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.

Long-term follow-up of participants with heart failure in the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT).

BACKGROUND: In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a randomized, double-blind, practice-based, active-control, comparative effectiveness trial in high-risk hypertensive participants, risk of new-onset heart failure (HF) was higher in the amlodipine (2.5-10 mg/d) and lisinopril (10-40 mg/d) arms compared with the chlorthalidone (12.5-25 mg/d) arm. Similar to other studies, mortality rates following new-onset HF were very high (≥50% at 5 years), and were similar across randomized treatment arms. After the randomized phase of the trial ended in 2002, outcomes were determined from administrative databases. METHODS AND RESULTS: With the use of national databases, posttrial follow-up mortality through 2006 was obtained on participants who developed new-onset HF during the randomized (in-trial) phase of ALLHAT. Mean follow-up for the entire period was 8.9 years. Of 1761 participants with incident HF in-trial, 1348 died. Post-HF all-cause mortality was similar across treatment groups, with adjusted hazard ratios (95% confidence intervals) of 0.95 (0.81-1.12) and 1.05 (0.89-1.25), respectively, for amlodipine and lisinopril compared with chlorthalidone, and 10-year adjusted rates of 86%, 87%, and 83%, respectively. All-cause mortality rates were also similar among those with reduced ejection fractions (84%) and preserved ejection fractions (81%), with no significant differences by randomized treatment arm. CONCLUSIONS: Once HF develops, risk of death is high and consistent across randomized treatment groups. Measures to prevent the development of HF, especially blood pressure control, must be a priority if mortality associated with the development of HF is to be addressed. Clinical Trial Registration- http://www.clinicaltrials.gov. Unique identifier: NCT00000542.

The benefit of cardiac resynchronization therapy and QRS duration: a meta-analysis.

BACKGROUND: Cardiac resynchronization therapy (CRT) improves outcomes in patients with heart failure (HF) because of reduced left ventricular systolic function and a wide QRS complex. Whether this benefit is consistent across all degrees of QRS widening is unclear. We performed a meta-analysis of randomized clinical trials to evaluate the impact of QRS duration on the efficacy of CRT. METHODS AND RESULTS: We searched MEDLINE and EMBASE databases for studies evaluating the efficacy of CRT in patients with HF. Only trials that reported subgroup data according to QRS duration were included. Hazard ratios (HR) with 95% confidence interval (CI) were calculated using a random effects model. Five trials involving 6,501 patients (4,437 with QRS ≥ 150 ms and 2,064 with QRS < 150 ms) were included. Three trials, enrolling patients with mild to moderate HF, compared CRT-implantable cardioverter defibrillator with CRT, whereas CRT versus medical therapy was compared in the other 2 trials, which included patients with advanced HF. Based on the pooled estimate across the 5 studies, CRT significantly decreased the primary endpoint of death or hospitalization for HF in patients with QRS ≥ 150 ms (HR = 0.58, 95% CI: 0.50-0.68; P < 0.00001), but not in patients with QRS < 150 ms (HR = 0.95, 95% CI: 0.83-1.10; P = 0.51). These results were consistent across all degrees of HF severity. CONCLUSIONS: The benefit of CRT seems to be dependent on QRS duration. Available data suggest a significant benefit associated with CRT in patients with QRS ≥ 150 ms, but not in patients with QRS < 150 ms. Further studies are needed to identify patients with QRS < 150 ms who might benefit from CRT.

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.

Safety of symptom-limited cardiopulmonary exercise testing in patients with chronic heart failure due to severe left ventricular systolic dysfunction.

BACKGROUND: To assess the safety of symptom-limited exercise testing in patients with New York Heart Association class II-IV heart failure symptoms due to left ventricular systolic dysfunction, we investigated the frequency of all-cause fatal and nonfatal major cardiovascular (CV) events among subjects enrolled in a prospective clinical trial (HF-ACTION). We hypothesized that exercise testing would be safe, as defined by a rate for all-cause death of <0.1 per 1,000 tests and a rate of nonfatal CV events <1.0 per 1,000 tests. METHODS: Before enrollment and at 3, 12, and 24 months after randomization, subjects were scheduled to complete a symptom-limited graded exercise test with open-circuit spirometry for analysis of expired gases. To ensure the accurate reporting of exercise test-related events, we report deaths and nonfatal major CV events per 1,000 tests at months 3, 12, or 24 after randomization. RESULTS: A total of 2,331 subjects were randomized into HF-ACTION. After randomization, 2,037 subjects completed 4,411 exercise tests. There were no test-related deaths, exacerbation of heart failure or angina requiring hospitalization, myocardial infarctions, strokes, or transient ischemic attacks. There was one episode each of ventricular fibrillation and sustained ventricular tachycardia. There were no exercise test-related implantable cardioverter defibrillator discharges requiring hospitalization. These findings correspond to zero deaths per 1,000 exercise tests and 0.45 nonfatal major CV events per 1,000 exercise tests (95% CI 0.11-1.81). CONCLUSIONS: In New York Heart Association class II-IV patients with severe left ventricular systolic dysfunction, we observed that symptom-limited exercise testing is safe based on no deaths and a rate of nonfatal major CV events that is <0.5 per 1,000 tests.

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.

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.

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.

Clinical outcomes in antihypertensive treatment of type 2 diabetes, impaired fasting glucose concentration, and normoglycemia: Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).

BACKGROUND: Optimal first-step antihypertensive drug therapy in type 2 diabetes mellitus (DM) or impaired fasting glucose levels (IFG) is uncertain. We wished to determine whether treatment with a calcium channel blocker or an angiotensin-converting enzyme inhibitor decreases clinical complications compared with treatment with a thiazide-type diuretic in DM, IFG, and normoglycemia (NG). METHODS: Active-controlled trial in 31 512 adults, 55 years or older, with hypertension and at least 1 other risk factor for coronary heart disease, stratified into DM (n = 13 101), IFG (n = 1399), and NG (n = 17 012) groups on the basis of national guidelines. Participants were randomly assigned to double-blind first-step treatment with chlorthalidone, 12.5 to 25 mg/d, amlodipine besylate, 2.5 to 10 mg/d, or lisinopril, 10 to 40 mg/d. We conducted an intention-to-treat analysis of fatal coronary heart disease or nonfatal myocardial infarction (primary outcome), total mortality, and other clinical complications. RESULTS: There was no significant difference in relative risk (RR) for the primary outcome in DM or NG participants assigned to amlodipine or lisinopril vs chlorthalidone or in IFG participants assigned to lisinopril vs chlorthalidone. A significantly higher RR (95% confidence interval) was noted for the primary outcome in IFG participants assigned to amlodipine vs chlorthalidone (1.73 [1.10-2.72]). Stroke was more common in NG participants assigned to lisinopril vs chlorthalidone (1.31 [1.10-1.57]). Heart failure was more common in DM and NG participants assigned to amlodipine (1.39 [1.22-1.59] and 1.30 [1.12-1.51], respectively) or lisinopril (1.15 [1.00-1.32] and 1.19 [1.02-1.39], respectively) vs chlorthalidone. CONCLUSION: Our results provide no evidence of superiority for treatment with calcium channel blockers or angiotensin-converting enzyme inhibitors compared with a thiazide-type diuretic during first-step antihypertensive therapy in DM, IFG, or NG.