MAPEC Trial: Recommend at least one antihypertensive at night to improve cardiovascular outcomes

Recommend taking at least one antihypertensive medication at night.  This simple, cost-effective intervention was recently shown in the MAPEC trial to modestly reduce cardiovascular events and mortality.

MAPEC Study Design

This Spanish study, called MAPEC, included 2,156 patients with untreated or resistant hypertension.  The intervention was simple – the control group took all antihypertensive medications in the morning, and the treatment group took one or more antihypertensives at bedtime.  All other medical decisions, such as antihypertensive selection, were at the discretion of the provider.

MAPEC followed patients for a median of 5.6 years with a primary composite endpoint of all-cause mortality and total cardiovascular events.  Interestingly, patients wore a 48-hour ambulatory BP monitor at least once per year.  This monitoring allowed for blood pressure measures every 20 minutes, thereby offering both daytime and nighttime BP values for analysis.

Proposed Mechanism of Benefit – Dippers vs. Non-Dippers

Under normal circumstances, nocturnal blood pressure should be at least 10% lower than daytime values.  This physiologic phenomenon is called “dipping”.  For reasons that are not fully understood, patients who do not dip (called “non-dippers”) have increased cardiovascular events.  In MAPEC, about 50% of the study patients were non-dippers at baseline.

The intervention in MAPEC was selected to encourage a “dipping” physiology.  When antihypertensives are exclusively taken in the morning, more patients will become non-dippers because the peak of the antihypertensive effect will occur during the day.  By moving at least one agent to bedtime administration, a dipping effect can be promoted.

Results

Patients randomized to the treatment arm (bedtime administration) demonstrated lower sleep-time blood pressure, a higher rate of controlled ambulatory blood pressure (62% vs. 53%, p<0.001), and a much lower incidence of the “non-dipper” physiology (34% vs. 62%, p<0.001).

Most importantly, those in the bedtime administration group had a reduction in the primary endpoint (composite of all-cause mortality and CV events) of 11.95 vs. 27.8 events per 1000 patient-years (HR 0.39, p<0.001, NNT 63 over 1 year).  Although the incidence was rare, all-cause mortality alone was also reduced (2.11 vs. 4.16 events per 1000 patient-years, p=0.008, NNT 488 over 1 year).

Discussion and Conclusions

Due to the design of the study, it is not clear whether bedtime administration was beneficial due to a higher rate of “dipping” physiology or simply because of superior blood pressure control.  Regardless of the mechanism, the results of the trial are impressive.

In reading through the trial, it is not clear why MAPEC has not received more attention in the medical community.  Its biggest weakness is the fact that the design was open label, single center, and antihypertensive selection was left to the discretion of the provider.  Perhaps due to this reason, the trial was published in the lesser-known journal of Chronobiology International where it has likely not enjoyed a large reading audience.

The results of this trial are simple: by switching at least one medication to bedtime administration, this cost-effective, simple intervention improved blood pressure control and modestly reduced cardiovascular events.

Reference

Hermida RC, Ayala DE, Mojón A, Fernández JR. Influence of circadian time of hypertension treatment on cardiovascular risk: results of the MAPEC study. Chronobiol Int. 2010 Sep;27(8):1629-51. PMID 20854139.

Photo by beaumontpete