HEAT-PPCI Published: Discrepant Finding of Heparin’s Superiority over Bivalirudin in Primary PCI Still Puzzles
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The HEAT-PPCI trial, published July 5, 2014, ahead of print in the Lancet, reports better efficacy and comparable safety with heparin than bivalirudin in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI).
HEAT-PPCI was previously presented in March 2014 at the annual American College of Cardiology/i2 Scientific Session in Washington, DC, where several members of the late-breaking trial panel vehemently criticized the study for gaining consent from participants only after treatment and during recovery.
| Methods |
| Researchers led by Rod H. Stables, MD, of the Liverpool Heart and Chest Hospital (Liverpool, England), analyzed data on 1,812 STEMI patients slated to receive primary PCI at their institution between February 2012 and November 2013, randomizing them to preprocedure unfractionated heparin (70 U/kg; n = 907) or bivalirudin (0.75 mg/kg bolus, 1.75 mg/kg/hour infusion; n = 905). Glycoprotein IIb/IIIa inhibitors (GPIs) were used as bailout medication in similar proportions of the bivalirudin and heparin groups (13% and 15%, respectively). |
| PCI was attempted in 82% of patients and resulted in similar procedural success between drug groups. More than 90% of these patients were implanted with a stent, and thrombus aspiration was performed in almost 60% of both groups. |
Both the composite primary efficacy endpoint of MACE (all-cause mortality, stroke, reinfarction, and unplanned TLR) and stent thrombosis were more common in the bivalirudin group at 28 days. However, BARC-defined major bleeding and any bleeding were similar between the groups (table 1).
Table 1. Clinical Outcomes at 28 Days
|
|
Bivalirudin (n = 905) |
Heparin (n = 907) |
RR (95% CI) |
P Value |
|
MACE |
8.7% |
5.7% |
1.52 (1.09-2.13) |
.01 |
|
Reinfarction |
2.7% |
0.9% |
3.01 (1.36-6.66) |
.004 |
|
Definite/Probable Stent Thrombosis |
3.4% |
0.9% |
3.91 (1.61-9.52) |
.001 |
|
Major Bleeding |
3.5% |
3.1% |
1.15 (0.70-1.89) |
.59 |
|
Any Bleeding |
12.5% |
13.5% |
0.93 (0.73-1.18) |
.54 |
Incidence of thrombocytopenia, median CK-MB release post procedure, and median door-to-first-device time did not differ between the groups. All results were maintained in prespecified subgroup analyses.
Potential Dosing Issues
“Now that the [study] is in print, the results are essentially the same, except there’s more detail provided so we are able to learn more about perhaps why some of the findings are the way they are,” said Gregg W. Stone, MD, of Columbia University Medical Center (New York, NY). “The main issue is still that the results from this single-center study, particularly involving the bivalirudin arm, are very different… from those of other large-scale multicenter trials.”
In an email with TCTMD, Robert W. Yeh, MD, MSc, of Massachusetts General Hospital (Boston, MA), said the efficacy difference seen here “is not too surprising.”
Bivalirudin’s association with a higher rate of acute stent thrombosis than heparin has been previously shown, he continued, and this “drives the majority of short-term reinfarctions in STEMI patients. [Making] bleeding into a separate endpoint from efficacy certainly helps to expose this difference more clearly.”
Dr. Stone told TCTMD in a telephone interview that it was likely that the HEAT-PPCI operators were underdosing bivalirudin. “The acute stent thrombosis rate was substantially higher and the activated clotting time [ACT] was more than 150 seconds lower than we would have expected [them] to be,” he said, adding that some of this might be attributed to using different ACT machines, but not all.
In addition, Dr. Stone explained, “a protocol called for rebolusing bivalirudin when the measured ACT was low.” The repeat dose was only required in 0-2% of patients in the EUROMAX and HORIZONS trials, he reported, but 13% needed it here, again suggesting original underdosing.
Dr. Yeh, however, said there is no “reason to suspect systematic bivalirudin underdosing. The ease and uniformity of dosing is actually one of the drug's greatest strengths. If anything, heparin dosing is much more variable, with greater potential for both under and overdosing.”
Despite his criticisms, Dr. Stone acknowledged that HEAT-PPCI included a broader-based sample than other multicenter trials since it included intubated patients and excluded higher-risk patients enrolled in other studies. However, “they interestingly did not report the incidence of cardiogenic shock,” he observed.
“The bottom line is we don’t understand exactly why the results of HEAT are as they are,” he commented. Results from every single-center trial need to be replicated in larger studies, Dr. Stone said, and “in fact, the multicenter trials were done and the results were not replicated. They were substantially better for bivalirudin.
“I think this is a little bit reminiscent of the difference between the TAPAS trial and the TASTE trial” regarding the efficacy of thrombus aspiration in acute MI, he continued. “TAPAS got results that were almost too good to believe and then [TASTE got] results which are closer to reality.”
Delayed Consent Stirs Controversy
Regarding ‘delayed consent,’ Dr. Stone said he has “substantial concerns…. My own belief is that this is not ethical.”
He referenced the fact that researchers have been obtaining consent from MI patients before treatment “for decades,” going to the patient’s guardian and using short consent forms if necessary. “Most patients are not in so much extremis that they cannot understand what you are talking to them about. At minimum, they know that you are asking to participate in an experiment,” he said.
Dr. Stone reported that about 50-60% of patients do not consent because the “reality is that when there are two options available, doctors always have a reason for choosing one.”
Feedback from Institutional Review Board chairmen and US Food and Drug Administration regulatory officials has also suggested “this would not be a considered a valid way to consent patients in the United States,” he said.
Yet Dr. Yeh had positive things to say about the approach.
“I may be on one side of the spectrum here, but I thought this was an absolutely fantastic feature of this trial. Trial generalizability and difficulty with enrollment are enormous limitations of traditional RCTs,” he commented. “In clinical practice, we know that patients are exposed to random variation in care without their consent all the time. Controlling that randomness in a way that allows for a more rigorous evaluation and comparison of therapies has great societal benefits, and doesn't seem to violate any more ethical principles than what currently happens in practice.”
Source:
Shahzad A, Kemp I, Mars C, et al. Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): an open-label, single centre, randomised controlled trial. Lancet. 2014;Epub ahead of print.
Disclosures:
- HEAT-PPCI was funded by AstraZeneca and The Medicines Company.
- Drs. Stone and Yeh report no relevant conflicts of interest.
- Dr. Stables reports receiving grants from AstraZeneca and The Medicines Company.
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