Effect of Obesity on Response to Spironolactone in Patients With Heart Failure With Preserved Ejection Fraction.

Obesity is common in heart failure with preserved ejection fraction (HFpEF). Whether obesity modifies the response to spironolactone in patients with HFpEF remains unclear. We aimed to investigate the effect of obesity, defined by body mass index (BMI) and waist circumference (WC), on response to spironolactone in patients with HFpEF enrolled in Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial. This was a post-hoc, exploratory analysis of the Americas cohort of Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial. BMI≥30 kg/m2 was used to define the obese group and WC≥102 cm in men and ≥88 cm in women were defined as high WC. In separate analyses, BMI and WC were treated as continuous variables. The effect of spironolactone versus placebo on outcomes was calculated by BMI and WC using Cox proportional hazard models. Obese patients were younger and had more co-morbidities. In multivariate analysis, spironolactone use was associated with a significant reduction in the primary end point, compared with placebo in obese [hazard ratio (HR = 0.618, 95% CI 0.460 to 0.831, p = 0.001), but not in nonobese subjects (HR = 0.946, 95% CI 0.623 to 1.437, p = 0.796; p for interaction = 0.056). There was a linear association between continuous BMI and the effect of spironolactone, with the effect becoming significant at 33kg/m2. Similar results were obtained for the WC-based analysis. In conclusion, use of spironolactone in obese patients with HFpEF was associated with a decreased risk of the primary end point, cardiovascular death and HF hospitalizations, compared with placebo. Further prospective randomized studies in obese subjects are required.

Utilization of guideline-directed medical therapy in patients with de novo heart failure with reduced ejection fraction: A Veterans Affairs study.

BACKGROUND: The utilization of guideline-directed medical therapy (GDMT) significantly reduces morbidity and mortality in patients with heart failure with reduced ejection fraction (HFrEF). Previous studies have documented the underutilization of GDMT in HFrEF. The present study aimed to determine reasons for underutilization and achievement of target doses of GDMT in patients with de novo diagnosis of HFrEF. METHODS: Patients presenting with de novo HFrEF at the Veterans Affairs Medical Center were included. Baseline demographic, clinical, and echocardiographic data were collected. The utilization of target doses of GDMT was assessed at the time of discharge and 1-, 3-, 6-, and 12-month follow-up. RESULTS: Of the 95 patients who met the criteria for de novo HFrEF, 48 were included in the final analysis. Dose titration of either beta-blocker or angiotensin converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARB) was attempted in 20 patients (42%) at 1 month, 21 patients (44%) at 3 months, 13 patients (27%) at 6 months, and 14 patients (29%) at 12 months. Nine (19%) patients were on a target dose of beta-blockers and three (6%) patients were on a target dose of an ACEi/ARB at 12 months. The most common reasons for underutilization were patient-level factors, such as hypotension, acute kidney injury/hyperkalemia, and patient noncompliance. CONCLUSIONS: Utilization and achievement of target doses of GDMT were suboptimal among patients discharged with de novo HFrEF during a 1-year follow-up. Although patient factors may limit the up-titration of therapies, concerted efforts are needed to support primary care physicians in improving adherence to target doses of GDMT in patients with HFrEF.

Prognostic Value of 6-Minute Walk Distance in Patients Undergoing Percutaneous Coronary Intervention: a Veterans Affairs Prospective Study.

The 6-minute walk distance (6MWD) test is a useful prognostic tool in chronic heart failure. Its usefulness after percutaneous coronary intervention is unknown. In a prospective observational study, patients underwent a 6MWD test within 2 weeks after percutaneous coronary intervention. The primary endpoint was major adverse cardiovascular events (MACE) (death, acute coronary syndrome, and heart failure admission) at one year. Receiver operating characteristic curves and area under the curve were used to determine the 6MWD test's predictive power, and the Youden index was used to measure its effectiveness. A total of 212 patients were enrolled (98% men; mean age, 65 ± 9 yr). Major comorbidities were hypertension in 187 patients (88%), dyslipidemia in 186 (88%), and diabetes mellitus in 95 (45%). Among the 176 patients (83%) who completed the 6MWD test, the incidence of MACE at one year was 22% (acute coronary syndrome in 17%; heart failure admission in 4%; and death in 3%). The area under the curve for MACE was 0.59, and 6MWD was shorter for patients with MACE than for those without (290 vs 326 m; P=0.03). For 39 patients with previous heart failure who completed the 6MWD test, the area under the curve was 0.64 for MACE and 0.78 for heart failure admission. The 6MWD test predicted reasonably well the incidence of MACE one year after percutaneous coronary intervention. In a subgroup of patients with previous heart failure, it fared even better in predicting heart failure admission. Larger studies are needed to confirm these findings.

Trans fatty acids linked to myocardial infarction and stroke: What is the evidence?

Consumption of industrially produced trans fatty acids (IP-TFAs) increases LDL cholesterol, either decreases or has no effect on HDL cholesterol, and increases markers of inflammation. Observational studies have shown that consumption of TFA produced by partial hydrogenation of vegetable oils (PHOs) is associated with increased mortality and incidence of MI and stroke rates. Regulatory initiatives to restrict PHOs to less than 2 g per day from food sources, along with concurrent initiatives to reduce tobacco exposure, have been associated with reduction in cardiovascular mortality and MI rates. What remains unknown is whether the consumption of amounts <2 g per day of PHOs is also harmful and whether TFAs present in milk and the meats of ruminant animals is beneficial or harmful.

Stable Angina Medical Therapy Management Guidelines: A Critical Review of Guidelines from the European Society of Cardiology and National Institute for Health and Care Excellence.

Most patients with stable angina can be managed with lifestyle changes, especially smoking cessation and regular exercise, along with taking antianginal drugs. Randomised controlled trials show that antianginal drugs are equally effective and none of them reduced mortality or the risk of MI, yet guidelines prefer the use of beta-blockers and calcium channel blockers as a first-line treatment. The European Society of Cardiology guidelines for the management of stable coronary artery disease provide classes of recommendation with levels of evidence that are well defined. The National Institute for Health and Care Excellence (NICE) guidelines for the management of stable angina provide guidelines based on cost and effectiveness using the terms first-line and second-line therapy. Both guidelines recommend using low-dose aspirin and statins as disease-modifying agents. The aim of this article is to critically appraise the guidelines' pharmacological recommendations for managing patients with stable angina.

Inappropriate sinus tachycardia-symptom and heart rate reduction with ivabradine: A pooled analysis of prospective studies.

BACKGROUND: Inappropriate sinus tachycardia (IST) is debilitating despite available treatment. Off-label use of ivabradine for IST prompted this systematic analysis of existing data quality and sample size estimates for adequately powered studies. OBJECTIVE: To determine clinical efficacy of ivabradine in IST from pooled prospective studies. METHODS: Analysis included ivabradine studies for IST participants without structural heart disease and with follow-up of ≥2 weeks. Heart rate and symptom reduction with ivabradine were estimated based on results of subjective change in symptoms assessed by various data instruments used in each study. Studies were assessed for quality using validated checklists. Sample sizes were calculated based on the magnitude of symptom reduction encountered after treatment with ivabradine. RESULTS: Nine studies met criteria, culminating in 145 patients pooled. Most patients were women (≥70%). Studies were small and not adequately powered, and all reported a decrease in maximum or mean resting heart rate or both, with complete or considerable amelioration of symptoms with ivabradine. Most studies had moderate quality with excellent consistency of study quality and narrow limits of agreement between the quality checklists. Sample size estimates for adequately powered studies with various placebo effects and comparisons with ß-blockade are reported. CONCLUSIONS: Ivabradine effectively reduces heart rate and symptoms in IST, but no study was adequately powered to account for the expected placebo effect on symptoms. A multicenter, randomized, placebo-controlled, active, comparative study with a ß-blocker is needed for confirmation. This is especially relevant given the ivabradine's potential teratogenic effect, as many IST patients are females of childbearing potential.

Drug Therapy for Stable Angina Pectoris.

Chronic stable angina pectoris refers to the predictable, reproducible occurrence of pressure or a choking sensation in the chest or adjacent areas caused by myocardial ischemia in association with physical or emotional stress, and cessation of exertion and or sublingual nitroglycerin invariably relieves the discomfort. It is a common presenting symptom of severe narrowing of one or more coronary arteries, non-obstructive coronary arteries, or even when the coronary arteries are angiographically normal. Patients often avoid activities which precipitate symptoms and have impaired quality of life. Most patients with angina pectoris can be managed with lifestyle changes, especially abstinence from smoking and regular exercise, and anti-anginal drugs. However, the choice of initial or combination antianginals as recommended in the guidelines is not evidence based. In addition, patients with stable angina due to coronary artery disease should also receive aspirin and a statin. Treatment of patients with angina and normal coronary arteries remains to be established. The aim of this article is to provide the readers not only with a guideline-based approach, which varies from one country to another, but also an individual-based approach, which takes into consideration circulatory status and the presence or absence of comorbidities in the treatment decision-making process. This manuscript primarily deals with drug therapy of stable angina pectoris and not coronary artery revascularization, which also provides angina relief but is usually reserved for patients who fail to respond to adequate drug therapy.

The risk of cardiovascular side effects with anti-anginal drugs.

INTRODUCTION: Angina pectoris is a common presenting symptom of underlying coronary artery disease or reduced coronary flow reserve. Patients with angina have impaired quality of life; and need to be treated optimally with antianginal drugs to control symptoms and improve exercise performance. A wide range of antianginal medications are approved for the treatment of angina, and often more than one class of antianginal drugs are used to adequately control the symptoms. This expert opinion highlights the likely cardiac adverse effects of available antianginal drugs, and how to minimize these in individual patients and especially during combination treatment. Areas covered: All approved antianginal drugs, including the older and newly approved medications with different mechanism of action to the older drugs as well as some of the unapproved herbal medications. The safety profiles and potential cardiac side effects of these medications when used as monotherapy or as combination therapy are discussed and highlighted. Expert opinion: Because of the different cardiac safety profiles and possible side effects, we recommend selection of initial drug or adjustment of therapy based on the resting heart rate; blood pressure, hemodynamic status; and resting left ventricular function, concomitant medications and any associated comorbidities.

Management of Stable Angina - Current Guidelines: A Critical Appraisal.

Guidelines provide recommendations to improve patient outcomes, but many of the recommendations made for treating patients with stable angina are opinion based rather than evidence based. Risk stratification to predict patients at an increased risk of myocardial infarction (MI) and sudden ischemic death, and selection of patients for possible revascularization, is based on expert opinion. Randomized trials have compared optimal medical therapy to revascularization, after the coronary anatomy was known, and yet routine coronary angiography to exclude left main disease is not recommended. What exactly is optimal antianginal treatment varies considerably from one country's guideline recommendations to another. None of the antianginal drugs reduce mortality or MI and these drugs are equally effective in treating angina pectoris; and yet beta-blockers and calcium channel blockers are recommended as first line therapy. Double and triple therapy with different classes of antianginal drugs is also expert opinion based rather than evidence based. Recommendations to reduce the incidence of MI and sudden death are appropriate; however the use of a potent, high dose statin, is recommended by AHA/ACC and NICE guidelines for all patients with ischemic heart disease, while the European guidelines recommend a target LDL goal in patients with coronary artery disease (CAD). Management of patients with stable angina pectoris with normal coronary arteries remains ambiguous. This short review critically appraises the recommendations for managing patients with stable angina pectoris.

Temporal Trends of Digoxin Use in Patients Hospitalized With Heart Failure: Analysis From the American Heart Association Get With The Guidelines-Heart Failure Registry.

OBJECTIVES: The aim of this study was to assess temporal trends and factors associated with digoxin use at discharge among patients admitted with heart failure (HF). BACKGROUND: Digoxin has class IIa recommendations for treating HF with reduced ejection fraction (HFrEF) in the United States. Digoxin use, temporal trends, and clinical characteristics of HF patients in current clinical practice in the United States have not been well studied. METHODS: An observational analysis of 255,901 patients hospitalized with HF (117,761 with HFrEF and 138,140 with preserved EF [HFpEF]) from 398 hospitals participating in the Get With The Guidelines-HF registry between January 2005 and June 2014 was conducted to assess the temporal trends and factors associated with digoxin use. RESULTS: Among 117,761 HFrEF patients, only 19.7% received digoxin at discharge. Digoxin prescriptions decreased from 33.1% in 2005 to 10.7% in 2014 (ptrend < 0.0001). Factors associated with digoxin use in HFrEF included atrial fibrillation (AF) (odds ratio [OR]: 2.14; 95% confidence intervals [CI]: 2.02 to 2.28), history of implantable cardioverter defibrillator use (OR: 1.39; 95% CI: 1.32 to 1.46), chronic obstructive pulmonary disease (OR: 1.13, 95% CI: 1.08 to 1.18), diabetes mellitus (OR: 1.10, 95% CI: 1.06 to 1.14), younger age (OR: 0.96, 95% CI: 0.95 to 0.97), lower blood pressure (OR: 0.96, 95% CI: 0.96 to 0.97), and having no history of renal insufficiency (OR: 0.91, 95% CI: 0.85 to 0.97). Use of digoxin in patients with HFpEF (n = 138,140) without AF was 9.8% in 2005, which decreased to 2.2% in 2014 (ptrend < 0.0001). CONCLUSIONS: One in 5 HFrEF patients received digoxin at discharge, with a significant downward temporal trend in use over the study period. Use of digoxin in HFpEF patients without AF was very low and decreased over the study period.

Management Strategies and Outcomes of ST-Segment Elevation Myocardial Infarction Patients Transferred After Receiving Fibrinolytic Therapy in the United States.

Fibrinolytic therapy is still used in patients with ST-segment elevation myocardial infarction (STEMI) when the primary percutaneous coronary intervention cannot be provided in a timely fashion. Management strategies and outcomes in transferred fibrinolytic-treated STEMI patients have not been well assessed in real-world settings. Using the Nationwide Inpatient Sample from 2008 to 2012, we identified 18 814 patients with STEMI who received fibrinolytic therapy and were transferred to a different facility within 24 hours. The primary outcome was in-hospital mortality. Secondary outcomes included gastrointestinal bleeding, bleeding requiring transfusion, intracranial hemorrhage (ICH), length of stay, and cost. The patients were divided into 3 groups: those who received medical therapy alone (n = 853; 4.5%), those who underwent coronary artery angiography without revascularization (n = 2573; 13.7%), and those who underwent coronary artery angiography with revascularization (n = 15 388; 81.8%). Rates of in-hospital mortality among the groups were 20% vs 6.6% vs 2.1%, respectively (P < 0.001); ICH was 8.5% vs 1.1% vs 0.6%, respectively (P < 0.001); and gastrointestinal bleeding was 1.1% vs 0.4% vs 0.4%, respectively (P = 0.011). Multivariate analysis identified increasing age, higher Charlson Comorbidity Index score, cardiogenic shock, cardiac arrest, and ICH as the independent predictors of not performing coronary artery angiography and/or revascularization in patients with STEMI initially treated with fibrinolytic therapy. The majority of STEMI patients transferred after receiving fibrinolytic therapy undergo coronary angiography. However, notable numbers of patients do not receive revascularization, especially patients with cardiogenic shock and following a cardiac arrest.

Challenges with nitrate therapy and nitrate tolerance: prevalence, prevention, and clinical relevance.

Nitrate therapy has been an effective treatment for ischemic heart disease for over 100 years. The anti-ischemic and exercise-promoting benefits of sublingually administered nitrates are well established. Nitroglycerin is indicated for the relief of an established attack of angina and for prophylactic use, but its effects are short lived. In an effort to increase the duration of beneficial effects, long-acting orally administered and topical applications of nitrates have been developed; however, following their continued or frequent daily use, patients soon develop tolerance to these long-acting nitrate preparations. Once tolerance develops, patients begin losing the protective effects of the long-acting nitrate therapy. By providing a nitrate-free interval, or declining nitrate levels at night, one can overcome or reduce the development of tolerance, but cannot provide 24-h anti-anginal and anti-ischemic protection. In addition, patients may be vulnerable to occurrence of rebound angina and myocardial ischemia during periods of absent nitrate levels at night and early hours of the morning, and worsening of exercise capacity prior to the morning dose of the medication. This has been a concern with nitroglycerin patches but not with oral formulations of isosorbide-5 mononitrates, and has not been adequately studied with isosorbide dinitrate. This paper describes problems associated with nitrate tolerance, reviews mechanisms by which nitrate tolerance and loss of efficacy develop, and presents strategies to avoid nitrate tolerance and maintain efficacy when using long-acting nitrate formulations.