Blood pressure, antihypertensive drug treatment and the risks of stroke and of coronary heart disease R Collins MRC/ICRF Clinical Trial Service Unit, University of Oxford, UK S MacMahon Clinical Trials Research Unit, University of Auckland, New Zealand Most evidence about the effects of blood pressure on the risks of cardiovascular disease derives from two principal sources: prospective non-randomised observational studies of the associations between blood pressure and the incidence of stroke and of coronary heart disease, and randomised trials of antihypertensive drug therapy. The focus of the first part of this chapter concerns the evidence from observational studies, which - despite the possibility of confounding by other risk factors - may be more relevant to the eventual effects of prolonged blood pressure differences on stroke and coronary heart disease risk.1 The focus of the second part concerns the evidence from randomised trials of antihypertensive drug treatment, which are more relevant to assessing how rapidly, and to what extent, the epidemiologically expected reductions in stroke or in coronary heart disease are produced by suddenly lowering blood pressure in middle and old age.2 at Pennsylvania State University on May 10, 2016 http://bmb.oxfordjournals.org/ Downloaded from BLOOD PRESSURE AND ANTIHYPERTENSIVE DRUG TREATMENT 27 3 EVIDENCE FROM PROSPECTIVE OBSERVATIONAL STUDIES Effects of prolonged blood pressure differences on stroke and on coronary heart disease The associations of blood pressure levels with the incidence of stroke and of coronary heart disease (CHD) have been investigated in a large number of prospective, observational studies involving populations from a variety of geographic regions.3 " 11 Typically these associations have been estimated by relating the measured blood pressure of participants at the start of the study to the occurrence of stroke and CHD over subsequent years. In most studies, the participants were predominantly middle-aged or older when blood pressures were initially measured. Differences in blood pressure levels between participants at this age are likely, as a result of the phenomenon of blood pressure 'tracking',12.'3 to have existed for a decade or more prior to measurement and to have persisted during follow-up. Consequently, estimates of the differences in 'usual' blood pressure between participants in these studies can be made, and these can be used to provide information about the effects of prolonged 'usual' blood pressure differences on stroke and on CHD risk.1 In general, however, analyses of most prospective observational studies have assessed not the effects of differences in 'usual' blood pressure, but rather those of 'baseline' blood pressures measured just at entry to the study. Such baseline blood pressure measurements are subject to substantial random fluctuations due both to the unreliability of the measurement process and to the frequent real, but transient, deviations of blood pressure from an individual's usual level. This largely random error in the estimation of the usual blood pressure of individuals results in systematic error (ie bias) in the estimation of the associations between usual blood pressure levels and the risks of stroke and of CHD.14.'5 Specifically, errors in the estimation of usual blood pressure levels result in substantial underestimation of the strength of these associations and, consequently, of the size of any difference in disease incidence associated with a given difference in blood pressure between individuals. The magnitude of this 'regression dilution' bias1 can be assessed in several ways; however, it is perhaps most simply and clearly demonstrated by comparing mean blood pressure levels at the start of a study with mean levels observed during follow-up, for groups defined on the basis of their initial baseline blood pressure measurement. For example, among participants in the Framingham Study,9 the average difference in diastolic blood pressure (DBP) between 5 consecutive groups categorised by baseline measurements was initially 11.4 mmHg whereas at Pennsylvania State University on May 10, 2016 http://bmb.oxfordjournals.org/ Downloaded from 2 7 4 HYPERTENSION after 4 years it was just 7.1 mmHg (Table 1). Similarly, the difference between the top and the bottom categories was initially 47.7 mmHg whereas after 4 years it was just 28.5 mmHg. These differences reflect the 'regression to the mean' of erroneously high or low initial blood pressure values. Analyses based on the baseline measurements alone would produce associations of disease risk with differences in blood pressure that were on average about 60% greater than the differences in blood pressure apparent after adjustment for regression to the mean. It is evident, therefore, that the true associations of risk with prolonged differences in usual DBP would be about 60% greater than those evident from analyses based only on crude initial blood pressure measurements. This can be graphically illustrated, using the blood pressure measurements and the relative risk of stroke in just the top and bottom categories of DBP in the Framingham Study (Fig. 1): it can be seen that the slope of the line joining these categories (and, as will be seen later, approximating the overall relationship of DBP with stroke) is