Clopidogrel (Iscover, Plavix) PBS listing extended to include acute coronary syndrome (ACS) in combination with aspirin

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Place in therapy | Clopidogrel prevents thrombotic events and deaths | Optimal duration of clopidogrel therapy is unknown | Potential risk for major bleeding | Risk of rebound cardiovascular events on cessation | Reason for PBS listing | Information for patients and carers | References

Clopidogrel and aspirin can now be prescribed in combination for acute coronary syndrome (ACS) as an authority (streamlined) item on the Pharmaceutical Benefits Scheme (PBS). The extended listing, which came into effect on 1 February 2009, includes the treatment of myocardial infarction (MI) or unstable angina to prevent early and long-term atherothrombotic events.

The Pharmaceutical Benefits Advisory Committee (PBAC) agreed that clopidogrel plus aspirin is more effective in ACS than aspirin therapy alone, but is associated with a higher risk of bleeding.1  In clinical trials of patients with ACS, the benefit of combined therapy exceeded risk. 2,3 In summary:

  • there is a higher risk of bleeding with combined therapy
  • for about every 3 serious cardiovascular events prevented in ACS patients without ST-segment-elevation, 1 patient will experience a major bleed requiring transfusion 2
  • there is a possibility of rebound cardiac effects after stopping clopidogrel
  • the optimal duration of combined therapy is unknown, and should be determined on an individual basis.

Place in therapy

Consider clopidogrel in combination with aspirin for patients with ACS (unstable angina, non-ST-segment-elevation MI or ST-segment-elevation MI).4,5 If possible, clopidogrel should be discontinued 5 days before coronary artery bypass surgery, and avoided in patients likely to undergo emergency coronary artery bypass surgery.6

Clopidogrel prevents thrombotic events and deaths

The extended listing was informed by two randomised, double-blind clinical trials. One study (CLARITY) enrolled patients with ST-segment-elevation MI3 and the other (CURE) enrolled patients with ACS without ST-segment-elevation.2

In the CLARITY study, in which 3491 patients were followed for 30 days, there was an absolute risk reduction of 6.7% in the primary outcome (occluded infarct-related artery on angiography, death or recurrent MI before angiography) in patients receiving clopidogrel and aspirin, compared with those receiving aspirin alone.3

In the CURE study, 12562 patients were randomised to receive clopidogrel and aspirin, or aspirin alone, for 3–12 months (mean treatment duration 9 months). The absolute risk of death from cardiovascular causes, non-fatal MI or stroke was reduced by 2.1% in patients receiving clopidogrel and aspirin, compared with those receiving aspirin alone.2

Optimal duration of clopidogrel therapy is unknown

The optimal duration of clopidogrel therapy in ACS is unknown. It will depend on individual medical circumstances and may be influenced by the category of ACS index event, type of stent implanted (if relevant), the absolute risk of further ischaemic events and the risk of bleeding (see Potential risk for major bleeding). The decision to discontinue antiplatelet therapy after ACS or stent implantation, including discontinuation for surgery, should be made in consultation with the patient's cardiologist.7,8 After withdrawing clopidogrel, low-dose aspirin (unless contraindicated) should be continued indefinitely.6

Current Australian guidelines recommend clopidogrel 75 mg daily in addition to aspirin in the medical management of high-risk non-ST-segment elevation ACS (duration of therapy not specified).6 Patients with ST-segment-elevation MI should take clopidogrel (75 mg daily) for at least 1 month after fibrinolytic therapy, and for up to 12 months after stent implantation*.6 The optimal duration of clopidogrel therapy may be greater in patients treated with a drug-eluting stent, compared with those treated with a bare metal stent.7,9

Formal studies assessing extended or indefinite periods of clopidogrel therapy, tapering of clopidogrel therapy, or bridging of clopidogrel cessation to transient high-dose aspirin have not been conducted in patients with ACS.


* Depending on the type of stent and circumstances of implantation.

Potential risk for major bleeding

Combined therapy is associated with a small absolute increased risk of bleeding. However, in clinical trials the benefit of clopidogrel and aspirin in patients with ACS with or without ST-segment-elevation outweighed the risk of major bleeding.

Data from the CURE study indicate that for about every 3 serious cardiovascular events prevented in ACS patients without ST-segment-elevation, 1 patient will experience a major bleed requiring transfusion.2 The risk of any major bleeding* in patients receiving clopidogrel and aspirin therapy was small, but it was higher than that of patients receiving aspirin alone at 12 months.2

In the CLARITY study, the incidence of major bleeding was not significantly greater in patients receiving clopidogrel and aspirin than those receiving aspirin alone during the day after angiography or at 30 days.3

The CURE trial excluded patients at high risk for severe heart failure or bleeding (not otherwise specified), and those taking oral anticoagulants. Therefore, use clopidogrel with caution in this population and inform patients that bleeding may take longer than usual to stop while taking clopidogrel. Monitor patients for signs of bleeding, particularly during the first few weeks of treatment and after invasive procedures or surgery. Advise patients or carers to immediately report unusual bleeding or bruising, abnormal nose bleeds or bloody or black bowel motions.4,5


* Major bleeding episodes were defined as substantially disabling bleeding, intraocular bleeding leading to the loss of vision, or bleeding necessitating transfusion of at least 2 units of blood.

Risk of rebound cardiovascular events on cessation

A retrospective study found an increased risk of death or acute MI (rebound effects) after stopping clopidogrel.10 The absolute increase in risk was small. This effect has not been confirmed in a randomised controlled trial, and it is not known how the increased risk after stopping clopidogrel compares to that of patients who have never received clopidogrel.

The cohort study included 3137 patients who received percutaneous coronary intervention (PCI) or medical treatment (mean duration of clopidogrel 302 and 278 days, respectively) for ACS. The risk of death or acute MI was greatest during the first 3 months after stopping clopidogrel and was nearly twice that found in the following 3 months. However, the absolute risk in the first 3 months after stopping was small; 0.57 deaths or acute MIs per 1000 patient days of follow up in PCI-treated patients and 1.31 in medically treated patients. The rate of events in medically treated patients during the first 3 months after stopping clopidogrel treatment was higher than that for the first 3 months of clopidogrel treatment, and the subsequent 9 months of treatment.

Any decision to discontinue clopidogrel therapy should be made in consultation with the patient's cardiologist and include an assessment of the individual risk of recurrent vascular events against the risk of major bleeding.

Reason for PBS listing

The PBAC recommended a streamlined authority listing of clopidogrel for the treatment of ACS in combination with aspirin. The decision was reached on the basis of acceptable cost-effectiveness compared with aspirin alone.

Information for patients and carers

Advise patients and carers of the following:

  • clopidogrel and aspirin can be used together for heart attack or unstable angina
  • both medicines can cause bleeding, and the risk of major bleeding is increased when they are used together
  • immediately report unusual bleeding or bruising, abnormal nose bleeds or bloody or black bowel motions
  • aspirin must be continued, even if clopidogrel is stopped.

 References

  1. Pharmaceutical Benefits Advisory Committee. March 2008 PBAC outcomes - positive recommendations. http://www.health.gov.au/internet/main/publishing.nsf/Content/pbacrec-mar08-positive (accessed 24 June 2008).
  2. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494-502. [PubMed]
  3. Sabatine MS, Cannon CP, Gibson CM, et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med 2005;352:1179-89. [PubMed]
  4. sanofi-aventis Australia Pty Ltd. Plavix product information. 21 August 2007. Australia.
  5. Bristol-Myers Squibb Australia Pty Ltd. Iscover product information. 21 August 2007. Australia.
  6. Acute Coronary Syndromes Guidelines Working Group. Guidelines for the management of acute coronary syndromes 2006. Med J Aust 2006;184:S1-32. [PubMed]
  7. Department of Veterans' Affairs. Doctors Therapeutic Brief 13 - Aspirin and clopidogrel in cardiovascular disease. http://www.dva.gov.au/health/veteransmates/modules.htm#13 (accessed 24th September 2008).
  8. Jackowski L, Stocks N, Rowett D. Reducing the risk of adverse thrombotic events: the role of aspirin and clopidogrel. Aust Fam Physician 2008;37:721-6. http://www.racgp.org.au/afp/200809/26759
  9. Australian Medicines Handbook, 2008
  10. 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. [PubMed]