Editor's Note: Commentary based on Ford I, Scott NW, Herd V, et al. A Randomized Controlled Trial of Platelet Activity Before and After Cessation of Clopidogrel Therapy in Patients With Stable Cardiovascular Disease. J Am Coll Cardiol 2014;63:233-9.

Background

Clopidogrel is widely used in addition to aspirin to inhibit platelet reactivity and to attenuate thrombotic events in patients with high-risk coronary artery disease (CAD) and also as monotherapy in patients with peripheral arterial disease (PAD). An earlier retrospective analysis has demonstrated the clustering of adverse events in the initial 90 days after stopping clopidogrel among medically- and percutaneous coronary intervention (PCI)-treated patients with acute coronary syndromes (ACS). The latter observation suggested the possibility of a "rebound" effect with the discontinuation of clopidogrel therapy.¹

Methods

Ford et al. randomly treated 171 patients with stable CAD (~88%) and/or PAD (~20%) who were on established low dose aspirin therapy with 75 mg clopidogrel or placebo for 30 days.² Platelet reactivity was assessed at pre-dose, just before discontinuation of study drug, and seven, 14, and 28 days after clopidogrel discontinuation by measuring platelet fibrinogen binding with and without stimulation with adenosine diphosphate (ADP) or thrombin receptor-activating peptide, p-selectin expression with and without ADP-stimulation using flow cytometry and by ADP-induced platelet aggregation (both maximal and after six minutes) using conventional aggregometry.

Results

The primary outcome of ADP-stimulated platelet fibrinogen binding and secondary endpoints including aggregation measurements and ADP-stimulated p-selectin expression were significantly lower during clopidogrel therapy (p<0.0001) compared to pre-treatment levels. The latter platelet function measurements returned to pre-treatment levels after seven days of discontinuation of clopidogrel therapy and remained stable for up to 28 days. There was no change in platelet function measurements in the placebo group overtime. Mixed model analyses showed no significant differences in the overall results between the clopidogrel group and placebo.

Conclusion

This study suggests that there is no "rebound" effect of platelet reactivity after discontinuation of clopidogrel therapy in stable patients with arterial vascular disease who were on established aspirin therapy.

Commentary/Perspective

There are some unmet needs associated with clopidogrel therapy even after its extensive use for the last 17 years. The duration of clopidogrel therapy required to optimally mitigate adverse outcomes in high-risk patients remains poorly defined and is an area of particular controversy in patients treated with drug-eluting coronary stents.³ Current practice guideline recommendations are limited because adequately sized randomized studies to address optimal P2Y12 duration have yet to be completed.⁴ Although earlier analyses demonstrated increased ischemic event occurrence in the early period after clopidogrel discontinuation (30-90 days), a recent systemic review suggested that the quality of evidence supporting the increased risk of adverse cardiac events associated with clopidogrel discontinuation was questionable, since most of the studies were retrospective and statistically flawed.⁵ Similar to patients with CAD, in a recent analysis of a large randomized secondary stroke prevention study, there was a 1.83% increase in absolute risk in the combined end point of stroke, myocardial infarction, vascular death within 30 days after the discontinuation of clopidogrel compared with the on-treatment study populations.⁶ The increased occurrence of ischemic events early after clopidogrel discontinuation has been attributed to potential "rebound" pharmacodynamic effect.

The clopidogrel "rebound" phenomenon has been addressed in a few small studies. However, a pre-treatment platelet reactivity measurement, a mandatory requirement to truly identify a "rebound" phenomenon, was not included in all of these studies.^7-9 The study by Ford et al. is the first large randomized pharmacodynamic study specifically designed to address the phenomenon of "rebound" in platelet reactivity after clopidogrel discontinuation. Platelet function was measured serially by various methods and assessment of pre-treatment platelet reactivity was included. The current study demonstrated an absence of "rebound" phenomenon in a stable patient population with arterial disease. Whether or not the results of the Ford study apply to patients undergoing coronary stent implantation is uncertain. We do know that platelet reactivity increases in the early period after stent implantation and tend to fall at 30 days thereafter during DAPT. It not inconceivable that patients treated with stents who discontinue clopidogrel may have higher platelet reactivity than they did at baseline due to the effect of the stent itself on platelet reactivity.¹⁰

The so-called "rebound" effect observed in previous studies appears to be a gradual recovery of platelet function and responsiveness to ADP caused by the exposure of unblocked of P2Y12 receptors. It is not surprising to observe increased ischemic event occurrence in the absence of adequate P2Y12 blockade in high risk patients since P2Y12 is a central platelet signaling pathway that amplifies platelet activation to all agonists that result in platelet degranulation.¹¹ Clopidogrel responsiveness and its potential relation to inter-individual variability in platelet function recovery after the cessation of clopidogrel therapy were not assessed in the study by Ford et al.¹² Similar to the Ford et al. study, we did not find any "rebound" platelet hyperreactivity 10 days after discontinuation of clopidogrel and ticagrelor in a previous study. We suggested that "rebound" is an unlikely explanation for the early occurrence of ischemic events that has been reported in clinical trials.¹³ Moreover, a recent study suggested that lack of stent healing at the time of cessation may influence the increased occurrence of cardiac events rather than "rebound" in platelet reactivity.¹⁴ Although the "rebound" platelet reactivity phenomenon thus far has not been supported, the specific underlying cause for increased occurrence of ischemic events after clopidogrel discontinuation and measures to overcome it is remain unclear. A recent study has addressed the latter concern by comparing the abrupt versus gradual discontinuation of clopidogrel therapy. Gradual discontinuation of DAPT was not found to be superior to abrupt discontinuation with respect to the occurrence of cardiac events.¹⁵ The PARIS registry analysis suggested that cardiac event occurrence was similar between patients who stayed on DAPT and those who discontinued as recommended by the treating physician, whereas increased adverse event occurrence was associated with the disruption of DAPT due to non-compliance or bleeding.¹⁶ We await the results of the large scale randomized DAPT trial (NCT # NCT00977938, Clinicaltrials.gov) to shed more light in the area of optimal DAPT duration.

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References

1. Ho PM, Peterson ED, Wang L, et al. Incidence of death and acute myocardial infarction associated with stopping clopidogrel after acute coronary syndrome. JAMA 2008;299:532-9.
2. Ford I, Scott NW, Herd V et al. A randomized controlled trial of platelet activity before and after cessation of clopidogrel therapy in patients with stable cardiovascular disease. J Am Coll Cardiol 2014;63:233-9.
3. Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol 2011;58:e44-122.
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8. Diehl P, Halscheid C, Olivier C, et al. Discontinuation of long term clopidogrel therapy induces platelet rebound hyperaggregability between 2 and 6 weeks post cessation. Clin Res Cardiol 2011;100:765–71.
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10. Gurbel PA, Bliden KP, Hiatt BL, O'Connor CM. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 2003;107:2908-13.
11. Gurbel PA, Bliden KP, Hayes KM, Tantry U. Platelet activation in myocardial ischemic syndromes. Expert Rev Cardiovasc Ther 2004;2:535-45.
12. Price MJ, Teirstein PS. Dynamics of platelet functional recovery following a clopidogrel loading dose in healthy volunteers. Am J Cardiol 2008;102:790-5.
13. Gurbel PA, Bliden KP, Antonino MJ, et al. Is there a rebound after cessation of antiplatelet therapy? First comparison of irreversible vs. reversible P2Y12 receptor blocker [abstr]. J Thromb Haemost. 2011;Suppl 2:O-MO-119.
14. Lemesle G, Torguson R, Bonello L, et al. Relation between clopidogrel discontinuation and early cardiovascular events after percutaneous coronary intervention with drug-eluting stents. EuroIntervention 2011;6:1053-9.
15. Fiedler KA, Mehilli J, Kufner S, et al. Randomised, double-blind trial on the value of tapered discontinuation of clopidogrel maintenance therapy after drug-eluting stent implantation. Intracoronary Stenting and Antithrombotic Regimen: CAUTION in Discontinuing Clopidogrel Therapy--ISAR-CAUTION. Thromb Haemost 2014;111:1041-9.
16. Mehran R, Baber U, Steg PG, et al. Cessation of dual antiplatelet treatment and cardiac events after percutaneous coronary intervention (PARIS): 2 year results from a prospective observational study. Lancet 2013;382:1714-22.

Keywords: Acute Coronary Syndrome, Aspirin, Blood Platelets, Coronary Artery Disease, Percutaneous Coronary Intervention, Peripheral Arterial Disease, Thrombosis, Ticlopidine

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