Therapeutic Trials and Their Meta Analyses

In recent years, therapeutic trials and meta-analyses have become the major guidelines for the management of patients with hypertension. Before analyzing their results, it is important to briefly review their historical background.

A Brief Historic Overview

From 1950 to 1980, the effectiveness of antihypertensive drug therapy was demonstrated for the first time in men in the Veterans Administration trials [1, 2]. Later, both men and women were studied [1, 2]. The effect of drug therapy on CV risk was easy to demonstrate in relatively small populations with severe or malignant hypertension, but much larger populations and longer follow-up times were needed for subjects with mild to moderate hypertension. The defined goal of these early studies was to reduce CV risk exclusively through reduction of diastolic blood pressure (DBP). DBP was the single entry criterion for the hypertensive population and the only criterion used to determine drug effectiveness [1, 2], Changes in SBP were frequently not published. During this period, therapeutic trials never included old subjects with isolated systolic hypertension, defined as DBP <90 mm Hg but SBP >160 mm Hg.

Circa 1990, it was shown that antihypertensive drugs reduced CV risk in subjects with isolated systolic hypertension or with systolic-diastolic hypertension and a disproportionate increase of SBP over DBP [3, 4], These trials included much older patients (>65 years) of both sexes and emphasized the importance of including women in study cohorts. As a consequence, results were frequently focused on SBP but the effects of drug treatment were also related to DBP, although in many trials, baseline DBP values were already normal or even low.

More recently, comparisons of the effectiveness of various antihypertensive agents have been performed [5, 6]. In most studies, it was not possible to clearly identify any difference between the effects of various antihypertensive agents at similar levels of BP reduction. In these trials, the target of antihypertensive drug therapy had become both SBP and DBP reduction. However, there was no consistent improvement in the reduction of CV events, when compared to the earlier primary trials. To test such conclusions, Staessen et al. [6] compared new and old antihypertensive drugs and computed pooled odds ratios from stratified tables. Compared with early drugs (diuretics and ^-blockers), calcium-channel blockers, angiotensin-converting enzyme inhibitors and an-giotensin II antagonists provided similar overall CV protection. However, some published results suggested that dihydropyridine calcium-channel blockers might offer a selective benefit in the prevention of stroke and inhibitors of the renin-angiotensin system in the prevention of heart failure [5, 6]. For prevention of myocardial infarction, the results were more equivocal. However, the prevention of myocardial infarction by antihypertensive therapy had been constantly the object of debate since the early phases of antihypertensive therapy. Finally, taken together, these results suggested that all antihypertensive drugs provided similar overall CV protection.

Effects of Antihypertensive Drug Treatment on CV Risk

During the 30-year evolution of therapeutic trials and meta-analyses, it is evident that (1) the clinical face of hypertension has considerably changed, from severe and malignant to milder forms of hypertension, including systolic hypertension in the aged; (2) the number of classes of antihypertensive agents has also increased, as a function of the discovery and commercialization of new antihypertensive agents; (3) the concomitant use of non-anti-hypertensive agents, such as statins, has also markedly increased, and (4) no consistent differences have been sought in the strategy of drug treatment between men and women despite the well-established lower CV risk in women [7].

During all these remarkable changes over time, the effects of drug treatment on CV risk remained quite stable [1, 2] (fig. 1). The major results over the years were the reduction of stroke and congestive heart failure, both clearly demonstrated from the initial studies. Another salutary result was the stabilization or even the improvement of renal function, although relatively few large therapeutic trials were performed on this subject. Finally, the beneficial effects of drug treatment on the prevention of myocardial infarction continued to be more difficult to demonstrate than that of stroke and undoubtedly remained lower than expected from the initial epidemiological predictions.

Effect of Drug Treatment on Brachial BP

An important aspect of all these therapeutic trials was the effect of anti-hypertensive agents on brachial BP determinations. Despite the heterogeneity of the different classes of antihypertensive agents, the resulting changes in BP were quite homogeneous for all trials. DBP was lowered to < 90 mm Hg in approximately 80% of treated patients but SBP remained 6140 mm Hg in approximately 60% [8-10] (fig. 2). These findings in many patients resulted in an increase in pulse pressure (PP), above that which rises normally and substantially with aging. This increased PP became a possible index of residual CV risk during therapy and therefore represented an important factor in the total evaluation of antihypertensive drug therapy (see chapter by Verdecchia and Angeli, pp 150-159). Finally, for most authors, the consistent reduction of CV risk and the homogeneity of the changes in BP under various treatments contrasted with the heterogeneity of the classes of antihypertensive agents. This disparity suggested a substantial cause-effect relationship between the reduction of BP (mainly SBP) and CV events [11-13].

To test whether such conclusions were valid, Staessen et al. [6] considered new outcome trials published in recent years (2005). For these trials, Staessen et al. [13] predicted outcome from achieved SBP using their previously published meta-regression models. The main finding of the overview was that re-

Trial Number of events, Odds ratios and 95% confidence limits (or group of trial) treatment:control (treatment:control)

Strokes Treatment better

Treatment worse

HDFP trial 102:158

SHEP 105:162 MRC 65-74 trial 101:134 13 others 157:272 -■All trials 525:835

(Heterogeneity x24 = 4.2; NS)


38% SD 4 reduction 2p < 0.00001

CHD events

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