John Urquhart

Adherence to prescribed antihypertensive drug treatments: longitudinal study of electronically compiled dosing histories

Objective To describe characteristics of dosing history in patients prescribed a once a day antihypertensive medication. Design Longitudinal database study. Setting Clinical studies archived in database for 1989-2006. Participants Patients who participated in the studies whose dosing histories were available through electronic monitoring. Main outcome measures Persistence with prescribed antihypertensive treatment and execution of their once a day drug dosing regimens. Results The database contained dosing histories of 4783 patients with hypertension. The data came from 21 phase IV clinical studies, with lengths ranging from 30 to 330 days and involving 43 different antihypertensive drugs, including angiotensin II receptor blockers (n=2088), calcium channel blockers (n=937), angiotensin converting enzyme inhibitors (n=665), β blockers (n=195), and diuretics (n=155). About half of the patients who were prescribed an antihypertensive drug had stopped taking it within one year. On any day, patients who were still engaged with the drug dosing regimen omitted about 10% of the scheduled doses: 42% of these omissions were of a single day’s dose, whereas 43% were part of a sequence of several days (three or more days—that is, drug “holidays”). Almost half of the patients had at least one drug holiday a year. The likelihood that a patient would discontinue treatment early was inversely related to the quality of his or her daily execution of the dosing regimen. Conclusions Early discontinuation of treatment and suboptimal daily execution of the prescribed regimens are the most common facets of poor adherence with once a day antihypertensive drug treatments. The shortfalls in drug exposure that these dosing errors create might be a common cause of low rates of blood pressure control and high variability in responses to prescribed antihypertensive drugs.

A new taxonomy for describing and defining adherence to medications.

Interest in patient adherence has increased in recent years, with a growing literature that shows the pervasiveness of poor adherence to appropriately prescribed medications. However, four decades of adherence research has not resulted in uniformity in the terminology used to describe deviations from prescribed therapies. The aim of this review was to propose a new taxonomy, in which adherence to medications is conceptualized, based on behavioural and pharmacological science, and which will support quantifiable parameters. A systematic literature review was performed using MEDLINE, EMBASE, CINAHL, the Cochrane Library and PsycINFO from database inception to 1 April 2009. The objective was to identify the different conceptual approaches to adherence research. Definitions were analyzed according to time and methodological perspectives. A taxonomic approach was subsequently derived, evaluated and discussed with international experts. More than 10 different terms describing medication-taking behaviour were identified through the literature review, often with differing meanings. The conceptual foundation for a new, transparent taxonomy relies on three elements, which make a clear distinction between processes that describe actions through established routines (Adherence to medications, Management of adherence) and the discipline that studies those processes (Adherence-related sciences). Adherence to medications is the process by which patients take their medication as prescribed, further divided into three quantifiable phases: Initiation, Implementation and Discontinuation. In response to the proliferation of ambiguous or unquantifiable terms in the literature on medication adherence, this research has resulted in a new conceptual foundation for a transparent taxonomy. The terms and definitions are focused on promoting consistency and quantification in terminology and methods to aid in the conduct, analysis and interpretation of scientific studies of medication adherence.

Identification and assessment of adherence-enhancing interventions in studies assessing medication adherence through electronically compiled drug dosing histories: a systematic literature review and meta-analysis.

BackgroundNon-adherence to medications is prevalent across all medical conditions that include ambulatory pharmacotherapy and is thus a major barrier to achieving the benefits of otherwise effective medicines.ObjectiveThe objective of this systematic review was to identify and to compare the efficacy of strategies and components thereof that improve implementation of the prescribed drug dosing regimen and maintain long-term persistence, based on quantitative evaluation of effect sizes across the aggregated trials.Data sourcesMEDLINE, EMBASE, CINAHL, the Cochrane Library, and PsycINFO were systematically searched for randomized controlled trials that tested the efficacy of adherence-enhancing strategies with self-administered medications. The searches were limited to papers in the English language and were included from database inception to 31 December 2011.Study selectionOur review included randomized controlled trials in which adherence was assessed by electronically compiled drug dosing histories. Five thousand four hundred studies were screened. Eligibility assessment was performed independently by two reviewers. A structured data collection sheet was developed to extract data from each study.Study appraisal and synthesis methodsThe adherence-enhancing components were classified in eight categories. Quality of the papers was assessed using the criteria of the Cochrane Handbook for Systematic Reviews of Interventions guidelines to assess potential bias. A combined adherence outcome was derived from the different adherence variables available in the studies by extracting from each paper the available adherence summary variables in a pre-defined order (correct dosing, taking adherence, timing adherence, percentage of adherent patients). To study the association between the adherence-enhancing components and their effect on adherence, a linear meta-regression model, based on mean adherence point estimates, and a meta-analysis were conducted.ResultsSeventy-nine clinical trials published between 1995 and December 2011 were included in the review. Patients randomized to an intervention group had an average combined adherence outcome of 74.3xa0%, which was 14.1xa0% higher than in patients randomized to the control group (60.2xa0%). The linear meta-regression analysis with stepwise variable selection estimated an 8.8xa0% increase in adherence when the intervention included feedback to the patients of their recent dosing history (EM-feedback) (pxa0<xa00.01) and a 5.0xa0% increase in adherence when the intervention included a cognitive-educational component (pxa0=xa00.02). In addition, the effect of interventions on adherence decreased by 1.1xa0% each month. Sensitivity analysis by selecting only high-quality papers confirmed the robustness of the model. The random effects model in the meta-analysis, conducted on 48 studies, confirmed the above findings and showed that the improvement in adherence was 19.8xa0% (95xa0% CI 10.7–28.9xa0%) among patients receiving EM-feedback, almost double the improvement in adherence for studies that did not include this type of feedback [10.3xa0% (95xa0% CI 7.5–13.1xa0%)] (pxa0<xa00.01). The improvement in adherence was 16.1xa0% (95xa0% CI 10.7–21.6xa0%) in studies that tested cognitive-educational components versus 10.1xa0% (95xa0% CI 6.6–13.6xa0%) in studies that did not include this type of intervention (pxa0=xa00.04). Among 57 studies measuring clinical outcomes, only 8 reported a significant improvement in clinical outcome.LimitationsDespite a common measurement, the meta-analysis was limited by the heterogeneity of the pooled data and the different measures of medication adherence. The funnel plot showed a possible publication bias in studies with high variability of the intervention effect.ConclusionsNotwithstanding the statistical heterogeneity among the studies identified, and potential publication bias, the evidence from our meta-analysis suggests that EM-feedback and cognitive-educational interventions are potentially effective approaches to enhance patient adherence to medications. The limitations of this research highlight the urgent need to define guidelines and study characteristics for research protocols that can guide researchers in designing studies to assess the effects of adherence-enhancing interventions.

Understanding forgiveness: minding and mining the gaps between pharmacokinetics and therapeutics.

The usual objective during long‐term pharmacotherapy is, in large part, to maintain continuity of action of the prescribed drug(s). Continuity of action arises from the continuity of execution of a prescribed dosing regimen that is pharmacologically sound in dose quantity and interval between successive doses. Interruptions in dosing can interrupt drug action, but the consequences vary according to length of interruption, drug, drug formulation, length of the patients prior exposure to the drug, and the disease being treated.

Rate-controlled Drug Dosage

SummaryPractical methods for rate-controlled drug dosing are bringing new capabilities to both therapeutics and experimental pharmacology, arising from the ability to maintain drug concentrations in plasma at desired levels for extended periods. Such dosing can prolong the duration of drug action and help to separate the beneficial effects of a drug from its undesirable actions. The new modes of drug release are distinguished from conventional sustained-release, depot, or slow-release products by the ability to specify precisely the release rate and duration in vivo on the basis of simple in vitro tests.Rate-controlled forms designed for research use now permit the ‘isonemic’ testing of drug effects — i.e. testing with drug concentrations in plasma maintained at constant levels. Thus, concentration-effect relationships become easier to discern than when testing is done with ordinary bolus dosage forms, which produce constantly fluctuating concentrations. Such testing appears to be basic in the effort to define the optimal regimen for many drugs. Published studies of various designs indicate that the usual regimens for a number of familiar drugs are sub-optimal, but can be improved with rate-controlled dosage.A variety of technologies are available for rate-controlled drug dosage. Infusion pumps and controllers are now widely used in hospital care, and demonstrate that rate-controlled delivery can assure the safe and effective use, for long durations, of drugs with narrow therapeutic indices and short half-lives, for example dopamine, nitroprusside, and dobutamine. More recently, rate-control is being incorporated into oral, transdermal, and various locally acting Pharmaceuticals for use in routine outpatient therapy. 2 systemically acting, rate-controlled products are now available for clinical use: a matrix form of oral theophylline that has made that drug safer to use than previously; and a transdermal scopolamine product that prevents motion sickness without the objectionable parasympatholytic actions of this drug. Rate-controlled products available for local use include an ocular insert that delivers pilocarpine at a low steady rate for I week after each administration and a T-shaped intrauterine device which continually delivers progesterone.A decade of intensive technical development preceded the availability of rate-controlled products. For the ocular, transdermal and intrauterine products presently available, the mechanism employed is drug diffusion through dense or microporous polymeric membranes. Membrane-controlled osmotic pumping of drug solution is the basis for other rate-controlled dosage forms for both laboratory and therapeutic use. There is a series of capsule-sized, 1- or 2-week implants that provide rate-controlled drug administration in laboratory animals. For clinical research, the same osmotic technology is used in drug delivery modules administered orally or rectally. For therapeutic use, a tablet-sized oral dosage form is in fact a small osmotic pump, releasing drug at a constant rate over 12 to 18 hours. Clinical trials with a number of major drugs in this form are now underway.One important contribution of these and other developments is to broaden the basis for selecting new chemical entities as candidates for therapeutic use: short half-life agents, as well as those with relatively narrow therapeutic indices, become practical for development as pharmaceuticals. Another contribution is to render safer or more effective the use of older drugs that have troublesome side effects or inconvenient regimens. Rate-controlled drug dosage is certainly no panacea; although the clinical application of this technique is still in its infancy, it appears to offer a new approach for improving the selectivity and duration of action of many drugs to enhance their efficacy, safety, and convenience.

Estimation of the comparative therapeutic superiority of QD and BID dosing regimens, based on integrated analysis of dosing history data and pharmacokinetics

Once-daily dosing almost invariably shows a slightly higher percentage of prescribed doses taken than does twice-daily dosing. Many pharmaceutical scientists, regulators, and prescribers have considered this finding to signify the therapeutic superiority of once-daily dosing. The therapeutically more relevant question, however, is not the percentage of prescribed doses taken but the comparative impact of missed doses on the pharmacologic effects of a drug under the two dosing regimens. A key point in this regard is that the pharmacokinetic equivalent of a single missed once-daily dose is 2–3 sequentially omitted twice-daily doses. Thus, an important parameter in comparing the two regimens is the probability of two or three twice-daily doses being sequentially omitted, versus the probability of missing a single once-daily dose. Our data indicate that the probability of sequential omission of 2–3 twice daily doses is half the probability of omission of a single once-daily dose. For that reason, a twice-daily regimen could prove to be superior to a once-daily regimen in maintaining drug concentrations within a therapeutically desirable range. A more important consideration, however, is to maintain not just the concentration of drug in plasma, but the drug’s therapeutic action. The duration of therapeutic drug action following a last-taken dose is not only drug-specific, but also, for some drug, dependent on the pharmacodynamic properties. Judging the comparative superiority of one dosing regimen over another requires knowledge of the drug’s duration action after a last-taken dose, plus knowledge of the comparative probabilities of the various patterns of dose omission. When applied to HIV protease inhibitors, a twice-daily regimen appears to be better than an once-daily regimen in maintaining therapeutically effective drug actions.

Effects on blood pressure and cardiovascular risk of variations in patients' adherence to prescribed antihypertensive drugs: role of duration of drug action.

Aim:u2002 To determine the effects of imperfect adherence (i.e. occasionally missing prescribed doses), and the influence of rate of loss of antihypertensive effect during treatment interruption, on the predicted clinical effectiveness of antihypertensive drugs in reducing mean systolic blood pressure (SBP) and cardiovascular disease (CVD) risk.

The Drugs Not Taken

![Figure][1] nnCREDIT: JUPITER IMAGESnnA missing element in current conceptions of personalized medicine, including the Policy Forum by S. H. Katsanis et al. (“A case study of personalized medicine,” 4 April, p. [53][2]), is data on the patients adherence to prescribed drug dosing regimens

Commentary on “A Framework for Quantifying the Influence of Adherence and Dose Individualization”

Drugs that provide long durations of action after a last‐taken dose are said to be “forgiving,” as they allow the patient a degree of latitude in the timing of sequential doses. New research, by Assawasuwannakit et al.,1 based on exemplary methods, enriches the pharmacometric analysis of forgiveness, which for several decades had been a simply descriptive reminder that the beneficial actions of some drugs can continue for hours or days after the disappearance of detectable drug.

Variability in Exposure to NSAIDs in Relation to Safety

Exposure to NSAIDs is highly variable. Leufkens found it so by auditing prescription refills relative to dosing instructions in patients who consistently used the same pharmacy: only 5% of patients prescribed NSAIDs had refill patterns commensurate with long-term consistency in daily intake of drug; a further 20% had refill intervals indicative of their taking ca. half the doses prescribed; the other 75% had very long refill intervals indicative of episodic use only (cf. 1). Recently, de Klerk and van der Linden used electronic monitors (MEMS®) in a 1-year, blinded trial in which patients were randomised between fixed, once-daily doses of piroxicam or tenoxicam. Only a small minority of patients were consistent in maintaining the prescribed once-daily regimen. An extra dose was taken on occasional days, but dose omissions accounted for most of the deviations from the regimen, in a between-patient spectrum ranging from occasional to frequent omissions. Of the omissions, about two thirds occurred singly, with the remainder occurring sequentially, creating runs of no-dose days of varying lengths (drug ‘holidays’). Patterns were similar for the two agents.