International Task Force for Prevention of
Coronary Heart Disease
CORONARY HEART DISEASE: REDUCING THE RISK
Comment:
This study examined the results of recent trials of statins with respect to the clinical benefit of cholesterol lowering. The reductions in coronary heart disease (CHD) and total mortality risk observed for the statins fell near the predictions from our previous meta-analysis. Based on the statin trial findings it was concluded that for every 10 percentage points of cholesterol lowering, CHD mortality risk is reduced by 15% (p<.001), and total mortality risk is reduced by 11% (p<.001). The effect of the statins on CHD and total mortality risk can be explained by their lipid-lowering ability and appears to be directly proportional to the degree to which they lower lipidsComment:
A five-year primary prevention trial of a cholesterol lowering diet and antismoking advice, showing a marked (about 50%) reduction in coronary events: statistical analysis suggested that most of the benefit accrued from lipid loweringComment:
The most powerful longitudinal epidemiological study establishing the risk factor status of plasma cholesterol level and blood pressure- The risk of CHD death increased from the lowest to the highest twentieths of the distribution of both risk factors, risk increased logarithmically with increasing plasma cholesterolblood pressure, cigarette smoking, and death from coronary heart disease. Overall findings and differences by age for 316099 white men. Arch Intern Med 152: 56-64
Comment:
The results of this study show that there is a strong graded relationship between serum cholesterol levels above 180 mg/dL, systolic blood pressure above 70 mmHg and diastolic blood pressure above 70 mmHg and mortality due to coronary heart disease (CHD). Smokers with serum cholesterol and systolic blood pressure levels in the highest quintiles have CHD death rates that were about 20 times higher than non smoking men with systolic blood pressure and cholesterol levels in the lowest quintile. Systolic and diastolic blood pressure, serum cholesterol and cigarettes per day are significant predictors of death due to CHD in all age groups. Systolic blood pressure is a stronger predictor than diastolic blood pressure. These results, together with the findings of clinical trials, offer strong support for intensified preventive efforts in all age groupsComment:
The West of Scotland Coronary Prevention Trial (WOSCOPS) was a double-blind trial of pravastatin in the treatment of moderate hypercholesterolaemia in primary prevention. 6595 men, 45 to 64 years of age, with a mean plasma cholesterol level of 272 mg/dL (7.0 mmol/L) and no history of myocardial infarction received 40 mg pravastatin or placebo. The average follow-up period was 4.9 years. Pravastatin lowered plasma cholesterol levels by 20% and LDL-cholesterol levels by 26%, whereas there was no change with placebo. There were 248 definite coronary events (nonfatal myocardial infarction, death from coronary heart disease) in the placebo group, and 174 in the pravastatin group (-31%). There were similar reductions in the risk of definite nonfatal myocardial infarctions (-31%), death from coronary heart disease (-28%), and death from all cardiovascular causes (32%). There was no excess of deaths from non cardiovascular causes in the pravastatin group. In WOSCOPS overall mortality was reduced by 22% in the treatment group, although this finding achieved only marginal statistical significance (p=0.051). Thus treatment with pravastatin significantly reduced the incidence of myocardial infarction and death from cardiovascular cause without adversely affecting the risk of death from non cardiovascular causes in men with moderate hypercholesterolaemia and no history of myocardial infarctionComment:
The pattern of a continuous, graded, strong relationship between serum cholesterol and six-year age-adjusted CHD death rate prevailed for nonhypertensive nonsmokers, nonhypertensive smokers, hypertensive nonsmokers and hypertensive smokers. These data of high precision show that the relationship between serum cholesterol and CHD is not a threshold one, with increased risk confined to the two highest quintile, but rather is a continuously graded one that powerfully affects risk for the great majority of middle aged menComment:
The authors assessed the potential benefit of treatment for low-risk and high-risk groups in the West of Scotland Coronary Prevention Study (WOSCOPS) population, and compared the benefits of primary and secondary prevention of CHD by lipid lowering with the benefit of blood pressure reduction in the primary prevention of stroke. There were a substantial number of men whose risk of coronary event was more than 10% at 5years in the WOSCOPS cohort. The absolute benefit of pravastatin treatment of hyperlipidaemia is less in the primary prevention of CHD than in secondary prevention, but is similar to that for primary prevention of stroke by treatment of mild to moderate hypertension in middle-aged menComment:
This report, which laid down for the first time the principles of prevention strategies, is still valid
Comment:
The Coronary Drug Project was a secondary prevention trial conducted between 1966 and 1975 to assess the long-term efficacy and safety of five lipid-influencing drugs in 8341 men, aged 30 to 64 years with ECG-documented myocardial infarction. The two oestrogen regimens and dextrothyroxine were discontinued early because of serious excess mortality. Only the clofibrate and nicotinic acid treatments were carried through. Clofibrate reduced cholesterol levels by 6.5%, but only slightly reduced CHD morbidity and mortality and had no effect on total mortality. Niacin treatment showed significant benefit in decreasing definite nonfatal recurrent myocardial infarction but did not decrease total mortality. Interestingly, the benefits of niacin therapy were still apparent at the end of a drug-free follow-up period of nearly 10 years. With a mean follow-up of 15 years, mortality from all causes in each of the drug groups, except for niacin, was similar to that in the placebo group. Mortality in the niacin group was 11% lower than in the placebo group (52.0 vs 58.0%; p=0.0004). This late benefit of niacin may indicate the translation into a mortality benefit over subsequent years of the earlier favourable effect of niacin in decreasing nonfatal re-infarction. Alternatively, it may be due to the cholesterol-lowering effect of niacin. Both mechanisms might also have been operatingComment:
In this trial, 8,000 patients (30-64 years old) with a history of coronary heart disease were originally enrolled between 1967 and 1969 and were randomised to receive conjugated oestrogens, dextrothyroxine, niacin (nicotinic acid) or clofibrate for 5 years. Both oestrogens and dexthrothyroxine were discontinued early due to serious excess mortality and only the clofibrate and nicotinic acid treatments were carried through. Clofibrate reduced cholesterol levels by 6.5% but produced only small reduction in CHD mortality/morbidity and had no effect on total mortality. Niacin lowered cholesterol levels by 10%. It reduced the 5-year incidence of non-fatal myocardial infarction to 8.9%, a significant improvement (p<0.01) compared to the 12.2% incidence in the control group. However, it did not affect 5-year total mortality (21.2% in treated patients vs 20.9% controls). Interestingly, the benefits of niacin therapy were still apparent at the end of a drug-free follow-up period of nearly 10 yearsComment:
Cholesterol lowering clinical trials using clinical event rates, and trials using angiographic end-points, are reviewed. By both end-points, lipid lowering treatments that reduce LDL-cholesterol levels lead with high consistency to a favourable out-come. Angiographic regression of atherosclerosis was observed in most but not all trials. A favourable angiographic outcome was strongly predictive of reduction in coronary events during prolonged follow-up, and the effects of lipid lowering on the arterial wall are discussed in the context of event reductionComment:
MAAS is a randomised double-blind clinical trial of 381 patients with CHD assigned to treatment with diet and either simvastatin 20 mg daily or placebo for 4 years. Quantitative coronary angiography was done at baseline and after 2 and 4 years. In the placebo group there were reductions in mean lumen diameter and in minimum lumen diameter. Treatment effects were + 0.06 mm and +0.08 mm. for mean and minimum lumen diameter, respectively (combined p=0.006). The trial showed that 20 mg simvastatin daily over 4 years reduces hyperlipidaemia and slows progression of diffuse and focal coronary atherosclerosisComment:
Advances in the treatment of cardiovascular disease have increased costs; annual cardiovascular health care expenditure in the USA currently exceed 100 billion dollars. Physicians and third-party payers need to assess the economic impact of treatment that reduce cardiovascular morbidity and mortality. In addition to reduce mortality and morbidity in CHD patients, in the 4S study simvastatin markedly reduces use of hospital services, thus offsetting most of its costComment:
This study investigated if aggressive lowering of LDL-cholesterol levels or low-dose anticoagulation could delay the progression of atherosclerosis in coronary artery saphenous vein bypass grafts. One thousand three hundred and fifty-one patients who had undergone bypass surgery one to eleven years before baseline and who had an LDL-cholesterol level between 130 and 175 mg/dL and at least one patent vein graft as seen on angiography were included. Patients were assigned to either aggressive or moderate treatment to lower LDL-cholesterol levels using lovastatin and, if needed, cholestyramine, or to treatment with warfarin or placebo. Angiography was repeated an average of 4.3 years after baseline. The primary angiographic outcome was the mean percentage per patient of grafts with a decrease of 0.6 mm or more in lumen diameter. The mean LDL-cholesterol level of patients who received aggressive treatment ranged from 93 to 97 mg/dL; with moderate treatment, the range was from 132 to 136 mg/dL (p<0.001). The mean international normalised ratio was 1.4 in the warfarin group and 1.1 in the placebo group (p<0.001). The mean percentage of grafts with progression of atherosclerosis was 27% for patients whose LDL-cholesterol level was lowered with aggressive treatment and 39% for those who received moderate treatment (p<0.001). There was no significant difference in angiographic outcome between the warfarin and placebo groups. The rate of revascularisation over four years was 29% lower in the group whose LDL-cholesterol level was lowered aggressively than in the group receiving moderate treatment (6.5 percent vs 9.2 percent, p=0.03). Thus aggressive lowering of LDL-cholesterol levels to below 100 mg/dL, but not low-dose warfarin treatment, reduced the progression of atherosclerosis in graftsComment:
In patients with high cholesterol levels, lowering cholesterol levels reduces the risk of coronary events; the effect of lowering cholesterol levels in the majority of patients with CHD, who have average levels, is less clear. In a double-blind trial lasting 5 years, either 40 mg pravastatin per day or placebo, were administered to 4159 patients with myocardial infarction who had plasma total cholesterol levels below 240 mg/dL (mean 209) and low density lipoprotein (LDL) cholesterol levels of 115 to 174 mg/dL (mean 139). The primary end point was a fatal coronary event or a nonfatal myocardial infarction. The frequency of primary endpoint was 10.2% in the pravastatin group and 13.2% in the placebo group, an absolute difference of 3 percentage points and 24% reduction in risk (p=0.003). The frequency of stroke was reduced by 31% in the pravastatin group (p=0.03). The reduction in coronary events was also greater in patients with higher pretreatment levels of LDL-cholesterol. Similar reductions were seen in other coronary endpoints while total mortality, which was not designed as a primary endpoint, dropped by a non-significant 9%. Subgroup analyses showed a similarly robust reduction in coronary events among various patient groups as was seen with 4S with one notable exception, analysis by baseline LDL-cholesterol. Although those analyses included only some 400 patients in each treatment group, and had wide confidence limits, they showed no tendency for improvement in major coronary events for patients whose entry LDL-cholesterol was below 125 mg/dL (3.2 mmol/L). These results of CARE demonstrated that the benefit of cholesterol-lowering therapy extends to the majority of patients with CHD who have average cholesterol levelsComment:
In the Scandinavian Simvastatin Survival Study (4S), a double-blind, placebo-controlled study in 4444 patients with angina pectoris or prior myocardial infarction and who were frankly hypercholesterolaemic (baseline LDL-cholesterol = 188 mg/dL (4.9 mmol/L). Following an average 5.4 years of follow-up, the active treatment group (simvastatin 27 mg/day on average) had a reduction in LDL-cholesterol of 35% (to 122 mg/dL) (3.2 mmol/L) that was associated with a 30% decline in total mortality (primary endpoint) and a 26-34% reduction in other secondary coronary and cardiovascular endpoints. Additional analyses tended to show similar reductions in risk of major coronary events for subgroups of patients classified by age, gender, smoking status, presence or absence of diabetes and concurrent treatment with either aspirin, beta-blockers or calcium-channel blockers. Results by baseline LDL-cholesterol also showed a consistent reduction in risk among the quartiles of this high cholesterol cohort. The lowest such quartile had an average LDL-cholesterol of < 170 mg/dL (4.39 mmol/L). The 4S study conclusively showed that long-term treatment with simvastatin is safe and improves survival in CHD patientsComment:
In patients with angina pectoris, the levels of fibrinogen, von Willebrand factor antigen, and t-PA antigen are independent predictors of subsequent acute coronary syndromes. In addition, low fibrinogen concentration characterise patients at low risk for coronary events despite increased serum cholesterol levels. These data are consistent with a pathogenic role of impaired fbrinolysis, endothelial cell injury and inflammatory activity in the progression of coronary heart diseaseComment:
The optimal extent of LDL-cholesterol reduction was studied by pooling data from 14 trials of lipid lowering in which the end point was quantitative coronary angiography. Absolute reduction in LDL-cholesterol, and average level of LDL-cholesterol during the trials, were both strongly predictive of favourable angiographic outcome. The occurrence of regression of atherosclerosis appeared greatest when LDL-cholesterol decreased by 3-4 mmol/L or when LDL-cholesterol level during the trial was about 3 mmol/L