Studies Explore Impact of Diabetes on Platelet Reactivity in Clopidogrel-Treated PCI Patients

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Patients with type 2 diabetes or metabolic syndrome undergoing elective percutaneous coronary intervention (PCI) are 3 to 4 times more likely to have high residual platelet reactivity after receiving a loading dose of clopidogrel than those with neither condition, according to a pharmacodynamic study published online September 14, 2014, ahead of print in the American Heart Journal. However, only diabetic patients retain high reactivity while on maintenance therapy.

In a related finding, switching type 2 diabetes patients undergoing PCI for ACS to prasugrel shortly after the procedure appears to overcome high on-clopidogrel reactivity. Results of the small randomized study were presented at the annual Transcatheter Cardiovascular Therapeutics scientific symposium in September 2014.

Higher Reactivity in Patients with Type 2 Diabetes, Metabolic Syndrome

Methods
In the first study, Laurent Feldman, MD, of Hôpital Bichat (Paris, France), and colleagues looked at 159 patients with stable CAD referred for PCI with DES. All patients were premedicated with a 600-mg loading dose of clopidogrel 6 to 24 hours before the procedure and were on 75-100 mg of aspirin daily for at least 24 hours prior to PCI. After the procedure, they received 75 mg of clopidogrel daily for at least 1 year and 75-100 mg of aspirin daily indefinitely.
Platelet aggregation was assessed immediately before PCI and about 4 months afterward via light transmittance aggregometry after addition of 5 µM ADP. Results were expressed as percent change in light transmittance after ADP addition, measured at peak (ADPmax) and 6 minutes (ADPlate). Vasodilator-stimulated phosphoprotein platelet reactivity index (VASP-PRI) was also measured. High on-clopidogrel reactivity was defined as ADPmax > 50% or ADPlate > 14% and VASP-PRI > 50%. 
The cohort was divided into patients with:
  • Type 2 diabetes (n = 64)
  • Metabolic syndrome (n = 50)
  • Neither condition (n = 45)

 


After clopidogrel loading, the prevalence of high on-clopiodgrel reactivity was higher among both type 2 diabetes and metabolic syndrome groups compared with the control group (P = .03 and P = .012, respectively). Then, after 4 months on dual antiplatelet therapy, the prevalence of high on-clopidogrel reactivity was higher in the diabetic group compared with the control group (P = .034) but not in the metabolic syndrome group (P = .58; table 1).

Table 1. High On-Clopidogrel Platelet Reactivity by Disease Status

 

Type 2 Diabetes

Metabolic Syndrome

Neither

After Loading Dose

46.0%

52.0%

20.9%

 

On Maintenance Therapy

50.9%

31.3%

23.8%


On multivariable analysis, independent predictors of high reactivity after clopidogrel loading were:

  • Type 2 diabetes (OR 3.62; 95% CI 1.34-9.80)
  • Metabolic syndrome (OR 4.00; 95% CI 1.39-11.46)
  • Age, per 1-year increase (OR 1.06; 95% CI 1.02-1.12)
  • Prior chronic clopidogrel therapy (OR 0.22; 95% CI 0.09-0.49)
  • Baseline plasminogen activator inhibitor-1, per 1 ng/mL increase (OR 1.01; 95% CI 1.00-1.02)

Only type 2 diabetes (OR 2.98; 95% CI 1.20-7.41) and age (per 1-year increase; OR 1.04; 95% CI 1.00-1.08) predicted high reactivity on maintenance therapy.

Ischemic events were rare, except for periprocedural MI. Only minor bleeding was reported, with lower rates in patients with type 2 diabetes and metabolic syndrome than in controls (10.5% and 24.0% vs 34.9%; global P value = .01). Overall, the incidence was lower in those with high reactivity on maintenance clopidogrel compared with optimal response to the therapy (11.1% vs 29.3%; P = .02).

Dr. Feldman and colleagues point out that because the study focused on stable, low-risk patients, following them for only 4 months, it was underpowered to assess clinical outcomes. However, they add, “it is well established that [high on-clopidogrel platelet reactivity] is associated with an increased risk of adverse cardiac events, including stent thrombosis, in particular, in [type 2 diabetes] patients.”

Baseline Reactivity an Important Contributor

“The fact that previous treatment with clopidogrel was a predictor of high on-clopidogrel reactivity underscores the importance of baseline reactivity as a key determinant of on-clopidogrel reactivity,” David J. Schneider, MD, of the University of Vermont School of Medicine (Colchester, VT), told TCTMD in an email.

Endorsing the authors’ testing strategy, he added that platelet reactivity “is the culmination of multiple factors—baseline reactivity, absorption, metabolism, genetic polymorphisms, and [drug-drug] interference. These multiple contributors argue that an endpoint assay that reflects the culmination of all of these factors is likely to be more predictive than an assay that measures only one component.”

Dr. Schneider noted that hyperglycemia has been associated with thrombotic complications and higher platelet reactivity. Together with the current results, this “suggests that improved glycemic control, particularly in patients with metabolic syndrome, may be beneficial with respect to platelet reactivity,” he said.

In an email with TCTMD, Paul A. Gurbel, MD, of Sinai Hospital of Baltimore (Baltimore, MD), called the increased prevalence of high reactivity in patients with type 2 diabetes but not those with metabolic syndrome during clopidogrel maintenance therapy “a major finding,” adding, however, that the mechanism remains unclear.

“This interesting study should be considered exploratory and warrants investigation in a larger population that would provide the opportunity for a more robust multivariate analysis,” he said.

Prasugrel Overcomes High Reactivity in Diabetic ACS Patients

Another pharmacodynamic study looked at whether type 2 diabetes patients undergoing stenting for ACS who demonstrate high platelet reactivity after clopidogrel pretreatment would benefit from an early switch to a more potent antiplatelet agent.

Methods
For the single-center VERDI trial, José M. Cubero, MD, PhD, and colleagues from the Virgen del Rocio University Hospital (Seville, Spain) randomized 50 patients with high platelet reactivity after clopidogrel loading and immediately before PCI (defined as PRU > 208 as measured by VerifyNow; Accumetrics; San Diego, CA) to standard-dose clopidogrel (n = 25) or 60 mg of prasugrel (n = 25).

 

Platelet function was assessed again 24 hours after PCI. Not only did the prasugrel group achieve a lower PRU than the clopidogrel group (median 38 vs 285) but a higher proportion of these patients fell below the high-reactivity threshold (100% vs 16%; primary endpoint; both P < .001).

There is comparatively little information about the pharmacodynamic effects of clopiodgrel compared with prasugrel in this acute population with diabetes, and this study contributes to the data, Dr. Gurbel noted. Consistent with previous studies of ACS patients with high reactivity after clopidogrel loading, prasugrel overcomes that problem in most patients, he added.

 


Sources:

1. Feldman L, Tubach F, Juliard J-M, et al. Impact of diabetes mellitus and metabolic syndrome on acute and chronic on-clopidogrel platelet reactivity in patients with stable coronary artery disease undergoing drug-eluting stent placement. Am Heart J. 2014;Epub ahead of print.
2. Cubero JM. VERifyNow in DIabetes high on-treatment platelet reactivity: a pharmacodynamic study on switching from clopidogrel to prasugrel (VERDI study). TCT 2014; Washington, DC.

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Disclosures
  • The Feldman study was supported by research grants from Bristol-Myers Squibb, the Fédération Française de Cardiologie, Sanofi, and the Société Française de Cardiologie.
  • The American Heart Journal paper contains no statement regarding conflicts of interest.
  • Dr. Cubero reports no relevant conflicts of interest.
  • Dr. Gurbel reports receiving consulting fees, honoraria, and grants from multiple pharmaceutical companies.
  • Dr. Schneider reports receiving grants and honoraria from AstraZeneca.

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