Achieving optimal adherence to medical therapy by telehealth: findings from the ORBITA medication adherence sub-study
D Thompson1,2
R Al-Lamee1
M Foley1
H M Dehbi3
S Thom1
J E Davies1
D P Francis1
P Patel4, 5,6
P Gupta4,5,6
On behalf of the ORBITA Investigators*.
  1. National Heart and Lung Institute, Imperial College London
  2. Institute of Cardiovascular Science, University College London
  3. Comprehensive Clinical Trials Unit at UCL, University College London
  4. Department of Chemical Pathology and Metabolic Diseases, University Hospitals of Leicester
  5. Department of Cardiovascular Sciences, University of Leicester
  6. NIHR Leicester Biomedical Research Unit in Cardiovascular Disease
Corresponding Author:
Dr. David Thompson
UCL Institute of Cardiovascular Science
Gower Street
London WC1E 6BT
Email: dm.thompson@ucl.ac.uk

Abstract

Introduction

The ORBITA trial of PCI versus a placebo procedure for patients with stable angina was conducted across 6 sites in the United Kingdom via home monitoring and telephone consultations. Patients underwent detailed assessment of medication adherence which allowed us to measure the efficacy of the implementation of the optimisation protocol and interpretation of the main trial endpoints.

Methods

Prescribing data were collected throughout the trial. Self-reported adherence was assessed, and urine samples collected at pre-randomisation and at follow-up for direct assessment of adherence using HPLC MS/MS.

Results

Self-reported adherence was >96% for all drugs in both treatment groups at both stages. The percentage of samples in which drug was detected at pre-randomisation and at follow-up in the PCI vs. OMT groups respectively was: clopidogrel, 96% vs. 90% and 98% vs. 94%; atorvastatin, 95% vs. 92% and 92% vs. 91%; perindopril, 95% vs. 97% and 85% vs. 100%; bisoprolol, 98% vs. 99% and 96% vs. 97%; amlodipine, 99% vs. 99% and 94% vs. 96%; nicorandil, 98% vs. 96% and 94% vs. 92%; ivabradine, 100% vs. 100% and 100% vs. 100%; and ranolazine, 100% vs. 100% and 100% vs. 100%.

Conclusions

Adherence levels were high throughout the study when quantified by self-reporting methods and similarly high proportions of drug were detected by urinary assay. The results indicate successful implementation of the optimisation protocol delivered by telephone, an approach that could serve as a model for treatment of chronic conditions, particularly as consultations are increasingly conducted online.

Introduction

The ORBITA (Objective Randomized Blinded Investigation with optimal medical Therapy of Angioplasty for stable angina) trial showed that the increment in exercise capacity following percutaneous coronary intervention (PCI) was lower than expected and not statistically different to the effect of a placebo procedure in patients with stable coronary artery disease (CAD) receiving optimal medical therapy (OMT)1. Patients were eligible for enrolment if they had single-vessel, angiographically-significant coronary artery disease for which PCI was clinically indicated on a pre-trial invasive coronary angiogram. Following enrolment patients commenced a 6-week medication optimisation phase during which their risk reduction and anti-anginal medication was optimised in accordance with clinical guidelines2. Some commentators highlighted that optimisation of medical therapy in ORBITA was intensive and could not be easily replicated in clinical practice3. Indeed, in clinical practice, guideline-directed medication optimisation prior to PCI is variable. Analysis of the CathPCI registry in the USA in 2011 showed that OMT (defined as aspirin, statin, a beta-blocker or documented intolerance) was achieved in just 44% of patients prior to PCI4. A Canadian registry study in 2014 showed that OMT (defined in this instance as statin, beta-blocker, and either an angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker) was achieved in only 33.9% of patients prior to PCI5. ORBITA was conducted in the UK, where targets for heart rate and blood pressure were achieved in less than 50% of patients when optimising anti-anginal therapy prior to elective PCI6. A single consultant cardiologist and research fellow (RAL) conducted the 6-week medication optimisation in telephone clinics one to three times per week. The trial patients were expected to achieve optimisation in a short, intensive period to ensure that patients did not experience undue delays in accessing PCI compared to usual clinical care. In addition to documentation of patterns of prescribing, patients’ self-reported adherence to therapy and urine samples for direct detection of urinary metabolites were collected. In this way the efficacy of the OMT protocol and possible treatment imbalances between the groups that could affect the main study endpoints could be assessed. Quantifying adherence in detail also allowed evaluation of any changes in medication taking behaviour that may have arisen following PCI.

Methods

Eligibility, study design and organisation.

The eligibility criteria for ORBITA and study sites have been described elsewhere7. Patients with stable coronary artery disease attributable to single-vessel coronary artery disease were eligible to participate. Detailed medication prescribing and adherence assessments were carried out on all ORBITA participants. Once enrolled patients entered the medication optimisation phase. Following this 6-week phase, patients travelled to the study coordinating centre, Imperial College Healthcare NHS Trust, London, UK, for further clinical assessment including cardiopulmonary exercise testing and dobutamine stress echocardiography. The research protocol coronary angiogram was then carried out at their local centre, during which they were randomised to either PCI or a placebo procedure. After 6-weeks of blinded follow-up patients returned for repeat testing and study unblinding at the coordinating centre. A favourable review of the study protocol was obtained from the London Central Research Ethics Committee and the trial received support from the NIHR Imperial Biomedical Research Centre, Foundation for Circulatory Health, Imperial College Healthcare Charity, Philips Volcano, NIHR Barts Biomedical Research Centre.

Personnel

Two research fellows were essential to the study team and had distinct predefined roles. The unblinded fellow (RAL) provided support in the catheterisation laboratory for the randomisation procedure and in doing so became unblinded to the randomised treatment assignment. The blinded fellow (DT) remained so throughout the study and performed all pre-randomisation and follow-up tests. RAL was based primarily in the coronary catheter laboratory and was responsible for enrolling new patients to the study as well as providing support to the site teams. RAL was the main clinical point of contact for patients from enrolment and throughout the medication optimisation phase until after randomisation. This enabled RAL to engage patients at enrolment and give instructions regarding standardised recording of home blood pressure, provide medication prescriptions and resolve issues with dispensing. RAL scheduled weekly telephone reviews with patients for introduction and titration of cardiovascular preventive and anti-anginal therapy. DT met patients for the first time at the pre-randomisation assessment visit in London and became the main clinical point of contact for patients in the blinded follow-up period. DT was not involved in medication optimisation but carried out a final check of protocol adherence before the patients proceeded to randomisation. The authors confirm that the PI for this study is Professor Darrel Francis and that he had direct clinical responsibility for patients.

Optimisation of medical therapy

At the enrolment assessment current medications were recorded before commencing the medical optimisation phase. Medications and doses were entered on the study electronic case report form and patients were provided with a home blood pressure monitor, an individualised prescription for optimised administration of medications, counselling regarding medication adherence and were asked to perform daily home measurements. Medications were then optimised during clinician assessments with RAL one to three times per week, in accordance with the study protocol.

Endpoints

Self-reported adherence was assessed for each medication by asking each patient “How many days in the preceding week did you take this medication?”8 This was carried out at pre-randomisation and at follow-up. Direct assessment of medication adherence was carried out using high performance liquid chromatography-tandem mass spectrometry (HPLC MS/MS) for detection of protocol-directed medications (Table 1) in urine samples at both pre-randomisation and at follow-up stages. The HPLC MS/MS methodology has been previously described9. All adherence data were collected as pre-specified secondary study endpoints.

Analysis

We present descriptive statistics for prescribed drug as a percentage of number of patients at each stage, self-reported adherence scores and percentages of detected drug present in the tested samples.
Table 1 ORBITA medical therapy protocol drugs detectable by HPLC MS/MS