Investigation of dual antiplatelet therapy after coronary stenting in patients with chronic kidney disease.

BACKGROUND: Dual antiplatelet therapy (DAPT) is currently the standard treatment for the prevention of ischemic events after stent implantation. However, the optimal DAPT duration remains elusive for patients with chronic kidney disease (CKD). Therefore, we aimed to compare the effectiveness and safety between long-term and short-term DAPT after coronary stenting in patients with CKD.
METHODS: This retrospective cohort study analyze data from the Taipei Medical University (TMU) Institutional and Clinical Database, which include anonymized electronic health data of 3 million patients that visited TMU Hospital, Wan Fang Hospital, and Shuang Ho Hospital. We enrolled patients with CKD after coronary stenting between 2008 and 2019. The patients were divided into the long-term (>6 months) and short-term DAPT group (≤ 6 months). The primary end point was major adverse cardiovascular events (MACE) from 6 months after the index date. The secondary outcomes were all-cause mortality and Thrombolysis in Myocardial Infarction (TIMI) bleeding.
RESULTS: A total of 1899 patients were enrolled; of them, 1112 and 787 were assigned to the long-term and short-term DAPT groups, respectively. Long-term DAPT was associated with similar risk of MACE (HR: 1.05, 95% CI: 0.65-1.70, P = 0.83) compare with short-term DAPT. Different CKD risk did not modify the risk of MACE. There was also no significant difference in all-cause mortality (HR: 1.10, 95% CI: 0.75-1.61, P = 0.63) and TIMI bleeding (HR 1.19, 95% CI: 0.86-1.63, P = 0.30) between groups.
CONCLUSIONS: Among patients with CKD and coronary stenting, we found that long-term and short-term DAPT tied on the risk of MACE, all-cause mortality and TIMI bleeding.

Introduction

Dual antiplatelet therapy (DAPT), comprising of aspirin and a P2Y12 inhibitor, lowers the risk of ischemic events in patients with coronary artery disease (CAD) and stent implantation [1, 2]. The efficacy of these combinations to prevent ischemic events was well established, however, the optimal duration of DAPT remained elusive and differs according to the type of coronary event and stent. Both the American Heart Association and European Society of Cardiology guidelines suggest at least 6 months of DAPT after stenting implantation for stable CAD and at least 3 months DAPT for high bleeding risk patients [3-5]. And, some scoring system recommended according to the guideline (e.g. PRECISE-DAPT score) to identify the high bleeding risk patients [5]. However, the use of these scoring systems in chronic kidney disease (CKD) patients was limited because those have been developed based on randomized control trials (RCTs) that excluded advanced CKD patients [6-8]. Furthermore, fewer evidences existed in CKD patients since these patients were under-represented in large clinical trials, though CKD patients are at risk of developing CAD [9].

CKD patients have been reported to have increased risk of ischemia events post stent implantation [10, 11]. The increased risk of ischemia in CKD patients not only comes from old age and comorbidities, but also non-traditional risk factors, namely, chronic inflammation, malnutrition, vascular calcification, and endothelial dysfunction [12, 13]. The increased blood coagulation profiles and increased factor VIII activity were also characterized in CKD patients [14]. In addition, the attenuated response of antiplatelet therapy further increased the risk of ischemic events in these patients [15]. Therefore, prolonged DAPT was considered a logic strategy for CKD patients post-stent implantation. However, those patients are also at higher risk of bleeding events, including gastrointestinal (GI) or cerebrovascular bleeding [16, 17]; and prolonged DAPT may associated with higher risk of bleeding [18]. The bleeding leads to a sudden discontinuation of DAPT, and this adverse event impacts on quality of life and CV-related morbidities [19]. Until now, there has been no consensus to judiciously determine the balance between ischemia and bleeding.

In CKD patients, whether a longer duration of DAPT associated with better CV outcomes, as compared to short DAPT is of interest. Therefore, we aimed to compare the effectiveness and safety between long-term and short-term DAPT in patients with CKD risk after receiving percutaneous coronary intervention (PCI) by a real-world data analysis. Using the Taipei Medical University (TMU)-Institutional and Clinical Database enables the study to reflect real-world practice involving CKD with different severity.

Material and methods

Ethical statement

This study has been reviewed by the Institutional Review Board of Taipei Medical University (TMU-JIRB No. N201707020). The need for informed consent was waived owing to the use of anonymized data.

Data source

Data were obtained from the Taipei medical University Institutional and Clinical Database [20, 21], which stores electronic health data of 3 million patients that visited TMU Hospital, Wan Fang Hospital, and Shuang Ho Hospital. These hospitals have a combined capacity of 3000 beds. The database contains information regarding patients’ demographic and clinical characteristics, outpatient visits, emergency room visits, hospital admissions, laboratory tests results, and drug prescriptions since 1997.

Patients

We included 10900 patients who underwent PCI between January 1, 2008 and December 31, 2019. The index date was defined as the first date by which PCI with implantation of drug-eluting stents or bare-metal stents was performed. The exclusion criteria were as follows: 1) PCI without stent implantation; 2) missing information in CKD stage or stage G1-G2 with albuminuria < 30mg/g; 3) DAPT not given within 28 days from the index date; 4) < 28 days or > 336 days DAPT users; 5) death, ischemic stroke or myocardial infarction within 168 days from the index date; 6) receiving warfarin or non-vitamin K antagonist oral anticoagulants (Fig 1). CKD risk on the index date was defined according to the estimated glomerular filtration rate (eGFR) and the amount of microalbuminuria for > 3 months, consistent with the Kidney Disease Outcomes Quality Initiative of the National Kidney Foundation definition and classification of CKD [22]. The eGFR was calculated using the serum creatinine (sCr) based on the Taiwanese modification of the Modification of Diet in Renal Disease (MDRD) equation: 1.309 × MDRD0.912 [23]. MDRD was calculated as follows: 175 × sCr-1.154 × age-0.203 × 0.742 (if female). All diagnoses and procedures from 1997 to 2015 and since 2016 were defined according to the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) and the International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10), respectively (S1 Table). Major, minor and minimal bleeding were defined according to the Thrombolysis In Myocardial Infarction (TIMI) definition [24]. The aim of this study is to compare the effectiveness and safety between long-term and short-term DAPT in patients with CKD risk after coronary stenting.

Fig 1

Flow chart of study subjects selection.

Exposure

The patients were divided into two groups according to the duration of DAPT as the long-term DAPT group (>6 months) and the short-term DAPT group (≤6 months). Medications prescribed were retrieved from pharmaceutical data and classified according to the Anatomical Therapeutic Chemical classification system of the World Health Organization (https://www.whocc.no). The use of DAPT was defined as the continuing use of DAPT comprising aspirin plus a platelet P2Y12 inhibitor (clopidogrel or ticagrelor) (S1 Table).

Study endpoints

We conducted a landmark analysis, for immortal time bias, to examine the effect of major adverse cardiac event (MACE), all-cause mortality, and bleeding. MACE was defined as a composite of CV death, ischemic stroke, and myocardial infarction. All endpoints were started to record 6 months after the index date, and the follow-up assessment comprised at least four records of outpatient or inpatient management every year. We linked (TMU) Institutional and Clinical Database with the “Cause of Death Data (death registry)” in Ministry of Health and Welfare by patients’ "identification number" [25]. The primary endpoint was the occurrence of MACE. The secondary endpoints were all-cause mortality and TIMI bleeding. TIMI major bleeding included intracranial hemorrhage, a decrease in hemoglobin concentration more than 5 g/dL, or an absolute decrease in hematocrit of at least 15%. TIMI minor bleeding included a decrease in hemoglobin concentration more than 3 g/dL and less than 5 g/dL or an absolute decrease in hematocrit of at least 10% when blood loss was observed and a decrease in hemoglobin concentration of at least 4 g/dL or an absolute decrease in hematocrit of at least 12%. TIMI minimal bleeding included any overt bleeding event that does not meet the criteria above [26]. The follow-up period started from 6 months after the index date until the occurrence of outcomes of interest, 18 months after the index date, or until August 31, 2016, whichever came first.

Covariates

We collected information regarding sex, age, CKD risk, stent type, coronary events type, and comorbidities (hypertension, diabetes mellitus, hyperlipidemia, peripheral arterial occlusion disease (PAOD), congestive heart failure (CHF), stroke, atrial fibrillation, and cancer) (S1 Table). Baseline comorbidities were identified from two or more records in either outpatient or admission claims within a 2-year period preceding the index date. Complex PCI was defined as chronic total occlusion, bifurcation, triple vessel disease, left main, or ≥3 stents implanted. They were then weighted to calculate the Charlson Comorbidity Index (CCI) excluding comorbidities as mentioned above [27]. In addition, we analyzed drugs used within a 2-year period prior to the index date, including angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), beta-blocker, proton pump inhibitor (PPI), and statins. Laboratory results, namely, eGFR, BUN, albumin, white blood cell, hemoglobin, platelet, sodium, potassium, calcium, phosphorus, parathyroid hormone, glycated hemoglobin, C-reactive protein, and N-terminal-proB-type natriuretic peptide, within a 6-month period prior to the index date were collected. We also analyzed individual patient’s PRECISE-DAPT score, which was developed to predict the risk of bleeding in patients with coronary stenting and DAPT [8].

Statistical analysis

Inverse probability of treatment weighting (IPTW) method, one of the propensity score methods that can be used without reducing power in a full cohort, was used to reduce confounding factors, as in observational studies [28-30]. The marginal probability of receiving exposure was derived from a logistic regression model by using baseline covariates of age, sex, CKD risk, stents type, coronary events type, year of the index date, length of stay, hypertension, diabetes mellitus, hyperlipidemia, PAOD, CHF, stroke, atrial fibrillation, cancer, CCI, PRECISE-DAPT score, ticagrelor, ACEI, ARB, beta-blocker, PPI, statins, and laboratory results. A standardized difference of < 0.1 suggests that baseline covariates were well balanced.

The risk estimates of MACE, all-cause mortality, and TIMI bleeding were summarized as the 95% confidence intervals (CIs) for incidence rate ratios from the Poisson regression model-weighted IPTW and as hazard ratios (HRs) and 95% CIs from the Cox proportional hazard regression model-weighted IPTW. The time to MACE was described using the Kaplan–Meier method-weighted IPTW and compared using the log-rank test.

Stratified analyses of MACE and bleeding were performed for the following covariates: sex, age, CKD risk, complex PCI, stents type, coronary events type, and PRECISE-DAPT score. Scatter plots, boxplots, and histograms were used to describe the distribution of DAPT duration by eGFR and PRECISE-DAPT score.

All data analyses were performed using SAS Enterprise Guide software, version 7.11 (SAS Institute, Cary, NC, USA). A two-tailed P value of < 0.05 was considered statistically significant.

Results

Baseline patient characteristics

In total, 1899 patients were included in the study; of them, 1112 and 787 patients were categorized to the long-term DAPT group and the short-term DAPT group, respectively. After IPTW, 795 (71.6%) and 563 (71.5%) of patients in the long-term and the short-term DAPT groups were male, respectively, and the mean (SD) age of the patients was 68.6 (12.0) and 68.7 (12.0), respectively. There were 598 (31.5%), 782 (41.2%), 296 (15.6%), and 221 (11.6%) of patients with CKD low, moderate, high and very high risk, respectively. 174 (15.6%) and 127 (16.2%) of patients in the long-term and short-term DAPT groups received stent implantation due to AMI in index admission. Meanwhile, 608 (54.7%) and 434 (55.1%) of patients in the long-term and the short-term DAPT groups had PRECISE-DAPT score ≥ 25, respectively. Baseline covariates after IPTW were well-balanced between the two groups. Other baseline characteristics, underlying comorbidities, index admission laboratory data and medication histories are presented in Table 1. In addition, the scattered DAPT duration according to eGFR and PRECISE-DAPT score were drawn in S1 and S2 Figs.

Table 1

Demographics of patients with percutaneous coronary intervention.

	Full Cohort			Stabilized IPTW
	DAPT ≤6 m (n = 787)	DAPT >6 m (n = 1,112)	ASD*	DAPT ≤6 m (n = 787)	DAPT >6 m (n = 1,110)	ASD*
	N (%)	N (%)		N (%)	N (%)
Sex
Male	530 (67.3)	829 (74.6)	0.16	563 (71.5)	795 (71.6)	0.00
Female	257 (32.7)	283 (25.4)	0.16	224 (28.5)	315 (28.4)	0.00
Age, year, mean(SD)	70.1 (11.7)	67.3 (12.1)	0.23	68.7 (12.0)	68.6 (12.0)	0.01
<45	18 (2.3)	48 (4.3)	0.11	25 (3.2)	38 (3.4)	0.01
45–54	68 (8.6)	131 (11.8)	0.10	84 (10.6)	115 (10.4)	0.01
55–64	177 (22.5)	278 (25.0)	0.06	181 (23.0)	261 (23.5)	0.01
65–74	228 (29.0)	343 (30.8)	0.04	241 (30.6)	337 (30.3)	0.01
75–84	218 (27.7)	239 (21.5)	0.15	188 (23.9)	269 (24.2)	0.01
≥85	78 (9.9)	73 (6.6)	0.12	67 (8.6)	91 (8.2)	0.01
CKD risk†
Low	247 (31.4)	365 (32.8)	0.03	247 (31.4)	351 (31.6)	0.01
Moderate	306 (38.9)	471 (42.4)	0.07	324 (41.2)	458 (41.2)	0.00
High	130 (16.5)	166 (14.9)	0.04	124 (15.8)	172 (15.5)	0.01
Very high	104 (13.2)	110 (9.9)	0.10	92 (11.7)	129 (11.6)	0.00
Complex PCI‡	256 (32.5)	396 (35.6)	0.07	264 (33.6)	378 (34.1)	0.01
Stents type
Drug-eluting stents	400 (50.8)	728 (65.5)	0.30	473 (60.1)	663 (59.8)	0.01
Bare-metal stents	387 (49.2)	384 (34.5)	0.30	314 (39.9)	447 (40.2)	0.01
Disease type
AMI	76 (9.7)	216 (19.4)	0.28	127 (16.2)	174 (15.6)	0.01
STEMI	31 (3.9)	107 (9.6)	0.23	62 (7.9)	83 (7.5)	0.02
NSTEMI	45 (5.7)	109 (9.8)	0.15	65 (8.2)	91 (8.2)	0.00
Non-AMI	711 (90.3)	896 (80.6)	0.28	660 (83.8)	936 (84.4)	0.01
Previous or coexisting medical condition
HTN	458 (58.2)	530 (47.7)	0.21	402 (51.1)	575 (51.8)	0.01
DM	275 (34.9)	361 (32.5)	0.07	256 (32.6)	364 (32.8)	0.01
Hyperlipidemia	342 (43.5)	394 (35.4)	0.17	297 (37.8)	421 (38.0)	0.00
PAOD	21 (2.7)	33 (3.0)	0.02	23 (3.0)	33 (3.0)	0.00
CHF	133 (16.9)	148 (13.3)	0.10	119 (15.1)	166 (14.9)	0.01
Stroke	56 (7.1)	65 (5.8)	0.05	49 (6.3)	74 (6.7)	0.02
Atrial fibrillation	29 (3.7)	21 (1.9)	0.11	21 (2.6)	28 (2.5)	0.01
Cancer	39 (5.0)	35 (3.1)	0.09	30 (3.8)	42 (3.8)	0.00
CCI, mean(SD)	0.85 (1.23)	0.69 (1.08)	0.14	0.75 (1.16)	0.76 (1.11)	0.01
0	417 (53.0)	687 (61.8)	0.18	457 (58.0)	640 (57.7)	0.01
1–2	305 (38.8)	344 (30.9)	0.17	272 (34.6)	384 (34.6)	0.00
≥3	65 (8.3)	81 (7.3)	0.04	58 (7.4)	86 (7.7)	0.01
PRECISE-DAPT score, mean(SD)	29.2 (12.3)	27.1 (12.2)	0.17	28.1 (12.2)	28.1 (12.3)	0.00
<25	318 (40.4)	547 (49.2)	0.18	353 (44.9)	502 (45.3)	0.01
≥25	469 (59.6)	565 (50.8)	0.18	434 (55.1)	608 (54.7)	0.01
Medications
Aspirin	787 (100.0)	1,112 (100.0)		787 (100.0)	1,110 (100.0)
Clopidogrel	757 (96.2)	991 (89.1)	0.27	725 (92.2)	1,020 (91.9)	0.01
Ticagrelor	95 (12.1)	307 (27.6)	0.40	167 (21.2)	235 (21.2)	0.00
ACEI	81 (10.3)	91 (8.2)	0.07	69 (8.8)	101 (9.1)	0.01
ARB	439 (55.8)	476 (42.8)	0.26	382 (48.5)	537 (48.4)	0.00
Beta-blocker	467 (59.3)	506 (45.5)	0.29	405 (51.5)	566 (51.0)	0.01
PPI	121 (15.4)	155 (13.9)	0.04	111 (14.2)	162 (14.6)	0.01
Statins	396 (50.3)	480 (43.2)	0.14	359 (45.6)	507 (45.7)	0.00
Laboratory
eGFR, g/dL, ml/min per 1.73 m2, mean(SD)	46.6 (24.2)	48.9 (20.9)	0.10	47.4 (23.5)	47.5 (21.4)	0.01
Hb, g/dL, mean(SD)	13.4 (1.7)	13.7 (1.6)	0.19	13.5 (1.6)	13.7 (1.7)	0.02
WBC, x103/uL, mean(SD)	8.7 (3.9)	9.2 (3.6)	0.19	8.8 (4.0)	9.2 (3.6)	0.00
Albumin, g/dL, mean(SD)	3.9 (0.3)	3.9 (0.3)	0.05	3.9 (0.3)	3.9 (0.3)	0.04
Na, mmol/L, mean(SD)	139.9 (3.7)	139.4 (3.0)	0.14	139.9 (3.6)	139.5 (2.9)	0.10
K, mmol/L, mean(SD)	4.4 (0.6)	4.3 (0.6)	0.18	4.4 (0.6)	4.3 (0.6)	0.07
Ca, mg/dL, mean(SD)	9.0 (0.4)	9.0 (0.4)	0.03	9.0 (0.4)	9.0 (0.4)	0.05
P, mg/dL, mean(SD)	4.6 (0.8)	4.5 (0.7)	0.07	4.6 (0.7)	4.6 (0.8)	0.01
PTH, pg/mL, mean(SD)	231 (35)	230 (32)	0.03	230 (31)	231 (32)	0.03
HbA1c, %, mean(SD)	6.9 (1.1)	6.8 (1.2)	0.06	6.9 (1.0)	6.9 (1.2)	0.00
NT-ProBNP, pg/mL, mean(SD)	1,124 (1,128)	1,025 (952)	0.10	1,102 (1,108)	1,047 (973)	0.05
CRP, mg/dL, mean(SD)	1.5 (1.7)	1.5 (2.3)	0.02	1.5 (1.7)	1.5 (2.3)	0.02
BUN, mg/dL, mean(SD)	31.9 (27.0)	29.1 (24.8)	0.11	31.0 (25.4)	30.3 (26.3)	0.03
PLT, x103/uL, mean(SD)	227.1 (66.9)	228.5 (70.9)	0.02	228.2 (66.8)	227.4 (70.5)	0.01

*Absolute standardized difference >0.1 for imbalance.

†Low: eGFR ≥60 with albuminuria 30–300 or eGFR 45–59 with albuminuria <30; moderate: eGFR ≥60 with albuminuria ≥300 or eGFR 45–59 with albuminuria 30–300 or eGFR 30–44 with albuminuria <30; high: eGFR 45–59 with albuminuria ≥300 or eGFR 30–44 with albuminuria ≥30 or eGFR <30; very high: dialysis.

‡Complex PCI: chronic total occlusion, bifurcation, triple vessel disease, left main, or ≥3 stents implanted.

Abbrevation: IPTW, Inverse Probability of Treatment Weighting; ASD, absolute standardized difference; DAPT, dual antiplatelet therapy; CKD, chronic kidney disease; DES, Drug-eluting stents; BMS, Bare-metal stents; PCI, percutaneous coronary intervention; AMI, acute myocardial infarction; STEMI, ST-elevation myocardial infarction; NSTEMI, non-ST-elevation myocardial infarction; HTN, Hypertension; DM, Diabetes mellitus; PAOD, peripheral arterial occlusion disease; CHF, congestive heart failure; CCI, Charlson comorbidity index; ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; PPI, proton pump inhibitor; Hb, hemoglobin; Na, sodium; K, potassium; Ca, calcium; P, phosphorus; HbA1c glycated hemoglobin; NT-ProBNP, pro B-Type Natriuretic Peptide.

Association between DAPT duration and risk of MACE and TIMI bleeding

Long-term DAPT was associated with similar risk of MACE (HR: 1.05, 95% CI: 0.65–1.70, P = 0.83) compared with short-term DAPT (Table 2). Further stratification according to myocardial infarction, ischemic stroke and CV death showed comparable risks between long-term and short-term DAPT. No significant differences in all-cause mortality (HR: 1.10, 95% CI: 0.75–1.61, P = 0.63) and risk of TIMI bleeding (HR: 1.19, 95% CI: 0.86–1.63, P = 0.30) between the two groups. There were no significant differences for TIMI bleeding in either TIMI major (HR: 1.63, 95% CI: 0.32–8.35, P = 0.56), TIMI minor (HR: 0.89, 95% CI: 0.43–1.85, P = 0.76) or TIMI minimal bleeding (HR: 1.24, 95% CI: 0.86–1.78, P = 0.25) between long and short DAPT group.

Table 2

Outcomes of PCI patients between DAPT >6 months and ≤6 months after IPTW.

	N	Event	Person months	IR per 1,000 person-months (95% CI)	IR ratio (95% CI)	HR (95% CI)	p
Primary outcome
MACE	1,897	88	30,112	2.9 (2.3–3.6)
DAPT ≤6 m	787	34	12,012	2.8 (1.9–3.9)	1.00 (ref.)	1.00 (ref.)
DAPT >6 m	1,110	54	18,100	3.0 (2.2–3.9)	1.06 (0.69–1.63)	1.05 (0.65–1.70)	0.83
CV death	1,897	32	30,511	1.0 (0.7–1.5)
DAPT ≤6 m	787	13	12,146	1.1 (0.6–1.9)	1.00 (ref.)	1.00 (ref.)
DAPT >6 m	1,110	19	18,365	1.0 (0.6–1.6)	0.91 (0.45–1.85)	0.91 (0.43–1.90)	0.80
Ischemic stroke	1,897	41	30,317	1.4 (1.0–1.8)
DAPT ≤6 m	787	14	12,097	1.2 (0.6–2.0)	1.00 (ref.)	1.00 (ref.)
DAPT >6 m	1,110	27	18,220	1.5 (1.0–2.2)	1.26 (0.66–2.39)	1.25 (0.63–2.48)	0.52
Myocardial infarction	1,897	16	30,483	0.5 (0.3–0.8)
DAPT ≤6 m	787	6	12,139	0.5 (0.2–1.1)	1.00 (ref.)	1.00 (ref.)
DAPT >6 m	1,110	9	18,344	0.5 (0.2–1.0)	1.02 (0.37–2.82)	1.02 (0.29–3.63)	0.98
Secondary outcome
All-cause mortality	1,897	121	30,291	4.0 (3.3–4.8)
DAPT ≤6 m	787	45	12,114	3.7 (2.7–5.0)	1.00 (ref.)	1.00 (ref.)
DAPT >6 m	1,110	75	18,178	4.1 (3.3–5.2)	1.11 (0.77–1.60)	1.10 (0.75–1.61)	0.63
TIMI bleeding	1,897	186	29,234	6.4 (5.5–7.4)
DAPT ≤6 m	787	67	11,694	5.7 (4.4–7.3)	1.00 (ref.)	1.00 (ref.)
DAPT >6 m	1,110	119	17,539	6.8 (5.6–8.1)	1.19 (0.88–1.60)	1.19 (0.86–1.63)	0.30
TIMI major	1,897	9	30,549	0.3 (0.1–0.5)
DAPT ≤6 m	787	3	12,170	0.2 (0.0–0.7)	1.00 (ref.)	1.00 (ref.)
DAPT >6 m	1,110	6	18,380	0.3 (0.1–0.7)	1.66 (0.38–7.17)	1.63 (0.32–8.35)	0.56
TIMI minor	1,897	32	30,385	1.0 (0.7–1.5)
DAPT ≤6 m	787	13	12,102	1.1 (0.6–1.9)	1.00 (ref.)	1.00 (ref.)
DAPT >6 m	1,110	18	18,282	1.0 (0.6–1.6)	0.90 (0.44–1.81)	0.89 (0.43–1.85)	0.76
TIMI minimal	1,897	146	29,496	4.9 (4.2–5.8)
DAPT ≤6 m	787	51	11,792	4.3 (3.2–5.7)	1.00 (ref.)	1.00 (ref.)
DAPT >6 m	1,110	95	17,704	5.4 (4.3–6.5)	1.24 (0.88–1.74)	1.24 (0.86–1.78)	0.25

*MACE: ischemic stroke, myocardial infarction, or CV death.

Abbrevation: CI, confidence interval; CV, cardiovascular; DAPT, dual antiplatelet therapy; HR, hazard ratio; IR, incidence rate; MACE, major adverse cardiac event; NA, not applicable; PCI, percutaneous coronary intervention; TIMI, thrombolysis in myocardial infarction.

Among the patients with CKD, two groups had comparable risk of MACE (log-rank P = 0.82) (Fig 2A). In our stratified analysis according to the PRECISE-DAPT score and DAPT duration were shown in Fig 2B. Meanwhile, as kidney function worsened, the risk of MACE significantly increased (log-rank P < .0001) (Fig 2C). Among the patients with different CKD risk, long DAPT and short DAPT had no significant difference in MACE (low; HR:2.02, 95% CI: 0.75–5.41, moderate; HR:0.68, 95% CI: 0.31–1.50, high; HR: 1.13, 95% CI: 0.37–3.50, very high; HR: 1.12, 95% CI: 0.44–2.85) (Fig 2D).

Fig 2

Kaplan-Meier plot of MACE and cumulative incidence of MACE after IPTW: (A) DAPT duration; (B) PRECISE-DAPT score and DAPT duration; (C) CKD risk; (D) CKD risk and DAPT duration.

The hazard ratio of MACE and bleeding were simultaneously increased with increasing PRECISE-DAPT score (Fig 3). The forest plots for the hazard ratio of MACE and bleeding between groups was shown in Fig 4. In this analysis, no subgroup patients had significant increased risks.

Fig 3

The associations between PRECISE-DAPT score and the hazard for the MACE and bleeding using restricted cubic splines after IPTW with five knots at the 5th, 27.5th, 50th, 72.5th, and 95th percentiles: (A) MACE; (B) bleeding.

Fig 4

Forest plot depicting the risk of MACE and bleeding associated with DAPT >6 months and ≤6 months after IPTW.

Abbreviation: AMI, acute myocardial infarction; Cl, confidence interval; CKD, chronic kidney disease; HR, hazard ratios; MACE, major adverse cardiac event; PCI, percutaneous coronary intervention. *p<0.05, **p<0.001.

Discussion

This study compared the effectiveness and safety between long-term (> 6 months) and short-term (≤6 months) DAPT after coronary stenting in patients with CKD. The following key findings were observed: (1) After IPTW adjustment, there was no significant difference in MACE outcome between long-term and short-term DAPT group and the same for the risk of TIMI bleeding (2) With the progress of CKD, increased MACE event was noted in patients with more advanced CKD. Furthermore, the risk of MACE and bleeding simultaneously increased as the PRECISE-DAPT score increased. (3) There was no statistically significant difference in MACE and TIMI bleeding rate between long and short term DAPT group in subgroup analysis including age, CKD risk, index admission disease type, stent type and PRECISE-DAPT score.

CKD is considered in the context of increased ischemic and bleeding risk that makes the decision of DAPT duration difficult. There are no reliable scoring systems to predict the risk of future events [31]. Optimal duration of DAPT after coronary artery stenting in CKD patients remains unclear as large randomized control trials were limited of evidences. There were only some post-hoc analysis and retrospective studies focusing on CKD populations. Two post-hoc analysis studies have reported short-term DAPT use may reduce the risk of bleeding without increasing ischemic event in CKD patients [18, 32]. On the contrary, a national cohort in Taiwan targeting dialysis patients and a meta-analysis enrolling patients with moderate CKD both found short-term DAPT use was not associated with lower bleeding rate or higher MACE event [33, 34]. In our study, we found both MACE and bleeding outcome were not significantly different between long-term and short-term DAPT group. There are some main reasons to explain the difference between our study and previous studies. Prior studies only focused on dialysis and drug-eluting stent patients. Our study includes diverse stage of CKD patients, including low CKD risk patients with eGFR>60 and moderately increased albuminuria. Different types of stents were also included. There were few studies to discuss the low-risk CKD population, especially considering the microalbuminuria level. Understanding those low CKD risk population’s optimal DAPT duration is crucial because the prior evidences showed increased risk of developing CAD in the patients with eGFR below 75 ml/min/1.73 m2 or with microalbuminuria [35, 36].

In subgroup analysis, we discovered that there was no significant difference regarding MACE and bleeding events in different ages or CKD risk, drug-eluting stent vs. bare-metal stent, AMI vs. Non-AMI. Recently, several studies that included advanced CKD or AMI patients have advocated the efficacy and safety of short DAPT use 3–6 months [1, 37, 38] or 1 month [39, 40]. Collectively, those findings along with these in the current study indicate that short DAPT use might be an alternative option.

High platelet reactivity and poor response to oral antiplatelet therapies may explain why long-term DAPT fails to be associated with lower risk of MACE events and short-term DAPT not related to lower bleeding episode in CKD patients. Previous studies showed that with respect to platelet inhibition, clopidogrel has inferior efficacy to prasugrel or ticagrelor in CKD patients [15, 41, 42]. In other word, in clopidogrel-based DAPT, CKD patients may not obtain the benefit of desirable CV outcomes compared to patients with normal renal function [43, 44]. Another possible reason which DAPT fails to reduce MACE event significantly could be poor metabolizer of CYP2C19 which has higher incidence in Asian population especially in Taiwanese [45]. In total, 95% of the patients in the current study used clopidogrel-based DAPT regimen, and this could partly explain why long-term DAPT did not reduce MACE events.

Another merit of the current study is to find that the PRECISE-DAPT score might not be an ideal tool to decide the duration of DAPT in CKD patients. Unlike prior PRECISE-DAPT score analysis showing longer DAPT exerted an ischemia benefit in lower PRECISE-DAPT score group (<25) in general population [8]; our study showed CKD patients with PRECISE-DAPT score < 25 had no significant difference of MACE outcome between long and short DAPT use. Moreover, there was no significant difference in bleeding for higher PRECISE-DAPT score group (≥25) between long and short DAPT, either. Our study found that both the hazard ratio of bleeding and MACE increased as the PRECISE-DAPT score increased; however, it is noted that PRECISE-DAPT score was only effective for bleeding risk and MACE prediction in CKD patients but not an effective predictive tool for DAPT duration determination.

There are several limitations in our study. First, the retrospective nature of the study limited the understanding for individual physician’s decision regarding DAPT duration. The discovery in this study might not represent the whole CKD population. However, it should still be substantial for the investigation regarding to DAPT use in CKD patients as the population were usually excluded in prior RCTs, and the current study could be one more piece in that puzzle via real world data analysis. Second, 95% of our patients were under clopidogrel treatment, however, some evidence has shown that new P2Y12 inhibitors, like ticagrelor or prasugrel, are more effective in preventing MACE events in CKD patients compared to clopidogrel [46]. A different result might be possible if more CKD patients using ticagrelor or prasugrel were included in the study for analysis. Third, the bleeding events might have been underestimated because of the use of a retrospective population-based cohort and an institutional clinical database; patients may have transferred to a different institution or did not comply with the planned follow-up visits after PCI. To eliminate the impact of this limitation, we assessed the outcomes only in patients who were followed up for at least four times within 1 year to ensure the follow up.

Conclusions

In this population-based cohort study, we found that among CKD patients undergoing coronary stenting, long-term and short-term DAPT tied on the risk of MACE and all-cause mortality. There was no significant difference in TIMI bleeding outcome between long-term and short-term DAPT patients.

Scatter plots, boxplots, and histograms of DAPT duration by eGFR.

(TIF)

Click here for additional data file.

Scatter plots, boxplots, and histograms of DAPT duration by PRECISE-DAPT score.

(TIF)

Click here for additional data file.

Diagnosis codes and medication codes.

(DOCX)

Click here for additional data file.

17 Jun 2021

PONE-D-21-13103

Investigation of dual antiplatelet therapy after coronary stenting in patients with chronic kidney diseas e

PLOS ONE

Dear Dr. chen,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Aug 01 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Hitesh Raheja, MD

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. Thank you for including your methods section:  "This study has been reviewed by the Institutional Review Board of TMU (TMU-JIRB No. N201707020). The need for informed consent was waived owing to the use of anonymized data."

1. Please add this information to your ethics statement in the online submission form.

2. Please amend your current ethics statement to include the full name of the ethics committee/institutional review board(s) that approved your specific study.

2. Please amend your current ethics statement to confirm that your named institutional review board or ethics committee specifically approved this study.

Once you have amended this/these statement(s) in the Methods section of the manuscript, please add the same text to the “Ethics Statement” field of the submission form (via “Edit Submission”).

For additional information about PLOS ONE ethical requirements for human subjects research, please refer to http://journals.plos.org/plosone/s/submission-guidelines#loc-human-subjects-research.

3. Thank you for providing the date(s) when patient medical information was initially recorded. Please also include the date(s) on which your research team accessed the databases/records to obtain the retrospective data used in your study.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Methods: Confusing ? as this is a retrospective chart review and the authors have mentioned they enrolled the patients, please make it clearer what is study type and data collected?

Fix both in abstract and methods

Define the clear aim in manuscript in methods

Reviewer #2: This is an interesting article about DAPT use in CKD patients. The authors demonstrated that longer (>6 months) vs. shorter (< 6 months) have similar MACE and TIMI bleeding risk. This article is in line with the recent published data about the safety of shorter DAPT. CKD patients are prone to bleeding but also have higher rates of ACS and ischemic events, which makes this paper interesting for readers.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Shyam Odeti

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

30 Jun 2021

Journal Requirements

Comment 1

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Response: Thank you for the kind reminder. We checked the references and confirmed no retracted paper in the reference list.

Comment 2

Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming.

Response: We follow your suggestion to revise the manuscript to meet PLOS ONE’s style requirements. We change level 1 heading to 18pt font and level 2 heading to 16pt font. And we also change our figure and table citation format to meet the style of PLOS ONE.

Comment 3

Thank you for including your methods section: "This study has been reviewed by the Institutional Review Board of TMU (TMU-JIRB No. N201707020). The need for informed consent was waived owing to the use of anonymized data."

1. Please add this information to your ethics statement in the online submission form.

2. Please amend your current ethics statement to include the full name of the ethics committee/institutional review board(s) that approved your specific study. Once you have amended this/these statement(s) in the Methods section of the manuscript, please add the same text to the “Ethics Statement” field of the submission form (via “Edit Submission”).

Response: Thank you for the comment. We have added this ethics statement in the online submission form and we also revised our description in method section (page 7, line 2, method section) to “This study has been reviewed by the Institutional Review Board of Taipei Medical University (TMU-JIRB No. N201707020). The need for informed consent was waived owing to the use of anonymized data.”

Comment 4

Thank you for providing the date(s) when patient medical information was initially recorded. Please also include the date(s) on which your research team accessed the databases/records to obtain the retrospective data used in your study.

Response: Thank you for the comment. Our research team applied to access Taipei Medical University Institutional and Clinical Database after this study was approved by the Institutional Review Board of Taipei Medical University. Our first analysis of this database was on February 06, 2020.

Reviewers’ comments

Reviewer #1:

Methods: Confusing ? as this is a retrospective chart review and the authors have mentioned they enrolled the patients, please make it clearer what is study type and data collected? Fix both in abstract and methods. Define the clear aim in manuscript in methods.

Response: Thank you for the valuable comment. Our study is a retrospective cohort study use anonymized data from Taipei Medical University (TMU) Institutional and Clinical Database. This database included 3 million patients’ electronic medical record form TMU Hospital, Wan Fang Hospital, and Shuang Ho Hospital respectively. The aim of our study is to compare the effectiveness and safety between long-term and short-term dual anti-platelet therapy in patients with chronic kidney disease after coronary stenting.

We revised the description in abstract (page 3, line 9, abstract section) to “This retrospective cohort study analyze data from the Taipei Medical University (TMU) Institutional and Clinical Database, which include anonymized electronic health data of 3 million patients that visited TMU Hospital, Wan Fang Hospital, and Shuang Ho Hospital. We also added the aim of our study in methods section (page 8, line 13) “The aim of this study is to compare the effectiveness and safety between long-term and short-term DAPT in patients with CKD risk after coronary stenting.”

Reviewer #2:

This is an interesting article about DAPT use in CKD patients. The authors demonstrated that longer (>6 months) vs. shorter (< 6 months) have similar MACE and TIMI bleeding risk. This article is in line with the recent published data about the safety of shorter DAPT. CKD patients are prone to bleeding but also have higher rates of ACS and ischemic events, which makes this paper interesting for readers

Response: Thank you for the comment. CKD patients are considered to have higher ischemia and bleeding risk compare to general populations. This is the reason why we want to conduct this study to compare the effectiveness and safety between long-term and short-term DAPT in these patients in real world setting.

Submitted filename: Response to Reviewers_20210629.docx

Click here for additional data file.

21 Jul 2021

Investigation of dual antiplatelet therapy after coronary stenting in patients with chronic kidney diseas e

PONE-D-21-13103R1

Dear Dr. chen,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Hitesh Raheja, MD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

26 Jul 2021

PONE-D-21-13103R1

Investigation of dual antiplatelet therapy after coronary stenting in patients with chronic kidney disease

Dear Dr. Chen:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Hitesh Raheja

Academic Editor

PLOS ONE