Effects of the adenosine A1 receptor antagonist rolofylline on renal function in patients with acute heart failure and renal dysfunction: results from PROTECT (Placebo-Controlled Randomized Study of the Selective Adenosine A1 Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function).

OBJECTIVES: This study sought to assess the effects of rolofylline on renal function in patients with acute heart failure (AHF) and renal dysfunction randomized in PROTECT (Placebo-Controlled Randomized Study of the Selective A(1) Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized With Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function). BACKGROUND: Small studies have indicated that adenosine A(1) receptor antagonists enhance diuresis and may improve renal function in patients with chronic heart failure or AHF. METHODS: A total of 2,033 patients with AHF, volume overload, estimated creatinine clearance between 20 and 80 ml/min, and elevated natriuretic peptide levels were randomized (2:1) within 24 h of hospital presentation to rolofylline 30 mg/day or intravenous placebo for up to 3 days. Creatinine was measured daily until discharge or day 7 and on day 14. Persistent worsening renal function was defined as an increase in serum creatinine ≥0.3 mg/dl at both days 7 and 14, or initiation of hemofiltration or dialysis or death by day 7. RESULTS: At baseline, mean ± SD estimated creatinine clearance was 51.0 ± 20.5 ml/min in the placebo group and 50.4 ± 20.0 ml/min in the rolofylline group. Changes in creatinine and estimated creatinine clearance were similar between placebo- and rolofylline-treated patients during hospitalization and at day 14. After 4 days, mean body weight was reduced by 2.6 and 3.0 kg in placebo and rolofylline patients, respectively (p = 0.005). Persistent worsening renal function occurred in 13.7% of the placebo group and 15.0% of the rolofylline group (odds ratio vs. placebo: 1.11 [95% confidence interval: 0.85 to 1.46]; p = 0.44). CONCLUSIONS: In this large, phase III clinical trial, the adenosine A(1) receptor antagonist rolofylline did not prevent persistent worsening renal function in AHF patients with volume overload and renal dysfunction. (A Study of the Selective A1 Adenosine Receptor Antagonist KW-3902 for Patients Hospitalized With Acute HF and Volume Overload to Assess Treatment Effect on Congestion and Renal Function [PROTECT-1], NCT00328692; and [PROTECT-2], NCT00354458).

A randomized controlled trial of the safety and promise of cognitive-behavioral therapy using imaginal exposure in patients with posttraumatic stress disorder resulting from cardiovascular illness.

OBJECTIVE: We investigated the physical safety of cognitive-behavioral therapy (CBT) utilizing imaginal exposure in patients who suffered from posttraumatic stress disorder (PTSD) following a life-threatening cardiovascular event. METHOD: In this phase I, prospective, single-blind trial conducted from April 2006 through April 2008, we randomly assigned 60 patients to receive either 3 to 5 sessions of imaginal exposure therapy (experimental group) or 1 to 3 educational sessions only (control group). Criteria for PTSD and other mental health disorders were evaluated according to DSM-IV using the full Structured Clinical Interview for DSM-IV (SCID). Safety assessments included patients' blood pressure and pulse before and after each study session and the occurrence of deaths, hospitalizations, repeat myocardial infarctions, or invasive procedures. We also investigated the effects of the treatment on PTSD symptoms (Impact of Event Scale and Posttraumatic Stress Disorder Scale), depression (Beck Depression Inventory-II), and the Clinical Global Impressions-Severity of Illness (CGI-S) scale. RESULTS: There were no significant differences between the experimental and control groups and between exposure and nonexposure sessions in any of the safety measures. In addition, confidence intervals were such that the nonsignificant effects of exposure therapy were not of clinical concern. For example, the mean difference in systolic pressure between control and exposure sessions was 0.5 mm Hg (95% CI, -6.1 to 7.1 mm Hg). Nonsignificant improvements were found on all psychiatric measures in the experimental group, with a significant improvement in CGI-S in the entire cohort (mean score difference, -0.6; 95% CI, -1.1 to -0.1; P = .02) and a significant improvement in PTSD symptoms in a subgroup of patients with acute unscheduled cardiovascular events and high baseline PTSD symptoms (mean score difference, -1.2; 95% CI, -2.0 to -0.3; P = .01). CONCLUSIONS: Cognitive-behavioral therapy that includes imaginal exposure is safe and promising for the treatment of posttraumatic stress in patients with cardiovascular illnesses who are traumatized by their illness. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00364910.

Haemodynamic effects of rolofylline in the treatment of patients with heart failure and impaired renal function.

AIMS: The direct effects of adenosine A1 receptor antagonists on haemodynamic parameters in patients with acute heart failure (HF) remain largely unknown. METHODS AND RESULTS: We evaluated the haemodynamic effects of the AA(1)RA rolofylline in 59 HF patients with concomitant renal impairment (estimated creatinine clearance 20-80 mL/min). Placebo or rolofylline 30 mg was administered as a 4 h infusion followed by intravenous (i.v.) loop diuretic administration. Haemodynamic measurements were carried out hourly up to 8 h post-dosing by pulmonary artery catheterization. Urine output, fractional excretion of sodium, potassium, urea, and uric acid, and blood urea nitrogen (BUN) and creatinine levels were also measured. In both groups, the changes from baseline in all haemodynamic indices except mean pulmonary artery pressure (PAP) were not clinically significant. Mean [95% confidence interval (CI)] PAP showed a placebo-adjusted decrease with rolofylline of -1.5 (-4.1, 1.1)mmHg at Hour 4 and -3.5 mmHg (95% CI: -6.2, -0.2) at Hour 8. There was a significant increase with rolofylline in diuresis [placebo-corrected mean (95% CI) change of 68 (20, 116)mL/h at Hour 2-4 and 103 (21, 185)mL/h at Hour 4-8] and in fractional excretion of sodium, potassium, and uric acid. Placebo-corrected changes in plasma levels of creatinine and BUN with rolofylline were non-significant. CONCLUSION: Single administration of rolofylline in patients with HF and impaired renal function produced a slight decrease in mean PAP and consistently increased diuresis and natriuresis without compromising renal function, both before and after administration of i.v. loop diuretics.

Screening for depression and suicidality in patients with cardiovascular illnesses.

The American Heart Association (AHA) and the American Psychiatric Association jointly recommend screening for depression in cardiology clinics. This includes screening for suicidality. It is not known how frequently patients disclose suicidal thinking (ideation) in this setting, and what proportion of those will turn out to have suicidal intent. Patients were screened for depression using a protocol identical to the one endorsed by the AHA in a cardiology community clinic in Elmhurst (Queens, New York). Depression was assessed using the Patient Health Questionnaire. Reports of suicidal ideation were immediately evaluated by a mental health professional. We determined the degree to which suicidal ideation was identified, the proportion of patients with suicidal intent of those reporting suicidal ideation, and the relation between depression and suicidal ideation in this setting. One thousand three patients were screened; 886 had complete Patient Health Questionnaire data. Of those, 12% (109 patients) expressed suicidal ideation. Four of those were hospitalized for suicidal intent (0.45% of all screened patients). Suicidal ideation and depression were correlated (point biserial correlation coefficient 0.478). In conclusion, suicidal ideation can and will be identified using the AHA depression screening recommendations, but only a very small fraction (0.45%) of screened patients will turn out to have suicidal intent. Discovery and stabilization of suicidal patients is an important benefit of the screening, but the fact that >12% of all screened patients will need to be immediately evaluated for suicidal intent has important implications for resource allocation to screening programs.

Hyponatraemia in acute heart failure is a marker of increased mortality but not when associated with hyperglycaemia.

UNLABELLED: Previous studies suggest that hyponatraemia is a marker of neurohormonal activation and increased mortality in patients with acute heart failure (AHF). Although diabetes is a common co-morbidity in heart failure, no prior study has considered the impact of serum glucose on this relationship. METHODS: Over four consecutive months we prospectively registered all patients admitted due to AHF. Sodium and glucose levels were determined immediately upon admission. Patients were followed through admission and for the next 6 months. Of 342 patients enrolled, complete data were available for 331 patients. RESULTS: Hyponatraemia (sodium <135 mmol/L) was detected in 22% of patients. However, 47% of patients with hyponatraemia had concomitant hyperglycaemia (glucose level >11 mmol/L). Hyponatraemia was associated with increased 6-month mortality (21 vs. 8%, p=0.002). This association was restricted to patients who had hyponatraemia without concomitant hyperglycaemia. The 6-month mortality of patients with and without hyponatraemia was 11% versus 10% (p=0.87) when hyperglycaemia was present versus 29% and 7% (p<0.001) when hyperglycaemia was absent. CONCLUSIONS: In this preliminary study, hyperglycaemia-associated hyponatraemia was present in a significant proportion of patients admitted with AHF. In patients with hyperglycaemia, hyponatraemia had no prognostic significance, whereas in patients without hyperglycaemia, hyponatraemia remained a powerful predictor of mortality. These results need confirmation in a larger study.

The association of the ankle-brachial index with incident coronary heart disease: the Atherosclerosis Risk In Communities (ARIC) study, 1987-2001.

BACKGROUND: Peripheral arterial disease (PAD), defined by a low ankle-brachial index (ABI), is associated with an increased risk of cardiovascular events, but the risk of coronary heart disease (CHD) over the range of the ABI is not well characterized, nor described for African Americans. METHODS: The ABI was measured in 12186 white and African American men and women in the Atherosclerosis Risk in Communities Study in 1987-89. Fatal and non-fatal CHD events were ascertained through annual telephone contacts, surveys of hospital discharge lists and death certificate data, and clinical examinations, including electrocardiograms, every 3 years. Participants were followed for a median of 13.1 years. Age- and field-center-adjusted hazard ratios (HRs) were estimated using Cox regression models. RESULTS: Over a median 13.1 years follow-up, 964 fatal or non-fatal CHD events accrued. In whites, the age- and field-center-adjusted CHD hazard ratio (HR, 95% CI) for PAD (ABI<0.90) was 2.81 (1.77-4.45) for men and 2.05 (1.20-3.53) for women. In African Americans, the HR for men was 4.86 (2.76-8.47) and for women was 2.34 (1.26-4.35). The CHD risk increased exponentially with decreasing ABI as a continuous function, and continued to decline at ABI values > 1.0, in all race-gender subgroups. The association between the ABI and CHD relative risk was similar for men and women in both race groups. A 0.10 lower ABI increased the CHD hazard by 25% (95% CI 17-34%) in white men, by 20% (8-33%) in white women, by 34% (19-50%) in African American men, and by 32% (17-50%) in African American women. CONCLUSION: African American members of the ARIC cohort had higher prevalences of PAD and greater risk of CHD associated with ABI-defined PAD than did white participants. Unlike in other cohorts, in ARIC the CHD risk failed to increase at high (>1.3) ABI values. We conclude that at this time high ABI values should not be routinely considered a marker for increased CVD risk in the general population. Further research is needed on the value of the ABI at specific cutpoints for risk stratification in the context of traditional risk factors.

Kidney function and risk of peripheral arterial disease: results from the Atherosclerosis Risk in Communities (ARIC) Study.

Chronic kidney disease (CKD) is associated with an increased risk for cardiovascular disease, but its association with peripheral arterial disease (PAD) is unclear. With the use of data from the Atherosclerosis Risk in Communities (ARIC) Study, 14,280 middle-aged adults were categorized on the basis of estimated GFR >/=90, 60 to 89, and 15 to 59 ml/min per 1.73 m(2) for normal kidney function, mildly decreased kidney function, and stages 3 to 4 CKD, respectively. Incident PAD was defined as a new onset of ankle-brachial index <0.9 assessed at regular examinations, new intermittent claudication assessed by annual surveillance, or PAD-related hospital discharges. Incidence rates and relative risks (RR) for PAD were compared across these categories. During a mean follow-up time of 13.1 yr (186,616 person-years), 1016 participants developed PAD. The incidence rates per 1000 person-years were 4.7, 4.9, and 8.6 for the normal kidney function, mildly decreased kidney function, and CKD groups, respectively. Compared with participants with normal kidney function, the age-, gender-, race-, and ARIC field center-adjusted RR for PAD was 1.04 (95% confidence interval [CI] 0.91 to 1.18) for those with mildly decreased kidney function and 1.82 (95% CI 1.34 to 2.47) for those with CKD. After additional adjustment for cardiovascular disease risk factors, an increase in risk for incident PAD still was observed in participants with CKD, with a multivariable adjusted RR of 1.56 (95% CI 1.13 to 2.14). Patients with CKD are at increased risk for incident PAD. Development of strategies for screening and prevention of PAD in this high-risk population seems warranted.

Clinical significance of a high ankle-brachial index: insights from the Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND: The clinical significance of a high ankle-brachial index (ABI), defined by the associated risk factor burden and ischemic risk, is largely unknown. METHODS: Using data from the Atherosclerosis Risk in Communities Study, we categorized 14,777 participants into normal (ABI between 0.9 and 1.3) and high ABI groups (ABI>1.3, >1.4, and >1.5) and compared the risk factor profile and CVD event rates of the normal ABI group to each high ABI group. RESULTS: The prevalence of high ABI was 5.5% for ABI>1.3, 1.2% for ABI>1.4, and 0.37% for ABI>1.5. Compared with participants with a normal ABI, those with ABI>1.3 had a lower prevalence of hypertension and current smoking. The ABI>1.3 group had a greater mean body mass index, but was characterized by fewer pack years of smoking and lower systolic and diastolic blood pressures than the normal ABI group. The prevalence of diabetes, left ventricular hypertrophy, claudication, and coronary heart disease and mean values of fibrinogen, factor VIII activity, von Willebrand factor, lipoprotein (a), and carotid and popliteal intimal-medial thickness were similar between the two ABI groups. The risk factor profiles of the ABI>1.4 and >1.5 groups were also not statistically significantly different from that of the normal ABI group. Over a mean follow-up time of 12.2 years, the age, sex, and race-adjusted CVD event rates per 1000 person years were 8.1 in the normal ABI group, 7.6 in the ABI>1.3 group, 7.6 in the ABI>1.4 group, and 7.4 in the ABI>1.5 group. The CVD event rates of the high ABI groups were similar to that of the normal ABI group. CONCLUSION: Individuals with a high ABI are not characterized by a more adverse atherosclerosis risk factor profile and do not suffer greater CVD event rates than those with a normal ABI.

The reliability of the ankle-brachial index in the Atherosclerosis Risk in Communities (ARIC) study and the NHLBI Family Heart Study (FHS).

BACKGROUND: A low ankle-brachial index (ABI) is associated with increased risk of coronary heart disease, stroke, and death. Regression model parameter estimates may be biased due to measurement error when the ABI is included as a predictor in regression models, but may be corrected if the reliability coefficient, R, is known. The R for the ABI computed from DINAMAP readings of the ankle and brachial SBP is not known. METHODS: A total of 119 participants in both the Atherosclerosis Risk in Communities (ARIC) study and the NHLBI Family Heart Study (FHS) had repeat ABIs taken within 1 year, using a common protocol, automated oscillometric blood pressure measurement devices, and technician pool. RESULTS: The estimated reliability coefficient for the ankle systolic blood pressure (SBP) was 0.68 (95% CI: 0.57, 0.77) and for the brachial SBP was 0.74 (95% CI: 0.62, 0.83). The reliability for the ABI based on single ankle and arm SBPs was 0.61 (95% CI: 0.50, 0.70) and the reliability of the ABI computed as the ratio of the average of two ankle SBPs to two arm SBPs was estimated from simulated data as 0.70. CONCLUSION: These reliability estimates may be used to obtain unbiased parameter estimates if the ABI is included in regression models. Our results suggest the need for repeated measures of the ABI in clinical practice, preferably within visits and also over time, before diagnosing peripheral artery disease and before making therapeutic decisions.

Risk factors for peripheral arterial disease incidence in persons with diabetes: the Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND: Some risk factors for peripheral arterial disease (PAD) have been identified, but little information is available on PAD risk factors in individuals with diabetes. METHODS: Using data from the Atherosclerosis Risk in Communities (ARIC) Study, we assessed the relation of traditional and non-traditional risk factors with the risk of PAD in 1651 participants with diabetes, but not PAD, at baseline. Incident PAD was defined as an ankle-brachial index (ABI)<0.9 assessed at regular examinations; hospital discharge codes for PAD, amputation, or leg revascularization; or claudication assessed by annual questionnaire. RESULTS: Over a mean of 10.3 years of follow-up, 238 persons developed incident PAD identified, yielding a PAD event rate of 13.9 per 1000 person years. Adjusted for sex, age, race, and center, the risk of developing PAD was increased 1.87-fold (95% confidence interval (95% CI): 1.36-2.57) in persons who were current smokers versus non-smokers, 2.27-fold (95% CI: 1.57-3.26) for baseline coronary heart disease (CHD) versus no baseline CHD, and 1.75-fold (95% CI: 1.18-2.60) for the highest quartile versus lowest quartile of triglycerides. We found no evidence of an association with other blood lipids or hypertension. Compared with the lowest quartiles, comparably-adjusted relative risks for the highest quartiles were 1.60 (95% CI: 1.10-2.33) for waist-to-hip ratio, 2.52 (95% CI: 1.70-3.73) for fibrinogen, 1.70 (95% CI: 1.17-2.47) for factor VIII, 1.73 (95% CI: 1.18-2.54) for von Willebrand factor, 2.15 (95% CI: 1.43-3.24) for white blood cell count, 1.81 (95% CI: 1.19-2.74) for serum creatinine, 0.55 (95% CI: 0.37-0.83) for serum albumin, and 2.73 (95% CI: 1.77-4.22) for carotid intima-media thickness. Persons who had a prior history of diabetes and were taking insulin had a relative risk of 1.97 (95% CI: 1.35-2.87) for future PAD events, compared with those with newly identified diabetes at baseline. In our final multivariable model, current smoking, prevalent CHD, elevated fibrinogen and carotid IMT, and a prior history of diabetes with insulin treatment were independently associated with greater PAD incidence. CONCLUSION: These markers might be useful to identify individuals with diabetes at particular risk for PAD.

Have studies of urinary tract infection and preterm delivery used the most appropriate methods?

Published investigations of the association between urinary tract infection (UTI) and preterm delivery used logistic regression or chi-squared tests. Because both exposure and outcome are time dependent, these methods were not optimal and did not account for person-time under observation, potentially an important feature given the variability of women's entry to prenatal care as well as of gestational lengths. Previous researchers probably classified as exposed some women whose UTI occurred after their pregnancies exceeded 37 weeks. We applied the previous analytical methods to 1990-93 births from two Durham, NC, USA, hospitals (n = 4053) and demonstrate survival methods as an alternative. Two logistic regression models were fitted with differing exposure definitions: model 1 in which exposed = UTI diagnosed after 20 weeks' gestation; and model 2 in which exposed = UTI diagnosed between 20 weeks' and 37 weeks' gestation. Model 3 used proportional hazards regression with person-time after 20 weeks and before UTI diagnosis as unexposed, and person-time after diagnosis as exposed. Models were fit with and without five time-constant potential confounders. Model 1 yielded an adjusted odds ratio (OR) of 0.8 [95% confidence interval (CI) 0.5, 1.2], and model 2, which did not include UTI diagnoses after 37 weeks, an adjusted OR of 0.9 [95% CI 0.6, 1.4]. The Cox model hazard ratio (HR) for preterm delivery was 1.1 (adjusted) [95% CI 0.7, 1.7]. As these results indicated some bias, but not remarkable differences, we conducted a sensitivity analysis using 100 samples of 80% of the original data set, with replacement to determine how large the differences might be in other, similar data sets. The Cox method consistently produced higher effect estimates than either logistic model. The two samples with the greatest differences between the Cox and logistic model estimates yielded an OR of 1.47 [95% CI 0.95, 2.29] for model 1 vs. HR of 2.06 [95% CI 1.39, 3.06] for model 3, and an OR of 1.41 [95% CI 0.88, 2.25] for model 2 vs. HR of 1.79 [95% CI 1.17, 2.71] for model 3 respectively. Previous published results on UTI and preterm delivery require cautious interpretation. Data on UTI timing should be gathered to allow appropriate analyses; survival methods account for person-time under observation and ensure that studied exposures precede effects.