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Cardiovascular Manifestations of Systemic Sclerosis: A Danish Nationwide Cohort Study

Background Cardiovascular involvement in systemic sclerosis (SSc) comprises a wide range of manifestations with prevalence and incidence that remain uncertain. Methods and Results In the Danish administrative registries between 1995 and 2015, all patients aged ≥18 years with a first diagnosis of SSc were matched by age and sex with controls (1:5) from the general population. Prevalence of cardiovascular diseases at the time of the SSc diagnosis and incidence during follow‐up were assessed by in‐ and outpatient discharge diagnoses. Conditional logistic and Cox proportional hazards regression models were used respectively to calculate odds ratios for prevalent cardiovascular diseases and hazard ratios (HRs) for incident diseases associated with SSc. Patients with SSc (n=2778; 76% women; mean±SD age: 55±15 years) had more established cardiovascular risk factors than their respective controls at baseline, including greater prevalence of hypertension (31.2% versus 21.0%, P<0.0001) and treated dyslipidemia (9.8% versus 8.5%, P=0.02). SSc was associated with an increased relative risk of developing most cardiovascular diseases, including myocardial infarction (HR: 2.08; 95% CI, 1.65–2.64), peripheral vascular disease (HR: 5.73; 95% CI, 4.63–7.09), pulmonary hypertension (HR: 21.18; 95% CI, 14.73–30.45), mitral regurgitation (HR: 4.60; 95% CI, 3.12–6.79), aortic regurgitation (HR: 3.78; 95% CI, 2.55–5.58), aortic stenosis (HR: 2.99; 95% CI, 2.25–3.97), pericarditis (HR: 8.78; 95% CI, 4.84–15.93), heart failure (HR: 2.86; 95% CI, 2.43–3.37), atrial fibrillation (HR: 1.75; 95% CI, 1.51–2.04), and venous thromboembolism (HR: 2.10; 95% CI, 1.65–2.67). Additional adjustment for medications and comorbidities yielded results similar to the main analyses. Conclusions In this nationwide study, SSc was associated with greater risks of distinct cardiovascular diseases for patients than for matched controls, suggesting a significant disease‐related adverse impact across the vascular bed and specific cardiac structures.

The accuracy and completeness of diagnostic coding in the National Patient Registry has been evaluated as consistently high for a variety of chronic comorbidities and cardiovascular diagnoses [1][2][3][4] , and we have previously found a positive predictive value of 94% for the SSc diagnosis in this registry. 5 The National Prescription Registry holds information on all prescription claims since 1995 with all drugs being classified according to the Anatomical Therapeutical Chemical classification system. Due to the reimbursement-driven policy, this registry is considered of high quality. 6

Study population
In the National Patient Registry, we identified all first-time diagnoses of SSc (ICD-10 codes M34 [except for M34.2]) that followed outpatient or inpatient visits between 1995 and 2015. We excluded patients with a prior diagnosis of SSc defined as an ICD-10 code of M34 in 1994 or an ICD-8 code of 734 anytime between 1978 and 1993. The controls consisted of five randomly selected age-and sex-matched individuals from the Central Population Registry. An index date was assigned to each control, which corresponded with the date of first registration of SSc for their respective case, in accordance with the principle of incidence density sampling. 7

Outcome variables and follow up
The primary outcome variables were defined by ICD-8 and ICD-10 codes, together with procedural codes (obtained via the National Patient Registry) and medication use (obtained via the Anatomical Therapeutic Chemical (ATC) Classification System coding in the National Prescription Registry). Table S1 shows the different variables, different registries, and the corresponding diagnosis or procedure/surgical codes for each outcome.

Comorbidity and Medications
Baseline comorbidity was assessed as a prevalent condition at any time before study inclusion.
Comorbidity included hypertension, atrial fibrillation, heart failure of any cause, myocardial infarction, ischemic stroke, aortic aneurism and dissection, aortic stenosis and regurgitation, mitral stenosis and regurgitation, conduction block (left bundle branch block and atrioventricular block), implantation of pacemaker or implantable cardioverter defibrillator, pericarditis, peripheral vascular disease, pulmonary hypertension, venous thromboembolism, treated dyslipidemia, and diabetes.
Baseline treatment was defined by at least one prescription dispensed for each respective drug up to 180 days before the study inclusion date. The following drugs were included: aspirin, nonsteroidal anti-inflammatory drugs, statins, oral anticoagulants, anti-platelet therapy and glucocorticoids.

Statistics
Continuous variables are presented as mean with standard deviation, categorical variables as absolute number and percentages. Tests for differences between groups were performed by the Pearson's Chi-squared/Fischer's exact test (categorical data) or by the Student t test (continuous data) where appropriate. Time at risk was measured from index date (date of SSc diagnosis) and individuals were censored at the date of first-time registration of the specific endpoint, migration or upon death. Conditional logistic regression models and Cox proportional hazards regression models were used to calculate the odds ratios (OR) for prevalent cardiovascular diseases and hazard ratios (HR) for incident diseases associated with SSc, respectively. Separate models were run for each endpoint. The main models were adjusted for age and sex. In addition, a multivariable Cox regression model (including all comorbidities and treatment in Table 1) was applied to investigate the association of SSc and outcomes after adjustment for various comorbidities and risk factors.
Two-sided p-values <0.05 were considered statistically significant for all analyses. All analyses were performed in SAS version 9.4 (Cary, NC, USA).

H02AB
Hypertension was defined by use of at least 2 antihypertensive drugs according to a validated algorithm 4 , diabetes was defined by use of a glucose-lowering drug while treated dyslipidemia was defined as the use of statins. ATC; anatomical therapeutic chemical classification system. ICD-10; International Classification of Diseases 10th revision. Fully adjusted HR was adjusted for medications (ASA, NSAID, Glucocorticoids, statins, OAC and platelet inhibitors) and co-morbidities, as specified in Table 1.