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Balancing Long-Term Risks of Ischemic and Bleeding Complications After Percutaneous Coronary Intervention With Drug-Eluting Stents

Am J Cardiol. 2015;116:686-93

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.1 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.2, 3, 4, 5, 6, 7, 8, and 9 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.10 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.11 and 12 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.13 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.14 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).

Table 1 Baseline characteristics according to clinical outcomes

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/m2) 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.

C-SES = cypher sirolimus eluting stent; E-ZES = endeavor zotarolimus eluting stent.

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.

Table 2 Clinical outcomes and temporal trends

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)
gr1

Figure 1 Monthly rates of the primary ischemic (cardiovascular death, non-periprocedural MI, or definite/probable stent thrombosis) and primary bleeding end points (GUSTO moderate/severe bleeding event) averaged throughout the study period and over specified time intervals (0 to 30 days, 1 to 12 months, and beyond 1 year) showed that the highest risk period was within the first month after PCI for both end points. Beyond 1-month post-PCI, risk of ischemic events was stable at 0.12% per month, whereas risk of bleeding events decreased with time at 0.04% per month beyond 1-year post-PCI.

Table 3 Multivariable predictors for ischemic and bleeding endpoints

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/m2 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 - -

E-ZES = endeavor zotarolimus eluting stent.

The relation between predicted long-term probabilities of ischemic and bleeding outcomes within individual subjects is depicted in Figure 2. Only 3.1% of patients had a higher predicted bleeding risk than ischemic risk, and when this was the case, the absolute difference between both risks was small (largest absolute risk difference was 0.9%; Figure 3). The predicted probabilities of ischemic and bleeding outcomes were strongly correlated (ρ = 0.76). No subjects with previous MI and coronary artery bypass graft surgery or ST-segment elevation MI presentation and very few with diabetes mellitus had a higher bleeding risk than ischemic risk. Although age and gender were predictors of events, 96.5% of elderly patients (≥75 years) and 87.2% of women in the study had a higher ischemic risk than bleeding (Figure 4).

gr2

Figure 2 Scatter plot showing individual predicted probabilities of long-term ischemic and bleeding events throughout the study period. The black line represents identical ischemic and bleeding risk within an individual subject. Most dots (96.9%) were below the black line, which represent a higher ischemic than bleeding risk, and there was a strong correlation between both risks (ρ = 0.76; p <0.001).

gr3

Figure 3 Distribution of the absolute difference in risk of ischemic and bleeding end points in individual subjects. Dotted vertical line represents identical ischemic and bleeding risk within an individual subject. Bars on the right side of the line correspond to subjects with greater ischemic risk than bleeding risk. Negative risk difference (left side of the line), representing a higher bleeding risk than ischemic risk, occurred infrequently (3.1% of subjects), and in those subjects, the risk difference was small.

gr4

Figure 4 Scatter plots showing individual predicted probabilities of long-term ischemic and bleeding events in subgroups. The black line represents identical ischemic and bleeding risk within an individual subject. The results for patients aged <75 years (A), those aged ≥75 years (B), men (C), and women (D) were consistent with the primary analysis (see Figure 2). Very few men and patients aged ≥75 years had a higher bleeding than ischemic risk.

Only 14.2% of the bleeding events occurred within 48 hours of the index PCI (37 subjects). Excluding these events from the primary analysis yielded similar results with all predictors of bleeding events remaining predictors of ischemic events. Using the TIMI major criteria as bleeding end point (206 events [2.2%]) also gave similar results regarding the primary analysis, the correlation between risks was 0.63, p <0.001, and the subjects at greater risk of bleeding than ischemic outcomes represented 1.6% of the sample.

Discussion

The current analysis performed on the data derived from 2 large prospective cohorts with broad inclusion criteria reflecting contemporary interventional cardiology practice, and with clinical event adjudication, showed that the predicted long-term risk of ischemic events (cardiovascular death/non-periprocedural MI/definite or probable stent thrombosis) was greater than the risk of bleeding events (moderate/severe bleeding) in the large majority of patients. In the small subset of patients that is at greater bleeding than ischemic risk, the absolute risk difference was small. Each of the significant predictors of long-term bleeding events was also a predictor of ischemic outcomes, and there was a strong correlation between individual predicted ischemic and bleeding events.

Prescription of DAPT after DES requires clinicians to weigh the individual patient's risk of bleeding and recurrent ischemic events based on his or her unique clinical presentation and characteristics. Furthermore, previous studies of adverse events after PCI have been limited to or strongly influenced by early periprocedural events, making conclusion regarding later risks challenging.15, 16, 17, 18, and 19 Only a few studies reported predictors of clinical events beyond 1 year. The logistic clinical SYNTAX score was designed to predict mortality at 1 year by combining the components of the age, creatinine, and left ventricular ejection fraction score, initially developed for elective cardiac surgery, and the Syntax score in data from 7 coronary stent trials and has been validated at 3 years.20, 21, and 22 The New York database risk score was developed to predict mortality up to 5 years from patients treated in 2003.23 Data from the CathPCI Registry in 2004 to 2007 were linked to the Center for Medicare and Medicaid Services and, therefore, limited to subjects ≥65 years, to provide median follow-up of 15 months and predict survival.23 All the earlier mentioned studies have included periprocedural events, which for both MI and bleeding are high frequency compared with later events, yet not modified by late treatment choices of adjunctive therapy. Our rich data set, including prospectively collected site-reported angiographic/procedural characteristics and centrally adjudicated events, allowed us to predict both the ischemic and bleeding risks for a period of 4 years. Furthermore, by excluding periprocedural MI and in sensitivity analysis, periprocedural bleeding, we were able to focus on late risks that could be affected by postprocedure treatment choices, such as duration of DAPT.

In our population of patients eligible for DES and subsequent DAPT, the long-term rate of non-periprocedural ischemic cardiovascular end points was only 6.3% at 4 years. Late ischemic events were at least partially stent related as the sirolimus-eluting stent was associated with a higher rate of stent thrombosis, and we adjusted for this effect in our models.12 and 24 However, beyond the stented segment, global ischemic risk of recurrent MI in other vascular territories and cardiac death attributable to plaque rupture represent another important target of long-term DAPT.25 In the DAPT trial, prolonged therapy with clopidogrel or prasugrel caused a significant decrease in stent thrombosis and MI unrelated to stent thrombosis and an increase in moderate/severe bleeding.3 Our study showed that the GUSTO moderate/severe bleeding risk beyond 1 year was low at 0.4% per year and the proportion of bleeding to ischemic event was similar to the DAPT trial with bleeding risk 3 to 4 times smaller than ischemic risk.3 Because of the degree of overlap between ischemic and bleeding risk factors, these subjects were not easily distinguishable from the remaining patients. This finding of considerable overlap could be related to the long-term nature of the risk prediction in our work, whereas previous studies focusing on shorter duration of follow-up tend to show different set of predictors between ischemic and bleeding events including more angiographic variables, which could reflect the greater burden of periprocedural events in these studies.26 and 27

Some limitations to this study need to be acknowledged. We compared the risk of moderate/severe bleeding to the composite risk of cardiovascular death/non-periprocedural MI/definite or probable stent thrombosis. The clinical weight of each event may not be equivalent, and this is not accounted for in our analyses. By being more restrictive for ischemic events, for example, excluding smaller periprocedural events, the conclusion that the risk of ischemic complications is usually greater than the risk of bleeding events in our data set is, therefore, conservative. Second, the use of moderate/severe GUSTO criteria to define bleeding events could lead to an underestimation of bleeding complications. However, these criteria represent meaningful clinical events on par with similarly important ischemic events. Because no mandatory laboratory tests were required in the post-PCI period according to the PROTECT protocol, the TIMI definition of bleeding was deemed less reliable than the GUSTO criteria. In sensitivity analyses, using adjudicated TIMI major bleeding events yielded similar results compared with our primary analysis. Opting for bleeding criteria that are more sensitive for clinically less important events could influence the conclusion regarding the balance between ischemic and bleeding risks. A possible limitation to the generalizability of our observations is that although the PROTECT sought to be broadly inclusive, it is possible that patients at very high risk of bleeding and ischemic complications were excluded as clinical trials tend to select healthier subjects. However, it is not known whether the bleeding risk would exceed the ischemic risk in the excluded population. Third, the only thienopyridine used in this study was clopidogrel. Newer oral P2Y12 antagonists, such as ticagrelor and prasugrel, are available for clinical use since the realization of this study, and with their more potent antiplatelet effect, they could alter the balance between ischemic and bleeding risks. Investigation of predictors of ischemic and bleeding risk in larger patients populations with extended follow-up and linkage to treatment benefit in randomized trial populations in the future will help to further refine the balance of these risks and benefits.

Disclosures

Relation with industry: Dr. Mattenone; Dr. Yeh: salary (Harvard Clinical Research Institute [HCRI]) and grant (HCRI); Dr. Camenzind: none; Dr. Steg: research support (NYU School of Medicine, Sanofi-Aventis, and Servier), consulting fees (Ablynx, Amarin, Astellas, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo-Lilly, GlaxoSmithKline, Medtronic, MSD, Novartis, Pfizer, Roche, Sanofi-Aventis, Servier, and The Medicines Company), and stockholding (Aterovax); Dr. Wijns: grant (to institution: Medtronic and Cordis), stockholding (Argonauts, Genae, and Cardio3BioSciences), and consultant fees (to institution: Medtronic, Cordis, and St. Jude); Dr. Mills: none; Dr. Gershlick: speaker fees (Abbott Vascular, Boston Scientific, Eli Lilly, Daiichi Snkyo Inc., The Medicines Company, Boehringer Ingelheim, and Medtronic); Dr. Belder: none; Dr. Ducrocq: speaker fees (Astra Zeneca and Eli Lilly), consultant fees (Astra Zeneca and Eli Lilly); and Dr. Mauri: grant support (Abbott Vascular, Cordis, Boston Scientific, Medtronic, Eli Lilly, Daiichi Sankyo Inc., Bristol Myers Squibb, and Sanofi-Aventis) and consultant fees (Biotronik, St. Jude, and Medtronic).

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Footnotes

a Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts

b Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts

c Cardiology Department, University of Geneva, Geneva, Switzerland

d Cardiology Department, DHU-FIRE, Hôpital Bichat, Paris, France

e Université Paris-Diderot, Paris, France

f INSERM U1148, Paris, France

g Cardiology Department, Cardiovascular Research Center Aalst, OLV Hospital, Aalst, Belgium

h Cardiology Department, Cardiothoracic Centre, Liverpool, United Kingdom

i Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom

j NIHR Leicester Cardiovascular Biomedical Research Unit, University Hospitals of Leicester Glenfield Hospital, Leicester, United Kingdom

k Cardiology Department, The James Cook University Hospital, Middlesbrough, United Kingdom

Corresponding author: Tel: (617) 732-8936; fax: (617) 525-8027.

See page 692 for disclosure information.

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