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Evidence Table 1Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins

Clinical TrialInclusion Criteria/Patient PopulationExclusion criteriaInterventionResults (mean changes in lipoprotein levels)Harms/CommentsFunding Source
Atorvastatin vs. Lovastatin
Davidson et al. 1997
R (3:1), DB, MC, PC, not ITT

1,049 patients randomized (n= 789 aorta, 260 lova)
52 weeks
Men and women 18–80 years with LDL ≥160 mg/dl and ≥145 mg/dl after 2 weeks dietary phase.

Mean baseline LDL-c
189–192 mg/dl
Impaired hepatic or renal function, Type I DM, uncontrolled DM, any unstable medical condition, noncompliant, enrolled in another trial, taking a drug with a potential for interaction. No numbers provided for exclusion.NCEP step 1 diet and aorta 10 mg qd or lova 20 mg qd for 52 weeks; or placebo for 16 weeks, then aorta 10 mg qd or lova 20 mg qd for 36 weeks. Doses doubled at 22 weeks if LDL-c goals (based upon their risk factors) not achieved.Efficacy analysis for 970 patients.
LDL-c reduction from baseline at week 16:
aorta 10 mg: 36%
lova 20 mg: 27%
placebo unchanged (p<0.05 vs. lova or placebo)
LDL-c reduction from baseline at week 52:
aorta: 37% (27% had dose doubled)
lova: 29% (49% had dose doubled)
(p<0.05 vs. lovastatin)
HDL at week 16: aorta and lova both increased 7% (p NS)
HDL at week 52: aorta and lova both increased 7% (p NS)
Trigs: aorta reduction 16%; lova reduction 8% (p<0.05)
Achieved LDL-c goal:
aorta 78% vs. lova 63%
Adverse drug events (ADEs) similar across groups. Only those ADEs occurring ≥2% were reported. Withdrawal due to ADEs occurred in 3% of aorta vs. 4% of lova patients; 8% of aorta vs. 7% of lova patients had a serious ADE (no details provided), including 1 patient developing pancreatitis in aorta group. Elevation in ALT >3x ULN occurred in 1 (0.1%) aorta, 3 (1.2%) lova, and 1 (0.7%) placebo patients. No patient experienced an increase in creatine kinase (CK) of >10 times ULN.

Equivalent doses not compared.
Parke-Davis Pharmaceuticals
Atorvastatin vs. Pravastatin
Assman et al. 1999
R (3:1), DB, MC, not ITT

297 patients randomized (n= 224 aorta, 73 parva) 52 weeks
Men or women 18–80 years with an LDL-c 160–250 mg/dl during dietary phase.

Mean baseline LDL-c
201 mg/dl.
Pregnant or breastfeeding women, BMI >32, impaired hepatic function, CK elevation, more than 14 alcoholic drinks per week, s/p MI, PTCA, CABG within the last 3 months or severe or unstable angina, uncontrolled hypertension. No numbers provided for exclusion.6-week dietary and placebo phase. NCEP step 1 diet.
Mild to moderate CHD risk (dose level 1: LDL-c goal <130 mg/dl): 10 mg qd aorta (n=145) vs. parva 20 mg qd (n=27).
Severe CHD risk (dose level 2: LDL-c goal <115 mg/dl): aorta 20 mg qd (n=79) vs. parva 40 mg qd (n=46).
If goal not reached, dose doubled at week 4, and again at week 8 and week 16. Maximum doses: aorta 80 mg qd, parva 40 mg qd.
Efficacy analysis for 279 patients.
LDL-c reduction from baseline at 1 year:
aorta: 39% (p< 0.05)
parva: 29%
HDL:
aorta increased 7%
parva increased 9% (NS)
Trigs:
aorta reduction 13% (p<0.05)
parva reduction 8%
Achieved LDL-c goal at last visit:
aorta\= 51% vs. parva 20% (p=0.0001)

35% aorta (20 mg-17%, 40 mg-12%, 80 mg-5%) vs. 88% parva (40 mg- 88%) patients had doses doubled at least once.
9 patients (4%) in aorta group withdrew as a result of ADEs vs. 2 patients (3%) in parva group.

2 patients receiving aorta (unknown dose) experienced an elevation in ALT >3 X upper limit of normal. No patient on parva experienced an elevation. Most commonly reported ADE with aorta was myalgia and rash each reported by 4 patients.

Most common ADE with parva was arthralgia in 2 patients. (unknown doses) 35% of aorta vs. 63% of parva patients categorized in the severe CHD risk or dose level II.

Equivalent doses not compared.
2 authors employed by Parke-Davis Pharmaceuticals.
Bertolini et al. 1997
R (3:1), DB, MC, not ITT

305 patients randomized (n= 227 aorta, 78 parva) 1 year
Men and women 18–80 years with LDL-c 160–250 mg/dl.

Mean baseline LDL-c 195 mg/dl
Pregnant or breastfeeding women, uncontrolled hypothyroidism, hypertension, DM, or other endocrine disorder, impaired hepatic or renal function, more than 14 alcoholic drinks per week, taking a drug with the potential for interaction with statins. No numbers provided for exclusion.6 week dietary phase NCEP step 1 diet and aorta 10 mg qd or parva 20 mg qd. If LDL-c remained ≥130 mg/dl at weeks 4 and 10, doses were doubled at week 16.Efficacy analysis for 299 patients
LDL-c reduction from baseline at week 16:
aorta 10 mg: 35%
parva 20 mg: 23% (p≤0.05)
LDL-c reduction from baseline at week 52:
aorta: 35% (24% had dose doubled)
parva: 23% (64% had dose doubled) (p<0.05).
HDL: aorta increased 7%, parva increased 10% (NS)
Trigs: aorta reduction 14%, parva reduction 3% (p<0.05).
Achieved LDL-c goal:
aorta 71% vs. parva 26%
Severe adverse drug events (ADEs) similar for aorta (7%) and parva (9%); 7 patients in the aorta and 2 in the parva group withdrawn from study as a result of a severe ADE (no details). No patient in either group had clinically important elevations in AST, ALT or CK.

Equivalent doses not compared.
2 authors employed by Parke-Davis Pharmaceuticals.
Deedwania P, et al 2007
R (1:1), DB, MC, ITT

893 patients randomized (n (mITT)= 446 (408) aorta, 445 (396) parva) 52 weeks
Men and women 65 to 85, history of CAD, baseline LDL-C levels between 100 mg/dL and 250 mg/dL, and 1 episode of myocardial ischemia with a total duration of 3 minutesAtrial fibrillation and heart failure NYHA III and IV4–6 week washout period, then randomized in a double-blind fashion to atorvastatin 80 mg/d or pravastatin 40 mg/d and were followed up for 12 months.LDL-c change from baseline:
3 months aorta −56.3 vs.. Prava −32.1 (p < 0.001)
12 months aorta −55.4 vs.. Prava −32.4 (p < 0.001)
HDL-c change from baseline:
3 months aorta 2.2 vs. Prava 5.8 (p < 0.001)
12 months aorta 5.0 vs. Prava 7.6 (p = 0.009)

MACE aorta vs parva at one year n(%)
Major Adverse Cardiovascular Events
36 (8.1) vs. 50 (11.2) (p = 0.114)
Cardiovascular death 4 (0.9) vs. 10 (2.2)
Nonfatal myocardial infarction 16 (3.6) vs. 16 (3.6)
Resuscitated cardiac arrest 1 (0.2) vs. 1 0 (0.0)
Urgent coronary revascularization 20 (4.5) vs. 29 (6.5)
Hospitalized for unstable angina 14 (3.1) vs. 22 (4.9)
Stroke 1 (0.2) vs. 3 (0.7)

all-cause mortality at 12 months
aorta(1.3% incidence [6 deaths]) vs. parva (4.0% incidence [18 deaths]) (HR, 0.33; 95% CI, 0.13 to 0.83; p= 0.014)
aorta vs. parva n(%)
Patients ≥ 1 adverse event, 273 (61.2) vs. 287 (64.5) (p = 0.31)
Patients who discontinued study drug due to AEs,
48 (10.8) vs. 46 (10.3) (p = 0.84)
Patients w/ serious AEs 90 (20.2) vs. 103 (23.1) (p = 0.28)
Patients with ALT or AST 3 x upper limit of normal, 19 (4.3) vs. 1 (0.2) (p < 0.001)
Pfizer, Inc.
Murakami T, et al 2006
RCT, DB, MC, not ITT

41 patients randomized (n= 11 aorta, 18 parva analyzed) 26 weeks
Clinical indications for cholesterol lowering therapy without DM
(HBA1C ≤ 5.8)

Baseline LDL-c
aorta 192(67.1)
parva 143(30.5)
Baseline HDL-c
aorta 52.3 (11.4)
parva 47.6 (14.4)
Drugs that effect glucose tolerance, disturbed liver and/or renal functionsAtorvastatin 5–10 mg/day vs. pravastatin 10–20 mg/day for 3–6 months3–6 months after
LDL-c
aorta 124 (48.6) vs.. parva 113 (17.7) (p =0.0186)
HDL-c
aorta 54.7 (14.6) vs. parva 51.5 (14.8) (p = ns)
None reportedNR
Nissen et al, 2004
R, DB, MC, PC

657 patients randomized
18 months
Men and women aged 30 to 75 years who required coronary angiography for a clinical indication and demonstrated at least 1 obstruction with angiographic luminal diameter narrowing of 20% or more. Lipid criteria required an LDL-c level between 125 mg/dL and 210 mg/dL after 4 to 10 week washout period.

Mean baseline LDL-c aorta 80mg: 150.2 mg/dL parva 40mg: 150.2 mg/dL
Not reportedAtorva 80 mg daily or parva 40 mg daily.Efficacy analysis on 502 patients.
LDL-c reduction from baseline at 18 months:
Atorva 80 mg: 46.3% (p<0.001)
Prava 40 mg: 25.2%

HDL-c increase from baseline at 18 months:
Atorva 80 mg: 2.9%
Prava 40 mg: 5.6% (p=0.06)

Trigs reduction from baseline at 18 months:
Atorva 80 mg: 20.0% (p<0.001)
Prava 40 mg: 6.8%
6.7% of parva and 6.4% of aorta group discontinued drug for adverse events. Most common reason was musculoskeletal complaints (3.4% parva, 2.8% aorta).

Equivalent doses not compared
Funded by Pfizer
Saklamaz et al, 2005
R, single center, blinding not reported

21 patients randomized
8 weeks treatment
Men and women (mean age 51.7 ± 9.1 years) with type IIa and Iib hyperlipidemia.

Mean baseline LDL-c
pravastatin: 186±36 mg/dL
atorvastatin: 174±10 mg/dL
Patients with endocrine, liver, hepatic, thyroid, and renal disorders, BMI of less than 30, and alcohol abuse.pravastatin 20 mg or atorvastatin 10 mg or fenofibrate 250 mg% LDL-c reduction from baseline at 12 weeks:
pravastatin 20: 24.2%
atorvastatin 10: 40.2% %

HDL-c increase from baseline at 12 weeks:
pravastatin 20: 3.4%
atorvastatin 10: 9.8%

trig reduction from baseline at 12 weeks:
pravastatin 20: 24.3%
atorvastatin 10: 20.1%
Adverse events not reported.Funding not reported
Atorvastatin vs. Simvastatin
Ballantyne et al, 2003 R, DB, MC

917 patients randomized(n=464 aorta, 453 simva)
24 weeks
Men and women 21–75 with LDL-c >130 mg/dL in CHD patients, >160 mg/dL in patients without CHD and with 2 or more risk factors, and >190 mg/dL in patients without CHD and with <2 risk factors; patients with diabetes were considered CHD equivalents; eligible LDL-c was >130 mg/dL in patients with HDL-c <40 mg/dL (men) and <50 mg/dL (women) plus 2 risk factors. All had triglyceride levels <400 mg/dL.

Mean baseline LDL-c
aorta: 187.5 mg/dL
simva:190.3 mg/dL
use of systematic immunosuppressive drugs or drugs known to interfere with simvastatin or atorvastatin metabolism. renal insufficiency or significant
proteinuria; secondary causes of hypercholesterolemia; type I diabetes; type 2 diabetes with hemoglobin A1C 10%; hepatic transaminase levels 30% above upper limit of normal (ULN); known active liver disease; and creatine kinase (CK)levels 50% above ULN
Atorva 80 mg qd or simva 80 mg qd for 24 weeks.Increase in HDL-c from baseline, average of weeks 18 and 24

Patients with baseline HDL-c <40mg/dL (n=267):
aorta: 2.1%
simva: 5.4% (NS)

Patients with baseline HDL-c >40mg/dL (n=650):
aorta: 2.1%
simva: 5.43% (NS)

Patients without metabolic syndrome (n=437):
aorta: 2.8%
simva: 5.6% (NS)
No difference between groups in number of drug-related clinical gastrointestinal adverse events. Most common GI adverse events were diarrhea (simva 1.3%; aorta 3.0%), constipation (simva 1.3%; aorta 1.5%), and nausea (simva 1.8%; aorta 0.9%).

Most common drug-related muscular AEs resulting in discontinuation were myalgia, arthralgia, muscular weakness, muscular cramp, musculoskeletal stiffness, and body ache.
Patients treated with aorta more likely to have elevations in ALT >3 times the upper limit of normal (difference −2.4%; 95% CI −4.3 to −0.7; p=0.007)

Equivalent doses not compared
Supported by a grant from Merck
Bays et al., 2005
R, Open-label, multicenter

315 patients randomized (n=82 atorvastatin, 76 simvastatin, 157 niacin ER plus lovastatin)
16 weeks treatment
Men and women with elevated LDL-c (>=160mg/dL, or, if coronary heart disease was present, >=130 mg/dL) and low HDL-c (<45 mg/dL for men and <50 mg/dL for women).

Mean baseline LDL-c
194 mg/dL
Known prior allergy or intolerability to any of the study drugs, H/O substance abuse or dependence within 12 months of screening, consumption of >14 alcoholic drinks per week, uncontrolled psychiatric disease, participation in another investigational study within 30 days of screening, or probucol administration within the previous year. H/O: active gallbladder disease; uncontrolled hypertension; renal insufficiency (serum creatinine ≥1.5 mg/dl); hepatic dysfunction (aspartate aminotransferase or alanine aminotransferase >1.3 times the upper limit of normal); fasting glucose ≥115 mg/dl; New York Heart Association class III/IV congestive heart failure; active gout symptoms or uric acid >1.3 times the upper limit of normal; active peptic ulcer disease; type 1 or 2 diabetes; fibromyalgia; cancer within the previous 5 years (except for basal cell carcinoma); unstable angina, myocardial infarction, coronary artery bypass graft, percutaneous transluminal coronary angioplasty, or stroke within prior 6 months; or any condition or laboratory abnormality which, in the opinion of the investigator, might be adversely affected by the study procedures or medications.6-week screening phase during which lipid modifying drugs were discontinued, then treatment for the first 8 weeks:
atorvastatin 10 mg or
simvastatin 10 mg
At week 8, dose increased for 4 weeks:
atorvastatin 20 mg or
simvastatin 20 mg
At week 12, dose increased for 4 weeks:
atorvastatin 40 mg or
simvastatin 40 mg
% LDL-c reduction from baseline at 8, 12, and 16 weeks (p vs aorta):
aorta 10/20/40: 38% (p<0.05)/45% (p<0.05)/49% (p<0.05)
simva 10/20/40: 28%/35%/39%

% HDL-c increase from baseline at 8, 12, and 16 weeks (p vs aorta):
aorta 10/20/40: 3% (p<0.05)/4% (p<0.05)/6% (p<0.05)
simva 10/20/40: 7%/8%/7%

% trig reduction from baseline at 8, 12, and 16 weeks (p vs aorta):
aorta 10/20/40: 20%/30% (p<0.05)/31% (p<0.05)
simva 10/20/40: 18%/15%/19%
Adverse events not reported.Funded by Kos Pharmaceuticals
Branchi et al. 2001
R, OL, not ITT

200 patients randomized (n= 100 aorta, 100 simva)
Up to 6 months
Men or women with hypercholesterolemia not controlled with diet.

Mean baseline LDL-c
Atorva 228.2 mg/dl
Simva 235.1 mg/dl
200 patients randomized, analysis performed on 199 patients. Patients with hepatic or renal impairment, uncontrolled Type 2 DM, Type 1 DM were excluded. No numbers provided for exclusion at each step.8-week dietary run-in, then randomization to:
aorta 10 mg or
simva 20 mg qd.
Efficacy analysis for 199 patients.
LDL-c reduction from baseline at 2 months:
aorta: 148.7 mg/dl (34.8%)
simva: 158.4 mg/dl (32.6%)(NS)
HDL increase from baseline at 2 months (n=235, adjusted for baseline values):
aorta: 4.3%
simva: 9.0% (p<0.05)
Trigs reduction from baseline at 2 months:
aorta: 27.4%
simva: 24.8% (NS)
Significant number withdrew from treatment after 2 months. 46 required an increase in dose (20 aorta vs. 26 simva); 10 refused to continue; 8 stopped treatment during a recent illness. No differences in ADEs noted.

55 aorta vs. 58 simva patients completed 6 months of follow up. Responses similar to that seen at 2 months observed. HDL still significantly increased in the simva vs. aorta group.

Dose equivalence
Atorvastatin 10 mg qd ≈ simvastatin 20 mg qd
Role and source of funding not reported.
Chan, et al, 2004

R, Blinded, SC

10 week dietary run-in;
18 weeks of treatment.

120 patients (n=60 simva; n=60 aorta)
Men and women 20–75 with Type 2 diabetes with mixed hyperlipidemia (serum trig 203.7–398.6 mg/dL and LDL-c >=131.5 mg/dL)

Mean baseline LDL -c:
aorta: 171.3 mg/dL
simva: 160.5 mg/dL
Not reported10 week NIH NCEP Step 1 dietary run-in and patients on lipid-lowering drugs did a 4 week wash-out before starting.

aorta: 10 mg/d for 9 weeks then increased to 20 mg/d for 9 weeks

simva: 20 mg/d for 9 weeks and then increased to 40 mg/d for 9 weeks.
% patients reaching the LDL-c target (<100 mg/dL)
aorta: 74.1%
simva: 75.4%
% patients reaching the TG target (151 mg/dL):
aorta: 27.8%
simva: 35.1%
% patients reaching both targets:
aorta: 22.2%
simva: 29.8%

LDL-c Change from baseline (approx. from table):
aorta 10 mg:-37%
aorta 20mg:−28%
simva 20mg:−42%
simva 40 mg:−40%

HDL-c Change from baseline (approx. from table):
aorta 10 mg:+4%
aorta 20mg:<=+1.0%
simva 20mg:+4%
simva 40 mg:+4.5%

Trig change from baseline (approx. from table):
aorta 10 mg:−20%
aorta 20mg:−25%
simva 20mg:−20%
simva 40 mg:−25%

no p-values given
No adverse events discussed in detail.

Atorva: 5 patients withdrew (8.3%)
Simva: 7 patients withdrew (11.7%) reason stated for both groups withdrawals: “mainly because of non-compliance”

Overall drug compliance was 91.5%.

No subject developed a significant rise in liver enzymes or in CPK during study.
No industry support mentioned
Crouse et al. 1999
R, OL, MC, not ITT

846 patients randomized
12 weeks
Men or women

Mean baseline LDL-c
212.7 mg/dl
Not reported4-week dietary run-in phase, then: aorta 20 mg qd (n=210) or aorta 40 mg qd (n=215) or simva 40 mg qd (n=202) or simva 80 mg qd (n=215)Efficacy analysis for 842 patients.
LDL-c reduction from baseline at 12 weeks:
aorta 20 mg: 45% *
aorta 40 mg: 51.1%
simva 40 mg: 42.7%
simva 80 mg: 49.2%
(*p<0.05 aorta 20 vs. simva 40)
HDL-c increase from baseline at 12 weeks:
aorta 20 mg: 4%
aorta 40 mg: 3%
simva 40 mg: 6.7% *
simva 80 mg: 6.6% *
(*p<0.01 aorta vs. simva)
Trig reduction from baseline at 12 weeks:
aorta 20 mg: 23.3%
aorta 40 mg: 29.6% *
simva 40 mg: 23%
simva 80 mg: 25.2%
(*p<0.01 aorta 40 vs. simva 80)
No safety data or details on patient population provided in this trial.

Primary endpoint in this study was effects of aorta or simva on HDL and Apolipoprotein A-1.

Dose equivalence
Atorva 20 mg > or ≈ Simva 40 mg.
Atorva 40 mg = Simva 80 mg
Merck supported and participated in study.
Dart A et al. 1997

R (3:1), DB, MC, not ITT

177 patients randomized (n= 132 atorvastatin, 45 simvastatin)
1 year
Men or women 18–80 years with an LDL-c 160-300 mg/dl during the dietary phase.

Mean baseline LDL-c
208-214 mg/dl
Pregnant or breastfeeding women, uncontrolled hypothyroidism, hypertension, DM, or other endocrine disorder, impaired hepatic or renal function, BMI>32, more than 14 alcoholic drinks per week, taking a drug with the potential for interaction with statins. No numbers provided for exclusion6-week dietary and placebo phase. NCEP step 1 diet and atorvastatin 10 mg qd or simvastatin 10 mg qd. Doses were doubled at week 16 if LDL-c was not < 130 mg/dl.Efficacy analysis for 177 patients.
LDL-c reduction from baseline at week 16:
Atorvastatin 10 mg: 37%
Simvastatin 10 mg: 30% (p<0.05)
LDL-c reduction from baseline at week 52:
Atorvastatin: 38% (48% had dose doubled)
Simvastatin: 33% (62% had dose doubled) (p<0.05)
HDL at week 16:
Atorvastatin increased 7%
Simvastatin increased 7% (p NS)
HDL at week 52:
Atorvastatin increased 7%
Simvastatin increased 7% (p NS)
Trigs:
Atorvastatin reduction 21%
Simvastatin reduction 12% (p<0.05)
Achieved LDL-c goal: aorta 46% vs. simva 27%
No clinically significant changes in ALT, AST or CK in either group. No differences in percentages of reported ADE between groups. None of the serious ADEs in either group thought to be due to the statin.

Most common ADE with atorvastatin was myalgia (3%). Most common ADE with simvastatin was arthralgia (7%) and chest pain (4%). 2 patients in each group withdrawn as a result of ADEs. Details only provided for 1 patient on atorvastatin who reported excessive sweating possibly related to treatment. No other details on ADEs provided.

Equivalent doses not compared.
Support and contribution by Parke- Davis Pharmaceutical Research Division
Farnier et al. 2000
R (2:1:2), OL, MC, ITT

272 patients randomized (n= 109 atorvastatin, 163 simvastatin)
12 weeks
Men or women 18–70 years with elevated LDL-c.

Mean baseline LDL-c
Atorvastatin 10 mg: 247 + 45 mg/dl
Simvastatin 10 mg: 242 + 47 mg/dl
Simvastatin 20 mg: 237 + 39 mg/dl.
331 patients entered prerandomization dietary placebo run-in phase, and 272 were randomized. Pregnant or breastfeeding women, BMI >32, impaired hepatic function, CK elevation, more than 4 alcoholic drinks per day, s/p MI, PTCA, CABG, CVA within the last 3 months, secondary hyperlipidemia, taking a drug with the potential for interaction with statins. No numbers provided for exclusion at each step.6-week placebo-dietary run-in phase then randomized to: Atorvastatin 10 mg, simvastatin 10 mg or simvastatin 20 mg qd for 6 weeks.Efficacy analysis for 272 patients.
LDL-c reduction from baseline at 6 weeks:
Atorva 10 mg: 37%
Simva 10 mg: 28.9%
Simva 20 mg: 33.8% (90% CI 0.66–5.7 aorta 10 mg vs. simva 20 mg)
HDL: (NS Atorva 10 mg vs. simva 20 mg)
aorta 10 mg increased 5.7%
simva 10 mg increased 2.2%
simvastatin 20 mg increased 3%
Trigs: (NS aorta 10 vs. simva 20)
aorta 10 mg reduction 19.2%
simva 10 mg reduction 4.6%
simva 20 mg reduction 16%1
Authors report no difference in incidence of ADEs between groups (aorta 10 mg = 11.9% vs. simva 10 mg =5.5% vs. simva 20 mg = 3.7%). Few details provided.

One patient in aorta group had an increase in ALT >3x ULN. No elevation in CK reported.

Dose equivalence
atorvastatin 10 mg qd ≈ simva 20 mg qd
Supported by grant from Parke-Davis.
Illingworth et al. 2001
R, DB, MC, not ITT

826 patients randomized (n= 408 aorta, 405 simva)
36 weeks
Men or women 21–70 years with elevated cholesterol.

Mean baseline LDL-c
Atorva 206 mg/dl
Simva 209 mg/dl
826 patients randomized. Efficacy analysis performed on 813 patients. Patients receiving immunosuppressants, azole antifungals, or anticoagulants were excluded. No numbers provided for exclusion at each step.4-week dietary run-in phase followed by randomization to 6 weeks of: aorta 20 mg or simva 40 mg qd, then 6 weeks of aorta 40 mg or simva 80 mg qd.

If CK < 5x ULN, patients were eligible for 24 weeks of aorta or simva 80 mg qd.
Efficacy analysis for 813 patients.
LDL-c reduction from baseline at 6 weeks: aorta 20 mg= 46.1% vs. simva 40 mg= 42.4%
LDL-c reduction from baseline at 2nd 6 weeks: aorta 40 mg= 51.3% vs. simva 80 mg= 48.8%
LDL-c reduction from baseline at 36 weeks: aorta 80 mg= 53.6% vs. simva 80mg= 48.1% (p< 0.001 for all 3 comparisons)
HDL increased:
Week 6: aorta 20 mg= 7.3% vs. simva 40 mg= 8.5% (NS)
Week 12: aorta 40 mg= 6.4% vs. simva 80 mg= 9.7% (p<0.001)
Week 18–36: aorta 80 mg= 3% vs. simva 80 mg= 7.5% (p<0.001)
Trigs reduction:
aorta 20 mg= 23.6% vs. simva 40 mg= 22.4%
aorta 40 mg= 31.6% vs. simva 80 mg= 25.9%
aorta 80 mg= 31.3% vs. simva 80 mg= 23.6% (p< 0.05 for all 3 comparisons)
HDL elevation was primary endpoint.

ADEs similar during first 12 weeks of study. At end of 24-week period, 23.4% of aorta 80 mg vs. 11.9% of simva 80 mg experienced an ADE. (p<0.001). Difference due primarily to GI ADE (diarrhea). More in aorta 80 mg group (12.2%) vs. simva 80 mg group (3.9%) experienced laboratory ADEs (p<0.001). More discontinued treatment due to laboratory ADEs in aorta 80 mg (4.1%) vs. simva 80 mg group (0.8%) (p<0.001).

Clinically significant elevations (>3x ULN) in ALT and AST observed significantly more often in aorta 80 mg vs. simva 80 mg group. ALT elevations especially prominent in women in aorta group. No myopathy reported in any group.

A significantly higher number of women randomized to the aorta group.
5 authors employed by Merck. Merck assisted in preparation of manuscript.
Insull et al. 2001
R, OL, MC, not ITT

1,424 patients randomized (n= 730 aorta, 694 simva)
First 6 weeks of planned
54 weeks
Men or women 18–80 years with or without CHD and with or without Type 2 DM with elevated LDL.

Mean baseline LDL-c
Atorva 181.2 mg/dl
Simva 181.9 mg/dl
Unknown number of patients beginning 8-week dietary phase. 1424 patients randomized and 1378 patients included in efficacy analysis. Pregnant or breastfeeding women, BMI >32, impaired hepatic function, CK elevation, s/p MI, PTCA, CABG, CVA or unstable angina within the last 1 month, secondary hyperlipidemia, significant medical or psychological abnormality, participation in another study, taking a drug with the potential for interaction with statins. No numbers provided for exclusion at each step.8-week dietary run-in with NCEP step 1 or 2 diet. Eligible patients randomized to: aorta 10 mg qd or simva 10 mg qd.Efficacy analysis for 1,378 patients.
LDL-c reduction from baseline at 6 weeks:
aorta 10 mg: 37.2%
simva 10 mg: 29.6% (p<0.0001)
Reaching NCEP goal at 6 weeks:
aorta 10 mg: 55.6%
simva 10 mg: 38.4% (p<0.0001)
HDL increased:
Atorva: 7.4%
Simva: 6.9% (NS)
Trigs reduction:
Atorva: 27.6%
Simva: 21.5% (p<0.0001)
No differences in treatment-related ADEs: aorta 5.8% vs. simva 2.9%. No reports of myopathy. 2 aorta patients had elevated ALT or AST >3x ULN.

Equivalent doses not compared.
Supported by grant from Parke-Davis.
Kadikoylu et al, 2003
R, DB

61 patients randomized (n=35 aorta, 26 simva) 24 weeks
Men and women with at least 2 coronary risk factors and LDL-c levels >130 mg/dL.

Mean baseline LDL-c
aorta: 168.5 mg/dL
simva: 172.1 mg/dL
Patients with pregnancy, lactation, malignancy, CHD, type 1 or uncontrolled type 2 diabetes mellitus (glycosylated hemoglobin >6%), TG concentrations >500 mg/dL, body mass index >35 kg/m2, prolonged prothrombin time (PT) and partial thromboplastin time (PTT), hypo/hyperfibrinogenemia, elevated serum creatine phosphokinase (CK) and liver enzyme levels at the upper limit of normal, thrombocytopenia (<100 × 103/mm3) or thrombocytosis (>400 × 103/mm3), history of hemorrhagic diathesis, acute or chronic hepatitis, chronic renal failure, alcohol abuse, secondary hypercholesterolemia due to hypothyroidism, obstructive liver disease, and nephrotic syndrome were excluded. Patients with hypersensitivities to statins, taking lipid-lowering drugs within 8 weeks, and employing concomitant use of drugs such as erythromycin, oral contraceptives, hormone replacement, systemic steroids, heparin, low-molecular weight heparin, oral anticoagulants, or immunosuppressive agents were not enrolled in the study.Atorva 10 mg qd or simva 10 mg qd. When target level of LDL-c was not reached at 12 weeks according to ATP-III, dosage was increased to 20 mg qd.LDL-c goal reached at 24 weeks (all patients): aorta: 85.7%
simva: 84.6% (NS)
Diabetics only (n=23): aorta: 64.3%
simva: 55.6% (NS)

LDL-c reduction from baseline at 24 weeks: aorta: 38.6%
simva: 33.6% (NS)

HDL-c increase from baseline at 24 weeks: aorta: 12.6%
simva:0.6% (NS)

Trigs change from baseline at 24 weeks: aorta:15.8%
simva:+2.0% (NS)
Adverse effects seen in 5 patients (14.2%) aorta and 3 patients (11.5%) in simva group (headache, diarrhea, constipation, myalgia).
Elevations in ALT>3 times the upper limit of normal and in CK >5 times the upper limit of normal did not occur.
No discontinuations due to adverse effects; no significant differences between groups in adverse effects, adverse effects not dose-related.

Equivalent doses not compared
Funding not reported
Karalis et al. 2002
R, OL, MC, not ITT

1,732 patients randomized
6 weeks
Men and women 18–80 years with LDL-c ≥190 mg/dl if no risk factors, or ≥160 mg/dl if 2 or more risk factors, or ≥130 mg/dl for those with CHD.

Mean baseline LDL-c
178–182 mg/dl
Body mass index 32 kg/m2; known hypersensitivity to statins; uncontrolled hypothyroidism, nephrotic syndrome, or renal dysfunction; diabetes mellitus type 1 or uncontrolled diabetes mellitus type 2 (hemoglobin A1c 10%); hepatic dysfunction; creatine phosphokinase levels 3 times the upper limit of normal; myocardial infarction, revascularization procedures, or severe or unstable angina within 3 months before screening; significant medical or psychological abnormalities that could compromise the patient’s safety in the study; use of any drugs known to affect lipid levels; immunosuppressive agents; or drugs associated with rhabdomyolysis in combination with statins.4-week dietary run-in followed by randomization to: aorta 10 mg qd (n=650) or aorta 80 mg qd (n=216) or simva 20 mg qd (n=650) or simva 80 mg qd (n=216)Efficacy analysis for 1694 patients.
LDL-c decrease from baseline at 6 weeks: aorta 10 mg= 37% vs. simva 20 mg = 35% (p<0.025)
aorta 80 mg= 53% vs. simva 80 mg= 47% (p<0.0001)
HDL increase from baseline: aorta 10 mg= 5% vs. simva 20 mg= 6%
aorta 80 mg= 2% vs. simva 80 mg= 6% (p<0.0001)
Trigs reduction from baseline: aorta 10 mg= 18% vs. simva 20 mg= 14% (p<0.025)
aorta 80 mg= 28% vs. simva 80 mg= 23% (p<0.025)
Patients in aorta 80 mg vs. simva 80 mg group reported higher incidence of ADEs (46% vs. 39%) and discontinuation due to ADEs (8% vs. 5%). Neither of these differences was statistically significant.

Dose equivalence
Atorva 10 mg>Simva 20 mg.
Atorva 80 mg>Simva 80 mg.
Pfizer supported and participated in the trial.
Kastelein et al, 2000
R, DB, PC

826 patients (n=406 aorta, 405 simva)
36 weeks
Men and women with LDL-c >160 mg/dL and triglycerides <350 mg/d

Mean baseline LDL-c
simva: 208.7 mg/dL
aorta: 205.8 mg/dL
NRAtorva 20 mg qd for 6 weeks, then 40 mg qd or simva 40 mg qd for 6 weeks then 80 mg qd.Increase in HDL-c (average of results from weeks 6 and 12): simva 9.1% vs
aorta 6.8% (p<0.001)
simvastatin 80mg: 9.7%
atorvastatin 40mg: 6.4% (p<0.001)
simva 40mg vs aorta 20mg (NS, percent change not reported)
No difference between the 2 drugs in tolerability profile after 12 weeks of treatment.

Dose equivalence
simva 80mg >aorta 40mg
simva 40mg ≈ aorta 20mg
Supported by a grant from Merck Research Laboratories
Marz et al. 1999
R (2:1) OL, MC, not ITT

2,856 patients randomized (n= 1897 aorta, 959 simva)
14 weeks
Men or women 35–75 years with CHD and LDL-c ≥130 mg/dl after the diet phase.

Mean baseline LDL-c
186–188 mg/dl
4,097 patients were screened. After the 6 week diet phase, 2,856 patients met the inclusion criteria. Pregnant or breastfeeding women, uncontrolled hypothyroidism, hypertension, DM, or other endocrine disorder, impaired hepatic or renal function, BMI>32, s/p MI, PTCA, CABG, CVA within the last 3 months, moderate to severe CHF, severe hyperlipidemia or hypertriglyceridemia, secondary hyperlipidemia, more than 14 alcoholic drinks per week, taking a drug with the potential for interaction with statins. Other drugs that were not allowed included NSAIDs and digitalis. No numbers provided for exclusion6-week diet phase then aorta 10 mg qd or simva 10 mg qd. Doses were doubled at weeks 5 and/or 10 if LDL-c was > 100 mg/dl.Number of patients in efficacy analysis not specified.
LDL-c reduction from baseline at week 14: aorta 10 mg: 37.6%
simva 10 mg: 31.9% (p<0.001)
Overall LDL-c reduction: 188–105 mg/dl in aorta vs. 186–112 mg/dl in simva group. (p<0.001)

38% aorta vs. 54% simva users increased to 40 mg qd.
ADEs were similar between groups occurring in 36.3% in the aorta vs. 35.7% in the simva group. Withdrawal due to ADE were similar between groups.

Serious ADEs occurred in 2% aorta vs. 3% simva (NS).

No differences in elevation in ALT or AST or CK during the trial between groups.

Dose equivalence
Atorvastatin 20 mg qd ≈ simvastatin 40 mg qd.
Sponsored by Parke-Davis and Pfizer
Mulder D, et al 2007

R(1:1), DB, MC, completers analysis

235 patients randomized (n= 116 aorta, 119 simva)
16 weeks
Men or women 30–75 years with elevated LDL-c >2.6.

Mean baseline LDL-c
Atorva10: 3.70 (0.83)
Simva10 : 3.59 (0.79)
all forms of secondary dyslipidemia; diabetes mellitus; dysfunction of the thyroid gland, unless adequately treated; acute CVD, surgical procedures or inflammatory disease; all conditions affecting plasma levels of cellular adhesion molecules; active liver disease or hepatic dysfunction; known allergic reaction to statins; clinically manifest heart failure or severe cardiac arrhythmias; uncontrolled hypertension, as defined by a systolic blood pressure >160 mmHg and/or a diastolic blood pressure >95 mmHg; severe or unstable angina pectoris; excessive alcohol consumption (over 4 units per day) or a history of drug abuse; use of systemic steroids or androgens; impaired renal function with plasma creatinine >150 μmol/l; a history of partial ileal bypass surgery; inadequate contraceptive measures, pregnancy or lactation in premenopausal women; baseline creatinine phosphokinase values >150% upper limit of normal.4 week run in, simva 40, then 16-week treatment phase starting on atorvastatin 40 mg or continuing with simvastatin 40 mg. After 8 weeks of treatment the dosage of atorvastatin was increased to 80 mg, whereas the dosage of simvastatin remained stable at 40 mg.Efficacy analysis for 1087 patients.
Total cholesterol change at 16 weeks: aorta -15.9% vs. simva 2.8% (p < 0.001)
LDL-c change at 16 weeks: aorta: -20.8% vs. simva: 3.7% (p < 0.001)
HDL change at 16 weeks: aorta: 4.4% vs. simva: 1.8% (p = 0.67) (*p<.001 vs. simva)
Trigs change eat 16 weeks: aorta: 15% vs. Simva -0.8 (p < 0.002)
155 adverse events occurred
simva: 52 mild; 17 moderate; 6 severe; aorta: 52 mild; 24 moderate; 4 severe).
No difference between treatment groups (p = 0.49).
Parke-Davis Pharmaceutical Research.
Olsson et al. 2003
R(1:1), DB, MC, ITT

1087 patients randomized (n= 552 aorta, 535 simva)
52 weeks
White men and women 35–75 years with cardiovascular disease and LDL-c > 155 mg/dl (4.0 mmol/L)

Mean baseline LDL-c
5.19 mmol/L (calculated 200 mg/dl)
Patients with fasting serum TG _>4.0 mmol/L or total cholesterol _>10.0 retool/L, secondary hypercholesterolemia, unstable angina, heterozygous and homozygous familial hypercholesterolemia, planned coronary artery surgery or angioplasty, and acute MI in patients already on lipid-lowering agents; currently treated with lipid- lowering or antiarrhythmic drugs or treated for congestive heart failure, presence of hemodynamically important valvular heart disease, active liver disease or hepatic dysfunction (defined as S- aspartate aminotransferase [S-AST] or S-alanine aminotransferase [S- ALT] _>2 times the upper limit of normal [ULN]), partial ileal bypass, creatine kinase [CK] _>10 times ULN, or other serious disease.Dietary counseling during 4-week run-in phase. Patients on lipid-lowering therapy added 4-week washout period, then randomized to: atorvastatin 20 mg or simvastatin 20 mg, both titrated to 40 mg.
Dose doubled at week 8 for patients not meeting NCEP target.
Efficacy analysis for 1087 patients.
LDL-c reduction at 8 (and 52) weeks:
aorta: 46%* (49%*)
simva: 40% (44%)
(*p<.001 vs. simva)
HDL increase at 8 (and 52) weeks:
aorta: -0.1%* (6.3%)
simva: 3.3% (8.3%)
(*p<.001 vs. simva)
Trigs reduction at 8 (and 52) weeks:
aorta: 23%* (24%*)
simva: 14% (16%)
(*p<.001 vs. simva)
Achieved NECP LDL-c goal at 8 (and 52) weeks:
aorta: 45%* (61%*)
simva: 24% (41%)
(*p<.001 vs. simva)

45% aorta vs. 24% simva patients remained at 20 mg
ADE comparable between groups. 12 (2.2%) aorta and 13 (2.4%) simva patients had muscular symptoms (e.g., myalgia, myositis). 1 serious drug- related ADE in simva patient, with exacerbation of arm fascitis.

Withdrawals due to ADE: 20/556 (3.6%) aorta vs. 14/537 (2.6%) simva. 6 withdrawals serious, with aorta heart failure, cerebral infarction and 2 malignancies; and simva acute MI and chest pain.

No significant changes in either group for S-ALT, S-AST or CK. 1 patient in each group withdrawn due to elevated liver aminotransferase.
Supported by Pfizer.
Praagh et al, 2004
R, OL, crossover, ITT not stated

49 patients randomized (50% to simvastatin and 50% to atorvastatin)
10 months (3 mos./drug)
Men or women 25-70 years with Frederickson IIa and IIb hyperlipoproteinemia with LDL-c >158 ml/dL and trigs <398 mg/dL.

Mean baseline LDL-c:
Simvastatin 20 mg: 182 mg/dL
Atorvastatin 10 mg: 174 mg/dL
Patients with diabetes mellitus, previous myocardial infarction, coronary heart disease, liver disease, renal dysfunction (serum creatinine >130 micromole/L) alcoholism, smoking habit, drug addiction, pregnancy, lactation, malignant disease, or had previously received lipid reducing therapy.8-week NCEP Step 1 dietary run-in then randomized to simva 20 mg/d or atorv 10 mg/d for 3 months.

Followed by 8-week washout period, then switched to alternate drug in corresponding dose for 3 months.
% LDL-c reduced from baseline after 3 months: Simva 20 mg:18.5%
Atorva 10 mg:28.9%
(p<0.001 for baseline vs. 3 month levels; p<0.001 for simva vs. aorta)

% HDL-c increased from baseline after 3 months: Simva 20 mg/d: +3.8%
Atorva 10 mg/d: + 9.2%
(p=not significant(n.s.) for baseline vs. 3 month levels; p=n.s. for simva vs. Atorva)

% Trig level decreased from baseline after 3 months: Simva 20 mg/d:15.2 %
Atorva 10 mg/d:29.5%
(p<0.01 for baseline vs. 3 month levels; p=n.s. for simva vs. aorta)

% patients reaching target LDL-c levels: Simva 20 mg/d: 28%
Atorva 10 mg/d: 44%
(no p-values given)
No serious adverse events reported nor discussed in detail.

No changes in physical examination findings or laboratory values occurred.
Industry role, if any, not specified
Recto et al. 2000
R, OL, MC, crossover, not ITT

258 (?) patients (n= 125 aorta, 126 simva)
12 weeks
Men or women 21–70 years with an LDL-c ≥ 130 mg/dl and trigs ≤ 350 mg/dl.

Mean baseline LDL-c
193.4 mg/dl
Secondary hyperlipoproteinemia; types I, 111, IV, or V hyperlipidemia; myocardial infarction, coronary angioplasty or coronary bypass surgery within 3 months of trial entry; acute coronary insufficiency; active liver disease; renal insufficiency; partial ileal bypass; obesity (body weight > 50% of ideal); uncontrolled or insulin-dependent diabetes mellitus; uncontrolled hypertension; and excessive alcohol consumption (> 10 drink/week).4-week dietary and placebo run-in phase, then randomized to: aorta 10 mg or simva 20 mg qd or to a higher dose aorta 20 or simva 40 mg qd for 6 weeks.

Followed by 1-week washout period, then switched to alternate drug in corresponding dose for 6 weeks.
Efficacy analysis for 251 patients.
LDL-c reduction from baseline at 6 weeks: aorta 10 mg: 36.7% + 13.3
simva 20 mg: 34.8% + 14
aorta 20 mg: 42.1% + 15.6
simva 40 mg: 41% + 15.9 (p>0.05 for aorta 10 mg vs. simva 20 mg, and aorta 20 mg vs. simva 40 mg)
HDL: (p>0.05)
Atorva 10 mg increased 8.1 %
Atorva 20 mg increased 8.5%
Simva 20 mg increased 8.7 %
Simva 40 mg increased 9.3 %
Trigs: (p>0.05)
Atorva 10 mg reduction 22%
Atorva 20 mg reduction 25%
Simva 20 mg reduction 21.5%
Simva 40 mg reduction 21.4%
No differences in ADEs reported between groups.

1 patient in simva 20 mg group withdrawn due to ADE vs. 2 in aorta 10 mg and 3 in aorta 20 mg group.

2 serious ADEs in aorta 20 mg group. Myalgia occurred in 1 simva 20 mg vs. 2 aorta 10 mg patients.

One patient in simva 40 mg group experienced elevation in ALT >3x ULN.

Dose equivalence
Atorva 10 mg qd ≈ simva 20 mg qd.
Atorva 20 mg ≈ simva 40 mg qd.
Study supported by grant from Merck.
Van Dam et al. 2000
R, SB, MC, not ITT

378 patients randomized (n= 185 atorvastatin, 193 simvastatin)
8 weeks
Men or women 18–80 years currently treated with simvastatin 20 or 40 mg qd and LDL-c levels > 100 mg/dl.

Mean baseline LDL-c Simvastatin
20 mg: 138 mg/dl
Simvastatin 40 mg: 145 mg/dl
Pregnant or breastfeeding women, BMI >32, impaired hepatic function, CK elevation, more than 4 alcoholic drinks per day, s/p MI, PTCA, CABG, CVA within the last 3 months, secondary hyperlipidemia, taking a drug with the potential for interaction with statins. No numbers provided for exclusion.4-week simvastatin run-in phase followed by randomization as follows:

Simvastatin 20 mg users: Atorvastatin 20 mg or simvastatin 20 mg.

Simvastatin 40 mg users: Atorvastatin 40 mg or simvastatin 40mg
Efficacy analysis for 324 patients.
Additional reduction in LDL-c when switching from simvastatin to: (p<0.05)
Atorva 20 mg: 14+ 14%
Simva 20 mg: 3.3 + 14%(p)
Atorva 40 mg: 2.85 +12.7%
Simva 40 mg: 14.6 + 15.2% (p)
HDL: (p>0.05)
Atorva 20 mg: reduction 1.41 + 10.3%
Simva 20 mg: increased 0.49 + 10.8%
Atorva 40 mg: reduction 1.07 + 11.8%
Simva 40 mg: increased 2.76 + 10.4
Trigs: (p>0.05)
Atorva 20 mg: reduction 10.9% + 25%
Simva 20 mg: reduction 4.21 + 32.5%
Atorva 40 mg: reduction 0.85 + 36%
Simva 40 mg: increased 8.4 + 36.6%
Achieved NCEP LDL-c goal: 28% aorta vs. 13% simva
Total 71 ADEs for 54 of 185 aorta patients vs. total 39 ADEs for 32 of 193 simva patients (p=0.005).

Although not much detail provided, most frequent ADEs were myalgia and headache. Myalgia was reported most commonly in aorta group. No mention if ADEs reported more often in the higher-dose groups. No reports of elevations in ALT, AST or CK during the study.

Overall, HDL reduced 1.3% in aorta vs. increased 1.3% in simva group (p=0.04).

Triglycerides reduced by 7.5% in aorta vs. increased 5.6% in simva group (p=0.005).

Equivalent doses not compared.
Supported by Parke- Davis and Pfizer Pharmaceuticals. One author employed by Parke-Davis.
Wu S, et al 2005
Cross-over

66 patients
8 months
Men and women, cholesterol level > 240mg/dlPregnant or lactating females, secondary hypertension of any etiology, history of malignant hypertension, sitting systolic blood pressure 210mmHg, history of myocardial infarction or angina pectoris, clinically important cardiac arrhythmia, history of unexplained syncope within 2 years, symptomatic heart failure, presence of hemodynamically significant obstructive valvular disease or cardiomyopathy, history of coronary angioplasty or coronary artery bypass surgery within the previous 6 months, clinically important malabsorption syndrome or gastric resection, cirrhosis of the liver, patient with only a single functioning kidney, unstable noninsulin-dependent diabetes mellitus (HbA1C 8%), elevated creatine kinase level, abnormal thyroid function, nephrotic syndrome, alcoholism, or medication known to be associated with rhabdomyolysis or other concurrent severe diseasesCross over aorta vs. simva phase one 3 months then stopped for two months then phase two for three monthsPhase one
LDL-c change at 12 weeks
aorta -35% vs. simva -25.5% (p <0.001)
HDL-c change at 12 weeks
aorta 18.5% vs. simva 13.0%

Phase two
LDL-c change at 12 weeks
aorta -34.1% vs. simva -25.9% (p < 0.01)
HDL-c change at 12 weeks
aorta 11.7% vs. simva 6.1%

Flatulence simva 1 patient aorta 1 patient
Diarrhea simva 1 patient aorta 1 patient
Abdominal pain simva 0 patient aorta 1 patient
Supported by Kaohsiung Veterans General Hospital, Gran No. VGHKS 91-41 and Veterans General Hospital, Tsin-Hua, Yang-Ming Research Program, Grant no. VTY92-G3-03
Atorvastatin vs. Multiple Statins
Andrews et al. 2001
R (4:1:1:1:1), OL, MC, not ITT

3,916 patients randomized
54 weeks
Men and women 18–80 years with elevated cholesterol, with or without CHD.

Mean baseline LDL-c
 176-179 mg/dl
7,542 patients screened and 3,916 patients randomized to study. Only 3,262 patients completed study. Patients with active liver disease, hepatic impairment, uncontrolled type 1 or 2 DM, or serum creatinine >2 mg/dl.Randomization to:
Atorva 10 mg qd
Fluva 20 mg qd
Lova 20 mg qd
Prava 20 mg qd or Simva 10 mg qd for 54 weeks.

Doses were doubled until LDL-c goal or maximum doses were reached.
Efficacy analysis for 3,757 patients (mean dose).
LDL-c reduction from baseline at 54 weeks:
aorta (24 mg) 42% (p<0.01 vs. other statins)
fulva (62 mg) 29%
lova (52 mg) 36%
parva (31 mg) 28%
simva (23 mg) 36%
HDL increase from baseline at 54 weeks (NS):
aorta 5%
fulva 6%
lova 5%
parva 6%
simva 6%
Trigs reduction from baseline at 54 weeks:
aorta 19% (p<0.01 vs other statins)
fulva 7%
lova 12%
parva 9%
simva 13%
Achieved LDL-c goal at 54 weeks (p not reported):
aorta 76%
fulva 37%
lova 49%
parva 34%
simva 58%
ALT elevation >3x ULN occurred in 10 (0.5%) aorta patients vs. 1 patient each (0.2%) in fulva, parva and simva groups. None in lova.

Withdrawal due to ADEs occurred in 7% aorta vs. 13% fulva vs. 8% lova vs. 4% parva vs. 8% simva patients.

Myalgia occurred similarly in all groups. Serious treatment related ADEs occurred in 2 aorta patients (elevated CK , muscle cramps and rash) and 1 patient in simva (gastroenteritis). No details on dose for withdrawals or serious ADEs.

Questionable why doses were not doubled for more patients to reach NCEP goals.

Equivalent doses not compared.
Supported by grant from Pfizer. One Pfizer employee acknowledged for analysis and interpretation of data.
Brown et al. 1998
R, OL, MC, not ITT

318 patients randomized (n= 80 aorta, 80 fulva, 81 lova, 77 simva)
54 weeks
Men and women 18–80 years with documented CHD and LDL-c 130- 250 mg/dl.

Mean baseline LDL-c
173 mg/dl
318 randomized, efficacy analysis performed on 308 patients.
Pregnancy or breast-feeding, secondary hyperlipoproteinemia, uncontrolled endocrine disorders, hepatic or renal impairment, MI, CABG, PTCA, unstable angina 1 month prior to screening, participation in another study, uncontrolled type 2 DM, type 1 DM, taking a drug with the potential for interaction with statins. No numbers provided for exclusion at each step.
Optional 8-week dietary phase, 4-week dietary run-in, then randomization to: aorta 10 mg, fulva 20 mg, lova 20 mg, or simva 10 mg qd.
Doses could be titrated at 12-week intervals until LDL-c goal or maximum dose reached (aorta 80 mg, fulva 40 mg, lova 80 mg, or simva 40 mg qd). If goal not reached with statin, colestipol added (aorta 8%, fulva 76%, lova 15%, simva 33%).
Efficacy analysis for 308 patients (median dose/day).
LDL reduction from baseline at 54 weeks:
aorta 20 mg: 41%
fulva 80 mg +colestipol 20 g: 30%*
lova 80 mg: 41%
simva 40 mg: 37%
HDL increase at 54 weeks:
aorta: 7%
fulva: 7%
lova: 12%
simva: 11%
Trigs reduction at 54 weeks:
aorta: 19% vs. fulva: 2%,* lova: 14%, simva: 15%
Achieved LDL-c goal at 54 weeks: aorta 83% vs. fulva 50%*, lova 81%, simva 75% (*p<0.05 vs. aorta)
ADEs similar across treatment groups at 54 weeks, except fluvastatin where patients also receiving colestipol experienced a 2-fold increase in GI ADEs.

Withdrawal for ADEs similar among groups, included 3 aorta, 4 fulva, and 2 each for lova and simva. 1 lova patient experienced pancreatitis. Two fulva patients had elevations in either ALT or AST >3x ULN. No myopathy observed.

No details on ADEs and statin dose.

Equivalent doses not compared; treat to target.
Study funded by Parke- Davis. One author employed by Parke- Davis.
Calza L, et al 2008

RCT (1:1:1), OL, SC, not ITT

94 patients randomized (n=28 rosuva, 34 parva, 32 aorta) 85 analyzed
1 year
Stable PI-based antiretroviral therapy at least 12 months, and presenting hypercholesterolemia (total cholesterol level >250 mg/dL) of at least 3-month duration and unresponsive to a hypolipidemic diet and physical exercise

LDL-C at baseline mg/dL
Rosuva 177 parva 173 aorta 180
Drug or alcohol abuse; genetic hyperlipidemia, diabetes, hypothyroidism, Cushings, acute or chronic myopathy, kidney disease, acute hepatitis, liver cirrhosis, treatment with corticosteroids, androgens, estrogens, growth hormones, thiazide diuretics, beta- blockers, thyroid preparations or other hypolipidemic drugsrosuvastatin (10 mg once daily), pravastatin (20 mg once daily) or atorvastatin (10 mg once daily)LDL-c change from baseline at 12 months:
rosuva -26.3%
parva -18.1% (vs. rosuva p=0.04)
aorta -20.3% (vs. rosuva p=0.02)
HDL-c change from baseline at 12 months:
rosuva 18.2%
parva 17.2% (vs. rosuva p=ns)
aorta 16% (vs. rosuva p=ns)
Rosuva vs. parva vs. aorta %
Nausea 7.7 vs. 3.2 vs. 0
Dyspepsia 11.5 vs. 9.7 vs. 7.1
Diarrhea 3.8 vs. 0 vs. 3.6
Meteorism 7.7 vs. 3.2 vs. 3.6
NR
Gentile et al. 2000
R, OL, MC, not ITT

412 patients randomized
24 weeks
Men and women 50–65 years with type 2 diabetes mellitus and LDL-c >160 mg/dl

Mean baseline LDL-c
199-218 mg/dl
412 patients randomized but only409 patients included in the efficacy analysis. Secondary causes of hyperlipidemia, type 1 DM, elevated CK, BMI >32 kg/m, uncontrolled HTN, MI, CABG, PTCA or established CAD, sensitivity to statins, or taking drugs with the potential for interaction with statins.6-week dietary run-in phase followed by randomization to: aorta 10 mg qd
lova 20 mg qd
parva 20 mg qd
simva 10 mg qd or placebo for 24 weeks.
Efficacy analysis for 409 patients
LDL-c reduction from baseline:
aorta 37% (*p<0.05 vs. other statins)
lova 21%
parva 23%
simva 26%
placebo 1%
HDL increase from baseline:
aorta 7.4%
lova 7.2%
parva 3.2% (p<0.05 vs. other statins)
simva 7.1%
placebo 0.5%
Trigs reduction from baseline:
aorta 24% (p<0.05 vs. other statins)
lova 11%
parva 12%
simva 14%
placebo 1%
ADEs similar for all groups. Withdrawal for ADEs: 1 aorta, 1 lova and 1 parva patient. No clinically important elevation in ALT, AST or CK observed in any group.

Equivalent doses not compared.
Supported in part (60%) by MURST, Italy.
Hadjibabaie M, et al
2006
RCT (1:1:1), OL, SC, not ITT

60 patients randomized (53 analyzed)(n=19 aorta, 18 simva, 16 lova)
12 weeks
Men and women 18-70 years old with T2DM and a LDL-c 100 mg/dl or more Baseline LDL-c levels mg/dl
aorta 151
simva 155
lova 144
Baseline HDL-c levels mg/dl
aorta 45
simva 45
lova 44
Hepatic or renal dysfunction, uncontrolled hypothyroidism, type 1 DM, pregnancy, current use of lipid lowering drugs, hormone replacement therapy, uncontrolled hypertension.atorvastatin 10 mg, simvastatin 20 mg, lovastatin 20 mg once daily for 12 weeksLDL-c change from baseline at 12 weeks:
aorta -37% (vs. simva or lova p < 0.05)
simva -19%
lova -22%
HDL-c (% change) at 12 weeks:
aorta 48 (6.6%)
simva 49 (8.8%)
lova 47 (6.8%)
Adverse events were similar between groups. No data reportedNR
Hunninghake et al.
1998
R, OL, MC, not ITT

344 patients randomized (n= 85 aorta, 82 fulva, 83 lova, 87 simva)
54 weeks
Men or women 18–80 years at risk for CHD and elevated cholesterol.

Mean baseline LDL-c
Atorva 205 mg/dl
Fluva 201 mg/dl
Lova 206 mg/dl
Simva 210 mg/dl
344 patients randomized, efficacy analysis performed on 337 patients. Pregnancy or breast-feeding, secondary hyperlipoproteinemia, uncontrolled endocrine disorders, hepatic or renal impairment, MI, CABG, PTCA, unstable angina 1 month prior to screening, participation in another study, uncontrolled type 2 DM, type 1 DM, taking a drug with the potential for interaction with statins. No numbers provided for exclusion at each step.8-week optional dietary phase, 4-week dietary run-in followed by randomization to aorta 10 mg, fulva 20 mg, lova 20 mg or simva 10 mg qd. Doses titrated at 12-week intervals until LDL-c goal achieved or maximum dosage reached (aorta 80 mg, fulva 40 mg , lova 80 mg, simva 40 mg qd).

If goal not reached with statin, colestipol added. Colestipol added = aorta 2%, fulva 67%, lova 24%, simva 24%.
Efficacy analysis for 337 patients (median dose/day).
LDL reduction from baseline at 54 weeks :
aorta 10 mg: 36%
fulva 40 mg: 22%*
lova 40 mg: 28%*
simva 20 mg: 33%
HDL increase at 54 weeks:
aorta 9 %
fulva 6 %
lova 10%
simva 11%
TRIGS reduction at 54 weeks:
aorta 20%
fulva +2%*
lova 16%
simva 11%
Achieved LDL-c goal at 54 weeks: aorta 95% vs. fulva 60%,* lova 77%,* simva 83%.* (*p<0.05 vs. aorta).
ADEs similar across treatment groups prior to addition of colestipol to statin therapy at 24 weeks. At 54 weeks there were more ADEs in the fulva and lova groups than in the aorta or simva groups primarily GI in nature.

Withdrawal for ADEs were 3% aorta, 4% fulva, 8% lova and 5% simva. One lova-treated patient experienced an elevation in ALT >3x ULN. Other clinically insignificant elevations in ALT or AST occurred in all groups. One patient receiving fulva experienced acute pancreatitis. No myopathy observed.

No details on ADE and statin dose.

Equivalent doses not compared; treat to target.
Funded by Parke- Davis. One author employed by Parke- Davis.
Insull W, et al 2007 (SOLAR)

RCT (1:1:1), OL, MC, ITT

1632 patients randomized (n = 542 rosuva, 544 aorta, 546 simva)
12 weeks
18 years or older, enrolled in a managed care health plan, and classified as high risk by NCEP ATP III; LDL 130–250 and TG <400 after dietary 6-week dietary run-inActive vascular disease, uncontrolled hypertension, a fasting serum glucose level of 180 mg/dL or higher or a hemoglobin A1c level of 9% or higher, active liver disease or dysfunction (alanine aminotransferase [ALT], aspartate aminotransferase, or bilirubin levels of ≥2 times the upper limit of normal [ULN]), unexplained serum creatine kinase (CK) elevation of more than 3 times the ULN, and a serum creatinine level of more than 2.0 mg/dL.6 week dietary lead-in, randomized to rosuvastatin at 10 mg/d, atorvastatin at 10 mg/d, or simvastatin at 20 mg/d, for 6 weeks. Patients not reaching the NCEP ATP III high-risk LDL-C goal of less than 100 mg/dL after 6 weeks had doses doubled to rosuvastatin at 20 mg, atorvastatin at 20 mg, or simvastatin at 40 mg for an additional 6 weeks.proportion of patients who achieved NCEP ATP III high-risk LDL-C goal (<100 mg/dL) at week 6
rosuva 65%
aorta 41% (p < 0.001 vs rosuva)
simva 39% (p < 0.001 vs rosuva)
proportion of patients who achieved NCEP ATP III high-risk LDL-C goal (<100 mg/dL) at week 12 observed cases
rosuva (n=501) 76%
aorta (n=489) 58% (p < 0.001 vs rosuva)
simva (n=493) 53% (p < 0.001 vs rosuva)
LDL-c change at 6 weeks
rosuva45%
aorta36% (p < 0.001 vs rosuva)
simva34% (p < 0.001 vs rosuva)
HDL-c change at 6 weeks
rosuva 7%
aorta 6%
simva 6%
LDL-c change at 12 weeks (observed cases)
rosuva (n=501)48%
aorta (n=489)41% (p < 0.001 vs rosuva)
simva (n=493)40% (p < 0.001 vs rosuva)
HDL-c change at 12 weeks (observed cases)
rosuva (n=501) 10%
aorta (n=489) 6% (p < 0.001 vs rosuva)
simva (n=493) 7% (p < 0.001 vs rosuva)
rosuva vs aorta vs. simva n( %)
Adverse events 662 vs. 579 vs. 618
Adverse events leading to death 0 (0.0) vs.3 (0.6) vs. 0 (0.0)
Adverse events leading to withdrawal 15 (3) vs. 20 (4) vs. 19 (3)
Serious adverse events not leading to death
18 (3) vs. 11 (2) vs. 13 (2)
Alanine aminotransferase >3 times the ULN at any visit
2 (0.4) vs. 1 (0.2) vs. 1 (0.2)
Creatine kinase >10 times the ULN at any visit
1 (0.2) vs.0 (0.0) vs. 0 (0.0)
Creatinine increase >100% 0 for all
AstraZeneca
Pharmaceuticals LP
Jones et al. 1998
Jones et al. 2004
R, OL, MC, not ITT

534 patients randomized
8 weeks
Men or women 18–80 years with
LDL ≥ 160 mg/dl.

Mean baseline LDL-c
Range 192–244 mg/dl
534 randomized, efficacy analysis performed on 522 patients. Secondary hyperlipidemia, type 1 or uncontrolled type 2 DM, hepatic or renal impairment, uncontrolled HTN, BMI >32 kg/m, MI, CABG, PTCA unstable angina within 3 months of study, hypersensitivity to statins, taking a drug with the potential for interaction with statins. No numbers provided for exclusion at each step.6-week dietary run-in phase, then
randomization to one of 15 treatment groups: aorta 10, 20, 40, 80 mg
fulva 20 or 40 mg
lova 20, 40, or 80 mg
parva 10, 20 or 40 mg
simva 10, 20 or 40 mg qd.
Efficacy analysis for 522 patients.
LDL reduction from baseline at 8 weeks: aorta 10 mg: 38% (n=73)/aorta 20 mg: 46% (n=51)
aorta 40 mg: 51% (n=61)/aorta 80 mg: 54% (n=10)
fulva 20 mg: 17% (n=12)/fulva 40 mg: 23% (n=12)
lova 20 mg: 29% (n=16)/lova 40 mg: 31% (n=16)
lova 80 mg: 48% (n=11)
parva 10 mg: 19% (n=14)/parva 20 mg: 24% (n=41)
parva 40 mg: 34% (n=25)
simva 10 mg: 28% (n=70)/simva 20 mg: 35% (n=49)
simva 40 mg: 41% (n=61)
HDL increase: All similar (ranging from 3% ot 9%), except aorta 80 mg and
fulva 40 mg, with reduction in HDL. Simva 40 mg increase significantly greater than aorta.
Trigs reduction: All similar, except aorta 40 mg produced a greater reduction.
ADEs similar across treatment groups.

1 patient on aorta 20 mg developed myalgia judged unrelated to treatment. No clinically important elevations in liver transaminase or CK.

Dose equivalence
Atorvastatin 10 mg ≈ lovastatin 40 mg ≈ pravastatin 40 mg ≈ simvastatin 20 mg qd.

Atorvastatin 20 mg ≈ lovastatin 80 mg ≈ simvastatin 40 mg qd.
Study funded by Parke-Davis. Parke-Davis Research played role in some portion of the study.
Schaefer et al. 2004
R, OL, MC, ITT crossover design

196 patients studied: 99 patients
randomized and 97 controls
36 weeks
Men and women with a mean age of 61.4 years with CHD and with LDL-c >130 mg/dl while off lipid-lowering drugs for 6 weeks.

Mean baseline LDL-c: Not reported
Evidence of renal impairment, hyperthyroidism, or liver dysfunction based on clinical chemistry testing, or had previous adverse reactions to statins.4 week dietary run-in, then randomization to a dosing schedule that increased every
4 weeks (12 weeks total):
fulva: 20 mg/d; 40 mg/d; 80 mg/d
parva: 20 mg/d; 40 mg/d (8 weeks at this max dose)
lova: 20 mg/d; 40 mg/d; 80 mg/d
simva: 20 mg/d; 40 mg/d (8 weeks at this max dose)
aorta: 20 mg/d; 40 mg/d; 80 mg/d for all 97 controls

After the 12th week, an 8 week placebo period occurred. Then the patients were crossed over between atorv and another statin for 12 weeks (dosage increased every 4 weeks as before).

36 weeks total
% change in lipoproteins data includes pre- and post-crossover data combined. Mean % change in fasting lipoproteins after treatment (p-values are for paired comparisons between same doses of statins):
fulva 20/40/80 vs aorta 20/40/80:
LDL-c:8%,17%,22% vs34%,45%,51% (all have p<0.0001)
HDL-c: +3%,+3%,+3% vs +2%,+6%,+1% (p not stated)
trigs:5%,1%, 0% vs20% (p<0.05),25% (p<0.001),33% (p<0.0001)

lova 20/40/80 vs aorta 20/40/80:
LDL-c:20%,28%,31% vs38%,45%,53% (all have p<0.0001)
HDL-c: +4%,+3%,+9% vs +8% (p<0.01),+3% (p not stated),+1% (p not stated)
trigs:10%,17%,19% vs27%,32%,32% (all have p<0.01)

parva 20/40/40 vs aorta 20/40/80:
LDL-c:22%,24%,26% vs39%,46%,50% (all have p<0.0001)
HDL-c: +9%,+10%,+11% vs +8%,+5%,+6% (p not stated for any)
trigs:4%,2%,5% vs9% (p not stated),18% (p<0.05),21% (p<0.05)
simva 20/40/40 vs aorta 20/40/80:
LDL-c:28%,39%,39% vs40% (p<0.001),47% (p<0.01),51%(p<0.001)
HDL-c: +9%,+7%,+10% vs +5%,+5%,+4% (p not stated for any)
trigs:5%,17%,15% vs27%(p<0.0001),25%(p not stated),32% (p<0.001)
No safety data (adverse events and withdrawals) reported or discussed.Supported by investigator-initiated research contracts from Parke-Davis/Pfeixer, and Otsuka America Pharmaceuticals, Inc.
Wolffenbuttel et al. 1998
R, OL, MC. cross-over, ITT

78 patients
4 weeks on each treatment
Men and women 18–70 years with LDL-c 160–240 mg/dl.

Mean baseline LDL-c
215 mg/dl
Patients not eligible when they used lipid-lowering drugs after visit 1, or had a history of serious or hypersensitivity reactions to statins; active cardiovascular disease (uncontrolled hypertension >200/>95 mmHg), heart failure NYHA class IV, recent unstable angina, MI, transient ischemic attack, cerebrovascular accident, coronary artery bypass surgery or angioplasty within the previous 2 months, or likely to undergo coronary artery intervention within 6 months after randomization; women who were pregnant or lactating or those not using an effective form of birth control; metabolic abnormalities, such as kidney insufficiency, uncontrolled hypothyroidism, homozygous familial hypercholesterolemia, or familial dysbetalipoproteinemia, active liver disease or liver enzyme [alanine aminotransferase (ALT), aspartate transaminase (AST)] elevations >1.5 ULN and unexplained CK elevations >3 ULN.4-week dietary run-in then randomized to: aorta 5 mg or aorta 20 mg or simva 10 mg or parva 20 mg qd for 4 weeks.

After washout, patients were switched to alternate treatment.
Efficacy analysis for 78 or 76 patients.
LDL-c reduction from baseline:
aorta 5 mg: 27%
aorta 20 mg 44% (p<0.05 vs. simva and parva)
parva 20 mg 24%
simva 10 mg 28%
HDL increase from baseline:
aorta 5 mg 2%
aorta 20 mg 8%
parva 20 mg 3%
simva 10 mg 1% (NS)
Trigs reduction from baseline:
aorta 5 mg 16%
aorta 20 mg 23% (p<0.05 vs. simva and parva)
parva 20 mg 11%
simva 10 mg 8%
ADEs were similar between groups and no serious ADEs or withdrawal from groups as a result of ADEs were reported.

Dose equivalence
Atorvastatin 5 mg = pravastatin 20 mg = simvastatin 10 mg qd
Supported by Parke- Davis; one author employed by Parke- Davis.
Fluvastatin vs. Lovastatin
Berger et al. 1996
R, OL, MC, ITT

270 patients randomized
6 weeks
Age ≥20 years, 45% male, with serum triglyceride levels <400 mg/dl, not following cholesterol- reducing diet, and (a) LDL-c ≥190 mg/dl and ≤2 CHD risk factors, or (b) ≥160 mg/dl and ≥2 CHD risk factors, or (c) ≥130 mg/dl and definite CHD.

Mean baseline LDL-c
187 mg/dl
Concurrent use of immunosuppressants5-week diet-only run-in phase, then randomization to: fulva 20 mg qd or lova 20 mg qdEfficacy analysis for 270 patients.
LDL-c reduction from baseline:
fulva: 18%
lova: 28% (p≤0.001)
HDL-c increase from baseline:
fulva and lova: ~8% (NS)
Trigs reduction from baseline:
fulva: 9%
lova: 10% (NS)
Achieved NCEP LDL-c goal:
fulva: 24%
lova: 37% (p=0.02)
Withdrawals due to AEs:
8 fulva vs. 3 lova.

Serious AEs (not considered drug related):
3 fulva vs. 5 lova.

Total AEs: 54% fulva vs. 47% lova.
Sponsored by Merck and Co.
Davidson et al, 2003
R, DB, MC, PC, 838 patients randomized (n=337 fulva, 501 lova)
6 weeks
Men and women >20 years with TG level ≤ 4.5 mmol/L and one of the following LDL-c levels after 6-week run-in on NCEP Step I diet: (1) > 3.4 mmol/L with evidence of CHD or other atherosclerotic disease; (2) >4.1 mmol/L with >2 other CHD risk factors but no CHD or other atherosclerotic disease; 30 >4.9 mmol/L without CHD or other atherosclerotic disease and <2 other CHD risk factors.

Mean baseline LDL-c
fulva 20 mg: 181.7 mg/dL
fulva 40 mg: 189.5 mg/dL
lova 10 mg: 189.5 mg/dL
lova 20 mg: 189.5 mg/dL
lova 40 mg: 185.6 mg/dL
Patients with myocardial infarction, coronary bypass surgery, or angioplasty in the prior 3 months; current coronary insufficiency; or clinically significant ventricular arrhythmias, pregnant or lactating women.Fluva 20 or 40 mg qd or lova 10, 20, or 40 mg qd for 6 weeks.LDL-c reduction from baseline at 6 weeks:
fulva 20 mg: 18.8%
fulva 40 mg: 22.6%
lova 10 mg: 21.6% (p<0.05 vs fulva 20 mg)
lova 20 mg: 27.3% (p<0.001 vs fulva 20 mg, p<0.05 vs fulva 40 mg)
lova 40 mg: 31.8% (p <0.001 vs fulva 40 mg)

HDL-c increase from baseline at 6 weeks (NS):
fulva 20 mg: 3.5%
fulva 40 mg: 4.3%
lova 10 mg: 4.9%
lova 20 mg: 5.7%
lova 40 mg: 6.1%

Trigs reduction from baseline at 6 weeks (NS):
fulva 20 mg: 3.3%
fulva 40 mg: 11.4%
lova 10 mg: 6.4%
lova 20 mg: 5.7%
lova 40 mg: 11.3%
No significant differences between treatments in any AE reported. Most common were GI disturbances, flatulence in 16 (3.2%) lova and 19 (5.6%) fulva patients 21 (4.2%) lova and 22 (6.5%) fulva patients withdrew due to adverse effects.
4 lova and 4 fulva patients reported serious adverse effects; only one (fecal occult blood/gastric ulcer in 1 patient treated with fulva 20mg considered treatment related.

Dose equivalence
lova 20 mg > fulva 40 mg
3 authors from Merck
Nash 1996
R, OL, MC, ITT

137 patients randomized 8 weeks
Men or women previously controlled on lovastatin 20 mg qd (LDL-c <150 mg/dl).

After dietary washout phase, LDL-c required >160 mg/dl, trigs <350 mg/dl.

Mean baseline LDL-c
Not reported
363 patients screened, 137 patients randomized. (Were large numbers of patients not randomized because their LDL-c upon washout was <160 mg/dl?) Homozygous familial hypercholesterolemia, MI, unstable angina, major surgery or PTCA 6 months prior to study, secondary causes of hyperlipidemia (alcoholism, DM, thyroid disease), pregnant or lactating women and those women who were unwilling to use alternate forms of birth control other than the pill.6-week dietary/placebo washout period then randomization to: fulva 20 mg qd or lova 20 mg qd.

After 4 weeks, fulva was increased to 40 mg qd.
Efficacy analysis for 137 patients.
LDL-c reduction from baseline at 8 weeks:
fulva: men and women 26%
lova: men 29%, women 26% (NS)
HDL-c increase from baseline at 8 weeks (NS):
fulva: men: 7 %, women 8%
lova: men 7%, women 4%
Trigs reduction from baseline at 8 weeks:
fulva: men 14%, women 10%
lova: men 12%, women 20%
Achieved LDL-c goal (<160 mg/dl) at 4 weeks:
fulva: 85%
lova: 91% (NS)
Achieved LDL-c goal (<160 mg/dl) at 8 weeks:
fulva: 89%
lova: 91% (NS)
Myalgia occurred in 1 fulva vs. 2 lova patients.

Musculoskeletal abnormalities existed significantly more often as a background medical condition in the lova group.

5 fulva and 1 lova patient experienced an increase in ALT or AST >3x ULN. No details on what dose of fulva patients experienced these ADEs.
Funded by Sandoz Pharmaceuticals.
Fluvastatin vs. Pravastatin
Jacotot et al. 1995
R, DB, MC, both ITT and on treatment analysis

134 patients randomized
16 weeks
Men and women 18–75 years with LDL ≥ 160 mg/dl and trigs ≤ 400 mg/dl

Mean baseline LDL-c
Fluva 216.4 mg/dl
Prava 226.9 mg/dl
134 randomized. Analysis included both on treatment and intention to treat population. Severe forms of hypercholesterolemia and those with impaired renal function were excluded. No details provided on numbers and reasons for excluding patients.6-week dietary/placebo run-in phase then, randomization to:
fulva 40 mg qd or
parva 20 mg qd for 4 weeks.

Doses doubled at 4 weeks and study continued another 12 weeks.
Efficacy analysis for 134 patients.
LDL-c reduction from baseline at 16 weeks:
fulva 40 mg bid: 29.6%
parva 40 mg qd: 26.1% (NS)
HDL-c increase from baseline at 16 weeks:
fulva 40 mg bid: 7.5%
parva 40 mg qd: 9% (p<0.001)
Trigs reduction from baseline at 16 weeks:
fulva 40 mg bid: 14.9%
parva 40 mg qd: 2.8% (p<0.001)
6 patients withdrew from study due to ADEs (3 in each group). No patient withdrew due to myopathic complaints or liver ADEs. More GI ADEs in fulva group. No patient experienced clinically significant elevation in ALT, AST or CK.

Dose equivalence
Fluvastatin 40 mg ≈ pravastatin 20 mg qd.
Fluvastatin 40 mg bid ≈ pravastatin 40 mg qd.
Funding and participation by Sandoz
Pharmaceuticals.
Fluvastatin vs. Simvastatin
Bevilacqua M, et al
2005

RCT, OL, SC, ITT

94 patients randomized (n = fulva 48, simva 46)
8 weeks
Men and women with T2DM, triglycerides > 2.3, HDL < 1.3 and elevated sdLDLSurgery, myocardial infarction, angioplasty in last 6 months, poorly controlled hypertension, liver disease, chronic renal failure, myopathy, alcohol/drug abuse, hypersensitivity to statins, pregnancy or lactation, lipid lowering therapy in last 8 weeks, use of oral contraceptives4 week dietary run-in; fluvastatin extended- release (XL) 80 mg and simvastatin 20 mg for 8 weeksLDL-c change from baseline at 8 weeks:
fulva -51% vs. simva -55.1 (p = ns)

HDL-c change from baseline at 8 weeks:
fulva 14.3 vs. simva 0 ( p < 0.01)
No severe AEs reported, Data = NRNR
Ose et al. 1995
R, DB, MC, ITT

432 patients randomized
6 weeks
Men and women 70 years of age or less and a total cholesterol >250 mg/dl.

Mean baseline LDL-c
213-232 mg/dl w/o CHD
247-267 mg/dl with CHD
432 patients randomized. Analysis for LDL-c reduction did not include 17 patients due to missing or inappropriately done labs. Older than 70, secondary hypercholesterolemia, unstable angina, MI or CABG within 2 months, trigs >350 mg/dl, women not using birth control, history of substance abuse, hepatic or renal impairment, baseline elevations in CK, uncontrolled DM.4-week dietary/placebo run-in, then randomized to: fulva 20 or 40 mg qd, or simva 5 or 10 mg qd for 6 weeks.Efficacy analysis for 432 patients.
LDL-c reduction from baseline at 6 weeks:
fulva 20 mg: 21.8%
fulva 40 mg: 25.9%
simva 5 mg: 25.7% (p<0.01 vs fulva 20 mg)
simva 10 mg: 29.9% (p<0.01 vs fulva 20 mg, p<0.05 vs fulva 40 mg)
HDL-c increase from baseline at 6 weeks:
fulva 20 mg: 6.3%
fulva 40 mg: 13%
simva 5 mg: 10.1%
simva 10 mg: 12.2% (p<0.01 vs fulva 20 mg)
Trigs reduction from baseline at 6 weeks:
fulva 20 mg: 10%
fulva 40 mg: 12.8%
simva 5 mg: 11.5%
simva 10 mg: 14.5%
Achieved NCEP LDL-c goal:
fulva 20 mg: 12%
fulva 40 mg: 21%
simva 5 mg: 24% (p<0.05 vs fulva 20 mg)
simva 10 mg: 25% (p<0.01 vs fulva 20 mg)
Number of patients reporting ADEs similar across all groups. GI ADEs were more frequent in fulva vs. simva groups, especially at 40 mg qd dose. One fulva patient had ALT >3x ULN.

Dose equivalence
Fluvastatin 40 mg qd = simvastatin 5 mg qd for reducing LDL-c.
Fluvastatin 40 mg qd = simvastatin 10 mg qd for NCEP goal reached.
Funded by Merck.
Schulte et al. 1996
R, DB

120 patients randomized
10 weeks
Men and women 26-74 years with LDL-c >185 mg/dl and trigs <300 mg/dl.

Median baseline LDL-c
Fluva 218.5 mg/dl
Simva 211.5 mg/dl
120 patients randomized, unclear number completing study. Active liver or gallbladder disease, elevated aminotransferases or other severe disabling disease, women with childbearing potential, drug or alcohol abuse problems, musculoskeletal diseases, or taking drugs with the potential for interaction with statins. No details provided on numbers and reasons for excluding patients.4-week dietary run-in phase and randomized to: fulva 40 mg qd or simva 20 mg qd for 4 weeks.

After 4 weeks, dose was doubled and continued for 6 more weeks.
Unclear if all patients included in efficacy analysis:
LDL-c reduction from baseline at 4 and 10 weeks:
fulva 40 mg: 23.8%
simva 20: 23.6%
fulva 80 mg: 30.6%
simva 40 mg: 34.4% (NS at 4 or 10 weeks)
HDL-c increase from baseline at 4 and 10 weeks:
fulva 40 mg: 7.1%
simva 20 mg: 8%
fulva 80 mg: 13.1%
simva 40 mg: 12.3% (NS at 4 or 10 weeks)
Trigs reduction from baseline at 4 and 10 weeks:
fulva 40 mg: 2.1%
simva 20 mg: +1%
fulva 80 mg: 1.2%
simva 40 mg: 2.3% (NS at 4 or 10 weeks)
Clinically insignificant differences in ADE. One patient in each group had elevations in AST or ALT >3x ULN. No clinically significant increase in CK was observed.

Dose equivalence
Fluvastatin 40 mg qd = simvastatin 20 mg qd.
Fluvastatin 80 mg qd = simvastatin 40 mg qd.
Funded by Astra.
Sigurdsson et al. 1998
R, DB, MC, not ITT

113 patients randomized
16 weeks
Men or women with CHD.

Mean baseline LDL-c
185-187 mg/dl
Patients with concomitant conditions such as myocardial infarction or CVA within the past 6 months, planned angioplasty or coronary bypass surgery during the previous 6 months, unstable angina, cardiac or renal failure, hepatic disease, uncontrolled hypertension, partial ileal bypass, secondary hypercholesterolemia, or hypersensitivity to HMG-CoA reductase inhibitors, history of alcohol or drug abuse, and concomitant treatment with lipid lowering agents within 6 weeks.8-week dietary and 2 week-placebo run-in phase, then randomized to: fulva 20 mg qd or simva 20 mg qd for 16 weeks.

Doses could be doubled at week 10 if TC
>200 mg/dl at week 6.
Efficacy analysis for 110 patients.
LDL-c reduction from baseline at 16 weeks:
fulva: 25.3%
simva: 39.9% (p<0.001)
HDL-c increase from baseline at 16 weeks:
fulva: 8.8%
simva: 11.1% (NS)
Trigs reduction from baseline at 16 weeks:
fulva: 23.1%
simva: 22.5% (NS)
Achieved LDL-c <200 mg/dl:
49.1% fulva vs. 87.3% simva (p<0.001)

63% fulva patients vs. 18% simva patients increased dose to 40 mg qd(p<0.001)
ADEs similar between groups, with a trend to more GI ADEs in the fulva vs. simva group (8 vs. 4). The difference was not significant. No clinically important elevations in ALT, AST, or CK.

Nonequivalent doses compared, treat to target.
Funded by grant from Merck. One author employed by Merck.
Merck also supplied lovastatin and placebo.
Lovastatin Extended Release vs. Lovastatin Immediate Release
Lukacsko et al, 2004

179 patients randomized
(n= 90 lova ER, 89 lova IR)
12 weeks; crossover
Men and women ages 21 to 70 with a TG level less than 350 mg/dL and plasma LDL-c within the following parameters:
>100 mg/dl for patients with a history of CHD, peripheral vascular disease (PVD), or cerebrovascular disease (CVD); 130 mg/dl or higher for patients without a history of CHD, PVD, or CVD, but with 2 or more risk factors for heart disease; or 160 mg/δ or higher for patients without a history of CHD, PVD, or CVD, but with less than 2 risk factors for heart disease.

Mean baseline LDL-c
182.5 mg/dl lova ER; 174.7 mg/dl lova
IR
History of underlying hepatic disease or elevation of serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) above 1.5 times the upper limit of normal (ULN) or clinically significant renal, gastrointestinal, metabolic, neurological, pulmonary, endocrine or psychiatric disorders, pregnant or became pregnant and failed to maintain 85% compliance with dosingLovastatin 20mg ER once daily vs lovastatin
20 mg IR once daily
Efficacy analysis for 179 patients.
LDL-c reduction from baseline at week 12 (from baseline to endpoint for treatment periods 2 and 4 combined, results for separate treatment periods not reported):
Lova ER: 26.4%
Lova IR: 23.1%
(difference −3.3%; p=0.0028; 95% CI −5.43% to −1.15%)

HDL-c increase from baseline to endpoint for treatment periods 2 and 4 combined (12 week treatment periods, results for separate treatment periods not reported):
Lova ER: 4.1%
Lova IR: 4.3%
(difference −0.2%; p=0.8584)
No apparent trends by treatment in the incidence of treatment emergent signs and symptoms.
Serious adverse events reported by 5 patients receiving ER lova (6 events: cholecystitis, accidental injury, cerebral ischemia, angina pectoris, enlarged uterine fibroids, and back pain), and 2 patients receiving IR lova (increased knee pain due to degenerative joint disease, and MI).

Dose equivalence:
lova ER > lova IR
Funded by Andrx
Laboratories, and all authors employed by same.
Lovastatin vs. Pravastatin
McPherson et al. 1992
R, DB, MC, not ITT

217 patients randomized
8 weeks
Men and women 18–75 years with LDL-c ≥190 mg/dl with no risk factors or ≥ 160 mg/dl in those with 2+ risk factors.

Mean baseline LDL-c
209–211 mg/dl
Hypersensitivity to HMG-CoA reductase inhibitors, plasma triglycerides> 4.0 mmol/L; impaired hepatic function or recent hepatitis; secondary hypercholesterolemia due to endocrine disease; insulin dependant or non insulin dependant diabetes with poor control; unstable angina or vaso spastic angina, myocardial infarction or coronary bypass surgery within previous 2 months; treatment with probucol within the last 6 months, history of drug/alcohol abuse, concurrent treatment with other investigational/immunosuppressive and lipid lowering agents6-week dietary/placebo and washout phase followed by randomization to:
lova 20 mg qd (n=73) or
parva 10 mg qd (n=74) or
parva 20 mg qd (n=70)
Efficacy analysis for 201 patients.
LDL-c reduction from baseline at 8 weeks:
lova 20 mg: 28%
parva 10 mg: 24.5%
parva 20 mg: 28.4% (all NS)
HDL-c increase from baseline at 8 weeks (p not reported):
lova 20 mg: 8.7%
parva 10 mg: 10.8%
parva 20 mg: 5.4%
Trigs reduction from baseline at 8 weeks:
lova 20 mg: 6.8%
parva 10 mg: 0.9%
parva 20 mg: 4.9%
High risk meeting NCEP goal:
lova: 29%, parva 10 mg: 25%, parva 20 mg: 26% (NS)
Moderate risk meeting NCEP goal:
lova 74%, parva 10 mg: 53%, parva 20 mg: 68% (NS)
Adverse effects not different between groups.

Difference in LDL-c lowering greater at 4 weeks in lova vs. parva 10 mg groups, however was not different at 8 weeks.

LDL-c lowering in lova vs. parva 20 mg groups not different at any time.

Dose equivalence
lova 20 mg = parva 20 mg ≈ parva 10 mg.
Merck funded the study.
Strauss et al. 1999
R, SB, Crossover, not ITT

31 patients randomized
12 weeks
Men and women with hypercholesterolemia

Mean baseline LDL-c
185 mg/dl
Prior intolerance to HMG CoA reductase inhibitors, baseline creatine kinase (CK) or liver function tests >2 times the upper limit of normal, and fasting
triglyceride levels >400 mg/dL.
4-week dietary run-in followed by randomization to: lova 10 mg qd or parva 10 mg qd for 4 weeks.

Then a 4 week washout period followed by crossover to alternate statin for 4 weeks.
Efficacy analysis for 30 patients.
LDL-c reduction from baseline at 4 weeks:
lova: 24%
parva: 19% (NS)
HDL-c increase from baseline at 4 weeks:
lova: 0.9%
parva: 1.6% (NS)
Trigs reduction from baseline at 4 weeks:
lova: 15.3%
parva: 19.4% (NS)
There were no differences in ADEs between groups. No cases of myopathy or clinical significant elevation in ALT or AST observed.

Dose equivalence
Lova 10 mg = parva 10 mg qd.
Merck and Bristol
Myers Squibb provided active drug only.
The Lovastatin Pravastatin Study Group 1993
R, DB, MC, not ITT

672 patients randomized
18 weeks
Men and women 25–75 years with hypercholesterolemia

Mean baseline LDL-c
194–196 mg/dl
Patients aged <25 or >75 yrs, secondary hypercholesterolemia, triglyceride level >300mg/dl, women who could not conceive and DM,7-week dietary/placebo run-in phase followed by randomization to:
lova 20 mg qd (n=339) or
parva 10 mg qd (n=333) for 6 weeks.
Then doses doubled to lova 40 mg qd or parva 20 mg qd for 6 weeks, then doubled to lova 80 mg (40 mg bid) qd or parva 40 mg qd for the remaining 6 weeks.
Unclear number of patients in efficacy analysis. 91% of patients completed trial.
LDL-c reduction from baseline at 6, 12 and 18 weeks:
lova 20 mg: 28% vs. parva 10 mg: 19%
lova 40 mg: 33% vs. parva 20 mg: 25%
lova 80 mg: 39% vs. parva 40 mg: 27%
(p<0.01 all comparisons)
HDL-c increase from baseline at 18 weeks:
lova 80 mg: 19%
parva 40 mg: 16% (NS)
Trigs reduction from baseline at 18 weeks:
lova 80 mg: 22%
parva 10 mg: 15% (p<0.05)
No differences between groups for ADEs. No cases of myopathy reported. Liver transaminase levels >3x ULN occurred in one lova vs. 2 parva patients.

Equivalent doses not compared.
Merck supported and participated in trial.
Weir et al. 1996
R, DB, MC, not ITT

426 patients randomized
12 weeks
Men and women 20–65 years with hypercholesterolemia

Mean baseline LDL-c
Lova 195 mg/dl
Prava 202 mg/dl
Patients with impaired hepatic or renal function, history of myocardial infarction or coronary artery bypass surgery within 6 months, history of cerebrovascular
accident associated with permanent sequelae, or peripheral vascular disease interfering with normal daily function, treatment with any investigational
drug or any lipid-lowering medication during the previous 6 weeks (6 months for probucol), history of depression, anxiety, or other psychiatric disorder, a sleep disorder, an irregular or changing work-shift schedule, or use of any psychotropic drugs or other centrally acting agents.
6-week dietary/placebo run-in followed by randomization to:
lova 40 mg qd (n=211) or
parva 40 mg qd (n=215).
Efficacy analysis for 423 patients.
LDL-c reduction from baseline at 12 weeks:
lova: 27.9%
parva: 23.6% (NS)
HDL-c increase from baseline at 12 weeks:
lova: 8.5%
parva: 8.2% (NS)
Trigs reduction from baseline at 12 weeks:
lova: 6%
parva: 8.6% (NS)
Achieved NECP LDL-c goal:
lova 45% vs. parva 26% (p<0.001)
Primary endpoint was quality of life. No difference in quality of life between groups.

No significant differences in ADEs or laboratory ADEs between groups.

Dose equivalence
Lova 40 mg = parva 40 mg qd.
Merck participated in study.
Lovastatin vs. Simvastatin
Farmer et al. 1992
R, DB, MC, not ITT

544 patients randomized
24 weeks
Men and women 30–85 years with hypercholesterolemia

Mean baseline LDL-c
191.4–193.4 mg/dl
Patients with history of drug, alcohol abuse, poor mental function, impaired hepatic function, unstable coronary insufficiency, serum creatinine >2mg/dl, concomitant use of hypolipidemic or immunosuppressant drugs, or history of allergic response to lovastatin or simvastatin, premenopausal women, patient with secondary hypercholesterolemia, nephrotic syndrome, chronic use of corticosteroids, untreated hypothyroidism or any other condition interfering with interpretation of results.6-week baseline dietary-placebo phase followed by randomization to:
lova 20 mg qd (n=137) or
lova 40 mg qd (n=134) or
simva 10 mg qd (n=134) or
simva 20 mg qd (n=135) for 24 weeks.
Efficacy analysis for 540 patients.
LDL-c reduction from baseline at 24 weeks:
lova 20 mg: 25.4%
lova 40 mg: 31.2%
simva 10 mg: 27.5% (NS)
simva 20 mg: 34.7% (p<0.05)
HDL-c increase from baseline at 24 weeks:
lova 20 mg: 4.2%
lova 40 mg: 7.4%
simva 10 mg: 4.6% (NS)
simva 20 mg: 4.6 (NS)
Trigs reduction from baseline at 24 weeks:
lova 20 mg: 10.5%
lova 40 mg: 10.3%
simva 10 mg: 3.9% (no significance reported)
simva 20 mg: 10.3% (NS)
Achieved NCEP LDL-c goal (p not reported):
lova 20 mg: 33%
lova 40 mg: 51%
simva 10 mg: 41%
simva 20 mg: 61%
No difference in ADEs between groups. Withdrawal for clinical or laboratory ADEs not different between groups. 1 patient in lova 40 mg group had ALT 3x ULN.

Dose equivalence
lova 20 mg = simva 10 mg qd
lova 40 mg < or ≈ simva 20 mg qd.
3 primary authors employed by Merck.
Frohlich et al. 1993
R, DB, MC, not ITT

298 patients randomized
18 weeks
Men and women 18–70 years with total cholesterol of 240–300 mg/dl (stratum 1) or >300 mg/dl (stratum 2)

Mean baseline LDL-c
Stratum 1: 200 mg/dl Stratum 2:
282–291 mg/dl
Secondary hypercholesterolemias and hypercholesterolemia with a ratio of total cholesterol: high density lipoprotein cholesterol less than 4, insulin dependant or unstable non insulin dependant diabetes patients, impaired hepatic function, impaired history of hepatitis, biliary disease, partial ileal bypass, unstable angina or intermediate syndrome, myocardial infarction, coronary bypass surgery within the previous 2 months, vasospastic angina or other serious vasospastic cardiovascular disease. Current treatment with other investigational drug, hypersensitivity to HMG-CoA reductase inhibitors, concurrent use of cimetidine, use of antacids or immunosuppressive agents, drug or alcohol abuse, overweight and with poor mental function.6-week dietary, 4 week-dietary-placebo run-in phase, then randomized to:
lova 20 mg (n=149) or
simva 10 mg (n=146).

Doses doubled at 6 and 12 weeks if TC >200 mg/dl
Efficacy analysis for 296 patients.
LDL-c reduction from baseline at 18 weeks:

Stratum 1 (mean dose):
lova 50 mg qd: 34.3%
simva 26.4 mg qd 34.6% (NS)

Stratum 2 (mean dose):
lova 71.7 mg qd: 37.2%
simva 36.9 mg qd.: 37.1% (NS)

HDL-c increase from baseline at 18 weeks:
Stratum 1 (mean dose):
lova 50 mg qd: 2.7%
simva 26.4 mg qd 7.0% (NS)

Stratum 2 (mean dose):
lova 71.7 mg qd: 8.8%
simva 36.9 mg qd: 5.3% (NS)
Patients in Stratum 2 experienced more laboratory ADEs in lova group vs. simva group (8.3% vs 0% , p<0.05). There were said to be minor and well within normal ranges. No other safety differences between groups. 1 major laboratory ADE occurred in lova group in Stratum 2, thought not to be drug-related.

Dose equivalence
lova 20 mg = simva 10 mg
lova 80 mg = simva 40 mg qd
Merck funded the study. Merck coordinated data and biostatistics groups.
Pravastatin vs. Simvastatin
Douste-Blazy et al. 1993
R, DB, MC, not ITT

273 patients randomized 6 weeks
Men and women 22–75 years with an LDL-c ≥160 mg/dl

Mean baseline LDL-c
Prava 222 mg/dl
Simva 224 mg/dl
Patients with plasma triglyceride levels >4.0mmol/L, total cholesterol: HDL cholesterol ratio of ≤4.0 or an LDL cholesterol<3.4 mmol/L, concomitant condions such as myocardial infarcon or coronary bypass surgery within the previous 2 months, unstable or prinzmetal's angina; ventricular ectopic beats> 5 per minute, coupling or the R on T phenomenon; impaired hepac funcon or liver transaminase levels>20% above the normal range, recent history if hepas, complete biliary obstrucon, CPK elevaons >50% above normal range, diabetes mellitus or fasng blood glucose >7.8mmol/L or paral ileal bypass, poor mental funcon, hypersensivity to HMG CoA reductase inhibitors, history or drug or alcohol abuse, and concurrent use of immunosuppressants or an invesgaonal drug4-week placebo/dietary run-in phase followed by randomization to: parva 20 mg qd (n=136) or simva 10 mg qd (n=137) for 6 weeks.Efficacy analysis for 268 patients.
LDL-c reduction from baseline at 6 weeks:
parva: 25%
simva: 28.3% (p<0.01)
HDL-c increase from baseline at 6 weeks:
parva: 6.1%
simva: 6.3% (NS)
Trigs reduction from baseline at 6 weeks:
parva: 12.9%
simva: 13.8% (NS)
Achieved LDL-c <130 mg/dl:
16% parva vs. 22% simva
Achieved LDL-c <160 mg/dl:
53% parva vs. 60% simva
Reported ADEs were similar between groups. Two patients in each group stopped the statin due to ADEs and were not serious. No patient withdrew due to a laboratory ADE.

Dose equivalence
parva 20 mg ≈ or < simva 10 mg qd.
Study supported by Merck.
Lambrecht et al. 1993
R, DB, MC, not ITT

210 patients randomized 6 weeks
Men or women 18–70 years with total cholesterol ≥250 mg/dl

Mean baseline LDL-c
Prava 214 mg/dl
Simva 219 mg/dl
Patients in whom hypercholesterolemia was secondary to conditions such as hypothyroidism, patients whose cholesterol to HDL ratio was ≤4, LDL cholesterol was <3.4 mmol/L, triglyceride concentrations were >4.0 mmol/L or those with combined hyperlipidemias in whom hypercholesterolemia was not a primary concern4-week dietary-placebo run-in phase, then randomized to:
parva 20 mg qd (n=105) or
simva 20 mg qd (n=105) for 6 weeks.
Efficacy analysis for 200 patients.
LDL-c reduction from baseline at 6 weeks:
parva: 29%
simva: 38% (p<0.01)
HDL-c increase from baseline at 6 weeks:
parva: 7.3%
simva: 6.7% (NS)
Trigs reduction from baseline at 6 weeks:
parva: 10.9%
simva: 14.3% (NS)
Achieved LDL-c <160 mg/dl:
78% simva vs. 64% parva (p=0.06)
Achieved LDL-c <130 mg/dl:
46% simva vs. 19% parva (p<0.01)
ADEs similar between groups. 3 ADEs reported >1%: myalgia (1.9%) and dyspepsia (1.9%) in simva group, and flatulence (1.9%) in parva group.

3 patients withdrawn due to ADEs: 1 in simva (malaise) and 2 in parva (malaise, nausea and palpitations; and flatulence) group. None of the events was considered serious. No clinically important changes in liver transaminases or CK.

Nonequivalent doses compared.
Industry support not reported.
Lefebvre et al. 1992
R, DB, MC, not ITT

291 patients randomized 6 weeks
Men and women 18–79 years with total cholesterol ≥240 mg/dl

Mean baseline LDL-c
Prava 219 mg/dl
Simva 223 mg/dl
Patients with plasma triglyceride levels >4.00 mmoL/L or a total cholesterol: HDL cholesterol ratio of <4.0, concomitant conditions such as myocardial infarction or coronary bypass surgery within the previous 2 months, or with other serious cardiovascular disease, established diabetes mellitus, hepatic or biliary disease or partial ileal bypass were excluded, poor mental function, history of drug or alcohol abuse or concurrent use of cimetidine, regular use of antacids, immunosuppressants such as cyclosporin or any investigational drug.4-week dietary-placebo run-in phase, then randomized to:
parva 10 mg qd (n=141) or simva 10 mg qd (n=142)
Efficacy analysis for 283 patients.
LDL-c reduction from baseline at 6 weeks:
parva: 22%
simva:32% (p<0.01)
HDL-c increase from baseline at 6 weeks:
parva: 5%
simva: 7% (p=0.06)
Trigs reduction from baseline at 6 weeks:
parva: 6%
simva: 13% (p<0.05)
ADEs similar between groups. No patient experienced a clinically significant increase in liver transaminases or CK. Authors report 9 laboratory ADEs in simva vs. 2 in parva groups. Details not provided for all incidents.

Equivalent doses not compared.
Study supported by Merck.
Lintott et al. 1993
R, DB, MC, not ITT

48 patients randomized 24 weeks
Men or women with hypercholesterolemia

Mean baseline LDL-c
Prava 243 mg/dl
Simva 250 mg/dl
combined hyperlipidemia or primary hypertriglyceridemia, patients with hepatic or renal function outside the normal range, secondary hyperlipidemia or a coronary event within the previous 3 months.6-week dietary-placebo phase then, randomization to:
parva 10 mg qd (n=24) or simva 10 mg qd (n=24) for 6 weeks.

At 12 and 18 weeks, doses doubled if LDL- c was >130 mg/dl to a maximum of 40 mg qd. At week 18, all patients switched to simva at 18-week dose.
Efficacy analysis for 47 patients.
LDL-c reduction from baseline at 6 weeks:
parva: 17%
simva: 29% (no p-value provided)
LDL-c reduction from baseline at 18 weeks:
parva: 27%
simva: 38% (p=0.001)
HDL-c increase from baseline at 18 weeks:
parva: 7%
simva: 11% (NS)
Trigs reduction from baseline at 18 weeks:
parva: unchanged at 18 weeks
simva: 11.8%

18/24 simva vs. 22/23 parva users titrated to maximum dose.
One simva patient experienced significant elevation in CK after beginning rigorous exercise program the day before. Simva was stopped and restarted with no further incident. One parva patient developed a rash and was withdrawn.

Titrate to target, nonequivalent doses compared.
Study supported by Merck.
Malini et al. 1991
R, OL, ITT

100 patients randomized 6 weeks
Men and women 18–70 years with total cholesterol ≥240 mg/dl

Mean baseline LDL-c
Prava 205 mg/dl
Simva 209 mg/dl
Patients with plasma triglyceride levels >4.00 mmoL/L or a total cholesterol: HDL cholesterol ratio of <4.0, concomitant conditions such as myocardial infarction or coronary bypass surgery within the previous 2 months, or with other serious cardiovascular, established DM, liver or biliary disease, or partial ileal bypass, poor mental function, history of drug or alcohol abuse, concurrent use of cimetidine, regular use of antacids, immunosuppressants or other investigational drugs,4-week dietary-placebo run in phase then randomized to:
parva 10 mg qd (n=50) or simva 10 mg qd (n=50)
Efficacy analysis for 100 patients.
LDL-c reduction from baseline at 6 weeks:
parva: 21.8%
simva 10 mg: 33.1% (p<0.01)
HDL-c increase from baseline at 6 weeks:
parva: 7%
simva: 10% (p<0.05)
Trigs reduction from baseline at 6 weeks:
parva: 5.8%
simva: 12.3% (p<0.01)
ADEs were reported in 4 parva patients vs. 2 simva patients. No patient withdrew from the study due to ADEs.

Dose equivalence

Equivalent doses not compared.
Industry support not reported.
Sasaki et al. 1997
R, OL, C, not ITT

74 patients randomized 16 weeks
Men or women with total cholesterol ≥220 mg/dl.

Mean baseline LDL-c
177.7 mg/dl
patients with hypersensitivity to drugs; pregnant or lactating women and those suspected of being pregnant or a combination of these; patients with acute myocardial infarction or stroke; with severe liver dysfunction; hyperlipidemia associated with hypothyroidism, obstructive gallbladder, biliary diseases, pancreatitis, or immunologic abnormalities such as collagen diseases, or a combination of these; alcoholics or heavy alcohol drinkers; patients with hyperlipidemia induced by steroid hormones or other drugs; and patients who were considered inappropriate for the study by the attending physician for any other reason.Observation period (duration not stated), then randomization to:
parva 10 mg qd or
simva 5 mg qd for 8 weeks - then switched to alternate statin for another 8 weeks.
Efficacy analysis for 72 patients.
LDL-c reduction from baseline at 8 weeks:
parva: 23.1%
simva: 31.1% (p<0.05)
HDL-c increase from baseline at 8 weeks:
parva: 6.6%
simva: 7.9% (NS)
Trigs reduction from baseline at 8 weeks:
parva: 5.8%
simva: 13% (NS)
Achieved LDL-c goal:
parva: 44.4% vs simva: 63.9% (p<0.05)
No differences between groups. No clinically important laboratory changes.
Dose equivalence
Simvastatin 5 and 10 mg > parva 10 mg qd
Funding not reported.
Stalenhoef et al. 1993
R, DB, MC, not ITT

48 patients randomized
18 weeks
Men and women with primary hypercholesterolemia LDL-c >180 mg/dl

Mean baseline LDL-c
316 mg/dl
Diabetes; use of lipid-lowering agents within the past 6 months, TG >=500 mg/dL, LDL-c >=250 mg/dL, documented history of CHD or other atherosclerotic disease, history of serious or hypersensitivity reactions to other statins; uncontrolled hypothyroidism; uncontrolled hypertension; acute liver disease or hepatic dysfunction; unexplained serum creatine kinase >3 x ULN; use of prohibited concomitant medications.6-week dietary/placebo run-in period followed by randomization to:
parva 10 mg qd (n=24) or
simva 10 mg qd (n=24) for 6 weeks.
Doses doubled at 12 and 18 weeks to a maximum 40 mg qd.
Efficacy analysis for 46 patients.
LDL-c reduction from baseline at 18 weeks:
parva 40 mg: 33% (mean doses)
simva 40 mg: 43% (p<0.01)
HDL-c increase from baseline at 18 weeks:
parva: 6%
simva: 8% (NS)
Trigs reduction from baseline at 18 weeks:
parva: 13%
simva: 15% (NS)
Two patients withdrew due to ADEs. No details provided. No clinically significant increases in ALT/AST or CK.

Nonequivalent doses compared.
Industry involvement not reported.
Steinhagen-Thiessen 1994
R, DB, MC, not ITT

281 patients randomized
12 weeks
Men or women 21–71 years with total cholesterol 220–280 mg/dl.

Mean baseline LDL-c
174–176 mg/dl
Patients with diabetes [fasting glucose >6.94 mmol/L (125 mg/dL)] ;use of lipid lowering agents within the past 6 months; TG 5.65 mmol/L (500 mg/dL); LDL-C ≥ 6.48 mmol/L (250 mg/dL); documented history of CHD or other atherosclerotic disease; a history of known familial hypercholesterolemia; a history of serious or hypersensitivity reactions to other statins; uncontrolled hypothyroidism; uncontrolled hypertension; acute liver disease or hepatic dysfunction [hepatic transaminases or bilirubin ≥ 1.5 the upper limit of normal (ULN)]; unexplained serum creatine kinase (CK) >3 xULN; and use of prohibited concomitant medications.4-week dietary/placebo run-in period followed by randomization to:
parva 10 mg qd (n=138) or
simva 5 mg qd (n=143) for 6 weeks.

At 6 weeks, simva increased to 10 mg qd.
Efficacy analysis for 273 patients.
LDL-c reduction from baseline at 6 weeks:
parva 10 mg: 17.7%
simva 5 mg: 23.3% (p<0.01)
LDL-c reduction from baseline at 12 weeks:
parva 10 mg: 16.5%
simva 10 mg: 26.8% (p<0.01)
HDL-c increase from baseline at 12 weeks:
parva 10 mg: 8.3%
simva 10 mg: 8.1% (NS)
Trigs reduction from baseline at 12 weeks:
parva 10 mg: 4.2%
simva 10 mg: 9.5% (NS)
Achieved LDL-c <130 mg/dl:
parva 10 mg: 32–33% vs. simva 5 mg: 45% vs. simva 10 mg 59%
Most common treatment-related ADE was musculoskeletal complaints in simva group vs. digestive disturbances in parva group. 3 patients withdrew due to ADEs: 1 rash and 1 hepatitis (patient later found to be Hep B positive) in simva group, both judged unrelated to treatment. No details on 3rd withdrawal. 1 parva patient with CK elevation >10x ULN. No further details provided.

Dose equivalence
Simvastatin 5 and 10 mg > parva 10 mg qd
Study supported by Merck.
Sweany et al., 1993
R, DB, MC, not ITT

550 patients
18 weeks
Men and women 18–71 years with LDL-c ≥ 160 mg/dl

Mean baseline LDL-c
Prava 212 mg/dl
Simva 207 mg/dl
Presence of myocardial infarction, coronary bypass surgery and angioplasty, within the previous 3 months, unstable angina, cardiac or renal failure, hepatic disease, diabetes mellitus, secondary hypercholesterolemia, and hyperlipidemia type III, treatment with lipid lowering agents within 6 weeks or with probucol within 6 months before baseline and treatment with immunosuppressive drugs.6-week dietary/placebo run-in phase, then randomized to:
parva 10 mg qd (n=275) or
simva 10 mg qd (n=275) for 6 weeks.

Doses doubled if LDL-c at weeks 6 and 12 were >130 mg/dl, up to a maximum of 40 mg qd for each statin.
Efficacy analysis number of patients not reported.
LDL-c reduction from baseline at 6 weeks:
parva: 19%
simva: 30% (p<0.01)
LDL-c reduction from baseline at 18 weeks: (mean dose)
parva 32 mg/d: 26%
simva 27 mg/d: 38% (p<0.01)
HDL-c increase from baseline at 18 weeks:
parva 12%
simva 15% (p<0.05)
Trigs reduction from baseline at 18 weeks:
parva 14%
simva 18% (p<0.05)
Achieved LDL-c <130 mg/dl
65% simva vs. 39% parva
5 patients in each group withdrew due to ADEs. Reasons in parva group: headache and tinnitus, rash, abdominal pain, GI complaints and dizziness. Reasons in simva group: GI in 3 patients, headache, and diarrhea and sinus tachycardia.

Myalgia reported by 1 simva and 3 parva users. 1 parva patient stopped due to myalgia and muscle cramps with CK 3–10x ULN. CK elevation in other myalgia reports not clinically significant. 2 simva patients had CK elevation > 10x ULN, attributed to exercise (simva continued without further problems). No clinically significant elevations in AST or ALT.

Nonequivalent doses compared. Treat to target.
Merck funded and participated in study.
Pravastatin vs. Misc
Gratsianskii N, et al 2007
RCT status unknown, unknown, SC, not ITT

Series 1 n=40 (n= 20 control, 20 parva)
Series 2 n=90 (n=30 aorta, 29 aorta, 31 parva)
Men and postmenopausal women receiving no hormone-replacement therapy with ACS without stable ST elevation on day 1 after the development of anginal attack, which was the cause of hospitalizationRecent ACS, receiving statins, and patients with evident systemic inflammation.Series 1- control vs. parva up to 60 mg for 14 days
Series 2- atorva10, atorva40 or prava40 for 14 days
LDL-c change at 14 days
Series 1- control (n=13) NR vs.. Prava (n=10) −34% (p < 0.05)
Series 2- atorva10 (n=23) −33% vs. atorva40 (n=23) −41% vs. Prava40 (n=25) −23% (atorva10 and prava40 vs. atorva40 p < 0.05)
NRNR
Rosuvastatin vs Atorvastatin
Ballantyne C, et al 2006 (MERCURY II)

RCT, OL, MC, AC, 1993 patients randomized (first 8 weeks rosuva20 = 392, atorva10 = 403, atorva20 = 395, simva20 = 402, simva40 = 401, second 8 weeks rosuva20 = 367, atorva10 = 185, atorva10 to rosuva10 191, atorva20 = 186, atorva20 to rosuva20 = 186, simva20 = 190, simva20 to rosuva10 = 183, simva40 = 191 simva 40 to rosuva20 = 189)
Men and women aged z18 years; high risk of CHD events; fasting LDL-C ≥130 yo<250 mg/dL; fasting TG <400 mg/dL

Baseline LDL-c
rosuva20 167.1
atorva10 169.0
atorva20 168.1
simva20 169.4
simva40 168.8
Pregnancy or lactation; history of homozygous familial percholesterolemia or known hyperlipoproteinemia types I, III, IV, or V; unstable arterial disease within 3 months of trial entry; uncontrolled hypertension; fasting serum glucose of >180 mg/dL; active liver disease or hepatic dysfunction; serum creatinine of >2.0 mg/dL; or unexplained serum creatine kinase (CK) levels >3 times ULN.6 week dietary lead in, then randomized to rosuvastatin 20 mg, atorvastatin 10 mg, atorvastatin 20 mg, simvastatin 20 mg, or simvastatin 40 mg for 8 weeks. Patients either remained on starting treatment or switched to lower or milligram-equivalent doses of rosuvastatin for 8 more weeks.LDL-c change at 8 weeks
rosuva20 −52.1%
atorva10 −37.1%* atorva20 −43.3%*
simva20 −34.2%* simva40 −41.2%*
HDL-c change at 8 weeks
rosuva20 6.9%
atorva10 5.3% atorva20 3.7%*
simva20 5.4% simva40 5.9%
* p < 0 .0001 compared with rosuvastatin 20 mg.
LDL-c change at 16 weeks
rosuva20 −51.6%
atorva10 −36.2% atorva10 to rosuva10 −46.6%*
atorva20 −43.4% atorva20 to rosuva20 −50.8%*
simva20 −32.1% simva20 to rosuva10 −45.1% *
simva40 −39.6% simva 40 to rosuva20 −53.7%*
*p < 0.001 for comparisons within treatment arms.
HDL-c change at 16 weeks
rosuva20 7.2%
atorva10 −6.1% atorva10 to rosuva10 7.5%
atorva20 4.0% atorva20 to rosuva20 5.3%
simva20 4.3% simva20 to rosuva10 6.3%
simva40 6.9% simva 40 to rosuva20 7.6%
First 8 weeks n (%) rosuva20 vs. atorva10 vs. atorva20 vs. simva20 vs. simva40
Any adverse event, 150 (38.4%) vs.144 (36.0%) vs.126 (32.1%) 126 (31.5%) vs.152 (38.0%)
Leading to death, 1 (0.3%) vs. 0 vs. 0 vs. 0 vs. 0
Leading to withdrawal, 15 (3.8%) vs. 12 (3.0%) vs. 7 (1.8%) vs. 16 (4.0%) vs. 9 (2.3%)
Serious adverse events, 6 (1.5%) vs. 11 (2.8%) vs. 8 (2.0%) vs. 8 (2.0%) vs. 4 (1.0%)
Second 8 weeks n (%) rosuva10 vs. rosuva20 vs. atorva10 vs. atorva20 vs. simva20 vs. simva40
Any adverse event, 130 (34.9%) vs. 278 (37.6%) vs. 60 (32.4%) 72 (38.9%) vs. 58 (30.9%) vs. 51 (27.1%)
Leading to death, 1 (0.3%) vs. 0 vs. 0 vs. 0 1 (0.5%) vs. 0
Leading to withdrawal, 9 (2.4%) vs. 7 (0.9%) vs. 1 (0.5%) vs. 4 (2.2%) vs. 1 (0.5%) vs. 1 (0.5%)
Serious adverse events, 5 (1.3%) vs. 12 (1.6%) vs. 4 (2.2%) vs. 3 (1.6%) vs. 5 (2.7%) vs. 3 (1.6%)
1 author from AstraZeneca
Berne et al, 2005 URANUS R, DB, MC, not ITT

469 patients randomized
16 weeks
Men or women with a history of type 2 diabetes for at least 3 months, being treated with diet, oral antidiabetic medication, insulin, or a combination of these treatments, and fasting LDL- C of >=3.3 mmol/L and triglycerides <6.0 mmol/L at enrollment.Type 1 diabetes, uncontrolled type 2 diabetes, uncontrolled hypothyroidism or hypertension, nephrotic syndrome or severe renal failure, active liver disease or hepatic dysfunction active arterial disease serum creatine kinase levels >3 X ULN, BMI >35, and known hypersensitivity to statins.6-week dietary run-in, then randomization to: rosuva 10 mg or aorta 10 mg for 4 weeks, then
12-week period of dose titration if patient had not reached European guideline goal (LDL-c <117 mg/dL):
rosuva 20 mg or aorta 20 mg for 4 weeks.
Further dose titrations up to rosuva 40 mg or aorta 40 mg or 80 mg were performed at weeks 8 and 12 if patients were still not at goal.
Efficacy analysis for 441 patients (least squares mean percentage change):
LDL-c reduction from baseline to 16 weeks:
rosuva 10 to 40 mg: −52.3%
aorta 10 to 80 mg: −45.5%
Difference: −6.7% (95% CI −8.8%, −4.7%; p<0.0001)

HDL-c increase from baseline to 16 weeks:
rosuva 10 to 40 mg: 5.3%
aorta 10 to 80 mg: 4.0%
Difference: 1.3% (95% CI −1.3%, 3.8%; p NS)

Trig reduction from baseline to 16 weeks:
rosuva 10 to 40 mg: −21.2%
aorta 10 to 80 mg: −21.1%
Difference: −0.1% (95% CI −5.6%, 5.3%; p NS)
Overall adverse events:
rosuva: 51%
aorta: 53%

Serious adverse events:
rosuva: 0.86%
aorta: 3.4%

Withdrawals due to adverse events:
rosuva: 1.3%
aorta: 3.0%

No cases of myopathy; myalgia in 3.4% of patients overall; no clinically important elevations in CK.
Supported by AstraZeneca
Betterridge D, et al 2007 (ANDROMEDA)

RCT, DB, MC, AC, 509 patients randomized (mITT)
(n=254(248) rosuva, 255(246) aorta)
16 weeks
Men and non-pregnant women aged at least 18 years who fulfilled
WHO criteria for a diagnosis ofT2DM
Type 1 diabetes; HbA 1c > 9.0%; a history of CVD or familial hypercholesterolemia; an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level = ≥1.5 × upper limit of normal (ULN); resting diastolic or systolic blood pressure of > 95 mmHg or > 200 mmHg, respectively; an unexplained serum creatine kinase (CK) level > 3 × ULN.4 week wash out, then rosuvastatin
10 mg or atorvastatin 10 mg for 8 weeks, after which doses were increased to 20 mg once daily for a second 8-week period.
LDL-c change from baseline at 8 weeks:
rosuva −51.8% vs.. aorta −40.3% (p = 0.001)
HDL-c change from baseline at 8 weeks:
rosuva 2.0% vs.. 3.6% aorta (p=0.170)

LDL-C < 2.5 mmol/l at 8 weeks
rosuva 94.1% vs.. atorva78.8% (p <0.001)
LDL-c change from baseline at 16 weeks:
rosuva −57.4% vs.. aorta −46.0% (p = 0.001)
HDL-c change from baseline at 16 weeks:
rosuva 1.9% vs.. 2.2 aorta (p=0.794)
LDL-C < 2.5 mmol/l at 16 weeks
rosuva 95.6% vs.. aorta 87.3% (p = 0.002)
Overall adverse events:
rosuva 48.4%, atorva 53.7%

Withdrawals due to adverse events:
rosuva 5.9%, atorva 5.1%

Most frequent adverse events: nasopharyngitis, lower respiratory tract infections, constipation, arthralgia, and diarrhea.

Myopathy or rhabdomyolysis
rosuva 0%, Atorva 0%
AstraZeneca
Binbrek A, et al 2006 (DISCOVERY-lpha)

RCT, (2:1) OL, MC, ITT

1506 patients randomized (n= rosuvastatin, 1002 patients; atorvastatin, 504 patients))
12 weeks
Male and female patients aged at least 18 years with primary hypercholesterolemia (LDL-C > 135 mg/dL] if LLT-naive or 120 mg/dL if switching; and triglycerides 400 mg/dL)and a 10-year coronary heart disease (CHD) risk >20% or a history of CHD or other established atherosclerotic diseaseFamilial hypercholesterolemia or dysbetalipoproteinemia; secondary dyslipidemia; hypersensitivity to statins; uncontrolled diabetes mellitus (DM) or hypertension;
unstable CVD (including unstable angina); active hepatic disease or hepatic dysfunction ; unexplained serum creatine kinase (CK) >3 x ULN; women of childbearing age not using contraception, or pregnant or breastfeeding; and current treatment with medications not allowed during the study (lipid-modifying agents [e.g., fibrates, niacin/nicotinic acid, bile acid sequestrants, other statins, probucol, fish oils, lipid-modifying dietary supplements, food additives] or agents known to interact with statins and increase the risk for muscular adverse events [AEs] [e.g., cyclosporine, clarithromycin, erythromycin, fluconazole, ketoconazole, itraconazole]).
Naive had 4 week dietary run- in, switched did not, rosuvastatin 10 mg or atorvastatin 10 mg for 12 weeks.LDL-c change from baseline at 12 weeks:
LLT-naïve rosuva −44.7% vs.. aorta −33.9% (p < 0.001)
Switched rosuva −32.0% vs.. aorta −26.5% (p = 0.006)
HDL-c change from baseline at 12 weeks:
LLT-naïve rosuva 4.7%% vs.. 1.7% aorta (p=0.109)
Switched rosuva 2.6% vs.. aorta 1.3% (p = 0.524)
Rosuva vs. aorta n(%)
Any AE 95 (9.5) vs. 52 (10.4)
Led to treatment discontinuation 23 (2.3) vs. 14 (2.8)
Serious t 12 (I .2) vs. 7 (I .4)[1 patient in each treatment group, the onset of the serious AE reported occurred before the commencement of study treatment]
Led to death I (0.1) vs. 2 (0.4)

Most frequent adverse events
Headache 9 (0.9) vs 7 (1.4)
Myalgia 6 (0.6) vs. 4 (0.8)
Nausea 6 (0.6) vs. 4 (0.8)
Dizziness 5 (0.5) vs. 4 (0.8)
Diarrhea 4 (0.4) vs. 4 (0.8)
AstraZeneca,
Blasetto et al, 2003;
Shepherd et al, 2003
R, DB, MC
5 trials prospectively designed to allow pooling

2153 patients randomized (n=394 rosuva 5 mg, 392 rosuva 10 mg, 396 aorta 10 mg, 240 rosuva 5mg, 226 rosuva 10 mg, 250 simva 20 mg, 255 prava 20 mg)
12 weeks
Men and women age 18 or older with LDL-c ≥ 160 mg/dL and <250 mg/dL and triglyceride levels < 400 mg/dL

Mean baseline LDL-c
3 pooled trials of rosuva vs aorta:
rosuva 5mg: 188 mg/dL
rosuva 10mg: 185 mg/dL
aorta 10mg: 187 mg/dL

2 pooled trials of rosuva vs parva and simva:
rosuva 5mg: 189 mg/dL
rosuva 10mg: 187 mg/dL
simva 20mg: 188 mg/dL
parva 20mg: 189 mg/δ
Patients were excluded if they had disorders or were taking other medications known to affect lipid values or to present a potential safety concernRosuva 5 mg or 10 mg; aorta 10 mg; simva
20 mg; parva 20 mg
3 pooled trials of rosuva vs aorta:
LDL-C reduction from baseline at week 12:
rosuva 5mg: 41.9% (p<0.001 vs aorta); rosuva 10mg: 46.7% (p<0.001 vs aorta); aorta 10mg: 36.4%
HDL-c increase from baseline at week 12:
rosuva 5mg: 8.2% (p<0.01 vs aorta); rosuva 10mg: 8.9% (p<0.001 vs aorta);
aorta 10mg: 5.5%
Trigs decrease from baseline at week 12:
rosuva 5mg: 16.4%; rosuva 10mg: 19.2%; aorta 10mg: 17.6% (NS)
Achieved ATP-III LDL-c goal at week 12:
rosuva 10 mg: 76% aorta 10 mg: 53% (p<0.001)
2 pooled trials of rosuva vs parva and simva:
LDL-C reduction from baseline at week 12:
rosuva 5mg: 40.6% (p<0.001 vs simva and parva); rosuva 10mg: 48.1% (p<0.001 vs simva and parva); parva 20mg 27.1%; simva 20mg 35.7%
HDL-c increase from baseline at week 12:
rosuva 5mg: 6.9%; rosuva 10mg: 9.1% (p<0.05 vs simva and parva); parva 20mg 6.2%; simva 20mg 6.2%
Trigs decrease from baseline at week 12:
rosuva 5mg: 14.9%; rosuva 10mg: 20.2% (p<0.01 vs simva and parva); parva 20mg 12.2%; simva 20mg 12.4%
No information on adverse events.

Equivalent doses not compared
Supported by AstraZeneca
Bots A, et al, 2005 (Dutch DISCOVERY)

RCT (3:1:1:1), DB, MC, AC, 1215 patients randomized (n=621 rosuva10, 189 atorva10, 194 simva20, 211 prava40 )
16 weeks
Aged 18 years with type IIa or type Iib hypercholesterolemia and a 10-year cardiovascular risk of >20% or a history of CHD or other established atherosclerotic disease, fasting LDL-C of >3.5 mmol/l if untreated (not receiving lipid-lowering therapy in the 4 weeks before enrolment) or fasting LDL-C of >3.1 mmol/l if currently being treated with a start dose of other lipid-lowering therapy.
Mean baseline LDL-C (SD)
rosuva 4.46 (0.75) aorta 4.35 (0.73)
simva 4.43 (0.70) parva 4.42 (0.75)
Familial hypercholesterolemia or type III hyperlipoproteinemia, secondary dyslipidemia (except diabetic dyslipidemia for patients with controlled diabetes), uncontrolled diabetes or hypertension, active liver disease or hepatic dysfunction, unstable CVD (including unstable angina), history of hypersensitivity to other statins, unexplained serum creatine kinase (CK) >3 times ULN and use of prohibited medications.12- week treatment with rosuvastatin 10 mg, atorvastatin 10 mg, simvastatin 20 mg or pravastatin 40 mg.LDL-c change at 12 weeks:
Naïve rosuva −45.6 atorva −37.6** simva −37.0** parva −32.9**
Treated previously rosuva −22.6 atorva −11.3** simva - −12.4* parva −6.9**
*p < 0.01 vs. rosuva; **p < 0.001 vs. rosuva;
HDL-c change at 12 weeks:
Naïve rosuva 6.3 aorta 5.1 simva 3.7* parva 2.4**
Treated previously rosuva 0.7 atorva −0.8 simva 1.1 parva −0.7
*p < 0.05 vs. rosuva. **p < 0.01 vs. rosuva
Rosuva vs. atorva vs. simva vs. prava n(%)
Myalgia 22 (3.5) vs. 3 (1.6) vs. 3 (1.5) vs 5 (2.4)
Headache 8 (1.3) vs. 8 (4.2) vs. 3 (1.5) vs. 3 (1.4)
Cough 12 (1.9) vs. 1 (0.5) vs. 2 (1.0) vs. 6 (2.8)
Fatigue 9 (1.4) vs. 1 (0.5) vs. 4 (2.1) vs. 5 (2.4)
Eczema 8 (1.3) vs. 4 (2.1) vs. 2 (1.0) vs. 2 (0.9)
Arthralgia 4 (0.6) vs. 2 (1.1) vs. 5 (2.6) vs. 4 (1.9)
Back pain 6 (1.0) vs. 2 (1.1) vs. 3 (1.5) vs. 4 (1.9)
Nausea 10 (1.6) vs. 1 (0.5) vs. 1 (0.5) vs. 2 (0.9)
Constipation 6 (1.0) vs. 1 (0.5) vs. 4 (2.1) vs. 4 (1.9)
Bronchitis (NOS) 6 (1.0) vs. 2 (1.1) vs. 1 (0.5) vs. 3 (1.4)
Diarrhea (NOS) 5 (0.8) vs. 2 (1.1) vs. 3 (1.5) vs. 2 (0.9)
Upper abdominal pain 5 (0.8) vs. 1 (0.5) vs. 2 (1.0) vs. 3 (1.4)
Chest pain 7 (1.1) vs. 1 (0.5) vs. 2 (1.0) vs. 2 (0.9)
Cystitis (NOS) 5 (0.8) vs. 3 (1.6) vs. 0 (0) vs.1 (0.5)
Hypertension (aggravated) 3 (0.5) vs. 2 (1.1) vs. 5 (2.6) vs. 1 (0.5)
Urinary tract infection (NOS) 5 (0.8) vs. 2 (1.1) vs. 1 (0.5) vs. 2 (0.9)
Dyspepsia 4 (0.6) 0 (0) 3 (1.5) 1 (0.5)
Influenza 2 (0.3) vs. 1 (0.5) vs. 2 (1.0) vs. 1 (0.5)
Nasopharyngitis 4 (0.6) vs. 0 (0) vs. 1 (0.5) vs. 2 (0.9)
NOS=not otherwise specified.
AstraZeneca
Brown et al, 2002 R, DB, MC, not ITT

477 patients randomized (n= 239 rosuva, 118 parva vs. 120 simva)
52 weeks
Men and women ≥18 years with LDL-c ≥160 and <250 mg/dl, and triglyceride levels ≤400 mg/dL

Mean baseline LDL-c
rosuva 5mg: 187.3 mg/dL
rosuva 10mg: 187.0 mg/dL
parva: 188.5 mg/dL
simva: 188.0 mg/dL
Active hepatic disease or dysfunction, active arterial disease within 3 months, <10-year history of malignancy (unless basal or squamous cell skin carcinoma), uncontrolled hypertension, history of ketoacidosis within 5 years, uncontrolled hypothyroidism, serum creatine kinase (CK) concentration>3 times the upper limit of normal (ULN), familial hypercholesterolemia, serum creatinine concentration> 220 mol/L, fasting serum glucose >180 mg/dL or HbA1c >9%, alcohol or drug abuse, use of concomitant medications known to affect lipid values or present a potential safety concern, and known hypersensitivity to statins. Women of childbearing potential not using a reliable form of contraception or who were pregnant or lactating were also excluded.6-week dietary run-in with NCEP Step 1 diet, then:
rosuva 5 mg or rosuva 10 mg or parva 20 mg or simva 20 mg for 12 weeks. Then 40-week titration period to reach NCEP (ATP 2) targets or maximum dose of rosuva 80 mg, parva 40 mg or simva 80 mg.
Efficacy analysis for 472 patients.
LDL-c reduction at 12 weeks:
rosuva 5 mg: 39% (p<0.001 vs parva 20 mg; p<0.05 vs simva 20mg)
rosuva 10 mg: 47% (p <0.001 vs parva 20 mg, ≤0.001 vs simva 20 mg)
parva 20 mg: 27%
simva 20 mg: 35%
HDL increase at 12 weeks:
rosuva 5 mg: 8.2%
rosuva 10 mg: 11.9% (p<0.05 vs parva 20 mg)
parva 20 mg: 8%
simva 20 mg: 9%
Trigs reduction at 12 weeks:
rosuva 5 mg: 17.6% (p<0.05 vs simva 20 mg)
rosuva 10 mg: 21.5% (p<0.01 vs parva 20 mg, p≤0.001 vs simva 20 mg)
parva 20 mg: 11%
simva 20 mg: 10%
Achieved ATP III LDL-c goal at 12 weeks:
rosuva 5 mg: 78%
rosuva 10 mg: 88%
parva 20 mg: 51%
simva 20 mg: 63%
(p-values not reported)
Withdrawals due to treatment-related adverse events:7 rosuva 5 mg, 7 rosuva 10 mg, 6 parva, 7 simva.
1 serious AE identified with treatment: simva patient with asthenia and chest pain, resolved with no change in treatment.

Transient elevations in ALT >3x ULN without symptoms: 2 rosuva 5 mg, 0 rosuva 10 mg, 5 parva, 2 simva

Equivalent doses not compared
3 authors employed by AstraZeneca
Clearfield M, et al 2006 (PULSAR)
RCT (1:1), OL, MC, ITT

996 patients randomized (n= 504 to rosuvastatin 10 mg, 492 to atorvastatin 20 mg)
6 weeks
Men and women, 18 years or more, hypercholesterolemia and either a history of CHD, clinical evidence of atherosclerosis or a CHD-risk equivalent , diabetes mellitus or ≥ 2 risk factors that confer a 10-year CHD- risk score > 20%
Baseline LDL-C
rosuva 165.1
aorta 164.9
History of statin-induced myopathy or a serious hypersensitivity to statins; patients considered to be unstable after a myocardial infarction (MI), unstable angina, myocardial revascularization or a transient ischemic attack or stroke; patients awaiting a planned myocardial revascularization; severe congestive heart failure; history of malignancy; history of known homozygous familial hypercholesterolemia; current active liver disease; uncontrolled hypothyroidism ; alcohol or drug abuse within the last 5 years, and initiation of hormone-replacement therapy or oral contraceptives within 3 months , women who were pregnant, breast- feeding or of child-bearing potential and not using a reliable form of contraception.6 week dietary lead in then 6 weeks of RCT rosuva vs.. aortaLDL-c change from baseline at week 6:
rosuva −44.6% vs. aorta −42.7% (p < 0.05)
HDL-c change from baseline at week 6:
rosuva 6.4% vs. atorva3.1% (p < 0.001)

NCEP ATP III nonHDL-C goal of < 130 mg/dL
rosuva 69.7% vs. aorta 65.0% (p = ns)
Rosuvastatin 10 mg vs. Atorvastatin 20 mg n(%)
Any adverse event 139 (27.5) vs. 128 (26.1)
Myalgia 24 (4.8) vs. 13 (2.6)
Urinary tract infection 13 (2.6) vs. 16 (3.3)
Headache 8 (1.6) vs. 7 (1.4)
Nausea 4 (0.8) vs. 9 (1.8)
Bone pain 8 (1.6) vs. 3 (0.6)
Muscle cramp 5 (1.0) vs. 3 (0.6)
Peripheral edema 3 (0.6) vs. 5 (1.0)
AstraZeneca
Davidson et al, 2002
R, DB, MC, PC.

519 patients randomized (n=132 placebo, 129 rosuva 5mg, 130 rosuva 10mg, 128 aorta 10mg)
12 weeks
Men and women age 18 and older with fasting LDL-c > 160 mg/dL and <250 mg/dL and fasting triglycerides < 400 mg/dL, and a score of 28 or less on section 1 of the Eating Pattern Assessment Tool (indicating compliance with NCEP step I diet).

Mean baseline LDL-c
rosuva 5mg: 188 mg/dL
rosuva 10mg: 185 mg/dL
aorta 10mg: 186 mg/dL
Active arterial disease within 3 months of trial entry, familial hypercholesterolemia, uncontrolled hypertension, active liver disease or hepatic dysfunction indicated by aspartate aminotransferase or alanine aminotransferase ≥1.5 times the upper limit of normal, serum creatine kinase >3 times the upper limit of normal, serum creatinine >220 mol/L (2.5 mg/dl), fasting serum glucose > 9.99 mmol/L (180 mg/dl), or glycated hemoglobin > 9%.6-week dietary run-in with NCEP Step 1 diet

12 week trial with NCEP Step 1 diet and rosuvastatin 5 or 10 mg, atorvastatin 10 mg, or placebo once a day
LDL-c reduction from baseline at week 12:
rosuva 5 mg: 40% (p< 0.01 vs aorta)
rosuva 10 mg: 43% (p<0.001 vs aorta)
aorta 10 mg: 35%

HDL-c increase from baseline at week 12:
rosuva 5 mg: 13% (p< 0.01 vs aorta)
rosuva 10 mg: 12% (p< 0.05 vs aorta)
aorta 10 mg: 8%

Triglycerides reduction from baseline at week 12:
rosuva 5 mg: 17%
rosuva 10 mg: 19%
aorta 10 mg: 19%
Withdrawals due to adverse events: 4 (3.1%) aorta, 6 (4.7%) rosuva 5mg, 4 (3.1%) rosuva 10mg.
No clinically significant elevations in CK or ALT/AST.
Types and incidences of adverse events similar across all treatment groups.
Adverse events related to study treatment: 18 rosuva 5mg (14.1%), 17 rosuva 10mg (13.2%), 25 aorta (19.7%).
Most frequently reported were constipation, flatulence, nausea, and myalgia.
Serious adverse events in 5 (3.9%) aorta patients (angina, coronary vascular disorder, tooth disorder, pathologic fracture, hypertension, cholelithiasis, ileus, and pneumonia); 3 (2.3%) rosuva 5mg patients (angina, heart failure, meningitis, bone disorder, infection), 0 in rosuva 10mg group. No serious adverse event was considered by the investigators to be related to study drug.

Equivalent doses not compared
Supported by a grant from AstraZeneca
Discovery-UK group, 2006
RCT (2:2:1), OL, MC, AC.

1874 patients randomized (1770 ITT) (n= 712 rosuva10, 709 aorta 10mg, 349 simva20)
12 weeks
18 years or more; with type Iia and IIb hypercholesterolemia, no previous statin treatment; LDL-C ≥ 3.5 mmol/L; fasting TG ≤ 4.52 mmol/L; a 10-year coronary heart disease (CHD) risk > 20%; or a history of CHD or other established atherosclerotic disease.

Baseline LDL-c mmol/L
rosuva10 4.5
atorva10 4.5
simva20 4.5
Active liver disease or hepatic dysfunction, known uncontrolled diabetes, uncontrolled hypertension and
unexplained serum creatine kinase (CK) 3 x the upper limit of normal (ULN).
Rosuvastatin 10 mg, atorvastatin 10 mg or simvastatin 20 mg once daily for 12 weeks.LDL-c change at 12 weeks:
rosuva10 –50%
atorva10 −42% (vs. rosuva p < 0.0001)
simva20 −40% (vs. rosuva p < 0.0001)
1998 European LDL-C goals were achieved
rosuva10 89%
atorva10 78% (vs. rosuva p < 0.0001)
simva20 72% (vs. rosuva p < 0.0001)
NCEP ATP III LDL-C goals
rosuva10 76%
atorva10 55% (vs. rosuva p < 0.0001)
simva20 50% (vs. rosuva p < 0.0001)
rosuva10 vs. atorva10 vs. simva20 patients who reported adverse events 47.7% vs. 46.5% vs. 46.4%.
Discontinued treatment as a result of an AE 4.8% vs. 3.7% vs. 4.1%
Lower respiratory tract infection 23 (3.1) vs. 24 (3.2) vs. 17 (4.7)
Headache 20 (2.7) vs. 12 (1.6) vs. 13 (3.6)
Constipation 23 (3.1) vs. 13 (1.7) vs. 5 (1.4)
Upper respiratory tract infection 11 (1.5) vs. 18 (2.4) vs. 11 (3.0)
Arthralgia 20 (2.7) vs. 11 (1.5) vs. 8 (2.2)
Cough 16 (2.1) vs. 12 (1.6) vs. 10 (2.7)
Pain in limb 21 (2.8) vs. 10 (1.3) vs. 5 (1.4)
Myalgia 12 (1.6) vs. 13 (1.7) vs. 8 (2.2)
Diarrhea 14 (1.9) vs. 13 (1.7) vs. 5 (1.4)
Nausea 13 (1.7) vs. 9 (1.2) vs. 7 (1.9)
AstraZeneca.
Faergeman O, et al 2008 (ECLIPSE)

RCT (1;1), OL, MC, AC.

1,036 patients were randomized (n (itt) = rosuva 522 (505), aorta 514(510).) 24 weeks
≥ 18 years with hypercholesterolemia and a history of CHD, LDL-C ≥160 to < 400 mg/dL, clinical evidence of atherosclerosis or a 10-year CHD risk score > 20%

Mean baseline LDL-c
rosuva 189.2 (21.0)
aorta 188.3 (20.4)
History of statin-induced myopathy or a serious hypersensitivity reaction to statins, clinical instability after a cardiovascular event, homozygous familial hypercholesterolemia, uncontrolled hypothyroidism, severe hepatic impairment, and women who were pregnant or breastfeeding or of childbearing potential but not using contraception, unexplained CK ≥3x ULN and SCr >2.0 mg/dL.6-week dietary lead-in period, randomized to daily treatment with rosuvastatin 10 mg or atorvastatin
10 mg for 6 weeks. Doses were increased incrementally (10–20– 40 mg rosuvastatin and 10–20–40–80 mg atorvastatin) every 6 weeks until the maximum doses were achieved (rosuvastatin 40 mg or atorvastatin 80 mg.
NCEP ATP III LDL-C goal of < 100 mg/dl at 24 weeks rosuva 83.6% vs. aorta 74.6% p < 0.001

LDL-c change at 24 weeks
rosuva –57.3 vs. aorta −52.2 p < 0.001
HDL-c change at 24 weeks
rosuva 8.4 vs. atorva1.8 p < 0.001
Rosuva vs. aorta n(%)
Any AE 282 (53.7) vs. 270 (52.5)
Mild AE 153 (29.1) vs. 169 (32.9)
Moderate AE 120 (22.9) vs. 94 (18.3)
Treatment-related AE 66 (12.6) vs. 74 (14.4)
Any SAE 33 (6.3) vs. 30 (5.8)
Treatment-related SAE 0 (0) vs. 2 (0.4)
AE leading to death 4 (0.8) vs.1 (0.2)
Treatment-related AE leading to death 0 (0) vs. 0 (0)
AE leading to premature discontinuation 39 (7.4) vs. 35 (6.8)
Treatment-related AE leading to discontinuation 25 (4.8) vs. 31 (6.0)
AstraZeneca.
Ferdinand et al, 2006

R, Open, MC

774 patients randomized (rosuva 391, atorva 383) 6 week treatment period
African-American men and women aged 18 or older who were diagnosed with type IIa or IIb hypercholesterolemia.

After dietary lead-in, patients were eligible for randomization if they had fasting LDL-C >=160 mg/dl and <=300 mg/dl and triglycerides <400 mg/dl.

Mean baseline LDL-c: mean(SD) mg/dL
Rosuva 10 mg: 191.8 (27.2), 20 mg: 189.6 (23.4)
Atorva 10 mg: 189.1(29.0), 20 mg 191.9 (26.6)
History of homozygous familial hypercholesterolemia or known type I, III, or V hyperlipoproteinemia; active arterial disease (e.g., unstable angina, MI, TIA, CVA, CABG or angioplasty within 3 months of trial entry); uncontrolled hypertension; poorly controlled diabetes; active liver disease or dysfunction; unexplained serum creatine kinase levels >3 times ULN, and serum creatinine 2.0 mg/dL.After a 6 week dietary lead-in, treatment for 6weeks:
rosuva 10 or 20 mg or aorta 10 or 20 mg
% LDL-c reduction from baseline at 6 weeks:
rosuva 10: −37.1% (p<0.017 vs aorta 10)
rosuva 20: −45.7% (p<0.017 vs aorta 20)
aorta 10: −31.8%
aorta 20: −38.5%

% HDL-c increase from baseline at 6 weeks:
rosuva 10: +7.0% (p<0.017 vs aorta 20)
rosuva 20: +6.5%
aorta 10: +5.6%
aorta 20: +3.7%

% trig reduction from baseline at 6 weeks:
rosuva 10: −16.0%
rosuva 20: −20.9%
aorta 10: −17.1%
aorta 20: −19.6%

% of patients meeting ATP III goal at 6 weeks:
rosuva 10: −66.1%
rosuva 20: −78.8%
aorta 10: −58.1%
aorta 20: −61.8% (no statistical comparisons)
Any adverse event:
rosuva 10/20: 34.4%
aorta 10/20: 33.6%

Myalgia: rosuva 10: 2.6% rosuva 20: 3.6%
aorta 10: 2.6%
aorta 20: 1.0%

Withdrawals due to AEs:
rosuva 10/20: n=13 (3.3%) aorta 10/20: n=5 (1.3%)

No deaths, myopathy, or rhabdomyolysis
Supported by AstraZeneca
Fonseca et al, 2005

R, Open, MC

1124 patients randomized (rosuva 561, atorva 563) 12 week treatment period
Patients age 18 and older with primary hypercholesterolemia, with fasting LDL-C =>5 mg/dL above their NCEP ATP III goal by risk category.

Mean baseline LDL-c: Statin-naïve: rosuva 171 mg/dL, atorva 174 mg/dL
Switched: rosuva 165 mg/dL, atorva 161 mg/dL
Familial hypercholesterolemia, fasting TG levels >400 mg/dL, aspartate aminotransferase or alanine aminotransferase >1.5 times ULN, unstable angina, serum creatine kinase >3 times ULN, serum creatinine >2.5 mg/dL, uncontrolled hypertension, uncontrolled diabetes, history of hypersensitivity to other statins, history of alcohol or drug abuse and the use of other hypolipidemic drugs or disallowed medication, such as those with known interactions with statins (e.g., cyclosporine); women of childbearing potential and not using a reliable form of contraception, or who were pregnant or lactating.Statin-naïve patients completed a 6-week dietary counseling period before entering the study, while switched patients entered the study directly with no dietary run-in. Treatment for 12 weeks: rosuva 10 mg (n=561) or aorta 10 mg (n=563)% LDL-c reduction from baseline at 12 weeks (statin-naïve patients):
rosuva 10 (n=358): −40.9%
aorta 10 (n=383): −34.8% (p<0.001)

% LDL-c reduction from baseline at 12 weeks (switched patients):
rosuva 10 (n=173): −35.3%
aorta 10 (n=161): −27.5% (p<0.01)

% HDL-c increase from baseline at 12 weeks (statin-naïve patients):
rosuva 10 (n=358): 3.9%
aorta 10 (n=383): 0.9% (p<0.05)

% HDL-c increase from baseline at 12 weeks (switched patients):
rosuva 10 (n=173): 2.5%
aorta 10 (n=161): 0.0% (NS)

% of patients achieving NCEP ATP III goal at 12 weeks:
rosuva 10 (n not reported): 71.2%
aorta 10 (n not reported): 61.4% (p<0.001)
Treatment-emergent adverse events:
rosuva 10: 25.7%
aorta 10: 21.2%

Serious adverse events: rosuva 10: 1.2% aorta 10: 2.0%

Discontinuations due to adverse events:
rosuva 10: 4.8%
aorta 10: 1.8%

No cases of rhabdomyolysis, myopathy or renal insufficiency were observed.
Supported by AstraZeneca
Herregods M, et al 2008 (Discovery-Belux)

RCT (1;1), OL, MC, AC.

938 patients were randomized (n = rosuva 478, aorta 460)
24 weeks but primary outcome at 12 weeks
Patients (> or = 18 years) with primary hypercholesterolemia, with a low- density lipoprotein (LDL-C) level > 120 mg/dl (on treatment) or > 135 mg/dl (naive subjects), and with a statin

Baseline LDL-c
Naïve rosuva 166.5
Switched rosuva 159.9
Naïve aorta 169.4
Switched aorta 149.9
History of major adverse event with another HMG-CoA reductase inhibitor, active liver disease, unsuitable cardiovascular disease, severe renal or hepatic impairment, treatment with cyclosporin or any disallowed drug.4 weeks of diet then randomized to rosuva 10 mg/day or aorta 10 mg/day for 12 weeks. Patients not at European LDL-C goal after 12 weeks and receiving ATV 10 were further switched to rosuva 10 mg for another 12 weeks. Patients not at goal with rosuva 10 mg were further titrated to rosuva 20 mg.LDL-c change from baseline at week 12: Naïve rosuva −47.4% (vs. naive aorta p < 0.001)
Switched rosuva --32.0% (vs. switched aorta p = 0.08)
Naïve aorta −38.1%
Switched aorta −26.3%
HDL-c change from baseline at week 12:
Naïve rosuva 4.8%
Switched rosuva 0.1%
Naïve aorta 4.1%
Switched aorta −0.2%
Patients that achieved 2003 European goal (LDL-c<100 mg/dl)
rosuva 72%
aorta 46%
rosuva vs. aorta
myalgia 2.7% vs. 2.8%
diarrhea 1.3% vs. 1.1%
fatigue 1.3% vs.. 1.4%
Nausea 1.3% vs. 0.4%
muscle cramp 0.4% vs. 1.1%
angina pectoris 0.8% vs. 0.4%
upper abdominal pain 0.6% vs. 0.4%
dizziness 0.8% vs. 0.2%
NR but 2 of authors work for AstraZeneca
Jones et al, 2003 (STELLAR)
R, OL, MC
2431 patients randomized (n=643 rosuva, 641 aorta, 655 simva, 492 parva)
6 weeks
Men and nonpregnant women age 18 or older with LDL-c >=160 and <250 mg/dL. Triglyceride levels <400 mg/dL.

Mean baseline LDL-c (mg/dL)
rosuva: 10mg 188; 20mg 187; 40mg 194 aorta: 10mg 189; 20mg 190; 40mg 189; 80mg 190 simva: 10mg 189; 20mg 189; 40mg 187; 80mg 190 parva: 10mg 189; 20mg 187; 40mg 190
History of sensitivity to statins; serious or unstable medical or psychological conditions; a history of heterozygous or homozygous familial hypercholesterolemia or familial dysbetalipoproteinemia; use of concomitant medications known to affect the lipid profile; a history of drug or alcohol abuse; unexplained increases in creatine kinase to > 3 times the upper limit of normal during the dietary lead-in period; alanine aminotransferase (ALT), aspartate aminotransferase (AST), or bilirubin values ≥ 1.5 times the upper limit of normal during the dietary lead-in period; and participation in another investigational drug trial within 4 weeks of trial enrollment.Rosuvastatin 10, 20, 40, or 80 mg; atorvastatin 10, 20, 40, or 80 mg; simvastatin 10, 20, 40, or 80 mg; pravastatin 10, 20, or 40 mg all once daily for 6 weeks.LDL-c reduction from baseline at week 6: rosuva: 10mg 45.8%; 20mg 52.4%; 40mg 55%
aorta: 10mg 36.8%; 20mg 42.6^; 40mg 47.8%; 80mg 51.1%
simva: 10mg 28.3%; 20mg 35.0%; 40mg 38.8%; 80mg 45.8%
parva: 10mg 20.1%; 20mg 24.4%; 40mg 29.7%
equivalent doses: rosuva 10mg > aorta 20mg (p=0.026) and simva 40mg (p<0.001)
rosuva 20mg > aorta 40mg (p<0.002) and simva 80mg (p<0.001)
rosuva 40mg >aorta 80mg (p=0.006)
HDL-c increase from baseline at week 6: rosuva: 10mg 7.7%; 20mg 9.5%; 40mg 9.6%
aorta: 10mg 5.7%; 20mg 4.8%; 40mg 4.4% 80mg 2.1%
simva: 10mg 5.3%; 20mg 6.0%; 40mg 5.2%; 80mg 6.8%
parva: 10mg 3.2%; 20mg 4.4%; 40mg 5.6%
equivalent doses: rosuva 10 mg = aorta 20 mg
rosuva 10mg = simva 40 mg
rosuva 20 mg > aorta 40mg (p<0.002)
rosuva 20 mg = simva 80 mg
Trigs reduction from baseline at week 6:
rosuva: 10mg 19.8%; 20mg 23.7%; 40mg 26.1%
aorta: 10mg 20.0%; 20mg 22.6%; 40mg 26.8%; 80mg 28.2%
simva: 10mg 11.9%; 20mg 17.6%; 40mg 14.8%; 80mg 18.2%
parva: 10mg 8.2%; 20mg 7.7%; 40mg 13.2%
Withdrawals due to adverse events: 23/643 rosuva (3.6%), 25/641 aorta (3.9%), 19/655 simva (2.9%), 11/492 parva (2.2%); 46% of all patients reported adverse events, 29 patients had serious adverse events. 2 rosuva 80mg patients developed acute renal failure of uncertain etiology.
Most common adverse events pain, pharyngitis, myalgia, headache.

Dose equivalence (LDL-c lowering)
rosuva 10mg > aorta 20mg and simva 40mg
rosuva 20mg > aorta 40mg and simva 80mg
rosuva 40mg >aorta 80mg
Supported by AstraZeneca
Jukema et al, 2005

R, open-label, multicenter

461 patients randomized 18 week treatment period
Men and women aged 40 to 80 years with established cardiovascular disease, fasting HDL-c <40 mg/dL at visit 1 and baseline, and triglycerides <=400 mg/dL at visit 1.

Mean baseline LDL-c: rosuva 139 mg/dL, atorva 143 mg/dL
Use of lipid-lowering drugs (including nicotinic acid), dietary supplements or food additives after enrollment, history of hypersensitivity to statins; pregnancy, lactations or childbearing potential without reliable contraceptive use; active arterial disease (unstable angina, MI, TIA, CVA, CABG or angioplasty) within 2 months of entry into the dietary lead-in phase; likely requirement for therapeutic coronary artery intervention within 6 months of randomization; uncontrolled hypertension; glycated hemoglobin >8% at enrollment, history of malignancy; uncontrolled hypothyroidism; homozygous familial hypercholesterolemia or type III hyperlipoproteinemia; history of alcohol and/or drug abuse; active liver disease; serum creatinine >180 μmol/L at enrollment; unexplained creatine kinase >3 times ULN at enrollment; received an investigational drug within 4 weeks before enrollment; serious or unstable medical or psychological conditions that could, in the opinion of the investigator, compromise the subject’s safety or successful participation in the trial.After a 6 week dietary lead-in, treatment for the first 6 weeks:
rosuva 10 mg (n=230) or aorta 20 mg (n=231)

At week 6, dosages increased for 6 weeks:
rosuva 20 mg or aorta 40 mg

At week 12, dosages increased for 6 weeks:
rosuva 40 mg or aorta 80 mg
% LDL-c reduction from baseline at 6, 12, and 18 weeks (p vs aorta): rosuva 10/20/40:44.0% (p<0.05)/50.4% (p<0.01)/55.3% (p<0.0001)
aorta 20/40/80:38.4%/45.1%/48.1%

% HDL-c increase from baseline at 6, 12, and 18 weeks: rosuva 10/20/40: 3.9%/5.5%/4.7%
aorta 20/40/80: 4.1%/3.1%/2.7%
All NS

% trig reduction from baseline at 6, 12, and 18 weeks (p vs aorta): rosuva 10/20/40:29.2% (p<0.05)/32.2%/35.4%
aorta 20/40/80:23.9%/27.3%/31.6%
Occurrence of deaths, serious adverse events and withdrawals due to adverse events was low, with no differences noted between treatment groups (data not reported).
1 death in rosuva group (sudden death), 1 in aorta (liver metastasis), neither considered related to study treatment.
2 treatment related serious adverse events in aorta group (both high creatine kinase activities)
Myalgia rosuva 7%, atorva 8%
Supported by AstraZeneca
Kurabayashi, 2008
Open label, multicenter
Patients with hypercholesterolemia who had received atorvastatin (10 mg) once daily for at least 4 weeks. Aged 20 years or more and classified as being at high risk (JAS2002GL category references.r3, references.r4, or C).

Mean baseline LDL-C: mean (SD) mg/dl
rosuva 102.9(25.1)
atorva 109.3(30.6)
Severe hypertension, type I diabetes, familial hypercholesterolemia, occurrence of cerebrovascular disease or myocardial infarction within the last 3 months, active hepatic disease, renal dysfunction, serum creatine kinase >1000 IU/L, hypothyroidism, pregnant women, women hoping to become pregnant.Atorvastatin 10 mg (continued treatment) vs rosuvastatin 5 mg (switched treatment) for 8 weeksPercent change (SD) from baseline, atorvastatin vs rosuvastatin: LDL-C: −1.2% (14.7) vs −6.0% (17.0); p<0.01
HDL-C: −1.7% (11.7) vs 0.1 (12.2); NS
Triglycerides: 5.2% (43.5) vs 12.9% (48.2); NS
atorvastatin vs rosuvastatin: Overall withdrawals: 3.3% vs 7.0%
Withdrawals due to AE: 0 vs 3.8%
Incidence of adverse events: 15.0% vs 15.8%
Increased creatine kinase: 3.4% vs 2.4%
1 serious AE (rosuvastatin, tibial fracture, not related to study drug)
Japan Heart Foundation
Lloret R, et al 2006 (STARSHIP trial)

RCT (1:1:1:1), OL, MC, AC.

696 (663 itt) patients were randomized (n = rosuva10 184, rosuva20 173, atorva10 168, atorva20 171)
6 weeks
Hispanic patients with low-density lipoprotein (LDL) cholesterol levels ≥ 130 and ≤300 mg/dl and triglyceride levels <400 mg/dl at medium or high risk of coronary heart disease

Mean baseline LDL-c
rosuva 10mg: 165mg/dL
rosuva 20mg: 160 mg/dL
atorva 10mg: 165mg/dL
atorva 20 mg:165mg/dL
history of homozygous familial hypercholesterolemia or known type I, III, or V hyperlipoproteinemia; active arterial disease (e.g., unstable angina, myocardial infarction, transient ischemic attack, cerebrovascular accident, coronary artery bypass grafting, or angioplasty within 3 months of entry); uncontrolled hypertension; poorly controlled diabetes; active liver disease or dysfunction indicated by hepatic transaminases or bilirubin levels ≥ 2 times the upper limit of normal; unexplained serum creatine kinase level > 3 times the upper limit of normal; and serum creatinine level > 2.0 mg/dl6-week dietary lead-in phase, during which all lipid-lowering treatments were discontinued, eligible patients were randomized to receive 10 or 20 mg of rosuvastatin or 10 or 20 mg of atorvastatin for 6 weeksLDL-c change at 6 weeks
rosuva10 −45% vs. atorva10 −36% (p < 0.0001)
rosuva20 −50% vs. atorva20 −42% (p < 0.0001)
HDL-c change at 6 weeks
rosuva10 5.5% vs. atorva10 3.5% (p=ns)
rosuva20 5.7% vs. atorva20 4.3% (p=ns)
achieving NCEP ATP III LDL cholesterol goals
rosuva10 78% vs. atorva10 60% (p=nr)
rosuva20 88% vs. atorva20 73% (p=nr)
rosuva10 vs. rosuva20 vs. atorva10 vs. atorva20 n (%)
Any adverse event
54 (30%) vs. 51 (30%) vs. 53 (32%) vs. 53 (31%)
Leading to death 0 (0%) vs. 0 (0%) vs. 0 (0%) vs. 0 (0%)
Leading to study discontinuation
4 (2.2%) vs. 7 (4.1%) vs. 3 (1.8%) vs. 2 (1.2%)
Serious adverse events
2 (1.1%) vs. 1 (0.6%) vs. 4 (2.4%) vs. 2 (1.2%)
AstraZeneca
Mazza F, et al, 2008
RCT, open-label, single center

106 patients randomized (n=52 rosuva, 54 aorta) 48 week treatment period
Male and female patients aged 18–65 years
with primary hypercholesterolemia (LDL-C level >200 mg/dL) and at high risk for CHD

Baselines LDL-c
rosuva 217.74 ± 60.5 aorta 232.57 ± 65.17 NS
Baseline HDL-c
rosuva 56.55 ± 13.94 aorta 54 ± 15.40 NS
Myocardial infarction, unstable angina, stroke, transient ischemic attack, or uncontrolled hypertension within 3 months of enrollment; diabetes mellitus and or/other endocrine disorders; active liver disease or persistent elevations in liver function tests; significant abnormalities in creatine phosphokinase (CK); renal disease and acute or. chronic renal failure; hypersensitivity to statins; concomitant use of corticosteroids,; use of immunosuppressants, macrolide antibacterials, azole antifungal agents and/or other lipid-lowering agents; diuretic or β-adrenoceptor blocker treatment for hypertension within 1 month of enrollment; drug or alcohol abuse; GI disorders; pregnancy and breast-feeding; ophthalmic abnormalities; night-shift work.randomized to rosuvastatin 10 mg or atorvastatin 20 mg plus diet (American Heart Association Step II diet)LDL-c change from baseline at 48 weeks: rosuva –44.32% vs.. aorta –30% (p < 0.005)

HDL-c change from baseline at 48 weeks: rosuva 4.52% vs.. aorta −2.04 (p=ns)
% mean change in lab values from baseline at 48 weeks: ALT (U/L ± SD) rosuva 24.64 (<0.005)
aorta 4.33 (NS )
No other adverse events were reported as occurring.
No sources of funding were used to assist in the preparation of this study
Milionis H, et al 2006 (ATOROS study)
RCT, open-label, single center

120 patients randomized (n=60 rosuva, 60 aorta) 24 week treatment period
Men and women with dyslipidemia, totla cholesterol>240mg/dL at week 4 and 2 and triglycerides <350mg/dL

Baseline LDL-c
rosuva 205 (42)
aorta 204 (40)
Baseline HDL-c
rosuva 48 (6)
aorta 48 (8)
Abnormal liver function tests; Impaired renal function;) Diabetes mellitus; Raised thyroid stimulating hormone (TSH) levels; any medical conditions that might preclude successful completion of the study.6-week dietary lead-in period, randomized to rosuvastatin 10 mg/day or atorvastatin 20 mg/day. After 6 weeks on treatment the dose of the statin was increased for 18 weeks if the treatment goal was not achieved. Mean doses rosuva 12.5 mg and aorta 27.5 mg.LDL-c change from baseline at 6 weeks: rosuva −43.9%
aorta: −41.6%
HDL-c change from baseline at 6 weeks: rosuva: 3.3%
aorta: −1.6%
Percentage of patients achieving LDL-c goal at 6weeks: rosuva 5 mg: 75%
aorta 10 mg: 71.7%
LDL-c at 24 weeks:
rosuva 105 (21) vs. aorta 113(49)
rosuva vs. aorta
Myalgia 5% vs. 5%
Nausea 0 vs. 2%
no company or institution supported it financially
Olsson et al, 2002 R, DB, MC

412 patients randomized (n=138 rosuva 5mg, 134 rosuva 10mg, 140 aorta 10mg)
52 weeks
Men and women age 18 and older with LDL-c level between 160 and <250 mg/dL and an EPAT score 28 or less.

Mean baseline LDL-c rosuva 5mg: 188.0 mg/dL rosuva 10mg:185.9 mg/dL aorta 10mg: 188.1mg/dL
Conventional exclusion criteria for lipid-modifying drugs under development were applied5 or 10 mg rosuva or 10 mg aorta for 12 weeks, then titrated up to 80 mg if NCEP ATP-II LDL-c goal not met, for a total of 52 weeks.LDL-c reduction from baseline at 12 weeks:
rosuva 5 mg: 46% (p<0.001 vs aorta)
rosuva 10 mg: 50% (p<0.001 vs aorta)
aorta 10 mg: 39%

Percentage of patients achieving NCEP ATP-II LDL-c goal at 12 weeks:
rosuva 5 mg: 86%
rosuva 10 mg: 89%
aorta 10 mg: 73%
(NS)

Percentage of patients achieving NCEP ATP-II LDL-c goal at 52 weeks:
rosuva 5 mg: 88%
rosuva 10 mg: 98%
aorta 10 mg: 87%
(NS)

HDL-c increase from baseline at 12 weeks:
rosuva 5 mg: 6% (NS vs aorta)
rosuva 10 mg: 8% (NS vs aorta)
aorta 10 mg: 6%

Trigs reduction from baseline at 12 weeks:
rosuva 5 mg: 15% (NS vs aorta)
rosuva 10 mg: 19% (NS vs aorta)
aorta 10 mg: 16%
Adverse events considered to be treatment related occurred in 29% of rosuva 5mg, 27% rosuva 10mg, and 35% aorta 10mg patients. Most frequently reported were myalgia and GI complaints.
Serious adverse events leading to withdrawal: rectal hemorrhage (rosuva 10mg(, serum creatinine elevation (rosuva 10mg), ALT/AST elevations (aorta 10mg). Total 28 withdrawals due to adverse events. Of these 5 rosuva 5mg, 5 rosuva 10mg, and 8 aorta 10mg had adverse events considered treatment- related.

Equivalent doses not compared
Supported by a grant from AstraZeneca
Paoletti et al., 2001
R, DB, MC, ITT

502 patients randomized
12 weeks
Men and women age≥18 years with hypercholesterolemia, fasting LDL- c ≥160 and <250 mg/dl, fasting trig ≤400 mg/dl

Mean baseline LDL-c
189 mg/dl
Active arterial disease within 3 months of trial entry; familial hypercholesterolemia; uncontrolled hypertension; active liver disease or hepatic dysfunction indicated by AST, ALT, or bilirubin of ≥ 1.5 times the upper limit of normal; CK> 3 times the upper limit of normal; serum creatinine > 220 mol/l ; fasting serum glucose >9.99 mmol/L or glycated hemoglobin >9%; history of alcohol or drug abuse; and use of cyclic hormonal therapy.Screening phase, then randomization to: rosuva 5 or 10 mg parva 20 mg or simva 20 mg or for 12 weeksEfficacy analysis for 495 patients.
LDL-c reduction from baseline at 12 weeks:
rosuva 5 mg: 42% (p<0.001 vs parva, p<0.005 vs simva)
rosuva 10mg: 49% (p<0.001 vs parva, p<0.001 vs simva)
parva: 28%
simva: 37%

HDL-c increase from baseline at 12 weeks:
rosuva 5 mg: 6%
rosuva 10mg: 7%
parva: 4%
simva: 4%
(NS)
Trigs reduction from baseline at 12 weeks:
rosuva 5 mg: 12%
rosuva 10mg: 18%
parva: 13%
simva: 14%
(NS)
Achieved NCEP ATP II LDL-c goal:
rosuva 5 mg: 71% rosuva 10mg: 87% parva: 53% simva: 64% (NS)
Serious AEs in 4 (3.5%) rosuva 10 mg patients (life-threatening cerebral hemorrhage, life threatening myocardial infarction, syncope, and cholecystitis plus cholelithiasis). No serious AEs considered by the investigator to be related to study treatment. Withdrawal due to AEs: rosuva 5 mg: 2 (1.6%) chest pain and infection, migraine rosuva 10 mg: 6 (5.2%) cerebral hemorrhage, diarrhea, CK increase and myalgia, headache and edema, urticaria) parva: 3 (2.2%) vasodilation and abdominal pain, dyspepsia, conjunctivitis) simva: 1 (0.8%) abdominal pain.

ADEs: parva 19/136 (14%) vs simva 23/129 (18%). Most common ADEs: constipation (3 vs. 2), diarrhea ((1 vs. 1),, dyspepsia (2 vs. 3), pruritus (1 vs. 4), abdominal pain (2 vs. 4).

ALT elevation in 2 simva, 3 rosuva 5 mg, and 1 rosuva 1 mg patients. No clinically significant ALT or CK elevations.

Equivalent doses not compared
Sponsored by and one author employed by AstraZeneca
Qu, 2009
Single center, double- blind
Outpatients with primary hypercholesterolemia.

Mean baseline LDL-C: 150.4 (SD 25.7) mg/dl
N=69
Liver disease or transaminase levels >1.5 times ULN, creatine kinase >1.5 times ULN, atrioventricular block and sinus bradycardia, acute or chronic renal failure, electrolyte disturbances, acute cerebrovascular disease or myocardial infarction within the preceding 3 months, or evidence of alcohol abuse.Atorvastatin 10 mg vs rosuvastatin 10 mg for 12 weeksPercent change from baseline, atorvastatin vs rosuvastatin:
LDL-C: −36.1% vs −47.5%; p<0.05
HDL-C: 6.6% vs 9.1%; NS
Triglycerides: 18.6% vs 20.5%; NS
No withdrawals reported. “No side effects related to the two agents were observed.”National Basic
Research Program and HI-TECH Technique and Development Program of China
Rawlings, 2009
Multicenter (2 cardiology clinics), double-blind
Men with stale atherosclerosis and fasting LDL-C levels >=100 mg/dL off statin therapy. Presence of atherosclerosis determined by >=50% stenosis in at least one coronary artery at cardiac catheterization, history of previous myocardial infarction, previous angioplasty, previous coronary artery bypass graft, previous ischemic stroke, or documented peripheral arterial disease.

Mean baseline LDL-C: 141 (SD 6)
mg/dl
N=30
Unstable angina or revascularization within 3 months of study enrollment, malignancy, chronic inflammatory disease, acute infection, history of myositis/myopathy, liver transaminases >2 times ULN, creatine phosphokinase greater than the ULN, and reluctance to discontinue statin therapy.Atorvastatin 40 mg vs rosuvastatin 10 mg for 4 weeksPercent change from baseline, atorvastatin vs rosuvastatin:
LDL-C: −45.2% vs −42.5%; p=0.28
HDL-C: 3.1% vs 1.6%; p=0.85
Triglycerides: −6.0% vs −40.2%; p=0.06
Not reportedNIH and Foundations
Schneck et al, 2003
R, DB, MC

374 patients randomized (n=165 aorta, 209 rosuva)
6 weeks
Men and women age 18 and older with hypercholesterolemia and without active arterial disease within 3 months of study entry or uncontrolled hypertension; LDL-c > 160 mg/dL but <250 mg/dL, triglycerides <400 mg/dL, and Eating Pattern Assessment Tool (to assess adherence to NCEP Step I diet) score of 28 or less.

Mean baseline LDL-c aorta: 10mg 38.2%; 20mg:43.3%; 40mg 48.4%; 80 mg 53.5% rosuva: 5mg 41.5%; 10mg 46.6%; 20mg 51.7%; 40mg 56.8%; 80mg 61.9%
Pregnant or lactating women or women of childbearing potential not using a reliable form of contraception, as well as patients with a history of heterozygous or homozygous familial hypercholesterolemia
or known type III hyperlipoproteinemia
Atorva 10, 20, 40, or 80 mg qd or rosuvastatin 5, 10, 20, 40, or 80 mg qd for 6 weeks.Reduction in LDL-c from baseline at 6 weeks:
aorta: 10mg 38.2%; 20mg:43.3%; 40mg 48.4%; 80 mg 53.5%
rosuva: 5mg 41.5%; 10mg 46.6%; 20mg 51.7%; 40mg 56.8%; 80mg 61.9%
(p<0.001 difference vs aorta across dose range)

Increase in HDL-c from baseline at 6 weeks:
aorta: 10mg 5.0%; 20mg 7.6%; 40mg 4.1%; 80mg 2.1%
rosuva: 5mg 7.4%; 10mg 6.0%; 20mg 9.1%; 40mg: 12.3%; 80mg 9.6%
(NS)

Reduction in trigs from baseline at 6 weeks:
aorta: 10mg: 17.5%; 20mg 25.6%; 40mg 27.2%; 80mg 34.5%
rosuva: 5mg 23.1%; 10mg 22.1%; 20mg 18.4%; 40mg 25.7%; 80mg 19.7%
(NS)
Any adverse event: 51.2% rosuva vs 47.9% aorta (NS); no consistent relation in occurrence of individual treatment-emergent adverse events to doses of either drug. Withdrawals due to adverse events infrequent (1 patient each in rosuva 10 mg, 20 mg, 80 mg groups, aorta 10 mg 40 mg, and 80 mg groups).
Most common adverse events pharyngitis, headache, and pain.

Dose equivalence (LDL-c lowering)
rosuva 5mg > aorta 20mg
rosuva 10mg > aorta 20mg
rosuva 20mg > aorta 40mg
rosuva 40mg > aorta 80mg
Supported by AstraZeneca Pharmaceuticals
Schuster et al. 2004
R,OL,MC,ITT

5-arm trial that included statin switching (to rosuvastatin) at 8 weeks

3140 patients randomized
16 weeks of treatment
Patients aged >=18 years, with CHD or other atherosclerotic disease, type 2 diabetes, a CHD risk >20% over 10 years, with LDL-c levels>=115 mg/dL and trig <400 mg/dL; LDL-c measurements had to be within 15% of each other during the lead-in period.

Baseline LDL-c levels:
Rosuv 10 mg: 164.9 mg/dL
Atorva 10 mg: 162.2 mg/dL
Atorva 20 mg: 167.5 mg/dL
Simva 20 mg: 165.5 mg/dL
Prava 40 mg: 163.8 mg/dL
Pregnant and lactating women, women not using reliable contraception, patients with a history of homozygous familial hypercholesterolemia or known type III hyperlipoproteinemia, with active arterial disease (e.g., unstable angina, myocardial infarction, transient ischemic attack, cerebrovascular accident, or coronary revascularization procedure within 2 months of screening), uncontrolled hypertension, active liver disease or hepatic dysfunction (hepatic transaminases or bilirubin levels >=1.5 times upper limit of normal [ULN]), unexplained serum creatine kinase elevation >3 times ULN, and serum creatinine >220 micromol/L.6 week dietary lead-in phase, then randomization to 5 arm trial system (drug a for 8 weeks then drug b or c for eight additional weeks):
rosuv 10 mg (n=538), to rosuv 10 mg (n=521);

aorta 10 mg (n=529), to rosuv 10 mg (n=276) or aorta 10 mg (n=240);
aorta 20 mg (n=925), to rosuv 10 mg (n=293), rosuv 20 mg (n=305), or aorta 20 mg (n=299);
simva 20 mg (n=543), to rosuv 10 mg (n=277) or simva 20 mg (n=250);

parva 40 mg (n=521), to rosuv 10 mg (n=253) or parva 40 mg (n=253).
% LDL-c reduction from baseline to 8 weeks:
Rosuv 10 mg (n=521): −47.0%
Atorva 10 mg (n=240): −37.2%
Atorva 20 mg (n=299): −43.7%
Simva 20 mg (n=250): −35.4%
Prava 40 mg (n=253): −31.0%
(p<0.0001 for all comparisons vs rosuva 10 mg)
% HDL-c increase from baseline to 8 weeks:
Rosuv 10 mg (n=521): +9.2%
Atorva 10 mg (n=240): +6.8% (p<0.01 vs rosuva 10 mg)
Atorva 20 mg (n=299): +5.7% (p<0.0001 vs rosuva 10 mg)
Simva 20 mg (n=250): +8.0% (NS vs rosuva 10 mg)
Prava 40 mg (n=253): +7.6% (NS vs rosuva 10 mg)
% trig reduction from baseline to 8 weeks:
Rosuv 10 mg (n=521): −18.9% (p<0.01 vs rosuva 10 mg)
Atorva 10 mg (n=240): −15.9% (NS vs rosuva 10 mg)
Atorva 20 mg (n=299): −18.3% (NS vs rosuva 10 mg)
Simva 20 mg (n=250): −13.5% (p<0.01 vs rosuva 10 mg)
Prava 40 mg (n=253): −10.5% (p<0.0001 vs rosuva 10 mg)
Proportion of patients achieving the ATP III LDL-c goals at week 8:
Rosuv 10mg (n=538): 80%
Atorva 10 mg (n=529): 63% (p<0.0001 vs rosuva 10 mg)
Atorva 20 mg (n=925): 74% (p<0.01 vs rosuva 10 mg)
Simva 20 mg (n=543): 54% (p<0.0001 vs rosuva 10 mg)
Prava 40 mg (n=521): 45% (p<0.0001 vs rosuva 10 mg)
“Occurrence of deaths, serious adverse events (SAE’s), and withdrawals due to adverse events (AE’s) were low, with no differences noted among the treatment groups.” 8 patients died during the trial, but those deaths occurred from “causes that would be expected in such a patient population (i.e., cardiovascular events=4, malignancy=2, pneumonia=1, and subdural hematoma=1”. No treatment-related AE’s leading to death nor any treatment- related SAE’s are reported. SAE’s or AE’s are not always categorized by drug type.

Myalgia - reported in 1.9% of patients in period 1 and 0.9% of patients in period 2.
No cases of myopathy were reported (creatine kinase >10 times ULN and muscle symptoms).
Atorva 20 mg and rosuv 10 mg each had 1 case of asymptomatic increase in creatine kinase >10 times ULN; both resolved during continued study treatment.
No patients had increases in hepatic transaminases >3 times ULN and >= consecutive measurements.
Sponsored by Astra Zeneca
Schwartz et al, 2004

R, DB, MC

382 patients randomized
24 week treatment period
Patients aged >18 years, with LDL- C levels >=160 and< 250 mg/dL, and trig levels <=400 mg/dL, and documented atherosclerosis, Type 2 diabetes, or both, assessed.

Patients with score of <=28 on Eating Pattern Assessment Tool, fasting LDL-C levels >160mg/dL and trig levels <400 mg/dL at 2 consecutive measurements were randomized.

Mean baseline LDL-c levels:
Rosuv 5/20/80: 188 mg/dL
Rosuv 10/40/80: 186 mg/dL
Atorv 10/40/80: 188 mg/dL
Pregnant women, patients currently taking concomitant drugs known to affect the lipid profile or to present a potential safety concern, a history of active arterial disease (e.g., unstable angina, myocardial infarction, transient ischemic attack, or cerebrovascular accident) or coronary revascularization procedure within 3 months of trial entry, heterozygous or homozygous familial hypercholesterolemia, uncontrolled hypertension, uncontrolled hyperthyroidism, history of malignancy, active liver disease or dysfunction indicated by AST or ALT of >= 1.5 times the upper limit of normal (ULN), serum creatine kinase >3 times ULN, serum creatinine >2.5mg/dL, or uncontrolled diabetes (fasting serum glucose >9.99 mmol/L or hemoglobin A1c>9% recorded during the lead-in period).After a 6 week dietary lead-in, treatment for the first 12 weeks:
rosuv 5 mg (n=127) once daily or
rosuv 10 mg (n=128) once daily or
atorv 10 mg (n=128) once daily

If LDL-c remained >50 mg/dl, then the doses were uptitrated at weeks 12 and 18 to:
rosuv 5 mg became 20 mg and then 80 mg (rosuv 5/20/80)
rosuv 10 mg became 40 mg and then 80 mg (rosuv 10/40/80)
atorv 10 mg became 40 mg and then 80 mg (atorv 10/40/80)
Efficacy analysis for 382 patients:
% LDL-C change from baseline
12 weeks :
Rosuva 5 mg: −39.81 (P=<0.1); Rosuva 10mg: −47.1 (P=<.001); Atorva 10 mg: .35.0;
18 weeks
Rosuva 5/20mg: −51.6 (P=<0.1); Rosuva 10/40mg: −58.8 (P=<0.001); Atovra 10/40: −47.2
24 weeks
Rosuva 5/20/80mg: −59.61 (P=<.001); Atorva 10/40/80 and 5/20/80:mg: − 52.0
% HDL-C increase from baseline
12 weeks
Rosuva 5: 6.6 (P=<.01); Rosuva 10mg: 7.7 (P=<.001); Atorva 10mg: 2.7
18 weeks
Rosuva 5/20: 8.3 (P=<.001); Rosuva 10/40mg:10 (<.001); Atorva 10/40: 1.4
24 weeks
Atorva 10/40/80: 0.9; Rosuva combined 5/20/80 & 10/40/80: 8 (P=<.001)
% Trig reduction from baseline
12 weeks
Rosuva 5mg: −17.4; Rosuva 10 mg: −19.8; Atorva 10 mg: −17.8
18 weeks
Rosuva 5/20mg: −20.7; Rosuva 10/40mg: −22.9; Atorva 10/40mg: −22.1
24 weeks
Rosuva combined 5/20/80 & 10/40/80: −24.61; Atorva 10/40/80: −27
“Although adverse events were frequently reported in these high-risk patients, they were generally mild and not attributed to trial medication.” Most common AEs pharyngitis, pain, myalgia

Any adverse event (AE):
rosuv 5/20/80: n=116 (91%)
rosuv 10/40/80: n=113 (88%)
atorv 10/40/80: n=101 (80%)

AEs considered treatment-related:
rosuv 5/20/80: n=36 (28%)
rosuv 10/40/80: n=38 (30%)
atorv 10/40/80: n=35 (28%)

Serious AEs:
rosuv 5/20/80: n=12 (9%)
rosuv 10/40/80: n=8 (6%)
atorv 10/40/80: n=7 (6%)

Withdrawals due to AEs:
rosuv 5/20/80: n=5 (4%)
rosuv 10/40/80: n=7 (6%)
atorv 10/40/80: n=6 (5%)
Sponsored by Astra Zeneca
Stalenhoef et al. 2005 R, DB, MC, PC, not ITT (COMETS)

401 patients randomized
12 weeks
Men and women >=18 years with the metabolic syndrome, defined by presence of at least 3 of the following: abdominal obesity, TG >=150 mg/dL, HDL-c <40mg/dL for men and <50mg/dL for women, blood pressure >=130/85 or receiving antihypertensive treatment, and fasting blood glucose >=110 mg/dL. Also required to have LDL-c >=130 mg/dL and additional multiple risk factors conferring a 10-year CHD risk score of >10%. Patients with diabetes excluded.Patients with diabetes [fasting glucose >6.94 mmol/L (125 mg/dL)] were excluded, use of lipid lowering agents within the past 6 months; TG ≥ 5.65 mmol/L (500 mg/dL); LDL-C ≥ 6.48 mmol/L (250 mg/dL); documented history of CHD or other atherosclerotic disease; a history of known familial hypercholesterolemia; a history of serious or hypersensitivity reactions to other statins; uncontrolled hypothyroidism; uncontrolled hypertension; acute liver disease or hepatic dysfunction [hepatic transaminases or bilirubin ≥1.5X the upper limit of normal (ULN)]; unexplained serum creatine kinase (CK) >3X ULN; and use of prohibited concomitant medications.After 4-week dietary lead-in rosuva 10 mg or aorta 10 mg or placebo for 6 weeks, then aorta rosuva 10 mg or aorta 20 mg for 6 weeks (placebo group also switched to rosuva 20 mg)Efficacy analysis for 397 patients:
LDL-c reduction from baseline to 6 weeks:
rosuva 10 mg: −42.7% (p<0.001 vs aorta)
aorta 10 mg: −36.6%
placebo: −0.3%
LDL-c reduction from baseline to 12 weeks:
rosuva 10 mg: −48.9% (p<0.001 vs aorta)
aorta 10 mg: −42.5%
HDL-c increase from baseline to 6 weeks:
rosuva 10 mg: 9.5% (p<0.01 vs aorta)
aorta 10 mg: 5.1%
placebo: 1.1%
HDL-c increase from baseline to 12 weeks:
rosuva 10 mg: 10.4% (p<0.01 vs aorta)
aorta 10 mg: 5.8%
Trig reduction from baseline to 6 weeks:
rosuva 10 mg: −19.1% (NS)
aorta 10 mg: −20.9%
placebo: −2.8%
Trig reduction from baseline to 12 weeks:
rosuva 10 mg: −22.9% (NS)
aorta 10 mg: −25.2%
Patients meeting NCEP ATP III goal at 6 weeks:
rosuva 10 mg: −83% (p<0.05 vs aorta)
aorta 10 mg: −72%
placebo: −10%
Patients meeting NCEP ATP III goal at 12 weeks:
rosuva 10 mg: −91% (p<0.001 vs aorta)
aorta 10 mg: −79%
Overall adverse events:
rosuva (weeks 1–6) 25.2%; (weeks 6–12) 22.2%
aorta: (weeks 1–6) 25.3%; (weeks 6–12) 20.7%

Serious adverse events:
rosuva: (weeks 1–6) 0%; (weeks 6–12) 0.6%
aorta: (weeks 1–6) 1.9%; (weeks 6–12) 0.7%

Withdrawals due to adverse events:
rosuva: (weeks 1–6) 1.2%; (weeks 6–12) 1.3%
aorta: (weeks 1–6) 1.9%; (weeks 6–12) 0.7%
Supported by AstraZeneca
Strandberg et al, 2004

R (2:1), OL, MC, 2-arm study, ITT

1024 patients randomized (n=686 to rosuv 10 mg/d, n=338 to atorv 10 mg/d)
12 weeks
Men and women >=18 years with LDL-c level >135 mg/dL for statin- naïve patients or >120 mg/dL in patients using the starting dose of another lipid-lowering drug. They had to be at high risk for CHD and have primary hypercholesterolemia.

Mean baseline LDL-c rosuva 10mg: 174 mg/dL aorta 10mg: 170 mg/dL
A history of serious adverse events or hypersensitivity to an hMG-CoA reductase inhibitor other than the study drugs; active hepatic disease; homozygous or heterozygous familial hypercholesterolemia (FH); unstable angina; elevated serum creatinine concentration (>220 micromol/L [2.5 mg/dL]) or treatment with a disallowed drug, such as those with known interactions with statins (i.e., cyclosporine).rosuv 10 mg/d atorv 10 mg PO OD

optional extension period for rosuv pts who did not have access to drug commercially, and for atorv pts who did not achieve the 1998 JTF goal for LDL-c after 12 weeks. Rosuv could be up-titrated at 12 wk intervals to 20 mg/d and then to 40 mg/d to achieve the 1998 JTF LDL-c goal (1998 target of <116 mg/dL; JTF 2003 target of <97 mg/dL).
Efficacy analysis for 911 patients (rosuv 10mg/d, n= 627; atorv 10mg/d, n= 284)

LDL-c levels at 12 weeks:
rosuv 10 mg: 89 mg/dL
atorv 10 mg: 104 mg/dL

% LDL-c reduction from baseline at 12 weeks:
rosuv 10 mg: −46.92 % change (p< 0.05 vs. atorv)
atorv 10 mg: −38.07 % change from baseline

% HDL-c increase 12 weeks after baseline:
rosuv 10 mg: 4.00 % increase (p<0.05 vs. atorv) atorv 10 mg: 1.88 increase

% decrease in trig levels at 12 weeks:
rosuv 10 mg: −14.55% (p<0.05 vs. atorv)
atorv 10 mg: −13.98%

% patients reaching JTF LDL-c targets after 12 weeks:
(1998 target of <116 mg/dL; 2003 target of <97 mg/dL)
rosuv: 83.4%; ~73% (p<0.001 vs. atorv)
atorv: 68.3%; ~51.1%
Patients experiencing any AE (estimated from graph):
Rosuv ~38% (n=261)
Atorv ~37% (n=125).
Rosuv: 1 patient had melena (later diagnosed as duodenal ulcer); 1 patient having a history of peptic ulcer disease and receiving concomitant treatment with a NSAID (diclofenac) had vomiting; 1 patient had myopathy accompanied by increased creatine levels Atorv: 1 patient had proteinuria found to be non-treatment related

AE's in rosuv vs. atorv:
n=AE incidence (%)/n=led to discontinuation (%)
muscle pain/myalgia: 18(2.6%)/13(1.9%) vs. 4(1.2%)/3(0.9%)
nausea: 12(1.7%)/7(1.0%) vs.5(1.5%)/3(0.9%)
increased ALT: 11(1.6%)/2(0.3%) vs. 1(0.3%)/0(0%)
increased AST: 8(1.2%)/0(0%) vs. 3(0.9%)/0(0%)
increased creatine kinase (CK): 6(0.9%)/0(0%) vs. 6(1.8%)/1(0.3%)
headache: 6(0.9%)/2(0.3%) vs. 4(1.2%)/3(0.9%)

Total withdrawals due to AEs (some patients experienced >1 adverse event):
Rosuv: n=24 (3.5%)
Atorv: n=10 (3.0%)
Supported by a grant from AstraZeneca
Wolffenbuttel et al. 2005
R, Open-label, MC

263 patients randomized (N=263)
18 week treatment period
Men and women with type 2 diabetes who had received treatment for diabetes for at least 3 months, older than 18 years, with fasting LDL-c concentrations of >=130 mg/dL in statin-naïve patients or >115 to <=193 in patients who had been taking a statin within the previous 4 weeks.
Normal to moderately elevated trig levels, and in acceptable metabolic control.

Mean baseline LDL-c:
rosuva: 163.3
aorta: 171.0
use of lipid-lowering drugs after visit 1, or a history of serious or hypersensitivity reactions to statins. presence of active cardiovascular disease (uncontrolled hypertension >200/>95 mmHg), heart failure NYHA class IV, recent unstable AP, myocardial infarction, transient Ischaemic attack, cerebrovascular accident, coronary artery bypass surgery or angioplasty within the previous 2 months, or likely to undergo coronary artery intervention within 6 months after randomization, pregnant or lactating women not using sufficient contraception, subjects with metabolic abnormalities, such as kidney insufficiency
(serum creatinine >220 lmol L)1), uncontrolled hypothyroidism [serum thyroid stimulating hormone (TSH) >1.5 upper limit of normal (ULN)],homozygous familial hypercholesterolemia or familial dysbetalipoproteinemia, active liver disease or liver enzyme (ALT,AST) elevations >1.5 ULN and unexplained CK elevations >3 ULN. Concomitant treatment with erythromycin, clarithromycin, azole antifungal agents, cyclosporin, antiviral agents, phenytoin, carbamazepine, phenobarbital, or nefazodone.
After a 6-week dietary lead-in, treatment for the first 6 weeks:
rosuva 10 mg or
aorta 20 mg

At week 6, dose increased for 6 weeks:
rosuva 20 mg or
aorta 40 mg

At week 12, dose increased for 6 weeks:
rosuva 40 mg or
aorta 80 mg
% LDL-c reduction from baseline at 6, 12, and 18 weeks (p vs aorta):
rosuva 10/20/40: 45.9% (p<0.05)/50.6% (p<0.05)/53.6% (p<0.01)
aorta 20/40/80: 41.3%/45.6%/47.8%

% HDL-c increase from baseline at 6, 12, and 18 weeks (p vs aorta):
rosuva 10/20/40: 0.7%/0.1%/−1.1%
aorta 20/40/80: −1.2%/−2.3%/−2.8%
All NS

% trig reduction from baseline at 6, 12, and 18 weeks:
rosuva 10/20/40: 18.8%/23.7%/22.7%
aorta 20/40/80: 16.3%/17.6%/23.7%
All NS

% of patients achieving LDL-c goals at 6, 12, and 18 weeks (p vs aorta):
Patients reaching LDL-c <100.5 (ADA guideline)
rosuva 10/20/40: 81.5%/83.8%/91.5% (p<0.05)
aorta 20/40/80:73.5%/78.8%/81.1%
Patients reaching LDL-c <96.8 (new EAS guideline)
rosuva 10/20/40: 77.7%/83.1%/90.0% (p<0.05)
aorta 20/40/80:70.5%/76.5%/78.0%
Overall adverse events:
rosuva: 47%
aorta: 50%

Serious adverse events:
rosuva: 5%
aorta: 2%

Withdrawals due to adverse events:
rosuva: 7%
aorta: 8%

Myalgia was the most frequently reported adverse event (5% rosuva, 11% aorta). No myopathy. One aorta patient developed abnormality in ALT (>3X ULN)
Supported by AstraZeneca
Rosuvastatin vs Simvastatin
Laks, 2008
Open-label, multicenter
Men and women aged 18 or older with primary hypercholesterolemia and a 10-year CV risk >20% or a history of CHD or other established atherosclerotic disease and fasting triglycrides <=4.52 mmol/L at visit 2 (week 0). All were statin-naïve (not received a statin in the past 6 months) or subjects on a start dose or other lipid lowering therapy, which was ineffective (i.e., had not reached their LDL-C goal at that dose).

Mean baseline LDL-C: 182.1 mg/dl N=504
Familial hypercholesterolemia, secondary dysliidemia of any cause, history of serious adverse effect or hypersensitivity to othe statins, pregnancy, breastfeeding, and women of childbearing potential not using contraception, malignancy, use of disallowed concomitant medications, history of alcohol or drug dependence, active liver disease or hepatic dysfunction, renal impairment, uncontrolled diabetes, unstable angina, uncontrolled hypertension, unexplained serum creatine kinase >3 times ULN, serious or unstable medical or psychological conditin that compromises safety or participation in the trial.Rosuvastatin 10 mg vs simvastatin 20 mg for 12 weeksLeast squares mean percent change (SE) from baseline, rosuvastatin vs simvastatin:
LDL-C: −38.79% (1.27) vs −32.03% (1.37); p<0.001
HDL-C: 0.66% (1.14) vs 2.26% (1.47); NS
Triglycerides: −14.47% (1.86) vs −14.43% (2.45); NS
rosuvastatin vs simvastatin:
Overall withdrawals: 9.0% vs 8.2%
Withdrawals due to AE: 7.2% vs 4.1%
Incidence of adverse events: 20.0% vs 21.8%
Serious AE: 1.2% vs 2.9%
Death: 0.3% vs 0% (acute MI, judged not related to study treatment)
Myalgia: 3.0% vs 0.6%
Increased creatine kinase: 3.4% vs 2.4%
1 serious AE (rosuvastatin, tibial fracture)
AstraZeneca
Switching statins
Kai T et al, 2008
Open-label, single-center
27 patients
6 month treatment period
Men and women aged 41–87 years with mild hypertension and dyslipidemia who had already been treated with simvastatin 10 mg/day for six months or more (mean 7.1 ± 1.9 months).Familial hypercholesterolemia, severe liver dysfunction (transaminase > 100 IU/l), severe renal failure (creatinine > 2.0 mg/dl), and a history of any contraindication to the use of statins.Switching from simvastatin 10mg/day to pravastatin 20mg/dayChange in mean levels (baseline vs 6 months of treatment)
Total cholesterol (mg/dl): 194 vs 193 (P=0.851)
Triglyceride (mg/dl): 102 vs 101 (P=0.693)
HDL-C (mg/dl): 72 vs 70 (P=0.988)
LDL-C (mg/dl): 103 vs 104 (P=0.782)
VLDL-C (mg/dl): 16 vs 17 (P=0.572)
LPa (mg/dl): 15 vs 16 (P=0.380)
LDL/HDL: 1.7 vs 1.6 (P=0.459)
Log TG/HDL: 0.14 vs 0.15 (P=0.939)
SBP (mmHg): 133 vs 132 (P=0.337)
DBP (mmHg): 70 vs 69 (P=0.578)
Adiponectin (μg/ml): 11.9 vs 13.1 (P=0.009)
CRP (mg/dl): 0.078 vs 0.062 (P=0.040)
FBS (mg/dl): 111 vs 108 (P=0.738)
CPK (IU/l): 99 vs 92 (P=0.142)
GOT (IU/l): 25 vs 24 (P=0.174)
GPT (IU/l) 22 vs 20 (P=0.059)
BUN (mg/dl): 17 vs 17 (P=0.659)
Creatinine (mg/dl): 0.76 vs 0.72 (P=0.019)

eGFR (ml/min/1.73m2): 68.6 vs 72.5 (P=0.016)
NRNone

From: Evidence Tables

Cover of Drug Class Review: HMG-CoA Reductase Inhibitors (Statins) and Fixed-dose Combination Products Containing a Statin
Drug Class Review: HMG-CoA Reductase Inhibitors (Statins) and Fixed-dose Combination Products Containing a Statin: Final Report Update 5 [Internet].
Smith MEB, Lee NJ, Haney E, et al.
Portland (OR): Oregon Health & Science University; 2009 Nov.
Copyright © 2009, Oregon Health & Science University, Portland, Oregon.

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