David F. Blackburn

Benefits and harms of antidiabetic agents in patients with diabetes and heart failure: systematic review

Objective To review the literature on the association between antidiabetic agents and morbidity and mortality in people with heart failure and diabetes. Design Systematic review and meta-analysis of controlled studies (randomised trials or cohort studies) evaluating antidiabetic agents and outcomes (death and admission to hospital) in patients with heart failure and diabetes. Data sources Electronic databases, manual reference search, and contact with investigators. Review methods Two reviewers independently extracted data. Risk estimates for specific treatments were abstracted and pooled estimates derived by meta-analysis where appropriate. Results Eight studies were included. Three of four studies found that insulin use was associated with increased risk for all cause mortality (odds ratio 1.25, 95% confidence interval 1.03 to 1.51; 3.42, 1.40 to 8.37 in studies that did not adjust for diet and antidiabetic drugs; hazard ratio 1.66, 1.20 to 2.31; 0.96, 0.88 to 1.05 in the studies that did). Metformin was associated with significantly reduced all cause mortality in two studies (hazard ratio 0.86, 0.78 to 0.97) compared with other antidiabetic drugs and insulin; 0.70, 0.54 to 0.91 compared with sulfonylureas); a similar trend was seen in a third. Metformin was not associated with increased hospital admission for any cause or for heart failure specifically. In four studies, use of thiazolidinediones was associated with reduced all cause mortality (pooled odds ratio 0.83, 0.71 to 0.97, I2=52%, P=0.02). Thiazolidinediones were associated with increased risk of hospital admission for heart failure (pooled odds ratio 1.13 (1.04 to 1.22), I2=0%, P=0.004). The two studies of sulfonylureas had conflicting results, probably because of differences in comparator treatments. Important limitations were noted in all studies. Conclusion Metformin was the only antidiabetic agent not associated with harm in patients with heart failure and diabetes. It was associated with reduced all cause mortality in two of the three studies.

Cardiovascular Morbidity Associated with Nonadherence to Statin Therapy

Study Objective. To measure the extent of cardiovascular morbidity associated with nonadherence to 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitor (statin) therapy.

Proportion and Risk Indicators of Nonadherence to Statin Therapy: A Meta-analysis

BACKGROUND Nonadherence to chronic disease medications is important. A growing body of literature suggests that better delivery of established therapies would save more lives than would discovery of innovations. Our first objective was to quantify the proportion of adherence to statin medications. The second objective was to provide estimates of risk indicators associated with nonadherence to statin medications. METHODS We performed a systematic literature review and meta-analysis of all studies published between database inception and June of 2011 that reviewed adherence, and risk indicators associated with nonadherence, to statin medications. RESULTS In the end, 67 studies met our inclusion and exclusion criteria and passed our methodological-quality evaluation. Among observational studies, 49.0% (95% confidence interval [CI], 48.9%-49.2%) of patients were adherent to statin medications at 1 year of follow-up. Among randomized trials, 90.3% (95% CI, 89.8%-90.8%) of patients were adherent to statin medications at 1 year of follow-up. The association between 147 variables and adherence to statin medications was determined. After meta-analysis, only 6 variables were associated with nonadherence to statin medications: primary prevention (rate ratio = 1.52; 95% CI, 1.50-1.53); new statin users (rate ratio = 1.46; 95% CI, 1.33-1.61); copayment (rate ratio = 1.28; 95% CI, 1.09-1.50; lower income status (rate ratio = 1.26; 95% CI, 1.16-1.37); fewer than 2 lipid tests performed (rate ratio = 1.38; 95% CI, 1.16-1.64), and not having hypertension (rate ratio = 1.16; 95% CI, 1.12-1.21). CONCLUSIONS This study provides some insight into the extent of nonadherence by study type along with 6 risk indicators associated with nonadherence to statin medications.

Changes in Adherence to Evidence-Based Medications in the First Year After Initial Hospitalization for Heart Failure Observational Cohort Study From 1994 to 2003

Background—The use of evidence-based medications in patients with heart failure has increased over the past 10 years. We aimed to determine whether adherence to these medications has also increased during this time. Methods and Results—A retrospective cohort was created using administrative databases from the province of Saskatchewan, Canada. Subjects discharged alive from their first hospitalization for heart failure between 1994 and 2003 were eligible. Those filling a prescription for a &bgr;-blocker (BB), angiotensin-converting enzyme inhibitor (ACEI), or angiotensin receptor blocker (ARB) within 6 months of discharge were followed for 1 year after the initial prescription. Of 8805 eligible patients, 67% of BB users (941/1414) and 74% of ACEI/ARB users (4441/5991) exhibited optimal adherence at 1 year (defined as ≥80% adherence calculated from pharmacy refill records). When grouped by year of initial heart failure hospitalization, the proportion of optimally adherent patients improved from 54% to 75% with BB and from 67% to 80% with ACEI/ARBs between 1994/1995 and 2002/2003 (P for trend <0.001 for both). Mean 1-year adherence improved from 71% to 83% for BB and 80% to 88% for ACEI/ARBs. After adjustment using multivariable logistic regression, subjects discharged in 2003 were significantly more likely to exhibit optimal adherence to a BB (odds ratio, 2.04; 95% CI, 1.21 to 3.44) or an ACEI/ARB (odds ratio, 1.65; 95% CI, 1.30 to 2.08) than those prescribed therapy in 1994/1995. Conclusions—One-year adherence to BB and ACEI/ARB is improving over time in patients discharged after first heart failure hospitalization. Patients taking multiple cardiac medications were not any less likely to exhibit optimal adherence than patients taking only 1 medication.

Diabetes and Cardiovascular Disease Interventions by Community Pharmacists: A Systematic Review

Objective: To systematically review and assess the quality of studies evaluating community pharmacist interventions for preventing or managing diabetes or cardiovascular disease (CVD) and/or their major risk factors. Data Sources: A comprehensive literature search was performed using MEDLINE (1950-February 2011), EMBASE (1980-February 2011), International Pharmaceutical Abstracts (1970-February 2011), Cumulative Index to Nursing and Allied Health Literature (1982-June 2007), and Cochrane Central Register of Controlled Trials (1898-February 2011). Search terms included: community pharmacy(ies), community pharmacist(s), cardiovascular, diabetes, and intervention. The grey literature was searched using the ProQuest Dissertations and Theses, Theses Canada, and OAlster databases. Study Selection and Data Extraction: Articles published in English or French with all study designs were considered for the review. Studies were included if they contained interventions designed to reduce the incidence, risk, or mortality of CVD or diabetes; affect clinical indicators of CVD or diabetes mellitus (including hypertension, dyslipidemia, or hemoglobin A1c); and/or improve adherence to treatment strategies. Only studies involving interventions carried out primarily by pharmacists in community pharmacy settings were included. Study quality was assessed using a checklist validated for both randomized and nonrandomized studies. Data Synthesis: A total of 4142 studies were initially identified, with 40 meeting our inclusion criteria. Eleven studies were randomized controlled trials, 4 were cluster randomized trials, and 2 studies had randomized before-after designs. The remaining studies were controlled before-after (n = 2), cohort (n = 4), and uncontrolled before-after (n = 17) designs. Interventions focused on diabetes (n = 12), hypertension (n = 9), medication adherence (n = 9), lipids (n = 5), evidence-based medication initiation or optimization (n = 3), risk factor prediction scores (n = 1), and body mass index (n = 1). All studies contained interventions focused at the patient level and the majority of studies (34/40) involved interventions directed at both the physician and patient. No specific intervention emerged as superior, and study quality was generally poor, making it difficult to determine the true effect of the interventions. Conclusions: Poor study quality, time-intensive interventions, and unproven clinical significance warrant the need for further high-quality studies of community pharmacist interventions for preventing or managing diabetes or CVD and/or their major risk factors.

Atenolol as initial antihypertensive therapy: an observational study comparing first-line agents

Objective The role of atenolol in the management of patients with hypertension is currently under scrutiny. Our aim was to evaluate the real-world consequences of recent clinical trial findings. Methods We conducted a retrospective, cohort study using linked administrative data from the province of Saskatchewan, Canada. Eligible subjects were first-ever users of antihypertensive medications between 1 January 1994 and 31 December 2003 and were grouped into four cohorts: atenolol, angiotensin-converting enzyme inhibitors (ACEI), thiazide diuretics, or calcium antagonists. Patients remained eligible during monotherapy only. Results We identified 19 249 eligible individuals (mean age 60.6 years) who were followed for a mean of 2.3 years (SD 2.0). The rate of myocardial infarction, unstable angina, stroke, or death occurred in similar frequencies among all cohorts: atenolol (2.3%), ACEI (3.6%), thiazide diuretics (2.9%), and calcium antagonists (3.9%). After adjustment for potential confounders, atenolol therapy was not associated with higher event rates than the other first-line agents, with hazard ratios ranging between 1.03 [95% confidence intervals (CI) 0.72–1.46] and 1.24 (95% CI 0.91–1.68) for all cohorts compared with atenolol. Similar results were observed upon stratifying the sample into subjects above and below 60 years of age. Conclusion The low event rates for all cohorts suggest that atenolol has not been associated with a significant burden of cardiovascular morbidity or mortality in its traditional role for uncomplicated hypertension. Further study is needed to identify the specific types of patients that should avoid atenolol as an antihypertensive agent.

First-Fill Medication Discontinuations and Nonadherence to Antihypertensive Therapy: An Observational Study

BACKGROUND Medication nonadherence is a barrier to successfully managing hypertension, but little is known about the contribution that immediate discontinuations have on antihypertensive (AHT) nonadherence. The purpose of this study was to determine the proportion of new AHT users who discontinue after a single dispensation, and to examine potential predictors of these discontinuations. METHODS This retrospective cohort study utilizing linked administrative data from Saskatchewan, Canada. Subjects were ≥40 years of age and received a new AHT between 1994-2002. The primary end point was the proportion of subjects who discontinued their AHT after the first dispensation (first-fill discontinuation). The proportion of nonadherence attributed to first-fill discontinuations was then calculated. Multivariate regression identified factors associated with first-fill discontinuations. RESULTS 52,039 subjects were included in the analyses. Mean age was 59.4 (s.d. 12.5) years, and 42% were male. Overall, 25,812/52,039 (50%) subjects were nonadherent at 1 year; first-fill discontinuations accounted for 39.1% (10,081/25,812) of this nonadherence. Approximately 20% (10,081/52,039) of all subjects discontinued all AHT therapy after the first fill. A higher chronic disease score (adjusted odds ratio (OR) 1.09, 95% confidence interval (CI) 1.08-1.11) and antidepressant medication usage during the observation year (adjusted OR 1.17, 95% CI 1.09-1.26) was associated with increased risk for first-fill discontinuations. Older age, starting AHT therapy after 1994, frequent physician visits, or use of a statin, acetylsalicylic acid, warfarin or antihyperglycemic during the observation year was associated with a lower risk for first-fill discontinuations. CONCLUSION A substantial proportion of nonadherence to AHT medications is due to discontinuations after only a single dispensation.

Non-adherence in type 2 diabetes: practical considerations for interpreting the literature.

The rising prevalence of type 2 diabetes poses a serious threat to human health and the viability of many health care systems around the world. Although several prescription medications can play a vital role in controlling symptoms and preventing complications, non-adherence to these therapies is highly prevalent and has been linked to increases in morbidity, mortality, and health care costs. Although a vast array of significant adherence predictors has been identified, the ability to explain or predict non-adherence with known risk-factors remains poor. Further, the definitions, outcomes, and various measures used in the non-adherence literature can be misleading for the unfamiliar reviewer. In this narrative review, a practical overview of important considerations for interpreting adherence endpoints and measures is discussed. Also, an organizational framework is proposed to consider published adherence interventions. This framework may allow for a unique appreciation into areas of limited knowledge and thus highlights targets for future research.

The Collaborative Cardiovascular Risk Reduction in Primary Care (CCARP) Study

Study Objective. To evaluate whether a simple pharmacist protocol, consisting of patient screening and cardiovascular risk stratification, identification and reminders about uncontrolled risk factors, and drug adherence support, can significantly reduce cardiovascular risk.

Atypical antipsychotics and hyperglycemic emergencies: multicentre, retrospective cohort study of administrative data.

OBJECTIVE To evaluate the relationship between initiation of atypical antipsychotic agents and the risk of hyperglycemic emergencies. METHOD We conducted a multicentre retrospective cohort study using administrative health data from 7 Canadian provinces and the UK Clinical Practice Research Datalink. Hospitalizations for hyperglycemic emergencies (hyperglycemia, diabetic ketoacidosis, hyperosmolar hyperglycemic state) were compared between new users of risperidone (reference), and new users of olanzapine, other atypical antipsychotics, and typical antipsychotics. We used propensity scores with inverse probability of treatment weighting and proportional hazard models to estimate the site-specific hazard ratios of hyperglycemic emergencies in the year following drug initiation separately for adults under and over age 66 years. Site-level results were pooled using meta-analytic methods. RESULTS Among 725,489 patients, 55% were aged 66+years; 5% of younger and 19% of older patients had pre-existing diabetes. Hyperglycemic emergencies were rare (1-2 per 1000 person years), but more frequent in patients with pre-existing diabetes (6-12 per 1000 person years). We did not find a significant difference in risk of hyperglycemic emergencies with initiation of olanzapine versus risperidone; however heterogeneity existed between sites. The risk of an event was significantly lower with other atypical (99% quetiapine) compared to risperidone use in older patients [adjusted hazard ratio, 95% confidence interval (CI): 0.69, 0.53-0.90]. CONCLUSIONS Risk for hyperglycemic emergencies is low after initiation of antipsychotics, but patients with pre-existing diabetes may be at greater risk. The risk appeared lower with the use of quetiapine in older patients, but the clinical significance of the findings requires further study.