This nationwide cohort analysis evaluated long-term clinical outcomes of standard versus prolonged DAPT in patients with CKD. To the best of our knowledge, the results of our analyses were derived from a cohort that included the largest number of patients with CKD who were treated with new-generation DES implantation. In addition, this study included patients who were very high-risk and usually excluded from randomized studies. The major findings of our study are as follows: (1) prolonged DAPT was associated with decrease in all-cause mortality, cardiovascular mortality, and myocardial infarction and increase in composite bleeding events in patients with CKD; (2) prolonged DAPT did not have a statistically significant impact on all-cause death, cardiovascular death, composite ischemic events, or composite bleeding events in patients with normal renal function.
Previous meta-analysis of randomized studies suggested potential benefit of short-term DAPT over prolonged DAPT for decreasing bleeding risk without significant increase in ischemia in overall population.16 On the strength of evidences favoring short-term DAPT with significant impact on bleeding risk, recent guidelines have emphasized to be aware of high bleeding risk to guide on DAPT duration [4, 5, 17, 18]. However, there is a distinct possibility that subset at extreme risk of ischemia might be often excluded from such randomized studies to guide short-term DAPT as an experimental strategy. Furthermore, there is no clear evidence or conclusive recommendation for determining duration of DAPT on CKD which should be considered as a risk factor for bleeding as well as ischemia.
Cardiac risk factors including old age, hypertension, diabetes mellitus, and heart failure are associated with CKD [2, 3]. Furthermore, many studies have suggested that CKD has an independent influence on the incidence and prognosis of ischemic cardiac events [1, 19–21]. CKD is also posited to increase bleeding risk in patients requiring antiplatelet therapy because CKD is associated concurrently with increased bleeding tendency with platelet dysfunction and abnormal coagulation cascades . Among patients with PCI, CKD has been accepted as a common risk factor for bleeding and ischemic events. A DAPT study, in which 11,648 patients undergoing PCI were randomly assigned to either aspirin monotherapy or continuing DAPT after 12-month DAPT after PCI, showed that patients with renal insufficiency (serum creatinine > 2 mg/dL) were associated with significantly increased risk of both ischemic (HR, 1.55; 95% CI, 1.03–2.32) and bleeding events (HR, 1.66; 95% CI, 1.04–2.66) . Post-hoc analysis of the PARIS prospective registry including 4,584 patients undergoing coronary stent implantation also claimed that CKD significantly increases the risk of cardiac death, MI, or stent thrombosis (HR, 2.76; 95% CI, 2.07–3.67) and BARC 3 or 5 bleeding (HR, 2.21; 95% CI, 1.53–3.19) after PCI . However, it is limited that the studies included all patients treated with a bare-metal stent or first-generation DES and that it is hard to understand how the association between duration of DAPT and ischemic/bleeding risk is influenced by CKD [20, 21].
Several studies have reported safety and efficacy of prolonged DAPT in patients with CKD who were treated with DES. A US Veterans Affairs study, including patients with CKD who are free of adverse event within a year between 2002 and 2006 (n = 4,880), suggested that prolonged DAPT (> 12 months) leaded to a lower risk of death or MI after PCI with first-generation DES implantation but not with bare-metal stent . Another study from the SWEDEHEART registry concluded that prolonged DAPT (> 3 months) was associated with similar risk of death, stroke, or MI regardless of underlying CKD status in patients with acute coronary syndrome, however, 75% patients received only bare-metal stent in the study . Previous meta-analysis of randomized trials to evaluate optimal DAPT duration did not conclude benefit or risk regarding prolonged DAPT in patients with CKD. A pooled analysis of 5 randomized trials including 1,273 patients with CKD did not demonstrate any clinical benefits of prolonged DAPT . Another meta-analysis was also inconclusive in the attempt to suggest a clinically beneficial effect of prolonged DAPT with 1,902 patients with CKD . We reviewed previous randomized trials comparing different DAPT durations in patients with CKD (Supplementary Table S13). Previous studies have encouraged potential benefit of shortening DAPT duration to reduce bleeding risk without significant change in ischemic risk. However, recent findings have warned of potential harm with short-term DAPT in patients with CKD. STOPDAPT-2 trial showed that 1-month DAPT followed by clopidogrel monotherapy reduced primary endpoint including both ischemic and bleeding events in overall population while sub-analysis showed that patients with severe CKD were associated with higher risk of the event (HR, 1.93; 95% CI, 0.65–5.75, pint=0.03) compared with 12-month DAPT . Recently, pre-specified analysis of the TWILIGHT study has been published to evaluate ticagrelor-based antiplatelet therapy comparing 3-month versus 12-month DAPT in patients with CKD. Although there were not any significant interactions between CKD and duration of DAPT in regard to adverse events, short-term DAPT leaded to a marginal increase in secondary event including death, MI, or stroke in patients with CKD (HR, 1.40; 95% CI, 0.88–2.22; p = 0.16; pint=0.11) . It has been consistently proven that prolonged DAPT leads to increase bleeding risk, however, there was no evidence if prolonged DAPT would potentiate such increase in relative risk of bleeding in the recent randomized trials (Supplementary Tables S14). We revealed that prolonged DAPT would be more effective to lower ischemic risk without significant change in increased bleeding risk in patients with worsening renal dysfunction beyond 1 year following PCI. Our study is also consistent with the most recent and large-scaled randomized trials to suggest possibility of potential benefit to improve efficacy outcomes with prolonged DAPT. However, it is still limited to weigh absolute benefit or harmfulness of prolonged DAPT, or to understand relative importance of each clinical outcome to the long-term prognosis. Therefore, individualized decision should be also emphasized in regard to the duration of DAPT in patients with CKD.
Due to inherent nature of retrospective, claim-based study, there were limitations in clarifying the detailed purpose or reasons for the decision of treatment in a patient. Therefore, we excluded patients who did not continue DAPT for at least 6 months or who continuously maintained DAPT for > 2 years to minimize selection bias. Majority of the patients continued DAPT beyond 12 months in our study, but the pattern of DAPT might be different in the other countries. There were 41% eligible patients among those with new-generation DES in our study, it could not be ruled out possibilities that a considerable number of excluded patients might have different risk profiles or findings with our study. There are possible hidden biases regarding decisions for treatment. We tried to adjust for as sufficient confounders including prescriptions, comorbidities, procedures, and demographic information including health behaviors as available in current database for minimizing residual bias. Nevertheless, our retrospective observational study should be inherently limited that risk characteristics and decisions for the treatment might be related to each other. Because antiplatelet therapy was decided by a physician without random assignment and the exact reasons for the discretion were not sufficiently understood, our study would not be sufficient to suggest conclusive findings. Lacking central adjudication of endpoints by an independent, blinded adjudication committee or use of operational definition for MI instead of conventional criteria using cardiac enzyme, electrocardiography or imaging would be also the limitations. However, conventional criteria for MI including symptom, changes in electrocardiogram, laboratory, or imaging findings might not be applicable in most claim-based studies, therefore we present various validations for securing our operational definition. Although aspirin plus clopidogrel had been most commonly used, regimen of DAPT was not considered in the current analysis. Prescription filling in claim-based system does not necessarily equate to actual medication consumption in real world practice. Since this study is not fully capable of determining causality between duration of DAPT and clinical outcomes, our study should be considered as hypothesis-generating and further prospective, large-scale studies are warranted.
In conclusion, our study suggests that patient-tailored decisions regarding the optimal duration of DAPT should be carefully considered to balance ischemic and bleeding risks in patients with CKD. Benefit of prolonged DAPT might be more profound over harmfulness of bleeding for patients with CKD after 1-year of new-generation DES implantation.