Subjects: 4444 M and F (only 19% F) with angina or previous MI and serum cholesterol of 5.5-8
mmol/L (212-309 mg/dL) on a diet

Design: Randomized, double-blind, placebo-controlled followed up to 5.4 years

Endpoints: 1° - mortality, 2° - major coronary events

Results:

• T-Chol - 25%, LDL - 35%, HDL + 8%
• 12% mortality in PL group vs 8% in simvastatin group RR 0.7 (95% CI 0.58-0.85, p=0.003)
• 42% decr. risk of coronary death RR 0.58 (95% CI, 0.46-0.73) with no increase in non-CHD mortality

Conclusion: Long term tx with simvastatin is safe and improves survival in CHD patients.

Subjects: 3583 M and 576 F (14% ) who were post MI with serum total cholesterol of
180-239mg/dL and LDL cholesterol from 115-174mg/dL

Design: Randomized, double-blind, placebo-controlled followed up to 5 years

Endpoints: 1° - fatal coronary event or a nonfatal MI

Results:

• T-Chol - 20%, LDL - 28%, HDL + 5%, TRG -14%
• 24% reduction in nonfatal MI or CHD death (95% CI, 9 to 26%, p=0.003)
• 27% reduction in need for CABG/PTCA (95% CI, 15 to 37%, p<0.001)

Subjects: 6595 men (45-64 yo) T-Chol mean of 272mg/dL

Design: Randomized, double-blind, placebo-controlled for 4.9 years

Endpoints: Combined incidence of nonfatal MI and death from CHD

Results:

• Pravastatin dec. T-Chol. by 20% and LDL-C by 26% with no change in PL
• 248 definite coronary events in PL vs. 174 in pravastatin group RR reduction in 31% (95% CI 17-43%, p<0.001)
• Definite nonfatal MI's decr 31%, p<0.001, and death from all CV causes decr. 32%, p=0.033
• 22% decr. in risk of death from any cause in pravastatin group (95% CI 0-40%; p = 0.051)

Subjects: 1351 patients post CABG (1-11 years), with baseline LDL (130-175) aggressive vs.
moderate treatment with lovastatin or lovastatin plus cholestyramine, vs. placebo. Also had a
warfarin vs. placebo arm.

Design: Randomized, double-blind, placebo-controlled, two-by-two factorial design followed up to
4.3 years

Endpoints: 1° - angiographic change in lumen diameter after targeting LDL of either 60-85 or 130-140 mg/dl and an INR of below 2

Results:

• Mean values of LDL cholesterol were 93-97 in the aggressive group vs. 132-136 in the less aggressive group (P<0.001).
• The mean INR was 1.4 in the warfarin group and 1.1 in the placebo group (p<0.001) .
• The mean percentage of graphs with progression of atherosclerosis was 27% with LDL in the aggressive vs. 39% in the moderate treatment group (p<0.001).
• No sign. difference in angiographic outcomes between warfarin vs. placebo groups.
• Rate of revascularization over 4 years was 29% lower in the group whose LDL was lowered aggressively compared to the moderate treatment group (6.5% vs. 9.2%, p = 0.03).

Conclusion: Aggressive lowering of LDL levels to below 100 mg/dl reduced progression of atherosclerosis in grafts. Low dose warfarin did not affect atherosclerosis.

Subjects: 9014 patients 31-75 years of age who were post AMI or hospitalization for unstable angina, with baseline average total, LDL, HDL and triglyceride levels of 218, 150, 36 and 142mg/dL respectively.

Design: Randomized, double-blind, placebo-controlled, design followed up to 6.1 years evaluating effects of once daily pravastatin at a dose of 40mg/day

Endpoints: 1° - death from CHD, overall mortality, mortality from CV causes.

Results: Pravastatin group T-chol vlaues fell by 39mg/dL from 218 which was 18 percentage points greater than that of placebo (P<0.001). LDL fell 25 percentage points more than placebo and triglycerides 11 percentage points more than placebo. HDL was increased from initial value of 36 by 5 percentage points more than placebo (p<0.001) for all comparisons.

Outcomes:

• Death from CHD was 6.4% in the pravastatin group as com pared to 8.3% in the placebo group (24% reduction p<0.001)
• Overall mortality was 22% lower in the pravastatin group (11%) vs placebo (14.1%) p<0.001
• Mortality from CV causes was 25% lower (7.3% vs 9.6%) for the treatment group p<0.001. (Interestingly, there were significant reductions in mortality from CHD and overall mortality
  among patients in Prava group defined by qualifying event (AMI vs. UA). Namely, mortality
  from CHD was 23% lower for prava group than placebo (p=0,004) and for UA patients a
  26% reduction in CHD mortality as well as a 26% recuction in overall mortality with
  Pravastatin vs. placebo (both P<0.004).
• Secondary endpoints: incidence of AMI ws 7.4% in Prava group vs. 10.3% in placebo (p<0.001) and the incidence of stroke was 3.7% vs. 4.5% for placebo p<0.048.
• No significant increase in incidence of adverse events that were ultimately attributed to study
  medication (3.2% vs. 2.7% for placebo , p=0.16) or serious adverse events.

Conclusion: Lowering cholesterol levels with pravastain in patients with a broad range of initial
cholesterol levels and a history of AMI or UA reduces risk of death from CHD, cardiovascular
disease and all causes combined. In addition, the risk of MI or stroke is significantly reduced.

Comments:

• Effective therapy for patients with more modest cholesterol levels (cf 4S study with average total cholesterol levels 44mg/dL higher at 261mg/dL)
• More in LIPID vs. 4S with CABG (41 vs 8%) and on ASA (82 vs. 37%)
• Extends the CARE study with similar average cholesterols at baseline (209 for CARE) but showed a reduction in CHD death and overall mortaliy (unlike CARE)
• Extends results to those with unstable angina (not a usual entry criteria for other secondary tirals)
• Supports stroke reduction (direct vs. sub-analysis from 4S study)
• Extends findings to females, diabetics; although not able to show a significant effect in these groups alone, it did not show a heterogeneity of treatment effects.
• Whether individual patients are treated will depend on cost-effectiveness analyses, individual risks and coexisting conditions.

Subjects: 5608 men and 997 women given either lovastatin 20-40mg daily or placebo in
addition to a low saturated fat, low cholesterol diet.

Design: Randomized, double-blind, placebo-controlled trial

Endpoints: 1° First acute major coronary event defined as fatal or nonfatal MI, unstable angina, or sudden cardiac death.

Results:

• After an average of 5.2 years, lovastatin reduced incidence of first acute major coronary event (183 vs 116 first events RR 0.63; 95% CI 0.50-0.79); p<0.001)
• MI was also reduced ; RR 0.6; 95% CI 0.43-0.83; P<0.002
• Unstable angina (87 vs60) RR 0.60 95% CI 0.49-0.95); P=0.02), coronary revascularization procedures, coronary events and cardiovascular events were also statistically reduced. Lovastatin reduced LDL 25% to 115mg/dL and increased HDL by 6% to 39mg/dL. Mean values of LDL cholesterol were 93-97 in the aggressive group vs. 132-136 in the less aggressive group. (P<0.001)

Conclusion: Lovastatin reduces the risk for the first acute major coronary event in men and women with average TC, and LDL levels below-average HDL levels. These findings support the inclusion of HDL in risk-factor assessment, confirm h benefit of LDL reduction to a target goal and suggest the need for reassessment of the NCEP guidelines

Subjects: 2531 men (<74 yo, median 64yo) with HDL-C < 40mg/dL, LDL-C < 140mg/dL and Trigs <300mg/dL)

Design: Randomized, double-blind, placebo-controlled trial for 5.1 years with gemfibrozil 1200mg/d vs. PL

Primary Endpoint: Coronary Heart disease death/nonfatal MI

Baseline Characteristics:

• Total-C 175 +/-25mg/dL
• LDL-C 111 +/-22mg/dL
• HDL-C 32 +/-5mg/dL
• Triglycerides 161 +/-68mg/dL

Results:

• Primary event occurred in 21.7% (275/1267) in PL group vs. 17.3% (219/1264) for gemfibrozil group.
• Absolute reduction in risk was 4.4% or 22% relative reduction in risk  (95% CI 7-35%; P<0.0006)
• 24% reduction in combined outcome (death from CHD, nonfatal AMI and stroke, p=0.001)
• % change in endpoints as follows for gemfibrozil vs. placebo: Total-C  - 3%, LDL-C 0% and Trigs -25%, HDL-C +8%

Conclusion: Gemfibrozil significantly reduced risk of major CV events in patients with CAD whose primary lipid abnormality was a low HDL-C. Thus, the rate of cardiac events is reduced by raising HDL-C and lowering Trigs independant of the LDL-C changes.

Subjects: 2763 postmenopausal women (<80yo, mean 66.7yo) with an intact uterus

Design: Randomized, double-blind, placebo-controlled trial for 4.1 years with conjugated equine estrogen (CEE) 0.625mg and medroxyprogesterone acetate (MPA) 2.5 mg vs. placebo

Primary Endpoint: Non-fatal MI or CHD death

Results:

• % change in endpoints as follows for CEE/MPA vs. placebo:  LDL-C -11% (baseline, 145mg/dL), Trigs +8% (baseline, 168mg/dL) and  HDL-C +10% (baseline, 50mg/dL), each p<0.001 vs. baseline

No statistcially significant difference in:

• CHD death/NFMI or other CV outcomes (33.1/1000 women/yr for HRT vs. 33.6/1000 women /yr for PL)
• cancers (eg. breast, endometrial) or cancer deaths
• non CHD or overall mortality

However CEE/MPA increased:

• venous thromboembolic events (34 vs. 12 events: P=0.002)
• gallbladder disease (84 vs. 62 episodes; P=0.05)

Conclusion: Since CEE/MPA did not reduce the risk of CV outcomes and it increased the incidence of venous thromboembolism events and gallbladder disease, DO NOT INITIATE CEE/MPA THERAPY IN OLDER POSTMENOPAUSAL WOMEN WITH CONFIRMED CHD FOR PREVENTION OF CHD, ALTHOUGH IT MAY BE APPROPRIATE TO CONTINUE CURRENT CEE/MPA THERAPY IN WOMEN ALREADY RECEIVING IT FOR >/= 1 YEAR

Purpose: To revaluate the clinical impact o raising HDL-C or decreasing Trigs on risk of cardiovascular events in patients with CAD and low HDL-C and high Trigs.

Design: double-blind trial comparing 400 mg of Bezafbrate per day vs. Placebo for 6.2 years

 Subjects: 3090 patients with previous MI or stable angina with total cholesterols of 180-250mg/dL, HDL-C <45mg/dL, trigs <300mg/dL and LDL <180mg/dL

 Endpoints: Primary is fatal or nonfatal MI or sudden death.

 Results:
Bezafibrate increased HDL by 18% and reduced trigs by 21%.
Fatal and nonfatal MI and sudden death was 13.6%on bezafibrate vs. 15% on placebo (p=0.26)
After 6.2 years the reduction in the cumulative probability of the primary end point was 7.3% (P=2.4)
Post-hoc analysis in the subgroup with high baseline trigs (>200mg/dL), the reduction in cumulative probability of the primary end point by bezafibrate was 39.5% (P=0.02).
Total and non-cardiac mortality rates were similar and adverse events and cancer were equally distributed.

 Conclusions:
Bezafibrate was safe and effective in elevating HDL-C levels and lowering trigs.
A trend in reduction of endpoints was noted by not was statistically significant

Methods: 20,536 UK adults (age 40-80 years) with coronary disease, other occlusive arterial disease, or diabetes were randomly allocated to receive 40mg simvastatin daily (average compliance: 85%) or matching placebo (average non-study statin use: 17%).  Analyses are of the first occurrence of particular events, and compare all simvastatin-allocated versus all placebo-allocated participants.  There "intention-to-treat" comparisons assess the effects of about two-thirds (85% minus 17%) taking a statin during the scheduled 5-year treatment period, which yielded an average difference in LDL cholesterol of 1.0mmol/L (about two-thirds of the effect of actual use of 40mg simvastatin daily).  Primary outcomes were mortality (for overall analyses) and fatal or non-fatal vascular events (for subcategory analyses), with subsidiary assessments of cancer and of other major morbidity.

Findings: All-cause mortality was significantly reduced (1328 [12.9%] deaths among 10,269 allocated simvastatin versus 1507 [14.7%] among 10,267 allocated placebo; p= 0.0003), due to a highly significant 18% (SE 5) proportional reduction in the coronary death rate (587 [5.7%] vs 707 [6.9%]; p= 0.0005), a marginally significant reduction in other vascular deaths (194 [1.9%] vs 230 [2.2%]; p= 0.07), and a non-significant reduction in non-vascular deaths (547 [5.3%] vs 570 [5.6%]; p= 0.4).  There were highly significant reductions of about one-quarter in the first event rate for non-fatal myocardial infarction or coronary death (898 [8.7%] vs 1212 [11.8%]; p< 0.0001), for non-fatal or fatal stroke (444 [4.3%] vs 585 [5.7%]; p< 0.0001), and for coronary or non-coronary revascularisation (939 [9.1% vs 1205 [11.7%]; p< 0.0001).  For the first occurrence f any of these major vascular events, there was a definite 24% (SE 3; 95% Cl 19-28) reduction in the event rate (2033 [19.8%] vs 2585 [25.2%] affected individuals; p< 0.0001).  During the first year the reduction in major vascular events was not significant, but subsequently it was highly significant during each separate year.  The proportional reduction in the event rate was similar (and significant) in each subcategory of participant studied, including: those without diagnosed coronary diesase who had cerebrovascular disease, or had peripheral artery disease, or had diabetes; men and, separtely, women; those aged either under or over 70 years at entry; and - most notably - even those who presented with LDL cholesterol below 3.0mmol/L (193mg/dL).  The benefits of simvastatin were additional to those of other cardioprotective treatments.  The annual excess risk of myopathy with this regimen was about 0.01%.  There were no significant adverse effects on cancer incidence or on hospitalisation for any other non-vascular cause.

Interpretation: Adding simvastatin to existing treatments safely produces substantial additional benefits for a wide range of high-risk patients, irrespective of their initial cholesterol concentrations.  Allocation to 40mg simvastatin daily reduced the rates of myocardial infarction, of stroke, and of revascularisation by about one-quarter.  After making allowance for non-compliance, actual use of this regimen would probably reduce these rates by about one-third.  Hence, among the many types of high-risk individual studied, 5 years of simvastatin would prevent about 70-100 people per 1000 from suffering at least one of these major vascular events (and longer treatment should produce further benefit).  The size of the 5-year benefit depends chiefly on such individuals' overall risk of major vascular events, rather than on their blood lipid concentrations alone.

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Last updated: January 27, 2004
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