Statin Fails to Meet Expectations
The surprising results arose from a study, referred to as ALLHAT-LLT, which involved a subset of about 10,400 patients who had enrolled in the larger Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial.
Patients who received usual care and those treated with pravastatin 40 mg/day were found equally likely to die of heart disease or any other cause or to have a myocardial infarction during six years of treatment. Usual care consisted of treatments recommended by each patient's physician but normally excluded the use of "vigorous cholesterol-lowering therapy," according to the report.
ALLHAT-LLT participants were recruited from 513 office-based practices and general medical and specialty clinics that were part of the main ALLHAT group. Study participants were 55 years or older with a serum triglycerides level of <350 mg/dL. Each enrollee had a low-density-lipoprotein (LDL) cholesterol level of 120189 mg/dL if no coronary heart disease was present or 100129 mg/dL if heart disease had been diagnosed.
Half of the ALLHAT-LLT patients were randomized to the usual care group, and half were assigned to take pravastatin and knew they were receiving the drug. Physicians were allowed to change the pravastatin dosage, discontinue use of the drug, and prescribe other lipid-lowering agents or interventions. All study participants were asked to follow the Step 1 diet described by the National Cholesterol Education Program.
The six-year mortality rate for both groups was about 15%; half of the deaths in each group were attributed to cardiovascular disease. Nonfatal cardiovascular events occurred at similar rates in both groupsabout 9% for patients in the pravastatin group and 10% for patients who received usual care.
Patients in the usual care group had decreased their total serum cholesterol levels by an average of 27 mg/dL after six years of treatment, compared with a 46-mg/dL reduction in the pravastatin group. During the same period, LDL cholesterol fell by 24 mg/dL in the usual care group and 42 mg/dL in the pravastatin group. The report described the comparative total cholesterol decrease in the pravastatin group as "modest" in light of the expected benefit demonstrated by hydroxymethylglutarylcoenzyme A reductase inhibitors, or statins, in other studies.
According to the report's authors, the study's design, in which the physicians knew whether their patients were assigned to statin therapy, may have blurred the line between the two treatment groups, contributing to the failure to find a benefit from pravastatin use. By year 6 of the study, 23% of the patients in the pravastatin group were no longer taking the study drug, but 26% of those in the usual care group were receiving a statin and 2% were taking another type of lipid-lowering medication.
Another factor that may have affected the study's results was the difficulty in enrolling enough patients to generate solid statistical findings. The study's initial design had called for the enrollment of 20,000 patients from the main ALLHAT population, but only half that number participated in ALLHAT-LLT. The widespread clinical acceptance of statins as effective lipid-lowering agents may have reduced the number of patients who were available for a physician-defined usual care regimen that did not include statin therapy.
Numerous clinical studies, the report noted, have demonstrated the benefits of statins for reducing cholesterol levels and preventing cardiovascular events and deaths. The authors claimed that the ALLHAT-LLT results should be examined in the context of the modest difference in cholesterol reduction that was observed between the two treatment groups. Under this view, the authors reported that the results of ALLHAT-LLT "are consistent with the current recommendations for cholesterol control in the prevention and treatment of cardiovascular disease."
- ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002; 288:2998-3007.