ARCTIC Analysis: Platelet Function Testing Does Not Enhance Secondary Prevention

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For patients undergoing percutaneous coronary intervention (PCI), tailoring antiplatelet therapy based on the results of platelet function testing makes no difference in the risk of recurrent ischemic events after hospital discharge. Nor did the strategy reduce bleeding events, according to a landmark analysis of the ARCTIC trial published online April 9, 2014, ahead of print in Circulation.

ARCTIC, originally published in the New England Journal of Medicine in November 2012, randomized 2,440 patients before stenting to conventional treatment or to monitoring with the VerifyNow P2Y12/aspirin point-of-care assays (Accumetrics, San Diego, CA) and drug adjustment if needed. The main trial findings showed no clinical benefit to the platelet testing strategy between randomization and 1 year.

For the new paper, Gilles Montalescot, MD, PhD, of Hôpital Pitié-Salpêtrière (Paris, France), and colleagues sought to understand whether excluding periprocedural events would reveal any advantage for platelet testing in terms of secondary prevention in 2,385 patients (98% of the entire ARCTIC cohort).

No Benefit Seen from Hospital Discharge to 1 Year

In the monitoring arm (n = 1,194), 7.6% of patients had high on-aspirin reactivity and 34.5% had high on-clopidogrel reactivity prior to stenting, results that led to adjustment of antiplatelet therapy in the cath lab. Measurements were repeated 2 to 4 weeks after hospital discharge, showing that prevalence of on-treatment reactivity had dropped to 3.9% for aspirin and 15.6% for clopidogrel. Antiplatelet drugs were readjusted based on those findings but not again during the year of follow-up.

Kaplan-Meier estimates showed no differences in the rates of ischemic outcomes (whether composite or individual components) or bleeding events between hospital discharge and 1-year follow-up (table 1).

Table 1. Outcomes from Hospital Discharge to 1 Year

 

Conventional
Treatment
(n = 1,191) 

Platelet Monitoring
(n = 1,194) 

P Value

Death, MI, Stent Thrombosis, Stroke/TIA, Urgent Revascularizationa

8.2%

9.1%

0.4848

Stent Thrombosis or Urgent Revascularizationb

4.7%

4.7%

0.9906

STEEPLE Major Bleeding

2.9%

1.9%

0.1078

STEEPLE Minor Bleeding

1%

0.7%

0.5009

aPrimary endpoint.
bMain secondary endpoint. 

“High on-treatment platelet reactivity is not only a marker of risk but also a risk factor that we can possibly modify with the antiplatelet drugs available. However, our findings suggest that the modifications of treatment do not impact clinical outcome,” the researchers note, adding that this discrepancy has been observed before for biomarkers such as HDL cholesterol. However, the ARCTIC data “do not call into question the benefit of dual antiplatelet therapy after coronary stenting, for which there is paramount evidence,” they emphasize.

Time for a Different Take on Testing?

In an editorial accompanying the paper, Deepak Voora, MD, of Duke University (Durham, NC), and Richard C. Becker, MD, of the University of Cincinnati College of Medicine (Cincinnati, OH), observe that the “secondary analysis by the ARCTIC investigators adds to an existing body of evidence that a strategy of tailored antiplatelet therapy around ex vivo platelet function is unlikely to benefit low-to-moderate-risk PCI patients prescribed clopidogrel.”

It remains untested whether such a strategy might benefit ACS patients undergoing PCI, they say, and while there also may be beneficial opportunities for lower-risk populations, this would require “more sensitive and comprehensive tools.”

Current tests “focus primarily on platelet aggregation and essentially ignore secretion, adhesion, tethering, and signaling,” as well as other biochemical and genetic processes, they explain. “Though measuring such diverse effects in a clinical setting is challenging, these molecules, coupled with the power of informatics, may provide translatable biomarkers for measuring the comprehensive effects of platelet inhibitors in human health and disease.”

In a telephone interview with TCTMD, Paul A. Gurbel, MD, of Sinai Hospital of Baltimore (Baltimore, MD), described these possibilities as ‘blue sky.’

“I think when you get to the measurement of the end product, which is the final platelet physiology, that’s got the greatest [potential] for finding utility. All of these other markers are upstream,” he said, whereas an ideal assay would attempt to approximate “what is going on in vivo. [Response to adenosine diphosphate is] still where we have the greatest hope.”

Is ARCTIC Itself the Problem?

According to Dr. Gurbel, the landmark analysis does not resolve the limitations of ARCTIC including a low-risk patient population, lack of standard definition for MI, and poor statistical power. “The study was inadequate to refute the utility of personalization,” he stressed, adding that “there’s nothing new here.”

Somjot S. Brar, MD, MPH, of Kaiser Permanente (Los Angeles, CA), also noted that the “drug adjustment in response to platelet function testing was likely ineffective [in ARCTIC]. For many patients, the dose of clopidogrel was increased in response to platelet function testing; a strategy that is likely ineffective.”

Instead, repeat testing is required to confirm response, Dr. Brar suggested in an email to TCTMD. “Alternatively, subjects could be switched to prasugrel, where the response to the medication is more uniform compared with clopidogrel,” he said, reporting that approximately 10% of patients in the treatment arm of ARCTIC were on prasugrel.

The editorial concurs that “it is conceivable that transition to either prasugrel or ticagrelor after discharge” could have shown an advantage for testing.

“We don’t have conclusive data that platelet function testing is useful in a moderate-to-low-risk group,” Dr. Gurbel commented. “However,… the study to adequately assess this has yet to be done. If you have flawed studies that are severely limited, do you use those to overcome what we know fundamentally about the biology of thrombosis?”

The ongoing TRANSLATE-POPS, ANTARCTIC, and TROPICAL ACS are all evaluating potential of platelet testing in higher-risk populations.

 

 


Sources:

1. Montalescot G, Rangé G, Silvain J, et al. High on-treatment platelet reactivity as a risk factor for secondary prevention after coronary stent revascularization: a landmark analysis of the ARCTIC study. Circulation. 2014;Epub ahead of print.

 

2. Voora D, Becker RC. A freeze on tailored antiplatelet therapy [editorial]? Circulation. 2014;Epub ahead of print.

 

Disclosures:

 

  • Dr. Montalescot reports receiving research grants to his institution or consulting/lecture fees from numerous pharmaceutical and device companies.
  • Drs. Voora and Becker report co-inventing a patent application related to diagnostic markers of platelet function.
  • Dr. Gurbel reports receiving consulting fees, honoraria, and grants from AstraZeneca, Boehringer Ingelheim, Daiichi, Haemonetics, Janssen, and Merck.
  • Dr. Brar reports no relevant conflicts of interest.

 

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