Meta-analysis: High Platelet Reactivity Linked to Increased Stroke Risk after PCI

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While high platelet reactivity on clopidogrel in patients undergoing percutaneous coronary intervention (PCI) is known to increase the risk of ischemic events, new data suggest it also may predispose to stroke risk. The study was published online March 17, 2014, ahead of print in the American Journal of Cardiology.

Investigators led by Nevio Taglieri, MD, of the University of Bologna (Bologna, Italy), conducted a meta-analysis of 14 studies (11,959 patients) published between 2006 and 2013 to evaluate stroke in patients who had platelet testing along with PCI. Indications for PCI included ACS and stable CAD.

Platelet reactivity was measured in the studies via:

• ADP-stimulated light transmission aggregometry (LTA; 7 centers)
• VerifyNow P2Y12 (Accumetrics, San Diego, CA; 5 centers)
• Multiple electrode aggregometry with ADP stimuli (Dynabite, Munich, Germany; 1 center)
• LTA and VerifyNow (1 center)

Follow-up averaged 12 months (range, 1 to 24 months) postprocedure. Prevalence of high platelet reactivity was 30% ±15% (range, 6% to 67%) and was higher in studies using VerifyNow than in those using LTA (42% ±13% vs 22% ±10%; P = 0.006).

Platelets Could Play a ‘Crucial Role’ in Stroke

Overall, the stroke rate was 0.9%. After pooled analysis, the risk of stroke was higher in patients with high platelet reactivity than in those without (1.2% vs 0.7%; RR 1.84; 95% CI 1.21-2.80). There was no heterogeneity among the studies (P = 0.5).

No individual study significantly influenced the summary effect estimate. Even when the study with the greatest effect estimate was removed, patients with high platelet reactivity were still at increased risk of stroke (RR 1.66; 95% CI 1.07-2.58).

Furthermore, adjustment for clinical profile (P for interaction = 0.39), duration of follow-up (P for interaction = 0.87), and laboratory method for platelet testing (P for interaction = 0.99) did not affect the relative increase in the risk of stroke related to high reactivity.

According to the study authors, the risk of stroke in PCI patients “has been historically associated with procedural factors with an incidence during hospitalization [of] less than 0.4%. However recent data show that the majority of events occur during follow-up, mainly related to risk factors [such] as diabetes, advanced age, left ventricular dysfunction, atrial fibrillation, acute coronary syndromes at presentation, [and] prior transient ischemic attack or stroke, probably due to [the] greater extent of cardiovascular disease, increased susceptibility to atherothrombosis or thromboembolism.”

They suggest that high platelet reactivity may be considered an “adjunctive risk factor” for stroke in CAD patients undergoing PCI. Although the study was not designed to identify a mechanism linking platelet reactivity and stroke risk, they say, the findings support the theory that platelet reactivity “may play a crucial role in determining this risk.”

However, Dr. Taglieri and colleagues urge caution while interpreting their results since the meta-analysis was based on aggregate data and lacks information on possible confounders that could allow adjustment for risk of stroke, likely due to the low incidence of stroke in patients undergoing PCI. They say future research should focus on attempting to clarify whether the association between high platelet reactivity and stroke is an independent risk factor or is mediated by other clinical factors.

Makes Biologic Sense

In a telephone interview with TCTMD, Paul A. Gurbel, MD, of Sinai Hospital of Baltimore (Baltimore, MD), said he believes the meta-analysis is the first to look at platelet reactivity as a driver of stroke.

He noted that although the pathophysiology of stroke is more heterogenous than the pathophysiology of acute MI or stent thrombosis, for example, and although the platelet function tests used in the meta-analysis were varied, “these data are fairly compelling that high platelet reactivity to ADP in the PCI patient is associated with risk for stroke. It makes biologic sense, and they did a sensitivity analysis, so overall I think this is well-done and deserving of further study.”

According to Dr. Gurbel, the findings raise the important issue of whether patients who have had a stroke prior to undergoing PCI are at risk for an additional stroke if they have known clopidogrel resistance. First, however, the findings require validation in a patient-based meta-analysis using data from a large registry, he said.

Study Details

Mean age of patients was 66 years, and most were male. Prevalence of smoking and diabetes ranged from 11%-56% and from 19%-44%, respectively.

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