Future of reperfusion therapy for acute myocardial infarction

Despite these findings, it has become more and more evident over the past 10 years that conservative and invasive management strategies are complementary rather than competing and ought to be tailored to the needs of the patient and the resources of the treatment centre. I recommend coronary angiography and, if appropriate, a revascularisation procedure for every patient admitted with an acute coronary syndrome.The FRISC II invasivemanagement trial validates the use of stents and antiplatelet agents with percutaneous procedures. In centres without facilities for revascularisation, risk stratification might help identify those patients who require urgent referral to a tertiary institution and those for whom the procedure can be delayed. Patients awaiting angiography can be effectively treated with subcutaneous heparin and antiplatelet and antianginal agents. Finally, angioplasty of the culprit lesion and delayed, complete surgical revascularisation should be considered for patients with unstable angina refractory to conservative treatment and who have multivessel disease, to minimise the risk of urgent coronary artery bypass grafting. J-J Goy Department of Cardiology, University Hospital, 1003 Lausanne, Switzerland 1 2 3

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Chierchia S. Current therapeutic strategies in unstable angina. Eur Heart J 1999; 1 (suppl N): 2–6. Théroux P, Lidon RM. Unstable angina:pathogenesis, diagnosis and treatment. Curr Probl Cardiol 1993; 18: 159–214. PRISM PLUS Study Investigators. Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q-wave infarction. N Engl J Med 1998; 338: 1488–97. Oler S, Whooley MA, Oler J, Grady D. Adding heparin to aspirin reduces the incidence of myocardial infarction and death in patients with unstable angina. JAMA 1996; 276: 811–15. Fragmin during Instability in Coronary Artery Disease (FRISC) study group. Low-molecular-weight heparin during instability in coronary artery disease. Lancet 1996; 347: 561–68. Hamm CW, Ravkilde J, Gerhardt W, et al. The prognostic value of serum troponin T in unstable angina. N Engl J Med 1992; 327: 146–50. The TIMI IIIB Investigators. Effects of tissue plasminogen activator and a comparison of early invasive and conservative strategies in unstable angina and non-Q-wave myocardial infarction. Circulation 1994; 89: 1545–56. The OASIS Registry Investigators. Variations between countries in invasive cardiac procedures and outcomes in patients with suspected unstable angina or myocardial infarction without initial ST elevation. Lancet 1998; 352: 507–14. Boden WE, O’Rourke RA, Crawford MH, et al. Outcomes in patients wtih acute non-Q-wave MI randomly assigned to an invasive as compared with a conservative management strategy. Veterans Affairs Non-Q-Wave Infarction Strategies in Hospital (VANQWISH) Trial Investigators. N Engl J Med 1998; 338: 1785–92.

Future of reperfusion therapy for acute myocardial infarction See page 716

The goal of reperfusion therapy is to achieve early and sustained full antegrade flow in the infarct-related artery (graded by the Thrombolysis in Myocardial Infarction investigators as TIMI-3) in as many patients as possible. However, in only half of all patients given fibrinolytic therapy is TIMI-3 flow reached, and up to a quarter of these have reocclusion, or intermittent patency, or both.1 In addition, in a quarter of those with angiographic evidence of epicardial blood flow, there is no reperfusion at the myocyte level.2 In the TIMI-14 study, however, TIMI-3 flow was obtained in the epicardial infarctrelated artery in 77% (95%CI 67–85) of eligible patients 90 min after start of the fibrinolytic regimen.3 This

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finding swings the battle for supremacy among the different reperfusion strategies in favour of fibrinolytic therapy as opposed to primary angioplasty. The TIMI-14 regimen consisted of half the standard dose of alteplase (tissue plasminogen activator), a low dose of intravenous heparin, abciximab, and aspirin. 65% of patients had TIMI-3 flow at 60 min. These findings are significant since only 54% (48–59) of patients given alteplase in the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO)-I study had TIMI-3 flow at 90 min,4 and since angioplasty commonly takes longer than an hour and a half to complete. Much of the inefficacy of other fibrinolytic regimens can be attributed to the lack of a platelet-directed approach, because plasminogen activator inhibitor 1 (PAI-1), secreted by platelets, is resistant to fibrinolytic therapy, and because fibrinolytic agents promote platelet aggregation. The importance of antiplatelet therapy was shown in the Second International Study of Infarct Survival (ISIS-2), in which aspirin reduced mortality by 20% at 35 days.5 There are over 100 known agonists of platelet activation. Glycoprotein IIb/IIIa receptor antagonists, such as abciximab, block the activated platelet-surface receptors that bind to fibrinogen, thereby inhibiting the final common pathway for platelet aggregation. In GUSTO-III, the 30-day mortality rate was the same with reteplase, which is given as a double bolus, as it was with alteplase.6 This finding was unexpected since TIMI-3 flow rates have been shown to be higher with reteplase than with alteplase (60% vs 45%) at 90 min,7 but may be due to the fact that reteplase activates platelets more than alteplase does, so epicardial blood flow at 90 min might not have translated into adequate nutritional myocyte blood flow. This concept is supported by a small study that showed greater platelet aggregation and receptor expression with reteplase than with alteplase.8 Primary angioplasty has the distinct advantage of lower bleeding rates than fibrinolytic therapy and, until now, was thought to produce higher TIMI-3 flow rates (73% in a core laboratory in GUSTO-IIb9 and 89% in recent trials10). Short-term follow-up studies have shown that primary angioplasty produces better clinical outcomes than does fibrinolytic therapy,11 but many of the fibrinolytic regimens used have since been superseded, and they were started later than is now thought optimum. In addition, primary angioplasty was done sooner than it might be in usual clinical practice because ready availability of a catheterisation laboratory was a prerequisite for the studies. Data from community registries of cases in which fibrinolytic infusions were started earlier, and primary angioplasty later, than in clinical trials show that fibrinolytic therapy was associated with lower mortality and lower costs than was angioplasty.11 In the GUSTO-IIb angioplasty substudy, the composite endpoint of death, reinfarction, or disabling stroke within 30 days was 13·7% with accelerated infusion of alteplase and 9·6% with primary angioplasty (p=0·03). By 6 months the difference was no longer significant (16·1% with alteplase and 14·1% with angioplasty).9 Although angioplasty improves TIMI-3 flow rates substantially, improvements in outcomes have, 695

surprisingly, not been more striking, probably because of logistic delays before reperfusion (figure), but perhaps also partly because of impairment of microvascular perfusion by platelet microemboli. Stenting reduces the need for repeat angioplasty, but it does not improve TIMI-3 flow rates or reduce mortality.10 Rescue angioplasty after fibrinolytic therapy has not been associated with improved outcomes, perhaps because fibrinolytic agents activate platelets, and platelet plugging prevents reflow in the microvasculature.12 Adjunctive therapy with glycoprotein IIb/IIIa antagonists may enhance the safety and clinical outcome of rescue angioplasty. In TIMI-14, TIMI-3 flow was reached in 32% (18–50) of patients who received abciximab alone. In the Glycoprotein Receptor Antagonist Patency Evaluation (GRAPE) pilot study, abciximab was given in the emergency room, and it produced TIMI-3 flow in only 18% (9–28) of patients.13 On its own, abciximab is therefore insufficient for optimum reperfusion. Streptokinase plus full-dose abciximab was associated with unacceptable bleeding rates in TIMI-14,3 perhaps because of the reduction in fibrinogen concentrations and generation of fibrin-degradation products. Reperfusion with streptokinase may be better improved by the addition of a direct thrombin inhibitor such as bivalirudin (Hirulog),14 and this combination may carry a lower risk of intracranial haemorrhage than do other fibrinolytic regimens.15 New fibrinolytics agents that have been developed to improve the efficacy of clot lysis and to enable bolus administration include tenecteplase, a mutant of native tissue plasminogen activator with lower plasma clearance, more fibrin specificity, and resistance to PAI-1. In the Assessment of the Safety and Efficacy of a New Thrombolytic Agent (ASSENT)-2 trial reported in today’s Lancet, the 30-day mortality rates with alteplase (6·15%) and tenecteplase (6·18%) were similar, but 696

major bleeding (requiring transfusion or other intervention or both, and including bleeding occurring with bypass surgery) was significantly lower with tenecteplase (4·68% vs 5·94%, p<0·01). Lanoteplase (n-PA), a deletion mutant of tissue plasminogen activator, was tested in the Intravenous n-PA for Treating Infarcting Myocardium Early (InTIME-II) trial. The 30day mortality rates with alteplase (6·60%) and lanoteplase (6·77%) were similar, and the rates of major bleeding (excluding intracranial haemorrhage) were the same (0·6%).16 Both of these agents have the advantage over alteplase of bolus administration, and therefore could easily be given in the community. The disadvantage of fibrinolytic therapy is the risk of stroke. In ASSENT-2, the stroke rates were 1·78% (intracranial haemorrhage 0·9%) with tenecteplase and 1·66% (intracranial haemorrhage 0·9%) with alteplase. In InTIME-II, they were 1·9% (intracranial haemorrhage 1·13%) with lanoteplase and 1·5% (intracranial haemorrhage 0·62%) with alteplase (p<0·01). In TIMI-14, the intracranial haemorrhage rate with alteplase plus abciximab was 1·9% (0·5–7·4).3 These rates have increased in association with the inclusion of higher-risk patients and better ascertainment of strokes, and are now bordering on the unacceptable. Strategies that lower this risk, especially for groups such as low-weight patients, women, and elderly people, should be investigated. One option might be to reduce or omit the bolus of adjunctive heparin, since heparin increases the risk of bleeding without improving TIMI flow rates, and since its major benefit is in preventing reocclusion. However, some heparin does seem necessary, because in TIMI-14 there was a trend towards a reduction in the percentage of patients with TIMI-3 flow rates (69% [56–79]) when the dose of heparin was reduced to a bolus of 30 IU/kg and an hourly infusion of 4 IU/kg.3 Promising developments on the horizon include fibrinolytic agents such as polyethylene glycolated staphylokinase and amideplase, which is a hybrid of alteplase and prourokinase, and adjunctive therapies such as clopidogrel, platelet adhesion molecule antagonists, complement inhibitors, and antiinflammatory agents. There are also trials evaluating lowmolecular-weight heparins, direct thrombin inhibitors, and various fibrinolytic agents with adjunctive use of IIb/IIIa receptor antagonists such as abciximab, tirofiban, and eptifibatide. A reperfusion strategy combining a fibrinolytic regimen with angioplasty might produce the best outcome.17 The optimum strategy might include early administration of aspirin, bolus fibrinolytic therapy (perhaps in the community), glycoprotein IIb/IIIa inhibitors, and a direct thrombin inhibitor such as bivalirudin, with measurement of myocardial proteins18 or non-invasive monitoring to identify failure of reperfusion.19 Lack of ST-segment resolution on a 12lead electrocardiogram at 60 min could identify candidates for angiography and rescue stenting if TIMI-3 flow is not present. Transfer of patients to a hospital with cardiac-catheterisation facilities is feasible in many places. Alternatively, angiography could be done at 60–90 min, with rescue stenting for the 10–20% of patients who do not have TIMI-3 flow. The newer fibrinolytic agents have not been shown to be any more effective than nature’s own fibrinolytic

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agent, tissue plasminogen activator. The combination of a fibrinolytic agent with a glycoprotein IIb/IIIa receptor antagonist is an important advance in the management of acute myocardial infarction. Whether this strategy offers cost savings remains to be seen. Another strategy aimed at improving the efficacy of streptokinase fibrinolysis with a low-rate of intracranial haemorrhage and without substantially increasing costs is being tested in the Hirulog Early Reperfusion/Occlusion (HERO)-2 trial. Primary angioplasty may have a major role in the future as techniques and adjunctive treatments are improved. However, its application is unlikely to become widespread because of its lack of availability and delays in the “time to balloon”. The ideal strategy might be a combination of a fibrinolytic regimen given in the community with transfer of some patients for rescue angioplasty. I was an investigator in ASSENT-2.

Harvey D White Cardiology Department, Green Lane Hospital, Auckland 1003, New Zealand 1

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White HD, Van de Werf FJJ. Clinical cardiology: new frontiers: thrombolysis for acute myocardial infarction. Circulation 1998; 97: 1632–46. Ito H, Tomooka T, Sakai N, et al. Lack of myocardial perfusion immediately after successful thrombolysis. Circulation 1992; 85: 1699–705. Antman EM, Giugliano RP, Gibson CM, et al. Abciximab facilitates the rate and extent of thrombolysis: results of the Thrombolysis in Myocardial Infarction (TIMI) 14 trial. Circulation 1999; 99: 2720–32. The 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, and 330: 516. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspiri n ,b o t h , or neither among 17 187 cases of suspected acute myocardial infa r c t i o n :I S I S - 2 . Lancet 1 9 8 8 ;i i :3 4 9 – 6 0 . The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO III) Investigators. A comparison of reteplase with alteplase for acute myocardial infarction. N Engl J Med 1997; 337: 1118–23. Bode C, Smalling RW, Berg G, et al. Randomized comparison of coronary thrombolysis achieved with double-bolus reteplase (recombinant plasminogen activator) and front-loaded, accelerated alteplase (recombinant tissue plasminogen activator) in patients with acute myocardial infarction. Circulation 1996; 94: 891–98. Gurbel PA ,S e r e b ru a ny V L ,S h u s t ov AR, et al. Effects of reteplase and alteplase on platelet aggregation and major receptor expression during the first 24 hours of acute myocardial infarction treatment. J Am Coll Cardiol 1998; 31: 1466–73. The Global Use of Strategies to Open Occluded Coronary A rt e ri e s in Acute Coronary Syndromes (GUSTO IIb) Angioplasty Substudy Investigators. A clinical trial comparing primary coronary angioplasty with tissue plasminogen activator for acute myocardial infarction. N Engl J Med 1997; 336: 1621–28. Ferguson JJ. Meeting highlights, 47th Annual Scientific Sessions of the American College of Cardiology: coronary stenting: STENT PAMI [presented by Grines C]. Circulation 1998; 97: 2378–79. Weaver WD, Simes RJ, Betriu A, et al. Comparison of primary coronary angioplasty and intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review. JAMA 1997; 278: 2093–98. Simoons ML, Arnold A E R ,B e rt riu A ,a l . Thrombolysis with tissue plasminogen activator in acute myocardial infarction: no additional benefit from immediate percutaneous coronary angioplasty. Lancet 1 9 8 8 ;i :1 9 7 – 2 0 3 . van den Merkhof LFM, Zijlstra F, Olsson H, et al. Abciximab in the treatment of acute myocardial infarction eligible for primary percutaneous transluminal coronary angioplasty: results of the Glycoprotein Receptor Antagonist Patency Evaluation (GRAPE) pilot study. J Am Coll Cardiol 1999; 33: 1528–32. White HD, Aylward PE, Frey MJ, et al. Randomized,double-blind comparison of hirulog versus heparin in patients receiving

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streptokinase and aspirin for acute myocardial infarction (HERO). Circulation 1997; 96: 2155–61. Kong D, Topol EJ, Bittl JA, et al. Clinical outcomes of bivalirudin for ischemic heart disease. Circulation (in press). Neuhaus K-L. A phase three trial of novel bolus thrombolytic lanoteplase (nPA ) :i n t r avenous nPA for treatment of infarcting myocardium early (Intime-II). Presented at the 48th Annual Scientific Sessions of the American College of Cardiology, New Orleans, March 1999. Ferguson JJ. Meeting highlights, 47th Annual Scientific Sessions of the American College of Cardiology: acute coronary syndromes: PACT [presented by Ross A]. Circulation 1998; 97: 2377. Stewart JT, French JK, Théroux P, et al. Early noninvasive identification of failed reperfusion after intravenous thrombolytic therapy in acute myocardial infarction. J Am Coll Cardiol 1998; 31: 1499–505. Schroder R, Dissmann R, Bruggemann T, et al. Extent of early ST segment elevation resolution: a simple but strong predictor of outcome in patients with acute myocardial infarction. J Am Coll Cardiol 1994; 24: 384–91.

Transmission of drug-resistant strains of HIV-1: unfortunate, but inevitable See page 729

The US Food and Drug Administration has licensed 15 antiretroviral drugs for the treatment of HIV-1 infection, 11 of these in the past 3·5 years. How best to use these agents is a complex issue, although guidelines developed by expert panels have been extremely helpful.1,2 Combinations of these drugs are capable of profound suppression of HIV-1 replication for long periods and have been referred to as highly active antiretroviral therapy (HAART). Among patients with access to HAART, HIV-1-related morbidity and mortality have declined sharply.3 However, despite these favourable results and initial enthusiasm about possible eradication of HIV-1 infection, HAART has created its own unique set of challenges. In this issue of The Lancet, S Yerly and colleagues assessed the prevalence of antiretroviral-drug-resistant HIV-1 variants among 82 patients with confirmed primary HIV-1 infection who were seen at the Geneva AIDS Centre between January, 1996, and July, 1998. Eight (10%) of these patients were infected with HIV-1 variants harbouring mutations that are associated with resistance to nucleoside-analogue reverse-transcriptase inhibitors. Alarmingly, 4% of patients were infected with HIV-1 variants harbouring primary genotypic and phenotypic resistance to protease inhibitors, which became available in 1995. One patient had acute HIV-1 infection after unprotected sex with an infected partner who had been treated with multiple antiretroviral agents from all available drug classes. Virus isolated from the plasma before seroconversion contained 12 mutations associated with resistance to nucleoside analogues and protease inhibitors. As in a previously reported patient,4 this patient had a poor virological response to combination antiretroviral therapy. A central issue that is raised by the data of Yerly and colleagues has less to do with resistance and more to do with transmission. Despite the striking declines in morbidity and mortality associated with the introduction of HAART, the incidence of HIV-1 infections in the USA has been steady at 40 000 per year for the past 9 years. Indeed, a misperception regarding the seriousness of HIV-1 infection in the era of HAART has contributed to an increase in high-risk sexual behaviour among some people.5 The transmission of drug-resistant strains of HIV-1 underscores the importance of intensifying 697