Angela Wadham

Effect of fixed dose combination treatment on adherence and risk factor control among patients at high risk of cardiovascular disease: randomised controlled trial in primary care

Objective To evaluate whether provision of fixed dose combination treatment improves adherence and risk factor control compared with usual care of patients at high risk of cardiovascular disease in primary care. Design Open label randomised control trial: IMPACT (IMProving Adherence using Combination Therapy). Setting 54 general practices in the Auckland and Waikato regions of New Zealand, July 2010 to August 2013. Participants 513 adults (including 257 indigenous Māori) at high risk of cardiovascular disease (established cardiovascular disease or five year risk ≥15%) who were recommended for treatment with antiplatelet, statin, and two or more blood pressure lowering drugs. 497 (97%) completed 12 months’ follow-up. Interventions Participants were randomised to continued usual care or to fixed dose combination treatment (with two versions available: aspirin 75 mg, simvastatin 40 mg, and lisinopril 10 mg with either atenolol 50 mg or hydrochlorothiazide 12.5 mg). All drugs in both treatment arms were prescribed by their usual general practitioners and dispensed by local community pharmacists. Main outcome measures Primary outcomes were self reported adherence to recommended drugs (antiplatelet, statin, and two or more blood pressure lowering agents) and mean change in blood pressure and low density lipoprotein cholesterol at 12 months. Results Adherence to all four recommended drugs was greater among fixed dose combination than usual care participants at 12 months (81% v 46%; relative risk 1.75, 95% confidence interval 1.52 to 2.03, P<0.001; number needed to treat 2.9, 95% confidence interval 2.3 to 3.7). Adherence for each drug type at 12 months was high in both groups but especially in the fixed dose combination group: for antiplatelet treatment it was 93% fixed dose combination v 83% usual care (P<0.001), for statin 94% v 89% (P=0.06), for combination blood pressure lowering 89% v 59% (P<0.001), and for any blood pressure lowering 96% v 91% (P=0.02). Self reported adherence was highly concordant with dispensing data (dispensing of all four recommended drugs 79% fixed dose combination v 47% usual care, relative risk 1.67, 95% confidence interval 1.44 to 1.93, P<0.001). There was no statistically significant improvement in risk factor control between the fixed dose combination and usual care groups over 12 months: the difference in systolic blood pressure was −2.2 mm Hg (−4.5 v −2.3, 95% confidence interval −5.6 to 1.2, P=0.21), in diastolic blood pressure −1.2 mm Hg (−2.1 v −0.9, −3.2 to 0.8, P=0.22) and in low density lipoprotein cholesterol −0.05 mmol/L (−0.20 v −0.15, −0.17 to 0.08, P=0.46). The number of participants with cardiovascular events or serious adverse events was similar in both treatment groups (fixed dose combination 16 v usual care 18 (P=0.73), 99 v 93 (P=0.56), respectively). Fixed dose combination treatment was discontinued in 94 participants (37%). The most commonly reported reason for discontinuation was a side effect (54/75, 72%). Overall, 89% (227/256) of fixed dose combination participants’ general practitioners completed a post-trial survey, and the fixed dose combination strategy was rated as satisfactory or very satisfactory for starting treatment (206/227, 91%), blood pressure control (180/220, 82%), cholesterol control (170/218, 78%), tolerability (181/223, 81%), and prescribing according to local guidelines (185/219, 84%). When participants were asked at 12 months how easy they found taking their prescribed drugs, most responded very easy or easy (224/246, 91% fixed dose combination v 212/246, 86% usual care, P=0.09). At 12 months the change in other lipid fractions, difference in EuroQol-5D, and difference in barriers to adherence did not differ significantly between the treatment groups. Conclusions Among this well treated primary care population, fixed dose combination treatment improved adherence to the combination of all recommended drugs but improvements in clinical risk factors were small and did not reach statistical significance. Acceptability was high for both general practitioners and patients, although the discontinuation rate was high. Trial registration Australian New Zealand Clinical Trial Registry ACTRN12606000067572.

Effectiveness of fixed dose combination medication ('polypills') compared with usual care in patients with cardiovascular disease or at high risk : A prospective, individual patient data meta-analysis of 3140 patients in six countries

AIMS To conduct a prospective, individual participant data (IPD) meta-analysis of randomised controlled trials comparing a polypill-based approach with usual care in high risk individuals. METHODS AND RESULTS Three trials comparing polypill-based care with usual care in individuals with CVD or high calculated cardiovascular risk contributed IPD. Primary outcomes were self-reported adherence to combination therapy (anti-platelet, statin and ≥ two blood pressure (BP) lowering agents), and difference in mean systolic BP (SBP) and LDL-cholesterol at 12 months. Analyses used random effects models. Among 3140 patients from Australia, England, India, Ireland, New Zealand and The Netherlands (75% male, mean age 62 years), median follow-up was 15 months. At baseline, 84%, 87% and 61% respectively were taking a statin, anti-platelet agent and at least two BP lowering agents. At 12 months, compared to usual care, participants in the polypill arm had higher adherence to combination therapy (80% vs. 50%, RR 1.58; 95% CI, 1.32 to 1.90; p < 0.001), lower SBP (-2.5 mmHg; 95% CI, -4.5 to -0.4; p = 0.02) and lower LDL-cholesterol (-0.1 mmol/L; 95% CI, -0.2 to 0.0; p = 0.04). Baseline treatment levels were a major effect modifier for adherence and SBP (p-homog < 0.0001 and 0.02 respectively) with greatest improvements seen among those under-treated at baseline. CONCLUSIONS Polypill therapy significantly improved adherence, SBP and LDL-cholesterol in high risk patients compared with usual care, especially among those who were under-treated at baseline.

Left ventricular mass and volume with telmisartan, ramipril, or combination in patients with previous atherosclerotic events or with diabetes mellitus (from the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial [ONTARGET])

The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) showed that the angiotensin receptor blocker telmisartan 80 mg was not inferior to the angiotensin-converting enzyme inhibitor ramipril 10 mg, and the combination no more effective than ramipril alone, in decreasing morbidity and mortality in patients with cardiovascular disease or high-risk diabetes. Although therapy targeting angiotensin II is known to decrease left ventricular (LV) mass and volume, the relative influence of angiotensin-converting enzyme inhibitor inhibitors and angiotensin receptor blocker, and their combination, on the heart remains unclear in this population. Magnetic resonance imaging was performed in 287 patients enrolled in ONTARGET, across 8 centers in 6 countries, at randomization and after 2-year treatment (90, 100, and 97 patients in the ramipril, telmisartan, and combination therapy groups, respectively). Baseline patient characteristics showed higher frequencies of coronary artery disease, Asian ethnicity, and use of statins and beta blockers than the main ONTARGET trial. LV mass decreased in all groups (p <0.0001 for each), but there were no significant differences in change in LV mass or volume among groups, except that LV mass index decreased more on combination versus telmisartan (p = 0.04). Key determinants of LV mass decrease were a history of hypertension (p = 0.03), baseline mass (p <0.0001), and decrease in systolic blood pressure (p <0.0001). The best magnetic resonance imaging predictor of composite events was end-systolic volume (p <0.0001). In conclusion, telmisartan and ramipril had similar effects on LV mass and volume, and combination therapy was not more effective, in high-risk patients with cardiovascular disease. These results are consistent with the major outcome findings of the main ONTARGET study.

Prospective meta-analysis of trials comparing fixed dose combination based care with usual care in individuals at high cardiovascular risk: The SPACE Collaboration

BACKGROUND An international collaboration of investigators will assess the benefits and risks of fixed dose combination (FDC) based care compared with usual care in populations at high risk of cardiovascular disease (CVD). Several trials are being conducted, as the effectiveness and economic impact of a FDC-based strategy may vary substantially between countries, given the varying influence of the health-care system within which the intervention is delivered. METHODS Individual patient data (IPD) will be provided by participating trials for combined IPD meta-analysis. RESULTS Primary outcomes will include self-reported current use of antiplatelet, statin, and combination (≥ 2) blood pressure lowering therapies at 12 months, and change in systolic blood pressure (SBP) and LDL cholesterol from baseline to 12 months. Non-inferiority margins of 3 mm Hg for SBP and 0.3 mmol/L for LDL cholesterol have been pre-specified. Secondary outcomes will include change in cholesterol fractions, diastolic blood pressure and creatinine from baseline to 12 months, quality of life, new onset diabetes mellitus, mortality (cardiovascular, non-cardiovascular and all cause) and a composite outcome of cardiovascular events (including all coronary heart disease events, heart failure events leading to death or requiring hospital admission, cerebrovascular events and peripheral arterial events). CONCLUSION The SPACE group of trials will assess, in a variety of healthcare settings, whether a FDC strategy for delivery of preventive medication has the potential to significantly improve prevention of cardiovascular disease in patients at high risk.

Effectiveness of a Binocular Video Game vs Placebo Video Game for Improving Visual Functions in Older Children, Teenagers, and Adults With Amblyopia: A Randomized Clinical Trial

Importance Binocular amblyopia treatment using contrast-rebalanced stimuli showed promise in laboratory studies and requires clinical trial investigation in a home-based setting. Objective To compare the effectiveness of a binocular video game with a placebo video game for improving visual functions in older children and adults. Design, Setting, and Participants The Binocular Treatment of Amblyopia Using Videogames clinical trial was a multicenter, double-masked, randomized clinical trial. Between March 2014 and June 2016, 115 participants 7 years and older with unilateral amblyopia (amblyopic eye visual acuity, 0.30-1.00 logMAR; Snellen equivalent, 20/40-20/200) due to anisometropia, strabismus, or both were recruited. Eligible participants were allocated with equal chance to receive either the active or the placebo video game, with minimization stratified by age group (child, age 7 to 12 years; teenager, age 13 to 17 years; and adult, 18 years and older). Interventions Falling-blocks video games played at home on an iPod Touch for 1 hour per day for 6 weeks. The active video game had game elements split between eyes with a dichoptic contrast offset (mean [SD] initial fellow eye contrast, 0.23 [0.14]). The placebo video game presented identical images to both eyes. Main Outcomes and Measures Change in amblyopic eye visual acuity at 6 weeks. Secondary outcomes included compliance, stereoacuity, and interocular suppression. Participants and clinicians who measured outcomes were masked to treatment allocation. Results Of the 115 included participants, 65 (56.5%) were male and 83 (72.2%) were white, and the mean (SD) age at randomization was 21.5 (13.6) years. There were 89 participants (77.4%) who had prior occlusion. The mean (SD) amblyopic eye visual acuity improved 0.06 (0.12) logMAR from baseline in the active group (n = 56) and 0.07 (0.10) logMAR in the placebo group (n = 59). The mean treatment difference between groups, adjusted for baseline visual acuity and age group, was −0.02 logMAR (95% CI, −0.06 to 0.02; P = .25). Compliance with more than 25% of prescribed game play was achieved by 36 participants (64%) in the active group and by 49 (83%) in the placebo group. At 6 weeks, 36 participants (64%) in the active group achieved fellow eye contrast greater than 0.9 in the binocular video game. No group differences were observed for any secondary outcomes. Adverse effects included 3 reports of transient asthenopia. Conclusions and Relevance The specific home-based binocular falling-blocks video game used in this clinical trial did not improve visual outcomes more than the placebo video game despite increases in fellow eye contrast during game play. More engaging video games with considerations for compliance may improve effectiveness. Trial Registration anzctr.org.au Identifier: ACTRN12613001004752

Polypill-based therapy likely to reduce ethnic inequities in use of cardiovascular preventive medications: Findings from a pragmatic randomised controlled trial

Objective The purpose of this study was to investigate the consistency of the proportional effect of fixed-dose combination therapy (the ‘polypill’) on the use of recommended cardiovascular preventative medications among indigenous Māori and non-indigenous adults in New Zealand. Methods We randomised Māori and non-Māori primary care patients at high risk of cardiovascular disease (either because of a prior event or with an estimated 5-year risk of a first event of at least 15%) to a polypill (containing aspirin, statin and two antihypertensives) or usual care for a minimum of 12 months. All patients had indications for all polypill components according to their general practitioner, and all medications (including the polypill) were prescribed by the patient’s general practitioner and dispensed at community pharmacies. The main outcome for this study was the use of all recommended medications (antiplatelet, statin and two antihypertensives) at 12 months. Heterogeneity in the effect of polypill-based care compared with usual care on this outcome by ethnicity was assessed by logistic regression. Results Baseline use of recommended medications was 36% (93/257) among Māori and 51% (130/156) among non-Māori participants. Polypill-based care was associated with an increase in the use of recommended medications among Māori (relative risk [RR]: 1.87; 95% confidence interval [CI]: 1.50–2.34) and non-Māori (RR: 1.66; 95% CI: 1.37–2.00) when compared with usual care at 12 months, and there was no statistically significant heterogeneity in this outcome by ethnicity (p = 0.92). Conclusion Polypill-based care is likely to reduce absolute inequities between Māori and non-Māori in the use of recommended cardiovascular preventative medications given baseline absolute differences and the consistency of the proportional effect of this intervention by ethnicity in this pragmatic trial in primary care.

Do polypills lead to neglect of lifestyle risk factors? Findings from an individual participant data meta-analysis among 3140 patients at high risk of cardiovascular disease.

Aim The aim of this study was to investigate whether polypill-based care for the prevention of cardiovascular disease (CVD) is associated with a change in lifestyle risk factors when compared with usual care, among patients with CVD or high calculated cardiovascular risk. Methods We conducted an individual participant data meta-analysis of three trials including patients from Australia, England, India, Ireland, the Netherlands and New Zealand that compared a strategy using a polypill containing aspirin, statin and antihypertensive therapy with usual care in patients with a prior CVD event or who were at high risk of their first event. Analyses investigated any differential effect on anthropometric measures and self-reported lifestyle behaviours. Results Among 3140 patients (75% male, mean age 62 years and 76% with a prior CVD event) there was no difference in lifestyle risk factors in those randomised to polypill-based care compared with usual care over a median of 15 months, either across all participants combined, or in a range of subgroups. Furthermore, narrow confidence intervals (CIs) excluded any major effect; for example differences between the groups in body mass index was −0.1 (95% CI −0.2 to 0.1) kg/m2, in weekly duration of moderate intensity physical activity was −2 (−26 to 23) minutes and the proportion of smokers was 16% vs 17% (RR 0.98, 0.84 to 1.15) at the end of trial. Discussion This analysis allays concern that polypill-based care may lead to neglect of lifestyle risk factors, at least among high-risk patients. Maximally effective preventive approaches should address lifestyle factors alongside pharmaceutical interventions, as recommended by major international guidelines.

Recruiting equal numbers of indigenous and non-indigenous participants to a ‘polypill’ randomized trial

IntroductionMāori are disproportionately affected by cardiovascular disease (CVD), which is the main reason for the eight year difference in life expectancy between Māori and non-Māori. The primary care-based IMPACT (IMProving Adherence using Combination Therapy) trial evaluates whether fixed dose combination therapy (a “polypill”) improves adherence to guideline-based therapy compared with current care among people at high risk of CVD. Interventions shown in trials to be effective do not necessarily reduce ethnic disparities, and may in fact widen them. Indigenous populations with poorer health outcomes are often under-represented in trials so the effect of interventions cannot be assessed for them, specifically. Therefore, the IMPACT trial aimed to recruit as many Māori as non-Māori to assess the consistency of the effect of the polypill. This paper describes the methods and results of the recruitment strategy used to achieve this.MethodsExperienced Māori researchers were involved in trial governance throughout trial development and conduct. The trial Steering Committee included leading Māori researchers and was committed to equal recruitment of Māori and non-Māori. Additional funding and Māori research nurses were sought to allow home-based assessment, establishment of the relationship between research nurse and participant, more family involvement prior to enrollment, continuity of the research nurse-participant relationship, and acknowledgement of other Māori culturally important procedures, interactions, language and manners. Primary care practices with high enrollment of Māori were targeted, with over-sampling of potentially eligible Māori patients, lower thresholds for screening of Māori and 6 months continued Māori recruitment after non-Māori recruitment had finished.ResultsA total of 257 Māori and 256 non-Māori participants were randomized. Four Māori and eight non-Māori participants were randomized per research nurse per month. Potentially eligible Māori were more likely than non-Māori to proceed to subsequent stages of recruitment. Differences between randomized Māori and non-Māori were evident (e.g. Maori were less likely to have established coronary artery disease).ConclusionsRecruitment of equal numbers of indigenous and non-indigenous participants is possible if it is prioritised, adequately resourced and self-determination is supported.Trial registrationThe trial is registered with the Australian New Zealand Clinical Trial Registry ACTRN12606000067572

Optical treatment of amblyopia in older children and adults is essential prior to enrolment in a clinical trial

Optical treatment alone can improve visual acuity (VA) in children with amblyopia, thus clinical trials investigating additional amblyopia therapies (such as patching or videogames) for children require a preceding optical treatment phase. Emerging therapies for adult patients are entering clinical trials. It is unknown whether optical treatment is effective for adults with amblyopia and whether an optical correction phase is required for trials involving adults.

The impact of a point-of-care testing device on CVD risk assessment completion in New Zealand primary-care practice: A cluster randomised controlled trial and qualitative investigation.

Objectives To assess the effect of a point of care (POC) device for testing lipids and HbA1c in addition to testing by community laboratory facilities (usual practice) on the completion of cardiovascular disease (CVD) risk assessments in general practice. Methods We conducted a pragmatic, cluster randomised controlled trial in 20 New Zealand general practices stratified by size and rurality and randomised to POC device plus usual practice or usual practice alone (controls). Patients aged 35–79 years were eligible if they met national guideline criteria for CVD risk assessment. Data on CVD risk assessments were aggregated using a web-based decision support programme common to each practice. Data entered into the on-line CVD risk assessment form could be saved pending blood test results. The primary outcome was the proportion of completed CVD risk assessments. Qualitative data on practice processes for CVD risk assessment and feasibility of POC testing were collected at the end of the study by interviews and questionnaire. The POC testing was supported by a comprehensive quality assurance programme. Results A CVD risk assessment entry was recorded for 7421 patients in 10 POC practices and 6217 patients in 10 control practices; 99.5% of CVD risk assessments had complete data in both groups (adjusted odds ratio 1.02 [95%CI 0.61–1.69]). There were major external influences that affected the trial: including a national performance target for CVD risk assessment and changes to CVD guidelines. All practices had invested in systems and dedicated staff time to identify and follow up patients to completion. However, the POC device was viewed by most as an additional tool rather than as an opportunity to review practice work flow and leverage the immediate test results for patient education and CVD risk management discussions. Shortly after commencement, the trial was halted due to a change in the HbA1c test assay performance. The trial restarted after the manufacturing issue was rectified but this affected the end use of the device. Conclusions Performance incentives and external influences were more powerful modifiers of practice behaviours than the POC device in relation to CVD risk assessment completion. The promise of combining risk assessment, communication and management within one consultation was not realised. With shifts in policy focus, the utility of POC devices for patient engagement in CVD preventive care may be demonstrated if fully integrated into the clinical setting. Trial registration Australian New Zealand Clinical Trials Registry ACTRN12613000607774