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Background: Radial artery access for coronary angiography or percutaneous coronary intervention (PCI) reduces the risk of death, bleeding, and vascular complications and is preferred over femoral artery access, leading to a class 1 indication by clinical practice guidelines. However, alternate upper extremity access such as distal radial and ulnar access are not mentioned in the guidelines despite randomized trials. We aimed to evaluate procedural outcomes with femoral, radial, distal radial, and ulnar access sites in patients undergoing coronary angiography or PCI., Methods: PubMed, EMBASE, and clinicaltrials.gov databases were searched for randomized clinical trials that compared at least 2 of the 4 access sites in patients undergoing PCI or angiography. Primary outcomes were major bleeding and access site hematoma. Intention-to-treat mixed treatment comparison meta-analysis was performed., Results: From 47 randomized clinical trials that randomized 38 924 patients undergoing coronary angiography or PCI, when compared with femoral access, there was a lower risk of major bleeding with radial access (odds ratio [OR], 0.46 [95% CI, 0.35-0.59]) and lower risk of access site hematoma with radial (OR, 0.34 [95% CI, 0.24-0.48]), distal radial (OR, 0.33 [95% CI, 0.20-0.56]), and ulnar (OR, 0.50 [95% CI, 0.31-0.83]) access. However, when compared with radial access, there was higher risk of hematoma with ulnar access (OR, 1.48 [95% CI, 1.03-2.14])., Conclusions: Data from randomized trials support guideline recommendation of class 1 for the preference of radial access over femoral access in patients undergoing coronary angiography or PCI. Moreover, distal radial and ulnar access can be considered as a default secondary access site before considering femoral access., Registration: URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: 42024512365., Competing Interests: Dr Bangalore is on the Advisory Board for Abbott Vascular, Boston Scientific, Biotronik, Amgen, Pfizer, Merck, Reata, Inari, and Truvic. The other authors report no conflicts.

Investigating the balance of risk for thrombotic and bleeding events after percutaneous coronary intervention (PCI) is especially relevant for patients at high bleeding risk (HBR). The Academic Research Consortium for HBR recently proposed a consensus definition in an effort to standardize the patient population included in HBR trials. The aim of this consensus-based document, the second initiative from the Academic Research Consortium for HBR, is to propose recommendations to guide the design of clinical trials of devices and drugs in HBR patients undergoing PCI. The authors discuss the designs of trials in HBR patients undergoing PCI and various aspects of trial design specific to HBR patients, including target populations, intervention and control groups, primary and secondary outcomes, and timing of endpoint reporting., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Procedural anticoagulation with bivalirudin (BIV), trans-radial intervention (TRI), and use of a vascular closure device (VCD) are thought to mitigate percutaneous coronary intervention (PCI)-related bleeding. We compared the impact of these bleeding avoidance strategies (BAS) for PCIs stratified by bleeding risk., Methods: We performed a retrospective cohort analysis of PCIs from 18 facilities within one health care system from 2009Q3 to 2017Q4. Bleeding risk was assessed per the National Cardiovascular Data Registry CathPCI bleeding model, with procedures stratified into 6 categories (first, second, third quartiles, 75th-90th, 90th-97.5th, and top 2.5th percentiles). Regression models were used to assess the impact of BAS on bleeding outcome., Results: Of 74 953 PCIs, 9.4% used no BAS, 12.0% used BIV alone, 20.8% used TRI alone, 26.8% used VCD alone, 5.4% used TRI+BIV, and 25.6% used VCD+BIV. The crude bleeding rate was 4.4% overall. Only 2 comparisons showed significant trends across all risk strata: VCD+BIV versus no BAS, odds ratio (95% CI) range: first quartile, 0.36 (0.18-0.72) to top 2.5th percentile, 0.50 (0.32-0.78); TRI versus no BAS, odds ratio (95% CI) range: first quartile, 0.15 (0.06-0.38) to top 2.5th percentile, 0.49 (0.28-0.86). TRI had lower odds of bleeding compared with BIV for all risk strata except the top 2.5th percentile. Addition of BIV to TRI did not change the odds of bleeding for any risk strata. Factors potentially limiting use of TRI (renal failure, shock, cardiac arrest, and mechanical circulatory support) were present in ≤10% of procedures below the 90th percentile., Conclusions: Among individual BAS, only TRI had consistently lower odds of bleeding across all risk strata. Factors potentially limiting TRI were found infrequently in procedures below the 90th percentile of bleeding risk. For transfemoral PCI, VCD+BIV had lower odds of bleeding compared with no BAS across all risk strata.

Background: Patients with atrial fibrillation on oral anticoagulation (OAC) undergoing cardiac catheterization face risks for embolic and bleeding events, yet information on strategies to mitigate these risks in contemporary practice is lacking., Methods: We aimed to describe the clinical/procedural characteristics of a contemporary cohort of patients with atrial fibrillation on OAC who underwent cardiac catheterization. Use of bleeding avoidance strategies and bridging therapy were described and outcomes including death, stroke, and major bleeding at 30 days and 1 year were compared by OAC type., Results: Of 13 404 patients in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II Registry from 2013 to 2016, 741 underwent cardiac catheterization (139 with percutaneous coronary intervention) in the setting of OAC. The patients' median age was 71, 61.8% were male, white (87.2%), had hypertension (83.7%), hyperlipidemia (72.1%), diabetes mellitus (31.6%), and chronic kidney disease (28.2%); 20.2% received warfarin while 79.8% received direct acting oral anticoagulant. One third of patients underwent radial artery access, and bivalirudin was used in 4.6%. Bridging therapy was used more often in patients on warfarin versus direct acting oral anticoagulant (16.7% versus10.0%). OAC was interrupted in 93.8% of patients. Patients on warfarin versus direct acting oral anticoagulant were equally likely to restart OAC (58.0% versus 60.7%), had similar use of antiplatelet therapy (44.0% versus 41.3%) after catheterization, and had similar rates of myocardial infarction and death at 1 year, but higher rates of major bleeding (43.3 versus 12.9 events/100 patient years) and stroke (4.9 versus 1.9 events/100 patient years)., Conclusions: In a real-world registry of patients with atrial fibrillation undergoing cardiac catheterization, most cases are elective, performed by femoral access, with interruption of OAC. Bleeding avoidance strategies such as radial artery access and bivalirudin were used infrequently and use of bridging therapy was uncommon. Nearly 40% of patients did not restart OAC postprocedure, exposing patients to risk for stroke. Further research is necessary to optimize the management of patients with atrial fibrillation undergoing cardiac catheterization.

Identification and management of patients at high bleeding risk undergoing percutaneous coronary intervention are of major importance, but a lack of standardization in defining this population limits trial design, data interpretation, and clinical decision-making. The Academic Research Consortium for High Bleeding Risk (ARC-HBR) is a collaboration among leading research organizations, regulatory authorities, and physician-scientists from the United States, Asia, and Europe focusing on percutaneous coronary intervention-related bleeding. Two meetings of the 31-member consortium were held in Washington, DC, in April 2018 and in Paris, France, in October 2018. These meetings were organized by the Cardiovascular European Research Center on behalf of the ARC-HBR group and included representatives of the US Food and Drug Administration and the Japanese Pharmaceuticals and Medical Devices Agency, as well as observers from the pharmaceutical and medical device industries. A consensus definition of patients at high bleeding risk was developed that was based on review of the available evidence. The definition is intended to provide consistency in defining this population for clinical trials and to complement clinical decision-making and regulatory review. The proposed ARC-HBR consensus document represents the first pragmatic approach to a consistent definition of high bleeding risk in clinical trials evaluating the safety and effectiveness of devices and drug regimens for patients undergoing percutaneous coronary intervention., (© 2019 The Authors. The European Heart Journal is published on behalf of the European Society of Cardiology, Inc., by Oxford University Press. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDerivs License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is non-commercial, and no modifications or adaptations are made.)

Identification and management of patients at high bleeding risk undergoing percutaneous coronary intervention are of major importance, but a lack of standardization in defining this population limits trial design, data interpretation, and clinical decision-making. The Academic Research Consortium for High Bleeding Risk (ARC-HBR) is a collaboration among leading research organizations, regulatory authorities, and physician-scientists from the United States, Asia, and Europe focusing on percutaneous coronary intervention-related bleeding. Two meetings of the 31-member consortium were held in Washington, DC, in April 2018 and in Paris, France, in October 2018. These meetings were organized by the Cardiovascular European Research Center on behalf of the ARC-HBR group and included representatives of the US Food and Drug Administration and the Japanese Pharmaceuticals and Medical Devices Agency, as well as observers from the pharmaceutical and medical device industries. A consensus definition of patients at high bleeding risk was developed that was based on review of the available evidence. The definition is intended to provide consistency in defining this population for clinical trials and to complement clinical decision-making and regulatory review. The proposed ARC-HBR consensus document represents the first pragmatic approach to a consistent definition of high bleeding risk in clinical trials evaluating the safety and effectiveness of devices and drug regimens for patients undergoing percutaneous coronary intervention.

Background: SAFE-PCI for Women (Study of Access Site for Enhancement of PCI for Women), a randomized controlled trial comparing radial and femoral access in women undergoing cardiac catheterization or percutaneous coronary intervention (PCI), was terminated early for lower than expected event rates. Whether this was because of patient selection or better access site practice among trial patients is unknown., Methods and Results: SAFE-PCI was conducted within the National Cardiovascular Data Registry CathPCI registry. Using the National Cardiovascular Research Infrastructure Identification, PCI date, and age, patients enrolled in SAFE-PCI were compared with trial-eligible female CathPCI registry patients 1 year before, during, and 1 year after SAFE-PCI enrollment. Patient and procedure characteristics, predicted bleeding and mortality, and post-PCI bleeding were compared between groups. Enrolled SAFE-PCI patients and registry patients from the 3 time periods were linked to Centers for Medicare and Medicaid Services data to compare 30-day death and unplanned revascularization rates. At 54 SAFE-PCI sites, there were 496 SAFE-PCI trial patients with a PCI visit within the CathPCI registry. There were 24 958 registry patients from 1 year before and 1 year after SAFE-PCI enrollment and 15 904 trial-eligible registry patients during trial enrollment. Trial patients were younger, had lower predicted bleeding and mortality, and had lower rates of post-PCI bleeding within 72 hours compared with registry patients. Among 12 212 Centers for Medicare and Medicaid Services-linked patients, there were no significant differences in 30-day death and unplanned revascularization among the 4 groups., Conclusions: Lower predicted risk of bleeding and mortality among SAFE-PCI trial patients compared with registry patients suggests that lower-risk patients were selectively enrolled for the trial. These data demonstrate how registry-based randomized trials may offer methods for enrollment feedback to curb selection bias in recruitment., Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01406236.

The treatment of patients requiring anticoagulation who develop acute coronary syndrome (ACS) and/or require percutaneous coronary intervention (PCI) must balance the reduction in major adverse cardiovascular events, stroke, and major bleeding. The development of direct oral anticoagulants (DOACs) for the treatment of atrial fibrillation has ushered in an era of potential treatment options for these complex patients. PURPOSE OF REVIEW: To review the clinical evidence underlying the use of DOACs for the treatment of patients with atrial fibrillation and ACS or PCI. RECENT FINDINGS: Three trials studied this particular patient population; WOEST showed that dual therapy with warfarin and clopidogrel decreased hemorrhage at 1 year compared with standard triple therapy (19.4 vs. 44.4% HR 0.36; 95% CI 0.26-0.50; P < 0.0001), without increasing thromboembolic events (11.1 vs. 17.6% HR 0.60; 95% CI 0.38-0.94; P = 0.025). PIONEER AF-PCI showed that 10-15 mg rivaroxaban plus P2Y 12 inhibitor for 12 months significantly lowered bleeding rates than standard triple therapy (16.8 vs. 26.7% HR 0.59; 95% CI 0.47-0.76; P < 0.001) and had equivalent rates of MACE. Finally, REDUAL-PCI compared two different doses of dabigatran (110 mg twice daily and 150 mg twice daily) plus P2Y 12 inhibitor with standard triple therapy and reported reduced ISTH bleeding with both doses; HR 0.52 with 110 mg dabigatran (95% CI 0.42-0.63, P < 0.001) and HR 0.72 with 150 mg dabigatran (95% CI 0.58-0.88; P = 0.002). The rate of the composite of thromboembolic events, death, or unplanned revascularizations was similar between pooled dabigatran dual therapy and triple therapy groups (13.7 vs 13.4% HR 1.04; 95% CI 0.84-1.29; P = 0.005). Recent evidence shows that DOACs plus one antiplatelet agent can decrease bleeding in patients with atrial fibrillation undergoing PCI for ACS. Although not powered to detect non-inferiority or superiority, large studies suggest rivaroxaban 10-15 mg plus P2Y 12 inhibitor for 12 months or dabigatran 150 mg twice daily plus P2y12 inhibitor for 12 months will have similar rates of MACE and stent thrombosis as triple therapy. In patients who have contraindications to DOACs, the strategy of INR-adjusted warfarin plus clopidogrel appears to be safer than warfarin plus dual antiplatelet therapy.

Background: During transradial (TR) access, it remains unclear whether differences in baseline patients characteristics and hemostasis care impact the rate of radial artery occlusion (RAO). We sought to compare the rate of RAO after TR access with the 6 French(Fr) Glidesheath Slender (GSS6Fr, Terumo, Japan) or a standard 5 Fr sheath in Japanese and non-Japanese patients., Methods and Results: The Radial Artery Patency and Bleeding, Efficacy, Adverse evenT (RAP and BEAT) trial randomized 1,836 patients undergoing TR coronary angiography and/or interventions to receive the GSS6Fr or the standard 5 Fr Glidesheath (GS5Fr, Terumo, Japan). Out of this study population, 1,087 were Japanese patients and 751 non-Japanese patients. The overall incidence of RAO was significantly higher in Japanese patients (3.6% vs. 1.2%, P = 0.002). Use of GSS6Fr was associated with higher rates of RAO than GS5Fr in Japanese patients (5% vs. 2.2%, P = 0.02) and with similar RAO rates in non-Japanese patients (1.3 vs. 1.1%, P = 1). The mean hemostasis time was significantly longer in Japanese patients (378 ± 253 vs. 159 ± 136 min, P < 0.001) and more Japanese patients had a hemostasis time of more than 6 hr (16.2% vs. 4.9%, P < 0.0001). Longer hemostasis time was an independent predictor of RAO (OR per additional hour 1.070, 95% CI 1.008-1.136, P = 0.03)., Conclusions: Use of GSS6Fr was associated with a higher rate of RAO than a standard 5 Fr sheath in Japanese patients but not in non-Japanese patients. Whether improvement in post-procedural care and reduced hemostasis time could impact the incidence of RAO in Japanese patients should be further assessed., (© 2018 The Authors Catheterization and Cardiovascular Interventions Published by Wiley Periodicals, Inc.)

Objectives: This study was conducted to determine the association between radial access, guided femoral access, and non-guided femoral access on postprocedural bleeding and vascular complications after percutaneous coronary intervention (PCI)., Background: Bleeding events and major vascular complications after PCI are associated with increased morbidity, mortality, and cost. While the radial approach has been shown to be superior to the femoral approach in reducing bleeding and vascular complications, whether the use of micropuncture, fluoroscopy, or ultrasound mitigates these differences is unknown., Methods: We conducted a post hoc analysis of women in the SAFE-PCI for Women trial who underwent PCI and had the access method identified (n = 643). The primary endpoint of postprocedure bleeding or vascular complications occurring within 72 hours or at discharge was adjudicated by an independent clinical events committee and was compared based on three categories of access technique: radial, guided femoral (fluoroscopy, micropuncture, ultrasound), or non-guided femoral (none of the aforementioned). Differences between the groups were determined using multivariate logistic regression using radial access as the reference., Results: Of the PCI population, 330 underwent radial access, 228 underwent guided femoral access, and 85 underwent non-guided femoral access. There was a statistically significant lower incidence of the primary endpoint with radial access vs non-guided femoral access; however, there was no significant difference between radial approach and femoral access guided by fluoroscopy, micropuncture, or ultrasound., Conclusions: This post hoc analysis demonstrates that while radial access is safer than non-guided femoral access, guided femoral access appears to be associated with similar bleeding events or vascular complications as radial access.

Aims: The 6 Fr Glidesheath Slender (GSS6Fr) is a recently developed thin-walled radial sheath with an outer diameter (OD) that is smaller than the OD of standard 6 Fr sheaths. The purpose of this trial was to clarify whether the use of this new slender sheath would result in similar rates of RAO to a standard 5 Fr sheath in unselected patients undergoing transradial (TR) coronary angiography and/or intervention, and to assess the relative importance of sheath size and haemostasis protocol on the rate of RAO., Methods and Results: We conducted a randomised, multicentre, non-inferiority trial comparing the GSS6Fr against the standard GS5Fr in patients undergoing TR coronary angiography and/or intervention. Patients in each group were subsequently randomised to undergo patent haemostasis or the institutional haemostasis protocol. The primary endpoint was the occurrence of RAO at discharge. A total of 1,926 patients were randomised in 12 centres. The incidence of RAO was 3.47% with GSS6Fr compared with 1.74% with GS5Fr (risk difference 1.73%, 95% CI: 0.51-2.95%; pnon-inferiority=0.150). Patients randomised to patent haemostasis had a similar rate of RAO compared with institutional haemostasis (2.61% vs. 2.61%, p=1). There was no difference with regard to all secondary endpoints, including vascular access-site complications, local bleeding and spasm., Conclusions: In this large multicentre randomised trial, the GSS6Fr was associated with a low event rate for the primary endpoint (RAO), although non-inferiority to the GS5Fr was not met, due to a lower than expected rate of RAO in the GS5Fr group. As compared to institutional haemostasis, the use of patent haemostasis was not associated with a reduced rate of RAO.

Background: Patients with chronic kidney disease (CKD) are at increased risk for bleeding, transfusion, and dialysis after cardiac catheterization. Whether rates of these complications are increased in this high-risk population undergoing transradial access compared with transfemoral access is unknown., Methods and Results: From the Veterans Affairs (VA) Clinical Assessment Reporting and Tracking program, we identified 229 108 patients undergoing cardiac catheterization between 2007 and 2014, of which 48 155 (21.0%) had baseline glomerular filtration rate (GFR) between 15 and 59 mL/min. We used multivariable Cox modeling to determine the independent association between transradial access and postprocedure transfusion as well as progression to new dialysis by degree of renal dysfunction. Overall, 35 979 (15.7%) of patients underwent Transradial access. Transradial patients tended to be slightly younger, but, overall, had similar rates of CKD compared to transfemoral patients (24.3% vs 27.1%). Transradial patients had longer fluoroscopy times (7.2 vs 6.0 minutes; P <0.001), but lower contrast use (85.0 vs 100.0 mL; P <0.001). The estimated rate of blood transfusion within 48 hours was lower among transradial patients (0.85% vs 1.01%) as were rates of new dialysis at 1 year (0.58% vs 0.71%). After multivariable adjustment, transradial access was associated with lower rates of progression to dialysis at 1 year overall (hazard ratio [HR], 0.83; 95% CI, 0.70-0.98), with no trend of increased risk for dialysis by degree of CKD compared with transfemoral access. Transradial access was associated with greater reduction in transfusion rates with increasing degree of CKD ( P value for trend=0.04: non-CKD: HR, 0.99; 95% CI, 0.73-1.34; GFR 45-59 mL/min: HR, 0.93; 95% CI, 0.70-1.23; GFR 30-44 mL/min: HR, 0.73; 95% CI, 0.51-1.03; GFR 15-29 mL/min: HR, 0.43; 95% CI, 0.20-0.90)., Conclusions: Among patients undergoing cardiac catheterization in the VA health system, transradial access was associated with lower risk for postprocedure transfusion within 48 hours among patients with more-severe CKD, and with lower risk of progression to end-stage renal disease at 1 year compared with transfemoral access. These data provide additional evidence that transradial access may provide significant benefit in this high-risk population., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Objectives: Periprocedural bleedings, often related to vascular access site, represent an important drawback of percutaneous coronary procedures and are associated with worse outcomes. Radial access (RA) and, potentially, femoral access (FA) with vascular closure device (VCD) are useful strategies in order to mitigate periprocedural bleedings; nevertheless, their relative efficacy is largely undetermined. We aimed to perform a systematic review and meta-analysis of available studies comparing the efficacy of RA and FA with hemostasis by VCD (FA + VCD) on the reduction of access-site complications and/or periprocedural bleedings., Methods: Published studies reporting outcomes on access-site complications and periprocedural bleedings were included in the analysis. Data were extracted by two independent reviewers; odds ratio (OR) and 95% confidence interval (CI) were calculated by random-effects model and were used as summary statistics., Results: We included in the analysis 13 studies, of which 5 were randomized. Access-site complications were reported by 11 studies, amounting to 157,031 patients (77,713 in the RA group and 79,318 in the FA + VCD group), whereas periprocedural bleedings were reported by 12 studies, amounting to 600,196 patients (137,277 in the RA group and 462,919 in the FA + VCD group). RA was associated with a significant reduction in access-site complications (OR, 0.25; 95% CI ,0.21-0.31; P<.001) and periprocedural bleedings (OR, 0.40; 95% CI, 0.34-0.48; P<.001) as compared with FA + VCD; the results were consistent among randomized and observational studies., Conclusions: This meta-analysis shows that RA is superior to FA + VCD in the reduction of access-site complications and periprocedural bleedings.

Background: Acute kidney injury (AKI) complicating percutaneous coronary intervention (PCI) is associated with adverse clinical outcomes. To date, no studies have evaluated the association of blood transfusion with AKI in patients undergoing PCI., Methods and Results: We used a retrospective cohort study of all patients with acute coronary syndrome undergoing PCI from CathPCI Registry (n=1 756 864). The primary outcome was AKI defined as the rise in serum creatinine post procedure ≥0.5 mg/dL or ≥25% above baseline values. AKI developed in 9.0% of study sample. Patients with AKI were older, more often women, and had high prevalence of comorbidities, including diabetes mellitus, hypertension, and advanced stages of chronic kidney disease at baseline. Blood transfusion was utilized in 2.2% of patients. In the overall sample, AKI developed in 35.1% of patients who received transfusion versus 8.4% of patients without transfusion (adjusted odds ratio, 4.87 [4.71-5.04]). In the subgroup of patients who sustained bleeding event and received transfusion, the rate of AKI was significantly increased across all preprocedure hemoglobin levels versus no blood transfusion. Similar findings were seen in the subgroup of patients with no bleeding event., Conclusions: Blood transfusion is strongly associated with AKI in patients with acute coronary syndrome undergoing PCI. Further investigation is needed to determine whether a restrictive blood transfusion strategy might improve PCI outcomes by reducing the risk of AKI., (© 2016 American Heart Association, Inc.)

Objectives: The aim of this study was to explore whether the use of bleeding avoidance strategies (BAS) explains variability in hospital-level bleeding following percutaneous coronary intervention., Background: Prior studies have reported that bleeding rates following percutaneous coronary intervention vary markedly among hospitals, but the extent to which use of BAS explains this variation is unknown., Methods: Using the American College of Cardiology National Cardiovascular Data Registry's CathPCI Registry, estimated hospital-level bleeding rates from 2,459,686 procedures at 1,358 sites were determined. A series of models were fit to estimate random-effect variance, adjusting for patient risk (using the validated CathPCI bleeding risk model, C statistic = 0.77) and various combinations of BAS (transradial access, bivalirudin, vascular closure device use). The rate of any BAS use was also estimated for each hospital, and the association between percentage BAS use and predicted bleeding rates was determined., Results: In total, 125,361 bleeding events (5.1%) were observed; patients experiencing bleeding events had lower rates of radial access (5.0% vs. 11.2%; p < 0.001), bivalirudin therapy (43.8% vs. 59.4%), and vascular closure device use (32.9% vs. 42.4%, p < 0.001) than those without bleeding. There was significant variation in bleeding rates across hospitals (median 5.0%; interquartile range [IQR]: 2.7% to 6.6%), which persisted after incorporating patient-level risk (median 5.1%; IQR: 4.0% to 4.4%). Patient factors accounted for 20% of the overall hospital-level variation, and radial access plus bivalirudin use accounted for an additional 7.8% of the overall hospital-level variation. The median hospital rate of any BAS use was 86.6% (IQR: 72.5% to 94.1%). A significant decrease in observed hospital-level bleeding was seen in hospitals above the median in BAS use (adjusted odds ratio: 0.90; 95% confidence interval: 0.88 to 0.93)., Conclusions: A modest proportion of the variation in hospitals' rates of bleeding following percutaneous coronary intervention is attributable to differential use of BAS. Further analyses are required to determine the remaining approximately 70% causes of variation in percutaneous coronary intervention bleeding seen among hospitals., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study sought to define the prevalence and prognostic impact of blood transfusions in contemporary percutaneous coronary intervention (PCI) practice., Background: Although the presence of anemia is associated with adverse outcomes in patients undergoing PCI, the optimal use of blood products in patients undergoing PCI remains controversial., Methods: A search of EMBASE and MEDLINE was conducted to identify PCI studies that evaluated blood transfusions and their association with major adverse cardiac events (MACE) and mortality. Two independent reviewers screened the studies for inclusion, and data were extracted from relevant studies. Random effects meta-analysis was used to estimate the risk of adverse outcomes with blood transfusions. Statistical heterogeneity was assessed by considering the I(2) statistic., Results: Nineteen studies that included 2,258,711 patients with more than 54,000 transfusion events were identified (prevalence of blood transfusion 2.3%). Crude mortality rate was 6,435 of 50,979 (12.6%, 8 studies) in patients who received a blood transfusion and 27,061 of 2,266,111 (1.2%, 8 studies) in the remaining patients. Crude MACE rates were 17.4% (8,439 of 48,518) in patients who had a blood transfusion and 3.1% (68,062 of 2,212,730) in the remaining cohort. Meta-analysis demonstrated that blood transfusion was independently associated with an increase in mortality (odds ratio: 3.02, 95% confidence interval: 2.16 to 4.21, I(2) = 91%) and MACE (odds ratio: 3.15, 95% confidence interval: 2.59 to 3.82, I(2) = 81%). Similar observations were recorded in studies that adjusted for baseline hematocrit, anemia, and bleeding., Conclusions: Blood transfusion is independently associated with increased risk of mortality and MACE events. Clinicians should minimize the risk for periprocedural transfusion by using available bleeding-avoidance strategies and avoiding liberal transfusion practices., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Post-percutaneous coronary intervention (PCI) bleeding complications are an important quality metric. We sought to characterize site-level variation in post-PCI bleeding and explore the influence of patient and procedural factors on hospital bleeding performance., Methods and Results: Hospital-level bleeding performance was compared pre- and postadjustment using the newly revised CathPCI Registry(®) bleeding risk model (c-index, 0.77) among 1292 National Cardiovascular Data Registry(®) hospitals performing >50 PCIs from 7/2009 to 9/2012 (n=1,984,998 procedures). Using random effects models, outlier sites were identified based on 95% confidence intervals around the hospital's random intercept. Bleeding 72 hours post-PCI was defined as: arterial access site, retroperitoneal, gastrointestinal, or genitourinary bleeding; intracranial hemorrhage; cardiac tamponade; nonbypass surgery-related blood transfusion with preprocedure hemoglobin ≥ 8 g/dL; or absolute decrease in hemoglobin value ≥ 3 g/dL with preprocedure hemoglobin ≤ 16 g/dL. Overall, the median unadjusted post-PCI bleeding rate was 5.2% and varied among hospitals from 2.6% to 10.4% (5th, 95th percentiles). Center-level bleeding variation persisted after case-mix adjustment (2.8%-9.5%; 5th, 95th percentiles). Although hospitals' observed and risk-adjusted bleeding ranks were correlated (Spearman ρ: 0.88), individual rankings shifted after risk-adjustment (median Δ rank order: ± 91.5; interquartile range: 37.0, 185.5). Outlier classification changed postadjustment for 29.3%, 16.1%, and 26.5% of low-, non-, and high-outlier sites, respectively. Hospital use of bleeding avoidance strategies (bivalirudin, radial access, or vascular closure device) was associated with risk-adjusted bleeding rates., Conclusions: Despite adjustment for patient case-mix, there is wide variation in rates of hospital PCI-related bleeding in the United States. Opportunities may exist for best performers to share practices with other sites., (© 2014 American Heart Association, Inc.)

Aims: The Bleeding Academic Research Consortium (BARC) classification has been proposed by consensus to standardize bleeding endpoint definition and reporting in cardiovascular clinical trials. There are no prospective studies on its prognostic impact., Methods and Results: We explored the association of BARC-defined bleeding with mortality and compared its prognostic value against two validated bleeding scales: the Thrombolysis in Myocardial Infarction (TIMI) and the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) scales. Non-coronary artery bypass graft (CABG)-related bleedings within the PRODIGY trial were prospectively adjudicated by a blinded Clinical Event Committee and analysed according to multiple statistical modelling. At 2 years, bleeding occurred in 143 patients (7.1%) according to BARC Type 2, 3, or 5; in 50 patients (2.5%) according to TIMI minor or major; and in 61 patients (3.1%) according to GUSTO moderate or severe. One hundred sixty-three patients died (8.1%). After multivariable modelling, BARC Type 2, 3, or 5 bleeding was associated with increased 2-year mortality [hazard ratio (HR): 3.77; 95% confidence interval (CI): 2.37-5.98]. Bleeding Academic Research Consortium Type 3 or 5 was associated with an increased mortality rate at 2 years (adjusted HR: 7.72; 95% CI: 4.75-12.54) similar to that provided by TIMI (HR: 7.64, 95% CI: 4.53-12.87) or GUSTO (HR: 7.36, 95% CI: 4.38-12.34) criteria., Conclusions: In a contemporary, all-comer percutaneous coronary intervention trial actionable BARC bleedings were associated with increased risk of mortality with BARC Type 3 or 5 bleedings providing a similar mortality risk to that posed by TIMI or GUSTO scales., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Transradial percutaneous coronary intervention (PCI) is associated with significant reductions in access site complications and major bleeding as compared with the transfemoral approach. Bivalirudin is now the most commonly used anticoagulant for transradial PCI in the United States, while weight adjusted unfractionated heparin remains the most common choice outside the United States. A growing number of reports suggest that transradial intervention may offer improved outcomes across a variety of clinical situations, including those at the highest risk of bleeding complications, such as those with acute myocardial infarction. The following review provides an overview of the studies evaluating anticoagulation in transradial PCI and a rationale for the combination of the transradial approach to coronary interventions with an optimal anticoagulant strategy to reduce both access site and nonaccess site-related bleeding., (Copyright © 2013 Wiley Periodicals, Inc.)

Dual antiplatelet therapy with aspirin and a P2Y12 receptor blocker is a key strategy to reduce platelet reactivity and to prevent thrombotic events in patients treated with percutaneous coronary intervention. In an earlier consensus document, we proposed cutoff values for high on-treatment platelet reactivity to adenosine diphosphate (ADP) associated with post-percutaneous coronary intervention ischemic events for various platelet function tests (PFTs). Updated American and European practice guidelines have issued a Class IIb recommendation for PFT to facilitate the choice of P2Y12 receptor inhibitor in selected high-risk patients treated with percutaneous coronary intervention, although routine testing is not recommended (Class III). Accumulated data from large studies underscore the importance of high on-treatment platelet reactivity to ADP as a prognostic risk factor. Recent prospective randomized trials of PFT did not demonstrate clinical benefit, thus questioning whether treatment modification based on the results of current PFT platforms can actually influence outcomes. However, there are major limitations associated with these randomized trials. In addition, recent data suggest that low on-treatment platelet reactivity to ADP is associated with a higher risk of bleeding. Therefore, a therapeutic window concept has been proposed for P2Y12 inhibitor therapy. In this updated consensus document, we review the available evidence addressing the relation of platelet reactivity to thrombotic and bleeding events. In addition, we propose cutoff values for high and low on-treatment platelet reactivity to ADP that might be used in future investigations of personalized antiplatelet therapy., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Importance: The optimal anticoagulant for patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS) managed with an invasive strategy remains controversial., Objective: To compare the clinical efficacy and safety of otamixaban, a novel intravenous direct factor Xa inhibitor, with that of unfractionated heparin plus downstream eptifibatide in patients with NSTE-ACS undergoing a planned early invasive strategy., Design, Setting, and Participants: Randomized, double-blind, active-controlled superiority trial that enrolled 13,229 patients with NSTE-ACS and a planned early invasive strategy, at 568 active sites in 55 countries and conducted between April 2010 and February 2013. A planned interim analysis was conducted for otamixaban dose selection., Interventions: Eligible participants were randomized to otamixaban (bolus and infusion, at 1 of 2 doses) or unfractionated heparin plus, at the time of percutaneous coronary intervention, eptifibatide. The otamixaban dose selected at interim analysis was an intravenous bolus of 0.080 mg/kg followed by an infusion of 0.140 mg/kg per hour., Main Outcomes and Measures: The primary efficacy outcome was the composite of all-cause death or new myocardial infarction through day 7., Results: Rates of the primary efficacy outcome were 5.5% (279 of 5105 patients) randomized to receive otamixaban and 5.7% (310 of 5466 patients) randomized to receive unfractionated heparin plus eptifibatide (adjusted relative risk, 0.99 [95% CI, 0.85-1.16]; P = .93). There were no differences for the secondary end points, including procedural thrombotic complications. The primary safety outcome of Thrombosis in Myocardial Infarction major or minor bleeding through day 7 was increased by otamixaban (3.1% vs 1.5%; relative risk, 2.13 [95% CI, 1.63-2.78]; P < .001). Results were consistent across prespecified subgroups., Conclusions and Relevance: Otamixaban did not reduce the rate of ischemic events relative to unfractionated heparin plus eptifibatide but did increase bleeding. These findings do not support the use of otamixaban for patients with NSTE-ACS undergoing planned early percutaneous coronary intervention., Trial Registration: clinicaltrials.gov Identifier: NCT01076764.

Objectives: This study sought to develop a model that predicts bleeding complications using an expanded bleeding definition among patients undergoing percutaneous coronary intervention (PCI) in contemporary clinical practice., Background: New knowledge about the importance of periprocedural bleeding combined with techniques to mitigate its occurrence and the inclusion of new data in the updated CathPCI Registry data collection forms encouraged us to develop a new bleeding definition and risk model to improve the monitoring and safety of PCI., Methods: Detailed clinical data from 1,043,759 PCI procedures at 1,142 centers from February 2008 through April 2011 participating in the CathPCI Registry were used to identify factors associated with major bleeding complications occurring within 72 h post-PCI. Risk models (full and simplified risk scores) were developed in 80% of the cohort and validated in the remaining 20%. Model discrimination and calibration were assessed in the overall population and among the following pre-specified patient subgroups: females, those older than 70 years of age, those with diabetes mellitus, those with ST-segment elevation myocardial infarction, and those who did not undergo in-hospital coronary artery bypass grafting., Results: Using the updated definition, the rate of bleeding was 5.8%. The full model included 31 variables, and the risk score had 10. The full model had similar discriminatory value across pre-specified subgroups and was well calibrated across the PCI risk spectrum., Conclusions: The updated bleeding definition identifies important post-PCI bleeding events. Risk models that use this expanded definition provide accurate estimates of post-PCI bleeding risk, thereby better informing clinical decision making and facilitating risk-adjusted provider feedback to support quality improvement., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Bleeding is a common, noncardiac, preventable complication of percutaneous coronary intervention. We compared the relative safety of radial access and bivalirudin in percutaneous coronary intervention., Methods and Results: From CathPCI Registry, we determined the association between the site of arterial access, bivalirudin, and periprocedural bleeding rates in 501 017 patients. Radial access patients receiving heparin (radial group) were compared with those receiving bivalirudin (radial combination group). Femoral access patients who had bivalirudin and a vascular closure device served as a reference group (femoral group). An inverse probability weighting analysis incorporating propensity scores was used to compare groups. The overall rate of bleeding was 2.59%. It was 2.71% in the femoral group, 2.5% in the radial group, and 1.82% in the radial combination groups (P<0.001). When compared with femoral group, the adjusted odds ratio for bleeding was significantly lower for patients with radial combination group (odds ratio, 0.79; 95% confidence interval, 0.72-0.86), but not for radial group (odds ratio, 0.96; 95% confidence interval, 0.88-1.05), unless patients treated with IIb/IIIa were excluded (radial group-IIb/IIIa odds ratio, 0.84; 95% confidence interval, 0.75-0.94).The number needed to treat to prevent 1 bleeding event with radial combination group was 138, whereas the number needed to treat to prevent 1 bleeding event in high-bleeding risk patients was 68., Conclusions: In this observational analysis, the combination of bivalirudin and radial access was associated with reduced bleeding event rate. This benefit was present across the entire spectrum of preprocedural risk of bleeding, with or without exposure to IIb/IIIa inhibitors. These data support an adequately powered randomized trial comparing bleeding avoidance strategies.

Objectives: This study sought to determine if there is an association between bleed location and clinical outcomes in acute coronary syndromes (ACS) patients., Background: The prognostic significance of bleeding location among ACS patients undergoing cardiac catheterization is not well known., Methods: We analyzed in-hospital bleeding events among 9,978 patients randomized in the SYNERGY (Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors) study. Bleeding events were categorized by location as access site, systemic, surgical, or superficial, and severity was graded using the GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) definition. We assessed the association of each bleeding location and severity with 6-month risk of death or myocardial infarction using a multicovariate-adjusted Cox proportional hazard model., Results: A total of 4,900 bleeding events were identified among 3,694 ACS patients with in-hospital bleeding. Among 4,679 GUSTO mild/moderate bleeding events, only surgical and systemic bleeds were associated with an increased risk of 6-month death or myocardial infarction (adjusted hazard ratio [HR]: 2.52 [95% confidence interval (CI): 2.16 to 2.94, and 1.40 [95% CI: 1.16 to 1.69], respectively). Mild/moderate superficial and access-site bleeds were not associated with downstream risk (adjusted HR: 1.17 [95% CI: 0.97 to 1.40], and 0.96 [95% CI: 0.82 to 1.12], respectively). Among 221 GUSTO severe bleeds, surgical bleeds were associated with the highest risk (HR: 5.27 [95% CI: 3.80 to 7.29]), followed by systemic (HR: 4.48 [95% CI: 2.98 to 6.72]), and finally access-site bleeds (HR: 3.57 [95% CI: 2.35 to 5.40])., Conclusions: Among ACS patients who develop in-hospital bleeding, systemic and surgical bleeding are associated with the highest risks of adverse outcomes regardless of bleeding severity. Although the most frequent among bleeds, GUSTO mild/moderate access-site bleeding is not associated with increased risk. These data underscore the importance of strategies to minimize overall bleeding risk beyond vascular access site management., (Copyright © 2013. Published by Elsevier Inc.)

With the large number of antithrombotic therapies available and under investigation for the treatment of non-ST-segment elevation acute coronary syndromes (NSTE ACS), practice guidelines now stress the importance of selecting an antithrombotic strategy according to the efficacy and safety profiles of the chosen agent. Contemporary trials have incorporated bleeding along with ischemic end points into a composite end point commonly referred to as net clinical benefit, which allows for simultaneous evaluation of the differences between benefit and harm for an investigational antithrombotic therapy. However, incorporating major bleeding into a composite end point that includes ischemic events is not warranted and is associated with many pitfalls. In this article, we discuss the validity of combining efficacy and safety end points to form a net clinical benefit composite end point with the traditional time-to-event analysis for trials evaluating antithrombotic therapies for NSTE ACS. We describe alternative statistical approaches for concurrent assessment of the safety and efficacy of antithrombotic therapies used to treat patients with NSTE ACS., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Background: Bleeding is a major limitation of antithrombotic therapy among invasively managed non-ST-segment elevation acute coronary syndromes (NSTE-ACS) patients; therefore, we examined the use of radial access and its association with outcomes among NSTE-ACS patients., Methods: Clinical characteristics and geographic variation in radial access were examined, as well as its association with bleeding, red blood cell transfusion and ischemic outcomes (96-hour death/myocardial infarction/recurrent ischemic/thrombotic bailout; 30-day death/myocardial infarction; 1-year death) in the EARLY versus delayed, provisional eptifibatide in acute coronary syndromes trial., Results: Of 9126 patients, 13.5% underwent radial-access catheterization. Female sex, age, weight, and prior revascularization were inversely associated with radial access, and its use varied widely by country (2%-97%). There were fewer GUSTO severe/moderate bleeds and red blood cell transfusions in the radial access group; however, it was attenuated after adjustment (odds ratio 0.73, 95% confidence intervals [CI] [0.50-1.06], P = .094 and 1.00 [0.71-1.40] P = .991). Ischemic outcomes did not differ by access site., Conclusions: In this post hoc analysis of a large clinical trial, there was significant international variation in use of radial access for NSTE-ACS patients undergoing invasive management, and it was preferentially used in those at lower risk for bleeding. Radial approach was not associated with a significant reduction in either bleeding or ischemic outcomes. Further study is needed to determine whether wider application of radial approach to acute coronary syndrome patients at high risk for bleeding improves overall outcomes., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Importance: Bleeding is the most common complication after percutaneous coronary intervention (PCI) and is associated with increased morbidity and health care costs. The incidence of bleeding-related mortality after PCI has not been described in a nationally representative population. Furthermore, the relationships among bleeding risk, bleeding site, and mortality are unclear., Objectives: To describe the association between bleeding events and in-hospital mortality after PCI and to estimate the adjusted population attributable risk (estimated as the proportion of mortality risk associated with bleeding events), risk difference, and number needed to harm (NNH) for bleeding-related in-hospital mortality after PCI., Design, Setting, and Patients: Data from 3,386,688 procedures in the CathPCI Registry performed in the United States between 2004 and 2011 were analyzed. The population attributable risk was calculated after adjustment for baseline demographic, clinical, and procedural variables. To calculate the NNH for bleeding-related mortality, a propensity-matched analysis was performed., Main Outcome Measures: In-hospital mortality., Results: There were 57,246 bleeding events (1.7%) and 22,165 in-hospital deaths (0.65%) in 3,386,688 PCI procedures. The adjusted population attributable risk for mortality related to major bleeding was 12.1% (95% CI, 11.4%-12.7%) in the entire CathPCI cohort. The propensity-matched population consisted of 56,078 procedures with a major bleeding event and 224 312 controls. In this matched cohort, major bleeding was associated with increased in-hospital mortality (5.26% vs 1.87%; risk difference, 3.39% [95% CI, 3.20%-3.59%]; NNH = 29 [95% CI, 28-31]; P < .001). The association between major bleeding and in-hospital mortality was observed in all strata of preprocedural bleeding risk (low: 1.62% vs 0.17%; risk difference, 1.45% [95% CI, 1.13%-1.77%], NNH = 69 [95% CI, 57-88], P < .001; intermediate: 3.27% vs 0.71%; risk difference, 2.56% [95% CI, 2.33%-2.79%], NNH = 39 [95% CI, 36-43], P < .001; and high: 8.16% vs 3.45%; risk difference, 4.71% [95% CI, 4.35%-5.07%], NNH = 21 [95% CI, 20-23], P < .001). Although both access-site and non-access-site bleeding were associated with increased in-hospital mortality (2.73% vs 1.87%; risk difference, 0.86% [95% CI, 0.66%-1.05%], NNH = 117 [95% CI, 95-151], P < .001; and 8.25% vs 1.87%; risk difference, 6.39% [95% CI, 6.04%-6.73%], NNH = 16 [95% CI, 15-17], P < .001, respectively), the NNH was lower for nonaccess bleeding., Conclusions and Relevance: In a large registry of patients undergoing PCI, postprocedural bleeding events were associated with increased risk of in-hospital mortality, with an estimated 12.1% of deaths related to bleeding complications.

Objectives: The authors sought to describe the association between post-procedural bleeding and long-term recurrent bleeding, major adverse cardiac events (MACE), and mortality among older patients undergoing percutaneous coronary intervention (PCI)., Background: Bleeding complications after PCI are associated with an increased risk for acute morbidity and long-term mortality, but the association of these bleeding complications with other events is unknown., Methods: Patients entered into the National Cardiovascular Data Registry (NCDR) CathPCI Registry (n = 461,311; 946 sites) from January 2004 to December 2008 were linked with claims from the Centers for Medicare & Medicaid Services and grouped according to in-hospital post-PCI bleeding. The association between post-PCI bleeding and 1-, 12-, and 30-month readmission for bleeding, MACE, and all-cause mortality was examined with Cox regression that included patient and procedural characteristics using no bleeding as the reference., Results: Overall, 3.1% (n = 14,107) of patients experienced post-PCI bleeding. Patients who bled were older, more often female, had more medical comorbidities, less often received bivalirudin, and more often underwent PCI via the femoral approach. After adjustment, bleeding after the index procedure was significantly associated with readmission for bleeding (adjusted hazard ratios [95% confidence interval]: 1 month, 1.54 [1.42 to 1.67]; 12 months, 1.52 [1.40 to 1.66]; 30 months, 1.29 [1.11 to 1.50]), MACE (1 month, 1.11 [1.07 to 1.15]; 12 months, 1.17 [1.13 to 1.21]; 30 months, 1.12 [1.06 to 1.19]) and all-cause mortality (1 month, 1.32 [1.26 to 1.38]; 12 months, 1.33 [1.27 to 1.40]); 30 months, 1.22 [1.15 to 1.30])., Conclusions: Post-PCI bleeding complications are associated with an increased risk for short- and long-term recurrent bleeding, MACE, and all-cause mortality. These data underscore the prognostic importance of periprocedural bleeding and the need for identifying strategies to reduce long-term bleeding risk among patients undergoing PCI., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: Bleeding complications have been associated with short-term mortality in patients with non-ST-segment elevation myocardial infarction (NSTEMI). Their association with long-term outcomes is less clear. This study examines mortality associated with in-hospital bleeding during NSTEMI over time intervals starting from hospital discharge and extending past 3 years., Methods and Results: We studied 32 895 NSTEMI patients aged ≥65 years, using patient-level data from the CRUSADE registry linked with Medicare claims data. We assessed the association of in-hospital major bleeding with short (30 days), intermediate (1 year), and long-term (3 years) mortality among hospital survivors overall, as well as in those patients treated with or without a percutaneous coronary intervention (PCI). We calculated adjusted hazard ratios (HRs) for mortality for bleeders vs. non-bleeders over time intervals from: (i) discharge to 30 days; (ii) 31 days to 1 year; (iii) 1 year to 3 years; and (iv) beyond 3 years. Overall, 11.9% (n = 3902) had an in-hospital major bleeding event. Cumulative mortality was higher in those who had a major bleed vs. those without at 30 days, 1 year, and 3 years. Even after adjustment, major bleeding continued to be significantly associated with higher mortality over time in the overall population: (i) discharge to 30 days [adjusted HR 1.33; 95% confidence interval (CI) 1.18-1.51]; (ii) 31 days to 1 year (1.19; 95% CI 1.10-1.29); (iii) 1 year to 3 years (1.09; 95% CI 1.01-1.18), and (iv) attenuating beyond 3 years (1.14; 95% CI 0.99-1.31). In-hospital bleeding among patients treated with PCI continued to be significantly associated with higher adjusted mortality even beyond 3 years (1.25; 95% CI 1.01-1.54)., Conclusion: In-hospital major bleeding is associated with short-, intermediate-, and long-term mortality among older patients hospitalized for NSTEMI-this association is strongest within the first 30 days, but remains significant long term, particularly among PCI-treated patients. Despite a probable early hazard related to bleeding, the longer duration of risk in patients who bleed casts doubt on its causal relationship with long-term mortality. Rather, major bleeding likely identifies patients with an underlying risk for mortality.

Objectives: The purpose of this study was to examine temporal trends in post-percutaneous coronary intervention (PCI) bleeding among patients with elective PCI, unstable angina (UA)/non-ST-segment elevation myocardial infarction (NSTEMI), and ST-segment elevation myocardial infarction (STEMI)., Background: The impact of bleeding avoidance strategies on post-PCI bleeding rates over time is unknown., Methods: Using the CathPCI Registry, we examined temporal trends in post-PCI bleeding from 2005 to 2009 among patients with elective PCI (n = 599,524), UA/NSTEMI (n = 836,103), and STEMI (n = 267,632). We quantified the linear time trend in bleeding using 3 sequential logistic regression models: 1) clinical factors; 2) clinical + vascular access strategies (femoral vs. radial, use of closure devices); and 3) clinical, vascular strategies + antithrombotic treatments (anticoagulant ± glycoprotein IIb/IIIa inhibitor [GPI]). Changes in the odds ratio for time trend in bleeding were compared using bootstrapping and converted to risk ratio., Results: An approximate 20% reduction in post-PCI bleeding was seen (elective PCI: 1.4% to 1.1%; UA/NSTEMI: 2.3% to 1.8; STEMI: 4.9% to 4.5%). Radial approach remained low (<3%), and closure device use increased marginally from 44% to 49%. Bivalirudin use increased (17% to 30%), whereas any heparin + GPI decreased (41% to 28%). There was a significant 6% to 8% per year reduction in annual bleeding risk in UA/NSTEMI and elective PCI, but not in STEMI. Antithrombotic strategies were associated with roughly half of the reduction in annual bleeding risk: change in risk ratio from 7.5% to 4% for elective PCI, and 5.7% to 2.8% for UA/NSTEMI (both p <0.001)., Conclusions: The nearly 20% reduction in post-PCI bleeding over time was largely due to temporal changes in antithrombotic strategies. Further reductions in bleeding complications may be possible as bleeding avoidance strategies evolve, especially in STEMI., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Prior studies have suggested that blacks with acute ST-segment-elevation myocardial infarction have increased bleeding risks with fibrinolysis relative to whites, yet these data were quite limited. Additionally, it is unknown whether there are racial differences in bleeding risks among patients with ST-segment-elevation myocardial infarction receiving primary percutaneous coronary intervention., Methods and Results: We evaluated data on blacks and whites with ST-segment-elevation myocardial infarction treated with either fibrinolysis or primary percutaneous coronary intervention from the National Registry of Myocardial Infarction (NRMI)-4 and 5 participating centers between July 2000 and December 2006. We compared differences between the 2 groups in rates of in-hospital major bleeding and mortality, adjusted with logistic regression analyses. In fibrinolytic-treated patients with ST-segment-elevation myocardial infarction, the bleeding rates were higher among blacks (n=2283) than whites (n=42 243; 10.9% versus 10.3%; adjusted odds ratio, 1.21; 95% confidence interval, 1.02-1.43). Similarly, in patients receiving primary percutaneous coronary intervention, the bleeding rates were higher in blacks (n=2826) than in whites (n=46 332; 10.3% versus 7.8%; adjusted odds ratio, 1.33; 95% confidence interval, 1.13-1.56). Bleeding was associated with higher risk of death in both ethnic groups. However, there was no overall racial difference in in-hospital mortality among those with bleeding or without bleeding treated with either fibrinolysis or primary percutaneous coronary intervention., Conclusions: Blacks with ST-segment-elevation myocardial infarction treated with either fibrinolysis or primary percutaneous coronary intervention had a higher risk of bleeding events than their white counterparts. Bleeding was associated with a similar increased risk of death in both ethnic groups treated by either reperfusion strategy.

Antiplatelet therapy serves an important role in the management of acute coronary syndromes and in reducing the risk of thrombotic complications from atrial fibrillation. There has been rapid development of newer and more potent antiplatelet therapies over the last several years that have further reduced ischemic complications, but with a trade-off of increased bleeding risk. Bleeding complications associated with antiplatelet and anticoagulant therapies are associated with significantly increased risk of adverse outcomes, including death. Understanding the risk of bleeding associated with antiplatelet agents is critical to developing strategies to mitigate this risk., (Copyright © 2012 S. Karger AG, Basel.)

Acute coronary syndromes (ACS) continue to have a large impact on morbidity and mortality in the United States. Over the last two decades, there have been several advancements in the care of patients with ACS. The use of combined antiplatelet and anticoagulants and early invasive risk stratification in high risk patients has improved the rates of major adverse cardiovascular events. However, this treatment strategy increases the risk for bleeding. Studies have found an association between bleeding and subsequent mortality and morbidity in ACS patients; therefore, minimizing bleeding risk has become a priority. This review describes the prevalence of bleeding during ACS management, risk for bleeding, and strategies to reduce bleeding risk.

Bleeding has recently emerged as an important outcome in the management of acute coronary syndromes (ACS), which is relatively frequent compared with ischaemic outcomes and has important implications in terms of prognosis, outcomes, and costs. In particular, there is evidence that patients experiencing major bleeding in the acute phase are at higher risk for death in the following months, although the causal nature of this relation is still debated. This position paper aims to summarize current knowledge regarding the epidemiology of bleeding in ACS and percutaneous coronary intervention, including measurement and definitions of bleeding, with emphasis on the recent consensus Bleeding Academic Research Consortium (BARC) definitions. It also provides an European perspective on management strategies to minimize the rate, extent, and consequences of bleeding. Finally, the research implications of bleeding (measuring and reporting bleeding in trials, the importance of bleeding as an outcome measure, and bleeding as a subject for future research) are also discussed.

Bleeding complications after coronary intervention are associated with prolonged hospitalization, increased hospital costs, patient dissatisfaction, morbidity, and 1-year mortality. Bleeding avoidance strategies is a term incorporating multiple modalities that aim to reduce bleeding and vascular complications after cardiovascular catheterization. Recent improvements in the rates of bleeding complications after invasive cardiovascular procedures suggest that the clinical community has successfully embraced specific strategies and improved patient care in this area. There remains controversy regarding the efficacy, safety, and/or practicality of 3 key bleeding avoidance strategies for cardiac catheterization and coronary intervention: procedural (radial artery approach, safezone arteriotomy), pharmacological (multiple agents), and technological (vascular closure devices) approaches to improved access. In this paper, we address areas of consensus with respect to selected modalities in order to define the role of each strategy in current practice. Furthermore, we focus on areas of controversy for selected modalities in order to define key areas warranting cautious clinical approaches and the need for future randomized clinical trials in this area., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to evaluate the relative frequency of access and nonaccess site bleeding, the association of these events with 1-year mortality, and the impact of randomized antithrombotic therapy., Background: Post-percutaneous coronary intervention (PCI) bleeding has been strongly associated with subsequent mortality. The extent to which access versus nonaccess site bleeding contributes to this poor prognosis and the role of antithrombotic therapies remains poorly understood., Methods: The incidence and impact of Thrombolysis In Myocardial Infarction (TIMI) major/minor 30-day bleeding and randomized antithrombotic therapy were examined in a combined dataset from the REPLACE-2 (Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events), Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY), and HORIZONS-AMI (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction) trials in 17,393 PCI patients., Results: The TIMI major/minor bleeding occurred in 5.3% of patients, 61.4% of which (3.3%) were nonaccess site bleeds. After multivariable adjustment, TIMI bleeding was associated with an increased risk of 1-year mortality (hazard ratio [HR]: 3.17, 95% confidence interval [CI]: 2.51 to 4.00, p < 0.0001). The HR of a nonaccess site bleed was approximately 2-fold that of an access site bleed: HR: 3.94, 95% CI: 3.07 to 5.15, p < 0.0001 versus HR: 1.82, 95% CI: 1.17 to 2.83, p = 0.008, respectively. Randomization to bivalirudin versus heparin + a glycoprotein IIb/IIIa inhibitor resulted in 38% and 43% relative reductions in TIMI major/minor and TIMI major bleeding, respectively (p < 0.0001 for both), with significant reductions in both access and nonaccess site bleeding., Conclusions: Nonaccess site bleeding after PCI is common, representing approximately two-thirds of all TIMI bleeding events, and is associated with a 4-fold increase in 1-year mortality. Use of bivalirudin rather than heparin + a glycoprotein IIb/IIIa inhibitor significantly decreases both nonaccess site as well as access site bleeding events by approximately 40%., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: studies have shown higher bleeding and mortality rates among African Americans who receive fibrinolytic therapy for ST-segment elevation myocardial infarction (STEMI) compared with whites; however, the relationship of bleeding risk to mortality has not been evaluated., Methods: we studied data from 32,260 STEMI patients receiving fibrinolysis enrolled in the US in 5 clinical trials. Bleeding was defined according to criteria from the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries study. Main outcome measure was adjusted 1-year mortality., Results: despite younger age (median: 57 years vs 61 years) and fewer comorbidities, moderate or severe bleeding occurred more frequently among African-Americans than whites (16.3% vs 14.1%; P=.0147, adjusted OR 1.36; 95% confidence interval [CI], 1.14-1.62; P=.0006) as did 1-year mortality (11.5% vs 9.4%). African-American race and moderate or severe bleeding were independently related to 1-year mortality (χ(2) 9.02, P=.0003 and 148.58, P<.0001, respectively). Mortality was highest among African Americans with bleeding (hazard ratio [HR] 2.83; 95% CI, 2.08-3.86) followed by whites with bleeding (HR 1.99; 95% CI, 1.78-2.22) and African Americans without bleeding (HR 1.33; 95% CI, 1.02-1.73) (referent whites without bleeding)., Conclusions: in STEMI patients receiving fibrinolysis, moderate or severe bleeding and mortality were significantly higher in African Americans compared with whites. Bleeding was associated with similarly increased mortality risk in both groups., (2011 Elsevier Inc. All rights reserved.)

Background: Major bleeding during an acute coronary syndrome (ACS) is associated with increased late ischemic events. Patients with bleeding are often discharged without antiplatelet therapy (AT). The association between discharge AT use and late ischemic outcomes among ACS patients with bleeding is uncertain., Methods: We examined discharge AT use among 8,582 ACS patients with in-hospital bleeding from a total of 26,451 patients enrolled in 4 randomized trials. After adjusting for the propensity to receive AT, we compared 6-month postdischarge outcomes between patients discharged with and those discharged without AT., Results: Almost 1 in 10 patients with bleeding was discharged without AT (n=826). Compared with those receiving discharge AT, those not receiving discharge AT had a higher risk of 6-month death, myocardial infarction, and stroke (14.3% vs 7.8%, propensity-adjusted hazard ratio [HR]=1.36, 95% confidence interval=1.01-1.85). Nonuse of AT at discharge was associated with worse outcomes among patients treated with percutaneous coronary intervention compared with those treated without it (adjusted HR=4.22 vs 1.13, interaction P=.0003). Discharge monotherapy was associated with worse outcomes than dual AT among patients receiving stents (adjusted HR=1.78, 95% CI=1.04-3.03)., Conclusions: Bleeding occurred commonly among patients with ACS. AT was often not used in these patients at discharge, and lack of discharge AT was associated with an increased risk of 6-month ischemic events. These data raise the possibility that lack of AT use among patients with in-hospital bleeding may contribute to their excess risk of long-term ischemic outcomes., (Copyright © 2010 Mosby, Inc. All rights reserved.)

The use of glycoprotein IIb/IIIa inhibitors (GPI) reduces ischemic events in patients undergoing percutaneous coronary intervention (PCI). However, the same properties that confer this benefit lead to an increased bleeding risk. Recent studies have shown a less robust net clinical benefit of GPI in the current era of routine thienopyridine and direct thrombin inhibitor use. To optimize the net clinical benefit of GPI, these agents need to be selectively used in patients most likely to benefit from their anti-ischemic effect, namely patients undergoing PCI for non-ST-segment elevation myocardial infarction, select patients undergoing primary PCI, and select patients undergoing PCI without appropriate pre-loading with a thienopyridine. Moreover, strategies to minimize bleeding should be applied in these patients and include shorter GPI infusions (in some patients), dose adjustments of heparin and GPI, careful access site management with more frequent use of the transradial approach, use of smaller sheaths, and identification of patients at high bleeding risk. This review provides an update of the current literature that supports these measures, an insight on the tailored use of GPI, and a potential direction for future research addressing combined antithrombotic therapies., (Copyright © 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Coronary artery plaque rupture results in platelet adhesion and activation, the release of adenosine diphosphate (ADP), thromboxane A(2), and the generation of thrombin. These factors propagate further platelet activation through a positive feedback mechanism, resulting in the formation of a platelet plug. The treatment of patients with ACS is centered upon the prompt initiation of both antiplatelet and anticoagulant agents. The widespread use of antiplatelet and anticoagulant agents has resulted in a significant reduction in morbidity and mortality but has also increased the risk for bleeding complications. Female gender, advanced age, low body mass index (BMI), low creatinine clearance, and the use of percutaneous coronary intervention have been consistently shown to be risk factors for bleeding. While bleeding was thought to be a necessary side effect and of little clinical significance in the past, it is now clear that bleeding is an independent predictor of adverse ischemic events and mortality. The mechanisms underlying this relationship are not yet fully elucidated and are likely multifactorial (direct effects of bleeding, increased incidence of blood transfusions, less use of antiplatelet agents in both the short and long term). Current treatment guidelines for the use of antithrombotic therapy recommend utilization of evidence-based therapies using clinical strategies shown to minimize the risk of bleeding should when possible. Novel therapies that minimize bleeding risk while providing protection against thrombotic events are needed and may improve outcomes among patients with ACS. Multiple platelet activation pathways and the coagulation cascade regulate hemostasis and thrombosis. Current antiplatelet and anticoagulant therapies for acute coronary syndromes (ACS) act on distinct sites in the pathways for platelet activation and coagulation. While these therapies are effective in reducing the morbidity and mortality associated with ACS, they are associated with a clinically significant increase in the risk of bleeding events. Novel therapies that minimize bleeding risk while providing protection against thrombotic events may improve outcomes in patients with ACS.

Context: The optimal unfractionated heparin regimen for percutaneous coronary intervention (PCI) in patients with non-ST-segment elevation acute coronary syndromes treated with fondaparinux is uncertain., Objective: To compare the safety of 2 unfractionated heparin regimens during PCI in high-risk patients with non-ST-segment elevation acute coronary syndromes initially treated with fondaparinux., Design, Setting, and Participants: Double-blind randomized parallel-group trial in 179 hospitals in 18 countries involving 2026 patients undergoing PCI within 72 hours, nested within a cohort of 3235 high-risk patients with non-ST-segment elevation acute coronary syndromes initially treated with fondaparinux enrolled from February 2009 to March 2010., Interventions: Patients received intravenously either low-dose unfractionated heparin, 50 U/kg, regardless of use of glycoprotein IIb/IIIa (GpIIb-IIIa) inhibitors or standard-dose unfractionated heparin, 85 U/kg (60 U/kg with GpIIb-IIIa inhibitors), adjusted by blinded activated clotting time (ACT)., Main Outcome Measures: Composite of major bleeding, minor bleeding, or major vascular access-site complications up to 48 hours after PCI. Key secondary outcomes include composite of major bleeding at 48 hours with death, myocardial infarction, or target vessel revascularization within day 30., Results: The primary outcome occurred in 4.7% of those in the low-dose group vs 5.8% in the standard-dose group (odds ratio [OR], 0.80; 95% confidence interval [CI], 0.54-1.19; P = .27). The rates of major bleeding were not different but the rates of minor bleeding were lower with 0.7% in the low-dose group vs 1.7% in the standard-dose group (OR, 0.40; 95% CI, 0.16-0.97; P = .04). For the key secondary outcome, the rates for low-dose group were 5.8% vs 3.9% in the standard-dose group (OR, 1.51; 95% CI, 1.00-2.28; P = .05) and for death, myocardial infarction, or target vessel revascularization it was 4.5% for the low-dose group vs 2.9% for the standard-dose group (OR, 1.58; 95% CI, 0.98-2.53; P = .06). Catheter thrombus rates were very low (0.5% in the low-dose group and 0.1% in the standard-dose group, P = .15)., Conclusion: Low-dose compared with standard-dose unfractionated heparin did not reduce major peri-PCI bleeding and vascular access-site complications., Trial Registration: clinicaltrials.gov Identifier: NCT00790907.

Background: Although bivalirudin compared with unfractionated heparin with glycoprotein IIb/IIIa inhibitors reduces bleeding and hospitalization costs in patients undergoing percutaneous coronary intervention (PCI), little is known about the economic impact of bivalirudin versus heparin alone and at what threshold of procedural bleeding risk bivalirudin would be considered cost-effective., Methods and Results: A validated model was used to predict risk of major bleeding for 81,628 National Cardiovascular Data Registry (NCDR) CathPCI Registry patients from 2004 to 2006 who received unfractionated heparin only. Costs were derived from multiple sources including wholesale acquisition costs (for drugs) and single-center data (for PCI-related complications). Based on ISAR-REACT 3, we assumed that bivalirudin would reduce the risk of major bleeding by 33% compared with unfractionated heparin alone. A Markov model was used to estimate lost life expectancy associated with a major bleed. Major bleeding was predicted to occur in 2.2% of patients. Bivalirudin for all patients was estimated to increase costs by $571 per patient, yielding cost-effectiveness ratios of $287,473 per bleeding event averted and $1,173,360 per quality-adjusted life-year gained. Bivalirudin was cost saving for patients with a predicted bleeding risk >20% (0.16% of CathPCI population). At willingness-to-pay thresholds of $50K and $100K per quality-adjusted life-year gained, bivalirudin was cost-effective for patients with a bleeding risk > or = 8% (2.5% patients) and > or = 5% (7.9% patients), respectively., Conclusions: This decision-analytic modeling study demonstrates that for patients undergoing PCI, substitution of bivalirudin for unfractionated heparin monotherapy is projected to increase costs for virtually all patients and would be considered cost-effective for only a minority of patients with a high bleeding risk. From a policy standpoint, studies such as this, aimed at identifying the appropriate risk threshold for initiating treatment, may help in the development of informed guidelines for the use of expensive therapies.

Context: Bleeding complications with percutaneous coronary intervention (PCI) are associated with adverse patient outcomes. The association between the use of bleeding avoidance strategies and post-PCI bleeding as a function of a patient's preprocedural risk of bleeding is unknown., Objective: To describe the use of 2 bleeding avoidance strategies, vascular closure devices and bivalirudin, and associated post-PCI bleeding rates in a nationally representative PCI population., Design, Setting, and Patients: Analysis of data from 1,522,935 patients undergoing PCI procedures performed at 955 US hospitals participating in the National Cardiovascular Data Registry (NCDR) CathPCI Registry from January 1, 2004, through September 30, 2008., Main Outcome Measure: Periprocedural bleeding., Results: Bleeding occurred in 30,654 patients (2%). Manual compression, vascular closure devices, bivalirudin, or vascular closure devices plus bivalirudin were used in 35%, 24%, 23%, and 18% of patients, respectively. Bleeding events were reported in 2.8% of patients who received manual compression, compared with 2.1%, 1.6%, and 0.9% of patients receiving vascular closure devices, bivalirudin, and both strategies, respectively (P < .001). Bleeding rates differed by preprocedural risk assessed with the NCDR bleeding risk model (low risk, 0.72%; intermediate risk, 1.73%; high risk, 4.69%). In high-risk patients, use of both strategies was associated with lower bleeding rates (manual compression, 6.1%; vascular closure devices, 4.6%; bivalirudin, 3.8%; vascular closure devices plus bivalirudin, 2.3%; P < .001). This association persisted following adjustment using a propensity-matched and site-controlled model. Use of both strategies was used least often in high-risk patients (14.4% vs 21.0% in low-risk patients, P < .001)., Conclusions: In a large national PCI registry, vascular closure devices and bivalirudin were associated with significantly lower bleeding rates, particularly among patients at greatest risk for bleeding. However, these strategies were less often used among higher-risk patients.