© 1990 S. Karger AG, Basel 0301 -0147/90/0207-0132S2.75/0
Haemostasis 1990;20(suppl 1): 132-141
Heparin and Secondary Prevention of Acute Myocardial Infarction A. Lotto, A. Colombo, G. Talarico, G. Fratianni, M. Lettino Cardiology Department, Ospedale Maggiore Policlinico, Milan, Italy
Key Words. Myocardial infarction, secondary prevention • Heparin
Introduction Postinfarction is commonly considered to begin at hospital discharge (usually within 2-3 weeks after admission) after an acute myocardial infarction (AMI). The early years following AMI are bur dened by a very high death rate. Among AMI patients who survive the 1st week, the mean mortality rate is 15% (range 2-50%, depend ing on the presence of several risk factors) and falls to 3-4%/year thereafter [1].
The identification of AMI patients with increased mortality and morbidity risk is based on the observtion of heart failure, residual inducible ischaemia, or severe ven tricular arrhythmias. Hence, subjects can be classified into three different prognostic groups: (1) ‘low-risk’ patients who experi enced an uncomplicated AMI and neither showed left ventricular failure during the acute phase of the disease nor presented an gina thereafter have a very good prognosis, with a death rate of 2% at 1-year follow-up
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 2/25/2018 5:04:59 PM
Abstract. Patients surviving acute myocardial infarction (AMI) may experience several clinical events (reinfarction, congestive heart failure, sudden death) still responsible for high mortality rates. AMI early complicated by residual angina, left ventricular dysfunction, or malignant arrhythmias has a worse prognosis. Secondary prevention of myocardial infarc tion and death has been the end point of many clinical trials in the past two decades. It is well known that beta blockers prevent sudden death if administered chronically after AMI. Meta analysis of controlled randomized trials demonstrated a significant reduction in reinfarction and vascular death with long-term antiplatelet treatment. Oral anticoagulants prevent fatal and non-fatal reinfarction and show a trend towards lower mortality rates, though treated patients have a higher incidence of haemorrhagic events, particularly stroke. Early adminis tration of heparin gave contradictory results on short-term prevention of myocardial infarc tion and death after AMI. Data on long-term heparin therapy point out a significant reduc tion in recurrent AMI and a trend towards a decrease in general mortality.
Heparin and Prevention of Acute Myocardial Infarction
often responsible for rhythm disturbances (beta blockers, calcium-heparin, antiplatelet agents).
Beta-Blockers Several randomized placebo-controlled clinical trials were carried out with different beta blockers during the postinfarction pe riod [7], and the larger ones demonstrated that beta blockade significantly lowers car diovascular morbidity and mortality [8-11], Among them, the International Study of In farct Survival [12] (ISIS I, 16,027 patients enrolled) reported a 27% reduction in early mortality (p < 0.04), using atenolol during the first 7 days after AMI. Patients on ateno lol maintained a 10% reduction of mortality at 1-year follow-up, even if they never as sumed the drug after hospital discharge. The early reinfarction rate in treated patients was higher than in the control group, although the difference was not statistically significant [ 12].
It is well known that beta blockers have a favourable influence on cardiovascular postinfarction morbidity and mortality if ad ministered within 4 months after AMI, pref erably 1-4 weeks after the ischaemic event [13], A still better cardioprotection is ob tained if beta blockers are administered to patients with ventricular arrhythmias dur ing the acute phase of AMI or with a com plicated myocardial infarction [6, 7], Agents with the least intrinsic sympathomimetic activity seem to bring about the greater ben efit [6]. Finally, when administered to patients older than 65 years, beta blockers often pro duce greater advantages than in younger people [14, 15].
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 2/25/2018 5:04:59 PM
[2]; patients in whom AMI is complicated by moderate (2) to severe (3) impairment of left ventricular function have a 1-year mortality rate of 10-25% [2]. Recurrent infarction is a major cause of death during the post-AMI period. Reinfarc tion can also induce either malignant ar rhythmias or heart failure which are lifethreatening to the patients. Norris et al. [3] examined 325 patients during a mean follow-up period of 42 months, when thrombolytic therapy was not in common use, and reported a reinfarction rate of 12% (40/325), with a 20% incidence of fatal AMI. On the other hand, the overall in-hospital reinfarction rate among patients random ized in the GISSI I study (n = 11,806) was 3%, and a further 3% incidence of AMI was observed at 1-year follow-up [4, 5]. During the past two decades secondary prevention of myocardial infarction and death has been the major aim of many clini cal trials. Good results have been obtained suppressing or controlling the most common cardiovascular risk factors present before the beginning of the disease (cigarette smoking, hypercholesterolaemia, hypertension, and oral contraceptives) [6], Pharmacological prevention has been proposed both during the acute phase of AMI and during the postinfarction period. In the first case, the major aim of therapy has been to obtain coronary thrombus lysis (thrombolytic therapy), to prevent further ischaemic attacks (heparin, heparin plus as pirin), or, at least, to reduce the size of infarction (thrombolytic or beta-blocking agents) and the risk of malignant arrhyth mias (beta blockers). Postinfarction therapy has been addressed to the prevention of ma jor arrhythmias and new ischaemic events,
133
Antiplatelet Drugs The experimental evidence of pharmaco logical inhibition of platelet activity her alded the era of controlled clinical trials on antiplatelet drugs in coronary artery disease two decades ago. After the first promising results by Elwood et al. [16] and the Coronary Drug Pro ject Research Group [17], the large study performed by the Aspirin Myocardial Infarc tion Study Research Group [18] (4,524 pa tients randomized to either ASA or placebo) unexpectedly found more vascular deaths among treated than among control patients. Many other ASA trials have been reported since then, and in each case the results were in favour of antiplatelet drugs, although sta tistical significance was achieved in none. Sulphinpyrazone trials provided contra dictory results. A significant reduction of re current non-fatal myocardial infarction was seen in the Anturan Reinfarction Italian Study [19], but not in the larger ART (1,620 randomized patients); moreover the signifi cant prevention in sudden death observed in the ART study has been challenged and re fused by a later FDA analysis [20]. Again, the Canadian Cooperative Study Group [21] and the trial by Cairns et al. [22] demon strated that ASA could prevent ischaemic events, while sulphinpyrazone could not, and that the ASA plus sulphinpyrazone com bination did not add any benefit to ASA alone. This applies well to dipyridamole in that a direct comparison between ASA and ASA plus dipyridamole in the study by the Persantine-Aspirin Reinfarction Study Re search Group [23] yielded no different re duction in vascular events after a mean fol low-up period of 3 years. The other notice
Lotto/Colombo/Talarico/Fratianni/Lettino
able study of ASA versus ASA plus dipyrida mole - American-Canadian Cooperative Study Group [24] -, which analyzed new vascular events in patients recovering from a transient ischaemic attack, gave similar re sults. We previously stated that none of the many reported studies of antiplatelet drugs in the secondary prevention of AMI was able to reach statistically significant reductions in proposed end points. The statistical group of the Oxford University [25] recently con ducted a careful reanalysis of all relevant, controlled, randomized trials of long-term antiplatelet drugs in the secondary pre vention of vascular disease. Among them, ten studies enrolled patients who had pre viously suffered AMI [16-19, 23, 26-30], Cumulative analysis of different trials was made possible by calculating the observed minus the expected number of typical events (i.e., vascular death, recurrent myocardial infarction) in the actively treated group alone. This calculation tends to give a nega tive result whenever treatment actually ex erts a protective effect. The approach ac counts for differences among different stud ies with respect to patient selection, defini tion of what constituted a myocardial infarc tion or vascular death, and many other er rors in the determination of who suffered a vascular event and who did not. All that is assumed is that the study faults were largely random among the trials, thereby avoiding any substantial bias in overall analysis. Based on this assumption, the meta-analysis showed a global favourable effect of long term antiplatelet treatment in the secondary prevention of AMI (table 1). In a total ran domized population of more than 18,000 patients followed for a mean duration of 3 years, a statistically significant 31 % reduc-
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 2/25/2018 5:04:59 PM
134
Heparin and Prevention of Acute Myocardial Infarction
135
Table 1. Non-fatal myocardial infarction in trials of antiplatelet drugs [from ref. 25] Study
AMIS Paris II Paris I Cardiff II ART CDP-A GDR Cardiff I Aris Gamis All trials
Reference No.
18 26 23 46 28 17 29 46 19 30
Basic data
Statistical data3
randomized patients
follow-up period, years
0 -E b
4,524 3,128 2,026 1,682 1,620 1,529 1,340 1,239 727 626
3 2 3-4 1 1-3 2 2 1 1-7 2
-19.9 -19.9 -7.9 -15.5 -3.3 -1.7 -14.1 -1.4 -9.1 -2.7
NS NS NS NS NS NS NS NS
Haemostasis 1990;20(suppl 1): 132-141
Heparin and Secondary Prevention of Acute Myocardial Infarction A. Lotto, A. Colombo, G. Talarico, G. Fratianni, M. Lettino Cardiology Department, Ospedale Maggiore Policlinico, Milan, Italy
Key Words. Myocardial infarction, secondary prevention • Heparin
Introduction Postinfarction is commonly considered to begin at hospital discharge (usually within 2-3 weeks after admission) after an acute myocardial infarction (AMI). The early years following AMI are bur dened by a very high death rate. Among AMI patients who survive the 1st week, the mean mortality rate is 15% (range 2-50%, depend ing on the presence of several risk factors) and falls to 3-4%/year thereafter [1].
The identification of AMI patients with increased mortality and morbidity risk is based on the observtion of heart failure, residual inducible ischaemia, or severe ven tricular arrhythmias. Hence, subjects can be classified into three different prognostic groups: (1) ‘low-risk’ patients who experi enced an uncomplicated AMI and neither showed left ventricular failure during the acute phase of the disease nor presented an gina thereafter have a very good prognosis, with a death rate of 2% at 1-year follow-up
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 2/25/2018 5:04:59 PM
Abstract. Patients surviving acute myocardial infarction (AMI) may experience several clinical events (reinfarction, congestive heart failure, sudden death) still responsible for high mortality rates. AMI early complicated by residual angina, left ventricular dysfunction, or malignant arrhythmias has a worse prognosis. Secondary prevention of myocardial infarc tion and death has been the end point of many clinical trials in the past two decades. It is well known that beta blockers prevent sudden death if administered chronically after AMI. Meta analysis of controlled randomized trials demonstrated a significant reduction in reinfarction and vascular death with long-term antiplatelet treatment. Oral anticoagulants prevent fatal and non-fatal reinfarction and show a trend towards lower mortality rates, though treated patients have a higher incidence of haemorrhagic events, particularly stroke. Early adminis tration of heparin gave contradictory results on short-term prevention of myocardial infarc tion and death after AMI. Data on long-term heparin therapy point out a significant reduc tion in recurrent AMI and a trend towards a decrease in general mortality.
Heparin and Prevention of Acute Myocardial Infarction
often responsible for rhythm disturbances (beta blockers, calcium-heparin, antiplatelet agents).
Beta-Blockers Several randomized placebo-controlled clinical trials were carried out with different beta blockers during the postinfarction pe riod [7], and the larger ones demonstrated that beta blockade significantly lowers car diovascular morbidity and mortality [8-11], Among them, the International Study of In farct Survival [12] (ISIS I, 16,027 patients enrolled) reported a 27% reduction in early mortality (p < 0.04), using atenolol during the first 7 days after AMI. Patients on ateno lol maintained a 10% reduction of mortality at 1-year follow-up, even if they never as sumed the drug after hospital discharge. The early reinfarction rate in treated patients was higher than in the control group, although the difference was not statistically significant [ 12].
It is well known that beta blockers have a favourable influence on cardiovascular postinfarction morbidity and mortality if ad ministered within 4 months after AMI, pref erably 1-4 weeks after the ischaemic event [13], A still better cardioprotection is ob tained if beta blockers are administered to patients with ventricular arrhythmias dur ing the acute phase of AMI or with a com plicated myocardial infarction [6, 7], Agents with the least intrinsic sympathomimetic activity seem to bring about the greater ben efit [6]. Finally, when administered to patients older than 65 years, beta blockers often pro duce greater advantages than in younger people [14, 15].
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 2/25/2018 5:04:59 PM
[2]; patients in whom AMI is complicated by moderate (2) to severe (3) impairment of left ventricular function have a 1-year mortality rate of 10-25% [2]. Recurrent infarction is a major cause of death during the post-AMI period. Reinfarc tion can also induce either malignant ar rhythmias or heart failure which are lifethreatening to the patients. Norris et al. [3] examined 325 patients during a mean follow-up period of 42 months, when thrombolytic therapy was not in common use, and reported a reinfarction rate of 12% (40/325), with a 20% incidence of fatal AMI. On the other hand, the overall in-hospital reinfarction rate among patients random ized in the GISSI I study (n = 11,806) was 3%, and a further 3% incidence of AMI was observed at 1-year follow-up [4, 5]. During the past two decades secondary prevention of myocardial infarction and death has been the major aim of many clini cal trials. Good results have been obtained suppressing or controlling the most common cardiovascular risk factors present before the beginning of the disease (cigarette smoking, hypercholesterolaemia, hypertension, and oral contraceptives) [6], Pharmacological prevention has been proposed both during the acute phase of AMI and during the postinfarction period. In the first case, the major aim of therapy has been to obtain coronary thrombus lysis (thrombolytic therapy), to prevent further ischaemic attacks (heparin, heparin plus as pirin), or, at least, to reduce the size of infarction (thrombolytic or beta-blocking agents) and the risk of malignant arrhyth mias (beta blockers). Postinfarction therapy has been addressed to the prevention of ma jor arrhythmias and new ischaemic events,
133
Antiplatelet Drugs The experimental evidence of pharmaco logical inhibition of platelet activity her alded the era of controlled clinical trials on antiplatelet drugs in coronary artery disease two decades ago. After the first promising results by Elwood et al. [16] and the Coronary Drug Pro ject Research Group [17], the large study performed by the Aspirin Myocardial Infarc tion Study Research Group [18] (4,524 pa tients randomized to either ASA or placebo) unexpectedly found more vascular deaths among treated than among control patients. Many other ASA trials have been reported since then, and in each case the results were in favour of antiplatelet drugs, although sta tistical significance was achieved in none. Sulphinpyrazone trials provided contra dictory results. A significant reduction of re current non-fatal myocardial infarction was seen in the Anturan Reinfarction Italian Study [19], but not in the larger ART (1,620 randomized patients); moreover the signifi cant prevention in sudden death observed in the ART study has been challenged and re fused by a later FDA analysis [20]. Again, the Canadian Cooperative Study Group [21] and the trial by Cairns et al. [22] demon strated that ASA could prevent ischaemic events, while sulphinpyrazone could not, and that the ASA plus sulphinpyrazone com bination did not add any benefit to ASA alone. This applies well to dipyridamole in that a direct comparison between ASA and ASA plus dipyridamole in the study by the Persantine-Aspirin Reinfarction Study Re search Group [23] yielded no different re duction in vascular events after a mean fol low-up period of 3 years. The other notice
Lotto/Colombo/Talarico/Fratianni/Lettino
able study of ASA versus ASA plus dipyrida mole - American-Canadian Cooperative Study Group [24] -, which analyzed new vascular events in patients recovering from a transient ischaemic attack, gave similar re sults. We previously stated that none of the many reported studies of antiplatelet drugs in the secondary prevention of AMI was able to reach statistically significant reductions in proposed end points. The statistical group of the Oxford University [25] recently con ducted a careful reanalysis of all relevant, controlled, randomized trials of long-term antiplatelet drugs in the secondary pre vention of vascular disease. Among them, ten studies enrolled patients who had pre viously suffered AMI [16-19, 23, 26-30], Cumulative analysis of different trials was made possible by calculating the observed minus the expected number of typical events (i.e., vascular death, recurrent myocardial infarction) in the actively treated group alone. This calculation tends to give a nega tive result whenever treatment actually ex erts a protective effect. The approach ac counts for differences among different stud ies with respect to patient selection, defini tion of what constituted a myocardial infarc tion or vascular death, and many other er rors in the determination of who suffered a vascular event and who did not. All that is assumed is that the study faults were largely random among the trials, thereby avoiding any substantial bias in overall analysis. Based on this assumption, the meta-analysis showed a global favourable effect of long term antiplatelet treatment in the secondary prevention of AMI (table 1). In a total ran domized population of more than 18,000 patients followed for a mean duration of 3 years, a statistically significant 31 % reduc-
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 2/25/2018 5:04:59 PM
134
Heparin and Prevention of Acute Myocardial Infarction
135
Table 1. Non-fatal myocardial infarction in trials of antiplatelet drugs [from ref. 25] Study
AMIS Paris II Paris I Cardiff II ART CDP-A GDR Cardiff I Aris Gamis All trials
Reference No.
18 26 23 46 28 17 29 46 19 30
Basic data
Statistical data3
randomized patients
follow-up period, years
0 -E b
4,524 3,128 2,026 1,682 1,620 1,529 1,340 1,239 727 626
3 2 3-4 1 1-3 2 2 1 1-7 2
-19.9 -19.9 -7.9 -15.5 -3.3 -1.7 -14.1 -1.4 -9.1 -2.7
NS NS NS NS NS NS NS NS
