In a primary care defined COPD population, this study examined the clinical profiles of people hospitalized for HF and for AF within a month post exacerbation. We observed that the odds of HF and of AF hospitalization were higher for people with severe, hospitalized exacerbations and with cardiovascular-related history. For HF analyses only, the odds of HF were also higher for people with microvascular factors (i.e., type II diabetes; obesity; CKD) and for people with pulmonary factors, namely those with worse GOLD grade of airflow limitation and higher levels of MRC breathlessness scores.
Heart failure
The pathophysiological links between COPD exacerbations and HF are recognized [
31‐
33]. Upon exacerbation, dynamic lung hyperinflation from airflow limitation alongside heightened inflammation and hypoxia, can lead to increased strain on both the lungs and heart. The increased cardiopulmonary pressure can then lead to impaired contraction or filling of the left ventricle, namely HF with preserved or with reduced ejection fraction, respectively [
31‐
33].
Few studies have investigated factors associated with HF in COPD alone, [
15,
34‐
36] of which only one [
15] investigated hospitalized exacerbation with concurrent HF, but did not quantify this relationship with ORs, and was conducted in the US National Inpatient Sample (NIS) database. The remaining were post-hoc analyses of trials focused on stable COPD [
34‐
36].
The strong magnitude of the association for exacerbation severity (hospitalization) but not for exacerbation frequency, suggests two points. First, from a healthcare service-level standpoint, patients hospitalized for exacerbations are more likely to be hospitalized for a future HF (i.e., re-admission) compared with patients whose exacerbation was managed in primary care. Second, clinically, exacerbation severity (e.g., greater intensity of inflammation) has a greater indication of a patients’ future cardiac state, rather than past exacerbation occurrence and management. Findings for older age were anticipated and align with previous studies [
15,
34‐
36].
The associations for history of HF, arrhythmia, type II diabetes, and CKD with post-exacerbation HF are unsurprising given their known independent relationships each with HF and exacerbations alone. Chronic, unmanaged HF can lead to future health service utilization for HF [
16,
37]. Arrhythmia-attributed cardiac remodeling can contribute to development of cardiomyopathy [
38]. Diabetes is a risk factor for substantial HF progression [
16,
39], and separately a population-based study in COPD patients demonstrated an increased risk of cardiovascular mortality with type II diabetes [
40]. Impaired renal hemodynamics and activation of the renin-angiotensin-aldosterone system (RAAS) can lead to HF, [
41] and separately reduced kidney function is associated with future HF [
42].
Our findings for cardiovascular medications indicate a certain treatment profile in primary care, leading up to the post-exacerbation HF hospitalization. The strongest association for diuretics suggests that leading up to future HF, patients perhaps are receiving treatment indicated for uncontrolled edema from existing HF, diabetic cardiomyopathy, or CKD for example.
GOLD and MRC as factors for post-exacerbation HF likewise were expected. Increased breathlessness and reduced lung function are not only symptoms of an imminent exacerbation or HF; equally, these factors can also indicate delayed diagnosis of unstable COPD or HF, [
16,
43] given their shared symptomology [
3,
12,
14]. Reduced lung function can contribute to worsening prognosis and precipitate a future exacerbation or HF [
16,
43].
Atrial fibrillation
The pathophysiological mechanisms implicating AF post COPD exacerbation are also established [
19,
44]. At time of exacerbation, drastic increases in lung hyperinflation and impaired intrathoracic pressures can cause increased pulmonary vascular resistance and damage, leading to alterations to atrial electrophysiology [
19,
44]. Compromised gas exchange in the lungs can induce systemic inflammation and oxidative stress too, and also put strain on pulmonary vasculature, leading to abnormal atrial structure and ion-channel remodeling, [
19,
44] while certain treatments prescribed upon exacerbation are arrhythmogenic [
19,
44].
Only four studies have investigated patient profiles for AF development in unstable COPD, all hospital-based [
18,
21‐
23], of which two conducted in the US National Inpatient Sample (NIS) database [
18,
22]. Two examined factors associated with AF diagnosis after exacerbation [
21,
22] one of which patients had existing AF [
21]. Two failed to quantify with ORs, only comparing baseline characteristics of exacerbating patients by status of concurrent AF [
18,
23].
Our findings for older age and male gender are not unexpected; studies similarly found these associations in exacerbating [
18,
22] and in stable COPD [
45]. Unsurprisingly, exacerbation severity associated with future AF, again adding to the existing evidence of stronger associations for hospitalized exacerbation [
1,
6] and again, likewise to HF, suggests a distinction between healthcare service-level patient pathways, and intensity versus frequency.
The associations we found for history of PH and arrhythmias aligns with what was anticipated clinically. Electrophysiological and structural changes to the atrium over time, from either AF itself [
20] or from chronic atrial stretching and fibrosis attributed to PH, [
46] can lead to future AF. While a study using Euro Heart Survey data showed COPD as a factor for progression of paroxysmal to persistent AF (aOR=1.51, 95%CI 0.95-2.39) [
20], neither of the two studies looking at patient profiles for post-exacerbation AF, looked at chronic, prevalent arrhythmias itself as a factor [
21,
22]. No studies have looked at PH, although the study among end-stage COPD patients in the NIS database found a weak association for pulmonary circulatory disorders (aOR=1.44, 95%CI 1.37-1.52) [
22], compared the OR of about 3 for PH. A study found raised pulmonary artery pressure to be associated with AF (p<0.05), but failed to quantify, and it was small, underpowered, and not generalizable as it restricted to hospitalized COPD patients with existing AF [
21].
The lack of associations for prior ACS, ischemic stroke, HF, and hypertension somewhat contradict the study among hospitalized, end-stage COPD patients, [
22] where an association was found for HF (aOR=2.42; 95%CI: 2.36-2.48) and coagulopathy (aOR=1.23; 95%CI:1.16-1.31), but again this may reflect the more severe prognosis of these patients versus those in our study.
Likewise to HF, findings for cardiovascular medications indicate a certain treatment profile in primary care, leading up to the post-exacerbation AF hospitalization. Although we were unable to adjudicate by specific subtype of AF,(e.g., paroxysmal, persistent) the strongest associations for positive inotropes, anti-arrhythmic drugs, and anticoagulants may suggest that leading up to future AF, patients perhaps are receiving treatment to manage abnormal heart rate and/or rhythm, and/or to prevent clotting. Future research could investigate the respective treatment profile relative to paroxysmal AF and to persistent AF [
47] to confirm and extend our findings.
Our null results for other comorbidities (i.e., depression and depressive symptoms, anxiety, BMI, CKD, and type-II diabetes) goes against studies finding an association for diabetes, [
18,
22] mixed findings for depression, [
18,
22] among other comorbidities. Yet these observed associations could be due to differing context; using the NIS database in a study population of only hospitalized, exacerbating, insured payors. GOLD airflow obstruction and MRC dyspnea score were not associated with post-exacerbation AF hospitalization, possibly as AF is often associated with vague symptoms of onset and not necessarily immediately thought about as a cause of increasing breathlessness in someone with COPD [
44,
48,
49].
Methodological considerations
A key strength is our generalizable COPD cohort, defined within the electronic healthcare record with detailed data to examine and adjust for a range of factors. Unlike other studies, this allowed us to look at two patient pathways: cardiovascular-related hospitalizations post primary-care exacerbation, and re-admissions post hospitalized exacerbation. Our exclusion criteria allowed us to quantify the odds of new onset HF and AF hospitalizations following exacerbation, by ensuring no evidence of AF or HF in the year prior to exacerbation. We chose to study two common cardiovascular conditions in COPD, AF and HF. We could not subdivide HF and AF more granularly, because of insufficient statistical power and the inability to obtain electrocardiogram or echocardiogram results to adjudicate.
We used validated codes to define COPD [
26] and COPD exacerbations [
27,
28] so misclassification is unlikely. Where possible, we used previously tested methods [
30] and codes to define our factors-of-interest and codes were checked by a pulmonologist and/or cardiologist. The nested case control matched design allowed us to control for unmeasurable potential clinical differences in disease management by clinicians, by matching patients on GP practice.
To minimize selection bias among patients with measured factors only, we adjusted only for covariates without substantial missing data. We reserved GOLD, MRC, and CKD for sensitivity analyses; the associations of these factors with HF are generalizable only to patients with measurements (e.g., patients with greater healthcare monitoring, provision, or access). For this reason, the relationship for ethnicity could not be quantified, and given the data sparsity. For the HF analysis, we were unable to quantify B-type natriuretic peptide testing as a factor (BNP or NT-proBNP) because of 90% missing data for BNP (data not shown).
Confounding by indication is possible, particularly for the associations observed for cardiovascular medications (cases could have been more likely prescribed cardiovascular medications to manage a prevalent co-morbidity (perhaps with delayed diagnosis) that posed future cardiovascular risk, compared with controls) [
50]. For example, although 12.8% of HF cases had prevalent HF diagnoses at baseline (201/1569), over 70% of HF cases were prescribed diuretics (1122/1569). Diuretics, particularly extended use of loop diuretics, can indicate possible, pre-HF diagnoses [
51], given HF diagnoses tend to be delayed in COPD patients [
14,
37,
51]. Taking this information together, this suggests a substantial proportion of cases could have been prescribed diuretics to manage possible-yet-undiagnosed HF, in which case, the later case-defining hospitalization was the delayed, first-time diagnosis of HF.
Our results for cardiovascular medications do not imply these medications are increasing the cardiovascular risk, rather they add to an understanding of the exacerbating patient profile. Furthermore, although these medications could indicate delayed CVD diagnosis, alternatively they could be medically indicated for management of a co-morbidity we did not adjust for, e.g., beta-blockers can be prescribed for thyroid conditions [
52].
Implications for clinical practice
Within the month-window following an exacerbation, largely exacerbation intensity and cardiovascular-related management and disease history were associated with odds of incident HF and AF. For HF specifically, existing type II diabetes, CKD, lung function (GOLD grade), and levels of breathlessness (MRC) had an association too—but not for AF. These factors can help better identify patients most at-risk for HF and AF, to streamline efforts to allocate screening, vigilant monitoring, and prevention.
At the time of a COPD exacerbation, particularly hospitalized exacerbation, we recommend preemptively monitoring markers of possible HF, through taking medication history of loop diuretics, [
51] and through BNP testing [
53]. At present however, HF prevention is narrow in scope, with guidelines for early identification of HF not explicitly considering unstable COPD [
53,
54]. Our results suggest that HF monitoring should widen to include patients with COPD exacerbations.
Upon exacerbation, particularly hospitalized exacerbation, we recommend proactively screening for AF (e.g., electrocardiogram) [
19] as AF commonly presents subclinically [
17]. Still, at present, AF screening is narrow in scope; it is primarily conducted in patients with existing or suspected AF with the goal of preventing stroke, with AF guidelines not explicitly considering unstable COPD [
17,
55]. Our results suggest that AF screening should widen to include patients with COPD exacerbations, to help prevent future AF—even before stroke.