Anticoagulation has been shown to reduce ischemic stroke in atrial fibrillation (AF). However, concerns remain regarding their safety and efficacy in those ≥70 years of age who comprise most AF patients. Of the 4060 patients (mean age, 65 years; range, 49–80 years) in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial, 2248 (55% of 4060) were 70–80 years of age, 1901 of whom were receiving warfarin. Propensity score for warfarin use, estimated for each of the 2248 patients, were used to match 227 of the 347 no-warfarin patients (in 1:1, 1:2 or 1:3 sets) with 616 warfarin patients, who were balanced on 45 baseline characteristics. All-cause mortality occurred in 18% and 33% of matched patients receiving and not receiving warfarin, respectively, during up to six (mean, 3.4) years of follow-up (hazard ratio {HR} when warfarin use was compared with its non-use, 0.58; 95% confidence interval {CI}, 0.43–0.77; p<0.001). All-cause hospitalization occurred in 64% and 67% of matched patients receiving and not receiving warfarin, respectively (HR associated with warfarin use, 0.93; 95% CI, 0.77–1.12; p=0.423). Ischemic stroke occurred in 4% and 8% of matched patients receiving and not receiving warfarin, respectively (HR associated with warfarin use, 0.57; 95% CI, 0.31–1.04; p=0.068). Major bleeding occurred in 7% and 10% of matched patients receiving and not receiving warfarin, respectively (HR associated with warfarin use, 0.73; 95% CI, 0.44–1.22; p=0.229). In conclusion, warfarin use was associated with reduced mortality in septuagenarian AF patients but had no association with hospitalization or major bleeding.

Background

Older age is an independent predictor of all-cause mortality in patients with mild to moderate heart failure (HF). Whether older age is also an independent predictor of mortality in patients with more advanced HF is unknown.

Methods

Of the 2707 Beta-Blocker Evaluation of Survival Trial (BEST) participants with ambulatory chronic HF (New York Heart Association class III/IV and left ventricular ejection fraction <35%), 1091 were elderly (≥65 years). Propensity scores for older age, estimated for each of the 2707 patients, were used to assemble a cohort of 603 pairs of younger and older patients, balanced on 66 baseline characteristics.

Results

All-cause mortality occurred in 33% and 36% of younger and older matched patients respectively during 4 years of follow-up (hazard ratio {HR} associated with age ≥65 years, 1.05; 95% confidence interval {CI}, 0.87—1.27; P=0.614). HF hospitalization occurred in 38% and 40% of younger and older matched patients respectively (HR, 1.01; 95% CI, 0.84–1.21; P=0.951). Among 603 pairs of unmatched and unbalanced patients, all-cause mortality occurred in 28% and 36% of younger and older patients respectively (HR, 1.34; 95% CI, 1.10–1.64; P=0.004) and HF hospitalization occurred in 34% and 40% of younger and older unmatched patients respectively (HR, 1.24; 95% CI, 1.03–1.50; P=0.024).

Conclusion

Significant bivariate associations suggest that older age is a useful marker of poor outcomes in patients with advanced chronic systolic HF. However, lack of significant independent associations suggests that older age per se has no intrinsic effect on outcomes in these patients.

Background

Right ventricular ejection fraction (RVEF) <20% is an independent predictor of poor outcomes in patients with advanced chronic systolic heart failure (HF). The aim of this study was to examine if the adverse effect of abnormally reduced RVEF varies by the receipt of beta-blockers.

Methods

In the Beta-Blocker Evaluation of Survival Trial (BEST), 2708 patients with chronic advanced HF and left ventricular ejection fraction <35%, receiving standard background therapy with renin-angiotensin inhibition, digoxin, and diuretics, were randomized to receive bucindolol or placebo. Of these 2008 had data on baseline RVEF, and 14% (146/1017) and 13% (125/991) of the patients receiving bucindolol and placebo respectively had RVEF <20%.

Results

Among patients in the placebo group, all-cause mortality occurred in 33% and 43% of patients with RVEF ≥20% and <20% respectively (unadjusted hazard ratios {HR}, 1.33; 95% confidence intervals {CI}, 0.99–1.78; p =0.055 and adjusted HR, 0.99; 95% CI, 0.71–1.37; p =0.934). Among those receiving bucindolol, all-cause mortality occurred in 28% and 49% of patients with RVEF ≥20% and <20% respectively (unadjusted HR, 2.15; 95% CI, 1.65–2.80; p <0.001 and adjusted HR, 1.50; 95% CI, 1.08–2.07; p =0.016). These differences were statistically significant (unadjusted and adjusted p for interaction, 0.016 and 0.053 respectively).

Conclusions

In ambulatory patients with chronic advanced systolic HF receiving renin-angiotensin inhibition, digoxin, and diuretics, RVEF <20% had no intrinsic association with mortality. However, in those receiving additional therapy with bucindolol, RVEF <20% had a significant independent association with increased risk of mortality.

Diabetes mellitus (DM) is a risk factor for incident heart failure (HF) in older adults. However, to what extent this association is independent of other risk factors remains unclear. Of the 5464 community-dwelling adults ≥65 years in the Cardiovascular Health Study without baseline HF, 862 had DM (fasting plasma glucose levels ≥126 mg/dl, or treatment with insulin or oral hypoglycemic agents). Propensity scores for DM were estimated for each of the 5464 participants and were used to assemble a cohort of 717 pairs of participants with and without DM, who were balanced on 65 baseline characteristics. Incident HF occurred in 31% and 26% of matched participants with and without DM, respectively, during over 13 years of follow-up (hazard ratio {HR} when DM was compared with no DM, 1.45; 95% confidence interval {CI}, 1.14–1.86; p=0.003). Among the 5464 pre-match participants, unadjusted and multivariable-adjusted HRs for incident HF associated with DM were 2.22 (95% CI, 1.94–2.55; p<0.001) and 1.52 (95% CI, 1.30–1.78; p<0.001), respectively. All-cause mortality occurred in 57% and 47% of matched participants with and without DM respectively (HR, 1.35; 95% CI, 1.13–1.61; p=0.001). Among matched participants, DM-associated HRs for incident peripheral arterial disease, incident acute myocardial infarction and incident stroke were 2.50 (95% CI, 1.45–4.32; p=0.001), 1.37 (95% CI, 0.97–1.93; p=0.072), and 1.11 (95% CI, 0.81–1.51; p=0.527), respectively. In conclusion, the association of DM with incident HF and all-cause mortality in community-dwelling older adults without HF is independent of major baseline cardiovascular risk factors.

Objectives.

Widowhood is associated with increased mortality. However, to what extent this association is independent of other risk factors remains unclear. In the current study, we used propensity score matching to design a study to examine the independent association of widowhood with outcomes in a balanced cohort of older adults in the United States.

Methods.

We used public-use copies of the Cardiovascular Health Study data obtained from the National Heart, Lung, and Blood Institute. Of the 5,795 community-dwelling older men and women aged 65 years and older in Cardiovascular Health Study, 3,820 were married and 1,436 were widows or widowers. Propensity scores for widowhood, estimated for each of the 5,256 participants, were used to assemble a cohort of 819 pairs of widowed and married participants who were balanced on 74 baseline characteristics. The 1,638 matched participants had a mean (± standard deviation) age of 75 (±6) years, 78% were women, and 16% African American.

Results.

All-cause mortality occurred in 46% (374/819) and 51% (415/819) of matched married and widowed participants, respectively, during more than 11 years of median follow-up (hazard ratio associated with widowhood, 1.18; 95% confidence interval, 1.03–1.36; p = .018). Hazard ratios (95% confidence intervals) for cardiovascular and noncardiovascular mortalities were 1.07 (0.87–1.32; p = .517) and 1.28 (1.06–1.55; p = .011), respectively. Widowhood had no independent association with all-cause or heart failure hospitalization or incident cardiovascular events.

Conclusions.

Among community-dwelling older adults, widowhood was associated with increased mortality, which was independent of confounding by baseline characteristics and largely driven by an increased noncardiovascular mortality. Widowhood had no independent association with hospitalizations or incident cardiovascular events.

Background

Heart failure (HF) patients often depend on driving for access to specialty care. We analyzed a public-use copy of the Cardiovascular Health Study (CHS) data to determine if HF is a risk factor for driving cessation and to identify other risk factors for driving cessation among those with HF.

Methods and results

Of the 5383 community-dwelling drivers ≥65 years (mean age, 73 years, 55% women, 13% African American), 839 had HF: 246 had baseline prevalent HF and 593 developed incident HF before driving cessation during 9 years of follow-up. Incident driving cessation occurred at rates of 3980 and 3709 per 10,000 person-years of follow-up for those with and without HF, respectively (unadjusted hazard ratio {HR} associated with HF as a time-varying variable, 2.13; 95% confidence interval {CI}, 1.83–2.47; p<0.001). This association remained unchanged after multivariable risk adjustment (HR, 1.43; 95% CI, 1.21–1.68; p<0.001). Among the 839 older drivers with HF, independent predictors for incident driving cessation were age ≥75 years (HR, 1.99; 95% CI, 1.44–2.73; p<0.001), female gender (HR, 1.93; 95% CI, 1.37–2.74; p<0.001), difficulty walking half a mile (HR, 1.47; 95% CI, 1.04–2.08; p=0.028), vision problems (HR, 1.47; 95% CI, 1.07–2.02; p=0.018), and stroke as a time-varying covariate (HR, 1.96; 95% CI, 1.38–2.79; p<0.001).

Conclusion

HF is an independent risk factor for incident driving cessation among community-dwelling older drivers. Several patient characteristics predicted driving cessation in older HF patients, which may be targets for interventions to prevent driving cessation among these patients.

Background

Most studies of heart failure (HF) in Medicare beneficiaries have excluded patients age <65 years. We examined baseline characteristics, quality of care, and outcomes among younger and older Medicare beneficiaries hospitalized with HF in the Alabama Heart Failure Project.

Methods

Of the 8049 Medicare beneficiaries discharged alive with a primary discharge diagnosis of HF in 1998–2001 from 106 Alabama hospitals, 991 (12%) were younger (age <65 years). After excluding 171 patients discharge to hospice care, 7867 patients were considered eligible for left ventricular systolic function (LVSF) evaluation and 2211 patients with left ventricular ejection fraction <45% and without contraindications were eligible for angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) therapy.

Results

Nearly half of the younger HF patients (45% versus 22% for ≥65 years; p<0.001) were African American. LVSF was evaluated in 72%, 72%, 70% and 60% (overall p<0.001) and discharge prescriptions of ACE inhibitors or ARBs were given to 83%, 77%, 75% and 75% of eligible patients (overall p=0.013) among those <65, 65–74, 75–84 and ≥85 years, respectively. During 9 years of follow-up, all-cause mortality occurred in 54%, 61%, 71% and 80% (overall p<0.001) and hospital readmission due to worsening HF occurred in 65%, 60%, 55% and 48% (overall p<0.001) of those <65, 65–74, 75–84 and ≥85 years, respectively.

Conclusion

Medicare beneficiaries <65 years with HF, nearly half of whom were African American, generally received better quality of care, had lower mortality, but had higher re-hospitalizations due to HF.

Aging is often associated with increased systolic blood pressure and decreased diastolic blood pressure. Isolated systolic hypertension or an elevated systolic blood pressure without an elevated diastolic blood pressure is a known risk factor for incident heart failure in older adults. In the current study, we examined whether isolated diastolic hypotension, defined as a diastolic blood pressure <60 mm Hg and a systolic blood pressure ≥100 mm Hg, is associated with incident heart failure. Of the 5795 Medicare-eligible community-dwelling adults age ≥65 years in the Cardiovascular Health Study, 5521 were free of prevalent heart failure at baseline. After excluding 145 individuals with baseline systolic blood pressure <100 mm Hg, the final sample included 5376 participants, of whom 751 (14%) had isolated diastolic hypotension. Propensity scores for isolated diastolic hypotension were calculated for each of the 5376 participants and used to match 545 and 2348 participants with and without isolated diastolic hypotension, respectively who were balanced on 58 baseline characteristics. During over 12 years of median follow-up, centrally-adjudicated incident heart failure developed in 25% and 20% of matched participants with and without isolated diastolic hypotension respectively (hazard ratio associated with isolated diastolic hypotension, 1.33; 95% confidence interval, 1.10–1.61; p=0.004). Among the 5376 pre-match individuals, multivariable-adjusted hazard ratio for incident heart failure associated with isolated diastolic hypotension was 1.29 (95% confidence interval, 1.09–1.53; p=0.003). As in isolated systolic hypertension, among community-dwelling older adults without prevalent heart failure, isolated diastolic hypotension is also a significant independent risk factor for incident heart failure.

Left ventricular diastolic dysfunction (LVDD) has been reported to have strong correlation with exercise capacity. However, this relationship has not been studied extensively in community-dwelling older adults. Data on pulse and tissue Doppler echocardiographic estimates of resting early (E) and atrial (A) transmitral peak inflow and early (Em) mitral annular velocities, and six-minute walk test were obtained from 89 community-dwelling older adults (mean age, 74; range, 65 -93 years; 54% women), without a history of heart failure. Overall, 47% had cardiovascular morbidity and 60% had normal diastolic function (E/A 0.75 -1.5 and E/Em <10). Among the 36 individuals with LVDD, 83%, 14% and 3% had grade I (E/A<0.75, regardless of E/Em), II (E/A 0.75–1.5 and E/Em ≥10) and III (E/A>1.5 and E/Em ≥10) LVDD respectively. Those with LVDD were older (77 versus 73 years; p=0.001) and tended to have a higher prevalence of cardiovascular morbidity (58% versus 40%; p=0.083). LVDD negatively correlated with six-minute walk distance (1013 versus 1128 feet; R=−0.25; p=0.017). This association remained significant despite adjustment for cardiovascular morbidity (R=−0.35; p=0.048), but lost significance when adjusted for age (R=−0.32; p=0.105), both age and cardiovascular morbidity (R=−0.38; p=0.161), and additional adjustment for sex, race, body mass index, and systolic blood pressure (R=−0.44; p=0.365). In conclusion, most community-dwelling older adults without heart failure had normal left ventricular diastolic function or grade-I LVDD. Although LVDD was associated with decreased performance on a six-minute walk test, that association was no longer evident after adjustment for age, body mass index and cardiovascular morbidity.

Background

The relationship between stage of chronic kidney disease (CKD) and incident heart failure (HF) remains unclear.

Methods

Of the 5,795 community-dwelling adults ≥65 years in the Cardiovascular Health Study, 5,450 were free of prevalent HF and had baseline estimated glomerular filtration rate (eGFR: ml/min/1.73 m2) data. Of these, 898 (16%) had CKD 3A (eGFR 45–59 ml/min/1.73 m2) and 242 (4%) had CKD stage ≥3B (eGFR <45 ml/min/1.73 m2). Data on baseline proteinuria were not available and 4,310 (79%) individuals with eGFR ≥60 ml/min/1.73 m2 were considered to have no CKD. Propensity scores estimated separately for CKD 3A and ≥3B were used to assemble two cohorts of 1,714 (857 pairs with CKD 3A and no CKD) and 557 participants (148 CKD ≥3B and 409 no CKD), respectively, balanced on 50 baseline characteristics.

Results

During 13 years of follow-up, centrally-adjudicated incident HF occurred in 19, 24 and 38% of pre-match participants without CKD (reference), with CKD 3A [unadjusted hazard ratio (HR) 1.40; 95% confidence interval (CI) 1.20–1.63; p < 0.001] and with CKD ≥3B (HR 3.37; 95% CI 2.71–4.18; p < 0.001), respectively. In contrast, among matched participants, incident HF occurred in 23 and 23% of those with CKD 3A and no CKD, respectively (HR 1.03; 95% CI 0.85–1.26; p = 0.746), and 36 and 28% of those with CKD ≥3B and no CKD, respectively (HR 1.44; 95% CI 1.04–2.00; p = 0.027).

Conclusions

Among community-dwelling older adults, CKD is a marker of incident HF regardless of stage; however, CKD ≥3B, not CKD 3A, has a modest independent association with incident HF.

We studied the impact of baseline systolic blood pressure (SBP) on outcomes in mild to moderate chronic systolic and diastolic heart failure (HF) patients in the Digitalis Investigation Group trial using propensity-matched design. Of the 7788 patients, 7785 had baseline SBP data and 3538 had SBP ≤120 mm Hg. Propensity scores for SBP ≤120 mm Hg, calculated for each of the 7785 patients, were used to assemble a matched cohort of 3738 patients with SBP ≤120 and >120 mm Hg who were well-balanced on 32 baseline characteristics. All-cause mortality occurred in 35% and 32% of matched patients with SBP ≤120 and >120 mm Hg respectively during 5 years of follow-up (hazard ratio {HR} when SBP ≤120 was compared with >120 mm Hg, 1.10; 95% confidence interval {CI}, 0.99–1.23; p=0.088). HRs (95% CIs) for cardiovascular and HF mortality associated with SBP ≤120 mm Hg were 1.15 (1.01–1.30; p=0.031) and 1.30 (1.08–1.57; p=0.006). Cardiovascular hospitalization occurred in 53% and 49% of matched patients with SBP ≤120 and >120 mm Hg respectively (HR for SBP ≤120 was compared with >120 mm Hg, 1.13; 95% CI, 1.03–1.24; P=0.008). HRs (95% CIs) for all-cause and HF hospitalization associated with SBP ≤120 mm Hg were 1.10 (1.02–1.194; p=0.017) and 1.21 (1.07–1.36; p=0.002). In conclusion, in patients with mild to moderate chronic systolic and diastolic HF, baseline SBP ≤120 mm Hg was associated with increased cardiovascular and HF mortality and all-cause, cardiovascular and HF hospitalization that was independent of other baseline characteristics.

Background

The impact of gender on major natural history endpoints in heart failure (HF) has not been examined in a propensity-matched study.

Methods

Of the 7788 chronic systolic and diastolic HF patients in the Digitalis Investigation Group trial 1926 were women. Propensity scores for female gender were used to assemble a cohort of 1669 pairs of men and women who were well-balanced on 32 measured baseline characteristics. Matched hazard ratios (HR) and 95% confidence intervals (CI) for outcomes associated with female gender were calculated using stratified Cox regression models.

Results

All-cause mortality occurred in 36% (rate, 1256/10,000 person-years) and 30% (rate, 1008/10,000 person-years) of matched men and women respectively during 5 years of follow up (HR when women were compared with men, 0.82, 95% CI, 0.72–0.94, P=0.004). Female gender was also associated with reduced cardiovascular mortality (matched HR, 0.85; 95% CI, 0.73–0.99, P=0.037) and a trend toward reduced non-cardiovascular mortality (matched HR, 0.73; 95% CI, 0.53–1.00; P=0.053). All-cause hospitalization occurred in 67% (rate, 4003/10,000 person-years) and 65% (rate, 3762/10,000 person-years) matched male and female patients respectively (HR for women, 1.03, 95% CI, 0.93–1.15, P=0.538). Female gender was not associated with cardiovascular or HF hospitalization but was associated with hospitalization due to unstable angina pectoris (matched HR, 1.38; 95%CI, 1.11–1.72; P=0.003) and stroke (matched HR, 0.65; 95%CI, 0.46–0.92; P=0.014).

Conclusions

In patients with chronic HF, female gender has a significant independent association with improved survival but has no association with all-cause, cardiovascular, or HF hospitalizations.

Aims

Abnormally low right ventricular ejection fraction (RVEF) is a predictor of poor outcomes in chronic heart failure (HF) patients with low left ventricular ejection fraction (LVEF). However, little is known about the relationship between LVEF and RVEF in these patients.

Methods and results

Of the 2707 Beta-blocker Evaluation of Survival Trial (BEST) participants with ambulatory chronic HF, New York Heart Association class III–IV symptoms, and LVEF ≤35%, 2008 patients had gated-equilibrium radionuclide angiographic data on baseline LVEF and RVEF. Patients were categorized into quartiles by LVEF ≥29% (n= 507), 23–28% (n= 513), 17–22% (n= 538), and <17% (n= 450). Logistic regression models were used to determine the association of LVEF quartiles (reference, ≥29%) with abnormally low RVEF (<20%). The prevalence of RVEF <20% for patients with LVEF quartiles ≥29, 23–28, 17–22, and <17% were 3, 6, 15, and 32%, respectively. Unadjusted odds ratios [95% confidence intervals (CIs)] for RVEF <20% (vs. ≥20%) associated with LVEF quartiles 23–28, 17–22, and <17% (reference, ≥29%) were 2.18 (1.14–4.17; P= 0.018), 6.32 (3.54–11.30; P< 0.001), and 16.67 (9.46–29.39; P< 0.001), respectively. Respective multivariable-adjusted odds ratios (95% CIs) were 1.82 (0.94–3.54; P= 0.076), 4.55 (2.48–8.35; P< 0.001), and 10.53 (5.70–19.44; P< 0.001), respectively. Heart failure symptoms and signs had unadjusted associations with low RVEF, but lacked intrinsic associations.

Conclusion

In patients with advanced systolic HF, LVEF has a strong dose-dependent relationship with RVEF which is independent of other characteristics, and low LVEF is useful as a surrogate marker of abnormally low RVEF in these patients.

The Southeastern region of the United States is known as the “Stroke Belt” because of the excess stroke mortality in this region as compared to the rest of the country. However, whether a similar geographic variation in heart failure mortality exists is unknown. Using the CDC WONDER’s publicly-available compressed mortality data files and the 2000 United States population as the standard, we estimated age-adjusted heart failure and stroke mortality rates per 100,000 for individuals of all ages, both sexes and all races during 1979–1998 in the United States, and mapped them at the state level. The age-adjusted heart failure mortality rate for the six contiguous Southeastern states (Alabama, Arkansas, Mississippi, Oklahoma, Louisiana, and Georgia) was 31.0/100,000, which was 69% higher than the national rate of 18.3/100,000. This geographic disparity was similar among African Americans (32.9/100,000 in the Southeast versus 21.7/100,000 nationally) and whites (30.8/100,000 in the Southeast versus 18.1/100,000 nationally). These findings suggest that in addition to the “Stroke Belt”, the Southeastern region of the United States may also be burdened by a “Heart Failure Belt”. To better understand the causes of the excess stroke mortality in the “Stroke Belt”, the National Institutes of Health has funded the REasons for Geographic and Racial Differences in Stroke (REGARDS) study (N=30,239, over half from the Southeastern region), which provide a unique opportunity to study the underlying causes of excess heart failure mortality in the “Heart Failure Belt”.

Aim

To determine if the association between hyperuricaemia and poor outcomes in heart failure (HF) varies by chronic kidney disease (CKD).

Methods and results

Of the 2645 systolic HF patients in the Beta-Blocker Evaluation of Survival Trial with data on baseline serum uric acid, 1422 had hyperuricaemia (uric acid ≥6 mg/dL for women and ≥8 mg/dL for men). Propensity scores for hyperuricaemia, estimated for each patient, were used to assemble a matched cohort of 630 pairs of patients with and without hyperuricaemia who were balanced on 75 baseline characteristics. Associations of hyperuricaemia with outcomes during 25 months of median follow-up were examined in all patients and in those with and without CKD (estimated glomerular filtration rate of <60 mL/min/1.73 m2). Hyperuricaemia-associated hazard ratios (HRs) and 95% confidence intervals (CI) for all-cause mortality and HF hospitalization were 1.44 (1.12–1.85, P = 0.005) and 1.27 (1.02–1.58, P = 0.031), respectively. Hazard ratios (95% CIs) for all-cause mortality among those with and without CKD were 0.96 (0.70–1.31, P = 0.792) and 1.40 (1.08–1.82, P = 0.011), respectively (P for interaction, 0.071), and those for HF hospitalization among those with and without CKD were 0.99 (0.74–1.33, P = 0.942) and 1.49 (1.19–1.86, P = 0.001), respectively (P for interaction, 0.033).

Conclusion

Hyperuricaemia has a significant association with poor outcomes in HF patients without CKD but not in those with CKD, suggesting that hyperuricaemia may predict poor outcomes when it is primarily a marker of increased xanthine oxidase activity, but not when it is primarily due to impaired renal excretion of uric acid.

Warfarin is often used in systolic heart failure (HF) patients to prevent adverse outcomes. However, its long term effect remains controversial. The objective of this study was to determine the association of warfarin use and outcomes in advanced chronic systolic HF patients without atrial fibrillation (AF), previous thromboembolic events or prosthetic valves. Of the 2708 BEST patients, 1642 were free of AF, without history of thromboembolic events and without prosthetic valves at baseline. Of these, 471 (29%) patients were receiving warfarin. Propensity scores for warfarin use were estimated for each patient and were used to assemble a matched cohort of 354 pairs of patients with and without warfarin use, who were balanced on 62 baseline characteristics. Kaplan-Meier and Cox regression analyses were used to estimate the association between warfarin use and outcomes during 4.5 years of follow-up. Matched participants had a mean (SD) age of 57 (13) years with 24% women and 24% African Americans. All-cause mortality occurred in 30% of matched patients in both groups receiving and not receiving warfarin (hazard ratio, 0.86; 95% confidence interval, 0.62–1.19; P=0.361). Warfarin use was not associated with cardiovascular mortality (hazard ratio, 0.97; 95% confidence interval, 0.68–1.38; P=0.855) or HF hospitalization (hazard ratio, 1.09; 95% confidence interval, 0.82–1.44; P=0.568). In conclusion, in chronic advanced systolic HF patients without AF or other recommended indications for anticoagulation, the prevalence of warfarin use was relatively high. However, despite therapeutic INR among those receiving warfarin, its use had no significant intrinsic association with mortality and hospitalization.

Background

Compared with serum potassium levels 4–5.5 mEq/L, those <4 mEq/L have been shown to increase mortality in chronic heart failure (HF). Expert opinions suggest that serum potassium levels >5.5 mEq/L may be harmful in HF. However, little is known about the safety of serum potassium 5–5.5 mEq/L.

Methods

Of the 7788 chronic HF patients in the Digitalis Investigation Group trial, 5656 had serum potassium 4–5.5 mEq/L. Of these, 567 had mild hyperkalemia (5–5.5 mEq/L) and 5089 had normokalemia (4–4.9 mEq/L). Propensity scores for mild hyperkalemia were used to assemble a balanced cohort of 548 patients with mild hyperkalemia and 1629 patients with normokalemia. Cox regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for association between mild hyperkalemia and mortality during a median follow-up of 38 months.

Results

All-cause mortality occurred in 36% and 38% of matched patients with normokalemia and mild hyperkalemia respectively (HR, 1.07; 95% CI, 0.90–1.26; P= 0.458). Unadjusted, multivariable-adjusted, and propensity-adjusted HRs for mortality associated with mild hyperkalemia were 1.33 (95% CI, 1.15–1.52; P<0.0001), 1.16 (95% CI, 1.01–1.34; P=0.040) and 1.13 (95% CI, 0.98–1.31; P=0.091) respectively. Mild hyperkalemia had no association with cardiovascular or HF mortality or all-cause or cardiovascular hospitalization.

Conclusion

Serum potassium 4–4.9 mEq/L is optimal and 5–5.5 mEq/L appears relatively safe in HF. Despite lack of an intrinsic association, the bivariate association of mild-hyperkalemia with mortality suggests that it may be useful as a biomarker of poor prognosis in HF.

Background

Little is known about the epidemiology of stroke in chronic systolic and diastolic heart failure (HF) patients in normal sinus rhythm (NSR) receiving angiotensin-converting enzyme (ACE) inhibitors. Because all HF patients in the Digitalis Investigation Group (DIG) trial (N=7788) were in NSR and nearly all were receiving ACE inhibitors, a survey-based stroke sub-study was conducted but its findings have never been published.

Methods

DIG investigators confirmed a total 222 cases of stroke of which 144 had neurological deficit ≥24 hours. We used logistic regression models to determine predictors of incident stroke among all 7788 patients and predictors of neurological deficit ≥24 hours and all-cause mortality among 222 stroke patients.

Results

Age ≥65 years (adjusted odds ratio {AOR}, 1.36; 95% confidence interval {CI}, 1.02–1.80; P=0.035), nonwhite race (AOR, 0.65; 95% CI, 0.42–0.99; P=0.047), hypertension (AOR, 1.46; 95% CI, 1.11–1.94; P=0.008), diabetes mellitus (AOR, 1.37; 95% CI, 1.03–1.82; P=0.030), and cardiomegaly (AOR, 1.39; 95% CI, 1.03–1.86; P=0.030) were independent predictors of stroke. However, among those with stroke, nonwhites had higher odds of neurological deficits ≥24 hours (AOR, 2.86; 95% CI, 1.01–8.07; P=0.047) and death (AOR, 3.28; 95% CI, 1.30–8.30; P=0.012).

Conclusion

Older age, hypertension, diabetes and cardiomegaly were associated with increased incidence of stroke among HF patients with NSR receiving ACE inhibitors. The association of race and stroke, however, was complex. While nonwhite race was associated with decreased risk of stroke, among those with stroke, nonwhite race was associated with increased stroke severity and mortality.

Background

The association between hyperuricemia and incident heart failure (HF) is relatively unknown.

Methods

Of the 5461 community-dwelling older adults, ≥65 years, in the Cardiovascular Health Study without HF at baseline, 1505 had hyperuricemia (baseline serum uric acid ≥6 mg/dL for women and ≥7 mg/dL for men). Using propensity scores for hyperuricemia, estimated for each participant using 64 baseline covariates, we were able to match 1181 pairs of participants with and without hyperuricemia.

Results

Incident HF occurred in 21% and 18% of participants respectively with and without hyperuricemia during 8.1 years of mean follow-up (hazard ratio {HR} for hyperuricemia versus no hyperuricemia, 1.30; 95% confidence interval {CI}, 1.05–1.60; P=0.015). The association between hyperuricemia and incident HF was significant only in subgroups with normal kidney function (HR, 1.23; 95% CI, 1.02–1.49; P=0.031), without hypertension (HR, 1.31; 95% CI, 1.03–1.66; P=0.030), not receiving thiazide diuretics (HR, 1.20; 95% CI, 1.01–1.42; P=0.044), and without hyperinsulinemia (HR, 1.35; 95% CI, 1.06–1.72; P=0.013). Used as a continuous variable, each 1 mg/dL increase in serum uric acid was associated with a 12% increase in incident HF (HR, 1.12; 95% CI, 1.03–1.22; P=0.006). Hyperuricemia had no association with acute myocardial infarction or all-cause mortality.

Conclusions

Hyperuricemia is associated with incident HF in community-dwelling older adults. Cumulative data from our subgroup analyses suggest that this association is only significant when hyperuricemia is a marker of increased xanthine oxidase activity but not when hyperuricemia is caused by impaired renal elimination of uric acid.

The impact of baseline systolic blood pressure (SBP) on outcomes in advanced chronic systolic heart failure (HF) patients has not been studied using propensity-matched design. Of the 2706 Beta-Blocker Evaluation of Survival Trial (BEST) participants with chronic HF, New York Heart Association class III–IV symptoms and left ventricular ejection fraction ≤35%, 1751 had SBP ≤120 (median, 108; range, 70–120) mm Hg and 955 had SBP >120 (median, 134; range 121–192) mm Hg. Propensity scores for SBP >120 mm Hg, calculated for each patient, were used to assemble a matched cohort of 545 pairs of patients with SBP ≤120 and >120 mm Hg, who were balanced on 65 baseline characteristics. Matched Cox regression models were used to estimate associations between SBP ≤120 mm Hg and outcomes over 4 years of follow-up. Matched participants had a mean (±SD) age of 62 (±12) years, 24% were women and 24% were African American. HF hospitalization occurred in 38% and 32% of patients with SBP ≤120 and >120 mm Hg respectively (hazard ratio when SBP ≤120 was compared with SBP >120 mm Hg, 1.33; 95% confidence interval, 1.04 1.69; P=0.023). All-cause mortality occurred in 28% and 30% of matched patients with SBP ≤120 and >120 mm Hg respectively (hazard ratio when SBP ≤120 was compared with SBP >120 mm Hg, 1.13; 95% confidence interval, 0.86 1.49; P=0.369). In conclusion, in patients with advanced chronic systolic HF, baseline SBP ≤120 mm Hg is associated with increased risk of HF hospitalization, but had no association with all-cause mortality.

Aims

To determine the association between obesity and outcomes in post-acute myocardial infarction (AMI) patients with systolic heart failure (HF).

Methods and results

Of the 6632 Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) participants, 6611 had data on baseline body mass index (BMI) and 6561 had BMI ≥ 18.5 kg/m2. Of these, 1573 were obese (BMI ≥ 30 kg/m2) and 4988 were non-obese (BMI 18.5–29.9 kg/m2). Propensity scores for obesity, estimated for each patient, were used to assemble a cohort of 1519 pairs of obese and non-obese patients who were balanced on 65 baseline characteristics. All-cause mortality occurred in 13.7 and 13.8% of matched obese and non-obese patients, respectively, during 16 months of median follow-up [matched hazard ratio (HR) for obesity 0.98; 95% confidence interval (CI) 0.79–1.21; P = 0.831]. Before matching, the obese group was younger (mean age, 62 vs. 64 years; P < 0.0001) and had more women (37 vs. 26%; P < 0.0001). The paradoxical pre-match association between obesity and reduced mortality (unadjusted HR 0.82; 95% CI 0.70–0.95; P = 0.008) disappeared when adjusted for age alone (age-adjusted HR 0.91; 95% CI 0.78–1.06; P = 0.206) but not for gender alone (gender-adjusted HR 0.79; 95% CI 0.68–0.92; P = 0.003). Obesity had no association with mortality in 1573 pairs of age-matched obese and non-obese patients (age-adjusted HR 0.94; 95% CI 0.77–1.13; P = 0.484).

Conclusion

In post-AMI patients with systolic HF, obesity provides no independent intrinsic survival benefit. The paradoxical unadjusted survival associated with obesity is largely explained by the younger age of obese patients.

Background

Little is known about the effects of hypokalemia on outcomes in patients with chronic heart failure (HF) and chronic kidney disease (CKD).

Methods and Results

Of the 7788 chronic HF patients in the Digitalis Investigation Group trial, 2793 had CKD, defined as estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2. Of these, 527 had hypokalemia (serum potassium <4 mEq/L) and 2266 had normokalemia (4–4.9 mEq/L). Propensity scores for hypokalemia were used to assemble a balanced cohort of 522 pairs of patients with hypokalemia and normokalemia. All-cause mortality occurred in 48% and 36% of patients with hypokalemia and normokalemia respectively during 57 months of follow-up (matched hazard ratio {HR} when hypokalemia was compared with normokalemia, 1.56, 95% confidence interval {CI}, 1.25–1.95; P<0.0001). Matched HR’s (95% CI’s) for cardiovascular and HF mortalities, and all-cause, cardiovascular and HF hospitalizations were 1.65 (1.29–2.11; P<0.0001), 1.82 (1.28–2.57; P<0.0001), 1.16 (1.00–1.35; P=0.036), 1.27 (1.08–1.50; P=0.004) and 1.29 (1.05–1.58; P=0.014) respectively. Among 453 pairs of balanced patients with HF and CKD, all-cause mortality occurred in 47% and 38% of patients with mild hypokalemia (3.5–3.9 mEq/L) and normokalemia respectively (matched HR, 1.31, 95% CI, 1.03–1.66; P=0.027). Among 169 pairs of balanced patients with eGFR <45 ml/min/1.73 m2, all-cause mortality occurred in 57% and 47% of patients with hypokalemia (<4 mEq/L) and normokalemia respectively (matched HR, 1.53, 95% CI, 1.07–2.19; P=0.020).

Conclusions

In patients with HF and CKD, hypokalemia is common and associated with increased mortality and hospitalization.

Background

Studies of the effect of right ventricular ejection fraction (RVEF) on outcomes in heart failure (HF) are limited by small sample size and short follow-up.

Methods and Results

We examined the effect of baseline RVEF on outcomes in 2008 Beta-Blocker Evaluation of Survival Trial participants with HF and left ventricular ejection fraction (LVEF) ≤35% during 24 months of mean follow-up. RVEF, estimated by gated-equilibrium radionuclide ventriculography, was used to categorize patients into four RVEF groups: ≥40% (n=733), 30–39% (n=531), 20–29% (n=473) and <20% (n=271). Unadjusted rates for all-cause mortality in patients with RVEF ≥40%, 30–39%, 20–29% and <20% were 27%, 32%, 35% and 47%, respectively. When compared to patients with RVEF ≥40%, unadjusted hazard ratios (HR) and 95% confidence intervals (CI) for all-cause mortality for those with RVEF 30–39%, 20–29% and <20% were 1.19 (0.97–1.46; P=0.087), 1.45 (1.17–1.78; P=0.001) and 1.98 (1.59–2.47; P<0.0001) respectively. Respective multivariable-adjusted HR’s (95% CI’s) for all-cause mortality associated with RVEF 30–39%, 20–29% and <20% were 1.07 (0.87–1.32; P=0.518), 1.12 (0.89–1.40; P=0.328) and 1.32 (1.02–1.71; P=0.034) respectively. Adjusted HR’s (95% CI’s) for other outcomes associated with RVEF <20% (compared to ≥40%) were: cardiovascular mortality, 1.33 (1.01–1.76; P=0.041); HF mortality, 1.61 (1.03–2.52; P=0.037); sudden cardiac death, 1.29 (0.87–1.91; P=0.212); all-cause hospitalization, 1.21 (1.00–1.47; P=0.056) and HF hospitalization, 1.39 (1.10–1.77; P=0.007).

Conclusions

Baseline RVEF <20% is a significant independent predictor of mortality and HF hospitalization in systolic HF.

Introduction

Left ventricular ejection fraction (LVEF) is a predictor of incident heart failure (HF). However, baseline LVEF is often unavailable in population studies of HF.

Meterial and methods

Of the 5324 Cardiovascular Health Study (CHS) participants free of baseline HF, 143 (3%) had LVEF < 45% and 1091 (21%) developed HF during 13 years of follow-up. Using public-use copies of the CHS data, we compared two predictor models of incident HF, with and without adjustment for baseline LVEF.

Results

Baseline impaired LVEF was a strong independent predictor of incident HF (adjusted hazard ratio, 2.78; P < 0.001) but had no impact on the direction, magnitude or significance of independent associations of the other predictors of incident HF such as age, sex, race, coronary artery disease, hypertension and diabetes.

Conclusion

Baseline LVEF is an important predictor for incident HF but is not essential in population studies of risk factors for incident HF.