Proof of concept in cardiovascular risk: the paradoxical findings in blood pressure and lipid abnormalities

Abstract

High blood pressure and lipoprotein abnormalities were identified by many cohort studies as the major risk factors for cardiovascular disease. Laboratory experiments apparently confirmed their role in the causation of atherosclerosis, but a proof of concept requires the corroboration by clinical trials in human beings. The size of benefit in clinical trials regarding the control of high blood pressure was within the estimations of risk provided by cohort studies. For a reduction of 10 mmHg in systolic blood pressure or 5 mmHg in diastolic blood pressure, the relative risk reduction of coronary heart disease was 22% (95% confidence interval 27%-17%) in a meta-analysis of clinical trials, close to the estimation of reduction of 25% (95% confidence interval 23%-27%) provided by a meta-analysis of cohort studies. The corresponding values for stroke were 41% (95% confidence interval 33%-48%) in clinical trials compared to a cohort risk prediction of 36% (95% confidence interval 34%-38%). This efficacy was shared by all blood pressure-lowering drugs. The same figure has not paradoxically happened with drugs that act over abnormalities of cholesterol and lipoproteins. Only statins, which have other beneficial actions as well, have consistently lowered the incidence of cardiovascular diseases, an efficacy that was not reproduced by older and newer quite potent lipid drugs. The adverse effects of these drugs may nullify their beneficial effects over lipoproteins and abnormalities of lipoproteins may only be surrogate markers of the underlying real risks.

Keywords: clinical trials; hypertension; lipoproteins; proof of concept.

Figure 1

Absolute risk for coronary heart disease by age and usual systolic and diastolic blood pressure. Reproduced with permission from The Lancet, Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002;360(9349):1903–1913. Copyright 2002, with permission from Elsevier.

Figure 2

Absolute risk for coronary heart disease by age and serum cholesterol levels. Reproduced with permission from The Lancet, Lewington S, Whitlock G, Clarke R, et al; Prospective Studies Collaboration. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet. 2007;370(9602):1829–1839. Copyright 2007, with permission from Elsevier.

Figure 3

Relative risk for (A) coronary heart disease and (B) stroke by standardized difference (10 mmHg of systolic blood pressure or 5 mmHg of diastolic blood pressure) between clinical trial arms in patients with and without previous cardiovascular disease, and the size effect prediction from cohort studies. Reproduced with permission from BMJ Publishing Group Limited. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ. 2009;338:b1665. Copyright 2009. Abbreviations: BP, blood pressure; CHD, coronary heart disease; CI, confidence interval; CVD, cardiovascular disease; RR, relative risk.