Highlights
- •
In a post hoc analysis of a recent Japanese clinical trial, more than half of the patients with acute coronary syndromes received anticoagulation with unfractionated heparin after percutaneous coronary intervention (PCI). This was especially true for patients with ST-segment elevation myocardial infarction or intraprocedural adverse angiographic findings.
- •
Post-PCI heparin administration was associated with significantly higher incidence of bleeding events without any benefit in reducing cardiovascular events within 30 days after PCI.
- •
Higher heparin doses per body weight and total doses were associated with higher rates of both bleeding and cardiovascular events.
The current guidelines for acute coronary syndrome (ACS) discourage the use of anticoagulation after percutaneous coronary intervention (PCI) without specific indications, although the recommendation is not well supported by evidence. In this post hoc analysis of the ShorT and OPtimal Duration of Dual AntiPlatelet Therapy-3 (STOPDAPT-3) trial, 30-day outcomes were compared between the 2 groups with and without post-PCI heparin administration among patients with ACS who did not receive mechanical support devices. The co-primary end points were the bleeding end point, defined as the Bleeding Academic Research Consortium type 3 or 5 bleeding, and the cardiovascular end point, defined as a composite of cardiovascular death, myocardial infarction, definite stent thrombosis, or ischemic stroke. Among 4,088 patients with ACS, 2,339 patients (57.2%) received post-PCI heparin. The proportion of patients receiving post-PCI heparin was higher among those with ST-elevation myocardial infarction compared with others (72.3% and 38.8%, p <0.001), and among patients with intraprocedural adverse angiographic findings compared with those without (67.6% and 47.5%, p <0.001). Post-PCI heparin compared with no post-PCI heparin was associated with a significantly increased risk of the bleeding end point (4.75% and 2.52%, adjusted hazard ratio 1.69, 95% confidence interval 1.15 to 2.46, p = 0.007) and a numerically increased risk of the cardiovascular end point (3.16% and 1.72%, adjusted hazard ratio 1.56, 95% confidence interval 0.98 to 2.46, p = 0.06). Higher hourly dose or total doses of heparin were also associated with higher incidence of both bleeding and cardiovascular events within 30 days. In conclusion, post-PCI anticoagulation with unfractionated heparin was frequently implemented in patients with ACS. Post-PCI heparin use was associated with harm in terms of increased bleeding without the benefit of reducing cardiovascular events. Trial identifier: STOPDAPT-3 ClinicalTrials.gov number, NCT04609111
The current guidelines discourage the use of anticoagulation after percutaneous coronary intervention (PCI) without specific indications in patients with acute coronary syndrome (ACS). , However, these guideline recommendations are not well supported by data, and therefore, post-PCI parenteral anticoagulation has been commonly implemented in patients with ACS in previous studies. The ShorT and OPtimal Duration of Dual AntiPlatelet Therapy-3 (STOPDAPT-3) trial was a randomized trial comparing aspirin-free prasugrel monotherapy with dual antiplatelet therapy (DAPT) in patients with planned PCI, with a focus on short-term bleeding and cardiovascular events. The detailed data on periprocedural anticoagulation with unfractionated heparin and oral antiplatelet or anticoagulant therapy were collected in this trial. The objective of the present study was to evaluate the prevalence of post-PCI heparin administration and its influence on short-term outcomes in patients with ACS as a post hoc analysis of the STOPDAPT-3 trial.
Methods
The STOPDAPT-3 trial was a physician-initiated, prospective, multicenter, open-label but adjudicator-blinded randomized controlled trial in Japan, evaluating the safety and efficacy of an aspirin-free strategy at PCI using cobalt-chromium everolimus-eluting stents (Xience; Abbott Laboratories, Chicago, Illinois). The design and the primary results at 1 month were previously reported. Briefly, the study population for the STOPDAPT-3 trial were patients with either ACS or high bleeding risk (HBR) according to the Academic Research Consortium (ARC) definition, who were planned for coronary stent implantation. The eligible patients were randomized in a 1-to-1 fashion either to the no-aspirin group or the DAPT group immediately before PCI, but after the confirmation of coronary lesions suitable for stent implantation by coronary angiography. Informed consent was obtained from all enrolled patients, even in emergent cases. Verbal consent was permitted if the patients were in serious clinical condition, and written consent was obtained from patients or their legal representatives after the stabilization of their condition. The Kyoto University Certified Review Board approved the study protocol. This trial was registered on ClinicalTrials.gov (NCT04609111).
The present study population included patients with ACS in the STOPDAPT-3 full analysis set. We excluded patients who received any mechanical circulatory support devices, such as intra-aortic balloon pumping, extracorporeal membrane oxygenation, or percutaneous left ventricular assist devices (Impella; Abiomed, Danvers, Massachusetts) during the index hospitalization because heparin use was mandatory in those patients. We also excluded patients without information on post-PCI heparin administration. The study patients were divided into the post-PCI heparin and no post-PCI heparin groups.
After the randomization, patients received the antiplatelet regimen as assigned. At PCI, bolus administration of 70- to 100-IU/kg unfractionated heparin was recommended, and activated clotting time during PCI was controlled between 250 and 400 seconds. There was no specific recommendation for post-PCI heparin administration, which was left to the discretion of the attending physicians. When post-PCI heparin was administered, the site investigators recorded the dose and duration of heparin infusion (units per day and hours). Bivalirudin, low-molecular-weight heparins such as enoxaparin, and glycoprotein IIb/IIIa inhibitors were not approved for patients with ACS in Japan. Administration of other medications such as oral anticoagulants was also left to the discretion of the attending physicians, although they were discouraged from changing the concomitant therapy based on the allocated groups.
The 2 co-primary end points in the STOPDAPT-3 trial were the bleeding end point, defined as the Bleeding Academic Research Consortium (BARC) type 3 or 5 bleeding, and the cardiovascular end point, defined as a composite of death from cardiovascular cause, myocardial infarction, definite stent thrombosis, or ischemic stroke evaluated at 30 days after randomization. Myocardial infarction and stent thrombosis were defined according to the ARC criteria. Other secondary end points were the same as those defined in the STOPDAPT-3 main analysis. The independent clinical event committee adjudicated all the clinical events comprising the co-primary end points on the basis of the source documents without knowledge of the assigned treatment groups.
In the current analysis, intraprocedural adverse angiographic findings were defined as follows: the presence of intracoronary thrombus, thrombosis after stenting, no-reflow, slow-flow, and final TIMI (Thrombolysis in Myocardial Infarction) flow grade ≤2 in the main branch or side branch. All of these findings were based on site reporting. Severe intraprocedural adverse angiographic findings were defined as no-reflow or slow-flow phenomenon during the procedure, and/or final TIMI flow ≤2 in the main or side branch. Nonsevere intraprocedural adverse angiographic findings were defined only as the presence of a thrombotic lesion or thrombosis after stenting.
Categorical variables were expressed as numbers and percentages and were compared using the chi-square test. Continuous variables were expressed as mean with SD or median with interquartile range (IQR) and were compared using Student’s t test or the Wilcoxon rank-sum test depending on their distributions. Cumulative incidences of the end points were estimated by the Kaplan–Meier method, and the differences were assessed by the log-rank test. The effects in the post-PCI heparin group relative to the no post-PCI heparin group on the co-primary bleeding and cardiovascular end points were evaluated using the multivariable Cox proportional hazard model, and were expressed as hazard ratios (HRs) and their 95% confidence intervals. In the multivariable Cox proportional hazard models, we used the following 9 risk-adjusting variables: age ≥75 years, type of ACS (ST-segment elevation myocardial infarction [STEMI], non–ST-segment elevation myocardial infarction, or unstable angina), cardiogenic shock, diabetes, ARC-HBR, current heart failure, radial access only at index procedure, intraprocedural adverse angiographic findings (severe, nonsevere only, or none), and the assigned antiplatelet therapy (no-aspirin or DAPT). , These risk-adjusting variables were chosen considering clinical importance based on the preliminary risk factor analyses for the co-primary bleeding and cardiovascular end points at 30 days ( Supplementary Tables 1 and 2 ). In the sensitivity analyses, we evaluated the outcomes in the propensity score–matched cohort and in the cohort excluding the patients with atrial fibrillation and oral anticoagulants ( Supplementary Methods ). Moreover, we performed subgroup analyses and assessed the formal interaction p values in the subgroups stratified by age (≥75 or <75 years), gender, body weight (tertiles), type of ACS (STEMI or non–ST-segment elevation ACS [NSTE-ACS]), diabetes, ARC-HBR, intraprocedural adverse angiographic findings, and the assigned groups (no-aspirin or DAPT).
We also evaluated the doses of post-PCI heparin in terms of the hourly or total dose per body weight (units/kg/h or units/kg). We analyzed the relation between the dose of post-PCI heparin and the body weight categories with a width of 10 kg. Moreover, patients who received post-PCI heparin administration were dichotomized on the basis of the median values for the hourly or total dose per body weight. The outcomes in the high- and low-dose groups, respectively, were assessed with the reference group of no post-PCI heparin.
Finally, we compared the mortality and cardiovascular outcomes between patients with and without BARC type 3 or 5 bleeding to explore the relation of bleeding events with mortality and cardiovascular outcomes.
A physician (H. Watanabe) and a statistician (T. Morimoto) performed all statistical analyses using JMP version 16.1 (JMP Statistical Discovery LLC, Cary, North Carolina) and SAS version 9.4 (SAS Institute, Cary, North Carolina). All p values were 2-sided, and p values <0.05 were considered statistically significant.
Results
Of the total 6,002 randomized patients in the STOPDAPT-3, the present study population included 4,088 patients with ACS who did not receive mechanical circulatory support devices ( Figure 1 ). There were 2,339 patients (57.2%) who received post-PCI heparin, and 1,749 patients (42.8%) who did not ( Figure 1 ). The proportion of patients receiving post-PCI heparin was higher in the STEMI subgroup than in the NSTE-ACS subgroup (72.3% and 38.8%, p <0.001), and in patients with intraprocedural adverse angiographic findings than in those without (67.6% and 47.5%, p <0.001) ( Supplementary Figure 1 ).
The prevalence of post-PCI heparin administration varied widely across the participating PCI centers. The prevalence of post-PCI heparin administration was higher in the centers enrolling larger numbers of patients in the STEMI subgroup, whereas there was no specific relation between the number of enrolled patients and the prevalence of post-PCI heparin administration in the NSTE-ACS subgroup ( Supplementary Figure 2 ). Moreover, there was no specific geographic difference in the prevalence of post-PCI heparin administration ( Supplementary Figure 3 ).
The patients in the post-PCI heparin group were younger, more often current smokers, more often had cardiogenic shock and STEMI, and less often had a history of PCI, anemia, hemodialysis, and HBR than those in the no post-PCI heparin group ( Table 1 ). The procedures in the post-PCI heparin group were more often emergent procedures conducted using a larger arterial sheath, and less often conducted using the radial approach than those in the no post-PCI heparin group. Patients in the post-PCI heparin group less often received antiplatelet and anticoagulant medications within 7 days before assignment, and more often received preprocedural heparin administration than those in the no post-PCI heparin group. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, beta blockers, high-intensity statins, and proton pump inhibitors were more frequently prescribed at discharge in the post-PCI heparin group than in the no post-PCI heparin group ( Table 1 ). The assigned antiplatelet therapy, no-aspirin or DAPT, was well balanced in both groups of patients with and without post-PCI heparin ( Supplementary Table 3 ).
| Post-PCI heparin N=2339 | No post-PCI heparin N=1749 | P value | |
|---|---|---|---|
| Patient demographics | |||
| Age, years | 69.3±12.1 | 70.5±11.6 | 0.001 |
| ≥75 years | 838(35.8) | 691(39.5) | 0.02 |
| Women | 503(21.5) | 385(22.0) | 0.70 |
| Body weight, kg | 65.1±13.6 | 64.5±12.9 | 0.16 |
| Body-mass index, kg/m 2 * | 24.1±3.8 | 24.1±3.7 | 0.98 |
| <25 kg/m 2 | 1492(63.8) | 1110(63.5) | 0.83 |
| Clinical presentation | |||
| ST-segment elevation myocardial infarction | 1623(69.4) | 621(35.5) | <0.001 |
| Door to wire crossing time within 24 hours of onset, min † | 45(35-54) | 44(34-55) | 0.80 |
| Non-ST-segment elevation acute coronary syndrome | 716(30.6) | 1128(64.5) | <0.001 |
| Non-ST-segment elevation myocardial infarction | 531(22.7) | 507(29.0) | <0.001 |
| Unstable angina | 185(7.9) | 621(35.5) | <0.001 |
| Cardiac arrest or ventricular fibrillation | 24(1.0) | 11(0.6) | 0.17 |
| Cardiogenic shock | 85(3.6) | 37(2.1) | 0.004 |
| Current heart failure | 371(15.9) | 265(15.2) | 0.54 |
| Past history and comorbidities | |||
| Prior percutaneous coronary intervention | 217(9.3) | 228(13.0) | <0.001 |
| Prior coronary artery bypass grafting | 23(1.0) | 19(1.1) | 0.75 |
| Prior myocardial infarction | 114(4.9) | 116(6.6) | 0.02 |
| Prior stroke | 138(5.9) | 126(7.2) | 0.09 |
| Prior heart failure | 392(16.8) | 294(16.8) | 0.97 |
| Atrial fibrillation | 127(5.4) | 119(6.8) | 0.07 |
| Chronic obstructive pulmonary disease | 56(2.4) | 53(3.0) | 0.21 |
| Peripheral artery disease | 47(2.0) | 62(3.5) | 0.003 |
| Hypertension | 1691(72.3) | 1310(74.9) | 0.06 |
| Hyperlipidemia | 1511(64.6) | 1103(63.1) | 0.31 |
| Diabetes | 1001(42.8) | 697(39.9) | 0.06 |
| With insulin therapy | 103(4.4) | 55(3.1) | 0.04 |
| Current smoker | 701(30.0) | 431(24.6) | <0.001 |
| Left ventricular ejection fraction, % † | 53.4±10.6 | 56.1±11.4 | <0.001 |
| <40% † | 183/2163(8.5) | 107/1612(6.6) | 0.04 |
| Moderate or severe mitral regurgitation | 45(1.9) | 31(1.8) | 0.72 |
| Anemia | 456(19.5) | 444(25.4) | <0.001 |
| Thrombocytopenia | 15(0.6) | 19(1.1) | 0.12 |
| Chronic kidney disease | 994(42.5) | 771(44.1) | 0.31 |
| Moderate | 860(36.8) | 642(36.7) | 0.97 |
| Severe | 96(4.1) | 61(3.5) | 0.31 |
| Hemodialysis | 38(1.6) | 68(3.9) | <0.001 |
| Liver cirrhosis | 7(0.3) | 4(0.2) | 0.66 |
| Cancer history | 189(8.1) | 145(8.3) | 0.81 |
| ARC-HBR | 861(36.8) | 728(41.6) | 0.002 |
| Angiographic characteristics | |||
| Multivessel disease | 851(36.4) | 665(38.0) | 0.28 |
| Left main coronary artery disease | 120(5.1) | 104(6.0) | 0.26 |
| Index Procedural characteristics | |||
| Emergent procedure | 2223(95.0) | 1259(72.0) | <0.001 |
| Radial approach | 1999(85.5) | 1539(88.0) | 0.02 |
| Radial approach only | 1933(82.6) | 1477(84.5) | 0.12 |
| Femoral approach | 354(15.1) | 246(14.1) | 0.34 |
| Brachial approach | 50(2.1) | 25(1.4) | 0.09 |
| Sheath size 7Fr or larger | 444(19.0) | 286(16.4) | 0.03 |
| Number of target lesions | 1.09±0.33 | 1.11±0.36 | 0.11 |
| Target of 2 vessels or more | 109(4.7) | 120(6.9) | 0.003 |
| Target of chronic total occlusion | 42(1.8) | 44(2.5) | 0.11 |
| Target of bifurcation | 514(22.0) | 380(21.7) | 0.85 |
| Target of bifurcation with 2-stent | 13(0.6) | 12(0.7) | 0.60 |
| Target of left main coronary artery | 58(2.5) | 71(4.1) | 0.005 |
| Target of left anterior descending artery | 1129(48.3) | 888(50.8) | 0.11 |
| Target of left circumflex | 382(16.3) | 301(17.2) | 0.46 |
| Target of right coronary artery | 845(36.1) | 563(32.2) | 0.009 |
| Target of bypass graft | 4(0.2) | 3(0.2) | 1.00 |
| Use of intravascular imaging | 2127(90.9) | 1617(92.5) | 0.08 |
| Use of intravascular ultrasound | 1728(73.9) | 1415(80.9) | <0.001 |
| Use of optical coherence tomography | 469(20.1) | 249(14.2) | <0.001 |
| Number of stents, [No.] | 1.16±0.50 | 1.19±0.50 | 0.07 |
| Minimum stent diameter, mm † | 3.04±0.52 | 3.04±0.53 | 0.78 |
| <3 mm † | 823/2286(36.0) | 636/1725(36.9) | 0.57 |
| Total stent length, mm † | 31.2±16.8 | 31.5±16.2 | 0.51 |
| >60 mm † | 160/2286(7.0) | 119/1725(6.9) | 0.90 |
| Femoral hemostatic device | 175(7.5) | 114(6.5) | 0.23 |
| Intraprocedural adverse angiographic findings ‡ | 1333(57.0) | 639(36.5) | <0.001 |
| Severe intraprocedural adverse angiographic findings ‡ | 400(17.1) | 164(9.4) | <0.001 |
| Non-severe intraprocedural adverse angiographic findings only ‡ | 933(39.9) | 475(27.2) | <0.001 |
| Thrombus ‡ | 1181(50.5) | 544(31.1) | <0.001 |
| Thrombosis after stenting ‡ | 40(1.7) | 23(1.3) | 0.31 |
| No-reflow ‡ | 49(2.1) | 16(0.9) | 0.002 |
| Slow-flow ‡ | 231(9.9) | 118(6.8) | <0.001 |
| Final TIMI flow ≤2 of main branch ‡ | 161(6.9) | 41(2.3) | <0.001 |
| Final TIMI flow ≤2 of side branch ‡ | 74(3.2) | 18(1.0) | <0.001 |
| Staged PCI within 30 days | 385(16.5) | 222(12.7) | <0.001 |
| Medication within 7 days before assignment § | |||
| Antiplatelet agents | 372(15.9) | 544(31.1) | <0.001 |
| Aspirin only | 254(10.9) | 409(23.4) | <0.001 |
| P2Y 12 inhibitor only | 89(3.8) | 79(4.5) | 0.26 |
| DAPT | 29(1.2) | 56(3.2) | <0.001 |
| Aspirin/Prasugrel | 12/29(41.4) | 33/56(58.9) | 0.12 |
| Aspirin/Clopidogrel | 16/29(55.2) | 21/56(37.5) | 0.12 |
| Anticoagulants | 82(3.5) | 103(5.9) | <0.001 |
| Warfarin | 16/82(19.5) | 14/103(13.6) | 0.28 |
| Direct oral anticoagulant | 66/82(80.5) | 89/103(86.4) | 0.28 |
| Pre-procedure heparin administration | 876(37.5) | 358(20.5) | <0.001 |
| Medication at the index PCI | |||
| Loading of prasugrel | 2337(99.9) | 1745(99.8) | 0.24 |
| Loading of aspirin | 1074(45.9) | 727(41.6) | 0.006 |
| Total heparin dose during PCI, units/Kg † | 117.1 (84.9-150.7) | 119.9 (100.8-145.5) | 0.002 |
| Measurement of intraprocedural activated clotting time | 1649(70.5) | 1133(64.8) | <0.001 |
| Activated clotting time, sec | 336.8±162.8 | 302.3±109.4 | <0.001 |
| Maximum activated clotting time, sec ∥ | 361.5±145.5 | 349.7±134.3 | 0.17 |
| Minimum activated clotting time, sec ∥ | 250.1±55.9 | 244.6±71.3 | 0.17 |
| Medications at discharge † , § | |||
| Antiplatelet agents | 2236/2245(99.6) | 1712/1715(99.8) | 0.19 |
| Aspirin only | 12/2245(0.5) | 6/1715(0.4) | 0.39 |
| Prasugrel only | 1123/2245(50.0) | 838/1715(48.9) | 0.47 |
| DAPT | 1099/2245(49.0) | 868/1715(50.6) | 0.30 |
| Aspirin/Prasugrel | 1096/2245(48.8) | 864/1715(50.4) | 0.33 |
| Anticoagulants | 219/2245(9.8) | 146/1715(8.5) | 0.18 |
| Warfarin | 51/219(23.3) | 20/146(13.7) | 0.02 |
| Direct oral anticoagulant | 168/219(76.7) | 126/146(86.3) | 0.02 |
| ACE inhibitors or ARB | 1883/2245(83.9) | 1246/1715(72.7) | <0.001 |
| Beta-blockers | 1635/2245(72.8) | 1035/1715(60.4) | <0.001 |
| Statins | 2189/2245(97.5) | 1638/1715(95.5) | <0.001 |
| High-intensity statin therapy ¶ | 1367/2245(60.9) | 759/1715(44.3) | <0.001 |
| Proton pump inhibitors | 2038/2245(90.8) | 1519/1715(88.6) | 0.02 |
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
