The database contained dosing histories of 4783 patients prescribed with once a day antihypertensive drug treatments. They came from 21 phase IV clinical studies, ranging in length between 30 and 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). The final dataset included data on 478
630 days of dosing history.
Figure 1 shows samples of chronology plots from four patients with different patterns of adherence. The first patient perfectly executed the dosing regimen and was persistent during an observation period of 60 days. The second patient also executed the dosing regimen reasonably well but discontinued treatment after 60 days, although he was expected to continue at least until the end of the observation period of 280 days. The third patient executed the regimen poorly, several doses were missed, and a long drug holiday occurred. Finally, at day 180, the patient discontinued treatment. The fourth patient took most of the scheduled doses and persisted for 307 days, but the time he took the drug varied greatly.
Fig 1 Sample chronology reports for four patients. Arrows indicate days on which medication was not taken
Figure 2 shows the results when we applied the definitions described in the methods. The persistence line represents the decline, over time since the start of treatment, in the proportion of patients who are still engaged with the dosing regimen. By the end of one year, almost half of the patients who were prescribed an antihypertensive medication have stopped taking the treatment, despite a dosing regimen of indefinitely long, continuous dosing specified in the protocol. The initial abrupt small drop in the persistence curve represents the proportion of patients who never engaged with the dosing regimen. These occurrences of non-acceptance represent 2% of the studied population. After the sharp small initial drop of non-acceptance, the persistence curve decreases gradually but progressively over time. For example, at day 200, 35% of the patients have already stopped the treatment—that is, 65% persist with treatment. On, for example, the 200th day, among patients still engaged with the dosing regimen, 10% did not take their medication (non-execution). The percentage of the patients comprising the inception cohort who took their dose on day 200 is thus 58% (90%×65%), constituting a measure of overall shortfall in drug intake. In terms of crude percentages, non-execution of the dosing regimen thus created a shortfall in drug intake that is an order of magnitude smaller than the shortfall created by early discontinuation/short persistence.
Fig 2 Time course of adherence/compliance parameters (execution, persistence)
On each day of treatment, about 10% of scheduled doses were omitted. The breakdown of these omissions is as follows: 42% were omission of a single day’s dose; 15% were omission of one or two consecutive days’ doses, and 43% were one of a longer, multi-day sequence of omitted doses (three or more days). Figure 3 shows the frequency of missing doses within and between patients. Almost 95% of the patients missed a single dose (that is, had an interval of over 30 hours since the last taken dose) at least once a year. Half of the patients missed a single day’s dose at a rate of one a month (12 a year); 48% of the patients took a drug holiday (>78 hours) at least once a year; and 13% had bi-monthly (six a year) drug holidays.
Fig 3 Frequency for delaying a dose by more than 30, 42, 54, 66, and 78 hours within and between patients
We identified periodic patterns in execution. There was a small but definite seasonal trend with a 2% reduction in execution between April and September (P<0.001). In a third of the patients we identified one or more days of the week on which errors occurred at exceptionally high rates: weekend doses were more likely to be missed than weekday doses (odds ratio 1.13, 95% confidence interval 1.12 to 1.15), but occasionally some patients had a particular weekday in which dosing errors were especially clustered. Finally, we classified patients as morning takers (n=4149) if they took more than 75% of doses between 3 am and 3 pm, or evening takers (n=283) if they took more than 75% of doses between 3 pm and 3 am, and “variable” (n=257) if they could not be classified as either. Figure 4 shows the proportion of missed doses by day of the week for each category of takers. Morning takers were more likely to take treatment correctly than evening takers (1.38, 1.36 to 1.41) and evening takers were more likely to take treatment correctly than variable takers (1.48, 1.45 to 1.52). Sunday morning was when morning takers missed most doses; Saturday evening was when evening takers missed most doses.
Fig 4 Proportion of days without drug intake by day of week for each category of takers: morning, evening, or variable
Figure 5 displays the estimates of persistence stratified by the degree of execution, clearly showing that the better the execution, the longer the persistence. The likelihood that a patient would discontinue treatment early was related to the quality of his/her daily execution of the dosing regimen (hazard ratio 0.84 for 10% increase in execution; 95% confidence interval 0.81 to 0.87).
Fig 5 Kaplan-Meier persistence curves stratified by proportion of prescribed drug taken