Robert E. Hobbs, MD, The Kaufman Center for Heart Failure, Department of
Cardiology, Cleveland Clinic Foundation, Cleveland, OH, USA.

Guidelines for managing heart failure recommend angiotension-converting enzyme (ACE) inhibitors, beta-blockers, diuretics, digoxin, and aldosterone antagonists as standard therapy in order to improve morbidity and mortality. Angiotensin receptor blockers (ARBs) are considered second-line agents for patients who are intolerant of ACE inhibitors due to cough or angioedema. Because ACE inhibitors do not completely block the formation of angiotensin II and aldosterone, add-on therapy with an ARB has been evaluated in several clinical trials. In general, the results were mixed. Combination therapy with an ACE inhibitor and an ARB may improve morbidity and probably mortality, but with an increased incidence of hypotension, hyperkalemia, and azotemia. This approach could be considered in patients who remain symptomatic despite optimal doses of standard agents.

Key words: angiotensin receptor blockers, ACE inhibitors, heart failure, vasodilators, hyperkalemia.

With the lifelong probability of developing hypertension estimated to be as high as 90%, it is little wonder that each subsequent hypertension treatment trial is met with much media frenzy. The 2002 ALLHAT indication that thiazide-like diuretics were at least as effective as calcium antagonists, ACE inhibitors or alpha-adrenergic blockers in reducing CV events in hypertensive patients made a major impact on physicians and patients alike, casting doubt on the efficacy of new drug classes over old and inexpensive standbys.

Predictably, the ALLHAT conclusions were barely digested when a new and apparently contradictory study appeared in the New England Journal of Medicine. The Second Australian National Blood Pressure Study (ANBP2) examined 6,083 hypertensive subjects aged 65-84 years in a prospective, randomised, open-label trial. The patients were tracked for an average of 4.1 years to determine the benefits of treatment with ACE inhibitors versus diuretics.

The treatment aim was to achieve a systolic blood pressure reduction of at least 20mmHg and a diastolic blood pressure reduction of at least 10mmHg. Blood pressure was recorded annually, and the primary endpoint was all CV events or death from any cause. While the diuretic group experienced greater blood pressure reduction than the ACE inhibitor group at years one and two, by the end of the study blood pressure had been similarly reduced in both groups, indicating that both treatments were equally effective in minimising BP.

In the diuretic group, 736 CV events or deaths from any cause were observed, versus 695 in the ACE inhibitor group, representing an 11% reduction in the total burden of CV events or death from any cause in the ACE inhibitor group. This result was significant for the male patients only, in which a 17% reduction was noted. A further breakdown of the results revealed a 12% reduction for all first CV events in the ACE inhibitor group compared with the diuretic group. There were no significant differences between treatment arms in rates of fatal CV or non-CV events, with the exception of the rate of fatal strokes which was in fact higher in the ACE inhibitor group.

The results of this trial at first seem to oppose those of ALLHAT, but upon closer examination the two trials are not necessarily comparable. Although the same classes of antihypertensives were used in each, the specific agents differed, rendering a general claim about diuretics versus ACE inhibitors inconclusive. The subjects in the ANBP2 also were comparatively healthy to those in ALLHAT.

It is important to remember that ALLHAT was not the first antihypertensive study, and ANBP2 will surely not be the last. The emergence of subsequent trials will inevitably "prove" the superiority of one class of agents over the others, but the bottom line is that different treatments are appropriate for different patients based on unique needs. A patient's history and response should determine the ideal course of therapy, not the latest piece of news that has snared the media's fancy.

Source

1. Wing LMH, Reid CM, Ryan P, et al. A comparison of outcomes with angiotensin-converting-enzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med 2003;348:583-92.

Introduction
The publication of the landmark Heart Outcomes Prevention Evaluation (HOPE) Study¹ in the New England Journal of Medicine in January 2000 was greeted by a great deal of excitement in the medical community. In essence, the trial confirmed beyond a doubt the cardiac and renal protective benefit of ACE inhibition and extended the patient base in whom ACE inhibition has been proven effective. Our understanding of the cardioprotective nature of ACE inhibitors has been built over the years by the various mega-studies that have been conducted, dating back to the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS),² published in 1987, which showed a 31% survival advantage for ACE inhibition in New York Heart Association (NYHA) class IV heart failure patients. Thirteen years and more than a dozen large trials later, the HOPE study has confirmed that patients need not be so sick--indeed, need only be considered at risk for cardiovascular events--for ACE inhibition to show similar benefits. Looking down the list, from CONSENSUS to HOPE and several landmark trials in between, one would be hard pressed to find a class of agents with a wealth of compelling evidence comparable to that accumulated for ACE inhibitors.

Main Results and Significance
The HOPE study investigators found that 17.

D'Arcy L. Little, MD
Chief Resident, Family Medicine, Sunnybrook Health Science Centre, North York, Ontario

Background

Angiotensin Converting Enzyme inhibitors (ACE inhibitors) interact with the body's renin-angiotensin-aldosterone axis. Angiotensinogen (alpha-2 globulin) is converted to angiotensin I or AG-I (inactive) by renin released by the kidney in response to renal ischemia, hypotension, hypovolemia or depletion of sodium ions. ACE inhibitors block the conversion of AG-I to AG-II. AG-II is a powerful vasoconstrictor, as well as a releaser of aldosterone (an adrenal cortical hormone that leads to sodium retention in the kidney), see Figure 1.

 

FIGURE 1

Despite the fact that elderly patients have lower levels of plasma renin than their younger counterparts, ACE inhibitors have been evolving as important agents in the treatment of several cardiovascular diseases in both younger and older patients.