efficacy or effectiveness in treating depressive symptoms? If a patient has responded to one agent in the past, is that agent better than current alternatives at treating depressive symptoms?

Original FindingsNew findings
Efficacy and effectiveness.
38 percent of patients did not respond during 6 to 12 weeks of treatment with second-generation antidepressants; 54 percent did not achieve remission. The evidence is insufficient to determine factors that can reliably predict response or nonresponse in individual patients.A pooled analysis of 9 RCTs, comparing duloxetine with placebo for 8–9 weeks, found duloxetine produced significantly greater baseline-to-endpoint mean change than placebo in HAMD17 total score, Maier and retardation subscales, and the Clinical Global Impressions-Severity of Illness scale in mild (HAMD17: < or =19; n=682), moderate (HAMD17: between 19 and 25, n=1099), or severe (HAMD17: > or =25; n=446) groups. Effective sizes were largest in the most severely depressed patients. (Shelton, Andorn et al. 2007)

An analysis of 62 RCTs of patients with depressive disorder, comparing paroxetine vs. placebo or other antidepressants (amisulpride, amitriptyline, bupropion, clomipramine, doxepin, fluvoxamine, fluoxetine, imipramine, lofepramine, mianserin, mirtazapine, moclobemide, maprotiline, nefazodone, nortriptyline, sertraline, tianeptine, venlafaxine), found paroxetine yielded consistently and significantly better remission (rate difference (RD): 10%, 95% CI 6 to 14), clinical response (RD: 17%, 95% CI 7 to 27), and symptom reduction (effect size: 0.2, 95% CI 0.1 to 0.3) than placebo. No consistent and significant difference was observed between paroxetine and other antidepressants. (Katzman, Tricco et al. 2007)
Seventy-two head-to-head comparisons (i.e., comparisons between medications conducted within trials) provided data on 35 of the potential comparisons between the 12 second-generation antidepressants addressed in this report. Five trials directly compared any non-SSRI second-generation antidepressant with any other non-SSRI second-generation antidepressant; of these, only one comparison was evaluated in more than one trial. Many efficacy trials were not powered to detect statistically or clinically significant differences, leading to inconclusive results.

Direct evidence from head-to-head trials was considered sufficient to conduct meta-analyses for four drug-drug comparisons. Differences in efficacy reflected in some of these meta-analyses are of modest magnitude and clinical implications remain to be determined.
2 direct comparison studies with escitalopram vs. venlafaxine XR, and indirect comparison, using 10 placebo-controlled studies, found escitalopram was non- inferior to venlafaxine XR (indirect comparison: mean −0.02, 95% CI: −0.16 to infinity; direct comparison: mean: 0.23, 95% CI: −0.01 to infinity). The results were consistent after controlling age, gender repartition and severity at baseline. (Eckert and Falissard 2006)

A prospective, 24-week open label study of 170 patients with major depressive disorder, comparing venlafaxine vs. paroxetine, found venlafaxine was comparable with paroxetine on response rate and remission, whereas paroxetine produced significantly higher remission rates at weeks 4, 8, 16, 20, 24 when remission was defined as HRSD =5. Conclusion: Venlafaxine treatment was similar to paroxetine according to the typical efficacy measures. However, the authors feel that paroxetine might be superior to venlafaxine if the stricter remission criterion is used. (Wu, Chen et al. 2007)

Pairwise comparisons of paroxetine and venlafaxine, mirtazapine, mianserin, or fluoxetine yielded inconsistent results across efficacy outcomes, using 62 RCTs of patients with depressive disorder. (Katzman, Tricco et al. 2007)
Citalopram vs. escitalopram (five studies; 1,545 patients): Patients on escitalopram had an additional treatment effect of a 1.25-point reduction (95-percent confidence interval [CI], 0.10–2.39) on the Montgomery-Asberg Depression Rating Scale (MADRS) compared with patients on citalopram. The relative risk (RR) of response was statistically significantly greater for escitalopram than for citalopram (RR: 1.14; 95-percent CI, 1.04–1.26). The number needed to treat (NNT) to gain one additional responder at week 8 with escitalopram was 14 (95-percent CI, 7–111). Both drugs are produced by the same manufacturer, which funded all available studies.2 placebo-controlled trials and a head-to-head superiority study show escitalopram was numerically better than citalopram in reducing Montgomery-Asberg Depression Rating Scale (MADRS). Meta-analysis of 5 clinical trials (3 placebo- controlled trials, 1 head-to-head superiority study, and 1 long-term non-inferiority study) showed statistically significant differences in favor of escitalopram in terms of reducing MADRS and increasing response. (Lançon, Verpillat et al. 2007)
Fluoxetine vs. paroxetine (seven studies; 950 patients): The study did not find any statistically significant differences in effect sizes on the Hamilton Depression Rating Scale (HAM-D) or response rates between fluoxetine and paroxetine. Fluoxetine had an additional reduction of 0.55 (95-percent CI, −1.4–0.36; P = 0.23) points on HAM-D compared with paroxetine; paroxetine led to a higher rate of responders than fluoxetine (RR 1.09; 95- percent CI, 0.99–1.21).An analysis of 12 RCTs of patients with depressive disorder, comparing paroxetine and fluoxetine, found inconsistent results across efficacy outcomes. (Katzman, Tricco et al. 2007)
Fluoxetine vs. sertraline (four studies; 940 patients): Patients on sertraline had an additional, statistically nonsignificant treatment effect of a 0.75-point reduction (95-percent CI, −0.45–1.95) on the Hamilton Rating Scale for Depression (HAM-D) scale compared with patients on fluoxetine. The relative risk of response was statistically significantly greater for sertraline than for fluoxetine (RR: 1.11; 95-percent CI, 1.01–1.21). The NNT to gain one additional responder at 6 to 12 weeks with sertraline was 14 (95- percent CI, 8–22).No new evidence
Fluoxetine vs. venlafaxine (eight studies; 1,814 patients): Patients on venlafaxine had an additional, statistically nonsignificant treatment effect of a 1.31-point reduction (95-percent CI, 0.10–2.39) on the HAM-D scale compared with patients on fluoxetine. The relative risk of response was statistically significantly greater for venlafaxine than for fluoxetine (RR: 1.12; 95 percent CI, 1.01–1.24). The NNT to gain one additional responder at 6 to 12 weeks with venlafaxine was 12 (95-percent CI, 7–50). All studies were funded by the makers of venlafaxine.A direct comparison of venlafaxine vs. fluoxetine among patients with major depressive disorder, followed up for 1 year, found no significant difference in time to rehospitalization.(Lin, Lin et al. 2008)

A meta-analysis of 34 RCTs, comparing venlafaxine to fluoxetine, found venlafaxine is statistically superior to fluoxetine. (Nemeroff, Entsuah et al. 2008)
Most trials were efficacy trials conducted in carefully selected populations under carefully controlled conditions. Only three trials met criteria for being an effectiveness trial, which is intended to have greater generalizability to typical practice. Of these trials, two were conducted in French primary care settings and one in primary care clinics in the United States. Findings were generally consistent with efficacy trials and did not reflect any substantial differences in comparative effectiveness in adults.No new evidence
Findings from indirect comparisons (i.e., comparisons of medications conducted across placebo-controlled trials rather than within a single trial) yielded no statistically significant differences in response rates. The precision of some of these estimates was low, leading to inconclusive results with wide confidence intervals. Nevertheless, point estimates of treatment effects from these analyses were consistent with those from direct evidence trials in indicating no or minimal differences in efficacy among available comparisons.Indirect comparison with escitalopram vs. venlafaxine XR, using 10 placebo- controlled studies, and two direct comparison studies found escitalopram was non- inferior to venlafaxine XR (indirect comparison: mean −0.02, 95% CI −0.16 to infinity; direct comparison: mean: 0.23, 95% CI: −0.01 to infinity). The results were consistent after controlling age, gender repartition and severity at baseline. (Eckert and Falissard 2006)
Overall, the strength of the evidence was moderate for both comparative efficacy and comparative effectiveness.
Although second-generation antidepressants appear similar in average efficacy and effectiveness, the studies were not designed to test variation among individuals in their responses to individual drugs. The second-generation antidepressants cannot be considered identical drugs. Evidence of moderate strength supports some differences among individual drugs with respect to onset of action and some measures (e.g., sexual functioning) that could affect health-related quality of life. These are statistically significant but of modest magnitude; potential benefits might be offset by specific adverse events. Nonetheless, some of these differences may influence the choice of a medication for specific patients.A meta-analysis of 34 RCTs, comparing venlafaxine and SSRIs (fluoxetine, sertraline, paroxetine, fluvoxamine, and citalopram), found venlafaxine had higher ITT remission rate than the SSRIs as a group (the overall difference is 5.9%, 95% CI 0.038 to 0.081; p<0.001). The number needed to treat (NNT) to benefit is 17 (95% CI 12−26). The difference vs. fluoxetine was significant (6.6%, 95% CI 0.030 to 0.095); smaller difference vs. paroxetine, sertraline, and citalopram were not significant. Venlafaxine therapy is statistically superior to SSRI as a class, but only to fluoxetine individually. The clinical significance of the modest advantage seems limited to the broad grouping of major depressive disorder. (Nemeroff, Entsuah et al. 2008)
Quality of life. Quality of life or functional capacity was infrequently assessed, usually as a secondary outcome. Eighteen studies (4,050 patients), mostly of fair quality, indicated no statistical differences in health-related quality of life. The strength of evidence is moderate.No new evidence
Speed of response. Seven studies, all of fair quality and funded by the maker of mirtazapine, reported that mirtazapine had a significantly faster onset of action than citalopram, fluoxetine, paroxetine, and sertraline. The NNT to yield one additional responder after 1 or 2 weeks of treatment is 7 (95-percent CI, 5–12); after 4 weeks of treatment, however, most response rates were similar. Again, this treatment effect was consistent across all studies, but whether this difference can be extrapolated to other second- generation antidepressants remains unclear. The strength of evidence is moderate.No new evidence
Response to a second agent. The Sequenced Treatment Alternatives to Relieve Depression (STAR-D) trial is the only well-done study looking at the question of response to a second agent among those failing initial therapy. Results show that about one in four of the 727 people who participated in the switch responded to sym-bupropion sustained release (SR), sertraline, and venlafaxine extended release (XR).A review of 5 randomized comparative studies (3 RCTs and 2 randomized open label studies) and 9 non-randomized non-comparative studies (2 switch studies, 5 open label switch studies, 1 post-hoc analysis, and 1 open case study) of >5,000 patients with treatment resistant depression shows venlafaxine is associated with modest rates of response and remission in patients who have failed previous SSRI treatment. However, the findings from the comparative studies do not uniformly find venlafaxine to be superior. The author supports the use of venlafaxine as a common switch agent following initial antidepressant failure. (Dunner 2007)
Treatment of Dysthymia
Efficacy and effectiveness. No head-to-head trial compared different medications in a population with dysthymia. In placebo-controlled trials, significant differences in population characteristics make the evidence insufficient to identify differences between treatments. One good-quality and four fair-quality placebo-controlled trials provide mixed evidence on the general efficacy and effectiveness of fluoxetine, paroxetine, and sertraline for the treatment of dysthymia. A fair-quality effectiveness study provides mixed evidence on the effectiveness of paroxetine compared to placebo.
A subgroup of patients older than 60 years showed a significantly greater improvement than those on placebo; a subgroup of patients younger than 60 years did not show any difference in effectiveness between paroxetine and placebo. The strength of evidence is low.
No new evidence
Treatment of Subsyndromal Depression
Efficacy and effectiveness. The only head-to-head evidence for treating patients with subsyndromal depression came from a nonrandomized, open-label trial comparing citalopram with sertraline. This study did not detect any differences in efficacy. Findings from two placebo-controlled trials (both fair quality) were insufficient to draw any conclusions about the comparative efficacy and effectiveness of second-generation antidepressants for the treatment of subsyndromal depression. The strength of evidence is low.No new evidence

Maintenance of Response or Remission (KQ 2a): For adults with a depressive syndrome, do antidepressants differ in their efficacy or effectiveness for maintaining response or remission (i.e., preventing relapse or recurrence)?

Original FindingsNew findings
Efficacy and effectiveness. Three head-to-head RCTs suggest that no substantial differences exist between fluoxetine and sertraline, fluvoxamine and sertraline, and trazodone and venlafaxine for maintaining response or remission (i.e., preventing relapse or recurrence of MDD). The strength of the evidence is moderate. Twenty- one placebo-controlled trials support the general efficacy and effectiveness of most second-generation antidepressants for preventing relapse or recurrence. No evidence exists for duloxetine. The overall strength of this evidence is moderate.A review of 5 placebo-controlled acute-phase studies found most of the relapse rate during new-generation antidepressant continuation treatment may be due to relapse in patients who were not true drug responders. (Zimmerman and Thongy 2007)

A meta-analysis of 1833 outpatients with major depressive disorder found the HAMD-sub-1-sub-7 remission rate was 40.3% for duloxetine, 38.3% for 2 SSRIs (paroxetine or fluoxetine), and 28.4% for placebo. Active treatments were superior to placebo. The difference between duloxetine and SSRIs was not statistically significant. Duloxetine therapy was significant more effective than therapy with the 2 SSRIs for patients with more severe depression, with remission rates of 35.9% vs. 28.6% (P=0.046). (Thase, Pritchett et al. 2007) An update of the orginal report, using four head-to-head trials and 23 placebo- controlled trials from 1980–2007, did not find statistically difference in relapse or recurrence prevention between duloxetine and paroxetine, fluoxetine and sertraline, and trazodone and venlafaxine. Compared with placebo, the class of second-generation antidepressants had a relatively large effect size that persists over time. The number of patients needed to treat is 5 (95% CI: 4–6). (Hansen, Gaynes et al. 2008)

Treatment of Treatment-Resistant Depression Syndrome or Relapse or Recurrence (KQ 2b): For adults receiving antidepressant treatment for a depressive syndrome that either has not responded (acute phase) or has relapsed (continuation phase) or recurred (maintenance phase), do alternative antidepressants differ in their efficacy or effectiveness?

Original FindingsNew findings
Efficacy and effectiveness. One head-to-head efficacy study and two effectiveness studies provide conflicting evidence on differences among second- generation antidepressants in treatment-resistant depression. The efficacy study (fair quality) suggests that venlafaxine is modestly more effective than paroxetine.
A good-quality effectiveness study suggests that no substantial differences exist among bupropion SR, sertraline, and venlafaxine XR, but a fair-quality effectiveness study suggests that venlafaxine is modestly more effective than citalopram, fluoxetine, mirtazapine, paroxetine, and sertraline. Given the conflicting results, the overall strength of the evidence is moderate.
A review of 5 randomized comparative studies (3 RCTs and 2 randomized open label studies) and 9 non-randomized non-comparative studies (2 switch studies, 5 open label switch studies, 1 post-hoc analysis, and 1 open case study) of >5,000 patients with treatment resistant depression supports the use of venlafaxine as a common switch agent following initial antidepressant failure. (Dunner 2007)
An 8-week double-blind, placebo controlled trial of elderly patients with recurrent major depressive disorder comparing duloxetine vs. placebo, found duloxetine significantly improved cognition, depression and some pain measures. Hamilton depression scale response (37.3% vs. 18.6%) and remission (27.4% vs. 14.7%) rates at endpoint were significantly higher for duloxetine than placebo. (Raskin, Wiltse et al. 2007)
Although several comparative studies included patients who had relapsed or who were experiencing a recurrent depressive episode, no study specifically compared one second-generation antidepressant with another as a second-step treatment in such patients.

Treatment of Depression in Patients With Accompanying Symptom Clusters (KQ 3a): Do medications differ in their efficacy and effectiveness in treating the depressive episode?

Original FindingsNew findings
Anxiety. Evidence from six head-to-head trials and one placebo-controlled trial (all fair quality) suggests that antidepressant medications do not differ substantially in antidepressive efficacy for patients with MDD and anxiety symptoms. The trials found no substantial differences in efficacy between fluoxetine, paroxetine, and sertraline; sertraline and bupropion; and sertraline and venlafaxine. One trial found statistically significant superiority of venlafaxine over fluoxetine. The strength of evidence is moderate.A prospective cohort study of 6,719 adult patients with depressive syndrome and associated with anxiety symptoms, treated with venlafaxine XR for 24 weeks, found venlafaxine XR was associated with significant decrease in the scores in the HAM depression rating and HAM-A anxiety rating. (Roca Benassar and Baca Baldomero 2006)
Insomnia. Three head-to-head trials that identified a specific insomnia group (all fair quality) provide limited evidence regarding comparative efficacy of medications for treating depression in patients with accompanying insomnia. One trial found statistically significant superiority for escitalopram over citalopram. The strength of evidence is low.No new evidence
Melancholia. Two head-to-head trials (both fair quality), one poor-quality head- to-head trial, and one fair-quality placebo-controlled study provide limited evidence on the comparative effects of medication for treating depression in patients with melancholia. In one, depression response rates for sertraline were superior to those for fluoxetine; in another, depression scores improved more for venlafaxine than for fluoxetine. The strength of evidence is low.No new evidence
Pain. One fair-quality trial that required baseline pain for inclusion found no difference in efficacy for duloxetine compared with placebo for treating depression in patients with pain of at least mild intensity. The strength of evidence is low.No new evidence
Psychomotor changes. One fair-quality head-to-head trial reported no statistically significant difference between fluoxetine and sertraline for treating depression in patients with psychomotor retardation. The same study found that sertraline was more efficacious than fluoxetine for treating depression in patients with psychomotor agitation. The strength of evidence is low.No new evidence
Somatization. No relevant study.

Treatment of Symptom Clusters in Patients with Accompanying Depression (KQ 3b): Do medications differ in their efficacy and effectiveness in treating the accompanying symptoms?

Original FindingsNew findings
Anxiety. Ten head-to-head trials and two placebo-controlled trials (all fair quality) provide evidence that antidepressant medications do not differ substantially in efficacy for treatment of anxiety associated with MDD. Trials found no substantial differences in efficacy between fluoxetine, paroxetine, and sertraline; sertraline and bupropion; sertraline and venlafaxine; citalopram and mirtazapine; and paroxetine and nefazodone. One trial found that venlafaxine was statistically significantly superior to fluoxetine. The strength of evidence is moderate.No new evidence
Insomnia. Six head-to-head trials (all fair quality) provide limited evidence about comparative effects of antidepressants on insomnia in patients with depression. The strength of evidence is low.An analysis of 10 double blind head-to-head trials of patients with major depressive disorder found bupropion and the SSRIs appear to be equally effective in treating insomnia in depression. (Papakostas, Kornstein et al. 2007)
Melancholia. No relevant study.No new evidence
Pain. Two head-to-head trials (one of fair and the other of poor quality) and three placebo-controlled trials (all fair quality) provide limited evidence about effects of antidepressants on pain symptoms in depressed patients. Two trials found no substantial difference in efficacy between duloxetine and paroxetine. The strength of evidence is low.A pooled analysis of 9 RCTs, comparing duloxetine with placebo for 8–9 weeks, found mildly (HAMD17: < or =19; n=682) and severely (HAMD17: > or =25; n=446) depressed patients with duloxetine exhibited significant reduction in visual analog scale overall pain severity. (Shelton, Andorn et al. 2007)

An 8-week double-blind, placebo controlled trial of elderly patients with recurrent major depressive disorder, comparing duloxetine vs. placebo, found duloxetine significantly improved Visual Analogue Scale scores for back pain and time in pain while awake vs. placebo. (Raskin, Wiltse et al. 2007)
Psychomotor changes. No relevant study.A meta-analysis of 44 placebo-controlled trials of patients with Parkinson’s disease (PD) and depression found a modestly positive and significant effect size result with SSRIs on motor function (d=0.34, p<0.05). (Frisina 2005)
Somatization. One open-label effectiveness trial found no statistically significant difference among three SSRIs for treating somatization in patients with depression. The strength of evidence is low.No new evidence

Differences in Harms (Adverse Events) (KQ 4): For adults with a depressive syndrome, do commonly used antidepressants differ in safety, adverse events, or adherence?

Original FindingsNew findings
General tolerability
Adverse events profiles. Constipation, diarrhea, dizziness, headache, insomnia, nausea, and somnolence were commonly and consistently reported adverse events. On average, 61 percent of patients in efficacy trials experienced at least one adverse event. Nausea and vomiting were found to be the most common reasons for discontinuation in efficacy studies. Overall, second-generation antidepressants have similar adverse events profiles, and the strength of evidence is high.An update of the orginal report, using four head-to-head trials and 23 placebo- controlled trials from 1980–2007, found the most common adverse event due to treatment of second generation antidepressants (including duloxetine, paroxetine, fluoxetine, sertraline, trazodone and venlafaxine) in continuation- and maintenance-phase studies was headache, followed by nausea (weighted mean incidence=15.5% and 7.4%, respectively). Compared with the incidence of adverse events in acute-phase studies, the relative incidence during long-term treatment was slightly lower. (Hansen, Gaynes et al. 2008)

In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial, among 2,876 patients with major depression, ratings of side effect frequency, intensity, and burden, as well as the number of serious adverse events, were significantly greater in the anxious depression group than those with nonanxious depression. (Fava, Rush et al. 2008)

A randomized study of 727 patients with nonpsychotic major depressive disorder and taking any of sustained-release bupropion hydrochloride, sertraline hydrochloride, or extended release venlafaxine hydrochloride, intolerance was less likely for Hispanic participants, more likely for those with previous suicide attempts or intolerance to citalopram. (Rush, Wisniewski et al. 2008)

A clinical trial of 35 adult cancer outpatients with depression, during chemotherapy, found sertraline was well tolerated. No severe adverse effects were observed. (Torta, Siri et al. 2008)

A retrospective cohort study of elderly patients prescribed SSRIs found the risk of poisoning during SSRI use was higher than nonuse. The adjusted hazard ratio (95% CI) of poisoning was higher during SSRI use vs nonuse (1.16 [1.07 to 1.25]) and varied between SSRI agents from 0.93 (0.74 to 1.16) for fluoxetine to 1.45 (1.23 to 1.71) for fluvoxamine. (Rahme, Dasgupta et al. 2008)

Analyses of RCTs, comparing escitalopram with placebo or other antidepressants (citalopram, fluoxetine, paroxetine, sertraline, venlafaxine), found nausea was the only AE with an incidence greater than or equal to 10% and 5 percentage points greater than with placebo during short-term treatment. In general, AEs of escitalopram were mild to moderate in severity. (Baldwin, Reines et al. 2007)

A meta-analysis of 7 double-blind placebo controlled trials of patients with MDD who received duloxetine found the most common treatment-emergent adverse events due to duloxetine in African-American and Caucasian patients included nausea, headache, constipation, dizziness and insomnia. The rate of occurrence of these events did not differ significantly between these two groups. (Bailey, Mallinckrodt et al. 2006)
Venlafaxine was associated with an approximately 10-percent (95-percent CI, 4–17 percent) higher incidence of nausea and vomiting than SSRIs as a class. In addition, pooled discontinuation rates because of adverse events in efficacy trials are statistically significantly higher for venlafaxine than for SSRIs (RR: 1.50; 95-percent CI, 1.21–1.84). The strength of evidence is high.A meta-analysis of 34 RCTs, comparing venlafaxine and SSRIs (fluoxetine, sertraline, paroxetine, fluvoxamine, and citalopram), found attrition rates due to adverse events were higher with venlafaxine than with SSRI therapy, 11% and 9%, respectively (p=0.0011). (Nemeroff, Entsuah et al. 2008)
In most studies, sertraline led to higher rates of diarrhea than comparator drugs (bupropion, citalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, venlafaxine). The incidence was 8-percent (95- percent CI, 3–11 percent) higher than with comparator drugs. Whether this finding can be extrapolated to comparisons of sertraline with other second- generation antidepressants remains unclear. The strength of evidence is moderate.No new evidence
Mirtazapine led to higher weight gains than comparator drugs (fluoxetine, paroxetine, venlafaxine, and trazodone). Mean weight gains compared to pretreatment ranged from 0.8 kg to 3.0 kg after 6 to 8 weeks of treatment. Paroxetine had higher weight gains than fluoxetine and sertraline. The strength of evidence is moderate.No new evidence
Trazodone was associated with an approximately 16-percent (3-percent less to 36 percent higher) higher incidence of somnolence than comparator drugs (bupropion, fluoxetine, mirtazapine, paroxetine, venlafaxine). Whether this finding can be extrapolated to comparisons of trazodone with other second-generation antidepressants remains unclear. The strength of evidence is moderate.No new evidence
Discontinuation syndromes (e.g., headache, dizziness, nausea) occurred in 0 to 86 percent of patients. Paroxetine and venlafaxine had the highest incidence of this problem, and fluoxetine the lowest incidence. The strength of evidence is moderate.A review of 385 patients taking paroxetine found 41 patients experienced the discontinuation syndrome. The occurrence of the discontinuation syndrome did not correlate with gender, maintenance dosage of paroxetine, or duration of treatment with the drug. The discontinuation syndrome occurred significantly more frequently in those patients in whom paroxetine was abruptly discontinued. (Himei and Okamura 2006)

Analyses of RCTs, comparing escitalopram with placebo or other antidepressants (citalopram, fluoxetine, paroxetine, sertraline, venlafaxine), found, compared with paroxetine, escitalopram resulted in significantly fewer discontinuation symptoms (average increase in Discontinuation Emergent Signs and Symptoms Scale of 1.6 vs. 3.9, p<0.01). (Baldwin, Reines et al. 2007)
Discontinuation rates. Overall discontinuation rates did not differ significantly between SSRIs as a class and bupropion, mirtazapine, nefazodone, trazodone, and venlafaxine. In the case of venlafaxine compared with SSRIs, higher discontinuation rates because of adverse events (11.5 percent vs. 8.5 percent) appear to be balanced by lower discontinuation rates because of lack of efficacy (3.5 percent vs. 4.4 percent). The strength of evidence is high.An analysis of the Medical Expenditure Panel Survey for 1996–2001 found 42.4% of patients discontinued antidepressant therapy during the first 30 days. 27.6% of the patients continued antidepressant treatment for more than 90 days.
Antidepressant discontinuation during the first 30 days were more common among Hispanics (53.8%) than non-Hispanics (43.7%), patients with few than 12 years of education than those with 12 or more years of education. (Olfson, Marcus et al. 2006)

A prospective cohort study of 6,719 adult patients with depressive syndrome and associated with anxiety symptoms, treated with venlafaxine XR for 24 weeks, found 81.8% of patients completed 24 weeks of treatment. (Roca Benassar and Baca Baldomero 2006)
An analysis of 62 RCTs found controlled-release paroxetine had significantly fewer dropouts due to adverse events than immediate-release paroxetine (RD: 5%, 95% CI 0.1 to 11). No other difference found between paroxetine and other antidepressants (amisulpride, amitriptyline, bupropion, clomipramine, doxepin, fluvoxamine, fluoxetine, imipramine, lofepramine, mianserin, mirtazapine, moclobemide, maprotiline, nefazodone, nortriptyline, sertraline, tianeptine, venlafaxine). (Katzman, Tricco et al. 2007)

Analyses of RCTs, comparing escitalopram with placebo or other antidepressants (citalopram, fluoxetine, paroxetine, sertraline, venlafaxine), the 8 week withdrawal rate due to AEs was higher with escitalopram than with placebo (7.3% vs 2.8%, p<0.001) but lower than with paroxetine (6.6% vs 9.0%; p<0.01) or venlafaxine (6.1% vs 13.2%, p<0.01). (Baldwin, Reines et al. 2007)

A meta-analysis of 7 double-blind placebo controlled trials of patients with MDD who received duloxetine found no significant difference in discontinuation rates due to adverse events between African-American and Caucasian patients. (Bailey, Mallinckrodt et al. 2006)
Severe adverse events .
Sexual dysfunction. Bupropion is associated with a lower incidence of sexual dysfunction than fluoxetine, paroxetine, and sertaline. The NNT to gain one additional person with high overall satisfaction of sexual functioning is 6 (95- percent CI, 4–9). In head-to-head trials, paroxetine consistently had higher rates of sexual dysfunction than comparators (fluoxetine, fluvoxamine, nefazodone, and sertraline; 16 percent vs. 6 percent). Underreporting of absolute rates of sexual dysfunction, however, is likely in these studies. Whether these findings can be extrapolated to comparisons of bupropion and paroxetine with other second-generation antidepressants is unclear. The strength of evidence is moderate.Analyses of RCTs, comparing escitalopram with placebo or other antidepressants (citalopram, fluoxetine, paroxetine, sertraline, venlafaxine), found AEs related to sexual dysfunction were similarly frequent with escitalopram and citalopram, but were higher with paroxetine. (Baldwin, Reines et al. 2007)
Other severe adverse events. The existing evidence on the comparative risk for rare but severe adverse events, such as suicidality, seizures, cardiovascular events (i.e., elevated systolic and diastolic blood pressure and elevated pulse/heart rate), hyponatremia, hepatotoxicity, and serotonin syndrome, is insufficient to draw firm conclusions. The strength of evidence is low. Clinicians should keep in mind the risk of such harms during any course of treatment with a second-generation antidepressant.A matched case-control study with Medicaid beneficiaries did not find antidepressant drugs are statistically associated with suicide attempts (OR: 1.10 95% CI 0.86–1.39) or suicide deaths (OR 0.90, 95% CI: 0.52–1.55) in adults. However, in children and adolescents, antidepressant drugs were significantly associated with suicide attempts (OR, 1.52, 95% 1.12–2.07) and suicide deaths (OR, 15.62; 95% CI, 1.65-infinity). (Olfson, Marcus et al. 2006)

A comparison of before and during 12 weeks of antidepressant treatment in 437 elderly patients with major depression found 7.8% with emergent suicidality, 12.6% with persistent suicidality, and 15.6% with resolved suicidality. Rates of emergent suicidality didn’t differ significantly between paroxetine-and nortriptyline-treated patients. (Szanto, Mulsant et al. 2007)

A observational cohort study in Denmark found patients who continued treatment with antidepressants had a decreased rate of suicide compared to those who purchased antidepressant once (rate ratio: 0.31, 95% CI: 0.26–0.36). The rate of suicide decreased consistently with the number of prescriptions. (Sondergard, Lopez et al. 2007)

A retrospective cohort study with 219,099 UK patients found venlafaxine was associated with an increased risk of attempted suicide, compared to citalopram, fluoxetine and dothiepin. For completed suicides, unadjusted and adjusted hazard ratio for venlafaxine compared with citalopram were 2.44 (95% 1.12 to 5.31) and 1.70 (95% CI 0.76–3.80), for venlafaxine compared with fluoxetine were 2.85 (95% CI 1.37 to 5.94) and 1.63 (95% CI 0.74 to 3.59). (Rubino, Roskell et al. 2007)

A retrospective cohort study of elderly patients prescribed SSRIs found the risk of suicide death was not higher during periods of SSRI use vs. nonuse. The adjusted risk of suicide death was not higher during SSRI use vs. nonuse (hazard ratio (95% CI)): any SSRI=0.64 (0.38 to1.07), paroxetine=0.71 (0.37 to 1.35), citalopram=1.16 (0.59 to 2.25), and sertraline=0.38 (0.16 to 0.93). (Rahme, Dasgupta et al. 2008)

An evaluation of 12 placebo controlled trials of MDD patients, comparing duloxetine vs. placebo didn’t find significant difference in the incidence of suicide-related events with duloxetine vs. placebo. (Acharya, Rosen et al. 2006)

Analyses of RCTs, comparing escitalopram with placebo or other antidepressants (citalopram, fluoxetine, paroxetine, sertraline, venlafaxine), did not find significant differences between escitalopram and placebo in incidence of suicidal behavior, measured by self-harm and suicidal thoughts. The incidence of cardiovascular events with escitalopram was similar to that with placebo. (Baldwin, Reines et al. 2007)

An open-label study of 62 patients aged 60+ with major depressive disorder, treated with venlafaxine XR for 12 weeks, found 24% (95% CI 7.3% to 40.7%) of initially normotensive participants and 54% (95% CI 34.3% to 74%) of those with preexisting hypertension experienced an increase in blood pressure. 29% (95% CI 14.6% to 43.4%) developed orthostatic hypotension. 2 experienced a clinically significant increase in QTc interval. 1 participant reported new-onset mild dizziness, 4 reported new-onset tachycardia or palpitation. Overall, 17 unique participants (28.8%, 95% CI 17.3% to 40.4%) experienced a new-onset cardiovascular problem. Systematic monitoring of cardiovascular parameters during treatment with venlafaxine-XR should be strongly recommended, especially in the elderly. (Johnson, Whyte et al. 2006)
Adherence
Efficacy studies do not indicate any substantial differences in adherence among second-generation antidepressants. The strength of evidence is moderate. One observational study indicated that extended-release formulations might have a better adherence rate than immediate-release medications. This finding, however, is likely attributable more to differences in dosing regimens than to differences in efficacy and harms. To what extent findings from highly controlled efficacy trials can be extrapolated to “real-world” settings remains uncertain. The evidence is insufficient to reach any conclusions about differences in adherence in effectiveness studies. The strength of evidence is low.An analysis of US nationally representative prescription database found adherence to bupropion therapy was better with the once daily bupropion XL than with the twice-daily bupropion SR formulation. (Stang, Young et al. 2007)

Efficacy, Effectiveness, and Harms for Selected Populations (KQ 5): How do the efficacy, effectiveness, or harms of treatment with antidepressants for a depressive syndrome differ for the elderly, other demographic population and patients with medical comorbidities?

Original FindingsNew findings
Age. Twelve head-to-head trials (one an effectiveness study), nine placebo-controlled trials, one retrospective cohort study, and one set of meta-analyses suggest that no major differences in efficacy and effectiveness exist among second-generation antidepressants in elderly or very elderly populations. The strength of the evidence is moderate. Harms such as hyponatremia and weight loss may differ in elderly or very elderly patients on active treatment vs. placebo, but the evidence on these two adverse events is limited to one small RCT and one observational study (both fair quality). The strength of the evidence is low.An analysis of 10 double blind head-to-head trials of patients with major depressive disorder found no age-related difference in efficacy between bupropion and the SSRIs. (Papakostas, Kornstein et al. 2007)

Analyses of RCTs, comparing escitalopram with placebo or other antidepressants (citalopram, fluoxetine, paroxetine, sertraline, venlafaxine), found the risk of AEs due to escitalopram was no higher in special patient populations, such as the elderly or those with hepatic dysfunction. (Baldwin, Reines et al. 2007)

An open-label study of 62 patients aged 60+ with major depressive disorder, treated with venlafaxine XR for 12 weeks, found 24% (95% CI 7.3% to 40.7%) of initially normotensive participants and 54% (95% CI 34.3% to 74%) of those with preexisting hypertension experienced an increase in blood pressure. 29% (95% CI 14.6% to 43.4%) developed orthostatic hypotension. 2 experienced a clinically significant increase in QTc interval. 1 participant reported new-onset mild dizziness, 4 reported new-onset tachycardia or palpitation. Overall, 17 unique participants (28.8%, 95% CI 17.3% to 40.4%) experienced a new-onset cardiovascular problem. Systematic monitoring of cardiovascular parameters during treatment with venlafaxine-XR should be strongly recommended, especially in the elderly. (Johnson, Whyte et al. 2006)
Sex. Indirect evidence from one fair-quality pooled analysis of head-to-head RCTs suggests that efficacy among second-generation antidepressants does not differ between men and women. This conclusion is supported by observational evidence. One fair-quality observational study indicated that harms, specifically the rates of sexual dysfunction, might differ between men and women. The strength of the evidence is low.An analysis of 10 double blind head-to-head trials of patients with major depressive disorder found greater improvement in efficacy in anxious/somatic symptoms of depression among women during SSRIs treatment than men. (Papakostas, Kornstein et al. 2007)
Race or ethnicity. One poor-quality RCT suggests that the efficacy of second-generation antidepressants does not differ for patients in different race or ethnic groups. This study, however, may not have been powered to detect a difference. The strength of the evidence is low.An analysis of the Medical Expenditure Panel Survey for 1996–2001 found antidepressant discontinuation during the first 30 days were more common among Hispanics (53.8%) than non-Hispanics (43.7%). (Olfson, Marcus et al. 2006)

A randomized study of 727 patients with nonpsychotic major depressive disorder and taking any of sustained-release bupropion hydrochloride, sertraline hydrochloride, or extended release venlafaxine hydrochloride, remission was more likely among those who were white. Intolerance was less likely for Hispanic participants. (Rush, Wisniewski et al. 2008)

An analysis of STAR*D patients with nonpsychotic major depressive disorder, treated with citalopram up to 14 weeks, found Black, and to a lesser extent Hispanic patients, had a poorer response to citalopram than white patients. After adjusting for baseline differences, the remission rates seemed to be more similar on the HRSD, but remained worse for blacks on the QIDS-SR. (Lesser, Castro et al. 2007)

A meta-analysis of 7 double-blind placebo controlled trials of patients with MDD who received duloxetine found no significant difference in duloxetine’s treatment effect between African-American and Caucasian patients. Discontinuation rates due to adverse events did not differ significantly between African-Americans and Caucasians. No adverse event led to discontinuation in more than one African-American patient. The rate of occurrence of AEs did not differ significantly between two groups. (Bailey, Mallinckrodt et al. 2006)
Comorbidities. The evidence for various comorbidities (e.g., HIV/AIDS, alcohol abuse, Alzheimer’s disease or other dementia, breast cancer, cardiovascular disease, stroke, and substance abuse) is limited to one head-to head study, a small number of placebo-controlled trials, and one systematic review. They provide limited evidence on the comparative efficacy of second-generation antidepressants in subgroups with different coexisting conditions. The strength of the evidence is low.A clinical trial of 35 adult cancer outpatients with depression, during chemotherapy, found sertraline could significantly decrease mean depression scores, analyzed by HADS and MADRS scales, HADS anxiety scores. No severe adverse effects were observed. (Torta, Siri et al. 2008)

A meta-analysis of 44 placebo-controlled trials of patients with Parkinson’s disease (PD) and depression found SSRIs produced a robust antidepressant effect on moderately depressed PD patients (d=0.44, p< 0.05). A modestly positive and significant effect size result was observed with SSRIs on motor function (d=0.34, p<0.05), and there were no significant side effects (d=−0.002, p=0.50). These results show that SSRIs can be used to treat depression without the fear of worsening PD. (Frisina 2005)

Analyses of RCTs, comparing escitalopram with placebo or other antidepressants (citalopram, fluoxetine, paroxetine, sertraline, venlafaxine), found the risk of AEs due to escitalopram was no higher in special patient populations, such as the elderly or those with hepatic dysfunction. (Baldwin, Reines et al. 2007)

CER 9 - Comparative Effectiveness of Percutaneous Coronary Interventions and Coronary Artery Bypass Grafting for Coronary Artery Disease

Summary statement: Since the publication of this report and its primary peer-reviewed publication (Bravata et al. Ann Intern Med. 2007), no new studies have been published that either significantly changed the summary results of this review or changed the strength of evidence for any of the key questions it addressed.

Key Questions and OutcomesSummary, Conclusions, and CommentsHas there been any new evidence that may change this conclusion?References
Procedural survival- Reported by 23 randomized controlled trials (RCTs)
- Procedural survival was slightly, but not significantly higher in PCI patients (PCI-CABG survival difference 0.1%; 95 percent Confidence Interval (CI): −0.3 to 0.6%).
- Procedural survival in RCTs was higher than that reported by large administrative databases and clinical registries.
A new report from the NY State Registry showed no difference in procedural mortality. (Data from this registry were already included in the evidence report.)

A meta-analysis of 4 of the included RCTs of multi-vessel disease found no difference in survival between the procedures.
Hannan et al.

Takagi et al.
Freedom from procedural stroke- Reported by 14 RCTs
- Freedom from procedural strokes was significantly more common after PCI (PCI-CABG difference in freedom from procedural stroke 0.6% CI: 0.2 to 1.0%; p=0.01).
New Evidence: None
Freedom from procedural myocardial infarction- Reported by 20 RCTs
- Definition of MI varied across trials; results were heterogeneous
- Freedom from procedural MI was slightly, but not significantly lower after CABG
New Evidence: None
Survival- Overall survival in RCTs was slightly higher after CABG than after PCI between one and five years of follow-up, but the absolute PCI-CABG survival difference was small at each time point (less than 1%) and not statistically significant.
- Five year survival was significantly higher after CABG in balloon-era trials (PCI-CABG survival difference −2.1%, CI: − 4.1 to −0.1%). However, in stent-era trials, five year survival was not significantly different (PCI-CABG survival difference 1.1%, CI: −1.4 to +3.7%).
- There was no significant difference in the PCI-CABG survival difference according to extent of disease.
-A 6-yr follow up study of the SoS trial was published. We combined these results with the 5 year data from other RCTs in an editorial accompanying the publication of the SoS report. Overall, it did not significantly change our results. See Figure 1 below from that editorial.
-A new report from the NY State Registry confirmed slightly improved survival with CABG at 18 months compared with PCI. (Data from this registry were already included in the evidence report and the new report was not significantly different from the prior one.)
-A meta-analysis of 4 of the included RCTs of multi-vessel disease found no difference in survival between the procedures.
Booth et al.

Hlatky & Bravata

Hannan et al.

Takagi et al.
Freedom from angina- Reported by 12 RCTs at 1-year and 7 RCTs at 3- and 5-years
- Freedom from angina was significantly greater after CABG (PCI-CABG difference in freedom from angina ranges from −5% to −8%; p value <0.0001 at 1-, 3-, and 5-years).
New Evidence: None
Freedom from repeat revascularization- Reported by 11 RCTs at 1-year and 9 RCTs at 5-years
- Patients assigned to PCI required 24% more repeat procedures than patients assigned to CABG at 1-year (p <0.0001), and 33% more at 5 years (p<0.0001).
A new report from the NY State Registry also confirmed a higher revascularization rate among stent recipients than CABG patients. (Data from this registry were already included in the evidence report.)

A meta-analysis of 4 of the included RCTs of multi-vessel disease found increased repeat revascularization after CABG than after PCI.
Hannan et al.

Takagi et al.
Freedom from myocardial infarction- 10 RCTs reported follow-up data
- There was no difference in freedom from MI between PCI and CABG.
New Evidence: None
Quality of life- Reported by 11 RCTs using a variety of different measures.
- Quality of life scores improved significantly more after CABG than after PCI between one and three years.
- Quality of life scores were correlated with the presence and severity of angina.
- Data available from an additional RCT: MASSII. Similar to what was found before, the CABG group had greater improvements in SF36 measured QOL than the PCI group.Favarato et al.
Cost- Reported by 10 RCTs, using a variety of methods.
- 9 RCTs found significantly lower initial costs for PCI than for CABG, but this difference narrowed substantially over subsequent follow-up.
A cost-effectiveness analysis of minimally invasive internal thoracic artery bypass vs PCI-stenting for LAD lesions found that stenting was the dominant strategy in the first two years; however CABG became more cost-effective over time as the revascularization rate for PCI increased.Rao et al.
Survival- 11 trials (including 77% of all randomized patients) reported 5 or more years of follow-up.
- The PCI-CABG survival difference in these 11 trials did not change
significantly between one and five years
- Four trials with longer follow-up showed no major changes in the PCI-CABG survival difference between five and seven to eight years of follow-up.
See the comment about the SoS trial above and Figure 1.
Freedom from angina- The initial significant advantage of CABG over PCI in freedom from angina grew progressively smaller between one year and five years of follow-up.New Evidence: None
Age- Outcomes by age reported by 3 studies
- There were more procedural complications in the older patients, especially stroke.
- Patients aged 65 years and older had lower overall survival
- The RCTs enrolled very few patients over 75 years of age, limiting conclusions about the comparative effectiveness of PCI and CABG in this population.
New Evidence: None (Please see Comment 1 below.)
Gender- Outcomes by gender reported by 3 studies.
- Women had lower overall survival, but the survival difference between PCI and CABG was similar to that in men
-Women had lower quality of life at baseline, but improved to a similar degree with CABG and PCI.
New Evidence: None
Race- Outcomes by race reported by only one study
- African-American patients had a lower survival regardless of PCI or CABG treatment.
New Evidence: None
Diabetes- Survival at 1 and 5 years in patients with diabetes was reported by 6 RCTs.
- The BARI trial found significantly better survival for patients with diabetes assigned to CABG (five-year survival of 80% vs 65%).
- None of the other five reports found a significant difference in survival between patients with and without diabetes.
-The pooled data from all trials showed no significant difference in survival after PCI vs after CABG (PCI-CABG survival difference −0.8%, CI: −8.3 to +6.6%)
New Evidence: None (Please see Comment 1 below.)
Obesity- Obesity did not consistently alter the comparative effectiveness of PCI and CABG.New Evidence: None
Other comorbidities- There was no evidence suggesting that hypertension, tobacco use, renal dysfunction and vascular disease increased risk differently among PCI and CABG recipients.New Evidence: None
Extent of disease- There was no significant difference by extent of disease among patients assigned to PCI or CABG
- In clinical registries, patients with extensive disease had improved survival with CABG, whereas patients with minimal disease had improved survival with PCI (interaction test was highly significant).
A new report from the NY State Registry was similar to what was seen in other prior registries—namely that patients with more extensive disease had improved survival with CABG. (Data from this registry were already included in the evidence report.)Hannan et al.
Left ventricular function- Few patients with poor left ventricular function were enrolled in RCTs
- There was no evidence that the PCI- CABG survival difference was modified by the degree of left ventricular dysfunction
New Evidence: None
Use of stents- 10 trials used bare metal stents, 11 used balloon angioplasty, and only the Seoul trial used drug-eluting stents.
- Survival at five years was significantly better after CABG in balloon-era trials, but there was no difference in survival in stent-era trials.
New Evidence: None
Use of minimally invasive techniquesNew Evidence: None
Use of mammary arteriesNew Evidence: None
Clinical presentationNew Evidence: None
Adjunctive therapiesNew Evidence: None
Process characteristicsNew Evidence: None
Prior revascularizationNew Evidence: None

Comments:

  1. The authors at the Stanford-UCSF Evidence-based Practice Center are currently preparing an addendum to the report of individual level patient data from the RCTs of the multi-vessel disease. We have already run this analysis but are expecting data from a final large RCT in the next few weeks and will redo our analyses. This will represent the most important update of the evidence report as it has the ability to address Key questions 2a-c and we have found two striking differences from the synthesis of the trial level data (namely, for diabetes and age). We hope to have the results ready for publication in the next few months.
  2. There have been a couple registry reports (which would not have met our inclusion criteria because they are too small (e.g., Javaid et al. Circulation 2007; 116[suppl I]:I-200-I-206) or do not adequately account for key covariates. However, none of these would have changed either our results or our overall confidence rating.
Figure 1. The difference at five years in the risk of death between PCI assigned and CABG assigned patients with multivessel disease in randomized trials. The reported numbers of deaths and patients randomized are listed on the left for each trial, for all balloon-era trials, for all stent-era trials, and for all trials. The risk difference and 95% confidence limits are plotted on the right. Homogeneity statistics for the overall effect from all trials: I2=21.8; Q=11.5, p=0.24.

Figure 1

The difference at five years in the risk of death between PCI assigned and CABG assigned patients with multivessel disease in randomized trials. The reported numbers of deaths and patients (more...)

CER 10 - Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors (ACEIs) and Angiotensin II Receptor Antagonists (ARBs) for Treating Essential Hypertension

Summary: The original evidence report was a synthesis of data from 69 reports of 61 studies that directly compared the long-term benefits and harms of ACEI vs ARBs. The authors initially considered an analysis of indirect comparisons but ultimately found too much heterogeneity of comparison arms to be able to synthesize these data. Since the publication of this report, there have been several publications of single arm studies but little additional comparative evidence. Specifically, no new studies have been published that either significantly changed the summary results of this review or changed the strength of evidence for any of the key questions it addressed.

Key Questions and OutcomesStrength of EvidenceSummary, Conclusions, and CommentsHas there been any new evidence that may change this conclusion?References
Key Question 1. For adult patients with essential hypertension, how do ACEIs and ARBs differ in the following health outcomes:
a. Blood pressure controlHighACEIs and ARBs appear to have similar long-term effects on blood pressure among individuals with essential hypertension. This conclusion is based on evidence from 50 studies (47 RCTs, 1 nonrandomized controlled clinical trial, 1 retrospective cohort study, and 1 case-control study) in which 13,532 patients receiving an ACEI or an ARB were followed for periods from 12 weeks to 5 years (median 16.5 weeks). Blood pressure outcomes were confounded by additional treatments and varying dose escalation protocols.New Evidence: None
b. Mortality and major cardiovascular eventsModerateDue to insufficient numbers of deaths or major cardiovascular events in the included studies, it was not possible to discern any differential effect of ACEIs vs. ARBs for these critical outcomes. In 9 studies that reported mortality, MI, or clinical stroke as outcomes among 3,356 subjects, 16 deaths and 13 strokes were reported. This may reflect low event rates among otherwise healthy patients and relatively few studies with extended followup.Hackam et al. performed a case- control study of the association of ACE inhibitors and aortic rupture in patients with AAA. They enrolled 15,326 patients admitted with AAA and found that patients on ACEIs had lower risk of rupture than patients on ARBs but this was not a statistically significant finding (OR 1.24; 0.71–2.18).

Two reviews published in the same issue of Circulation 2006 (vol 114) evaluated the association of ARBs and MI (see Hall and Strauss). Only one of these included any direct ACEI vs ARB comparison evidence (namely from the CHARM-Added trial). The evidence from this would neither change the conclusion or the quality rating for the risk of MI in this report.
Hackam et al.i

Hall and Straussii
c. Quality of lifeLowNo differences were found in measures of general quality of life; this is based on 4 studies, 2 of which did not provide quantitative data.New Evidence: None
d. Rate of use of a single antihypertensiveHighThere was no statistically evident difference in the rate of treatment success based on use of a single antihypertensive for ARBs compared to ACEIs. The trend toward less frequent addition of a second agent to an ARB was heavily influenced by retrospective cohort studies, where medication discontinuation rates were higher in ACEI-treated patients, and by RCTs with very loosely defined protocols for medication titration and switching.New Evidence: None
e. Risk factor reduction and other intermediate outcomesModerate (lipid levels, markers of carbohydrate metabolism/diabetes control, progression of renal disease) to Low progression to type 2 diabetes and LV mass/function)There were no consistent differential effects of ACEIs vs. ARBs on several potentially important clinical outcomes, including lipid levels, progression to type 2 diabetes mellitus, markers of carbohydrate metabolism/diabetes control, measures of LV mass or function, and progression of renal disease (either based on creatinine, GFR, or proteinuria). Relatively few studies assessed these outcomes over the long term.The original evidence report was a synthesis of data from 69 reports of 61 studies that directly compared the long-term benefits and harms of ACEI vs ARBs. The authors initially considered an analysis of indirect comparisons but did not include these in the evidence report because of heterogeneity in the treatment and study designs. Elliott and Meyer performed a network meta-analysis (which facilitates the inclusion of both direct and indirect comparison trials) to evaluate the incident diabetes in 22 clinical trials of antihypertensive drugs. They found that ARBs and ACE inhibitors are the antihypertensive agents least associated with incident hypertension but did not find a robust difference between the two. Given the novelty of this method, this would not change the conclusion or level of confidence.Elliott and Meyeriii
Key Question 2. For adult patients with essential hypertension, how do ACEIs and ARBs differ in safety, adverse events, tolerability, persistence, and adherence?High (cough, withdrawals due to adverse events) to Moderate persistence/adherence) to Low angioedema)ACEIs have been consistently shown to be associated with greater risk of cough than ARBs: pooled odds ratio (Peto) = 0.32. For RCTs, this translates to a difference in rates of cough of 6.7 percent (NNT = 15); however, for cohort studies with lower rates of cough, this translates to a difference of 1.1 percent (NNT = 87). This is generally consistent with evidence reviewed regarding withdrawals due to adverse events, in which the NNT is on the order of 27— that is, 1 more withdrawal per 27 patients treated with an ACEI vs. an ARB. There was no evidence of differences in rates of other commonly reported specific adverse events.

Angioedema was reported only in patients treated with ACEIs; however, because angioedema was rarely explicitly reported in the included studies, it was not possible to estimate its frequency in this population.

ACEIs and ARBs have similar rates of adherence based on pill counts; this result may not be applicable outside the clinical trial setting. Rates of continuation with therapy appear to be somewhat better with ARBs than with ACEIs; however, due to variability in definitions, limitations inherent in longitudinal cohort studies, and relatively small sample sizes for ARBs, the precise magnitude of this effect is difficult to quantify.
New Evidence: None
Key Question 3. Are there subgroups of patients based on demographic characteristics (age, racial and ethnic groups, sex), use of other medications concurrently, or comorbidities for which ACEIs or ARBs are more effective, associated with fewer adverse events, or better tolerated?Very lowEvidence does not support conclusions regarding the comparative effectiveness, adverse events, or tolerability of ACEIs and ARBs for any particular patient subgroup.New Evidence: None
i

Hackam, D. G., D. Thiruchelvam and D. A. Redelmeier (2006). “Angiotensin-converting enzyme inhibitors and aortic rupture: a population-based case-control study.” Lancet 368(9536): 659–65.

ii

Hall, A. S. and M. H. Strauss (2007). “More about the “ARB MI paradox”.” Heart 93(9): 1011–4.

iii

Elliott, W. J. and P. M. Meyer (2007). “Incident diabetes in clinical trials of antihypertensive drugs: a network meta-analysis.” Lancet 369(9557): 201–7.

CER 12 - Comparative Effectiveness of Treatments To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis

Author, year, agent, trial name, countryInclusions/Exclusion Criteria, Sample#Study design, interventionOutcomes AssessedFindingsQuality/Notes
1. COMPARATIVE BENEFITS IN FRACTURE REDUCTION
a. BISPHOSPHONATES
Alendronate
(65) Jamal, 2007, FIT, ? (Included in LBD final version)Menopausal women (6458 for total study; 581 w/severely reduced renal function (GFR <45ml/min)RCT of Alendronate vs. placeboClinical, vertebral frx, AEsAlendronate reduced the risk of clinical fractures to a similar degree in those with (OR: 0.78; 95% CI: 0.51–1.21) and without reduced renal function (OR: 0.80; 95% CI; 0.70–0.93; p for interaction = 0.89). Alendronate reduced the risk of spine fractures to a similar degree in those with (OR: 0.72; 95% CI: 0.31–1.7) and without reduced renal function (OR: 0.50; 95% CI: 0.32–0.76; p for interaction = 0.44). No diffs in AEs by renal function.
(115) Black, 2006, FITPostmenopausal women with a mean of 5 years prior alendronate treatment (1099)RCT 5, 10 mg/d Alendronate or placebo X 5 yrsFrx incidence as exploratory outcome measure to assess persistence of effx 5-year cumulative risk nonvertebral frx (RR 1.00, 0.76–1.32) did not differ between continuers and discontinuers; Continuers had significant ↓clinical vertebral frx (2.4% vs/5.3% for placebo; RR 0.45, 0.24–0.85) but NO difference in morphometric vertebral frx (11.3% for placebo and 9.8% for alendronate; RR, 0.86; 95% CI, 0.60–1.22)
(146) Hochberg, 2005, multicenter, FITPostmenopausal women with OP, 55–80 yoa (3658)RCT of alendronate, 5mg/d x 2 yrs followed by 10mg for 1–2.5 add’l yearsClinical frx↓ Relative risk for hip, clinical spine, and wrist fractures: constant across age groups, without evidence of a decline at older ages. ALE ↓ risk of clinical fracture by 53% at the hip (RR = 0.47; 95% CI = 0.27–0.81; p≤ 0.01), 45% at the spine (RR = 0.55; 95% CI = 0.37–0.83; p < 0.01), and 31% at the wrist (RR = 0.69; 95% CI = 0.50–0.98; p = 0.038). In addition, alendronate produced a significant risk reduction of 40% (RR = 0.60; 95% CI = 0.47–0.77; p≤ 0.01) for the composite event of clinical hip, spine, and wrist fractures. Effectiveness was somewhat greater in women with T≤−2.5 cf. T≤−2.0.Absolute risk reduction increased with age because of ↑ risk with age: absolute risk reduction for the composite event (hip, spine, and wrist fractures together) for alendronate treatment versus placebo was 65, 80, 111, and 161 women with fractures per 10,000 Person-yrs for the 55 to ≤ 65, 65 to ≤ 70, 70 to ≤ 75, and 75–85 year age groups, respectively;
(116) Bauer, 2006, FITPostmenopausal women 55–80 years, femoral neck T-score≤−1.6 (6,186); with (T≤2.5 or prevalent vertebral frx)(3,495) or without (T≥2.5 or no prevalent vertebral frx)(2,689) OPRCT Alendronate 5–10mg/d vs. placebo, mean FU 3.2 yrsRisk of incident vertebral and non- vertebral frx in ALN vs. placebo stratified by baseline BM marker levels 492 nonvertebral and 294 morphometric vertebral fractures. ALN-induced↓ in non-vertebral fracture cf placebo was a fn of PINP: (p = 0.03 for trend). E.g., among osteoporotic women in the lowest tertile of pretreatment PINP (≤41.6 ng/ml), ALN vs PBO relative hazard for nonvertebral fracture=0.88 (95% CI: 0.65, 1.21) compared with a relative hazard of 0.54 (95% CI: 0.39, 0.74) among those in the highest tertile of PINP, ≥ 56.8 ng/ml). Results similar among women without baseline OP. Similar (but non-sign) trends observed with baseline levels of BSALP.
Conversely, vertebral frx treatment efficacy among OP women did not differ significantly according to pretreatment marker levels. Vertebral frx treatment efficacy among non-OP women was related to baseline BSALP (p = 0.05 for trend).
Findings suggest bisphosphonate treatment may be more effective in women with elevated bone turnover
Clodronate
(55) McCloskey, 2007, UKCommunity-dwelling women (≥ 75 yoa) (5,596 Intention to treat)3-year RCT of oral clodronate (800 mg/d) vs. placeboFracture incidence and AE114 new hip frx during the 3-year treatment phase: 56 (2.0%) women in the clodronate group and 58 (2.1%) women in the placebo group (HR, 1.02; 95% CI, 0.71–1.47). Clodronate decreased the incidence of any clinical fracture by 20% (264 women [9.5%] versus 337 [12.1%] in the placebo group; HR, 0.80; 95% CI, 0.68–0.94). Clodronate also decreased the incidence of OP-associated nonhip fractures by 29% (5.2% versus 7.4%; HR, 0.71; 95% CI, 0.57–0.87). AE not significant.Effect of CLO independent of baseline BMD but NNT less w/OP
Ibandronate
(32) Cranney, 2008, 8 trialsPostmenopausal womenPooled analysis of 8 randomized trials of ibandronate to compare higher vs. lower doses: Expressed as annual cumulative exposure (ACE) ≥ 10.8mg (monthly, quarterly, or bimonthly dosing) vs. ACE=5.5 mgNon-vertebral frxDose-response trend with increasing ACE doses (7.2–12 mg). (HR 0.62 [95% CI 0.396–0.974, p=0.038 for the latter) Significant reduction for ≥ 10.8mg vs. 7.2 and 10.8 vs. 5.5 mg (38%).
(110) Cooper, 2006, BONE, North American and EuropePostmenopausal women with osteoporosis at relatively low risk for frx (2,946)RCT of 2.5 mg/d vs. intermittent regimen (20mg every other day plus dose-free intervals for 12 doses/3 mos) ibandronate (IB) vs. placeboVertebral, non-vertebral frx, AE profileDaily, intermittent IB ->↓vertebral frx risk(p≤0.0006); incidences non- vertebral frx similar in all groups except higher risk women (femoral neck T-score≤−3)(p=0.012) Safety profile similar for both regimens and placebo(study underpowered to identify changes in non-vertebral frx risk)
Risedronate
(1) Watts, 2008, risedronate, VERT-NA, USPostmenopausal women (759)3 years on 5 mg Risedronate+Ca+D, discontinued risedronate 1 year cf placebo+CA+DNew vertebral fractures after 1 yr ( persistence of effx )46% lower incidence of new vertebral fractures in risedronate discontinuers vs placebo (RR 0.54 [95% CI, 0.34, 0.86, p=0.009])
(5) Siris, 2008, risedronate, posthoc analysis of 4 trials (BMD Multinational, BMD NA, VERT Multinational, VERT NA)Postmenopausal women with osteopenia and no fractures (620) Sensitivity analysis excluded women with osteopenia at femoral neck (FN) but w/BMD T- score <-2.5SD at lumbar spine (LS)Post hoc analysis of 4 trials: 1.5–3 yrs 5mg/d risedronateFragility fractures73% decreased risk of fragility frx over 3 years vs. placebo (2.2% vs. 6.9%, p=0.023); similar in sensitivity analysis
(29) Delmas, 2008, US?Postmenopausal women with OP (1292)Randomized, double- blind, multi-center study: 150 mg risedronate, once-a-month oral dose (and daily placebo) vs. 5 mg/d, 2 yearsFractures and AEFrx data not reported in abstract, but two regimens determined not to be different in efficacy. AE rates, AEs that led to withdrawal (9.5% daily vs. 8.6% monthly), and upper GI AEs were similar.
(30) Delmas, 2008Postmenopausal women w/OP (1229)Randomized, double- blind study of 75,g risedronate on 2 consecutive days/month (2CMD) vs. 5 mg/dFractures, AEsNew vertebral fracture rate=1% in both groups. Both treatments were well-tolerated and safe.
(121) Watts, 2005, 3 trialsPostmenopausal women receiving risedronate (2.5 or 5mg/d up to 3 yrs) (3979)Meta-analysis of women taking risedronateIncidence of non- vertebral frx stratified by changes in LS and FN BMD Nonvertebral frx incidence in risedronate-trx pts was not predicted by change in BMD. Changes in LS and FN BMD explained only 12% (2%–21%, p=0.014) and 7% 2%–13%, p=0.005), respectively of risedronate’s nonvertebral frx efficacy.
(136) Palomba, 2005, multicenterPostmenopausal OP women with inflammatory bowel disease (IBD) in remission (90)RCT of risedronate (35mg/wk), 12 mosLumbar and thoracic spinal fracturesRisedronate signif ↓frx incidence (12.5 vs. 34.1%, p<0.05) throughout study. RR new vertebral frx after 1 yr=0.36 (0.14–0.85)
Zoledronic acid
(58, 59 one article?)No description of pts.Double blind RCT of IVRate of frx and mortalityRisk of any new clinical fracture ↓
Lyles, 2007except all w/in 90 days of surgical repair of hip frx, mean age 74.5 y (2127)ZOL (5mg) + vit D + CA vs. placebo + vit D + CA, med. FU 1.9 yrsafter hip frx35% in ZOL vs. placebo (8.6% vs. 13.9%, P=0.001); New clinical vertebral fracture: 1.7% vs. 3.8% (P=0.02); new nonvertebral fracture rate: 7.6% vs. 10.7% (P=0.03). AEs: 101 of 1054 ZOL patients (9.6%) and 141 of placebo 1057 patients (13.3%) died, (28% ↓ in deaths from any cause in the ZOL group (P=0.01)). The most frequent AEs in ZOL patients were pyrexia, myalgia, and bone and musculoskeletal pain. No cases of osteonecrosis of the jaw were reported, and no AEs on frx healing noted. The rates of renal and cardiovascular AEs, including atrial fibrillation and stroke, were similar in the two groups
(81) Black, 2007, USPostmenopausal women with OP, mean age 73 y, (3889) Annual 15-minute infusion of zoledronic acid (5mg) vs. placebo at baseline, 12 mos, 24 mos, followed through 36 mos.New vertebral frx (primary) in pts not taking concomitant meds; hip frx in all pts; safety (secondary), AEsZOL-> 70% ↓ in morphometric vertebral frx over 3 years cf placebo (3.3% vs. 10.9%, RR 0.30, 95% CI, 0.24–0.38); ZOL-> 41% ↓ risk hip frx (1.4% vs. 2.5%, HR 0.59, 95% CI, 0.42–0.83). ZOL-> ↓ Non-vertebral frx(25%), clinical (33%), clinical vertebral frx (77%) (p<0.001) AEs, including change in renal fn, similar in two study grps except Atrial fib↑ in ZOL grp (50 vs. 20, p<0.001)
Comparison of Bisphosphonates
(54) McClung, 2007Postmenopausal women with LBD previously treated with ALN ≥ 1yr (225)Single dose zoledronic acid (ZOL) 5g vs. oral ALN 70 mg/wkAEs (and bone markers)Overall AE rate comparable betw grps (ZOL 86.7% vs. ALN 80.4%): Headache more common w/ZOL than ALNPatients preferred ZOL 1x/yr over ALN
(42) Silverman, 2007Postmenopausal women (≥65 yoa) (12,215 risedronate; 21,615 alendronate)Retrospective record abstraction: Risedronate, alendronate, once-a-weekIncidence of hip, nonvertebral fractures in the year following treatment initiation507 nonvertebral fractures and 109 hip fractures. Incidence of nonvertebral fractures in the risedronate cohort (2.0%) was 18% lower (95% CI 2%–32%) than in the alendronate cohort (2.3%). Incidence of hip fractures in the risedronate cohort (0.4%) was 43% lower (95% CI 13%–63%) than in the alendronate cohort (0.6%)Consistent across a number of sensitivity analyses (not specified in abstract)
(93) Nguyen, 2006, meta-analysisPostmenopausal women with low BMD or osteoporosis (18,667) followed 1–4 yearsMeta-analysis of 12 RCTs of women taking etidronate, alendronate, risedronate, clodronate.Incidence of hip frx42% ↓ risk of hip frx (RR 0.58, 95% credible interval 0.42–0.8); absolute rate reduction 52 frx/10,000 women for 3 years of treatment. Probability bisphosphonates better than placebo at reducing risk by at least 30% was 0.90.Bayesian analysis
(56) Mamdani, 2007 (Canada)Bisphosphonate-naïve women with prior Hx of frx (≥66 yoa) (20,587)Administrative data used to cf users of 1st vs. 2nd generation bisphosphonates etidronate+Ca(19,127) vs. Alendronate or risedronate (1,460)Hospital admissions for first(?) frx292 admissions over >23,000 person- years of follow-up; frx risk the same for each group: adjusted rate ratio=1.0; 95% CI 0.6, 1.6)Abstract was ambiguous re: frx hx of participants
b. SELECTIVE ESTROGEN RECEPTOR MODULATORS
Raloxifene
(27) Ensrud, 2008, RUTH, US?Postmenopausal women ≥55 yoa w/CHD or at high risk for CHD, but not selected based on osteoporosis or frx riskRandom assignment to 60 mg/d raloxifene or placebo, median 5.6 yrs follow-upNon-vertebral and clinical vertebral frxNon-vertebral frx: no difference between raloxifene and placebo (incl hip/femur, wrist)
Vertebral frx: raloxifene ↓ frx risk (64 vs. 97; HR, 0.65, 0.47–0.89)
Effx consistent across frx risk categories, incl age, smoking status, physical activity, prior Hx, Fx Hx hip frx, DM, previous use of HRT, thyroid hormone use, statin use, weight loss, BMI, frx-specific summary risk score
(85) Seeman, 2007, meta-analysisPostmenopausal women w/OP(?) (n not included)RCT, Raloxifene 60 mg/d, 120/150mg/dVertebral frx data from prospectively scheduled spinal radiographsIntention to treat analysis: RLX 60: OR 0.60 (0.49–0.74) RLX 120/150: 0.51 (0.41, 0.64)Assessment of consistency of effx. No signif. heterogeneity; 3 prevention studies, 2 arms of MORE, and 3 add’l treatment studies
(117) Barrett-Connor, 2006,Postmenopausal women with CHD or multiple risk factors for CHD, (mean age 67.5 years) (10,101)RCT 60mg raloxifene/d vs. placebo, median FU 5.6 yearsEffects on CHD, BC vs. clinical vertebral frxRaloxifene had no effect on risk for primary coronary events and reduced risk of invasive BC. No significant difference in rates of death from any cause or total stroke, but ↑risk fatal stroke (59 vs. 39, HR 1.49, 1.00–2.24; absolute risk increase 0.7/1000 woman-years) and VT (103 vs. 71; HR 1.44, 1.06–1.95, absolute risk increase 1.2/1000 woman-years). Risk clinical vertebral frx↓ 964 vs. 97; HR 0.65; 0.47–0.89; absolute risk reduction 1.3/1000)
(126) Siris, 2005, MORE/COREWomen enrolled in a 4-year study assessing the efficacy of raloxifene (RAL) for preventing OP followed 4 add’l years to assess effx on BC risk and frx risk (4011)Women who had been taking 60 or 120mg RAL/d were continued on 60mg/d and followed 4 add’l years; substudy assessed risk among women who were≥80% compliant and did not take other bone agentsNew non-vertebral frxRisk of at least one new nonvertebral frx did not differ between placebo and trx grps. (22.9 vs. 22.8%); same with risk of at least one new frx at one of six sites (17.5%). In women with prevalent vertebral frx, no overall effect on nonvertebral frx risk but a decreased risk at six major nonvertebral sites (HR 0.78, 0.63–0.96).No findings reported in abstract for compliant subset; abstract reported limitations for assessing frx risk
Comparison of Bazedoxifene w/raloxifene
(6) Silverman, 2008, bazedoxifene (B)Healthy postmenopausal women (55–85 yoa) with osteoporosis (6,847 intent-to-treat)3-year, Randomized, double-blind, placebo and active controlled: 20, 40 mg/d B vs. 60 mg/d raloxifene vs. placeboIncidence of new vertebral and non-vertebral fracture and AEIncidence of new vertebral frx signif lower in 20 mg B (2.3%), 40 mg (2.5%), raloxifene (2.3%) cf. placebo; RR reduction 42%, 37%, 42%, resp.
Incidence of non-vertebral frx: no difference; In subset of women at higher risk (lower T score or prior fractures), 20 mg B showed 50% and 44% RR non-vertebral frx cf. placebo (p=0.02) and raloxifene (p=0.05) Incidence vasodilatation, leg cramps, VT higher with B and raloxifene cf. placebo
D. PARATHYROID HORMONE (TERIPARATIDE)
(67) Greenspan, 2007, 168 centers in 9 countriesPostmenopausal women with LBD at hip or lumbar spine (2532)RCT of 100 mug recombinant human PTH (subcut) + Ca (700mg/d) and Vit D3 (400u/d) vs. placebo+ Ca (700mg/d) and Vit D3 (400u/d) daily; Duration???New or worsened vertebral frx (primary outcome); safety (secondary outcome)67.2% of those who received at least one dose completed study(?) PTH decreased frx risk but magnitude of redux changed with sensitivity analysis including assumptions about frx incidence in pts who did not complete study. Assuming no frx: RR 0.42 (95% CI, 0.24 to 0.72, p=0.001); Assuming same frx incidence as completers: 0.60 (0.36–1.00, p=0.05); Assuming frx incidence of placebo grp: 0.62 (0.37–1.04, p=0.07). PTH increased risk for hypercalciuria (24%, 20–27%), hypercalcemia (23%, 21–26%), nausea (14%, 11–16%)
(52) Miller, 2007 FPTPostmenopausal women w/osteoporosis and renal impairment (n not specified in abstract)RCT of daily subcutaneous injections of teriparatide 20 or 40 mcg/day vs. placeboFracture risk and AE by GFR (as index of renal function)Teriparatide-mediated vertebral and nonvertebral fracture risk reductions were similar and did not differ significantly between patients with normal or impaired renal function (treatment-by-subgroup interactions p>0.05?). The incidences of treatment-emergent and renal-related AEs were consistent across treatment assignment in the normal, mildly impaired, and moderately impaired renal function subgroups.
Teriparatide-induced changes in mean GFR were unaffected by baseline renal function (treatment-by-renal function interaction p>0.05 for normal, mildly impaired, or moderately impaired subgroups).
(134) Prince, 2005, FPT followupFormer FPT participants (20, 40ug teriparatide(TP)/d vs. placebo, 4 yrs) allowed to continue on or begin TP (1262)Observation study of followup; approx 60% received some TP during followup (FU).Non-vertebral fragility frxHR for frx in each TP group rel to placebo were significant for the 50-month period that included treatment and FU (p≤0.03). During FU, HR differed signif between 40ug (and combined) grps and placebo but not 20ug vs placebo; no difference between 20 and 40. Frx incidence in former placebo and treatment groups diverged in FU (p=0.0009)Results support sustained effect of TP in reducing risk of nonvertebral fragility frx up to 30 mos after discontinuation
G. AND H. CALCIUM/VITAMIN D
(41) Tang, 2007 Meta-analysisIndividuals 50 and over with osteoporosis(?) 17 trials (52,625)Calcium alone or combined with vitamin DFractures of all typesTreatment associated with a 12% risk reduction in fractures of all types (risk ratio 0.88, 95% CI 0.83–0.95; p=0.0004); The fracture risk reduction was significantly greater (24%) in trials in which the compliance rate was high (p<0.0001). Treatment effect for calcium ≥ 1200 mg > for Ca <1200 mg (0.80 vs. 0.94; p=0.006), and TE for vitamin D ≥ 800 IU > for D<800 IU (0.84 vs. 0.87; p=0.03)
(57) Lyons, 2007, Wales UKIndividuals in 314 residential care homes (2,624 women, 816 men)Double blind RCT of vitamin D supplementation (100,000 IU D2)Incidence of first frx (intention to treat)205 first fractures occurred in the intervention group during a total of 2,846 person years of follow-up (7 fractures per 100 people per year of follow-up) vs. 218 first fractures in the control group over 2,860 person years of follow-up. HR 0.95 (95% confidence interval 0.79–1.15) not statistically significant
(102) Jackson, 2006, WHIPostmenopausal women enrolled in WHI, 50–79 yoa (36,282)RCT 1000mg/d elemental Ca (CaCO3)+400IU Vit D3/d vs. placebo; avge FU 7 yrsHip and spinal frx, AEsHR hip frx=0.88 (0.72–1.08)
HR spinal frx=0.900.90 (0.74 to 1.10), and HR total fractures=0.96 (0.91 to 1.02). (no signif diff)
Risk of renal calculi increased with calcium plus vitamin D (HR, 1.17; 1.02 to 1.34). Excluding data from non-adherent women->HR for hip fracture of 0.71 (0.52 to 0.97).
Intention-to-treat analysis; Effects did not vary significantly according to prerandomization serum vitamin D levels
I. EXERCISE
(96) Lock, 2006, USIndividuals at high risk for osteoporosis (>1,656)Meta-analysis of 6 RCTs on exercise (3), multifactorial interventions (2), and sunlight (1)Risk of spinal, hip frxExercise assoc with nonsignificant ↓ risk of spinal frx 9RR 0.52, 95% CI 0.17–1.60); multifactorial interventions assoc with borderline significant ↓ hip frx (RR 0.37, 0.13–1.03); Exposure to sunlight assoc with a non-significantly lower risk of hip fracture (RR=0.17, 95% CI=0.02 to 1.35). No indications of AE.
(J) Comparisons of Bisphosphonates w/SERMS
(118) Adami, 2006, ICARO, ItalyPostmenopausal women treated w/ALN, RIS, or raloxifene≥1 year w/compliance≥50%Observational multicenter study cf. ALN, RIS, raloxifeneRisk factors for an “inadequate clinical response” (ICR)to drug therapy, defined as the occurrence of new vertebral or nonvertebral fragility frx in patients prescribed, for at least 1 year, alendronate, risedronate, or raloxifene, with compliance≥50%220/880 pts treated w/antiresorptives for median of 2 years were ICR (25%). ICRs had more pretrx frx and longer trx (2.8 vs. 1.8 yrs). Adjusting for confounders, significant determinants of ICR were poorer compliance and less frequent use of Ca and Vit D.Major determinants of poor response in clinical setting cf. RCTs identified
(38) Adami, 2008Postmenopausal women with severe osteoporosis (862), 10.7% with inadequate clinical treatment response (ICR, i.e., fracture during treatment of at least 1 year duration)Alendronate, risedronate, raloxifene, doses not specified in abstractFracture risk during treatmentBMI, follow-up duration, # prevalent vertebral fractures, treatment modality, proportion of patients taking calcium and vitamin D supplements, and compliance with treatment did not differ between ICR and non-ICR groups; ICR patients were significantly older and had ↑# vertebral deformities
(48) Recker, 2007Postmenopausal women with no low bone mass, no prior fractures, and no prior OP treatment, mean age 66 (1423)RCT of Raloxifene (RLX, 60 mg/d) vs. alendronate (ALN, 10 mg/d) 5 years (stopped prematurely due to low enrollment)≥1 new vertebral or non-vertebral fracture; AE, discontinuation due to AEAfter 312±254 days, 22 women in the ALN grp and 20 in the RLX grp had new vertebral or non-vertebral frx; 4 in the ALN group and none in the RLX group had moderate/severe vertebral fractures, a pre-specified endpoint (P=0.04)(insufficient power to cf); # w/≥ 1 AE similar in each group, and discontinuation due to AE similar; Need for colonoscopy, diarrhea, and nausea were more common in ALN group (each p<0.05); 1 case BC and one VTE in each grp;
Comparison of Parathyroid Hormone with Bisphosphonates
(45) Saag, 2007Men and women with osteoporosis, 22–89 yoa who had received GC>3 months (428)18-month double-blind RCT cf. teriparatide (20ug/d) vs. alendronate (10mg/d)New vertebral and non-vertebral fracture incidence an AE as secondary outcomesTeriparatide resulted in fewer new vertebral fractures than alendronate (0.6% vs. 6.1%, P=0.004); incidence of nonvertebral fractures was similar in the two groups (5.6% vs. 3.7%, P=0.36); no AE info in abstract
(40) Vestergard, 2007 Meta-analysisNot specified in abstractRCTs of PTH alone or in combination with antiresorptivesVertebral and non-vertebral frx risk, AEPTH alone or in combination with antiresorptive drugs reduced vertebral [relative risk (RR)=0.36, 95% confidence interval (CI): 0.28–0.47, p<0.01] and non-vertebral (RR=0.62, 95% CI: 0.48–0.82, p<0.01) fracture risk; No significant effect of study duration on fracture risk; major adverse events were hypercalcaemia, nausea and discomfort at the injection sites
STRONTIUM RANELATE
(7) Seeman, 2008, strontium ranelate, SOTI, TROPOS, ItalyPostmenopausal women with LS and/or FN osteopenia (1431)Pooled data from two 3- yr randomized trials of 2g/d Sr or placeboRisk of new vertebral fracturesLS osteopenia: 41%↓ risk vertebral frx (RR 0.59, 0.43–0.82) in women with no prevalent frx; 59%↓ (RR = 0.41; 95% CI, 0.17–0.99) in the 447 patients with no prevalent fractures, and 38%↓ (RR = 0.62; 95% CI, 0.44–0.88) in the 719 patients with prevalent fractures. Osteopenia at both sites: 52%↓ frx risk (RR = 0.48; 95% CI, 0.24–0.96)Abstract conclusion alluded to safety but no AE data
(87) Roux, 2006, multi-nationalPostmenopausal women, avge age 74 y (5082)2 pooled RCTs: strontium ranelate 2g/d vs. placebo, 3-year FUVertebral frx, risk of first vertebral frx, non-vertebral frxSr->↓risk vertebral (RR 0.60, 0.53–69, p<0.001) and non-vertebral (RR 0.85, 0.74–0.99, p = 0.03) frx Women < 70 yoa: 37%↓Vertebral frx (p=0.003); Women 70–80 yoa: 42% (p< 0.001); Women≥80 years: 32% (p = 0.013). RR of vertebral fracture was 0.28 (0.07–0.99) in osteopenic and 0.61 (0.53–0.70) in osteoporotic women; Risk of experiencing 1st vertebral frx (n=2605) ↓ by 48% (p<0.001). Risk of experiencing 2nd vertebral frx (1100) ↓ by 45% (p< 0.001). Risk of experiencing >2 vertebral frx (1365) ↓ by 33% (p< 0.001;). BMD, Fx Hx OP, baseline BMI, and addiction to smoking were not determinants of efficacyCox model for cf and RR
(119) Adami, 2006, TROPOS, ItalyPostmenopausal women w/OP (5091)Double-blind RCT of strontium ranelate (2g/d orally) over 3 yearsIncidence of non-vertebral and other major (hip, wrist, pelvis, sacrum, ribs, sternum, clavicle, humerus) frx16%↓ risk non-vertebral frx (p=0.04)
19%↓ risk other major frx (p=0.031)
36%↓ risk hip frx in women ≥74 yoa who were treated with Sr ranelate (n=982)
AE incidence comparable between grps
KQ2. FRACTURE REDUCTION FOR VARIOUS RISK GROUPS
(65) Jamal, 2007, FIT, ?Menopausal women (6458 for total study; 581 w/severely reduced renal function (GFR <45ml/min)RCT of Alendronate vs. placeboClinical, vertebral frx, AEsAlendronate reduced the risk of clinical fractures to a similar degree in those with (OR: 0.78; 95% CI: 0.51–1.21) and without reduced renal function (OR: 0.80; 95% CI; 0.70–0.93; p for interaction = 0.89). Alendronate reduced the risk of spine fractures to a similar degree in those with (OR: 0.72; 95% CI: 0.31–1.7) and without reduced renal function (OR: 0.50; 95% CI: 0.32–0.76; p for interaction = 0.44). No diffs in AEs by renal function.
(146) Hochberg, 2005, multicenter, FITPostmenopausal women with OP, 55–80 yoa (3658)RCT of alendronate, 5mg/d x 2 yrs followed by 10mg for 1–2.5 add’l yearsClinical frx↓ Relative risk for hip, clinical spine, and wrist fractures: constant across age groups, without evidence of a decline at older ages. ALE ↓ risk of clinical fracture by 53% at the hip (RR = 0.47; 95% CI = 0.27–0.81; p≤ 0.01), 45% at the spine (RR = 0.55; 95% CI = 0.37–0.83; p < 0.01), and 31% at the wrist (RR = 0.69; 95% CI = 0.50–0.98; p = 0.038). In addition, alendronate produced a significant risk reduction of 40% (RR = 0.60; 95% CI = 0.47–0.77; p≤ 0.01) for the composite event of clinical hip, spine, and wrist fractures. Effectiveness was somewhat greater in women with T≤− 2.5 cf. T≤ −2.0.Absolute risk reduction increased with age because of ↑ risk with age: absolute risk reduction for the composite event (hip, spine, and wrist fractures together) for alendronate treatment versus placebo was 65, 80, 111, and 161 women with fractures per 10,000 Person-yrs for the 55 to ≤ 65, 65 to ≤ 70, 70 to ≤ 75, and 75–85 year age groups, respectively;
(116) Bauer, 2006, FITPostmenopausal women 55–80 years, femoral neck T-score≤ −1.6 (6,186); with (T≤2.5 or prevalent vertebral frx)(3,495) or without (T≥2.5 or no prevalent vertebral frx)(2,689) OPRCT Alendronate 5–10mg/d vs. placebo, mean FU 3.2 yrsRisk of incident vertebral and non-vertebral frx in ALN vs. placebo stratified by baseline BM marker levels 492 nonvertebral and 294 morphometric vertebral fractures. ALN-induced↓ in non-vertebral fracture cf placebo was a fn of PINP: (p = 0.03 for trend). E.g., among osteoporotic women in the lowest tertile of pretreatment PINP (≤41.6 ng/ml), ALN vs PBO relative hazard for nonvertebral fracture=0.88 (95% CI: 0.65, 1.21) compared with a relative hazard of 0.54 (95% CI: 0.39, 0.74) among those in the highest tertile of PINP, ≥56.8 ng/ml). Results similar among women without baseline OP. Similar (but non-sign) trends observed with baseline levels of BSALP.
Conversely, vertebral frx treatment efficacy among OP women did not differ significantly according to pretreatment marker levels. Vertebral frx treatment efficacy among non-OP women was related to baseline BSALP (p = 0.05 for trend).
Findings suggest bisphosphonate treatment may be more effective in women with elevated bone turnover
(110) Cooper, 2006, BONE, North American and EuropePostmenopausal women with osteoporosis at relatively low risk for frx (2,946)RCT of 2.5 mg/d vs. intermittent regimen (20mg every other day plus dose-free intervals for 12 doses/3 mos) ibandronate (IB) vs. placeboVertebral, non-vertebral frx in women with higher vs. lower BMD, AE profileDaily, intermittent IB ->↓vertebral frx risk(p≤0.0006); incidences non- vertebral frx similar in all groups except higher risk women (femoral neck T-score≤−3)(p=0.012) Safety profile similar for both regimens and placebo(study underpowered to identify changes in non-vertebral frx risk)
(121) Watts, 2005, 3 trialsPostmenopausal women receiving risedronate (2.5 or 5mg/d up to 3 yrs) (3979)Meta-analysis of women taking risedronateIncidence of non-vertebral frx stratified by changes in LS and FN BMD Nonvertebral frx incidence in risedronate-trx pts was not predicted by change in BMD. Changes in LS and FN BMD explained only 12% (2%–21%, p=0.014) and 7% 2%–13%, p=0.005), respectively of risedronate’s nonvertebral frx efficacy.
(27) Ensrud, 2008, RUTH, US?Postmenopausal women ≥55 yoa w/CHD or at high risk for CHD, but not selected based on osteoporosis or frx riskRandom assignment to 60 mg/d raloxifene or placebo, median 5.6 yrs follow-upNon-vertebral and clinical vertebral frxNon-vertebral frx: no difference between raloxifene and placebo (incl hip/femur, wrist)
Vertebral frx: raloxifene ↓ frx risk (64 vs. 97; HR, 0.65, 0.47–0.89)
Effx consistent across frx risk categories, incl age, smoking status, physical activity, prior Hx, Fx Hx hip frx, DM, previous use of HRT, thyroid hormone use, statin use, weight loss, BMI, frx-specific summary risk score
(126) Siris, 2005, MORE/COREWomen enrolled in a 4-year study assessing the efficacy of raloxifene (RAL) for preventing OP followed 4 add’l years to assess effx on BC risk and frx risk (4011)Women who had been taking 60 or 120mg RAL/d were continued on 60mg/d and followed 4 add’l years; substudy assessed risk among women who were≥80% compliant and did not take other bone agentsNew non-vertebral frxRisk of at least one new nonvertebral frx did not differ between placebo and trx grps. (22.9 vs. 22.8%); same with risk of at least one new frx at one of six sites (17.5%).
In women with prevalent vertebral frx , no overall effect on nonvertebral frx risk but a decreased risk at six major nonvertebral sites (HR 0.78, 0.63–0.96).
No findings reported in abstract for compliant subset; abstract reported limitations for assessing frx risk
(52) Miller, 2007 FPTPostmenopausal women w/osteoporosis and renal impairment (n not specified in abstract)RCT of daily subcutaneous injections of teriparatide 20 or 40 mcg/day vs. placeboFracture risk and AE by GFR (as index of renal function)Teriparatide-mediated vertebral and nonvertebral fracture risk reductions were similar and did not differ significantly between patients with normal or impaired renal function (treatment-by-subgroup interactions p>0.05?). The incidences of treatment-emergent and renal-related AEs were consistent across treatment assignment in the normal, mildly impaired, and moderately impaired renal function subgroups. Teriparatide-induced changes in mean GFR were unaffected by baseline renal function (treatment-by-renal function interaction p>0.05 for normal, mildly impaired, or moderately impaired subgroups).
(102) Jackson, 2006, WHIPostmenopausal women enrolled in WHI, 50–79 yoa (36,282)RCT 1000mg/d elemental Ca (CaCO3)+400IU Vit D3/d vs. placebo; avge FU 7 yrsHip and spinal frx, AEsHR hip frx=0.88 (0.72–1.08)
HR spinal frx=0.900.90 (0.74 to 1.10), and HR total fractures=0.96 (0.91 to 1.02). (no signif diff)
Risk of renal calculi increased with calcium plus vitamin D (HR, 1.17; 1.02 to 1.34). Excluding data from non-adherent women->HR for hip fracture of 0.71 (0.52 to 0.97).
Intention-to-treat analysis; Effects did not vary significantly according to prerandomization serum vitamin D levels
(38) Adami, 2008Postmenopausal women with severe osteoporosis (862), 10.7% with inadequate clinical treatment response (ICR, i.e., fracture during treatment of at least 1 year duration)Alendronate, risedronate, raloxifene, doses not specified in abstractFracture risk during treatmentBMI, follow-up duration, # prevalent vertebral fractures, treatment modality, proportion of patients taking calcium and vitamin D supplements, and compliance with treatment did not differ between ICR and non-ICR groups; ICR patients were significantly older and had ↑# vertebral deformities
KQ3. ADHERENCE AND PERSISTENCE EFFECTS
(115) Black, 2006, FITPostmenopausal women with a mean of 5 years prior alendronate treatment (1099)RCT 5, 10 mg/d Alendronate or placebo X 5 yrsFrx incidence as exploratory outcome measure to assess persistence of effx 5-year cumulative risk nonvertebral frx (RR 1.00, 0.76–1.32) did not differ between continuers and discontinuers; Continuers had significant ↓clinical vertebral frx (2.4% vs/5.3% for placebo; RR 0.45, 0.24–0.85) but NO difference in morphometric vertebral frx (11.3% for placebo and 9.8% for alendronate; RR, 0.86; 95% CI, 0.60–1.22)
(1) Watts, 2008, risedronate, VERT-NA, USPostmenopausal women (759)3 years on 5 mg Risedronate+Ca+D, discontinued risedronate 1 year cf placebo+CA+DNew vertebral fractures after 1 yr ( persistence of effx )46% lower incidence of new vertebral fractures in risedronate discontinuers vs placebo (RR 0.54 [95% CI, 0.34, 0.86, p=0.009])
(126) Siris, 2005, MORE/COREWomen enrolled in a 4-year study assessing the efficacy of raloxifene (RAL) for preventing OP followed 4 add’l years to assess effx on BC risk and frx risk (4011)Women who had been taking 60 or 120mg RAL/d were continued on 60mg/d and followed 4 add’l years; substudy assessed risk among women who were≥80% compliant and did not take other bone agentsNew non-vertebral frxRisk of at least one new nonvertebral frx did not differ between placebo and trx grps. (22.9 vs. 22.8%); same with risk of at least one new frx at one of six sites (17.5%).
In women with prevalent vertebral frx, no overall effect on nonvertebral frx risk but a decreased risk at six major nonvertebral sites (HR 0.78, 0.63–0.96).
No findings reported in abstract for compliant subset ; abstract reported limitations for assessing frx risk
(134) Prince, 2005, FPT followupFormer FPT participants (20, 40ug teriparatide(TP)/d vs. placebo, 4 yrs) allowed to continue on or begin TP (1262)Observation study of followup; approx 60% received some TP during followup (FU).Non-vertebral fragility frxHR for frx in each TP group rel to placebo were significant for the 50-month period that included treatment and FU (p≤0.03). During FU, HR differed signif between 40ug (and combined) grps and placebo but not 20ug vs placebo; no difference between 20 and 40. Frx incidence in former placebo and treatment groups diverged in FU (p=0.0009)Results support sustained effect of TP in reducing risk of nonvertebral fragility frx up to 30 mos after discontinuation
(118) Adami, 2006, ICARO, ItalyPostmenopausal women treated w/ALN, RIS, or raloxifene≥1 year w/compliance≥50%Observational multicenter study cf. ALN, RIS, raloxifeneRisk factors for an “inadequate clinical response” (ICR)to drug therapy, defined as the occurrence of new vertebral or nonvertebral fragility frx in patients prescribed, for at least 1 year, alendronate, risedronate, or raloxifene, with compliance≥50%220/880 pts treated w/antiresorptives for median of 2 years were ICR (25%). ICRs had more pretrx frx and longer trx (2.8 vs. 1.8 yrs). Adjusting for confounders, significant determinants of ICR were poorer compliance and less frequent use of Ca and Vit D.Major determinants of poor response in clinical setting cf. RCTs identified
(38) Adami, 2008Postmenopausal women with severe osteoporosis (862), 10.7% with inadequate clinical treatment response (ICR, i.e., fracture during treatment of at least 1 year duration)Alendronate, risedronate, raloxifene, doses not specified in abstractFracture risk during treatmentBMI, follow-up duration, # prevalent vertebral fractures, treatment modality, proportion of patients taking calcium and vitamin D supplements, and compliance with treatment did not differ between ICR and non-ICR groups; ICR patients were significantly older and had ↑# vertebral deformities
KQ4. ADVERSE EFFECTS
(65) Jamal, 2007, FIT, ?Menopausal women (6458 for total study; 581 w/severely reduced renal function (GFR <45ml/min)RCT of Alendronate vs. placeboClinical, vertebral frx, AEsAlendronate reduced the risk of clinical fractures to a similar degree in those with (OR: 0.78; 95% CI: 0.51–1.21) and without reduced renal function (OR: 0.80; 95% CI; 0.70– 0.93; p for interaction = 0.89). Alendronate reduced the risk of spine fractures to a similar degree in those with (OR: 0.72; 95% CI: 0.31–1.7) and without reduced renal function (OR: 0.50; 95% CI: 0.32–0.76; p for interaction = 0.44). No diffs in AEs by renal function.
(55) McCloskey, 2007, UKCommunity-dwelling women (≥75 yoa) (5,596 Intention to treat)3-year RCT of oral clodronate (800 mg/d) vs. placeboFracture incidence and AE114 new hip frx during the 3-year treatment phase: 56 (2.0%) women in the clodronate group and 58 (2.1%) women in the placebo group (HR, 1.02; 95% CI, 0.71–1.47). Clodronate decreased the incidence of any clinical fracture by 20% (264 women [9.5%] versus 337 [12.1%] in the placebo group; HR, 0.80; 95% CI, 0.68–0.94). Clodronate also decreased the incidence of OP-associated nonhip fractures by 29% (5.2% versus 7.4%; HR, 0.71; 95% CI, 0.57–0.87). AE not significant.Effect of CLO independent of baseline BMD but NNT less w/OP
(110) Cooper, 2006, BONE, North American and EuropePostmenopausal women with osteoporosis at relatively low risk for frx (2,946)RCT of 2.5 mg/d vs. intermittent regimen (20mg every other day plus dose-free intervals for 12 doses/3 mos) ibandronate (IB) vs. placeboVertebral, non-vertebral frx in women with higher vs. lower BMD, AE profileDaily, intermittent IB ->↓vertebral frx risk(p≤0.0006); incidences non- vertebral frx similar in all groups except higher risk women (femoral neck T-score≤−3)(p=0.012) Safety profile similar for both regimens and placebo(study underpowered to identify changes in non-vertebral frx risk)
(29) Delmas, 2008, US?Postmenopausal women with OP (1292)Randomized, double- blind, multi-center study: 150 mg risedronate, once-a-month oral dose (and daily placebo) vs. 5 mg/d, 2 yearsFractures and AEFrx data not reported in abstract, but two regimens determined not to be different in efficacy. AE rates, AEs that led to withdrawal (9.5% daily vs. 8.6% monthly), and upper GI AEs were similar.
(30) Delmas, 2008Postmenopausal women w/OP (1229)Randomized, double- blind study of 75,g risedronate on 2 consecutive days/month (2CMD) vs. 5 mg/dFractures, AEsNew vertebral fracture rate=1% in both groups. Both treatments were well-tolerated and safe.
(58, 59 one article?) Lyles, 2007 HORIZON (#3581 – included in final version of LBD)No description of pts. except all w/in 90 days of surgical repair of hip frx, mean age 74.5 y (2127)Double blind RCT of IV ZOL (5mg once a year) + vit D + CA vs. placebo + vit D + CA, med. FU 1.9 yrsRate of frx and mortality after hip frx, other AEsRisk of any new clinical fracture ↓ 35% in ZOL vs. placebo (8.6% vs. 13.9%, P=0.001); New clinical vertebral fracture: 1.7% vs. 3.8% (P=0.02); new nonvertebral fracture rate: 7.6% vs. 10.7% (P=0.03). AEs: 101 of 1054 ZOL patients (9.6%) and 141 of placebo 1057 patients (13.3%) died, (28% ↓ in deaths from any cause in the ZOL group (P=0.01)). The most frequent AEs in ZOL patients were pyrexia, myalgia, and bone and musculoskeletal pain. No cases of osteonecrosis of the jaw were reported, and no AEs on frx healing noted. The rates of renal and cardiovascular AEs, including atrial fibrillation and stroke, were similar in the two groups. No cases of osteonecrosis of the jaw were reported.
(81) Black, 2007, US HORIZON (#3578 – included in final LBD)Postmenopausal women with OP, mean age 73 y, (3889) Annual 15-minute infusion of zoledronic acid (5mg) vs. placebo at baseline, 12 mos, 24 mos, followed through 36 mos.New vertebral frx (primary) in pts not taking concomitant meds; hip frx in all pts; safety (secondary), AEsZOL-> 70% ↓ in morphometric vertebral frx over 3 years cf placebo (3.3% vs. 10.9%, RR 0.30, 95% CI, 0.24–0.38); ZOL-> 41% ↓ risk hip frx (1.4% vs. 2.5%, HR 0.59, 95% CI, 0.42–0.83). ZOL-> ↓ Non-vertebral frx(25%), clinical (33%), clinical vertebral frx (77%) (p<0.001) AEs, including change in renal fn, similar in two study grps except serious Atrial fib↑ in ZOL grp (50 vs. 20, p<0.001) but most were more than 30 days after infusion when ZOL would have dispersed. No cases of osteonecrosis of the jaw reported. Possible ONJ reported 1 case each in control and treated.
Cummings, 2007* FIT (#3577 – included in final LBD)Editorial/review of FIT participantsAlendronate treatmentIncidence of atrial fibrillationIncrease in serious AF but not total AF in women who took alendronate*Cummings SR, Schwartz AV, Black DM; Alendronate and Atrial Fibrillation; NEJM 356(18):1895– 6; 2007
(117) Barrett-Connor, 2006,Postmenopausal women with CHD or multiple risk factors for CHD, (mean age 67.5 years) (10,101)RCT 60mg raloxifene/d vs. placebo, median FU 5.6 yearsEffects on CHD, BC vs. clinical vertebral frxRaloxifene had no effect on risk for primary coronary events and reduced risk of invasive BC. No significant difference in rates of death from any cause or total stroke, but ↑risk fatal stroke (59 vs. 39, HR 1.49, 1.00– 2.24; absolute risk increase 0.7/1000 woman-years) and VT (103 vs. 71; HR 1.44, 1.06–1.95, absolute risk increase 1.2/1000 woman-years). Risk clinical vertebral frx↓ 964 vs. 97; HR 0.65; 0.47–0.89; absolute risk reduction 1.3/1000)
(6) Silverman, 2008, bazedoxifene (B)Healthy postmenopausal women (55–85 yoa) with osteoporosis (6,847 intent-to-treat)3-year, Randomized, double-blind, placebo and active controlled: 20, 40 mg/d B vs. 60 mg/d raloxifene vs. placeboIncidence of new vertebral and non- vertebral fracture and AEIncidence of new vertebral frx signif lower in 20 mg B (2.3%), 40 mg (2.5%), raloxifene (2.3%) cf. placebo; RR reduction 42%, 37%, 42%, resp. Incidence of non-vertebral frx: no difference; In subset of women at higher risk (lower T score or prior fractures), 20 mg B showed 50% and 44% RR non-vertebral frx cf. placebo (p=0.02) and raloxifene (p=0.05) Incidence vasodilatation, leg cramps, VT higher with B and raloxifene cf. placebo
(67) Greenspan, 2007, 168 centers in 9 countriesPostmenopausal women with LBD at hip or lumbar spine (2532)RCT of 100 mug recombinant human PTH (subcut) + Ca (700mg/d) and Vit D3 (400u/d) vs. placebo+ Ca (700mg/d) and Vit D3 (400u/d) daily; Duration???New or worsened vertebral frx (primary outcome); safety (secondary outcome)67.2% of those who received at least one dose completed study(?)PTH decreased frx risk but magnitude of redux changed with sensitivity analysis including assumptions about frx incidence in pts who did not complete study. Assuming no frx: RR 0.42 (95% CI, 0.24 to 0.72, p=0.001); Assuming same frx incidence as completers: 0.60 (0.36–1.00, p=0.05); Assuming frx incidence of placebo grp: 0.62 (0.37–1.04, p=0.07). PTH increased risk for hypercalciuria (24%, 20–27%), hypercalcemia (23%, 21–26%), nausea (14%, 11– 16%)
(52) Miller, 2007 FPTPostmenopausal women w/osteoporosis and renal impairment (n not specified in abstract)RCT of daily subcutaneous injections of teriparatide 20 or 40 mcg/day vs. placeboFracture risk and AE by GFR (as index of renal function)Teriparatide-mediated vertebral and nonvertebral fracture risk reductions were similar and did not differ significantly between patients with normal or impaired renal function (treatment-by-subgroup interactions p>0.05?). The incidences of treatment-emergent and renal-related AEs were consistent across treatment assignment in the normal, mildly impaired, and moderately impaired renal function subgroups. Teriparatide-induced changes in mean GFR were unaffected by baseline renal function (treatment-by- renal function interaction p>0.05 for normal, mildly impaired, or moderately impaired subgroups).
(102) Jackson, 2006, WHIPostmenopausal women enrolled in WHI, 50–79 yoa (36,282)RCT 1000mg/d elemental Ca (CaCO3)+400IU Vit D3/d vs. placebo; avge FU 7 yrsHip and spinal frx, AEsHR hip frx=0.88 (0.72–1.08) HR spinal frx=0.900.90 (0.74 to 1.10), and HR total fractures=0.96 (0.91 to 1.02). (no signif diff) Risk of renal calculi increased with calcium plus vitamin D (HR, 1.17; 1.02 to 1.34). Excluding data from non-adherent women->HR for hip fracture of 0.71 (0.52 to 0.97).Intention-to-treat analysis; Effects did not vary significantly according to prerandomization serum vitamin D levels
(48) Recker, 2007Postmenopausal women with no low bone mass, no prior fractures, and no prior OP treatment, mean age 66 (1423)RCT of Raloxifene (RLX, 60 mg/d) vs. alendronate (ALN, 10 mg/d) 5 years (stopped prematurely due to low enrollment)≥ 1 new vertebral or non- vertebral fracture; AE, discontinuation due to AEAfter 312±254 days, 22 women in the ALN grp and 20 in the RLX grp had new vertebral or non-vertebral frx; 4 in the ALN group and none in the RLX group had moderate/severe vertebral fractures, a pre-specified endpoint (P=0.04)(insufficient power to cf); # w/≥1 AE similar in each group, and discontinuation due to AE similar; Need for colonoscopy, diarrhea, and nausea were more common in ALN group (each p<0.05); 1 case BC and one VTE in each grp;
(40) Vestergard, 2007 Meta-analysisNot specified in abstractRCTs of PTH alone or in combination with antiresorptivesVertebral and non- vertebral frx risk, AEPTH alone or in combination with antiresorptive drugs reduced vertebral [relative risk (RR)=0.36, 95% confidence interval (CI): 0.28– 0.47, p<0.01] and non-vertebral (RR=0.62, 95% CI: 0.48–0.82, p<0.01) fracture risk; No significant effect of study duration on fracture risk; major adverse events were hypercalcaemia, nausea and discomfort at the injection sites
Sorensen, 2008 Denmark (not identified in search)
BMJ. 2008 April 12; 336(7648): 813–816. HT Sørensen, Christensen S, Mehnert F, Pedersen L, Chapurlat RD, Cummings SR, Baron JA Use of bisphosphonates among women and risk of atrial fibrillation and flutter: population based case-control study
13,586 female patients with atrial fibrillation and flutter and 68 054 population controlsPopulation based case- control studyAdjusted relative risk of AF among users of bisphosphonates (or use of bisphosphonates among AF patients and controls?)435 cases (3.2%) and 1958 population controls(2.9%) were current users of bisphosphonates for osteoporosis. Etidronate and alendronate were used with almost the same frequency among cases and controls. The adjusted relative risk of current use of bisphosphonates compared with non-use was 0.95 (95% confidence interval 0.84 to 1.07). New users had a relative risk of 0.75 (95% confidence interval 0.49 to 1.16), broadly similar to the estimate for continuing users (relative risk 0.96, 95% confidence interval 0.85 to 1.09). The relative risk estimates were independent of number of prescriptions and the position of the atrial fibrillation and flutter diagnosis in the discharge record, and were similar for inpatients and outpatients.Conclusion No evidence was found that use of bisphosphonates increases the risk of atrial fibrillation and flutter
Majumdar SR 2008 (editorial/review) Oral Bisphosphonates and AF; BMJ 336(7648): 784–785 Evidence does not support a role for bisphosphonates in causing AF
Heckbert SR, Li G, Cummings SR, Smith NK, Psaty BM, 2008 Use of Alendronate and Risk of Incident Atrial Fibrillation in Women Arch Intern Med. 2008;168(8):826–831Women with a Hx of AF in Group Health (727) and controls (1057)population-based case- control studyEver having used alendronateMore AF case patients than controls had ever used alendronate (6.5% [n=47] vs 4.1% [n=40]; P=.03). Compared with never use of any bisphosphonate, ever use of alendronate was associated with a higher risk of incident AF (odds ratio, 1.86; 95% confidence interval, 1.09–3.15) after adjustment for the matching variables, a diagnosis of osteoporosis, and a history of cardiovascular diseaseEver use of alendronate was associated with an increased risk of incident AF in clinical practice

AE: adverse events; AF: atrial fibrillation; ALN: alendronate; BONE: Oral iBandronate Osteoporosis vertebral fracture trial in North American and Europe; DM: diabetes mellitus; FN: femoral neck; Fx: family; FIT: Fracture Intervention Trial; FPT: Fracture Prevention Trial; FU: follow-up; HRT: hormone replacement therapy; Hx: history; LS: lumbar spine; PINP: N-terminal propeptide of type 1 collagen; VT venous thromboembolism

CER 13 - Comparative Effectiveness of Therapies for Clinically Localized Prostate Cancer

Original FindingsNew findings
Comparative Efficacy and Safety
No one therapy can be considered the preferred treatment for localized prostate cancer patient must make trade offs between estimated treatment effectiveness, necessity, and adverse effects. All treatment options result in adverse effects (primarily urinary, bowel, and sexual), although the severity and frequency may vary between treatments. Even if differences in therapeutic effectiveness exist, differences in adverse effects, convenience, and costs are likely to be important factors in individual patient decision-making. Patient satisfaction with therapy is high and associated with several clinically relevant outcome measures.Author/Year: Wong, 2006
Study Objective: Compare treatment with observation in men with low or intermediate risk prostate cancer
Study Design: Observational Cohort using SEER data (SEER: Surveillance, Epidemiology and End Results)
Sample Size: 44,630 (32, 022 Receiving treatment, 12,607 in the observation group)
Findings: At 12 years of follow up, active treatment was associated with significantly better survival (adjusted hazard ratio of 0.69, 95% CI 0.66–0.72). Adjusted hazard ratio for specific treatment, were: radical prostatectomy 0.50 (91% CI 0.47– 0.53). Radiation 0.81 (95% CI 0.78–0.85).
Author/Year: Sandra, 2008
Study Objective: Identify determinants of health-related quality of life after primary treatment of prostate cancer
Study Design: Prospective observational cohort at 6 University-affiliated hospitals
Sample Size: 1201 patients with previously untreated T1 or T2 prostate cancer who elected primary surgery
Findings: Each primary therapy had distinct differences in health related quality of life. Prostatectomy had substantial effects on sexual and urinary incontinence symptoms while radiotherapy and brachytherapy had effects on bowel or rectal symptoms and urinary irritation with the use of hormonal therapy further effecting sexual symptoms and vitality.
The addition of neoadjuvant hormonal therapy to RP did not improve survival or cancer recurrence rates, defined by PSA recurrence, but increased AEs.Author/Year: Albertson, 2007
Study Objective: Compare treatment with surgery or radiation to observation in men less than 75 years old with clinically localized prostate cancer
Study Design: Observational Cohort using Connecticut tumor registry data.
Sample Size: 1,618 (for receiving surgery, 702 for receiving external beam radiation, and 114 in the observation group
Findings: At 13 years of follow up, prostate cancer mortality was 2.2–3.8 times higher in patients receiving external beam radiation than patients receiving surgery.

Author/Year: Sandra, 2008
Study Objective: Identify determinants of health-related quality of life after primary treatment of prostate cancer
Study Design: Prospective observational cohort at 6 University-affiliated hospitals
Sample Size: 1201 patients with previously untreated T1 or T2 prostate cancer who elected primary surgery
Findings: Each primary therapy had distinct differences in health related quality of life. Prostatectomy had substantial effects on sexual and urinary incontinence symptoms while radiotherapy and brachytherapy had effects on bowel or rectal symptoms and urinary irritation with the use of hormonal therapy further effecting sexual symptoms and vitality.
ADT combined with EBRT (ADT + EBRT) may decrease overall and disease- specific mortality but increase AEs compared with EBRT alone in high-risk patients defined by PSA levels and Gleason histologic score. One RCT found that conformal EBRT combined with 6 months of ADT reduced all-cause mortality, disease-specific mortality, and PSA failure compared with conformal EBRT alone after a median followup of 4.5 years. There were significant increases in gynecomastia and impotence in the ADT + EBRT group compared with EBRT alone.Author/Year: D’Amico 2007
Study Objective: Compare androgen depravation therapy and radiation therapy to radiation therapy alone in men with localized prostate cancer.
Study Design: RCT
Sample Size: 206
Findings: At a median of 7.6 years of follow up, men receiving radiation therapy alone had a significant increase in overall mortality (hazard ratio = 1.8, 95% CI 1.1, 2.9) compared to men receiving radiation therapy plus androgen deprivation therapy. The effect was most pronounced in men with no or minimal comorbidities

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