CEC Identifies ‘Prognostically Important’ MIs: CHAMPION PHOENIX

Adjudication found MIs that were not simply “CK leaks” but rather infarctions linked to worse prognosis at 30 days.

CEC Identifies ‘Prognostically Important’ MIs: CHAMPION PHOENIX

The clinical events committee (CEC) of the CHAMPION PHOENIX trial identified three times as many myocardial infarctions as the site investigators, and the majority of these were periprocedural MIs, a new analysis shows. Moreover, these CEC-adjudicated clinical events yielded prognostically useful information.

The findings, which were published earlier this month in Circulation: Cardiovascular Interventions, suggest that CEC adjudication adds “sensitivity in the assessment of MI” and that strategies to screen patients for periprocedural MIs, such as assessment of biomarkers before and after PCI, would identify people at risk of adverse events, say investigators.

“This is a long-standing debate, not just in interventional cardiology but across different fields, about whether the events we should be capturing in trials are ones the investigators captured or ones that have been adjudicated,” Deepak Bhatt, MD (Brigham and Women’s Hospital, Boston, MA), the lead investigator of CHAMPION PHOENIX and one of the authors of this latest analysis, told TCTMD. “Like most debates, I don’t think there is one right answer that fits all situations. The right answer is: it depends.”

With certain clinical endpoints, there is significant concordance between the investigator-reported and CEC-adjudicated events. With periprocedural MI, however, not all events might be captured by an operator caring for a patient.

“When complications arise in the cath lab, sometimes people get busy, so of course they’re not as worried about documenting things for a trial but instead are busy taking care of the patient,” Bhatt explained. “With complications, they can sometimes be the least well-documented in terms of reporting. Adjudication can sometimes catch these events.”

The current study, said Bhatt, shows that the CEC is not simply capturing unimportant creatine kinase (CK) “leaks” but rather clinical events that are associated with worse prognosis at 30 days. “It’s reassuring that adjudication isn’t just producing biochemically-driven data. In this case, both site- and CEC-adjudicated data are moving in the same direction,” he said.

For Sanjay Kaul, MD (Cedars Sinai Medical Center, Los Angeles, CA), who was not involved in the analysis, the results highlight the importance of CECs capturing these important events in randomized controlled trials. Like Bhatt, Kaul noted there is typically significant overlap between the investigator-reported and CEC-adjudicated events, but said that is not always the case with biomarker-defined clinical events, such as periprocedural MIs. “In CHAMPION PHOENIX, only 20% of the CEC-adjudicated MIs were picked up by investigators, who either don’t have timely access to biomarkers or don’t typically pay much attention to biomarkers in clinical assessment,” Kaul told TCTMD via email. 

Published nearly 6 years ago in the New England Journal of Medicine, the CHAMPION PHOENIX study showed that the intravenous ADP-inhibitor cangrelor (Kengreal; The Medicines Company) reduced the risk of death, MI, ischemia-driven revascularization, or stent thrombosis at 48 hours when compared with the use of clopidogrel in patients undergoing elective or urgent PCI. The risk of MI was reduced 20% with the use of cangrelor.

Computer Algorithm to ID Potential MIs  

As part of the CEC adjudication for the trial, a computer program analyzed data from the electronic case report form, including cardiac biomarkers and ECG changes, and identified suspected events. Two investigators blinded to treatment independently reviewed CK-MB and troponin values relative to the time of randomization and PCI then, if an MI was suspected, sent the case to the CEC for adjudication. Two physicians of the CEC independently adjudicated the MI events (if a consensus was not reached, the case was sent to an additional three physicians for review). For the site-reported MIs, a standard case report form collected information about events.  

Of the 10,942 patients who had at least one MI at 48 hours, 462 events were identified by the CEC compared with 143 identified by the site investigators. Among the MIs identified by the CEC, just 92 of the events were also reported by the site investigators while 370 were not reported by the site. Of the 143 MIs reported by site investigators, the CEC confirmed MI in 64.3% of patients and did not confirm the MI in 51 patients.

The rate of CEC-adjudicated MI at 48 hours was 3.8% in the 5,472 patients treated with cangrelor and 4.7% in the 5,470 patients treated with clopidogrel (OR 0.80; 95% CI 0.67-0.97). In contrast, the rate of site investigator-reported MI at 48 hours was 1.1% and 1.5% in the cangrelor- and clopidogrel-treated patients (OR 0.72; 95% CI 0.52-1.01).

After multivariable adjustment, CEC-adjudicated MI was associated with a more than fivefold increased risk of death at 30 days (OR 5.35; 95% CI 2.56-11.17) while site-reported MI was associated with more than a ninefold higher risk of death at 30 days (OR 9.08; 95% CI 4.01-20.5). Additionally, MIs identified by the CEC, but not the site investigators, were also associated with a significantly higher risk of death at 30 days (OR 4.69; 95% CI 1.94-11.3), whereas site-reported MI, but not CEC-adjudicated events, was associated with a 15-fold higher risk of death at 30 days.

“In general, you want any treatment effect to be concordant between the two types of analyses,” Bhatt said, referring to the investigator-reported and CEC-adjudicated analyses. “There’s probably a bit more precision and sensitivity in looking for a beneficial or adverse effect when adjudication is in play.”

If a trial budget can afford it, adjudication does seem to add value to the scientific question being addressed. Deepak Bhatt

To TCTMD, Kaul noted that the strength of the association between investigator-reported MIs and 30-day outcomes is nearly three times greater than the stricter CEC-adjudicated events, which indicates greater risk discrimination of the investigator-reported events. “This is not surprising because investigators are more likely to capture clinically-relevant MIs, [such as those based on ischemic symptoms, angiographic evidence, or ECG changes],” he said.

The ability to pick up periprocedural MIs can be challenging, said Kaul, and a computer-aided protocol is likely to be more accurate in capturing these events, as demonstrated in the present study. He also noted that roughly 42% of patients enrolled in CHAMPION PHOENIX had a NSTEMI/STEMI diagnosis at the time of presentation while 58% underwent ad hoc PCI for stable ischemic heart disease. In contrast, the CHAMPION PCI and CHAMPION PLATFORM studies included a larger proportion of patients with an MI diagnosis at the time of presentation.

“It had been suggested that ascertainment of post-PCI MIs was masked by biomarker elevations related to a pre-PCI MI, obscuring cangrelor’s efficacy in CHAMPION PCI and CHAMPION PLATFORM,” said Kaul. “Not surprisingly, more stable ischemic heart disease patients were recruited in CHAMPION PHOENIX to make it easier to detect periprocedural MI. One could argue whether ad hoc PCI is the optimal [setting for] use of an expensive, short-acting intravenous agent.”

To TCTMD, Bhatt noted that CEC adjudication does add some costs to a clinical trial. In their paper, the investigators estimated that adjudication adds roughly 3% to 6% to total costs. Some have argued that eliminating CEC adjudication might be an option if trying to keep the costs of a trial down, which isn’t an unreasonable argument in a rigorous, double-blind trial, said Bhatt. “However, in the absence of that, it could potentially be problematic,” he said. “If a trial budget can afford it, adjudication does seem to add value to the scientific question being addressed.”  

Cangrelor is currently indicated as an adjunct to PCI to reduce the risk of periprocedural MI, repeat coronary revascularization, and stent thrombosis in patients who have not been treated with a P2Y12 platelet inhibitor and who are not being given a glycoprotein IIb/IIIa inhibitor. 

Disclosures
  • CHAMPION PHOENIX was funded by The Medicines Company.
  • Bhatt reports receiving research funding or unfunded research support from Abbott, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Idorsia, Ironwood, Ischemix, Lilly, Medtronic, PhaseBio, Pfizer, Regeneron, Roche, Sanofi, Synaptic, The Medicines Company, FlowCo, Merck, Novo Nordisk, PLx Pharma, and Takeda; being a site co-investigator for Biotronik, Boston Scientific, St. Jude Medical, and Svelte; being a trustee for ACC; serving as an advisory board member, director, or chair for Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, Regado Biosciences; the Boston VA Research Institute, the Society of Cardiovascular Patient Care, TobeSoft; the American Heart Association Quality Oversight Committee; serving on a range of data safety monitoring committees; receiving honoraria for editorial or committee activities for a range of publications and organizations; and receiving royalties from Elsevier.

We Recommend

Comments