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Rebound Effect on Stopping Clopidogrel

  • Authors: News Author: Sue Hughes
    CME Author: Charles Vega, MD
  • CME Released: 2/8/2008; Reviewed and Renewed: 3/2/2009
  • Valid for credit through: 3/2/2010
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Target Audience and Goal Statement

This article is intended for primary care clinicians, cardiologists, and other clinicians who care for patients who have had acute coronary syndrome.

The goal of this activity is to provide medical news to primary care clinicians and other healthcare professionals in order to enhance patient care.

Upon completion of this activity, participants will be able to:

  1. Specify recommendations regarding the use of clopidogrel after acute coronary syndrome.
  2. Identify the effect of cessation of clopidogrel after acute coronary syndrome on the outcomes of all-cause mortality and acute myocardial infarction.


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  • Sue Hughes

    Sue Hughes is a journalist for, part of the WebMD Professional Network. She has been with since 2000. Previously, she was science editor of Scrip World Pharmaceutical News. Graduating in pharmacy from Manchester University, UK, she started her career as a hospital pharmacist before moving as a journalist to a UK pharmacy trade publication. She can be reached at [email protected]


    Disclosure: Sue Hughes has disclosed no relevant financial relationships.


  • Brande Nicole Martin

    Brande Nicole Martin is the News CME editor for Medscape Medical News.


    Disclosure: Brande Nicole Martin has disclosed no relevant financial information.

CME Author(s)

  • Charles P Vega, MD

    Associate Professor; Residency Director, Department of Family Medicine, University of California, Irvine


    Disclosure: Charles Vega, MD, has disclosed an advisor/consultant relationship to Novartis, Inc.

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Rebound Effect on Stopping Clopidogrel

Authors: News Author: Sue Hughes CME Author: Charles Vega, MDFaculty and Disclosures

CME Released: 2/8/2008; Reviewed and Renewed: 3/2/2009

Valid for credit through: 3/2/2010


from Heartwire — a professional news service of WebMD

February 8, 2008 — A clustering of adverse events in the initial 90 days after stopping clopidogrel among both medically treated and percutaneous coronary intervention (PCI)-treated patients with acute coronary syndrome (ACS) has been seen in a new observational study, supporting the possibility of a clopidogrel rebound effect [1].

The study, published in the February 6, 2008 issue of the Journal of the American Medical Association, was conducted by a group led by Dr Michael Ho (Denver VA Medical Center, CO). They conclude that additional studies are needed to confirm this observation, to determine its mechanism, and to identify strategies to reduce early events after clopidogrel cessation.

How to deal with it

Senior author Dr John Rumsfeld (Denver VA Medical Center) told heartwire : "This is a red flag, suggesting an increased risk of events on stopping clopidogrel. There have been many anecdotal reports of this phenomenon, but this is the first study conducted specifically to look for it." Rumsfeld said there were two possibilities as to how to deal with it: keep the patient on clopidogrel for longer periods or taper the dose when stopping. "We need to study each of these possibilities to find out which one is best. But until we know for sure, physicians should discuss with each patient how they want to handle the situation after they have taken clopidogrel for a year after an ACS event. A patient who is doing well on clopidogrel, has no bleeding issues or other side effects, and can afford it may want to stay on the drug long term. If they want to come off the dug, then tapering the dose over a few weeks may be a good idea. Or perhaps the dose of aspirin could be doubled for a while. I can't recommend any of these things as we haven't got the data; they are just suggestions," he said.

Serebruany: "Clear clinical message"

Commenting on the study for heartwire , antiplatelet expert Dr Victor Serebruany (HeartDrug Research, Towson, MD) said: "This is an extremely important paper with a clear clinical message — abrupt discontinuation of clopidogrel is indeed associated with worsened cardiovascular outcomes. Everybody has been talking about the potential hazards of stopping clopidogrel, but now we have some solid outcome evidence."

Serebruany says there is an obvious need to optimize the clopidogrel withdrawal schedule, with a gradual tapering of the dose over at least three weeks. "If the drug is abruptly stopped, the bone marrow needs some time to catch up. It will still be making new platelets that are ultra aggressive because clopidogrel has been on board. Considering the platelet life span of about 10 to 14 days, we need to be sure that these new aggressive platelets are at least partially inhibited after stopping clopidogrel. We need more data on this obviously, but it is common sense to me to taper the dose. I don't think people need to take clopidogrel forever. That would be overkill."

In the paper, Ho et al note that clopidogrel is recommended for the treatment of ACS patients following the positive results of the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial, in which the drug was given for an average of nine months following hospital discharge. Current guidelines recommend clopidogrel therapy for at least one month and ideally up to one year for patients treated medically or with a bare-metal stent and for at least one year for patients treated with a drug-eluting stent following hospitalization for ACS. Because a rebound increase in events has been reported with other antithrombotic drugs, they conducted the current study to assess the incidence and timing of mortality or myocardial infarction (MI) after stopping treatment with clopidogrel in 3137 patients with ACS discharged from 127 Veterans Affairs (VA) hospitals between 2003 and 2005. Half the patients had received medical treatment for ACS and the other half had received PCI.

Results showed that among both medically treated patients and those who had received PCI, there was an increase in events in death/MI in the first 90 days after stopping clopidogrel.

Incidence of death/MI at various time periods after stopping clopidogrel

Patients Mean duration of clopidogrel treatment (d) Death/MI
0 -9 0 d
after stopping
91 - 180 d
after stopping
181 - 270 d
after stopping
Medically treated (n = 1568) 302 163 57 26
PCI treated (n = 1569) 278 73 29 8

In multivariable analysis, including adjustment for duration of clopidogrel treatment, the first 90-day interval after stopping treatment with clopidogrel was associated with a significantly higher risk of death/MI than the interval of 91 to 180 days in both medically treated and PCI patients.

Incidence rate ratio (IRR) of death/MI in first 90 days after stopping clopidogrel vs the interval of 91 - 180 days

Patients IRR (95% CI)
Medically treated 1.98 (1.46-2.69)
PCI treated 1.82 (1.17-2.83)

Rumsfeld commented to heartwire : "This rebound of events is not surprising. It happens with lots of other drugs. For example, blood pressure and heart rate increase when beta blockers are stopped, and a rebound effect is also seen with aspirin, but we don't routinely stop those drugs — they are given indefinitely. Clopidogrel is unique in that it is given for a predefined term of therapy and is then stopped. We just stop it because that is what happened in the CURE trial. In the large secondary-prevention studies of aspirin, patients did not stop taking aspirin at the end of the study but were recommended to continue indefinitely. Cost must be an issue here. If clopidogrel cost the same amount as aspirin, perhaps we would be recommending indefinite use of this drug as well."

He noted that other groups are looking now in different databases to see whether they can identify the same thing, and he suggested that a mechanistic study needs to be conducted in which platelet activity is measured before and after stopping clopidogrel to confirm that it is a rebound effect.

This study was supported by the Quality Enhancement Research Initiative of the US Department of Veterans Affairs. Dr. Ho is supported by VA Health Services Research and Development Career Development Award. Dr. Peterson is supported by a grant from the National Institute on Aging and has received honoraria and research support from the partnership between Bristol-Myers Squibb and Sanofi. A contributing editor of the Journal of the American Medical Association, Dr. Peterson was not involved in the editorial review or decision to publish this article. The remaining study authors have disclosed no relevant financial relationships.


  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(5):532-539.

The complete contents of Heartwire , a professional news service of WebMD, can be found at, a Web site for cardiovascular healthcare professionals.

Clinical Context

Clopidogrel is recommended after ACS, regardless of whether patients require PCI after the cardiac event. However, the duration of clopidogrel therapy may vary depending on the type of treatment rendered. For patients who have had ACS who are treated medically or with a bare metal stent, clopidogrel therapy should be continued for at least 1 month and, ideally, for 1 year. Patients who have received drug-eluting stents should be treated for at least 1 year with clopidogrel.

There is some concern regarding the risks associated with discontinuation of clopidogrel treatment. Previous research has found an increased risk for ACS in the period immediately after discontinuation of aspirin and heparin among patients with a history of coronary artery disease. The current research focuses on the risk for ACS among men after discontinuation of clopidogrel treatment.

Study Highlights

  • All patients discharged from the VA hospital with a diagnosis of acute myocardial infarction or unstable angina between 2003 and 2005 were eligible for study analysis. These diagnoses were culled from patient records and were made with use of standard diagnostic criteria for ACS. Patients who had had an adverse event related to clopidogrel therapy were not included in the study.
  • Clopidogrel use was measured with use of VA pharmacy records.
  • The primary study outcome was the relationship between use of clopidogrel and the combined endpoint of hospitalization for acute myocardial infarction and all-cause mortality. Researchers examined 90-day periods after discontinuation of clopidogrel for this outcome.
  • 3137 patients provided data for analysis. The mean age was 66 years, and 98.2% were men.
  • Among medically treated patients, the mean duration of clopidogrel therapy was 302 days. 34.8% of subjects took clopidogrel for more than 12 months. The mean duration of clopidogrel therapy among patients treated with PCI was 278 days.
  • The median follow-up period after discontinuation of clopidogrel was 196 days among medically treated subjects and 203 days among subjects treated with PCI. During this period, the combined outcome of all-cause mortality or acute myocardial infarction occurred in 17.1% of medically treated subjects and 7.9% of patients who received PCI.
  • Among medically treated patients, 60.8% of study events occurred between 0 and 90 days after discontinuation of clopidogrel, whereas 21.3% and 9.7% of events occurred between 91 and 180 days and 181 and 270 days after cessation of clopidogrel, respectively. The respective rates of study events among patients treated with PCI were 58.9%, 23.4%, and 6.5% for clopidogrel cessation at 0 to 90 days, 91 to 180 days, and 181 to 270 days.
  • Compared with the period of 91 to 180 days after cessation of clopidogrel, the period of 0 to 90 days after discontinuation of clopidogrel increased the risk for study events by 1.98 on multivariable analysis of medically treated patients. The respective incident risk ratio among PCI-treated patients was 1.82. The increased risk associated with earlier cessation of clopidogrel was also significant for the outcome of acute myocardial infarction alone.
  • The risk for early cessation of clopidogrel persisted regardless of the duration since the original ACS event.
  • 20.8% of subjects had 1 or more diagnostic codes entered for bleeding during follow-up. When these patients were excluded from analysis, the risk for early cessation of clopidogrel for the primary outcome remained significant.

Pearls for Practice

  • Current recommendations call for clopidogrel treatment for at least 1 month after ACS for patients treated with medications or bare metal stents and for at least 1 year for patients treated with placement of drug-eluting stents.
  • In the current study, cessation of clopidogrel during a 0- to 90 day interval after ACS increased the risk for the combined outcome of mortality and acute myocardial infarction, regardless of whether patients received PCI or medical therapy only.

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