Vanessa Selak

Integrated electronic decision support increases cardiovascular disease risk assessment four fold in routine primary care practice

Background A decade of cardiovascular disease (CVD) risk-based guidelines, education programmes and widespread availability of paper-based risk prediction charts have not significantly influenced targeting of CVD risk management in New Zealand primary care practice. A web-based decision support system (PREDICT-CVD), integrated with primary care electronic medical record software was developed as one strategy to address this problem. Methods A before-after audit of 3564 electronic patient records assessed the impact of electronic decision support on documentation of CVD risk and CVD risk factors. Participants were patients meeting national guideline criteria for CVD risk assessment, registered with 84/107 (78.5%) general practitioners (GPs) in one large primary care organization who used electronic patient medical records, and had PREDICT-CVD installed. The GPs received group education sessions, practice IT support and a small risk assessment payment. Four weeks of practice visit records were audited from 1 month after installation of PREDICT-CVD, and during the same 4-week period 12 months earlier. Results Less than 3% of eligible patients had a documented CVD risk before PREDICT-CVD installation. This increased four-fold (RR = 4.0; 95% confidence interval 2.4–6.5) after installation and documentation of all relevant CVD risk factors also increased significantly. Conclusion Documentation of CVD risk in primary care patient records in New Zealand is negligible, despite being recommended as a prerequisite for targeted treatment for over 10 years, suggesting that previous strategies were ineffective. We demonstrate that integrated electronic decision support can quadruple CVD risk assessment in just one cycle of patient visits.

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.

The Efficacy and Tolerability of ‘Polypills’: Meta-Analysis of Randomised Controlled Trials

Background To assess the blood pressure and lipid-lowering efficacy and tolerability of ‘polypills’ used in cardiovascular disease prevention trials. Methodology/Principal Findings Systematic review and meta-analysis. Search strategy: The Cochrane Central Register of Controlled Trials, Medline, and PubMed databases were searched for eligible trials. Study inclusion criteria: Randomised controlled trials of at least six weeks duration, which compared a ‘polypill’ (that included at least one anti-hypertensive and one lipid-lowering medication) with a placebo (or one active component). Outcome measures: Change from baseline in systolic and diastolic blood pressures, and total and LDL-cholesterol; discontinuation of study medication and reported adverse effects. Of 44 potentially eligible studies, six trials (including 2,218 patients without previous cardiovascular disease) fulfilled the inclusion criteria. Compared with placebo, ‘polypills’ reduced systolic blood pressure by −9.2 mmHg (95% confidence interval (CI): −13.4, −5.0) diastolic blood pressure by −5.0 mmHg (95%CI: −7.4, −2.6), total cholesterol by −1.22 mmol/L (95%CI: −1.60, −0.84) and LDL-cholesterol by −1.02 mmol/L (95%CI: −1.37, −0.67). However, those taking a ‘polypill’ (vs. placebo or component) were more likely to discontinue medication (20% vs 14%) (Odds ratio: 1.5 (95% CI: 1.2, 1.9)). There was no significant difference in reported adverse effects amongst those on a ‘polypill’ (36% vs. 28%) (OR: 1.3 (95%CI: 0.7, 2.5)). There was high statistical heterogeneity in comparisons for blood pressure and lipid-lowering but use of random-effects and quality-effects models produced very similar results. Conclusions/Significance Compared with placebo, the ‘polypills’ reduced blood pressure and lipids. Tolerability was lower amongst those on ‘polypills’ than those on placebo or one component, but differences were moderate. Effectiveness trials are needed to help clarify the status of ‘polypills’ in primary care and prevention strategies.

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.

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.

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

Polypills for the secondary prevention of cardiovascular disease: effective in improving adherence but are they safe?

International guidelines recommend blood pressure-lowering therapy, statins and aspirin for people who have had a cardiovascular event but use of these medications is low, particularly for lower income countries. Clinical trials have demonstrated that combining these medications into a single pill or capsule (a ‘polypill’) improves adherence, systolic blood pressure and low density lipoprotein cholesterol compared with usual care in secondary prevention. Uptake of polypill-based care has been underwhelming, possibly due to safety concerns. Overall, results from the clinical trials of polypill use among people who have had a cardiovascular event show no immediate safety concerns. Increased use and adherence to medications will always be associated with side effects however use within a combination medication has not been shown to be any less safe than individual component medications. Research investigating the relative consequences of nonadherence to a polypill compared with individual components would be useful.

Fixed Low-Dose Triple Combination Antihypertensive Medication vs Usual Care for Blood Pressure Control in Patients With Mild to Moderate Hypertension in Sri Lanka: A Randomized Clinical Trial

Importance Poorly controlled hypertension is a leading global public health problem requiring new treatment strategies. Objective To assess whether a low-dose triple combination antihypertensive medication would achieve better blood pressure (BP) control vs usual care. Design, Setting, and Participants Randomized, open-label trial of a low-dose triple BP therapy vs usual care for adults with hypertension (systolic BP >140 mm Hg and/or diastolic BP >90 mm Hg; or in patients with diabetes or chronic kidney disease: >130 mm Hg and/or >80 mm Hg) requiring initiation (untreated patients) or escalation (patients receiving monotherapy) of antihypertensive therapy. Patients were enrolled from 11 urban hospital clinics in Sri Lanka from February 2016 to May 2017; follow-up ended in October 2017. Interventions A once-daily fixed-dose triple combination pill (20 mg of telmisartan, 2.5 mg of amlodipine, and 12.5 mg of chlorthalidone) therapy (n = 349) or usual care (n = 351). Main Outcomes and Measures The primary outcome was the proportion achieving target systolic/diastolic BP (<140/90 mm Hg or <130/80 mm Hg in patients with diabetes or chronic kidney disease) at 6 months. Secondary outcomes included mean systolic/diastolic BP difference during follow-up and withdrawal of BP medications due to an adverse event. Results Among 700 randomized patients (mean age, 56 years; 58% women; 29% had diabetes; mean baseline systolic/diastolic BP, 154/90 mm Hg), 675 (96%) completed the trial. The triple combination pill increased the proportion achieving target BP vs usual care at 6 months (70% vs 55%, respectively; risk difference, 12.7% [95% CI, 3.2% to 22.0%]; P < .001). Mean systolic/diastolic BP at 6 months was 125/76 mm Hg for the triple combination pill vs 134/81 mm Hg for usual care (adjusted difference in postrandomization BP over the entire follow-up: systolic BP, −9.8 [95% CI, −7.9 to −11.6] mm Hg; diastolic BP, −5.0 [95% CI, −3.9 to −6.1] mm Hg; P < .001 for both comparisons). Overall, 419 adverse events were reported in 255 patients (38.1% for triple combination pill vs 34.8% for usual care) with the most common being musculoskeletal pain (6.0% and 8.0%, respectively) and dizziness, presyncope, or syncope (5.2% and 2.8%). There were no significant between-group differences in the proportion of patient withdrawal from BP-lowering therapy due to adverse events (6.6% for triple combination pill vs 6.8% for usual care). Conclusions and Relevance Among patients with mild to moderate hypertension, treatment with a pill containing low doses of 3 antihypertensive drugs led to an increased proportion of patients achieving their target BP goal vs usual care. Use of such medication as initial therapy or to replace monotherapy may be an effective way to improve BP control. Trial Registration anzctr.org.au Identifier: ACTRN12612001120864; slctr.lk Identifier: SLCTR/2015/020