Adjunctive Cilostazol versus High Maintenance Dose of Clopidogrel in Patients with Hyporesponsiveness to Chronic Clopidogrel Therapy

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Abstract

Purpose

Whether addition of cilostazol is superior to increasing dose of clopidogrel in patients with hyporesponsiveness to chronic clopidogrel therapy is unknown.

Materials and Methods

We studied 73 patients with hyporesponsiveness to clopidogrel on standard dual antiplatelet therapy for more than 2 weeks. Clopidogrel hyporesponsiveness was defined as percent inhibition of P2Y12 reaction units (PRU) <30% on VerifyNow P2Y12 assay. Patients were randomly assigned to increased dose of clopidogrel (aspirin 100 mg+clopidogrel 150 mg daily: group A, n=38) or to receiving additional cilostazol (aspirin 100 mg+clopidogrel 75 mg+cilostazol 100 mg bid daily: group B, n=35).

Results

Baseline percent inhibition of PRU and PRU was similar between 2 groups (13.0±10.2% versus 11.8±9.7%, p=0.61, and 286.3±54.7 versus 295.7±53.7, p=0.44, respectively). At follow-up, percent inhibition of PRU was higher and PRU was lower significantly in group B than in group A (38.5±17.9% versus 28.3±16.6%, p=0.02, and 207.3±68.2 versus 241.3±76.7, p=0.050, respectively). Among those still showing hyporesponsiveness to clopidogrel at follow-up (21 patients in group A, 10 patients in group B), 12 patients completed further crossover study. Compared to the baseline, magnitude of change in percent inhibition of PRU and PRU showed an improved tendency after the crossover (from 2.7±8.7% to 15.8±18.4%, p=0.08, and from -18.6±58.0 to -61.9±84.3, p=0.08).

Conclusion

Adjunctive cilostazol improved clopidogrel responsiveness better than the higher maintenance dose of clopidogrel in hyporesponsive patients with chronic clopidogrel therapy.

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Most cited references 17

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Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation.

B Rensing, Tilman M Hackeng, A. M. Harmsze … (2010)

Context High on-treatment platelet reactivity is associated with atherothrombotic events following coronary stent implantation. Objective To evaluate the capability of multiple platelet function tests to predict clinical outcome. Design, Setting, and Patients Prospective, observational, single-center cohort study of 1069 consecutive patients taking clopidogrel undergoing elective coronary stent implantation between December 2005 and December 2007. On-treatment platelet reactivity was measured in parallel by light transmittance aggregometry, Verify Now P2Y12 and Platelet works assays, and the IMPACT-R and the platelet function analysis system (PFA-100) (with the Dade PFA collagen/adenosine diphosphate (ADP) cartridge and Innovance PFA P2Y). Cutoff values for high on-treatment platelet reactivity were established by receiver operating characteristic curve (ROC) analysis. Main Outcome Measurement The primary end point was defined as a composite of all-cause death, nonfatal acute myocardial infarction, stent thrombosis, and ischemic stroke. The primary safety end point included TIMI (Thrombolysis In Myocardial Infarction) criteria major and minor bleeding. Results Kaplan-Meier analysis demonstrated that at 1-year follow-up, the primary end point occurred more frequently in patients with high on-treatment platelet reactivity when assessed by light transmittance aggregometry (52 [11.7%; 95% confidence interval {CI}, 8.9%-15.0%] vs 36 [6.0%;95%CI, 4.2%-8.2%] P.001; n=1049),Verify Now (54 [13.3%; 95% CI, 10.2%-17.0%] vs 37 [5.7%; 95% CI, 4.1%-7.8%]P.001; n=1052), Platelet works (33 [12.6%; 95% CI, 8.8%-17.2%] vs 21 [6.1%;95% CI, 3.8%-9.2%] P=.005; n=606), and Innovance PFA P2Y (18 [12.2%; 95%CI; 7.4%-18.6%] vs 28 [6.3%; 95% CI, 4.3%-8.9%] P=.02; n=588). ROC-curve analysis demonstrated that light transmittance aggregometry (area under the curve[AUC], 0.63; 95% CI, 0.58-0.68), Verify Now (AUC, 0.62; 95% CI, 0.57-0.67), and Platelet works (AUC, 0.61; 95% CI, 0.53-0.69) had modest ability to discriminate between patients with and without primary end point at 1-year follow-up. The IMPACT-R(n=905) and the Siemens PFA Collagen/ADP (n=812) were unable to discriminate between patients with and without the primary end point at 1-year follow-up (all AUCs included 0.50 in the CI). None of the tests identified patients at risk for bleeding. Conclusions Of the platelet function tests assessed, light transmittance aggregometry,Verify Now, Platelet works, and Innovance PFA P2Y were significantly associated with the primary end point. However, the predictive accuracy of these 4 tests was only modest. None of the tests provided accurate prognostic information to identify patients at higher risk of bleeding following stent implantation. Trial Registration clinical trials.gov Identifier: NCT00352014 [corrected].

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Variability in platelet responsiveness to clopidogrel among 544 individuals.

Deepak Bhatt, Victor L. Serebruany, Eric Topol … (2005)

We sought to describe the responses of patients to clopidogrel using ex vivo measures of platelet aggregation and activation in a large, heterogeneous population. Recently, a number of reports, using various definitions, have dichotomized patients who are treated with clopidogrel into a minority of "non-responders" and a majority of "responders." Such classifications imply that treatment leads to an all-or-none response, with potentially important clinical implications. We conducted secondary post-hoc analyses of a dataset consisting of volunteers (n = 94) and patients after coronary stenting (n = 405), with heart failure (n = 25), and after stroke (n = 20). The response of subjects to clopidogrel followed a normal, bell-shaped distribution, with a mean and standard deviation of 41.9 +/- 20.8% when aggregation was induced by 5 mumol/l of adenosine diphosphate. When hyporesponsiveness and hyper-responsiveness to clopidogrel were considered to be two standard deviations less than and greater than the mean, respectively, the prevalence of hyporesponsiveness and hyper-responsiveness in these patients was 4.2% and 4.8%, respectively. Pretreatment platelet activity and clinical characteristics were not associated with responsiveness to clopidogrel. Individuals receiving clopidogrel exhibit a wide variability in response that follows a normal distribution. The clinical implications of this variability are unknown but potentially are important. Clinical trials are needed to define whether hyporesponders to clopidogrel are at increased risk for thrombotic events and whether hyper-responders are at increased risk for bleeding. If so, the individualization of antiplatelet therapy, including clopidogrel dosing, may be possible in the future but will require the ability to easily and reproducibly measure responsiveness by a method that has been proven to be predictive of clinical events.

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Prognostic significance of post-clopidogrel platelet reactivity assessed by a point-of-care assay on thrombotic events after drug-eluting stent implantation.

Stephen Ernst, D Schatz, S Sawhney … (2008)

The aim of this study was to determine whether platelet reactivity on clopidogrel therapy, as measured by a point-of-care platelet function assay, is associated with thrombotic events after percutaneous coronary intervention (PCI) with drug-eluting stents (DESs). Platelet reactivity on clopidogrel (post-treatment reactivity) was measured with the VerifyNow P2Y12 assay (Accumetrics Inc., San Diego, CA, USA) in 380 patients undergoing PCI with sirolimus-eluting stents. Receiver-operating characteristic curve analysis was used to derive the optimal cut-off value for post-treatment reactivity in predicting 6 month out-of-hospital cardiovascular (CV) death, non-fatal MI, or stent thrombosis. The mean post-treatment reactivity was 184 +/- 85 PRU (P2Y12 reaction units). The optimal cut-off for the combined endpoint was a post-treatment reactivity > or =235 PRU [area under the curve 0.711 (95% confidence interval 0.529-0.893), P = 0.03], which was similar to the threshold of the upper tertile (231 PRU). Patients with post-treatment reactivity greater than the cut-off value had significantly higher rates of CV death (2.8 vs. 0%, P = 0.04), stent thrombosis (4.6 vs. 0%, P = 0.004), and the combined endpoint (6.5 vs. 1.0%, P = 0.008). High post-treatment platelet reactivity measured with a point-of-care platelet function assay is associated with post-discharge events after PCI with DES, including stent thrombosis. Investigation of alternative clopidogrel dosing regimens to reduce ischaemic events in high-risk patients identified by this assay is warranted.

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Author and article information

Journal

Journal ID (nlm-ta): Yonsei Med J

Journal ID (iso-abbrev): Yonsei Med. J

Journal ID (publisher-id): YMJ

Title: Yonsei Medical Journal

Publisher: Yonsei University College of Medicine

ISSN (Print): 0513-5796

ISSN (Electronic): 1976-2437

Publication date (Print): 01 January 2013

Publication date (Electronic): 28 November 2012

Volume: 54

Issue: 1

Pages: 34-40

Affiliations

[1 ]Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

[2 ]Department of Laboratory Medicine & Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Author notes

Co-corresponding authors: Dr. Joo-Yong Hahn, Department of Medicine, Cardiac and Vascular Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul 135-710, Korea. Tel: 82-2-3410-3418, Fax: 82-2-3410-3849, jyhahn@ 123456skku.edu and Dr. Soo-Youn Lee, Department of Laboratory Medicine & Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul 135-710, Korea. Tel: 82-2-3410-1834, Fax: 82-2-3410-2719, suddenbz@ 123456skku.edu

Article

DOI: 10.3349/ymj.2013.54.1.34

PMC ID: 3521288

PubMed ID: 23225796

SO-VID: 4390d41b-10e2-43ef-92f1-54e63f19b379

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 21 September 2011

Date revision received : 25 January 2012

Date accepted : 06 February 2012

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Adjunctive Cilostazol versus High Maintenance Dose of Clopidogrel in Patients with Hyporesponsiveness to Chronic Clopidogrel Therapy

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Abstract

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Materials and Methods

Results

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Negative Pressure Wound Therapy

Most cited references 17

Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation.

Variability in platelet responsiveness to clopidogrel among 544 individuals.

Prognostic significance of post-clopidogrel platelet reactivity assessed by a point-of-care assay on thrombotic events after drug-eluting stent implantation.

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