No Rebound Effect after Clopidogrel Cessation in Stable Patients

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After planned clopidogrel cessation, platelet reactivity soon returns to baseline levels, showing no evidence of a rebound effect in patients with stable coronary artery disease (CAD) or peripheral artery disease (PAD), according to a study published online November 6, 2013, ahead of print in the Journal of the American College of Cardiology.

Some research has suggested that an excess of cardiovascular events following clopidogrel cessation may be due to a spike in platelet reactivity caused by the drug’s discontinuation. However, in those studies platelet reactivity prior to commencement of clopidogrel was not assessed, leaving the issue unsettled.

For the current study, investigators led by Isobel Ford, PhD, of the University of Aberdeen School of Medicine and Dentistry (Aberdeen, Scotland), randomized 171 CAD or PAD patients on aspirin therapy to clopidogrel (75 mg/day) or placebo for 30 days. Blood samples were collected in the morning at baseline (24 hours before commencing treatment), just before treatment discontinuation, and then at 7, 14, and 28 days after discontinuation.

The randomized groups were well matched, and compliance was also good for both, with only 2 patients missing more than 2 capsules.

Overall, 159 patients provided all samples and were included in the final analysis (81 from the clopidogrel arm and 78 from the placebo arm). On-treatment platelet reactivity, indicated by ADP-stimulated platelet fibrinogen binding (the primary endpoint), decreased in the clopidogrel group during treatment, then gradually returned to baseline levels after therapy cessation. ADP-stimulated fibrinogen binding remained essentially unchanged in the placebo group (table 1).

Table 1. ADP-Stimulated Fibrinogen Binding

 

Baseline

On Treatment

7 Days Post

14 Days Post

28 Days Post

Clopidogrel

73.9%

30.9%a

69.2%

75.6%

77.3%

Placebo

71.3%

72.1%

74.1%

69.4%

73.2%

a P < 0.0001 for the difference between on-treatment and baseline levels.

Multiple secondary outcome measures, including ADP-stimulated platelet P-selectin expression and platelet aggregation, showed a similar pattern. The only exception was unstimulated fibrinogen binding. Again, platelet reactivity in the placebo group was essentially unchanged for these measures throughout the study period.

In addition, there was no evidence for a treatment-time interaction, indicating that the results were stable over time.

Results Reassuring

In an e-mail communication with TCTMD, Dr. Ford said that the results should be reassuring to physicians worried about potentially higher event rates due to clopidogrel cessation. “Previously published small studies that indicated the possibility of rebound did not include a baseline, pretreatment measurement and therefore were unable to prove if platelet activity after stopping clopidogrel was any higher than it would have been without the drug, or if it was merely returning to baseline,” she explained.

An earlier study that also contradicted the hypothesis of a rebound effect showed no difference in platelet aggregation after tapering clopidogrel compared with stopping it abruptly. Sorin J. Brener, MD, of Weill Cornell Medical College (New York, NY), told TCTMD in a telephone interview that the new study should put the idea of tapering in this patient population to rest. “That concept was never completely clear,” he observed, “and nobody knew exactly how to taper even if you [wanted] to do that. [The current finding] basically suggests that stopping cold doesn’t make a difference, so that’s good news.”

Dr. Brener noted that the study does not address what might happen if both aspirin and clopidogrel were discontinued simultaneously, and its conclusion is restricted to stable patients. Furthermore, he added, the incidence of diabetes in the study was lower than in the general population, which may skew the results slightly.

In an e-mail communication with TCTMD, Dominick J. Angiolillo, MD, PhD, of the University of Florida College of Medicine (Jacksonville, FL), agreed that the current findings are not particularly surprising given recent results. However, he cautioned, ischemic events may recur after clopidogrel discontinuation due to withdrawal of protection rather than rebound.

 


Source: Ford I, Scott NW, Herd V, et al. A randomised controlled trial of platelet activity before and after cessation of clopidogrel therapy in patients with stable cardiovascular disease. J Am Coll Cardiol. 2013;E-pub ahead of print.

 

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Disclosures
  • Dr. Ford reports no relevant conflicts of interest.
  • Dr. Brener reports serving as a peer reviewer for the paper.
  • Dr. Angiolillo reports receiving grants or research support and consulting fees or honoraria from multiple pharmaceutical companies.

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