Factors Associated With Coronary Angiography Performed Within 6 Months of Randomization to the Conservative Strategy in the ISCHEMIA Trial.

BACKGROUND: ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) did not find an overall reduction in cardiovascular events with an initial invasive versus conservative management strategy in chronic coronary disease; however, there were conservative strategy participants who underwent invasive coronary angiography early postrandomization (within 6 months). Identifying factors associated with angiography in conservative strategy participants will inform clinical decision-making in patients with chronic coronary disease. METHODS: Factors independently associated with angiography performed within 6 months of randomization were identified using Fine and Gray proportional subdistribution hazard models, including demographics, region of randomization, medical history, risk factor control, symptoms, ischemia severity, coronary anatomy based on protocol-mandated coronary computed tomography angiography, and medication use. RESULTS: Among 2591 conservative strategy participants, angiography within 6 months of randomization occurred in 8.7% (4.7% for a suspected primary end point event, 1.6% for persistent symptoms, and 2.6% due to protocol nonadherence) and was associated with the following baseline characteristics: enrollment in Europe versus Asia (hazard ratio [HR], 1.81 [95% CI, 1.14-2.86]), daily and weekly versus no angina (HR, 5.97 [95% CI, 2.78-12.86] and 2.63 [95% CI, 1.51-4.58], respectively), poor to fair versus good to excellent health status (HR, 2.02 [95% CI, 1.23-3.32]) assessed with Seattle Angina Questionnaire, and new/more frequent angina prerandomization (HR, 1.80 [95% CI, 1.34-2.40]). Baseline low-density lipoprotein cholesterol <70 mg/dL was associated with a lower risk of angiography (HR, 0.65 [95% CI, 0.46-0.91) but not baseline ischemia severity nor the presence of multivessel or proximal left anterior descending artery stenosis >70% on coronary computed tomography angiography. CONCLUSIONS: Among ISCHEMIA participants randomized to the conservative strategy, angiography within 6 months of randomization was performed in <10% of patients. It was associated with frequent or increasing baseline angina and poor quality of life but not with objective markers of disease severity. Well-controlled baseline low-density lipoprotein cholesterol was associated with a reduced likelihood of angiography. These findings point to the importance of a comprehensive assessment of symptoms and a review of guideline-directed medical therapy goals when deciding the initial treatment strategy for chronic coronary disease. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01471522.

Factors associated with coronary angiography performed within 6 months of randomization to the conservative strategy in the ISCHEMIA Trial

BACKGROUND: ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) did not find an overall reduction in cardiovascular events with an initial invasive versus conservative management strategy in chronic coronary disease; however, there were conservative strategy participants who underwent invasive coronary angiography early postrandomization (within 6 months). Identifying factors associated with angiography in conservative strategy participants will inform clinical decision-making in patients with chronic coronary disease. METHODS: Factors independently associated with angiography performed within 6 months of randomization were identified using Fine and Gray proportional subdistribution hazard models, including demographics, region of randomization, medical history, risk factor control, symptoms, ischemia severity, coronary anatomy based on protocol-mandated coronary computed tomography angiography, and medication use. RESULTS: Among 2591 conservative strategy participants, angiography within 6 months of randomization occurred in 8.7% (4.7% for a suspected primary end point event, 1.6% for persistent symptoms, and 2.6% due to protocol nonadherence) and was associated with the following baseline characteristics: enrollment in Europe versus Asia (hazard ratio [HR], 1.81 [95% CI, 1.14­2.86]), daily and weekly versus no angina (HR, 5.97 [95% CI, 2.78­12.86] and 2.63 [95% CI, 1.51­4.58], respectively), poor to fair versus good to excellent health status (HR, 2.02 [95% CI, 1.23­3.32]) assessed with Seattle Angina Questionnaire, and new/more frequent angina prerandomization (HR, 1.80 [95% CI, 1.34­2.40]). Baseline low-density lipoprotein cholesterol <70 mg/dL was associated with a lower risk of angiography (HR, 0.65 [95% CI, 0.46­0.91) but not baseline ischemia severity nor the presence of multivessel or proximal left anterior descending artery stenosis >70% on coronary computed tomography angiography. CONCLUSIONS: Among ISCHEMIA participants randomized to the conservative strategy, angiography within 6 months of randomization was performed in <10% of patients. It was associated with frequent or increasing baseline angina and poor quality of life but not with objective markers of disease severity. Well-controlled baseline low-density lipoprotein cholesterol was associated with a reduced likelihood of angiography. These findings point to the importance of a comprehensive assessment of symptoms and a review of guideline-directed medical therapy goals when deciding the initial treatment strategy for chronic coronary disease.

Effects of initial invasive vs. initial conservative treatment strategies on recurrent and total cardiovascular events in the ISCHEMIA trial.

AIMS: The International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial prespecified an analysis to determine whether accounting for recurrent cardiovascular events in addition to first events modified understanding of the treatment effects. METHODS AND RESULTS: Patients with stable coronary artery disease (CAD) and moderate or severe ischaemia on stress testing were randomized to either initial invasive (INV) or initial conservative (CON) management. The primary outcome was a composite of cardiovascular death, myocardial infarction (MI), and hospitalization for unstable angina, heart failure, or cardiac arrest. The Ghosh-Lin method was used to estimate mean cumulative incidence of total events with death as a competing risk. The 5179 ISCHEMIA patients experienced 670 index events (318 INV, 352 CON) and 203 recurrent events (102 INV, 101 CON). A single primary event was observed in 9.8% of INV and 10.8% of CON patients while ≥2 primary events were observed in 2.5% and 2.8%, respectively. Patients with recurrent events were older; had more frequent hypertension, diabetes, prior MI, or cerebrovascular disease; and had more multivessel CAD. The average number of primary endpoint events per 100 patients over 4 years was 18.2 in INV [95% confidence interval (CI) 15.8-20.9] and 19.7 in CON (95% CI 17.5-22.2), difference -1.5 (95% CI -5.0 to 2.0, P = 0.398). Comparable results were obtained when all-cause death was substituted for cardiovascular death and when stroke was added as an event. CONCLUSIONS: In stable CAD patients with moderate or severe myocardial ischaemia enrolled in ISCHEMIA, an initial INV treatment strategy did not prevent either net recurrent events or net total events more effectively than an initial CON strategy. CLINICAL TRIAL REGISTRATION: ISCHEMIA ClinicalTrials.gov number, NCT01471522, https://clinicaltrials.gov/ct2/show/NCT01471522.

An unusual case of infective endocarditis presenting as acute myocardial infarction.

A 39-year-old Zimbabwean man presented with a 1 week history of fever, general malaise and acute onset chest pain. He had a urethral stricture, which had been managed with an indwelling supra-pubic catheter. The electrocardiography on admission showed inferior ST-T segments elevation. His chest pain and electrocardiography changes resolved subsequent to thrombolysis, and he remained haemodynamically stable. The 12 h troponin I was increased at 10.5 µg/l (NR <0.04 µg/l). Echocardiography confirmed severe mitral regurgitation and a flail anterior mitral valve leaflet with an independently oscillating mobile vegetation. Enterococci faecalis were grown on blood cultures. A diagnosis of enterococci infective endocarditis with concomitant acute myocardial infarction due to possible septic emboli was made. Despite the successful outcome from thrombolysis in the setting of acute myocardial infarction with infective endocarditis, the case highlights the current lack of definitive data on the optimal acute management of such an unusual clinical scenario. Although there is serious concern that thrombolytic treatment for myocardial infarction in the setting of infective endocarditis may be associated with higher risk of cerebral haemorrhage, there is little documented evidence supporting the safety of primary percutaneous coronary intervention with these patients.

An unusual case of infective endocarditis presenting as acute myocardial infarction.

A 39-year-old Zimbabwean man presented with a 1 week history of fever, general malaise and acute-onset chest pain. He had a urethral stricture, which had been managed with an indwelling supra-pubic catheter. The electrocardiography on admission showed inferior ST-T segments elevation. His chest pain and electrocardiography changes resolved subsequent to thrombolysis, and he remained haemodynamically stable. The 12-h troponin I was increased at 10.5 microg/l (NR <0.04 microg/l). Echocardiography confirmed severe mitral regurgitation and a flail anterior mitral valve leaflet with an independently oscillating mobile vegetation. Enterococci faecalis were grown on blood cultures. A diagnosis of enterococci infective endocarditis with concomitant acute myocardial infarction due to possible septic emboli was made. Despite the successful outcome from thrombolysis in the setting of acute myocardial infarction with infective endocarditis, the case highlights the current lack of definitive data on the optimal acute management of such an unusual clinical scenario. Although there is serious concern that thrombolytic treatment for myocardial infarction in the setting of infective endocarditis may be associated with higher risk of cerebral haemorrhage, there is little documented evidence supporting the safety of primary percutaneous coronary intervention with these patients.

Intracardiac devices for stroke prevention.

Stroke is a significant cause of serious disability and death worldwide. A substantial proportion of strokes are related to an underlying cardiac embolic source, most commonly in association with atrial arrhythmias (fibrillation/flutter). Atrial fibrillation is considered a major risk factor for stroke. Although long-term prophylactic oral anticoagulation has been shown to be very effective in reducing stroke in patients with atrial fibrillation, it has a number of major limitations and is not feasible in all patients. In such cases, the use of percutaneously (transvenous) implanted left atrial appendage occlusive devices or surgical appendage obliteration is being explored. Similarly, the presence of a patent foramen ovale, especially in the presence of an atrial septal aneurysm, is now recognized as an important potential mediator of paradoxical cardiogenic embolism. Percutaneous patent foramen ovale closure is becoming increasingly established as a safe and effective means of preventing recurrent strokes in the presence of a patent foramen ovale. In this account, the authors discuss the intracardiac devices and techniques available and the relative merits of their use for stroke prevention.

The clinical relevance of raised cardiac troponin I in the absence of significant angiographic coronary artery disease.

OBJECTIVES: Cardiac troponins are highly sensitive and specific markers of myocardial cell injury. We wished to determine the clinical relevance of raised troponins in the absence of significant angiographic coronary artery disease. DESIGN AND METHODS: We assessed patients admitted to our hospital over the past 3 years with troponin-positive chest pain and no angiographically significant coronary disease. RESULTS: The study included 67 patients, all of whom had symptoms of "chest pain" and elevated (>0.2 microg/L) troponin I on admission. Thirty-four (51%) patients had alternative causes for myocyte injury other than coronary ischaemia. In the remaining 33 (49%) patients we could find no other associated features or diagnoses. Follow up was obtained in 29 (88%) of these 33 patients (mean follow up 58+/-13 weeks, range 17-156 weeks). During the follow up period, three (4.5%) patients were readmitted with further ischaemic events. CONCLUSIONS: Myocardial damage can occur in the absence of significant angiographic coronary disease and other causes of raised troponins should be considered according to the clinical presentation. Troponin-positive cases with angiographically "normal" coronary arteries can re-present with future cardiac events and should still be considered for aggressive risk management.

Cardiac troponin T and I and creatine kinase-MB as markers of myocardial injury and predictors of outcome following percutaneous coronary intervention.

AIMS: This study was performed to determine the most sensitive biochemical marker for the detection of cardiac myocyte damage potentially sustained during percutaneous coronary intervention (PCI) and to assess whether such a marker can be used to identify patients at increased risk of poor subsequent clinical outcome. METHODS AND RESULTS: We studied 109 consecutive patients presenting with clinical stable and unstable angina and undergoing PCI at our institution. Blood was sampled for creatine kinase-MB (CK-MB), cardiac Troponin T (cTnT) and I (cTnI) immediately before and at 6, 14 and 24 h post-PCI. Five patients with raised cardiac markers pre-PCI were excluded from further analysis. The occurrence of major adverse cardiac events (MACE) was documented in-hospital, at 30 days and at long-term clinical follow up of up to 20 months. MACE occurred in 26/109 (24%) patients: death=1, QWMI=4, NQWMI=5, repeat PCI=16 (nine target vessel revascularisations and seven de-novo lesions), CABG=5. cTnI had the highest detection rate for myocardial damage, with 58 cTnI-positive patients, 38 cTnT-positive patients and 28 CK-MB-positive patients in the 24 h following PCI (Pearson's Chi square test, P<0.01). The type of interventional strategy per se was not significantly associated with post-procedural cardiac marker concentrations (Kruskal-Wallis ANOVA, P>0.05). There was a significant association between post-procedural cardiac marker concentrations of CK-MB, cTnT and cTnI and the occurrence of procedural angiographic complications (P=0.0003, 0.0002, 0.001, respectively). All three markers, at each sampling time point between 6 and 24 h post-PCI, showed a significant predictive relationship with MACE in-hospital and at long-term follow up (ROC curve AUC analysis, P<0.05). All three markers provided equally predictive information at each of the three post-procedural sampling time points between 6 and 24 h following PCI. All levels of cardiac marker elevation above the clinically discriminant cut-off values were significantly predictive of outcome at long-term follow up. CONCLUSIONS: cTnI proved to be the most sensitive marker in detecting myocardial necrosis following PCI. CK-MB, cTnT and cTnI all provided similarly reliable prognostic information, with cTnT and cTnI being marginally superior in predicting MACE at follow up.

Direct stenting may limit myocardial injury during percutaneous coronary intervention.

BACKGROUND: Direct coronary stenting has been shown to be safe and feasible, with a demonstrable reduction in cost, procedural time and radiation exposure. Direct stenting may limit distal embolization of atherosclerotic plaque and consequently reduce myocardial cell injury following percutaneous coronary intervention, which may have important prognostic implications. METHODS AND RESULTS: We assessed cardiac troponin I (cTnI) release in the 24 hours following direct coronary stenting (DS) as compared to stenting with balloon predilatation (PD) in a total of 311 patients and 440 vessels/lesions (vessel to lesion ratio = 1:1) (DS: n = 107 patients and 149 vessels/lesions; PD: n = 204 patients and 291 vessels/lesions). The 2 groups were well matched except for a greater proportion of diabetic patients in the PD group (21%) compared to the DS group (11%) (p < 0.05). There were no significant differences in the distribution of target lesion site or angiographic complexity between the 2 groups. Primary angiographic success was achieved in 97% of vessels in the DS group and 98% of vessels in the PD group (p = NS). DS failed in 7/114 patients (6%) deemed suitable for DS by the operator, but all stents were subsequently successfully deployed following balloon predilatation. Abciximab (ReoPro , Eli Lilly Company, Indianapolis, Indiana) was used in 11 patients (10%) in the DS group and 24 patients (12%) in the PD group ( p = 0.68). The post-procedural median (IQR) peak cTnI concentrations were 0.2 0.1 g/L in the DS group and 0.5 0.3 g/L in the PD group (p = 0.02). Post-procedural cTnI concentrations were > 0.2 g/L in 11 patients (10%) in the DS group and in 53 patients (26%) in the PD group (X2 = 58.6; p < 0.0001). The rate of major adverse cardiac events at 6 18 month follow-up was 8% in the DS group and 15% in the PD group (X2 = 38.5; p = 0.02). CONCLUSION: Direct stenting without balloon predilatation is associated with lower post-procedural cTnI concentrations and lower incidence of major adverse events compared to traditional stenting with predilatation.

Interpretation of plasma brain natriuretic peptide concentrations may require adjustment for patient's age.

BACKGROUND: Brain natriuretic peptide (BNP) is increasingly recognized as a practical, reliable and accurate indicator of left ventricular function and may have an important prognostic role in determining outcome following myocardial infarction and heart failure. METHODS AND RESULTS: We studied a total of 60 patients referred for dobutamine-stress echocardiography to evaluate possible reversible myocardial ischaemia. There was no echocardiographic evidence of structural or functional heart disease in any of the patients included in the study. Blood was sampled for BNP at rest, prior to dobutamine-stress. We found a significant linear correlation between BNP concentrations and patients' age, in the absence of structural or functional heart disease (r(s) = 0.53, 95% CI 0.25-0.73, P<0.0001). CONCLUSION: Our observations suggest the need for consideration of patient's age when interpreting BNP concentrations in the population.

Cardiac troponin I for risk stratification following percutaneous coronary artery intervention in acute coronary syndromes.

The cardiac troponins have been shown to provide prognostic information allowing risk stratification of patients with acute coronary syndromes (ACS). The benefit of early percutaneous coronary intervention (PCI) in this setting has been highlighted by the FRISC II study. We assessed the pattern of release of cardiac troponin I (cTnI) following PCI in patients with ACS and evaluated its prognostic value for major adverse cardiac events (MACE): death, Q-wave myocardial infarction (QWMI), and repeat revascularization at follow-up. cTnI was sampled at baseline and 6, 14, and 24 hr following PCI in 73 patients presenting with unstable and post-MI angina. Clinical follow-up was obtained in all 73 patients at a mean period of 43 +/- 19.9 weeks (range, 11-68 weeks). Patients were stratified into two groups according to whether cTnI remained unchanged or fell below baseline 24 hr post-PCI (group 1, n = 47) or increased above baseline 24 hr following PCI (group 2, n = 26). MACE occurred in 4 (8.5%) of patients in group 1 (QWMI = 1, CABG = 1, re-PCI = 2) and in 19 (73%) of patients in group 2 (death = 1, QWMI = 2, CABG = 2, re-PCI = 14; chi-square = 32.34, P < 0.0001). The positive predictive value of rising cTnI within 24 hr following PCI for MACE at follow-up was 0.73 and the negative predictive value was 0.92 (specificity = 83%, sensitivity = 86%; odds ratio = 29.18, 95% CI = 7.62-110.64, P < 0.0001). cTnI is an inexpensive and widely applicable tool that offers reliable prognostic information for the risk stratification of patients undergoing coronary revascularization in the setting of acute coronary syndromes and may identify a group of patients at particular risk of repeat PCI.