Characteristics and outcome of a first acute myocardial infarction in patients with ankylosing spondylitis

Ankylosing spondylitis (AS) is a chronic, inflammatory disease, primarily involving the spine as well as peripheral joints and entheses [1]. Well-known cardiovascular complications of AS include cardiac conduction disorders and aortic regurgitation [2]. Recent studies have shown that patients with AS also have an increased risk of atherosclerotic comorbidity such as acute myocardial infarction (AMI) and stroke compared with the general population [3‐5]. In total, patients with AS have a higher both overall and cardiovascular disease (CVD)–related mortality compared with the general population [6, 7].

Inflammation may have an impact on the development of accelerated atherosclerosis in AS [8], but an increased frequency of traditional risk factors (diabetes mellitus, hypertension, hyperlipidemia, and smoking) may also add to the risk of AMI [3, 9]. Moreover, there are indications that patients with chronic inflammatory diseases might have an altered outcome after an CVD event [3, 10, 11]. Since AS also affects the entheses of the thorax, chest pain is common among these patients as part of the rheumatic disease, which could result in an atypical clinical presentation that may be misinterpreted by both patients and caregivers [12]. The course and pattern of AMI in AS patients compared with general population controls have not previously been studied systematically.

With this background we wanted to study (1) clinical characteristics of as well as (2) CVD-related and general mortality after a first incident AMI and (3) the initiation and prescription of cardioprotective secondary preventive pharmacotherapies after first incident AMI in a population-based cohort of patients with prevalent AS compared with the general population.

Baseline data and variables used to characterize the AMI are presented as frequencies (percentage of individuals with available data, %) or means (standard deviation, SD) as appropriate. Differences between the groups were tested using chi² tests, t test, or Mann-Whitney U test as appropriate. One-year time-to-event was summarized by Kaplan-Meier method and survival distributions were compared by log-rank test. We used Cox regression models, with time since AMI as timescale, adjusted for age and sex, to assess the hazard ratios (HRs) of mortality. The assumption of proportional hazards was assessed through inspection of survival curves and insertion of a time-interaction product in the models. Stratified analyses were performed by sex and STEMI/non-STEMI type of AMI event. A p value < 0.05 was considered statistically significant, and all p values were two sided. Missing data was regarded as random; however, where missing data were more than 25% that variable was excluded from further analysis, no imputation was made. Number of individuals with valid data on each variable is given in the “Results” section.

All analyses were carried out with SAS software package version 9.3 (SAS Institute, Cary, NC, USA) and the graphics were drawn in R 3.6.1. The study was conducted in accordance with the principles outlined in the Declaration of Helsinki and principles of Good Clinical Practice (GCP). The study protocol was approved by the Regional Ethics Committee in Stockholm, Sweden (registration number 2015/1844-31/2).

We identified 292 patients with AS and a first AMI, and 1276 matched general population comparators (Table 1). Patient characteristics and prevalence of comorbidities at admission for AMI are presented in Table 1. No statistically significant differences in body mass index (BMI) or smoking habits were observed for AS compared with population comparators, but most of the analysed comorbidities were more common in the patients with AS (Table 1). Patients with AS had also significantly more often been prescribed non-steroidal anti-inflammatory drugs (NSAIDs). Data on comorbidities for women and men, respectively, are given in Supplementary Tables 2a and 2b.

For individuals from the cohorts that were also identified in SWEDEHEART (n = 237 (81%), n women = 34 (14%), among the patients with AS; n = 1093 (86%), n women = 122 (11%) among the matched general population comparators), the mean age was 66.7 ± 10.6 years for AS and 67.1 ± 10.1 years for general population comparators.

The patients with AS were followed for 251.4 person years, whereas the general population comparators were followed for 1118.3 person years giving 22.3 (17.1–29.0) deaths/100 person years among patients with AS and 16.5 (14.2–19.0) deaths/100 person years among general population comparators (p = 0.05). During the 365 days of follow-up, 19.2% (56/292) of the patients with AS and 14.4% (184/1276) of the general population comparators died (Fig. 1). Over the first 30 days, the corresponding mortality was 8.9% (26/292 patients with AS) and 9.3% (118/1276 comparators). The 1-year mortality after AMI among women with AS was 23.9% (11/46) compared with 22.5% (39/173) in the general population, and among men 18.3% (45/246 patients with AS) and 13.2% (145/1103 comparators).

Patients with AS did not have a statistically significant increased mortality during the first 30 days after AMI (HR [95% CI] = 0.9 [0.6;1.5]) nor during the whole first year (HR [95% CI] = 1.3 [0.9;1.8]). However, over the 31–365-day period, the mortality was significantly increased (HR [95% CI] = 2.0 [1.3;3.2]).

The assumption of proportional hazards was fulfilled for the first 30 days but was violated for the whole 1-year follow-up as well as the day 31–365 follow-up. Time-stratified analysis indicated proportional hazards up to approximately day 220, with no difference in hazard rate during days 0–220.

Stratified analysis by sex and STEMI/ non-STEMI, respectively, showed no differences in 1-year mortality after a first AMI between AS patients and the general population comparators in any of the subgroups (data not shown).

In this population-based and nationwide cohort study, the 30-day all-cause mortality after AMI in patients with AS did not differ from that in general population. Also, when taking only CVD-related death into account, there was no difference in mortality between patients with AS and general population comparators. However, mortality day 31 through 365 was increased in patients with AS. Rather than an inferior CV outcome in AS, this difference in HR in short- and long-time follow-up after AMI may be regarded as a return to the baseline risk, based on the well-documented overall increased mortality risk in patients with AS [6, 7, 13, 14].

At admission, the clinical history in patients with AS differed in several aspects from that in general population, in particular with regard to an increased occurrence of CVD, but also other comorbidities such as pulmonary disease, renal disease, diabetes mellitus, and history of serious infections. Such increased prevalence of comorbidities at admission for AMI in rheumatic disease has been shown before [11, 15]. This increase could partly be explained by a detection bias due to an increased awareness and screening for comorbidities in the AS patients. On the other hand, it has also been shown that comorbidities in chronic diseases are often undertreated [16]. Taken together, this increased burden of comorbidities could in part explain the increased mortality during longer follow-up in the present study, in particular since cause-specific death of CVD, the well-known leading cause for death in AS [6, 7, 13, 14], was not significantly increased in the AS patients.

It may seem counter-intuitive that the mortality days 0–30 did not differ between AS patients and controls, considering the higher occurrence of comorbidities in AS patients. However, for all individuals, the risk for death after an AMI is highest in close proximity to the infarction which may diminish the relative effect of underlying comorbidities. Also, there were no differences in onset of symptoms, delay between symptom onset until first ECG was taken, or interventions given during hospitalisation between patients with AS and general population comparators. This is further reflected in the lack of significant differences in CVD risk factors measured for secondary prevention after 1 year of follow up.

To our knowledge, there are no other studies describing short-term outcome and characteristics of AMI in patients with AS. In RA, we have in the same setting described an impaired outcome after the AMI, even after taking AMI type and comorbidities into account [10]. In the present study, there were no difference in the evaluated characteristics at discharge in patients with AS compared with the general population comparators. When considering patients with RA compared with general population, tendencies for a decreased myocardial function have been observed in RA [10]. AS has been associated with cardiac conduction disturbances and aortic regurgitation [2] and studies have also found an increased risk of atrial fibrillation in AS compared with general population [17, 18]. In the present analyses, with limited number of cases included on the basis of AMI, we could not detect any increase in atrial fibrillation although we, as expected, found an increased occurrence of cardiac valve disease at admission in AS patients. We also found an increased occurrence of diagnosed ischemic heart disease and congestive heart failure at admission in AS patients compared with the general population comparators, suggesting that this population may have a relatively poor long-term CVD outcome [19].

Treatment with non-steroidal anti-inflammatory drugs (NSAIDs) has been associated, through several mechanisms, with increased risk of adverse outcomes in patients with CVD [20]. In AS, treatment with NSAID is important for pain relief and to reduce musculoskeletal pain and stiffness. Among the patients with AS who experienced an AMI, 27% had been prescribed NSAIDS, which is considerably more than among the general population comparators. However, these numbers are slightly lower than the general prescription among patients with AS in the same setting, where the prescription of NSAIDs was 55.5% [21]. Both these estimates may underestimate the use of NSAID, since they only take into account dispensed prescriptions.

There are several limitations of the present study. First, due to differences in indication of admission to coronary intensive care units or other specialized facilities in patients over 80 years of age, the overall coverage of this age group in SWEDEHEART is lower. As a result, approximately one-fifth of the study population, similarly for AS and their comparators, were not included in the analysis of AMI treatment. Whereas this restriction will not in itself introduce bias, it may pose a limitation to the generalisability, especially in older patients. Second, the proportion that died from AMI or sudden cardiac death before being hospitalized is not known.

There are also several strengths. First, the use of nationwide patient registers with high reported validity and close to complete coverage enabled adequate identification of AS, AMI, relevant comorbidities, and other covariates [22]. We identified AMI, length of hospitalisation, and deaths from linkage to national and virtually complete register. Second, the accuracy of data entered in SWEDEHEART compared with data found in patient records is high [23], which argues against that misclassification of AMI would negatively influence internal validity. Third, the ICD code for AS in the NPR has previously been shown to have high positive predictive value for fulfilling both the modified New York criteria as well as the Assessment of SpondyloArthritis International Society (ASAS) classification criteria [24].

The results of this study suggest that patients with AS have a higher comorbidity burden at admission for first AMI. Still, in this study, there was no increase in CVD-related mortality after a first AMI in patients with AS compared with general population, although the all-cause mortality was higher. There is a tendency for less use of cardioprotective drugs at discharge among the patients with AS. Taken together, this might indicate that in patients with AS suffering a first AMI, more attention should be given to other comorbidities causing an excess in mortality.