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*.
- National Heart and Lung Institute, Imperial College London
- Institute of Cardiovascular Science, University College London
- Comprehensive Clinical Trials Unit at UCL, University College London
- Department of Chemical Pathology and Metabolic Diseases, University
Hospitals of Leicester
- Department of Cardiovascular Sciences, University of Leicester
- 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