What Does ALLHAT Tell Us About Dyslipidemia From the Hypertension Specialist Perspective?

No study has engendered more controversy and debate about the appropriate treatment of hypertension than the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). However, the results and implications of the lipid-lowering substudy of this trial, known as ALLHAT-LLT, are often overlooked. Of course, patients with hypertension often present with concomitant dyslipidemia, another important and potentially modifiable cardiovascular (CV) risk factor. Treating hypertension but leaving dyslipidemia untreated in these patients may expose them to unnecessary CV risk. ALLHAT-LLT was designed as a multicenter, unblinded, randomized trial of 10,355 participants (about one third of the entire ALLHAT cohort) comparing usual care vs treatment with an HMG CoA-reductase inhibitor (pravastatin 40 mg daily) in moderately hypercholesterolemic patients with hypertension and at least one other CV risk factor enrolled in ALLHAT. In this edition of the Journal, the ALLHATLLT investigators present long-term open-label followup of the study results based on passive surveillance of national databases over approximately 10 years. Although these data are subject to methodological short-comings, they are consistent with the original findings of ALLHAT-LLT and have 4 important implications for the treatment of dyslipidemia in patients with hypertension. First, for most patients with hypertension who do not have established coronary heart disease (CHD) at baseline, HMG CoA-reductase inhibitors (statins) should not be prescribed with the expectation of decreasing mortality, at least over the next few years. Ever since the initial publication of the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial, which was stopped early because of an apparent decrease in the secondary endpoint of total mortality, there has been much debate about whether statin therapy reduces overall mortality. In ALLHAT-LLT, there was no difference in total mortality in the main study or in the extended follow-up. Since total mortality was the prespecified primary endpoint in ALLHAT-LLT, this result, which is also supported by a recent high-quality meta-analysis, does not support the supposition that statins reduce mortality in primary prevention. Whether or not the results of the JUPITER trial represent a statistical anomaly, a consequence of the unique inclusion criteria (high-sensitivity C-reactive protein), the statin used in the study (rosuvastatin), or potential bias on the part of the sponsor (as has been suggested by some) is unknown. Moreover, whether longer duration of treatment assignment (only 4.8 years in ALLHAT-LLT) would lead to a difference in total mortality is also unknown. In any event, we should be honest with our patients that use of statin therapy in primary prevention is recommended to decrease overall CV events rather than to save or extend lives. This conclusion leads directly to the second important implication of this paper, that the results of ALLHATLLT should not dissuade practitioners from using statins in hypertensive patients with dyslipidemia to prevent CV events. The negative findings of ALLHAT-LLT with regards to overall CV events in both the main study and in the extension arm have been seen as disappointing to advocates of statin therapy in primary prevention. However, the negative results are likely the result of methodological issues rather than dismissive of the study hypothesis. The open-label design and changing landscape of lipid-lowering therapy over the course of the study likely biased the results. By year 4, adherence to active therapy with pravastatin had dropped to 80% and cross-over to statin therapy occurred in 17%; the overall difference in change in low-density lipoprotein cholesterol (LDL-C) was thus significantly attenuated: 28% in the pravastatin group compared with 11% in the usual care group at year 4. Other studies of statin therapy in patients with hypertension have been associated with a much larger difference in LDL-C between treatment groups. Most notably, in the ASCOT-LLA, 19,342 patients with hypertension and other CV risk factors were randomized in blinded fashion to either atorvastatin or placebo. ASCOT-LLA was planned for an average followup of 5 years but was terminated prematurely after a median follow-up of 3.3 years because of a highly significant reduction in nonfatal myocardial infarction and fatal CHD, the primary endpoint. Given the strength of the study design and the definitive result, ASCOT-LLA should be used to justify the use of statin therapy in patients with hypertension and dyslipidemia to prevent CV events if the LDL-C is above cut-points suggested by the National Cholesterol Education Panel for their level of risk, which will be mostly moderate or moderately high given our current guidelines. Address for correspondence: Michael J. Bloch, MD, Department of Medicine, University of Nevada School of Medicine, Renown Institute for Heart and Vascular Health, 1500 East Second Street, Suite 302, Reno, NV 89502 E-mail: michael@bluesprucemed.com