Objectives Patients with rheumatoid arthritis (RA) are at increased risk of acute coronary syndrome (ACS) and suffer from poorer short-term outcomes after ACS. The aims of this study were to assess long-term outcomes in patients with RA with ACS compared with non-RA patients with ACS, and to investigate whether the use of secondary preventive drugs could explain any differences in ACS outcome.
Methods We performed a cohort study based on 1135 patients with RA and 3184 non-RA patients who all developed an incident ACS between 2007 and 2010. We assessed 1-year and overall relative risks for ACS recurrence and mortality, as well as prescriptions of standard of care secondary preventive drugs.
Results The risk of ACS recurrence, and of mortality, was increased in RA, both at 1 year after adjusting for baseline comorbidities (HR=1.30(95% CI 1.04 to 1.62) and 1.38(95% CI 1.20 to 1.59), respectively) and throughout the complete (mean 2 years) follow-up (HR=1.27(95% CI 1.06 to 1.52) and 1.50(95% CI 1.34 to 1.68), respectively). Among certain subgroups of ACS, there was a tendency of lower usage of statins, whereas there were no apparent differences in others. The increased rates of ACS recurrence and mortality remained in subgroup analyses of individuals whose prescription pattern indicated both adequate initiation and persistence to secondary preventive treatments.
Conclusions Patients with RA suffer from an increased risk of ACS recurrence and of death following ACS compared with general population, which in the present study could not readily be explained by differences in usage of secondary preventive drugs.
- rheumatoid arthritis
- acute coronary syndrome
- secondary prevention
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Patients with rheumatoid arthritis (RA) are not only at increased risk of ischaemic heart disease (IHD)1; we recently reported that patients with RA and acute coronary syndrome (ACS) more often also present with sudden cardiac death or ST elevation myocardial infarction (MI), suffer from increased short-term mortality compared with non-RA patients with ACS, but also that the mortality differences were explained neither by underlying comorbidities nor by differences in ACS type.2
In addition to the impaired short-term prognosis,2–6 smaller studies have suggested an increased risk of ACS recurrence as well as an increased longer term mortality following ACS in patients with RA.4 7 8 In the general population, suboptimal initiation of and adherence to secondary preventive pharmacotherapies are both linked to ACS recurrence as well as to poor long-term ACS outcomes.9 Therefore, suboptimal initiation and/or adherence to such pharmacotherapies might be one, and importantly a modifiable, explanation for a worse prognosis in patients with RA who develop ACS. The few existing studies on this topic are, however, contradictory; indicating lower usage as well as no difference in the use of secondary preventive drugs after ACS in patients with RA compared.8 10 11
Sparked by our recent and disturbing findings regarding the clinical presentation and short-term outcome after ACS in RA, the specific aims of this study were to assess whether the risk of (1) recurrent ACS, and (2) long-term overall mortality following ACS, or (3) the initiation of, and adherence to, evidence-based cardioprotective secondary preventive pharmacotherapies after incident ACS differ between patients with RA compared with the general population.
We performed a cohort study based on one cohort of patients with prevalent RA and incident ACS matched to non-RA patients with incident ACS.
Swedish residents have access to publicly funded healthcare, including specialised care at rheumatology/internal medicine clinics for patients with RA, and coronary intensive care units for patients with ACS. Drugs are subsidised; after reaching an upper annual spending limit for prescription drugs (approximately US$217 per year (February 2017)), subsequent prescriptions are free of charge. A unique personal identity number (PIN) is assigned to all Swedish residents at birth or immigration.12
In this study, the PIN was used as a key to link several nationwide population-based and virtually complete registers together to define an RA cohort, a general population comparator cohort, and to collect relevant information on exposures, outcomes and covariates.
To identify individuals with RA, ACS events and comorbidities of interest the National Patient Register (NPR) was used. This register includes diagnoses for admissions and specialised outpatient care in Sweden, has full coverage for inpatient care since 1987 and covers outpatient specialised care since 2001.13 Information on mortality was collected from the Cause of Death Register that, similar to NPR, holds information on deaths including cause(s) of death coded according to the International Statistical Classification of Diseases (ICD; version 10 since 1996). Information on dispensed pharmacotherapies was collected from the Prescribed Drug Register (PDR), including information on all dispensed drugs from Swedish pharmacies since July 2005. Dispensed drugs are coded according to Anatomical Therapeutic Chemicals (ATC) classifications and reported with drug dose and quantity.14 The Total Population Register stores demographic information and was used to identify the general population comparators. The register linkages and the study population have been described in detail elsewhere.2
The study population comprised patients with prevalent RA (n=1135) and all their individually matched general population comparator subjects (n=3184), non-RA patients, who developed a first ever incident ACS between 2007 and 2010.
Prevalent, that is, actively monitored, RA was defined as individuals above 18 years of age (no upper age limit) with at least two visits listing RA in the NPR, of which at least one at an internal medicine or rheumatology department. This definition has a predictive value of approximately 90%.15 To ensure that the RA disease was subject to active monitoring, one of the visits listing RA had to occur in 2006, 2007, 2008 or 2009. For each patient with RA, up to five general population comparator subjects were matched by age, sex, area of residency and educational level.
ACS was defined as a first ever registered diagnosis of MI or unstable angina in the NPR (for RA: within 1 year after the visit defining actively monitored disease) between 2007 and 2010. None of the ACS events were identified in immediate relation to the visit listing RA that defined inclusion into the cohort. This study population has been described in detail previously.2 The ICD codes used to detect ACS have a positive predictive value of 95%.16 Online supplementary table 1 lists the ICD codes used.
Supplementary file 1
Recurrent ACS and mortality
Recurrent ACS was defined as a new registration of ACS in the NPR 30 days or more after incident ACS date (to avoid misdiagnosis of registrations related to the incident ACS). Mortality (from any cause) was defined as 1-year mortality and as mortality during the complete follow-up period, which ended 31 December 2011.
Secondary preventive drugs
Standard of care secondary preventive pharmacotherapies were assessed as dispensed prescriptions of aspirin, P2Y12 inhibitors, beta blockers, renin-angiotensin system (RAS)-blocking agents and lipid-lowering agents categorised as −7 to 90, 91–180, 181–270 or 271–365 days after the ACS event. The ATC codes used are listed in online supplementary table S1.
Baseline data were compiled and presented as frequencies and per cents for categorical variables, and means or medians with SD or IQR as appropriate for continuous variables. Pre-existing comorbidities and pharmacotherapies were defined as a diagnosis in the NPR or a dispensed drug in the prescribed drug register more than 90 days prior to the ACS to avoid potential influence from the ACS itself (see online supplementary table S1 for codes). The type of ACS, based on the registered ICD code in the NPR (transmural, subendocardial, unspecific or unstable angina), was also compiled and presented with the descriptive data.
Recurrent ACS was calculated as events per 100 person-years. All-cause mortality during follow-up was analysed using the Kaplan-Meier method. We used Cox regression with time since ACS as timescale, adjusted for age and sex to assess the relative risk (RR) (HRs) of recurrent ACS, and of death. These models were further adjusted for confounding using a propensity score (PS), in turn calculated using a multivariate model including status at start of follow-up according to demographics (age and sex), pre-existing comorbidities (stable angina pectoris, cerebrovascular lesion, venous thromboembolic disease, atrial fibrillation, heart failure, cardiomyopathy, diabetes type I/II, chronic obstructive pulmonary disease, renal failure yes/no) and pre-existing pharmacotherapies (insulin, oral antidiabetics, warfarin, acetylsalicylic acid, P2Y12 inhibitors, nitroglycerine, diuretics, RAS-blocking agents, beta blockers, calcium antagonists, lipid-reducing agents yes/no). The Cox model was further adjusted with the PS in combination with ACS type.
Numbers and proportions of the study population with dispensed prescriptions of each drug, and combinations of one, two and three of the drugs under study, were calculated separately by time period following ACS (−7 to 90 days, 91–180 days, 181–270 days, 271–365 days). Only subjects alive at the end of each time period under study were included in each assessment. Logistic regression models adjusted for age and sex were used to obtain p values for differences in treatment initiation and adherence; a two-tailed p value <0.05 was considered significant.
To refine our findings, a series of sensitivity analyses were performed. Recurrent ACS, mortality and dispensed prescriptions of secondary preventive drugs were assessed and stratified by type of ACS (transmural MI, subendocardial MI, unspecific MI and unstable angina). To investigate whether any difference (between patients with RA and non-RA patients) in the use of secondary preventive pharmacotherapies could explain any increased ACS recurrence, or mortality, we performed sensitivity analyses of (1) subjects fulfilling a combination of at least three different secondary preventive drugs during the first time period after ACS for 1-year analysis, and (2) subjects fulfilling a combination of at least three drugs during at least two of (any) time periods for the complete follow-up period. To rule out that pre-existing usage of each drug affected results on filled prescriptions during the first time period, (1) the first time window was broadened to −30 (days before) to 90 and (2) in two additional sensitivity analyses, all subjects with a previous filling of any of the prescriptions under study were excluded.
All analyses were carried out with SAS software package V.9.3 (SAS Institute). This study was approved by the ethics committee in Stockholm, Sweden.
A total of 1135 patients with RA, and 3184 non-RA patients, with incident ACS were identified (table 1, figure 1). A total of 904 (79.6%) of the patients with RA and 2742 (86.1%) non-RA patients were alive at 90 days following ACS, and were included in the analysis of secondary preventive drugs during this time period (−7 to +90 days). At 365 days after the ACS, 803 (70.7%) patients with RA and 2536 (79.6%) non-RA patients were still alive and included in the analysis of secondary preventive drug use during the last time period under study (271–365 days).
The rate of recurrent ACS was higher among patients with RA compared with non-RA patients, both during the first year following ACS and during the complete follow-up period (mean 2.3±1.5 years), corresponding to an approximately 30% increased recurrence risk (1-year HR 1.35 (95% CI 1.09 to 1.68); complete follow-up HR 1.34 (95% CI 1.12 to 1.60)). Further adjustment for the PS, alone and in combination with ACS type slightly decreased the HRs, which remained significantly increased (fully adjusted HR 1 year 1.28 (95% CI 1.03 to 1.60); complete follow-up 1.25 (95% CI 1.05 to 1.50)). Additional adjustment for filled prescriptions of secondary preventive drugs did not alter the HRs (figure 2, table 2).
The mortality following ACS was higher among patients with RA compared with non-RA patients with ACS (figure 3). During the first year, approximately 30% of patients with RA died compared with 20% of non-RA patients, corresponding to a RR of 1.6 (HR 1.59 (95% CI 1.39 to 1.82)). During the complete follow-up period, 45% of the patients with RA with ACS versus 30% (mean 2.3±1.5 years) of the non-RA patients with ACS died, resulting in a HR of 1.73 (95% CI 1.55 to 1.93). The reported underlying cause of approximately 80% of deaths among both patients with RA and non-RA patients (79.5% vs 78.6%) was due to IHD or IHD-related complications (sudden cardiac arrest, arrhythmias, heart failure , conduction abnormalities or other complications related to IHD). These HRs remained significantly increased after adjustment for the PS alone and ACS type (fully adjusted HR 1 year 1.38 (95% CI 1.20 to 1.59); complete follow-up 1.50 (95% CI 1.34 to 1.68)) (table 2).
Secondary preventive drug use after ACS
Figure 4A–G shows the proportion of study subjects with ACS (of any type) filling prescriptions for each, and combinations of two or three drugs during each time period after the ACS.
A significantly lower (between 3% and 7% lower) proportion of patients with RA filled prescriptions of statins during all of the observed time periods (figure 4E). During some of the time periods, a significantly lower proportion of patients with RA also filled fewer prescriptions of antiplatelets and RAS-blocking agents, whereas there was no difference in beta blockers during any of the time periods (figure 4). In total, 89% of the patients with RA and 93% of the non-RA patients filled prescriptions for at least two secondary preventive drugs during the first time period following ACS (p=0.0009). By contrast, there was no appreciable difference during the following three time periods. The proportion of patients with RA that filled prescriptions for at least three secondary preventive drugs was lower than among the non-RA patients, during all time periods, for example, 75% vs 81% (p=0.0001) during the first 90 days, and 60% vs 66% (p=0.001) in the interval 271–365 days.
Stratifying the RR of recurrence and mortality by type of ACS resulted in a higher relative mortality risk (HR 2.4 both at 1 year and complete follow-up period) for patients with RA with unstable angina compared with non-RA patients with unstable angina. For all other ACS types, mortality HRs remained similar to the HRs of the primary analysis. Recurrence HRs also remained similar, but with a poorer statistical precision especially in subgroups with fewer events, to the primary analysis (see online supplementary figures 1 and 2 and table 2). When the study population was restricted to those subjects filling prescriptions of at least three preventive drugs, the HRs for recurrent ACS, and for all-cause mortality, remained similar to the main analysis or were even more pronounced (see online supplementary table 7). Stratifying the results by sex did not reveal any major differences in relative mortality risk, whereas there was a tendency of a more pronounced increased recurrence risk among women compared with men.
When stratifying the use of secondary preventive drugs by ACS type (transmural, subendocardial, unspecific and unstable angina), most of the differences observed in the main analysis diminished or disappeared. Of the 144 statistical comparisons made (nine drugs/drug combinations during four time periods stratified by four ACS types), 26 (18%) comparisons remained statistically significant, in which 12 (8%) within the first time period, in comparison with the 17/36 (47%) significant statistical comparisons (nine drugs/drug combinations during four time periods) of the original analysis. Among study subjects with transmural MI, there were, with the exception for a lower proportion of patients with RA filling prescriptions of RAS-blocking agents time period 3 and dual antiplatelet treatment time period 4, no remaining statistically significant differences. Among other ACS subtypes, patients with RA filled significantly fewer prescriptions of statins and dual antiplatelets during several time periods (see online supplementary tables 3–6). Separate analyses among men and women did not reveal any difference in filling of prescriptions.
In this population-based and nationwide cohort study, which to our knowledge is the largest assessment of ACS recurrence, mortality and secondary preventive drug use after ACS in patients with RA, we found indications of increased risk for both recurrent ACS and for death following ACS in patients with RA. The observed risk increases could be readily explained neither by confounding from other comorbidities and/or therapies nor by ACS phenotype. Furthermore, we found that when taking ACS phenotype into account, the use of secondary preventive drugs was not consistently much lower in patients with RA than in the general population, neither when assessed separately nor when assessed in combination. The maximum differences in proportions, although statistically significant, amounted to 5% units or less. The increased risk of recurrence and death could not be readily explained by differences in usage of secondary preventive drugs among patients with RA compared with non-RA patients, although undertreatment cannot be discarded as potential explanation for the increased recurrence and mortality. Importantly, however, the impaired outcome after ACS persisted also among those individuals whose patterns of fillings of secondary preventive drugs indicated compliance with a three-drug secondary preventive regimen.
Even though the present study could not link the impaired long-term prognosis following ACS in patients with RA to poor pharmacoprevention, it is important to acknowledge that patients with RA constitute a heterogeneous group of patients frequently on several pre-existing prescribed medications and with several comorbid conditions, which both are factors that have been associated with non-adherence to secondary preventive therapies.17 Furthermore, adherence to secondary preventive drugs has repeatedly been pointed out to leave room from improvement18 and is associated with adverse outcomes in terms of recurrent events and mortality rates in the general population19 as well as RA.10 20 Thus, even if similarly used in RA, drug adherence should thus be as carefully managed in patients with RA just as in the general population.
Results from previous studies on initiation and/or adherence to secondary preventive drugs in patients with RA have been contradictory. In-hospital initiation of aspirin, statins and beta blockers was reported to be lower in a cohort of 90 RA subjects with MI compared with matched controls.10 In another study, based on an RA cohort of similar size, there was no significant difference in secondary preventive drugs received neither in-hospital nor at discharge comparing RA subjects and matched controls.8 In a larger population-based Danish cohort study, a lower initiation of aspirin, beta blockers and statins was observed, and persisted throughout follow-up.11 Except for potential variations related to the different geographic regions and clinical settings, there are also major differences in study designs and methodological approaches. For instance, when we stratified our results by ACS subtype (which was not the case in the previous studies), most of our observed differences disappeared. Our analyses also revealed that most of the observed differences in drug use (if any) pertained to subjects with unspecific or subendocardial MI, in contrast to virtually no difference among subjects with transmural MI. Even though these subtypes, which are based on registered ICD codes, cannot strictly be translated into ST-segment elevation MI (STEMI) versus non-ST-segment elevation MI, one may assume that a majority of subjects with transmural MI were diagnosed with STEMI and therefore underwent percutaneous coronary intervention according to existing clinical guidelines, whereas subjects with subendocardial and unspecific MI potentially suffered from more minor MIs and instead were more prone to receive conservative treatment. Invasive in-hospital treatment has been associated with increased adherence to secondary preventive drugs.21 22 Conversely, less ‘critical’ events in patients with a high overall burden of disease may be associated with poorer drug adherence. Across time periods, a majority (>70%) of the lower prescription rates among patients with RA were observed in the first 6 months after ACS. It is plausible that clinical concerns regarding comorbidity, drug interactions and toxicity lead to a delay of drug initiation in this group of patients.
The increased ACS recurrence and mortality in the RA cohort in our present study corroborate findings from previous studies.4 6 8 10 11 Importantly, we could extend these findings by demonstrating that the impaired outlook remained also after adjustment for several important cardiovascular risk factors.
Major strengths of this study include the possibility to use population-based and prospectively recorded data to identify RA, ACS, drug use as well as comorbidities of interest.23 Additionally, the algorithms used to detect RA and ACS have high validity.15 16 The size of the study population and the extended duration of follow-up, where virtually all outcomes of interest could be captured via linkage to other nationwide registry, are other strengths.
There are several potential limitations to take into consideration when interpreting the results from our study. First, although we could adjust for a large number of potential confounders we lacked information on certain traditional prognostic risk factors such as smoking, body mass index and actual lab values for blood lipid levels and glucose intolerance. We also lacked information on inflammatory activity which has been associated with cardiovascular disease onset and has been suggested to be associated with recurrent ischaemic episodes. Potentially, the increased inflammatory burden following ACS on top of the underlying inflammation in RA could partly explain the poorer outcomes following ACS. Second, we did not have access to information on target parameters such as blood lipid levels and blood pressure making it difficult to determine whether individual treatments were appropriate. Third, secondary prevention following ACS includes pharmacotherapies and lifestyle-related factors such as implementation or maintaining an adequate level of physical activity, dietary recommendations, stress management, and so on; we did not have access to such information. Finally, we based our definition of drug usage on (patterns of) filled prescriptions, which not necessarily equates actual drug compliance. The potential differences in disease characteristics, such as accumulated inflammatory activity, in patients with prevalent RA compared with incident RA might pose a limitation to the generalisability of the reported results to patients with new-onset RA.
In conclusion, our study suggests that by and large, the use of secondary preventive drugs in RA is not markedly lower than in ACS in general, yet patients with RA are at increased risk of recurrent ACS as well as mortality following ACS. Consequently, from an aetiological point of view, additional factors are likely to drive the impaired outlook and will be important to identify. Clinically, among patients with coronary artery disease, those with RA should be recognised as patient at elevated risk among whom preventive measures may be of particular importance.
Supplementary file 2
Supplementary file 3
Contributors All authors have made substantial contributions to the conception or design of the work, or the acquisition, analysis or interpretation of data.
Funding The Swedish Research Council, The Swedish Foundation for Strategic Research, Stockholm County Council (ALF), The Heart Lung Foundation, The Swedish Cancer Society, Karolinska Institutet (Strategic Research Area Epidemiology). Funders had no impact on the design or interpretation of the study or its results.
Competing interests AM and MH have nothing to declare. TJ reports personal fees from Astra Zeneca, personal fees from MSD, personal fees from Aspen, outside the submitted work. SWJ reports a fee for short talk at conference for Swedish cardiologists and general practitioners January 2016, arranged by Merck, Sharp & Dome. JA and Karolinska Institutet had research agreements with Abbvie, BMS, MSD, Pfizer, Roche, Astra-Zeneca, Lilly, Samsung and UCB, mainly in the context of safety monitoring of biologics via ARTIS/The Swedish Biologics Register. For these, JA has been principal investigator. Karolinska Institutet has received remuneration for JA participating in ad boards arranged by Pfizer and Lilly.
Provenance and peer review Not commissioned; externally peer reviewed.