Cardiovascular and metabolic risk Open access Original research BMJ Open Diab Res Care: first published as 10.1136/bmjdrc-2020-001803 on 7 January 2021. Downloaded from Peripheral artery disease, lower limb revascularization, and amputation in diabetes patients with and without coronary artery disease: a cohort study from the Western Denmark Heart Registry Kevin Kris Warnakula Olesen ,1 Christine Gyldenkerne,1 Troels Thim,1 Reimar Wernich Thomsen,2 Michael Maeng1 To cite: Olesen KKW, ABSTRACT Gyldenkerne C, Thim T, et al. Introduction Patients with diabetes have increased Significance of this study Peripheral artery disease, risk of lower limb revascularization and amputation due lower limb revascularization, to higher risk of peripheral artery disease (PAD) and What is already known about this subject? and amputation in diabetes peripheral neuropathy. The additive effect of coronary ► Patients with diabetes have increased risk of low- patients with and without er limb amputation due to higher risk of peripheral coronary artery disease: a artery disease (CAD) is less clear. We examined the risk of PAD, lower limb revascularization, and amputation artery disease and peripheral neuropathy. The role cohort study from the Western of concomitant coronary artery disease (CAD) is Denmark Heart Registry. in diabetes and non- diabetes patients with and without unclear. BMJ Open Diab Res Care CAD in patients examined by coronary angiography 2021;9:e001803. doi:10.1136/ (CAG). What are the new findings? bmjdrc-2020-001803 Research design and methods We included all ► Patients with diabetes are at higher risk of lower patients undergoing CAG between 2003 and 2016 in limb amputation despite absence of CAD. Western Denmark. Patients with previous CAD, PAD, ► However, CAD significantly exacerbates amputation ► Supplemental material is lower limb revascularization, or amputation were published online only. To view, risk among patients with diabetes, especially in pa- excluded. Patients were stratified by diabetes and please visit the journal online tient with multivessel CAD. CAD status and followed for a maximum of 10 years. (http:// dx. doi. org/ 10. 1136/ ► Diabetes patients without CAD were more likely to Outcomes were PAD, lower limb revascularization, bmjdrc- 2020- 001803). undergo distal amputations, rather than proximal and amputation. We estimated 10- year cumulative http://drc.bmj.com/ amputations, which were associated with CAD. incidences and adjusted HRs (aHRs) using patients Received 1 August 2020 neither diabetes nor CAD as reference. How might these results change the focus of Revised 27 October 2020 Results A total of 118 787 patients were included, of research or clinical practice? Accepted 22 November 2020 whom 41 878 (35%) had neither diabetes nor CAD, 5735 ► Continued screening and treatment of macrovascu- (5%) had diabetes alone, 59 427 (50%) had CAD alone, lar and microvascular disease is necessary in all pa- and 11 747 (10%) had both diabetes and CAD. Median tients with diabetes to reduce the risk of amputation. follow- up was 6.9 years. Diabetes patients without CAD However, patients with diabetes and CAD may re- on October 2, 2021 by guest. Protected copyright. had higher risk of PAD (3.5%, aHR 1.73, 95% CI 1.51 quire additional screening, management, and treat- to 1.97), lower limb revascularization (1.6%, aHR 1.55, ment of peripheral artery disease and microvascular © Author(s) (or their 95% CI 1.16 to 2.05), and lower limb amputation (2.4%, disease to reduce the risk of lower limb amputation. employer(s)) 2021. Re- use aHR 5.51, 95% CI 4.09 to 7.43) compared with patients This, however, needs to be explored in a randomized with neither diabetes nor CAD. CAD was associated with permitted under CC BY-NC. No setting. commercial re- use. See rights 2.5- fold and 1.8- fold higher risk of PAD and amputation, and permissions. Published respectively, among patients without diabetes, and by BMJ. associated with 3.9- fold and 9.5- fold higher risk of 1 Department of Cardiology, PAD and lower limb amputation among patients with INTRODUCTION Aarhus Universitetshospital, diabetes. Diabetes is associated with a higher risk Aarhus, Denmark Conclusions Despite absence of obstructive CAD, 2 Department of Clinical patients with diabetes remained at higher risk of PAD, of atherosclerotic cardiovascular disease Epidemiology, Aarhus University lower limb revascularization, and lower limb amputation. including ischemic stroke, coronary artery Hospital, Aarhus, Denmark Diabetes was more strongly associated with amputation disease (CAD), and peripheral artery disease 1 2 Correspondence to than CAD, but CAD exacerbated the risks of PAD, (PAD). Patients with diabetes also have Dr Kevin Kris Warnakula revascularization, and amputation in patients with an increased risk of microvascular disease, Olesen; kevole@ clin. au. dk diabetes. including peripheral neuropathy, which can BMJ Open Diab Res Care 2021;9:e001803. doi:10.1136/bmjdrc-2020-001803 1 Cardiovascular and metabolic risk BMJ Open Diab Res Care: first published as 10.1136/bmjdrc-2020-001803 on 7 January 2021. Downloaded from cause foot ulcers. Poor glycemic control, type of diabetes, Lastly, patients who either died or emigrated <30 days previous lower limb revascularization, hypertension, and after CAG were excluded. high level of comorbidity are all associated with increased 3 risk of amputation in patients with diabetes. Atheroscle- Diabetes rosis in one vascular bed is often associated with pres- Diabetes was defined as at least one of the following: (1) ence or development of atherosclerosis in other vascular dietary treatment for diabetes, oral diabetes treatment, 4 beds. Considering the combination of increased athero- or receiving insulin treatment (±oral diabetes treatment) thrombotic risk and the risk of microvascular disease, recorded in the Western Denmark Heart Registry, (2) patients with diabetes have a higher risk of lower limb a previous diabetes diagnosis registered in the Danish ischemia and amputation. The absence of obstructive National Patient Registry before start of follow- up, or (3) CAD is associated with a low risk of myocardial infarction redeeming ≥1 prescription(s) of insulin or non-insulin and an intermediate risk of ischemic stroke in patients diabetes medication 6 months before or 30 days after 5–7 with diabetes. However, does the absence of obstruc- CAG. tive CAD ensure a low risk of PAD, lower limb revascular- ization, and amputation in patients with diabetes? Coronary artery disease We conducted a cohort study of diabetes and non- CAD was defined as ≥1 obstructive stenoses (≥50% lumen diabetes patients with and without obstructive CAD to narrowing) or non- obstructive stenosis in ≥2 coronary estimate the risk of PAD, lower limb revascularization, vessels by CAG according to the Western Denmark Heart and lower limb amputation. We hypothesized that the Registry.12 absence of obstructive CAD by coronary angiography (CAG) would be associated with low risks of PAD, lower limb revascularization, and lower limb amputation in Outcomes both diabetes and non- diabetes patients. PAD was defined as a primary or secondary discharge diagnoses of PAD during hospitalization or visit to outpa- tient clinic (online supplemental table S1). Lower limb revascularization was defined as thrombectomy, percuta- METHODS neous transluminal angioplasty, or arterial bypass surgery Setting distal from the infrarenal aorta. Lower limb amputation All Danish residents are assigned a unique 10-digit iden- was defined as an amputation from hip down.10 The level tifier at birth or immigration. This identifier is used of the amputation was evaluated as separate outcomes throughout every national and regional registry, thus (hip/femur amputation, knee/lower leg amputation, allowing accurate cross- linkage of data between regis- and ankle/foot/toe amputation). tries. The Civil Registration System contains information on vital status of every resident in Denmark,8 hereby 9 Statistical analysis reducing loss to follow-up (<0.3%). The Danish National Follow- up started 30 days after CAG to allow for any CAG- Patients Registry records every discharge diagnoses for related changes in comorbidities and medications to be in- hospital admission and visits to outpatient clinics http://drc.bmj.com/ 10 registered. Follow- up continued until outcome, emigra- in national Danish healthcare system. The Danish tion, death, end of follow-up (31 December 2018) with National Prescription Registry contains information on a maximum of 10 years of follow- up. Events occurring every dispensed prescription from a Danish pharmacy 11 more than 10 years after start of follow-up were censored. since 1994. The Western Denmark Heart Registry has Event rates per 100 person- years were estimated. The registered every cardiac procedure in Western Denmark 10- year cumulative incidence proportions accounting since 1999, and it contains detailed patient- related and for the competing risk of all-cause death were calculated. on October 2, 2021 by guest. Protected copyright. procedural information that includes the presence and 12 Crude and adjusted HRs (aHRs) were estimated using extent of CAD. Cox proportional regression analysis and non-diabetes patients without CAD as reference. The central assump- Patient selection tion of proportional hazards was evaluated by log–log We included all patients examined by CAG from 1 January plots and found to be satisfied. HR were adjusted for age, 2003 to 31 December 2016 (figure