Background
The index trial: REDUCE-AMI
Protocol component | Index trial: REDUCE-AMI | Target trial | Target trial emulation using SWEDEHEARTa |
---|---|---|---|
Eligibility criteria | • Age ≥ 18 years from 11th Sept 2017 to time when 379 primary endpoints have occurred • Day 1–7 of hospitalization for type 1 myocardial infarction in participating hospitals in Sweden, Estonia, and New Zealand • Obstructive coronary artery disease documented by coronary angiography • Normal ejection fraction (EF ≥ 50%) confirmed by post-MI echocardiography • No contraindications for beta blockers • No beta blocker indications other than as secondary prevention according to treating physician • No conditions that may influence the patient’s ability to comply with study protocol | Same as index trial apart from: • 1st Sept 2010 to 10th Sept 2017 in Sweden only •Day 1–30 after hospitalization for type 1 myocardial infarction on which coronary angiography is performed • “Contraindications for beta blockers” operationalized as bradycardia, Av-block II-III, hypotension, syncope, asthma, COPD, or stroke in previous 3 years • “No beta blocker indication” operationalized as no beta blocker use in previous 3 years, heart rate ≥ 120, systolic blood pressure ≥ 180, diastolic blood pressure ≥ 120, history of chronic heart failure, or atrial flicker/flutter • “Conditions that may influence ability to comply” operationalized as psychiatric disorders or dementia in previous 3 years • On statins and antithrombotics at baseline | Same as target trial • All diagnoses (apart from beta blocker indications and dementia) identified as primary or secondary diagnosis in either the inpatient or outpatient sub registers of the Patient Register within three years of baseline • Beta blocker indications and dementia and identified using SWEDEHEART registry • Beta blocker use identified from the prescribed drug register in prior 3 years or a record of beta blocker use on admission to hospital from SWEDEHEART registry • Statins and antithrombotics identified from the prescribed drug register |
Treatment strategies | (1) Beta blockers—Long-term oral beta blockers (metoprolol succinate or bisoprolol) unless a contraindication arises. The treating physician encouraged to aim for a dose of ≥ 100 mg for metoprolol succinate and ≥ 5 mg for bisoprolol (2) No beta blockers unless indicated for reasons other than secondary prevention following myocardial infarction—Discouraged to use beta blockers as long as there is no other indication than strictly secondary prevention after myocardial infarction | Same as index trial • Contraindications to beta blockers operationalized as above • Indications for beta blockers operationalized as hypertension, angina, arrhythmia, heart failure | Same as target trial apart from: • Prescription dates from Prescribed Drug register. If no record, but SWEDEHEART indicates beta blocker at discharge, prescription date set at discharge • Contra- and indications, primary or secondary diagnosis in inpatient or outpatient register • Metoprolol and bisoprolol assumed to be daily dose of 100 mg and 5 mg respectively • Date of non-adherence based on number of pills and pill dose, divided by daily dose (continuous if gap < 180d) |
Treatment assignment | Individuals are randomly assigned to a treatment strategy and are aware of their assignment | Same as index trial | • Individuals assigned to strategy data compatible with at baseline and assignment to beta blockers operationalized as a prescription. Assignment assumed random within levels of baseline covariates in Supplementary Table 1 |
Outcomes | Primary: Death or myocardial infarction identified from the Swedish Total Population register and SWEDEHEART respectively Secondary: Each component of primary outcome | Same as index trial | Same as target trial |
Follow-up | Starts at assignment, ends at first outcome, migration, or end of follow up (yet to be defined) | Same as index trial apart from: • End of follow at the earliest of 31st December 2017 or five years after start of follow up | Same as target trial apart from: • Unable to identify migration date |
Contrasts | Intention to treat effect | Intention-to-treat and per protocol effects | Same as target trial |
Statistical analysis | • Absolute risks estimated via Kaplan Meier • Hazard ratios estimated using Cox regression | Same as index trial apart from: Absolute risks estimated using pooled logistic regression model with adjustment for unbalanced baseline covariates via IP weighting. Hazard ratio estimated from same model without product terms with time Per protocol analysis similar except individuals censored when they deviate from assigned treatment, and IP weighting to adjust for baseline and time-varying variables | Same as target trial. Baseline covariates listed in Supplementary Table 1 |
The observational analysis
The target trial
The observational emulation of the target trial
Sensitivity analyses
Results
Beta blockers | No beta blockers | Missing | SMD | SMD after IP weighting | |
---|---|---|---|---|---|
9728 | 1198 | ||||
Characteristics and prior diagnoses | |||||
Age | 64.0 [56.0, 72.0] | 67.0 [58.0, 74.0] | 0 | 0.181 | 0.031 |
Female | 2060 (21.2) | 235 (19.6) | 0 | 0.039 | 0.041 |
Smoking status | 1.7 | 0.126 | 0.034 | ||
Never smoker | 3948 (41.3) | 535 (45.4) | |||
Ex-smoker (> 1 month) | 3387 (35.4) | 427 (36.2) | |||
Smoker | 2226 (23.3) | 216 (18.3) | |||
Hypertension | 2968 (30.6) | 390 (32.6) | 0.2 | 0.044 | 0.037 |
Diabetes | 1065 (11.0) | 108 (9.0) | 0.1 | 0.065 | 0.042 |
Myocardial infarction | 388 (4.0) | 80 (6.7) | 0.1 | 0.12 | 0.028 |
Stroke | 223 (2.3) | 43 (3.6) | 0.1 | 0.077 | 0.057 |
Percutaneous coronary intervention | 271 (2.8) | 76 (6.3) | 0.1 | 0.171 | 0.036 |
Cardiac surgery | 83 (0.9) | 27 (2.3) | 0.1 | 0.113 | 0.044 |
Renal disease | 131 (1.3) | 14 (1.2) | 0 | 0.016 | 0.007 |
Cancer | 54 (0.6) | 8 (0.7) | 0 | 0.191 | 0.026 |
Presentation | |||||
NSTEMI | 5492 (56.5) | 786 (65.6) | 0 | 0.189 | 0.012 |
Cardiopulmonary resuscitation | 159 (1.7) | 5 (0.4) | 0.9 | 0.122 | 0.098 |
Thrombolysis | 41 (0.4) | 4 (0.3) | 0.1 | 0.014 | 0.019 |
Cardiogenic shock | 38 (0.4) | 9 (0.8) | 0.2 | 0.048 | 0.031 |
ECG ryhthm | 0.2 | 0.068 | 0.047 | ||
Sinus | 9620 (99.1) | 1176 (98.3) | |||
Atrial flicker/flutter | 0 (0.0) | 0 (0.0) | |||
Other | 88 (0.9) | 20 (1.7) | |||
ECG QRS annotation | 0.9 | 0.066 | 0.046 | ||
Normal | 8079 (83.8) | 970 (81.5) | |||
Pacemaker | 6 (0.1) | 1 (0.1) | |||
Left bundle branch block | 100 (1.0) | 13 (1.1) | |||
Pathological Q-wave | 601 (6.2) | 82 (6.9) | |||
Right bundle branch block | 256 (2.7) | 41 (3.4) | |||
Other | 597 (6.2) | 83 (7.0) | |||
ECG ST- & T-wave changes | 0.4 | 0.234 | 0.043 | ||
Normal | 2459 (25.4) | 362 (30.3) | |||
ST-elevation | 4142 (42.8) | 391 (32.7) | |||
ST-depression | 1602 (16.5) | 190 (15.9) | |||
Pathological T-wave | 897 (9.3) | 149 (12.5) | |||
During hospitalization | |||||
Percutaneous coronary intervention | 8887 (91.4) | 1135 (94.7) | 0 | 0.133 | 0.016 |
Angiography finding | 0 | 0.136 | 0.075 | ||
1 vessel, not left main | 5126 (52.7) | 680 (56.8) | |||
2 vessels, not left main | 2685 (27.6) | 340 (28.4) | |||
3 vessels not left main | 1454 (14.9) | 136 (11.4) | |||
Left main + 1 vessel | 75 (0.8) | 7 (0.6) | |||
Left main + 2 vessels | 136 (1.4) | 11 (0.9) | |||
Left main + 3 vessels | 231 (2.4) | 20 (1.7) | |||
Left main | 21 (0.2) | 4 (0.3) | |||
Stenosis class | 10.3 | 0.087 | 0.050 | ||
A | 550 (6.3) | 84 (7.6) | |||
B1 | 2538 (29.2) | 329 (29.7) | |||
B2 | 2876 (33.1) | 378 (34.1) | |||
C | 1324 (15.2) | 161 (14.5) | |||
B1 bifurcation | 459 (5.3) | 55 (5.0) | |||
B2 bifurcation | 686 (7.9) | 68 (6.1) | |||
C bifurcation | 261 (3.0) | 32 (2.9) | |||
Proportion stenosis | 4.5 | 0.131 | 0.084 | ||
< 70% | 210 (2.3) | 43 (3.7) | |||
70–89% | 1391 (15.0) | 200 (17.2) | |||
90–99% | 3497 (37.7) | 456 (39.3) | |||
100% | 4171 (45.0) | 462 (39.8) | |||
Intravenous beta blockers | 749 (7.7) | 18 (1.5) | 0 | 0.299 | 0.111 |
Intravenous diuretics | 325 (3.3) | 24 (2.0) | 0 | 0.083 | 0.052 |
Intravenous inotropic drugs | 118 (1.2) | 12 (1.0) | 0 | 0.02 | 0.053 |
Intravenous nitrates | 633 (6.5) | 51 (4.3) | 0.1 | 0.1 | 0.051 |
Concomitant medications | |||||
Angiotensin 2 receptor blockers | 1747 (18.0) | 231 (19.3) | 0 | 0.034 | 0.063 |
ACE inhibitors | 6784 (69.7) | 713 (59.5) | 0 | 0.215 | 0.016 |
Calcium channel blockers | 1657 (17.0) | 257 (21.5) | 0 | 0.112 | 0.023 |
Diuretics | 1212 (12.5) | 161 (13.4) | 0 | 0.029 | 0.041 |
Nitrates | 8490 (87.3) | 1050 (87.6) | 0 | 0.011 | 0.022 |
Diabetes treatment | 1130 (11.6) | 107 (8.9) | 0 | 0.089 | 0.006 |
Measurements | |||||
Heart rate | 72.0 [63.0, 83.0] | 63.0 [55.0, 74.0] | 0 | 0.603 | 0.088 |
Systolic blood pressure (mm/Hg) | 148.0 [130.0, 160.0] | 145.0 [130.0, 160.0] | 0 | 0.069 | 0.004 |
Diastolic blood pressure (mm/Hg) | 85.0 [75.0, 95.0] | 80.0 [73.0, 90.0] | 0 | 0.218 | 0.034 |
LDL cholesterol (mmol/L) | 3.3 [2.7, 4.0] | 3.3 [2.6, 4.0] | 15.5 | 0.033 | 0.029 |
HDL cholesterol (mmol/L) | 1.2 [1.0, 1.4] | 1.2 [1.0, 1.4] | 13.7 | 0.084 | 0.016 |
Creatinine (µmol/L) | 78.0 [68.0, 90.0] | 81.0 [70.0, 93.0] | 4.4 | 0.148 | 0.005 |
Body mass index (kg/m2) | 27.0 [25.0, 30.0] | 27.0 [24.0, 29.0] | 2.4 | 0.124 | 0.014 |
Intention-to-treat effect: the effect of prescription versus no prescription of beta blockers at baseline
Outcome | Beta blockers | No beta blockers | Risk difference (95% CI) | Risk ratio (95% CI) | ||
---|---|---|---|---|---|---|
Events | Risk, % (95% CI) | Events | Risk, % (95% CI) | |||
Intention-to-treata | ||||||
Composite | 637 | 10.2 (9.4, 11.1) | 88 | 11.9 (8.5, 15.3) | − 1.7 (− 5.5, 1.9) | 0.86 (0.64, 1.23) |
Death | 324 | 5.6 (4.9, 6.3) | 45 | 5.9 (3.7, 8.4) | − 0.3 (− 2.9, 1.9) | 0.96 (0.65, 1.48) |
Myocardial infarction | 353 | 5.3 (4.7, 5.8) | 47 | 6.9 (4.4, 9.7) | − 1.6 (− 4.5, 1.0)) | 0.76 (0.53, 1.22) |
Per-protocola,b | ||||||
Composite | 523 | 10.2 (9.3, 11.2) | 75 | 11.0 (7.6, 14.4) | − 0.8 (− 4.5, 2.8) | 0.92 (0.69, 1.37) |
Death | 259 | 5.6 (4.9, 6.5) | 41 | 5.7 (3.5, 8.5) | − 0.1 (− 2.8, 2.2) | 0.99 (0.67, 1.60) |
Myocardial infarction | 295 | 5.2 (4.6, 5.9) | 37 | 5.9 (3.3, 8.5) | − 0.7 (− 3.3, 2.1) | 0.88 (0.60, 1.59) |
Time of follow up termination | Events | Hazard ratio (95% CI) | |
---|---|---|---|
Beta blockers | No beta blockers | ||
Intention-to-treata | |||
3 years | 454 | 65 | 0.75 (0.54, 1.12) |
4 years | 545 | 83 | 0.69 (0.51, 0.99) |
5 years | 637 | 88 | 0.78 (0.59, 1.12) |
Per-protocola,b | |||
3 years | 390 | 56 | 0.79 (0.57, 1.25) |
4 years | 457 | 70 | 0.74 (0.56, 1.11) |
5 years | 523 | 75 | 0.84 (0.64, 1.24) |