Daniel Satran

Long-term survival in patients with refractory angina

AIMS An increasing number of patients with severe coronary artery disease (CAD) are not candidates for traditional revascularization and experience angina in spite of excellent medical therapy. Despite limited data regarding the natural history and predictors of adverse outcome, these patients have been considered at high risk for early mortality. METHODS AND RESULTS The OPtions In Myocardial Ischemic Syndrome Therapy (OPTIMIST) program at the Minneapolis Heart Institute offers traditional and investigational therapies for patients with refractory angina. A prospective clinical database includes detailed baseline and yearly follow-up information. Death status and cause were determined using the Social Security Death Index, clinical data, and death certificates. Time to death was analysed using survival analysis methods. For 1200 patients, the mean age was 63.5 years (77.5% male) with 72.4% having prior coronary artery bypass grafting, 74.4% prior percutaneous coronary intervention, 72.6% prior myocardial infarction, 78.3% 3-vessel CAD, 23.0% moderate-to-severe left-ventricular (LV) dysfunction, and 32.6% congestive heart failure (CHF). Overall, 241 patients died (20.1%: 71.8% cardiovascular) during a median follow-up 5.1 years (range 0-16, 14.7% over 9). By Kaplan-Meier analysis, mortality was 3.9% (95% CI 2.8-5.0) at 1 year and 28.4% (95% CI 24.9-32.0) at 9 years. Multivariate predictors of all-cause mortality were baseline age, diabetes, angina class, chronic kidney disease, LV dysfunction, and CHF. CONCLUSION Long-term mortality in patients with refractory angina is lower than previously reported. Therapeutic options for this distinct and growing group of patients should focus on angina relief and improved quality of life.

Treatment of refractory angina in patients not suitable for revascularization

A growing number of patients, particularly those with advanced, chronic coronary artery disease, experience symptoms of angina that are refractory to treatment with β-blockers, calcium-channel blockers, and long-acting nitrates, despite revascularization. The management of patients with refractory angina who are unsuitable for further revascularization is strikingly different across the world, and is contingent on local resources and available expertise. Mortality in this patient population has decreased, but enhancing quality of life remains a challenge. New treatment principles are emerging in current practice, such as metabolic modulation, therapeutic angiogenesis, and novel interventional techniques (coronary in-flow redistribution and approaches to chronic total occlusion). The contemporary management of refractory angina encourages individualized, patient-centred care in interdisciplinary, specialized clinics. Global initiatives are required to address complex clinical problem-solving for patients with refractory angina. In this Review, we discuss the epidemiology of refractory angina, and provide an update on the pharmacological, noninvasive, and interventional options that are available to these patients or are under development.

Myocardial Fibrosis From Severe Carbon Monoxide Poisoning Detected by Cardiac Magnetic Resonance Imaging

Carbon monoxide (CO) poisoning is a leading cause of toxicological morbidity and mortality. We recently reported 37% of patients with moderate to severe CO poisoning suffered myocardial injury.1 In follow-up, 24% of patients died at a median of 7.6 years, a mortality rate 3 times higher than expected compared with age- and sex-specific US mortality rates. Myocardial injury was the major predictor of mortality: 38% of patients who sustained myocardial injury died compared with 15% without myocardial injury. The precise mechanisms responsible for the increase in mortality …

Phase I cardiovascular cell therapy clinical trials: Are we running with scissors?

The results of unblinded phase I and early randomized placebo-controlled cardiovascular stem cell clinical trials are encouraging, but considerable uncertainty exists regarding mechanism(s) of benefit, ideal cell(s), and method(s) of delivery for specific patient populations. Questions with regard to dosing, timing of delivery, and long-term safety also remain. These issues have led prominent cardiologists to voice concerns that our enthusiasm is misplaced, and we have “jumped the gun” in our haste to provide novel therapeutic options when mechanistic questions and safety have not been definitively addressed. Some have even suggested that cardiovascular stem cell therapy is at “a crossroads” and a moratorium should be placed on new clinical trials. We disagree, but with a few caveats. Well-designed clinical trials have the potential to complement and even stimulate basic science and preclinical research. In our excitement to bring new cell therapy–based treatments to very ill patients, we need to ensure that clinical studies are conducted such that we will be able to measure the effect of treatment and detect safety issues. In this issue of the Journal, Kovacic et al report the results of an open-label, safety, and feasibility trial in 20 patients with refractory ischemia. Patients received subcutaneous granulocyte-colony stimulating factor (G-CSF) at 10 μg/kg per day for 5 days in conjunction with “controlled induction of myocardial ischemia” using an exercise treadmill test on days 4 and 6 during G-CSF administration. Three months after randomization, patients received a second course of G-CSF at 10 μg/kg per day for 5 days with the stress test to induce myocardial ischemia. After the second course, patients were randomized to receive intracoronary CD133 cells (n = 10) versus intracoronary infusion of unselected cells (n = 6). During the 6-month follow-up, there were no deaths but 4 patients (20%) had a myocardial infarction. In addition, cardiac biomarkers (troponin I) were elevated on an additional 17 occasions in 8 patients. The authors noted the patients who completed the study (n = 16) had an improvement in angina frequency, exercise time, and the Duke treadmill score. However, there was no significant difference in ischemic burden as measured by dobutamine stress echocardiogram or persantine

Rebuttal: Response to severe coronary disease not amenable to revascularization—Are the series clearly defined?

We appreciate the kind words from Lozano et al. regarding our recent manuscript describing the prevalence and 3-year mortality in patients with coronary disease not amenable to traditional revascularization [1,2]. We agree that definitions represent a major challenge for this patient population. As we noted in our manuscript, ‘‘refractory angina’’ is poorly addressed in current ACC/AHA guidelines, and no national database or Medicare claims code exists to further characterize this patient population [2,3]. As Kornowski noted in his excellent accompanying editorial, a number of parameters are required to better determine prognosis in patients with refractory angina, including symptom severity (i.e., Canadian Cardiovascular Society Class), ischemic burden, specific angiographic characteristics, and left ventricular (LV) function [4]. We would add the adequacy of medical therapy including anti-platelet agents and aggressive risk factor modification. We believe the best working definition of refractory angina comes from the European Society of Cardiology Task Force on Refractory Angina: ‘‘a chronic condition (greater than 3 months) characterized by the presence of angina caused by coronary insufficiency in the presence of CAD which cannot be controlled by a combination of medical therapy, angioplasty and coronary artery bypass surgery [5].’’ Although this may represent the best available definition, it includes a number of obvious ambiguities and the Task Force also noted that ‘‘descriptive epidemiological studies are urgently needed [5].’’ The focus of our manuscript was to more completely describe the angiographic characteristics in a contemporary series of consecutive patients presenting to a single center cardiac catheterization laboratory. The fact that nearly 30% of patients had incomplete revascularization and that 7–16% of patients were not candidates for further revascularization illustrates the importance of improving therapeutic options for this challenging patient population [2]. We were not familiar with the series by Lozano et al. as it was published in Spanish. Baseline characteristics and comorbidities may account for some of the disparity in outcomes between our respective cohorts: Lozano et al. specifically mention LV dysfunction as an example. However, in our overall OPTIMIST population of 1,200 consecutive patients, 23% had moderate-severe LV dysfunction (LVEF < 40%) and 32% had congestive heart failure. As expected, both factors predict mortality, but by Kaplan–Meier analysis, the mortality was only 6% per year even amongst these high-risk subgroups. We completely agree that to advance our understanding of patients with refractory angina, it is very important to define both the patient population and predictors of adverse outcome. To that end, our manuscript entitled, ‘‘Longterm survival in patients with refractory angina,’’ attempts that in over 1,200 patients and is currently under review [6]. We encourage Lozano et al. to continue their important work to improve the care and awareness of this challenging patient population.