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The randomized AIM-HIGH trial tested the addition of high-dose, extended-release niacin to statins in individuals who are at risk for cardiovascular events and have well-controlled LDL levels, but also have low HDL and elevated triglyceride levels. In the wake of the National Heart, Lung, and Blood Institute's early termination of AIM-HIGH, the editors of CardioExchange, an online forum for cardiology news and discussion, posed the following question to one of the principal investigators of AIM-HIGH and to five other experts from the cardiovascular-medicine and scientific communities:
Is the halting of AIM-HIGH the death knell for the “HDL hypothesis”: the idea that clinical benefit can be achieved by raising HDL-cholesterol levels?
The interviewees' responses prompted a lively conversation, which you can access and join by registering for CardioExchange.
No, emphatically, this trial does not sound the death knell for the HDL hypothesis. VA-HIT clearly showed 10 years ago that gemfibrozil can reduce death, MI, and stroke, absent any LDL change. But the baseline LDL in VA-HIT was 111 mg/dL; in AIM-HIGH it was 71 mg/dL — a huge difference. We must continue to pursue research in higher-risk ACS and acute-MI patients whose HDL levels are low — and perhaps include more de novo or statin-naive patients, as we often see in real-world practice. —William E. Boden, MD, co–principal investigator of the AIM-HIGH trial; Medical Director of Cardiovascular Services, Kaleida Health; Chief of Cardiology, Buffalo General Hospital and Millard Fillmore Gates Circle Hospital; Professor of Medicine and Preventive Medicine, University at Buffalo
Another one bites the dust! As I have maintained before, HDL is a very complex molecule that is involved in many metabolic pathways. Simply modifying the molecule qualitatively or quantitatively is not ipso facto going to translate into cardioprotective effects. It is hard to argue that a randomized, controlled, outcomes-based trial is not an important tool to bust myths and entrenched beliefs! —Sanjay Kaul, MD, Director, Cardiology Fellowship Training Program, Cedars-Sinai Medical Center, Los Angeles; Professor of Medicine, UCLA School of Medicine
The discontinuation of this trial is disappointing. Of course, judging from a press release alone is extremely difficult for someone not associated with the study. Did the complexity of the relatively small study population of 1718 Niaspan-treated participants — with heterogeneous risk factors (metabolic syndrome, high blood pressure, diabetes) and varying drug treatments (e.g., with and without ezetimibe) — influence the conclusion that niacin was not effective in preventing heart attacks and strokes? If so, how? (It's somewhat surprising to see the ILLUMINATE trial [JW Cardiol Nov 5 2007] mentioned in the NIH press release without noting that off-target effects are likely to have played a major role in that study's results.) —Monty Krieger, PhD, Whitehead Professor of Molecular Genetics, Department of Biology, Massachusetts Institute of Technology (basic-science researcher who discovered the first HDL receptor)
The hypothesis is not dead, but it is certainly on life support. It is clear that HDL “raising” is too simplistic and that HDL “manipulation” is a more appropriate potential therapeutic target. Nevertheless, the enticing combination of niacin plus statin therapy to improve cardiovascular risk has been dealt a serious blow. It can be resurrected only by a convincing subgroup analysis from AIM-HIGH or by a clear benefit demonstrated in HPS2-THRIVE. —Amit Khera, MD, MSc, Assistant Professor, UT Southwestern Medical Center
The HDL hypothesis may still be viable from the standpoint of future research, but this study is another disappointment to all of us who hope to further improve outcomes in patients at risk for cardiovascular disease. From the perspective of contemporary clinical care, we must step back and recognize that the evidence for lipid-modifying therapy, in terms of meaningful patient outcomes, supports only the use of statins, with little current role for agents that raise HDL. Other lipid-modifying therapies, including niacin (which failed in AIM-HIGH) and fibrates simply should not be used regularly, if at all. My perspective would change if a study or studies showed that lipid-modifying therapies that raise HDL have important clinical benefits beyond improving a patient's lab-test result. —Frederick A. Masoudi, MD, MSPH, FACC, FAHA, Associate Professor of Medicine, University of Colorado Denver; Denver Health Medical Center
This study does not overturn the strong evidence from animal models that some forms of HDL raising are likely beneficial. Nor does it prove that other approaches that involve both LDL lowering and HDL elevation, such as CETP inhibition, will fail. AIM-HIGH showed that the HDL-raising effect of extended-release niacin does not benefit patients whose LDL is tightly controlled at 40 to 80 mg/dL. This could indicate that the anti-atherogenic effects of HDL are not important in the absence of an ongoing atherogenic stimulus. Or it may imply that niacin's particular mechanism of HDL elevation, which is unknown, is not beneficial. The data highlight, once again, the importance of testing specific hypotheses in carefully designed clinical trials. —Alan R. Tall, MD, Tilden Weger Bieler Professor of Medicine, Columbia University School of Medicine