To our best knowledge, this is the largest population-based study to investigate the effectiveness, safety, and major limb outcomes for the four NOACs vs. warfarin in Asian population comorbid with AF and DM. Our results indicated that NOACs were associated with a lower risk of MACE, MALE, and all major bleeding when compared to warfarin among AF patients comorbid with DM. Second, the advantage of effectiveness, major limb outcome, and safety for NOAC over warfarin persisted in four NOAC subgroups (P interaction all > 0.05) and in high risk subgroups. Third, NOAC reduced MACE more in diabetic AF patients with a high atherosclerotic burden including the elderly, and the presence of IHD or PAD.
Comparisons of four NOACs vs. warfarin in diabetic AF population
The meta-analysis of the four landmark NOAC trials indicated that NOACs signiﬁcantly reduced the composite efﬁcacy endpoint when compared to warfarin both in non-valvular AF patients with diabetes and in those without diabetes, with no signiﬁcant interaction by diabetes status and treatment.[22-24] In a post hoc analysis of ARISTOTLE trial, a signiﬁcant interaction was noted between diabetes status and treatment regarding the risk of major bleeding (P interaction = 0.0034), suggesting that apixaban reduces more major bleeding than warfarin only among AF patients without diabetes. A post hoc analysis of the RE-LY trial showed a comparable risk of major bleeding in AF patients with diabetes treated with dabigatran 110 mg twice daily vs. warfarin (HR: 0.91; 95% CI: [0.70-1.19]), which was in contrast to a significantly lower risk of major bleeding (HR: 0.76; 95% CI: [0.64-0.90]) in non-diabetic patients treated with dabigatran 110 mg twice daily vs. warfarin. In the post hoc analysis of ROCKET-AF study, rivaroxaban showed a comparable risk of major bleeding to warfarin either in the diabetic or non-diabetic subgroup, and there was no signiﬁcant interaction between diabetic status and the risk of bleeding. Finally, in the post hoc analysis of ENGAGE-AF TIMI 48 trial, edoxaban had a significantly lower risk of major bleeding than warfarin both in the diabetic (HR: 0.78; 95% CI: [0.63-0.95]) and non-diabetic subgroups (HR: 0.81; 95% CI: [0.69-0.95]) (P interaction > 0.10).[23, 24] In summary, the advantage of NOACs over warfarin in efficacy generally persisted in diabetic subgroup treated with four NAOCs, whereas the advantage of safety profiles regarding to the risk of major bleeding for NOACs over warfarin had some conflicting results in diabetic AF population treated with NOACs, especially in case of apixaban and dabigatran 110 mg.
The present study indicated that NOACs was associated with a significantly lower MACE than warfarin in those diabetic AF population with a high atherosclerotic burden like the presence of concomitant IHD or PAD (Figure 4). For AF patient comorbid with IHD or PAD, guidelines recommend the use of oral anticoagulant (OAC) rather than APT.[9, 10] However, there are no data or guideline recommendations specifically focused on the optimal treatment for diabetic AF patients with concomitant IHD or PAD.[10, 26, 27] Previous studies have indicated that warfarin may increase vascular calcification and osteoporotic bone fracture via inhibition of the activation of matrix and bone G1a protein, and may increase coronary or peripheral vascular calcification, thus potentially influencing symptoms and outcomes in patients with IHD or PAD.[28-33] Furthermore, patients with IHD or PAD have a higher risk of bleeding events compared to those without IHD or PAD, and the bleeding events may further increase the risk of ischemic events in the IHD or PAD, for example, discontinuation of OAC due to bleeding may cause consequent ischemic event like AMI or critical limb ischemia. Our present study demonstrates the benefit of NOACs over warfarin regarding to the effectiveness and safety outcomes even in a very high risk patient population comorbid with AF, diabetes, and IHD/PAD.
Major limb outcomes for NOACs vs. warfarin in diabetic AF population
Data regarding to the major adverse limb events for AF patients treated with NOAC vs. warfarin are limited. We are only aware of one retrospective study investigating the major limb outcomes for diabetic AF patients treated with NOAC vs. warfarin. Baker et al. studied 10,700 and 13,946 diabetic AF patients treated with rivaroxaban and warfarin, respectively, by using a claims database in USA, whereby rivaroxaban was associated with a 25% reduced risk of MACE and a 63% reduced risk of MALE compared to warfarin, with no difference in major bleeding. Our present study shows that NOACs, with nearly 50% of whom treated with rivaroxaban, were also associated with a significantly lower risk of MALE than warfarin in diabetic AF patients. Although there is no difference for the advantage on MALE for different NOACs over warfarin (P interaction = 0.81 within four NOACs), the other three NOACs except for rivaroxaban showed non-significantly lower risk of MALE than warfarin among the diabetic patients, possibly due to a smaller sample size of other three NOACs when compared to rivaroxaban (Figure 3).
Recently, the COMPASS trial showed a strategy of combined therapy with aspirin and rivaroxaban (2.5 mg twice per day) or rivaroxaban alone (5mg twice per day) was associated with a significantly lower risk of major adverse limb events than aspirin alone in ~27,000 patients with stable atherosclerotic vascular disease, nearly 45% of whom had comorbid diabetes. Although the COMPASS trial differ from our present study in that it did not enroll AF patients, used a lower dose of rivaroxaban, and used aspirin but not warfarin as a comparator, the COMPASS trial firstly demonstrated that anticoagulant regimen with rivaroxaban indeed provide an extra benefit in improving MALE outcome in patients with a high atherosclerotic burden when compared to the current standard treatment. Until now, there are no large randomized controlled studies evaluating the major limb outcome for AF patients with a high atherosclerotic burden or AF treated with other three NOACs.
The present study has several limitations. First, our study is a retrospective cohort study. Although the use of inverse propensity score weighting with adjustment of several variables allowed the balance of baseline comorbidities among the study groups, selection bias and residual confounding by unobserved or unmeasured variables could not be excluded in the present study. Second, misclassification and miscoding of the baseline comorbidities and study outcomes is a potential limitation. Third, laboratory data such as international normalized ratio (INR) for patients treated with warfarin were not obtained in the NHIRD database; indeed, Asian populations treated with warfarin generally have a much lower time in therapeutic range (TTR) for an INR target 2.0 to 3.0 compared to other regions of the world.[36, 37] Hence, the superiority of NOACs over warfarin may be partly due to low TTR for those patients treated with warfarin in the present study. Fourth, four NOACs and warfarin prescribed had varying rates of renal excretion and, thus, decisions regarding the use of a specific NOAC or warfarin would have been guided by the renal function of each patient (e.g., a perceived risk may result in conscious avoidance in use of NOACs in specific patient populations). Renal function lab data for each patient are lacking in the NHIRD, and ICD coding indicating an impaired renal function was dependent on each physician’s choice. Therefore, residual confounding factors including the renal function across the exposure groups could not be excluded. In addition, there was a high prevalence of low-dose NOAC prescriptions in the present AF cohort. The lack of both body weight and renal function data makes us difficult to determine if those AF patients treated with low-dose NOACs were correctly prescribed with an “adjusted” or “off-label” low-dose NOACs. Fifth, glycated hemoglobin is directly associated with risk of stroke in diabetic patients with AF; however, we are unable to determine the quality of glycemic control for each diabetic AF patient due to lack of glycated hemoglobin data. Finally, for the issue of MALE outcome, we were unable to differentiate whether the outcome of lower limb amputation or revascularization was due to a pure cardio-embolic event caused by AF itself or an atherothrombotic event caused by DM related atherosclerosis and peripheral artery disease (PAD). Diabetic patients have a higher prevalence of PAD than other populations, and the underlying pathology for PAD related critical limb ischemia is mainly mediated by atherothrombotic events. Nevertheless, the COMPASS trial has demonstrated that use of a NOAC was beneficial in reducing atherothrombotic events in PAD patients, whereby nearly 45% had comorbid diabetes.