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. Author manuscript; available in PMC: 2014 Oct 30.
Published in final edited form as: AIDS Care. 2007 Jul;19(6):775–780. doi: 10.1080/09540120600708501

What is a missed dose? Implications for construct validity and patient adherence

A P SANKAR 1, D C NEVEDAL 1, S NEUFELD 1, M R LUBORSKY 1
PMCID: PMC4214549  NIHMSID: NIHMS637188  PMID: 17573598

Abstract

The construct ‘missed dose’ is central to many assessments of medication adherence. However, few studies have investigated how patients or clinicians conceptualize missed doses or the extent of the concordance or discordance between clinicians and patients. To address this gap we conducted semi-structured interviews with 45 seropositive African American adults taking HAART and 17 of their clinicians. Results reveal large variability in missed dose conceptions among both patients and physicians and significant differences between the two groups. Overall, patients reported a stricter definition of missed dose than did clinicians. Fifty-five percent of patients thought that a pill-taking delay of six hours beyond the prescribed dosing time constituted a missed dose, by comparison, only one physician agreed with this assessment. More than one-third of patients thought that the proper response to a missed dose would be to skip it altogether, but only about 12% of clinicians agreed. These findings have implications for the construct validity of self-report measures of adherence, for patient adherence behaviours based on missed dose conceptions and for patient-physician relationships and communication within the clinical environment.

Introduction

Accurate assessment of adherence is vital to clinical care of people with HIV and in research on medication efficacy as well as predictors and correlates of adherence behaviour. While considerable attention is directed to the validity of measurement techniques and technologies, less is devoted to a core construct in these measures: the notion of a ‘missed dose’. Nor is there shared agreement or guidelines on the proper action to take in response to a missed dose. Determining when a dose is missed affects the accurate measurement of adherence through self-report; it also has implications for adherence behaviour, due to patient beliefs regarding the appropriate response to a missed dose.

Background

Patient self-report measures of medication adherence are diverse. In slightly different ways, some asked for doses missed or skipped in the last 2–4 days (Chesney et al., 2000; Kimmerling et al., (2003); Moss et al., 2004; Oyugi et al., 2004; Wagner, 2002; Walsh et al., 2002; Weaver et al., 2005). Others asked about missed doses in the past 1–2 weeks (Golin et al., 2002; Miller et al., 2004; Powell-Cope et al., 2003) or queried the number of days in the past month in which at least one dose of each of their HIV medications was missed (Halkitis et al., 2003).

In all of the studies, the concept of missed dose is treated as unproblematic, leaving unquestioned possible differences in missed dose understandings. Some differences in patient understandings were reported. Murphy et al. (2000) reported that one-quarter of the patients felt they were adherent if they took their medication some time within a twenty-four hour period. Recently, Llabre et al. (2004) called for future studies to fix the time by which doses are missed to enhance comparability of adherence rates across measures. In this study we show conceptualizations of missed dose are issues not only of adherence measurement but also, we suggest, of clinical relevance.

Methods

Using a qualitative approach we identified the categories and reasoning patients and clinicians use when they talk about missed doses. Qualitative data are supplemented with sociodemographic and clinic data (medications, medical history) and standardized psychosocial measures.

Sample

The sample (N=45 patients, 17 clinicians) was drawn from a five-year longitudinal qualitative study of antiretroviral therapy adherence (N=120 African Americans with HIV; 30 clinicians providing their treatment). The sample for the study reported here consists of the first 45 participants enrolled in the parent study and all of the clinicians (N=17) providing their care. The sample was recruited from the infectious disease clinics of two inner city hospitals. The clinics’ combined census is approximately 2,800 and they serve a mix of Medicaid and privately insured patients.

Measures

Measures included a set of ten questions assessing the meaning of a missed dose, the time at which a late dose is considered missed, the appropriate response to a missed doses were not and whether missing doses was discussed with the physician. The development of questionnaire items was based on ‘side-talk’ recorded in interviews conducted in the parent study. Side-talk refers to the clarifications respondents make in answering interview questions; in this case the side-talk centered around the meaning of missing or skipping a dose (e.g. ‘I took it later than usual’). Information from drug package inserts helped determine the specific time intervals about which we queried respondents. The final instrument used structured and open-ended items and was administered to patients and clinicians.

Procedures

Interviews were conducted in respondents’ homes and in the clinicians’ offices and were tape recorded and transcribed verbatim. The transcripts were then coded and the results reviewed in team meetings. Simple statistical tests (chi-square, t-tests) were employed to determine relationships among study variables.

Findings

Sample characteristics

The patient sample was entirely African American and middle aged (mean age 41.5 years). More than one-half completed high school and one-quarter had some post-secondary education. Women comprised one-quarter of the sample. Three-fourths were unemployed. The clinician sample was 60% female, ranging in age from 27–62 years old.

Definition of a missed dose

When asked ‘What is a missed dose’, 30% of the patients stated that it was simply a dose not taken without describing its timing (e.g. ‘it means I didn’t take the dose at all’). A number of patients (36%) included a time element in their definitions, implicitly suggesting that if a dose is delayed for a particular length of time, then it is regarded as missed. For example, a missed dose means ‘I didn’t take it on schedule’ or ‘it has gone way beyond the time to take that particular dose’. For others, (11%) forgetting was part of their definition of missed dose: ‘that means you forgot to take your medicines’. Several patients (16%) said a missed dose represented a moral failing on their part, e.g. ‘you doing wrong, something’s going on’ or ‘for me I feel guilty. I don’t feel right’.

Responding to the same open-ended question, 35% of clinicians said that a missed dose was simply one that was not taken (‘any dose that was totally missed’). For an additional 41% of clinicians the timing of the dose was part of the definition. Twelve percent said a dose that is more than a day late is missed (‘a dose that is not taken on the calendar day it is prescribed’), 18% referenced the next dosing time (‘a dose that’s taken later than a half-life after its target time’) and 12% said a dose is missed if it is not taken within a short time of its schedule (‘greater than two hours late’). Several clinicians (18%) defined missed dose as what they consider to be a problematic general pattern of non-adherence (‘if they miss more than 10%’) (see Table I).

Table I.

Delay thresholds for missing a dose.

If pill-taking delay is … …then dose is missed
Patients (N= 45) Clinicians (N= 17)
at most 2 hours late 8 agree (18%) 0 agree
more than 2 but at most 6 hours late 15 agree (33%) 1 agrees (6%) (3 think it depends on Rx)
more than 6 but at most 12 hours late 10 agree (22%) 5 agree (29%) (2 think it depends on Rx)
more than 12 but at most 24 hours late 4 agree (9%) 1 agrees (6%)
more than 24 hours late 6 agree (13%) 3 agree (18%)
Question not asked/ missing data 2 2

Missed dose parameters

A focused set of questions was designed to explore the boundary between late and missed doses. Participants were asked to select the time period after which a late dose would be considered missed. Twenty-four percent of patients regarded more than two hours late as ‘missed’:

‘Two hours late is missed, that’s what the directions say.’

‘That’s doctor’s orders…it’s not good to take my medication past an hour after.’

A dose delayed for six hours was considered missed by an additional 31% of the patients, with little explanation:

‘After about four hours, as long as I’m within eight hours of the next dose.’

Several (11%) patients indicated that six hours late represents a dividing line between late and missed:

‘Six hours late is pushing it…wouldn’t go any more than two or maybe three hours.’

‘Six hours is a kind of a gray area.’

An additional 11% of patients agreed that a dose delayed for twelve hours late is missed, and again several (9%) patients viewed 12 hours late as a dividing line between late and missed. Except for one person (‘taking a dose late is delayed, not missed, whatever the length of time’) everyone regarded being a day late with taking a dose as having missed. However, several (13%) patients reported that more than 12 hours late and up to a day late was not missed:

‘I wouldn’t consider it a missed dose and my doctor’s told me it’s not a missed dose either (twelve hours late)’.

We compared the patients’ missed-dose time-frames to the number of pills they took per day, dosing frequency and composition of their HAART regimen. No relationship (p >0.05) was found. In contrast, no clinician considered two hours late a missed dose (compared to patients: chi-square=19.2; p <0.001). For one-half of the clinicians, six hours represented a dividing line between late and missed:

‘Six hours is getting there…that’s an iffy one.’

‘A missed dose is when it’s more than 50% of the time to your next dose.’

Six hours may be missed depending on the drug:

‘Drugs with a short half-life, it is probably important.’

Few (18%) clinicians reported that taking a dose anytime up to the next dosing time is okay (12 hours late if twice per day dosing schedule). Still others (18%) asserted that they would not regard a dose as missed if taken anytime during a calendar day.

Appropriate responses to a missed dose

We asked: ‘What do you do when you realize you have missed a dose?’. One-half (47%) of patients believed a missed dose should be taken immediately upon realizing it is missed; but they often stated it is dependent on how much time elapsed—patients wish to avoid taking pills ‘too close’ together. Generally, from the point of view of the patient, the midpoint between dosing times is the latest that a dose can be taken safely:

‘If beyond midpoint between doses, just let it go; take the next one, ok.’

‘Take if within time bracket; otherwise wait until next dose, I’ll go six (midway).’

This half-way rule was used by many patients when judging whether to skip a medication until the next dosing time. The strategy of some other patients was to take the missed dose as soon as possible but then stagger their next dosing times gradually getting back on schedule, making sure to leave an adequate time between doses:

‘Instructions from doctor, take as soon as possible, then not take the next one for eight hours.’

‘If six hours late, then take next day six hours late and gradually work back to regular schedule.’

Several patients (11%) stated that they took their dose if they remembered anytime during the day; otherwise they continue their regular schedule the next day. Over one-third (38%) of respondents said any missed dose should be skipped (wait until the next dosing time):

‘You’re supposed to wait until the next dose.’

‘I just miss it and then take it the next day.’

Of the patients who believe that a dose three hours late is missed, 86% reported they skip the dose and wait until the next dose to take the medication.

When asked: ‘What should patients do when they realize they have missed a dose?’ one-third (35%) of clinicians stated the dose should be taken as soon as the patient remembers it, without qualification:

‘Double up. Make up for it the next day.’

‘Most of the drugs don’t have cumulative toxicity so they can take it.’

One-half (53%) said it depends whether the dosing delay was within the timing window where it was safe to take the medication:

‘Within midway between the two doses we would usually have them take the meds; otherwise skip to the next dose.’

‘Take next scheduled dose if it’s farther away than that two hour window.’

However, no clinicians reported how their beliefs about dosing time-frames were moderated by medication regimens. Thus, similar to their patients, they relied heavily on rules of thumb, particularly a ‘halfway’ rule when judging the appropriate patient response to a missed dose. A small minority (12%) of clinicians recommended simply skipping to the next dosing time (see Table II).

Table II.

Patient and clinician recommended responses to a missed dose.

Recommended action Patient (N=45) Clinician (N=17)
Take as soon as possible 14(31%) 6(35%)
Take if within specified timeframe; skip if outside timeframe 10(22%) 9(53%)
Skip missed dose 17(38%) 2(12%)
Patient reports s/he does not miss 2(4%) N/A

Patients were asked, ‘Do you add in an extra dose later on, say the next day?’ (Clinicians were asked, ‘Do you ever recommend adding an extra dose…’). Patients reported a strong aversion to ‘doubling-up’ on their medications. Sixty-nine percent of patients stated that they thought taking an extra dose or doubling-up was inappropriate (the remainder, 31%, were not asked this question):

‘No, because my doctor would say you should never double your doses of medication.’

‘They say don’t double up. Got to start over, go to the next day.’

About one-half (53%) of the clinicians said that a missed dose should not be made up. One clinician recommended doubling-up and the remainder were not asked their opinion on this topic:

‘But they shouldn’t take two pills for the next dose. That they shouldn’t do.’

‘And you cannot double up. That’s a general rule of thumb for all prescription medication.’

Thus, there is broad agreement between patients and clinicians about the need to space out pill-taking times and about the inadvisability of ‘doubling-up’ on medications.

Communication with clinicians

To assess possible clinician-patient misunderstanding, patients were asked if they had discussed their medication adherence with their physician, including the appropriate recommended actions regarding late or missed doses. Thirty-one percent reported they never spoke with physicians about missing doses:

‘No. She wants to think the best about me, ok.’

‘I tell ‘em no, I haven’t missed it…’cause I don’t want ‘em to get mad at me.’

Overall, 70% of patients discussed their adherence problems with their physician. A number of patients reported their physician was flexible, responsive and provided valuable information:

‘She just gave me like confidence…knowledge about medication, basic things I need to do but she understands my point.’’

Others reported their physician was stricter or admonished them:

‘A while back, he told me to stop being my own doctor.’

Those patients who had the most restrictive definition of a missed dose (two hours late) were most likely (all but one) to have talked about missed doses with their physician (compared to patients with less restrictive notions of missed dose: chi-square = 4.45; p = 0.03). All patients who viewed missed dose as a moral failing had spoken with their physicians.

Patients repeatedly expressed the desire for very clear guidelines about dose timing and appropriate procedures for correcting a missed dose. When in doubt, many adopted the strictest interpretation of vague guidelines.

Discussion

Study limitations

Limitations include a small and non-random sample of patients and physicians. The patient sample was entirely African American. Thus generalizability of the findings to a wider setting requires additional investigation. Yet, restricting the sample to African Americans is also strength because few studies have investigated adherence among this population.

Documented in this study are critical gaps in doctor-patient communication about the most basic category, a ‘missed dose’ of medication, vital to effective treatment. The variety of misunderstandings poses threats to the validity of research measures of adherence, to the vitality of the patients and effectiveness of clinicians. The good news is the gap is empirically identifiable and changeable; the bad news is that untreated it continues to limit our ability to improve adherence and to advance research. The key gaps and suggested next steps are described below.

Adherence assessment

The variety of ideas about a missed dose indicates that reports across patients may not be comparable nor readily equate with researcher definitions. Thus, they remain an unaddressed threat to the validity of measures that rely on the patient to enumerate doses missed in a given time period.

Patient adherence

Patients held more restrictive definitions of a missed dose than clinicians, regardless of the particular regimen. Furthermore, patients and clinicians differ on the appropriate response. For example, 38% of patients say a missed dose should be skipped but only 12% of clinicians agree.

These contrasting views adversely impact adherence. Too narrow views of a missed dose, coupled with patient beliefs that the right response is to skip the dose totally, conflict with clinicians’ knowledge that such doses may only be late and should be taken as soon as possible. Thus, the end result may be poorer adherence, which could be readily prevented.

Clinical management

In the broadest sense, patient and clinician beliefs about missed doses are roughly similar: both generally believe that dosing times should not be too close together and avoid ‘doubling-up’; patients and clinicians implicitly (sometimes explicitly) invoke the ‘half-way’ rule when deciding to take or skip doses. Twenty percent of patients report they take a missed dose when they realize it is missed, just as clinicians recommend. Roughly half of the patients had read the pharmaceutical inserts accompanying their medication and knew the rules to follow if they missed a dose.

Yet, several major miscommunications were clear. First, we observed variation in clinician opinions about missed doses that, while not necessarily causing the variability in patient views, may impede communication of consistent, uniform and clinically appropriate set of medication guidelines to patients.

Second, part of the patient-physician differences identified in this study may be due to holdovers, ideas retained from previous medical regimens or from prior clinic guidelines. Good clinical practice can uncover these holdover beliefs and instruct patients about current guidelines.

Several future steps are clear. While further study is required to characterize the (mis)understandings of a missed dose across diverse populations, some effective first steps can be taken today. We suggest development of educational materials, such as a brief ‘frequently asked questions’ brochure for patients and also brief questions for providers to use to gauge and redress incorrect understandings about doses. Standard research techniques exist to help reformulate the items used to assess adherence behaviour. For example, cognitive testing methods, qualitative methods and other survey development tools can be used to clarify the parameters and anchor points to improve the standardization of measures (Luborsky, 1995; Perkinson, 1994; Sudman et al., 1996). The need is urgent for systematic development because mere ad hoc rewordings cannot provide the empirical base need to conceptualize and revise measures.

For providers and clinical practices several recommendations are identified. Grand rounds and continuing education should be utilized for refining and reviewing a group practice’s shared definitions of missed dose and the appropriate response. Individual providers should assess each patient’s understanding of a missed dose and appropriate response. Attention should be given to assess patient understandings of previous ART regimens and facilitate ‘unlearning’ of past regimens.

Researchers need to extend and refine these findings in larger samples and in diverse patient groups to gauge for ethnic, age and regional variations. Refinement of the measures using qualitative studies of self-report instruments can improve the construct validity by determining how to clarify the meanings of core constructs and terms to individuals being interviewed.

These findings about miscommunication provide an opportunity to enhance patient understandings and clinical communication that may lead to ways to improve adherence and improve the quality of lives of people living with HIV.

Acknowledgments

The authors wish to thank the National Institute of Allergies and Infectious Disease, RO1 AI 49113 for their funding.

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