Finlay A. McAlister

Treatment of Type 2 Diabetes and Outcomes in Patients With Heart Failure: A Nested Case–Control Study From the U.K. General Practice Research Database

OBJECTIVE Diabetes and heart failure commonly coexist, and prior studies have suggested better outcomes with metformin than other antidiabetic agents. We designed this study to determine whether this association reflects a beneficial effect of metformin or a harmful effect of other agents. RESEARCH DESIGN AND METHODS We performed a case-control study nested within the U.K. General Practice Research Database cohort in which diagnoses were assigned by each patients primary care physician. Case subjects were patients 35 years or older, newly diagnosed with both heart failure and diabetes after January 1988, and who died prior to October 2007. Control subjects were matched to case subjects based on age, sex, clinic site, calendar year, and duration of follow-up. Analyses were adjusted for comorbidities, A1C, renal function, and BMI. RESULTS The duration of concurrent diabetes and heart failure was 2.8 years (SD 2.6) in our 1,633 case subjects and 1,633 control subjects (mean age 78 years, 53% male). Compared with patients who were not exposed to antidiabetic drugs, the current use of metformin monotherapy (adjusted odds ratio 0.65 [0.48–0.87]) or metformin with or without other agents (0.72 [0.59–0.90]) was associated with lower mortality; however, use of other antidiabetic drugs or insulin was not associated with all-cause mortality. Conversely, the use of ACE inhibitors/angiotensin receptor blockers (0.55 [0.45–0.68]) and β-blockers (0.76 [0.61–0.95]) were associated with reduced mortality. CONCLUSIONS Our results confirm the benefits of trial-proven anti-failure therapies in patients with diabetes and support the use of metformin-based strategies to lower glucose.

Chronic Kidney Disease and Mortality Risk: A Systematic Review

Current guidelines identify people with chronic kidney disease (CKD) as being at high risk for cardiovascular and all-cause mortality. Because as many as 19 million Americans may have CKD, a comprehensive summary of this risk would be potentially useful for planning public health policy. A systematic review of the association between non-dialysis-dependent CKD and the risk for all-cause and cardiovascular mortality was conducted. Patient- and study-related characteristics that influenced the magnitude of these associations also were investigated. MEDLINE and EMBASE databases were searched, and reference lists through December 2004 were consulted. Authors of 10 primary studies provided additional data. Cohort studies or cohort analyses of randomized, controlled trials that compared mortality between those with and without chronically reduced kidney function were included. Studies were excluded from review when participants were followed for < 1 yr or had ESRD. Two reviewers independently extracted data on study setting, quality, participant and renal function characteristics, and outcomes. Thirty-nine studies that followed a total of 1,371,990 participants were reviewed. The unadjusted relative risk for mortality in participants with reduced kidney function compared with those without ranged from 0.94 to 5.0 and was significantly more than 1.0 in 93% of cohorts. Among the 16 studies that provided suitable data, the absolute risk for death increased exponentially with decreasing renal function. Fourteen cohorts described the risk for mortality from reduced kidney function, after adjustment for other established risk factors. Although adjusted relative hazards were consistently lower than unadjusted relative risks (median reduction 17%), they remained significantly more than 1.0 in 71% of cohorts. This review supports current guidelines that identify individuals with CKD as being at high risk for cardiovascular mortality. Determining which interventions best offset this risk remains a health priority.

Meta-Analysis: Secondary Prevention Programs for Patients with Coronary Artery Disease

Cardiovascular disease remains the most common cause of office visits, hospitalizations, and death in the United States: More than 13 million Americans have documented coronary artery disease (CAD), and costs for CAD are expected to exceed

Anemia Is Common in Heart Failure and Is Associated With Poor Outcomes Insights From a Cohort of 12 065 Patients With New-Onset Heart Failure

393 billion in 2005 (1). Control of the CAD epidemic requires a multifaceted strategy targeting the currently recognized modifiable risk factors for CAD that account for more than 90% of risk, regardless of sex, age, or region (2). This strategy should include primary prevention maneuvers (for the general population and high-risk individuals) and secondary prevention programs (for patients with established CAD). Despite the abundant evidence base for CAD prevention (3), health outcomes studies consistently demonstrate gaps in applying this evidence to clinical practice; these gaps contribute to suboptimal patient outcomes (4). Secondary prevention programs are often proposed as a way to improve management and outcomes. Although several reviews have shown that cardiac rehabilitation reduces mortality in survivors of myocardial infarction (MI) (5-8), these conclusions are informed largely by trials that tested supervised exercise programs versus no exercise postinfarction. Since exercise training confers substantial physiologic and clinical benefits and activity levels are inversely proportional to cardiovascular mortality (9), it is not surprising that trials of exercise programs found positive effects on survival. However, few trials included in these reviews evaluated secondary prevention programs that were not primarily exercise-based. In an earlier review (10), we identified 12 randomized trials (9803 patients) of nonexercise-based secondary prevention programs in patients with established CAD. We demonstrated improvements in risk factor profiles and processes of care (particularly the prescription of proven efficacious therapies) but indeterminate effect on rates of death or recurrent MIs (10). Because current guidelines recommend that secondary prevention programs should not be restricted to supervised exercise programs but should address the full range of modifiable risk factors (11), we conducted a systematic review to update earlier work and to determine the effects of different types of secondary prevention programs (particularly those with a structured exercise component versus those without). Methods Data Sources We searched MEDLINE (19662004); the Cochrane Central Register of Controlled Trials, Issue 4, 2004; EMBASE (19802004); CINAHL (19822004); SIGLE (19802004); and PubMed (January 2004December 2004). We also conducted a cited reference search for our previous review (10) in Web of Science (19992004). We based the searches on the following terms: case management, comprehensive health care, disease management, health services research, home care services, clinical protocols, patient care planning, quality of health care, rehabilitation, nurse led clinics, special clinics, and myocardial ischemia. We hand-searched reference lists of all identified studies, review articles, and references provided by the Centers for Medicare & Medicaid Services and content experts (search strategy available upon request). We limited our search to English-language publications (no abstracts), and the search extends from 1966 to 2004 (we completed the search on 16 December 2004). Study Selection Two investigators independently reviewed the titles and abstracts of all citations to identify studies reporting the effect of secondary prevention programs on mortality, MI, or hospitalization rates in patients with CAD. Both investigators obtained the full text of potentially relevant articles and reviewed them by using prestandardized data abstraction forms and eligibility criteria defined a priori. Any discrepancies were resolved by consensus. We excluded studies if they were not randomized, if they did not include a usual care group, if the outcomes for CAD patients were not reported or were not obtainable from the study investigators, if they evaluated single-modality interventions except exercise (such as telephone follow-up), if they tested interventions delivered to inpatients, or if the interventions were not provided by health professionals (for example, mailed reminders, self-help groups, or self-directed interventions). Data Extraction and Quality Assessment Two investigators extracted all outcome data independently, and a third investigator checked the data. We assigned outcomes according to the intention-to-treat principle and by using the definitions from the primary studies. When necessary, we contacted original investigators to clarify the data for any trial published in the past decade. Authors for 10 of these 21 studies provided further data. Two investigators independently assigned each intervention to 1 of 3 groups: 1) programs that incorporated education and counseling about coronary risk factors with a supervised exercise program (either in a group setting, per traditional comprehensive cardiac rehabilitation programs, or individually delivered), 2) programs that included education and counseling about coronary risk factors but had no exercise component (either delivered in a group setting or individually), and 3) supervised exercise programs only. Data Synthesis and Analysis We performed analyses by using RevMan 4.2 (Update Software, Oxford, United Kingdom). Our outcomes of interest were all-cause mortality and recurrent MIs. Because the outcomes were relatively common, we calculated risk ratios and used the I2 statistic to assess for heterogeneity in each outcome of interest. We combined studies by using the DerSimonian and Laird random-effects model. For the primary analysis, we used data from the longest follow-up period reported in each trial. In a priori sensitivity analyses, we pooled data for 3 follow-up periods (12, 24, and 60 months). To evaluate whether different types of secondary prevention programs had different effects, we calculated the summary risk ratio for each program type and used adjusted indirect comparisons to compare different types of interventions, according to the method of Song and colleagues (12). Role of the Funding Source An earlier version of this evidence report was produced under contract to the Agency for Healthcare Research and Quality, Rockville, Maryland (contract no. 290-02-0023). The funding source had no role in the collection, analysis, or interpretation of the data or in the decision to submit the manuscript for publication. Results Study Selection and Evaluation We identified 6345 citations from electronic databases (n= 6207), reference lists (n= 45), and the Centers for Medicare & Medicaid Services (n= 93). After the initial screening, we reviewed 254 full manuscripts and excluded 179 of these studies after detailed evaluation (Figure 1). Figure 1. Flow of trials through the selection process. Sixteen disagreements among the reviewers about eligibility of the studies occurred for a value of 0.81. All disagreements were resolved by consensus. Of the randomized trials that were eligible for inclusion (13-87), 9 were reported in more than 1 publication. The second publication reported different end points in 2 cases (13-16), results from different follow-up periods in 5 cases (13, 17-26), and results from the subgroup of patients with cardiac disease in 1 case (27, 28). The ninth trial (the World Health Organization [WHO] trial) (29) included 24 collaborating centers; however, the original investigators excluded 7 sites because of poor participant follow-up and 4 sites because of statistically significant differences between the intervention and control groups at baseline. We included the outcome data from the remaining 13 sites as 1 trial for our analysis, an approach validated by the nonsignificant test results for statistical heterogeneity for all-cause mortality and MI. While the 2 Finnish centers in the WHO trial published their results separately (and for several follow-up periods), we included only their 3-year outcome data with the other 11 WHO sites for consistency of data presentation (30-32). Studies Included in the Systematic Review Table 1 presents summary data from the 63 unique randomized trials that were eligible for our systematic review (13-87). Our search retrieved 51 trials that were not included in our previous systematic review (which was limited to literature published before 1999 and excluded any studies with exercise components) (10) and 26 trials that were not included in a more recent systematic review of cardiac rehabilitation (which was limited to literature published before 2003 and included few individual counseling programs) (8). Table 1. Description of Included Studies Qualitative Data Synthesis In all trials, patients who were randomly assigned to the control groups received usual care (this was generally undefined). Table 1 describes the types of secondary prevention programs; few trials described the intensity of the interventions. Almost all trials enrolled highly selected study samples: Forty-five trials recruited patients after acute MI or a coronary revascularization procedure. Thirty-five trials excluded elderly patients, and 19 trials excluded women (Table 1). Indeed, women constituted fewer than 50% of study participants in all but 2 trials. No trial was double-blind (which is not surprising, considering the nature of the intervention), and very few trials described randomization procedures or accounted for discrepancies between sample sizes at recruitment and follow-up. As a result, Jadad quality scores clustered around 2 (Table 2). Furthermore, only 15 (24%) trial reports described adequate allocation concealment. Table 2. Methodologic Quality of Included Studies No trial reported side effects with the secondary prevention programs beyond the adverse clinical outcomes described later. Quantitative Data Synthesis All-Cause Mortality Only 1 of the 40 trials reporting this outcome f

Renal insufficiency and heart failure: prognostic and therapeutic implications from a prospective cohort study.

Background—Although previous work has suggested that anemia is associated with an increased mortality in selected patients with congestive heart failure (CHF), little is known about the prevalence and predictors of anemia, or whether anemia is an independent prognostic factor in unselected, community-based patients with CHF. Methods and Results—We analyzed a population-based cohort of patients with new-onset CHF from a database of patients discharged from 138 acute-care hospitals in Alberta, Canada, between April 1993 and March 2001. Logistic regression, Kaplan-Meier survival analyses, and Cox proportional hazards model were used. Among the 12 065 patients with CHF (median age 78 years), 17% had anemia, 58% of whom had anemia of chronic disease. After adjustment for clinical and demographic variables, patients with anemia were more likely to be older (odds ratio [OR] 1.01 per year) and female (OR 1.2 [95% confidence interval 1.1 to 1.3]) and to have a history of chronic renal insufficiency (OR=3.2 [95% confidence interval 2.8 to 3.6]), or hypertension (OR 1.3 [95% confidence interval 1.2 to 1.5]). Hazard ratios for mortality, adjusting for covariates, were 1.34 (1.24 to 1.46) in anemic patients, and 1.36 (1.23 to 1.50) in those patients with anemia of chronic disease. Conclusions—In this large cohort of community-dwelling patients with CHF, anemia is common and an independent prognostic factor for mortality. Further research into the mechanisms of anemia in CHF and randomized controlled trials to test whether correction of anemia improves prognosis in CHF are needed.

Telemonitoring or structured telephone support programmes for patients with chronic heart failure: systematic review and meta-analysis

Background—The prevalence, prognostic import, and impact of renal insufficiency on the benefits of ACE inhibitors and &bgr;-blockers in community-dwelling patients with heart failure are uncertain. Methods and Results—We analyzed data from a prospective cohort of 754 patients with heart failure who had ejection fraction, serum creatinine, and weight measured at baseline. Median age was 69 years, and 43% had an ejection fraction ≥35%. By the Cockcroft-Gault equation, 118 patients (16%) had creatinine clearances ≤30 mL/min and 301 (40%) had creatinine clearances between 30 and 59 mL/min. During follow-up (median 926 days), 385 patients (37%) died. Even after adjustment for all other prognostic factors, survival was significantly associated with renal function (P =0.002) in patients with either systolic or diastolic dysfunction; patients exhibited a 1% increase in mortality for each 1-mL/min decrease in creatinine clearance. The associations with 1-year mortality reductions were similar for ACE inhibitors (OR 0.46 [95% CI 0.26 to 0.82] versus OR 0.28 [95% CI 0.11 to 0.70]) and &bgr;-blockers (OR 0.40 [95% CI 0.23 to 0.70] versus OR 0.41 [95% CI 0.19 to 0.85]) in patients with creatinine clearances <60 mL/min versus ≥60 mL/min, although these drugs were used less frequently in patients with renal insufficiency. Conclusions—Renal insufficiency is more prevalent in patients with heart failure than previously reported and is an independent prognostic factor in diastolic and systolic dysfunction. ACE inhibitors and &bgr;-blockers were associated with similar reductions in mortality in patients with and without renal insufficiency.

Body mass index and mortality in heart failure: A meta-analysis

Objective To determine whether remote monitoring (structured telephone support or telemonitoring) without regular clinic or home visits improves outcomes for patients with chronic heart failure. Data sources 15 electronic databases, hand searches of previous studies, and contact with authors and experts. Data extraction Two investigators independently screened the results. Review methods Published randomised controlled trials comparing remote monitoring programmes with usual care in patients with chronic heart failure managed within the community. Results 14 randomised controlled trials (4264 patients) of remote monitoring met the inclusion criteria: four evaluated telemonitoring, nine evaluated structured telephone support, and one evaluated both. Remote monitoring programmes reduced the rates of admission to hospital for chronic heart failure by 21% (95% confidence interval 11% to 31%) and all cause mortality by 20% (8% to 31%); of the six trials evaluating health related quality of life three reported significant benefits with remote monitoring, and of the four studies examining healthcare costs with structured telephone support three reported reduced cost and one no effect. Conclusion Programmes for chronic heart failure that include remote monitoring have a positive effect on clinical outcomes in community dwelling patients with chronic heart failure.

The 2008 Canadian Hypertension Education Program recommendations for the management of hypertension: Part 1 - blood pressure measurement, diagnosis and assessment of risk.

BACKGROUND In patients with chronic heart failure (CHF), previous studies have reported reduced mortality rates in patients with increased body mass index (BMI). The potentially protective effect of increased BMI in CHF has been termed the obesity paradox or reverse epidemiology. This meta-analysis was conducted to examine the relationship between increased BMI and mortality in patients with CHF. METHODS We searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, Scopus, and Web of Science to identify studies with contemporaneous control groups (cohort, case-control, or randomized controlled trials) that examined the effect of obesity on all-cause and cardiovascular mortality. Two reviewers independently assessed studies for inclusion and performed data extraction. RESULTS Nine observational studies met final inclusion criteria (total n = 28,209). Mean length of follow-up was 2.7 years. Compared to individuals without elevated BMI levels, both overweight (BMI approximately 25.0-29.9 kg/m(2), RR 0.84, 95% CI 0.79-0.90) and obesity (BMI approximately > or =30 kg/m(2), RR 0.67, 95% CI 0.62-0.73) were associated with lower all-cause mortality. Overweight (RR 0.81, 95% CI 0.72-0.92) and obesity (RR 0.60, 95% CI 0.53-0.69) were also associated with lower cardiovascular mortality. In a risk-adjusted sensitivity analysis, both obesity (adjusted HR 0.88, 95% CI 0.83-0.93) and overweight (adjusted HR 0.93, 95% CI 0.89-0.97) remained protective against mortality. CONCLUSIONS Overweight and obesity were associated with lower all-cause and cardiovascular mortality rates in patients with CHF and were not associated with increased mortality in any study. There is a need for prospective studies to elucidate mechanisms for this relationship.

The effects of inhaled corticosteroids in chronic obstructive pulmonary disease: a systematic review of randomized placebo-controlled trials

OBJECTIVE To provide updated, evidence-based recommendations for the diagnosis and assessment of adults with hypertension. OPTIONS AND OUTCOMES The diagnosis of hypertension is dependent on appropriate blood pressure measurement, the timely assessment of serially elevated readings, degree of blood pressure elevation, method of measurement (office, ambulatory, home) and associated comorbidities. The presence of cardiovascular risk factors and target organ damage should be ascertained to assess global cardiovascular risk and determine the urgency, intensity and type of treatment required. EVIDENCE MEDLINE searches were conducted from November 2006 to October 2007 with the aid of a medical librarian. Reference lists were scanned, experts were contacted, and the personal files of authors and subgroup members were used to identify additional studies. Content and methodological experts assessed studies using prespecified, standardized evidence-based algorithms. Recommendations were based on evidence from peer-reviewed, full-text articles only. RECOMMENDATIONS Recommendations for blood pressure measurement, criteria for hypertension diagnosis and follow-up, assessment of global cardiovascular risk, diagnostic testing, diagnosis of renovascular and endocrine causes of hypertension, home and ambulatory monitoring, and the use of echocardiography in hypertensive individuals are outlined. Key messages in 2008 include continued emphasis on the expedited, accurate diagnosis of hypertension, the importance of global risk assessment and the need for ongoing monitoring of hypertensive patients to identify incident type 2 diabetes. VALIDATION All recommendations were graded according to strength of the evidence and voted on by the 57 members of the Canadian Hypertension Education Program Evidence-Based Recommendations Task Force. All recommendations reported here received at least 70% consensus. These guidelines will continue to be updated annually.

Meta-analysis: beta-blocker dose, heart rate reduction, and death in patients with heart failure.

Although inhaled corticosteroids are commonly used to treat patients with chronic obstructive pulmonary disease (COPD), their effect on clinical outcomes such as exacerbation and mortality is unknown. This systematic review was conducted to determine whether inhaled corticosteroids improve clinical outcomes for patients with stable COPD. All placebo-controlled randomized trials of inhaled corticosteroids given for at least 6 months for stable COPD were identified by searching MEDLINE (1966-2000), EMBASE (1980-2001), CINAHL (1982-2000), SIGLE (1980-2000), the Cochrane Controlled Trial Registry, and the bibliographies of published studies. We independently extracted data from each of the studies using a specified protocol, and determined the summary risk ratios (RRs) and 95% confidence intervals (CIs) for exacerbations and deaths. Nine randomized trials (3976 patients with COPD), including four with a systemic steroid run-in phase, were identified. Use of inhaled corticosteroid therapy reduced the rate of exacerbations (RR = 0.70; 95% CI: 0.58 to 0.84), with similar benefits in those who were and were not pretreated with systemic steroids. Inhaled corticosteroid therapy was also associated with increased rates of oropharyngeal candidiasis (RR = 2.1; 95% CI: 1.5 to 3.1), skin bruising (RR = 2.1; 95% CI: 1.6 to 2.8), and lower mean cortisol levels. No effects were seen on all-cause mortality (RR = 0.84; 95% CI: 0.60 to 1.18) in the five trials that measured this outcome. This systematic review demonstrates a beneficial effect of inhaled corticosteroids in reducing rates of COPD exacerbation. Further research is required to define the long-term effects of these medications and the benefit/risk ratio for patients with COPD.