Unstable coronary artery disease – need for long term antithrombotic treatment Aspirin alone is not sufficient, I would associate an anticoagulant

The main arguments for this statement are the following: in patients with unstable coronary artery disease there is: development of instability despite ongoing aspirin in half of the patients; reactivation of instability after reduction or cessation of heparin in many patients despite ongoing aspirin treatment; high event rate during the first 3 months despite ongoing aspirin; remaining unstable lesions longer than the usual 3–5 days of protection by heparin treatment; elevation of coagulation activity and a remaining prothrombotic state for at least 3–6 months. Around 10 years ago it was convincingly demonstrated that aspirin in daily doses from 75 mg will reduce the risk for myocardial infarction and death by at least 50% in patients with unstable coronary artery disease, i.e. unstable angina or non-Q-wave myocardial infarction, as well in the acute phase as during long term treatment [1–4]. However since the presentation of the salutary effects of aspirin in all conditions with manifestations of atherosclerotic disease [5], most patients at risk for development of unstable lesions will already be treated with aspirin. Today in at least 50% of patients entering hospital with unstable coronary artery disease, this syndrome will have evolved while on aspirin [4, 6, 7]. Therefore, in order to stabilise the thrombotic activity at the lesion, additional antithrombotic treatment is needed. Such a stabilisation is usually accomplished by addition of heparin infusion [3, 4, 8] or a high dose twice daily subcutaneous low molecular weight (lmw) heparin [9]. However, for practical reasons the heparin treatment is usually terminated after 3–5 days [10]. During the first days after termination of heparin or lowering the dose lmw heparin, there is a reactivation of instability with an increased risk of clinical recurrences of angina and myocardial infarction [7, 9, 11, 12]. Also on long term basis there is a fairly high event rate after termination of heparin despite ongoing aspirin, with a 10–15% risk of myocardial infarction or death over the next 3–6 months (Table 1). Thus, it seems that the coronary lesion remains unstable, and is associated with an increased risk for reactivation of the thrombotic process for a longer period than the conventional 3–5 days of added heparin treatment. The risk for recurrences might also be related to a remaining elevation of coagulation activity and a lasting prothrombotic state [13]. Long term outcome – death or new MI – in recent non-angioplasty trials of aspirin treated patients with unstable coronary artery disease Long term outcome – death or new MI – in recent non-angioplasty trials of aspirin treated patients with unstable coronary artery disease The supportive evidence for this statement is based on the findings in recent randomised placebo-controlled studies of adding heparin to aspirin in unstable coronary artery disease which has shown: convincing effects of the combination in short term trials over 5 days; evidence for maintained benefits during 6 weeks continued treatment; less myocardial damage during long term treatment; better effects of long term treatment in high risk patients; better long term efficacy in patients with adequate anticoagulation; maintained reduced activation of coagulation during long term treatment. After very promising results in a few smaller trials [3, 4, 8, 16], the FRISCI study [9] definitely proved that the addition of heparin to aspirin reduces the risk of recurrence and myocardial infarction by at least 50% in unstable coronary artery disease (Table 2). Despite signs of reactivation a few days after reducing the lmw heparin dose, there were remaining lower rates of recurrences and myocardial infarctions at the termination of the 6 weeks lmw heparin treatment [9]. In the further evaluation of the FRISCI trial several other findings supported the beneficial long term effects. The actively treated group had less signs of myocardial damage as indicated by less reduction of QRS scores in repeated 12-lead ECGs during the long term treatment. High risk patients, i.e. those with elevation of troponin-T, had a further 50% reduction in event rate during the prolonged treatment period [17]. During the long term treatment the anti-Xa levels were better maintained in women than in men; in this period there was a better protective effect against new cardiac events in women than in men [18]. Finally the coagulation activity, i.e. both thrombin generation and activity, remained suppressed during the long term treatment although there was some recovery of thrombin generation indicating a return to a prothrombotic state after reduction of dose [19]. Effects of heparins in addition to aspirin on myocardial infaction and death in unstable coronary artery disease Effects of heparins in addition to aspirin on myocardial infaction and death in unstable coronary artery disease The severe unstable lesion is not healed after a few days of heparin therapy. During continued treatment with lmw heparin the obtained benefits in event rate are maintained, and there are less signs of myocardial damage than on aspirin alone. The long term benefits are more pronounced in high risk patients and in patients with an adequate long term dose. Subcutaneous lmw heparin can be used as a as the long term anticoagulant with good compliance and excellent safety in patients with unstable coronary artery disease. The available data suggest that a combination of aspirin and an anticoagulant should be used in patients with unstable coronary artery disease in the following situations: in the acute phase in all patients with suspected instability and objective signs of ischemia until clinical stabilisation and noninvasive or invasive risk stratification in long term treatment in high risk patients until revascularisation. New large scale clinical trials, evaluating the benefits of long term more intense antithrombotic treatment after an episode of unstable coronary artery disease, are urgently needed. The FRISCII trial, which recently has started, will evaluate the effects of 3 months randomized continued treatment with a twice daily dose of lmw heparin or placebo in patients who also are randomised to an early invasive or noninvasive treatment policy. This study will hopefully provide a better basis for recommendations of combinations of anticoagulants and aspirin after the acute phase in unstable coronary artery disease.