Reference: N Engl J Med. 2023 Aug 24;389(8):687-699
Practice Point: Consider a lower than usual threshold for starting pitavastatin in adults with HIV to reduce the risk of major cardiovascular events.
EBM Pearl: Stopping a clinical trial prematurely for efficacy sacrifices precision and runs the risk of underestimating harms.
HIV, like other chronic inflammatory conditions, is associated with an increased risk of MACE (major adverse cardiovascular events). People with HIV might be particularly apt candidates for statin therapy, given the anti-inflammatory benefits of statins that go beyond what might be expected solely from lipid control. One concern with universal statin use is that many HIV drugs tend to interact with statins. Pitavastatin, an otherwise less-commonly used statin, has been reported to have less drug-drug interactions than most.
The REPRIEVE trial was a large multinational trial looking at the primary prevention of MACE events in middle-aged people with HIV published in NEJM a few months ago. It was widely publicized for better than expected efficacy at an interim analysis, at which point the trial was stopped early for benefit. At first glance, this seems to promise a potentially practice-changing shift. This trial was large - 7769 patients with HIV with low or undetectable viral loads and a median 10-year ASCVD risk of 4.5%, which is below the typical threshold for statin benefit. Participants were randomized 1:1 to pitavastatin 4 mg or placebo daily. The groups were well balanced regarding risks, antiretroviral regimens, and demographic features. The primary outcome was a compositie occurrence of MACE. The trial was stopped early after an interim analysis demonstrated a 30% reduction in MACE events in the pravastatin group (HR 0.65 CI 0.48-0.9 with an absolute risk reduction going from 7.3 to 4.8 events per 1000 patient years). In terms of adverse events, there was a slightly higher risk of myopathy and diabetes in the statin arm.
We have two concerns; one is minor quibbling and the other more significant. First, the authors use the term “estimand” twice in the text. However, there is no estimand section nor a clearly defined list of estimands and intercurrent events in the paper or protocol, as recommended by the 2019 ICH guidelines on trial design using the estimand framework. We understand - the estimand framework is relatively new (we described it here a couple of months ago) - but using this term in 2023 when the framework hasn’t been applied seems a little disingenuous to us.
The second concern is about the decision to stop the trial early for benefit. Stopping early for benefit seems like a slam dunk for investigators - “Look, our intervention is so powerful it’s unethical to deprive people in the placebo group of its benefits!” Halting a trial has well-described benefits and harms, and institutional review boards should be free to follow pre-specified rules, as they did in this case. But the rules of the game are set by the investigators themselves. Investigators set short- or long-term periods of evaluation based at least partly on logistical considerations that don’t necessarily apply in the real world, and there are short-term benefits to researchers for stopping a trial early. A longer study period likely would have demonstrated additional harms, some potentially as yet unconsidered, and it’s highly likely that more people would have dropped off protocol over time. Stopping a study early does not automatically resolve real world uncertainty about a clinical question. Given the findings, it’s possible that other statins may also be efficacious, but it has been reported that most other statins have a higher likelihood of interactions with antiretroviral therapy. The researchers in this study calculate an NNT for a 5-year benefit of 106 (almost 3 times the benefit to low-risk patients without HIV), with a 95% confidence interval between 64 and 303. There is a difference between telling someone that 64 people would have to take a medication daily for five years to prevent one additional heart attack or stroke versus 303 people having to take it to see that benefit. Any trial design open to the possibility of ending the trial early for efficacy risks sacrificing precision in calculating the NNT. Unfortunately, there is a long history of RCT’s that were stopped early and subsequently followed by meta-analysis either showing an efficacy/effectiveness gap or unexpected harms. To use a sports analogy, a trial that is stopped early for efficacy is similar to a win for a sports team with an asterisk next to the “W.”
For more information, see the topic Statins for Primary and Secondary Prevention of Cardiovascular Disease in DynaMed.
DynaMed EBM Focus Editorial Team
This EBM Focus was written by Dan Randall, MD, Deputy Editor at DynaMed. Edited by Alan Ehrlich, MD, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School; Katharine DeGeorge, MD, MS, Senior Deputy Editor at DynaMed and Associate Professor of Family Medicine at the University of Virginia; Nicole Jensen, MD, Family Physician at WholeHealth Medical; Vincent Lemaitre, PhD, Medical Editor at DynaMed; Elham Razmpoosh, PhD, Postdoctoral fellow at McMaster University; and Sarah Hill, MSc, Medical Writer at DynaMed.