Sumeet Subherwal

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.

The prevalence and outcomes of transradial percutaneous coronary intervention for ST-segment elevation myocardial infarction: analysis from the National Cardiovascular Data Registry (2007 to 2011).

OBJECTIVES The purpose of this study was to examine use and describe outcomes of radial access for percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI). BACKGROUND Transradial PCI (TRI) is associated with reduced risk of bleeding and vascular complications, as compared with femoral access PCI (FPCI). Studies have suggested that TRI may reduce mortality among patients with STEMI. METHODS We examined 294,769 patients undergoing PCI for STEMI at 1,204 hospitals in the CathPCI Registry between 2007 and 2011. Patients were grouped according to access site used for PCI. The temporal trend in the rate of radial versus femoral approach was determined. For minimization of confounding, an inverse probability weighting analysis incorporating propensity scores was used to compare procedural success, post-PCI bleeding, door-to-balloon times, and in-hospital mortality between radial and femoral access. RESULTS Over the 5-year period, the use of TRI versus FPCI in STEMI increased from 0.9% to 6.4% (p < 0.0001). There was no difference in procedural success. TRI was associated with longer median door-to-balloon time (78 vs. 74 min; p < 0.0001) but lower adjusted risk of bleeding (odds ratio [OR]: 0.62; 95% CI: 0.53 to 0.72; p < 0.0001) and lower adjusted risk of in-hospital mortality (OR: 0.76; 95% CI: 0.57 to 0.99; p = 0.0455). CONCLUSIONS In this large national database, use of radial access for PCI in STEMI increased over the study period. Despite longer door-to-balloon times, the radial approach was associated with lower bleeding rate and reduced in-hospital mortality. These data provide support to execute an adequately powered randomized controlled trial comparing radial and femoral approaches for PCI in STEMI.

Clinical ResearchInterventional CardiologyThe Prevalence and Outcomes of Transradial Percutaneous Coronary Intervention for ST-Segment Elevation Myocardial Infarction: Analysis From the National Cardiovascular Data Registry (2007 to 2011)

OBJECTIVES The purpose of this study was to examine use and describe outcomes of radial access for percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI). BACKGROUND Transradial PCI (TRI) is associated with reduced risk of bleeding and vascular complications, as compared with femoral access PCI (FPCI). Studies have suggested that TRI may reduce mortality among patients with STEMI. METHODS We examined 294,769 patients undergoing PCI for STEMI at 1,204 hospitals in the CathPCI Registry between 2007 and 2011. Patients were grouped according to access site used for PCI. The temporal trend in the rate of radial versus femoral approach was determined. For minimization of confounding, an inverse probability weighting analysis incorporating propensity scores was used to compare procedural success, post-PCI bleeding, door-to-balloon times, and in-hospital mortality between radial and femoral access. RESULTS Over the 5-year period, the use of TRI versus FPCI in STEMI increased from 0.9% to 6.4% (p < 0.0001). There was no difference in procedural success. TRI was associated with longer median door-to-balloon time (78 vs. 74 min; p < 0.0001) but lower adjusted risk of bleeding (odds ratio [OR]: 0.62; 95% CI: 0.53 to 0.72; p < 0.0001) and lower adjusted risk of in-hospital mortality (OR: 0.76; 95% CI: 0.57 to 0.99; p = 0.0455). CONCLUSIONS In this large national database, use of radial access for PCI in STEMI increased over the study period. Despite longer door-to-balloon times, the radial approach was associated with lower bleeding rate and reduced in-hospital mortality. These data provide support to execute an adequately powered randomized controlled trial comparing radial and femoral approaches for PCI in STEMI.

Temporal Trends in and Factors Associated With Bleeding Complications Among Patients Undergoing Percutaneous Coronary Intervention: A Report From the National Cardiovascular Data CathPCI Registry

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.

Temporal Trends and Geographic Variation of Lower-Extremity Amputation in Patients With Peripheral Artery Disease: Results From U.S. Medicare 2000–2008

OBJECTIVES This study sought to characterize temporal trends, patient-specific factors, and geographic variation associated with amputation in patients with lower-extremity peripheral artery disease (LE PAD) during the study period. BACKGROUND Amputation represents the end-stage failure for those with LE PAD, and little is known about the rates and geographic variation in the use of LE amputation. METHODS By using data from the Centers for Medicare & Medicaid Services (CMS) from January 1, 2000, to December 31, 2008, we examined national patterns of LE amputation among patients age 65 years or more with PAD. Multivariable logistic regression was used to adjust regional results for other patient demographic and clinical factors. RESULTS Among 2,730,742 older patients with identified PAD, the overall rate of LE amputation decreased from 7,258 per 100,000 patients with PAD to 5,790 per 100,000 (p < 0.001 for trend). Male sex, black race, diabetes mellitus, and renal disease were all independent predictors of LE amputation. The adjusted odds ratio of LE amputation per year between 2000 and 2008 was 0.95 (95% CI: 0.95-0.95, p < 0.001). CONCLUSIONS From 2000 to 2008, LE amputation rates decreased significantly among patients with PAD. However, there remains significant patient and geographic variation in amputation rates across the United States.

Laboratory and Clinical Outcomes of Pharmacogenetic vs. Clinical Protocols for Warfarin Initiation in Orthopedic Patients

Summary.  Background: Warfarin is commonly prescribed for prophylaxis and treatment of thromboembolism after orthopedic surgery. During warfarin initiation, out‐of‐range International Normalized Ratio (INR) values and adverse events are common. Methods: In orthopedic patients beginning warfarin therapy, we developed and prospectively validated pharmacogenetic and clinical dose refinement algorithms to revise the estimated therapeutic dose after 4 days of therapy. Results: The pharmacogenetic algorithm used the cytochrome P450 (CYP) 2C9 genotype, smoking status, peri‐operative blood loss, liver disease, INR values and dose history to predict the therapeutic dose. The R2 was 82% in a derivation cohort (n = 86) and 70% when used prospectively (n = 146). The R2 of the clinical algorithm that used INR values and dose history to predict the therapeutic dose was 57% in a derivation cohort (n = 178) and 48% in a prospective validation cohort (n = 146). In 1 month of prospective follow‐up, the percent time spent in the therapeutic range was 7% higher (95% CI: 2.7–11.7) in the pharmacogenetic cohort. The risk of a laboratory or clinical adverse event was also significantly reduced in the pharmacogenetic cohort (Hazard Ratio 0.54; 95% CI: 0.30–0.97). Conclusions: Warfarin dose adjustments that incorporate genotype and clinical variables available after four warfarin doses are accurate. In this non‐randomized, prospective study, pharmacogenetic dose refinements were associated with more time spent in the therapeutic range and fewer laboratory or clinical adverse events. To facilitate gene‐guided warfarin dosing we created a non‐profit website, http://www.WarfarinDosing.org.

Missed Opportunities Despite Improvement in Use of Cardioprotective Medications Among Patients With Lower-Extremity Peripheral Artery Disease, Underuse Remains

Background— Patients with peripheral artery disease (PAD) are at high risk of cardiovascular events and benefit from aggressive secondary prevention; however, changes in the use of cardioprotective medications after incident diagnosis of PAD have not been well described. Methods and Results— We used Danish nationwide administrative registries (2000–2007) to identify 2 groups with incident PAD: PAD alone (n=34 160) and PAD with history of coronary artery disease (CAD) (n=9570). With the use of a comparator with incident CAD alone (n=154 183), we assessed temporal trends and comparative use of cardioprotective medications. Relative differences in medication use were examined by using multivariable logistic regression. Use of medications improved temporally among both groups: for PAD alone, any antiplatelet use increased from 29% to 59% from 2000 to 2007 ( P <0.0001), whereas statin use increased 6-fold (9%–56%; P <0.0001). However, use of these therapies by 18 months after incident diagnosis for both PAD groups remained modest and lower in comparison with CAD alone (any antiplatelet, 53% versus 66%; statins, 40% versus 52%; angiotensin-converting enzyme inhibitors, 20% versus 29%). Relative to CAD alone, patients with PAD alone were less likely to use any antiplatelet (adjusted odds ratio, 0.50; 95% confidence interval, 0.49–0.52), statins (adjusted odds ratio, 0.50; 95% confidence interval, 0.48–0.52), or angiotensin-converting enzyme inhibitors (adjusted odds ratio, 0.51; 95% confidence interval, 0.49–0.53) by 18 months. Conclusions— Despite improvement in the use of cardioprotective medications over time, patients with PAD alone remain less likely than those with CAD alone to use these agents. # Clinical Perspective {#article-title-45}Background— Patients with peripheral artery disease (PAD) are at high risk of cardiovascular events and benefit from aggressive secondary prevention; however, changes in the use of cardioprotective medications after incident diagnosis of PAD have not been well described. Methods and Results— We used Danish nationwide administrative registries (2000–2007) to identify 2 groups with incident PAD: PAD alone (n=34 160) and PAD with history of coronary artery disease (CAD) (n=9570). With the use of a comparator with incident CAD alone (n=154 183), we assessed temporal trends and comparative use of cardioprotective medications. Relative differences in medication use were examined by using multivariable logistic regression. Use of medications improved temporally among both groups: for PAD alone, any antiplatelet use increased from 29% to 59% from 2000 to 2007 (P<0.0001), whereas statin use increased 6-fold (9%–56%; P<0.0001). However, use of these therapies by 18 months after incident diagnosis for both PAD groups remained modest and lower in comparison with CAD alone (any antiplatelet, 53% versus 66%; statins, 40% versus 52%; angiotensin-converting enzyme inhibitors, 20% versus 29%). Relative to CAD alone, patients with PAD alone were less likely to use any antiplatelet (adjusted odds ratio, 0.50; 95% confidence interval, 0.49–0.52), statins (adjusted odds ratio, 0.50; 95% confidence interval, 0.48–0.52), or angiotensin-converting enzyme inhibitors (adjusted odds ratio, 0.51; 95% confidence interval, 0.49–0.53) by 18 months. Conclusions— Despite improvement in the use of cardioprotective medications over time, patients with PAD alone remain less likely than those with CAD alone to use these agents.

The association of in-hospital major bleeding with short-, intermediate-, and long-term mortality among older patients with non-ST-segment elevation myocardial infarction

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.

Patterns of use and comparative effectiveness of bleeding avoidance strategies in men and women following percutaneous coronary interventions: an observational study from the National Cardiovascular Data Registry.

OBJECTIVES This study sought to compared the use and effectiveness of bleeding avoidance strategies (BAS) by sex. BACKGROUND Women have higher rates of bleeding following percutaneous coronary intervention (PCI). METHODS Among 570,777 men (67.5%) and women (32.5%) who underwent PCI in the National Cardiovascular Data Registrys CathPCI Registry between July 1, 2009 and March 31, 2011, in-hospital bleeding rates and the use of BAS (vascular closure devices, bivalirudin, radial approach, and their combinations) were assessed. The relative risk of bleeding for each BAS compared with no BAS was determined in women and men using multivariable logistic regressions adjusted for clinical characteristics and the propensity for receiving BAS. Finally, the absolute risk differences in bleeding associated with BAS were compared. RESULTS Overall, the use of any BAS differed slightly between women and men (75.4% vs. 75.7%, p = 0.01). When BAS was not used, women had significantly higher rates of bleeding than men (12.5% vs. 6.2%, p < 0.01). Both sexes had similar adjusted risk reductions of bleeding when any BAS was used (women, odds ratio: 0.60, 95% confidence interval [CI]: 0.57 to 0.63; men, odds ratio: 0.62, 95% CI: 0.59 to 0.65). Women and men had lower absolute bleeding risks with BAS; however, these absolute risk differences were greater in women (6.3% vs. 3.2%, p < 0.01). CONCLUSIONS Women continue to have almost twice the rate of bleeding following PCI. The use of any BAS was associated with a similarly lower risk of bleeding for men and women; however, the absolute risk differences were substantially higher in women. These data underscore the importance of applying effective strategies to limit post-PCI bleeding, especially in women.

High mortality risks after major lower extremity amputation in Medicare patients with peripheral artery disease

BACKGROUND Little is known regarding the contemporary outcomes of older patients with peripheral artery disease (PAD) undergoing major lower extremity (LE) amputation in the United States. We sought to characterize clinical outcomes and factors associated with outcomes after LE amputation in patients with PAD. METHODS Using data from the Centers for Medicare and Medicaid Services from January 1, 2000, to December 31, 2008, we examined the national patterns of mortality after major LE amputation among patients 65 years or older with PAD. Cox proportional hazards models were used to investigate the association between clinical variables, comorbid conditions, year of index amputation, geographic variation, and major LE amputation. RESULTS Among 186,338 older patients with identified PAD who underwent major LE amputation, the mortality rate was 13.5% at 30 days, 48.3% at 1 year, and 70.9% at 3 years. Age per 5-year increase (hazard ratio [HR] 1.29, 95% CI 1.29-1.29), history of heart failure (HR 1.71, 95% CI 1.71-1.72), renal disease (HR 1.84. 95% CI 1.83-1.85), cancer (HR 1.71, 95% CI 1.70-1.72), and chronic obstructive pulmonary disease (HR 1.33, 95% CI, 1.32-1.33) were all independently associated with death after major LE amputation. Subjects who underwent above knee amputation had a statistically higher hazard of death when compared with subjects who underwent LE amputation at more distal locations (HR with above the knee amputation 1.31, 95% CI 1.25-1.36). CONCLUSIONS Older patients with PAD undergoing major LE amputation still face a slightly high mortality risk, with almost half of all patients with PAD dying within a year of major LE amputation.