ALLHAT -- Criticisms and Contradictions: An Expert Interview With Michael A. Weber, MD

Linda Brookes, MSc

Disclosures

February 21, 2003

The highly publicized conclusion of the Antihypertension and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) was presented in mid-December of last year at a press conference in the National Press Club in Washington, DC (see Related Links for more details on the press conference and other ALLHAT related articles). As announced by the trial investigators, the results showed that thiazide-like diuretics "are unsurpassed in lowering blood pressure, reducing clinical events, and tolerability, and . . . are less costly," and that they "should be considered first for pharmacologic therapy in patients with hypertension."[1]

The results and their manner of presentation have drawn criticism by the past President of the American Society of Hypertension, Michael A. Weber, MD, Professor of Medicine and Associate Dean for Research at the State University of New York, Downstate College of Medicine, Brooklyn. While acknowledging that ALLHAT confirmed the value of diuretics either as single agents or in combination with other drugs in hypertension, in a commentary published in the Journal of Clinical Hypertension, Dr. Weber challenges the design, results, and interpretation of the results of the largest-ever hypertension study.[2]

Dr. Weber elaborated his criticisms in an exclusive interview granted to Medscape Cardiology, wherein he questioned some of the ethics of ALLHAT, denounced the way in which the results of the trial were announced to the media, and expressed his concerns about the incorporation of the ALLHAT recommendations into the upcoming Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VII) guidelines.

Michael Weber: "We Beg to Differ..."

According to Dr. Weber, many hypertension specialists do not accept the ALLHAT investigators' conclusions, and this dissension was further captured in an article in The Wall Street Journal (February 13)[3] that reported skepticism among physicians about ALLHAT. Coincidentally, the results of the large Second Australian National Blood Pressure Study (ANBP2), which contradict those of ALLHAT by showing superiority of ACE inhibitors over diuretics as first-line therapy in elderly hypertensive patients, have just been published in The New England Journal of Medicine.[4]

No Valid Claim to Superiority in ALLHAT

 

The scientifically correct interpretation of ALLHAT was that there was no valid basis for any individual drug to claim superiority.

The first point emphasized by Dr. Weber was that the primary endpoint of ALLHAT, fatal coronary heart disease and nonfatal myocardial infarction (MI), showed no differences between the diuretic (chlorthalidone), the ACE inhibitor (lisinopril), or the calcium channel blocker (CCB; amlodipine). All claims that chlorthalidone was better than the other 2 drugs rested solely on secondary endpoints. Thus, according to Dr. Weber, the scientifically correct interpretation of ALLHAT was that there was no valid basis for any individual drug to claim superiority. A generous conclusion, he suggested to Medscape, would be that there is not going to be a big difference in antihypertensive effect among any of these drugs.

Trial Design: A "Big Issue"

 

Dr. Weber emphasized that the main problem with ALLHAT was its design.

In his conversation with Medscape, Dr. Weber emphasized that the main problem with ALLHAT was its design. According to the trial protocol, if patients did not achieve goal pressure on a properly titrated dose of the initial study drug, the physician could add a second drug, provided that second drug was not a study drug. As a result, and unlike ANBP2, the trial did not achieve equal blood pressure control with the diuretic, ACE inhibitor, and CCB-based regimens. Rather, because the ALLHAT research protocol prohibited the use of diuretics, ACE inhibitors, or CCBs as additive treatments, beta-blockers were the main drugs added. According to Dr. Weber, this clearly helped chlorthalidone, the eventual "winner," since administration of a diuretic and a beta-blocker provides a logical and effective blood pressure-lowering combination. Even the addition of a beta-blocker to a CCB would be useful. The logical addition to an ACE inhibitor, however, would be a diuretic or a CCB, neither of which was permitted in the trial.

In the end there was a difference in systolic blood pressure (SBP) of about 2 mm Hg, favoring chlorthalidone over lisinopril. Thus, unlike ANBP2, which achieved equal blood pressure reductions with the diuretic and ACE inhibitor regimens and found an additional cardiovascular event benefit for the ACE inhibitor, the failure to achieve equal antihypertensive effect with the unusual ACE inhibitor treatment protocol clouded interpretation of many of ALLHAT's clinical outcomes. ALLHAT should have been set up as 2 separate trials, Dr. Weber maintained, comparing a diuretic and an ACE inhibitor in the same way as was done in ANBP2, so that equal blood pressure control was obtained in both treatment groups. This would make it possible to clarify whether either treatment had an "additional" benefit beyond its blood pressure-lowering effect.

Stroke Claim Questioned

One claim for superiority of chlorthalidone in ALLHAT was that it reduced the rate of stroke by 15% compared with lisinopril. However, as Dr. Weber noted, this could be completely accounted for by the greater stroke rate in black patients on lisinopril. In this respect, he particularly criticized the use of the combination of an ACE inhibitor and a beta-blocker in black patients. Neither drug class alone is very effective in black patients, and a combination of 2 not very good drugs was "absolutely inappropriate," he stated. He pointed to the 4-mm Hg discrepancy in SBP favoring chlorthalidone over lisinopril in black patients and the "huge" 40% excess stroke rate in black patients randomized to lisinopril. Dr. Weber questioned how those responsible for monitoring safety in ALLHAT could have let these patients be exposed to this risk.

Heart Failure vs Mortality as Endpoints

 

"We can argue until the cows come home about who has heart failure, who has had an attack of angina, who had a heart attack, etc, but the one thing you cannot fight about is who is alive and who is dead."

The main claim for chlorthalidone's superiority was based on the secondary endpoint of heart failure, a surprising finding, since much previous clinical evidence had pointed to the superiority of ACE inhibitors for the treatment of heart failure. "Heart failure is a totally impossible diagnosis to make," Dr. Weber told Medscape. "We can argue until the cows come home about who has heart failure, who has had an attack of angina, who had a heart attack, etc., but the one thing you cannot fight about is who is alive and who is dead." In ALLHAT, all-cause mortality, the most important secondary endpoint, was identical for lisinopril and chlorthalidone, and 4% lower with amlodipine, he noted. Mortality differences in favor of the ACE inhibitor and the CCB would have been greater but for the blood-pressure discrepancies, he claims. Because ANBP2 managed to eliminate a blood-pressure difference between the diuretic and ACE inhibitor groups, the results indicate that ACE inhibitors do have an effect beyond blood pressure lowering. This effect is probably related to MIs, but not to stroke, Dr. Weber suggested.

Costs of Drugs Not So Different

One of the principal points seized upon by the general news media reports of the ALLHAT results concerned the purported price differential among the study drugs. Dr. Weber pointed out that, contrary to the conclusion of the ALLHAT investigators, the costs of current antihypertensive drugs, including the thiazide diuretics, are relatively inexpensive, with generic ACE inhibitors and some long-acting dihydropyridine CCBs now available in the United States. Dr. Weber told Medscape that the message widely disseminated in the lay press, that somehow doctors had been persuaded to prescribe newer, expensive agents rather than cheap diuretics, was "appalling" and "just not true." He believes that the clinical trial data on which the newer drugs' approval was based still vindicates their position in the treatment of hypertension. He further pointed out that, in any case, blood-pressure control in most hypertensive patients calls for combination therapy that may include drugs from classes not included in ALLHAT, such as the angiotensin II type-1 receptor blocker, losartan. Losartan is shortly expected to receive an indication for the treatment of hypertension on the basis of data from the Losartan Intervention For Endpoint Reduction (LIFE) study, which revealed a significant decrease in the risk of stroke in hypertensive patients with left ventricular hypertrophy.[5]

Treatment Implications

Both ALLHAT and ANBP2 indicate that treatment for hypertension in white patients should probably begin with an ACE inhibitor, with addition of a diuretic if more blood pressure control is needed, Dr. Weber believes. For black patients, the same treatments may be given in reverse.

ALLHAT Results Announcement "Irresponsible," Says Weber

Finally, the way in which the ALLHAT results were announced (at a press conference in Washington, December 2002) was described by Dr. Weber as "flamboyant, irresponsible posturing." He feels that blame for this must lie with Claude Lenfant, MD, Director of the National Heart, Lung, and Blood Institute (NHLBI), an agency that "supposedly is providing service in the true interests of science and should be scrupulously objective and conservative in interpreting the results of research." He suggested that if a pharmaceutical company had announced such conclusions on behalf of chlorthalidone at a similar press conference, it would be seen as flouting the law. "The whole tone of how this has been handled is upsetting," Dr. Weber said.

Implications for Hypertension Treatment Guidelines (JNC VII)

The latest amended hypertension guidelines of the Joint National Committee, JNC VII, are due to be announced in May, during the annual meeting of the American Society of Hypertension in New York City. Dr. Weber, who is not on the JNC VII committee, told Medscape that he believes that the final report is likely to recommend a diuretic as universal first-line therapy for treatment of hypertension, following the ALLHAT conclusions. He finds this particularly troubling in that half of the JNC VII committee is composed of people who were also ALLHAT investigators and were also appointed by the same person, NHLBI Director Lenfant, who appointed the ALLHAT officers.

Dr. Weber appreciates that although the results of 3 other landmark clinical trials -- ANBP2, International Verapamil SR/Trandolapril Study (INVEST), due to be reported at the annual scientific session of the American College of Cardiology in March,[6] and LIFE[6] -- will be available for the JNC VII committee's consideration, the committee will be under pressure to give strongest weight to the ALLHAT results. If the resulting guideline recommendations do not incorporate the results of these other trial results, however, Dr. Weber believes that their integrity will be compromised and that others will challenge the guidelines and start to develop alternatives.

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