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J Am Coll Cardiol, 2007; 49:40-42, doi:10.1016/j.jacc.2006.10.028
(Published online 13 December 2006). © 2007 by the American College of Cardiology Foundation |
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Cardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts.
* Reprint requests and correspondence: Dr. Marc A. Pfeffer, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115. (Email: mpfeffer{at}rics.bwh.harvard.edu).
In the 1950s, while the medical community considered hypertension to be "essential" for organ perfusion, the actuarials of life insurance companies had already quantitated the negative impact of higher BP on longevity and had adjusted premium rates accordingly (2). The concepts of coronary heart disease risk factors born from decades of careful epidemiologic observations from the Framingham Heart Study decisively establish the importance of elevated arterial pressure as a risk for premature cardiac death (3). Long-term follow-up data from the registry of MRFIT (Multiple Risk Factor Intervention Trial) of over 300,000 middle-aged men also left an indelible imprint on physicians regarding the graded hazard of higher arterial BPs (4).
Although hypertension is a promiscuous risk factor, importantly involved in the pathogenesis of most major cardiovascular morbidities such as stroke, myocardial infarction, aneurysm formation, and rupture as well as the development of the syndrome of congestive heart failure, elevated BP is the major population-attributable risk factor for heart failure. Indeed, recent estimates from the Framingham study indicate that in 40% of men and 60% of women persistent hypertension is the predominant contributing factor for the development of heart failure (5).
The full impact and the importance of these epidemiologic observations could only be realized in the late 1960s to early 1970s, after the pioneering Veterans Administration Cooperative Studies. Led by the late Dr. Edward Fries and using the developing tool of the randomized placebo-controlled trial, 2 Veterans Administration trials showed in patients with severe hypertension that pharmacologic therapy to lower arterial pressure would reduce the risk of experiencing major cardiovascular events (6,7). From these humble beginnings, many more extensive randomized placebo-controlled trials have firmly and irrefutably established the importance of lowering BP to reduce cardiovascular risk. Indeed, the benefits of antihypertensive therapy are so clear that the era of placebo-controlled trials in hypertension has been completed with definitive evidence of reductions in risk of cardiovascular death, stroke, and myocardial infarction and an approximate halving of the incidence of heart failure (8–10). Today’s debates focus on whether a particular class of antihypertensive therapy offers more clinical benefits beyond its peripherally determined BP lowering effects without any further question regarding the vital importance of reducing BP in patients with hypertension (11).
Despite these clear data showing that lower BP is better, physicians caring for critically ill patients, such as those presenting with decompensated heart failure or acute myocardial infarction, have had a very different perspective. In these settings, lower arterial pressure portends poor outcomes (12–14), especially when coupled with clinical evidence of pulmonary congestion, the hallmark of a tenuous hemodynamic condition produced by inadequate cardiac output. Even in less acute settings such as ambulatory patients referred for cardiac transplant evaluation (15), or participants in heart failure clinical trials (16), lower arterial BP consistently emerges as an independent prognostic factor for higher rates of death.
Approximately 3 decades ago, Cohn and Franciosa (17) reasoned that using an arterial vasodilator to reduce peripheral resistance could "unload" the failing left ventricle, thereby improving stroke volume and cardiac output without necessarily further lowering arterial pressure. In animal and early human studies, he honed this concept of afterload reduction with acute nitroprusside infusions. It is quite fitting that the V-HeFT (Veterans Administration Heart Failure Trial) study served as the pioneers for testing this unloading concept on ambulatory patients with symptomatic heart failure and depressed left ventricular function (18). In this truly "classic" trial, there were 2 experimental "unloaded" groups, prazosin and the combination of hydralazine and isosorbide dinitrate in addition to placebo. In this first trial to show a favorable alteration in the prognosis of patients with heart failure, survival was improved with the combination of hydralazine and isosorbide dinitrate, and the mortality rate for the group on prazosin was similar to that for placebo. However, at 1 year, BP change in the groups were –0.3 mm Hg, +0.6 mm Hg, and –4.6 mm Hg in the placebo, hydralazine and isosorbide dinitrate, and prazosin groups, respectively. This clear dissociation between BP lowering (greatest with prazosin, least with hydralazine and isosorbide dinitrate) and clinical outcomes was an early indication that the benefit of using antihypertensive agents in patients with heart failure was not necessarily reflected by or related to changes in arterial BP. The MERIT-HF (Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure) study provided another notable example whereby antihypertensive therapy (beta-blocker) in patients with heart failure resulted in an increase in BP compared with placebo and, much more importantly, a major improvement in survival (19). More recent improvement in cardiac function with nonpharmacologic approaches to heart failure such as cardiac resynchronization therapy in patients with a prolonged QRS duration further illustrate the paradoxical but not currently unforeseen relationship between an increase in BP and improvement in clinical outcomes in these patients (20).
In this historical context, it has now been 2 decades after the first demonstration of the efficacy of the combination of hydralazine and isosorbide dinitrate was re-evaluated in a contemporarily relevant fashion, i.e., on top of angiotensin-converting enzyme inhibitors and beta-blockers (21) in an African-American population with New York Heart Association functional class III and IV heart failure and reduced systolic function by the A-HeFT study investigators. Although the trial was designed with a complex combined outcome of mortality, morbidity, and assessment of quality of life primary efficacy measure, it was stopped before scheduled completion by its safety monitoring committee because of a clear reduction in the more straightforward outcome of death. The new information from Anand et al. (1), indicating that although overall there was a lowering of arterial pressure with the combined vasodilators, the improvements in clinical outcomes were not related to the BP changes, comes full circle with the original V-HeFT study (1,18).
That these seasoned heart failure investigators up-titrated this potent antihypertensive regimen 3 to 5 days after randomization assessing tolerability by telephone clearly underscores that, in contrast to hypertension, the BP response was not a therapeutic target in ambulatory heart failure patients. The word ambulatory is added as a qualifier and reminder that in more compromised patients with impaired cardiac function there is a major concern of reducing central arterial pressure below autoregulatory ranges for cerebral, renal, or cardiac perfusion. In this context, the treating physician "loves" every mm Hg and wants to administer vasodilators without producing a decrease in peripherally determined BP. However, in the majority of the walking well patients, the medical community has learned to "hate" hypertension and we use the sphygmomanometer to direct therapy to prevent patients from developing hypoperfusing hypotensive conditions in which the same agents are administered without the objection of reducing arterial pressure. This apparent paradox underscores the fundamental tenet of the individualization of medical care.
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2 Dr. Pfeffer consulted for NitroMed for 1 day.
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