Thomas E. Love

Effects of Digoxin on Morbidity and Mortality in Diastolic Heart Failure The Ancillary Digitalis Investigation Group Trial

Background— About half of the 5 million heart failure patients in the United States have diastolic heart failure (clinical heart failure with normal or near-normal ejection fraction). Except for candesartan, no drugs have been tested in randomized clinical trials in these patients. Although digoxin was tested in an appreciable number of diastolic heart failure patients in the Digitalis Investigation Group ancillary trial, detailed findings from this important study have not previously been published. Methods and Results— Ambulatory chronic heart failure patients (n=988) with normal sinus rhythm and ejection fraction >45% (median, 53%) from the United States and Canada (1991 to 1993) were randomly assigned to digoxin (n=492) or placebo (n=496). During follow-up with a mean length of 37 months, 102 patients (21%) in the digoxin group and 119 patients (24%) in the placebo group (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.63 to 1.07; P=0.136) experienced the primary combined outcome of heart failure hospitalization or heart failure mortality. Digoxin had no effect on all-cause or cause-specific mortality or on all-cause or cardiovascular hospitalization. Use of digoxin was associated with a trend toward a reduction in hospitalizations resulting from worsening heart failure (HR, 0.79; 95% CI, 0.59 to 1.04; P=0.094) but also a trend toward an increase in hospitalizations for unstable angina (HR, 1.37; 95% CI, 0.99 to 1.91; P=0.061). Conclusions— In ambulatory patients with chronic mild to moderate diastolic heart failure and normal sinus rhythm receiving angiotensin-converting enzyme inhibitor and diuretics, digoxin had no effect on natural history end points such as mortality and all-cause or cardiovascular hospitalizations.

Comparison of cold and warm ischemia during partial nephrectomy in 660 solitary kidneys reveals predominant role of nonmodifiable factors in determining ultimate renal function

PURPOSE Factors that determine renal function after partial nephrectomy are not well-defined, including the impact of cold vs warm ischemia, and the relative importance of modifiable and nonmodifiable factors. We studied these determinants in a large cohort of patients with a solitary functioning kidney undergoing partial nephrectomy. MATERIALS AND METHODS From 1980 to 2009, 660 partial nephrectomies were performed at 4 centers for tumor in a solitary functioning kidney under cold (300) or warm (360) ischemia. Data were collected in institutional review board approved registries and followup averaged 4.5 years. Preoperative and postoperative glomerular filtration rates were estimated via the Chronic Kidney Disease-Epidemiology Study equation. RESULTS At 3 months after partial nephrectomy median glomerular filtration rate decreased by equivalent amounts with cold or warm ischemia (21% vs 22%, respectively, p = 0.7), although median cold ischemic times were much longer (45 vs 22 minutes respectively, p <0.001). On multivariable analyses increasing age, larger tumor size, lower preoperative glomerular filtration rate and longer ischemia time were associated with decreased postoperative glomerular filtration rate (p <0.05). When percentage of parenchyma spared was incorporated into the analysis, this factor and preoperative glomerular filtration rate proved to be the primary determinants of ultimate renal function, and duration of ischemia lost statistical significance. CONCLUSIONS This nonrandomized, comparative study suggests that within the relatively strict parameters of conventional practice, ie predominantly short ischemic intervals and liberal use of hypothermia, ischemia time was not an independent predictor of ultimate renal function after partial nephrectomy. Long-term renal function after partial nephrectomy is determined primarily by the quantity and quality of renal parenchyma preserved, although type and duration of ischemia remain the most important modifiable factors, and warrant further study.

Electronic Health Records and Quality of Diabetes Care

BACKGROUND Available studies have shown few quality-related advantages of electronic health records (EHRs) over traditional paper records. We compared achievement of and improvement in quality standards for diabetes at practices using EHRs with those at practices using paper records. All practices, including many safety-net primary care practices, belonged to a regional quality collaborative and publicly reported performance. METHODS We used generalized estimating equations to calculate the percentage-point difference between EHR-based and paper-based practices with respect to achievement of composite standards for diabetes care (including four component standards) and outcomes (five standards), after adjusting for covariates and accounting for clustering. In addition to insurance type (Medicare, commercial, Medicaid, or uninsured), patient-level covariates included race or ethnic group (white, black, Hispanic, or other), age, sex, estimated household income, and level of education. Analyses were conducted separately for the overall sample and for safety-net practices. RESULTS From July 2009 through June 2010, data were reported for 27,207 adults with diabetes seen at 46 practices; safety-net practices accounted for 38% of patients. After adjustment for covariates, achievement of composite standards for diabetes care was 35.1 percentage points higher at EHR sites than at paper-based sites (P<0.001), and achievement of composite standards for outcomes was 15.2 percentage points higher (P=0.005). EHR sites were associated with higher achievement on eight of nine component standards. Such sites were also associated with greater improvement in care (a difference of 10.2 percentage points in annual improvement, P<0.001) and outcomes (a difference of 4.1 percentage points in annual improvement, P=0.02). Across all insurance types, EHR sites were associated with significantly higher achievement of care and outcome standards and greater improvement in diabetes care. Results confined to safety-net practices were similar. CONCLUSIONS These findings support the premise that federal policies encouraging the meaningful use of EHRs may improve the quality of care across insurance types.

Effect of Food Additives on Hyperphosphatemia Among Patients With End-stage Renal Disease: A Randomized Controlled Trial

CONTEXT High dietary phosphorus intake has deleterious consequences for renal patients and is possibly harmful for the general public as well. To prevent hyperphosphatemia, patients with end-stage renal disease limit their intake of foods that are naturally high in phosphorus. However, phosphorus-containing additives are increasingly being added to processed and fast foods. The effect of such additives on serum phosphorus levels is unclear. OBJECTIVE To determine the effect of limiting the intake of phosphorus-containing food additives on serum phosphorus levels among patients with end-stage renal disease. DESIGN, SETTING, AND PARTICIPANTS Cluster randomized controlled trial at 14 long-term hemodialysis facilities in northeast Ohio. Two hundred seventy-nine patients with elevated baseline serum phosphorus levels (>5.5 mg/dL) were recruited between May and October 2007. Two shifts at each of 12 large facilities and 1 shift at each of 2 small facilities were randomly assigned to an intervention or control group. INTERVENTION Intervention participants (n=145) received education on avoiding foods with phosphorus additives when purchasing groceries or visiting fast food restaurants. Control participants (n=134) continued to receive usual care. MAIN OUTCOME MEASURE Change in serum phosphorus level after 3 months. RESULTS At baseline, there was no significant difference in serum phosphorus levels between the 2 groups. After 3 months, the decline in serum phosphorus levels was 0.6 mg/dL larger among intervention vs control participants (95% confidence interval, -1.0 to -0.1 mg/dL). Intervention participants also had statistically significant increases in reading ingredient lists (P<.001) and nutrition facts labels (P = .04) but no significant increase in food knowledge scores (P = .13). CONCLUSION Educating end-stage renal disease patients to avoid phosphorus-containing food additives resulted in modest improvements in hyperphosphatemia. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00583570.

Incident Heart Failure Hospitalization and Subsequent Mortality in Chronic Heart Failure: A Propensity-Matched Study

OBJECTIVE Hospitalization for worsening heart failure (HF) is common and associated with high mortality. However, the effect of incident HF hospitalization (compared with no HF hospitalization) on subsequent mortality has not been studied in a propensity-matched population of chronic HF patients. METHODS In the Digitalis Investigation Group trial, 5501 patients had no HF hospitalizations (4512 alive at 2 years after randomization) and 1732 patients had HF hospitalizations during the first 2 years (1091 alive at 2 years). Propensity scores for incident HF hospitalization during the first 2 years after randomization were calculated for each patient and used to match 1057 patients (97%) who had 2-year HF hospitalization with 1057 patients who had no HF hospitalization. We used matched Cox regression analysis to estimate the effect of incident HF hospitalization during the first 2 years after randomization on post-2-year mortality. RESULTS Compared with 153 deaths (rate, 420/10,000 person-years) in the no HF hospitalization group, 334 deaths (rate, 964/10,000 person-years) occurred in the HF hospitalization group (hazard ratio 2.49; 95% confidence interval 1.97-3.13; P < .0001). The hazard ratios (95% confidence intervals) for cardiovascular and HF mortality were 2.88 (2.23-3.74; P < .0001) and 5.22 (3.34-8.15; P < .0001), respectively. CONCLUSIONS Hospitalization for worsening HF was associated with increased risk of subsequent mortality in ambulatory patients with chronic HF. These results highlight the importance of HF hospitalization as a marker of disease progression and poor outcomes in chronic HF, reinforcing the need for prevention of HF hospitalizations and strategies to improve postdischarge outcomes.

Hypokalemia and Outcomes in Patients with Chronic Heart Failure and Chronic Kidney Disease: Findings from Propensity-Matched Studies

Background—Little is known about the effects of hypokalemia on outcomes in patients with chronic heart failure (HF) and chronic kidney disease. Methods and Results—Of the 7788 patients with chronic HF in the Digitalis Investigation Group trial, 2793 had chronic kidney disease, defined as estimated glomerular filtration rate <60 mL/min per 1.73 m2. Of these, 527 had hypokalemia (serum potassium <4 mEq/L; mild) and 2266 had normokalemia (4 to 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 when hypokalemia was compared with normokalemia, 1.56; 95% CI, 1.25 to 1.95; P<0.0001). Matched hazard ratios (95% CIs) for cardiovascular and HF mortalities and all-cause, cardiovascular, and HF hospitalizations were 1.65 (1.29 to 2.11; P<0.0001), 1.82 (1.28 to 2.57; P<0.0001), 1.16 (1.00 to 1.35; P=0.036), 1.27 (1.08 to 1.50; P=0.004), and 1.29 (1.05 to 1.58; P=0.014), respectively. Among 453 pairs of balanced patients with HF and chronic kidney disease, all-cause mortality occurred in 47% and 38% of patients with mild hypokalemia (3.5 to 3.9 mEq/L) and normokalemia, respectively (matched hazard ratio, 1.31; 95% CI, 1.03 to 1.66; P=0.027). Among 169 pairs of balanced patients with estimated glomerular filtration rate <45 mL/min per 1.73 m2, all-cause mortality occurred in 57% and 47% of patients with hypokalemia (<4 mEq/L; mild) and normokalemia, respectively (matched hazard ratio, 1.53; 95% CI, 1.07 to 2.19; P=0.020). Conclusions—In patients with HF and chronic kidney disease, hypokalemia (serum potassium <4 mEq/L) is common and associated with increased mortality and hospitalization.

Hyperuricaemia, chronic kidney disease, and outcomes in heart failure: potential mechanistic insights from epidemiological data

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 m(2)). 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.

Context and Healthcare Access: Looking Beyond the Individual

Background:Although health is influenced by an individuals characteristics and choices, accumulating evidence suggests that contextual attributes may influence a variety of health outcomes. Whether these factors also represent “upstream” factors affecting ones ability to enter the healthcare system is less clear, however. Objective:The objective of this study was to assess associations between contextual characteristics and an individuals report of having a usual source of health care. Research Design:Cross-sectional, survey-weighted data assessing demographics, insurance status, needs, and healthcare access were obtained through telephone survey in 1998 and were linked with county-level data from the 1998 Area Resource File and the 1990 US Census. Subjects:A state-representative sample of 16,261 adult residents, living in urban, suburban, and rural settings throughout Ohio comprised this study. Measures:Operational measures for social, economic, and health system characteristics were used in multilevel logistic regression models to test associations with an individuals report of a usual source of care. Results:The weighted proportion of individuals reporting no usual source of care was 18.0%. Although individuals’ current health, insurance status, income, demographics, educational attainment, and social support were closely associated with this outcome, significant associations remained for county-level characteristics representing the level of poverty and degree of urbanization. Conclusions:Persisting health status disparities increase the need for programs that promote equitable access to health care. Policy interventions may be more effective if they look beyond individual characteristics to incorporate strategies that address economic factors in areas where healthcare access is inequitable.

Relation of Baseline Systolic Blood Pressure and Long-Term Outcomes in Ambulatory Patients With Chronic Mild to Moderate Heart Failure

We studied the impact of baseline systolic blood pressure (SBP) on outcomes in patients with mild to moderate chronic systolic and diastolic heart failure (HF) in the Digitalis Investigation Group trial using a propensity-matched design. Of 7,788 patients, 7,785 had baseline SBP data and 3,538 had SBP ≤ 120 mm Hg. Propensity scores for SBP ≤ 120 mm Hg, calculated for each of the 7,785 patients, were used to assemble a matched cohort of 3,738 patients with SBP ≤ 120 and >120 mm Hg who were well-balanced in 32 baseline characteristics. All-cause mortality occurred in 35% and 32% of matched patients with SBPs ≤ 120 and >120 mm Hg respectively, during 5 years of follow-up (hazard ratio [HR] when SBP ≤ 120 was compared to >120 mm Hg 1.10, 95% confidence interval [CI] 0.99 to 1.23, p = 0.088). HRs for cardiovascular and HF mortalities associated with SBP ≤ 120 mm Hg were 1.15 (95% CI 1.01 to 1.30, p = 0.031) and 1.30 (95% CI 1.08 to 1.57, p = 0.006). Cardiovascular hospitalization occurred in 53% and 49% of matched patients with SBPs ≤ 120 and > 120 mm Hg, respectively (HR 1.13, 95% CI 1.03 to 1.24, p = 0.008). HRs for all-cause and HF hospitalizations associated with SBP ≤ 120 mm Hg were 1.10 (95% CI 1.02 to 1.194, p = 0.017) and 1.21 (95% CI 1.07 to 1.36, p = 0.002). In conclusion, in patients with mild to moderate long-term systolic and diastolic HF, baseline SBP ≤ 120 mm Hg was associated with increased cardiovascular and HF mortalities and all-cause, cardiovascular, and HF hospitalizations that was independent of other baseline characteristics.

Association between hyperuricemia and incident heart failure among older adults: A propensity-matched study

BACKGROUND The association between hyperuricemia and incident heart failure (HF) is relatively unknown. METHODS Of the 5461 community-dwelling older adults, >or=65 years, in the Cardiovascular Health Study without HF at baseline, 1505 had hyperuricemia (baseline serum uric acid >or=6 mg/dL for women and >or=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.