Shelley Wood

May 30, 2014

LAS VEGAS, NV — It's been two months since the presentation of HEAT-PPCI ignited a debate on ethical trial conduct and outlier data in real-world STEMI patients treated with bivalirudin (Angiomax, the Medicines Company) or heparin. Depending on who was asked, the Liverpool, UK trial was a brave and ingenious approach to resolving a basic unanswered question in acute-MI care or a rash and dangerous regression into the dark ages of human experimentation.

That controversy was back in the spotlight here at the Society for Cardiovascular Angiography and Interventions (SCAI) 2014 Scientific Sessions as part of a session entitled "From Clinical Trials to Clinical Practice." And here, under a blazing Las Vegas sky, experts seemed to greet the study with considerably more warmth than was seen back in the gloom and slush of the nation's capital during the American College of Cardiology (ACC) 2014 Scientific Sessions in early spring.

At SCAI, Dr David Cox (Lehigh Valley Heart Specialists, Allentown, PA) provided an overview of the conflicting data and outstanding questions from HORIZONS , EuroMAX , and HEAT-PPCI. He also offered some published estimates of bivalirudin use in the US, where the drug costs significantly more than the old bystander heparin. In a CathPCI registry publication from 2012, he noted, bivalirudin use was 56% across all PCI procedures. In NCDR data on STEMI patients published in 2013, bivalirudin was used in 30% of radial cases and 34% of femoral PCIs.

Given its substantial usage, the question is whether the single-center HEAT trial—which showed significantly higher major adverse cardiac event (MACE) rates with bivalirudin, a more than threefold higher rate of stent thrombosis, and no benefits in terms of reduced bleeding—should influence practicing physicians and cath-lab budgets. Especially since, as several high-profile panelists fumed during the ACC presentation, patients randomized in HEAT did not give their consent to participate until they were recovering postprocedure.

The Ethics of HEAT

Dr David Cohen (St Luke's Health System, Kansas City, MO), one of the panel discussants, fielded the first question at SCAI about the trial ethics.

"I've thought about it a lot," he admitted.

Fortuitously for Cohen, he ran into a medical ethicist at a Passover Seder immediately after ACC 2014, "so I took advantage of that to describe this trial to him and ask him whether he thought it was ethical or not. Frankly, this randomized controlled trial happens every day, with no consent whatsoever, in everybody's practice in the United States. These are two approved agents that get used, and depending on whose day you show up in the lab, people will get randomized to this without clinical data being collected."

The medical ethicist, Cohen continued, "was very comfortable with this, given these two approved agents, and particularly given the setting, when time is of the essence and where patients are barely informed to begin with, so he thought that was all a very good rationale, that this was an ethical trial, and a good way to answer an important question. So I took that to heart."

Dr Martin Leon (Columbia University, New York, NY), also on the SCAI discussion panel, agreed.

"I think that the whole issue of informed consent in the environment of STEMI is problematical. So I'm listening carefully to David, and I agree, these are two approved agents, and the ethical questions will still be [debated], but they didn't bother me. I was more disturbed by the outcomes and how to explain the discordance with some of the prior trials. . . . Why was the acute stent thrombosis rate so much higher? Why were their no benefits associated with bleeding— was it really the 80% radial approach?"

Burning Questions

Dr Roxana Mehran (Mount Sinai Medical Center, New York, NY), the panel cochair, who'd also been part of the contentious ACC panel discussion, had additional questions.

"[HEAT] was a single-center, yet all-inclusive, very well-conducted study by dedicated investigators, and that really should be said first and foremost: they should be congratulated," she said. "But I believe wholeheartedly that whenever you see a single-center trial [with results that are at odds with other multicenter studies] you really need to examine it."

That said, she continued, "I do agree, the heat is on regarding bivalirudin: with 80% radial and the use of more potent [antiplatelet] agents, we still saw stent thrombosis, which was consistent with EuroMAX and HORIZONS-AMI."

Mehran's key concerns: the lack of a benefit in bleeding and the ascertainment of reinfarctions in HEAT. "Those were my big issues with the trial, and I believe we need to repeat it in a large prospective randomized trial."

Mehran, along with Dr Michael Kim (Northshore University Hospital, Manhasset, NY), pointed to a lack of information on the true incidence of non–access-site bleeds in HEAT. "You have to look for this to find it, and you need to make sure you define it using standardized definitions," she argued. "This is really hard to do in low-funded studies, and it's important to note that, because non–access-site bleeds are important bleeds that need to be avoided."

One theory worth exploring is the potential benefits of a prolonged infusion with bivalirudin, which has shown a signal of benefit in reducing stent thrombosis while diminishing the risk of bleeds. "If we don't think bleeding is important, then we've misunderstood the past 15 years of clinical research," Cox commented. "I still think we probably have to progress to a randomized controlled trial to get the answer, especially since the new P2Y12 drugs don't seem to help us [with reducing acute stent thrombosis].

A Cooling-Off Period

A new trial, of course, would take years to produce results. In the meantime, a number of new analyses have been published or presented in the past two months addressing the question of bivalirudin vs heparin when routine GP IIb/IIIa inhibitors are dropped. These include BRIGHT, BRAVE 4, and NAPLES 3 at ACC 2014 and a new analysis from EuroMAX, released at last week's EuroPCR 2014 meeting and published simultaneously in the European Heart Journal. heartwire has learned that the new kingpin, HEAT-PPCI, will be published in a major journal in a matter of weeks.

Cardiologists say that hospital administrators are already nudging their cath-lab directors to take a second look at bivalirudin and ponder a return to the cheaper, older heparin.

"I'd say anecdotally that HEAT-PPCI has already caused many people to rethink their anticoagulant strategy in the cath lab," Dr Sunil Rao (Duke University, Durham NC) told heartwire . "Ultimately they may end up sticking with what they're already doing, but as long as they are having conversations to revisit what they are doing in the face of new data, that's an important thing."

Costs are the key driver of these discussions, he added, since other practice patterns are changing, in particular the move toward more radial PCI, which may itself trim back the bleeding advantage seen with bivalirudin. "We weren't having these [cost-cutting] conversations a few years ago. It was all, what can we add? Now are all talking about what we can take away."

Dr Peter Berger (Geisinger Health System, Danville, PA), likewise, is already putting some changes in place. "In my health system, patients and practice patterns more closely resemble those in HEAT than most of the other trials in which bivalirudin was studied, and HEAT was a relatively large trial." As such, "HEAT probably ought to influence our practice patterns more than those other trials, not less."

Berger, who is the chair of cardiology at Geisinger, says the changes under consideration include a move to a lower dose of heparin with potent P2Y12 inhibition in STEMI patients. "We also plan to use heparin alone in the other types of patients where vastly more expensive drugs offer no improvement in clinical outcome, such as the stable and unstable angina, biomarker-negative patients [similar to patients] in the ISAR 3 and 3A studies and those in the NAPLES 3 study, among others."

As an aside, Berger added, "I do feel that most of the criticism that has been leveled against the HEAT trial was been extraordinary unfair" and "ill-tempered."

There was no sign of that kind of sniping at SCAI yesterday, where the tone was universally thoughtful and questioning. The lone UK cardiologist on the panel, Dr Keith Oldroyd (Golden Jubilee National Hospital, Glasgow, Scotland), was not involved in HEAT-PPCI but says his center does not use bivalirudin.

As such, he said mildly, "We are very comfortable with the results."

Berger had no disclosures. Cohen disclosed being an advisory board/board member for and receiving grant or research support from Medtronic, Eli Lilly, and AstraZeneca, as well as being on the speaker's bureau for AstraZeneca. Cox disclosed being an advisory board/board member for Medtronic, Boston Scientific, and Abbott Vascular. Kim disclosed grants/research support from Philips Healthcare. Mehran disclosed grants or research support from Lilly/Daiichi Sankyo, Bristol-Myers Squibb/Sanofi, CardioKinetix, and the Medicines Company; consulting for Covidien, BSC, Janssen, Merck, May Medical, Regado Biosciences, Abbott Vascular, AstraZeneca, and Bristol-Myers Squibb; and being on an advisory board or board member for CSL Behring and Sanofi. Oldroyd disclosed being on the speaker's bureau for AstraZeneca and St Jude Medical and receiving grants/research support from St Jude. Rao disclosed grant/research support from Ikaria and Abbott Vascular; consulting for Daiichi Sankyo/Lilly, Zoll, AstraZeneca, the Medicines Company, and Terumo; and being on the speaker's bureau for Abbott Vascular and the Medicines Company.

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