An overall result of this study was that the various maneuvers executed between the start and end of the study resulted in the normalization of blood pressure in 53% of the patients who had been persistently hypertensive by OBP measurement despite treatment with multiple drugs. The various maneuvers included: start of both home blood pressure monitoring and drug regimen compliance monitoring at week 0, exclusion of uncontrolled hypertension caused by a white-coat effect, change of the drug regimen in Groups B and C at week 4, and the commencement of a compliance-enhancement program in Group C at week 4. In the persistently hypertensive groups B and C, 39% achieved normalization of blood pressure. In the present study, a number of factors made it impossible to deduce which of the various maneuvers, including compliance-improvement, played the dominant role in the normalization of blood pressure, nor is it evident what sorts of reductions in the number of drugs or doses prescribed might be possible in correctly dosing former poor compliers, without loss of control over blood pressure.
A fortunate aspect of the present study is that the maneuvers performed were fairly simple and cost effective, and without discernible hazards, so that repetition with better collection of data and simplified designs may allow identification of the most important maneuvers.
Compliance in week 0–4 was monitored with up to 3 MEMS boxes in individual patients. Since – as in previous studies – no difference could be observed between 1 or more MEMS boxes, we decided to continue on 1 MEMS box for Cande/TZD
During the run-in period, the percentage of prescribed doses taken, which is one of several ways to express drug regimen compliance, fluctuated to a slight extent, but remained essentially constant in Group A. In contrast, the patients who were destined to comprise Groups B and C showed a more or less continuous decline in percentage of prescribed doses taken, from the mid-point to the end of the 4-week run-in period, during which time the mean percentage of prescribed doses taken declined from 93% to 62%.
Remarkably, compliance in Groups B and C improved immediately following the visit at week 4 and continued, as shown in Figure 4, to fluctuate from day to day in the region between 85% and 100% of prescribed doses taken. A possible explanation of this phenomena is the switch to a more efficient therapy and a QD regimen.
A notable finding was a substantially higher incidence of omitted doses on weekends (Fridays-Saturdays-Sundays) than on weekdays (Mondays thru Thursdays). This phenomenon was also reported in a previous work by Mallion et al. . This prominent effect does not show up in Figure 4, as the data are plotted on an ordinal day basis, rather than a calendar day basis – an object lesson in how some methods of displaying averaged time-series data can camouflage important features.
Following the change to candesartan/HCTZ in Groups B&C significant BP reductions could be observed with all three methods of BP monitoring. Since ABPM is more useful than OBPM in stratifying cardiovascular risk in patients with refractory hypertension, we used the normalization criteria of ABPM. It is remarkable that a normalization rate of 39% was achieved as monitored by ABPM in groups B&C. This beneficial finding is in keeping with results of prior studies, and may in part be due to the relatively long duration of action of candesartan, which could be expected to have the effect of allowing antihypertensive action to persist in the face of delayed or omitted doses [11–14]. The better blood pressure control at week 12 may be explained by both improved compliance and switch to Candesartan/TZD. However, our study design did not allow to give a good estimate of the relative contribution of each factor. But Burnier et al could demontrated in a prior study that monitoring of compliance alone was associated with a significant improvement of blood pressure at 2 months (systolic/diastolic blood pressure:156/106 +/- 23/11 versus 145/97 +/- 20/15 mmHg, P < 0.01) .
Drug regimen compliance after week 4 was not different in the three groups, staying essentially constant over time, very close to correct dosing each day, with of course the exception of the 'weekend effect', the pressure correlates of which we did not explore. Relatively long-acting antihypertensive agents, e.g., candesartan, can 'forgive' dose omissions occurring on weekends, whereas relatively short-acting drugs, that cannot maintain pressure control for at least 48 hrs after a last-taken dose, cannot .
Limitations of the study
Clearly the transactions between investigative staff and patients had substantial though variably sustained impact. We do not know – and it is an important omission that should be avoided in future studies – what the dosing histories and thus the compliance levels were in the period prior to the start of the run-in period. One naturally wonders if it were not generally poor in many or most of the patients before the start of the study, whereupon the first measurements showed it to be high in all patients, perhaps a forerunner of the abrupt jump in compliance that we see in Groups B and C immediately after the week 4 visit. Perhaps – but we can only speculate and take the point in designing future studies – the patients who were to comprise Group A were, prior to the start of the study, poorly compliant, but received enough motivation from the various maneuvers made at the start of the study, so that their compliance rose and their blood pressures concomitantly normalized, where they remained throughout the 12-week study. A high priority, therefore, is to master – as some investigators have [16, 17] – the art of introducing electronic monitoring in an unperturbing manner, so that valid pre-study dosing histories can be captured.
For reasons that this study does not reveal, the week 4 visit restored average compliance in Groups B and C to the same high range it had in the first 2 weeks after of the initial visit at the start of the study. One naturally wonders whether maneuvers begun at the start of the study, 4 weeks previously, had not had a similar effect, akin to that which we see after week 4, of improving a previously unsatisfactory compliance. It is also a matter of conjecture about which of the various maneuvers uniquely associated with the conduct of the study played the biggest role in (a) achieving a sustained increase in compliance in Groups B and C, and (b) achieving blood pressure control in a fraction of the patients in Groups B and C.
Another limitation of the study was the rather short duration of the study. It is well known that long term, "real life " compliance may not be reflected by short observation periods 1 or 2 months.