Evidence based drug therapy : are optimal doses and multiple medication therapies realistic in patients with chronic heart failure

Background: Chronic Heart Failure (CHF) has a high mortality and morbidity. Large scale randomised controlled trials have proven the benefits of beta blockade and ACE inhibitors in reducing mortality in patients with CHF and expert guidelines mandate their use. In spite of these recommendations, important therapies are under-prescribed and under-utilised.

Method: 1015 consecutive patients enrolled in CHF management programs across Australia were surveyed during 2005-2006 to determine prescribing patterns in heart failure medications. These patients were followed-up for a period of 6 months.

Results: The survey revealed that beta blockers were prescribed to 80% of patients (more than 85% were on sub-optimal doses) and 70% were prescribed Angiotensin converting enzyme (ACE) inhibitors (approximately 50% were on sub-optimal dose). 19% of patients were prescribed Angiotensin receptor blockers (ARBs). By 6 months <25% of the patients who were on sub-optimal dose beta blockers or ACE inhibitors at baseline, had been up-titrated to maximum dose (p<0.0001). In CHF programs, were nurses were able to titrate medications, 75% of patients reached optimal dose of beta blockers compared to those programs with no nurse-led medication titration, where only 25% of patients reached optimal dose (p<0.004). When examining optimal dosage for any two of these mandatory medications, less patients were on optimal therapy. Beta blockers and ACE inhibitors, were both prescribed in combination in 60% of patients. While beta blockers and ARBs were prescribed to 15% of patients.

Conclusion: Whilst prescribing rates for a single medication strategy of beta blockers, or ACE inhibitors were greater than 70%, an increase in dosage of these medications and utilisation of proven combination therapy of these medications was poor. It is suggested that clinical outcomes for this cohort of patients could be further improved by adherence to evidence-based practice, ESC guidelines, and optimisation of these medications by heart failure nurses in a CHF program. On the basis of these findings and in the absence of ready access to a polypill, focussing on evidence-based practice to increase utilisation and optimal dosage of combination medication therapy is critical.

Heterogeneity in service delivery and inequity in access are common characteristics of chronic heart failure management programs

Background: The prevalence of heart failure in Australia is similar to that of Europe. In Australia, chronic heart failure management programs (CHF-MPs) have become part of standard care for patients with Chronic Heart Failure (CHF). However, heterogeneity among programs is common which can result in variable patient outcomes.

Method: A national survey was undertaken of 59 post-discharge CHF-MPs identified from within the Australian health care system. Two had ceased operating and one centre declined to participate in the study. A 33-item investigator-developed questionnaire, examining the characteristics and interventions used within each CHF-MP, was sent to the remaining 56 CHF-MPs. A response rate of 100% was achieved.

Results: Our survey revealed a disproportional distribution of CHF-MPs across the Australian continent: the State of Victoria had 3.6 CHF-MPs/million population, New South Wales had 3.7 CHF-MPs/million population, Queensland had 1 program/million population, South Australia had 0.3 CHF-MPs/million population and Western Australia had 1 program/million population.Overall, 8000 postdischarge CHF pts (median: 126; IQR: 26-260) were managed via CHF-MPs. Approximately 40,000 CHF pts are discharged from metropolitan institutions nationally, this represents only 22% of the potential caseload for these cost-effective CHF-MPs. Only 8% of these programs were located within rural regions. The majority of CHF-MPs were located within an acute metropolitan hospital (52%) and 36% were community based (all associated with a hospital). Heterogeneity of CHF-MPs in applied models of care was evident with 75% of CHF-MPs offering CHF outpatient clinics and 77% conducting home visits. Of the programs offering home visits 78% were funded by regional government (p<0.048). There were no nurse-led CHF outpatient clinics. A hybrid approach to CHF-MPs was common with many CHF-MPs comprising an outpatient clinic, home visits and inpatient visits. Various medications were titrated by nurses in 43% of CHF-MPs. In the programs that allowed nurses to titrate medications 79% were located in an acute hospital (p<0.011).

Conclusion: Variability of service availability is of concern within the context of universal coverage. In addition, heterogeneity between programs and the diversity in models of care delivery highlights the inconsistency and questions the quality of health related outcomes. We are currently analysing health outcome data from the 1015 patients managed in these CHF-MPs to describe the relationship between quality of care and health outcomes.

FT-IR investigation of Ion association in plasticized solid polymer electrolytes

FT-IR spectroscopy has been utilized to monitor ion association in plasticized solid polymer electrolytes (SPEs). The SPEs were prepared from a random copolymer of ethylene oxide (EO) and propylene oxide (PO) and the salt lithium trifluoromethanesulfonate (lithium triflate, LiTf). Tetraethylene glycol dimethyl ether (tetraglyme) and N,N‘-dimethylformamide (DMF) were chosen as model plasticizers. Despite having a similar dielectric constant to that of the polymer host, ε ~ 5, the incorporation of tetraglyme into the SPEs resulted in increased ion association. The addition of a higher dielectric constant solvent , DMF, ε = 36.7, resulted in decreased ion association in the SPE. The effects of salt concentration (0.05−1.25 mol dm^-3) and temperature (25−100 °C) upon ion association in SPEs were also investigated. At low salt concentrations, ion association was found to increase with temperature, however, at 1.25 mol dm^-3 the temperature dependence of ion association was dominated by concentration effects. There appears to be a maximum in the fraction of “free” ions at a LiCF₃SO₃ concentration of 0.4 mol dm^-3, preceded by a minimum at approximately 0.2 mol dm^-3, consistent with the molar conductivity behavior previously observed in these electrolytes.

Triflate ion association in plasticized polymer electrolytes

Ion association in plasticised solid polymer electrolytes (SPEs) has been monitored using FT-IR spectroscopy. The SPEs were prepared from a random co-polymer of ethylene oxide (EO) and propylene oxide (PO) and the salt lithium trifluoromethane sulfonate (lithium triflate, LiTf). Tetraethylene glycol dimethylether (tetraglyme, ε˜5) and N,N'-dimethyl formamide (DMF, ε = 36.7) were chosen as model plasticisers. Decreased ion association resulted from plasticization with DMF, indicating that the addition of a higher dielectric constant solvent increases the fraction of dissociated ions in the SPE. The incorporation of tetraglyme into these SPEs results in increased ion association, despite the similar dielectric constants of the plasticiser and polymer host. The effects of salt concentration (0.05–1.25 mol dm^{− 3} solvent) upon ion association in SPEs was also investigated. There appears to be a minimum in the number of “free” ions at a LiTf concentration of 0.2 mol dm^{− 3} solvent followed by a maximum at approximately 0.4 mol dm^{− 3} solvent, consistent with the molar conductivity behaviour previously observed in these electrolytes.

Room temperature fast-ion conduction in imidazolium halide salts

Fast-ion conduction has been observed in the iodide and bromide salts of 1-methyl-3-ethylimidazolium at ambient temperatures. The melting point of these two compounds is above 350 K and even at 273 K the ionic conductivity in the solid-state is greater than 10⁻³S cm⁻¹. Cation diffusion coefficients have been measured using fringe field gradient and/or pulse field gradient ¹H NMR techniques, which indicated cation diffusion coefficients of the order of 10⁻¹⁰ m² s⁻¹ in the solid-state. Remarkably, these values are up to an order of magnitude higher than the cation diffusion coefficient in the supercooled liquid at 293 K. The activation energy for diffusion in the solid-state is extremely small, as is typical of solid-state fast-ion conductors and indicates a change in transport mechanism from the melt to the crystal. The inability to detect an ¹²⁷I signal together with the modelling of the conductivity using the Nernst–Einstein equation suggests that the solid-state conduction is primarily due to cation diffusion. The solid-state fast-ion conduction is most likely related to vacancy diffusion along the cation layers in the crystal. The temperature dependence of the NMR signal intensity indicates that the number of mobile species is increasing with increasing temperature with an activation energy of approximately 20–30 kJ mol⁻¹.

The Melbourne Diabetes Prevention Study (MDPS) : study protocol for a randomized controlled trial

Background
Worldwide, type 2 diabetes (T2DM) prevalence has more than doubled over two decades. In Australia, diabetes is the second highest contributor to the burden of disease. Lifestyle modification programs comprising diet changes, weight loss and moderate physical activity, have been proven to reduce the incidence of T2DM in high risk individuals.

As part of the Council of Australia Governments, the State of Victoria committed to develop and support the diabetes prevention program ‘Life! Taking action on diabetes’ (Life!) which has direct lineage from effective clinical and implementation trials from Finland and Australia. The Melbourne Diabetes Prevention Study (MDPS) has been set up to evaluate the effectiveness and cost-effectiveness of a specific version of the Life! program.

Methods/design
We intend to recruit 796 participants for this open randomized clinical trial; 398 will be allocated to the intervention arm and 398 to the usual care arm. Several methods of recruitment will be used in order to maximize the number of participants. Individuals aged 50 to 75 years will be screened with a risk tool (AUSDRISK) to detect those at high risk of developing T2DM. Those with existing diabetes will be excluded. Intervention participants will undergo anthropometric and laboratory tests, and comprehensive surveys at baseline, following the fourth group session (approximately three months after the commencement of the intervention) and 12 months after commencement of the intervention, while control participants will undergo testing at baseline and 12 months only.

The intervention consists of an initial individual session followed by a series of five structured-group sessions. The first four group sessions will be carried out at two week intervals and the fifth session will occur eight months after the first group session. The intervention is based on the Health Action Process Approach (HAPA) model and sessions will empower and enable the participants to follow the five goals of the Life! program.

Discussion
This study will determine whether the effect of this intervention is larger than the effect of usual care in reducing central obesity and cardiovascular risk factors and thus the risk of developing diabetes and cardiovascular disease. Also it will evaluate how these two options compare economically.

Nurse-led titration of angiotensin converting enzyme inhibitors, beta-adrenergic blocking agents, and angiotensin receptor blockers for people with heart failure with reduced ejection fraction

BACKGROUND: Heart failure is associated with high mortality and hospital readmissions. Beta-adrenergic blocking agents, angiotensin converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs) can improve survival and reduce hospital readmissions and are recommended as first-line therapy in the treatment of heart failure. Evidence has also shown that there is a dose-dependent relationship of these medications with patient outcomes. Despite this evidence, primary care physicians are reluctant to up-titrate these medications. New strategies aimed at facilitating this up-titration are warranted. Nurse-led titration (NLT) is one such strategy. OBJECTIVES: To assess the effects of NLT of beta-adrenergic blocking agents, ACEIs, and ARBs in patients with heart failure with reduced ejection fraction (HFrEF) in terms of safety and patient outcomes. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials in the Cochrane Library (CENTRAL Issue 11 of 12, 19/12/2014), MEDLINE OVID (1946 to November week 3 2014), and EMBASE Classic and EMBASE OVID (1947 to 2014 week 50). We also searched reference lists of relevant primary studies, systematic reviews, clinical trial registries, and unpublished theses sources. We used no language restrictions. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing NLT of beta-adrenergic blocking agents, ACEIs, and/or ARBs comparing the optimisation of these medications by a nurse to optimisation by another health professional in patients with HFrEF. DATA COLLECTION AND ANALYSIS: Two review authors (AD & JC) independently assessed studies for eligibility and risk of bias. We contacted primary authors if we required additional information. We examined quality of evidence using the GRADE rating tool for RCTs. We analysed extracted data by risk ratio (RR) with 95% confidence interval (CI) for dichotomous data to measure effect sizes of intervention group compared with usual-care group. Meta-analyses used the fixed-effect Mantel-Haenszel method. We assessed heterogeneity between studies by Chi(2) and I(2). MAIN RESULTS: We included seven studies (1684 participants) in the review. One study enrolled participants from a residential care facility, and the other six studies from primary care and outpatient clinics. All-cause hospital admission data was available in four studies (556 participants). Participants in the NLT group experienced a lower rate of all-cause hospital admissions (RR 0.80, 95% CI 0.72 to 0.88, high-quality evidence) and fewer hospital admissions related to heart failure (RR 0.51, 95% CI 0.36 to 0.72, moderate-quality evidence) compared to the usual-care group. Six studies (902 participants) examined all-cause mortality. All-cause mortality was also lower in the NLT group (RR 0.66, 95% CI 0.48 to 0.92, moderate-quality evidence) compared to usual care. Approximately 27 deaths could be avoided for every 1000 people receiving NLT of beta-adrenergic blocking agents, ACEIs, and ARBs. Only three studies (370 participants) reported outcomes on all-cause and heart failure-related event-free survival. Participants in the NLT group were more likely to remain event free compared to participants in the usual-care group (RR 0.60, 95% CI 0.46 to 0.77, moderate-quality evidence). Five studies (966 participants) reported on the number of participants reaching target dose of beta-adrenergic blocking agents. This was also higher in the NLT group compared to usual care (RR 1.99, 95% CI 1.61 to 2.47, low-quality evidence). However, there was a substantial degree of heterogeneity in this pooled analysis. We rated the risk of bias in these studies as high mainly due to a lack of clarity regarding incomplete outcome data, lack of reporting on adverse events associated with the intervention, and the inability to blind participants and personnel. Participants in the NLT group reached maximal dose of beta-adrenergic blocking agents in half the time compared with participants in usual care. Two studies reported on adverse events; one of these studies stated there were no adverse events, and the other study found one adverse event but did not specify the type or severity of the adverse event. AUTHORS' CONCLUSIONS: Participants in the NLT group experienced fewer hospital admissions for any cause and an increase in survival and number of participants reaching target dose within a shorter time period. However, the quality of evidence regarding the proportion of participants reaching target dose was low and should be interpreted with caution. We found high-quality evidence supporting NLT as one strategy that may improve the optimisation of beta-adrenergic blocking agents resulting in a reduction in hospital admissions. Despite evidence of a dose-dependent relationship of beta-adrenergic blocking agents, ACEIs, and ARBs with improving outcomes in patients with HFrEF, the translation of this evidence into clinical practice is poor. NLT is one strategy that facilitates the implementation of this evidence into practice.