MEDICATIONS: STATIN THERAPY VS. USUAL CARE SIMILAR IN REDUCING RISK OF DEATH OR CORONARY HEART DISEASE EVENTS IN PATIENTS WITH ELEVATED CHOLESTEROL AND HYPERTENSION

December 18, 2002 — Pravastatin, a statin drug used to reduce cholesterol, does not reduce the death rate or incidence of coronary heart disease events in patients with moderately high cholesterol and well-controlled high blood pressure, when compared to usual care, according to an article in the December 18 issue of The Journal of the American Medical Association.

According to background information given in the article, the role of levels of low-density lipoprotein cholesterol (LDL-C, the "bad" cholesterol) play in the development of coronary heart disease (CHD) is well established. Trials in the 1970s and 1980s showed that lowering LDL-C reduced the incidence of CHD-related events such as heart attack, but the average reduction in LDL-C for these trials was only 10 percent. In the 1980s, a more powerful class of drugs, statins, were developed which could reduce total cholesterol by approximately 20 percent or more. Studies have demonstrated that statins administered to individuals with risk factors for CHD reduce CHD events. However, many of these studies were too small to assess all-cause mortality or outcomes in important subgroups.

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT) evaluated the impact of sustained cholesterol reductions on deaths in an older population with high blood pressure and moderately high cholesterol with at least one other CHD risk factor using pravastatin in all patients vs. usual care, which could include lowering cholesterol using statins if the patient's physician chose to prescribe it.

ALLHAT-LLT was a randomized, non-blinded trial conducted from February 1994 through March 2002 at 513 North American clinical centers. Jeffrey L. Probstfield, M.D., of the University of Washington Medical Center in Seattle, and Barry R. Davis, M.D., Ph.D., from the University of Texas — Houston Health Science Center, and colleagues enrolled 10,355 people aged 55 or older with high LDL-C levels (120 to 180 mg/dL) in their study. All participants also were enrolled in ALLHAT, a study comparing treatments to lower blood pressure. The average age of the participants was 66 years, 49 percent were women, 38 percent black, and 23 percent Hispanic. Fourteen percent had a history of CHD and 35 percent of participants had type 2 diabetes. Of the participants, 5,170 were assigned to the pravastatin group (40 mg/day) and 5,185 were assigned to usual care.

Participants were followed up for an average of 4.8 years. During the course of the trial, 32 percent of the usual care patients with CHD and 29 percent of participants without CHD started taking cholesterol-lowering drugs. At year four, total cholesterol levels were reduced by 17 percent with pravastatin vs. 8 percent with usual care. Among the random sample who had LDL-C assessed, levels were reduced by 28 percent with pravastatin vs. 11 percent with usual care.

The researchers found that death rates were similar for the two groups, with six-year death rates of 14.9 percent for pravastatin vs. 15.3 percent with usual care. CHD-related events, such as heart attack and stroke, were not significantly different between the two groups, with six-year CHD event rates of 9.3 percent for pravastatin and 10.4 percent for usual care.

"ALLHAT-LLT demonstrated no significant difference between pravastatin and usual care groups in all-cause mortality or combined fatal and nonfatal CHD," the authors write. "However, in the context of the modest cholesterol differential, the results are consistent with the evidence from other large trials. Indeed, the overall findings from the nine 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. In the absence of evidence for increases in any category of noncardiovascular mortality, the ALLHAT-LLT results should be interpreted as consistent with current recommendations for cholesterol control in the prevention and treatment of cardiovascular disease. These results emphasize the need for obtaining an adequate reduction in LDL-C in clinical practice when lipid-lowering therapy is implemented."

Editor's Note: This study was supported by a contract with the National Heart, Lung, and Blood Institute. The ALLHAT investigators acknowledge contributions of study mediations supplied by Pfizer (amlodipine and doxazosin), AstraZeneca (atenolol and lisinopril), and Bristol-Myers Squibb (pravastatin), and financial support provided by Pfizer. For the financial disclosures of the authors, please see the JAMA article.

Editorial: The ALLHAT Lipid Lowering Trial — Less Is Less

In an accompanying editorial, Richard C. Pasternak, M.D., of Massachusetts General Hospital and Harvard Medical School, Boston, discusses factors that may have contributed to the similarity between the outcomes of the pravastatin and usual care groups.

"By year 6 of the study, only 70.3 percent of patients in the treatment group were still taking the protocol-specified 40 mg of pravastatin, whereas 28.5 percent of the usual care group was receiving a lipid-lowering drug (26.1 percent received a statin)," writes Dr. Pasternak. Studies supporting the use of statins were published early during the course of ALLHAT-LLT, increasing the number of physicians prescribing statins for patients in the usual care group, particularly those at the highest risk of heart disease.

Another issue he includes is the fact that "because of reduced adherence and the large degree of crossover, the difference in total cholesterol and the apparent difference in LDL-C between the 2 groups were modest and substantially less than the differences reported in other statin trials."

"Physicians might be tempted to conclude that this large study demonstrates that statins do not work; however, it is well known that they do," writes Dr. Pasternak. "Rather, it appears that statins may be less effective in the primary care setting in which they were used in ALLHAT-LLT. 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 routine practice becomes closer to the conditions achieved in randomized clinical trials, there will continue to be a gap between optimal care based on the best knowledge and actual care in clinical practice," Dr. Pasternak writes.