Dose escalation for stereotactic arrhythmia radioablation of recurrent ventricular tachyarrhythmia - a phase II clinical trial.

BACKGROUND: Stereotactic arrhythmia radioablation (STAR) is delivered with a planning target volume (PTV) prescription dose of 25 Gy, mostly to the surrounding 75-85% isodose line. This means that the average and maximum dose received by the target is less than 35 Gy, which is the minimum threshold required to create a homogenous transmural fibrosis. Similar to catheter ablation, the primary objective of STAR should be transmural fibrosis to prevent heterogenous intracardiac conduction velocities and the occurrence of sustained ventricular arrhythmias (sVA) caused by reentry. We hypothesize that the current dose prescription used in STAR is inadequate for the long-term prevention of sVA and that a significant increase in dose is necessary to induce transmural scar formation. OBJECTIVE: A single arm, multi-center, phase II, dose escalation prospective clinical trial employing the i3 + 3 design is being conducted to examine the safety of a radiation dose-escalation strategy aimed at inducing transmural scar formation. The ultimate objective of this trial is to decrease the likelihood of sVA recurrence in patients at risk. METHODS: Patients with ischemic or non-ischemic cardiomyopathy and recurrent sVA, with an ICD and history of ≥ 1 catheter ablation for sVA will be included. This is a prospective, multicenter, one-arm, dose-escalation trial utilizing the i3 + 3 design, a modified 3 + 3 specifically created to overcome limitations in traditional dose-finding studies. A total of 15 patients will be recruited. The trial aims to escalate the ITV dose from 27.0 Gy to an ITV prescription dose-equivalent level of maximum 35.1 Gy by keeping the PTV prescription dose constant at 25 Gy while increasing the dose to the target (i.e. the VT substrate without PTV margin) by step-wise reduction of the prescribing isodose line (85% down to 65%). The primary outcome of this trial is safety measured by registered radiation associated adverse events (AE) up to 90 days after study intervention including radiation associated serious adverse events graded as at least 4 or 5 according to CTCAE v5, radiation pneumonitis or pericarditis requiring hospitalization and decrease in LVEF ≥ 10% as assessed by echocardiography or cardiac MRI at 90 days after STAR. The sample size was determined assuming an acceptable primary outcome event rate of 20%. Secondary outcomes include sVA burden at 6 months after STAR, time to first sVA recurrence, reduction in appropriate ICD therapies, the need for escalation of antiarrhythmic drugs, non-radiation associated safety and patient reported outcome measures such as SF-36 and EQ5D. DISCUSSION: DEFT-STAR is an innovative prospective phase II trial that aims to evaluate the optimal radiation dose for STAR in patients with therapy-refractory sVA. The trial has obtained IRB approval and focuses on determining the safe and effective radiation dose to be employed in the STAR procedure. TRIAL REGISTRATION: NCT05594368.

The Meaning of SARS-CoV-2 Antibodies in a Patient with a Systemic Reaction to the mRNA-1273 SARS-CoV-2 Vaccine after Previous Natural Immunization.

OBJECTIVES: There is limited experience regarding the meaning of SARS-CoV-2 antibodies after vaccination in patients with naturally acquired immunity. METHODS: We describe the case of a patient who received the first dose of the mRNA-1273 SARS-CoV-2 vaccine 6 months after his recovery from moderately severe COVID-19. RESULTS: Our patient had a positive nucleocapsid SARS-CoV-2 IgG/IgM titre with 78.7 multiple of cut-off indicating persistent humoral immune response 6 months after infection. After vaccination, he developed prolonged systemic symptoms (fever, fatigue, nausea, diarrhoea and myalgia) for a duration of 6 days. CONCLUSION: SARS-CoV-2 nucleocapsid antibodies provide information about naturally acquired immunity. For the assessment of immune response to vaccination, measurement of the SARS-CoV-2 spike antibody titre before and after vaccination is essential. Patients with naturally acquired immunity might develop a prolonged systemic reaction to the first dose of the mRNA-1273 SARS-CoV-2 vaccine. LEARNING POINTS: Patients with naturally acquired immunity might develop a prolonged systemic reaction after receiving an mRNA SARS-CoV-2 vaccine.Depending on the clinical situation of SARS-CoV-2 infection and/or vaccination, different antibody titres should be determined.The SARS-CoV-2 nucleocapsid antibodies provide information on whether or not natural immunization has taken place. To quantify the immune response induced by vaccination, the SARS-CoV-2 spike antibody titre before and after vaccination has to be measured.

Incidence of major adverse cardiac events following non-cardiac surgery.

AIMS: Major adverse cardiac events (MACE) triggered by non-cardiac surgery are prognostically important perioperative complications. However, due to often asymptomatic presentation, the incidence and timing of postoperative MACE are incompletely understood. METHODS AND RESULTS: We conducted a prospective observational study implementing a perioperative screening for postoperative MACE [cardiovascular death (CVD), acute heart failure (AHF), haemodynamically relevant arrhythmias, spontaneous myocardial infarction (MI), and perioperative myocardial infarction/injury (PMI)] in patients at increased cardiovascular risk (≥65 years OR ≥45 years with history of cardiovascular disease) undergoing non-cardiac surgery at a tertiary hospital. All patients received serial measurements of cardiac troponin to detect asymptomatic MACE. Among 2265 patients (mean age 73 years, 43.4% women), the incidence of MACE was 15.2% within 30 days, and 20.6% within 365 days. CVD occurred in 1.2% [95% confidence interval (CI) 0.9-1.8] and in 3.7% (95% CI 3.0-4.5), haemodynamically relevant arrhythmias in 1.2% (95% CI 0.9-1.8) and in 2.1% (95% CI 1.6-2.8), AHF in 1.6% (95% CI 1.2-2.2) and in 4.2% (95% CI 3.4-5.1), spontaneous MI in 0.5% (95% CI 0.3-0.9) and in 1.6% (95% CI 1.2-2.2), and PMI in 13.2% (95% CI 11.9-14.7) and in 14.8% (95% CI 13.4-16.4) within 30 days and within 365 days, respectively. The MACE-incidence was increased above presumed baseline rate until Day 135 (95% CI 104-163), indicating a vulnerable period of 3-5 months. CONCLUSION: One out of five high-risk patients undergoing non-cardiac surgery will develop one or more MACE within 365 days. The risk for MACE remains increased for about 5 months after non-cardiac surgery. TRIAL REGISTRATION: https://www.clinicaltrials.gov. Unique identifier: NCT02573532.

Incidence and outcomes of unstable angina compared with non-ST-elevation myocardial infarction.

OBJECTIVE: Assess the relative incidence and compare characteristics and outcome of unstable angina (UA) and non-ST-elevation myocardial infarction (NSTEMI). DESIGN: Two independent prospective multicentre diagnostic studies (Advantageous Predictors of Acute Coronary Syndromes Evaluation [APACE] and High-Sensitivity Troponin in the Evaluation of Patients With Acute Coronary Syndrome [High-STEACS]) enrolling patients with acute chest discomfort presenting to the emergency department. Central adjudication of the final diagnosis was done by two independent cardiologists using all clinical information including serial measurements of high-sensitivity cardiac troponin (hs-cTn). All-cause death and future non-fatal MI were assessed at 30 days and 1 year. RESULTS: 8992 patients were enrolled at 11 centres. UA was adjudicated in 8.9%(95% CI 8.0 to 9.7) and 2.8% (95% CI 2.3 to 3.3) patients in APACE and High-STEACS, respectively, and NSTEMI in 15.1% (95% CI 14.0 to 16.2) and 13.4% (95% CI 12.4 to 14.3). Coronary artery disease was pre-existing in 73% and 76% of patients with UA. At 30 days, all-cause mortality in UA was substantially lower as compared with NSTEMI (0.5% vs 3.7%, p=0.002 in APACE, 0.7% vs 7.4%, p=0.004 in High-STEACS). Similarly, at 1 year in UA all-cause mortality was 3.3% (95% CI 1.2 to 5.3) vs 10.4% (95% CI 7.9 to 12.9) in APACE, and 5.1% (95% CI 0.7 to 9.5) vs 22.9% (95% CI 19.3 to 26.4) in High-STEACS, and similar to non-cardiac chest pain (NCCP). In contrast, future non-fatal MI in APACE was comparable in UA and NSTEMI (11.2%, 95% CI 7.8 to 14.6 and 7.9%, 95% CI 5.7 to 10.2), and higher than in NCCP (0.6%, 95% CI 0.2 to 1.0). CONCLUSIONS: The relative incidence and mortality of UA is substantially lower than that of NSTEMI, while the rate of future non-fatal MI is similar.

Incremental diagnostic and prognostic value of the QRS-T angle, a 12-lead ECG marker quantifying heterogeneity of depolarization and repolarization, in patients with suspected non-ST-elevation myocardial infarction.

BACKGROUND: The value of the 12-lead ECG in the diagnosis of non-ST-elevation myocardial infarction (NSTEMI) is limited due to insufficient sensitivity and specificity of standard ECG criteria. The QRS-T angle reflects depolarization-repolarization heterogeneity and might assist in detecting patients with a NSTEMI (diagnosis) as well as predicting patients with an increased mortality risk (prognosis). METHODS: We prospectively enrolled 2705 consecutive patients with symptoms suggestive of NSTEMI. The QRS-T angle was automatically derived from the standard 10 s 12-lead ECG recorded at presentation to the ED. Patients were followed up for all-cause mortality for 2 years. RESULTS: NSTEMI was the final diagnosis in 15% (n = 412) of patients. QRS-T angles were significantly greater in patients with NSTEMI compared to those without (p < 0.001). The use of the QRS-T angle in addition to standard ECG criteria indicative of ischemia improved the diagnostic accuracy for NSTEMI as quantified by the area under the ROC curve from 0.68 to 0.72 (p < 0.001). An algorithm for the combined use of standard ECG criteria and the QRS-T angle improved the sensitivity of the ECG for NSTEMI from 45% to 78% and the specificity from 86% to 91% (p < 0.001 for both comparisons). The 2-year survival rates were 98%, 97% and 87% according to QRS-T angle tertiles (p < 0.001). CONCLUSION: In patients with suspected NSTEMI, the QRS-T angle derived from the standard 12-lead ECG provides incremental diagnostic accuracy on top of standard ECG criteria indicative of ischemia, and independently predicts all-cause mortality during 2 years of follow-up.

Daytime variation of perioperative myocardial injury in non-cardiac surgery and effect on outcome.

OBJECTIVE: Recently, daytime variation in perioperative myocardial injury (PMI) has been observed in patients undergoing cardiac surgery. We aim at investigating whether daytime variation also occurs in patients undergoing non-cardiac surgery. METHODS: In a prospective diagnostic study, we evaluated the presence of daytime variation in PMI in patients at increased cardiovascular risk undergoing non-cardiac surgery, as well as its possible impact on the incidence of acute myocardial infarction (AMI), and death during 1-year follow-up in a propensity score-matched cohort. PMI was defined as an absolute increase in high-sensitivity cardiac troponin T (hs-cTnT) concentration of ≥14 ng/L from preoperative to postoperative measurements. RESULTS: Of 1641 patients, propensity score matching defined 630 with similar baseline characteristics, half undergoing non-cardiac surgery in the morning (starting from 8:00 to 11:00) and half in the afternoon (starting from 14:00 to 17:00). There was no difference in PMI incidence between both groups (morning: 50, 15.8% (95% CI 12.3 to 20.3); afternoon: 52, 16.4% (95% CI 12.7 to 20.9), p=0.94), nor if analysing hs-cTnT release as a quantitative variable (median morning group: 3 ng/L (95% CI 1 to 7 ng/L); median afternoon group: 2 ng/L (95% CI 0 to 7 ng/L; p=0.16). During 1-year follow-up, the incidence of AMI was 1.2% (95% CI 0.4% to 3.2%) among morning surgeries versus 4.1% (95% CI 2.3% to 6.9%) among the afternoon surgeries (corrected HR for afternoon surgery 3.44, bootstrapped 95% CI 1.33 to 10.49, p log-rank=0.03), whereas no difference in mortality emerged (p=0.70). CONCLUSIONS: Although there is no daytime variation in PMI in patients undergoing non-cardiac surgery, the incidence of AMI during follow-up is increased in afternoon surgeries and requires further study. CLINICAL TRIAL REGISTRATION: NCT02573532;Results.

Prospective validation of prognostic and diagnostic syncope scores in the emergency department.

BACKGROUND: Various scores have been derived for the assessment of syncope patients in the emergency department (ED) but stay inconsistently validated. We aim to compare their performance to the one of a common, easy-to-use CHADS2 score. METHODS: We prospectively enrolled patients ≥ 40 years old presenting with syncope to the ED in a multicenter study. Early clinical judgment (ECJ) of the treating ED-physician regarding the probability of cardiac syncope was quantified. Two independent physicians adjudicated the final diagnosis after 1-year follow-up. Major cardiovascular events (MACE) and death were recorded during 2 years of follow-up. Nine scores were compared by their area under the receiver-operator characteristics curve (AUC) for death, MACE or the diagnosis of cardiac syncope. RESULTS: 1490 patients were available for score validation. The CHADS2-score presented a higher or equally high accuracy for death in the long- and short-term follow-up than other syncope-specific risk scores. This score also performed well for the prediction of MACE in the long- and short-term evaluation and stratified patients with accuracy comparative to OESIL, one of the best performing syncope-specific risk score. All scores performed poorly for diagnosing cardiac syncope when compared to the ECJ. CONCLUSIONS: The CHADS2-score performed comparably to more complicated syncope-specific risk scores in the prediction of death and MACE in ED syncope patients. While better tools incorporating biochemical and electrocardiographic markers are needed, this study suggests that the CHADS2-score is currently a good option to stratify risk in syncope patients in the ED. TRIAL REGISTRATION: NCT01548352.

Comparison of high-sensitivity cardiac troponin I and T for the prediction of cardiac complications after non-cardiac surgery.

BACKGROUND: We aimed to directly compare preoperative high-sensitivity cardiac troponin (hs-cTn) I and T concentration for the prediction of major cardiac complications after non-cardiac surgery. METHODS: We measured hs-cTnI and hs-cTnT preoperatively in a blinded fashion in 1022 patients undergoing non-cardiac surgery. The primary endpoint was a composite of major cardiac complications including cardiac death, cardiac arrest, myocardial infarction, clinically relevant arrhythmias, and acute heart failure within 30 days. We hypothesized that the type of surgery may impact on the predictive accuracy of hs-cTnI/T and stratified all analyses according to the type of surgery. RESULTS: Major cardiac complications occurred in 108 (11%) patients, 58/243 (24%) patients undergoing vascular surgery and 50/779 (6%, P < .001) patients undergoing non-vascular surgery. Using regulatory-approved 99th percentile cut-off concentrations, preoperative hs-cTnI elevations were less than one-fifth as common as preoperative hs-cTnT elevations (P < .001). Among patients undergoing vascular surgery, preoperative hs-cTnI concentrations, but not hs-cTnT, was an independent predictor of cardiac complications (adjusted odds ratio (aOR) 1.5, 95% confidence interval (95% CI) 1.0-2.1). The area under the receiver-operating characteristics curve (AUC) was 0.67 (95% CI, 0.59-0.75) for hs-cTnI versus 0.59 (95% CI 0.51-0.67, P = .012) for hs-cTnT. In contrast, among patients undergoing non-vascular surgery both preoperative hs-cTnI and hs-cTnT were independent predictors of the primary endpoint (aOR 1.6, 95% CI 1.3-2.0, and aOR 3.0, 95% CI 2.0-4.6, respectively) and showed higher predictive accuracy (AUC 0.77, 95% CI, 0.71-0.83, and 0.79, 95% CI 0.73-0.85, P = ns). CONCLUSIONS: Preoperative hs-cTnI and hs-cTnT concentrations predict major cardiac complications after non-vascular surgery, while, in patients undergoing vascular surgery, hs-cTnI may have better accuracy.

Automatically computed ECG algorithm for the quantification of myocardial scar and the prediction of mortality.

BACKGROUND: Myocardial scar is associated with adverse cardiac outcomes. The Selvester QRS-score was developed to estimate myocardial scar from the 12-lead ECG, but its manual calculation is difficult. An automatically computed QRS-score would allow identification of patients with myocardial scar and an increased risk of mortality. OBJECTIVES: To assess the diagnostic and prognostic value of the automatically computed QRS-score. METHODS: The diagnostic value of the QRS-score computed automatically from a standard digital 12-lead was prospectively assessed in 2742 patients with suspected myocardial ischemia referred for myocardial perfusion imaging (MPI). The prognostic value of the QRS-score was then prospectively tested in 1151 consecutive patients presenting to the emergency department (ED) with suspected acute heart failure (AHF). RESULTS: Overall, the QRS-score was significantly higher in patients with more extensive myocardial scar: the median QRS-score was 3 (IQR 2-5), 4 (IQR 2-6), and 7 (IQR 4-10) for patients with 0, 5-20 and > 20% myocardial scar as quantified by MPI (p < 0.001 for all pairwise comparisons). A QRS-score ≥ 9 (n = 284, 10%) predicted a large scar defined as > 20% of the LV with a specificity of 91% (95% CI 90-92%). Regarding clinical outcomes in patients presenting to the ED with symptoms suggestive of AHF, mortality after 1 year was 28% in patients with a QRS-score ≥ 3 as opposed to 20% in patients with a QRS-score < 3 (p = 0.001). CONCLUSIONS: The QRS-score can be computed automatically from the 12-lead ECG for simple, non-invasive and inexpensive detection and quantification of myocardial scar and for the prediction of mortality. TRIAL-REGISTRATION: http://www.clinicaltrials.gov . Identifier, NCT01838148 and NCT01831115.

Diagnostic and prognostic value of QRS duration and QTc interval in patients with suspected myocardial infarction.

BACKGROUND: While prolongation of QRS duration and QTc interval during acute myocardial infarction (AMI) has been reported in animals, limited data is available for these readily available electrocardiography (ECG) markers in humans. METHODS: Diagnostic and prognostic value of QRS duration and QTc interval in patients with suspected AMI in a prospective diagnostic multicentre study were prospectively assessed. Digital 12-lead ECGs were recorded at presentation. QRS duration and QTc interval were automatically calculated in a blinded fashion. Final diagnosis was adjudicated by two independent cardiologists. The prognostic endpoint was all-cause mortality during 24 months of follow-up. RESULTS: Among 4042 patients, AMI was the final diagnosis in 19% of patients. Median QRS duration and median QTc interval were significantly greater in patients with AMI compared to those with other final diagnoses (98 ms [IQR 88-108] vs. 94 ms [IQR 86-102] and 436 ms [IQR 414-462] vs. 425 ms [IQR 407-445], p < 0.001 for both comparisons). The diagnostic value of both ECG signatures however was only modest (AUC 0.56 and 0.60). Cumulative mortality rates after 2 years were 15.9% vs. 5.6% in patients with a QRS > 120 ms compared to a QRS duration ≤ 120 ms (p < 0.001), and 11.4% vs. 4.3% in patients with a QTc > 440 ms compared to a QRS duration ≤ 440 ms (p < 0.001). After adjustment for age and important ECG and clinical parameters, the QTc interval but not QRS duration remained an independent predictor of mortality. CONCLUSIONS: Prolongation of QRS duration > 120 ms and QTc interval > 440 ms predict mortality in patients with suspected AMI, but do not add diagnostic value.

Perioperative Myocardial Injury After Noncardiac Surgery: Incidence, Mortality, and Characterization.

BACKGROUND: Perioperative myocardial injury (PMI) seems to be a contributor to mortality after noncardiac surgery. Because the vast majority of PMIs are asymptomatic, PMI usually is missed in the absence of systematic screening. METHODS: We performed a prospective diagnostic study enrolling consecutive patients undergoing noncardiac surgery who had a planned postoperative stay of ≥24 hours and were considered at increased cardiovascular risk. All patients received a systematic screening using serial measurements of high-sensitivity cardiac troponin T in clinical routine. PMI was defined as an absolute high-sensitivity cardiac troponin T increase of ≥14 ng/L from preoperative to postoperative measurements. Furthermore, mortality was compared among patients with PMI not fulfilling additional criteria (ischemic symptoms, new ECG changes, or imaging evidence of loss of viable myocardium) required for the diagnosis of spontaneous acute myocardial infarction versus those that did. RESULTS: From 2014 to 2015 we included 2018 consecutive patients undergoing 2546 surgeries. Patients had a median age of 74 years and 42% were women. PMI occurred after 397 of 2546 surgeries (16%; 95% confidence interval, 14%-17%) and was accompanied by typical chest pain in 24 of 397 patients (6%) and any ischemic symptoms in 72 of 397 (18%). Crude 30-day mortality was 8.9% (95% confidence interval [CI], 5.7-12.0) in patients with PMI versus 1.5% (95% CI, 0.9-2.0) in patients without PMI (P<0.001). Multivariable regression analysis showed an adjusted hazard ratio of 2.7 (95% CI, 1.5-4.8) for 30-day mortality. The difference was retained at 1 year with mortality rates of 22.5% (95% CI, 17.6-27.4) versus 9.3% (95% CI, 7.9-10.7). Thirty-day mortality was comparable among patients with PMI not fulfilling any other of the additional criteria required for spontaneous acute myocardial infarction (280/397, 71%) versus those with at least 1 additional criterion (10.4%; 95% CI, 6.7-15.7, versus 8.7%; 95% CI, 4.2-16.7; P=0.684). CONCLUSIONS: PMI is a common complication after noncardiac surgery and, despite early detection during routine clinical screening, is associated with substantial short- and long-term mortality. Mortality seems comparable in patients with PMI not fulfilling any other of the additional criteria required for spontaneous acute myocardial infarction versus those patients who do. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02573532.

0/1-Hour Triage Algorithm for Myocardial Infarction in Patients With Renal Dysfunction.

BACKGROUND: The European Society of Cardiology recommends a 0/1-hour algorithm for rapid rule-out and rule-in of non-ST-segment elevation myocardial infarction using high-sensitivity cardiac troponin (hs-cTn) concentrations irrespective of renal function. Because patients with renal dysfunction (RD) frequently present with increased hs-cTn concentrations even in the absence of non-ST-segment elevation myocardial infarction, concern has been raised regarding the performance of the 0/1-hour algorithm in RD. METHODS: In a prospective multicenter diagnostic study enrolling unselected patients presenting with suspected non-ST-segment elevation myocardial infarction to the emergency department, we assessed the diagnostic performance of the European Society of Cardiology 0/1-hour algorithm using hs-cTnT and hs-cTnI in patients with RD, defined as an estimated glomerular filtration rate <60 mL/min/1.73 m2, and compared it to patients with normal renal function. The final diagnosis was centrally adjudicated by 2 independent cardiologists using all available information, including cardiac imaging. Safety was quantified as sensitivity in the rule-out zone, accuracy as the specificity in the rule-in zone, and efficacy as the proportion of the overall cohort assigned to either rule-out or rule-in based on the 0- and 1-hour sample. RESULTS: Among 3254 patients, RD was present in 487 patients (15%). The prevalence of non-ST-segment elevation myocardial infarction was substantially higher in patients with RD compared with patients with normal renal function (31% versus 13%, P<0.001). Using hs-cTnT, patients with RD had comparable sensitivity of rule-out (100.0% [95% confidence interval {CI}, 97.6-100.0] versus 99.2% [95% CI, 97.6-99.8]; P=0.559), lower specificity of rule-in (88.7% [95% CI, 84.8-91.9] versus 96.5% [95% CI, 95.7-97.2]; P<0.001), and lower overall efficacy (51% versus 81%, P<0.001), mainly driven by a much lower percentage of patients eligible for rule-out (18% versus 68%, P<0.001) compared with patients with normal renal function. Using hs-cTnI, patients with RD had comparable sensitivity of rule-out (98.6% [95% CI, 95.0-99.8] versus 98.5% [95% CI, 96.5-99.5]; P=1.0), lower specificity of rule-in (84.4% [95% CI, 79.9-88.3] versus 91.7% [95% CI, 90.5-92.9]; P<0.001), and lower overall efficacy (54% versus 76%, P<0.001; proportion ruled out, 18% versus 58%, P<0.001) compared with patients with normal renal function. CONCLUSIONS: In patients with RD, the safety of the European Society of Cardiology 0/1-hour algorithm is high, but specificity of rule-in and overall efficacy are decreased. Modifications of the rule-in and rule-out thresholds did not improve the safety or overall efficacy of the 0/1-hour algorithm. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00470587.

Combining high-sensitivity cardiac troponin and B-type natriuretic peptide in the detection of inducible myocardial ischemia.

BACKGROUND: Single biomarker approaches provide only moderate accuracy in the non-invasive detection of exercise-induced myocardial ischemia. We therefore assessed the combination of the two most promising single biomarkers: high-sensitivity cardiac troponin I (hs-cTnI) and B-type natriuretic peptide (BNP). METHODS: Consecutive patients with suspected myocardial ischemia referred to stress myocardial perfusion single-photon emission tomography imaging (MPI) were enrolled. Clinical judgment (CJ) of the treating cardiologist regarding myocardial ischemia, quantified using a visual analogue scale, and blood concentrations of hs-cTnI and BNP were determined before and after stress. The presence of myocardial ischemia was adjudicated by independent cardiologists using MPI, blinded to biomarker measurements. Death and acute myocardial infarction (AMI) during follow-up were the prognostic endpoints. RESULTS: Among 1142 consecutive patients inducible myocardial ischemia was found in 456 (40%) of all patients. For the detection of inducible myocardial ischemia, CJ before exercise stress testing (CJb) showed an area under the receiver-operating-characteristics curve (AUC) of 0.66 (95%CI 0.63-0.69), hs-cTnI 0.70 (95%CI 0.67-0.73, p=0.07 vs CJb), and BNP 0.66 (95%CI 0.62-0.69, p=0.98). The use of a dual-biomarker strategy combining hs-cTnI and BNP with CJb did not provide a significant advantage over the combination of hs-cTnI alone and CJb (AUC 0.74, 95%CI 0.72-0.77 vs AUC 0.74, 95%CI 0.71-0.77, p=0.16). Hs-cTnI showed good prognostic value for AMI (HR 1.6, 95%CI 1.3-1.9), and BNP for death (HR 1.6, 95%CI 1.3-2.1). CONCLUSION: A dual-biomarker strategy combing BNP and hs-cTnI does not further increase diagnostic accuracy on top of clinical judgment and hs-cTnI alone. SUMMARY AND HIGHLIGHTS: We included 1142 consecutive patients with suspected inducible ischemia, and evaluated the added value of the biomarkers high-sensitivity cardiac troponin (hs-cTn) and B-type natriuretic peptide (BNP), alone and in combination, on top of clinical judgment. CLINICAL TRIAL REGISTRATION: Biochemical and Electrocardiographic Signatures in the Detection of Exercise-induced Myocardial Ischemia (BASEL VIII), NCT01838148, https://clinicaltrials.gov/ct2/show/NCT01838148.

Prospective Validation of a Biomarker-Based Rule Out Strategy for Functionally Relevant Coronary Artery Disease.

BACKGROUND: This study aimed to prospectively advance a rule-out strategy for functionally significant coronary artery disease (CAD) by use of high-sensitivity cardiac troponin I (hs-cTnI) from bench to bedside, by application of a 3-step approach: validation in serum, correlation in plasma, and application on a clinical platform. METHODS: Patients without known CAD referred for rest/stress myocardial perfusion single-photon emission tomography/computer tomography (MPI-SPECT/CT) were assigned to 3 consecutive cohorts: validation, correlation, and application. Functionally relevant CAD was adjudicated with the use of expert interpretation of MPI-SPECT/CT and, if available, coronary angiography. In the validation cohort resting hs-cTnI was measured in serum before stress testing with the research Erenna system, in serum and plasma in the correlation cohort with the research Erenna system, and in plasma in the application cohort with the clinical Clarity system. RESULTS: Overall, functionally relevant CAD was adjudicated in 21% (304/1478) of patients. In the validation cohort (n = 613), hs-cTnI concentrations were significantly higher in patients with functionally relevant CAD (median 2.8 ng/L vs 1.9 ng/L, P < 0.001) as compared to patients without functionally relevant CAD and allowed a rule out with 95% sensitivity in 14% of patients. In the correlation cohort (n = 606), hs-cTnI concentrations in serum and plasma strongly correlated (Spearman r = 0.921) and had similar diagnostic accuracy as quantified by the area under the receiver operating characteristic curve (0.686 vs 0.678, P = 0.425). In the application cohort (n = 555), very low hs-cTnI plasma concentrations (< 0.5 ng/L) ruled out functionally relevant CAD with 95% sensitivity in 10% of patients. CONCLUSIONS: A single resting plasma hs-cTnI measurement can safely rule out functionally relevant CAD in around 10% of patients without known CAD.

Effect of Definition on Incidence and Prognosis of Type 2 Myocardial Infarction.

BACKGROUND: Uncertainties regarding the most appropriate definition and treatment of type 2 myocardial infarction (T2MI) due to supply-demand mismatch have contributed to inconsistent adoption in clinical practice. OBJECTIVES: This study sought a better understanding of the effect of the definition of T2MI on its incidence, treatment, and event-related mortality, thereby addressing an important unmet clinical need. METHODS: The final diagnosis was adjudicated in patients presenting with symptoms suggestive of myocardial infarction by 2 independent cardiologists by 2 methods: 1 method required the presence of coronary artery disease, a common interpretation of the 2007 universal definition (T2MI2007); and 1 method did not require coronary artery disease, the 2012 universal definition (T2MI2012). RESULTS: Overall, 4,015 consecutive patients were adjudicated. The incidence of T2MI based on the T2MI2007 definition was 2.8% (n = 112). The application of the more liberal T2MI2012 definition resulted in an increase of T2MI incidence of 6% (n = 240), a relative increase of 114% (128 reclassified patients, defined as T2MI2012reclassified). Among T2MI2007, 6.3% of patients received coronary revascularization, 22% dual-antiplatelet therapy, and 71% high-dose statin therapy versus 0.8%, 1.6%, and 31% among T2MI2012reclassified patients, respectively (all p < 0.01). Cardiovascular mortality at 90 days was 0% among T2MI2012reclassified, which was similar to patients with noncardiac causes of chest discomfort (0.2%), and lower than T2MI2007 (3.6%) and type 1 myocardial infarction (T1MI) (4.8%) (T2MI2012reclassified vs. T2MI2007 and T1MI: p = 0.03 and 0.01, respectively). CONCLUSIONS: T2MI2012reclassified has a substantially lower event-related mortality rate compared with T2MI2007 and T1MI. (Advantageous Predictors of Acute Coronary Syndromes Evaluation [APACE] Study; NCT00470587).