Philip R. Liebson

Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial.

BACKGROUND AND METHODS In the Cardiac Arrhythmia Suppression Trial, designed to test the hypothesis that suppression of ventricular ectopy after a myocardial infarction reduces the incidence of sudden death, patients in whom ventricular ectopy could be suppressed with encainide, flecainide, or moricizine were randomly assigned to receive either active drug or placebo. The use of encainide and flecainide was discontinued because of excess mortality. We examined the mortality and morbidity after randomization to encainide or flecainide or their respective placebo. RESULTS Of 1498 patients, 857 were assigned to receive encainide or its placebo (432 to active drug and 425 to placebo) and 641 were assigned to receive flecainide or its placebo (323 to active drug and 318 to placebo). After a mean follow-up of 10 months, 89 patients had died: 59 of arrhythmia (43 receiving drug vs. 16 receiving placebo; P = 0.0004), 22 of nonarrhythmic cardiac causes (17 receiving drug vs. 5 receiving placebo; P = 0.01), and 8 of noncardiac causes (3 receiving drug vs. 5 receiving placebo). Almost all cardiac deaths not due to arrhythmia were attributed to acute myocardial infarction with shock (11 patients receiving drug and 3 receiving placebo) or to chronic congestive heart failure (4 receiving drug and 2 receiving placebo). There were no differences between the patients receiving active drug and those receiving placebo in the incidence of nonlethal disqualifying ventricular tachycardia, proarrhythmia, syncope, need for a permanent pacemaker, congestive heart failure, recurrent myocardial infarction, angina, or need for coronary-artery bypass grafting or angioplasty. CONCLUSIONS There was an excess of deaths due to arrhythmia and deaths due to shock after acute recurrent myocardial infarction in patients treated with encainide or flecainide. Nonlethal events, however, were equally distributed between the active-drug and placebo groups. The mechanisms underlying the excess mortality during treatment with encainide or flecainide remain unknown.

2014 AHA/ACC Guideline for the Management of Patients With Non-ST-Elevation Acute Coronary Syndromes A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines

Preamble e346 1. Introduction e347 2. Overview of Acs e349 3. Initial Evaluation and Management e350 4. Early Hospital Care e359

Clinical Practice Guideline2014 AHA/ACC Guideline for the Management of Patients With Non–ST-Elevation Acute Coronary Syndromes: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines

Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIR.0000000000000134 The writing committee gratefully acknowledges the memory of Dr. Francis M. Fesmire (representative of the American College of Emergency Physicians), who died during the development of this document but contributed immensely to our understanding of non–ST-elevation acute coronary syndromes. *Writing committee members are required to recuse themselves from voting on sections to which their specific relationships with industry and other entities may apply; see Appendix 1 for recusal information. †ACC/AHA Representative. ‡ACC/AHA Task Force on Practice Guidelines Liaison. §American College of Physicians Representative. ║American Academy of Family Physicians Representative. ¶Society of Thoracic Surgeons Representative. #ACC/AHA Task Force on Performance Measures Liaison. **Society for Cardiovascular Angiography and Interventions Representative. ††Former Task Force member; current member during the writing effort. This document was approved by the American Heart Association Science Advisory and Coordinating Committee and the American College of Cardiology Board of Trustees in August 2014. The online-only Comprehensive Relationships Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/ doi:10.1161/CIR.0000000000000134/-/DC1. The online-only Data Supplement files are available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/ CIR.0000000000000134/-/DC2. The American Heart Association requests that this document be cited as follows: Amsterdam EA, Wenger NK, Brindis RG, Casey DE Jr, Ganiats TG, Holmes DR Jr, Jaffe AS, Jneid H, Kelly RF, Kontos MC, Levine GN, Liebson PR, Mukherjee D, Peterson ED, Sabatine MS, Smalling RW, Zieman SJ. 2014 ACC/AHA guideline for the management of patients with non–ST-elevation acute coronary syndromes: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines. Circulation. 2014;130:e344–e426. This article is copublished in the Journal of the American College of Cardiology. Copies: This document is available on the World Wide Web sites of the American Heart Association (my.americanheart.org) and the American College of Cardiology (www.cardiosource.org). A copy of the document is available at http://my.americanheart.org/statements by selecting either the “By Topic” link or the “By Publication Date” link. To purchase additional reprints, call 843-216-2533 or e-mail kelle.ramsay@wolterskluwer.com. Expert peer review of AHA Scientific Statements is conducted by the AHA Office of Science Operations. For more on AHA statements and guidelines development, visit http://my.americanheart.org/statements and select the “Policies and Development” link. Permissions: Multiple copies, modification, alteration, enhancement, and/or distribution of this document are not permitted without the express permission of the American Heart Association. Instructions for obtaining permission are located at http://www.heart.org/HEARTORG/General/ Copyright-Permission-Guidelines_UCM_300404_Article.jsp. A link to the “Copyright Permissions Request Form” appears on the right side of the page. 2014 AHA/ACC Guideline for the Management of Patients With Non–ST-Elevation Acute Coronary Syndromes A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines

Long-term Effects on Sexual Function of Five Antihypertensive Drugs and Nutritional Hygienic Treatment in Hypertensive Men and Women: Treatment of Mild Hypertension Study (TOMHS)

Problems with sexual function have been a long-standing concern in the treatment of hypertension and may influence the choice of treatment regimens and decisions to discontinue drugs. The Treatment of Mild Hypertension Study (TOMHS) provides an excellent opportunity for examination of sexual function and effects of treatment on sexual function in men and women with stage I diastolic hypertension because of the number of drug classes studied, the double-blind study design, and the long-term follow-up. TOMHS was a double-blind, randomized controlled trial of 902 hypertensive individuals (557 men, 345 women), aged 45 to 69 years, treated with placebo or one of five active drugs (acebutolol, amlodipine maleate, chlorthalidone, doxazosin maleate, or enalapril maleate). All participants received intensive lifestyle counseling regarding weight loss, dietary sodium reduction, alcohol reduction (for current drinkers), and increased physical activity. Sexual function was ascertained by physician interviews at baseline and annually during follow-up. At baseline, 14.4% of men and 4.9% of women reported a problems with sexual function. In men, 12.2% had problems obtaining and/or maintaining an erection; 2.0% of women reported a problem having an orgasm. Erection problems in men at baseline were positively related to age, systolic pressure, and previous antihypertensive drug use. The incidences of erection dysfunction during follow-up in men were 9.5% and 14.7% through 24 and 48 months, respectively, and were related to type of antihypertensive therapy. Participants randomized to chlorthalidone reported a significantly higher incidence of erection problems through 24 months than participants randomized to placebo (17.1% versus 8.1%, P = .025). Incidence rates through 48 months were more similar among treatment groups than at 24 months, with nonsignificant differences between the chlorthalidone and placebo groups. Incidence was lowest in the doxazosin group but was not significantly different from the placebo group. Incidence for acebutolol, amlodipine, and enalapril groups was similar to that in the placebo group. In many cases, erection dysfunction did not require withdrawal of medication. Disappearance of erection problems among men with problems at baseline was common in all groups but greatest in the doxazosin group. Incidence of reported sexual problems in women was low in all treatment groups. In conclusion, long-term incidence of erection problems in treated hypertensive men is relatively low but is higher with chlorthalidone treatment. Effects of erection dysfunction with chlorthalidone appear relatively early and are often tolerable, and new occurrences after 2 years are unlikely. The rate of reported sexual problems in hypertensive women is low and does not appear to differ by type of drug. Similar incidence rates of erection dysfunction in placebo and most active drug groups caution against routine attribution of erection problems to antihypertensive medication.

Comparison of Five Antihypertensive Monotherapies and Placebo for Change in Left Ventricular Mass in Patients Receiving Nutritional-Hygienic Therapy in the Treatment of Mild Hypertension Study (TOMHS)

BACKGROUND Increased left ventricular mass (LVM) by echocardiography is associated with increased risk of cardiovascular disease. Thus, it is of interest to compare the effects of both pharmacological and nonpharmacological approaches to the treatment of hypertension on reduction of LVM. METHODS AND RESULTS Changes in LV structure were assessed by M-mode echocardiograms in a double-blind, placebo-controlled clinical trial of 844 mild hypertensive participants randomized to nutritional-hygienic (NH) intervention plus placebo or NH plus one of five classes of antihypertensive agents: (1) diuretic (chlorthalidone), (2) beta-blocker (acebutolol), (3) alpha-antagonist (doxazosin mesylate), (4) calcium antagonist (amlodipine maleate), or (5) angiotensin-converting enzyme inhibitor (enalapril maleate). Echocardiograms were performed at baseline, at 3 months, and annually for 4 years. Changes in blood pressure averaged 16/12 mm Hg in the active treatment groups and 9/9 mm Hg in the NH only group. All groups showed significant decreases (10% to 15%) in LVM from baseline that appeared at 3 months and continued for 48 months. The chlorthalidone group experienced the greatest decrease at each follow-up visit (average decrease, 34 g), although the differences from other groups were modest (average decrease among 5 other groups, 24 to 27 g). Participants randomized to NH intervention only had mean changes in LVM similar to those in the participants randomized to NH intervention plus pharmacological treatment. The greatest difference between groups was seen at 12 months, with mean decreases ranging from 35 g (chlorthalidone group) to 17 g (acebutolol group) (P = .001 comparing all groups). Within-group analysis showed that changes in weight, urinary sodium excretion, and systolic BP were moderately correlated with changes in LVM, being statistically significant in most analyses. CONCLUSIONS NH intervention with emphasis on weight loss and reduction of dietary sodium is as effective as NH intervention plus pharmacological treatment in reducing echocardiographically determined LVM, despite a smaller decrease in blood pressure in the NH intervention only group. A possible exception is that the addition of diuretic (chlorthalidone) may have a modest additional effect on reducing LVM.

Impact of Different Partition Values on Prevalences of Left Ventricular Hypertrophy and Concentric Geometry in a Large Hypertensive Population: The LIFE Study

Left ventricular (LV) hypertrophy and concentric remodeling have been defined by using a variety of indexation methods and partition values (PVs) for LV mass and relative wall thickness (RWT). The effects of these methods on the distribution of LV geometric patterns in hypertensive subjects remain unclear. Echocardiograms were obtained in 941 patients with stage I to III hypertension and LV hypertrophy by ECG. LV mass was calculated by using different methods of indexation for body size and different PVs to identify hypertrophy: LV mass/body surface area (g/m(2)) PV for men/women 116/104, 125/110, or 125/125; LV mass/height (g/m) PV 143/102 or 126/105; and LV mass/height(2.7) (g/m(2.7)) PV 51/51 or 49.2/46.7. RWT was calculated by either 2xend-diastolic posterior wall thickness (PWT)/end-diastolic LV internal dimension (LVID) or end-diastolic interventricular septum dimension+end-diastolic PWT/end-diastolic LVID. LV hypertrophy or remodeling was present in 63% to 86% of subjects, and LV hypertrophy was present in 42% to 77%. By any index, eccentric hypertrophy was the common LV geometric pattern. Use of interventricular septum dimension+PWT/LVID to calculate RWT slightly increased the prevalence of normal geometry and eccentric hypertrophy compared with the use of 2xPWT/LVID. Subjects with LV hypertrophy identified by only LV mass/height(2.7) PV 49.2/46.7 were more obese, whereas those identified by only LV mass/body surface area PV 116/104 were taller and thinner than those in the 2 concordant groups with or without LV hypertrophy by both criteria. By either criterion, there were no significant differences between different LV geometric patterns in clinical cardiovascular disease. Hypertensive patients with LV hypertrophy by ECG have a high prevalence of geometric abnormalities, especially eccentric hypertrophy, irrespective of method of indexation or PV. LV mass indexation by body surface area or height(2.7) identifies lean and obese subjects, respectively. We found no difference in prevalent cardiovascular disease in subjects identified by either criterion, suggesting a similar high risk.

Echocardiographic correlates of left ventricular structure among 844 mildly hypertensive men and women in the Treatment of Mild Hypertension Study (TOMHS).

BackgroundEchocardiography provides a noninvasive means of assessing left ventricular (LV) structure and evidence of LV wall remodeling in hypertensive persons. The relation of demographic, biological, and other factors with LV structure can be assessed. Methods and ResultsLV structure was assessed by M-mode echocardiograms for 511 men and 333 women with mild hypertension (average blood pressure, 140/91 mm Hg). Measurements ofLV wall thicknesses and internal dimensions were made, and estimates of LV mass indexes and other derivations of structure were calculated. LV hypertrophy criteria were based on previously reported echocardiographic population studies of normal subjects. These measures were compared by age, sex, race, body mass index, systolic blood pressure, antihypertensive drug use, physical activity, alcohol intake, cigarette smoking, and urinary sodium excretion. Despite virtual absence of ECG-determined LV hypertrophy, 13% of men and 20%o ofwomen had echocardiographically determined LV hypertrophy indexed by body surface area (g/m2), and 24% of men and 45% of women had LV hypertrophy indexed by height (g/m). Black participants had slightly higher mean levels of wall thickness than nonblack participants but similar LV mass. Systolic blood pressure and urinary sodium excretion were significantly and independently associated with LV mass index and LV hypertrophy using both g/m2 and g/m. Body mass index was significantly related to LV mass index and LV hypertrophy using g/m. Smoking was significantly associated with LV mass index, i.e., using continuous measurement but not using the dichotomy for LV hypertrophy. ConclusionThis study of a large population of men and women with mild primary hypertension, largely without ECG evidence of LV hypertrophy, showed a substantial percentage of participants with echocardiographically determined LV hypertrophy. LV mass indexes correlated positively with systolic blood pressure, body mass index, urinary sodium excretion, and smoking.

Relation between electrocardiography and echocardiography for left ventricular mass in mild systemic hypertension (results from Treatment of Mild Hypertension Study).

Clinical recognition of hypertensive cardiac involvement depends primarily on use of noninvasive methods. The performance of 8 electrocardiographic (ECG) criteria sets were compared with an echocardiographic standard in the treatment of Mild Hypertension Study. Electrocardiograms were computer processed to define the following ECG criteria sets: (1) Casale/Devereux, (2) Cornell product, (3) Cornell voltage, (4) 12-lead voltage product, (5) sum of 12-lead voltage, (6) Rautaharju, (7) Sokolow-Lyon, and (8) Romhilt-Estes. Echocardiographic left ventricular (LV) mass index was calculated by using the Penn convention on a biracial population of 834 men and women. Correlations between ECG and echocardiographic LV mass index were modest (<0.40). ECG-LV hypertrophy sensitivity at 95% specificity was < 34%. The Casale/Devereux ECG criteria showed the highest average sensitivity (17%) at 95% specificity for all race-sex groups. Whites had significantly higher correlation values than blacks. ECG correlations with LV mass index were consistently improved by including systolic blood pressure and body mass index. ECG criteria sets appear to be optimized for white men. The study findings confirm the poor ECG sensitivity and correlation with echocardiographic LV mass and suggest: (1) further refinement of ECG criteria alone in white men is unlikely to improve its relationship with LV mass; and (2) combining the electrocardiogram with other non-ECG variables or noninvasive measurements offers the best strategy for improving ECG sensitivity and its prognostic value.

Unstable angina and non-Q wave myocardial infarction: does the clinical diagnosis have therapeutic implications?

OBJECTIVES The goal of this review is to reevaluate the unstable coronary syndromes in the setting of new therapies and biochemical markers. BACKGROUND Patients with acute coronary syndromes comprise a large subset of many cardiology practices. Patients with unstable angina (UA) and non-Q wave myocardial infarction (NQMI) may sustain a small amount of myocardial loss but have significant amounts of viable, yet ischemic, myocardium, placing them at high risk for future cardiac events. In the past, enzyme differentiation of NQMI from UA was considered important to assess prognosis and direct therapy. METHODS Manuscripts published in peer-reviewed journals over the past three decades were reviewed and selected for this review. Recent abstracts were also considered and cited where appropriate. RESULTS In the late 1990s, although UA and NQMI remain parts of a spectrum, it is apparent that the distinction between these two entities is no longer sufficient to identify high risk patients; rather, specific electrocardiographic changes, aspects of the clinical history, newer biochemical markers, and angiographic findings help to better distinguish higher risk individuals from a large patient population with unstable coronary syndromes and these factors usually determine therapy. CONCLUSIONS Based on these results, it is likely that newer therapies such as glycoprotein IIb/IIIa receptor antagonists, low molecular weight heparins, and coronary stents will be directed toward these high risk patients.

Echocardiographic studies of regression of left ventricular hypertrophy in hypertension.

The availability of echocardiography has allowed direct determinations of left ventricular wall thickness and calculation of left ventricular mass. As a result, the past decade has witnessed a remarkable evolution in our understanding of structural changes in the heart. Moreover, cardiac hypertrophy was found to be reversible by some forms of therapy. In general, reduction of left ventricular mass became evident after 8 to 12 weeks of antihypertensive therapy. Sympatholytics (including methyldopa and reserpine), converting enzyme inhibitors (captopril and enalapril), and calcium entry blockers led to significant regression of left ventricular hypertrophy. On the other hand, arteriolar vasodilators (hydralazine, trimazosin, and minoxidil) were not associated with regression of hypertrophy despite adequate blood pressure control. Finally, data regarding diuretics and β-blockers are controversial. These differences in results among various antihypertensive drugs reflect the multiplicity of factors modulating left ventricular hypertrophy.