Abstract
Purpose
The study aimed to investigate the associations between impaired spirometry such as obstructive pattern and preserved ratio impaired spirometry (PRISm) and occurrent cardiovascular events and deaths in patients with acute myocardial infarction.
Patients and Methods
Cohort study of 517 patients with age ≥40 years and ≥10 pack-years of smoking, hospitalized for myocardial infarction at eight sites in Sweden and the United Kingdom. The Vitalograph® COPD-6 device was used to assess the ratio of forced expiratory volume in 1 and 6 seconds (FEV1/FEV6) and FEV1 as a percentage of the predicted value (FEV1%pred). Obstructive pattern was defined as FEV1/FEV6 <0.7, PRISm as FEV1/FEV6 >0.7 and FEV1%pred <80, and normal findings as FEV1/FEV6 ≥0.7 and FEV1%pred ≥80. Follow-up data were obtained from national registers or follow-up visits. Multivariable Cox regression was used to analyze the associations of obstructive pattern and PRISm with the incidence of acute ischemic cardiovascular events or major adverse cardiovascular events (MACE), respectively, within one year.
Results
Obstructive pattern was found in 95 (18%), PRISm in 192 (37%) and normal spirometry in 230 (45%) patients. A cardiovascular event occurred in 21 (4%) and MACE in 28 (5%). Compared with normal spirometry, PRISm was independently associated with both new cardiovascular events (HR (95% CI) 3.44 (1.07–11.0)) and MACE (4.94 (1.63 to 15.0)), and obstructive pattern with MACE (3.87 (1.08–13.8)). Further adjustment for cardiac or COPD treatment did not substantially change the results.
Conclusion
About half of patients with acute myocardial infarction and a ≥10 pack-year smoking history have abnormal spirometry findings. Both obstructive pattern and PRISm are independently associated with increased risk for MACE within one year. We suggest that spirometry should be considered as a routine assessment in patients with smoking history and recent myocardial infarction.
Keywords: chronic obstructive pulmonary disease, COPD, obstructive pattern, preserved ratio impaired spirometry, PRISm, acute ischemic cardiovascular events, major adverse cardiovascular events, MACE
Plain Language Summary
Impaired spirometry such as obstructive pattern as in chronic obstructive pulmonary disease (COPD) and preserved ratio impaired spirometry (PRISm) are associated with increased risk of mortality in the general population
The present study investigated the prevalence and associations of obstructive pattern and PRISm with and occurrent cardiovascular events and deaths in patients with acute myocardial infarction, in cohorts from Sweden and the United Kingdom
We found that about half of patients with acute myocardial infarction and a ≥10 pack-year smoking history have abnormal spirometry findings
In patients with acute myocardial infarction and a ≥10 pack-year smoking history, obstructive pattern and PRISm are both associated with increased one-year risk of occurrent acute ischemic cardiovascular events and cardiovascular deaths
Introduction
Several large cohort studies have established chronic obstructive pulmonary disease (COPD) as an independent risk factor for cardiovascular disease and mortality.1–4 Patients with a history of myocardial infarction represent a high-risk group in whom coexisting COPD has consistently been associated with increased morbidity and mortality.5
COPD is considered in patients with respiratory symptoms and/or a history of exposure to risk factors, and is confirmed by spirometry demonstrating an obstructive pattern with low ratio of forced expiratory volume in one second to forced vital capacity (FEV1/FVC).6 Another type of abnormal lung function pattern that has gained increasing interest is preserved ratio impaired spirometry (PRISm). In PRISm, the FEV1/FVC ratio is normal but FEV1 is decreased.7 PRISm is a heterogeneous condition that may include both a restrictive pattern of similarly reduced FEV1 and FVC, and pre-COPD where FEV1 is low but FVC is normal. Patients with PRISm often experience respiratory symptoms and functional limitations, and transitions to COPD over time have been reported in 25% of cases.8
The prognostic significance of PRISm compared with obstructive and normal spirometry results has been investigated in several population-based studies where PRISm was associated with higher risks of incident cardiovascular disease as well as all-cause and cardiovascular mortality.8–15 In the selected population of patients with a previous myocardial infarction, a single study has been published, reporting a higher all-cause mortality risk.16 However, data on the associations of PRISm and obstructive pattern with the risk of future cardiovascular events in patients with newly diagnosed myocardial infarction are lacking.
We previously reported that the Vitalograph® COPD-6 device may be used to identify patients at risk of underlying respiratory disease among those hospitalised for myocardial infarction, demonstrating a prevalence of significant obstructive pattern of around 20% in patients with acute myocardial infarction and a ≥10 pack-year smoking history.17 The aim of the present study was to explore the patterns of abnormal spirometry findings in the same cohort and to test our hypothesis that obstructive pattern and PRISm were associated with increased risk of new cardiovascular events and deaths within one year.
Materials and Methods
Study Design and Data Collection
This was a cohort study of 517 patients consecutively recruited at seven hospitals in Sweden from February 2022 to March 2023 and at one hospital in the United Kingdom from January to November 2022.17 Inclusion criteria were ongoing hospitalization due to acute myocardial infarction, age ≥40, ≥10 pack years of smoking (regardless of current smoking status), and ability and willingness to provide written consent. Important exclusion criteria were current ischemic chest pain (eg. awaiting revascularization), acute pulmonary oedema, cardiogenic shock or other acute conditions in which forced respiratory manoeuvers could not be performed.
Baseline data on sex, age, comorbid diabetes, systolic blood pressure, current smoking status, body mass index (BMI) and relevant treatment at discharge in terms of beta-blockers, angiotensin-converting enzyme/angiotensin receptor inhibitors (ACE/AII-inhibitors), antiplatelet therapy (aspirin and P2Y12 inhibitors), oral anticoagulants, statins, long-acting muscarinic antagonists (LAMA), long-acting beta-2-agonists (LABA) and inhaled corticosteroids (ICS), were obtained from clinical records and, in Sweden, also from the national quality register Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies (SWEDEHEART).18 Follow-up data on cardiovascular events and mortality were obtained from the national Patient and Cause of Death registers (Sweden),19,20 and from follow-up visits (United Kingdom).
Baseline information on lung function in both sub-cohorts was collected by performing microspirometry using the Vitalograph® COPD-6 device, which examines the ratio of forced expiratory volume in 1 and 6 seconds (FEV1/FEV6) and FEV1 as percentage of the predicted value (FEV1%pred).21 The standard procedure includes three exhalations, with the best results of FEV1/FEV6, FEV1 and FEV6 saved in the device. An obstructive pattern is confirmed by establishing a FEV1/FVC ratio below 0.7, and the COPD-6 device was originally developed as a screening instrument with ≥0.73 as a cut-off for ruling out obstructive disease.22,23 However, as the maximum breath volume is usually exhaled in less than six seconds, several devices for FEV1/FEV6 assessment have also been proven valuable for COPD diagnosis, using FEV1/FEV6 <0.7 to define obstruction,24–26 with very good correlation to ordinary spirometry.27 In the present paper, baseline lung function data were used to further classify patients based on FEV1/FEV6 and FEV1%pred as normal spirometry (defined as FEV1/FEV6 ≥0.7 and FEV1%pred >80), PRISm (FEV1/FEV6 ≥0.7 and FEV1%pred <80) and obstructive pattern (FEV1/FEV6 <0.7).27
A cardiovascular event was defined as an ischemic cardiovascular event consisting of a new myocardial infarction (fatal or non-fatal) (ICD-10, I21) or an ischemic stroke (I63), within one year. A cardiovascular death was defined as death due to any condition within ICD-10 chapter I within one year. Major adverse cardiovascular events (MACE) were defined as an ischemic cardiovascular event or cardiovascular death within one year.
Statistical Analysis
Patient characteristics were presented as mean and standard deviation for continuous variables (all approximately normally distributed) and as numbers and percentages for categorical variables. Crosstabulations with chi-square test and Kaplan-Meier curves were used to explore patient characteristics, cardiovascular events and MACE in patients with obstructive pattern, PRISm and normal spirometry. As a sub-analysis of the PRISm group, these patients were further divided into PRISm with restrictive pattern (ie, low FEV6 in percentage of predicted (FEV6%pred) as a proxy for low vital capacity in addition to low FEV1%pred)28 and PRISm with isolated low FEV1%pred as a marker of pre-obstructive disease sometimes referred to as COPD 0.
Univariable and multivariable Cox regression, with adjustment for sex, age, comorbid diabetes and systolic blood pressure, used lung function pattern (in the three categories) as the explanatory variable, and all-cause death, cardiovascular events and MACE, respectively, as outcome variables. The models were repeated using obstructive pattern as the reference variable to allow a head-to-head analysis of obstructive pattern and PRISm, and with a binary variable of any pathological spirometry finding (obstructive pattern or PRISm) vs normal spirometry as the explanatory variable. The confounders were based on previous knowledge of risk factors for cardiovascular events and death. The main models were also repeated with further adjustment for relevant treatment at discharge as described above. Due to few missing data in the main model, complete case analysis was used. All analyses were performed using IBM SPSS version 26 (IBM Corporation, Armonk, NY, USA), and statistical significance was defined as a two-sided p < 0.05.
Ethics Approval and Consent to Participate
The study complies with the Declaration of Helsinki. The Swedish sub-study was approved by the Swedish Ethical Review Authority (Dnr 2021–05615-01), and the United Kingdom sub-study by the National Health Service Yorkshire & the Humber (Bradford/Leeds) Research Ethics Committee (Ref 22/YH/0015). All participants provided written informed consent.
Results
Patient characteristics were mostly similar in both sub-cohorts, with a mean age of 65 years and the majority being male (Table 1). The proportion of patients receiving oral anticoagulants was somewhat higher in Sweden, while current smoking and treatment at discharge with beta-blockers, antiplatelet therapy, LAMA and LABA were slightly more common in the UK (Table 1).
Table 1.
Patient Characteristics, Treatments and Spirometry Results at Baseline, and Events at One-year Follow-Up, Distributed Over Sub-Cohorts
| Sweden | UK | All | |
|---|---|---|---|
| Baseline characteristics | |||
| Male sex, n (%) | 229 (76) | 159 (74) | 388 (75) |
| Age, mean (SD)* | 68 (10) | 60 (10) | 65 (11) |
| Systolic BP, mean (SD)* | 147 (27) | 123 (19) | 137 (27) |
| Diabetes, n (%) | 67 (22) | 34 (16) | 101 (20) |
| Current smoking, n (%)* | 114 (38%) | 124 (58%) | 238 (46%) |
| BMI, n (%) | |||
| <20 | 4 (1.5) | 7 (4) | 11 (2) |
| 20.0–24.9 | 60 (22) | 44 (24) | 104 (23) |
| 25.0–29.9 | 119 (44) | 70 (37) | 189 (41) |
| ≥30 | 86 (32) | 66 (35) | 152 (33) |
| Treatment at discharge | |||
| Beta-blockers, n (%)* | 226 (75) | 186 (87) | 412 (80) |
| ACE/AII-inhibitors, n (%) | 236 (78) | 180 (84) | 416 (81) |
| Antiplatelet therapy, n (%)* | 279 (92) | 213 (99) | 492 (95) |
| Oral anticoagulants* | 44 (15) | 14 (7) | 58 (11) |
| Statins, n (%) | 272 (90) | 203 (94) | 475 (92) |
| LAMA, n (%)* | 18 (6) | 28 (13) | 46 (9) |
| LABA, n (%)* | 29 (10) | 37 (17) | 66 (13) |
| ICS, n (%)* | 31 (10) | 34 (16) | 65 (13) |
| Spirometry pattern | |||
| Normal, n (%) | 137 (45) | 93 (43) | 230 (45) |
| PRISm, n (%) | 111 (37) | 81 (38) | 192 (37) |
| Obstructive, n (%) | 54 (18) | 41 (19) | 95 (18) |
| One year follow-up events | |||
| MI, n (%) | 10 (3) | 5 (2) | 15 (3) |
| CVL, n (%) | 3 (1) | 1 (1) | 4 (1) |
| CV death, n (%) | 7 (2) | 1 (1) | 8 (2) |
| All-cause death | 12 (4) | 5 (2) | 17 (3) |
| CV events | 13 (4) | 6 (3) | 19 (4) |
| MACE* | 20 (7) | 6 (3) | 26 (5) |
Note: Statistical differences between countries are indicated by an asterisk.
Abbreviations: ACE/AII-inihibitors, angiotensin converting enzyme/angiotensin II-receptor inhibitors; BMI, body mass index; BP, blood pressure; CV, cardiovascular; CVL, cerebrovascular lesion; ICS, inhaled corticosteroids; LABA, long-acting beta-2 agonists; LAMA, long-acting muscarinic antagonists; MACE, major adverse cardiovascular events; MI, myocardial infarction; PRISm, preserved ratio impaired spirometry; SD, standard deviation; UK, United Kingdom.
Obstructive pattern was found in approximately one-fifth of the merged population, while PRISm and normal spirometry were observed in about two-fifths each (Table 1). Within one year, a cardiovascular event occurred in 21 patients (4%) and the composite of MACE in 28 patients (5%) (Table 1). Total one-year mortality was 17 (3%) of whom 8 patients died from cardiovascular disease (Table 1).
The proportions of patients with current smoking, cardiovascular events and MACE were higher among those with PRISm and obstructive pattern than among patients with normal spirometry (Table 2 and Figure 1). Obesity was more frequent in patients with normal spirometry and PRISm compared with obstructive pattern (Table 2). The majority (94%) of the patients with PRISm, and all of the patients with both PRISm and MACE, had a restrictive pattern with both low FEV1 and FEV6. Among those with complete data on height and weight, BMI ≥30 was found in 40% of patients with restrictive PRISm compared with only 10% of patients with pre-obstructive pattern (COPD 0).
Table 2.
Patient Characteristics and Outcomes Distributed Over Spirometry Pattern
| Normal Spirometry | PRISm | Obstructive | p-value | |
|---|---|---|---|---|
| Male sex, n (%) | 178 (77) | 138 (72) | 72 (76) | 0.420 |
| Age, mean (SD) | 64 (11) | 65 (11) | 66 (10) | 0.149 |
| Systolic BP, mean (SD) | 140 (26) | 135 (27) | 133 (26) | 0.026 |
| Diabetes, n (%) | 38 (17) | 48 (25) | 15 (16) | 0.054 |
| Current smoking, n (%) | 87 (38) | 99 (52) | 52 (55) | 0.003 |
| BMI, n (%) | 0.001 | |||
| <20 | 1 (1) | 4 (2) | 6 (7) | |
| 20.0–24.9 | 39 (19) | 39 (23) | 26 (32) | |
| 25.0–29.9 | 93 (46) | 63 (37) | 33 (40) | |
| ≥30 | 70 (35) | 65 (38) | 17 (21) | |
| Beta-blockers | 181 (79) | 159 (83) | 72 (76) | 0.335 |
| Antiplatelet therapy | 219 (95) | 181 (94) | 92 (97) | 0.633 |
| Oral anticoagulants | 18 (8) | 26 (14) | 14 (15) | 0.087 |
| Statins | 210 (91) | 177 (92) | 88 (93) | 0.906 |
| ACE/AII inhibitors | 188 (81) | 148 (77) | 82 (86) | 0.175 |
| LAMA | 3 (1) | 25 (13) | 18 (19) | <0.001 |
| LABA | 16 (7) | 33 (17) | 17 (18) | 0.002 |
| ICS | 19 (8) | 28 (15) | 18 (19) | 0.017 |
| CV events, n (%) | 4 (2) | 10 (5) | 5 (5) | 0.112 |
| MACE, n (%) | 4 (2) | 15 (8) | 7 (7) | 0.009 |
| CV death, n (%) | 1 (0) | 5 (3) | 2 (2) | 0.176 |
| Death, all cause, n (%) | 3 (1) | 9 (5) | 5 (5) | 0.075 |
Abbreviations: ACE/AII inhibitors, angiotensin converting enzyme/angiotensin II receptor inhibitors; BMI, body mass index; BP, blood pressure; CV, cardiovascular; ICS, inhaled corticosteroids; LABA, long-acting beta-2-agonists; LAMA, long-acting muscarinic antagonists; MACE, major adverse cardiovascular events; PRISm, preserved ratio impaired spirometry; SD, standard deviation.
Figure 1.
Proportions of CV events and MACE in different spirometry patterns.
Abbreviations: CV, cardiovascular; MACE, major adverse cardiovascular events; PRISm, preserved ratio impaired spirometry.
The risks of cardiovascular events and MACE were higher in both PRISm and with obstructive pattern compared with normal spirometry (Figure 2). In the multivariable Cox regression analyses, PRISm was independently and statistically significantly associated with MACE and cardiovascular events, and obstructive pattern with cardiovascular events (Table 3 and Figure 3). When the reference category was changed to obstructive pattern, no significant differences in the adjusted risk for CV events (HR (95% CI) 0.98 (0.33 to 2.91), p = 0.969) or MACE (1.28 (0.49 to 3.32), p = 0.617) were found for PRISm compared with obstructive pattern. Using the combined binary variable of obstructive pattern /PRISm vs normal spirometry, abnormal spirometry was independently associated with an increased risk for cardiovascular events (HR (95% CI) 3.46 (1.14 to 10.5) and MACE (4.58 (1.56 to 13.4).
Figure 2.
Kaplan-Meier curves of time to cardiovascular event and MACE in patients with obstructive, PRISm or normal spirometry patterns.
Abbreviations: CV, cardiovascular; MACE, major adverse cardiovascular events; PRISm, preserved ratio impaired spirometry.
Table 3.
Results from Univariable and Multivariable Cox Regression, with Adjustment for Sex, Age, Diabetes and Systolic Blood Pressure
| CV Events | MACE | |||
|---|---|---|---|---|
| Unadjusted HR (95% CI) | Adjusted HR (95% CI) | Unadjusted HR (95% CI) | Adjusted HR (95% CI) | |
| Spirometry pattern | ||||
| Normal | Ref | Ref | Ref | Ref |
| PRISm | 3.12 (0.98–9.96) | 3.44 (1.07–11.0) | 3.12 (0.98–9.96) | 4.94 (1.63–15.0) |
| Obstructive | 3.16 (0.85–11.8) | 3.51 (0.93–13.3) | 3.16 (0.85–11.8) | 3.87 (1.08–13.8) |
| Male sex | 1.24 (0.41–3.73) | 1.26 (0.41–3.84) | 1.24 (0.41–3.73) | 1.15 (0.45–2.90) |
| Age | 1.02 (0.98–1.06) | 1.01 (0.96–1.05) | 1.02 (0.98–1.06) | 1.03 (0.99–1.07) |
| Systolic BP | 1.02 (1.00–1.03) | 1.02 (1.00–1.04) | 1.01 (1.00–1.03) | 1.01 (1.00–1.03) |
| Diabetes | 1.10 (0.36–3.30) | 0.89 (0.29–2.72) | 1.10 (0.36–3.30) | 0.79 (0.30–2.13) |
Abbreviations: BP, blood pressure; CI, confidence interval; CV, cardiovascular; HR, hazard ratio; MACE, major adverse cardiovascular events; PRISm, preserved ratio impaired spirometry.
Figure 3.
Associations of PRISm and obstructive spirometry with CV events and MACE. Results from Cox regression, respectively, with adjustment for sex, age, diabetes and systolic blood pressure.
Abbreviations: CI, confidence interval; CV, cardiovascular; MACE, major adverse cardiovascular events; PRISm, preserved ratio impaired spirometry.
Neither PRISm (HR (95% CI) 3.19 (0.86 to 11.9) nor obstructive pattern (2.00 (0.40 to 10.0) demonstrated an independent statistically significant association with all-cause mortality.
When the main Cox regression model was repeated with further adjustment for cardiac and COPD discharge treatment, the numerical risk estimates of cardiovascular events and MACE in patients with PRISm and obstructive pattern were only slightly reduced (Table 4). In this material, antiplatelet treatment was the therapy with a statistically significant association with a reduced risk of MACE (Table 4).
Table 4.
Results from Univariable and Multivariable Cox Regression, with Adjustment for Sex, Age, Diabetes, Systolic Blood Pressure and Treatment
| CV Events | MACE | |
|---|---|---|
| Adjusted HR (95% CI) | Adjusted HR (95% CI) | |
| Spirometry pattern | ||
| Normal | Ref | Ref |
| PRISm | 2.93 (0.86–9.96) | 4.52 (1.44–14.2) |
| Obstructive | 3.26 (0.82–12.9) | 3.61 (0.97–13.4) |
| Male sex | 1.57 (0.45–5.52) | 1.71 (0.61–4.80) |
| Age | 1.01 (0.96–1.06) | 1.02 (0.98–1.07) |
| Systolic BP | 1.02 (1.00–1.04) | 1.02 (1.00–1.03) |
| Diabetes | 1.00 (0.33–3.09) | 0.80 (0.29–2.21) |
| Beta-blockers | 0.50 (0.18–1.44) | 0.52 (0.21–1.29) |
| ACE/AII-inhibitors | 1.63 (0.26 to 7.37) | 0.83 (0.30 to 2.26) |
| Antiplatelet therapy | 0.17 (0.01 to 2.10) | 0.15 (0.03 to 0.87) |
| Oral anticoagulants | 0.28 (0.04 to 2.22) | 0.66 (0.18 to 2.48) |
| Statins | 0.80 (0.10 to 6.38) | 0.36 (0.10 to 1.32) |
| LAMA | 3.21 (0.41 to 25.0) | 2.90 (0.46 to 18.4) |
| LABA | 1.75 (0.14 −21.8) | 1.12 (0.13 to 10.1) |
| ICS | 0.40 (0.06–2.89) | 0.57 (0.10–3.06) |
Abbreviations: ACE/AII inhibitors, angiotensin converting enzyme/angiotensin receptor inhibitors;)BP, blood pressure; CI, confidence interval; CV, cardiovascular; HR, hazards ratio; ICS, inhaled corticosteroids; LABA, long-acting beta-2-agonists; LAMA, long-acting muscarinic antagonists; MACE, major adverse cardiovascular events; PRISm, preserved ratio impaired spirometry; SD, standard deviation.
Discussion
Main Findings
In this study of patients with a history of myocardial infarction and a ≥10 pack-year smoking history, impaired spirometry, whether consistent with an obstructive pattern or with PRISm, was associated with increased cardiovascular risk compared with those with normal spirometry. The associations remained robust in multivariable models adjusted for baseline use of standard cardiac therapies and COPD inhaled treatments, underscoring the independent prognostic value in this high-risk group. Importantly, these prognostically significant findings were identified using a simple and feasible COPD-6 device for in-hospital screening.
Our results are consistent with several population-based studies, where COPD and PRISm have been reported as major prognostic risk factors for cardiovascular disease and mortality.8–16 Our study extends previous knowledge of associations with all-cause and cardiovascular mortality in patients with myocardial infarction to include associations with cardiovascular events and MACE. As for all-cause mortality, we believe that the absence of a significant association with impaired spirometry could be due to low number of deaths in the present study.
Spirometry Patterns and Potential Underlying Conditions
As our study population had a clear tobacco exposure, we find it very reasonable to assume that an established obstructive pattern most likely is due to underlying COPD. As COPD is an established independent risk factor for heart disease,1–4 this assumption is supported by our reported association of an obstructive pattern with a higher risk of MACE.
The relatively high prognostic importance of PRISm deserves further discussion. As described, PRISm is a heterogeneous condition that may include both a restrictive pattern of similarly reduced FEV1 and FVC and the condition sometimes referred to as pre-COPD or COPD 0, where FEV1 is low but FVC is normal. Previous population-based studies have found both restrictive and obstructive spirometry patterns to be associated with all-cause as well as respiratory and cardiovascular mortality.29,30 Restrictive patterns may be explained by intrapulmonary conditions such as pulmonary fibrosis, or by extrapulmonary conditions like obesity, thoracic deformations or neuromuscular diseases. In patients with acute myocardial infarction, secondary severe heart failure with fluid retention in the interstitial space may theoretically cause intrapulmonary restriction, but a detected PRISm with both reduced FEV1 and FEV6 would most likely be due to obesity.
In our study, the majority of the patients with PRISm had a restrictive pattern, and BMI ≥30 was much more common in patients with restrictive PRISm compared with patients with pre-COPD pattern with isolated low FEV1%pred. Thus, we speculate that the increased risk associated with PRISm in our study is driven by restrictive disease, probably most commonly due to metabolic syndrome with obesity, rather than solely pre-stage COPD. Heart failure with pleural effusion and interstitial fluid retention or interstitial lung disease were not exclusion criteria and could potentially have caused restriction in patients with normal or low BMI.
However, it is very important to keep in mind that in patients with COPD and a comorbid restrictive condition, the obstruction may be masked. If the vital capacity or FEV6 is reduced both by higher residual volume due to emphysema (as part of COPD) and by reduced total lung capacity due to pulmonary or extrapulmonary restriction, the otherwise low ratio may be normalized. This means that we cannot exclude, especially in this setting with all patients having a significant smoking history, that at least some of the patients with PRISm in our population had both COPD and restrictive disease, which would contribute to the increased risk.
Treatment Interventions
The fact that a majority of patients already had guideline-recommended treatment for secondary prevention after myocardial infarction at discharge from the initial hospitalization, may explain why differences in outcome events due to cardiovascular treatment at discharge were largely not found.
ICS has been suggested to reduce mortality in patients with COPD when used with long-acting bronchodilators, by decreasing the risk for both exacerbations and cardiovascular events.31,32 Further adjustment for ICS usage did not reduce the estimates in our study, but we speculate that this may at least partly be due to low power with only a few patients using ICS.
Clinical Implication and Need for Further Research
We suggest that all patients with myocardial infarction and a smoking history should be considered for spirometry, and that patients with abnormal findings should be further referred to a pulmonologist or to a primary care physician. Further pulmonary investigation of patients with PRISm and no obvious untreated clinical heart failure could include body plethysmography and arterial blood gas analysis to identify obesity hypoventilation syndrome or overlap syndrome (COPD and obesity hypoventilation syndrome), which may require nocturnal home ventilation therapy, or computed tomography scanning to identify interstitial lung disease, which may warrant specific treatment.
The ongoing randomized controlled trial THARROS (clinicaltrials.gov nr NCT06283966) aims to investigate the utility of budesonide in combination with long-acting dual bronchodilators in preventing cardiorespiratory events in patients with COPD and comorbid cardiovascular disease or risk factors. However, future randomized controlled trials on the role of ICS in populations including PRISm are also warranted.
Strengths and Limitations
The major strengths of the study are the consecutive recruitment at multiple centers in two different countries, the longitudinal design and the completeness of follow-up data due to mandatory public health registers. Limitations include relatively limited power due to a small sample size, the absence of full spirometry or body plethysmography, lack of information on the potential confounder of occupational and environmental exposure to smoke, dust and gas, and some differences in data collection between countries. However, FEV1/FEV6 has been shown to correlate well with FEV1/FVC (27), and the COPD-6 device is reliable for the diagnosis of obstructive disease.24–26 As for event data collection, we believe the nature of our outcome events is fully captured by follow-up visits in secondary care or registers, as acute cardiovascular events are usually not managed outside hospitals.
Conclusion
About half of patients with acute myocardial infarction and a ≥10 pack-year smoking history have abnormal spirometry findings. Both findings of obstructive pattern and PRISm are independently associated with increased risk of MACE within one year. We suggest that spirometry should be considered a routine assessment in patients with a smoking history and a recent myocardial infarction.
Acknowledgments
We thank all participating research nurses who performed the COPD-6 assessment.
Funding Statement
This work was funded by Externally Sponsored Research Grants from AstraZeneca.
Data Sharing Statement
Data cannot be made freely available as they are subject to secrecy in accordance with the Swedish Public Access to Information and Secrecy Act, but can be made available to researchers upon request, after approval from the Swedish Ethical Review Authority has been obtained: www.etikprovningsmyndigheten.se/en/.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
J. Sundh reports personal fees for educational activities and lectures from AstraZeneca, Boehringer Ingelheim, Chiesi, Novartis and Taked a. W.A.E. Parker reports research support and personal fees from AstraZeneca. J. Oldgren reports institutional research grants/support from Amgen, AstraZeneca, Bayer, Novo Nordisk, and Roche Diagnostics. P. Andell reports institutional lecture fees from AstraZeneca and Novo Nordisk/Amgen. C. Reitan has participated in research projects funded by AstraZeneca and Merck. R. Hofmann reports institutional lecture and advisory board fees from AstraZeneca and BMS/Pfizer. D. Erlinge has received honorarium for advisory board/speaker fees from Amgen, AstraZeneca, Chiesi, Sanofi, NovoNordisk, InfraredX/Nipro and Kaminari Medical. A. Åkerblom is an employee of Boehringer Ingelheim. S Sederholm Lawesson has received lecture fees from Pfizer, Novo Nordisk, Astra Zeneca, Novartis, Amarin, Boehringer Ingelheim and Bayer; research fees from Astra Zeneca and Amgen to her clinical institution and has served at Advisory Boards for Novartis and Novo Nordisk. K.V. Konstantinidis, M Patel, J El Khoury and R Surujbally are employees of AstraZeneca. C Janson has received honoraria for educational activities and lectures from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Orion, and TEVA, and has served on advisory boards arranged by AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Orion, and TEVA. A. Björkenheim reports personal fees for educational activities and lectures from Bayer, Medtronic and Abbott. S James has received research grants to his institution from Amgen, Novo Nordisk, Astra Zeneca, Novartis, Merck and compensation for valve proctoring from Medtronic. H McMellon has received fees for being study coordinator for Novo Nordisk UK, outside the submitted work. R.F. Storey reports institutional research grants/support from AstraZeneca and Cytosorbents; and personal fees from Abbott, Alfasigma, AstraZeneca, Boehringer Ingelheim/Lilly, Bristol Myers Squibb/Johnson & Johnson, Chiesi, Cytosorbents, Daiichi Sankyo, Idorsia/Viatris, Novartis, Novo Nordisk, Pfizer, PhaseBio, Thrombolytic Science and Tabuk. The authors report no other conflicts of interest in this work.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data cannot be made freely available as they are subject to secrecy in accordance with the Swedish Public Access to Information and Secrecy Act, but can be made available to researchers upon request, after approval from the Swedish Ethical Review Authority has been obtained: www.etikprovningsmyndigheten.se/en/.