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Therapeutics

Dalteparin reduced death and MI at 1 but not 3 months in unstable coronary artery disease managed noninvasively

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ACP J Club. 2000 May-June;132:82. doi:10.7326/ACPJC-2000-132-3-082

Related Content in this Issue
• Companion Abstract and Commentary: An invasive strategy reduced the combined rate of death and myocardial infarction in unstable coronary artery disease


Source Citation

Long-term low-molecular-mass heparin in unstable coronary-artery disease: FRISC II prospective randomised multicentre study. FRagmin and Fast Revascularisation during InStability in Coronary artery disease. Investigators. Lancet. 1999;354:701-7. [PubMed ID: 10475180]


Abstract

Question

In patients receiving noninvasive treatment for unstable coronary artery disease (CAD), does dalteparin reduce myocardial infarction (MI) and death?

Design

Randomized (allocation concealed*), blinded {patients, clinicians, and outcome assessors}†,* placebo-controlled trial with 6-month follow-up.

Setting

58 Scandinavian centers.

Patients

Patients were eligible if they had symptoms of ischemia with the last episode occurring ≤ 48 hours before enrollment. Myocardial ischemia was confirmed by ST depression or T-wave inversion on electrocardiography or by elevated biochemical markers (creatine kinase-MB or troponin-T). Only patients who had a contraindication to early revascularization or had been randomized to the noninvasive strategy in the FRISC II study were included in this analysis. 2267 patients were randomized, and 2105 entered the double-blind treatment period (median age 67 y, 68% men). Follow-up was 93% for the primary outcome and 99% for secondary outcomes.

Intervention

Randomization was stratified by center, and all patients initially received open-label treatment with subcutaneous dalteparin, 120 IU/kg of body weight every 12 h for ≥ 5 days. Patients were allocated to dalteparin (n = 1140) or placebo (n = 1127) in twice-daily subcutaneous injections for 3 months. Dalteparin was given in doses of 5000 IU for men who weighed < 70 kg and women who weighed < 80 kg and 7500 IU for all others.

Main outcome measures

The primary outcome was a composite of death and MI at 3 months. The secondary outcome was a composite of death, MI, and need for revascularization at other time points.

Main results

Dalteparin did not reduce the primary composite outcome at 3 months (P = 0.17) or 6 months (P > 0.2) more than did placebo. Dalteparin led to a greater decrease in the primary composite outcome at 1 month (P = 0.002) and in the secondary composite outcome at 3 months (P = 0.03) than did placebo (Table).

Conclusion

In patients who received noninvasive management for unstable coronary disease, dalteparin reduced death and myocardial infarction at 1 month but not at 3 months.

*See Glossary.

†Information provided by author.

Sources of funding: Pharmacia and Upjohn and Swedish Heart-Lung Foundation.

For correspondence: Dr. L. Wallentin, Department of Cardiology, Cardiothoracic Centre, University Hospital, S-751 85 Uppsala, Sweden. FAX 46-18-506638.


Table. Dalteparin vs placebo in patients receiving noninvasive treatment for unstable coronary artery disease‡

Outcomes Dalteparin Placebo RRR (95% CI) NNT (CI)
Death, MI, or both at 1 mo 3.1% 5.8% 47% (20 to 65) 37 (23 to 102)
Death, MI, or need for revascularization at 3 mo 29% 33% 13% (2 to 23) 24 (13 to 208)

‡MI = myocardial infarction. Other abbreviations defined in Glossary; RRR, NNT, and CI calculated from data in article.


Commentary

Clear evidence supports the use of heparin and antiplatelet therapy in patients who have unstable CAD with no ST elevation (1). Low-molecular-weight heparin (LMWH) has attracted recent interest because it may be more efficacious, cost-effective, and easier to give than intravenous unfractionated heparin; LMWH does not require regular monitoring of anticoagulation intensity and infusion-dose adjustment.

The FRISC-II study shows a substantial benefit of dalteparin in reducing the composite outcome of death, MI, and revascularization procedures at 3 months in patients with unstable CAD, but the primary study outcome (a composite of death and MI) was only significantly decreased at 1 month. The dose of dalteparin chosen for this trial seemed to suppress markers of ongoing thrombogenesis (2). It is not clear, however, whether an increased incidence of major bleeding in patients receiving dalteparin contributed to the decreasing treatment effect between 6 weeks and 3 months.

In the FRIC study (3), dalteparin and unfractionated heparin led to a similar combined rate of death, MI, and recurrent ischemia. However, another LMWH, enoxaparin, showed substantial benefits over unfractionated heparin in the ESSENCE study (4). Although some differences may result from the trial design, subtle differences may also be present among the LMWHs. It is not clear whether LMWH is more effective than standard unfractionated heparin in all groups of patients. More work is needed to compare the different types of heparins available.

Although previous studies comparing invasive and noninvasive strategies have been equivocal, the FRISC-II study suggests that an early invasive strategy is preferable to a noninvasive one in patients with unstable CAD and leads to a substantial reduction in death and MI (4). Nevertheless, the positive results of FRISC-II could be related to improvements in the management of unstable CAD and to the better outcomes of more recent invasive and revascularization procedures. Further, this study does not take into account the possible difference in outcomes between patients treated with dalteparin and those treated with unfractionated heparin during the initial period of open-label antithrombotic treatment before randomization. It is also unclear whether the serious adverse event rates were significantly different between invasive and noninvasive groups and between dalteparin and placebo groups.

An early invasive strategy should be used, especially in such high-risk patients as older persons; men; and persons with longer duration of angina, rest pain, ST depression on electrocardiography, and elevated levels of troponin T. In FRISC-II, more patients had revascularization after the initial hospital stay in the noninvasive strategy group, which suggests that a noninvasive strategy may simply be delaying the invasive procedure and subsequent revascularization while subjecting these patients to an increased risk for MI or death in the interim.

Long-term LMWH has a substantial role in high-risk patients with unstable CAD who have contraindications for or who are awaiting revascularization. Nevertheless, patients with unstable CAD should be considered for early invasive treatment in addition to standard antithrombotic and anti-ischemic therapy, especially if high-risk factors are present.

Sridhar Kamath, MBBS
Gregory Y.H. Lip, MD
City Hospital
Birmingham, England, UK


References

1. Oler A, Whooley MA, Oler J, Grady D. Adding heparin to aspirin reduces the incidence of myocardial infarction and death in patients with unstable angina. A meta-analysis. JAMA. 1996;276:811-5. [PubMed ID: 8769591]

2. Ernofsson M, Strekerud F, Toss H, et al. Low-molecular weight heparin reduces the generation and activity of thrombin in unstable coronary artery disease. Thromb Haemost. 1998;79:491-4. [PubMed ID: 9531028]

3. Klein W, Buchwald A, Hillis SE, et al. Comparison of low-molecular weight heparin with unfractionated heparin acutely and with placebo for 6 weeks in the management of unstable coronary artery disease. Fragmin in unstable coronary artery disease study. Circulation. 1997;96:61-8. Erratum. 1998;97:413. [PubMed ID: 9236418]

4. Cohen M, Demers C, Gurfinkel EP, et al. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Study Group. N Engl J Med. 1997;337:447-52. [PubMed ID: 9250846]