- Email: [email protected]
GUSTO V: the bottom line of fibrinolytic reperfusion therapy
COMMENTARY
COMMENTARY
GUSTO V: the bottom line of fibrinolytic reperfusion therapy See page 1905 Two of the largest advances in the treatment of acute myocardial infarction have been the coronary care unit, which provides continuous monitoring of the electrocardiogram and rapid defibrillation, and reperfusion therapy. Either a fibrinolytic drug or angioplasty (with or without stenting) can be used as the first procedure to establish reperfusion. The greatest benefit occurs with the shortest time to obtain complete reperfusion (Thrombolysis in Myocardial Infarction [TIMI] flowgrade 3). Most of the delay is in the time patients take to seek medical care, and this factor does not seem to be influenced by public information campaigns.1 About 75% of patients treated by primary angioplasty attain TIMI-3 flow 100 min after admission to hospital,2 whereas only 50–55% of patients treated with alteplase have TIMI-3 flow at 90 min—and this proportion does not substantially improve over the subsequent hours.3 Some of the delay in starting thrombolytic treatment can be reduced by giving the drug before admission. However, angioplasty seems to be the most successful reperfusion method, but its use is restricted by logistical issues. Thus, the search is on for improving reperfusion with fibrinolytic agents. Several drugs that could provide additional benefit to thrombolytic therapy have been investigated. The addition of heparin has not improved early patency rates or prevented reocclusion,4 and has increased the frequency of bleeding, particularly cerebral bleeding.
Compared with the addition of heparin to thrombolytic therapy, hirudin, a direct inhibitor of thrombin, provided only a marginal decrease in mortality but a similar increased frequency of bleeding. Aspirin, in addition to streptokinase,5 decreased mortality and has shown the benefit of inhibiting platelet aggregation. Antagonists to the glycoprotein IIb/IIIa receptor, such as abciximab, eptifibatide, or tirofiban, block the final common pathway of platelet aggregation. These drugs, given intravenously, have significantly improved the outcome of elective coronary angioplasty. The combination of a fibrinolytic agent and a glycoprotein blocker, such as abciximab, has been extensively evaluated in dose-finding and dose-confirming studies. The addition of full-dose abciximab to half-dose alteplase6 or to half-dose reteplase7 resulted in nearly 80% of patients achieving complete reperfusion at 90 min without a substantial increase in side-effects. Not only was patency improved, but electrocardiographic signs of tissue reperfusion were also significantly better with the combination. The combination needed to be tested in a phase III trial with mortality as an endpoint. In today’s Lancet the results from GUSTO V relay both good news and bad news. The good news is the report of the lowest 30-day mortality (less than 6%) ever observed in a megatrial with a fibrinolytic agent. The bad news is that the concept of an improvement in early patency rates leading to a decrease in mortality was not confirmed. This link had previously been shown in
Characteristics and outcome of patients in the GUSTO and ASSENT-2 fibrinolytic megatrials* Year of publication Patients (n)
GUSTO I8 1993 41 021
GUSTO IIb9 1996 4131
GUSTO III10 1997 15 059
ASSENT-211 1999 16 949
GUSTO V 2001 16 588
Clinical Age (years) Age over 75 (%) Women (%) Diabetes (%) Hypertension (%) Current smokers (%) Anterior infarction (%)
62 12 25 15 n/a 43 39
63 n/a 24 16 40 41 n/a
63 14 27 16 39 41 48
61 13 23 16 n/a 44 40
61 14 25 16 34 45 37
Time to treatment (h)
2·8
Drugs post-randomisation -blockade (%) ACE inhibitors (%)
n/a n/a
Death within 30 days (%)
7·2
n/a 73 39 6·1
2·7 n/a n/a 7·3
2·8 81 54 6·2
3·0 77 57 5·7
*Data from references 8—11. ACE=angiotensin-converting enzyme. n/a=data not available.
1898
THE LANCET • Vol 357 • June 16, 2001
COMMENTARY
several other megatrials of reperfusion therapy in acute myocardial infarction, of which GUSTO I3 is the most convincing. One explanation for this discrepancy could be that the use of adjunctive therapy, such as inhibitors of angiotensin-converting enzyme, is more important than a survival advantage bestowed by an improvement in patency rates. Time to treatment and patient characteristics, as reported in fibrinolytic megatrials, have changed little in the past 8 years (panel); only the proportion of anterior myocardial infarction seems to be decreasing. The GUSTO V investigators may have opted for primary angioplasty in these high-risk patients who, therefore, were ineligible for the trial. The abciximab group could show a higher long-term survival than the reteplase-only group, but this seems unlikely since in nearly all fibrinolytic megatrials most of the benefit is seen early. Therefore, in GUSTO V the bottom-line in current fibrinolytic reperfusion therapy seems to have been reached and speeding up early reperfusion with drugs does not seem worthwhile. Of course, the results of the much smaller ASSENT-3 trial, in which abciximab and half-dose tenecteplase/tissue-plasminogen activator (2000 patients) is compared with full-dose tenecteplase/ tissue-plasminogen activator (4000 patients), will be of interest. Further improvement in fibrinolytic therapy may come from other agents not directly aimed at early patency—ie, from anticoagulants preventing reocclusion, or from drugs that decrease reperfusion injury or inflammation. The alternative to pharmacological reperfusion is coronary angioplasty, which achieves similar patency rates to the combination of a fibrinolytic and abciximab. But angioplasty also modifies the culprit lesion and the decrease in stenosis may contribute to a lower reocclusion rate.12 The time to reperfusion with angioplasty, however, will always be longer than with fibrinolytic therapy. Therefore, medical treatment preangioplasty is likely to improve the results of primary angioplasty. So far, the best angiographic results have been achieved with half-dose bolus alteplase,13 but a combination of half-dose fibrinolytic agent with a glycoprotein blocker before primary angioplasty may be even more helpful. This approach is being investigated in the CADILLAC-2 and FINESSE trials. The results in today’s report from GUSTO V do not show the outcome of the small subgroup of patients who underwent early (within 6 h) percutaneous coronary intervention. Such a subgroup analysis may well generate hypotheses worthy of further study. What may future management of myocardial infarction with ST-elevation involve? Probably early medical treatment with a bolus of a fibrinolytic, or a combination of a fibrinolytic and a glycoprotein blocker—followed immediately by angioplasty. Freek W A Verheugt Division of Cardiology, Heartcenter, University Medical Center St Radboud, 6525 Nijmegen, Netherlands (e-mail: [email protected]) 1
2 3
4
Lupker RV, Raczynski JM, Osganian S, et al. Effect of a community intervention in patient delay and emergency medical service use in acute coronary heart disease: the Rapid Early Action for Coronary Treatment (REACT). JAMA 2000; 284: 60–67. White HD. Future of reperfusion therapy for acute myocardial infarction. Lancet 1999; 354: 695–96. GUSTO Angiographic Investigators. The effects of tissue plasminogen activator, streptokinase, or both on coronary-artery patency, ventricular function, and survival after acute myocardial infarction. N Engl J Med 1993; 329: 1615–22. Verheugt FWA, Meijer A, Lagrand WK, Van Eenige MJ.
THE LANCET • Vol 357 • June 16, 2001
5
6
7 8
9
10 11
12
13
Reocclusion, the flipside of coronary thrombolysis. J Am Coll Cardiol 1996; 27: 766–73. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group). Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988; 2: 349–60. Antman EM, Giugliano RP, Gibson CM, et al. Abciximab facilitates the rate and extent of thrombolysis: results of the thrombolysis in myocardial infarction-14 (TIMI-14) trial. Circulation 1999; 99: 2720–32. SPEED. Trial of abciximab with and without low-dose reteplase for acute myocardial infarction. Circulation 2000; 101: 2788–94. GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993; 329: 673–82. GUSTO-IIb Investigators. A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes. N Engl J Med 1996; 335: 775–82. GUSTO-III Investigators. A comparison of reteplase with alteplase for acute myocardial infarction. N Engl J Med 1997; 337: 1118–23. ASSENT-2 Steering Committee. Single bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the ASSENT-2 randomised trial. Lancet 1999; 354: 1716–22. Veen G, De Boer MJ, Zijlstra F, Verheugt FWA. Improvement in 3 months angiographic outcome suggested after primary angioplasty for acute myocardial infarction (Zwolle trial) compared with successful thrombolysis (APRICOT trial). Am J Cardiol 1999; 84: 763–67. Ross AM, Coyne KS, Reiner JS, et al. A randomized trial comparing primary angioplasty with a strategy of short-acting thrombolysis and immediate planned rescue angioplasty in acute myocardial infarction: the PACT trial. J Am Coll Cardiol 1999; 34: 1954–62.
Glycoprotein IIb/IIIa receptor blockers in acute coronary syndromes: Gusto IV-ACS See page 1915 Maarten Simoons and colleagues are to be congratulated for carrying out an excellent randomised controlled trial, reported in today’s Lancet, testing the efficacy of a glycoprotein IIb/IIIa inhibitor among patients with an acute coronary syndrome (ACS) not undergoing early revascularisation. An ACS was defined as chest pain and either ST-segment depression or a positive troponin T or I test. In addition to receiving aspirin and unfractionated or low-molecular-weight heparin, patients were randomly assigned placebo, a bolus of abciximab and a 24 h infusion, or bolus of abciximab and a 48 h infusion. The groups did not differ in the frequency of death and myocardial infarction at 30 days (the primary endpoint). Subgroup analysis showed that a raised troponin concentration, and several other variables, could identify patients at increased risk of subsequent events. But even in these high-risk subgroups, there was no decrease in mortality or morbidity with abciximab. These results seem counterintuitive in that they challenge the dogma that intracoronary thrombosis is the root evil in ACS, and measures to prevent platelet aggregation must be beneficial. The results are also at variance with those from other large randomised trials of glycoprotein IIb/IIIa inhibitors in this patient population. Simoons and colleagues,1 and others,2,3 have previously shown that there is angiographic resolution of intracoronary thrombus in patients receiving abciximab for 18–24 h. So why was there no benefit from abciximab when given as first-line medical therapy in ACS? None of the explanations offered by the investigators are satisfying. One explanation could be that with this dose and duration of abciximab, a waning of the antithrombotic effect may have occurred in some patients with high-grade coronary stenoses. Kereiakes and coworkers4 observed that during a continuous infusion of abciximab there was large variation in the inhibition of 1899
COMMENTARY
GUSTO V: the bottom line of fibrinolytic reperfusion therapy See page 1905 Two of the largest advances in the treatment of acute myocardial infarction have been the coronary care unit, which provides continuous monitoring of the electrocardiogram and rapid defibrillation, and reperfusion therapy. Either a fibrinolytic drug or angioplasty (with or without stenting) can be used as the first procedure to establish reperfusion. The greatest benefit occurs with the shortest time to obtain complete reperfusion (Thrombolysis in Myocardial Infarction [TIMI] flowgrade 3). Most of the delay is in the time patients take to seek medical care, and this factor does not seem to be influenced by public information campaigns.1 About 75% of patients treated by primary angioplasty attain TIMI-3 flow 100 min after admission to hospital,2 whereas only 50–55% of patients treated with alteplase have TIMI-3 flow at 90 min—and this proportion does not substantially improve over the subsequent hours.3 Some of the delay in starting thrombolytic treatment can be reduced by giving the drug before admission. However, angioplasty seems to be the most successful reperfusion method, but its use is restricted by logistical issues. Thus, the search is on for improving reperfusion with fibrinolytic agents. Several drugs that could provide additional benefit to thrombolytic therapy have been investigated. The addition of heparin has not improved early patency rates or prevented reocclusion,4 and has increased the frequency of bleeding, particularly cerebral bleeding.
Compared with the addition of heparin to thrombolytic therapy, hirudin, a direct inhibitor of thrombin, provided only a marginal decrease in mortality but a similar increased frequency of bleeding. Aspirin, in addition to streptokinase,5 decreased mortality and has shown the benefit of inhibiting platelet aggregation. Antagonists to the glycoprotein IIb/IIIa receptor, such as abciximab, eptifibatide, or tirofiban, block the final common pathway of platelet aggregation. These drugs, given intravenously, have significantly improved the outcome of elective coronary angioplasty. The combination of a fibrinolytic agent and a glycoprotein blocker, such as abciximab, has been extensively evaluated in dose-finding and dose-confirming studies. The addition of full-dose abciximab to half-dose alteplase6 or to half-dose reteplase7 resulted in nearly 80% of patients achieving complete reperfusion at 90 min without a substantial increase in side-effects. Not only was patency improved, but electrocardiographic signs of tissue reperfusion were also significantly better with the combination. The combination needed to be tested in a phase III trial with mortality as an endpoint. In today’s Lancet the results from GUSTO V relay both good news and bad news. The good news is the report of the lowest 30-day mortality (less than 6%) ever observed in a megatrial with a fibrinolytic agent. The bad news is that the concept of an improvement in early patency rates leading to a decrease in mortality was not confirmed. This link had previously been shown in
Characteristics and outcome of patients in the GUSTO and ASSENT-2 fibrinolytic megatrials* Year of publication Patients (n)
GUSTO I8 1993 41 021
GUSTO IIb9 1996 4131
GUSTO III10 1997 15 059
ASSENT-211 1999 16 949
GUSTO V 2001 16 588
Clinical Age (years) Age over 75 (%) Women (%) Diabetes (%) Hypertension (%) Current smokers (%) Anterior infarction (%)
62 12 25 15 n/a 43 39
63 n/a 24 16 40 41 n/a
63 14 27 16 39 41 48
61 13 23 16 n/a 44 40
61 14 25 16 34 45 37
Time to treatment (h)
2·8
Drugs post-randomisation -blockade (%) ACE inhibitors (%)
n/a n/a
Death within 30 days (%)
7·2
n/a 73 39 6·1
2·7 n/a n/a 7·3
2·8 81 54 6·2
3·0 77 57 5·7
*Data from references 8—11. ACE=angiotensin-converting enzyme. n/a=data not available.
1898
THE LANCET • Vol 357 • June 16, 2001
COMMENTARY
several other megatrials of reperfusion therapy in acute myocardial infarction, of which GUSTO I3 is the most convincing. One explanation for this discrepancy could be that the use of adjunctive therapy, such as inhibitors of angiotensin-converting enzyme, is more important than a survival advantage bestowed by an improvement in patency rates. Time to treatment and patient characteristics, as reported in fibrinolytic megatrials, have changed little in the past 8 years (panel); only the proportion of anterior myocardial infarction seems to be decreasing. The GUSTO V investigators may have opted for primary angioplasty in these high-risk patients who, therefore, were ineligible for the trial. The abciximab group could show a higher long-term survival than the reteplase-only group, but this seems unlikely since in nearly all fibrinolytic megatrials most of the benefit is seen early. Therefore, in GUSTO V the bottom-line in current fibrinolytic reperfusion therapy seems to have been reached and speeding up early reperfusion with drugs does not seem worthwhile. Of course, the results of the much smaller ASSENT-3 trial, in which abciximab and half-dose tenecteplase/tissue-plasminogen activator (2000 patients) is compared with full-dose tenecteplase/ tissue-plasminogen activator (4000 patients), will be of interest. Further improvement in fibrinolytic therapy may come from other agents not directly aimed at early patency—ie, from anticoagulants preventing reocclusion, or from drugs that decrease reperfusion injury or inflammation. The alternative to pharmacological reperfusion is coronary angioplasty, which achieves similar patency rates to the combination of a fibrinolytic and abciximab. But angioplasty also modifies the culprit lesion and the decrease in stenosis may contribute to a lower reocclusion rate.12 The time to reperfusion with angioplasty, however, will always be longer than with fibrinolytic therapy. Therefore, medical treatment preangioplasty is likely to improve the results of primary angioplasty. So far, the best angiographic results have been achieved with half-dose bolus alteplase,13 but a combination of half-dose fibrinolytic agent with a glycoprotein blocker before primary angioplasty may be even more helpful. This approach is being investigated in the CADILLAC-2 and FINESSE trials. The results in today’s report from GUSTO V do not show the outcome of the small subgroup of patients who underwent early (within 6 h) percutaneous coronary intervention. Such a subgroup analysis may well generate hypotheses worthy of further study. What may future management of myocardial infarction with ST-elevation involve? Probably early medical treatment with a bolus of a fibrinolytic, or a combination of a fibrinolytic and a glycoprotein blocker—followed immediately by angioplasty. Freek W A Verheugt Division of Cardiology, Heartcenter, University Medical Center St Radboud, 6525 Nijmegen, Netherlands (e-mail: [email protected]) 1
2 3
4
Lupker RV, Raczynski JM, Osganian S, et al. Effect of a community intervention in patient delay and emergency medical service use in acute coronary heart disease: the Rapid Early Action for Coronary Treatment (REACT). JAMA 2000; 284: 60–67. White HD. Future of reperfusion therapy for acute myocardial infarction. Lancet 1999; 354: 695–96. GUSTO Angiographic Investigators. The effects of tissue plasminogen activator, streptokinase, or both on coronary-artery patency, ventricular function, and survival after acute myocardial infarction. N Engl J Med 1993; 329: 1615–22. Verheugt FWA, Meijer A, Lagrand WK, Van Eenige MJ.
THE LANCET • Vol 357 • June 16, 2001
5
6
7 8
9
10 11
12
13
Reocclusion, the flipside of coronary thrombolysis. J Am Coll Cardiol 1996; 27: 766–73. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group). Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988; 2: 349–60. Antman EM, Giugliano RP, Gibson CM, et al. Abciximab facilitates the rate and extent of thrombolysis: results of the thrombolysis in myocardial infarction-14 (TIMI-14) trial. Circulation 1999; 99: 2720–32. SPEED. Trial of abciximab with and without low-dose reteplase for acute myocardial infarction. Circulation 2000; 101: 2788–94. GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993; 329: 673–82. GUSTO-IIb Investigators. A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes. N Engl J Med 1996; 335: 775–82. GUSTO-III Investigators. A comparison of reteplase with alteplase for acute myocardial infarction. N Engl J Med 1997; 337: 1118–23. ASSENT-2 Steering Committee. Single bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the ASSENT-2 randomised trial. Lancet 1999; 354: 1716–22. Veen G, De Boer MJ, Zijlstra F, Verheugt FWA. Improvement in 3 months angiographic outcome suggested after primary angioplasty for acute myocardial infarction (Zwolle trial) compared with successful thrombolysis (APRICOT trial). Am J Cardiol 1999; 84: 763–67. Ross AM, Coyne KS, Reiner JS, et al. A randomized trial comparing primary angioplasty with a strategy of short-acting thrombolysis and immediate planned rescue angioplasty in acute myocardial infarction: the PACT trial. J Am Coll Cardiol 1999; 34: 1954–62.
Glycoprotein IIb/IIIa receptor blockers in acute coronary syndromes: Gusto IV-ACS See page 1915 Maarten Simoons and colleagues are to be congratulated for carrying out an excellent randomised controlled trial, reported in today’s Lancet, testing the efficacy of a glycoprotein IIb/IIIa inhibitor among patients with an acute coronary syndrome (ACS) not undergoing early revascularisation. An ACS was defined as chest pain and either ST-segment depression or a positive troponin T or I test. In addition to receiving aspirin and unfractionated or low-molecular-weight heparin, patients were randomly assigned placebo, a bolus of abciximab and a 24 h infusion, or bolus of abciximab and a 48 h infusion. The groups did not differ in the frequency of death and myocardial infarction at 30 days (the primary endpoint). Subgroup analysis showed that a raised troponin concentration, and several other variables, could identify patients at increased risk of subsequent events. But even in these high-risk subgroups, there was no decrease in mortality or morbidity with abciximab. These results seem counterintuitive in that they challenge the dogma that intracoronary thrombosis is the root evil in ACS, and measures to prevent platelet aggregation must be beneficial. The results are also at variance with those from other large randomised trials of glycoprotein IIb/IIIa inhibitors in this patient population. Simoons and colleagues,1 and others,2,3 have previously shown that there is angiographic resolution of intracoronary thrombus in patients receiving abciximab for 18–24 h. So why was there no benefit from abciximab when given as first-line medical therapy in ACS? None of the explanations offered by the investigators are satisfying. One explanation could be that with this dose and duration of abciximab, a waning of the antithrombotic effect may have occurred in some patients with high-grade coronary stenoses. Kereiakes and coworkers4 observed that during a continuous infusion of abciximab there was large variation in the inhibition of 1899