INFLUENCE OF CIRCADIAN TIME OF HYPERTENSION TREATMENT ON CARDIOVASCULAR RISK: RESULTS OF THE MAPEC STUDY

Figures & data

FIGURE 1  Flow-chart of subjects participating in the study.

TABLE 1 Baseline characteristics of patients investigated according to treatment-time (either all hypertension medications upon awakening or ≥1 medications at bedtime)

Variable*	Awakening	Bedtime	p between groups
Demographic characteristics
Patients, n	1084	1072
Sex, % men	49.6	47.3	.281
Diabetes, %	21.3	19.6	.299
Obstructive sleep apnea, %	9.1	7.5	.160
Metabolic syndrome, %	61.3	57.6	.080
Cigarette smoking, %	13.1	12.4	.630
Obesity, %	69.8	72.6	.160
Duration of hypertension, yrs	6.8 ± 8.0	6.6 ± 7.7	.614
Previous cardiovascular events, %	5.3	5.2	.975
Anthropometric variables and office BP
Age, yrs	56.3 ± 13.7	55.0 ± 13.4	.021
Height, cm	161.4 ± 9.7	161.1 ± 9.6	.418
Weight, kg	78.5 ± 15.9	77.4 ± 14.6	.074
BMI, kg/m^2	30.1 ± 5.2	29.8 ± 4.8	.161
Waist, cm	97.0 ± 12.9	95.8 ± 11.7	.022
Clinic SBP, mm Hg^†	154.4 ± 20.3	155.7 ± 19.4	.144
Clinic DBP, mm Hg^†	87.4 ± 11.5	88.5 ± 11.0	.023
Clinic PP, mm Hg^†	67.0 ± 14.9	67.2 ± 15.2	.818
Clinic HR, beats/min^†	74.0 ± 12.0	74.9 ± 12.9	.078
Clinical laboratory test values
Glucose, mg/dL	110.3 ± 32.3	107.8 ± 32.6	.071
Creatinine, mg/dL	0.98 ± 0.26	0.96 ± 0.22	.028
Uric acid, mg/dL	5.8 ± 1.8	5.7 ± 1.6	.015
Total cholesterol, mg/dL	210.8 ± 40.7	212.2 ± 37.7	.417
Triglycerides, mg/dL	118.7 ± 67.4	114.6 ± 66.1	.155
HDL-cholesterol, mg/dL	47.7 ± 15.0	48.4 ± 15.2	.244
LDL-cholesterol, mg/dL	139.0 ± 34.6	140.2 ± 33.5	.424
Fibrinogen, mg/dL	329.4 ± 83.1	322.7 ± 77.9	.094
Erythrocyte sedimentation rate, mm	15.2 ± 12.4	14.8 ± 12.3	.472
Glomerular filtration rate^‡	77.2 ± 20.1	78.2 ± 16.7	.201
Ambulatory BP
Awake SBP mean, mm Hg	134.3 ± 15.7	134.2 ± 13.8	.855
Asleep SBP mean, mm Hg	122.7 ± 17.4	122.7 ± 15.3	.935
48-h SBP mean, mm Hg	130.7 ± 15.5	130.5 ± 13.6	.827
Sleep-time relative SBP decline, %	8.5 ± 7.9	8.5 ± 7.6	.870
Awake DBP mean, mm Hg	81.9 ± 11.5	82.4 ± 10.8	.331
Asleep DBP mean, mm Hg	70.4 ± 10.4	71.0 ± 9.5	.154
48-h DBP mean, mm Hg	78.2 ± 10.7	78.7 ± 10.0	.252
Sleep-time relative DBP decline, %	13.7 ± 8.5	13.5 ± 8.0	.496
Non-dipper, %	55.4	53.0	.252

*The sleep-time relative BP decline, an index of BP dipping, is defined as the percent decline in mean BP during the hours of nocturnal sleep relative to the mean BP during the hours of diurnal activity, and calculated as: [(awake BP mean − asleep BP mean)/awake BP mean] × 100. Non-dipper: patients with sleep-time relative SBP decline <10%, using data sampled by ABPM for 48 consecutive hours.

Note. Values are shown as mean ± SD.

^†Values correspond to the average of six conventional BP measurements obtained for each subject at the clinic before starting ABPM.

^‡Glomerular filtration rate (mL/min/1.73 m²) was estimated using the MDRD-4 equation (Levey et al., 1999).

TABLE 2 Final characteristics of patients investigated according to treatment-time (either all hypertension medications upon awakening or ≥1 medications at bedtime)

Variable*	Awakening	Bedtime	p between groups
Patients, n		1084	1072
Primary endpoints, events/1000 patient-yrs (event-number in parenthesis)
Total events	27.80 (187)	11.95 (68)	<.001
Total death	4.16 (28)	2.11 (12)	.008
Cardiovascular	2.08 (14)	0.53 (3)	.006
Other cause	2.08 (14)	1.58 (9)	.250
CVD events	11.00 (74)	5.27 (30)	<.001
Cerebrovascular events	3.57 (24)	1.23 (7)	.001
Heart failure	4.91 (33)	1.41 (8)	<.001
Other events	4.16 (28)	1.93 (11)	.004
Hypertension treatment
Number of medications	2.1 ± 1.2	2.0 ± 1.4	.302
1 medication, %	43.4	43.0	.868
2 medications, %	16.3	15.9	.766
≥ 3 medications, %	40.3	41.1	.697
ARB, %	58.8	60.1	.535
ACEI, %	20.3	17.1	.055
CCB, %	38.1	40.6	.239
α-Blocker, %	16.1	17.2	.488
β-Blocker, %	22.7	20.0	.122
Diuretic, %	53.9	45.8	<.001
Clinic and ambulatory BP
Clinic SBP, mm Hg^†	144.4 ± 23.0	142.6 ± 20.1	.065
Clinic DBP, mm Hg^†	81.4 ± 13.2	81.1 ± 12.1	.693
Clinic PP, mm Hg^†	63.0 ± 16.2	61.5 ± 14.6	.024
Clinic HR, beats/min^†	72.4 ± 13.0	73.0 ± 13.1	.345
Awake SBP mean, mm Hg	124.9 ± 15.1	125.3 ± 12.9	.546
Asleep SBP mean, mm Hg	116.1 ± 17.9	110.9 ± 13.9	<.001
48-h SBP mean, mm Hg	122.1 ± 15.1	120.8 ± 12.6	.029
Sleep-time relative SBP decline, %	7.0 ± 9.1	11.4 ± 7.3	<.001
Awake DBP mean, mm Hg	74.7 ± 10.4	75.9 ± 10.2	.005
Asleep DBP mean, mm Hg	65.2 ± 10.4	63.1 ± 9.4	<.001
48-h DBP mean, mm Hg	71.6 ± 9.8	71.9 ± 9.5	.475
Sleep-time relative DBP decline, %	12.3 ± 10.7	16.6 ± 8.7	<.001
Non-dipper, %	61.6	34.4	<.001
Controlled ambulatory BP, %	52.8	62.2	<.001
Changes in clinic and ambulatory BP from baseline
Clinic SBP, mm Hg	−10.0 ± 17.7	−13.1 ± 19.7	<.001
Clinic DBP, mm Hg	−6.0 ± 10.7	−7.4 ± 10.8	.004
Clinic PP, mm Hg	−4.0 ± 11.2	−5.7 ± 12.2	.001
Clinic HR, beats/min	−1.6 ± 10.6	−1.9 ± 11.1	.410
Awake SBP mean, mm Hg	−9.4 ± 13.3	−8.9 ± 13.4	.401
Asleep SBP mean, mm Hg	−6.6 ± 12.5	−11.8 ± 13.2	<.001
48-h SBP mean, mm Hg	−8.6 ± 12.3	−9.7 ± 12.5	.028
Sleep-time relative SBP decline, %	−1.5 ± 6.7	2.9 ± 7.4	<.001
Awake DBP mean, mm Hg	−7.2 ± 8.5	−6.5 ± 8.9	.035
Asleep DBP mean, mm Hg	−5.2 ± 8.3	−7.9 ± 8.5	<.001
48-h DBP mean, mm Hg	−6.6 ± 7.9	−6.8 ± 8.1	.534
Sleep-time relative DBP decline, %	−1.4 ± 7.8	3.1 ± 8.3	<.001

*CVD events include myocardial infarction, angina pectoris, and coronary revascularization. Cerebrovascular events include hemorrhagic stroke, ischemic stroke, and transient ischemic attack. Other events include acute arterial occlusion of the lower extremities, rupture of aortic aneurisms, and thrombotic occlusion of the retinal artery. Comparison of event rates between groups was done by the Mantel log-rank test. The sleep-time relative BP decline, an index of BP dipping, is defined as the percent decline in mean BP during the hours of nocturnal sleep relative to the mean BP during the hours of diurnal activity, and calculated as: [(awake BP mean − asleep BP mean)/awake BP mean] × 100. Non-dipper: patients with sleep-time relative SBP decline <10%, using data sampled by ABPM for 48 consecutive hours.

Note. Values are shown as mean ± SD.

^†Values correspond to the average of six conventional BP measurements obtained for each subject at the clinic before starting ABPM.

FIGURE 2  Kaplan-Meier survival curves as a function of time-of-day of hypertension treatment, i.e., for subjects ingesting either all their medication upon awakening or ≥1 medications at bedtime.

FIGURE 3  Relative risks (with 95% confidence intervals) of CVD events (adjusted by age, sex, and diabetes) as a function of time-of-day of hypertension treatment, i.e., for subjects ingesting either all their medication upon awakening or ≥1 medications at bedtime. Total events include death (from all causes), CVD events, cerebrovascular events (stroke and transient ischemic attack), heart failure, acute arterial occlusion of the lower extremities, rupture of aortic aneurisms, and thrombotic occlusion of the retinal artery. Major events include CVD deaths, myocardial infarction, ischemic stroke, and hemorrhagic stroke. CVD events include myocardial infarction, angina pectoris, and coronary revascularization.

TABLE 3 Relative risk of total CVD events associated with changes in clinic and ambulatory (ABPM) blood pressure (BP) during follow-up

Parameters	Adjusted relative risk	Further adjusted by 48-h mean
SBP
Clinic BP	0.98 (0.95–1.01)	0.99 (0.96–1.03)
Awake mean	0.96 (0.92–1.00)	1.27 (1.08–1.51)^†
Asleep mean	0.92 (0.88–0.96)*	0.88 (0.81–0.96)^†
48-h mean	0.94 (0.90–0.98)^†	—
Sleep-time relative decline	0.88 (0.81–0.95)*	0.87 (0.81–0.94)*
DBP
Clinic BP	0.91 (0.86–0.96)*	0.96 (0.90–1.02)
Awake mean	0.90 (0.84–0.96)^†	1.56 (1.22–1.99)*
Asleep mean	0.82 (0.77–0.88)*	0.78 (0.69–0.89)*
48-h mean	0.85 (0.79–0.91)*	—
Sleep-time relative decline	0.87 (0.81–0.93)*	0.86 (0.80–0.92)*

Note. Relative risk (95% confidence intervals) for each 5 mm Hg decrease in BP or each 5% absolute increase in sleep-time relative BP decline, between the first and the last ABPM profile of each subject. Adjustments were applied for the only significant influential characteristics (sex, age, diabetes, and hypertension treatment) along with further adjustment for change in 48-h BP mean during follow-up (right column). The sleep-time relative BP decline, an index of BP dipping, is defined as the percent decline in BP during the hours of nocturnal sleep relative to the mean BP during the hours of diurnal activity, and calculated as the: [(awake BP mean − asleep BP mean)/awake BP mean] × 100. Significance of the results: *p < .001; ^†p < .01.

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