One might have thought that the debate regarding initial therapy for the management of hypertension had been settled after publication of numerous clinical trials including the recently reported Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).1,2
As reported and reviewed in The Journal of Clinical Hypertension and other journals,1–5 ALLHAT was a randomized, blinded trial that concluded that coronary heart disease event outcomes were similar with a diuretic-based regimen when compared with an angiotensin-converting enzyme (ACE) inhibitor- or calcium channel blocker (CCB)-based program. However, results, with some secondary outcomes (i.e., heart failure with the CCB/diuretic comparison and combined cardiovascular disease events with the ACE inhibitor/diuretic comparison) favored the diuretic regimen. There were some problems with the protocol and addon medication choices in this trial. Editorials criticizing this study have recently been published.6 In addition, statements have been made that the National Heart, Lung, & Blood Institute/National Institutes of Health, sponsors of the study, were playing “politics” in the recent recommendations to use a thiazide diuretic as preferred therapy in the management of hypertension.
Results of the recently published Australian National Study (ANBP 2) in the New England Journal of Medicine7 have been used to refute the ALLHAT results and to pose the question, who should be believed? The ANBP 2 hypertension treatment trial reported that an ACE inhibitor-based regimen proved to be marginally more effective than a diuretic regimen in reducing morbidity and mortality outcome. But the ANBP 2 study evaluated a different population. Fewer than 5% of the patients were black; in ALLHAT 35% were black. It is well known that black individuals respond better to diuretics than to ACE inhibitors. In fact, in ALLHAT diuretics reduced systolic blood pressure in black subjects by 4-mm Hg more than the ACE inhibitor. There were 40% fewer strokes in blacks than in whites in the diuretic-based compared with the ACE inhibitor-based group. Most of the difference in benefits between medications in ALLHAT related to a better outcome in black patients. As noted in an editorial in the last issue of JCH,5 it is conceivable that if diuretics had been used as a second-step drug in the ACE inhibitor group, the differences in blood pressures would have been less and differences in outcome minimized.
The ANBP 2 study was not blinded to medications and only 60% of patients remained on the initial study drug. More than 25% of patients crossed over from diuretics to the ACE inhibitor and vice versa. Although the ACE inhibitor group in this trial experienced fewer cardiovascular events than the diuretic group, most of the benefit occurred in male patients. There were no statistically significant differences in outcome between ACE inhibitor and diuretic use in women. This is difficult to explain.
It is easy to criticize the ANBP 2 trial; faults can also be found with ALLHAT. A perfect trial has not been designed or carried out. But are the results of ALLHAT and ANBP 2 truly different or are we nitpicking them to the point of confusion? We can believe both results with some qualifications.
When will we learn that the debate about the treatment of hypertension is not about “my drug is better than your drug” or “my study is better than your study”? It should be about getting as many people to goal blood pressures as possible with the least intrusion on their life or their pocketbook. The ALLHAT study did not report that ACE inhibitors or CCBs were not highly effective or useful. Numerous previous trials have reported that these agents reduced morbidity and mortality in hypertensive patients with or without diabetes, with or without renal disease. Numerous publications have detailed their usefulness in management; the ALLHAT study results in no way suggested that these agents not be used, that they were dangerous, or that they were not effective.
What the ALLHAT results should have done was put to rest some of the arguments that have been repeatedly advanced through the years against the use of diuretics. These arguments had centered around: 1) metabolic changes; 2) lack of effectiveness in reducing coronary heart disease events; and 3) possible deleterious effects in diabetics. These have led to less use of diuretics over the years. This clearly was the wrong approach to treatment if more hypertensives were to be controlled at goal levels. Despite the trial results, many investigators are reluctant to believe the ALLHAT data. Is it because diuretics are effective, inexpensive, and well tolerated—and that there is the concern that if more diuretics are used, the use of other medications will decrease? This is a truly narrow view of the approach to management of hypertension.
There is little reason to continue the ongoing, intense, and often heated discussions. Hypertension is a ubiquitous disease; there is a need for many different kinds of therapies. If at the moment only 24 or 25 million people of the 40 million with hypertension are under treatment and if at the moment only about 30% of all hypertensives are well controlled at goal levels, it is obvious that there is a need to improve treatment efforts. This is what we should be discussing, not whether one study is better than another. This may seem naive, i.e., to believe that we can approach the problem with total objectivity, but it is apparent that more heated debates will only serve to confuse, not clarify. If the number of patients under therapy was increased by five or 10 million, and goal pressures were more vigorously pursued, everyone would benefit. Since goal pressure may not be achieved in many patients with fewer than two or three medications, it is obvious that there will be a need for the use of different antihypertensive drugs, not just diuretics or ACE inhibitors. There is little doubt regarding the benefits of ACE inhibitors, CCBs, and medications that were not studied in ALLHAT or ANBP 2, the angiotensin receptor blockers, as well as β blockers and diuretics. There is little doubt that all of these drugs either separately or in various combinations should and will be used more, not less, frequently in the future if we set appropriate treatment targets. What ALLHAT was telling us is let's get over the nagging concerns about diuretics and get on with the business of treating more patients effectively. Objections to ALLHAT are muddying the waters—the results indicate that diuretics are effective agents and should be used in the management of most hypertensive patients either as first-step or add-on therapy.
Many studies have shown that all of the presently available drugs are effective.8 ALLHAT and ANBP 2 appear to report somewhat different results; these can be explained, but are the subtle differences enough to result in confusing messages to practitioners? Let's avoid the inevitable meta-analyses that will follow these studies. When studies are pooled, and include trials with different populations, different randomization techniques and different durations, conclusions are not always helpful. Undoubtedly, some debates will continue and may be useful, but we should try not to forget the overall objectives of treating hypertension—to reduce morbidity and mortality. It should be remembered that a rising tide lifts all ships. If we treat hypertension more effectively, if we treat more patients with appropriate medications that have been shown to be effective, everyone will benefit.