A senior researcher in biomedical ethics (David Shaw, Institute of Biomedical Ethics, University of Basel, Basel, Switzerland) has said that the controversial use of delayed consent in HEAT-PPCI (Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention)—in which patient consent was not sought until after randomisation—was ethical and was actually preferable to obtaining consent immediately.
HEAT-PPCI, which was presented at this year’s American College of Cardiology meeting (29–31 March, Washington DC, USA), has raised questions about the supposed benefits of bivalirudin (Angiox, The Medicines Company) over unfractionated heparin because it showed—contrary to previous studies—that heparin significantly reduces the risk of major adverse ischaemic events in patients undergoing primary percutaneous coronary intervention (PCI) compared with bivalirudin with no increase in bleeding complications. However, the investigators of the study were criticised for using a delayed consent approach in the study.
Adeel Shahzad, Institute of Cardiovascular Medicine and Science, Liverpool Heart and Chest Hospital NHS Foundation Trust, Liverpool, UK, and others used delayed consent to address the “common limitation of the randomised control trial: recruitment of only a modest proportion of the potential, eligible population”. Therefore, they randomly allocated all patients presenting to their hospital‘s primary PCI service to a study treatment (heparin or bivalirudin) and did not attempt to obtain the patients’ consent to be enrolled in the study until after the drug had been administered. Gregg Stone (Columbia University Medical Center/New-York-Presbyterian Hospital, New York, USA), who was an investigator in a study (HORIZON-AMI) that indicated bivalirudin did have benefits over heparin in PCI, was extremely critical of this approach. He told MedPage Today that the use of delayed consent in HEAT-PPCI might “violate the Helsinki accords”, which prohibit experimentation without consent except in extreme cases, and added that he had “never seen anything like this” in his career.
However, writing in a commentary that has been published alongside HEAT-PPCI in The Lancet, Shaw calls the use of delayed consent in the study “entirely ethical” and argues that the Helskinki accords recognise delayed consent as an “acceptable method” of respecting patients’ autonomy in emergency research. He adds that it is “particularly appropriate” in studies, such as a HEAT-PPCI, that compare drugs “for licensed indications in conditions of equipoise”, noting that “In routine clinical care, it would be perfectly normal for a doctor to choose either heparin or bivalirudin without involvement of the patient in the decision.” Another argument that Shaw makes is that if patients had objected to the use of delayed consent, they would have withdrawn from study but he points that “only four refused” their consent when they were asked. Shahzad et al also claim that the patients in the study did not object to the delayed consent approach, saying that the strategy “was well received” by the patients.
As well as defending the use of delayed consent in HEAT-PPCI, Shaw claims it was preferable to attempting to obtain consent from “potentially incompetent patients needing extremely urgent cardiac treatment”. In his view, attempting to get consent from patients before randomisation could have increased the risk of harm by delaying treatment and could have affected recruitment. He adds without the study, given that it showed heparin to significantly reduced the rate of the primary efficacy outcome (a composite of all-cause mortality, cerebrovascular mortality, reinfarction, or unplanned target lesion revascularisation) compared with bivalirudin (5.7% vs. 8.7%, respectively; p=0.01), doctors “around the world” would have continue to use “an interior treatment”. “The results of HEAT-PPCI mean that resources will not be wasted on bivalirudin, a more expensive and less effective treatment than heparin. These findings are why this type of head-to-head research is important,” Shaw explains. He concludes his commentary by saying the study has blazed “a trail for future research of this type.”
He told Cardiovascular News: “Delayed consent is appropriate in several different circumstances: in emergency research where getting consent is impossible or would increase risk to patients, in minimal risk studies, and where the trial involves randomisation of two routine treatments. In HEAT-PPCI, all three of these factors were present. (Delayed consent is also sometimes used in psychological research to avoid biasing participants.)”