PCSK9 Inhibitors for Acute Coronary Syndrome
PracticeUpdate: Could you please provide a brief overview of the results of the ODYSSEY Outcomes trial?
Dr. Bhatt: The ODYSSEY Outcomes trial is a really major trial in cardiovascular medicine. It set out to examine what the role of the PCSK9 inhibitor alirocumab versus placebo might be in patients who’d had an acute coronary syndrome 1 to 12 months prior to randomization. Such patients were randomized to alirocumab versus placebo and followed for several years, and the median follow-up ended up being around 2.7 years with some patients really followed up to four years and slightly beyond. The study overall found a significant reduction in major adverse cardiovascular events of 15 percent or so relative risk reduction.
In particular, it appeared that the benefits of this therapy started to accrue after a year or so post randomization in this stabilized ACS population. The benefits were concordant in the individual components of the MACE endpoint with significant reductions in MI and stroke as well.
PracticeUpdate: How does this compare to current standard therapy for patients with acute coronary syndrome?
Dr. Bhatt: The patients in ODYSSEY Outcomes were treated with excellent background therapy including a very high rate of statin use including high intensity statin use. In patients despite this therapy who remain at high risk, it would appear that the addition of a PCSK9 inhibitor could further reduce their risk of future ischemic events.
Within ODYSSEY Outcomes, in particular, the subgroup of patients with an LDL cholesterol at baseline greater than or equal to 100 achieved an even greater relative absolute risk reduction than in the overall trial. This was true for MACE, but also true for all-cause mortality with an endpoint. In fact, in the overall trial, all-cause mortality was nominally lower, but in the subgroup with an LDL cholesterol greater than or equal to 100, there the effects both on MACE and mortality seem much more robust, so in clinical practice, what I think I would do is if I had a patient who’d had an acute coronary syndrome and say I'm seeing them a month or two after that initial event, I would measure their LDL cholesterol, I would make sure they were already on a maximally tolerated high potency statin such as atorvastatin or rosuvastatin, and if their LDL were still above 100, I would likely add ezetimibe, but despite all that, if the LDL remained 100, that’s the sort of patient I think would be an appealing target for PCSK9 inhibition.
PracticeUpdate: Based on the results of the ODYSSEY and FOURIER trial, what is the role for PCSK9 inhibitors for patients with coronary artery disease?
Dr. Bhatt: The results of ODYSSEY Outcomes apply most strictly to patients who’ve had an acute coronary syndrome 1 to 12 months prior. Whether those results should be further extrapolated to other patients such as those with coronary artery disease, of course, the purist would say no. On the other hand, the FOURIER trial did examine a much broader population with stable atherosclerotic disease, and there, the overall trial was positive with a significant reduction in MACE. In fact, of a similar magnitude as in ODYSSEY Outcomes; however, there was no reduction in mortality noted in that trial, so if it weren’t a matter of cost, there are many patients with coronary artery disease, especially those with elevated LDL cholesterol, that would likely benefit from this form of therapy.
On the other hand, given the costs of these drugs, right now, it would seem that the most cost effective population in which to use them might be what we identified in ODYSSEY Outcomes, that is patients with a ACS in the past 1 to 12 months with an LDL cholesterol still greater than or equal to 100, they are given what we observe with alirocumab the absolute risk reductions perhaps would justify this expensive therapy.
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