Universal Definition of MI Shifts Advantage Toward Cangrelor in PCI

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Nearly 3 years ago, the CHAMPION trials found that the novel antiplatelet cangrelor failed to reduce ischemic events compared with clopidogrel in the context of percutaneous coronary intervention (PCI). But new findings from the February 2012 issue of the American Heart Journal highlight what can happen with a change in perspective—when researchers reanalyzed results using the universal definition of myocardial infarction (MI), cangrelor significantly improved outcomes.

Cangrelor (The Medicines Company, Parsippany, NJ) is an intravenous P2Y12 inhibitor that directly and reversibly blocks platelet activation and aggregation with immediate onset.

CHAMPION PCI and CHAMPION PLATFORM, both published in the New England Journal of Medicine in December 2009, randomized patients to cangrelor (bolus of 30 µg/kg plus infusion of 4 µg/kg/min) or clopidogrel (loading dose of 600 mg) either before or soon after PCI in ACS patients. Initially, researchers found no difference in the primary composite of death, MI, or ischemia-driven revascularization at 48 hours in either study, and the trials were terminated early.

MI was defined as the appearance of new Q waves (duration > 0.03 sec) in 2 contiguous ECG leads or cardiac biomarkers at least 3 times the upper limit of normal (ULN), as well as at least 50% rise above baseline when biomarkers were initially elevated.

Taking a Second Look

For the current analysis, Harvey D. White, DSc, of Auckland City Hospital (Auckland, New Zealand), and colleagues pooled results from 13,049 subjects in both studies and calculated periprocedural MI according to the universal definition: in patients with normal baseline troponin values, elevations of cardiac biomarkers greater than 3 times the 99th percentile upper reference limit. If baseline troponin levels were abnormal, only Q-wave MIs were included.

There was no difference in the primary endpoint or MI between cangrelor and clopidogrel when using the original CHAMPION definition. But using the universal definition accentuated the gap between the 2 study drugs (table 1).

Table 1. Outcomes at 48 Hours According to MI Definition

 

Cangrelor
(n = 6,543)

Clopidogrel
(n = 6,506)

OR (95% CI)

P Value

CHAMPION
  Primary Endpointa
  MI

7.3%

7.0%

7.5%

6.9%

0.97 (0.85-1.11)

1.01 (0.88-1.16)

0.6455

0.8510

Universal
  Primary Endpointa
  MI

3.1%

2.6%

3.8%

3.0%

0.82 (0.68-0.99)

0.87 (0.71-1.08)

0.0374

0.2023

a Death/MI/ischemia-driven revascularization.

Stent thrombosis was 0.4% with clopidogrel and 0.2% with cangrelor (OR 0.44; 95% CI 0.22-0.87; P = 0.018), while TIMI major bleeding and transfusion rates were similar for both drugs. However, clinically significant bleeding was higher with cangrelor than with clopidogrel (4.3% vs. 3.1%; P = 0.0002), as was groin hematoma (2.8% vs. 2.1%; P = 0.0045).

At 30 days, the absolute difference in the primary endpoint using the universal definition remained steady but had lost statistical significance.

In the approximately 60% of patients who were clopidogrel naive prior to enrollment, the primary endpoint only showed a trend favoring cangrelor but notably the drug imparted statistically significant reductions in mortality (0.2% vs. 0.4%; OR 0.45; 95% CI 0.20-0.98; P = 0.045) and stent thrombosis (0.2% vs. 0.5%; OR 0.45; 95% CI 0.22-0.93; P = 0.0304).

Definition Removes Uncertain Cases

In an e-mail communication with TCTMD, Dr. White said that in ACS patients it can be challenging to distinguish between biomarkers rising from the initial event prior to PCI and those related to ischemic complication associated with PCI. “The universal definition requires a stable or falling baseline with 2 biomarker samples 6 hours apart,” he explained, noting that CK-MB rises too late to determine whether levels are stable within this time frame. “Therefore, to avoid overlapping biomarker curves we excluded patients with unstable [baseline troponin].”

Importantly, he said, this approach excluded “59.5% of the periprocedural MIs that the [clinical events committee] had adjudicated when they didn’t take into account the baseline troponin levels.”

Stephen G. Ellis, MD, of the Cleveland Clinic (Cleveland, OH), told TCTMD in an e-mail communication that the answer to whether the universal definition is suitable in this instance is complex.

Looking only at Q-wave MIs in the 57% of patients with NSTEMI, who presumably have elevated troponins at baseline, is “probably too strict,” he said. “Conversely, for the 1,620 patients with stable angina [12.2% of the cohort], a 3 times [ULN] increase in troponin would qualify as an MI, which most . . . would say is too liberal a definition.” Based on the paper, it appears that stable patients account for approximately half of the benefit, Dr. Ellis observed.

In an e-mail communication with TCTMD, David P. Faxon, MD, of Harvard Medical School (Boston, MA), said that the current paper provides “an interesting post-hoc analysis. It makes sense that cangrelor would reduce periprocedural events given how it works. The problem with the [CHAMPION] trials was that the definition of periprocedural MI was too liberal, and this analysis supports that.”

However, he added, “[t]here has been a lot of discussion on what is a reasonable definition, and I am not sure the universal definition is very good either.”

Real-world Context

Overall, the “demonstrated difference [between the 2 drugs] is very modest,” Dr. Ellis noted.

“Most patients in the ‘real world’ would have been pretreated with clopidogrel or received prasugrel or ticagrelor at the time of PCI, so the benefit of cangrelor in this analysis may have been magnified,” he commented. “I count a difference of 24 probably meaningful MIs out of 13,000 patients.”

That being said, Dr. Ellis continued, cangrelor can be useful. “The prolonged effect of all current ADP inhibitors poses a clinical problem for some patients, especially those needing an urgent surgical procedure. In such patients the short duration of action of cangrelor would be very beneficial,” he suggested. “They weren't studied in CHAMPION.”

According to the paper, the relative benefits from cangrelor in terms of reducing ischemic events and stent thrombosis are comparable to what has been seen with prasugrel and ticagrelor, 2 drugs that have the asset of acting more quickly than clopidogrel. “There remains a need for an intravenous formulation of a P2Y12 inhibitor in patients who cannot tolerate or who may not fully absorb oral drugs such as patients with cardiogenic shock or those who are heavily sedated, nauseated, or vomiting,” the authors note.

Cangrelor, being rapidly reversible, could indeed prove valuable in the minority of patients requiring same-day cardiac or noncardiac surgical procedures, Dr. White and colleagues observe, adding that “surgery after cangrelor could potentially be performed much sooner [than is the case with other antiplatelets], with restoration of platelet function observed within 60 minutes of drug discontinuation.”

 

Source:

White HD, Chew DP, Dauerman HL, et al. Reduced immediate ischemic events with cangrelor in PCI: A pooled analysis of the CHAMPION trials using the universal definition of myocardial infarction. Am Heart J. 2012;163:182-190.

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Disclosures
  • The CHAMPION trials were funded by The Medicines Company.
  • Dr. White reports receiving research grants from AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, Merck Sharpe & Dohme, the National Institutes of Health, Pfizer, Roche, Sanofi-Aventis, Schering Plough, and The Medicines Company as well as consulting for Regado Biosciences.
  • Dr. Faxon reports serving on the data and safety monitoring boards of the CHAMPION trials.
  • Dr. Ellis reports serving as a consultant to Daiichi Sankyo and Eli Lilly.

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