Post-myocardial infarction beta-blocker therapy is based on studies from the early 1980s. Since then, the diagnostics for myocardial infarction have become more sensitive, revascularisation has improved survival and there are now improved secondary prophylaxis drugs. We therefore believe it is time for new research, and that the indication for routine beta-blocker therapy following myocardial infarction should be reviewed.
It was pointed out as early as in 2007 that (1) post-myocardial infarction beta-blocker therapy is based on three studies from 1981 – 1982 (2 – 4) (Table 1). The clinical manifestations of myocardial infarction are the same now as in the early 1980s, but the diagnostics, treatment and patient population have all changed. The introduction of high-sensitivity troponin assays has changed the diagnostics. The pathogenesis and therapeutic effect may both be different now from in the past, because the relative distribution of various causal factors has changed. A patient with acute myocardial infarction in the 1970s was often a smoker, slender and with high total cholesterol. In 2015, the patient is an overweight, pre-diabetic non-smoker with low HDL cholesterol and high triglyceride levels. In the past, left-ventricular remodelling after severe myocardial infarction was a major problem and involved loss of contractile tissue followed by dilation of the left ventricle, a reduced ejection fraction and heart failure development. Today such infarctions are less common, as most patients are revascularised early and survive the infarction with a well preserved heart function. Are we actually looking at the same disease?
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Table 1 Long-term studies of post-infarction beta-blocker therapy. GMT = Gothenburg Metoprolol Trial; NTS = Norwegian Timolol Study; BHAT = The β-blocker Heart Attack Trial; LVEF = Left ventricular ejection fraction ; n.a. = not available; mo. = months CAPRICORN = Carvedilol Post-infarct Survival Control in LV dysfunction study; RR = Relative risk
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GMT, n = 1 395 from 1981 (3)
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NTS, n = 1 884 from 1981 (2)
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BHAT, n = 3 838 from 1982 (4)
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CAPRICORN, n = 1 959 from 2001
Patients with LVEF < 40 % (5)
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Therapy/follow-up
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Drug
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Metoprolol
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Timolol
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Propranolol
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Carvedilol
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Time from infarction to inclusion (average)
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< 48 hours (11 ± 3)
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6 – 27 days (14)
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5 – 12 days (14)
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3 – 21 days (n.a.)
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Initially intravenously
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15 mg on admission
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no
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no
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no
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Post-infarction target dose
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100 mg × 2
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10 mg × 2
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60 – 80 mg × 3¹
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25 mg × 2
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Time to target dose
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2 days
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2 days
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2 days
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4 – 6 weeks
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Average follow-up (min–max)
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3 mo. (n.a.)
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17 mo. (12 – 33)
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25 mo. (n.a.)
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15 mo. (n.a.)
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Concomitant therapy
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Thrombolysis/primary PCI
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no
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no
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no
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45 %
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Acetyl salicylic acid
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n.a.
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n.a.
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22 %
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86 %
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Anticoagulation
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n.a.
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n.a.
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9 %
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n.a.
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ACE inhibitor
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no
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no
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no
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98 %
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Statin
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no
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no
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no
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n.a.
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Mortality reduction
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RR 36 % (p < 0.03)
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RR 45 % (p < 0.001)
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RR 27 % (p < 0.005)
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HR 0.77 (0.60 – 0.98) (p = 0.03)
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[i]
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The efficacy of any treatment depends on the point of departure in relation to the maximum that can be achieved, and the lower limit for a clinically relevant result. Reduced efficacy may be due to the treatment only working when there is a certain relative distribution of causal factors, or to the factors that are affected being already almost maximally reduced.
New prevalence data show that a large number of coronary patients remain on beta-blocker therapy for several years after an infarction. This applies to both genders of all ages, with and without heart failure.
In the NOR-COR Study for Coronary Prevention, the use of beta-blockers after myocardial infarction, percutaneous coronary intervention (PCI) or aortocoronary bypass surgery was registered on discharge and after a follow-up period of 1.7 years (5) (Table 2). The figures for prescription of beta-blockers were 85 % on discharge and 72 % after 1.7 years, which correspond to figures from the big European registry survey EUROASPIRE IV (6). Is the evidence base for routine beta-blocker treatment following myocardial infarction good enough?
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Table 2 Percentage of patients in the NOR-COR study who were using beta-blockers on discharge and at the follow-up visit. NSTEMI = non-ST-segment elevation myocardial infarction, STEMI = ST-segment elevation myocardial infarction
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Discharge, %¹
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Follow-up, %¹
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All, N = 1 127
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85
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72
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Gender
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Men, n = 890
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85
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72
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Women, n = 237
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84
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73
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Age, years
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< 60, n = 364
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85
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71
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60 – 75, n = 625
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85
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73
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> 75, n = 138
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86
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74
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Time since index hospitalisation
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8 weeks – 6 mo., n = 233
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72
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6 – 12 mo., n = 242
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74
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12 – 24 mo., n = 347
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74
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24 – 36 mo., n = 305
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71
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Diagnosis on discharge
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NSTEMI, n = 561
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83
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70
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STEMI, n = 335
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89²
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74
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Stable coronary disease, n = 231
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82
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75
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Angiography during index hospitalisation
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Open vessels/wall changes, n = 69
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74²
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61²
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Single-vessel disease, n = 622
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84
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72
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Multiple-vessel disease, n = 435
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88
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75
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Revascularisation during index hospitalisation
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|
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Percutaneous coronary intervention, n = 748
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84
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72
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Aortocoronary bypass, n = 147
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91²
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81²
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Patients without heart failure
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All, N = 979
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83
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70
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Drammen Hospital, n = 496
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86²
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77³
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Vestfold Hospital, n = 483
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81
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63
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Percutaneous coronary intervention, n = 816
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83
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69
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Aortocoronary bypass, n = 126
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90²
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79²
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[i]
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What do new studies indicate?
A single literature search revealed no major studies with follow-up of ≥ three months of patients with a normal left ventricular ejection fraction.
The Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT) (n = 45 852 patients, metoprolol versus placebo within 24 hours, four-week follow-up) revealed no effect on total mortality, and a reduction of reinfarction and ventricular fibrillation was counterbalanced by increased risk of cardiogenic shock (7). Nor have beta-blockers been found to influence cardiovascular events in patients with stable coronary disease (8).
Two new registry studies have brought the problem to the fore:
In the biggest study, based on the Reduction of Atherothrombosis for Continued Health (REACH) Registry, 44 708 patients from general practice were included in the period 2003 – 2004 (9) (Table 3). The patients were from 44 countries worldwide, and 31 % had suffered myocardial infarction. After a follow-up period of 3.6 years, there was no difference in cardiovascular mortality between patients with and without beta-blockers when propensity score matching was used. In this analysis, attempts are made retrospectively to eliminate bias factors in the two groups (Table 4).
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Table 3 Beta-blocker after myocardial infarction. Two registry studies. n.a. = not available; PCI = percutaneous coronary intervention
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REACH: infarction 100 % (9)
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CORONOR: infarction 62 % (10)
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β-blocker +
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β-blocker –
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p
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β-blocker +
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β-blocker –
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p
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n ( %)
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9 451 (67)
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4 592 (33)
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< 0.001
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3 320 (79)
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864 (21)
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< 0.001
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Age, average (SD)
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66 (10)
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69 (10)
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< 0.001
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66 (12)
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69 (11)
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< 0.001
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Men, %
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76
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78
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n.s.
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78
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78
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n.s.
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Concomitant therapy, %
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Acetyl salicylic acid
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81
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73
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< 0.001
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n.a.
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n.a.
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Other platelet inhibitors
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27
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25
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0.02
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n.a.
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n.a.
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Platelet inhibitors combined
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n.a.
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n.a.
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97
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93
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< 0.001
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Angiotensin-converting-enzyme inhibitors
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57
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46
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< 0.001
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62
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49
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< 0.001
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Angiotensin-2 blockers
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17
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21
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< 0.001
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n.a.
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n.a.
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Statins
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82
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69
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< 0.001
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93
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89
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< 0.001
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Previous PCI, %
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n.a.
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n.a.
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79
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74
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n.s.
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Previous aortocoronary bypass
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n.a.
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n.a.
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21
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21
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n.s.
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[i]
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Table 4 Propensity score analysis to correct for confounding with and without beta-blockers
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REACH (9)
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CORONOR (10)
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β-blocker +
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β-blocker ÷
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p¹
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β-blocker +
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β-blocker ÷
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p¹
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n (%)
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3 379
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3 379
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839
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839
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Age, average (SD), years
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69 (10)
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69 (10)
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69 (11)
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69 (11)
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Men, %
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75
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75
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79
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78
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Suffered infarction, %
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100
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100
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49
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50
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Concomitant therapy, %
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|
|
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Acetyl salicylic acid
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76
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76
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n.a.
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n.a.
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Another platelet inhibitor
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23
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24
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n.a.
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n.a.
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|
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Platelet inhibitors combined
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n.a.
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n.a.
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93
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93
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Angiotensin-converting-enzyme inhibitors
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49
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48
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48
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49
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Angiotensin-2 blockers
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21
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20
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n.a.
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n.a.
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Statins
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74
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75
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89
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89
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Previous percutaneous coronary intervention
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n.a.
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n.a.
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84
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85
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Previous aortocoronary bypass
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n.a.
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n.a.
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21
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21
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Follow-up, average, years
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3.6
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3.6
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2.0
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2.0
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Cardiovascular mortality, n (%)
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273 (8.0)
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291 (8.6)
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13 (1.5)²
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32 (3.8) 2
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n.a.
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Annual rate, %
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2.2
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2.4
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0.8
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1.9
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n.a.
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Hazard rate for cardiovascular mortality
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|
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With β-blockers (95 % CI)
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0.91 (0.76 – 1.09)
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0.43 (0.22 – 0.82)
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0.011
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[i]
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CORonariens stables en region NORd-Pas-de-Calais (the CORONOR study) included 4 184 patients from northern France, 2 612 (62 %) of whom had suffered infarctions (10). The follow-up time was two years, and a statistically significant reduction in cardiovascular mortality was seen. There were few events, and type 2 errors therefore cannot be excluded. The same statistical method was used as for the study based on REACH.
The CORONOR and REACH studies are accompanied by commentaries by, respectively, Floyd (11) and Danchin & Laurent (12), who examine some weaknesses of the studies. Non-beta-blocker users may have stopped because of side effects or because of contraindications that affected their prognosis. The type of beta-blocker and indication for treatment are not known, and no information is provided about left ventricular function. The conclusion is that more research is needed.
A meta-analysis of randomised, controlled studies included 102 003 patients from 60 studies, 12 of which were published in the revascularisation period (1991 – 2013) (13). Beta-blockers had no effect on mortality, whereas the 30-day incidence of reinfarction and angina were reduced at the expense of increased incidence of heart failure and cardiogenic shock. The other 48 studies were published during the pre-revascularisation period (1966 – 1999), when beta-blockers reduced mortality, infarction and angina alike.
Another, recent meta-analysis included 10 observational studies of treatment with beta-blockers after PCI-treated infarction (14). Of the patients in this analysis, 25 168 had been given beta-blockers and 15 705 had not. The primary endpoint was total mortality. In adjusted analyses, this was reduced with beta-blockers, but the effect was only present in study populations with a reduced ejection fraction and low consumption of other medicinal secondary prophylaxis. There was no effect on cardiac mortality, reinfarction or hospitalisations for heart failure. The authors conclude that there is now no evidence for routine beta-blocker therapy for sufferers of myocardial infarction, and that new studies are necessary for further clarification.
International guidelines
The European guidelines of 2013 on treatment of stable coronary disease argue that the efficacy of beta-blockers is uncertain because the studies on post-infarction patients were conducted prior to the implementation of other secondary prophylactic therapy (15).
That same year it was pointed out in similar guidelines for ST elevation infarction that long-term beta-blocker therapy is well established, but that the uncertainties referred to above were recognised (16).
In the 2015 guidelines for non-ST-elevation infarction, early beta-blocker therapy is recommended for patients with persistent ischaemic symptoms, provided this is not contraindicated (17). Patients without severe heart failure can be offered long-term therapy.
In the American guidelines of 2012, it is pointed out that beta-blockers are efficacious in patients who have suffered myocardial infarction in the last three years and/or have left ventricular dysfunction (18).
Adverse effects
Frequently reported adverse effects of beta-blockers are fatigue, impaired exercise capacity, sleeping problems, life-threatening bradyarrhythmia and hypotension (15). However, a recent critical review showed that only five of 33 described adverse effects (hyperglycaemia, diarrhoea, dizziness, intermittent claudication and bradycardia) were more prevalent in patients treated with beta-blockers than in others (19).
Side effects are disagreeable nonetheless, and their nature may be such as to mask another disease, which may remain undiagnosed for a long time as a result.
Should patients today have beta-blockers?
Diagnostic criteria, initial treatment and follow-up of myocardial infarction have changed drastically since the 1980s. In view of the large numbers who use beta-blockers, the problems associated with side effects and masking of other disease are highly relevant. Therapy must therefore be based on the results of prospective, randomised studies performed on a relevant patient population.
No such documentation exists for today’s post-infarction patients. The time is ripe for performing a study on patients who have been optimally treated by present standards. A central exclusion criterion must be severe infarctions that predispose the patient to left ventricular remodelling, where both an angiotensin convertase inhibitor and beta-blocker are indicated regardless.
