Longer version

Spin doctors soft pedal data on antihypertensives

New Paltz, New York, USA
jeanne.lenzer{at}verizon.net

Jeanne Lenzer

freelance journalist

The results of a major study that compared different classes of antihypertensives have drug company spin doctors working overtime. It’s no easy job to save market share for expensive antihypertensive drugs when headlines read "When Cheaper Is Also Better," as one did in the New YorkTimes on 19 December 2002.

The "antihypertensive and lipid lowering to prevent heart attack trial" (ALLHAT), published in the 18 December issue of JAMA (2002;288;2981-97), shows that calcium channel blockers and angiotensin converting enzyme (ACE) inhibitors used to treat hypertension were no better than a diuretic. In some instances they were not quite as safe—even though they were substantially more expensive.

But the spin doctors are swinging into action to counter the clear message of ALLHAT that cheaper is better, even if that means just playing it down. Kevin Brode, vice president of sales and marketing at marketRx, a firm that provides strategic marketing information to the pharmaceutical industry, isn’t too worried about who the winner will be. "Doctors say they’ll change their prescribing habits after a negative study," he said, "but their prescription behaviour tends not to bear this out."

Why not? "The reality is no one promotes a diuretic," said Mr Brode. "So you’ve got one study that says yes, you should [use a diuretic], then starting the day after, you’ve got a $10bn [£6.2bn;€9.5bn] industry. . . and 55 promotional events . . . for an ACE inhibitor coming back in and saying ‘Here’s why my ACE inhibitor is safe and here’s why you should be using this.’ I mean, it’s promotion. Can ALLHAT stand up to that?"

Mr Brode, despite his rosy predictions regarding sales, didn’t challenge the ALLHAT results, saying instead: "Great data. Very solid. Didn’t surprise anybody . . . but nobody’s promoting diuretics."

But if Dr Curt Furberg, chair of the ALLHAT steering committee, has his way, that won’t be the case. He and other ALLHAT staff are staying on to disseminate the data. He says that expensive calcium channel blockers and ACE inhibitors may be costing an excess of $8bn to $10bn—without providing any benefit to patients, and in some instances adding more risk.

Why was so much money wasted for so many years on drugs that weren’t as good? Dr Furberg says, "We just didn’t know." But why didn’t they know?

The practice of testing new medicines against placebo, rather than against the best treatment available, has contributed to a general lack of knowledge. But spin doctoring clearly triumphed when a head-to-head comparison provided at least one answer. In March 2000 the ALLHAT researchers halted the ? blocker arm of the trial when it was found that doxazosin (Cardura) was inferior to a diuretic. Patients on Cardura, dubbed a “miracle drug” by a Pfizer executive, experienced a 25% higher rate of cardiovascular disease and twice the rate of congestive heart failure as patients on a diuretic, results published in the 19 April 2000 issue of JAMA show.

Pfizer, aware of the results before publication, launched a sophisticated damage control campaign in early 2000. Sales of Cardura, estimated at $800m (£500m;€760m) worldwide in 2000, continued virtually unaffected by the study for the rest of the year.

Just how Pfizer managed this feat is revealed by internal drug company documents filed in January 2001 as part of a "citizen’s petition" against Pfizer. The plan included using an outside research agency to study doctors’ awareness of the ALLHAT results. When the agency found that "knowledge of the trial’s preliminary results is minimal for all specialties," they took steps to avoid sullying that lack of awareness.

Pfizer decided not to issue a public statement about the ALLHAT results because doing so "would likely draw more media attention to the situation." They instructed their drug reps to provide information about ALLHAT "only when asked." Finally, two enterprising Pfizer employees were praised as "quite brilliant" for "sending their key doctors to sightsee" during a presentation at the annual American College of Cardiology conference in California in 2000. The doctors, from Italy, were brought to California by Pfizer. The tour, according to the Pfizer email praising the reps, kept the doctors from attending Dr Furberg’s presentation of the ALLHAT results.

But Pfizer was not alone in blunting the response to ALLHAT results. The American College of Cardiology (ACC) issued an alert in March 2000 urging doctors to "discontinue use" of Cardura. However, another Pfizer memo dated 28 March 2000 and stamped "confidential" says that Pfizer was "successful in getting the ACC to agree to a clarification" of the ACC press release. The "clarification" that the ACC agreed upon replaced its initial press release on the ACC website within just hours of the original posting and changed the recommendation that Cardura be discontinued to a much milder recommendation that doctors "reassess" its use. It may have added to Pfizer’s standing with the ACC that Pfizer has contributed more than $500 000 (£312 000;€474 000) annually to the college in recent years.

In the end, Cardura sales did quite well for the balance of the year with US sales alone at $344m (£214m;€326m) in 2000, making it the 73rd highest branded drug. But woes greater than ALLHAT would eventually bring the sales down as generic doxazosin sales took off in 2001, taking it from the 150th highest generic seller in 2000 to 34th place in 2001.

Corporate damage control in response to the most recent ALLHAT results is already evident. King pharmaceuticals, maker of the ACE inhibitor Altace (ramipril), issued a press release on 19 December 2002 stating, "Recently reported ALLHAT trial does not address benefits of Altace; Altace benefits proven in landmark HOPE trial."

Although the antihypertensive arm of ALLHAT has received some degree of media attention, there has been virtually no coverage of the ALLHAT lipid study that was published simultaneously in JAMA. The lipid arm studied 10 355 patients with elevated LDL-cholesterol levels who were randomised to receive pravastatin or usual care. The outcome showed no statistically significant reduction in cardiovascular disease event rates or in deaths. Although other studies have cast doubt on the value of statins in primary prevention, this study included somewhat higher risk patients who constituted a "hybrid" population between primary and secondary prevention, according to ALLHAT researchers. Although higher risk is generally associated with better benefit, in this study no benefit was found.

Barry R Davis, principal investigator and director of ALLHAT, says lack of coverage was understandable because "we know [statins] work." Dr Furberg agrees with Dr Davis saying that there is "overwhelming" evidence from other studies showing that statins work. Further, both researchers say that their trial may not have shown benefit for several reasons. Firstly, 30% of the usual care group received statins, which narrowed the margin of benefit. Secondly, by the sixth year of the study 83% of patients in the treatment arm were still taking pravastatin or another statin. Another point both investigators stressed is that the cholesterol reductions were modest and that greater reductions would have given greater benefit.

But other doctors aren’t as quick to dismiss the ALLHAT lipid results as readily as the ALLHAT investigators themselves. Dr Marcia Angell, former editor in chief of the New England Journal of Medicine,cautions, "There is a lot of conventional wisdom that makes people go beyond their data or sometimes ignore their data, and that’s dangerous." Dr Angell also says that the questions raised about the study results should be "hypothesis generating" and cannot be assumed as fact until they are tested.

Dr Angell says a first step would be to start by doing a subgroup analysis of the usual care of patients who didn’t receive statins—an analysis that Dr Furberg says was not performed. In response to Dr Angell, he says this analysis may be performed in the future but he adds that the results would be "hard to interpret because there is no comparable control group."

What’s true of ALLHAT, says Dr Angell, "may be true of an awful lot of drugs. A lot of newer drugs may not only not be better—they may be worse." The problem continues, she said, because "most drug companies don’t want a head to head [study]. And the FDA [Food and Drug Administration] allows trials to run that are rigged where a drug is tested against placebo or a drug of the same class that is inadequately dosed, or they look at the wrong group of people or the wrong endpoints so their drug looks good." She adds, "This is a big argument for having the NIH [National Institutes of Health] do studies."

Dr Jerome R Hoffman, professor of medicine and emergency medicine at the University of California at Los Angeles, wonders why the ALLHAT investigators dismiss their own results regarding statins: "If they felt the answer was already in, how could they justify doing that arm of the study? I somehow doubt that we would have heard so little about this if the results had been positive." In any case, he says, statins should be understood in a larger perspective. "Even among high risk patients, you have to treat many people for a long time in order to benefit one, while a substantial percentage of those so treated will have troublesome side effects. That benefit may be worth the risk in this group, but it’s certainly harder to justify in patients at low baseline risk—who have the same adverse effects but get much less benefit. ALLHAT’s suggestion that the same caveat may be true for intermediate risk patients is terribly important, and should be addressed carefully, rather than swept under the rug."

Dr Hoffman adds, "When dealing with interventions whose marginal benefit comes at substantial cost—both economic and medical—we have to ask not only how much are we willing to spend for a tiny potential gain, but also what do we sacrifice in the name of such a gain? Inevitably when we spend dollars on extremely expensive medicines we take those dollars from less sexy but much more important public health interventions. Ultimately, we abdicate our responsibility, as well as risk the public health, if we allow proprietary companies, whose primary interest has to be selling their wares, to guard the public hen house."