Although trials comparing antiplatelet strategies after percutaneous coronary intervention report average risks of bleeding and ischemia in a population, there is limited information to guide choices based on individual patient risks, particularly beyond 1 year after treatment. Patient-level data from Patient Related Outcomes With Endeavor vs Cypher Stenting Trial (PROTECT), a broadly inclusive trial enrolling 8,709 subjects treated with drug-eluting stents (sirolimus vs zotarolimus-eluting stent), and PROTECT US, a single-arm study including 1,018 subjects treated with a zotarolimus-eluting stent, were combined. The risk of ischemic events, cardiovascular death/non-periprocedural myocardial infarction (MI)/definite or probable stent thrombosis, and bleeding events, Global Use of Strategies to Open Occluded Arteries moderate or severe bleed, were predicted using logistic regression. At median follow-up of 4.1 years, major bleeding occurred in 260 subjects (2.8%) and ischemic events in 595 (6.3%). Multivariate predictors of bleeding were older age, smoking, diabetes mellitus, congestive heart failure, and chronic kidney disease (all p <0.05). Ischemic events shared all the same predictors with bleeding events and gender, body mass index, previous MI, previous coronary artery bypass graft surgery, ST-segment elevation MI on presentation, stent length, and sirolimus-eluting stent use (all p <0.05). Within individual subjects, bleeding and ischemic risks were strongly correlated; 97% of subjects had a greater risk of ischemic events than bleeding. In conclusion, individual patient risks of ischemia and bleeding are related to many common risk factors, yet the predicted risks of ischemic events are greater than those of major bleeding in the large majority of patients in long-term follow-up.
Although clinical studies regarding duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) generally summarize average treatment effects, in clinical practice, treatment choices are made for individual patients according to their perceived risks for benefit and harm based on their unique clinical presentation and characteristics. Since the first reports of an increase in very late stent thrombosis with drug-eluting stents (DES), the appropriate antiplatelet regimen has been a matter of debate. Although several trials evaluating duration of DAPT were underpowered to detect differences in infrequent events such as stent thrombosis, a meta-analysis showed that the extended duration of DAPT was associated with a reduction in stent thrombosis at the expense of an increase in clinically significant bleeding. A decision analytic model evaluating this balance at the population level found that a small reduction in ischemic events is needed to offset the higher bleeding risk associated with longer duration of DAPT. Determining this balance for individual patients requires understanding the correlation between both risks. We sought to estimate individual patient risks of long-term ischemic and bleeding complications after PCI with DES and to compare the magnitude of these risks in individual patients and subgroups.
Methods
The study population consisted of 9,727 subjects enrolled in the Patient Related Outcomes With Endeavor vs Cypher Stenting Trial (PROTECT) or in the PROTECT US study. The PROTECT trial was a large, broadly inclusive, multicenter randomized controlled trial comparing the long-term safety of 2 different DES, the Endeavor zotarolimus-eluting stent (Medtronic Inc, Santa Rosa, CA), and the Cypher sirolimus-eluting stent (Cordis J&J, Fremont, CA); 8,709 subjects were randomized from May 2007 to December 2008 and have reached at least 4 -year follow-up. The PROTECT US study was a single-arm study following the PROTECT inclusion/exclusion criteria of 1,018 patients who received an Endeavor zotarolimus-eluting stent and were followed for at least 3 years. Both excluded patients with previous bare-metal stent in the last 12 months, previous DES, previous brachytherapy, or need for oral anticoagulation. Long-term use of DAPT was recommended for a minimum of 3 months up to 12 months or longer according to guidelines and treating physicians.
The primary ischemic end point for the current analysis was a composite of cardiovascular death, myocardial infarction (MI), and Academic Research Consortium definite/probable stent thrombosis. MI was defined according to the universal definition. Periprocedural MI events (occurring within 48 hours from PCI) were excluded (not the patients) to evaluate more precisely the long-term ischemic risk. The primary bleeding end point was the occurrence of a Global Use of Strategies to Open Occluded Arteries (GUSTO) moderate/severe bleeding event. GUSTO severe bleed is defined by the occurrence of an intracranial hemorrhage or a bleed resulting in hemodynamic compromise requiring treatment, and GUSTO moderate bleed requires blood transfusion without hemodynamic compromise. All end points were adjudicated by an independent clinical event committee. Detailed baseline characteristics were available for analysis, such as demographic factors, risk factors for coronary artery disease, cardiovascular history, and presentation for index procedure and angiographic/procedural data.
Baseline/procedural characteristics are presented as mean and SD for continuous covariates and proportion for categorical covariates, and they were compared using the Student’s t tests and chi-square tests, respectively. Temporal distribution of the primary end points and their individual components was assessed by reporting crude rates (number of events in patients at risk) for the time periods: 0 to 30 days, 1 to 12 months, and beyond 12 months. In estimating these rates, we allowed subjects with an event in >1 time period to be considered as having an event in each time period to avoid underestimation of late risks. Patients who completed the 4-year follow-up in the PROTECT and the 3-year follow-up in PROTECT US were analyzed by logistic regression. Using the same candidate list of covariates, a separate multivariable model was built for each primary outcome. A backward selection method was used to select covariates with a p value <0.05 to stay in the final model. Internal validation and model calibration were done by the bootstrapping method described by Harrell (1,000 bootstrap samples) using the rms package in R statistical software. Using this method, intercepts, beta coefficients, and C-statistics were corrected for overoptimism and potential overfitting of the models and, therefore, led to a more conservative estimation of the predicted risks of both primary end points. Goodness-of-fit was assessed by the Hosmer-Lemeshow test. Individual predicted probabilities of long-term ischemic and bleeding events were calculated using the optimism-corrected multivariate models and were presented on a scatter plot for purpose of comparison. Correlation between both risks was also assessed by means of the Pearson’s correlation coefficient. Subgroup analyses were performed to assess the balance of ischemic and bleeding risks in elderly patients aged ≥75 years. Finally, sensitivity analyses were performed to evaluate robustness of the bleeding primary end point by censoring events occurring within 48 hours of index PCI and using the Thrombolysis In Myocardial Infarction (TIMI) major bleeding criteria. All analyses were performed using SAS 9.2 (Cary, North Carolina) and R, version 3.0.2 (R Foundation for Statistical Computing, Vienna, Austria). Statistical significance level was a p value <0.05 for all analyses.
Results
Complete follow-up was available for 9,410 patients (96.7% of 9,727 patients). Baseline/procedural characteristics of patients according to the occurrence of each primary end point are listed in Table 1 . Median follow-up duration was 4.1 years (interquartile range 4.0 to 5.0). Use of DAPT was assessed at 1, 6, 12, 24, 36, and 48 months and was 96%, 94%, 87%, 39%, 32%, and 27%, respectively. Median DAPT use was 507.0 days (interquartile range 366.0 to 1,119.0).
| Variable | Ischemic Event | Bleeding Event | ||
|---|---|---|---|---|
| No (n=8815) | Yes (n=595) | No (n=9150) | Yes (n=260) | |
| Age, mean ± SD (years) | 62.1 ± 10.5 | 66.2 ± 11.2 ∗ | 62.2 ± 10.6 | 67.3 ± 10.1 † |
| Age ≥ 75 years old | 1079 (12.2%) | 152 (25.6%) | 1165 (12.7%) | 66 (25.4%) |
| Male | 6705 (76.1%) | 458 (77.0%) | 6691 (76.4%) | 172 (66.2%) † |
| Body mass index, mean ± SD (kg/m 2 ) | 28.0 ± 4.6 | 28.4 ±5.7 | 28.1 ± 4.7 | 27.9 ± 5.6 |
| Active smoking | 2170 (24.6%) | 151 (25.4%) | 2261 (24.7%) | 60 (23.1%) |
| Hypertension | 5719 (64.9%) | 441 (74.1%) ∗ | 5967 (65.2%) | 193 (74.2%) † |
| Diabetes | 2378 (27.0%) | 262 (44.0%) ∗ | 2548 (27.9%) | 92 (35.4%) † |
| Prior myocardial infarction | 1695 (19.2%) | 175 (29.4%) ∗ | 1820 (19.9%) | 50 (19.2%) |
| Prior percutaneous coronary intervention | 1096 (12.4%) | 96 (16.1%) ∗ | 1161 (12.7%) | 31 (11.9%) |
| Known peripheral vascular disease | 414 (4.7%) | 53 (8.9%) ∗ | 442 (4.8%) | 25 (9.6%) † |
| Prior stroke | 261 (3.0%) | 34 (5.7%) ∗ | 283 (3.1%) | 12 (4.6%) |
| Prior coronary artery bypass graft surgery | 446 (5.1%) | 55 (9.2%) ∗ | 484 (5.3%) | 17 (6.5%) |
| Prior congestive heart failure | 260 (3.0%) | 49 (8.2%) ∗ | 289 (3.2%) | 20 (7.7%) † |
| Creatinine clearance, mL/min | ||||
| ≥60 | 7099 (80.5%) | 379 (63.7%) ∗ | 7308 (79.9%) | 170 (65.4%) † |
| 30-59 | 1120 (12.7%) | 151 (25.4%) ∗ | 1196 (13.1%) | 75 (28.9%) † |
| <30 | 44 (0.5%) | 20 (3.4%) ∗ | 56 (0.6%) | 8 (3.1%) † |
| Missing | 552 (6.3%) | 45 (7.6%) ∗ | 590 (6.4%) | 7 (2.7%) † |
| Presentation | ||||
| Stable angina | 5073 (57.6%) | 317 (53.3%) ∗ | 5252 (57.4%) | 138 (53.1%) |
| Non-ST elevation acute coronary syndrome | 3077 (34.9%) | 218 (36.6%) ∗ | 3194 (34.9%) | 101 (38.9%) |
| ST elevation myocardial infarction | 665 (7.5%) | 60 (10.1%) ∗ | 704 (7.7%) | 21 (8.1%) |
| Stent | ||||
| C-SES | 3934 (44.6%) | 301 (50.6%) ∗ | 4126 (45.1%) | 109 (41.9%) |
| E-ZES | 4881 (55.4%) | 294 (49.4%) ∗ | 5024 (54.9%) | 151 (58.1%) |
| Left main percutaneous coronary intervention | 103 (1.2%) | 13 (2.2%) ∗ | 110 (1.2%) | 6 (2.3%) |
| Lesion length > 18 mm | 3823 (43.4%) | 299 (50.3%) ∗ | 4007 (43.8%) | 115 (44.4%) |
| Stent length (mm) | 31.1 ± 20.6 | 35.4 ± 24.2 ∗ | 31.3 ± 20.8 | 32.1 ± 23.3 |
| Vessel diameter ≤2.75 mm | 3500 (39.7%) | 278 (46.7%) ∗ | 3677 (40.2%) | 101 (39.0%) |
| Bifurcation | 1854 (21.0%) | 140 (23.5%) | 1939 (21.2%) | 55 (21.2%) |
| Multivessel intervention | 1648 (18.7%) | 145 (24.4%) ∗ | 1751 (19.1%) | 42 (16.2%) |
| Saphenous vein graft intervention | 27 (0.3%) | 7 (1.2%) ∗ | 33 (0.4%) | 1 (0.4%) |
| In-stent restenosis | 124 (1.4%) | 6 (1.0%) | 124 (1.4%) | 6 (2.3%) |
| Stent number | ||||
| 0 | 84 (0.9%) | 9 (1.5%) ∗ | 86 (0.9%) | 7 (2.7%) † |
| 1 | 5191 (58.9%) | 286 (48.1%) ∗ | 5333 (58.3%) | 144 (55.4%) † |
| 2 | 2270 (25.8%) | 185 (31.1%) ∗ | 2386 (26.1%) | 69 (26.5%) † |
| ≥3 | 1270 (14.4%) | 115 (19.3%) ∗ | 1345 (14.7%) | 40 (15.4%) † |
∗ p <0.05 for the comparison of no ischemic event versus ischemic event.
† p <0.05 for the comparison of no bleeding event versus bleeding event.
The long-term event rate was 6.3% (n = 595) for the composite ischemic outcome and 2.8% (n = 260) for the bleeding outcome. Of these, 75 patients (0.8%) had both an ischemic and a bleeding event. Temporal trends for both combined end points and their individual components are listed in Table 2 and Figure 1 . Multivariable predictors of long-term ischemic and bleeding complications are presented in Table 3 . All 5 independent predictor of bleeding events (age, smoking, diabetes, previous congestive heart failure, and chronic kidney disease) were also predictors in the final ischemic model. Both multivariable models had acceptable discriminative power with optimism-corrected c-statistic 0.68 for the ischemic model and 0.64 for the bleeding model. Model fit for both end points was good with Hosmer-Lemeshow p values of 0.48 and 0.85, respectively.
| Event | Overall | Event Rate | ||
|---|---|---|---|---|
| 0-30 days | Month 1-12 | 12 month – 4 year | ||
| ISCHEMIC ENDPOINT | ||||
| Cardiovascular death, non-periprocedural myocardial infarction or definite/probable stent thrombosis | 595 (6.32%) | 0.89% | 1.29% | 4.40% (1.44%/yr) |
| Cardiovascular death | 347 (3.69%) | 0.44% | 0.75% | 2.72% (0.88%/yr) |
| Non-periprocedural myocardial infarction | 268 (2.85%) | 0.44% | 1.00% | 2.11% (0.69%/yr) |
| Definite/probable stent thrombosis | 185 (1.97%) | |||
| Acute | 0.10% | N/A | N/A | |
| Subacute | 0.68% | N/A | N/A | |
| Late | N/A | 0.29% | N/A | |
| Very late | N/A | N/A | 1.14% (0.37%/yr) | |
| BLEEDING ENDPOINT | ||||
| GUSTO Moderate/Severe bleeding | 260 (2.76%) | 0.68% | 0.98% | 1.36% (0.44%/yr) |
| Moderate | 133 (1.41%) | 0.24% | 0.59% | 0.82% (0.26%/yr) |
| Severe | 127 (1.35%) | 0.44% | 0.52% | 0.54% (0.17%/yr) |
| Variable | ISCHEMIC ENDPOINT | BLEEDING ENDPOINT | ||
|---|---|---|---|---|
| Odds ratio | 95% confidence interval | Odds ratio | 95% confidence interval | |
| Age, per 10 years | 1.37 | 1.25 – 1.50 | 1.38 | 1.22 – 1.56 |
| Male | 1.36 | 1.12 – 1.66 | – | – |
| Body mass index, per kg/m 2 | 1.03 | 1.01 – 1.04 | – | – |
| Active smoking | 1.49 | 1.22 – 1.81 | 1.34 | 1.03 – 1.75 |
| Diabetes mellitus | 1.77 | 1.50 – 2.09 | 1.24 | 1.00 – 1.55 |
| Prior myocardial infarction | 1.47 | 1.23 – 1.76 | – | – |
| Prior coronary artery bypass graft surgery | 1.41 | 1.06 – 1.87 | – | – |
| Prior congestive heart failure | 1.75 | 1.27 – 2.39 | 1.73 | 1.15 – 2.60 |
| Creatinine clearance, mL/min | ||||
| ≥ 60 | Reference | Reference | Reference | Reference |
| 30-59 | 1.93 | 1.55 – 2.41 | 1.61 | 1.23 – 2.11 |
| < 30 | 5.41 | 3.14 – 9.32 | 2.79 | 1.43 – 5.41 |
| Missing | 1.61 | 1.19 – 2.18 | 0.56 | 0.30 – 1.07 |
| Presentation | ||||
| Stable angina | Reference | Reference | – | – |
| Non-ST elevation acute coronary syndrome | 1.14 | 0.96 – 1.35 | ||
| ST elevation myocardial infarction | 1.71 | 1.29 – 2.26 | ||
| E-ZES | 0.80 | 0.68 – 0.93 | – | – |
| Total stent length, per 10 mm | 1.07 | 1.03 – 1.10 | – | – |
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