Is There More to Life Than Blood Pressure? (2005)

In view of the long history of the medical discipline of hypertension, it is noteworthy that the newest issue in hypertension is—of all things—high blood pressure (BP). It is now decades since actuaries in the life insurance industry pointed out the clear relationship between BP and mortality and since early clinical trialists demonstrated that BP-lowering therapy improved prognosis. Yet the conclusions of the most recent national and international guidelines for hypertension management continue to focus on the primacy of BP as a risk factor and the need to bring it under control. In fairness, the Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7)1 provides up-to-date evidence to support criteria and goals for diagnosing and treating hypertension that are more aggressive than previous guidelines. Compared with more traditional approaches, it not only sets these treatment targets, but urges that they be achieved rapidly. Two of the clinical trials upon which JNC 7 depended for its recommendations were the Hypertension Optimal Treatment (HOT)2 trial and the United Kingdom Prospective Diabetes Study (UKPDS).3 These studies demonstrated that close BP control, as compared with less rigorous traditional therapy, provided significant further benefits in preventing clinical events in hypertensive diabetic patients. Even stronger validation of the JNC 7 recommendation has come recently from two pieces of evidence reported from the Valsartan Antihypertensive Long-Term Use Evaluation (VALUE)4, 5 trial. First of all, the VALUE investigators, who compared valsartan and amlodipine-based treatments in highrisk hypertensive patients, showed that achieving a systolic BP goal of <140 mm Hg—regardless of which drug regimen was being used—provided clear outcome benefits as compared with not achieving that goal. In fact, overall, there was a 45% relative risk reduction for stroke, a 25% reduction in cardiac events, and a 21% reduction in mortality in patients achieving BP control by 6 months of treatment.4 Secondly, patients classified as immediate responders—based on BP effects measured after just 1 month of treatment—were 17% less likely to have a subsequent stroke, 12% less likely to have a cardiac event, and 10% less likely to have a fatal outcome than patients whose BPs responded more slowly.4 These VALUE results were greeted with jubilation by commentators who felt that the primacy of BP control in the management of hypertension was now established beyond all reasonable doubt.6, 7 In fact, one of these editorials went even further, claiming in essence that BP is not just the main issue, but the only issue in hypertension therapy. Simply stated, it concluded that the VALUE4, 5 trial had “put the concept of prognostic benefit beyond BP lowering to rest.”6 One uncertainty, however, that has not been put entirely to rest has been the claim that even apparently small differences in achieved BPs during therapy can amplify into relatively large differences in the relative risks of major clinical end points. At first sight, a number of clinical trials in hypertension appear to support this point of view. Apart from HOT2 and VALUE,4, 5 another major study, in which apparently small differences in BP were felt to explain significant differences in outcomes was the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack (ALLHAT)8 trial. It is not clear by looking at treatment cohorts as a whole in these various trials whether apparently small mean BP differences of 2–4 mm Hg between differing treatment arms can tell the full story regarding those patients who actually experience events. It is possible, after all, that some of the unfortunate individual patients who experienced events might have had particularly poor control of their BPs; findings that easily could have been hidden when BP values were averaged across large treatment groups. Differential BP responses to treatment among patients is not surprising, for it is well established that hypertension is a heterogeneous condition. Although all patients with hypertension share the characteristic of an elevated BP, it is evident that different causes—and so, potentially different optimal approaches to treatment—can underlie this finding. This concept has been recently reviewed.9 There are several striking examples of hypertension heterogeneity. The renin hypothesis, for instance, is predicated on the idea that some patients have a form of hypertension that is driven primarily by the vasoconstrictor effects of the renin-angiotensin system (high-renin hypertension), whereas some other patients have hypertension that depends primarily on expanded plasma volume (low-renin hypertension).10 Clearly, patients in the first of these groups will respond best to drugs like angiotensin receptor blockers, whereas those in the second group might do better with diuretics or calcium channel blockers.10 Body weight is another indicator of differing hypertension mechanisms. Not only are such factors as neuroendocrine, renal, and cardiovascular (CV) findings different in obese and lean hypertensive patients, but there are important clinical outcome differences between them depending on the type of therapy they receive.11, 12 Despite all the talk about BP, many experts in hypertension still believe that differing therapies may provide benefits that go beyond their BP effects. Studies such as the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE),13 the Second Australian National Blood Pressure study (ANBP2),14 and the Nordic Diltiazem (NORDIL)15 trial are examples of one drug exhibiting superior end point benefits over another despite having the same or even lesser BP-lowering effects. Even in the ALLHAT7 study, it could be argued that the claimed superiorities of a diuretic (usually paired with a β blocker) over other regimens was not seen in preventing the primary study end point of coronary events despite a clear overall BP advantage, especially in black patients. Indeed, the current Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) was just stopped prematurely because, according to the press release of its Organizing Committee, a diuretic-β blocker combination (somewhat similar to the one in ALLHAT except that in this trial a β blocker was the primary comparative medication) was found to be significantly inferior to an angiotensin-converting enzyme inhibitor—calcium channel blocker combination in preventing major CV outcomes. A major report by Lewington et al.16 has provided some of the most powerful data to demonstrate how small BP differences could account for large relative effects on clinical events. This is shown very clearly in the Figure, but careful scrutiny of this information shows an equally dramatic finding: the powerful relationship of age to events. Remarkably, this Figure shows, for instance, that people in their 60s with normal systolic BPs (<120 mm Hg) have a similar prognosis to that of people in their 40s with severe hypertension (>180 mm Hg systolic). From a BP point of view, the data from this report have been used to make the argument that a 20 mm Hg increase in systolic BP can account for a doubling of the risk of a fatal coronary event, but it is equally evident, and potentially of major clinical importance, that this same doubling of mortality can be explained separately by an 8- to 10-year increase in age. Studies with such modern imaging tools as coronary intravascular ultrasound show that there is inexorable progression of atherosclerosis with age that often cannot be fully explained by the usual CV risk factors. Obviously, no matter how BP-focused we may be, attacking this age-related progressive vascular disease is inevitably part of optimizing treatment outcomes in our patients, regardless of whether or not they are hypertensive. In this respect, there has been some tantalizing recent news. In the Comparison of Amlodipine vs. Enalapril to Limit Occurrences of Thrombosis (CAMELOT)17 study performed in people with coronary disease but with essentially normal BPs, a high dose of a dihydropyridine calcium channel blocker, despite only minimal BP effects, prevented progression of intravascular ultrasound-measured coronary atheroma volume, seemingly doing better than either a placebo or a low-dose angiotensin-converting enzyme inhibitor. The Reversal of Atherosclerosis With Aggresive Lipid Lowering (REVERSAL)18 trial, using high-dose statin therapy (that incidentally reduced plasma high-sensitivity C-reactive protein) in patients with coronary disease, was also able to demonstrate that progression of atheroma size could be prevented. These findings with calcium antagonists and statins appear to identify an exciting direction for research. Other drugs with potential value might include high doses of blockers of the renin-angiotensin system, advanced glycosylation end-product crosslink breakers like alagebrium, peroxisomal proliferatoractivated receptors, γ, α, and δ, and sophisticated conventional and biologic anti-inflammatory products. Based on what we are starting to learn about age itself being a powerful vascular risk factor, is there a potential for innovative therapies to turn back the clock? Should we be testing prophylactic therapy with such strategies, even in the absence of traditional risk factors? For those of us with a special interest in hypertension–and bearing in mind that so many of our patients are at vulnerable ages–this CV paradigm should be well worth pursuing.