Primary angioplasty should be first line treatment for acute myocardial infarction
http://www.100md.com
《英国医生杂志》
Royal Hallamshire Hospital, Sheffield S10 2JF kevin.channer@sth.nhs.uk
The UK government is considering establishing a national primary angioplasty service for patients with acute myocardial infarction. David Smith and Kevin Channer debate whether moving away from first line thrombolysis is appropriate or practical
Thrombolysis is the established treatment for patients with an acute ST segment elevation myocardial infarction based on large trials in the past two decades.1 Studies show that treatment within an hour after onset of symptoms results in a 6.5% absolute reduction in mortality compared with placebo; this benefit falls quickly with time to 3.7% at 1-2 hours, 2.6% at 2-3 hours, 2.9% at 3-6 hours, 1.8% at 6-12 hours, and 0.9% at 12-24 hours.2 However, thrombolysis also causes an absolute increase in stroke of 0.4% (half of which are fatal), an absolute increase of 0.7% in major non-cerebral bleeds, and a 3% increase in early non-fatal reinfarction.1
Although thrombolysis saves lives in hospital, it has no later benefits; the survival curves of patients given placebo or thrombolysis exactly superimpose after 35 days, or even after discharge from hospital.3 4 The mechanism for the reduction in hospital mortality is unclear since all causes of death are reduced. It is not accounted for by a reduction in infarct size because this effect is small (6% at 4 days and only 2% at 10-28 days),5 and a reduction in infarct size would confer a long term survival advantage, which is not seen.
Implementing policy
Hospital mortality from acute myocardial infarction has been falling,6 but the contribution made by thrombolysis is difficult to ascertain.7 The National Service Framework for Coronary Heart Disease focused on the need to give thrombolysis quickly. This led to targets for treatment of within 60 minutes of an emergency call and within 30 minutes of arrival in hospital by April 2002 (reducing to 20 minutes by April 2003).8 Trusts have changed their models of care to achieve this target. Changes include prehospital thrombolysis by ambulance paramedics (which trials show give a 2% absolute reduction in mortality9), rapid triage of patients admitted with chest pain, and administration by nurses rather than doctors. For the first time in the United Kingdom, a national strategy for the implementation of data from randomised controlled trials is beginning to show results.10
Evidence for angioplasty is weak
Any fundamental change in management of ST elevation myocardial infarction must be driven by significant improvements in outcome. Patients with a patent, infarct related artery have a better prognosis than those with persistently occluded arteries. Large randomised trials comparing different thrombolytic drugs with differing early patency rates showed no mortality benefit from patency.11 12 If a difference in patency were important, then a difference in long term prognosis would have been expected, but this has not been seen.3 4 The move to primary angioplasty is driven by the holy grail of infarct related artery patency but the evidence that it affects hospital mortality is limited.
Comparative trials between primary angioplasty and thrombolysis have recruited only patients eligible for thrombolysis. All have been selective and have typically recruited only a minority of eligible, usually younger, patients. A recent meta-analysis of over 7000 patients showed an absolute 2% improvement in mortality for patients having angioplasty13; fewer patients had early non-fatal reinfarction, recurrent ischaemia, and strokes.
The earlier studies were mainly done in centres of excellence, but a large Danish study could be used as a model for implementation in the United Kingdom.14 In this study, patients were transferred from district general hospitals to regional centres for primary angioplasty; there was no significant mortality benefit compared with on-site thrombolysis, and the only benefits were in recurrent ischaemia requiring intervention and reinfarction. Although these events have been argued to affect survival, early placebo controlled thrombolysis trials showed that the increase in reinfarction after thrombolysis was not associated with increased early or late mortality. Moreover, the Danish study did not count reinfarction after angioplasty, further biasing against thrombolysis. Thus, the only relevant comparator for the two treatment strategies is all cause mortality, which was not reduced by angioplasty in the study.14
Of more importance for the United Kingdom, interventionalists in the United States have been unable to replicate the trial results, and registry data recording the results of primary angioplasty in practice show less benefit than expected from the trials. This is explained by the delays incumbent in this approach, which requires clinical evaluation in the emergency room and then transfer to a cardiac catheterisation laboratory, coronary angiography, and angioplasty. The average time delay in 661 centres was 1 hour 56 minutes, with more than half of patients waiting over two hours before balloon inflation, which was associated with an increase in mortality of 41-62%.15 A meta-analysis of published randomised trials shows that when the time delay related to angiography (that is the door to balloon minus the door to needle time) exceeds 60 minutes, the mortality benefits of primary angioplasty over thrombolysis are lost (figure).16 For every 10 minute delay, there is a 1% reduction in the composite end point of death, reinfarction, or stroke, so that by 90 minutes there is no measurable difference between primary angioplasty and immediate thrombolysis.
Absolute risk reduction in 4-6 week mortality (top) and combined end point of death, reinfarction, or stroke after primary angioplasty as a function of angiography related time delay (door to balloon minus door to needle time).13 Circle sizes reflect sample size of individual study; values >0 represent benefit; values <0 represent harm; solid line=weighted meta-regression. Adapted from Boersma et al9
Practical issues
Thrombolysis took decades to become established as the standard, and in the United Kingdom structural changes to the way patients are managed have been driven by the results of the many randomised controlled trials showing the benefits of this treatment. To provide a national service for primary angioplasty for patients with acute myocardial infarction demands a big increase in cardiac catheter facilities and staff. Treatment would need to be delivered by consultants because it requires a high level of training and experience, and consultants are in short supply. None of the regional centres has sufficient numbers to provide a 24 hour primary angioplasty service. The result will be patchy implementation and confusion among general physicians, who continue to supervise the management of most patients admitted with myocardial infarction. Thrombolysis will be delayed while negotiations with cardiologists about the most appropriate therapy take place.
The reality will be postcode primary angioplasty offered to those lucky patients who present to regional centres during the day. In other cases the benefits of early reperfusion by thrombolysis will be reduced.
Conclusion
The importance of time to reperfusion in reducing mortality cannot be overestimated. However, the absolute effect depends on when delays occur in the natural course of infarction. It is right to emphasise earlier thrombolysis because this has been shown to deliver larger mortality benefits. The benefits of angioplasty over thrombolysis are too small in patients presenting early not to be offset by the delays that occur with this approach. The same or bigger benefit would be achieved by prehospital thrombolysis.—Kevin S Channer
Contributors and sources: For 15 years I have supervised the care of patients on a coronary care unit and have overseen the rationalisation and standardisation of the treatment of acute myocardial infarction. We introduced the first chest pain specialist nurse in the region in my centre and have some of the best door to needle times. Part of my research has been in implementation strategies for evidence based medicine.
Competing interests: None declared.
References
Fibrinolytic Therapy Trialists' (FTT) Collaborative Group. Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients. Lancet 1994;343: 311-22.
Boersma E, Maas ACP, Deckers JW, Simoons ML. Early thrombolytic treatment in acute myocardial infarction: reappraisal of the golden hour. Lancet 1996;348: 771-75.
Franzosi MG, Santoro E, De Vita C, Geraci E, Lotto A, Maggioni AP, et al. Ten year follow up of the first megatrial testing thrombolytic therapy in patients with acute myocardial infarction. Results of the GISSI-1 study. Circulation 1998;98: 2659-65.
Baigent C, Collins R, Appleby P, Parish S, Sleight P, Peto R. ISIS-2: 10 year survival among patients with suspected acute myocardial infarction in randomised comparison of intravenous streptokinase, oral aspirin, both or neither. BMJ 1998;316: 1337-43.
Granger CB, White HD, Bates ER, Ohman EM, Califf RM. A pooled analysis of coronary arterial patency and left ventricular function after intravenous thrombolysis for acute myocardial infarction. Am J Cardiol 1994;74: 1220-8.
Capewell S, Livingston BM, MacIntyre K, Chalmers JW, Boyd J, Finlayson A et al. Trends in case-fatality in 117 718 patients admitted with acute myocardial infarction in Scotland. Eur Heart J 2000;21: 1833-40.
Brown N, Young T, Gray D, Skene AM, Hampton J. Inpatient deaths from acute myocardial infarction, 1982-92: analysis of data in the Nottingham heart attack register. BMJ 1997;315: 159-64.
Department of Health. National service framework for coronary heart disease. London: DoH, 2000. www.nelh.nhs.uk/nsf/chd/nsf/main/mainreport.htm (accessed 26 Apr 2004).
Boersma E. Pre-hospital fibrinolytic therapy. In: Verheught FWA, ed. Fibrinolytic therapy in clinical practice. New York: Martin Dunitz, 2003: 111-30.
Royal College of Physicians. Myocardial infarction national audit project. www.rcplondon.ac.uk/college/ceeu/ceeu_ami_home.htm (accessed 26 April 2004).
Gruppo Italiano per lo Studio della Sopravivenza nell'infarcto Miocardico. GISSI-2: a factorial randomised trial of alteplase versus streptokinase and heparin versus no heparin among 12490 patients with acute myocardial infarction. Lancet 1990;336: 65-71.
Third International Study of Infarct Survival Collaborative Group. ISIS-3: a randomised comparison of streptokinase vs tissue plasminogen activator vs anistreplase and of aspirin plus heparin vs aspirin alone among 41299 cases of suspected acute myocardial infarction. Lancet 1992;339: 753-70.
Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet 2003;361: 13-20.
Andersen HR, Nielsen TT, Rasmussen K, Thuesen L, Kelbaek H, Thayssen P, et al. A comparison of coronary angioplasty with fibrinolytic therapy in acute myocardial infarction. N Engl J Med 2003;349: 733-42.
Cannon CP, Gibson CM, Lambrew CT, Shoultz DA, Levy D, French WJ, et al. Relationship of symptom-onset-to-balloon time and door-to-balloon time with mortality in patients undergoing angioplasty for acute myocardial infarction. JAMA 2000;283: 2941-7.
Nallamothu BK, Bates ER. Percutaneous coronary intervention versus fibrinolytic therapy in acute myocardial infarction: is timing (almost) everything? Am J Cardiol 2003;92: 824-6.(Kevin S Channer, consulta)
The UK government is considering establishing a national primary angioplasty service for patients with acute myocardial infarction. David Smith and Kevin Channer debate whether moving away from first line thrombolysis is appropriate or practical
Thrombolysis is the established treatment for patients with an acute ST segment elevation myocardial infarction based on large trials in the past two decades.1 Studies show that treatment within an hour after onset of symptoms results in a 6.5% absolute reduction in mortality compared with placebo; this benefit falls quickly with time to 3.7% at 1-2 hours, 2.6% at 2-3 hours, 2.9% at 3-6 hours, 1.8% at 6-12 hours, and 0.9% at 12-24 hours.2 However, thrombolysis also causes an absolute increase in stroke of 0.4% (half of which are fatal), an absolute increase of 0.7% in major non-cerebral bleeds, and a 3% increase in early non-fatal reinfarction.1
Although thrombolysis saves lives in hospital, it has no later benefits; the survival curves of patients given placebo or thrombolysis exactly superimpose after 35 days, or even after discharge from hospital.3 4 The mechanism for the reduction in hospital mortality is unclear since all causes of death are reduced. It is not accounted for by a reduction in infarct size because this effect is small (6% at 4 days and only 2% at 10-28 days),5 and a reduction in infarct size would confer a long term survival advantage, which is not seen.
Implementing policy
Hospital mortality from acute myocardial infarction has been falling,6 but the contribution made by thrombolysis is difficult to ascertain.7 The National Service Framework for Coronary Heart Disease focused on the need to give thrombolysis quickly. This led to targets for treatment of within 60 minutes of an emergency call and within 30 minutes of arrival in hospital by April 2002 (reducing to 20 minutes by April 2003).8 Trusts have changed their models of care to achieve this target. Changes include prehospital thrombolysis by ambulance paramedics (which trials show give a 2% absolute reduction in mortality9), rapid triage of patients admitted with chest pain, and administration by nurses rather than doctors. For the first time in the United Kingdom, a national strategy for the implementation of data from randomised controlled trials is beginning to show results.10
Evidence for angioplasty is weak
Any fundamental change in management of ST elevation myocardial infarction must be driven by significant improvements in outcome. Patients with a patent, infarct related artery have a better prognosis than those with persistently occluded arteries. Large randomised trials comparing different thrombolytic drugs with differing early patency rates showed no mortality benefit from patency.11 12 If a difference in patency were important, then a difference in long term prognosis would have been expected, but this has not been seen.3 4 The move to primary angioplasty is driven by the holy grail of infarct related artery patency but the evidence that it affects hospital mortality is limited.
Comparative trials between primary angioplasty and thrombolysis have recruited only patients eligible for thrombolysis. All have been selective and have typically recruited only a minority of eligible, usually younger, patients. A recent meta-analysis of over 7000 patients showed an absolute 2% improvement in mortality for patients having angioplasty13; fewer patients had early non-fatal reinfarction, recurrent ischaemia, and strokes.
The earlier studies were mainly done in centres of excellence, but a large Danish study could be used as a model for implementation in the United Kingdom.14 In this study, patients were transferred from district general hospitals to regional centres for primary angioplasty; there was no significant mortality benefit compared with on-site thrombolysis, and the only benefits were in recurrent ischaemia requiring intervention and reinfarction. Although these events have been argued to affect survival, early placebo controlled thrombolysis trials showed that the increase in reinfarction after thrombolysis was not associated with increased early or late mortality. Moreover, the Danish study did not count reinfarction after angioplasty, further biasing against thrombolysis. Thus, the only relevant comparator for the two treatment strategies is all cause mortality, which was not reduced by angioplasty in the study.14
Of more importance for the United Kingdom, interventionalists in the United States have been unable to replicate the trial results, and registry data recording the results of primary angioplasty in practice show less benefit than expected from the trials. This is explained by the delays incumbent in this approach, which requires clinical evaluation in the emergency room and then transfer to a cardiac catheterisation laboratory, coronary angiography, and angioplasty. The average time delay in 661 centres was 1 hour 56 minutes, with more than half of patients waiting over two hours before balloon inflation, which was associated with an increase in mortality of 41-62%.15 A meta-analysis of published randomised trials shows that when the time delay related to angiography (that is the door to balloon minus the door to needle time) exceeds 60 minutes, the mortality benefits of primary angioplasty over thrombolysis are lost (figure).16 For every 10 minute delay, there is a 1% reduction in the composite end point of death, reinfarction, or stroke, so that by 90 minutes there is no measurable difference between primary angioplasty and immediate thrombolysis.
Absolute risk reduction in 4-6 week mortality (top) and combined end point of death, reinfarction, or stroke after primary angioplasty as a function of angiography related time delay (door to balloon minus door to needle time).13 Circle sizes reflect sample size of individual study; values >0 represent benefit; values <0 represent harm; solid line=weighted meta-regression. Adapted from Boersma et al9
Practical issues
Thrombolysis took decades to become established as the standard, and in the United Kingdom structural changes to the way patients are managed have been driven by the results of the many randomised controlled trials showing the benefits of this treatment. To provide a national service for primary angioplasty for patients with acute myocardial infarction demands a big increase in cardiac catheter facilities and staff. Treatment would need to be delivered by consultants because it requires a high level of training and experience, and consultants are in short supply. None of the regional centres has sufficient numbers to provide a 24 hour primary angioplasty service. The result will be patchy implementation and confusion among general physicians, who continue to supervise the management of most patients admitted with myocardial infarction. Thrombolysis will be delayed while negotiations with cardiologists about the most appropriate therapy take place.
The reality will be postcode primary angioplasty offered to those lucky patients who present to regional centres during the day. In other cases the benefits of early reperfusion by thrombolysis will be reduced.
Conclusion
The importance of time to reperfusion in reducing mortality cannot be overestimated. However, the absolute effect depends on when delays occur in the natural course of infarction. It is right to emphasise earlier thrombolysis because this has been shown to deliver larger mortality benefits. The benefits of angioplasty over thrombolysis are too small in patients presenting early not to be offset by the delays that occur with this approach. The same or bigger benefit would be achieved by prehospital thrombolysis.—Kevin S Channer
Contributors and sources: For 15 years I have supervised the care of patients on a coronary care unit and have overseen the rationalisation and standardisation of the treatment of acute myocardial infarction. We introduced the first chest pain specialist nurse in the region in my centre and have some of the best door to needle times. Part of my research has been in implementation strategies for evidence based medicine.
Competing interests: None declared.
References
Fibrinolytic Therapy Trialists' (FTT) Collaborative Group. Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients. Lancet 1994;343: 311-22.
Boersma E, Maas ACP, Deckers JW, Simoons ML. Early thrombolytic treatment in acute myocardial infarction: reappraisal of the golden hour. Lancet 1996;348: 771-75.
Franzosi MG, Santoro E, De Vita C, Geraci E, Lotto A, Maggioni AP, et al. Ten year follow up of the first megatrial testing thrombolytic therapy in patients with acute myocardial infarction. Results of the GISSI-1 study. Circulation 1998;98: 2659-65.
Baigent C, Collins R, Appleby P, Parish S, Sleight P, Peto R. ISIS-2: 10 year survival among patients with suspected acute myocardial infarction in randomised comparison of intravenous streptokinase, oral aspirin, both or neither. BMJ 1998;316: 1337-43.
Granger CB, White HD, Bates ER, Ohman EM, Califf RM. A pooled analysis of coronary arterial patency and left ventricular function after intravenous thrombolysis for acute myocardial infarction. Am J Cardiol 1994;74: 1220-8.
Capewell S, Livingston BM, MacIntyre K, Chalmers JW, Boyd J, Finlayson A et al. Trends in case-fatality in 117 718 patients admitted with acute myocardial infarction in Scotland. Eur Heart J 2000;21: 1833-40.
Brown N, Young T, Gray D, Skene AM, Hampton J. Inpatient deaths from acute myocardial infarction, 1982-92: analysis of data in the Nottingham heart attack register. BMJ 1997;315: 159-64.
Department of Health. National service framework for coronary heart disease. London: DoH, 2000. www.nelh.nhs.uk/nsf/chd/nsf/main/mainreport.htm (accessed 26 Apr 2004).
Boersma E. Pre-hospital fibrinolytic therapy. In: Verheught FWA, ed. Fibrinolytic therapy in clinical practice. New York: Martin Dunitz, 2003: 111-30.
Royal College of Physicians. Myocardial infarction national audit project. www.rcplondon.ac.uk/college/ceeu/ceeu_ami_home.htm (accessed 26 April 2004).
Gruppo Italiano per lo Studio della Sopravivenza nell'infarcto Miocardico. GISSI-2: a factorial randomised trial of alteplase versus streptokinase and heparin versus no heparin among 12490 patients with acute myocardial infarction. Lancet 1990;336: 65-71.
Third International Study of Infarct Survival Collaborative Group. ISIS-3: a randomised comparison of streptokinase vs tissue plasminogen activator vs anistreplase and of aspirin plus heparin vs aspirin alone among 41299 cases of suspected acute myocardial infarction. Lancet 1992;339: 753-70.
Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet 2003;361: 13-20.
Andersen HR, Nielsen TT, Rasmussen K, Thuesen L, Kelbaek H, Thayssen P, et al. A comparison of coronary angioplasty with fibrinolytic therapy in acute myocardial infarction. N Engl J Med 2003;349: 733-42.
Cannon CP, Gibson CM, Lambrew CT, Shoultz DA, Levy D, French WJ, et al. Relationship of symptom-onset-to-balloon time and door-to-balloon time with mortality in patients undergoing angioplasty for acute myocardial infarction. JAMA 2000;283: 2941-7.
Nallamothu BK, Bates ER. Percutaneous coronary intervention versus fibrinolytic therapy in acute myocardial infarction: is timing (almost) everything? Am J Cardiol 2003;92: 824-6.(Kevin S Channer, consulta)