Abhinav Chandra

Current Diagnosis and Management of Immune Related Adverse Events (irAEs) Induced by Immune Checkpoint Inhibitor Therapy

The indications of immune checkpoint inhibitors (ICIs) are set to rise further with the approval of newer agent like atezolimumab for use in patients with advanced stage urothelial carcinoma. More frequent use of ICIs has improved our understanding of their unique side effects, which are known as immune-related adverse events (irAEs). The spectrum of irAEs has expanded beyond more common manifestations such as dermatological, gastrointestinal and endocrine effects to rarer presentations involving nervous, hematopoietic and urinary systems. There are new safety data accumulating on ICIs in patients with previously diagnosed autoimmune conditions. It is challenging for clinicians to continuously update their working knowledge to diagnose and manage these events successfully. If diagnosed timely, the majority of events are completely reversible, and temporary immunosuppression with glucocorticoids, infliximab or other agents is warranted only in the most severe grade illnesses. The same principles of management will possibly apply as newer anti- cytotoxic T lymphocytes-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1/PD-L1) antibodies are introduced. The current focus of research is for prophylaxis and for biomarkers to predict the onset of these toxicities. In this review we summarize the irAEs of ICIs and emphasize their growing spectrum and their management algorithms, to update oncology practitioners.

Identifying Patients for Early Discharge: Performance of Decision Rules Among Patients with Acute Chest Pain

BACKGROUND The HEART score and North American Chest Pain Rule (NACPR) are decision rules designed to identify acute chest pain patients for early discharge without stress testing or cardiac imaging. This study compares the clinical utility of these decision rules combined with serial troponin determinations. METHODS AND RESULTS A secondary analysis was conducted of 1005 participants in the Myeloperoxidase In the Diagnosis of Acute coronary syndromes Study (MIDAS). MIDAS is a prospective observational cohort of Emergency Department (ED) patients enrolled from 18 US sites with symptoms suggestive of acute coronary syndrome (ACS). The ability to identify participants for early discharge and the sensitivity for ACS at 30 days were compared among an unstructured assessment, NACPR, and HEART score, each combined with troponin measures at 0 and 3h. ACS, defined as cardiac death, acute myocardial infarction, or unstable angina, occurred in 22% of the cohort. The unstructured assessment identified 13.5% (95% CI 11.5-16%) of participants for early discharge with 98% (95% CI 95-99%) sensitivity for ACS. The NACPR identified 4.4% (95% CI 3-6%) for early discharge with 100% (95% CI 98-100%) sensitivity for ACS. The HEART score identified 20% (95% CI 18-23%) for early discharge with 99% (95% CI 97-100%) sensitivity for ACS. The HEART score had a net reclassification improvement of 10% (95% CI 8-12%) versus unstructured assessment and 19% (95% CI 17-21%) versus NACPR. CONCLUSIONS The HEART score with 0 and 3 hour serial troponin measures identifies a substantial number of patients for early discharge while maintaining high sensitivity for ACS.

Challenges in Enrollment of Minority, Pediatric, and Geriatric Patients in Emergency and Acute Care Clinical Research

STUDY OBJECTIVE Emergency department (ED) -based clinical research has the potential to include patient populations that are typically underrepresented in clinical research. The objective of this study is to assess how emergency clinical care and research processes, informed consent, and patient demographic factors (age, sex, and ethnicity/race) affect enrollment and consent in clinical research in the ED. METHODS This was an analysis of prospectively collected data of all patients (aged 2 to 101 years) eligible for one of 7 clinical research studies from February 2005 to April 2007 in an academic ED. We measured rates of enrollment and consent in the clinical studies. RESULTS One thousand two hundred two of the 4418 patients screened for participation in 7 clinical studies were clinically eligible for enrollment. Of the 868 patients who were able to provide a voluntary decision regarding consent, 639 (73.6%) agreed to participate; an overall enrollment rate of 53.2%. The mean age of patients enrolled was 51.8 years (range 3 to 98 years). Black patients (49.2% enrollment) and Latino patients (18.4% enrollment) were less likely to be enrolled in comparison with white patients (58.3% enrollment) (adjusted odds ratio [OR] of enrollment for blacks=0.64; 95% confidence interval [CI] 0.50 to 0.82; adjusted OR of enrollment for Latinos=0.16; 95% CI 0.08 to 0.33). Enrollment rates were lower among pediatric (40.0%) and geriatric patients (49.1%) in comparison with adult patients ages 18 to 64 years (55.5%) (adjusted OR of enrollment for pediatric patients=0.70, 95% CI 0.34 to 1.43; adjusted OR of enrollment for geriatric patients=0.69, 95% CI 0.53 to 0.90). Unique issues contributing to underenrollment included challenges in consent among pediatric and elderly patients, language issues in Latino patients, reduced voluntary consent rates among black patients, and perhaps underuse of minimal risk waivers. CONCLUSION In a large academic ED, minority, pediatric, and geriatric patients were less likely to be enrolled in acute care clinical research studies than middle-aged whites. Enrollment and consent strategies designed to enhance research participation in these important patient populations may be necessary to address disparities in the development and application of evidence-based emergency and acute care.

Rapid Emergency Department Heart Failure Outpatients Trial (REDHOT II) A Randomized Controlled Trial of the Effect of Serial B-Type Natriuretic Peptide Testing on Patient Management

Background— B-type natriuretic peptide is useful to diagnose heart failure. We determined whether the use of serial B-type natriuretic peptide measurements to guide treatment improves the outcome in patients with acute heart failure. Methods and Results— We conducted a randomized controlled trial of patients with acute heart failure in 10 academic and community emergency departments. The experimental group received serial B-type natriuretic peptide testing (at 3, 6, 9, and 12 hours then daily). The control group received usual care. Our outcomes were hospital length of stay, 30-day readmission rate, and all-cause mortality. There were 219 controls and 228 experimental patients. Mean age was 64 years, 49% were women, 58% were blacks, and 34% were whites. Groups were similar in baseline characteristics. Comparing the serial testing with the control group, there was no difference in length of stay (6.5 days [95% CI, 5.2 to 7.9] versus 6.5 days [95% CI, 5.6 to 7.3]; difference, 0.1 [95% CI, −1.7 to 1.5]), in-hospital mortality (2.2% [95% CI, 0.9 to 5.0] versus controls, 3.2% [95% CI, 1.6 to 6.5]; difference, 1.0% [95% CI, −2.3 to 4.5]), 30-day mortality (3.7% [95% CI, 1.8 to 7.5] versus 5.5% [95% CI, 3.0 to 9.8]; difference, 1.8% [95% CI, −2.8 to 6.5]), or hospital revisit rate (20.2% [95% CI, 15.0 to 26.6] versus 23.7% [95% CI, 18.0 to 30.6]; difference, 3.5% [95% CI, −5.1 to 12.1]). Conclusions— In this study of 447 patients hospitalized for suspected heart failure, we were unable to demonstrate a benefit of serial testing with B-type natriuretic peptide in terms of hospital length of stay, mortality, or readmission rate. Received October 7, 2008; accepted April 2, 2009.Background—B-type natriuretic peptide is useful to diagnose heart failure. We determined whether the use of serial B-type natriuretic peptide measurements to guide treatment improves the outcome in patients with acute heart failure. Methods and Results—We conducted a randomized controlled trial of patients with acute heart failure in 10 academic and community emergency departments. The experimental group received serial B-type natriuretic peptide testing (at 3, 6, 9, and 12 hours then daily). The control group received usual care. Our outcomes were hospital length of stay, 30-day readmission rate, and all-cause mortality.There were 219 controls and 228 experimental patients. Mean age was 64 years, 49% were women, 58% were blacks, and 34% were whites. Groups were similar in baseline characteristics. Comparing the serial testing with the control group, there was no difference in length of stay (6.5 days [95% CI, 5.2 to 7.9] versus 6.5 days [95% CI, 5.6 to 7.3]; difference, 0.1 [95% CI, −1.7 to 1.5]), in-hospital mortality (2.2% [95% CI, 0.9 to 5.0] versus controls, 3.2% [95% CI, 1.6 to 6.5]; difference, 1.0% [95% CI, −2.3 to 4.5]), 30-day mortality (3.7% [95% CI, 1.8 to 7.5] versus 5.5% [95% CI, 3.0 to 9.8]; difference, 1.8% [95% CI, −2.8 to 6.5]), or hospital revisit rate (20.2% [95% CI, 15.0 to 26.6] versus 23.7% [95% CI, 18.0 to 30.6]; difference, 3.5% [95% CI, −5.1 to 12.1]). Conclusions—In this study of 447 patients hospitalized for suspected heart failure, we were unable to demonstrate a benefit of serial testing with B-type natriuretic peptide in terms of hospital length of stay, mortality, or readmission rate.

Clevidipine in acute heart failure: Results of the A Study of Blood Pressure Control in Acute Heart Failure - A Pilot Study (PRONTO)

BACKGROUND Rapid blood pressure (BP) control improves dyspnea in hypertensive acute heart failure (AHF). Although effective antihypertensives, calcium-channel blockers are poorly studied in AHF. Clevidipine is a rapidly acting, arterial selective intravenous calcium-channel blocker. Our purpose was to determine the efficacy and safety of clevidipine vs standard-of-care intravenous antihypertensive therapy (SOC) in hypertensive AHF. METHODS This is a randomized, open-label, active control study of clevidipine vs SOC in emergency department patients with AHF having systolic BP ≥160 mm Hg and dyspnea ≥50 on a 100-mm visual analog scale (VAS). Coprimary end points were median time to, and percent attaining, a systolic BP within a prespecified target BP range (TBPR) at 30 minutes. Dyspnea reduction was the main secondary end point. RESULTS Of 104 patients (mean [SD] age 61 [14.9] years, 52% female, 80% African American), 51 received clevidipine and 53 received SOC. Baseline mean (SD) systolic BP and VAS dyspnea were 186.5 (23.4) mm Hg and 64.8 (19.6) mm. More clevidipine patients (71%) reached TBPR than did those receiving SOC (37%; P = .002), and clevidipine was faster to TBPR (P = .0006). At 45 minutes, clevidipine patients had greater mean (SD) VAS dyspnea improvement than did SOC patients (-37 [20.9] vs -28 mm [21.7], P = .02), a difference that remained significant up to 3 hours. Serious adverse events (24% vs 19%) and 30-day mortality (3 vs 2) were similar between clevedipine and SOC, respectively, and there were no deaths during study drug administration. CONCLUSIONS In hypertensive AHF, clevidipine safely and rapidly reduces BP and improves dyspnea more effectively than SOC.

Rapid Emergency Department Heart Failure Outpatients Trial (REDHOT II)CLINICAL PERSPECTIVE

Background— B-type natriuretic peptide is useful to diagnose heart failure. We determined whether the use of serial B-type natriuretic peptide measurements to guide treatment improves the outcome in patients with acute heart failure. Methods and Results— We conducted a randomized controlled trial of patients with acute heart failure in 10 academic and community emergency departments. The experimental group received serial B-type natriuretic peptide testing (at 3, 6, 9, and 12 hours then daily). The control group received usual care. Our outcomes were hospital length of stay, 30-day readmission rate, and all-cause mortality. There were 219 controls and 228 experimental patients. Mean age was 64 years, 49% were women, 58% were blacks, and 34% were whites. Groups were similar in baseline characteristics. Comparing the serial testing with the control group, there was no difference in length of stay (6.5 days [95% CI, 5.2 to 7.9] versus 6.5 days [95% CI, 5.6 to 7.3]; difference, 0.1 [95% CI, −1.7 to 1.5]), in-hospital mortality (2.2% [95% CI, 0.9 to 5.0] versus controls, 3.2% [95% CI, 1.6 to 6.5]; difference, 1.0% [95% CI, −2.3 to 4.5]), 30-day mortality (3.7% [95% CI, 1.8 to 7.5] versus 5.5% [95% CI, 3.0 to 9.8]; difference, 1.8% [95% CI, −2.8 to 6.5]), or hospital revisit rate (20.2% [95% CI, 15.0 to 26.6] versus 23.7% [95% CI, 18.0 to 30.6]; difference, 3.5% [95% CI, −5.1 to 12.1]). Conclusions— In this study of 447 patients hospitalized for suspected heart failure, we were unable to demonstrate a benefit of serial testing with B-type natriuretic peptide in terms of hospital length of stay, mortality, or readmission rate. Received October 7, 2008; accepted April 2, 2009.Background—B-type natriuretic peptide is useful to diagnose heart failure. We determined whether the use of serial B-type natriuretic peptide measurements to guide treatment improves the outcome in patients with acute heart failure. Methods and Results—We conducted a randomized controlled trial of patients with acute heart failure in 10 academic and community emergency departments. The experimental group received serial B-type natriuretic peptide testing (at 3, 6, 9, and 12 hours then daily). The control group received usual care. Our outcomes were hospital length of stay, 30-day readmission rate, and all-cause mortality.There were 219 controls and 228 experimental patients. Mean age was 64 years, 49% were women, 58% were blacks, and 34% were whites. Groups were similar in baseline characteristics. Comparing the serial testing with the control group, there was no difference in length of stay (6.5 days [95% CI, 5.2 to 7.9] versus 6.5 days [95% CI, 5.6 to 7.3]; difference, 0.1 [95% CI, −1.7 to 1.5]), in-hospital mortality (2.2% [95% CI, 0.9 to 5.0] versus controls, 3.2% [95% CI, 1.6 to 6.5]; difference, 1.0% [95% CI, −2.3 to 4.5]), 30-day mortality (3.7% [95% CI, 1.8 to 7.5] versus 5.5% [95% CI, 3.0 to 9.8]; difference, 1.8% [95% CI, −2.8 to 6.5]), or hospital revisit rate (20.2% [95% CI, 15.0 to 26.6] versus 23.7% [95% CI, 18.0 to 30.6]; difference, 3.5% [95% CI, −5.1 to 12.1]). Conclusions—In this study of 447 patients hospitalized for suspected heart failure, we were unable to demonstrate a benefit of serial testing with B-type natriuretic peptide in terms of hospital length of stay, mortality, or readmission rate.

Acute Detection of ST-Elevation Myocardial Infarction Missed on Standard 12-Lead ECG With a Novel 80-Lead Real-Time Digital Body Surface Map: Primary Results From the Multicenter OCCULT MI Trial

STUDY OBJECTIVE Although 80-lead ECG body surface mapping is more sensitive for ST-elevation myocardial infarction (STEMI) than the 12-lead ECG, its clinical utility in chest pain in the emergency department (ED) has not been studied. We sought to determine the prevalence, clinical care patterns, and clinical outcomes of patients with STEMI identified on 80-lead but not on 12-lead (80-lead-only STEMI). METHODS The Optimal Cardiovascular Diagnostic Evaluation Enabling Faster Treatment of Myocardial Infarction trial was a multicenter prospective observational study of moderate- to high-risk chest pain patients presenting to the ED. Patients received simultaneous 12-lead and 80-lead ECGs as part of their initial evaluation and were treated according to the standard of care, with clinicians blinded to the 80-lead results. The primary outcome of the trial was door-to-sheath time in patients with 80-lead-only STEMI versus patients with STEMI identified by 12-lead alone (12-lead STEMI). Secondary outcomes included angiographic and clinical outcomes at 30 days. RESULTS One thousand eight hundred thirty patients were evaluated, 91 had a discharge diagnosis of 12-lead STEMI, and 25 patients met criteria for 80-lead-only STEMI. Eighty-four of the 91 12-lead STEMI patients underwent cardiac catheterization, with a median door-to-sheath time of 54 minutes, versus 14 of the 25 80-lead-only STEMI patients, with a door-to-sheath time of 1,002 minutes (estimated treatment difference in median=881; 95% confidence interval 181 to 1,079 minutes). Clinical outcomes and revascularization rates, however, were similar between 80-lead-only STEMI and 12-lead STEMI patients. CONCLUSION The 80-lead ECG provides an incremental 27.5% increase in STEMI detection versus the 12-lead. Patients with 80-lead-only STEMI have adverse outcomes similar to those of 12-lead STEMI patients but are treated with delayed or conservative invasive strategies.

CLUE: a randomized comparative effectiveness trial of IV nicardipine versus labetalol use in the emergency department

IntroductionOur purpose was to compare the safety and efficacy of food and drug administration (FDA) recommended dosing of IV nicardipine versus IV labetalol for the management of acute hypertension.MethodsMulticenter randomized clinical trial. Eligible patients had 2 systolic blood pressure (SBP) measures ≥180 mmHg and no contraindications to nicardipine or labetalol. Before randomization, the physician specified a target SBP ± 20 mmHg (the target range: TR). The primary endpoint was the percent of subjects meeting TR during the initial 30 minutes of treatment.ResultsOf 226 randomized patients, 110 received nicardipine and 116 labetalol. End organ damage preceded treatment in 143 (63.3%); 71 nicardipine and 72 labetalol patients. Median initial SBP was 212.5 (IQR 197, 230) and 212 mmHg (IQR 200,225) for nicardipine and labetalol patients (P = 0.68), respectively. Within 30 minutes, nicardipine patients more often reached TR than labetalol (91.7 vs. 82.5%, P = 0.039). Of 6 BP measures (taken every 5 minutes) during the study period, nicardipine patients had higher rates of five and six instances within TR than labetalol (47.3% vs. 32.8%, P = 0.026). Rescue medication need did not differ between nicardipine and labetalol (15.5 vs. 22.4%, P = 0.183). Labetalol patients had slower heart rates at all time points (P < 0.01). Multivariable modeling showed nicardipine patients were more likely in TR than labetalol patients at 30 minutes (OR 2.73, P = 0.028; C stat for model = 0.72)ConclusionsPatients treated with nicardipine are more likely to reach the physician-specified SBP target range within 30 minutes than those treated with labetalol.Trial registrationClinicalTrials.gov: NCT00765648

The Rapid Impact on Mortality Rates of a Dedicated Care Team Including Trauma and Emergency Physicians at an Academic Medical Center

BACKGROUND Trauma center designation can result in improved patient outcomes after injuries. Whereas the presence of trauma teams has been associated with improved trauma patient outcomes, the specific components, including the role of emergency medicine (EM)-trained, board-certified emergency physicians, have not been defined. OBJECTIVE To assess the outcomes of patients before and after the establishment of a dedicated trauma team that incorporated full-time EM-trained physicians with trauma specialists at a Level I trauma center at an academic institution. METHODS Secondary analysis of prospectively collected trauma registry data was performed to compare mortality rates of all treated trauma patients before and after this intervention. RESULTS The establishment of a dedicated specialty trauma team incorporating full-time EM presence including EM-trained, board-certified emergency physicians was associated with a reduction in overall non-DOA (dead on arrival) mortality rate from 6.0% to 4.1% from the time period preceding (1999-2000) to the time period after (2002-2003) this intervention (1.9% absolute reduction in mortality, 95% confidence interval [CI] 0.7%-3.0%). Among patients who were most severely injured (Injury Severity Score [ISS] ≥ 25), mortality rates decreased from 30.2% to 22.0% (8.3% absolute reduction in mortality, 95% CI 2.1%-14.4%). In comparison, there was minimal change in national mortality rates for patients with ISS ≥ 25 during the same time period (33% to 34%). CONCLUSIONS The implementation of a dedicated full-time trauma team incorporating both trauma surgeons and EM-trained, board-certified or -eligible emergency physicians was associated with improved mortality rates in trauma patients treated at a Level I academic medical center, including those patients presenting with the most severe injuries.

An Analysis of the Association of Society of Chest Pain Centers Accreditation to American College of Cardiology/American Heart Association Non–ST-Segment Elevation Myocardial Infarction Guideline Adherence

STUDY OBJECTIVE Since 2003, the Society of Chest Pain Centers (SCPC) has provided hospital accreditation for acute coronary syndrome care processes. Our objective is to evaluate the association between SCPC accreditation and adherence to the American College of Cardiology/American Heart Association (ACC/AHA) evidence-based guidelines for non-ST-segment elevation myocardial infarction (NSTEMI). The secondary objective is to describe the clinical outcomes and the association with accreditation. METHODS We conducted a secondary analysis of data from patients with NSTEMI 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 in 2005. The analysis explored differences between SCPC-accredited and nonaccredited hospitals in evidence-based therapy given within the first 24 hours (including aspirin, beta-blocker, glycoprotein IIb/IIIa inhibitors, heparin, and ECG within 10 minutes). RESULTS Of 33,238 patients treated at 21 accredited hospitals and 323 nonaccredited hospitals, those at SCPC-accredited centers (n=3,059) were more likely to receive aspirin (98.1% versus 95.8%; odds ratio [OR] 1.73; 95% confidence interval [CI] 1.06 to 2.83) and beta-blockers (93.4% versus 90.6%; OR 1.68; 95% CI 1.04 to 2.70) within 24 hours than patients at non-SCPC-accredited centers (n=30,179). No difference was observed in obtaining a timely ECG (40.4% versus 35.2%; OR 1.28; 95% CI 0.98 to 1.67), administering a glycoprotein IIb/IIIa inhibitor (OR 1.30; 95% CI 0.93 to 1.80), or administering heparin (OR 1.12; 95% CI 0.74 to 1.70). Also, there was no significant difference in risk-adjusted mortality for patients treated at SCPC hospitals versus nonaccredited hospitals (3.4% versus 3.5%; adjusted OR 1.17; 95% CI 0.88 to 1.55). CONCLUSION SCPC-accredited hospitals had higher NSTEMI ACC/AHA evidence-based guideline adherence in the first 24 hours of care on 2 of the 5 measures. No difference in outcomes was observed. Further studies are needed to better understand the association between SCPC accreditation and improved care for patients with acute coronary syndrome.