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HEAT-PPCI and Its Impact on One Clinical Practice in the UK
The interventional cardiology community in the United Kingdom has eagerly awaited the results of the HEAT-PPCI trial, which were initially presented at the American College of Cardiology Scientific Sessions in 2014 and then published roughly 3 months later in The Lancet.
The UK’s National Institute for Health and Care Excellence (NICE) recommended in 2011 that our National Health Service use bivalirudin (Angiomax, The Medicines Company) as the antithrombotic of choice for STEMI patients undergoing primary PCI (PPCI). This decision was based primarily on the results of a single study, HORIZONS-AMI, which had found an advantage of bivalirudin compared with heparin plus mandatory glycoprotein inhibitors (GPIs). The majority of UK centers adopted this strategy. I work in a large PPCI center in the Northeast of England (>500 cases/year) and for the past 2 years we have used bivalirudin as our default antithrombotic.
Despite the trial results and guideline recommendations, many UK operators have harbored a degree of skepticism about bivalirudin. There was concern that the seminal trials — which includes EUROMAX in addition to HORIZONS-AMI — had not used an appropriate comparator with bivalirudin (heparin plus mandated GPIs) and that the results may not be generalizable to contemporary UK PPCI practice.
First, in the United Kingdom, the majority of PPCI cases are performed radially, which is likely to reduce any potential bleeding benefit of bivalirudin. For example, in my center, all of our PCI operators use radial access by default and our radial rate for STEMI is >90%. However, in HORIZONS-AMI, only 6% of the cases utilized the radial route. Secondly, in the United Kingdom there is widespread use of the new, more potent antiplatelet agents in place of clopidogrel (the agent used in HORIZONS-AMI), which may reduce any potential ischemic benefit of GPIs: We use ticagrelor (Brilinta, AstraZeneca) in all of our STEMI patients. Finally, GPI use during PCI in the United Kingdom has been steadily falling over the last decade and many operators have questioned whether they are needed at all in STEMI patients. For instance, the BRAVE-3 study, published in Circulation in 2009, had already suggested that GPI offered no advantage over heparin alone in PPCI patients who had been pretreated with high-dose clopidogrel.
HEAT-PPCI and Current UK Practice
The HEAT-PPCI trial was felt to much more closely mirror contemporary UK practice. This trial was conducted by Rod Stables, MD, Adeel Shazhad, MD, and colleagues at the Cardiothoracic Centre in Liverpool, one of the United Kingdom’s largest PCI centers with a solid track record for conducting interventional cardiology trials. They compared antithrombotic therapy with bivalirudin vs. heparin in patients undergoing PPCI for STEMI. Radial access was used in 80% of cases, and prasugrel (Effient, Daiichi Sankyo/Eli Lilly) or ticagrelor was used as the second oral antiplatelet agent in 88% of patients. Crucially, GPIs were not given routinely with heparin and were only given selectively as a “bailout” therapy in both arms. Finally, a novel delayed consent process was used whereby all eligible patients were randomly assigned and consent was sought from patients afterward, making this a true “all-comers” trial. As a result, 97% of all eligible STEMI patients were included in the trial.
Paul D. Williams
The headline results are in marked contrast to previous large randomized controlled trials, like HORIZONS-AMI and EUROMAX, which had suggested a benefit of bivalirudin over heparin, primarily as a result of a reduction in bleeding. In HEAT-PPCI, there was no difference in bleeding between the two groups; however, there was a higher rate of ischemic events in the bivalirudin group, driven by a higher rate of early stent thrombosis. The finding of a benefit in the primary efficacy endpoint with no difference in the primary safety endpoint was a clear win for heparin: an established and vastly cheaper drug.
Discrepancies with HEAT-PPCI were also observed in a more recent trial, BRIGHT, which was presented in September at Transcatheter Cardiovascular Therapeutics in Washington, D.C. This Chinese multicenter trial compared heparin monotherapy (at a dose of 100 U/kg), heparin plus a GPI (tirofiban) and a Chinese manufactured version of bivalirudin in both STEMI and non-STEMI patients. The investigators reported no difference in ischemic outcomes between the three arms. As expected, heparin plus GPI use had the highest rate of bleeding, but in this study bivalirudin had a lower rate of bleeding than heparin monotherapy.
Following both the presentation and publication of HEAT-PPCI, heated criticisms of the study ensued, focusing on two unrelated issues: the ethics of the consent process and the validity of the results.
Ethics of Consent
Discussion of the consent process has been covered in an excellent editorial in The Lancet by David Shaw, PhD, from the Institute for Biomedical Ethics at the University of Basel, Switzerland. Three separate ethical review committees approved the trial design of HEAT-PPCI. Shaw had no concerns about the trial either; in fact, he felt that the use of delayed consent may even have been too conservative. Here are some of Shaw’s comments: “HEAT-PPCI’s use of delayed consent was entirely ethical. … Far from being unethical, the study sets a high standard for consent in pragmatic trials. … It would also have been unethical to prevent this trial from being done because of misplaced concerns about consent. … The contribution of HEAT-PPCI to ethical trial design should not be underestimated.”
This trial design perhaps seemed less controversial to UK cardiologists, as it is common in UK practice for STEMI patients to not undergo a formal consent process prior to PCI. The rationale for this is that informed consent is an oxymoron when a patient is critically unwell, in severe pain, usually loaded with opiates and there is a time-critical nature to the intervention (“time is muscle”). In my center, we briefly tell the patient about the procedure as they are being wheeled from the ambulance into the cath lab, but do not delay reperfusion by asking the patient to read and sign a lengthy consent form.
A Closer Look at the Results
In determining the reliability of the findings from HEAT-PPCI, one has to look closely at the outcomes. For instance, the lack of difference in bleeding between the two arms can be readily explained, since GPI use unquestionably leads to increased bleeding. As a result, it is not surprising that previous studies reported a significant difference in bleeding complications in the heparin group, with dramatically higher rates of GPI use in the heparin arm (HORIZONS-AMI, 98%; EUROMAX, 69%) vs. the bivalirudin arm (HORIZONS-AMI, 8%; EUROMAX, 11%). The dose of heparin used may also be relevant. HEAT-PPCI used an initial dose of 70 U/kg, whereas most other studies of heparin monotherapy have used higher doses.
The finding of worse ischemic outcomes with bivalirudin is also not unexpected. Both HORIZONS-AMI and EUROMAX showed a significantly higher rate of acute stent thrombosis in the bivalirudin arm and this finding was replicated in HEAT-PPCI. The most likely explanation for this is that bivalirudin has a much shorter half-life than heparin: When the infusion is stopped at the end of the procedure, the patient is potentially at risk of this serious complication until the oral antiplatelet agents have been absorbed and are effective.
UK Reaction
In terms of the UK reaction to HEAT-PPCI, the vast majority of UK operators I have spoken with do not find the results surprising, and feel that the trial is very relevant to UK interventional practice and are considering a change in their practices. I have heard no concerns raised over the trial conduct. Although this was a single-center trial, it is felt that the true “all-comers” nature of the trial make the results more rather than less generalizable to real-world cases.
When HEAT-PPCI was presented, the interventional cardiologists at my center met to discuss the results. We were particularly interested in the finding (consistent with previous studies) that bivalirudin was associated with a higher rate of stent thrombosis, but with no signal of clinical benefit. In the United Kingdom, we are increasingly aware of health care costs and the huge potential of savings with heparin monotherapy. We decided to wait until the paper was published before making any definitive decisions.
Now that the full study is available, we have discussed and digested the paper in depth. As a group, we found the study so compelling that we have agreed to change our departmental policy. STEMI patients in our region are identified in the ambulance by a pre-hospital ECG and brought directly to our institution for PPCI. They will be taken straight from the ambulance to the cath lab, preloaded with aspirin and ticagrelor and briefly verbally consented; however, their procedure will not be delayed to sign a consent form. They will then receive heparin 70 U/kg with a mandated ACT check and will undergo their procedure via radial arterial access. GPI will only be given in the event of slow flow or massive thrombus. We believe this is the current state-of-the-art care for STEMI — and we will save our unit £250,000 per year in drug costs.