Raban Jeger

Ten-Year Trends in the Incidence and Treatment of Cardiogenic Shock

Context Are the incidence and management of cardiogenic shock changing? Contribution This analysis of hospital registry data from Switzerland showed that rates of cardiogenic shock in patients with acute coronary syndromes declined from 1997 to 2006. Declining rates were due to decreased rates of shock development during hospitalization rather than a change in rates of shock at admission. Use of percutaneous coronary intervention increased, and in-hospital mortality decreased. Implication The incidence and mortality of cardiogenic shock in hospitalized patients in Switzerland decreased during the past decade, possibly because of changes in management of patients with acute coronary syndromes. The Editors The incidence of cardiogenic shock complicating the acute coronary syndrome (ACS) differs depending on the exact definitions of cardiogenic shock, but it has been estimated to be between 5% and 10% (1). Recent findings of population-based studies show slightly lower incidence rates of 3.2% to 8.6%, but data on temporal trends are conflicting (24). Since the implementation of guideline-recommended early revascularization for cardiogenic shock (5, 6), mortality rates have steadily decreased below 50% (2, 3). This is important because survivors of cardiogenic shock have a long-term outcome similar to that of patients without cardiogenic shock (7, 8). Although decreased mortality rates have been ascribed to improved treatment with higher rates of percutaneous coronary intervention (PCI) and intra-aortic balloon counterpulsation, a strong relationship between improved therapeutic management and lower mortality rates has not been established in population-based studies (4). Also, we still do not know whether early invasive treatment of ACS may prevent hemodynamic deterioration in patients at risk and whether temporal trends in overall cardiogenic shock rates are similar among patients with cardiogenic shock on admission and those who develop cardiogenic shock during hospitalization. The AMIS (Acute Myocardial Infarction in Switzerland) Plus Registry is a nationwide survey collecting data on hospital admissions for ACS since 1997. Using this database, we analyzed temporal trends in incidence, therapeutic management, and mortality rates of patients with cardiogenic shock during the past decade and assessed predictors of mortality and shock development during hospitalization. Our a priori hypothesis was that in-hospital mortality decreased during the past decade. Methods The AMIS Plus Registry Since 1997, 70 of the 106 acute cardiac care hospitals in Switzerland have participated in the AMIS Plus Registry (911). All participating hospitals have either a catheterization laboratory (18 hospitals) or direct access to a tertiary care center guaranteeing PCI within 90 minutes for all patients (52 hospitals). The 70 participating hospitals are a representative sample of acute care hospitals in Switzerland in terms of size, available skills, and quality grading (10, 11). The Swiss Societies of Internal Medicine, Cardiology, and Intensive Care Medicine founded the AMIS Plus Registry project. A steering committee that includes members of the founding medical societies guides the project. The Swiss National Ethical Committee for Clinical Studies and the Board for Data Security approved the registry. Data Collection Investigators at participating centers collect data for the registry by using identical Web-based or written questionnaires. The questionnaire has 140 items that address medical history, cardiovascular risk factors, symptoms, out-of-hospital management, clinical presentation, early in-hospital management, reperfusion therapy, hospital course, diagnostic tests used or planned, length of stay, and discharge medication and destination. A data coordinating center checks data for plausibility and consistency. Investigators returned incomplete questionnaires to the participating centers for completion (19% in 2003). This approach helps ensure that few data are missing (<1% overall and 0% for therapeutic interventions) (11). Patient Enrollment Patients were enrolled in the registry if their final diagnosis met 1 of the 3 following definitions: acute myocardial infarction, defined as symptoms or electrocardiographic (ECG) changes compatible with ACS (or both) and cardiac markers at least twice the upper limit of normal; ACS with minimum necrosis, defined as symptoms or ECG changes compatible with ACS (or both) and cardiac markers lower than twice the upper limit of normal but still abnormal; or unstable angina, defined as symptoms or ECG changes compatible with ACS (or both) and normal cardiac markers. In this study, we included all patients with ACS entered in the AMIS Plus Registry between 1 January 1997 and 31 December 2006 from the participating hospitals. We excluded patients with unclear or noncardiac causes of ACS. We analyzed and compared patients who had ACS and cardiogenic shock with patients who had ACS without cardiogenic shock. Definitions We classified patients who had ST-segment elevation or new left bundle-branch block on their initial ECG as having ST-segment elevation ACS. We classified patients who had ST-segment depression or T-wave abnormalities in the absence of ST-segment elevation on the initial ECG as having nonST-segment elevation ACS. Patients with cardiogenic shock were those with cardiogenic shock on admission and those who developed cardiogenic shock during hospitalization as a complication of ACS. We defined cardiogenic shock at admission and during hospitalization similarly at participating centers by using the Killip definition of hypotension (systolic blood pressure <90 mm Hg) and evidence of peripheral vasoconstriction (oliguria, cyanosis, or sweating) (12). When they became available, we advised investigators at PCI sites to follow current guidelines recommending the performance of revascularization within 36 hours after shock onset (5, 6), but we did not record the exact timing of PCI. Statistical Analysis We present descriptive statistics as means (SDs), medians with interquartile ranges, or percentages. We compared categorical variables and temporal trends by using the chi-square test and continuous variables by using the t test. Our primary outcome of interest was in-hospital death, although we also examined major adverse cardiac events during hospitalization (reinfarction, cerebrovascular events, and shock). We used multivariable logistic regression models to examine predictors of in-hospital death and predictors of cardiogenic shock development during hospitalization. We included in these models all of the following available covariates evaluated at admission: age; sex; history of coronary artery disease, hypertension, diabetes, and dyslipidemia; current smoking status; Killip class if applicable; ST-segment elevation ACS; symptom-to-admission delay greater than 6 hours; cardiopulmonary resuscitation before admission; cardioversion or defibrillation before admission; atrial fibrillation; heart rate; systolic and diastolic blood pressures; obesity (body mass index >30 kg/m2); Charlson Comorbidity Index score (13); the use of various medications, such as acetylsalicylic acid, clopidogrel, glycoprotein IIb/IIIa inhibitors, -blockers, angiotensin-converting enzyme inhibitors, lipid-lowering drugs, and thrombolytics; primary PCI; intra-aortic balloon counterpulsation; and coronary artery bypass graft surgery. We forced all candidate variables into the final models. We simultaneously adjusted odds ratios for all other predictors. We conducted analyses by using commercially available statistical software (SPSS version 14.0, SPSS, Chicago, Illinois). All P values were 2-sided and were considered statistically significant if 0.050 or less. Role of the Funding Source The AMIS Plus Registry project was supported by the following sources (all in Switzerland; then were grouped by city, rather than by grant size or any other preferential factor): Swiss Heart Foundation and Novartis Pharma Schweiz, Bern; A. Menarini, Bayer (Schweiz), Pfizer, SPSS (Schweiz), and St. Jude Medical, Zurich; AstraZeneca, Zug; Biotronik Schweiz, Bristol-Myers Squibb, and Schering, Baar; Boehringer Ingelheim (Schweiz), Basel; Boston Scientific, Solothurn; Cordis, Johnson & Johnson, Spreitenbach; GlaxoSmithKline, Mnchenbuchsee; Invatec, Schaffhausen; Medtronic Schweiz, Tolochenaz; MCM medsys, Kirchberg; Merck Sharp & Dohme Chibret, Opfikon-Glattbrugg; Nycomed Pharma, Dbendorf; Sanofi-Aventis (Suisse) and Servier (Suisse), Meyrin; and Takeda Pharma, Lachen. The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. Results Patients From January 1997 to December 2006, 23696 patients with ACS were enrolled in the AMIS Plus Registry (Figure 1 and Table 1). Overall, 1977 patients (8.3%) had cardiogenic shock. Of these, 564 patients (2.3% of those with ACS and 28.5% of those with cardiogenic shock) had cardiogenic shock on admission and 1413 patients (6.0% of those with ACS and 71.5% of those with cardiogenic shock) developed cardiogenic shock during hospitalization. Baseline risk for cardiovascular disease was higher among patients with cardiogenic shock than among those without (Table 1); this difference was mainly driven by patients who developed cardiogenic shock during hospitalization. Patients with cardiogenic shock on admission were similar to patients without cardiogenic shock in terms of sex and age. Figure 1. Study flow diagram. Table 1. Baseline Characteristics, Treatment, and In-Hospital Outcome Multivariable Analysis In the ACS group, variables indicative of higher baseline risk, such as older age, history of diabetes, higher Killip classes, ST-segment elevation ACS, cardiopulmonary resuscitation on admission, faster heart rate, lower systolic blood pressure, higher Charlson Comorbid

Long-term outcome of patients with silent versus symptomatic ischemia six months after percutaneous coronary intervention and stenting

OBJECTIVES We sought to evaluate the incidence of silent ischemia versus symptomatic ischemia six months after percutaneous coronary intervention (PCI) and its impact on prognosis and to test the utility of myocardial perfusion single-photon emission computed tomography (SPECT), or MPS, for risk stratification in these patients. BACKGROUND Silent ischemia is frequent after PCI. However, little is known about silent ischemia and long-term outcome after PCI and stenting. METHODS In 356 consecutive patients with successful PCI and stenting and follow-up MPS after six months, long-term follow-up (4.1 +/- 0.3 years) was performed. The MPS images were interpreted by defining summed stress, rest, and difference scores (summed difference score [SDS] = extent of ischemia) and related to symptoms and outcome. Critical events included cardiac death, myocardial infarction, and target vessel revascularization. RESULTS Eighty-one patients (23%) had evidence of target vessel ischemia, which was silent in 62%. The only independent predictor of silent ischemia was SDS (odds ratio 0.64, p = 0.001). During follow-up, 67 critical events occurred. For patients with an SDS of 0, 1-4, and >4, the critical event rates were 17%, 29%, and 69%, respectively. Similarly, patients without ischemia, silent ischemia, and symptomatic ischemia had 17%, 32%, and 52% of critical events, respectively. Diabetes (relative risk 1.98, p = 0.03) and SDS (relative risk 1.2, p < 0.001) were independent predictors of critical events. The MPS image added incremental information for the prediction of critical events. CONCLUSIONS Six months after PCI and stenting, 23% of patients had target vessel ischemia, which was silent in 62%. Silent ischemia predicted a worse outcome than did no ischemia and tended to have a better outcome than symptomatic ischemia. This was closely related to the extent of ischemia. The SDS added incremental value to pre-scan findings with respect to diagnosis and prognosis, indicating the utility of MPS for risk stratification after PCI and stenting.

Cardiovascular outcomes in high-risk patients with osteoarthritis treated with Ibuprofen, Naproxen, or Lumiracoxib.

Background: Evidence suggests that both selective cyclooxygenase (COX)-2 inhibitors and non-selective non-steroidal anti-inflammatory drugs (NSAIDs) increase the risk of cardiovascular events. However, evidence from prospective studies of currently available COX-2 inhibitors and non-selective NSAIDs is lacking in patients at high cardiovascular risk who are taking aspirin. Objective: To determine the cardiovascular outcomes in high risk patients with osteoarthritis treated with ibuprofen, naproxen or lumiracoxib. Methods: The Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET) of 18 325 patients with osteoarthritis comprised two parallel substudies, comparing lumiracoxib (COX-2 inhibitor) with either ibuprofen or naproxen. A post hoc analysis by baseline cardiovascular risk, treatment assignment, and low-dose aspirin use was performed. The primary composite end point was cardiovascular mortality, non-fatal myocardial infarction, and stroke at 1 year; a secondary end point was the development of congestive heart failure (CHF). Results: In high risk patients among aspirin users, patients in the ibuprofen substudy had more primary events with ibuprofen than lumiracoxib (2.14% vs 0.25%, p = 0.038), whereas in the naproxen substudy rates were similar for naproxen and lumiracoxib (1.58% vs 1.48%, p = 0.899). High risk patients not taking aspirin had fewer primary events with naproxen than with lumiracoxib (0% vs 1.57%, p = 0.027), but not for ibuprofen versus lumiracoxib (0.92% vs 0.80%, p = 0.920). Overall, CHF developed more often with ibuprofen than lumiracoxib (1.28% vs 0.14%; p = 0.031), whereas no difference existed between naproxen and lumiracoxib. Conclusions: These data suggest that ibuprofen may confer an increased risk of thrombotic and CHF events relative to lumiracoxib among aspirin users at high cardiovascular risk. The study indicates that naproxen may be associated with lower risk relative to lumiracoxib among non-aspirin users. This study is subject to inherent limitations, and therefore should be interpreted as a hypothesis-generating study.

Predictors for efficacy of percutaneous mitral valve repair using the MitraClip system: the results of the MitraSwiss registry

Background Percutaneous mitral valve repair (MVR) using the MitraClip system has become a valid alternative for patients with severe mitral regurgitation (MR) and high operative risk. Objective To identify clinical and periprocedural factors that may have an impact on clinical outcome. Design Multi-centre longitudinal cohort study. Setting Tertiary referral centres. Patients Here we report on the first 100 consecutive patients treated with percutaneous MVR in Switzerland between March 2009 and April 2011. All of them had moderate–severe (3+) or severe (4+) MR, and 62% had functional MR. 82% of the patients were in New York Heart Association (NYHA) class III/IV, mean left ventricular ejection fraction was 48% and the median European System for Cardiac Operative Risk Evaluation was 16.9%. Interventions MitraClip implantation performed under echocardiographic and fluoroscopic guidance in general anaesthesia. Main outcome measures Clinical, echocardiographic and procedural data were prospectively collected. Results Acute procedural success (APS, defined as successful clip implantation with residual MR grade ≤2+) was achieved in 85% of patients. Overall survival at 6 and 12 months was 89.9% (95% CI 81.8 to 94.6) and 84.6% (95% CI 74.7 to 91.0), respectively. Univariate Cox regression analysis identified APS (p=0.0069) and discharge MR grade (p=0.03) as significant predictors of survival. Conclusions In our consecutive cohort of patients, APS was achieved in 85%. APS and residual discharge MR grade are important predictors of mid-term survival after percutaneous MVR.

Safety and efficacy of drug-eluting stents in women: a patient-level pooled analysis of randomised trials

BACKGROUND The safety and efficacy of drug-eluting stents (DES) in the treatment of coronary artery disease have been assessed in several randomised trials. However, none of these trials were powered to assess the safety and efficacy of DES in women because only a small proportion of recruited participants were women. We therefore investigated the safety and efficacy of DES in female patients during long-term follow-up. METHODS We pooled patient-level data for female participants from 26 randomised trials of DES and analysed outcomes according to stent type (bare-metal stents, early-generation DES, and newer-generation DES). The primary safety endpoint was a composite of death or myocardial infarction. The secondary safety endpoint was definite or probable stent thrombosis. The primary efficacy endpoint was target-lesion revascularisation. Analysis was by intention to treat. FINDINGS Of 43,904 patients recruited in 26 trials of DES, 11,557 (26·3%) were women (mean age 67·1 years [SD 10·6]). 1108 (9·6%) women received bare-metal stents, 4171 (36·1%) early-generation DES, and 6278 (54·3%) newer-generation DES. At 3 years, estimated cumulative incidence of the composite of death or myocardial infarction occurred in 132 (12·8%) women in the bare-metal stent group, 421 (10·9%) in the early-generation DES group, and 496 (9·2%) in the newer-generation DES group (p=0·001). Definite or probable stent thrombosis occurred in 13 (1·3%), 79 (2·1%), and 66 (1·1%) women in the bare-metal stent, early-generation DES, and newer-generation DES groups, respectively (p=0·01). The use of DES was associated with a significant reduction in the 3 year rates of target-lesion revascularisation (197 [18·6%] women in the bare-metal stent group, 294 [7·8%] in the early-generation DES group, and 330 [6·3%] in the newer-generation DES group, p<0·0001). Results did not change after adjustment for baseline characteristics in the multivariable analysis. INTERPRETATION The use of DES in women is more effective and safe than is use of bare-metal stents during long-term follow-up. Newer-generation DES are associated with an improved safety profile compared with early-generation DES, and should therefore be thought of as the standard of care for percutaneous coronary revascularisation in women. FUNDING Women in Innovation Initiative of the Society of Cardiovascular Angiography and Interventions.

Cost-effectiveness of drug-eluting stents in patients at high or low risk of major cardiac events in the Basel Stent KostenEffektivitäts Trial (BASKET): an 18-month analysis

BACKGROUND Our aim was to determine whether drug-eluting stents are good value for money in long-term, everyday practice. METHODS We did an 18-month cost-effectiveness analysis of the Basel Stent KostenEffektivitäts Trial (BASKET), which randomised 826 patients 2:1 to drug-eluting stents (n=545) or to bare-metal stents (281). We used non-parametric bootstrap techniques to determine incremental cost-effectiveness ratios (ICERs) of drug-eluting versus bare-metal stents, to compare low-risk (> or =3.0 mm stents in native vessels; n=558, 68%) and high-risk patients (<3.0 mm stents/bypass graft stenting; n=268, 32%), and to do sensitivity analyses by altering costs and event rates in the whole study sample and in predefined subgroups. Quality-adjusted life-years (QALYs) were assessed by EQ-5D questionnaire (available in 703/826 patients). FINDINGS Overall costs were higher for patients with drug-eluting stents than in those with bare-metal stents (11,808 euros [SD 400] per patient with drug-eluting stents and 10,450 euros [592] per patient with bare-metal stents, mean difference 1358 euros [717], p<0.0001), due to higher stent costs. We calculated an ICER of 64,732 euros to prevent one major adverse cardiac event, and of 40,467 euros per QALY gained. Stent costs, number of events, and QALYs affected ICERs most, but unrealistic alterations would have been required to achieve acceptable cost-effectiveness. In low-risk patients, the probability of drug-eluting stents achieving an arbitrary ICER of 10,000 euros or less to prevent one major adverse cardiac event was 0.016; by contrast, it was 0.874 in high-risk patients. INTERPRETATION If used in all patients, drug-eluting stents are not good value for money, even if prices were substantially reduced. Drug-eluting stents are cost effective in patients needing small vessel or bypass graft stenting, but not in those who require large native vessel stenting.

Drug-coated balloons for treatment of coronary artery disease: updated recommendations from a consensus group

AbstractAims Drug-coated balloon catheters (DCB) are a new clinical treatment modality for coronary and peripheral artery disease. The goal of the consensus group is to develop recommendations for the clinical use of DCB based on randomized clinical trials and the best available clinical evidence. The present paper gives an update on the recommendations against the background of a variety of new data published since the first paper was presented.Methods and results The general concept of our recommendations for the coronary use of DCB includes the preparation of the lesion to facilitate drug delivery and to estimate the need for stent implantation, especially after relevant dissections. Lesion preparation includes conventional angioplasty. In more complex lesions, additional treatments and imaging or functional measurements are helpful. In case of no flow-limiting dissection and an acceptable but not stent-like primary result, DCB use without additional stent implantation may be considered. The proposed advantages of the DCB only concept over a direct stent approach include reduced restenosis rates in indications where DES show limited efficacy, the reduction of DAPT especially in patients with contraindications for prolonged DAPT, and the option of leaving no foreign object behind resulting in vascular restoration with potentially plaque regression instead of neo-atherosclerosis.ConclusionsDCB allow for local drug delivery in endovascular therapy leaving no permanent implant behind.

Drug-Eluting Stents Compared with Bare Metal Stents Improve Late Outcome after Saphenous Vein Graft but Not after Large Native Vessel Interventions

Objectives: To define long-term efficacy of different stent types in saphenous vein graft (SVG) interventions. Methods: In BASKET (Basel Stent Cost Effectiveness Trial), major adverse cardiac events (MACE), i.e. cardiac death, myocardial infarction and symptom-driven target vessel revascularization (TVR) were assessed after 18 months comparing drug-eluting stents (DES) versus bare metal stents (BMS), and SVG and large native vessels (≧3.0 mm). Results: Large vessel interventions were performed in 605 patients. Patients with SVG interventions (n = 47, 8%) were older and had more often hypertension, prior myocardial infarction, prior revascularization and multivessel disease and less frequent ST-elevation myocardial infarction than patients with large native vessel interventions (n = 558, 92%). Stent number and length were higher in SVG than in large native vessel interventions. Baseline characteristics were similar for DES and BMS. In SVG stenting, long-term outcome was better in DES- than in BMS-treated patients (MACE 21 vs. 62%, p = 0.007, mainly due to TVR 18 vs. 46%, p = 0.045), but for large native vessel stenting, no significant difference was noted (MACE: 13 vs. 16%, p = 0.40). Conclusions: Among patients with SVG disease, treatment with DES resulted in a better long-term outcome than treatment with BMS. In contrast, no DES benefit was found in similarly sized native vessels regarding MACE.

Long-Term Efficacy and Safety of Biodegradable-Polymer Biolimus-Eluting Stents: Main Results of the Basel Stent Kosten-Effektivitäts Trial- PROspective Validation Examination II (BASKET-PROVE II), A Randomized, Controlled Noninferiority 2-Year Outcome Trial

Background— Biodegradable-polymer drug-eluting stents (BP-DES) were developed to be as effective as second-generation durable-polymer drug-eluting stents (DP-DES) and as safe >1 year as bare-metal stents (BMS). Thus, very late stent thrombosis (VLST) attributable to durable polymers should no longer appear. Methods and Results— To address these early and late aspects, 2291 patients presenting with acute or stable coronary disease needing stents ≥3.0 mm in diameter between April 2010 and May 2012 were randomly assigned to biolimus-A9–eluting BP-DES, second-generation everolimus-eluting DP-DES, or thin-strut silicon-carbide–coated BMS in 8 European centers. All patients were treated with aspirin and risk-adjusted doses of prasugrel. The primary end point was combined cardiac death, myocardial infarction, and clinically indicated target-vessel revascularization within 2 years. The combined secondary safety end point was a composite of VLST, myocardial infarction, and cardiac death. The cumulative incidence of the primary end point was 7.6% with BP-DES, 6.8% with DP-DES, and 12.7% with BMS. By intention-to-treat BP-DES were noninferior (predefined margin, 3.80%) compared with DP-DES (absolute risk difference, 0.78%; −1.93% to 3.50%; P for noninferiority 0.042; per protocol P=0.09) and superior to BMS (absolute risk difference, −5.16; −8.32 to −2.01; P=0.0011). The 3 stent groups did not differ in the combined safety end point, with no decrease in events >1 year, particularly VLST with BP-DES. Conclusions— In large vessel stenting, BP-DES appeared barely noninferior compared with DP-DES and more effective than thin-strut BMS, but without evidence for better safety nor lower VLST rates >1 year. Findings challenge the concept that durable polymers are key in VLST formation. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01166685.

Bivalirudin Versus Heparin Anticoagulation in Transcatheter Aortic Valve Replacement: The Randomized BRAVO-3 Trial.

BACKGROUND Anticoagulation is required during transcatheter aortic valve replacement (TAVR) procedures. Although an optimal regimen has not been determined, heparin is mainly used. Direct thrombin inhibition with bivalirudin may be an effective alternative to heparin as the procedural anticoagulant agent in this setting. OBJECTIVES The goal of this study was to determine whether bivalirudin offers an alternative to heparin as the procedural anticoagulant agent in patients undergoing TAVR. METHODS A total of 802 patients with aortic stenosis were randomized to undergo transfemoral TAVR with bivalirudin versus unfractionated heparin during the procedure. The 2 primary endpoints were major bleeding within 48 h or before hospital discharge (whichever occurred first) and 30-day net adverse clinical events, defined as the combination of major adverse cardiovascular events (all-cause mortality, myocardial infarction, or stroke) and major bleeding. RESULTS Anticoagulation with bivalirudin versus heparin did not meet superiority because it did not result in significantly lower rates of major bleeding at 48 h (6.9% vs. 9.0%; relative risk: 0.77; 95% confidence interval [CI]: 0.48 to 1.23; p = 0.27) or net adverse cardiovascular events at 30 days (14.4% vs. 16.1%; relative risk: 0.89; 95% CI: 0.64 to 1.24; risk difference: -1.72; 95% CI: -6.70 to 3.25; p = 0.50); regarding the latter, the prespecified noninferiority hypothesis was met (pnoninferiority < 0.01). Rates of major adverse cardiovascular events at 48 h were not significantly different (3.5% vs. 4.8%; relative risk: 0.73; 95% CI: 0.37 to 1.43; p = 0.35). At 48 h, the bivalirudin group had significantly fewer myocardial infarctions but more acute kidney injury events than the heparin group; at 30 days, these differences were no longer significant. CONCLUSIONS In this randomized trial of TAVR procedural pharmacotherapy, bivalirudin did not reduce rates of major bleeding at 48 h or net adverse cardiovascular events within 30 days compared with heparin. Although superiority was not shown, the noninferiority hypothesis was met with respect to the latter factor. Given the lower cost, heparin should remain the standard of care, and bivalirudin can be an alternative anticoagulant option in patients unable to receive heparin in TAVR. (International, Multi-center, Open-label, Randomized Controlled Trial in Patients Undergoing TAVR to Determine the Treatment Effect [Both Safety and Efficacy] of Using Bivalirudin Instead of UFH [BRAVO-2/3]; NCT01651780).