The ALLHAT hypertension trial is bringing renewed calls for more comparative trials of pharmaceutical agents.

"If FDA is not doing it, someone else needs to address the issue about comparing drugs," ALLHAT Steering Committee Chair Curt Furberg, MD/PhD, Wake Forest University, said Dec. 17 during a press conference in Washington, D.C., releasing the results of the Antihypertensive & Lipid Lowering Treatment to Prevent Heart Attack Trial.

The study found that the diuretic chlorthalidone was associated with better outcomes than the calcium channel blocker amlodipine and the ACE inhibitor lisinopril (see ¹ [A#00640510008]).

"We're reaching a situation now for most conditions in medicine where we have multiple choices," Furberg noted.

"The whole issue about comparing drugs is a much, much bigger one" than is covered by ALLHAT, he said. "I think it would have to involve an act of Congress."

Furberg noted that FDA approval standards require drugs to show an absolute benefit rather than a relative one.

"Right now the FDA is approving a drug if it is 10% effective and safe, and if it is 40% effective and safe....For clinical practice that is not good enough. We all need to know which drug is 40% effective."

Furberg, a member of FDA's drug safety advisory committee, has been a long-time advocate for clinical trials showing clear clinical benefit, especially for follow-on compounds in an established class (² Also see "Risk Cmte. Member Furberg Is On Record Pro Long Trials, Con Pfizer Drugs" - Pink Sheet, 7 January, 2002., p. 6).

He is also a long-time skeptic of the calcium channel blocker class. In 1996, FDA's cardio-renal panel reviewed a report by Furberg and Bruce Psaty, MD, University of Washington, on the potential for increased long-term risks from CCBs (³ Also see "IMMEDIATE-RELEASE NIFEDIPINE LABELING WILL WARN AGAINST OFF-LABEL USES, FDA INDICATES FOLLOWING CALCIUM CHANNEL BLOCKER ADVISORY COMMITTEE REVIEW" - Pink Sheet, 29 January, 1996., p. 3).

As a "first step," Furberg said Dec. 17, FDA should "require companies to show that the drugs reduce the complications of hypertension" rather than only approving drugs based on their blood pressure lowering potential.

The Cardiovascular & Renal Drugs Advisory Committee's Jan. 6 review of Merck's Cozaar (losartan) for reduction of cardiovascular morbidity/mortality risk in hypertensive patients with left ventricular hypertrophy may provide the first opportunity for FDA to discuss the results of the trial publicly.

While losartan is a different class (angiotensin II receptor antagonist) than the drugs studied in ALLHAT, it is closely related to the ACE inhibitor category and the need for comparative trials could be debated. [Editors' note: To ⁴ sign up for webcast or video of the Cozaar advisory committee meeting, visit www.FDAAdvisoryCommittee.com.]

Angiotensin II receptor blockers were approved after the ALLHAT study was initiated. Sankyo/Forest's Benicar , the seventh member of the class, was launched in May (⁵ Also see "Sankyo/Forest Benicar Launch Set For May; Seventh Angiotensin II Inhibitor" - Pink Sheet, 29 April, 2002., p. 4).

ALLHAT steering committee member Paul Whelton, MD, Tulane University, told the press conference that angiotensin II receptor antagonists should be tested against diuretics.

"Now that we know the results of ALLHAT, it is incumbent upon new drugs, new agents to be tested against the diuretic. I think that has to be the gold standard," he said.

"While it is good to have these agents for other indications in addition to lowering blood pressure, in terms of just head-to-head comparisons for benefit from any antihypertensive therapy, we need the kind of studies we had in ALLHAT," he said.

ALLHAT Steering Committee Vice-Chair Jackson Wright, MD/PhD, Case Western Reserve University, however, suggested that the trial results do not necessitate a re-evaluation of FDA approval criteria.

"Providers have the information that is necessary," he declared. "Patient care...should be the responsibility of the physician as opposed to the FDA."

The cost implications of the ALLHAT findings are significant, particularly looking retrospectively at the amount that would have been saved if prescribers had used diuretics first-line throughout the 1980s and 1990s.

"A full cost-effectiveness analysis is now underway, but if a million patients switched over it might save about a half billion dollars per year," ALLHAT Clinical Trials Center Director Barry Davis, MD/PhD, University of Texas, said.

"A patient could save anywhere from $250 to $650 per year if they were on calcium channel blockers or ACE inhibitors and switched over to a diuretic."

The National Heart, Lung & Blood Institute will pursue several tracks to disseminate the ALLHAT data.

"We have informed and trained 700 investigators around the country and they have agreed to disseminate the information locally," Furberg said. "We are going to go full-press with what we call academic detailing and hope that we are going to have a major impact on the utilization and improved care for patients with hypertension," he said.

NHBLI also plans to work with health insurers to integrate the results into clinical practice.

"We are going to work very actively with healthcare insurers, with those who have an important role in formularies, pharmacies, everyone who can help get this message out and into practice," ALLHAT Steering Committee member Paul Whelton, MD, Tulane University, said.

Managed care groups are likely to embrace the findings in shaping formularies.

Medco's Generics First program is sampling the diuretic hydrochlorothiazide to physicians (⁶ Also see "Medco “Generics First” Doubles Reach: PBM Will Call On 3,400 Physicians" - Pink Sheet, 11 November, 2002., p. 13). While the PBM does not expect to switch promotions to the product used in ALLHAT, chlorthalidone, because of its existing supply arrangements, its does anticipate increased physician interest in diuretics.

NHLBI will also issue new treatment guidelines for hypertension favoring diuretics by May.

"I am appointing a committee to produce a seventh report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure," NHBLI Director Claude Lenfant, MD, said.

"We usually take 12 to 18 months to produce these reports," Lenfant said, but "we have a commitment from the chair of the group and the participants that the report will be completed by May." The committee will be chaired by Aram Chobanian, MD, Boston University.

ALLHAT Study Brings Calls For Comparative Trials, Greater Focus On Costs

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