Thus, a brief review of methods for gathering drug dosing histories in ambulatory patients is a logical part of this chapter.
METHODOLOGICAL ISSUES IN
COMPILING DRUG DOSING HISTORIES OF AMBULATORY PATIENTS
Until
the later 1980s, the available methods (clinical judgment, interviews, patient
diaries, counts of returned, unused dosage forms, spot checks of drug
concentration in plasma) were unreliable and biased by the ease with which
patients can and do easily censor evidence for omitted doses. Thus, a brief
review of methods for gathering drug dosing histories in ambulatory patients is
a logical part of this chapter.
A
leading reason for the weakness of clinical judg-ment about patient adherence
is that the doctor– patient relation is based on trust, which, when there is no
reliable, contradictory source of information, leads most physicians to take at
face value what patients tell them about their adherence to the prescribed drug
dosing regimen. The result is strongly biased towards over-estimation of the
patient’s adher-ence to the prescribed dosing regimen. What patients tell their
physician or other health care personnel is strongly coloured by two factors:
(a) recall of day-by-day drug intake is often poor, unless the patient goes to
extraordinary but infrequently made efforts to keep records of what was taken
and when; (b) there is a pervasive reluctance among patients to inform the
prescribing physician that they have never started taking the medicine, or have
started it but executed the dosing regimen poorly, or have completely
discontin-ued taking the medicine much sooner than the physi-cian had
prescribed.
Reliability
problems are obvious with interviews and diary entries, because patients can
say or write what-ever they choose, and whenever they chose to make diary
entries. Recent work with a special diary that captured and stored the time of
each diary entry has shown that only 11% of diary entries bore a credible temporal
relation to the event being entered into the diary (Stone, Schiffman, Schwartz,
2002).
An
often-misunderstood method is the direct measure-ment of drug concentration in
plasma. This method, which has an aura of ultimate objectivity, runs head-long
into the prevalent bias called ‘white-coat compli-ance’ (Feinstein, 1990). This
phenomenon occurs in patients whose adherence is poor most of the time, but
shifts suddenly to correctness during the day or two prior to a scheduled visit
to the physician or other caregivers. With 1–2 days of correct dosing having
preceded the sampling of drug concentration, the measured value of drug
concentration will, with the vast majority of conventionally formulated drugs,
reflect drug intake for only 1–2 days. What happened before that brief period
of time, or what happens after-wards, is unknown. The source of these numbers
is pharmacokinetic theory, which teaches that measured drug concentration in
plasma at a given time will reflect drug intake during a period of prior time
equal to 3–4 times the drug’s plasma half-life. It turns out that 87% of the
several hundred most commonly used drugs have plasma half-lives of 12 hours or
less (Benet, Oie and Schwartz, 1995). Thus, the measure-ment of drug
concentration in plasma, as done in the usual way, with blood sampling done at
the time of a scheduled visit, will, in most instances, reflect drug intake
only during the period of white-coat compli-ance. If a measured drug
concentration is zero, it signifies that no drug was taken during four prior
half-lives, that is 2 days or less for the vast majority of drugs.
With
dosage form counts (‘pill counts’), many patients can and do discard untaken
dosage forms before returning the drug package to the clinical staff – a
prob-lem clearly identified in two studies reported about 15 years ago (Pullar et al., 1989; Rudd et al., 1989). Since then, numerous studies have compared
electronically compiled dosing histories with results of pill counts, with
uniform demonstration of exaggerated results with pill counts (Urquhart, 1997).
Yet, to their shame, clini-cal researchers continue to perform counts of
returned, untaken dosage forms, and solemnly report the results as if the
method had not been thoroughly discredited, except in the infrequent instance
when a patient returns all dispensed medicine untaken.
The
usual result of pill-count data is that somewhere in the low 90% range of trial
patients were satisfac-torily compliant. ‘Satisfactorily’ usually means that
the patient has returned few enough dosage forms to support the conclusion that
>80% of prescribed doses were taken. This almost universally applied,
‘>80% is OK’ criterion has no roots in pharmacological science, and is
supported only by uncritical repetition, having started in the 1970s as a
self-evident guess (Sackett and Haynes, 1976). Yet, as already noted, such
infor-mation is not only drug-specific but product-specific.
The
inherently unscientific folly of universally applying the ‘80% is OK’ criterion
is revealed by the well-documented fact that the pharmaceutical prod-ucts with
which there is the greatest use-experience of all can fail to act even when all
prescribed doses are taken, but are mistimed. The products in ques-tion are the
low-dose, combined oestrogen–progestin, oral contraceptives. As the UK
labelling indicates, being more than 12 hours late in taking the once-daily
‘pill’ already increases the risk of breakthrough ovula-tion and conception
during the part of the monthly cycle in which ovulation is most likely
(Guillebaud, 1993). Thus, a patient who routinely takes a daily ‘pill’, but
wobbles in dose-taking between doing so at the usual 7 am or, exceptionally, at
bed-time, creates intervals between doses that exceed 36 hours, which would
appear to be the mean point at which the risk of breakthrough ovulation starts
to rise. (Note that the 36-hour mean implies that half the patients can be
expected to have an even shorter margin for dose-timing error than 36 hours.)
Clearly, then, in the case of these most widely used products, the ‘80% is OK’
criterion, which means missing one dose in 5, and thus a series of 48-hour or
longer intervals between doses, would allow many instances of breakthrough
ovulation and correspondingly high likelihood of unwanted conception.
Thus,
another factor having a major bearing on the question of ‘how much adherence is
enough?’ is the degree of ‘forgiveness’ that each pharmaceu-tical product
provides. At one extreme of forgive-ness is bendroflumethazide, a thiazide
diuretic widely used in the treatment of hypertension in the United Kingdom,
and which has a once-daily dosing regi-men, though it is able to maintain
anti-hypertensive action for over 6 days after a missed dose (Girvin and
Johnston, 2004). At the other extreme of forgiveness are, as just discussed,
the low-dose, combined oestro-gen/progestin oral contraceptives, with their
minis-cule average of 12 hours of safety margin beyond the recommended 24-hours
interval between once-daily doses. In the latter instance, one can have product
fail-ure simply from errors in dose-timing, even though 100% of prescribed
doses had been taken. In the former instance, one should be able to omit
several sequential daily doses and still have continuity of anti-hypertensive
action.
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