New York, NY - A feature story in the New York Times tracking the legacy of the ALLHAT trial reports that six years after the trial results were announced, use of diuretics remains much lower than many people predicted back in 2002 [1].

"The aftereffects of the study show how hard it is to change medical practice, even after a government-sanctioned trial costing $130 million produced what appeared to be solid evidence," Times reporter Andrew Pollack writes.

Dr Curt Furberg was chair of the study until resigning in August 2004 out of frustration over the lack of effort put into disseminating the "ALLHAT message." He told the Times that diuretic use "should have more than doubled" in recent years, since it was the safest and cheapest drug studied, with efficacy equal to that of the brand-name drugs in the trial. "The impact was disappointing," Furberg is quoted as saying in the Times.

In the massive ALLHAT trial (with more than 44 000 patients), an alpha-blocker arm of the study was stopped early after trial monitors saw a sharp uptick in heart-failure hospitalizations among patients randomized to this treatment. In the other three arms of the trial, risk of subsequent CHD death or nonfatal MI was similar among patients treated with a diuretic, a calcium-channel blocker (CCB), or an ACE inhibitor, but ACE-inhibitor-treated patients had a 15% increased risk of stroke and a 19% increased risk of heart failure, and CCB-treated patients had a 38% increased risk of heart failure.

The Times article notes that the proportion of hypertension patients treated with a diuretic rose from 30% to 35% before the ALLHAT results, to around 40% the year following their release, but prescriptions have more or less plateaued ever since. Other drugs going off patent, newer drugs coming on the market, and the introduction of combination two-in-one pills are some of the more innocuous reasons diuretics failed to gain more traction, Pollack's article notes. Quoting Dr John M Flack (Wayne State University, Detroit, MI), who was not involved in the study, the main issue probed by ALLHAT—which drug to start with in hypertensive patients—was "an outdated question that doesn't have huge relevance to the majority of people's clinical practices."

Also quoted in the article, Dr Carolyn M Clancy, director of the federal Agency for Healthcare Research and Quality, acknowledged that although randomized clinical trials are the best way to answer a question like the one tackled in ALLHAT, they are expensive and time-consuming. "You might be answering a question that, by the time you are done, no longer feels quite as relevant," she told the Times.

But Pollack's article, which runs more than 2700 words in length, also chronicles some of the less benign factors that limited the increased use of diuretics, most notably the aggressive marketing by brand-name drug-makers, like Pfizer, manufacturer of both the alpha blocker and the CCB used in ALLHAT. Court documents show that a Pfizer sales executive boasted that Pfizer employees "were quite brilliant in sending their key physicians to sightsee rather than hear Curt Furberg slam Pfizer once again!" referring to an ALLHAT presentation at an American cardiology meeting. When the ALLHAT results came out, Pfizer "set out to accentuate the positive," Pollack writes, noting that a news release, as well as a print ad in a medical journal, lauded the positive results for its CCB but failed to mention its heart-failure risk documented in the trial.

Other companies also played a role in diminishing the switch to generic diuretics, Pollack points out. In a major marketing push, Novartis spent millions promoting its new angiotensin-receptor blocker valsartan (Diovan), which was too new to have been studied in ALLHAT, the Times article notes.

Furberg, a long-time critic of CCBs, told the Times that "the pharmaceutical industry ganged up and attacked, discredited the findings." Indeed, the motive for some ALLHAT naysayers—including some who had leadership positions in the ALLHAT trial—may have been financial, Pollack suggests. For example, steering-committee member Dr Richard H Grimm Jr (University of Minnesota, Minneapolis) received more than $200 000 from Pfizer the year after ALLHAT came out, roughly half of which came from giving 100 Pfizer-sponsored talks about ALLHAT, he told the Times.

Others, however, suggest that government agencies "overstated" the trial results as a means of reducing medical spending, Pollack writes, quoting Dr Michael Weber (Health Science Center, Brooklyn, NY), who told the Times: "There was a feeling there was a political and economic agenda as much as a scientific agenda. They pushed beyond what the data allowed them to say."

When one adds to the controversy all of the subsequent hypertension trials that have emerged over the past six years, the result is a trial that to this day has never had the impact that many investigators expected.