Douglas S. Lee

Cyclo-oxygenase-2 inhibitors versus non-selective non-steroidal anti-inflammatory drugs and congestive heart failure outcomes in elderly patients: a population-based cohort study

BACKGROUND Non-selective, non-steroidal anti-inflammatory drugs (NSAIDs) are associated with an increased risk of congestive heart failure, but little is known about the cardiovascular effects of a newer group of NSAIDS called selective cyclo-oxygenase (COX)-2 inhibitors. We aimed to compare rates of admission for congestive heart failure in elderly patients who were newly dispensed COX-2 inhibitors or non-selective NSAIDs. METHODS In this population-based retrospective cohort study we identified NSAID-naive individuals aged 66 years or older, who were started on rofecoxib (n=14,583), celecoxib (n=18,908), and non-selective NSAIDs (n=5,391), and randomly selected non-NSAID users as controls (n=100,000). FINDINGS Relative to non-NSAID users, patients on rofecoxib and non-selective NSAIDS had an increased risk of admission for congestive heart failure (adjusted rate ratio 1.8, 95% CI 1.5-2.2, and 1.4, 1.0-1.9, respectively), but not celecoxib (1.0, 0.8-1.3). Compared with celecoxib users, admission was significantly more likely in users of non-selective NSAIDs (1.4, 1.0-1.9) and rofecoxib (1.8, 1.4-2.4). Risk of admission for rofecoxib users was higher than that for non-selective NSAID users (1.5, 1.1-2.1). Of patients with no admission in the past 3 years, only rofecoxib users were at increased risk of subsequent admission relative to controls (1.8, 1.4-2.3). INTERPRETATION These findings suggest a higher risk of admission for congestive heart failure in users of rofecoxib and non-selective NSAIDs, but not celecoxib, relative to non-NSAID controls.

Relation of Disease Pathogenesis and Risk Factors to Heart Failure With Preserved or Reduced Ejection Fraction Insights From the Framingham Heart Study of the National Heart, Lung, and Blood Institute

Background— The contributions of risk factors and disease pathogenesis to heart failure with preserved ejection fraction (HFPEF) versus heart failure with reduced ejection fraction (HFREF) have not been fully explored. Methods and Results— We examined clinical characteristics and risk factors at time of heart failure onset and long-term survival in Framingham Heart Study participants according to left ventricular ejection fraction ≤45% (n=314; 59%) versus >45% (n=220; 41%) and hierarchical causal classification. Heart failure was attributed to coronary heart disease in 278 participants (52%), valvular heart disease in 42 (8%), hypertension in 140 (26%), or other/unknown causes in 74 (14%). Multivariable predictors of HFPEF (versus HFREF) included elevated systolic blood pressure (odds ratio [OR]=1.13 per 10 mm Hg; 95% confidence interval [CI], 1.04 to 1.22), atrial fibrillation (OR=4.23; 95% CI, 2.38 to 7.52), and female sex (OR=2.29; 95% CI, 1.35 to 3.90). Conversely, prior myocardial infarction (OR=0.32; 95% CI, 0.19 to 0.53) and left bundle-branch block QRS morphology (OR=0.21; 95% CI, 0.10 to 0.46) reduced the odds of HFPEF. Long-term prognosis was grim, with a median survival of 2.1 years (5-year mortality rate, 74%), and was equally poor in men and women with HFREF or HFPEF. Conclusions— Among community patients with new-onset heart failure, there are differences in causes and time-of-onset clinical characteristics between those with HFPEF versus HFREF. In people with HFREF, mortality is increased when coronary heart disease is the underlying cause. These findings suggest that heart failure with reduced left ventricular systolic function and heart failure with preserved left ventricular systolic function are partially distinct entities, with potentially different approaches to early detection and prevention.

Gamma Glutamyl Transferase and Metabolic Syndrome, Cardiovascular Disease, and Mortality Risk The Framingham Heart Study

Objective—To determine whether serum &ggr;-glutamyl transferase (GGT) predicts cardiovascular disease (CVD) morbidity and mortality, accounting for temporal changes in known CVD risk factors and C-reactive protein (CRP). Methods and Results—In 3451 Framingham Study participants (mean age 44 years, 52% women) we examined the relations of GGT with CVD risk factors, and prospectively determined the risk of new-onset metabolic syndrome, incident CVD, and death. GGT was positively associated with body mass index, blood pressure, LDL cholesterol, triglycerides, and blood glucose in cross-sectional analysis (P<0.005). On follow-up (mean 19 years), 968 participants developed metabolic syndrome, 535 developed incident CVD, and 362 died. The risk of metabolic syndrome increased with higher GGT (multivariable-adjusted hazard ratio [HR] per SD increment log-GGT, 1.26 [95%CI; 1.18 to 1.35]). Adjusting for established CVD risk factors (as time-dependent covariates updated quadriennially) and baseline CRP, a 1-SD increase in log-GGT conferred a 13% increase in CVD risk (P=0.007) and 26% increased risk of death (P<0.001). Individuals in the highest GGT quartile experienced a 67% increase in CVD incidence (multivariable-adjusted HR 1.67, 95%CI; 1.25 to 2.22). Conclusion—An increase in serum GGT predicts onset of metabolic syndrome, incident CVD, and death suggesting that GGT is a marker of metabolic and cardiovascular risk.

Comparison of coding of heart failure and comorbidities in administrative and clinical data for use in outcomes research

Background:Despite the potential usefulness of administrative databases for evaluating outcomes, coding of heart failure and associated comorbidities have not been definitively compared with clinical data. Objective:To compare the predictive value of heart failure diagnoses and secondary conditions identified in a large administrative database with chart-based records. Methods:The authors studied 1808 patient records sampled from 14 acute care hospitals and compared clinically recorded data with administrative records from the Canadian Institute for Health Information. The impact of comorbidity coding in the administrative data set according to the Charlson classification was examined in models of 30-day mortality. Results:The positive predictive value (PPV) of a primary diagnosis ICD-9 428 was 94.3% using the Framingham criteria and 88.6% using criteria previously validated with pulmonary capillary wedge pressure. There was reduced prevalence of secondary comorbid conditions in administrative data in comparison with clinical chart data. The specificities and PPV/negative predictive values of administratively identified index comorbidities were high. The sensitivities of index comorbidities were low, but were enhanced by examination of hospitalizations within 1 year prior to the index heart failure admission. Using information from prior hospitalizations modestly enhanced 30-day mortality model performance; however, the odds ratio point estimates of the index and enhanced administrative data sets were consistent with the clinical model. Conclusion:The ICD-9 428 primary diagnosis is highly predictive of heart failure using clinical criteria. Examination of hospitalization data up to 1 year prior to the index admission improves comorbidity detection and may provide enhancements to future studies of heart failure mortality.

Association of temporal trends in risk factors and treatment uptake with coronary heart disease mortality, 1994-2005.

CONTEXT Coronary heart disease (CHD) mortality has declined substantially in Canada since 1994. OBJECTIVE To determine what proportion of this decline was associated with temporal trends in CHD risk factors and advancements in medical treatments. DESIGN, SETTING, AND PATIENTS Prospective analytic study of the Ontario, Canada, population aged 25 to 84 years between 1994 and 2005, using an updated version of the validated IMPACT model, which integrates data on population size, CHD mortality, risk factors, and treatment uptake changes. Relative risks and regression coefficients from the published literature quantified the relationship between CHD mortality and (1) evidence-based therapies in 8 distinct CHD subpopulations (acute myocardial infarction [AMI], acute coronary syndromes, secondary prevention post-AMI, chronic coronary artery disease, heart failure in the hospital vs in the community, and primary prevention for hyperlipidemia or hypertension) and (2) population trends in 6 risk factors (smoking, diabetes mellitus, systolic blood pressure, plasma cholesterol level, exercise, and obesity). MAIN OUTCOME MEASURES The number of deaths prevented or delayed in 2005; secondary outcome measures were improvements in medical treatments and trends in risk factors. RESULTS Between 1994 and 2005, the age-adjusted CHD mortality rate in Ontario decreased by 35% from 191 to 125 deaths per 100,000 inhabitants, translating to an estimated 7585 fewer CHD deaths in 2005. Improvements in medical and surgical treatments were associated with 43% (range, 11% to 124%) of the total mortality decrease, most notably in AMI (8%; range, -5% to 40%), chronic stable coronary artery disease (17%; range, 7% to 35%), and heart failure occurring while in the community (10%; range, 6% to 31%). Trends in risk factors accounted for 3660 fewer CHD deaths prevented or delayed (48% of total; range, 28% to 64%), specifically, reductions in total cholesterol (23%; range, 10% to 33%) and systolic blood pressure (20%; range, 13% to 26%). Increasing diabetes prevalence and body mass index had an inverse relationship associated with higher CHD mortality of 6% (range, 4% to 8%) and 2% (range, 1% to 4%), respectively. CONCLUSION Between 1994 and 2005, there was a decrease in CHD mortality rates in Ontario that was associated primarily with trends in risk factors and improvements in medical treatments, each explaining about half of the decrease.

Evaluation of Early Complications Related to De Novo Cardioverter Defibrillator Implantation : Insights From the Ontario ICD Database

OBJECTIVES This study examined the predictors of early complications after defibrillator implantation. BACKGROUND Although implantable cardioverter-defibrillators are widely used, predictors of procedural complications and the consequences of these events have not been determined. METHODS In a prospective, multicenter, population-based clinical outcomes registry of all newly implanted defibrillator patients at 18 centers in Ontario, Canada, we examined 45-day complications and all-cause mortality from February 2007 to May 2009. Complications were determined longitudinally and were categorized as direct implant-related or indirect events. RESULTS Among 3,340 patients (mean age 63.8 +/- 12.5 years, 78.5% men), major complications occurred in 4.1% of de novo procedures. Compared with those undergoing a single-chamber device, implantation of a cardiac resynchronization defibrillator (adjusted hazard ratio [HR]: 2.17, 95% confidence interval [CI]: 1.38 to 3.43, p < 0.001) or dual-chamber device (adjusted HR: 1.82, 95% CI: 1.19 to 2.79, p = 0.006) was associated with increased risk of major complications. Major complications were increased in women (adjusted HR: 1.49, 95% CI: 1.02 to 2.16, p = 0.037) and when left ventricular end-systolic dimension exceeded 45 mm (adjusted HR: 1.54, 95% CI: 1.08 to 2.20, p = 0.018). Major complications (excluding death) occurring early after defibrillator implantation were associated with increased adjusted risk of subsequent death up to 180 days after defibrillator implant (adjusted HR: 3.70, 95% CI: 1.64 to 8.33, p = 0.002). Direct implant-related complications were associated with increased risk of early death (adjusted HR: 24.89, p = 0.01), whereas indirect clinical complications conferred increased risk of near-term death (adjusted HR: 12.35, p < 0.001) after defibrillator implantation. CONCLUSIONS Complications after de novo defibrillator implantation were strongly associated with device type. Major complications were associated with increased risk of mortality.

Introduction to the Analysis of Survival Data in the Presence of Competing Risks.

Competing risks occur frequently in the analysis of survival data. A competing risk is an event whose occurrence precludes the occurrence of the primary event of interest. In a study examining time to death attributable to cardiovascular causes, death attributable to noncardiovascular causes is a competing risk. When estimating the crude incidence of outcomes, analysts should use the cumulative incidence function, rather than the complement of the Kaplan-Meier survival function. The use of the Kaplan-Meier survival function results in estimates of incidence that are biased upward, regardless of whether the competing events are independent of one another. When fitting regression models in the presence of competing risks, researchers can choose from 2 different families of models: modeling the effect of covariates on the cause-specific hazard of the outcome or modeling the effect of covariates on the cumulative incidence function. The former allows one to estimate the effect of the covariates on the rate of occurrence of the outcome in those subjects who are currently event free. The latter allows one to estimate the effect of covariates on the absolute risk of the outcome over time. The former family of models may be better suited for addressing etiologic questions, whereas the latter model may be better suited for estimating a patient’s clinical prognosis. We illustrate the application of these methods by examining cause-specific mortality in patients hospitalized with heart failure. Statistical software code in both R and SAS is provided.

Care and Outcomes of Patients Newly Hospitalized for Heart Failure in the Community Treated by Cardiologists Compared With Other Specialists

Background—It is not known whether subspecialty care by cardiologists improves outcomes in heart failure patients from the community over care by other physicians. Methods and Results—Using administrative data, we monitored 38 702 consecutive patients with first-time hospitalization for heart failure in Ontario, Canada, between April 1994 and March 1996 and examined differences in processes of care and clinical outcomes between patients attended by physicians of different disciplines. We found that patients attended by cardiologists had lower 1-year risk-adjusted mortality than those attended by general internists, family practitioners, and other physicians (28.5% versus 31.7%, 34.9%, and 35.9%, respectively; all pairwise comparisons, P <0.001). The 1-year risk-adjusted composite outcome of death and readmission for heart failure was also lower for the cardiologists compared with family practitioners and other physicians but not general internists (54.7% versus 58.1%, 58.3%, and 55.4%; P <0.001, P <0.001, and P =0.39, respectively). Multivariable hierarchical modeling demonstrated a significant physician-level effect for both outcomes in favor of the cardiologists, particularly against non-general internists. Cardiologist care was associated with higher adjusted rates of invasive interventions and postdischarge prescriptions of heart failure medications. Conclusions—In this population-based cohort, heart failure patients attended by cardiologists in hospital had lower risk of death as well as the composite risk of death or readmission than patients attended by noncardiologists. These data raise the need to identify specialty-driven differences in processes of care for heart failure patients, which may explain the observed disparity in clinical outcomes that presently favor cardiologist care.

Left Ventricular Remodeling and Ventricular Arrhythmias After Myocardial Infarction

Background—The relation between left ventricular (LV) remodeling and ventricular arrhythmias after myocardial infarction is poorly documented. We investigated the relations between LV size, hypertrophy, and function and ventricular arrhythmias in 263 patients from the Survival and Ventricular Enlargement (SAVE) study, using quantitative 2D echocardiography and ambulatory ECG monitoring after myocardial infarction. Methods and Results—Transthoracic 2D echocardiograms and arrhythmia monitoring were performed at baseline (mean, 11 days) and 1 and 2 years after infarction. LV size, short-axis muscle (mass) area (LVMA), and function were quantified from 2D echocardiograms. The prevalence of ventricular tachycardia (VT) and frequent ventricular ectopy (premature ventricular contractions [PVCs] >10/h) was assessed from ambulatory ECG. VT and PVCs >10/h occurred in 20% and 29% of patients at baseline, in 22% and 35% at 1 year and 23% and 39% at 2 years, respectively. VT and PVCs >10/h at baseline and 1 and 2 years were significantly related to LV size, LVMA, and function. Furthermore, changes in LV size and function from baseline to 2 years predicted both VT and PVCs >10/h. The study was underpowered to detect treatment effect of ACE inhibitors and &bgr;-adrenergic receptor blockers but did not alter the relations between ventricular arrhythmias, LV size, and function. Conclusions—Quantitative echocardiographic assessment of LV size, LVMA, and function and changes in these measurements over time predict ventricular arrhythmias after infarction. Altered LV architecture and function during postinfarction LV remodeling provide an important substrate for triggering high-grade ventricular arrhythmias.

Effectiveness of Public Report Cards for Improving the Quality of Cardiac Care The EFFECT Study: A Randomized Trial

CONTEXT Publicly released report cards on hospital performance are increasingly common, but whether they are an effective method for improving quality of care remains uncertain. OBJECTIVE To evaluate whether the public release of data on cardiac quality indicators effectively stimulates hospitals to undertake quality improvement activities that improve health care processes and patient outcomes. DESIGN, SETTING, AND PATIENTS Population-based cluster randomized trial (Enhanced Feedback for Effective Cardiac Treatment [EFFECT]) of 86 hospital corporations in Ontario, Canada, with patients admitted for acute myocardial infarction (AMI) or congestive heart failure (CHF). INTERVENTION Participating hospital corporations were randomized to early (January 2004) or delayed (September 2005) feedback of a public report card on their baseline performance (between April 1999 and March 2001) on a set of 12 process-of-care indicators for AMI and 6 for CHF. Follow-up performance data (between April 2004 and March 2005) also were collected. MAIN OUTCOME MEASURES The coprimary outcomes were composite AMI and CHF indicators based on 12 AMI and 6 CHF process-of-care indicators. Secondary outcomes were the individual process-of-care indicators, a hospital report card impact survey, and all-cause AMI and CHF mortality. RESULTS The publication of the early feedback hospital report card did not result in a significant systemwide improvement in the early feedback group in either the composite AMI process-of-care indicator (absolute change, 1.5%; 95% confidence interval [CI], -2.2% to 5.1%; P = .43) or the composite CHF process-of-care indicator (absolute change, 0.6%; 95% CI, -4.5% to 5.7%; P = .81). During the follow-up period, the mean 30-day AMI mortality rates were 2.5% lower (95% CI, 0.1% to 4.9%; P = .045) in the early feedback group compared with the delayed feedback group. The hospital mortality rates for CHF were not significantly different. CONCLUSION Public release of hospital-specific quality indicators did not significantly improve composite process-of-care indicators for AMI or CHF. TRIAL REGISTRATION http://clinicaltrials.gov Identifier: NCT00187460.