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Three Part Question

[In a patient with a clinical diagnosis of ACS who is already on Warfarin] is [the addition of Clopidogrel to Aspirin better than Aspirin alone] in [reducing mortality]?

Clinical Scenario

It is a busy shift in the A&E, and you receive a courtesy call from the paramedics of a 65 years old gentleman with chest pain.
When you see the patient you find out that he had crushing central chest pain with radiation to his left arm, diaphoresis, and nausea for about one hour, but he is pain free now.
On further questioning you find that he is receiving Warfarin anticoagulation for previous pulmonary Embolism.
You think of treating him for ACS, and decide that he should receive the Aspirin, but not the LMWH. But you are puzzled whether giving Clopidogrel is of any proven benefit or not?

Search Strategy

Medline using the OVID interface 1966 - week 3 November 2009 (including in process, non indexed). :
[exp Ticlopidine/ or clopidogrel.mp.] AND [warfarin.mp. or exp Warfarin] LIMIT to (English language and humans and "all adult (19 plus years)")

EMBASE 1996-week 50 2009:
[clopidogrel.mp. or exp Clopidogrel] AND [warfarin.mp. or exp Warfarin] AND [acute coronary syndrome.mp. or exp acute coronary syndrome/ or exp unstable angina pectoris] LIMIT to (human and English language and (adult <18 to 64 years> or aged <65+ years>))

Cochrane Library:
Search for the terms Clopidogrel LIMITED to English language

Search Outcome

167 papers were found on the Medline search, of which none were relevant to the three part question.
85 papers were found on the EMBASE search, none were relevant to the three part question.
No relevant review in the Cochrane database.

Comment(s)

After the publish of multiple randomized control trials and the change in international guidelines, the use of Clopidogrel in addition to Aspirin in high risk acute coronary syndrome (ACS) became the standard of care in most medical centers. On the other hand some of the patients attending to the hospitals with ACS are already on Warfarin for various reasons (AF, thrombo-embolic diseases, mechanical prosthetic heart valves, etc). These patients produce a dilemma in their ACS management, as the balance between anti-thrombotic and anti-coagulation therapy from one side and the potential risk of bleeding on the other side is often a fine line and requires significant expertise. After searching the available literature, unfortunately I was unable to find any study to address whether adding Clopidogrel to Aspirin in patients presenting with acute coronary syndrome who are already on Warfarin, will reduce the mortality or add any significant benefit. Few studies Brulotte et.al. (2007) and Konstantino et.al. (2006) addressed the risk of bleeding in the patients receiving the combination of Aspirin + Clopidogrel +Warfarin (sometimes called triple antithrombotic therapy or cardiac triple therapy) and interestingly they had conflicting results. Some other studies were assessing the safety of starting the three above medication after having an ACS (i.e. adding the Warfarin to the standard treatment of Aspirin and Clopidogrel as an intervention for treating ACS, rather than adding the Clopidogrel to patients already on Warfarin for some other indication). Most of these studies were retrospective and included a small number of patients. Anderson et.al. in the joint guidelines published by the American Heart Association (AHA) and the American College of Cardiology (ACC) (2007) admits the difficulty of decision making in patients presenting with unstable angina/non STEMI and are therapeutically anticoagulated with Warfarin. This guideline suggest using clinical judgment in regard to starting these patients on anti-platelets or anticoagulant therapy, but generally advise on starting anti-platelet therapy even in patients therapeutically anticoagulated with Warfarin, especially if an invasive strategy is planned and implantation of a stent is anticipated. The approach in the above scenario will depend on the experience of the treating physician and the overall clinical picture of the patient.

Clinical Bottom Line

There is no evidence to determine whether adding Clopidogrel to Aspirin in patients suffering from an acute coronary syndrome who are already on Warfarin will reduce the mortality. Good quality evidence based studies are required to clarify the best medical practice in such situations, until then clinical judgment should be used and local advice should be sought.