Philip Joseph

Accelerated care versus standard care among patients with hip fracture: the HIP ATTACK pilot trial

Background: A hip fracture causes bleeding, pain and immobility, and initiates inflammatory, hypercoagulable, catabolic and stress states. Accelerated surgery may improve outcomes by reducing the duration of these states and immobility. We undertook a pilot trial to determine the feasibility of a trial comparing accelerated care (i.e., rapid medical clearance and surgery) and standard care among patients with a hip fracture. Methods: Patients aged 45 years or older who, during weekday, daytime working hours, received a diagnosis of a hip fracture requiring surgery were randomly assigned to receive accelerated or standard care. Our feasibility outcomes included the proportion of eligible patients randomly assigned, completeness of follow-up and timelines of accelerated surgery. The main clinical outcome, assessed by data collectors and adjudicators who were unaware of study group allocations, was a major perioperative complication (i.e., a composite of death, preoperative myocardial infarction, myocardial injury after noncardiac surgery, pulmonary embolism, pneumonia, stroke, and life-threatening or major bleeding) within 30 days of randomization. Results: Of patients eligible for inclusion, 80% consented and were randomly assigned to groups (30 to accelerated care and 30 to standard care) at 2 centres in Canada and 1 centre in India. All patients completed 30-day follow-up. The median time from diagnosis to surgery was 6.0 hours in the accelerated care group and 24.2 hours in the standard care group (p < 0.001). A major perioperative complication occurred in 9 (30%) of the patients in the accelerated care group and 14 (47%) of the patients in the standard care group (hazard ratio 0.60, 95% confidence interval 0.26–1.39). Interpretation: These results show the feasibility of a trial comparing accelerated and standard care among patients with hip fracture and support a definitive trial. Trial registration: ClinicalTrials.gov, no. NCT01344343.

Exploring Gene-Environment Relationships in Cardiovascular Disease

Identifying gene-environment interactions that affect cardiovascular disease or associated cardiometabolic diseases may identify novel pathways of cardiovascular disease development, and improve our understanding of how genetic factors impact cardiovascular risk. Several studies have identified environmental or behavioural factors that alter genetic risks associated with cardiovascular disease, lipid traits, diabetes/metabolic syndrome, obesity, and hypertension. Though some interactions have been consistently observed, most require replication in additional studies. Moreover, further research is needed to identify the mechanisms underlying these interactions, and their clinical impact. This review will examine the current evidence supporting gene-environment interactions in cardiometabolic diseases, and highlight additional steps that are needed to determine the clinical utility of these observations.

Effectiveness of Quality Improvement Interventions at Reducing Inappropriate Cardiac Imaging A Systematic Review and Meta-Analysis

Background—Between 5% and 25% of cardiac imaging tests are performed for inappropriate indications. Studies have examined the impact of appropriate use criteria–based quality improvement initiatives on inappropriate testing, but they have not been systematically evaluated. Methods and Results—We performed a systematic review of studies evaluating quality improvement initiatives aimed at reducing inappropriate cardiac imaging. The primary outcome was the proportion of inappropriate tests based on appropriate use criteria. Studies were analyzed using a random effects meta-analysis model, and heterogeneity was examined using subgroup analyses. We identified 6 observational studies and 1 randomized control trial. Most interventions (n=6) had a formal education component, and 5 included a mechanism for physician audit and feedback. Although these interventions were associated with lower odds of inappropriate testing (odds ratio, 0.44 [95% confidence interval, 0.32–0.61]; P<0.001), significant heterogeneity was observed (I2=70%), which was best explained by the utilization of physician audit and feedback. Interventions that employed physician audit and feedback were associated with significantly lower odds of inappropriate testing (odds ratio, 0.36 [95% confidence interval, 0.31–0.41]; P<0.001; I2=0%), whereas those that did not had no effect (odds ratio, 0.89 [95% confidence interval, 0.61–1.29]; P=0.51; I2=0%; P value for difference <0.001). All studies had potential sources of bias that could have affected the observed estimates. Conclusions—Interventions using physician audit and feedback are associated with lower odds of inappropriate cardiac testing. Further research is needed to evaluate a greater diversity of intervention types, with improved study designs.

Promises and challenges of pharmacogenetics: an overview of study design, methodological and statistical issues

Pharmacogenetics is the study of inherited variation in drug response. The goal of pharmacogenetics is to develop novel ways of maximizing drug efficacy and minimizing toxicity for individual patients. Personalized medicine has the potential to allow for a patients genetic information to predict optimal dosage for a drug with a narrow therapeutic index, to select the most appropriate pharmacological agent for a given patient and to develop cost-effective treatments. Although there is supporting evidence in favour of pharmacogenetics, its adoption in clinical practice has been slow because of sometimes conflicting findings among studies. This failure to replicate findings may result from a lack of high-quality pharmacogenetic studies, as well as unresolved methodological and statistical issues. The objective of this review is to discuss the benefits of incorporating pharmacogenetics into clinical practice. We will also address outstanding methodological and statistical issues that may lead to heterogeneity among reported pharmacogenetic studies and how they may be addressed.

The Mini‐Mental State Examination, Clinical Factors, and Motor Vehicle Crash Risk

To examine the association between Mini‐Mental State Examination (MMSE) score and motor vehicle crash (MVC) risk in a large cohort of community‐dwelling participants with cardiovascular disease (CVD) or diabetes mellitus.

Reducing the Global Burden of Cardiovascular Disease, Part 1: The Epidemiology and Risk Factors

Current global health policy goals include a 25% reduction in premature mortality from noncommunicable diseases by 2025. In this 2-part review, we provide an overview of the current epidemiological data on cardiovascular diseases (CVD), its risk factors, and describe strategies aimed at reducing its burden. In part 1, we examine the global epidemiology of cardiac conditions that have the greatest impact on CVD mortality; the predominant risk factors; and the impact of upstream, societal health determinants (eg, environmental factors, health policy, and health systems) on CVD. Although age-standardized mortality from CVD has decreased in many regions of the world, the absolute number of deaths continues to increase, with the majority now occurring in middle- and low-income countries. It is evident that multiple factors are causally related to CVD, including traditional individual level risk factors (mainly tobacco use, lipids, and elevated blood pressure) and societal level health determinants (eg, health systems, health policies, and barriers to CVD prevention and care). Both individual and societal risk factors vary considerably between different regions of the world and economic settings. However, reliable data to estimate CVD burden are lacking in many regions of the world, which hampers the establishment of nationwide prevention and management strategies. A 25% reduction in premature CVD mortality globally is feasible but will require better implementation of evidence-based policies (particularly tobacco control) and integrated health systems strategies that improve CVD prevention and management. In addition, there is a need for better health information to monitor progress and guide health policy decisions.

Assessing the quality of published genetic association studies in meta-analyses: the quality of genetic studies (Q-Genie) tool.

BackgroundAdvances in genomics technology have led to a dramatic increase in the number of published genetic association studies. Systematic reviews and meta-analyses are a common method of synthesizing findings and providing reliable estimates of the effect of a genetic variant on a trait of interest. However, summary estimates are subject to bias due to the varying methodological quality of individual studies. We embarked on an effort to develop and evaluate a tool that assesses the quality of published genetic association studies. Performance characteristics (i.e. validity, reliability, and item discrimination) were evaluated using a sample of thirty studies randomly selected from a previously conducted systematic review.ResultsThe tool demonstrates excellent psychometric properties and generates a quality score for each study with corresponding ratings of ‘low’, ‘moderate’, or ‘high’ quality. We applied our tool to a published systematic review to exclude studies of low quality, and found a decrease in heterogeneity and an increase in precision of summary estimates.ConclusionThis tool can be used in systematic reviews to inform the selection of studies for inclusion, to conduct sensitivity analyses, and to perform meta-regressions.

Aliskiren alone or with other antihypertensives in the elderly with borderline and stage 1 hypertension: the APOLLO trial

AIMS We studied the unclear question whether blood pressure (BP) lowering reduces cardiovascular disease (CVD) in elderly individuals with systolic BP <160 mm Hg. METHODS AND RESULTS We initiated a randomized placebo-controlled stratified 2 × 2 factorial clinical trial evaluating the effects of BP lowering in 11 000 elderly individuals with systolic blood pressure (SBP) between 130 and 159 mm Hg, for 5 years. Following 5-week active run-in, participants were randomized to aliskiren (300 mg) or placebo, and to an additional antihypertensive [hydrochlorothiazide (25 mg) or amlodipine (5 mg)], or their respective placeboes. Study was terminated by sponsor after 1759 subjects (age 72.1 ± 5.2 years, 88% receiving at least one antihypertensive) were randomized and followed for 0.6 year. Study drugs were well tolerated with few serious adverse events during run-in and after randomization, with no significant differences between treatment groups. By design, three levels of BP reductions were achieved, adjusted mean BP reductions of 3.5/1.7 mm Hg (P < 0.001) by aliskiren, 6.8/3.3 mm Hg (P < 0.001) by hydrochlorothiazide or amlodipine, and 10.3/5.0 mm Hg (P < 0.001) by double therapy compared with placebo. Twenty-five major CVD events occurred. Non-significant trends towards fewer CVD events with greater BP reductions are evident: hazard ratios (HR) 0.82 [95% confidence interval (CI): 0.37-1.81] for 3.5 mm Hg SBP reduction; HR 0.45 (95% CI: 0.19-1.04) for 6.8 mm Hg; and HR 0.25 (0.05-1.18) for 10.3 mm Hg reduction for primary composite of CV death, MI, stroke, or significant heart failure. CONCLUSIONS Sizeable reductions in BP, with potential for substantial CVD reduction, can be safely achieved using combinations of BP drugs in the elderly with normal high and Stage 1 hypertension. CLINICAL TRIAL REGISTRATION NCT01259297.

Pharmacogenetics in cardiovascular disease: the challenge of moving from promise to realization: concepts discussed at the Canadian Network and Centre for Trials Internationally Network Conference (CANNeCTIN), June 2009.

Pharmacogenetics in cardiovascular medicine brings the potential for personalized therapeutic strategies that improve efficacy and reduce harm. Studies evaluating the impact of genetic variation on pharmacologic effects have been undertaken for most major cardiovascular drugs, including antithrombotic agents, β‐adrenergic receptor blockers, statins, and angiotensin‐converting enzyme inhibitors. Across these drug classes, many polymorphisms associated with pharmacodynamic, pharmacokinetic, or surrogate outcomes have been identified. However, their impact on clinical outcomes and their ability to improve clinical practice remains unclear. This review will examine the current clinical evidence supporting pharmacogenetic testing in cardiovascular medicine, provide clinical guidance based on the current evidence, and identify further steps needed to determine the utility of pharmacogenetics in cardiovascular care.

Impact of a Genetic Risk Score on Myocardial Infarction Risk Across Different Ethnic Populations

BACKGROUND Myocardial infarction (MI) risk varies by ethnicity, although the influence of genetic factors remains unclear. Using a genetic risk score (GRS), we examined the association between 25 coronary artery disease (CAD)-related single nucleotide polymorphisms and MI across 6 ethnic groups. METHODS We studied 8556 participants in the INTERHEART case-control study from 6 ethnic groups: Europeans, South Asians, Southeast Asians, Arabs, Latin Americans, and Africans. Associations between the GRS and MI were tested in each group by logistic regression and overall by meta-analysis. RESULTS Overall, the GRS increased the odds of MI by 1.07 (95% confidence interval [CI], 1.04-1.09) per risk allele in the unadjusted model, with little change (odds ratio, 1.06; 95% CI, 1.04-1.09) after adjusting for demographic and modifiable factors. In Europeans, South Asians, Southeast Asians, and Arabs, the GRS was significantly associated with MI, with minimal heterogeneity observed. In these groups, a score > 23 risk alleles (highest 4 quintiles) was associated with only a 5% difference in population attributable risk (PAR) (36% to 41%) for MI. The GRS was not significant in Latin Americans or Africans. In the overall cohort, modest changes, beyond clinical factors, in PAR (88% to 91%), concordance statistic (0.73 to 0.74), and continuous net reclassification improvement (12%) were observed with the GRS. CONCLUSIONS A CAD GRS is associated with MI across a multiethnic cohort, with significant and consistent effects across 4 distinct ethnicities. However, it only modestly improves MI risk prediction beyond clinical factors.