Shelley Wood

May 28, 2013

PARIS, France — Blazing new ground, investigators of the How Effective Are Antithrombotic Therapies in Primary Percutaneous Coronary Intervention (HEAT-PPCI) trial have set themselves the lofty goal of randomizing every single acute-MI patient admitted to their hospital, without first getting their consent. That means that the roughly 5% of AMI patients who die in the early days of the study will be full trial participants, despite having never actually agreed to be in it.

The aim is to make sure that the single-center, 1800-patient study population is truly representative of the real world, principal investigator Dr Rod Stables (Liverpool Heart and Chest Hospital, UK) told heartwire .

Stables presented the unique design and preliminary enrollment results here last week at the EuroPCR 2013 meeting.

"The whole world recognizes that randomized, controlled trials represent the purest and most scientific form of evaluation of treatment strategies, but they also have a number of limitations," he said. Trials tend to recruit highly selected, unrepresentative populations; thus the results cannot reliably be translated to all-comer patients. "There are lots of factual papers that show, for example, that the elderly, women, ethnic minorities, and patients who are most sick often tend to be excluded from randomized trials."

HEAT and Light

HEAT-PPCI is randomizing AMI patients 1:1 to either heparin or bivalirudin (Angiomax, the Medicines Company) at the time of cath-lab admission for PCI. The two agents have never been directly compared in a large randomized trial that does not include GP IIb/IIIa inhibitors. The primary efficacy end point is major adverse cardiac events at 28 days, and the primary safety outcome is bleeding at the same time point. Secondary end points include periprocedural enzyme spikes, minor bleeds, stent thrombosis, acquired thrombocytopenia, door-to-first-device time, and platelet-function studies.

The idea for the trial grew in part out of the PhD thesis of cardiologist and research fellow Dr Adeel Shahzad (Liverpool Heart and Chest Hospital). "Some observers were afraid that our unilateral and unannounced action--to randomize and include these patients--might disappoint or aggravate the patients and make them feel negatively toward their data being used," Stables said. But that hasn't proved to be the case.

"We've enrolled 1300 patients so far, and only one has officially refused to consent," Shahzad told heartwire . Consent is still pending in 16% of treated patients, and 29 patients died before granting consent.

Stables believes HEAT-PPCI is the largest randomized single-center CV trial in the UK and the first to attempt this ambitious format, which was ultimately approved by the hospital ethics board. Liverpool Heart and Chest Hospital is the regional PCI hub, he noted, and has been enrolling patients at a rate of 20.5 patients per week, "24/7." "There won't be many hospitals in the world who do 20, 22 primary PCIs a week."

Heaven Consent?

In a unique twist, HEAT-PPCI has applied for and been granted detailed access to patient data through Section 251 of the 2006 UK National Health Service act. Christine Mars, the research nurse who spearheaded this component of the trial, explained that investigators were required to demonstrate to the governmental body that their study met specific criteria, including whether their reasons for seeking the data were in the public interest, whether their research was related to a medicinal product, and whether approaching relatives to obtain the data would do more harm than good. "We felt that we certainly did meet those criteria," Mars told heartwire .

The key issue in an AMI trial is that "the faster these patients get treated, the better," with some literature suggesting that outcomes are worse for every minute of delay, Stables said. But the standard for informed consent in clinical trials requires that patients be given ample time to weigh the decision and be in a state of mind that allows them to make a sensible and rationale decision.

"Our patients not only are under time pressure, but they are all in the throes of an MI, they are in pain and distress, they may have been medicated with powerful opiates that may affect decision-making," Stables said. "Our view was that it would not be possible to obtain any form of meaningful informed consent in this setting, even if one tried."

Nothing Wild or Unproven

Stables notes that other trials of primary PCI in AMI have tried to balance risks and ethical consent by "attempting to perform partial consent with an initial announcement read to the patient," who is later reapproached after his or her procedure.

In HEAT-PPCI, he said, both treatments are approved, guideline-recommended, and in routine use, "which is far more acceptable than if we were doing something wild or unproven," he points out. In the trial, investigators have typically waited until one or two days after the procedure to ask patients about their willingness to participate.

"For the patient, it ensures that their treatment pathway is not hindered, delayed, or compromised in any way," Stables said.

For the grieving families of those who don't survive an AMI, they are spared the decision of whether or not to release data and information during a difficult time.

The most important thing is the patient, but with this novel trial design, the science will also be center stage.

"This will lead to results that relate to real-world practice and can be applied universally. And in fact, what we found is, because our entire institution is following a rigorous and continuously observed protocol, it is conceivable that the general level of patient care at our hospital has become more complete, more consistent, and that tiny bit more professional for each and every patient."

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