Oral anticoagulants' benefit in unstable angina Wed, 07 Feb 2001 17:07:57


San Francisco, CA - Long-term administration of oral anticoagulants seems to have an additional benefit to aspirin in reducing event rates in unstable angina patients. However, high rates of noncompliance with anticoagulants in many countries may prevent this benefit from ever being seen, and the combination of aspirin plus clopidogrel, if shown to be effective in the ongoing Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial, is more likely to be accepted into clinical practice, according to a subgroup analysis of the Organisation to Assess Strategies for Ischemic Syndromes (OASIS) trial.

Although many medications given in the acute phase of unstable angina have now been shown to reduce event rates, it is believed that chronic administration of certain drugs may produce further reductions in events. However, the only chronically administered agent to have shown benefit in this indication thus far is aspirin. And, despite the use of aspirin, 10-15% of patients still experience death or MI by 1 year, while 20% of patients are readmitted to hospital with unstable angina.

The OASIS investigators, led by Dr Salim Yusuf (McMaster University, Hamilton, ON), therefore set out to test whether additional therapy with oral anticoagulants would be beneficial in these patients. The main OASIS trial compared hirudin with heparin in 10141 unstable angina patients. The anticoagulation subgroup analysis included 3712 patients who were randomized 12-48 hours later to oral anticoagulation therapy (ie warfarin) to a target INR of 2.5 or standard therapy.

Overall results showed only a small, nonsignificant benefit in patients allocated to receive warfarin at 5 months. The composite endpoint of cardiovascular death, MI, or stroke occurred in 7.6% of warfarin patients versus 8.3% of those in the control group (relative risk (RR) 0.90, p=0.4).
High-compliance areas showed improved outcomes
However, the researchers note that this overall result is likely to be an underestimate due to the high rates of noncompliance to oral anticoagulants in some countries or centers. In a subgroup analysis based on compliance, they found that those countries or centers with a high compliance showed improved outcomes, lower rates of cardiac interventions and higher bleeding rates in patients allocated to warfarin.

In good-compliance countries (use of oral anticoagulants above 70% at 35 days) there was a significant reduction in the primary outcome of cardiovascular death, MI or stroke in the oral anticoagulant group (6.1% vs 8.9%, p =0.02). The secondary outcome (primary endpoint plus refractory angina) in good compliance countries showed a similar pattern (11.9% vs 16.5%, p =0.005), as did both primary and secondary outcomes when good compliance centers were analyzed separately.

The prime reason for poor compliance was the conduct of invasive procedures, and the overall rates of such procedures in the good-compliance countries were significantly lower than in the poor-compliance countries.

Combining the overall data from this study with three smaller trials of warfarin in unstable angina/non Q-wave infarction, shows a promising risk reduction of death, MI and stroke of about 17%, they note, which "further supports the possibility that oral anticoagulants are effective when given in addition to aspirin."
Meta-analysis of all trials evaluating moderate intensity oral anticoagulation on top of aspirin in unstable angina (endpoint= death/MI or stroke).

Study	Oral anticoagulant	Control	RR	p value
	5.1%	13.1%	0.39	0.051
	7.7%	8.6%	0.89	0.32
	0%	3.1%	0.29	0.28
	7.6%	11%	0.69	0.39
	7.4%	8.8%	0.83	0.1

The researchers say that these exploratory analyses need confirmation in prospective trials of oral anticoagulation. However, they add that these trials need to be conducted in countries or centers where there is a more conservative approach to the use of invasive procedures, unless special attention is paid to maintaining high compliance.

Routine invasive strategy best? Investigator says more data is needed In the discussion, the researchers say, "There is an urgent need to conduct randomized trials that evaluate the effects of long-term antithrombotic therapies as well as determine whether a liberal invasive strategy is helpful in patients with unstable angina." In an interview with heartwire, Yusuf notes that this paper was written before the results of the TACTICS study were known. TACTICS, which was reported in November 2000 at the American Heart Association meeting, showed routine early revascularization was associated with a better outcome in unstable angina patients than a conservative medical approach in which revascularization was only carried out if symptoms continued. Yusuf says that although the TACTICS results are promising, more data are needed. "Part of the endpoint was hospitalization for unstable angina which is subjective and potentially open to bias in ascertainment in an open trial. However, MI was reduced, which is reassuring. Longer-term follow-up is needed plus results of RITA-3," he said. Yusuf also points out that TACTICS was conducted against a background of routine use of intravenous Gp IIb/IIIa inhibitors. "The cost of this combined approach is quite prohibitive, except in high-risk patients," he says.

Clopidogrel: CURE study
The authors note that several trials have shown that the combination of aspirin and clopidogrel has a synergistic effect and may be superior to warfarin in preventing subacute coronary occlusion. This combination is also safer than oral anticoagulants.

This combination is now being tested in unstable angina in the (CURE) study, the results of which are to presented at the American College of Cardiology meeting in March 2001. If shown to be effective, "this relatively simple regimen is more likely to be accepted into clinical practice," the authors comment.