ALLHAT: Diuretic the best bet as a first step in hypertension

Susan Jeffrey

December 17, 2002

Washington, DC - Long-awaited results of the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) show that the incidence of fatal CHD and nonfatal MI, the primary end point, was identical with the diuretic chlorthalidone, the ACE inhibitor lisinopril (Zestril® - AstraZeneca), and the calcium antagonist amlodipine (Norvasc® - Pfizer)[1]. However, better results in secondary outcomes and a lower cost give the diuretic the edge as the first-line antihypertensive agent of choice, the researchers conclude. Results were presented at a press conference to coincide with their publication in the Journal of the American Medical Association.

Steering committee chairperson Dr Curt D Furberg (Wake Forest University Baptist Medical Center, Winston-Salem, NC) told heartwire that given current prescribing practices, by the researcher's calculations, it is possible that some $10 billion is spent each year on less-than-optimal drug treatments for hypertension, causing some 60 000 unnecessary events.

We have documented that we are not spending drug dollars wisely and in addition to that waste, we are also causing a large number of events that could be averted if people switched to diuretics.

"We have documented that we are not spending drug dollars wisely and in addition to that waste, we are also causing a large number of events that could be averted if people switched to diuretics," he said.

For new patients, diuretics should be the first choice, and for patients already on multiple drugs for hypertension, a diuretic should be among them, based on these data, the researchers conclude.

A fourth arm of the trial testing the alpha blocker doxazosin (Cardura® - Pfizer) was discontinued in January of 2000, when it became clear that cardiovascular events and hospitalizations for congestive heart failure were higher with this agent compared with chlorthalidone. Those results were published previously by the Journal of the American Medical Association.

Theoretical, but unproven, advantages of new agents

When ALLHAT was launched in 1994, the aim was to compare outcomes with newer antihypertensive agents with standard diuretic treatment with chlorthalidone. While they may have theoretical advantages over diuretics and have been shown to reduce cardiovascular events vs placebo, the value of the new agents relative to diuretics has not been shown, the researchers write.

The trial, supported by the National Heart, Lung, and Blood Institute, compared doxazosin, lisinopril, and amlodipine with chlorthalidone; agents were selected to represent their class, and the ALLHAT paper notes that it should be possible then to extrapolate the results seen in this study to all agents in these classes.

More than 44 000 patients were initially randomized, but that number dropped to 33 357 after the halt of the doxazosin arm. Eligible patients were 55 years of age or older, with hypertension and at least 1 other risk factor. They were randomized to receive chlorthalidone (12.5 mg to 25 mg/day, n=15 255), amlodipine (2.5 mg to 10 mg/day, n=9048), or lisinopril (10 mg to 40 mg/day, n=9054). Almost 50% of participants were women, and 35% were black.

Those previously treated for hypertension continued on their drugs until the morning after randomization, when they began the study drug, unless a tapering period was required for safety reasons. If blood pressure was not controlled below 140/90 mm Hg with the step-1 drug, open-label treatment with atenolol, clonidine, or reserpine was allowed at the physician's discretion, but none of the drugs in any of the classes of agents being tested was allowed according to the protocol.

The primary end point was the combined incidence of fatal CHD or nonfatal MI by intention to treat. Secondary outcomes were all-cause mortality, stroke, combined CHD (fatal CHD, nonfatal MI, coronary revascularization, or angina with hospitalization), or combined cardiovascular disease (combined CHD plus stroke, treated angina without hospitalization, heart failure, and peripheral arterial disease).

After a mean follow-up of 4.9 years, a primary outcome event occurred in 2956 of the patients, with virtually identical frequency in each group.

ALLHAT: Primary end point


6-year rate of events (%)

Relative risk

(95% CI)

p vs chlorthalidone




11.4 0.99 (0.91-1.08) 0.81


11.3 0.98 (0.90-1.07) 0.65

 All-cause mortality was also not different between groups. Five-year systolic pressures were significantly higher with both amlodipine (0.8 mm Hg, p<0.03) and lisinopril (2 mm Hg, p<0.001) compared with chlorthalidone, but 5-year diastolic pressures favored amlodipine (0.8 mm Hg lower than chlorthalidone, p<0.001).

While there was no difference in the primary outcome, differences were seen in several secondary outcomes. These outcomes were similar between amlodipine and chlorthalidone, with the exception of a higher 6-year rate of heart failure with amlodipine.

Secondary outcomes: Amlodipine vs chlorthalidone

End point

Amlodipine (%)

Chlorthalidone (%)

Relative risk (95% CI)


6-year rate of heart failure

10.2 7.7 1.38


When lisinopril and chlorthalidone were compared, secondary outcomes in lisinopril-treated patients showed higher 6-year rates of combined CVD, stroke, and heart failure.

Secondary outcomes: Lisinopril vs chlorthalidone

End point

Lisinopril (%)

Chlorthalidone (%)

Relative risk (95% CI)


6-year rate of combined CVD

33.3 30.9 1.10

6-year rate of stroke

6.3 5.6 1.15

6-year rate of heart failure

8.7 7.7 1.19

Safety outcomes showed similar rates of hospitalization for gastrointestinal bleeding between groups, but angioedema occurred 4 times more often in patients randomized to lisinopril than to chlorthalidone.

Cholesterol levels were higher and the prevalence of hypokalemia and new diabetes was more common with chlorthalidone compared with the other groups after 2 and 4 years of follow-up, the researchers note. "Overall, these metabolic differences did not translate into more cardiovascular events or into higher all-cause mortality in the chlorthalidone group compared with the other 2 groups," they add.

The treatment effects were consistent across all subgroups by sex and diabetic and baseline CHD status. For stroke and combined CVD, however, there was a significant differential effect by race, with higher risks for these outcomes seen among black participants on lisinopril.

ALLHAT steering committee member Dr Jackson T Wright Jr (Case Western Reserve University, General Clinical Research Center, Cleveland) told heartwire that the results would appear to run counter to findings in the African-American Study of Kidney Disease and Hypertension (AASK) trial, of which he was the principal investigator. In AASK, an ACE inhibitor was superior to both a CCB and a beta blocker in preventing progression to renal disease. However, he noted, in that study, cardiovascular outcomes were not the main interest.

"In patients with kidney disease or with major risk for renal events, ACE inhibitors clearly should be considered, but in those where cardiovascular events are the greater risk, the thiazide-type diuretic is the preferred agent," Wright said.

Several subgroup analyses of the ALLHAT data are under way, including a cost-effectiveness analysis.

End of a "passionate" debate

In an editorial accompanying the publication, Dr Lawrence J Appel (Johns Hopkins University, Baltimore) writes, "Quite simply, [ALLHAT] is one of the most important trials in antihypertensive therapy." Experts have "passionately debated" which agent is best for initiation of therapy, a question with "enormous clinical, public health, and economic implications." The major finding of ALLHAT, a "striking and unequivocal null result," is particularly noteworthy, he writes, "because there is no cost-quality trade-off; the most effective therapy is also the least expensive."

"An important next step is to update policy documents to emphasize the unambiguous role of thiazide diuretics as initial therapy," Appel says. "Concomitantly, a concerted effort should be made to educate physicians, medical residents, and other healthcare professionals, as well as those who develop guidelines for provider networks and health maintenance organizations."

Quite simply, ALLHAT is one of the most important trials in antihypertensive therapy.

Finally, although ALLHAT answers the question of what drug to start with, Appel makes the point that by 5 years, patients were taking an average of 2 drugs. So which drug should be used next? "While physicians may be tempted to use an on-patent CCB or ACE inhibitor, there is an impressive armamentarium of low-cost, off-patent drugs that can be used as add-on therapy after diuretics," he writes, including a CCB, 3 ACE inhibitors, and several beta blockers. "A logical strategy that incorporates these low-cost agents may differ from those that are more popular, but contemporary strategies may be somewhat artificial because of the heavy influence of marketing that preferentially leads to the use of expensive medications."

Market forces

Dr Robert M Califf (Duke University Medical Center, Durham, NC) was a member of the Data and Safety Monitoring Board for ALLHAT. The lesson of these findings, he says, is that a newer drug is not necessarily a better drug, despite heavy marketing to the contrary. "It's one thing to say we have new drugs and they're a little bit better, but I think this should really cause us to stop and think about defining what 'better' means in terms of real outcomes and not sales pitches," Califf told heartwire .

In particular, a lot of "hype" had focused on ACE inhibitors, he said, and most would have predicted lisinopril would reduce mortality. "If anything, ACE inhibitors were probably the biggest losers in the trial," he said. "If you add up everything, particularly their relative inefficacy in black people, there's really no particular advantage to starting with an ACE inhibitor." Amlodipine, on the other hand, had previously "taken a huge beating, and it came out looking pretty good, although still not as good as the diuretics."

The real news here is, who knows what other inexpensive generic drugs that are actually better are not being used because there's no one out there selling them to doctors?

"The real news here is, who knows what other inexpensive generic drugs that are actually better are not being used because there's no one out there selling them to doctors, who depend on sales reps for their information?" Califf said.

The impact of market forces in the general adoption of these findings has actually been anticipated by the ALLHAT investigators, who, Furberg told heartwire , have already put in place an "elaborate" system for dissemination of these results, in which investigators will be heavily involved.

We anticipate that if we leave it to the regular market forces, our message will not get across.

"We're doing that because we anticipate that if we leave it to the regular market forces, our message will not get across," Furberg said. "We know that from the experience in the doxazosin arm. The company [Pfizer] put a spin on the findings and undermined them. So we anticipate some spin; we don't know what it's going to be."

Dissemination and adoption of the final ALLHAT results, then, is considered a key outcome, so that more comparative, industry-independent trials such as this one will continue to be funded by NIH. "If it doesn't affect practice, then I'm not sure that ALLHAT was a success," he said.

Quarrel with conclusions

The surprising ALLHAT results, in particular the poor showing made by the ACE inhibitors, are already being met with some resistance in the clinical community. Perhaps most vocal of the physicians heartwire spoke to is Dr Michael Weber (SUNY Downstate College of Medicine, Brooklyn, NY), who says he "strongly" disagrees with the conclusions made by the ALLHAT investigators that diuretics should be the preferred first step for hypertension therapy.

"The results of the study were driven very much by the experience in the black patients, in whom I would acknowledge that the data do seem to support the idea that a diuretic may be the most appropriate starting point for their therapy," Weber said.

The findings with lisinopril, though, may reflect the fact that ACE inhibitors are known not to work as well in African Americans, as evidenced by the overall poorer blood pressure control in the lisinopril group, he said. Compounding this was that by design, the add-on therapy was a beta blocker, which, he said, "is not logical because they're not sufficiently complementary in their actions. The treatment of choice to add to an ACE inhibitor like lisinopril would be a diuretic or a calcium channel blocker and of course they were prohibited by the study design. That is a major issue, and as a result, blood pressure control was significantly poorer in the lisinopril group, and that can explain a lot of observations in this paper."

Here is a huge clinical trial that's taken a lot of time, a lot of money, a lot of energy, and the participation of a lot of investigators, and in the end, it comes out with a superficial economic and political conclusion that seems to run counter to the scientific findings.

He also found the high incidence of heart failure in the amlodipine and to some extent, lisinopril groups "surprising," given that ACE inhibitors in particular are actually an effective treatment for heart failure. He speculated that the diuretic effects of chlorthalidone, which would relieve the clinical signs of heart failure such as edema and rales, would perhaps mask the existence of HF in some of those patients.

Finally, he pointed out that all-cause mortality was not different among the 3 groups, as would be expected if chlorthalidone were really preventing serious CV events. Mortality even trended toward being higher with chlorthalidone in nonblack subjects than in either of the other drug groups, he said, and "to me, that's not the basis of superiority."

"Here is a huge clinical trial that's taken a lot of time, a lot of money, a lot of energy, and the participation of a lot of investigators, and in the end, it comes out with a superficial economic and political conclusion that seems to run counter to the scientific findings," Weber concluded.

As for the "passionate debate" described by Appel, Weber dismissed this as an old quarrel with no current clinical relevance. Whichever agent is used to start therapy in new hypertensives, the fact is most patients end up on a combination of therapies. "It really seems to be arguing over trivia when you say, well, I would start with A rather than B, when in the end you're going to finish up with A plus B, or at least you ought to finish up with A plus B."

Dr Franz Messerli (Ochsner Clinic Foundation, New Orleans) said the "most disappointing aspect" of the ALLHAT findings was the results seen with lisinopril. "It deflates HOPE (the Heart Outcomes Prevention Evaluation) completely, because it would indicate that there is no specific cardioprotective or vascular protective effect of the ACE inhibitor," Messerli said. "This is particularly true with the stroke protection that was touted in HOPE to be independent of blood pressure."

He also made the point that the ACE inhibitor was probably disadvantaged by the fact that add-on therapy was often with a beta blocker. "In most physicians' minds, this is not a very efficacious combination," Messerli said.

Another trial similar to ALLHAT, called the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), is comparing an ACE inhibitor/calcium channel blocker combination, amlodipine and perindopril, with a diuretic/beta blocker combination, atenolol and bendrofluazide. "That's a logical way of doing it, and obviously we look forward to the results of this trial," he said.

Messerli and Weber are currently preparing an editorial outlining some of these views that they expect will be published in an upcoming issue of the Lancet.

Still a place for ACE inhibitors

Furberg acknowledged that the order of add-on therapies probably disadvantaged the ACE inhibitor in this trial, noting that in "real life" patients on ACE inhibitors would receive diuretics, not beta blockers.

"The complicating issue with the interpretation of ALLHAT is that we didn't get the same blood pressure reduction with the ACE inhibitor, and so if the ACE inhibitors come out a little bit behind, we don't know if that is because of an ACE inhibitor effect or that we didn't get the same blood pressure reduction, and that applies primarily to African Americans," he said. Because blood pressure reduction was similar with the diuretic and the CCB, the superiority of the diuretic in that comparison is clear, he said, but more information from studies other than ALLHAT will be required to get a clearer answer on the ACE inhibitors, particularly in African American populations.

But, he adds, "ACE inhibitors have proven effects in a lot of other patient groupsheart failure, postinfarction, and so onand so particularly in patients with comorbidity, I think they should be considered."

MEDIAPULSE: ALLHAT hits the newsstands


ALLHAT was all over the health news pages in wake of the trial, from the New York Times to the Daily Oklahomanto the Sydney Morning Herald.

For the most part, the take-home message was the same one that came with the ALLHAT press release: cheap, generic diuretics are as good or better than the newer, more expensive drugs. Patients should not discontinue what they are currently using but should consult a doctor about incorporating a diuretic into their treatment.

Add a comment from a cardiologist working at the local medical center or university, and 90% of the coverage is accounted for.

Both the Wall Street Journal and the New York Times go further, devoting column inches to the question of whether marketing hype for new drugs causes effective generic options to be overlooked.

The Journal quotes Dr Robert Califf as observing, "You'd like your doctor to recommend what is best for you based on knowledge, not on what a drug company sales rep told him." The Journal also notes that drug companies push branded drugs through funding of CME, patient advocacy groups, and marketing campaigns, all of which stopped for diuretics when they began to go off patent.

In the face of an ad-driven culture that favors the new, "the older drugs are going to get left behind whether they're better or not," says Dr. Califf.

The Times relies on Dr Curt Furberg, who says that the companies trumpeted the new drugs and bashed diuretics "more based on opinion than fact." Furberg claims it's now obvious that a lot of money was wasted, and possible harm was done to patients in pushing the newer drugs instead of using the diuretics

Both articles note that the pharmaceutical industry has been quick to point out that most patients require more than 1 drug to control blood pressure and that not all patients can tolerate diuretics.

The Times quotes a representative from Merck, Christopher Loder, who says that marketing efforts had not induced doctors to prescribe the wrong drugs. "Physicians still are in control. Doctors will not prescribe a medicine unless it delivers value."

-Laurent Castellucci


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