Effects of Blood Pressure Control With Perindopril/Indapamide on the ...

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Oct 29, 2010 - hypertensive patients independently of blood pressure reduction. Methods .... hypertension, or family history of hypertension before 55 years.
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Effects of Blood Pressure Control With Perindopril/Indapamide on the Microcirculation in Hypertensive Patients Haytem Debbabi1, Philippe Bonnin1 and Bernard I. Levy1 Background Microvascular rarefaction and endothelium dysfunction are hallmarks of hypertension. We assessed whether antihypertensive treatments affect the microcirculation and whether the fixed-dose combination perindopril/indapamide (per/ind) modifies the microcirculation of hypertensive patients independently of blood pressure reduction. Methods One hundred ninety-three consecutive patients were enrolled into one of four groups depending on their blood pressure and existing treatment: (i) controlled hypertensive patients treated with per/ind (controlled-per/ind), (ii) controlled hypertensive patients treated with agents other than angiotensin-converting enzyme (ACE) inhibitors or diuretics (controlled-other), (iii) uncontrolled hypertensive patients treated with agents other than ACE inhibitors or diuretics (uncontrolled-other), (iv) untreated normotensive subjects. Macro- and microcirculation parameters were evaluated once in every patient. We used intravital video microscopy to measure dermal capillary density in the dorsum of the fingers. Microvascular endothelial function was assessed by measuring the perfusion

increases after pilocarpine iontophoresis and central hemodynamic parameters by tonometry. Results Capillary density was significantly higher in controlled-per/ind patients (99 ± 12 capillaries/mm2) than in all other groups (P < 0.05). Controlledper/ind patients had a significantly greater endothelial response to pilocarpine than patients from all other groups (P < 0.05). Central hemodynamic parameters were similarly improved in both controlled groups compared with the uncontrolled-other group (P < 0.05). Conclusions Thus, hypertensive patients with blood pressure controlled with the combination per/ind had normalized capillary density and endothelial function, whereas other antihypertensive treatments, excluding ACE inhibitors or diuretics, had less effect despite similar blood pressure control. Keywords: antihypertensive treatments; blood pressure; capillary density; endothelial function; hypertension; microcirculation Am J Hypertens 2010; 23:1136-1143 © 2010 American Journal of Hypertension, Ltd.

The microcirculation mediates the exchange of gases, ­nutrients, and metabolites between blood and tissues, regu­ lates perfusion rates in response to metabolic requirements, determines peripheral vascular resistance, and thus influ­ ences systemic arterial pressure and other components of the macro­circulation. In essential hypertension, arteriole con­ striction and decrease in the number of vessels per unit of ­tissue volume result in increased peripheral resistance.1–3 The microvascular rarefaction participates, in turn, in a reduction of tissue perfusion.4 Microvascular rarefaction, defined as reduced spatial density of microvascular networks, has been a consistent finding in hypertension5,6 and could contribute to the increased systemic vascular resistance observed in hypertension.7–10 1Department of Non-Invasive Investigations, PARCC Inserm U790, Inserm U965, Lariboisière Hospital, AP-HP, University Paris Diderot, Paris, France. Correspondence: Bernard I. Lévy ([email protected])

Received 31 August 2009; first decision 29 October 2010; accepted 24 April 2010; advance online publication 27 May 2010. doi:10.1038/ajh.2010.115 © 2010 American Journal of Hypertension, Ltd. 1136

The inflammation processes and reactive oxygen species involved in essential hypertension impair endothelial func­ tion, especially the nitric oxide pathway, thereby decreasing platelet stabilization and increasing vasomotor tone. Increase in arterial pressure induces changes in the macrocircula­ tion such as increases in large artery stiffness and pulse wave velocity (PWV).7 Thus, alterations of the microcirculation in hypertensives are believed to lead to reduced tissue perfusion and to possible tissue damage and to contribute to changes in ­structure and function of the large arteries. Antihypertensive agents that also have an effect on micro­ vascular remodeling might thus provide significant clinical benefits. Although some classes of antihypertensive agents, such as diuretics, are believed to have little beneficial action on the microcirculation, experimental and clinical studies suggest that other classes of antihypertensive agents, such as angiotensinconverting enzyme (ACE) inhibitors, improve microvessel structure and network density.11–16 Interestingly, the addition of a blood volume–lowering agent, such as a thiazide-like diuretic, to an ACE inhibitor appears to confer additional benefits.17

OCTOBER 2010 | VOLUME 23 NUMBER 10 | 1136-1143 | AMERICAN JOURNAL OF HYPERTENSION

original contributions

Effects of Blood Pressure Control With Perindopril/Indapamide

Perindopril (per) and indapamide (ind) are both welle­ stablished, effective agents that are used as first-line anti­ hypertensive treatments. per is a long-acting ACE inhibitor; ind is an indoline derivative of chlorsulfonamide that has both diuretic and antihypertensive properties. The per/ind combination increased the capillary density in ischemic tissue of spontaneously hypertensive rats and in the myocardium of stroke-prone hypertensive rats.18 In nor­ motensive rats, the per/ind combination also induced an early and sustained effect on the postischemic revasculariza­ tion process.19 In a previous study, we observed an increased ­capillary density in effectively treated essential hypertensive vs. untreated hypertensive patients, suggesting a cause-to-effect relationship between blood pressure and capillary density.9 We thus aimed to test the hypothesis of a specific, non­ pressure dependent, effect of the per/ind combination on micro­circulatory parameters in blood pressure–controlled hypertensive patients receiving per/ind or other antihyper­ tensive agents; comparisons with uncontrolled hypertensive patients and with normotensive control subjects were also per­ formed. An open-label, cross-sectional study using noninva­ sive techniques in a group of patients with different levels of blood pressure and treatment was performed. Methods

Study design. In this open-label, cross-sectional, French, community-based, multicenter, general practitioners enrolled patients at the inclusion visit into one of four groups depend­ ing on their blood pressure status and existing treatment from January 2006 to November 2006 (Figure 1): 1. controlled hypertensive patients treated with per/ind (controlled-per/ind); 2. controlled hypertensive patients treated with antihyper­ tensive agents other than ACE inhibitors alone or ­combined with diuretics (controlled-other); 3. uncontrolled hypertensive patients treated with anti­ hypertensive agents other than ACE inhibitors alone or ­combined with diuretics (uncontrolled-other); and 4. normotensive untreated subjects (normotensive). Existing treatments were maintained, and no indications regarding treatment doses were specified. In order to define a homogenous population for each group, patients in the differ­ ent groups were matched for sex and age. Up to 21 days after inclusion, noninvasive clinical investigations of the micro- and macrocirculation were performed at the Lariboisière Hospital (Paris, France). All patients provided informed consent. The study was performed in accordance with the ethical princi­ ples stated in the Declaration of Helsinki 1964 and revised in Tokyo, 2004; the clinical trial was approved by the local ethical committee and registered (registration CCPPRB no. 05058). Patient population. Caucasian men or women, 45–70 years of age, with a body mass index ≤32 kg/m2 were included. Specific criteria for each group were as follows: patients who had been AMERICAN JOURNAL OF HYPERTENSION | VOLUME 23 NUMBER 10 | OCTOBER 2010

Group 1 Controlled hypertensive patients treated with perindopril/indapamide (N = 50) Group 2

Controlled hypertensive patients treated with antihypertensive drugs other than ACE inhibitors and/or diuretics (N = 52)

Group 3 Uncontrolled hypertensive patients treated with antihypertensive drugs other than inhibitors and/or diuretics (N = 43)

Group 4 Normotensive patients (N = 48)

Day 0 Inclusion visit General practitioners

Up to day 21 Clinical investigations Lariboisiere Hospital

Figure 1 | Study design. In this open-label, cross-sectional, French, prospective study, general practitioners enrolled consecutive patients at the inclusion visit into one of four groups depending on their blood pressure status and existing treatment: (i) controlled hypertensive patients treated with perindopril/indapamide (controlled-per/ind; N = 50); (ii) controlled hypertensive patients treated with antihypertensive agents other than ACE inhibitors alone or combined with diuretics (controlled-other; N = 52); (iii) uncontrolled hypertensive patients treated with antihypertensive agents other than ACE inhibitors alone or combined with diuretics (uncontrolledother; N = 43); (iv) normotensive patients (normotensive; N = 48). Up to 21 days after inclusion, noninvasive clinical investigations of the microcirculation and macrocirculation were performed at the Lariboisière Hospital (Paris, France). ACE, angiotensin-converting enzyme.

controlled (systolic blood pressure (SBP) 6  months and in the controlled-other group if they were receiving for >6 months monotherapy or two-drug therapy that did not include an ACE inhibitor and/or a diuretic. Patients with essential arterial hypertension who had been uncontrolled (SBP >140 and/or DBP >90 mm Hg) for at least 4 months and had undergone treatment for 6 months to 10 years were included in the uncontrolled-other group if they were receiving monotherapy or two-drug therapy that did not include an ACE inhibitor and/or a diuretic. Patients who were normotensive (SBP/DBP 5 cigarettes/ day during the previous 6 months, suffered from alcoholism or drug abuse, presented with recent, clinically significant laboratory abnormalities, or were pregnant, breast-feeding, or at risk of becoming pregnant during the study. Patients were also excluded if they had type 1 or 2 diabetes, secondary hyper­ tension, chronic glaucoma treated with β-blocker eye drops, symptomatic or treated cardiac failure, left ­ventricular hyper­ trophy (defined from electrical and echocardiographic data), chronic or acute renal failure (defined as serum ­creatinine ≥17 mg/l and/or creatinine clearance 2.5 g/l (6.5 mmol/l), Raynaud’s syndrome, lower limb ­arteritis, any cutaneous alteration of hands and forearms, a history of cere­brovascular stroke or transient ischemia within 6 months of inclusion, or a history of coronary artery disease, myocardial infarction, or coronary revascularization in their past. Patients were also excluded if they had a dermatologic or systemic pathology likely to interfere with the microcirculation, such as Ehlers–Danlos disease, Marfan’s syndrome, collagenosis, a history of phlebitis of the upper limb, neuropathy of the upper limb (carpal tunnel syndrome, hemi- or monoplegia, polyra­ diculoneuropathy), or lymphedema of the upper limb. Measurements Inclusion visit: General practitioners measured blood pressure with a mercury sphygmomanometer or an automatic device after at least 10 min of rest. Three measurements were taken at 2-min intervals in the supine position. At least three study visits were required to confirm the diagnosis of controlled or uncontrolled hypertension. Investigational visit: All measurements were performed in the morning at the Lariboisière Hospital on patients who had not yet taken their antihypertensive medication for the day, had fasted for at least 2 h, and had not smoked or had any ­caffeine since the previous evening. Patients remained in a semisupine position for at least 20 min before investigation. Capillary density was assessed by intravital video capillaro­ scopy in the skin of the dorsum of the middle phalanx of the nondominant hand (Figure  2).20 The video microscope was equipped with an epi-illuminated fiberoptic microscope con­ taining a 100 W mercury vapor lamp light source and a M200 objective (Moritex Micro-Scopeman MS-500C; Moritex, Tokyo, Japan) for a final ×200 magnification. Microscopic images were transferred for storage and further analysis via a video image converter (Microvision, Evry, France). For each studied patient, four images corresponding to a microscopic field of 1 mm2 each were analyzed before venous congestion (basal) and during venous congestion. A blood pressure cuff was applied to the wrist, and the cuff was then inflated and maintained at 60 mm Hg for 2 min; further images were then recorded during venous congestion. Skin temperature was monitored throughout the study with a temperature probe on the dorsum of the left index finger (Perimed, Järfälla, Sweden). Intralaboratory reproducibility was better than 2%.9 Endothelium-dependent vasodilation of the microcircu­ lation of the forearm skin was evaluated by pilocarpine ion­ tophoresis in combination with laser Doppler velocimetry (Periflux 5000 system; Perimed). Mean laser Doppler signal, expressed in an arbitrary perfusion unit, was measured under basal conditions (4 min) after iontophoresis of 3 pilocarpine 2% doses (3 × 2 min, endothelium-dependent response) and after heat hyperemia (5 min, endothelium-­independent response). Pilocarpine 2% was delivered with an anodal current (0.1 mA for 10 s) at 2-min intervals. Hyperemia was induced using a heat probe that heated the skin to 44 °C for 5 min. The changes in laser Doppler signal after pilocarpine and heating 1138

Effects of Blood Pressure Control With Perindopril/Indapamide

NS NS P = 0.03

110

P = 0.04 P = 0.02 NS

99 ± 12

100

94 ± 12

92 ± 11 90

80 ± 10 80

70

60

Normotensive N = 48

Controlled-per/ind N = 50

Controlled-other N = 52

Uncontrolled-other N = 43

Figure 2 | Capillary density during venous congestion. Capillary density was assessed by intravital video capillaroscopy in the skin of the dorsum of middle phalanx of the nondominant hand. Mean values ± standard deviations are presented. NS, not significant; other, antihypertensive treatment other than an angiotensin-converting enzyme inhibitor or a diuretic; per/ind, treatment with perindopril/indapamide.

were expressed as percent values of the mean basal signal. We ­ reviously evidenced a close ­correlation between endothelium p function assessed by the flow-­dependent brachial artery dila­ tation and the laser Doppler response to acetylcholine.21 Central hemodynamic parameters were measured by applana­ tion tonometry using the SphygmoCor system (AtCor Medical, previously PWV Medical, West Ryde, Australia). Radial pressure waves were recorded and aortic augmentation index (adjusted to a heart rate of 75 bpm), radial and aortic SBP and DBP, radial and aortic pulse pressure, mean blood pressure, left ventricular ejection time, and subendocardial viability ratio were measured or calculated. Subendocardial blood flow at maximal coronary vasodilatation, i.e., during diastole, is represented by the area between aortic pressure and zero line in diastole. This area is termed the diastolic pressure time index and when multiplied by heart rate is an index of blood supply to left ventricular sub­ endocardial muscle per minute. To assess adequacy of blood flow, however, we must know not only how much blood is sup­ plied, but how much is needed. The needs of a layer of left ven­ tricular muscle for oxygen are roughly proportional to the area under the left ventricular pressure curve in systole. This systolic area may be termed the systolic pressure time index and mul­ tiplied by heart rate it reflects the need of the left ventricle for oxygen per minute. The two areas thus reflect supply (diastolic pressure time index) and demand (systolic pressure time index) and their ratio, called Buckberg’s index, should give information about the adequacy of ­subendocardial blood flow. PWV was calculated from carotid-artery and femoral­artery pulse wave measurements. The carotid–femoral PWV was measured on the right side of the patient and fed into the SphygmoCor system. The transducer was positioned between the common carotid artery at the base of the neck and the ­femoral artery on the same side at the hollow of the groin. OCTOBER 2010 | VOLUME 23 NUMBER 10 | AMERICAN JOURNAL OF HYPERTENSION

original contributions

Effects of Blood Pressure Control With Perindopril/Indapamide

Brachial blood pressure measurements were taken with a semiautomatic oscillometric device (Dinamap Pro 400V2; General Electric, Waukesha, WI) with a cuff on the dominant arm after 15 min of rest. Three readings at 1- to 2-min intervals with the patient in a semisupine position were obtained. SBP, DBP, and mean blood pressure were measured. Statistics. The primary variable was defined as the density of capillaries in the skin after venous congestion. All other microand macrocirculation variables recorded were prospectively defined as secondary criteria. Descriptive statistics were provided for quantitative vari­ ables (mean, standard deviation) and for qualitative variables (number and percentage per class). For capillary density during venous congestion, an analysis of covariance was performed adjusted on basal capillary density and age. Pairwise comparisons between groups were performed using this analysis of covariance model, without adjustment for multiple comparisons in this preliminary approach. For the other criteria, difference between groups was assessed with a two-tailed Student’s t-test for independent samples or with nonparametric test for nonnormal distribution. A type error of 5% was set for all test procedures.

As little information was available about microcirculation parameters in controlled- and uncontrolled-treated hyper­ tensive patients, study cohort size was determined using our previous data from capillary density studies.9,20 Sample size was set at 50 patients per group based on a difference of 6 ­capillaries/mm2 in capillary density and a standard deviation of 10 for a power of 80%. Results Disposition and demographics

Of the 229 patients enrolled in the study, 193 were evaluable. The most frequent reasons for exclusion from the analysis were SBP criteria not respected (n = 14) and antihypertensive medi­ cation not fitting the group’s definition (n = 7). No adverse event–related withdrawals were reported. Overall, patient characteristics were distributed evenly among groups (Table 1). SBP and DBP values were similar in both controlled groups (per/ind and other; P = 0.71). The duration of hypertension ­varied from