HEAT-PPCI in Print: 'It's Pretty Bloody Detailed'

Shelley Wood

July 04, 2014

LIVERPOOL, UK — The HEAT-PPCI trial that caused such a sensation earlier this year is now published in the Lancet, accompanied by two editorials and a comprehensive online appendix that, according to the senior investigator, should put to rest the many questions raised about this ground-breaking and controversial study in recent months[1–3].

Dr Adeel Shahzad (Liverpool Heart and Chest Hospital, UK) first presented the How Effective Are Antithrombotic Therapies in Primary PCI (HEAT-PPCI) results during what will be remembered as one of the most electric American College of Cardiology (ACC) 2014 Scientific Sessions late-breakers in years—as much for the surprising trial findings as for their largely hostile reception by the panel discussants.

As previously reported by heartwire , HEAT-PPCI was an open-label, single-center STEMI trial that randomized patients to bivalirudin (Angiomax, the Medicines Company) or low-dose unfractionated heparin, with GPIIb/IIIa inhibitors used in both arms for bailout only. That strategy is recommended in the European Society of Cardiology guidelines but was never previously tested in the early bivalirudin studies, which typically used heparin plus GPIIb/IIIa inhibitors as the comparator arm.

The trial was also unique for its delayed informed consent—a design that passed approval of three separate ethical review committees but nevertheless has proved a major bone of contention in discussions of the trial. All consecutive adults presenting with acute MI (AMI) to Liverpool Heart and Chest Hospital were randomized to one of the two approved antithrombotic therapies at the time of emergency angiography, with consent obtained when patients were recovering postprocedure or from family members. A full 97% of all AMI patients evaluated for primary PCI during the study period were enrolled in the trial; only four out of the 1917 trial participants refused or withdrew consent.

What's New in the Lancet?

Speaking with heartwire , senior investigator Dr Rod Stables (Liverpool Heart and Chest Hospital) said that the published HEAT-PPCI results are almost identical to those presented at ACC 2014. In brief, patients in the heparin-treated group had fewer ischemic events (driven by fewer stent thrombosis, reinfarctions, unplanned revascularizations) than bivalirudin-treated patients, with no differences in major bleeding. (See below for detailed results.)

Now available in the published paper are details on many of the issues raised following the formal trial presentation and subsequently at major medical meetings around the globe. For example, said Stables, the online appendix offers a several-page exposition on how activated clotting time was monitored during the trial. One criticism of the study had been that bivalirudin may have been underdosed, Stables noted. "We provide quite a detailed [explanation that would] allow any observer who had questions in this respect to feel satisfied. This deals with the possibility that in some way the body weights of the patients were inaccurately estimated and gives a detailed data exposition of the degree of accuracy obtained in patient weight, so it's pretty bloody detailed."

Also in the online appendix are detailed definitions of trial end points including the definition of reinfarction, about which, Stables acknowledges, there remains a lack of consensus guidance on how reinfarction in the acute phase should be defined in clinical research trials.

"We are very confident that our approach to the definition of reinfarction and the definitions that are published in detail in the online annex are robust, mirror clinical common sense, and will find near-universal approval with practicing cardiologists," he said.

Other questions have been raised about how bleeding events were identified and adjudicated in the trial. On this point, Stables explained, events were actually managed and adjudicated at four different levels in addition to the data safety and monitoring board's review.

"It is impossible for me to give you a 100% guarantee that somewhere an event might have occurred and not been reported, but the chances of that are relatively low," Stables said. "More important, the subtext of the question is: Do I believe in any way that some kind of malevolent and systemic bias was applied to selectively amplify bleeding in one group or suppress it in another or have a modest combination of both? I totally refute that assertion and will back that up by the fact that the clinical records were completed by nontrial staff. They are checked and reported by the clinical coding department, and they have been the subject of a number of independent audits" by medical practitioners who performed quarterly reviews on random cross-section samples.

Also, he notes, "dotted around the paper" are other details that researchers have been keenly interested in—namely, how patient consent and follow-up was ascertained.

The only change in outcome measures in the published paper vs the ACC 2014 presentation is for a prespecified analysis of outcomes according to whether PCI had been performed by radial vs femoral access. Numbers presented at the ACC were as-treated, whereas the paper includes the intention-to-treat analysis, and "it really doesn't materially change anything," Stables notes.

He hopes to publish further details on the radial vs femoral subanalysis but notes that the majority of operators in HEAT-PPCI are default radial operators, and most were able to do more than 90% of procedures via a radial route. As such, patients treated via a femoral access route tended to be those already at higher risk of adverse events, including patients in cardiogenic shock, with preexisting bypass grafts, and/or needing hemodynamic support.

HEAT-PPCI: Main Results

Approximately four out of five patients undergoing emergency angiography in HEAT-PPCI were ultimately treated with PCI, and GPIIb/IIIa inhibitor use was similar in both study groups (13% in the bivalirudin group and 15% in the heparin group).

The primary efficacy outcome (all-cause mortality, stroke, reinfarction, or unplanned target lesion revascularization) occurred in 8.7% of bivalirudin-treated patients and 5.7% of heparin-treated patients, a significant difference (p=0.01).

An advantage with heparin was seen for all components of the primary efficacy end point (although not significant for mortality or stroke) and was driven primarily by the significant increases in new MI or reinfarction in the bivalirudin group (24 vs 8, p=0.004). All but one of these events was linked to definite, angiographically confirmed stent thrombosis, independently adjudicated.

Moreover, major bleeding (defined as type 3–5 by Bleeding Academic Research Consortium [BARC] definition) was no different between groups, at 3.5% and 3.1% for the bivalirudin and heparin groups, respectively (p=0.59). This lack of difference has proved, for many, to be the most difficult finding to digest in HEAT-PPCI, given the reductions in bleeding with bivalirudin seen in HORIZONS-AMI and REPLACE 2 .

That's a point picked up in an accompanying editorial by Drs Peter Berger and James C Blankenship (Geisinger Health System, Danville, PA) who note that comparisons with other major trials of bivalirudin vs unfractionated heparin are inappropriate, because most other trials included prolonged infusions of GPIIb/IIIa inhibitors in the heparin arm or higher doses of heparin, as was used in the heparin monotherapy arm of the European Ambulance Acute Coronary Syndrome Angiography (EUROMAX) study.

In HEAT-PPCI, Berger and Blankenship note, the dose of heparin at 70 U/kg is "less than that in most previous trials in which heparin was administered as monotherapy."

The editorialists also point to the fact that the more potent and rapidly acting P2Y12 inhibitors prasugrel (Effient, Lilly/Daiichi Sankyo) and ticagrelor (Brilinta, AstraZeneca) were used in about 90% of patients, a higher rate than in previous trials. Whether that explains why stent thrombosis rates in the heparin group did not, in the words of the editorialists, "catch up" with the higher rates in the bivalirudin group needs further analysis, Stables said, adding that HEAT-PPCI doesn't offer much insight on this theory.

Potential Cost Savings

Both the Berger/Blankenship editorial, as well as the paper itself, note that heparin is significantly cheaper than bivalirudin, the latter costing roughly 400 times more than the former.

As such, the HEAT-PPCI findings "might provide an opportunity, rare in modern healthcare, to provide improved outcomes at much reduced cost," Shahzad et al write. "In our center, routine use of heparin rather than bivalirudin . . . would reduce immediate drug costs in our annual 1000 PPCI cases by £500 000."

That means that even if the results in the heparin group had been similar to those in the bivalirudin group, Berger and Blankenship write, "it would have still been a win for heparin. A drug that costs less than a 400th of another that has similar efficacy and safety ought to be used preferentially."

Berger has previously told heartwire that his cath lab has already instituted changes based on the HEAT-PPCI results presented at ACC 2014.

Heated Ethical Debate

The second editorial in the Lancet, by Dr David Shaw (Institute for Biomedical Ethics, University of Basel, Switzerland), deals exclusively with the pragmatic design of the trial and its patient informed consent and argues that HEAT-PPCI "blazed a trail."

To heartwire , Shaw cited the "violent" reaction, on ethical grounds, that the HEAT-PPCI trial met with at the ACC meeting and says he now believes some of that reaction was "overblown," although he adds that, as a former university ethics committee member, he understands why the trial met with so much controversy.

Having had months to review and think about the trial, Shaw now believes that HEAT-PPCI was ground breaking. "The use of delayed consent respected patients' autonomy, while also increasing recruitment to an essential trial that has the potential to improve future patient care."

He hopes the controversy surrounding HEAT-PPCI will reinvigorate discussion about what truly is best for patients, both those in the trial and those on whom the trial answers could have a profound impact. "It would also have been unethical to prevent this trial from being done because of misplaced concerns about consent. Had HEAT-PPCI not been done, doctors around the world would have carried on giving patients inferior treatment."

Other Experts React

Not everyone has come around to Shaw's viewpoint. Speaking with heartwire , Dr Roxana Mehran (Mount Sinai Medical School, New York, NY) says further trials should be done to verify the HEAT-PPCI trial findings, but that these could still be conducted with a more traditional prerandomization consent process.

"There are short consent forms for exactly this purpose and many, many centers, including ours, would accept a short consent from family members or patients prior to STEMI trial enrollment, and you certainly can do that to include all-comers," she said. "Just because we need the answer to a question doesn't mean we don't need to ask patients [for consent]."

Mehran would like to see the results replicated in a multicenter study with clear definitions of reinfarction and special attention paid to ascertainment of bleeding events, particularly in US cath labs, where use of radial PCI is so much lower. "But this is really a landmark study . . . [and] a great thing, to have us stop and think about the role of bivalirudin and heparin in the setting of more potent agents, the role of radial access in reducing our complications, and the reduced need for GPIIb/IIIa inhibitors. . . . We can't walk away from these data. These data are intriguing, and they should make us stop and think."

Dr Sunil Rao (Duke University, Durham, NC), also commenting on the HEAT-PPCI publication for heartwire , said he, too, would like to see the results replicated in a multicenter trial.

"Single-center studies often magnify treatment effects, [although] the publication makes it clear that this study is robust and was extremely well executed," Rao said in an email.

He believes the cardiology community "still needs to wrestle with" the decision to randomize prior to patient informed consent. "For example, the issue of not requiring informed consent when two 'standard-of-care' strategies are being tested is something that is being debated."

He also thinks that the very high rate of radial PCI likely influenced the results. "I think HEAT-PPCI is a very important trial that will have an impact on clinical practice, but I would like to see the results corroborated in another trial that involves multiple centers."

Stables, to heartwire , sighed when the "single-center trial" argument was broached.

"HEAT mirrors expected findings that can be inferred from the existing data and is not some unique venture that is at odds with the existing wisdom. It fits very nicely and, to me, it completes the picture rather than opens the question. When people say it is a single-center trial, I say: identify for me the specific concerns that you have and we'll discuss them and I will attempt to allay your concerns or acknowledge them. . . . Many of the limitations traditionally associated with single-center trials are not a material or legitimate concern in HEAT."

Asked about the ethical concerns and whether these have deflected from the primary findings of the trial, Stables paused even longer before responding.

"I'm sure that must be true for a small minority of individuals, but I think it's difficult to wish to take that position," he offered carefully. "It is important in humanity to respect peoples' ethical or religious or other important views and never seek to denigrate or dismiss those views on the basis of supposition or theory. So I will try to never take that view so I can at least participate in the ethical debate in an open and collaborative manner."

All of our news and features coverage of HEAT-PPCI can be found here .

Stables disclosed receiving grants from the Medicines Company and grants and personal fees from AstraZeneca during the conduct of the study. All other authors had no conflicts of interest. Berger disclosed receiving grants from Janssen, the Medicines Company, AstraZenca, Eli Lilly, Sanofi, DRDI Holdings, and GeneNews and personal fees from Janssen and Medicure. Blankenship disclosed receiving no personal fees but receiving trial funding from numerous companies listed in the paper. Shaw had no conflicts of interest. 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. Mehran disclosed being on the advisory board for and receiving research grants from the Medicines Company.

 

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