Influence of fixed-dose combination perindopril/amlodipine on target organ damage in patients with arterial hypertension with and without ischemic heart disease (results of EPHES trial)

Figures & data

Table 1 Study protocol

Evaluation/visits	Visit 1	Visit 2	Visit 3	Visit 4	Visit 5	Visit 6	Visit 7	Visit 8
Periods	−2–0 day	1 day	2 weeks	4 weeks	6 weeks	10 weeks	6 months	12 months
Anamnesis	+
Questioner test	+							+
BMI		+						+
Office SBP, DBP, HR	+	+	+	+	+	+	+	+
ECG	+							+
24-hour ABPM		+						+
Doppler EchoCG		+						+
Pulse wave analysis (PWVa,		+						+
PWVm, Aix @75, aorta SBP)
Hematology	+
Biochemical analysis with GFR calculation		+						+
Albuminuria		+						+
Carotid IMT		+						+
Measurement ABI		+						+
Antihypertensive drug treatment		+	+	+	+	+	+	+
Adverse events	+	+	+	+	+	+	+	+

Abbreviations: ABI, ankle brachial index; ABPM, ambulatory blood pressure monitoring; Aix@75, augmentation index adjusted to HR 75 beats per minute; BMI, body mass index; DBP, diastolic blood pressure; EchoCG, echocardiography; ECG, electrocardiography; GFR, glomerular filtration rate; HR, heart rate; IMT, intima-media thickness; PWVa, aorta pulse wave velocity; PWVm, muscular pulse wave velocity; SBP, systolic blood pressure.

Table 2 Baseline characteristics of patient groups (mean±SE, n (%))

Characteristics	First group without IHD, n=30	Second group with IHD, n=30
Mean age, years	46.2±5.4	56.2±4.8
Hypertension duration, years	6.8±3.2	7.8±3.2
Screening office SBP, mmHg	156.4±3.8	148.4±2.8
Screening office DBP, mmHg	96.3±2.2	91.1±2.2
Screening office HR, beats per minute	78.1±2.8	68.4±2.1**
BMI, kg/m^2	34.2±2.1	32.1±2.5
Male/female, n (%)	14 (46.7)/16 (53.3)	23 (76.7)/7 (23.3)**
History of angina, n (%)		24 (80)
Positive exercise test, n (%)		18 (60)
Coronary angiography without stenting, n (%)		5 (16.7)
History of coronary stenting, n (%)		10 (30)
Diabetes mellitus, n (%)	2 (6.7)	8 (26.7)*
History of heart failure of NYHA functional class I–II, n (%)	14 (46.7)	21 (70)
History of atrial fibrillation, n (%)	1 (3.3)	6 (20)*
Albuminuria, n (%)	12 (40)	18 (60)
Baseline antihypertensive therapy:	n=18 (60%)	n=30 (100%)***
ACEis, n (%)	10 (55.6)	15 (50)
Beta-blockers, n (%)	12 (66.7)	29 (96.7)**
CCBs, n (%)	8 (44.4)	2 (6.7)**
Diuretics, n (%)	9 (50)	12 (40)
Monotherapy, n (%)	10 (55.6)	3 (10)**
Combination therapy, n (%)	8 (44.4)	27 (90)**
Statins, n (%)	19 (63.3)	30 (100)***
ASA, n (%)	14 (46.7)	30 (100)***
Nitrates on demands, n (%)	–	24 (80)

Notes: Significance of differences between groups:

* P<0.05,

** P<0.02,

*** P<0.001.

Abbreviations: ASA, acetylsalicylic acid; BMI, body mass index; CCB, calcium channel blocker; DBP, diastolic blood pressure; HR, heart rate; ACEi, angiotensin-converting enzyme inhibitor; IHD, ischemic heart disease; NYHA, New York Heart Association; SBP, systolic blood pressure.

Figure 1 Dynamics of office SBP, DBP, and HR on therapy in groups: ^#Significant in comparison with baseline in the same group. *Significant in comparison with group of patients without IHD at the same period.

Abbreviations: DBP, diastolic blood pressure; HR, heart rate; IHD, ischemic heart disease; SBP, systolic blood pressure.

Figure 2 Lowering of 24-hour, daytime, and nighttime SBP and DBP in the treatment groups.

Abbreviations: DBP, diastolic blood pressure; IHD, ischemic heart disease; SBP, systolic blood pressure.

Table 3 Dynamics of ABPM patterns in the patient groups

Patterns	Without IHD (n=30)			With IHD (n=30)
	Baseline	12 months	P-value	Baseline	12 months	P-value
24-hour SBP, mmHg	140.2±1.9	117.8±1.4	<0.001	139.8±2.0	118.9±1.3	<0.001
24-hour DBP, mmHg	83.4±2.2	75.2±1.1	<0.001	85.8±2.7	73.2±1.2	<0.001
24-hour HR, beats per minute	74.2±2.9	72.3±1.8	NS	69.3±2.7	66.1±2.8	NS
DI for SBP, %	10.6±0.8	17.8±1.9	<0.005	9.2±0.7	10.9±0.9**	NS
Daytime SBP, mmHg	148.8±2.3	129.2±1.4	<0.001	146.4±2.8	129.8±1.1	<0.001
Daytime DBP, mmHg	90.7±1.8	82.3±1.1	<0.001	89.7±1.8	75.6±1.3*	<0.001
Daytime HR, beats per minute	80.2±2.4	79.2±1.8	NS	73.2±2.4***	69.9±1.8*	NS
Variability of daytime SBP, mmHg	17.4±0.1	14.1±0.2	<0.001	18.8±0.1*	12.1±0.2*	<0.001
Variability of daytime DBP, mmHg	14.8±0.2	13.7±0.3	<0.005	16.1±0.1*	13.2±0.2	<0.001
Nighttime SBP, mmHg	132.2±1.8	106.1±1.3	<0.001	133.2±2.1	108.1±1.3	<0.001
Nighttime DBP, mmHg	76.1±2.6	68.3±1.0	<0.01	82.1±2.3	70.7±1.0	<0.001
Nighttime HR, beats per minute	68.3±3.5	65.4±1.9	NS	65.4±3.5	62.4±1.9	NS
Variability of nighttime SBP, mmHg	15.2±0.2	12.7±0.3	<0.001	16.7±0.3*	12.2±0.3	<0.001
Variability of DBP, mmHg	10.1±0.1	10.3±0.2	NS	14.3±0.2*	11.3±0.2**	<0.001
Morning surge of SBP, mmHg	68.9±5.6	49.9±4.4	<0.02	66.4±4.3	50.9±4.6	<0.02
Prevalence of patients with morning surge of SBP >55 mmHg, n (%)	18 (60)	6 (20)	<0.005	25 (83.3)***	14 (46.7)***	<0.005
Prevalence of “non-dipper” patients, n (%)	15 (50%)	7 (23.3)	<0.05	16 (53.3%)	12 (40)	NS

Notes: Significance between groups at the same period of treatment:

* P<0.001,

** P<0.005,

*** P<0.05.

Abbreviations: ABPM, ambulatory blood pressure monitoring; DBP, diastolic blood pressure; DI, daily index; HR, heart rate; IHD, ischemic heart disease; NS, not clinically significant; SBP, systolic blood pressure.

Figure 3 Dynamics of central SBP and Aix@75 in the treatment groups.

Abbreviations: Aix@75, augmentation index adjusted to heart rate 75; IHD, ischemic heart disease; SBP, systolic blood pressure.

Table 4 Dynamics of TOD patterns in the treatment groups

Patterns	Without IHD (n=30)			With IHD (n=30)
	Baseline	12 months	P2–3	Baseline	12 months	P5–6
1	2	3	4	5	6	7
PWVe, m/s	11.9±0.7	9.4±0.8	0.05	13.9±0.8	9.5±0.7	0.01
PWVm, m/s	10.9±0.9	10.4±0.8	NS	11.1±0.7	10.3±0.9	NS
Ankle-brachial index	1.00±0.05	1.1±0.08	NS	0.9±0.05	1.0±0.08	NS
IMTmax, mm	1.1±0.03	1.0±0.04	NS	1.30±0.02*	1.2±0.03**	0.05
Albuminuria, mg/day	53.3±5.6	15.8±3.2	0.001	72.5±7.6	14.8±3.1	0.001
Calculated GFR, ml/min/1.73 m^2	87.9±8.7	83.6±9.1	NS	65.2±10.1	68.6±7.1	NS
LVMI, g/m^2	108.8±5.5	88.3±5.3	0.02	125.9±5.5***	108.3±6.3***	0.05
E/A	0.93±0.06	1.3±0.08	0.001	0.73±0.05**	1.2±0.08	0.001
E/E´	9.9±0.2	7.6±0.5	0.001	15.9±0.2*	7.3±0.4	0.001
Cornel index, mm∙ms	2440.1±67.9	1987.2±66.8	0.001	2948.4±77.2*	2687.2±56.8*	0.01
Left atrium size, mm	41.1±0.2	38.1±0.3	0.001	42.5±0.5**	41.1±0.4*	0.05

Notes: Significance of differences between groups.

* P<0.001,

** P<0.02,

*** P<0.05.

Abbreviations: GFR, glomerular filtration rate; IHD, ischemic heart disease; IMTmax, maximal intima-media thickness; LVMI, left ventricular mass index; NS, not clinically significant; PWVe, aorta pulse wave velocity; PWVm, muscular pulse wave velocity.

Table 5 Studies evaluating the effects of high BP variability on TOD and cardiovascular events

Study	Population	Variability	Influence
Parati et al^Citation26	Hospitalized patients with essential arterial hypertension	24-hour variability	Increased TOD rate
Frattola et al^Citation27	Patients with arterial hypertension	Daytime SBP variability	More prominent TOD
Mancia et al^Citation28	Patients with arterial hypertension	24-hour variability	Increased IMT
Sega et al^Citation29	General population	Total variability	More LVMI
Sander et al^Citation30	General population	Daytime variability	IMT progression
McMullan et al^Citation31	Patients with chronic kidney disease	SBP variability	Increased total and cardiovascular death
Kawai et al^Citation34	Patients with arterial hypertension	Daytime SBP variability Nighttime SBP variability	Increased renal artery resistance Increased IMT
Cay et al^Citation35	Normotensive patients	24-hour SBP and DBP variability	Increased restenosis risk after percutaneous coronary interventions
Ozawa et al^Citation36	Patients with type 2 diabetes	Nighttime SBP and DBP variability	Increased rate of cardiovascular events
Sakakura et al^Citation37	Elderly patients	Daytime SBP variability	Cognitive dysfunction, poor quality of life
Iwata et al^Citation38	Patients with arterial hypertension	Nighttime SBP variability	More atherosclerotic plaques
Schillaci et al^Citation39	Patients with arterial hypertension	24-hour variability	Increased arterial stiffness
Schutte et al^Citation40	Normotensive Afro-Americans	24-hour variability	LVH

Abbreviations: BP, blood pressure; DBP, diastolic blood pressure; IMT, intima-media thickness; LVH, left ventricular hypertrophy; LVMI, left ventricular mass index; SBP, systolic blood pressure; TOD, target organ damage.

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