Data sources
The Western Denmark Heart Registry is a clinical database that provides prospective registration of all patients in Western Denmark undergoing cardiac intervention such as coronary angiography (CAG), PCI, and CABG since 1999. The registry has previously been described in detail [11]. Using each patient’s unique 10-digit identifier, patients can be linked with other national health care registries, including the Danish National Prescription Registry, the Civil Registration System, the Danish Register of Causes of Death, and the Danish National Patient Registry [12,13,14,15].
Patient selection
Patients undergoing CAG were identified using first-time procedures registered in the Western Denmark Heart Registry from 2004 through 2016 (n = 146,191) (Fig. 1). If a patient had multiple CAGs registered during this time, the first was considered the index examination. Four patients < 18 years and 51,181 patients with no CAD were excluded from this analysis. Since we aimed to assess risk following the first-time diagnosis of chronic coronary syndrome by CAG, we excluded 8159 patients with previous MI, PCI, or CABG. Patients referred for CAG due to a different indication than chronic coronary syndrome were also excluded (n = 57,375).
CAD
Presence and extent of CAD were entered into the database by the interventional cardiologist immediately following examination. CAD was classified as either obstructive disease in 1, 2, or 3 vessels (with obstructive disease defined as > 50% diameter stenosis and FFR ≤ 0.80 if measured) or as diffuse CAD defined as non-significant CAD involving > 1 vessel. Patients with only a single stenosis < 50% or FFR > 0.80 if measured were classified as no CAD and excluded from the study.
Diabetes
Diabetes was defined as either (1) diet treatment only, non-insulin anti-diabetic treatment, or insulin (± non-insulin anti-diabetic treatment) as registered in the Western Denmark Heart Registry, (2) diabetes diagnosis prior to CAG in the Danish National Patient Registry, or (3) collecting one or more prescriptions of insulin or non-insulin anti-diabetic treatment less than six months before CAG according to the Danish National Prescription Registry [12].
Comorbidity
Comorbidities were ascertained through the Danish National Patient Registry relying on diagnoses prior to CAG with full look-back (from 1977 and onwards). Information regarding smoking status, body mass index (BMI), and hypertension was ascertained through the Western Danish Heart Registry. We estimated burden of comorbidity using a modified Charlson’s Comorbidity Index score, in which ‘Diabetes, type I and II’ and ‘Diabetes with end-organ failure’ were excluded in the final score [16].
Medication
Records of treatment with aspirin, adenosine diphosphate (ADP) receptor inhibitor, angiotensin-converting enzyme (ACE) inhibitor/angiotensin II receptor blocker (ARB), beta-blocker, and statin were collected from the Danish National Prescription Database. Medical treatment prior to CAG was defined as one or more redeemed prescriptions six months or less before CAG. Changes in medical treatment because of the CAG or peri-procedural diagnosis were investigated by looking at redeemed prescriptions six months or less after CAG in patients who completed six months of follow-up (n = 29,071) (Additional file 1: Tables S1 and S2).
Outcomes
The primary outcome was major adverse cardiovascular event (MACE); a composite of MI, ischemic stroke, and all-cause death. Secondary outcomes were the individual components of MACE, cardiac death, PCI, and CABG.
MI and ischemic stroke were identified in the Danish National Patient Registry [17, 18]. Vital status (alive, death, or emigration) was obtained through the Danish Civil Registration System [15]. Cardiac death included deaths resulting from ischemic heart disease, sudden cardiac death, heart failure, or sudden death, unspecified, according to death certificates from the Danish Register of Causes of Death [14].
Anatomical Therapeutic Chemical (ATC) codes used in the Danish Prescription Registry and International Classification of Diseases 10 (ICD-10) codes used in the Danish National Health Registry and the Danish Register of Causes of Death are listed in supplemental material of previous work [19].
Statistical analysis
Patients with chronic coronary syndrome were stratified by diabetes status at the time of examination and year of index CAG (2004–2006, 2007–2009, 2010–2012, and 2013–2016). We estimated two-year risks (cumulative incidence proportions) of MACE, MI, ischemic stroke, all-cause death, cardiac death, PCI, and CABG. Follow-up continued until an outcome event, death, emigration, or 24 months after CAG. Cumulative incidence proportion curves were constructed. We estimated the incidence rate ratio (IRR) using a modified Poisson regression with a robust variance–covariance estimator using the natural log of person-years as the offset [20]. IRRs were adjusted for sex, age, hypertension, previous ischemic stroke, peripheral artery disease, smoking, statin treatment, antiplatelet treatment, and oral anticoagulant treatment. Analyses of MACE, ischemic stroke, cardiac death, and all-cause death were additionally adjusted for atrial fibrillation and heart failure [21]. Patients examined between 2004 and 2006 were used as reference group throughout analyses.
We performed a number of sensitivity analyses. First, two-year MACE risks were compared between patients with and without diabetes (Additional file 1: Table S3). Secondly, we conducted a subgroup analysis of patients diagnosed with obstructive CAD at index CAG (n = 23,858) (Additional file 1: Tables S4 and S5). Other analyses included stratifying by sex and age above or below 70 years (Additional file 1: Tables S6, S7, S8, and S9). Lastly, we performed an analysis of revascularization patterns as a consequence of the angiographic findings defined as PCI or CABG within three months after index CAG (Additional file 1: Table S10). Stata/MP 16.0 (StataCorp LLC, College Station, TX, USA) was used for all analyses.