Article Text

Original research
Postdischarge major bleeding, myocardial infarction, and mortality risk after coronary artery bypass grafting
  1. Erik Björklund1,2,
  2. Philip Enström1,3,
  3. Susanne J Nielsen1,3,
  4. Hans Tygesen1,2,
  5. Andreas Martinsson1,4,
  6. Emma C Hansson1,3,
  7. Martin Lindgren1,4,
  8. Carl-Johan Malm1,3,
  9. Aldina Pivodic5,6,
  10. Anders Jeppsson1,3
  1. 1 Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
  2. 2 Department of Medicine, Southern Älvsborg Hospital, Borås, Sweden
  3. 3 Department of Cardiothoracic Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden
  4. 4 Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden
  5. 5 Department of Clinical Neuroscience, University of Gothenburg, Gothenburg, Sweden
  6. 6 APNC Sweden, Gothenburg, Sweden
  1. Correspondence to Dr Erik Björklund, Department of Molecular and Clinical Medicine, University of Gothenburg Institute of Medicine, Goteborg 40530, Sweden; erik.bjorklund{at}gu.se

Abstract

Objective To investigate the incidence and mortality risk associated with postdischarge major bleeding after coronary artery bypass grafting (CABG), and relate this to the incidence of, and mortality risk from, postdischarge myocardial infarction.

Methods All patients undergoing first-time isolated CABG in Sweden in 2006–2017 and surviving 14 days after hospital discharge were included in a cohort study. Individual patient data from the SWEDEHEART Registry and five other mandatory nationwide registries were merged. Piecewise Cox proportional hazards models were used to investigate associations between major bleeding, defined as hospitalisation for bleeding, with subsequent mortality risk. Similar Cox proportional hazards models were used to investigate the association between postdischarge myocardial infarction and mortality risk.

Results Among 36 633 patients, 2429 (6.6%) had a major bleeding event and 2231 (6.1%) had a myocardial infarction. Median follow-up was 6.0 (range 0–11) years. Major bleeding was associated with higher mortality risk <30 days (adjusted HR (aHR)=20.2 (95% CI 17.3 to 23.5)), 30–365 days (aHR=3.8 (95% CI 3.4 to 4.3)) and >365 days (aHR=1.8 (95% CI 1.7 to 2.0)) after the event. Myocardial infarction was associated with higher mortality risk <30 days (aHR=20.0 (95% CI 16.7 to 23.8)), 30–365 days (aHR=4.1 (95% CI 3.6 to 4.8)) and >365 days (aHR=1.8 (95% CI 1.7 to 2.0)) after the event.

Conclusions The increase in mortality risk associated with a postdischarge major bleeding after CABG is substantial and is similar to the mortality risk associated with a postdischarge myocardial infarction.

  • Myocardial Infarction
  • Coronary Artery Bypass

Data availability statement

Data may be obtained from a third party and are not publicly available. The data underlying this article were provided by a third party, the Swedish National Board of Health and Welfare, under ethics approval. The data can be accessed upon request to the third party.

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WHAT IS ALREADY KNOWN ON THIS TOPIC

  • Postdischarge major bleeding events after percutaneous coronary intervention and medically managed acute coronary syndrome have been associated with a marked increase in mortality risk, similar to the increase in mortality risk associated with a postdischarge myocardial infarction. It is unknown if this is also true after coronary artery bypass grafting (CABG).

WHAT THIS STUDY ADDS

  • This study for the first time describes the incidence of postdischarge major bleeding and demonstrates a marked increase in subsequent mortality risk in a CABG population.

  • The increase in mortality risk following major bleeding was similar to that of a postdischarge myocardial infarction.

  • Thus, the findings from other coronary artery disease populations regarding the prognostic impact of postdischarge major bleeding and myocardial infarction are also applicable following CABG.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

  • The study highlights the importance of meticulous consideration of bleeding risk when deciding on the optimal antithrombotic treatment after CABG. Further, bleeding events should be considered to have the same prognostic impact as myocardial infarction when designing clinical trials evaluating antithrombotic regimens after CABG.

Introduction

Platelet inhibition with acetylsalicylic acid is recommended for all patients without contraindications after coronary artery bypass grafting (CABG) to reduce the risk of ischaemic events. More intense platelet inhibition, using dual antiplatelet therapy, is recommended for CABG patients presenting with acute coronary syndrome.1 2 Dual antiplatelet therapy may also be considered after elective CABG to improve vein graft patency.1 Furthermore, a significant proportion of CABG patients are treated with oral anticoagulants because of concomitant conditions, such as atrial fibrillation or valvular disease.3

However, antithrombotic therapy comes at the cost of increased bleeding risk.4 5 Previous studies have demonstrated a comparable increase in mortality risk following a postdischarge bleeding event and myocardial infarction (MI), respectively, in patients treated with percutaneous coronary intervention (PCI) and in general acute coronary syndrome populations.6–11 The incidence of postdischarge major bleeding after CABG and its association with mortality risk is not known.

Knowledge of the incidence and severity in terms of subsequent mortality risk after postdischarge major bleeding events in relation to postdischarge MI is important for physicians when deciding on the intensity and duration of antithrombotic therapy after CABG. The objectives of this study were, therefore, (1) to investigate the incidence of postdischarge major bleeding after CABG and its association with subsequent mortality risk, and (2) to relate this to the incidence and mortality risk associated with postdischarge MI.

Methods

Study population and study design

The Swedish Cardiac Surgery Registry was used to identify the study population in this cohort study. All patients ≥18 years of age in Sweden undergoing first-time isolated CABG between 2006 and 2017 were considered for inclusion. Patients who died during hospital admission or within 14 days of hospital discharge and patients discharged after 16 December 2017 were excluded. A flow chart of patient inclusion and exclusion is presented in figure 1. The exposures of interest were postdischarge major bleeding and MI, and the investigated outcome was death from any cause. Patient characteristics, comorbidities, socioeconomic factors and time-updated use of cardiovascular drugs were registered and adjusted for in the statistical analysis. Comorbidities were recorded at start of follow-up and thus included both chronic conditions and comorbidities debuting during the index admission; data on left ventricular ejection fraction and renal function were recorded preoperatively. Start of follow-up was 15 days after hospital discharge and is referred to as ‘baseline’. The choice to start follow-up 15 days after discharge was to exclude patients dying early after discharge which often is directly related to complications to the surgery. It also allows time to obtain baseline data on dispensed prescriptions after discharge, similar to a previous study from our group.5 Patients were followed until death, emigration or 31 December 2017.

Figure 1

Flow diagram describing patient selection, exposures of interest and mortality outcome. *These patients were included in both the analysis investigating major bleeding and the analysis investigating myocardial infarction. CABG, coronary artery bypass grafting.

Data sources and definitions

Individual patient data from five mandatory nationwide registries were merged and pseudonymised by the official authority Statistics Sweden, as previously described.12 The merging of patient data was based on the personal identification number which is given to all Swedish residents at birth or shortly after immigration. The Swedish Cardiac Surgery Registry is a part of the SWEDEHEART Registry and contains information, including preoperative status and postoperative complications, on cardiac surgery procedures in Sweden since 1992, with a coverage of 98–99%.13 14 The National Patient Register has full coverage of diagnoses on hospital admission according to the International Classification of Diseases, Ninth Revision (ICD-9) and 10th Revision (ICD-10), with a validity of 85–95%.15 The Swedish Prescribed Drug Register has information on all prescriptions dispensed from Swedish pharmacies since July 2005 (according to the Anatomical Therapeutic Chemical (ATC) classification). The Swedish Cause of Death Register comprises data on all deaths of persons registered in Sweden. The Longitudinal Integration Database for Health Insurance and Labor Market Studies (LISA) Register contains data on social variables. The Swedish Population Register contains basic demographic data, including date of emigration where applicable.

Major bleeding and MI were defined as a new hospitalisation with a primary diagnosis according to the ICD-10 of bleeding or MI, respectively; the ICD codes used are listed in online supplemental table S1. Bleeding events were further subclassified, according to bleeding site, as intracranial, gastrointestinal, pericardial or ‘other bleeding’ location.

Supplemental material

All relevant comorbidities registered in the Swedish Cardiac Surgery Registry and National Patient Register until start of follow-up were registered as baseline data; the ICD codes used are listed in online supplemental table S2. Data on socioeconomic variables were retrieved from the LISA Register at baseline. Preoperative data on left ventricular ejection fraction and kidney function were gathered from the Swedish Cardiac Surgery Registry. The Chronic Kidney Disease Epidemiology Collaboration formula was used to calculate estimated glomerular filtration rate (eGFR) based on preoperative creatinine levels.16 Time-updated use of platelet inhibitors, anticoagulants, beta blockers, renin angiotensin system (RAS) inhibitors and statins was defined as dispensed prescriptions in the Swedish Prescribed Drug Register and updated every third month as previously described.12 ATC codes used are listed in online supplemental table S3.

This study has been composed according to the recommendations in the Strengthening the Reporting of Observational Studies in Epidemiology reporting guideline.17 The study was performed in accordance with the Declaration of Helsinki.

Patient and public involvement

Patients were not involved in the design or conduct of the study. The authors intend to disseminate the study results to the patients included in the study as well as healthcare professionals caring for the patients included in the study.

Statistical analysis

Continuous variables are presented as mean with SD, median with range or median with 25th–75th percentiles where appropriate. Categorical variables are presented as frequency with percentage. For comparison between two groups, Fisher’s exact test was used for dichotomous variables, Mantel-Haenszel χ2 trend test for ordered categorical variables, χ2 test for unordered categorical variables and Mann-Whitney U test for continuous variables. Piecewise Cox proportional hazards models for the effect of major bleeding and MI, respectively, on subsequent mortality risk were developed. Major bleeding and MI were handled as a time-updated covariate in the respective models, meaning that patients contributed follow-up time to the ‘no event’ group until they had an event, at which time they started contributing follow-up time to the ‘bleeding’ or ‘myocardial infarction’ group, respectively. The model was adjusted for age, sex, year of surgery, left ventricular ejection fraction, eGFR category, time-updated use of platelet inhibitors, oral anticoagulants, beta blockers, RAS inhibitors and statins, and other baseline variables that were associated with mortality risk based on a separately performed stepwise (forward) regression model applying p<0.10. This resulted in further adjustment for use of left internal mammary artery, number of distal anastomoses, clinical heart failure, diabetes, peripheral vascular disease, smoking, history of cancer, stroke, chronic respiratory disease, renal failure, any previous bleeding requiring medical attention, atrial fibrillation, hyperlipidaemia, asthma, previous PCI, previous MI, hypertension, transient ischaemic attack, haemorrhagic stroke, subarachnoid haemorrhage, education level and marital status. To estimate the time-dependent risk of mortality after an event, HRs compared with the ‘no event’ group were calculated for <30, 30–365 and >365 days after first incidence of major bleeding and MI, respectively, similar to the methodology used by Marquis-Gravel et al.11 Interaction analyses for mortality risk were studied in patients with major bleeding and MI, respectively, for the following subgroups: age (≥75/<75 years), gender, atrial fibrillation, kidney function (eGFR≥60/<60 mL/min/1.73 m2) and multimorbidity (≥3 of diabetes, hypertension, chronic respiratory disease, previous stroke, previous MI, atrial fibrillation, clinical heart failure, eGFR<60 mL/min/1.73 m2).

Similar piecewise Cox proportional hazards models were used to estimate the mortality risk for different bleeding locations compared with patients with no bleeding. Because of the small number of cases of pericardial bleeding (n=5), these patients were included in the ‘other bleeding’ group.

Altogether, 287 patients suffered both major bleeding and an MI during follow-up. These patients were included in both the analysis investigating major bleeding and the analysis investigating MI. An analysis excluding patients suffering both major bleeding and MI was performed as a sensitivity analysis, with a similar piecewise Cox proportional hazards model as described above. Another sensitivity analysis excluding patients using anticoagulants was also performed.

Missing data were handled as a separate category in the adjustments. All tests were two tailed and interpreted at the 0.05 significance level. Statistical analyses were performed using SAS software V.9.4 (SAS Institute).

Results

General

In total, 36 633 patients were included, mean age 68.1 (SD 9.1) years; 29 427 (80.3%) were men. Median follow-up was 6.0 (25th-75th percentiles 3.0–9.0) years; a total of 6683 (18.2%) patients died and 177 (0.5%) patients emigrated during follow-up. Baseline characteristics are described in table 1 and use of platelet inhibitors and anticoagulants during follow-up is described in figure 2. Use of platelet inhibitors and anticoagulants for patients with major bleeding and MI, respectively, is described in online supplemental figures S1 and S2.

Figure 2

Use of platelet inhibitors and anticoagulants during follow-up. P2Y12 indicates use of any oral P2Y12 inhibitor (clopidogrel, prasugrel or ticagrelor). ASA, acetylsalicylic acid; DAPT, dual antiplatelet therapy; OAC, oral anticoagulant.

Table 1

Baseline characteristics at start of follow-up 15 days after hospital discharge for patients with major bleeding, myocardial infarction and patients with no event

Postdischarge major bleeding

Altogether, 2429 (6.6%) patients suffered at least one major bleeding event at a median of 3.5 years (25th–75th percentiles 1.3–6.2 years) after start of follow-up. Patients suffering a major bleeding event were older, more often female and carried a higher burden of comorbidities (except for hyperlipidaemia, previous PCI and asthma) compared with patients with no bleeding event (table 1).

Gastrointestinal bleeding was the most common bleeding site, occurring in 1187 (49%) of major bleeding events, intracranial bleeding occurred in 388 (16%) of events and five (0.2%) were pericardial. The cumulative incidence of major bleeding, adjusted for the competing risk of death, is presented in figure 3. The crude incidence of major bleeding was highest in the first 30 days after baseline, with 3.3 (95% CI 2.7 to 4.0) events per 100 patient-years, compared with 1.3 (95% CI 1.2 to 1.4) events per 100 patient-years 30–365 days after baseline and 1.1 (95% CI 1.0 to 1.1) events per 100 patient-years >365 days after baseline.

Figure 3

Cumulative incidence of all-cause mortality, major bleeding and myocardial infarction after coronary artery bypass grafting with death as competing risk for major bleeding and myocardial infarction. Patients at risk are shown underneath the x-axis.

In total, 1041 (42.9%) of the patients with a major bleeding event died during follow-up. The crude mortality rate was highest in the first 30 days after the event (table 2). In the fully adjusted model, major bleeding was associated with higher mortality at <30 days (adjusted HR (aHR)=20.2 (95% CI 17.3 to 23.5)), 30–365 days (aHR=3.8 (95% CI 3.4 to 4.3)) and >365 days (aHR=1.8 (95% CI 1.7 to 2.0)), all p<0.001, after the event compared with patients without bleeding events (figure 4).

Figure 4

Adjusted mortality risk for major bleeding and myocardial infarction, respectively, at <30, 30–365 and >365 days after the event. *Adjusted for age, sex, year of surgery, left ventricular ejection fraction, estimated glomerular filtration rate category, time-updated use of platelet inhibitors, oral anticoagulants, beta blockers, renin angiotensin system inhibitors, use of left internal mammary artery, clinical heart failure, peripheral vascular disease, stroke, any previous bleeding, atrial fibrillation, hyperlipidaemia, previous percutaneous coronary intervention, previous myocardial infarction, hypertension, anastomoses, transient ischaemic attack, subarachnoid haemorrhage and haemorrhagic stroke, chronic respiratory disease, asthma, diabetes, renal failure and cancer, as well as smoking, marital status and education level. aHR, adjusted HR.

Table 2

Crude incidence rates and adjusted HRs (aHRs) for death after major bleeding and myocardial infarction

The mortality risk by bleeding localisation is described in figure 5. Intracranial bleeding was associated with the largest increase in mortality risk, especially within the first 30 days after the event (aHR=80.2 (95% CI 64.8 to 99.3)). Number of deaths and crude mortality rate by bleeding localisation are reported in online supplemental table S4.

Figure 5

Mortality risk after a bleeding event, by bleeding localisation, at <30, 30–365 and >365 days after the event. *Adjusted for age, sex, year of surgery, left ventricular ejection fraction, estimated glomerular filtration rate category, time-updated use of platelet inhibitors, oral anticoagulants, beta blockers, renin angiotensin system inhibitors, use of left internal mammary artery, clinical heart failure, peripheral vascular disease, stroke, any previous bleeding, atrial fibrillation, hyperlipidaemia, previous percutaneous coronary intervention, previous myocardial infarction, hypertension, anastomoses, transient ischaemic attack, subarachnoid haemorrhage and haemorrhagic stroke, chronic respiratory disease, asthma, diabetes, renal failure and cancer, as well as smoking, marital status and education level. aHR, adjusted HR.

There were significant interactions for the associations of major bleeding on subsequent mortality risk with more pronounced increase in mortality risk in the following subgroups: patients <75 years, without atrial fibrillation, with <3 comorbidities and with eGFR ≥60 mL/min/1.73 m2 (online supplemental figure S3).

Postdischarge MI

In total, 2231 (6.1%) patients were hospitalised for MI during follow-up at a median of 3.3 years (25th–75th percentiles 1.0–6.2 years) after start of follow-up. Patients suffering an MI were more often female and carried a higher burden of comorbidities (except for previous haemorrhagic stroke, atrial fibrillation, history of cancer, asthma and chronic respiratory disease) compared with patients with no MI (table 1).

The cumulative incidence of MI, adjusted for the competing risk of death, is presented in figure 3. The crude incidence of MI was highest in the first 30 days of follow-up, with 3.1 (95% CI 2.5 to 3.8) events per 100 patient-years compared with 1.4 (95% CI 1.3 to 1.6) events per 100 patient-years 30–365 days after baseline and 1.0 (95% CI 0.9 to 1.0) event per 100 patient-years >365 days after baseline. In total, 762 (34.2%) of the patients with an MI died during follow-up, with the highest crude mortality rate in the first 30 days after the event (table 2). In the fully adjusted model, MI was associated with higher mortality at <30 days (aHR=20.0 (95% CI 16.7 to 23.8)), 30–365 days (aHR=4.1 (95% CI 3.6 to 4.8)) and >365 days (aHR=1.8 (95% CI 1.7 to 2.0)), all p<0.001, after the event compared with patients without MI (figure 4).

There was no interaction for the associations of MI on subsequent mortality risk for any of the investigated subgroups (online supplemental figure S4).

Sensitivity analyses

During follow-up, 2142 (5.9%) patients suffered a major bleeding and 1944 (5.3%) patients suffered a MI in the sensitivity analysis where patients with both major bleeding and MI were excluded. Patients suffering a major bleeding had different baseline characteristics compared with patients suffering a MI (online supplemental table S5). Patients with major bleeding were older, more often male and more often had atrial fibrillation, previous hospitalisation for bleeding, clinical heart failure and history of cancer. By contrast, patients with MI more often had acute coronary syndrome <6 weeks before surgery as indication for CABG, as well as previous MI, diabetes, hypertension, hyperlipidaemia and history of PCI at baseline.

The results of the sensitivity analysis excluding patients with both major bleeding and MI were in line with the main analysis. The aHRs for mortality <30 days were 20.5 (95% CI 17.5 to 24.1) for major bleeding and 21.7 (95% CI 18.0 to 26.1) for MI, 3.8 (95% CI 3.4 to 4.3) and 4.1 (95% CI 3.5 to 4.9), respectively, at 30–365 days after the event and 1.7 (95% CI 1.6 to 1.9) and 1.8 (95% CI 1.6 to 2.0), respectively, at >365 days after the event, all compared with patients without major bleeding or MI (online supplemental figure S5).

The results of the sensitivity analysis excluding patients on oral anticoagulants at baseline were in line with the main analysis (online supplemental figure S6).

Discussion

In this nationwide cohort of CABG patients, two main findings emerged: (1) postdischarge major bleeding events were associated with a markedly increased mortality risk which was most pronounced during the first 30 days after the event; and (2) the incidence and increase in mortality risk associated with a postdischarge major bleeding event were similar to those associated with a MI (figure 6).

Figure 6

Visual summary describing the incidence and time-dependent mortality risk associated with a post-discharge major bleeding and myocardial infarction respectively after CABG

The massive increase in mortality risk in the first 30 days after major bleeding events, with an approximately 20-fold increase in mortality risk overall, and an 80-fold increase for patients with intracranial bleeding, indicates a strong direct effect of major bleeding on mortality. However, the remaining increase in mortality risk, both at 30–365 and >365 days, suggests that also indirect effects of bleeding on mortality are at play. It has been suggested that interruption of antiplatelet treatment following a bleeding event, and thereby an increase in the risk for ischaemic events, is one mechanism behind the increase in mortality after major bleeding in patients with coronary artery disease.18 However, in the present study, we adjusted for use of antiplatelet and anticoagulant medications both before and after the event through time-updated covariates, which indicates that other mechanisms were involved. The possibility of major bleeding only being a risk marker for mortality cannot be ruled out, but we made extensive adjustments for covariates and the increase in long-term mortality risk after bleeding has been reported in studies in post-PCI patients and patients with medically managed acute coronary syndrome as well.6 8 10 11

Given the indications for CABG, including left main disease and three-vessel disease, diabetes and reduced left ventricular ejection fraction, CABG patients as a group have extensive coronary artery disease and a high burden of comorbidities. As such, it could be hypothesised that new MI would be detrimental for these patients. At the same time, CABG patients are protected by the ‘surgical collateralization’ compared with PCI patients.19 However, the results of the current study of post-CABG patients are in line with previous studies of post-PCI patients6–10 and patients with medically treated acute coronary syndrome,11 all indicating a prognostically similar impact of postdischarge major bleeding and MI. This suggests that direct comparisons of bleeding risk and ischaemic risk, preferably by using validated risk scores, can be made for patients with coronary artery disease regardless of revascularisation method.

The findings of the present study indicate that major bleeding should be included with ischaemic events in composite endpoints when investigating antithrombotic strategies after CABG. The findings also suggest that strategies to reduce postdischarge bleeding, for example, by initiating proton pump inhibitors among selected patients, screening for Helicobacter pylori infection or systematically using bleeding risk prediction tools when deciding on antiplatelet intensity and duration, could potentially further improve long-term survival after CABG.

Study limitations

We did not have sufficient data to analyse the specific cause of death and could therefore not determine whether patients dying outside of hospitals did so because of bleeding, MI or other causes. We could not use bleeding definitions commonly used in clinical trials, since we did not have data on transfusions and haemoglobin levels. Even though not directly comparable to other definitions, we argue that our definition of major bleeding (hospitalisation with a primary diagnosis of bleeding) is relevant from a clinical and epidemiological perspective. Patient characteristics and comorbidities adjusted for in the statistical models were not updated during follow-up and do not take into account changes in patient status over time. This is a relevant limitation considering that the median time to major bleeding and MI was 3.5 and 3.3 years, respectively. The increase in mortality risk after an event may reflect both a direct association from the event as well as associations mediated via other comorbidities debuting after the event, since comorbidities were not updated and therefore not adjusted for. Despite extensive adjustment for baseline variables and time-updated use of secondary prevention medications throughout follow-up, there is always the risk of unmeasured confounders not included in the statistical analysis.

Considering these limitations, the study also had strengths. The large study population with nationwide real-world data from validated registries indicates high external validity.

Conclusions

In a large, nationwide, contemporary cohort of CABG patients, postdischarge major bleeding events were associated with significantly higher short-term and long-term mortality risks, comparable with that in patients suffering from a postdischarge MI. The incidence of postdischarge major bleeding and MI was also similar. Therefore, trials investigating antithrombotic treatment regimens after CABG should include major bleeding events when determining the net clinical effect of the regimen and clinicians are urged to make the same effort to reduce bleeding events as for minimising the risk for new MIs after CABG.

Data availability statement

Data may be obtained from a third party and are not publicly available. The data underlying this article were provided by a third party, the Swedish National Board of Health and Welfare, under ethics approval. The data can be accessed upon request to the third party.

Ethics statements

Patient consent for publication

Ethics approval

This study involves human participants and was approved by the Regional Research Ethical Committee in Gothenburg (EPN 139-16). The Regional Research Ethical Committee in Gothenburg waived the need for individual patient consent. All cardiac surgery patients in Sweden are notified that patient data are registered in national quality registries and can be used for research after approval from the research ethics committee. Participating in the quality register is voluntary and a patient may at anytime request to delete his/her data.

References

Supplementary materials

  • Supplementary Data

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Footnotes

  • Presented at Preliminary findings from this cohort study were presented as an e-poster at the ESC Congress in August 2021.

  • Contributors EB and AJ are guarantors with full access to all the data in the study and take responsibility for the integrity of the data, the accuracy of the data analysis and the decision to publish. Study concept and design: EB, C-JM, HT, AJ. Acquisition, analysis or interpretation of data: EB, SJN, AJ. Drafting of the manuscript: EB, ECH, AJ. Critical revision of the manuscript for important intellectual content: EB, C-JM, SJN, ECH, HT, PE, AM, ML, AP, AJ. Statistical analysis: AP. Obtained funding: AJ, EB. Administrative, technical or material support: SJN.

  • Funding This work was supported by grants from the Swedish Heart-Lung Foundation (20210433 to AJ), the Swedish state under the agreement between the Swedish government and the county councils concerning economic support of research and education of doctors (ALF agreement, ALFGBG-966204 to AJ), Västra Götaland Region (VGFOUREG-969376 to AJ), Nils Winberg Family’s Foundation and Sparbanken Sjuhärads stiftelse för forskning vid Södra Älvsborg Sjukhus (research grant to EB).

  • Competing interests AJ has received fees for consultancy from AstraZeneca, Werfen and LFB Biotechnologies, all unrelated to the present work.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.