This discussion between William E. Boden, lead investigator of the AIM-HIGH trial, and CardioExchange’s Harlan M. Krumholz follows John Ryan’s interview with Dr. Boden last week about the results from HPS2-THRIVE.
Boden: Harlan, I have a scenario for you: A 55-year-old man with recent acute MI undergoes PCI of the infarct artery and returns to the CCU post-procedure. His fasting admission labs show a total-cholesterol level of 149 mg/dL, LDL 105 mg/dL, HDL 23 mg/dL, triglycerides 190 mg/dL, and non-HDL 126 mg/dL. Following evidence-based practice guidelines (PROVE-IT), the patient is started on atorvastatin 80 mg daily (which, by the way, may further reduce HDL at that dose). You’ll likely get his LDL at or near 70 mg/dL, and because his non-HDL level is <130 mg/dL, this doesn’t become a necessary secondary treatment target. Does AIM-HIGH or HPS-2 THRIVE even apply here? A lot of evidence from many sources shows that such a very low HDL level is a powerful predictor of CV events. So I’d prescribe niacin and tell the patient I can’t be certain he’ll live longer or have a lower rate of MI/stroke. But I also tell him that many academicians and opinion leaders would decry my practice because they believe that any RCT result applies equally to all patients without exception.
Krumholz: I wish I had an effective drug to prescribe, but prescribing one that has no evidence of benefit and may be harmful is just something that I could not recommend. I see these drugs as having thousands of effects, and the biomarker of interest likely represents just a small number of them. What I need to know is the net effect, and I am not confident I can predict that based on the movement of the single biomarker.
Boden: There is evidence of clinical outcome improvement (i.e., CHD death/MI reduction) from VA-HIT for gemfibrozil; there is similar clinical outcome improvement for niacin from the Coronary Drug Project. Numerous studies show niacin’s benefit on surrogate outcome measures (i.e., quantitative coronary angiography, IVUS, cIMT, etc.). What more evidence do you need?
Krumholz: The CDP was conducted between 1966 and 1975 — eons ago. And the effect was on nonfatal MI, a secondary endpoint; 5-year mortality was the primary endpoint. I know about the study of the survivors long-term, but that’s hardly definitive evidence. Yes, gemfibrozil was positive in VA-HIT, but I’m not sure the relevance to our discussion of niacin. I think we should drop the use of this billion-dollar drug.
Boden: So do you think that flawed study design could have made some contribution to these “failed” outcomes trials? The LDL story is simple and straightforward. The epidemiology of the direct linear relationship between elevated LDL and increased incident CV risk is supported by many RCTs of statin benefit where the drug—which inhibits HMG coenzyme reductase—lowers LDL and CV risk. It’s a clean cause and effect with a drug that acts solely on the LDL receptor.
By contrast, we have no “pure” HDL drug — that is, no available agent that singularly affects HDL alone. Niacin lowers triglycerides, LDL (modestly), and lipoprotein(a); raises HDL and apolipoprotein-A1; and shifts LDL particle size and number from small, dense pattern B (atherogenic) to large, fluffy, buoyant pattern A (non-atherogenic) LDL.
Finally, Lavigne and Karas have a new meta-analysis of all niacin RCTs that includes AIM-HIGH — in all, 11 RCTs involving 9959 patients with established CHD treated with niacin (alone or combined with other agents). The primary composite outcome measure was CVD events. The odds ratio for niacin was 0.66 (95% CI, 0.49–0.89; P=0.007). Notably, the magnitude of on-treatment HDL difference between treatment arms was not significantly associated with the magnitude of the effect of niacin on outcomes (P=0.86), suggesting that the reduction in CVD events with niacin may be occurring through a mechanism not reflected by — or independent of — changes in HDL concentration.
My concluding thought is that HDL is exceedingly complex—far more so than LDL. For me, AIM-HIGH has been a humbling experience, and one from which I have learned some important lessons of how I might structure and design the next RCT. So, yes, I have not given up on niacin, although I acknowledge that I will likely become part of a grudgingly declining minority of physician-scientists.
Krumholz: That’s great that you are not giving up on niacin, and you may be right about HDL, but we have to face the facts about the trials. They have failed to be supportive, and despite concerns about their flaws, they were developed by some of the best minds in our profession (including yours) and had millions of dollars devoted to them. I just feel that we cannot justify millions of people being prescribed a drug that has failed in two recent, large, prominent trials, which actually had signals of harm (we are awaiting more news about that from HPS2-THRIVE). A meta-analysis that leverages secondary outcomes is hardly strong evidence, particularly given that most of those studies were not in the modern era. Please continue to study strategies that will lower risk and help us find ways to help patients. But please do not say that we should ignore your multimillion-dollar NIH trial, especially after its findings have apparently been validated by a larger, multimillion-dollar industry trial.
Where do you come down in this debate? And stay tuned for for further insights on this topic from Peter P. Toth.