- Email: [email protected]
Management of unstable coronary-artery disease
CORRESPONDENCE 1
FRagmin and Fast Revascularisation during InStability in Coronary artery disease (FRISC II) Investigators. Invasive compared with non-invasive treatment in unstable coronary-artery disease. FRISC II prospective randomised multicentre trial. Lancet 1999; 354: 708–15.
Sir—The FRISC II investigators1 have masterfully written the results, of what is truly a failed superiority trial of long-term dalteparin treatment in unstable coronary-artery disease, to selectively emphasise favourable effects and de-emphasise those less favourable. First, according to the primary endpoint, the investigators were unable to show that long-term dalteparin was superior to placebo (p=0·17). Moreover, whatever small benefit that might exist at 3 months had disappeared at 6 months. Selective emphasis on the effect at 1 month seems to be data-derived, and not particularly helpful to a practising clinician because treatment was continued beyond this timepoint. Second, why the investigators placed selective emphasis on the apparent differential effect among patients with and without raised concentrations of troponin-T is not clear. The p value for the troponin-T subgroup was not significant and the upper bound of the 95% CI for relative risk crossed unity in this and all other subgroups. If this was based on the relative risk of 0·7, why was emphasis not placed on the effect of smokers (relative risk 0·48)? Or, if the emphasis was placed on the putative magnitude of the absolute risk reduction (2·7%), why not also emphasise the effect on those with a previous acute myocardial infarction (absolute risk reduction 3·3%)? Perhaps it would be helpful to know whether a statistical test of interaction was done on any of the predefined subgroups. Finally, the impact of dalteparin on bleeding was downplayed. Although the investigators were careful to include tests of significance to support their (positive outcome) views, none were provided in their table 5 (safety during double-blind treatment period). Are not the differences in bleeding risk highly significant? The text comments only on “a raised risk of major bleeding episodes in the dalteparin compared with the placebo group. Minor bleeds were more common in the dalteparin group than in the placebo group”. The conclusions seem excessive when considered in light of the study findings. The investigators were unable to show that long-term
THE LANCET • Vol 355 • February 12, 2000
dalteparin was superior to placebo, and that any small and marginally significant reduction in the risk of death and acute myocardial infarction at 30 days (1·2% absolute) was transient and counterbalanced by a larger and highly significant risk of major bleeds (1·8% absolute). Their contention that dalteparin is only effective in a routine invasive strategy should be contrasted with the ESSENCE and TIMI II trials,2,3 In these studies the short-term use of enoxaparin led to a reduced rate of death and acute myocardial infarction at 43 days (absolute risk reduction 1·5%, relative risk 0·82, p=0·02),3 that persisted at 1 year (ESSENCE), 4 which was accomplished while avoiding the need for revascularisation rather than requiring a routine invasive strategy.4 The net result is that not only is enoxaparin a costeffective strategy in the treatment of acute coronary syndromes, but also that it may lead to cost savings5—a rarity in modern medicine. David Massel Cardiac Care Unit, Division of Cardiology, London Health Sciences Centre, University of Western Ontario, London, Ontario, Canada N6A 4G5 (e-mail: [email protected]) 1
2
3
4
5
FRagmin and Fast Revascularisation during InStability in Coronary artery disease (FRISC II) Investigators. Longterm low-molecular-mass heparin in unstable coronary-artery disease: FRISC II prospective randomised multicentre study. Lancet 1999; 354: 701–07. Cohen M, Demers C, Gurfinkel EP, et al. Comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. N Engl J Med 1997; 337: 447–52. Antman EM, Cohen M, Radley D, et al. Assessment of the treatment effect of enoxaparin for unstable angina/non-Qwave myocardial infarction: TIMI IIBESSENCE meta-analysis. Circulation 1999; 100: 1602–08. Goodman S, Langer A, Demers C, et al. One year follow-up of the ESSENCE trial (enoxaparin vs heparin in unstable angina/non Q wave myocardial infarction): sustained clinical benefit. Can J Cardiol 1998; 14: 122F (abstr). Mark DB, Cowper PA, Berkowitz SD, et al. Economic assessment of low-molecularweight heparin (enoxaparin) versus unfractionated heparin in acute coronary syndrome patients. Results from the ESSENCE randomized trial. Circulation 1998; 97: 1702–07.
Authors’ reply Sir—We are grateful for the opportunity to clarify points raised on the two FRISC II studies; one invasive and one medical. Two questions concern the validity of the invasive versus non-invasive comparison in the FRISC II trial
based on the lack of complete 180 days follow-up in 24 patients and the difficulty in defining myocardial infarctions at revascularisation procedures. The 6 months results of the FRISC II invasive trial was based on the locked clean file at the codebreak after 6 months follow-up of the FRISC II medical trial. At this moment in the invasive and noninvasive groups, respectively, nine and three patients were prematurely withdrawn from follow-up at their own request, two and five patients had their last follow-up visit before 150 days, and four patients and one patient were lost to follow-up for other reasons. However, in the survival curves all patients were included until the day of their last contact. At 12 months of follow-up, the vital status of all patients had been established. With regard to the composite of death and myocardial infarction, the complete 12 months follow-up shows 10·4% versus 14·1%, (relative risk 0·74 [CI 0·60–0·92], p=0·005), in the invasive and noninvasive groups, respectively. At the moment there is a significant reduction in mortality of 2·2% versus 3·9% (p=0·016) and in myocardial infarction of 8·6% versus 11·6% (p=0·015). Thus, including every patient and regardless of the occurrence and definition of myocardial infarction, the invasive strategy reduces mortality and halves the symptoms and severity of angina and need for readmission. The definite 12-months results will be published shortly. The other two questions raised concern the interpretation of the outcome of the randomised long-term dalteparin treatment in the FRISC II medical trial. From a strictly formal standpoint the FRISC II medical trial did not show efficacy of prolonged dalteparin treatment, because the primary endpoint of death or myocardial infarction was not significantly reduced at 90 days. However, the confidence interval allows a 40% improvement as well as a 10% worsening at this time point. According to the protocol these events were also to be followed over time and to be analysed—ie, after 1 month. The additional analysis at 1 month showed a 47% relative reduction in death or myocardial infarction, which is very unlikely to be haphazard with a 95% confidence interval allowing not less than 20% and even up to 65% decrease in death or myocardial infarction at 30 days. The event curve also supports the argument that this did not occur by chance, because the
573
CORRESPONDENCE
event rates were significantly reduced at 15 days, 30 days, 45 days, and 60 days. The existence of a significant treatment effect was, furthermore, corroborated by the significant 13% relative reduction (p=0·031) in the composite of death, myocardial infarction, or revascularisation at the 3-months primary endpoint. Among the predefined subgroups, the largest difference in efficacy of long-term dalteparin treatment was found between the cohorts with and without raised concentrations of troponin-T at randomisation. Although not reported in the primary publication,1 the reduction in the rates of death and myocardial infarction, which was significant at 30 and 60 days, occurred only in patients with troponin-T elevation, whereas there was no effect in patients without this finding. Similarly, the significant reduction of the triple composite endpoint from 30 days to 90 days was only observed in patients with raised concentrations of troponin-T.2 These results support our previous finding of a protective effect of long-term dalteparin treatment in patients with raised concentrations of troponin-T. 3 As stated in the FRISC II medical trial, there was a raised risk of serious bleeding during the 3 months of continued low-molecular-weight heparin treatment, which was significant and in accordance with the findings of the TIMI-11B 3 and FRAX.I.S trials. 4 However, the bleeding rate was associated with the duration of treatment. Therefore, during a shorter treatment period of 7–30 days, if needed while waiting for revascularisation, the raised risk of bleeding was thought to be compensated for by the reduced risk of cardiac events. After the FRISC II invasive trial it will, for ethical reasons, be difficult to repeat the FRISC II medical trial in high-risk patients within a noninvasive treatment strategy. Therefore, the clinical use of prolonged low-molecular-weight heparin in high-risk patients has to be based on the currently available evidence. The FRISC II trial showed that an invasive strategy with coronary angiography and, if appropriate, revascularisation before hospital discharge reduces death and myocardial infarction in unstable coronary-artery disease with signs of ischaemia on electrocardiogram or by raised biochemical markers. However, with limited resources a certain waiting time for invasive procedures might be unavoidable at many centres. Therefore, the proved efficacy, and
574
relative safety of fixed dose dalteparin for outpatients can be a useful bridgeto-revascularisation during the few weeks time for patients at high risk of cardiac events. Lars Wallentin for the writing committee of the FRISC II trials Departments of Cardiology and Thoracic Surgery, Uppsala University Hospital, S-751 85 Uppsala, Sweden (e-mail: [email protected]) 1
2
3
4
Lindahl B, Diderholm E, Kontny F, et al and the FRISC II study group Long-term treatment with l.m.w. heparin (dalteparin) reduces cardiac events in unstable coronary artery disease with troponin T elevation—a FRISC II substudy (suppl). Circulation 1999; 18: 498. Lindahl B, Venge P, Wallentin L. Troponin T identifies patients with unstable coronary artery disease who benefit from long-term antithrombotic protection. Fragmin in Unstable Coronary Artery Disease (FRISC) Study Group. J Am Coll Cardiol 1997; 29: 43–8. Antman EM, McCabe CH, Gurfinkel EP, et al. Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-Qwave myocardial infarction. Results of the thrombolysis in myocardial infarction (TIMI) 11B trial. Circulation 1999; 100: 1593–601. FRAX.I.S. trialists. Comparison of two treatment durations (6 days and 14 days) of a low molecular weight heparin with a 6-day treatment of unfractionated heparin in the initial management of unstable angina or non-Q wave myocardial infarction. Eur Heart J 1999; 20: 1553–62.
Sir—The FRISC II Investigators1,2 describe the results of a complex but well-designed trial that addresses a number of previously unanswered questions about the management of unstable coronary-artery disease, namely, the relative benefits of medical management with long-term lowmolecular-weight heparin or invasive therapy. There has, until now, been a lack of evidence to support an early revascularisation strategy, and in his commentary,3 J-J Goy concentrates on this aspect of the trial. He does, however, state that invasive and medical management should be complementary rather than competing strategies, and I would like to focus on this point. Unlike the USA and France, where resources are available to carry out early invasive therapy in most patients, resources and facilities are limited in the UK, and it is not uncommon for patients to wait several months for their procedure. A substantial proportion of patients (eg, elderly patients with severe disease or those with previous open heart surgery) are not always appropriate candidates for invasive therapy. For these reasons, the results of the medical side of the study are particularly interesting. As well as
showing the benefit of revascularisation, this study provides evidence that extended (up to 30 days) medical management with dalteparin reduces the risk of death and myocardial infarction to a greater extent than 5–8 day therapy. The continued high risk of cardiac events that occurs for some months after the initial episode accords with these findings, although previous studies do not. In the FRISC II studies, all patients were treated with lowmolecular-weight heparin, dalteparin, and then randomised to continue on active therapy or to be switched to placebo. The primary endpoint of death and myocardial infarction showed a significant reduction of 47% at 30 days with long-term dalteparin compared with acute therapy, with a suggestion that this benefit is extended to about 60 days. In fact, the triple endpoint of death, myocardial infarction, and revascularisation showed a significant benefit at 30 days (24% reduction in risk, p=0·001), with a smaller benefit at 90 days (13% reduction, p=0·031). Furthermore, dalteparin was of particular benefit in patients with ischaemic signs or a raised cardiac marker (troponin T), who were at higher risk of developing subsequent cardiac events. Therefore, although these studies show that high-risk patients with unstable coronary-artery disease do benefit from invasive therapy, the evidence in favour of medical management with low-molecularweight heparin should not be overlooked. Patients receiving dalteparin who were not revascularised early had a lower risk during the first 2 months than patients in the early invasive group. This finding indicates an important role for such agents in bridging therapy while patients are being assessed for revascularisation, or in patients for whom invasive therapy is inappropriate. Alexander T Cohen Department of Medicine, Guy’s, King’s, and St Thomas’ School of Medicine, London SE5 9PJ, UK 1
2
3
FRagmin and Fast Revascularisation during InStability in Coronary artery disease (FRISC II) Investigators. Long-term lowmolecular-mass heparin in unstable coronary-artery disease: FRISC II prospective randomised multicentre study. Lancet 1999; 354: 701–07. FRagmin and Fast Revascularisation during InStability in Coronary artery disease (FRISC II) Investigators. Invasive compared with non-invasive treatment in unstable coronary-artery disease: FRISC II prospective randomised multicentre study. Lancet 1999; 354: 708–15. Goy JJ. Contemporary approach to management of unstable angina. Lancet 1999; 354: 694.
THE LANCET • Vol 355 • February 12, 2000
FRagmin and Fast Revascularisation during InStability in Coronary artery disease (FRISC II) Investigators. Invasive compared with non-invasive treatment in unstable coronary-artery disease. FRISC II prospective randomised multicentre trial. Lancet 1999; 354: 708–15.
Sir—The FRISC II investigators1 have masterfully written the results, of what is truly a failed superiority trial of long-term dalteparin treatment in unstable coronary-artery disease, to selectively emphasise favourable effects and de-emphasise those less favourable. First, according to the primary endpoint, the investigators were unable to show that long-term dalteparin was superior to placebo (p=0·17). Moreover, whatever small benefit that might exist at 3 months had disappeared at 6 months. Selective emphasis on the effect at 1 month seems to be data-derived, and not particularly helpful to a practising clinician because treatment was continued beyond this timepoint. Second, why the investigators placed selective emphasis on the apparent differential effect among patients with and without raised concentrations of troponin-T is not clear. The p value for the troponin-T subgroup was not significant and the upper bound of the 95% CI for relative risk crossed unity in this and all other subgroups. If this was based on the relative risk of 0·7, why was emphasis not placed on the effect of smokers (relative risk 0·48)? Or, if the emphasis was placed on the putative magnitude of the absolute risk reduction (2·7%), why not also emphasise the effect on those with a previous acute myocardial infarction (absolute risk reduction 3·3%)? Perhaps it would be helpful to know whether a statistical test of interaction was done on any of the predefined subgroups. Finally, the impact of dalteparin on bleeding was downplayed. Although the investigators were careful to include tests of significance to support their (positive outcome) views, none were provided in their table 5 (safety during double-blind treatment period). Are not the differences in bleeding risk highly significant? The text comments only on “a raised risk of major bleeding episodes in the dalteparin compared with the placebo group. Minor bleeds were more common in the dalteparin group than in the placebo group”. The conclusions seem excessive when considered in light of the study findings. The investigators were unable to show that long-term
THE LANCET • Vol 355 • February 12, 2000
dalteparin was superior to placebo, and that any small and marginally significant reduction in the risk of death and acute myocardial infarction at 30 days (1·2% absolute) was transient and counterbalanced by a larger and highly significant risk of major bleeds (1·8% absolute). Their contention that dalteparin is only effective in a routine invasive strategy should be contrasted with the ESSENCE and TIMI II trials,2,3 In these studies the short-term use of enoxaparin led to a reduced rate of death and acute myocardial infarction at 43 days (absolute risk reduction 1·5%, relative risk 0·82, p=0·02),3 that persisted at 1 year (ESSENCE), 4 which was accomplished while avoiding the need for revascularisation rather than requiring a routine invasive strategy.4 The net result is that not only is enoxaparin a costeffective strategy in the treatment of acute coronary syndromes, but also that it may lead to cost savings5—a rarity in modern medicine. David Massel Cardiac Care Unit, Division of Cardiology, London Health Sciences Centre, University of Western Ontario, London, Ontario, Canada N6A 4G5 (e-mail: [email protected]) 1
2
3
4
5
FRagmin and Fast Revascularisation during InStability in Coronary artery disease (FRISC II) Investigators. Longterm low-molecular-mass heparin in unstable coronary-artery disease: FRISC II prospective randomised multicentre study. Lancet 1999; 354: 701–07. Cohen M, Demers C, Gurfinkel EP, et al. Comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. N Engl J Med 1997; 337: 447–52. Antman EM, Cohen M, Radley D, et al. Assessment of the treatment effect of enoxaparin for unstable angina/non-Qwave myocardial infarction: TIMI IIBESSENCE meta-analysis. Circulation 1999; 100: 1602–08. Goodman S, Langer A, Demers C, et al. One year follow-up of the ESSENCE trial (enoxaparin vs heparin in unstable angina/non Q wave myocardial infarction): sustained clinical benefit. Can J Cardiol 1998; 14: 122F (abstr). Mark DB, Cowper PA, Berkowitz SD, et al. Economic assessment of low-molecularweight heparin (enoxaparin) versus unfractionated heparin in acute coronary syndrome patients. Results from the ESSENCE randomized trial. Circulation 1998; 97: 1702–07.
Authors’ reply Sir—We are grateful for the opportunity to clarify points raised on the two FRISC II studies; one invasive and one medical. Two questions concern the validity of the invasive versus non-invasive comparison in the FRISC II trial
based on the lack of complete 180 days follow-up in 24 patients and the difficulty in defining myocardial infarctions at revascularisation procedures. The 6 months results of the FRISC II invasive trial was based on the locked clean file at the codebreak after 6 months follow-up of the FRISC II medical trial. At this moment in the invasive and noninvasive groups, respectively, nine and three patients were prematurely withdrawn from follow-up at their own request, two and five patients had their last follow-up visit before 150 days, and four patients and one patient were lost to follow-up for other reasons. However, in the survival curves all patients were included until the day of their last contact. At 12 months of follow-up, the vital status of all patients had been established. With regard to the composite of death and myocardial infarction, the complete 12 months follow-up shows 10·4% versus 14·1%, (relative risk 0·74 [CI 0·60–0·92], p=0·005), in the invasive and noninvasive groups, respectively. At the moment there is a significant reduction in mortality of 2·2% versus 3·9% (p=0·016) and in myocardial infarction of 8·6% versus 11·6% (p=0·015). Thus, including every patient and regardless of the occurrence and definition of myocardial infarction, the invasive strategy reduces mortality and halves the symptoms and severity of angina and need for readmission. The definite 12-months results will be published shortly. The other two questions raised concern the interpretation of the outcome of the randomised long-term dalteparin treatment in the FRISC II medical trial. From a strictly formal standpoint the FRISC II medical trial did not show efficacy of prolonged dalteparin treatment, because the primary endpoint of death or myocardial infarction was not significantly reduced at 90 days. However, the confidence interval allows a 40% improvement as well as a 10% worsening at this time point. According to the protocol these events were also to be followed over time and to be analysed—ie, after 1 month. The additional analysis at 1 month showed a 47% relative reduction in death or myocardial infarction, which is very unlikely to be haphazard with a 95% confidence interval allowing not less than 20% and even up to 65% decrease in death or myocardial infarction at 30 days. The event curve also supports the argument that this did not occur by chance, because the
573
CORRESPONDENCE
event rates were significantly reduced at 15 days, 30 days, 45 days, and 60 days. The existence of a significant treatment effect was, furthermore, corroborated by the significant 13% relative reduction (p=0·031) in the composite of death, myocardial infarction, or revascularisation at the 3-months primary endpoint. Among the predefined subgroups, the largest difference in efficacy of long-term dalteparin treatment was found between the cohorts with and without raised concentrations of troponin-T at randomisation. Although not reported in the primary publication,1 the reduction in the rates of death and myocardial infarction, which was significant at 30 and 60 days, occurred only in patients with troponin-T elevation, whereas there was no effect in patients without this finding. Similarly, the significant reduction of the triple composite endpoint from 30 days to 90 days was only observed in patients with raised concentrations of troponin-T.2 These results support our previous finding of a protective effect of long-term dalteparin treatment in patients with raised concentrations of troponin-T. 3 As stated in the FRISC II medical trial, there was a raised risk of serious bleeding during the 3 months of continued low-molecular-weight heparin treatment, which was significant and in accordance with the findings of the TIMI-11B 3 and FRAX.I.S trials. 4 However, the bleeding rate was associated with the duration of treatment. Therefore, during a shorter treatment period of 7–30 days, if needed while waiting for revascularisation, the raised risk of bleeding was thought to be compensated for by the reduced risk of cardiac events. After the FRISC II invasive trial it will, for ethical reasons, be difficult to repeat the FRISC II medical trial in high-risk patients within a noninvasive treatment strategy. Therefore, the clinical use of prolonged low-molecular-weight heparin in high-risk patients has to be based on the currently available evidence. The FRISC II trial showed that an invasive strategy with coronary angiography and, if appropriate, revascularisation before hospital discharge reduces death and myocardial infarction in unstable coronary-artery disease with signs of ischaemia on electrocardiogram or by raised biochemical markers. However, with limited resources a certain waiting time for invasive procedures might be unavoidable at many centres. Therefore, the proved efficacy, and
574
relative safety of fixed dose dalteparin for outpatients can be a useful bridgeto-revascularisation during the few weeks time for patients at high risk of cardiac events. Lars Wallentin for the writing committee of the FRISC II trials Departments of Cardiology and Thoracic Surgery, Uppsala University Hospital, S-751 85 Uppsala, Sweden (e-mail: [email protected]) 1
2
3
4
Lindahl B, Diderholm E, Kontny F, et al and the FRISC II study group Long-term treatment with l.m.w. heparin (dalteparin) reduces cardiac events in unstable coronary artery disease with troponin T elevation—a FRISC II substudy (suppl). Circulation 1999; 18: 498. Lindahl B, Venge P, Wallentin L. Troponin T identifies patients with unstable coronary artery disease who benefit from long-term antithrombotic protection. Fragmin in Unstable Coronary Artery Disease (FRISC) Study Group. J Am Coll Cardiol 1997; 29: 43–8. Antman EM, McCabe CH, Gurfinkel EP, et al. Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-Qwave myocardial infarction. Results of the thrombolysis in myocardial infarction (TIMI) 11B trial. Circulation 1999; 100: 1593–601. FRAX.I.S. trialists. Comparison of two treatment durations (6 days and 14 days) of a low molecular weight heparin with a 6-day treatment of unfractionated heparin in the initial management of unstable angina or non-Q wave myocardial infarction. Eur Heart J 1999; 20: 1553–62.
Sir—The FRISC II Investigators1,2 describe the results of a complex but well-designed trial that addresses a number of previously unanswered questions about the management of unstable coronary-artery disease, namely, the relative benefits of medical management with long-term lowmolecular-weight heparin or invasive therapy. There has, until now, been a lack of evidence to support an early revascularisation strategy, and in his commentary,3 J-J Goy concentrates on this aspect of the trial. He does, however, state that invasive and medical management should be complementary rather than competing strategies, and I would like to focus on this point. Unlike the USA and France, where resources are available to carry out early invasive therapy in most patients, resources and facilities are limited in the UK, and it is not uncommon for patients to wait several months for their procedure. A substantial proportion of patients (eg, elderly patients with severe disease or those with previous open heart surgery) are not always appropriate candidates for invasive therapy. For these reasons, the results of the medical side of the study are particularly interesting. As well as
showing the benefit of revascularisation, this study provides evidence that extended (up to 30 days) medical management with dalteparin reduces the risk of death and myocardial infarction to a greater extent than 5–8 day therapy. The continued high risk of cardiac events that occurs for some months after the initial episode accords with these findings, although previous studies do not. In the FRISC II studies, all patients were treated with lowmolecular-weight heparin, dalteparin, and then randomised to continue on active therapy or to be switched to placebo. The primary endpoint of death and myocardial infarction showed a significant reduction of 47% at 30 days with long-term dalteparin compared with acute therapy, with a suggestion that this benefit is extended to about 60 days. In fact, the triple endpoint of death, myocardial infarction, and revascularisation showed a significant benefit at 30 days (24% reduction in risk, p=0·001), with a smaller benefit at 90 days (13% reduction, p=0·031). Furthermore, dalteparin was of particular benefit in patients with ischaemic signs or a raised cardiac marker (troponin T), who were at higher risk of developing subsequent cardiac events. Therefore, although these studies show that high-risk patients with unstable coronary-artery disease do benefit from invasive therapy, the evidence in favour of medical management with low-molecularweight heparin should not be overlooked. Patients receiving dalteparin who were not revascularised early had a lower risk during the first 2 months than patients in the early invasive group. This finding indicates an important role for such agents in bridging therapy while patients are being assessed for revascularisation, or in patients for whom invasive therapy is inappropriate. Alexander T Cohen Department of Medicine, Guy’s, King’s, and St Thomas’ School of Medicine, London SE5 9PJ, UK 1
2
3
FRagmin and Fast Revascularisation during InStability in Coronary artery disease (FRISC II) Investigators. Long-term lowmolecular-mass heparin in unstable coronary-artery disease: FRISC II prospective randomised multicentre study. Lancet 1999; 354: 701–07. FRagmin and Fast Revascularisation during InStability in Coronary artery disease (FRISC II) Investigators. Invasive compared with non-invasive treatment in unstable coronary-artery disease: FRISC II prospective randomised multicentre study. Lancet 1999; 354: 708–15. Goy JJ. Contemporary approach to management of unstable angina. Lancet 1999; 354: 694.
THE LANCET • Vol 355 • February 12, 2000