Elsevier

The Lancet

Volume 354, Issue 9180, 28 August 1999, Pages 701-707
The Lancet

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Long-term low-molecular-mass heparin in unstable coronary-artery disease: FRISC II prospective randomised multicentre study

https://doi.org/10.1016/S0140-6736(99)07350-XGet rights and content

Summary

Background

Short-term treatment with subcutaneous low-molecular-mass heparin in addition to aspirin is effective in unstable coronary-artery disease. We assessed the efficacy of long-term treatment with dalteparin in patients managed with a non-invasive treatment strategy.

Methods

2267 patients from three Scandinavian countries (median age 67 years, 68% men) with unstable coronaryartery disease were randomly assigned to continue double-blind subcutaneous dalteparin twice daily or placebo for 3 months, after at least 5 days' treatment with open-label dalteparin. The composite primary endpoint was death or myocardial infarction. Analysis was by intention to treat.

Findings

During the 3 months of double-blind treatment, there was a non-significant decrease in the composite endpoint of death or myocardial infarction of 6·7% and 8·0% in the dalteparin and placebo groups, respectively (risk ratio 0·81 [95% Cl 0·60–1·10], p=0·17). At 30 days, this decrease was significant (3·1 vs 5·9%, 0·53 [0·35–0·80]; p=0·002). In the total cohort there was at 3 months a decrease in death, myocardial infarction, or revascularisation (29·1 vs 33·4%, 0·87 [0·77–0·99]; p=0·031). The initial benefits were not sustained at 6-month follow-up.

Interpretation

Long-term dalteparin lowers the risk of death, myocardial infarction, and revascularisation in unstable coronary-artery disease at least during the first month of therapy. These early protective effects could be used to lower the risk of events in patients waiting for invasive procedures.

Introduction

During the past few years, several trials have shown the efficacy of short-term treatment with subcutaneous low-molecular-mass heparin in addition to aspirin in unstable coronary-artery disease.1, 2, 3 However, the optimum duration of this combination treatment is unknown. Thrombi at the coronary lesion and a raised coagulation activity persist for months after an episode of instability.4, 5, 6 Accordingly, the risk of cardiac events is increased for several months after an acute episode.1, 2, 3, 7, 8, 9, 10 Furthermore, there is reactivation of the coagulation activity and a raised event rate after short-term intense antithrombotic treatment is stopped.1, 7, 11, 12 In the FRagmin during InStability in Coronary artery disease (FRISC) trial,1 long-term treatment with the low-molecular-mass heparin dalteparin led to an additional improvement in patients at higher risk (ie, with raised troponin-T concentrations) who were treated with a low rate of early invasive procedures.13 Therefore, the effects of long-term antithrombotic treatment in unstable coronaryartery disease might be dependent on the treated population as well as on the proportion of patients treated with early invasive procedures.

We aimed in this prospective randomised multicentre study to assess the effects of long-term treatment with dalteparin compared with placebo in patients undergoing a non-invasive treatment strategy.

Section snippets

Patients

We recruited patients between June 17, 1996, and August 28, 1998, in 58 Scandinavian centres. Patients were eligible for inclusion if they had symptoms of ischaemia that were increasing or occurring at rest or that warranted the suspicion of acute myocardial infarction, with the last episode within 48 h before the start of dalteparin or heparin treatment. Myocardial ischaemia had to be verified by electrocardiography (ST depression ≥0·1 mV or T-wave inversion ≥0·1 mV) or by raised biochemical

Study design

The FRISC II medical study was a prospective, randomised, multicentre trial with parallel groups and a factorial design. The comparison of long-term dalteparin treatment with placebo was double-blind, and that of invasive and non-invasive strategies was open (figure 1). Randomisation was done by telefax contact with an independent organisation (Clinical Data Care, Lund, Sweden). Patients fulfilling the entry criteria were eligible if the last episode of chest pain had occurred within 48 hours

Endpoints

Myocardial infarction was defined by the occurrence of two of the three conventional criteria—typical chest pain, diagnostic electrocardiography recording (mainly new Q wave), or raised biochemical marker of myocardial damage, according to the following definitions. For non-procedural myocardial infarction: concentration of CK-MB mass higher than the local hospital's diagnostic limit for myocardial infarction at one measurement; catalytic activity of CK, CK-B, or CK-MB higher than the local

Statistical analysis

Our hypothesis was that there would be a 35% relative decrease in the primary composite endpoint with a placebo event rate of 10% in the double-blind treatment period. Recruitment of 2100 patients into the double-blind treatment period was therefore required to reach 80% power with 2α=0·05.

We did statistical analyses according to intention to treat. The primary efficacy analysis included patients who had received at least one injection of double-blind treatment and only events occurring from

Results

2267 patients were included in this part of the FRISC II trial (figure 2, table 1). Of these patients, 1235 constituted the non-invasive part of the invasive and non-invasive randomisation, 666 had contraindications to treatment, and 366 were enrolled after the end of recruitment to the invasive and non-invasive comparison. During open-label dalteparin treatment, 162 patients were withdrawn because of: patients' request (63), adverse events (52), death (16), and other reasons (31). Therefore,

Discussion

The FRISC II trial involved mainly patients at high risk of further events (based on the occurrence of chest pain at rest, raised concentrations of troponin-T and ST depression on electrocardiography at entry in most patients).15, 16 The twice-daily dose of dalteparin adjusted for bodyweight and sex was based on previous experiences of clinical efficacy, risks of bleeding, and anti-Xa concentrations in the FRISC trial.17 We also based the duration of treatment on the FRISC experiences, which

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