There is a scarcity of data on ischemic and bleeding events in patients who experienced major bleeding after percutaneous coronary intervention (PCI). Moreover, there also is a shortage of data on comparative outcomes between patients with and without interruption of an antithrombotic drug after major bleeding. We evaluated the incidence and prognostic impacts of ischemic (myocardial infarction or ischemic stroke) and bleeding (Bleeding Academic Research Consortium type 3 or 5) events after major bleeding in 12,691 consecutive patients who underwent first PCI in the Coronary Revascularization Demonstrating Outcome Study in Kyoto PCI registry cohort-3. In the entire cohort, incidence of the first ischemic event and bleeding event was 2.3 per 100 person-years and 3.8 per 100 person-years, respectively. Major bleeding (Bleeding Academic Research Consortium type 3) occurred in 2,142 patients during a median follow-up of 5.7 years. In patients with major bleeding, cumulative 30-day, 1-year, and 5-year incidence of an ischemic event was 2.6%, 4.8%, and 13.2% (3.2 per 100 person-years), respectively, whereas that of a bleeding event was 6.3%, 16.1%, and 29.2% (8.5 per 100 person-years), respectively. Ischemic and bleeding events were independently associated with mortality (hazard ratio 2.36, 95% confidence interval 1.87 to 2.96, p <0.001, and hazard ratio 2.85, 95% confidence interval 2.42 to 3.37, p <0.001). The cumulative 180-day incidence of ischemic and bleeding events was not significantly different between patients with and without interruption of an antithrombotic drug in patients with major bleeding. In conclusion, the incidence of an ischemic event after the first major bleeding was approximately 1/3 of that of recurrent major bleeding, and the rates of ischemic and bleeding events after the first major bleeding were higher than the rates of first events in the general PCI population. Both ischemic events and bleeding events were strongly associated with subsequent mortality. The incidence of ischemic and recurrent bleeding events was not different between patients with and without interruption of an antithrombotic drug.
Bleeding is a common complication in patients who undergo percutaneous coronary intervention (PCI) because patients need to undergo antiplatelet therapy (APT) to prevent an ischemic event. In patients who undergo PCI, approximately 10% of patients have atrial fibrillation, and the incidence of bleeding in this population is even higher because they are recommended to receive both oral anticoagulants (OACs) and APT. It has been reported that major bleeding after PCI is associated with subsequent mortality risk. , Therefore, it is crucially important not only to prevent bleeding but also to focus on appropriate management after bleeding. It is essential to understand the ischemic and recurrent bleeding risks after the first major bleeding when considering appropriate management after major bleeding in patients who underwent PCI. However, there is a scarcity of data on the incidence and prognostic impacts of ischemic and recurrent bleeding events in patients who experience major bleeding after PCI. Moreover, it has been argued that one of the mechanisms for excess mortality risk after major bleeding might be subsequent thrombotic events because of the interruption of antithrombotic therapy when major bleeding occurred. However, there is also a shortage of data about comparative clinical outcomes between patients with and without interruption of antithrombotic therapy after major bleeding. Therefore, we sought to evaluate the incidence and prognostic impacts of ischemic and recurrent major bleeding events in patients who experienced major bleeding after PCI and compared the ischemic and recurrent bleeding events between patients with and without interruption of antithrombotic therapy after the first major bleeding using a large Japanese observational database.
Methods
The Coronary Revascularization Demonstrating Outcome Study in Kyoto (CREDO-Kyoto) PCI/coronary artery bypass grafting (CABG) registry cohort-3 is a physician-initiated, non–company-sponsored, multicenter registry enrolling consecutive patients who underwent first coronary revascularization with PCI or isolated CABG without combined noncoronary surgery in 22 Japanese centers between January 2011 and December 2013 ( Supplementary Appendix ). The design and patient enrollment were described previously. In 14,927 patients enrolled in the registry, there were 12,691 patients who underwent PCI using a stent as the first coronary revascularization procedure, excluding 60 patients who refused study participation, 1609 patients who underwent CABG, and 567 patients who underwent PCI without stent implantation. In 12,691 patients who underwent the first PCI using a stent, major bleeding (Bleeding Academic Research Consortium [BARC] type 3 or 5) occurred in 2,229 patients. In 2,229 patients with major bleeding, we excluded 87 patients whose first major bleeding was fatal (BARC type 5), and therefore, the present study population consisted of 2,142 patients with major bleeding who were eligible for evaluating clinical outcomes after the first major bleeding ( Figure 1 ).
The relevant ethics committees in all the participating centers approved the study protocol. Because of the retrospective enrollment, written informed consent from the patients was waived; however, we excluded those patients who refused participation in the study when contacted for follow-up. This strategy is concordant with the guidelines of the Japanese Ministry of Health, Labor, and Welfare.
Bleeding during follow-up was defined according to the BARC classification. BARC type 3 or 5 bleeding was regarded as major bleeding. Major bleeding was classified into the following categories without overlap according to the location and cause of bleeding: gastrointestinal, access site, surgery-related, intracranial, genitourinary, and others.
In this study, an ischemic event was a composite of myocardial infarction or ischemic stroke after the first major bleeding, whereas a bleeding event was recurrent major bleeding defined as the BARC type 3 or 5 bleeding after the first major bleeding. All-cause death and stent thrombosis were also evaluated as outcome measures. Myocardial infarction and stent thrombosis were adjudicated according to the Academic Research Consortium (ARC) definition. An ischemic stroke was defined as an ischemic stroke with neurological symptoms lasting >24 hours.
Duration of dual APT (DAPT) and management of OACs during follow-up was left to the discretion of each attending physician. Data on the status of APT and OACs were collected throughout the follow-up period. Discontinuation of an antithrombotic drug was defined as a stop of any antithrombotic drugs (APT or OAC) within 2 days from the onset of the first major bleeding regardless of the duration of stopping. Interruption of the antithrombotic drug after the first major bleeding was defined as a stop of any antithrombotic drugs (APT or OAC) within 2 days from the onset of the first major bleeding lasting for >5 days per a previous report. Complete interruption of the antithrombotic drug was defined as an interruption of all antithrombotic drugs (APT and/or OAC), whereas partial interruption was defined as a continuation of at least 1 antithrombotic drug despite interruption of at least 1 antithrombotic drug.
Baseline characteristics were not evaluated at the time of the first major bleeding but were evaluated at the time of index PCI. Definitions for baseline characteristics were described previously.
Baseline data were collected from hospital charts according to the prespecified definitions by the experienced clinical research coordinators in an independent clinical research organization. Follow-up data were collected from hospital charts or obtained by contacting patients/relatives or referring physicians. All outcome measures were adjudicated by the clinical event committee ( Supplementary Appendix ).
We first estimated the cumulative incidence of myocardial infarction or ischemic stroke and major bleeding in the entire cohort of 12,691 patients who underwent PCI using stent with the Kaplan-Meier method, in which the time of index PCI was regarded as time 0. We also calculated cumulative incidence accounting for competing risk of all-cause death as a sensitivity analysis. In addition, we estimated the incidence per 100 person-years. These incidence rates were used as reference values when we evaluated incidence of ischemic events and bleeding events after the first major bleeding. We then conducted the following analyses in the study population of 2,142 patients with major bleeding.
Categorical variables were presented as numbers and percentages and compared with the chi-square test. Continuous variables were expressed as mean ± SD or median and interquartile range (IQR). Continuous variables were compared with Student’s t test or Wilcoxon-ranked sum test based on their distributions. The cumulative incidence of outcome measures after the first major bleeding was estimated by the Kaplan-Meier method, in which the time of the first major bleeding was regarded as time 0. We also calculated cumulative incidence accounting for competing risk of all-cause death as a sensitivity analysis. In addition, incidence rates of ischemic events and bleeding events were also presented by 100 person-years. We estimated the cumulative incidence of ischemic events and bleeding events, and all-cause death stratified by the strata based on the timing of the first major bleeding after index PCI (interval from index PCI to the first major bleeding: within 30 days [early bleeding], beyond 30 days and within 365 days [late bleeding], and beyond 365 days [very late bleeding]), bleeding site, and bleeding with or without transfusion, and the differences were assessed with the log-rank test.
We also evaluated prognostic impacts of the ischemic events and bleeding events on mortality. The effects of ischemic events and bleeding events for all-cause death were expressed as hazard ratios (HRs) and their 95% confidence intervals (CIs). The multivariable HRs were estimated by the Cox proportional hazard models adjusting for the 20 clinically relevant factors listed in Table 1 . Ischemic events and bleeding events were included as time-updated covariates.
| Entire cohort | Major bleeding | p value | ||
|---|---|---|---|---|
| Yes | No | |||
| Variable | (n = 12,691) | (n = 2,229) | (n = 10,462) | |
| Age (years) | 69.5 ± 11.1 | 72.4 ± 10.3 | 68.8 ± 11.2 | <0.001 |
| Age ≥ 75 * | 4,460 (35.1%) | 1,005 (45.1%) | 2,455 (33.0%) | <0.001 |
| Men * | 9,282 (73.1%) | 1,551 (69.6%) | 7,731 (73.9%) | <0.001 |
| Body mass index (kg/m 2 ) | 23.8 ± 3.6 | 23.2 ± 3.5 | 23.9 ± 3.6 | <0.001 |
| <25.0 * | 8,523 (67.2%) | 1,645 (73.8%) | 6,878 (65.7%) | <0.001 |
| Acute coronary syndrome * | 5,184 (40.8%) | 1,071 (48.0%) | 4,113 (39.3%) | <0.001 |
| Acute myocardial infarction | 4,986 (39.3%) | 1,045 (46.9%) | 3,941 (37.7%) | |
| Hypertension * | 10,446 (82.3%) | 1,867 (83.8%) | 8,579 (82.0%) | 0.048 |
| Diabetes mellitus * | 4,859 (38.3%) | 909 (40.8%) | 3,950 (37.8%) | 0.008 |
| Current smoker * | 3,517 (27.7%) | 555 (24.9%) | 2,962 (28.3%) | 0.001 |
| Heart failure * | 2,937 (23.1%) | 765 (34.3%) | 2,172 (20.8%) | <0.001 |
| LVEF (%) | 58.6 ± 13.0 | 56.0 ± 14.2 | 59.2 ± 12.7 | <0.001 |
| ≤40 | 1,086 (9.8%) | 286 (15.1%) | 800 (8.7%) | <0.001 |
| Mitral regurgitation grade ≥3/4 | 858 (7.7%) | 225 (11.6%) | 633 (6.8%) | <0.001 |
| Prior myocardial infarction * | 1,402 (11.0%) | 277 (12.4%) | 1,125 (10.8%) | 0.02 |
| Prior stroke * | 1,614 (12.7%) | 374 (16.8%) | 1,240 (11.9%) | <0.001 |
| Peripheral vascular disease * | 1,162 (9.2%) | 314 (14.1%) | 848 (8.1%) | <0.001 |
| eGFR <30 (mL/min/1.73 m 2 ) * | 549 (4.3%) | 172 (7.7%) | 377 (3.6%) | <0.001 |
| Hemodialysis * | 569 (4.5%) | 193 (8.7%) | 376 (3.6%) | <0.001 |
| Atrial fibrillation * | 1,183 (9.3%) | 312 (14.0%) | 871 (8.3%) | <0.001 |
| Hemoglobin <11.0 g/dl * | 1,527 (12.0%) | 444 (19.9%) | 1,083 (10.4%) | <0.001 |
| Platelet <100 × 10 9 /L * | 247 (1.9%) | 85 (3.8%) | 162 (1.6%) | <0.001 |
| Chronic obstructive pulmonary disease * | 508 (4.0%) | 111 (5.0%) | 397 (3.8%) | 0.01 |
| Liver cirrhosis * | 321 (2.5%) | 87 (3.9%) | 234 (2.2%) | <0.001 |
| Malignancy | 1,602 (12.6%) | 396 (17.8%) | 1,206 (11.5%) | <0.001 |
| Active malignancy * | 247 (1.9%) | 82 (3.7%) | 165 (1.6%) | <0.001 |
| Severe frailty * , † | 523 (4.1%) | 144 (6.5%) | 379 (3.6%) | <0.001 |
| ARC-HBR | 6,045 (47.6%) | 1,449 (65.0%) | 4,596 (43.9%) | <0.001 |
| Procedural characteristics of index PCI | ||||
| Number of target narrowing | 1.50 ± 0.79 | 1.54 ± 0.82 | 1.49 ± 0.79 | 0.009 |
| Target of proximal LAD | 7,851 (61.9%) | 1,362 (61.1%) | 6,489 (62.0%) | 0.42 |
| Target of unprotected LMCA | 579 (4.6%) | 164 (7.4%) | 415 (4.0%) | <0.001 |
| Target of chronic total occlusion | 1,221 (9.6%) | 211 (9.5%) | 1,010 (9.7%) | 0.78 |
| Target of bifurcation | 5,172 (40.8%) | 882 (39.6%) | 4,290 (41.0%) | 0.21 |
| Bifurcation with 2 stents | 524 (4.1%) | 102 (4.6%) | 422 (4.0%) | |
| Emergency procedure | 5,068 (39.9%) | 1,041 (46.7%) | 4,027 (38.5%) | <0.001 |
| Total number of stents | 1 (1-2) | 1 (1-3) | 1 (1-2) | 0.001 |
| Total stent length (mm) | 28 (18-52) | 30 (18-56) | 28 (18-52) | 0.03 |
| Minimum stent size (mm) | 2.75 (2.5-3.0) | 2.75 (2.5-3.0) | 2.75 (2.5-3.0) | 0.23 |
| DES use | 10,334 (81.4%) | 1,678 (75.3%) | 8,656 (82.7%) | <0.001 |
| New-generation DES use | 10,183 (80.2%) | 1,655 (74.2%) | 8,528 (81.5%) | |
| IVUS or OCT use | 9,519 (75.0%) | 1,595 (71.6%) | 7,924 (75.7%) | <0.001 |
| Staged PCI | 2,646 (20.8%) | 485 (21.8%) | 2,161 (20.7%) | 0.24 |
| Access site | <0.001 | |||
| Radial | 4,818 (38.0%) | 669 (30.0%) | 4,163 (39.8%) | |
| Femoral | 6,619 (52.2%) | 1,320 (59.2%) | 5,293 (50.7%) | |
| Brachial | 1,241 (9.8%) | 239 (10.7%) | 994 (9.5%) | |
| Medications at index PCI hospitalization discharge | ||||
| Thienopyridine | 12,624 (99.5%) | 2,214 (99.3%) | 10,410 (99.5%) | 0.3 |
| Ticlopidine | 343 (2.7%) | 68 (3.1%) | 275 (2.6%) | |
| Clopidogrel | 12,168 (95.9%) | 2,127 (95.4%) | 10,041 (96.0%) | |
| Unknown | 113 (0.9%) | 19 (0.9%) | 94 (0.9%) | |
| Aspirin | 12,599 (99.3%) | 2,202 (98.8%) | 10,397 (99.4%) | 0.003 |
| Cilostazol | 338 (2.7%) | 93 (4.2%) | 245 (2.3%) | <0.001 |
| Statins | 9,900 (78.0%) | 1,585 (71.1%) | 8,315 (79.5%) | <0.001 |
| Beta-blockers | 4,950 (39.0%) | 948 (42.5%) | 4,002 (38.3%) | <0.001 |
| ACE-I/ARB | 8,186 (64.5%) | 1,439 (64.6%) | 6,747 (64.5%) | 0.95 |
| OAC | 1,270 (10.0%) | 331 (14.8%) | 939 (9.0%) | <0.001 |
| Warfarin | 1,109 (8.7%) | 305 (13.7%) | 804 (7.7%) | |
| DOAC | 163 (1.3%) | 27 (1.2%) | 136 (1.3%) | |
| Proton pump inhibitors or histamine type-2 receptor blockers | 9,825 (77.4%) | 1,732 (77.7%) | 8,093 (77.4%) | 0.72 |
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
