ALLHAT lipid-lowering trial shows no benefit from pravastatin

Susan Jeffrey

December 17, 2002

Washington, DC - Surprising results of an unblinded but randomized comparison of pravastatin (Pravachol® - Bristol-Myers Squibb) vs "usual care" in patients with hypertension and moderate hypercholesterolemia enrolled in the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT) show that pravastatin did not significantly reduce either all-cause mortality or fatal or nonfatal coronary heart disease (CHD) in these patients.

However, by the end of the trial, the differential in cholesterol levels between the 2 groups was only modest, 9.6% in total cholesterol and 16.7% in LDL cholesterol, compared with other large statin trials showing a benefit from treatment, the researchers point out. The results, part of a larger trial comparing 4 antihypertensive agents, the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), were presented at a press conference here today to coincide with their publication in the December 18, 2002 issue of the Journal of the American Medical Association.

Dr Barry R Davis (University of Texas-Houston Health Science Center), director and principal investigator for the ALLHAT Clinical Trials Center, pointed out that they'd intended at the outset that patients in the usual care group would not receive statins, so that a difference in cholesterol would be achieved between groups.

"What had happened was over the course of the last 8 years, trials have shown the benefits of cholesterol lowering, and so we didn't anticipate the people assigned to usual care would be getting as much statin as they did," Davis told heartwire . "The cholesterol differential between the 2 groups was a lot less than we expected, and so we feel that's probably the reason why we didn't see a significant effect on clinical outcomes."

Those on a statin did have substantial cholesterol lowering, he added, supporting current treatment guidelines.

A statement from the American Heart Association on these findings echoes Davis's assessment. "The findings on statin treatment should be examined more closely," AHA president Dr Robert O Bonow (Northwestern University Medical Center, Chicago) says in the release. "The lack of difference between the usual care group and those randomized to receive a statin may be explained by the inclusion of statins in the usual care group for secondary prevention."

ALLHAT subset

While previous studies have shown the benefits of cholesterol lowering in preventing cardiovascular events and mortality, many of the studies were too small to assess all-cause mortality or effects of lipid-lowering in populations underrepresented in other trials, including women and minority groups, the researchers write.  

Patients in this study were a subset of 10355 subjects of ALLHAT subjects with hypertension, who were 55 years of age or older but were also moderately hypercholesterolemic, as well as having at least 1 other risk factor. Eligible patients had LDL cholesterol between 120 mg/dL to 189 mg/dL or between 100 mg/dL to 129 mg/dL if CHD was already present. Triglycerides were lower than 350 mg/dL. Patients were randomized to treatment with 40 mg of pravastatin or usual care, but the trial was not blinded. "Usual care" could include statins at the physician's discretion.

The average age of the cohort was 66 years, 49% were women, 38% were African American, and 23% were Hispanic.

After 4.8 years of follow-up, 32% of usual care patients with CHD and 29% of those without CHD started on statin treatment. By year 4, total cholesterol levels were reduced by 17% with pravastatin vs 8% in the usual care group. In a random sampling of subjects, LDL levels were reduced by 28% with pravastatin vs 11% with usual care.

All-cause mortality was similar between the 2 groups, and CHD event rates were also not significantly different.

ALLHAT-LLT: 6-year mortality and CHD event rates with pravastatin vs usual care

End point

Pravastatin (%)

Usual care (%)

RR (95% CI)

p

All-cause mortality 14.9 15.3 0.99
(0.89-1.11)
0.88
Fatal CHD and nonfatal MI 9.3 10.4 0.91
(0.79-1.04)
0.16

Although there was no difference seen in these end points, the researchers write that, given the small differential in cholesterol, the results should be viewed as consistent with the evidence from other large trials.

"Indeed, the overall findings from the 9 large long-term statin trials (including ALLHAT-LLT) leave little doubt regarding the broad efficacy and safety of this treatment in the prevention and treatment of atherosclerotic cardiovascular disease," the investigators conclude in their report.

"These results emphasize the need for obtaining an adequate reduction in LDL-C in clinical practice when lipid-lowering therapy is implemented."

The statin arm of a trial similar to ALLHAT, the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), stopped its statin comparison in October of 2002, when it was found those on atorvastatin (Lipitor® - Pfizer) in that comparison had significantly fewer heart attacks and strokes compared with untreated patients. The halt of the statin comparison in ASCOT was reported at that time by heartwire . The comparison of antihypertensive strategies in that trial continues.

Robust lipid lowering for robust risk reduction

In an editorial accompanying the publication, Dr Richard C Pasternak (Massachusetts General Hospital, Harvard Medical School) writes, "Physicians might be tempted to conclude that this large study demonstrates that statins do not work; however, it is well known that they do. Rather, it appears that statins are less effective in the primary care setting in which they were used in ALLHAT-LLT."

He notes, "Statins have been proven efficacious in a wide array of primary and secondary prevention randomized, blinded, controlled trials. ALLHAT-LLT shows that the effectiveness may be limited in a setting that more closely mirrors clinical practice."

Until clinical practice comes closer to conditions seen in clinical trials, he says, "there will continue to be a gap between optimal care based on the best knowledge and actual care in clinical practice."

Pasternak also points out that the ALLHAT-LLT findings suggest that lowering LDL remains central to the benefits of statin therapy. "Much has been made of the 'pleiotropic' effects of statins, suggesting that such effects may be non-dose related," he says. "Although other data are inconsistent with this point, ALLHAT-LLT indirectly suggests that robust LDL-C lowering is necessary to achieve robust risk lowering."

In an interview with heartwire , Dr Robert M Califf (Duke University Medical Center), a member of the Data and Safety Monitoring Committee for ALLHAT, said that, given the small changes in lipids seen, he interprets these data, too, to be consistent with what is already known about statin treatment. However, he said, "I do think it raises an interesting question, because it's basically an effectiveness trial, the kind of trial that we talk about a lot but hasn't been done all that often. It does raise the question if, in the real world, you started out treating a bunch of people with pravastatin, how well they're really going to do."

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