Evidence Table 3Placebo-controlled trials of patients with atherosclerosis

Author
Year
Study Name
Study CharacteristicsPatient CharacteristicsInterventionStudy Duration (mean)Mean Baseline LDL- cPercent LDL- c Reduction from baselinePrimary EndpointPrimary Endpoint Results (clinical health outcome only)Clinical Outcomes MeasuredClinical Outcome ResultsComments/Conclusions
Bestehorn et al. 1997
Multicenter Coronary Intervention Study (CIS)
Randomized, double- blind, placebo- controlled, intent to treat analysis for clinical events.254 men 30-55 years with at least 3 coronary segments with a lumen diameter of ≥20% and TC of 207-350 mg/dl.Simvastatin 20 mg qpm or placebo qpm. Simvastatin was increased to 40 mg qpm if LDL-c>90 mg/dl2.3 years164.5 mg/dl (4.25 mmol/L)35%Global change score and the per- patient mean change in MLD as assessed by coronary angiography.N/AClinical events were reported spontaneously.There were no significant differences in clinical events with simvastatin vs. placebo. Overall, there were 15 events in the simvastatin and 19 in the placebo groups.There were no statistical differences in clinical events in the simvastatin vs. placebo groups. Fair to poor in quality to assess differences in clinical event due to duration of trial, however was a relatively small sample size.
Blankenhorn et al. 1993
The Monitored Atherosclerosis Regression Study (MARS)
Randomized, double- blind placebo- controlled, not intent to treat analysis.270 men or women younger than 70 years and CHD in 2 coronary segments 50% or >Lovastatin 80 mg qpm or placebo qpm.2.2 years151 mg/dl (3.91 mmol/L)38%Per-patient change in percent diameter stenosis between groups as determined by quantitative coronary angiography.N/ACardiac and noncardiac events, mortality and coronary revascularization were reported in the safety analysis.22 lovastatin vs. 31 placebo recipients had one or more of the following: MI, PTCA, CABG, CHD death or hospitalization for USA. (NS) Also no difference in overall death.MARS was not designed with sufficient power to detect differences in clinical events. However there was a trend in favor of lovastatin. Fair-poor in quality to assess differences in clinical events.
Crouse et al. 1995
Pravastatin, Lipids, and Atherosclerosis in the Carotid Arteries (PLAC-II)
Randomized, double- blind, placebo- controlled, not intent to treat analysis.Men and women with CHD as evidenced by ≥ stenosis of 1 or > coronary artery or history of MI with elevated LDL-c.Pravastatin 20 mg qpm or placebo qpm. If LDL-c was not <110 mg/dl pravastatin was increased to 40 mg qpm.3 years167.5 mg/dl (4.33 mmol/L)28%Change in the mean of the maximal IMT measurement across time determined by B- mode ultrasonography.N/APrespecified clinical events: Fatal coronary events or nonfatal MI, all- cause mortality, all deaths plus nonfatal MI.For the combined endpoint of nonfatal MI and any death, there was a significant reduction in the pravastatin vs. placebo group (5 vs. 13, respectively). P=0.04,RRR=61%, ARR=1/100 persons, NNT=10PLAC-II prespecified analysis of clinical events. The only significant difference was in the combined endpoint of nonfatal MI plus any deaths. Not much detail provided in clinical event section, for observation of other clinical events that were not significantly reduced with pravastatin. Fair-poor in quality to assess difference in clinical events. Small sample size.
Furberg et al. 1994
Asymptomatic Carotid Artery Progression Study (ACAPS)
Randomized, double- blind, placebo- controlled, intent to treat analysis.919 men or women 40- 79 years with early carotid atherosclerosis and elevated LDL-cLovastatin 20 mg qpm or placebo qpm. Lovastatin was titrated to 40 mg qd if LDL-c >90-100 mg/dl. Warfarin 1 mg qd or placebo qd.3 years (last 300 randomized only received 33 months of follow up156.6 mg/dl (4 mmol/L)28%Progression of a summary measure via B-mode ultrasonography: the mean of the maximum IMT measurements from the 12 walls, near and far, of the common carotid, the bifurcation, and the internal carotid arteries bilaterally measured by B-mode ultrasonography.N/AOne of the secondary endpoints in the trial was to determine the treatment effects on major atherosclerotic events.5 (all nonfatal MI) major cardiovascular events occurred in the lovastatin vs. 14 in the lovastatin- placebo groups (4-CHD deaths, 5-strokes, 5- nonfatal MI). p=0.04, ARR=2 events/100 persons, NNT=5. Overall mortality: One death in lovastatin vs. 8 deaths in lovastatin-placebo groups p=0.02, ARR 1.5 events/100 persons, NNT=65. All 6 cardiovascular deaths occurred in lovastatin-placebo groups.The secondary objective of major atherosclerotic events was significantly reduced in the lovastatin vs. the lovastatin-placebo groups in patients with early carotid atherosclerosis. Fair-good in quality to determine differences in clinical events.
Herd et al. 1997
Lipoprotein and Coronary Atherosclerosis Study (LCAS)
Randomized, double- blind, placebo- controlled, not intent to treat analysis.429 men or women 35- 75 years with ≥1 coronary atherosclerotic lesion causing 30-75% diameter stenosis.Fluvastatin 20 mg bid or placebo bid. Cholestyramine up to 12 g/day was given to those with LDL-c ≥160 mg/dl after dietary phase.2.5 years146.2 ± 20.1 mg/dl (3.78 mmol/L)22.5% (fluvastatin alone)Within patient per-lesion change in MLD of qualifying lesion as assessed by coronary angiography.N/AAny cardiac, cerebrovascular, peripheral vascular, and fatal events. Also time to first CABG, PTCA, MI, hospitalization for USA or all-cause mortality.Any cardiac morbid or fatal event occurred in 12.7% of fluvastatin vs. 18.9% placebo. Time to these events showed a trend towards benefit with fluvastatin. Need for revascularization was reduced with fluvastatin 8.9% vs. 13.4% with placebo. No statistical significance provided.LCAS was not designed with sufficient power to detect differences in clinical events. However, there was a trend observed in favor of fluvastatin. In this study, there were 909 patients screened, but only 429 randomized. The major reasons were for lipid ineligibility and lack of cooperation. There were some minor difference in baseline characteristics between groups. Fair-poor in quality to determine differences in clinical events.
Jukema et al. 1995
The Regression Growth Evaluation Statin Study (REGRESS)
Randomized, double- blind, placebo- controlled, not intent to treat analysis.885 men with clinical evidence of CHD and TC 155-310mg/dl (4-8 mmol/L)Pravastatin 40 mg qpm or placebo qpm.2 years166 mg/dl (4.3 mmol/L)29%Change in average mean segment diameter per patient and change in average minimum obstruction diameter per patient determined by coronary arteriography.N/APrespecified clinical events: Fatal and nonfatal MI, CHD death, nonscheduled PTCA or CABG, Stroke or TIA, and all-cause death.After 2 years of treatment, 89% of pravastatin vs. 81% of placebo recipients were free from clinical events (p=0.002). Although nonsignificant, there were 12 nonfatal MI in the placebo vs. 7 in the pravastatin groups (ARR 1.2/100 persons, NNT=83). Unscheduled PTCA were reduced significantly in the pravastatin vs. placebo groups (p=0.004, RRR=57%, ARR 5.8/100 persons, NNT=17).REGRESS prespecified analysis of clinical events.
The only significant difference in individual events was the reduced need for unscheduled PTCA in the pravastatin vs. placebo groups. This significant reduction accounted for the overall reduction in new clinical events in the pravastatin group. Difficult to tell if intent to treat population was included in overall clinical event analysis. Fair in quality to assess differences in clinical events.
Pitt et al. 1995
Pravastatin
Limitation of Atherosclerosis in Coronary Arteries (PLAC- I)
Randomized, double- blind, placebo- controlled, not intent to treat analysis.408 men or women with CHD as evidenced by 1 or > stenosis ≥ 50% or recent MI or PTCA and LDL-c ≥ 130 mg/dlPravastatin 40 mg
qpm or placebo
qpm.
3 years164 mg/dl (4.24 mmol/L)28%Change in average MLD and change in percent diameter stenosis as determined by coronary arteriography.N/APrespecified clinical events: Fatal and nonfatal MI, nonfatal infarction or CHD death, nonfatal infarction or death from any cause and total clinic events (nonfatal MI, nonfatal completed stroke, death PTCA and CABG).There were 17 MI in placebo vs. 8 in pravastatin (P≤0.05, RRR=60%, ARR=4.5/100 persons, NNT=22). Although not statistically significant, there were 37 PTCA in placebo vs. 25 in pravastatin. A total of 81 events occurred in placebo vs. 55 in pravastatin (NS).PLAC-1 prespecified analysis of clinical events. The only significant difference in individual events was a reduction in the rate of MI in the pravastatin vs. placebo groups. All randomized patients were included in the clinical event analysis. Fair in quality to assess differences in clinical events, although a relatively small study population.
Salonen et al. 1995
Kuopio
Atherosclerosis
Prevention Study (KAPS)
Randomized, double- blind, placebo- controlled, not intent to treat analysis.Men 44–65 years with LDL-c≥4 mmol/L (155 mg/dl). Only 10% had history of MI (Primary prevention study)Pravastatin 40 mg
qpm or placebo
qpm.
3 years185 mg/dl (4.8 mmol/L)27.40%Rate of carotid atherosclerotic progression measured as the linear slope over annual ultrasound examinations in the average of maximum carotid IMT of the far wall of up to 4 arterial segments.N/AClinical events were reported spontaneously.The number of cardiovascular events reported during the trial were not statistically significantly different between groups. However, there was a trend to less clinical cardiovascular events in the pravastatin group, primarily MI.KAPS was not designed to sufficiently determine differences in clinical cardiac events between groups.
However, there was a trend in favor of pravastatin.
Fair-poor in quality to determine differences in clinical events between groups.
Sato et al. 2001Randomized, unblinded, intent to treat analysis for clinical events.329 men and women <70 years with CHD documented by coronary angiography with normal cholesterol.Pravastatin 10 mg
qpm.
2 years200 mg/dl (TC) (5.2 mmol/L). LDL-c not provided8.5% (TC)Mean segment diameter and minimum obstruction diameter were used to evaluate progression as assessed by coronary angiography.N/APrespecified clinical events: Fatal and nonfatal MI, CHD death, nonscheduled PTCA or CABG, Stroke or TIA, and all-cause death. (using criteria defined by REGRESS)The incidence of clinical events was lower in the pravastatin groups vs. placebo but this difference was not significant. All-cause mortality was significantly reduced in the pravastatin vs. placebo groups (p=0.043)Prespecified clinical events. There was a trend to a reduction in clinical cardiac events in the pravastatin vs. placebo groups, however the difference was not significant. There was a significant reduction in overall mortality with pravastatin vs. placebo. Fair in quality to assess difference in clinical events. Small sample size.
Simoons 1994
Multicentre Anti- Atheroma Study
Randomized, double- blind, placebo- controlled, intent to treat analysis for clinical events.404 men and women 30– 67 years with 2 or > coronary artery segments occluded and hyper- cholesterolemia.Simvastatin 20 mg
qpm or placebo
qpm.
4 years169 mg/dl (4.38 mmol/L)31%Per-patient average of mean lumen diameters of all coronary segments(diffuse atherosclerosis) and the per- patient average of MLD of all segments that were atheromatous at baseline, follow up or both (focal atherosclerosis) as assessed by coronary angiography.N/AClinical events were reported spontaneously.After 4 years, there was no difference in clinical events between groups. There were a greater number of MI in the simvastatin vs placebo groups. There were more revascularizations in the placebo vs. simvastatin groups. Neither of these were statistically different. Overall, there were 40 cardiac events in the simvastatin vs. 51 in the placebo groups (NS).There were no statistical differences in clinical events in the simvastatin vs. placebo groups. Fair to poor in quality to assess differences in clinical event due to duration of trial, however was a relatively small sample size.
Teo et al. 2000
The Simvastatin/Enala pril Coronary
Atherosclerosis
Trial (SCAT)
Randomized, double- blind, placebo- controlled, intent to treat analysis for clinical events.460 men and women 21 year or >, atherosclerosis in 3 or >
coronary segments, TC
160–240 mg/dl
Simvastatin 10 mg qpm or placebo qpm and enalapril 2.5 mg bid or placebo (2X2).
Simvastatin could be titrated to 40 mg qpm.
47.8 months130 mg/dl (3.36 mmol/L)30.50%Changes in absolute mean segment lumen diameter, absolute minimum segment lumen diameter, and maximum percent lumen diameter stenosis.N/APrespecified clinical events: death, MI, stroke, hospitalization for angina, revascularization and cancer.The only significant difference in clinical events between simvastatin and placebo was a reduction in the number of revascularizations (6 vs. 12%, p=0.020and angioplasties (3 vs. 9% p=0.02).There was a significant reduction in revascularization, specifically angioplasty in the simvastatin vs. placebo. No differences were noted in any other clinical events. Fair in quality to assess differences in clinical events since clinical events were prespecified.
Waters et al. 1994
The Canadian Coronary
Atherosclerosis
Intervention Trial (CCAIT)
Randomized, double- blind, placebo- controlled, not intent to treat analysis.331 men or women up to 70 years at higher risk for CHD events with diffuse CHD and TC
220–300 mg/dl.
Lovastatin 20 mg
qpm or placebo
qpm. Lovastatin was titrated to 40 and then 40 mg bid if LDL-c >130 mg/dl.
2 years173 mg/dl (4.5 mmol/L)29%Comparison between groups for coronary change score (per- patient mean of the MLD for all lesions measured as determined by coronary angiography.N/ACardiac and noncardiac events, mortality and revascularization were reported in the safety analysis.Patients had one or more events: lovastatin 14 patients (2 deaths from cardiac causes, 5 MI, 8 USA), placebo 18 patients (1 death from cardiac causes, 6 MI, 13 USA) (NS).CCAIT was not designed with sufficient power to detect differences in clinical events. However, there was a trend in favor of lovastatin. Mean lovastatin dose=36 mg/d and 69% met NCEP goal). Fair-poor in quality to assess differences in clinical events.

BID=twice a day, CHD=coronary heart disease, IMT=intimal-medial thickness, MLD=minimum lumen diameter, MI=myocardial infarction, qpm=every evening

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.

PubMed Health. A service of the National Library of Medicine, National Institutes of Health.