Amit N. Vora

Fibrinolysis Use Among Patients Requiring Interhospital Transfer for ST-Segment Elevation Myocardial Infarction Care: A Report From the US National Cardiovascular Data Registry

IMPORTANCE Guidelines for patients with ST-segment elevation myocardial infarction (STEMI) recommend timely reperfusion with primary percutaneous coronary intervention (pPCI) or fibrinolysis. Among patients with STEMI who require interhospital transfer, it is unclear how reperfusion strategy selection and outcomes vary with interhospital drive times. OBJECTIVE To assess the association of estimated interhospital drive times with reperfusion strategy selection among transferred patients with STEMI in the United States. DESIGN, SETTING, AND PARTICIPANTS We identified 22,481 patients eligible for pPCI or fibrinolysis who were transferred from 1771 STEMI referring centers to 366 STEMI receiving centers in the Acute Coronary Treatment and Intervention Outcomes Network Registry-Get With the Guidelines database between July 1, 2008, and March 31, 2012. MAIN OUTCOMES AND MEASURES In-hospital mortality and major bleeding. RESULTS The median estimated interhospital drive time was 57 minutes (interquartile range [IQR], 36-88 minutes). When the estimated drive time exceeded 30 minutes, only 42.6% of transfer patients treated with pPCI achieved the first door-to-balloon time within 120 minutes. Only 52.7% of eligible patients with a drive time exceeding 60 minutes received fibrinolysis. Among 15,437 patients with estimated drive times of 30 to 120 minutes who were eligible for fibrinolysis or pPCI, 5296 (34.3%) received pretransfer fibrinolysis, with a median door-to-needle time of 34 minutes (IQR, 23-53 minutes). After fibrinolysis, the median time to transfer to the STEMI receiving center was 49 minutes (IQR, 34-69 minutes), and 97.1% underwent follow-up angiography. Patients treated with fibrinolysis vs pPCI had no significant mortality difference (3.7% vs 3.9%; adjusted odds ratio, 1.13; 95% CI, 0.94-1.36) but had higher bleeding risk (10.7% vs 9.5%; adjusted odds ratio, 1.17; 95% CI, 1.02-1.33). CONCLUSIONS AND RELEVANCE In the United States, neither fibrinolysis nor pPCI is being optimally used to achieve guideline-recommended reperfusion targets. For patients who are unlikely to receive timely pPCI, pretransfer fibrinolysis, followed by early transfer for angiography, may be a reperfusion option when potential benefits of timely reperfusion outweigh bleeding risk.

Fibroblast growth factor-23, cardiovascular prognosis, and benefit of angiotensin-converting enzyme inhibition in stable ischemic heart disease.

OBJECTIVES This study sought to test 2 hypotheses: 1) fibroblast growth factor (FGF)-23 identifies patients with stable ischemic heart disease (SIHD) at high risk of cardiovascular events independent of clinical factors, renal function, and established cardiovascular biomarkers; and 2) FGF-23 identifies patients who derive greater clinical benefit from angiotensin-converting enzyme inhibitor therapy. BACKGROUND FGF-23 is an endocrine regulator of mineral metabolism and markedly elevated levels are associated with cardiovascular events in patients with chronic kidney disease. Data in patients with SIHD are more sparse. METHODS FGF-23 levels were measured in 3,627 patients with SIHD randomly assigned to trandolapril or placebo within the PEACE (Prevention of Events With Angiotensin-Converting Enzyme) trial and followed up for a median of 5.1 years. RESULTS After adjustment for clinical risk predictors, left ventricular ejection fraction, markers of renal function, and established cardiovascular biomarkers, FGF-23 concentration was independently associated with an increased risk of cardiovascular death or heart failure among patients allocated to placebo (quartile 4 hazard ratio: 1.73; 95% confidence interval, 1.09 to 2.74; p = 0.02) and significantly improved metrics of discrimination. Furthermore, among patients in the top quartile of FGF-23 levels, trandolapril significantly reduced cardiovascular death or incident heart failure (hazard ratio: 0.45; 95% confidence interval: 0.28 to 0.72), whereas there was no clinical benefit in the remaining patients (hazard ratio: 1.07; 95% confidence interval: 0.75 to 1.52; p interaction = 0.0039). This interaction was independent of and additive to stratification based on renal function. CONCLUSIONS Elevated levels of FGF-23 are associated with cardiovascular death and incident heart failure in patients with SIHD and identify patients who derive significant clinical benefit from angiotensin-converting enzyme inhibitor therapy regardless of renal function. (Prevention of Events With Angiotensin-Converting Enzyme Inhibitor Therapy [PEACE]: NCT00000558).

Sex Differences in Platelet Reactivity and Cardiovascular and Psychological Response to Mental Stress in Patients With Stable Ischemic Heart Disease: Insights From the REMIT Study

BACKGROUND Although emotional stress is associated with ischemic heart disease (IHD) and related clinical events, sex-specific differences in the psychobiological response to mental stress have not been clearly identified. OBJECTIVES We aimed to study the differential psychological and cardiovascular responses to mental stress between male and female patients with stable IHD. METHODS Patients with stable IHD enrolled in the REMIT (Responses of Mental Stress-Induced Myocardial Ischemia to Escitalopram) study underwent psychometric assessments, transthoracic echocardiography, and platelet aggregation studies at baseline and after 3 mental stress tasks. Mental stress-induced myocardial ischemia (MSIMI) was defined as the development or worsening of regional wall motion abnormality, reduction of left ventricular ejection fraction (LVEF) ≥8% by transthoracic echocardiography, and/or ischemic ST-segment change on electrocardiogram during 1 or more of the 3 mental stress tasks. RESULTS In the 310 participants with known IHD (18% women, 82% men), most baseline characteristics were similar between women and men (including heart rate, blood pressure, and LVEF), although women were more likely to be nonwhite, living alone (p < 0.001), and unmarried (p < 0.001); they also had higher baseline depression and anxiety (p < 0.05). At rest, women had heightened platelet aggregation responses to serotonin (p = 0.007) and epinephrine (p = 0.004) compared with men. Following mental stress, women had more MSIMI (57% vs. 41%; p < 0.04), expressed more negative (p = 0.02) and less positive emotion (p < 0.001), and demonstrated higher collagen-stimulated platelet aggregation responses (p = 0.04) than men. Men were more likely than women to show changes in traditional physiological measures, such as blood pressure (p < 0.05) and double product. CONCLUSIONS In this exploratory analysis, we identified clear, measurable, and differential responses to mental stress in women and men. Further studies should test the association of sex differences in cardiovascular and platelet reactivity in response to mental stress and long-term outcomes. (Responses of Myocardial Ischemia to Escitalopram Treatment [REMIT]; NCT00574847).

Aortic valve surgery and survival in patients with moderate or severe aortic stenosis and left ventricular dysfunction

AIMS We aimed to determine the frequency of aortic valve surgery (AVR) with or without coronary artery bypass grafting (CABG), among patients with moderate/severe aortic stenosis (AS) and left ventricular systolic dysfunction (LVSD), and its relationship with survival. METHODS AND RESULTS The Duke Echocardiographic Database (N = 132 804) was queried for patients with mean gradient ≥25 mmHg and/or peak velocity ≥3 m/s and LVSD (left ventricular ejection fraction ≤50%) from 1 January 1995-28 February 2014. For analyses purposes, AS was defined both by mean gradient and calculated aortic valve area (AVA) criteria. Time-dependent indicators of AVR in multivariable Cox models were used to assess the relationship of AVR and all-cause mortality. A total of 1634 patients had moderate (N = 1090, 67%) or severe (N = 544, 33%) AS by mean gradient criteria. Overall, 287 (26%) patients with moderate AS and 263 (48%) patients with severe AS underwent AVR within 5 years of the qualifying echo. There were 863 (53%) deaths observed up to 5 years following index echo. After multivariable adjustment in an inverse probability weighted regression model, AVR was associated with higher 5-year survival amongst patients with moderate AS and severe AS whether classified by AVA or mean gradient criteria. Over all, AVR ± CABG compared with medical therapy was associated with significantly lower mortality [hazard ratio, HR = 0.49 (0.38, 0.62), P < 0.0001]. Compared with CABG alone, CABG + AVR was associated with better survival [HR = 0.18 (0.12, 0.27), P < 0.0001]. CONCLUSIONS In patients with moderate/severe AS and LVSD, mortality is substantial and amongst those selected for surgery, AVR with or without CABG is associated with higher survival. Research is required to understand factors contributing to current practice patterns and the possible utility of transcatheter approaches in this high-risk cohort.

Quality-of-Life Outcomes After Transcatheter Aortic Valve Replacement in an Unselected Population: A Report From the STS/ACC Transcatheter Valve Therapy Registry

Importance In clinical trials, transcatheter aortic valve replacement (TAVR) has been shown to improve symptoms and quality of life. As this technology moves into general clinical practice, evaluation of the health status outcomes among unselected patients treated with TAVR is of critical importance. Objective To examine the short- and long-term health status outcomes of surviving patients after TAVR in the context of an unselected population. Design, Setting, and Participants This observational cohort study included patients with severe aortic stenosis who underwent TAVR in the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy (TVT) Registry from November 1, 2011, to March 31, 2016, at more than 450 clinical sites. Main Outcomes and Measures Disease-specific health status was assessed at baseline and at 30 days and 1 year after TAVR using the Kansas City Cardiomyopathy Questionnaire overall summary (KCCQ-OS) score (range, 0-100 points; higher scores indicate less symptom burden and better quality of life). Factors associated with health status at 1 year after TAVR were examined using multivariable linear regression, with adjustment for baseline health status and accounting for clustering of patients within sites. Results The 30-day analytic sample included 31 636 patients, and the 1-year cohort included 7014 surviving patients (3454 women [49.2%] and 3560 men [50.8%]; median [interquartile range] age, 84 [78-88] years). The mean (SD) baseline KCCQ-OS score was 42.3 (23.7), indicating substantial health status impairment. Surviving patients had, on average, large improvements in health status at 30 days that persisted to 1 year, with a mean improvement in the KCCQ-OS score of 27.6 (95% CI, 27.3-27.9) points at 30 days and 31.9 (95% CI, 31.3-32.6) points at 1 year. Worse baseline health status, older age, higher ejection fraction, lung disease, home oxygen use, lower mean aortic valve gradients, prior stroke, diabetes, pacemaker use, atrial fibrillation, slow gait speed, and nonfemoral access were significantly associated with worse health status at 1 year. Overall, 62.3% of patients had a favorable outcome at 1 year (alive with reasonable quality of life [KCCQ-OS score, ≥60] and no significant decline [≥10 points] from baseline), with the lowest rates seen among patients with severe lung disease (51.4%), those undergoing dialysis (47.7%), or those with very poor baseline health status (49.2%). Conclusions and Relevance In a national, contemporary clinical practice cohort of unselected patients, improvement in health status after TAVR was similar to that seen in the pivotal clinical trials. Although the health status results were favorable for most patients, approximately 1 in 3 still had a poor outcome 1 year after TAVR. Continued efforts are needed to improve patient selection and procedural/postprocedural care to maximize health status outcomes of this evolving therapy.

Long-term outcomes associated with hospital acquired thrombocytopenia among patients with non–ST-segment elevation acute coronary syndrome

BACKGROUND Acquired thrombocytopenia after a non-ST-segment-elevation-acute coronary syndrome (NSTE-ACS) has been associated with increased in-hospital mortality and hemorrhagic complications, but longer term outcomes are unclear. We examined the association between thrombocytopenia and long-term outcomes after accounting for thrombocytopenia severity and discharge medication use. METHODS Data from 7,435 NSTE-ACS patients enrolled in the SYNERGY trial were analyzed. Severe thrombocytopenia was defined as a nadir platelet count <100 × 10(9)/L or a ≥ 50% drop from baseline. Mild thrombocytopenia was defined as a nadir platelet count between 100 and 149 × 10(9)/L with a <50% drop from baseline. The primary outcomes of interest were in-hospital GUSTO moderate-severe bleeding and 1-year mortality. RESULTS Overall, 675 patients (9.1%) developed mild thrombocytopenia and 139 patients (1.9%) developed severe thrombocytopenia. In-hospital bleeding risks were higher in patients with mild (7.7%, adjusted HR 1.63, 95% CI 1.16-2.29) or severe (28.2%, adjusted HR 6.93, 95% CI 4.55-10.56) thrombocytopenia than in patients without thrombocytopenia (5.2%). One-year mortality rates were 6.5%, 8.1%, and 28.1% among patients with no, mild, and severe thrombocytopenia, respectively (log rank P < 0.001) but only severe thrombocytopenia remained significantly associated with increased mortality after adjustment: HR 4.07, 95% CI 2.86-5.78. Patients who developed severe thrombocytopenia were less likely to be discharged on guideline-recommended antiplatelet therapy. The relationship between severe thrombocytopenia and mortality was attenuated by but persisted after adjusting for discharge medication use (HR 2.83, 95% CI 1.49-5.38). CONCLUSIONS Thrombocytopenia occurs commonly during the course of NSTE-ACS care; even mild decreases are associated with clinically meaningful bleeding. Patients who developed severe thrombocytopenia were less likely to be discharged on guideline-recommended antiplatelet therapy; this may contribute to their higher associated long-term mortality.

Temporal Trends in the Risk Profile of Patients Undergoing Outpatient Percutaneous Coronary Intervention A Report from the National Cardiovascular Data Registry’s CathPCI Registry

Background—Because of recent changes in criteria for coverage for inpatient hospital stays, most nonacute percutaneous coronary intervention (PCI) procedures are reimbursed on an outpatient basis regardless of underlying patient risk. Downstream effects of these changes on the risk profile of patients undergoing outpatient PCI have not been evaluated. Methods and Results—Using the American College of Cardiology National Cardiovascular Data Registry’s CathPCI Registry, we assessed temporal trends in risk profiles and rates of hospital admission among 999 279 patients undergoing PCI qualifying for outpatient reimbursement. We estimated mortality and bleeding risk using validated models from the registry. From 2009 to 2014, the proportion of outpatients not admitted to a hospital after PCI increased from 32.8% to 66.3% (P<0.001). Patients who were admitted after PCI were older, had greater comorbidities, and experienced more post-PCI complications (all P<0.001). Among those not admitted, the proportion of patients at high risk for predicted mortality increased significantly from 17.0% to 19.8% during the study period (P<0.001). In contrast, 16.7% of patients admitted after PCI were at low risk for mortality. Conclusions—Among patients undergoing PCI procedures that qualify for outpatient reimbursement, there has been a temporal decrease in postprocedure hospital admission. Concomitantly, the proportion of these outpatients at high risk for mortality has significantly increased over time. These data suggest that current reimbursement classification could be improved by incorporating patient risk to appropriately match the necessary resources to the needed level of care.

Blood Transfusion and the Risk of Acute Kidney Injury Among Patients With Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention

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.

Data monitoring committees: Promoting best practices to address emerging challenges:

Background and Purpose: Data monitoring committees are responsible for safeguarding the interests of study participants and assuring the integrity and credibility of clinical trials. The independence of data monitoring committees from sponsors and investigators is essential in achieving this mission. Creative approaches are needed to address ongoing and emerging challenges that potentially threaten data monitoring committees’ independence and effectiveness. Methods: An expert panel of representatives from academia, industry and government sponsors, and regulatory agencies discussed these challenges and proposed best practices and operating principles for effective functioning of contemporary data monitoring committees. Results and Conclusions: Prospective data monitoring committee members need better training. Options could include didactic instruction as well as apprenticeships to provide real-world experience. Data monitoring committee members should be protected against legal liability arising from their service. While avoiding breaches in confidentiality of interim data remains a high priority, data monitoring committees should have access to unblinded efficacy and safety data throughout the trial to enable informed judgments about risks and benefits. Because overly rigid procedures can compromise their independence, data monitoring committees should have the flexibility necessary to best fulfill their responsibilities. Data monitoring committee charters should articulate principles that guide the data monitoring committee process rather than list a rigid set of requirements. Data monitoring committees should develop their recommendations by consensus rather than through voting processes. The format for the meetings of the data monitoring committee should maintain the committee’s independence and clearly establish the leadership of the data monitoring committee chair. The independent statistical group at the Statistical Data Analysis Center should have sufficient depth of knowledge about the study at hand and experience with trials in general to ensure that the data monitoring committee has access to timely, reliable, and readily interpretable insights about emerging evidence in the clinical trial. Contracts engaging data monitoring committee members for industry-sponsored trials should have language customized to the unique responsibilities of data monitoring committee members rather than use language appropriate to consultants for product development. Regulatory scientists would benefit from experiencing data monitoring committee service that does not conflict with their regulatory responsibilities.

Characteristics of Patients Undergoing Cardiac Catheterization Before Noncardiac Surgery: A Report From the National Cardiovascular Data Registry CathPCI Registry

IMPORTANCE Many patients undergo cardiac catheterization and/or percutaneous coronary intervention (PCI) before noncardiac surgery even though these procedures are not routinely indicated. Data on this cohort of patients are limited. OBJECTIVE To describe the characteristics, angiographic findings, and treatment patterns of clinically stable patients undergoing cardiac catheterization and/or PCI before noncardiac surgery in a large national registry. DESIGN, SETTING, AND PARTICIPANTS This study is a retrospective, descriptive analysis of National Cardiac Data Registry CathPCI Registry diagnostic catheterization and PCI data from July 1, 2009, through December 31, 2014. Data analysis was performed from April 21, 2015, to January 4, 2016. The study included 194 444 patients from 1046 sites who underwent coronary angiography before noncardiac surgery. Patients with acute coronary syndrome, cardiogenic shock, cardiac arrest, or emergency catheterization were excluded. MAIN OUTCOMES AND MEASURES Demographic characteristics, preprocedure noninvasive testing results, angiographic findings, and treatment recommendations are summarized. Among the 27 838 patients who underwent PCI, procedural details, inpatient outcomes, and discharge medications are reported. RESULTS Of the 194 444 included patients, 113 590 (58.4%) were male, the median age was 65 years (interquartile range, 57-73 years), and 162 532 (83.6%) were white. Most were overweight or obese (152 849 [78.6%]), and 78 847 (40.6%) had diabetes mellitus. Most patients were asymptomatic (117 821 [60.6%]), although 112 302 (57.8%) had been taking antianginal medications within 2 weeks of the procedure. Prior noninvasive stress testing was reported in 126 766 (65.2%), and results were positive in 109 458 (86.3%) of those with stress data. Obstructive disease was present in 93 447 (48.1%). After diagnostic angiography, revascularization with PCI or bypass surgery was recommended in 46 380 patients (23.8%) in the overall cohort, 27 191 asymptomatic patients (23.1%), and 45 083 patients with obstructive disease (48.3%). In the 27 191 patients undergoing PCI, 367 treated lesions (1.3%) were in the left main artery and 3831 (13.8%) in the proximal left anterior descending artery. A total of 11 366 patients (40.8%) received drug-eluting stents. Complications occurred in a few patients, with a catheterization-related mortality rate of 0.05%. CONCLUSIONS AND RELEVANCE In the largest contemporary US cohort reported to date, most patients undergoing diagnostic catheterization before noncardiac surgery are asymptomatic. The discovery of obstructive coronary artery disease is common, and although randomized clinical trials have found no benefit in outcomes, revascularization is recommended in nearly half of these patients. The overall findings highlight management patterns in this population and the need for greater evidence-based guidelines and practices.