Are there any studies of the combination of acetylsalicylic acid (Trombyl), clopidogrel (Plavix), w

Fråga: Are there any studies of the combination of acetylsalicylic acid (Trombyl), clopidogrel (Plavix), warfarin (Waran) and dalteparin (Fragmin)? How long is the duration of effect after discontinuation of clopidogrel (Plavix)? A 54-year-old woman was treated with acetylsalicylic acid 75 mg daily and clopidogrel 75 mg daily after acute myocardial infarction. The patient was admitted to hospital with deep venous thrombosis. Treatment with warfarin and dalteparin was started and clopidogrel was discontinued. INR was 1.8 on day 4. Dalteparin was discontinued day 8. The same day the patient died from an intracerebral haemorrhage.

Sammanfattning: Intracerebral haemorrhage is a well-known, serious side effect of treatment with anticoagulants and platelet aggregating inhibitors. There are no studies or reports concerning the combined use of clopidogrel, acetylsalicylic acid, warfarin and heparin. There are reports on combination of two drugs and a few on combination of three drugs. A synergistic effect may develop with the combination of several drugs.

After discontinuation of clopidogrel, its effect gradually declines during five to seven days.

Svar: Acetylsalicylic acid (ASA) and clopidogrel are inhibitors of platelet aggregation. Clopidogrel irreversibly inhibits the binding of adenosindifosfat to its receptors on the platelets and thereby the activation of the GPIIb-IIIa complex and aggregation. The action of ASA is not altogether known, but its main effect is irreversible inactivation of the enzyme cyklooxygenase, which takes part in the production of thromboxan A2 in the platelets. After discontinuation of treatment the normal ability to aggregate returns with the production of new platelets. About 10-15 % of the platelet pool is newly formed per day. It takes about 5 days to regain normal platelet haemostatic function after withdrawal of salicylic acid and 5-7 days after clopidogrel, which has a more pronounced effect than salicylic acid.

Low-molecular-weight heparin produces an anticoagulant effect mainly through inhibition of Xa by antithrombin. Warfarin is a vitamin K antagonist leading to the production of non-active factors VII, IX, X as well as non-active proteins C and S.

There are no clinical studies on the combination of all four drugs. Nor are there any case reports.

The risk of intracerebral haemorrhage is increased by warfarin in proportion to the intensity of anticoagulation (1). The addition of ASA may increase this risk. This remains controversial, according to a metaanalysis of six randomised clinical trials (2). However, the authors recommend that ASA, even in low doses, should be added only with caution to conventional intensities of anticoagulation. In a study of 42 patients with intracerebral haemorrhage who had been on oral anticoagulants, the addition of ASA was not found to be a significant risk factor (3).

In the CURE trial 12 562 patients with acute coronary syndrome were treated with either clopidogrel and ASA or placebo and ASA. The incidence of intracerebral haemorrhage was 0.1 % in both groups (4).

One case report describes a 49-year-old woman, who underwent coronary angiography. She was treated with clopidogrel 75 mg daily, ASA 75 mg daily and dalteparin 10 000 IU twice daily, while waiting for coronary surgery. The patient was released from hospital the day after the angiography and continued treatment. She returned three days later with abdominal bleeding, which caused her death, despite operation and intensive care. The medication was judged unnecessarily risky (5)

According to the manufacturer of clopidogrel, simultaneous treatment with clopidogrel and warfarin is not recommended because of the increased risk of bleeding complications. It is recommended that the combination of clopidogrel and ASA is used with caution. The same recommendation is given for the combination of clopidogrel and heparin (6).

A synergistic effect develops when several drugs are combined (7). However, clinical situations like in the present case are likely to occur. ASA and clopidogrel do not protect from venous thrombosis and when a patient presents with this diagnosis it is indicated to change to warfarin and (low molecular) heparin. Side effects may be minimized by close monitoring of anticoagulant therapy and possibly by later than usual start of warfarin treatment, considering the prolonged effect of clopidogrel.

It is recommended that this case is reported to the regional Adverse Drug Reaction Monitoring centre.