Unstable coronary artery disease: need for long-term antithrombotic treatment?: Aspirin alone may not be the ideal antithrombotic strategy, but that's what we have adequate trial data for

There is no doubt that a solid rationale exists for long-term antithrombotic treatment after an episode of coronary instability. This is related to: Although aspirin, in doses as low as 75 mg daily, has produced a dramatic reduction in the risk of cardiac death or nonfatal myocardial infarction (MI) after an episode of coronary instability (reviewed in [4]), 5–7% of patients with unstable angina will still experience a major cardiovascular event during the first 3 months despite aspirin prophylaxis [1, 2].

• raised event rate for at least 12 weeks after the acute episode [1, 2] and,

• activation of coagulation for several months after the acute event [3].

What about adding heparin to aspirin in this setting? Three relatively small studies have addressed this question by randomizing unstable angina patients, within 24–72 h after admission, to either aspirin alone or to the combination of aspirin and heparin [2, 5, 6]. Table 1 summarizes the results in terms of the combined end-point of cardiac death or nonfatal MI, after 5–6 days of follow-up. Combined treatment was associated with numerically, though not significantly, lower event rates than aspirin alone in all three trials and an overview [7] suggests that this may not simply reflect the play of chance. Thus, although no single randomized trial had the statistical power for reliable intertreatment comparisons, an overview of these three small studies suggests a 56% reduction in the risk of important cardiovascular events with the combination of aspirin and heparin vs. aspirin alone. This degree of statistical uncertainty was reflected in the 4th ACCP Consensus Conference on Antithrombotic Therapy giving a grade B recommendation for the use of i.v. heparin therapy in patients hospitalized with unstable angina [7]. More recently, the FRISC study group has examined the effects of a low-molecular-weight heparin, dalteparin, in a placebo-controlled trial of 1506 patients with unstable angina or non-Q-wave MI treated with aspirin 75 mg daily [8]. It is important to emphasize that the primary aim of the FRISC study was to compare aspirin alone and aspirin with dalteparin in their ability to prevent death or MI during the first 6 days, with adequate statistical power to test the hypothesis of a 50% difference between the two, as suggested by the overview of previous trials. It was only a secondary aim of the study to compare the longer-term benefits of the combined treatment at a reduced once-daily fixed dose of dalteparin for another 5–6 weeks vs. aspirin alone, and the study was not sized to address these additional questions with adequate statistical power. Table 2 summarizes the results of the FRISC study during its three phases. Dalteparin use (weight-adjusted b.i.d. regimen for 6 days) was associated with a highly significant 60% reduction in the risk of death or MI during the acute phase of the study. This result is consistent with the hypothesis generated by an overview of earlier trials, as discussed above. However, when dalteparin treatment was switched to a fixed, once-daily reduced regimen for the next 35–45 days, the additional increments in event rates between 6 and 40 days and between 40 and 150 days were not prevented by this therapeutic strategy any better than aspirin alone, as detailed in Table 2. As a consequence, no statistically significant differences in event rates could be detected between dalteparin and placebo at 40 and 150 days. A similar lack of efficacy of the same regimen of dalteparin was reported at the ESC Congress in Birmingham by the FRIC study group [9]. Thus, the results of two separate trials in approximately 3000 patients with unstable coronary artery disease are consistent in showing no significant improvement in outcome during prolonged treatment with low-dose dalteparin once daily at home [8, 9].

Table 2

Rates of death or myocardial infarction during the three phases of the FRISC study [8]

Time of assessment (days)	Cardiac death or nonfatal MI
	Placebo (%)		Dalterparin (%)		Risk ratio	P
Acute phase (6)	4.8		1.8		0.37	0.001
		+5.9		+6.2
Home-treatment (40)	10.7		8.0		0.75	0.07
		+4.8		+6.0
Follow-up (150)	15.5		14.0		0.90	0.41

Table 1

Aspirin vs. aspirin plus heparin in the acute management of unstable angina [7]

Study (n)	Aspirin	Heparin	Cardiac death or nonfatal MI
	mg/day		Aspirin (%)	Aspirin+heparin (%)	P
RISC (n=796)	75	Bolus q. 6 h	3.7	1.4	NS
Théroux (n=479)	650	Bolus, infusion	3.3	1.6	NS
ATACS (n=214)	162.5	Bolus, infusion	8.3	3.8	NS
Overview					<0.05

So, where do we stand at the end of 1996? As far as the acute management of unstable coronary syndromes is concerned the additional information provided by the FRISC study strengthens the ACCP recommendation of combined antiplatelet-anticoagulant treatment for the first 5–6 days, to reduce the risk of new cardiac events and to allow time for risk stratification and selection of a long-term treatment strategy. The latter clearly includes continued use of low-dose aspirin, if no contraindications exist. However, available trial data do not support the continued use of dalteparin although they do suggest that it may warrant further assessment. In particular, the results of the FRISC and FRIC studies suggest the need of reexamining both the adequacy of the dose and the question of how to handle dalteparin (or heparin) withdrawal in order to prevent reactivation. Until improved long-term efficacy of combining low-molecular-weight heparin with aspirin vs. aspirin alone is clearly established by new ongoing trials, physicians should not underestimate the additional bleeding risk associated with such combination. Thus, even with the reduced once-daily regimen used in the FRISC study, there was a doubling of minor bleeding [8] and the study was not large enough to assess reliably an effect of combination therapy on major bleeding given its low (<1%) rate of occurrence.

Acknowledgements

I am grateful to Professor Lars Wallentin for helpful discussions on this topic and to Andre Harris for expert editorial assistance.