October 1, 2017 Public Citizen Calls for Halt to Unethical NIH-Sponsored Clinical Trial Involving Heart Attack Patients Throughout the U.S. and Canada

Health Letter, October 2017

By Michael Carome, M.D.

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On Aug. 1, 2017, Public Citizen’s Health Research Group (HRG) called for the immediate suspension of a clinical trial that is expected to involve thousands of heart attack patients throughout the U.S. and Canada because of potentially serious ethical and regulatory violations. HRG’s concerns about the trial were detailed in a letter submitted to the U.S. Department of Health and Human Services’ Office for Human Research Protections (OHRP) and the U.S. Department of Veterans Affairs’ (VA) Office of Research Oversight (ORO).

Researchers conducting the Myocardial Ischemia and Transfusion (MINT) trial have begun randomly assigning hospitalized patients suffering acute heart attacks and significant anemia to one of two blood transfusion strategies. Half are being assigned to a “liberal” strategy group in which they are transfused sooner at a higher red blood cell (RBC) level, and the other half are being assigned to a “restrictive” strategy group in which they are transfused only when they hit a significantly lower RBC level. The researchers are measuring how many subjects die or have another heart attack within 30 days in each group.

Prior studies already strongly suggest that a restrictive transfusion strategy is more likely than a liberal strategy to lead to further heart attacks and death.[1], [2],[3], [4], [5], [6] For example, a pilot trial that was published in the American Heart Journal in 2013 used a design very similar to the MINT trial design and enrolled 110 patients, most of whom were having a heart attack or symptoms of an impending heart attack. Thirteen percent of subjects assigned to a restrictive transfusion strategy died within 30 days, compared with only two percent of those assigned to a liberal transfusion strategy. This difference was statistically significant.

The planned number of subjects in the MINT trial is 3,500, to be enrolled at several dozen medical institutions throughout the U.S. and Canada. In March and April 2016, researchers at 67 institutions provided letters of support to the MINT trial’s principal investigator expressing their commitment to, or interest in, participating in the trial. (In some cases, researchers may have withdrawn support, or an institution may not have given approval.) Among the institutions that expressed interest in participating were four VA hospitals.

The study is being funded by the National Institutes of Health, making it subject to the jurisdiction of OHRP. Any participation by VA medical centers also would make the trial subject to oversight by the VA’s ORO.

Based on a review of the MINT trial’s protocol, sample consent form and other background information, HRG is concerned that the trial lacks adequate protections for its human subjects and violates basic ethical principles governing such research. Among the specific concerns presented in HRG’s letter to OHRP and the VA’s ORO were the following:

The restrictive transfusion strategy may be putting the subjects’ health and lives at unacceptable risk;

The trial protocol fails to provide key information that an Institutional Review Board (IRB) would need to determine whether the study meets approval criteria, including a description of current usual care blood transfusion practices for heart attack patients who are hospitalized at the institutions that are to enroll subjects; and

The sample consent form fails to adequately describe the purpose of the research, the risks of the trial, and whether the transfusion strategies being tested are experimental.

One of the most troubling ethical lapses in the MINT trial that was highlighted in HRG’s letter is the failure of the consent form to fully disclose to potential subjects the possible risks of using a restrictive blood transfusion strategy. HRG argues that a reasonable person who is considering enrolling in this trial certainly would want to know about prior research results that strongly suggest that use of a restrictive strategy in heart attack patients increases the chances of dying or having another heart attack, but the consent form makes no mention of these risks.

HRG called on OHRP and the VA’s ORO to suspend enrollment in the trial immediately and require that the researchers take the following actions:

Conduct detailed surveys or observational studies of current blood transfusion practices for heart attack patients hospitalized at the participating institutions;

Revise the protocol to describe all prior evidence from randomized clinical trials that compared liberal with restrictive blood transfusion strategies and to explain how the MINT trial will affect the care of the patients at the institutions that are to enroll subjects;

Revise the consent forms so that they adequately describe the purpose of the research, the current evidence that strongly suggests that a restrictive transfusion strategy is less safe than a liberal one for heart attack patients, and risks of being randomly assigned to the restrictive transfusion strategy group; and

Submit the revised protocol and consent forms for review by the OHRP, the VA’s ORO and the IRBs responsible for reviewing the trial.

The VA’s ORO has acknowledged receipt of HRG’s letter, but HRG is still awaiting a response from OHRP.

References

[1] Carson JL, Terrin ML, Noveck H, et al. Liberal or restrictive transfusion in high-risk patients after hip surgery. N Engl J Med. 2011;365:2453-2462.

[2] Murphy GJ, Pike K, Rogers CA, et al. Liberal or restrictive transfusion after cardiac surgery. N Engl J Med. 2015;372(11):997-1008.

[3] Carson JL, Brooks MM, Abbott JD, et al. Liberal versus restrictive transfusion thresholds for patients with symptomatic coronary artery disease. Am Heart J. 2013;165(6):964-971.e1.

[4] Patel NN, Avlonitis VS, Jones HE, et al. Indications for red blood cell transfusion in cardiac surgery: A systematic review and meta-analysis. Lancet Haematol. 2015;2(12):e543-553.

[5] Docherty AB, O’Donnell R, Brunskill S, et al. Effect of restrictive versus liberal transfusion strategies on outcomes in patients with cardiovascular disease in a non-cardiac surgery setting: systematic review and meta-analysis. BMJ. 2016;352:i1351.

[6] Cortés-Puch I, Wiley BM, Klein HG, et al. Restrictive red blood cell transfusion strategies in patients with cardiovascular disease: A meta-analysis. American Thoracic Society 2017 Conference. May 19-24, 2017. Washington, DC.