Elizabeth Ofili

Effectiveness-Based Guidelines for the Prevention of Cardiovascular Disease in Women—2011 Update: A Guideline From the American Heart Association

Substantial progress has been made in the awareness, treatment, and prevention of cardiovascular disease (CVD) in women since the first women-specific clinical recommendations for the prevention of CVD were published by the American Heart Association (AHA) in 1999.1 The myth that heart disease is a “mans disease” has been debunked; the rate of public awareness of CVD as the leading cause of death among US women has increased from 30% in 1997 to 54% in 2009.2 The age-adjusted death rate resulting from coronary heart disease (CHD) in females, which accounts for about half of all CVD deaths in women, was 95.7 per 100 000 females in 2007, a third of what it was in 1980.3,4 Approximately 50% of this decline in CHD deaths has been attributed to reducing major risk factors and the other half to treatment of CHD including secondary preventive therapies.4 Major randomized controlled clinical trials such as the Womens Health Initiative have changed the practice of CVD prevention in women over the past decade.5 The investment in combating this major public health issue for women has been significant, as have the scientific and medical achievements. Despite the gains that have been made, considerable challenges remain. In 2007, CVD still caused ≈1 death per minute among women in the United States.6 These represent 421 918 deaths, more womens lives than were claimed by cancer, chronic lower respiratory disease, Alzheimer disease, and accidents combined.6 Reversing a trend of the past 4 decades, CHD death rates in US women 35 to 54 years of age now actually appear to be increasing, likely because of the effects of the obesity epidemic.4 CVD rates in the United States are significantly higher for black females compared with their white counterparts (286.1/100 000 versus …

Racial and ethnic differences in access to medical care

The authors’ review of the health services literature since the release of the landmark Report of the Secretary’s Task Force Report of Black and Minority Health in 1985 revealed significant differences in access to medical care by race and ethnicity within certain disease categories and types of health services. The differences are not explained by such factors as socioeconomic status (SES), insurance coverage, stage or severity of disease, comorbidities, type and availability of health care services, and patient preferences. Under certain circumstances when important variables are controlled, racial and ethnic disparities in access are reduced and may disappear. Nonetheless, the literature shows that racial and ethnic disparities persist in significant measure for several disease categories and service types. The complex challenge facing current and future researchers is to understand the basis for such disparities and to determine why disparities are apparent in some but not other disease categories and service types.

Ultrafiltration in Decompensated Heart Failure with Cardiorenal Syndrome

BACKGROUND Ultrafiltration is an alternative strategy to diuretic therapy for the treatment of patients with acute decompensated heart failure. Little is known about the efficacy and safety of ultrafiltration in patients with acute decompensated heart failure complicated by persistent congestion and worsened renal function. METHODS We randomly assigned a total of 188 patients with acute decompensated heart failure, worsened renal function, and persistent congestion to a strategy of stepped pharmacologic therapy (94 patients) or ultrafiltration (94 patients). The primary end point was the bivariate change from baseline in the serum creatinine level and body weight, as assessed 96 hours after random assignment. Patients were followed for 60 days. RESULTS Ultrafiltration was inferior to pharmacologic therapy with respect to the bivariate end point of the change in the serum creatinine level and body weight 96 hours after enrollment (P=0.003), owing primarily to an increase in the creatinine level in the ultrafiltration group. At 96 hours, the mean change in the creatinine level was -0.04±0.53 mg per deciliter (-3.5±46.9 μmol per liter) in the pharmacologic-therapy group, as compared with +0.23±0.70 mg per deciliter (20.3±61.9 μmol per liter) in the ultrafiltration group (P=0.003). There was no significant difference in weight loss 96 hours after enrollment between patients in the pharmacologic-therapy group and those in the ultrafiltration group (a loss of 5.5±5.1 kg [12.1±11.3 lb] and 5.7±3.9 kg [12.6±8.5 lb], respectively; P=0.58). A higher percentage of patients in the ultrafiltration group than in the pharmacologic-therapy group had a serious adverse event (72% vs. 57%, P=0.03). CONCLUSIONS In a randomized trial involving patients hospitalized for acute decompensated heart failure, worsened renal function, and persistent congestion, the use of a stepped pharmacologic-therapy algorithm was superior to a strategy of ultrafiltration for the preservation of renal function at 96 hours, with a similar amount of weight loss with the two approaches. Ultrafiltration was associated with a higher rate of adverse events. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00608491.).

Low-Dose Dopamine or Low-Dose Nesiritide in Acute Heart Failure With Renal Dysfunction The ROSE Acute Heart Failure Randomized Trial

IMPORTANCE Small studies suggest that low-dose dopamine or low-dose nesiritide may enhance decongestion and preserve renal function in patients with acute heart failure and renal dysfunction; however, neither strategy has been rigorously tested. OBJECTIVE To test the 2 independent hypotheses that, compared with placebo, addition of low-dose dopamine (2 μg/kg/min) or low-dose nesiritide (0.005 μg/kg/min without bolus) to diuretic therapy will enhance decongestion and preserve renal function in patients with acute heart failure and renal dysfunction. DESIGN, SETTING, AND PARTICIPANTS Multicenter, double-blind, placebo-controlled clinical trial (Renal Optimization Strategies Evaluation [ROSE]) of 360 hospitalized patients with acute heart failure and renal dysfunction (estimated glomerular filtration rate of 15-60 mL/min/1.73 m2), randomized within 24 hours of admission. Enrollment occurred from September 2010 to March 2013 across 26 sites in North America. INTERVENTIONS Participants were randomized in an open, 1:1 allocation ratio to the dopamine or nesiritide strategy. Within each strategy, participants were randomized in a double-blind, 2:1 ratio to active treatment or placebo. The dopamine (n = 122) and nesiritide (n = 119) groups were independently compared with the pooled placebo group (n = 119). MAIN OUTCOMES AND MEASURES Coprimary end points included 72-hour cumulative urine volume (decongestion end point) and the change in serum cystatin C from enrollment to 72 hours (renal function end point). RESULTS Compared with placebo, low-dose dopamine had no significant effect on 72-hour cumulative urine volume (dopamine, 8524 mL; 95% CI, 7917-9131 vs placebo, 8296 mL; 95% CI, 7762-8830 ; difference, 229 mL; 95% CI, -714 to 1171 mL; P = .59) or on the change in cystatin C level (dopamine, 0.12 mg/L; 95% CI, 0.06-0.18 vs placebo, 0.11 mg/L; 95% CI, 0.06-0.16; difference, 0.01; 95% CI, -0.08 to 0.10; P = .72). Similarly, low-dose nesiritide had no significant effect on 72-hour cumulative urine volume (nesiritide, 8574 mL; 95% CI, 8014-9134 vs placebo, 8296 mL; 95% CI, 7762-8830; difference, 279 mL; 95% CI, -618 to 1176 mL; P = .49) or on the change in cystatin C level (nesiritide, 0.07 mg/L; 95% CI, 0.01-0.13 vs placebo, 0.11 mg/L; 95% CI, 0.06-0.16; difference, -0.04; 95% CI, -0.13 to 0.05; P = .36). Compared with placebo, there was no effect of low-dose dopamine or nesiritide on secondary end points reflective of decongestion, renal function, or clinical outcomes. CONCLUSION AND RELEVANCE In participants with acute heart failure and renal dysfunction, neither low-dose dopamine nor low-dose nesiritide enhanced decongestion or improved renal function when added to diuretic therapy. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01132846.

Discovering the full spectrum of cardiovascular disease: Minority Health Summit 2003: report of the Obesity, Metabolic Syndrome, and Hypertension Writing Group.

This article provides an overview of our current understanding of the epidemiology of obesity, the metabolic syndrome, and hypertension among racial/ethnic groups. Three presentations made at the conference by the present writing group are summarized and updated with other information on ethnic groups, and recommendations developed by the writing group for programs, public policy, and research are put forward.

Early and Sustained Benefit on Event-Free Survival and Heart Failure Hospitalization From Fixed-Dose Combination of Isosorbide Dinitrate/Hydralazine Consistency Across Subgroups in the African-American Heart Failure Trial

Background— We previously reported that the fixed-dose combination of isosorbide dinitrate and hydralazine hydrochloride (FDC I/H) significantly decreased the risk of all-cause death and first hospitalization for heart failure (HF) and improved quality of life in patients with New York Heart Association class III or IV heart failure in the African-American Heart Failure Trial (A-HeFT). The current analyses further define the effect of FDC I/H on the timing of event-free survival (mortality or first hospitalization for HF) and time to first hospitalization for HF, as well as effects by subgroups and effects on cause-specific mortality. Methods and Results— Kaplan-Meier analyses of the 1050 A-HeFT patients on standard neurohormonal blockade demonstrated that FDC I/H produced a 37% improvement in event-free survival (P<0.001) and a 39% reduction in the risk for first hospitalization for HF (P<0.001). These benefits appeared to emerge early (at ≈50 days of treatment) and were sustained through the duration of the trial. Subgroup analyses of treatment effect by age, sex, baseline blood pressure, history of chronic renal insufficiency, presence of diabetes mellitus, cause of HF, and baseline medication usage demonstrated consistent beneficial effect of FDC I/H on the primary composite score and event-free survival across all subgroups. Mortality from pump failure was reduced by 75% (P=0.012). Conclusions— FDC I/H treatment of black patients with moderate to severe HF who were taking neurohormonal blockers produced early and sustained significant improvement in event-free survival and hospitalization for HF in the A-HeFT cohort, with significant reduction in mortality from cardiovascular and pump failure deaths. The treatment effects on the primary composite end point and event-free survival were consistent across subgroups.

The Efficacy and Safety of Low- and High- Dose Fixed Combinations of Irbesartan/Hydrochlorothiazide in Patients With Uncontrolled Systolic Blood Pressure on Monotherapy: The INCLUSIVE Trial

This multicenter, prospective, open‐label, single‐arm study determined the efficacy and safety of irbesartan/hydrochlorothiazide (HCTZ) fixed combinations in patients (n=1005), aged 18 years and older, with uncontrolled systolic blood pressure (SBP) of 140–159 mm Hg (130–159 mm Hg for type 2 diabetes mellitus) after at least 4 weeks of antihypertensive monotherapy. Treatment was sequential: placebo (4–5 weeks), HCTZ 12.5 mg (2 weeks), irbesartan/HCTZ 150/12.5 mg (8 weeks), and irbesartan/HCTZ 300/25 mg (8 weeks). Enrolled patients (n=844) were aged 57.3±11.2 years; 52% were women, 23% were African American, and 14% were Hispanic. Thirty percent had type 2 diabetes mellitus, 46% had metabolic syndrome, and baseline blood pressure was 154.0±10.3/91.3±8.8 mm Hg. The mean change in SBP from placebo end to the primary end point, Week 18 (intent‐to‐treat population, n=736) was −21.5±14.3 mm Hg (p<0.001). The mean change in diastolic blood pressure (DBP) was −10.4 ±8.7 mm Hg (p<0.001). The mean Week 18 SBP/DBP was 132.9±13.8/81.1±9.7 mm Hg. Overall, 77% (95% confidence interval, 74%–80%) of patients achieved SBP goal (<140 mm Hg; <130 mm Hg for type 2 diabetes mellitus); 83% (95% confidence interval, 80%–86%) achieved DBP goal (<90 mm Hg; <80 mm Hg for type 2 diabetes mellitus); and 69% (95% confidence interval, 66%–72%) achieved dual SBP/DBP goal. Treatments were well tolerated. This irbesartan/HCTZ treatment regimen achieved SBP goals in more than 75% of patients uncontrolled on monotherapy.

Effects of Xanthine Oxidase Inhibition in Hyperuricemic Heart Failure Patients: The Xanthine Oxidase Inhibition for Hyperuricemic Heart Failure Patients (exact-hf) Study

Background— Oxidative stress may contribute to heart failure (HF) progression. Inhibiting xanthine oxidase in hyperuricemic HF patients may improve outcomes. Methods and Results— We randomly assigned 253 patients with symptomatic HF, left ventricular ejection fraction ⩽40%, and serum uric acid levels ≥9.5 mg/dL to receive allopurinol (target dose, 600 mg daily) or placebo in a double-blind, multicenter trial. The primary composite end point at 24 weeks was based on survival, worsening HF, and patient global assessment. Secondary end points included change in quality of life, submaximal exercise capacity, and left ventricular ejection fraction. Uric acid levels were significantly reduced with allopurinol in comparison with placebo (treatment difference, –4.2 [–4.9, –3.5] mg/dL and –3.5 [–4.2, –2.7] mg/dL at 12 and 24 weeks, respectively, both P<0.0001). At 24 weeks, there was no significant difference in clinical status between the allopurinol- and placebo-treated patients (worsened 45% versus 46%, unchanged 42% versus 34%, improved 13% versus 19%, respectively; P=0.68). At 12 and 24 weeks, there was no significant difference in change in Kansas City Cardiomyopathy Questionnaire scores or 6-minute walk distances between the 2 groups. At 24 weeks, left ventricular ejection fraction did not change in either group or between groups. Rash occurred more frequently with allopurinol (10% versus 2%, P=0.01), but there was no difference in serious adverse event rates between the groups (20% versus 15%, P=0.36). Conclusions— In high-risk HF patients with reduced ejection fraction and elevated uric acid levels, xanthine oxidase inhibition with allopurinol failed to improve clinical status, exercise capacity, quality of life, or left ventricular ejection fraction at 24 weeks. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00987415.Despite guideline-recommended therapy for patients with heart failure (HF), morbidity and mortality rates remain unacceptably high.1 Given the public health burden of HF, there is a clear need for improved therapies. A growing body of evidence suggests that increased oxidative stress contributes to ventricular and vascular remodeling and disease progression in HF.2 Xanthine oxidase (XO) is a potential source of oxidative stress, and may be an important target for therapy.3 During purine metabolism, increased XO activity leads to the production of superoxide and uric acid (UA). Significant hyperuricemia is present in about 25% of patients with HF and reduced ejection fraction,4, 5 and is associated with worsening symptoms, exercise intolerance and reduced survival.6–8 Serum UA levels are included in HF risk scores,8, 9 and may help to select high-risk patients for XO inhibition. Allopurinol is a potent inhibitor of XO that may reverse several pathophysiological processes in HF, including decreased calcium sensitivity, mechanoenergetic uncoupling, increased anaerobic metabolism, and energy depletion.10 Studies in animals and humans with HF have shown that allopurinol can increase myocardial efficiency and reduce oxygen consumption.11, 12 Magnetic resonance spectroscopy has demonstrated that allopurinol increases myocardial high-energy phosphates and adenosine triphosphate flux, thereby improving mechanoenergetic coupling.13 Impaired endothelial function improves in a dose-dependent fashion with chronic XO inhibition in HF,14, 15 and observational studies in HF patients with gout suggest that treatment with allopurinol is associated with improved survival.16–18 Notably, allopurinol use is treated as a marker of improved survival in the Seattle Heart Failure Model.8 Hare et al.19 randomized 405 patients with moderate to severe HF and reduced ejection fraction to 6 months of treatment with oxypurinol (the active metabolite of allopurinol) or placebo. Although oxypurinol had no clinical benefit in the overall study population, a sub-group of patients with hyperuricemia (UA level ≥9.5 mg/dL) responded favorably with improved clinical status and trends towards decreased all-cause and cardiovascular death. Based on these findings, we hypothesized that in patients with symptomatic HF and reduced LVEF, who have elevated serum UA levels, treatment with high-dose allopurinol for 24 weeks would improve a composite clinical outcome of survival, worsening HF and patient global assessment.

Endothelial Nitric Oxide Synthase (NOS3) Polymorphisms in African Americans With Heart Failure : Results From the A-HeFT Trial

BACKGROUND Genetic heterogeneity at the endothelial nitric oxide synthase (NOS3) locus influences heart failure outcomes. The prevalence of NOS3 variants differs in black and white cohorts, but the impact of these differences is unknown. METHODS AND RESULTS Subjects (n = 352) in the Genetic Risk Assessment of Heart Failure (GRAHF) substudy of the African-American Heart Failure Trial were genotyped for NOS3 polymorphisms: -786 T/C promoter, intron 4a/4b, and Glu298Asp and allele frequencies and compared with a white heart failure cohort. The effect of treatment with fixed-dose combination of isosorbide dinitrates and hydralazine (FDC I/H) on event-free survival and composite score (CS) of survival, hospitalization, and quality of life (QoL) was analyzed within genotype subsets. In GRAHF, NOS3 genotype frequencies differed from the white cohort (P < .001). The -786 T allele was associated with lower left ventricular ejection fraction (LVEF) (P = .01), whereas the intron 4a allele was linked to lower diastolic blood pressure and higher LVEF (P = .03). Only the Glu298Asp polymorphism influenced treatment outcome; therapy with FDC I/H improved CS (P = .046) and QoL (P = .03) in the Glu298Glu subset only. CONCLUSIONS In black subjects with heart failure, NOS3 genotype influences blood pressure and left ventricular remodeling. The impact of genetic heterogeneity on treatment with FDC I/H requires further study.

Ethnic differences in electrocardiographic criteria for left ventricular hypertrophy: the LIFE study

BACKGROUND African Americans have greater precordial QRS voltages than whites, with concomitant higher prevalences of electrocardiographic (ECG) left ventricular hypertrophy (LVH) and lower specificity of ECG LVH criteria for the identification of anatomic hypertrophy. However, the high mortality associated with LVH in African American patients makes more accurate ECG detection of LVH in these patients a clinical priority. METHODS Electrocardiograms and echocardiograms were obtained at study baseline in 120 African American and 751 white hypertensive patients enrolled in the Losartan Intervention For Endpoint (LIFE) echocardiographic substudy. The ECG LVH was determined using Sokolow-Lyon, 12-lead sum, and Cornell voltage criteria. Echocardiographic LVH was defined by LV mass indexed to height(2.7) >46.7 g/m(2.7) in women and >49.1 g/m(2.7) in men. RESULTS After adjusting for ethnic differences in LV mass, body mass index, sex, and prevalence of diabetes, mean Sokolow-Lyon and 12-lead sum of voltage were significantly higher, but Cornell voltage was lower, in African Americans than in whites. As a consequence of these differences, when identical partition values were used in both ethnic groups, Sokolow-Lyon and 12-lead voltage criteria had lower specificity in African Americans than whites (44% v 69%, P = .007 and 44% v 59%, P = .10) but had greater sensitivity in African Americans (51% v 27%, P < .001 and 62% v 45%, P = .003). In contrast, Cornell voltage specificity was higher (78% v 62%, P = .09) but sensitivity was slightly lower (49% v 57%, P = 0.16) in African Americans. However, when overall test performance was compared using receiver operating curve analyses that were independent of partition value selection, ethnic differences in test performance disappeared, with no differences in accuracy of any of the ECG voltage criteria for the identification of LVH between African American and white hypertensive individuals. CONCLUSIONS When standard, non-ethnicity-specific thresholds for the identification of LVH are used, Sokolow-Lyon and 12-lead voltage overestimate and Cornell voltage underestimates the presence and severity of LVH in African American relative to white individuals. However, these apparent ethnic differences in test performance disappear when ethnic differences in the distribution of ECG LVH criteria are taken into account. These findings demonstrate that ethnicity-specific ECG criteria can equalize detection of anatomic LVH in African American and white patients.