Sunil V. Rao

Standardized Bleeding Definitions for Cardiovascular Clinical Trials A Consensus Report From the Bleeding Academic Research Consortium

Advances in antithrombotic therapy, along with an early invasive strategy, have reduced the incidence of recurrent ischemic events and death in patients with acute coronary syndromes (ACS; unstable angina, non–ST-segment–elevation myocardial infarction [MI], and ST-segment–elevation MI).1,–,4 However, the combination of multiple pharmacotherapies, including aspirin, platelet P2Y12 inhibitors, heparin plus glycoprotein IIb/IIIa inhibitors, direct thrombin inhibitors, and the increasing use of invasive procedures, has also been associated with an increased risk of bleeding. Editorial see p 2664 Bleeding complications have been associated with an increased risk of subsequent adverse outcomes, including MI, stroke, stent thrombosis, and death, in patients with ACS and in those undergoing percutaneous coronary intervention (PCI),5,–,10 as well as in the long-term antithrombotic setting.11,12 Thus, balancing the anti-ischemic benefits against the bleeding risk of antithrombotic agents and interventions is of paramount importance in assessing new therapies and in managing patients. Prior randomized trials comparing antithrombotic agents suggest that a reduction in bleeding events is associated with improved survival.13,14 Because prevention of major bleeding may represent an important step in improving outcomes by balancing safety and efficacy in the contemporary treatment of ACS, bleeding events have been systematically identified as a crucial end point for the assessment of the safety of drugs during the course of randomized clinical trials, and are an important aspect of the evaluation of new devices and interventional therapies.15 Unlike ischemic clinical events (eg, cardiac death, MI, stent thrombosis), for which there is now general consensus on end-point definitions,16,17 there is substantial heterogeneity among the many bleeding definitions currently in use. Lack of standardization makes it difficult to optimally organize key clinical trial processes such as adjudication, and even more difficult to interpret relative …

Radial versus femoral access for coronary angiography and intervention in patients with acute coronary syndromes (RIVAL): a randomised, parallel group, multicentre trial

BACKGROUND Small trials have suggested that radial access for percutaneous coronary intervention (PCI) reduces vascular complications and bleeding compared with femoral access. We aimed to assess whether radial access was superior to femoral access in patients with acute coronary syndromes (ACS) who were undergoing coronary angiography with possible intervention. METHODS The RadIal Vs femorAL access for coronary intervention (RIVAL) trial was a randomised, parallel group, multicentre trial. Patients with ACS were randomly assigned (1:1) by a 24 h computerised central automated voice response system to radial or femoral artery access. The primary outcome was a composite of death, myocardial infarction, stroke, or non-coronary artery bypass graft (non-CABG)-related major bleeding at 30 days. Key secondary outcomes were death, myocardial infarction, or stroke; and non-CABG-related major bleeding at 30 days. A masked central committee adjudicated the primary outcome, components of the primary outcome, and stent thrombosis. All other outcomes were as reported by the investigators. Patients and investigators were not masked to treatment allocation. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, NCT01014273. FINDINGS Between June 6, 2006, and Nov 3, 2010, 7021 patients were enrolled from 158 hospitals in 32 countries. 3507 patients were randomly assigned to radial access and 3514 to femoral access. The primary outcome occurred in 128 (3·7%) of 3507 patients in the radial access group compared with 139 (4·0%) of 3514 in the femoral access group (hazard ratio [HR] 0·92, 95% CI 0·72-1·17; p=0·50). Of the six prespecified subgroups, there was a significant interaction for the primary outcome with benefit for radial access in highest tertile volume radial centres (HR 0·49, 95% CI 0·28-0·87; p=0·015) and in patients with ST-segment elevation myocardial infarction (0·60, 0·38-0·94; p=0·026). The rate of death, myocardial infarction, or stroke at 30 days was 112 (3·2%) of 3507 patients in the radial group compared with 114 (3·2%) of 3514 in the femoral group (HR 0·98, 95% CI 0·76-1·28; p=0·90). The rate of non-CABG-related major bleeding at 30 days was 24 (0·7%) of 3507 patients in the radial group compared with 33 (0·9%) of 3514 patients in the femoral group (HR 0·73, 95% CI 0·43-1·23; p=0·23). At 30 days, 42 of 3507 patients in the radial group had large haematoma compared with 106 of 3514 in the femoral group (HR 0·40, 95% CI 0·28-0·57; p<0·0001). Pseudoaneurysm needing closure occurred in seven of 3507 patients in the radial group compared with 23 of 3514 in the femoral group (HR 0·30, 95% CI 0·13-0·71; p=0·006). INTERPRETATION Radial and femoral approaches are both safe and effective for PCI. However, the lower rate of local vascular complications may be a reason to use the radial approach. FUNDING Sanofi-Aventis, Population Health Research Institute, and Canadian Network for Trials Internationally (CANNeCTIN), an initiative of the Canadian Institutes of Health Research.

Red blood cell transfusion: A Clinical practice guideline from the AABB

DESCRIPTION Although approximately 85 million units of red blood cells (RBCs) are transfused annually worldwide, transfusion practices vary widely. The AABB (formerly, the American Association of Blood Banks) developed this guideline to provide clinical recommendations about hemoglobin concentration thresholds and other clinical variables that trigger RBC transfusions in hemodynamically stable adults and children. METHODS These guidelines are based on a systematic review of randomized clinical trials evaluating transfusion thresholds. We performed a literature search from 1950 to February 2011 with no language restrictions. We examined the proportion of patients who received any RBC transfusion and the number of RBC units transfused to describe the effect of restrictive transfusion strategies on RBC use. To determine the clinical consequences of restrictive transfusion strategies, we examined overall mortality, nonfatal myocardial infarction, cardiac events, pulmonary edema, stroke, thromboembolism, renal failure, infection, hemorrhage, mental confusion, functional recovery, and length of hospital stay. RECOMMENDATION 1: The AABB recommends adhering to a restrictive transfusion strategy (7 to 8 g/dL) in hospitalized, stable patients (Grade: strong recommendation; high-quality evidence). RECOMMENDATION 2: The AABB suggests adhering to a restrictive strategy in hospitalized patients with preexisting cardiovascular disease and considering transfusion for patients with symptoms or a hemoglobin level of 8 g/dL or less (Grade: weak recommendation; moderate-quality evidence). RECOMMENDATION 3: The AABB cannot recommend for or against a liberal or restrictive transfusion threshold for hospitalized, hemodynamically stable patients with the acute coronary syndrome (Grade: uncertain recommendation; very low-quality evidence). RECOMMENDATION 4: The AABB suggests that transfusion decisions be influenced by symptoms as well as hemoglobin concentration (Grade: weak recommendation; low-quality evidence).

Baseline Risk of Major Bleeding in Non–ST-Segment–Elevation Myocardial Infarction The CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines) Bleeding Score

Treatment of non–ST-segment elevation myocardial infarction (NSTEMI) has traditionally focused on preventing or minimizing ischemic complications with potent antithrombotic medications and catheter-based interventions.1–3 Yet these reductions in recurrent ischemic events have come at the cost of increased major bleeding,4–7 which is itself associated with worse clinical outcomes.7–13 Bleeding complications have received attention recently, in part because newer antithrombotic agents for NSTEMI have unique ischemia and bleeding profiles. Some agents demonstrate low rates of major bleeding with similar efficacy,5,14 while others demonstrate higher rates of major bleeding with superior efficacy.15 Given the importance of safety and efficacy,12 the recent American College of Cardiology (ACC)/American Heart Association (AHA) practice guidelines placed renewed emphasis on risk stratification to guide treatment for NSTEMI.3 While tools for ischemic risk stratification are well described (i.e., TIMI, PURSUIT, and GRACE risk scores),16–18 bleeding risk stratification is more limited. The few bleeding risk stratification models in existence include treatments known to influence bleeding or are derived from subgroups or trial populations not representative of those at greatest risk.10,13,19 Consequently, better estimation of baseline risk of bleeding in NSTEMI patients is needed to facilitate optimal treatment selection. Using data from the Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines (CRUSADE) Quality Improvement Initiative, we developed and validated a scoring system to estimate baseline risk of in-hospital major bleeding in patients with NSTEMI. The CRUSADE bleeding score provides a tool that equips clinicians with the means to consider safety outcomes when making treatment decisions for patients with NSTEMI.Background— Treatments for non–ST-segment–elevation myocardial infarction (NSTEMI) reduce ischemic events but increase bleeding. Baseline prediction of bleeding risk can complement ischemic risk prediction for optimization of NSTEMI care; however, existing models are not well suited for this purpose. Methods and Results— We developed (n=71 277) and validated (n=17 857) a model that identifies 8 independent baseline predictors of in-hospital major bleeding among community-treated NSTEMI patients enrolled in the Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines (CRUSADE) Quality Improvement Initiative. Model performance was tested by c statistics in the derivation and validation cohorts and according to postadmission treatment (ie, invasive and antithrombotic therapy). The CRUSADE bleeding score (range 1 to 100 points) was created by assignment of weighted integers that corresponded to the coefficient of each variable. The rate of major bleeding increased by bleeding risk score quintiles: 3.1% for those at very low risk (score ≤20); 5.5% for those at low risk (score 21–30); 8.6% for those at moderate risk (score 31–40); 11.9% for those at high risk (score 41–50); and 19.5% for those at very high risk (score >50; Ptrend <0.001). The c statistics for the major bleeding model (derivation=0.72 and validation=0.71) and risk score (derivation=0.71 and validation=0.70) were similar. The c statistics for the model among treatment subgroups were as follows: ≥2 antithrombotics=0.72; <2 antithrombotics=0.73; invasive approach=0.73; conservative approach=0.68. Conclusions— The CRUSADE bleeding score quantifies risk for in-hospital major bleeding across all postadmission treatments, which enhances baseline risk assessment for NSTEMI care.

Consensus and Update on the Definition of On-Treatment Platelet Reactivity to Adenosine Diphosphate Associated With Ischemia and Bleeding

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.

Trends in the Prevalence and Outcomes of Radial and Femoral Approaches to Percutaneous Coronary Intervention: A Report From the National Cardiovascular Data Registry

OBJECTIVES Our goal was to compare trends in the prevalence and outcomes of the radial and femoral approaches to percutaneous coronary intervention (PCI) in contemporary clinical practice. BACKGROUND There are few current data on the use and outcomes of the radial approach to PCI (r-PCI) in clinical practice. METHODS Data from 593,094 procedures in the National Cardiovascular Data Registry (606 sites; 2004 to 2007) were analyzed to evaluate trends in use and outcomes of r-PCI. Logistic regression was used to evaluate the adjusted association between r-PCI and procedural success, bleeding complications, and vascular complications. Outcomes in elderly patients, women, and patients with acute coronary syndrome were specifically examined. RESULTS Although the proportion of r-PCI procedures has recently increased, it only accounts for 1.32% of total procedures (n = 7,804). Compared with the femoral approach, the use of r-PCI was associated with a similar rate of procedural success (adjusted odds ratio: 1.02 [95% confidence interval: 0.93 to 1.12]) but a significantly lower risk for bleeding complications (odds ratio: 0.42 [95% confidence interval: 0.31 to 0.56]) after multivariable adjustment. The reduction in bleeding complications was more pronounced among patients <75 years old, women, and patients undergoing PCI for acute coronary syndrome. CONCLUSIONS The use of r-PCI is rare in contemporary clinical practice, but it is associated with a rate of procedural success similar to the femoral approach and with lower rates of bleeding and vascular complications, even among high-risk groups. These results suggest that wider adoption of r-PCI in clinical practice may improve the safety of PCI.

Relation of angiographically defined coronary artery disease to plasma lipoprotein subfractions and apolipoproteins.

The relation of coronary artery disease to plasma lipoproteins was examined in 104 men aged 35-65 years undergoing coronary angiography for suspected myocardial ischaemia. A score reflecting the number, degree, and length of stenoses in seven major coronary arteries was assigned to each angiogram. Lipid concentrations in lipoprotein subfractions were measured after preparative ultracentrifugation; plasma apolipoprotein concentrations were measured by electroimmunoassay. Men with high coronary scores tended to have lower plasma high-density lipoprotein (HDL) cholesterol concentrations and higher low-density lipoprotein (density 1.019-1.063 g/ml) cholesterol concentrations than subjects of similar age with low coronary scores (p approximately equal to 0.1). The strongest relation, however, was with the cholesterol concentration in the HDL2 subfraction (density 1.063-1.125 g/ml) of HDL, which averaged 44% lower in the severely affected patients (p less than 0.005). No associations were found between the coronary score and HDL3 cholesterol, the cholesterol content of lipoproteins of density less than 1.019 g/ml, plasma triglyceride, or the concentrations of apolipoproteins AI, AII, and E. The high coronary scores associated with low HDL2 concentrations reflected an increase in the number of both partial and complete stenoses distributed throughout the coronary tree. In contrast the sizes of the lesions and the proportion producing complete occlusion were unrelated to HDL2.

Radial versus femoral access in patients with acute coronary syndromes undergoing invasive management: a randomised multicentre trial

BACKGROUND It is unclear whether radial compared with femoral access improves outcomes in unselected patients with acute coronary syndromes undergoing invasive management. METHODS We did a randomised, multicentre, superiority trial comparing transradial against transfemoral access in patients with acute coronary syndrome with or without ST-segment elevation myocardial infarction who were about to undergo coronary angiography and percutaneous coronary intervention. Patients were randomly allocated (1:1) to radial or femoral access with a web-based system. The randomisation sequence was computer generated, blocked, and stratified by use of ticagrelor or prasugrel, type of acute coronary syndrome (ST-segment elevation myocardial infarction, troponin positive or negative, non-ST-segment elevation acute coronary syndrome), and anticipated use of immediate percutaneous coronary intervention. Outcome assessors were masked to treatment allocation. The 30-day coprimary outcomes were major adverse cardiovascular events, defined as death, myocardial infarction, or stroke, and net adverse clinical events, defined as major adverse cardiovascular events or Bleeding Academic Research Consortium (BARC) major bleeding unrelated to coronary artery bypass graft surgery. The analysis was by intention to treat. The two-sided α was prespecified at 0·025. The trial is registered at ClinicalTrials.gov, number NCT01433627. FINDINGS We randomly assigned 8404 patients with acute coronary syndrome, with or without ST-segment elevation, to radial (4197) or femoral (4207) access for coronary angiography and percutaneous coronary intervention. 369 (8·8%) patients with radial access had major adverse cardiovascular events, compared with 429 (10·3%) patients with femoral access (rate ratio [RR] 0·85, 95% CI 0·74-0·99; p=0·0307), non-significant at α of 0·025. 410 (9·8%) patients with radial access had net adverse clinical events compared with 486 (11·7%) patients with femoral access (0·83, 95% CI 0·73-0·96; p=0·0092). The difference was driven by BARC major bleeding unrelated to coronary artery bypass graft surgery (1·6% vs 2·3%, RR 0·67, 95% CI 0·49-0·92; p=0·013) and all-cause mortality (1·6% vs 2·2%, RR 0·72, 95% CI 0·53-0·99; p=0·045). INTERPRETATION In patients with acute coronary syndrome undergoing invasive management, radial as compared with femoral access reduces net adverse clinical events, through a reduction in major bleeding and all-cause mortality. FUNDING The Medicines Company and Terumo.

Contemporary mortality risk prediction for percutaneous coronary intervention: results from 588,398 procedures in the National Cardiovascular Data Registry.

OBJECTIVES We sought to create contemporary models for predicting mortality risk following percutaneous coronary intervention (PCI). BACKGROUND There is a need to identify PCI risk factors and accurately quantify procedural risks to facilitate comparative effectiveness research, provider comparisons, and informed patient decision making. METHODS Data from 181,775 procedures performed from January 2004 to March 2006 were used to develop risk models based on pre-procedural and/or angiographic factors using logistic regression. These models were independently evaluated in 2 validation cohorts: contemporary (n = 121,183, January 2004 to March 2006) and prospective (n = 285,440, March 2006 to March 2007). RESULTS Overall, PCI in-hospital mortality was 1.27%, ranging from 0.65% in elective PCI to 4.81% in ST-segment elevation myocardial infarction patients. Multiple pre-procedural clinical factors were significantly associated with in-hospital mortality. Angiographic variables provided only modest incremental information to pre-procedural risk assessments. The overall National Cardiovascular Data Registry (NCDR) model, as well as a simplified NCDR risk score (based on 8 key pre-procedure factors), had excellent discrimination (c-index: 0.93 and 0.91, respectively). Discrimination and calibration of both risk tools were retained among specific patient subgroups, in the validation samples, and when used to estimate 30-day mortality rates among Medicare patients. CONCLUSIONS Risks for early mortality following PCI can be accurately predicted in contemporary practice. Incorporation of such risk tools should facilitate research, clinical decisions, and policy applications.

Transradial Approach for Coronary Angiography and Interventions: Results of the First International Transradial Practice Survey

OBJECTIVES The aim of this study was to evaluate practice of transradial approach (TRA). BACKGROUND TRA has been adopted as an alternative access site for coronary procedures. METHODS A questionnaire was distributed worldwide with Internet-based software. RESULTS The survey was conducted from August 2009 to January 2010 among 1,107 interventional cardiologists in 75 countries. Although pre-TRA dual hand circulation testing is not uniform in the world, >85% in the U.S. perform Allen or oximetry testing. Right radial artery is used in almost 90%. Judkins catheters are the most popular for left coronary artery angiographies (66.5%) and right coronary artery angiographies (58.8%). For percutaneous coronary intervention (PCI), 6-F is now standard. For PCI of left coronary artery, operators use standard extra back-up guiding catheters in >65% and, for right coronary artery 70.4% use right Judkins catheters. Although heparin remains the routine antithrombotic agent in the world, bivalirudin is frequently used in the U.S. for PCI. The incidence of radial artery occlusion before hospital discharge is not assessed in >50%. Overall, approximately 50% responded that their TRA practice will increase in the future (68.4% in the U.S.). CONCLUSIONS TRA is already widely used across the world. Diagnostic and guiding-catheters used for TRA remain similar to those used for traditional femoral approach, suggesting that specialized radial catheters are not frequently used. However, there is substantial variation in practice as it relates to specific aspects of TRA, suggesting that more data are needed to determine the optimal strategy to facilitate TRA and optimize radial artery patency after catheterization.