Great Expectations Fulfilled

“The greater danger for most of us lies not in setting our aim too high and falling short; but in setting our aim too low, and achieving our mark.”— Michelangelo

Charles Dickens wrote the novel, Great Expectations, the semiautobiographical genre following the journey of the life of a child into adulthood and maturity. In that context, expectations may refer to the degree or probability that something will occur as well as a prospect of future good or benefit. For those with an interest in hypertension, “great expectations” also referred to the belief held by some that the geometric increase in cardiovascular risk associated with increases in blood pressure (BP) above optimal values, due to hypertension, could be reversed to a similar degree by lowering BP in persons in whom BP was already increased.

Data are now available that permit assessment of these expectations. Recently, Law and colleagues ¹ used Medline (1966–2007) to conduct a meta‐analysis to determine the quantitative efficacy of different classes of BP‐lowering drugs in preventing coronary heart disease (CHD) and stroke and determine which patients with high BP should receive treatment. They selected randomized trials of BP‐lowering drugs recording CHD events and strokes. Differences in BP between study drug and placebo (or control group not receiving the study drug) (“BP difference trials”) were studied in 108 trials while 46 trials compared drugs (“drug comparison trials”). Seven trials with 3 randomized groups fell into both categories. The results were interpreted in the context of those expected from the largest published meta‐analysis of cohort studies, totaling 958,000 people. ²

Law and his coinvestigators identified a population of 464,000 people and placed them into 3 mutually exclusive categories: participants with no history of cardiovascular disease, those with a history of CHD, and those with a history of stroke. In the BP difference trials, β‐blockers had a special effect over and above that due to BP reduction in preventing recurrent CHD events in persons with a history of CHD: 29% risk reduction (95% confidence interval [CI], 22%–34%) compared with 15% (95% CI, 11%–19%) in trials of other drugs. The extra effect was limited to the first few years after myocardial infarction, with a risk reduction of 31% compared with 13% in people with CHD with no recent infarct (P=.04). In the other BP difference trials (excluding CHD events in trials of β‐blockers in persons with CHD), there was a 22% reduction in CHD events (95% CI, 17%–27%) and a 41% (95% CI, 33%–48%) reduction in stroke, for a BP reduction of 10 mm Hg systolic or 5 mm Hg diastolic, similar to the reductions of 25% (CHD) and 36% (stroke) expected for the same difference in BP from the cohort study meta‐analysis—thus, indicating that the benefit is explained by BP reduction itself. The 5 main classes of BP‐lowering drugs (thiazides, β‐blockers, angiotensin‐converting enzyme inhibitors, angiotensin receptor blockers, and calcium channel blockers) were similarly effective (within a few percentage points) in preventing CHD events and strokes, with the exception that calcium channel blockers had a greater preventive effect on stroke (relative risk, 0.92; 95% CI, 0.85–0.98). The percentage reductions in CHD events and stroke were similar in people with and without cardiovascular disease and regardless of BP before treatment (down to 110 mm Hg systolic and 70 mm Hg diastolic. The meta‐analysis also showed that drugs other than calcium channel blockers (with the exception of noncardioselective β‐blockers) reduced the incidence of heart failure by 24% (95% CI, 19%–28%) and calcium channel blockers by 19% (95% CI, 6%–31%).

The authors concluded that, with the exception of the extraprotective effect of β‐blockers given shortly after a myocardial infarction and the minor additional effect of calcium channel blockers in preventing stroke, all the classes of BP‐lowering drugs have a similar effect in reducing CHD events and stroke for a given reduction in BP. The proportional reduction in cardiovascular disease events was the same or similar regardless of pretreatment BP and the presence or absence of existing cardiovascular disease.

The profound beneficial effect of lowering BP is demonstrated in a striking fashion by the sheer volume of data involved in this meta‐analysis of 147 randomized clinical trials. And, the relationship between predicted benefit from prospective epidemiologic studies is reassuring. BP, the biomarker of hypertension, is truly the biomarker par excellence.

The data from this study also illustrate the futility of looking for a magic cutpoint for BP reduction in patients treated with antihypertensive drugs. It is just as absurd to look for a specific goal threshold for BP lowering (down to optimal) in an individual as it is to look for a specific threshold in increased BP for defining hypertension. Finally, when two BP drugs or regimens are compared and BP is equally lowered by both (best determined by ambulatory BP monitoring) and one provides more favorable cardiovascular benefit than the other, one must consider that the less‐favorable drug has off‐setting negative effects.

We must continue to refine the various phenotypes of hypertension so that specific drugs can be developed. However, until that time, lowering the BP of patients with hypertension is job number one. With the number of drugs available at present, this most often can be accomplished without producing adverse effects that interfere with the quality of life.

We should quit wasting time and money chasing the obvious. From a Bayesian perspective, the “prior” is so robust, that any future trials results seeking to define the lower limit for BP reduction are not likely to alter the current belief that “lower is better” (down to optimal) for an individual, all other things being equal. Nevertheless, the treatment of hypertension should be personalized and it should be remembered that it is the disease hypertension, and not just the BP, that is being treated. Thus, the physician will determine for each patient the BP that will best further the patient’s goals of an increase in the quality and duration of life.