Net Adverse Cardiac Events Research Articles

Impact of coronary artery disease on clinical outcomes after TAVR: Insights from the BRAVO-3 randomized trial.

To determine the prognostic impact of coronary artery disease (CAD) in patients randomized to bivalirudin or unfractionated heparin (UFH) during transcatheter aortic valve replacement (TAVR). CAD is a common comorbidity amongpatients undergoing TAVR and studies provide conflicting data on its prognostic impact. The Bivalirudin on Aortic Valve Intervention Outcomes-3 (BRAVO-3) randomized trial compared the use of bivalirudin versus UFH in 802 high-surgical risk patients undergoing transfemoral TAVR for severe symptomatic aortic stenosis. Patients were stratified according to the presence or absence of history of CAD as well as periprocedural anticoagulation. The coprimary endpoints were net adverse cardiac events (NACE; a composite of all-cause mortality, myocardial infarction, stroke, or major bleeding) and major Bleeding Academic Research Consortium (BARC) bleeding ≥3b at 30 days postprocedure. Among 801 patients, 437 (54.6%) had history of CAD of whom 223 (51.0%) received bivalirudin. There were no significant differences in NACE (adjusted odds ratio [OR]: 1.04; 95% confidence interval [CI]: 0.69-1.58) or BARC ≥ 3b bleeding (adjusted OR: 0.84; 95% CI: 0.51-1.39) in patients with vs without CAD at 30 days. Among CAD patients, periprocedural use of bivalirudin was associated with similar NACE (OR: 0.80; 95% CI: 0.47-1.35) and BARC ≥ 3b bleeding (OR: 0.64; 95% CI: 0.33-1.25) compared with UFH, irrespective of history of CAD (p-interaction = 0.959 for NACE; p-interaction = 0.479 for major bleeding). CAD was not associated with a higher short-term risk of NACE or major bleeding after TAVR. Periprocedural anticoagulation with bivalirudin did not show any advantage over UFH in patients with and without CAD.

Assessment of Paclitaxel Drug-Coated Balloon Only Angioplasty in STEMI

BackgroundPrimary percutaneous coronary intervention (pPCI) with drug-eluting stents (DES) has emerged as the standard of care, but stent-related events have persisted. Drug-coated balloon (DCB)–only angioplasty is an emerging technology, although it is not fully evaluated compared with DES in the context of pPCI. ObjectivesThe aim of this study was to investigate the safety of DCB-only angioplasty compared with second-generation DES in pPCI. MethodsAll-cause mortality and net adverse cardiac events (cardiovascular mortality, acute coronary syndrome, ischemic stroke or transient ischemic attack, major bleeding, and unplanned target lesion revascularization [TLR]) were compared among all patients treated with DCBs only or with second-generation DES only for first presentation of ST-segment elevation myocardial infarction (STEMI) due to de novo disease between January 1, 2016, and November 15, 2019. Patients treated with both DCBs and DES were excluded. Data were analyzed using Cox regression models, Kaplan-Meier estimator plots and propensity score matching. ResultsAmong 1,139 patients with STEMI due to de novo disease, 452 were treated with DCBs and 687 with DES. After a median follow-up period of >3 years, all-cause mortality was 49 of 452 and 62 of 687 in the DCB and DES groups, respectively (P = 0.18). On multivariable Cox regression analysis, there was no difference in mortality between DCBs and DES in the full and propensity score–matched cohorts. Age, frailty risk, history of heart failure, and family history of ischemic heart disease remained significant independent predictors of mortality. There was no difference in any of the secondary endpoints, including unplanned TLR. ConclusionsDCB-only angioplasty appears safe compared with DES for STEMI in terms of all-cause mortality and all net adverse cardiac events, including unplanned TLR. DCB may be an efficacious and safe alternative to DES in selected patient groups. (Drug Coated Balloon Only vs Drug Eluting Stent Angioplasty; NCT04482972)

Use of Bivalirudin for Chronic Total Occlusion Percutaneous Intervention: Insights From the PROGRESS-CTO Registry.

There are limited data on the use of bivalirudin for chronic total occlusion (CTO) percutaneous coronary intervention (PCI). We compared CTO-PCIs performed using bivalirudin vs unfractionated heparin in the Prospective Global Registry for the Study of Chronic Total Occlusion Intervention (PROGRESS-CTO; NCT02061436). The primary endpoint was net adverse cardiac events (NACE), defined as major adverse cardiac events (MACE) and vascular complications. Between 2012 and 2022, a total of 73 of 9723 procedures (0.75%) were performed using bivalirudin. The J-CTO score (2.4 ± 1.2 vs 2.4 ± 1.3; P=.73) and the PROGRESS-CTO score (1.4 ± 0.9 vs 1.2 ± 1.0; P=.31) were similar in both groups, and the retrograde approach was used less often in the bivalirudin group (15% vs 30%; P<.01). Procedural success (89% vs 85%; P=.35), in-hospital NACE (1.4% vs 2.1%; P>.99), incidence of MACE (0% vs 0.76%; P=.64), and vascular access complications (1.4% vs 0.9%; P=.48) were not different between the 2 groups. On multivariable analysis, use of bivalirudin was not associated with an increased risk of NACE (odds ratio, 0.99; 95% confidence interval, 0.13-7.27). Bivalirudin is infrequently used during retrograde CTO-PCI. While the incidence of adverse events was similar with unfractionated heparin, larger studies are needed to assess the safety of bivalirudin.

Ticagrelor versus prasugrel in acute coronary syndrome: sex-specific analysis from the RENAMI Registry.

The use of potent P2Y12 inhibitors (ticagrelor & prasugrel) in acute coronary syndrome (ACS) patients undergoing percutaneous coronary interventions (PCI) is a class I recommendation. We performed a sex-specific analysis comparing the difference in efficacy and safety outcomes between ticagrelor and prasugrel in a real-world ACS population. Data from the multicenter REgistry of New Antiplatelets in patients with Myocardial Infarction (RENAMI) for 4424 ACS patients who underwent PCI and were treated with ticagrelor or prasugrel between 2012 to 2016 were analyzed. Mean follow-up was 17±9 months. After propensity score matching, there was no significant difference in the occurrence of primary endpoint of net adverse cardiac events between ticagrelor and prasugrel in men (HR: 0.94; 95% CI: 0.69-1.29; P=0.71), or women (HR: 1.17; 95% CI: 0.63-2.20; P=0.62; P interaction [sex] = 0.40). Similarly, no differences were found in the occurrence of any of the secondary endpoints (MACE, all cause death, re-infarction, stent thrombosis, BARC major bleeding and BARC any bleeding) between the two P2Y12 groups between men and women. In this real-world ACS population, no relative difference in efficacy or safety outcomes were found between ticagrelor and prasugrel between sexes.

Impact of anemia on short-term outcomes after TAVR: A subgroup analysis from the BRAVO-3 randomized trial.

To determine the prognostic impact of anemia in patients randomized to bivalirudin or unfractionated heparin (UFH) during transcatheter aortic valve replacement (TAVR). Whether the periprocedural use of bivalirudin as compared with UFH in anemic patients undergoing TAVR has an impact on outcomes remains unknown. The BRAVO-3 trial compared the use of bivalirudin versus UFH in 802 high risk patients undergoing transfemoral TAVR for severe symptomatic aortic stenosis. Patients were stratified according to the presence (defined as hemoglobin levels <13 g/dl in men and <12 g/dl in women) or absence of anemia. The primary outcomes were net adverse cardiac events (NACE; a composite of all-cause mortality, myocardial infarction, stroke, or bleeding) and major bleeding (Bleeding Academic Research Consortium ≥3b) at 30 days. Among 798 patients with available baseline hemoglobin levels, 427 (54%) were anemic of whom 221 (52%) received bivalirudin. There were no significant differences in NACE and major bleeding at 30 days between patients with and without anemia, irrespective of the type of anticoagulant used (pinteraction =0.71 for NACE, pinteraction =1.0 for major bleeding). However, anemic patients had a higher risk of major vascular complications (adjusted OR 2.43, 95% CI 1.42-4.16, p=0.001), and acute kidney injury (adjusted OR 1.74, 95% CI 1.16-2.59, p=0.007) compared to non-anemic patients at 30 days. Anemia was not associated with a higher risk of NACE or major bleeding at 30 days after TAVR without modification of the treatment effects of periprocedural anticoagulation with bivalirudin versus UFH.

Combinations of bleeding and ischemic risk and their association with clinical outcomes in acute coronary syndrome

BackgroundClinical predictors of future ischemic events in patients with acute coronary syndrome (ACS) are also risk factors for bleeding, with patients often at high-risk of both outcomes. We aimed to define the clinical outcomes and provision of guideline-recommended care in ACS management for different combinations of ischemic and bleeding risk defined using a combined GRACE and CRUSADE score. MethodsA retrospective observational analysis of a national ACS database was performed for patients with ACS admitted to three tertiary centres from January 2010 to March 2016. Patients were stratified into 9 groups based on possible CRUSADE-GRACE risk combinations. Multiple logistic regression was used to estimate adjusted odds ratios (ORs [95% CI]) for outcomes (in-hospital net adverse cardiac events (NACE), in-hospital all-cause mortality, 30-day mortality and treatment strategy). ResultsA total of 17,701 patients were included in the analysis. We observed a graded risk of mortality and adverse events in the high-risk GRACE strata (Groups 3, 6 and 9). Almost a third of patients with ACS were at a ‘dual high-risk’ (Group 9, 32%) and were independently associated with higher in-hospital NACE (composite of cardiac mortality, all-cause bleeding and re-infarction): aOR 6.33 [3.55, 11.29], all-cause mortality: aOR 14.17 [5.27, 38.1], all-cause bleeding: aOR 4.82 [1.96, 11.86], and 30-day mortality: aOR 10.79 [5.33, 21.81]. This group was also the least likely to be offered coronary angiography (aOR 0.24 [0.20, 0.29]) and dual anti-platelet therapy (aOR 0.26 [0.20, 0.34]). ConclusionsOne in five patients presenting with an ACS are high ischemic and high bleeding risk, and these patients are more likely to experience poor clinical outcomes and reduced odds of receiving guideline-recommended therapy.

64 Older (higher risk) patients with non-st-elevation acute coronary syndrome (nsteacs) have the most to gain from invasive therapy: a population study in south wales 2004–2014

Background and aimCardiovascular disease is the biggest killer in Wales, with non-ST-elevation acute coronary syndrome (NSTEACS) forming the commonest diagnosis. NSTEACS patients are at risk of death, reinfarction and ischaemia,...

Increased morbidity, mortality and length of in-hospital stay for patients with acute coronary syndrome with pre-morbid psychiatric diagnoses

BackgroundPsychiatric and cardiac comorbidities form the top two budget categories for health systems in high-income countries with evidence that psychiatric pre-morbidities lead to worse outcomes in patients with acute coronary syndrome (ACS). There are no studies examining this relationship in a national multicentre population level study in the UK, and no studies examining their impact on length of in-hospital stay (LoS) in ACS. Recognizing at-risk populations and reducing LoS in ACS is an essential part of improving patient care and cost-effectiveness. MethodsWe investigated the impact of psychiatric diagnoses on morbidity, all-cause mortality and LoS amongst 57,668 ACS patients between Jan-2004 and Dec-2014 using the Secure-Anonymized-Information-Linkage (SAIL) databank. Demographics, admissions, cardiac and psychiatric comorbidities were identified using coded data. ResultsThere were a total of 3857 out of 57,668 patients who had a pre-morbid psychiatric diagnosis. The mean LoS in patients without psychiatric comorbidities was 9.78days (95% CI: 9.66–9.91). This was higher (p<0.01) in the presence of any psychiatric diagnosis (14.72), dementia (20.87), schizophrenia (15.67), and mood disorders (13.41). Patients with psychiatric comorbidities had worse net adverse cardiac events (HR 1.18, 95% CI: 1.16–1.21) and mortality rates (HR 1.26, 95% CI: 1.23–1.30). ConclusionsOur results demonstrate that psychiatric comorbidities have a significant and clinically important impact on morbidity, mortality and LoS in ACS patients in Wales, UK. Clinicians' awareness and active management of psychiatric conditions amongst ACS patients is needed to reduce poor outcomes and LoS and ultimately the risk for patients and financial burden for the health-service.

Impact of proton pump inhibitors and dual antiplatelet therapy cessation on outcomes following percutaneous coronary intervention: Results From the PARIS Registry.

Proton pump inhibitors (PPI) may decrease the availability of clopidogrel by competitive antagonism, leading to a potential increase in ischemic events. We evaluated patients from the all-comer PARIS registry treated with dual antiplatelet therapy (DAPT) with aspirin and clopidogrel following coronary stenting for outcomes stratified by PPI use. Two-year major adverse cardiovascular events (MACE), composite of cardiac death, myocardial infarction, definite or probable stent thrombosis or target lesion revascularization (TLR), and net adverse cardiac events (NACE), composite of MACE or Bleeding Academic Research consortium (BARC) type 3 or 5 bleeding were assessed. We also explored associations between PPI use and patterns of 2-year DAPT cessation. The cohort comprised 4635 patients (23% PPI users) with mean age 64.4 ±11.4 years. Two year adjusted risk of MACE (HR: 1.27, 95% CI: 1.04-1.55), NACE (HR: 1.21, 95% CI: 1.01-1.44) and TLR (HR: 1.33, 95% CI: 1.04-1.71) were significantly higher in PPI users vs. non-users, without a difference in bleeding. Although the incidence of 2-year DAPT discontinuation and interruption was similar, DAPT disruption was significantly lower among PPI users vs. non-users (10.0% vs. 14.7%, P <0.0001). Compared to non-PPI users on continued DAPT, disruption was associated with higher MACE in both PPI users (HR: 2.34, 95% CI: 1.38-3.97) and non-users (HR: 1.41, 95% CI: 1.02-1.94) but greater BARC 3,5 bleeding only in non-PPI users (HR: 2.06, 95% CI: 1.21-3.51). In clopidogrel treated PCI patients, the 2-year adjusted risk of MACE and NACE was significantly higher in PPI users driven by higher TLR compared to non-PPI users, without a difference in bleeding. PPI use was associated with lower incidence of DAPT disruption without an increase in disruption related bleeding compared to non-PPI users on DAPT. © 2016 Wiley Periodicals, Inc.

The Ideal Anticoagulation Strategy in ST-Elevation Myocardial Infarction

Heparin has been the principal anticoagulant in the management of ST-elevation myocardial infarction (STEMI) but has several limitations. Although glycoprotein IIb/IIIa inhibitors have been major adjuncts in previous years, in the era of novel P2Y12 receptor inhibitors they may have a greater role in bailout. Low molecular weight heparins have been extensively studied in fibrinolysis trials but data in primary percutaneous coronary intervention (PCI) are scarce. The direct thrombin inhibitor bivalirudin overcomes several shortcomings of heparins and has demonstrated a significant reduction in bleeding outcomes and net adverse cardiac events at the cost of increased acute stent thrombosis. This review discusses the pharmacology and clinical trial evidence for different anticoagulant treatment options in STEMI with a proposed selection strategy in contemporary primary PCI.

Bivalirudin Versus Heparin Plus Glycoprotein IIb/IIIa Inhibitors in Patients with Diabetes Mellitus Undergoing Percutaneous Coronary Intervention: A Meta-Analysis of Randomized Controlled Trials.

Diabetes mellitus (DM) is a pro-thrombotic state with enhanced thrombin generation and platelet reactivity. For most patients undergoing percutaneous coronary intervention (PCI), bivalirudin demonstrates efficacy comparable with that of heparin and glycoprotein IIb/IIIa inhibitors (GPIs). Yet, because of their pro-thrombotic condition, we hypothesized that patients with DM may benefit from more aggressive dual antithrombin and antiplatelet therapy. The aim of this paper was to provide a systematic review comparing outcomes of PCI with bivalirudin versus heparin plus GPI in patients with DM using meta-analytical techniques. Eligible studies needed to have reported a subgroup analysis of outcomes among diabetic patients. Six trials comprising 5924 diabetic patients were eligible. At 30 days, bivalirudin was associated with a reduction in net adverse cardiac events [relative risk (RR) 0.81, 95% confidence interval (CI) 0.70-0.93, p=0.002] and major bleeds (RR 0.68, 95% CI 0.49-0.95; p=0.02), with no difference in composite ischemia (RR 0.92, 95% CI 0.74-1.14; p=0.43) or mortality (RR 0.71, 95% CI 0.45-1.13; p=0.15). At 1 year, bivalirudin was associated with a significant reduction in all-cause mortality (RR 0.73, 95% CI 0.54-1.00, p=0.05) despite similar composite ischemia (RR 1.02, 95% CI 0.56-1.21, p=0.811). In conclusion, thrombin inhibition with bivalirudin alone was associated with reduced 30-day major bleeding and 1-year all-cause mortality compared with heparin plus GPI in diabetic patients undergoing PCI.

Switching from high-dose clopidogrel to prasugrel in ACS patients undergoing PCI: a single-center experience

Prasugrel has been shown to be superior to clopidogrel in the setting of ACS patients undergoing coronary angioplasty. However, few data have been reported so far on those patients who switch from clopidogrel to prasugrel after coronary angioplasty. Aim of the current study was to evaluate the safety of prasugrel loading dose administration in ACS patients undergoing PCI and pretreated with high-dose clopidogrel. From May 2010 to December 2011 150 ACS patients undergoing coronary angioplasty and pretreated with high-dose clopidogrel, were switched to prasugrel loading dose soon after the procedure. They were matched (ratio 1:2) according to sex and age with a group of 300 ACS patients undergoing angioplasty and treated with high-dose clopidogrel only from May 2010 to December 2011. All demographic clinical and angiographic were collected. Primary endpoint was the rate of major bleeding complications (according to ACUITY trial definition) at 30-day follow-up. Secondary endpoints were: TIMI major and minor bleeding, definite stent thrombosis, major adverse cardiac events (MACE) and Net adverse cardiac events (NACE) at 30-day followup. The two groups of patients showed similar baseline demographic, and clinical characteristics. Most of the patients had unstable angina or non-ST segment elevation myocardial infarction. Almost (about 95 %) all patients underwent radial approach. No difference was observed in major bleeding complications according to both ACUITY (2.0 vs 2.0 %) and TIMI Major (0.7 vs 1.3 %) definition. No difference between the two groups was observed in terms of in-stent thrombosis, MACE and NACE at 30-day follow-up. Our observational study showed that switching to prasugrel with loading dose soon after angioplasty among ACS patients who were pretreated with clopidogrel seems to be well tolerated without overt evidence of heightened major bleeding. Future large randomized trials are certainly needed to confirm these findings.

Retrospective multicenter observational study of the interventional management of coronary disease in the very elderly: The NINETY

Objectives: The aim of this observational, multicenter study was to describe the outcome of very elderly patients undergoing percutaneous coronary intervention (PCI). Background: There is a paucity of data among nonagenarians undergoing PCI. Methods: All consecutive patients 90 years of age or older undergoing PCI with stent implantation between April 2002 and June 2009 were included in the study. The primary endpoint was the long term rate of net adverse cardiac events (NACE), that is, death, myocardial infarction (MI), target lesion revascularization, and life threatening or major bleedings. Results: One hundred forty-six nonagenarians were divided in three groups according to clinical setting: 27 (group A) stable angina or silent ischemia, 85 (group B) unstable angina or non-ST elevation MI, and 34 (group C) with ST elevation MI (STEMI). At 30 days, the incidence of NACE was significantly lower in patients in Group A vs. B or C (0% vs. 17.3% vs. 31.2%, p = 0.006), and the frequency of definite stent thrombosis was higher in Group C vs. A or B (9.4% vs. 0% vs. 0%, p = 0.007), respectively. Up to a median follow up of 24 months, NACE rate was 33.3% in group A, 49.3% in group B, and 50% in group C (p = 0.32). There were no significant differences between groups in the individual components of the primary endpoint. Conclusions: PCI in nonagenarians is safe and feasible with acceptable major bleeding rates. However, long term results show high mortality rates particularly in the STEMI group.

Retrospective multicenter observational study of the interventional management of coronary disease in the very elderly: The NINETY

The aim of this observational, multicenter study was to describe the outcome of very elderly patients undergoing percutaneous coronary intervention (PCI). There is a paucity of data among nonagenarians undergoing PCI. All consecutive patients 90 years of age or older undergoing PCI with stent implantation between April 2002 and June 2009 were included in the study. The primary endpoint was the long-term rate of net adverse cardiac events (NACE), that is, death, myocardial infarction (MI), target lesion revascularization, and life-threatening or major bleedings. One hundred forty-six nonagenarians were divided in three groups according to clinical setting: 27 (group A) stable angina or silent ischemia, 85 (group B) unstable angina or non-ST elevation MI, and 34 (group C) with ST elevation MI (STEMI). At 30 days, the incidence of NACE was significantly lower in patients in Group A vs. B or C (0% vs. 17.3% vs. 31.2%, P = 0.006), and the frequency of definite stent thrombosis was higher in Group C vs. A or B (9.4% vs. 0% vs. 0%, P = 0.007), respectively. Up to a median follow-up of 24 months, NACE rate was 33.3% in group A, 49.3% in group B, and 50% in group C (P = 0.32). There were no significant differences between groups in the individual components of the primary endpoint. PCI in nonagenarians is safe and feasible with acceptable major bleeding rates. However, long-term results show high mortality rates particularly in the STEMI group.

Comparison of Bivalirudin Versus Bivalirudin Plus Glycoprotein IIb/IIIa Inhibitor Versus Heparin Plus Glycoprotein IIb/IIIa Inhibitor in Patients With Acute Coronary Syndromes Having Percutaneous Intervention for Narrowed Saphenous Vein Aorto-Coronary Grafts (the ACUITY Trial Investigators)

Clinical outcomes in patients with acute coronary syndromes randomized in the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial who underwent percutaneous coronary intervention (PCI) of saphenous vein grafts (SVGs) were examined. The ACUITY trial assessed the safety and efficacy of bivalirudin alone versus bivalirudin plus a glycoprotein (GP) IIb/IIIa inhibitor versus heparin plus a GP IIb/IIIa inhibitor in 13,819 patients with moderate- and high-risk acute coronary syndromes, 7,789 of whom underwent PCI. A total of 329 patients (4.2%) underwent PCI of SVGs in ACUITY. The primary end points at 30 days were composite ischemia or major adverse cardiac events (death, myocardial infarction, or unplanned target vessel revascularization), major bleeding (unrelated to coronary artery bypass grafting), and net adverse clinical events (composite ischemia or major bleeding). The rates of ischemic, bleeding, and net clinical end points were similar with bivalirudin monotherapy, bivalirudin plus a GP IIb/IIIa inhibitor, and heparin plus a GP IIb/IIIa inhibitor. Net adverse clinical outcome rates at 30 days were 22%, 26%, and 22% (p = 0.67), respectively, for the 3 groups. Major adverse cardiac event rates at 1 year were 37%, 37%, and 43% (p = 0.95), respectively. Minor bleeding unrelated to coronary artery bypass grafting at 30 days was significantly lower with bivalirudin alone compared with heparin plus a GP IIb/IIIa inhibitor (26% vs 38%, p = 0.05). In conclusion, bivalirudin is an effective anticoagulant in PCI of SVGs in acute coronary syndromes, with similar rates of major adverse cardiac events and net adverse cardiac events and lower minor bleeding complications in comparison with heparin plus a GP IIb/IIIa inhibitor or bivalirudin plus a GP IIb/IIIa inhibitor.

Primary percutaneous coronary intervention for ST-elevation myocardial infarction using an intravenous and subcutaneous enoxaparin low molecular weight heparin regimen

Enoxaparin use in PCI has been investigated, however its role in primary PCI is less known. To evaluate the role of combination IV + SC enoxaparin in primary PCI in STEMI. 83 consecutive patients with STEMI who underwent primary PCI between January 1, 2005 and January 15, 2008 were included. Anticoagulation was based on our institution's STEMI protocol; either IV + SC enoxaparin, or IV unfractionated heparin (UFH). Clinical endpoints included MACE, bleeding and net adverse cardiac events (NACE). 45 patients received UFH and 37 received IV + SC enoxaparin. There was no difference in the rate of mortality, MACE, or NACE. There was a trend toward more TIMI major and GUSTO moderate and severe bleeding in the UFH group. Application of IV + SC enoxaparin strategy for primary PCI in STEMI appears both safe and efficacious. A prospective randomized trial will be necessary to evaluate the safety and efficacy more thoroughly.

Bleeding Is Bad…. Isn’t It?

Advances in antithrombin and antiplatelet therapy have traditionally been associated with reductions in myocardial infarction and other thrombotic events in patients who have experienced an acute coronary syndrome (ACS), are undergoing a percutaneous coronary intervention (PCI), or are receiving long-term therapy for secondary prevention of stable vascular disease. Although individual trials of antithrombotic therapy have rarely been able to demonstrate that the reduction in ischemic events leads to a reduction in mortality (the most important end point), meta-analyses have often suggested that this is the case.1 And because myocardial infarction is an independent correlate of mortality, a link between a reduction in ischemic events and reduced mortality makes intuitive sense. Article p 2793 Unfortunately, more potent anticoagulants and antiplatelet agents are also associated with an increased risk of bleeding, especially when used in combination with one another, as is usually the case. Furthermore, there is a well-established body of evidence that indicates an association between bleeding and ischemic events.2,3 It has been unclear, however, whether the link between bleeding and thrombosis is the result of bleeding after the initial development of a thrombotic complication (and its treatment) or if bleeding precedes the development of an ischemic complication and actually leads to (actually causes) thrombosis. In support of the former possibility is that patients who, because of the presence of thrombus, undergo a longer or more complicated procedure, receive a higher dose or longer duration of antithrombotic medication, or require an intra-aortic balloon pump are surely more prone to bleed. However, the possibility that hemorrhage actually leads to thrombosis rather than results from it is supported by the observation that hemorrhage is a potent stimulus for thrombosis; all patients would surely die if bleeding did not trigger at least a local thrombotic reaction. Furthermore, as the Global Registry of …