Benefit and risk of prolonged dual antiplatelet therapy after drug-eluting stent implantation in patients with chronic kidney disease: a nationwide cohort study

doi:10.21203/rs.3.rs-1349452/v1

Download PDF

Research Article

Benefit and risk of prolonged dual antiplatelet therapy after drug-eluting stent implantation in patients with chronic kidney disease: a nationwide cohort study

https://doi.org/10.21203/rs.3.rs-1349452/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Purpose: The optimal duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) with drug-eluting stent in patients with chronic kidney disease (CKD) is not clearly established. This study purposed to compare clinical outcomes of patients with 6-12 (standard) versus 12-24 months (prolonged) DAPT according to CKD.

Methods: Using a nationwide, claim-based database, we retrospectively evaluated association between DAPT duration and clinical outcomes including death, composite ischemic event, and composite bleeding event between 1 and 3 years after PCI. CKD was defined as estimated glomerular filtration rate <60 mL/min/1.73m². Of 73,941 eligible patients, 13,425 (18.2%) had CKD and 49,019 (66%) were prescribed prolonged DAPT. Prolonged DAPT had no significant impact on the risk of clinical outcomes in patients with normal renal function.

Results: In patients with CKD, prolonged DAPT was associated with a lower risk of all-cause death (HR 0.85, 95% CI 0.76–0.95) and composite ischemic events (HR 0.87, 95% CI 0.78–0.96) and a higher risk of composite bleeding events (HR 1.18, 95% CI 1.02–1.37). Benefit of prolonged DAPT on reducing composite ischemic event increased significantly in patients with worsened renal dysfunction (P_interaction=0.02) while there was no significant interaction between its bleeding risk and renal dysfunction (P_interaction=0.22).

Conclusion: While standard DAPT would be recommended in patients with normal renal function, tailored decision for DAPT duration would be considered in those with CKD to balance between ischemic and bleeding risks.

Trial registration: ClinicalTrial.gov (NCT04715594).

drug-eluting stents

chronic kidney disease

dual antiplatelet therapy

percutaneous coronary intervention

Chronic kidney disease (CKD) is an independent risk factor for incidence and outcomes of cardiovascular disease [1]. CKD accelerates vascular calcification as well as atherosclerotic processes, extending the complexity and burden of coronary artery disease [2]. Myocardial infarction (MI) and cardiovascular mortality significantly limit life expectancy in patients with CKD compared to those with normal renal function [3]. Although dual antiplatelet therapy (DAPT) has been a standard treatment strategy for minimizing ischemic risk after percutaneous coronary intervention (PCI) with drug-eluting stents (DES) for the last two decades, it is associated with increasing bleeding risk. Recent advancements in pharmacotherapy and interventional devices have facilitated a shift in the balance between ischemic and bleeding risks toward minimizing bleeding risk for achieving optimal clinical outcomes after PCI [4, 5]. Large-scale clinical studies and subsequent analyses have suggested an optimal duration of DAPT after PCI, which currently is recommended to be based on scoring systems or using certain criteria correlated with bleeding risk of patients [5, 6]. However, it is uncertain whether DAPT should be extended or shortened for patients with CKD who are vulnerable to both ischemic and bleeding events. In this study, we sought to investigate the clinical implication of duration of DAPT in patients with CKD who underwent new-generation DES implantation.

This is a nationwide retrospective study conducted using the national health claims database from the National Health Insurance Service of Korea, which is the sole insurer managed by the Korean government. This database includes information representing the entire Korean population, which includes 97.1% of the subjects covered by health insurance and the remaining 2.9% affiliated with the medical aid program. Our database contains claimed medical costs, drug prescriptions, medical devices and procedures, and comorbidities presented as International Classification of Diseases, Tenth Revision (ICD-10) codes [7]. We obtained death certificates and ICD-10 codes from the National Institute of Statistics of Korea to determine a cause of death. This study was approved by the Institutional Review Board in our institute. Informed consent was waived because personal information was anonymized and de-identified according to the confidentiality guidelines of the Korean Health Insurance Review and Assessment Service. This study is registered at ClinicalTrial.gov (NCT04715594).

Study population

The study flow is illustrated in Fig. 1. The CONNECT DES cohort includes 273,670 patients (≥ 20 years old) who were treated with first- or new-generation DES between January 2005 and December 2016 from the 52 million inhabitants included in the Korean National Health Insurance Service database (Supplementary material). Among 273,670 patients of the original cohort, 94,362 who had the following characteristics were excluded from this study: implanted with first-generation DES (n = 69,316); prior PCI (or coronary artery bypass surgery) (n = 5,517) because clinical events during follow-up cannot be discriminated whether those were caused by prior PCI (or coronary artery bypass surgery) or index PCI; implanted with DES not commonly used worldwide (n = 8,511); omitted DAPT ≥ 7 days (n = 5,483); and missing medical information (n = 5,535). After this, 179,308 patients treated with next-generation DES at the first-ever coronary revascularization were included. Then, we excluded patients (n = 4,223) who died within 1 year after PCI to minimize immortal time bias [8]. Patients who were prescribed oral anticoagulant (n = 4,669) or who had DAPT for < 6 months (n = 18,936) or ≥ 24 months (n = 61,369) were excluded to minimize selection bias. Patients who received renal replacement therapy or did not have information of renal function also were excluded (n = 16,170). Finally, we included 73,941 patients with available information of renal function for the analysis. Duration of DAPT was categorized as standard or prolonged if continued for 6–12 months (n = 24,940) or for 12–24 months (n = 49,001), respectively.

Estimation of renal insufficiency

Inhabitants in the Korean National Health Insurance Service have been recommended to receive biannual health checkups, which include a standardized health questionnaire and physical and laboratory examinations including serum creatinine level. The estimated glomerular filtration rate (eGFR) was calculated from the serum creatinine level standardized to isotope dilution mass spectrometry using the 4-variable Modification of Diet in Renal Disease study equation as follows: (eGFR, mL/min/1.73m²) = 175 × (serum creatinine, mg/dL)^−1.154 × (age)^−0.203 × 0.742 (if female) [9]. We excluded subjects with end-stage renal disease who had regular insurance claims with a treatment code of hemodialysis (O7010, O7020) or peritoneal dialysis (O7070) for ≥ 30 days before index PCI. Patients who had undergone kidney transplantation (R3280) at index PCI and throughout the study period were not eligible for the analysis. Patients were categorized according to renal function as follows: eGFR ≥ 90 (normal renal function), 60–89 (mild renal insufficiency), and < 60 (CKD) mL/min/1.73m² [10].

Definitions

DAPT is considered to be continued if a patient has been prescribed aspirin and P2Y₁₂ inhibitors including clopidogrel, prasugrel, or ticagrelor without discontinuation for > 7 days. The duration of DAPT was identified using prescription data with Korean Drug and Anatomical Therapeutic Chemical codes [11]. Diabetes mellitus was defined as prescription of oral hypoglycemic agent or insulin. The Charlson comorbidity index was calculated based on comorbid conditions with varying assigned weights by diagnostic codes [12]. Clinical outcomes were all- cause death, composite ischemic events (cardiovascular death, myocardial infarction, or ischemic stroke), and composite bleeding events (hemorrhagic stroke, gastrointestinal bleeding, or genitourinary bleeding requiring admission or medical intervention), and each component of an ischemic or bleeding event at 3 years after PCI. We observed adverse events between 12 months and 36 months after index PCI to minimize immortal time bias. We adjudicated cardiovascular death using the death certificates from the National Statistical Office of Korea, which provided with an accuracy of 92% for specific cause of death [7, 13]. Cardiovascular death was identified by a death certificate with at least one cardiovascular diagnosis (acute MI, stroke, heart failure, or sudden cardiac death).¹¹ MI was defined by the ICD-10 codes corresponding to acute MI [7] and one or more of the following conditions: (1) concurrent presence of claims for coronary angiography, (2) admission via the emergency department, or (3) performance of cardiac biomarker assessment more than 4 times. Validity of MI was described in Supplementary Method. Detailed definitions of study outcomes including each component of adverse events are summarized in Supplementary Table S1. There was no patient or public involvement in the design, analysis, interpretation, or writing a draft of the study.

Statistical analysis

Continuous variables are reported as mean and standard deviation, and categorical variables are presented as frequency and percentage. We used multivariable logistic regression models to calculate propensity scores for prolonged DAPT, adjusting for covariates of age, sex, household income, health behaviors, region of hospital, baseline comorbidities, medications, and procedure-related characteristics (Supplementary Table S2). Subsequently, the stabilized inverse probability of treatment weighting (sIPTW) was used to balance covariates between standard and prolonged DAPT. We considered the covariate distribution balanced if the standardized mean difference was < 0.1 for each covariate between the groups. We observed incidence of the first adverse event during the study period and plotted the results using the Kaplan–Meier method. A Cox proportional hazard regression model was used to identify the hazard ratio (HR) of prolonged DAPT for each clinical outcome of interest after testing proportional hazard assumptions with scaled Schoenfeld residuals and Kolmogorov-type Supremum Tests before and after sIPTW [14]. The significance of interaction between duration of DAPT and category of severity of renal insufficiency as an ordinal term was tested in Cox models for clinical outcomes. The cause-specific hazard model was used to consider death as a competing risk when comparing the incidences of cardiovascular death and other components of clinical outcomes [15]. A proportional hazards regression restricted cubic spline model was used to visualize the continuous association between eGFR and each adverse event stratified by duration of DAPT after sIPTW using the 'rms' package in R. We performed series of sensitive analysis to validate consistency of our findings (Supplementary Method). A two-sided p-value < 0.05 was considered significant. Statistical analyses were conducted using SAS version 9.4 (SAS Institute, Cary, NC, USA) and R version 3.6 (The R Foundation, www.R-project.org).

A total of 73,941 DES-treated patients was included in this study: 15,275 (20.7%) with normal renal function, 45,241 (61.2%) with mild renal insufficiency, and 13,425 (18.2%) with CKD; 24,940 (33.7%) patients with standard DAPT and 49,001 (66.3%) with prolonged DAPT. Aspirin plus clopidogrel rather than aspirin plus ticagrelor (or prasugrel) was prescribed in 58,704 patients (79.3%) and its use was more encouraged in patients with CKD (Supplementary Table S3). After implementing sIPTW, there was no significant difference in severity of renal dysfunction between patients with standard and prolonged DAPT. Propensity scores associated with treatment and covariates were balanced between patients with standard and prolonged DAPT (Supplementary Table S4, Supplementary Figure S1). All covariates were balanced between patients with standard versus prolonged DAPT in each stratum regarding renal dysfunction (Table 1).

Table 1

Baseline characteristics according to renal function after implementing stabilized inverse probability of treatment weighting
Characteristics	Normal		Mild renal insufficiency		Chronic kidney disease
Characteristics	Standard DAPT	Prolonged DAPT	Standard DAPT	Prolonged DAPT	Standard DAPT	Prolonged DAPT
N	5,114	10,113	15,239	29,978	4,581	8,928
Mean eGFR, mL/min/1.73 m²	114 ± 82	116 ± 97	74 ± 8	74 ± 8	49 ± 11	49 ± 11
Demography
Age, years	60.8 ± 11.8	60.7 ± 11.4	63.3 ± 10.4	63.3 ± 10.3	70.4 ± 10.0	70.4 ± 10.0
Female	1,248 (24)	2,442 (24)	4,196 (28)	8,222 (27)	1,766 (39)	3,450 (39)
Body mass index, kg/m²	24.6 ± 3.2	24.6 ± 3.2	24.8 ± 3.0	24.8 ± 3.0	24.7 ± 3.2	24.7 ± 3.1
Income
Quartile 1 (least deprived)	1,134 (22)	2,191 (22)	3,328 (22)	6,505 (22)	1,027 (22)	2,052 (23)
Quartile 2	849 (17)	1,761 (17)	2,599 (17)	5,062 (17)	695 (15)	1,314 (15)
Quartile 3	1,280 (25)	2,457 (24)	3,503 (23)	6,964 (23)	998 (22)	1,950 (22)
Quartile 4 (most deprived)	1,851 (36)	3,705 (37)	5,809 (38)	11,446 (38)	1,860 (41)	3,613 (40)
Systolic blood pressure, mmHg	128 ± 15	129 ± 16	128 ± 16	128 ± 16	130 ± 17	130 ± 17
Fasting glucose, mg/dL	113 ± 40	112 ± 37	112 ± 36	112 ± 36	118 ± 46	117 ± 45
Total cholesterol, mg/dL	183 ± 50	183 ± 54	184 ± 50	185 ± 51	181 ± 50	180 ± 50
Current smoker	1,500 (29)	3,155 (31)	3,876 (25)	7,568 (25)	778 (17)	1,411 (16)
Comorbidities
Hypertension	2,985 (58)	5,836 (58)	9,514 (62)	18,715 (62)	3,462 (76)	6,806 (76)
Diabetes mellitus	1,544 (30)	3,023 (30)	4,399 (29)	8,719 (29)	1,980 (43)	3,737 (42)
Insulin-dependent	148 (3)	299 (3)	535 (4)	1026 (3)	412 (9)	793 (9)
Dyslipidemia	2,283 (45)	4,412 (44)	6,696 (44)	13,217 (44)	1,803 (39)	3,579 (40)
Heart failure	500 (10)	1,001 (10)	1,696 (11)	3,341 (11)	830 (18)	1,563 (18)
Chronic liver disease	561 (11)	1,089 (11)	1,586 (10)	3,144 (10)	406 (9)	804 (9)
Chronic pulmonary disease	300 (6)	655 (6)	1,019 (7)	1,927 (6)	428 (9)	814 (9)
Peripheral arterial occlusive disease	156 (3)	294 (3)	507 (3)	984 (3)	189 (4)	413 (5)
Atrial fibrillation or flutter	98 (2)	179 (2)	356 (2)	683 (2)	149 (3)	309 (3.5)
Prior malignancy	214 (4)	418 (4)	682 (4)	1,310 (4)	247 (5)	523 (6)
Prior stroke or TIA	327 (6)	658 (6.5)	1,103 (7)	2,128 (7)	549 (12)	1,082 (12)
Prior ICH	24 (0.5)	38 (0.4)	68 (0.4)	125 (0.4)	21 (0.5)	57 (0.6)
Anemia	178 (3)	341 (3)	560 (4)	1115 (4)	735 (16)	1417 (16)
Charlson comorbidity index	1.7 ± 1.5	1.7 ± 1.5	1.8 ± 1.6	1.8 ± 1.5	2.6 ± 2.0	2.6 ± 1.9
Medication prior to PCI
Anti-platelet agent	1,854 (36)	3,669 (36)	6,251 (41)	12,315 (41)	2,417 (53)	4,667 (52)
β-Blockers	1,733 (34)	3,530 (35)	5,869 (39)	11,384 (38)	2,434 (53)	4,782 (54)
RAAS blocker	971 (19)	1,885 (19)	3,110 (20)	6,081 (20)	1455 (32)	2,859 (32)
Presentation as AMI	869 (17)	1,818 (18)	2,631 (17)	5,079 (17)	780 (17)	1,455 (16)
Number of stents	1.2 ± 0.4	1.2 ± 0.4	1.2 ± 0.4	1.2 ± 0.4	1.2 ± 0.5	1.2 ± 0.5
Values are the mean ± standard deviation or n (%). Standard DAPT, DAPT between 6 and 12 months; Prolonged DAPT, DAPT between 12 and 24 months. Standardized mean difference in all covariates between standard versus prolonged DAPT in each stratum were < 0.06. Abbreviations: AMI, acute myocardial infarction; BP-DES, biodegradable polymer drug-eluting stent; DAPT, dual antiplatelet therapy; ICH, intracranial hemorrhage; PCI, percutaneous coronary intervention; RAAS, renin-angiotensin-aldosterone-system; TIA, transient ischemic attack.

After implementing sIPTW, prolonged DAPT did not have a statistically significant impact on adverse clinical events including all-cause death (3.2% vs. 3.2% in standard vs. prolonged DAPT, respectively; HR, 0.99; 95% CI, 0.82–1.20), cardiovascular death (2.7% vs. 2.3%; HR, 1.15; 95% CI 0.93–1.43), composite ischemic events (4.4% vs. 4.1%; HR, 1.08; 95% CI, 0.92–1.27), or composite bleeding events (5.2% vs. 5.0%; HR, 1.04; 95% CI, 0.90–1.21) in patients with normal renal function. However, it was associated with a lower risk of all–cause death (9.4% vs. 10.9% in standard vs prolonged DAPT, respectively; HR, 0.85; 95% CI, 0.76–0.95), cardiovascular death (8.2% vs. 9.5%; HR, 0.85; 95% CI, 0.75–0.95), composite ischemic events (11.1% vs. 12.5%; HR, 0.87; 95% CI, 0.78–0.96), and a higher risk of composite bleeding events (6.7% vs. 5.7%; HR, 1.18; 95% CI, 1.02–1.37) in patients with CKD (Tables 2; Fig. 2).

Table 2

Incidence and hazard risk of adverse clinical events according to renal function and dual antiplatelet therapy
Adverse event	Normal			Mild renal insufficiency			Chronic kidney disease			P_interaction
Adverse event	S-DAPT	P-DAPT	HR (95% CI)	S-DAPT	P-DAPT	HR (95% CI)	S-DAPT	P-DAPT	HR (95% CI)	P_interaction
N	5,114	10,113		15,239	29,978		4,581	8,928
All-cause death	163 (3.2)	320 (3.2)	0.99 (0.82–1.20)	596 (3.9)	1,015 (3.4)	0.86 (0.78–0.95)^e	500 (10.9)	842 (9.4)	0.85 (0.76–0.95)^e	.20
Cardiovascular death	120 (2.3)	273 (2.7)	1.15 (0.93–1.43)	496 (3.3)	853 (2.8)	0.87 (0.78–0.97)^c	437 (9.5)	732 (8.2)	0.85 (0.75–0.95)^d	.02
Composite ischemic event^†	210 (4.1)	449 (4.4)	1.08 (0.92–1.27)	770 (5.1)	1,414 (4.7)	0.93 (0.85–1.02)	574 (12.5)	987 (11.1)	0.87 (0.78–0.96)^e	.02
Composite bleeding event^‡	257 (5.0)	527 (5.2)	1.04 (0.90–1.21)	763 (5.0)	1,693 (5.6)	1.13 (1.04–1.23)^e	259 (5.7)	597 (6.7)	1.18 (1.02–1.37)^c	.22
Myocardial infarction	128 (2.5)	300 (3.0)	1.18 (0.96–1.46)	528 (3.5)	911 (3.0)	0.87 (0.78–0.97)^c	448 (9.8)	765 (8.6)	0.87 (0.77–0.97)^c	.02
Ischemic stroke	87 (1.7)	173 (1.7)	1.01 (0.78–1.31)	277 (1.8)	583 (1.9)	1.07 (0.93–1.24)	167 (3.6)	304 (3.4)	0.93 (0.77–1.12)	.43
Hemorrhagic stroke	8 (0.2)	15 (0.1)	0.89 (0.38–2.07)	10 (0.1)	37 (0.1)	1.81 (0.91–3.60)	8 (0.2)	8 (0.1)	0.47 (0.17–1.25)	.42
Gastrointestinal bleeding	174 (3.4)	356 (3.5)	1.03 (0.86–1.24)	508 (3.3)	1,127 (3.8)	1.13 (1.02–1.26)^c	167 (3.6)	415 (4.7)	1.28 (1.07–1.54)^d	.09
Genitourinary bleeding	81 (1.6)	178 (1.8)	1.11 (0.85–1.44)	268 (1.8)	587 (2.0)	1.12 (0.97–1.29)	98 (2.1)	204 (2.3)	1.07 (0.84–1.37)	.83
Values are presented as incidence (percentage) or hazard ratio (HR; 95% confidence interval [CI]). Stabilized inverse probability of treatment weighing analysis was performed for yielding the incidence and hazard ratio of prolonged DAPT for each adverse event. ^aComposite of cardiovascular death, myocardial infarction, and ischemic stroke. ^bComposite of hemorrhagic stroke, gastrointestinal bleeding, and genitourinary bleeding. P value for each analysis was indicated by asterisks as follows: p < 0.05 (^c), < 0.01 (^d), and < 0.005 (^e). S-DAPT and P-DAPT indicate standard- and prolonged dual antiplatelet therapy, respectively.

There was a statistically significant interaction between severity of renal dysfunction and prolonged DAPT on composite ischemic events at 3 years (p for interaction, p_int=0.02). Prolonged DAPT also had a profound effect on decreasing risk of cardiovascular death (p_int=0.02) or MI (p_int=0.02) according to renal dysfunction. However, there was no significant interaction between presence of CKD and DAPT duration for composite bleeding events (p_int=0.22) (Table 2). A value of eGFR higher than 75 mL/min/1.73 m² did not impact the risks of adverse events including all-cause death, cardiovascular death, and composite ischemic events. However, as renal function less than 75 mL/min/1.73 m² gradually deteriorated, the risk of these clinical events rapidly increased. As renal function worsened, prolonged DAPT was associated with a smaller increase in the risk of these clinical events (Supplementary Figure S2). Sensitivity analysis showed consistent findings that prolonged DAPT is associated with lower risk of composite ischemic event in patients with worsened renal function irrespective of statistical models, criteria of MI, stent type, and population (Supplementary Tables S6-S12).

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 [22]. 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) [20]. 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 [21]. 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 [23]. 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 [24]. 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 [25]. Another meta-analysis was also inconclusive in the attempt to suggest a clinically beneficial effect of prolonged DAPT with 1,902 patients with CKD [26]. 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, p_int=0.03) compared with 12-month DAPT [27]. 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; p_int=0.11) [28]. 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.

Authors’ Contributions:

All authors: conception and design of the study. CK: writing the manuscript. CK, D-WC, C-MN: Acquisition, analysis, or interpretation of data of the study. YS, S-JH, C-MA, J-SK, B-KK, Y-GK, DC, E-CP, YJ, C-MN and M-KH: conception and critical revision of the manuscript for important intellectual content. All authors contributed to read and approved the final manuscript.

Funding:

This work was supported by the Cardiovascular Research Center, Seoul, Korea. The funder had no role in the design and conduct of the study; data collection, management, statistical analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Availability:

Because of strict policy for securing privacy protection, our cohort database is only available and to be analyzed on the intranet of Korean National Health Insurance Service database and will not be shared.

COMPLIANCE WITH ETHICAL STANDARDS

Conflict of interest:

None in all authors.

Ethics Approval and Consent to Participate:

This study was approved by the Institutional Review Board in Severance Hospital, Yonsei University College of Medicine. Informed consent was waived because personal information was anonymized and de-identified according to the confidentiality guidelines of the Korean Health Insurance Review and Assessment Service.

Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004;351:1296-1305
Sarnak MJ, Amann K, Bangalore S, et al. Chronic kidney disease and coronaryartery disease. J Am Coll Cardiol 2019;74:1823-1838
Gansevoort RT, Correa-Rotter R, Hemmelgarn BR, et al. Chronic kidney disease and cardiovascular risk: Epidemiology, mechanisms, and prevention. Lancet 2013;382:339-352
Costa F, van Klaveren D, James S, et al. Derivation and validation of the predicting bleeding complications in patients undergoing stent implantation and subsequent dual antiplatelet therapy (PRECISE-DAPT) score: A pooled analysis of individual-patient datasets from clinical trials. Lancet 2017;389:1025-1034
Costa F, Van Klaveren D, Feres F, et al. Dual antiplatelet therapy duration basedon ischemic and bleeding risks after coronarystenting. J Am Coll Cardiol 2019;73:741-754
Neumann FJ, Sousa-Uva M, Ahlsson A, et al. 2018 ESC/EACTS guidelines on myocardial revascularization. Eur Heart J 2019;40:87-165
Choi EK. Cardiovascular research using the Korean national health information database. Korean Circ J 2020;50:754-772
Cho IS, Chae YR, Kim JH, et al. Statistical methods for elimination of guarantee-time bias in cohort studies: a simulation study. BMC Med Res Methodol 2017;17:126.
Levey AS, Coresh J, Greene T, et al. Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann Intern Med 2006;145:247-254
National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: Evaluation, classification, and stratification. Am J Kidney Dis 2002;39:S1-266
Kim J, Kang D, Park H, et al. Long-term β-blocker therapy and clinical outcomes after acute myocardial infarction in patients without heart failure: Nationwide cohort study. Eur Heart J 2020;41:3521-3529
Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: Development and validation. J Chronic Dis 1987;40:373-383
Won TY, Kang BS, Im TH, Choi HJ. The study of accuracy of death statistics. J Korean Soc Emerg Med 2007;18:256-262
Lin DY, Wei L-J, Ying Z. Checking the cox model with cumulative sums of martingale-based residuals. Biometrika 1993;80:557-572
Austin PC, Lee DS, Fine JP. Introduction to the analysis of survival data in the presence of competing risks. Circulation 2016;133:601-609
Navarese EP, Andreotti F, Schulze V, et al. Optimal duration of dual antiplatelet therapy after percutaneous coronary intervention with drug eluting stents: meta-analysis of randomised controlled trials. BMJ. 2015;350:h1618.
Knuuti J, Wijns W, Saraste A, et al. 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J. 2020;41:407-477.
Collet JP, Thiele H, Barbato E, et al. 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J. 2021;42:1289-1367.
Sarnak MJ, Levey AS, Schoolwerth AC, et al. Kidney disease as a risk factor for development of cardiovascular disease: A statement from the american heart association councils on kidney in cardiovascular disease, high blood pressure research, clinical cardiology, and epidemiology and prevention. Circulation 2003;108:2154-2169
Yeh RW, Secemsky EA, Kereiakes DJ, et al. Development and validation of a prediction rule for benefit and harm of dual antiplatelet therapy beyond 1 year after percutaneous coronary intervention. JAMA 2016;315:1735-1749
Baber U, Li SX, Pinnelas R, et al. Incidence, patterns, and impact of dual antiplatelet therapy cessation among patients with and without chronic kidney disease undergoing percutaneous coronary intervention: Results from the PARIS registry (Patterns of Non-Adherence to Anti-Platelet Regimens in Stented Patients). Circ Cardiovasc Interv 2018;11:e006144
Capodanno D, Angiolillo DJ. Antithrombotic therapy in patients with chronic kidney disease. Circulation 2012;125:2649-2661
Siddiqi OK, Smoot KJ, Dufour AB, et al. Outcomes with prolonged clopidogrel therapy after coronary stenting in patients with chronic kidney disease. Heart 2015;101:1569-1576
Carrero JJ, Varenhorst C, Jensevik K, et al. Long-term versus short-term dual antiplatelet therapy was similarly associated with a lower risk of death, stroke, or infarction in patients with acute coronary syndrome regardless of underlying kidney disease. Kidney Int 2017; 91:216-226.
Hwang D, Park KW, Lee JM, et al. Efficacy and safety of dual antiplatelet therapy after coronary stenting in patients with chronic kidney disease. Am Heart J 2018;197:103-112
Mavrakanas TA, Chatzizisis YS, Gariani K, et al. Duration of dual antiplatelet therapy in patients with ckd and drug-eluting stents: A meta-analysis. Clin J Am Soc Nephrol 2019;14:810-822
Watanabe H, Domei T, Morimoto T, et al. Effect of 1-Month Dual Antiplatelet Therapy Followed by Clopidogrel vs 12-Month Dual Antiplatelet Therapy on Cardiovascular and Bleeding Events in Patients Receiving PCI: The STOPDAPT-2 Randomized Clinical Trial. JAMA 2019; 321:2414-2427.
Stefanini GG, Briguori C, Cao D, et al. Ticagrelor monotherapy in patients with chronic kidney disease undergoing percutaneous coronary intervention: TWILIGHT-CKD. Eur Heart J 2021;42:4683-4693.

Supplementv13.docx

Download PDF

Version 1

posted

You are reading this latest preprint version

Benefit and risk of prolonged dual antiplatelet therapy after drug-eluting stent implantation in patients with chronic kidney disease: a nationwide cohort study

Status:

Version 1

Abstract

Figures

Introduction

Methods

Study population

Estimation of renal insufficiency

Definitions

Statistical analysis

Results

Discussion

Declarations

Authors’ Contributions:

Funding:

Data Availability:

COMPLIANCE WITH ETHICAL STANDARDS

Conflict of interest:

Ethics Approval and Consent to Participate:

References

Supplementary Files

Status:

Version 1