Journal of Non Invasive Vascular Investigation Category: Clinical Type: Research Article
Effects of Candesartan versus Amlodipine on Capillary Rarefaction, Pulse Wave Velocity and Central Blood Pressure in Patients with Essential Hypertension
- Tarek F Antonios1*, Rajendra P Raghuraman2, Christine Carney3, Helen Mullahy3, Oluwabusola Ogunseitan3, Duolao Wang4
- 1 Department Of Clinical Sciences, Tarek F Antonios, Blood Pressure Unit, St George’s University Hospitals NHS Foundation Trust Vascular Biology Research Centre, Molecular&Clinical Sciences Research Institute,St. George’s, University Of London, , St George’s University Hospitals NHS Foundation Trust, London SW17 0RE, United Kingdom
- 2 Department Of Clinical Sciences, Vascular Biology Research Centre, Molecular & Clinical Sciences Research Institute, St George’s University Hospitals NHS Foundation Trust, London, United Kingdom
- 3 Blood Pressure Unit, St George’s University Hospitals NHS Foundation Trust, London, United Kingdom
- 4 Biostatistics Unit, Liverpool School Of Tropical Medicine, United Kingdom
*Corresponding Author:Tarek F Antonios
Department Of Clinical Sciences, Tarek F Antonios, Blood Pressure Unit, St George’s University Hospitals NHS Foundation Trust Vascular Biology Research Centre, Molecular&Clinical Sciences Research Institute,St. George’s, University Of London, , St George’s University Hospitals NHS Foundation Trust, London SW17 0RE, United Kingdom
Tel: +44 208725 5627,
Fax:+44 208 725 2722
Received Date: Jun 29, 2017 Accepted Date: Aug 03, 2017 Published Date: Aug 21, 2017
Methods: We recruited twenty-two individuals with mild-to-moderate hypertension. After a 2-week placebo run-in period, patients who remained hypertensive (≥140/90 mmHg) were randomized to 8-weeks treatment with Candesartan tablets 8mg daily (with forced titration to 16mg) or Amlodipine tablets 5mg daily (with forced titration to 10mg). The capillary microcirculation was studied using CapiScope system CAM1. Pulse wave velocity, central BP and aortic Augmentation Index were also measured.
Results: We observed significant reductions in brachial BP, and central BP after 4 and 8 weeks treatment with either candesartan or amlodipine but there was no significant effect on basal (functional) or maximal (structural) capillary densities, or pulse wave velocity.
Conclusion: Eight weeks treatment of hypertension with either amlodipine or candesartan significantly reduced brachial and central BP but was not sufficient to induce a regression in functional or structural microvascular abnormalities.
ARB = Angiotensin Receptor Blocker
ACEi = Angiotensin Converting Enzyme inhibitor
BCD = Basal Capillary Density
BP = Blood Pressure
CCB = Calcium Channel Blocker
CI = Confidence Intervals
cSBP = Central Aortic Pressure
MCD = Maximal Capillary Density
PWV = Pulse Wave Velocity
SHR = Spontaneously Hypertensive Rats
SE = Standard Error
The aim of the CAMIRA trial was to assess in a randomized, double blind, placebo controlled two-arm parallel group clinical trial. The effects of treatment of hypertension with the Angiotensin Receptor Blocker (ARB) candesartan versus the dihydropyridine Calcium Channel Blocker (CCB) amlodipine on micro vascular rarefaction and other indices of vascular function in individuals with mild-to-moderate essential hypertension.
After a 2-weeks single-blind placebo run-in period, patients who remained hypertensive (systolic BP 140–180 mmHg and/or diastolic BP 90-110 mmHg) were randomized to 8-weeks treatment with either candesartan 8mg orally once daily (with forced titration to 16mg once daily after 2 weeks) or amlodipine 5mg orally once daily (with forced titration to 10mg once daily after 2 weeks). Total study duration was 10 weeks.
Blood pressure measurement
Intravital capillary microscopy studies (Capillaroscopy)
Maximization of capillaries
Carotid-Femoral Pulse Wave Velocity (PWV) measurements
Aortic Augmentation Index (AI) & central Aortic Pressure (cSBP)
Statistical significance was declared when the p-value was <0.05. All statistical analysis was carried out using the IBM SPSS 22, USA.
|Waist circumference, cm||101.4(13.0)|
|Hip circumference, cm||107.3(11.9)|
|Blood Pressure, mmHg|
|Mean Blood Pressure, mmHg|
|Heart rate, beats/m||72.1(10.1)|
|Ischaemic Heart Disease||10(47.6%)|
|Serum sodium, mmol/L||139.6(2.0)|
|Serum potassium, mmol/L||4.3(0.3)|
|Serum glucose, mmol/L||4.8(0.56)|
|Total cholesterol, mmol/L||5.1(1.0)|
|24h Urinary sodium, mmol||115(72)|
|24h Urinary potassium, mmol||53(18)|
At the end of the 2 weeks single blind placebo run-in period mean sitting BP was144/94±14/9mmHg (p=0.07 and p=0.057 respectively compared to baseline levels). In six subjects the BP dropped significantly on placebo, so much so they did not meet the inclusion criteria and were therefore excluded form the randomized phase. There were no significant changes in other clinical or laboratory parameters. Table 2 shows the baseline characteristics of the randomized subjects. In total 9 subjects were randomized to candesartan and 6 subjects were randomized to amlodipine. Table 3 shows the longitudinal changes in BMI, sitting and standing systolic and diastolic BP, pulse rate, central systolic BP, PWV, basal and maximal capillary densities and aortic augmentation from baseline.
|Variable||All (N=15)||Amlodipine Group (N=6)||Candesartan Group (N=9)|
|Male, n (%)||5(33.3)||2(33.3)||3(33.3)|
|Waist circumference, cm||101.5(12.3)||95.3(9.9)||105.7(12.4)|
|Hip circumference, cm||110.7(7.7)||109.0(1.5)||111.8(9.9)|
|Heart rate, b/m||72.6(8.3)||66.2(6.0)||76.9(6.8)|
|Smoking n (%)|
|Ischaemic heart disease||7(46.7)||3(50.0)||4(44.4)|
|Blood pressure, mmHg|
|Central blood pressure,||144/92(14/10)||139/94(16/14)||148/91(13/6)|
|Pulse wave velocity, m/sec||9.7(1.2)||9.5(1.3)||9.9(1.2)|
|Basal Capillary Density (per field)||49.6(6.2)||51.7(5.5)||48.1(6.5)|
|Maximal Capillary density (per field)||53.2(6.7)||53.8(7.8)||52.7(6.2)|
|Results are presented as Mean (SD)|
|Variable||All||Candesartan||Amlodipine||Between Groupst testp-value||t-test Overallp-value|
|Mean (SE) change||Mean (SE) change||Mean (SE) change|
|Sitting Systolic BP (mmHg)|
|4 weeks treatment||-19.0(3.7)||-19.4(5.6)||-18.5(4.8)||0.25||<0.0001|
|8 weeks treatment||-26.3(4.0)||-29.4(5.6)||-21.8(5.4)||0.94||<0.0001|
|Sitting Diastolic BP (mmHg)|
|4 weeks treatment||-13.8(1.8)||-11.8(2.5)||-16.5(2.5)||0.93||<0.0001|
|8 weeks treatment||-16.1(1.3)||-15.9(1.8)||-16.4(2.3)||0.49||<0.0001|
|Sitting Mean BP (mmHg)|
|4 weeks treatment||-15.0(2.4)||-14.5(3.3)||-15.8(3.8)||0.8||<0.0001|
|8 weeks treatment||-18.7(2.4)||-20.6(2.7)||-16.1(4.5)||0.39||<0.0001|
|Standing Systolic BP (mmHg)|
|4 weeks treatment||-21.9(5.0)||-24.8(5.3)||-17.4(10.2)||0.63||<0.0001|
|8 weeks treatment||-26.5(4.8)||-30.1(4.0)||-20.3(11.6)||0.88||<0.0001|
|Standing Diastolic BP (mmHg)|
|4 weeks treatment||-11.8(2.5)||-11.0(3.2)||-13.2(4.4)||0.99||<0.0001|
|8 weeks treatment||-16.1(2.1)||-16.4(1.8)||-15.5(5.4)||0.24||<0.0001|
|Basal Capillary Density (capillaries per field)|
|4 weeks treatment||-0.4(1.4)||0(1.5)||-1.0(2.8)||0.73||0.76|
|8 weeks treatment||1.2(1.6)||2.2(2.1)||-0.2(2.7)||0.48||0.48|
|Maximal Capillary Density (capillaries per field)|
|4 weeks treatment||1.5(1.7)||0.4(2.0)||3.0(3.0)||0.48||0.38|
|8 weeks treatment||1.8(1.3)||0.6(1.6)||3.5(2.3)||0.3||0.2|
|Pulse Wave Velocity (meters per second)|
|4 weeks treatment||-0.1(0.3)||-0.3(0.5)||0.04(0.4)||0.8||0.67|
|8 weeks treatment||0.1(0.4)||0.5(0.5)||-0.5(0.7)||0.25||0.79|
|Central Systolic BP (mmHg)|
|4 weeks treatment||-18.4(4.8)||-18.5(7.3)||-18.2(5.3)||0.98||0.002|
|8 weeks treatment||-22.6(4.0)||-24.9(6.0)||-18.8(4.2)||0.5||<0.0001|
|Augmentation Index (%)|
|4 weeks treatment||-7.6(2.5||-4.3(3.2)||-13.0(2.7)||0.09||0.01|
|8 weeks treatment||-9.2(2.0)||-8.4(3.1)||-10.5(1.7)||0.64||0.001|
Blood pressure changes
Central systolic blood pressure and aortic augmentation changes
Pulse wave velocity
Capillary density changes
Preclinical studies have suggested that treatment with antihypertensive medications may reverse or even prevent microvascular rarefaction, although inconsistent results were obtained with different classes of drugs . One study that compared the effects of different antihypertensive treatments on capillary density in Spontaneously Hypertensive Rats (SHR) led to the conclusion that despite their similar effectiveness in decreasing BP, functional rarefaction was reversed by losartan, nifedipine and enalapril, while structural rarefaction was normalized only by losartan and enalapril while atenolol had no noticeable effect . It was therefore suggested that dihydropyridine CCB and rennin-angiotensin system blockers were effective in this regard, while data on diuretics and beta-blockers were inconclusive. These selective desirable effects on the microcirculation have been implicated in explaining the beneficial effects of these drugs in reducing micro albuminuria and preserving renal function.
Very little, however, is known about the effects of treatment of human essential hypertension on capillary rarefaction which may be related to end-organ damage, as suggested by the association between hypertensive myocardial disease and reduced myocardial capillary density . Few observational and open label studies have shown inconsistent or even contradictory results about the reversal of microvascular rarefaction with antihypertensive treatments [10,13,20,21]. It was postulated that treatment of hypertension and a reduction in BP represents a necessary but not a sufficient circumstance for inducing a regression in microvascular abnormalities, because drugs with similar hemodynamic profile may have dissimilar effects on small artery morphology . In a previous open-label pilot study in individuals with treatment-naive mild-to-moderate essential hypertension, we found that 6-weeks treatment with the ARB irbesartan resulted in significant lowering of both systolic and diastolic BP and significant increase in maximal capillary density (with venous congestion) . In another observational study we reported that capillary density was 25-30% higher in treated compared with untreated hypertensive patients but was significantly lower than in age-matched normotensive controls .
Debbabi and colleagues, in an observational study, evaluated skin capillary density in hypertensive patients who were treated with different antihypertensive drugs and who had their BP well controlled below 140/90mmHg for at least 12 months. They found that basal (functional) and maximal (structural) skin capillary densities in treated hypertensive patients were significantly higher when compared to never-treated hypertensive patients or to normotensive subjects. 20 The finding of a higher capillary density in treated hypertensive patients is very curious and rather difficult to construe . In another open-label cross-sectional study the same group reported that only hypertensive patients who were treated and adequately controlled with perindopril/indapamide combination for more than 6 months had significantly higher maximal capillary density than both patients treated and controlled by other drugs, and normotensive individuals . They suggested that the normalization of the skin capillary density could be, at least partially, BP independent as equivalent BP control is not synonymous with equivalent microvascular benefits and suggest different long-term results for end-organ damage. Of interest in their study is that most of the patients in the controlled-other group (48%) were treated with an ARB .
Several other studies have shown similar negative effects of ARBs on capillary rarefaction. Kaiser and colleagues in an open-label randomized design studied skin capillary density in 44 subjects with mild to moderate essential hypertension before and after six months treatment with either a beta-blocker (metoprolol) or an ARB (olmesartan) . Interestingly, they found that only treatment with metoprolol resulted in a significant reversal of rarefaction and an increase in capillary density whilst treatment with olmesartan had no significant effect on capillary density. Treatment with valsartan showed conflicting results as one study showing significant increase in capillary density after only 4 weeks while another study showed no significant effect on capillary density [25,26]. These results are interesting in that they contradict what has been suggested that drugs that block the rennin-angiotensin system e.g. ACEi and ARBs may be more efficacious than other drugs such as beta-blockers in reversing the microcirculatory abnormalities in hypertension .
On the other hand, several other studies have shown no effect of hypertension treatment on capillary rarefaction. Penna et al., evaluated functional and structural capillary density in treated and well-controlled patients with essential hypertension . They found that treated hypertensive patients had lower mean functional capillary density at baseline, during post-occlusive reactive hyperemia and during venous congestion suggesting that treatment and control of BP, regardless of the type of therapy used, does not necessarily results in reversing capillary rarefaction. De Ciuceis and colleagues, in an open-label design, studied the effects of treatment of hypertension on structural alterations of retinal arterioles, skin capillary density, arterial dispensability and oxidative stress with a CCB alone and the combination of a CCB with either an ACE inhibitor or a diuretic in patients with mild to moderate essential hypertension . All their patients were treated with lercanidipine for 4 weeks and then either enalapril (n=10) or hydrochlorothiazide (n=10) was added for 6 months. They found no change in basal capillary density at any point in the study. After 4 weeks of treatment with lercanidipine alone, maximal capillary density was slightly but not significantly increased. After 6 months of treatment with the combination of lercanidipine and enalapril, the increase in maximal capillary density was statistically significant. The change in maximal capillary density with the combination of lercanidipine and hydrochlorothiazide was not statistically significant. Similar to our study, the authors found no change in PWV between groups or between any time points despite the fact that central SBP was significantly reduced. More recently, the same group, in another randomized open-label design, studied the effects of one-year treatment of hypertension with either ramipril or aliskiren and found no significant effects on capillary rarefaction . The results from our present study and the aforementioned studies suggest that the reduction and normalization of BP values may not be sufficient for obtaining a regression of microvascular rarefaction in essential hypertension even after one year . These findings also suggest that the improvement of capillary rarefaction and other microcirculatory abnormalities with selective ARBs or ACEi drugs may not represent a class effect but rather drug-specific additional properties of these particular drugs on the microcirculation . Our finding of no significant change in PWV in treated hypertensive patients is not novel, as other groups have found similar results [10,30-32].
We acknowledge that our study has several limitations. Our inability to find a significant effect of both candesartan and amlodipine treatment on capillary rarefaction can be feasibly explained by the small number of subjects who completed the study (type 2 error) or the shorter duration of active treatment with these 2 drugs. Additionally we could not rule out any persisting effects of previous antihypertensive medications our subjects received before enrolling in this study. It is also conceivable that amlodipine and candesartan may genuinely lack substantial microvascular effects as other studies have shown that treatment with amlodipine did not improve coronary flow reserve in hypertensive patients [33,34]. Similarly in the spontaneously hypertensive rat amlodipine and candesartan did not show any significant reverse arteriolar remodeling compared to placebo .
In conclusion, this study has shown that 4 weeks and 8 weeks treatment with candesartan or amlodipine resulted in significant reductions of both systolic and diastolic brachial BP and central systolic BP but had no significant effect on basal (functional) or maximal (structural) capillary densities. These results indicate that normalization of BP with amlodipine or candesartan treatment does not necessarily results in reversal of capillary rarefaction in essential hypertension. The study also showed that both candesartan and amlodipine significantly reduced Aortic Augmentation Index but had no significant effect on pulse wave velocity.
CONFLICTS OF INTEREST AND SOURCE OF FUNDING
Details of ethics approval: The London-Surrey Borders Research Ethics committee approved this study. (REC: 08/H0806/72)
Trial registration: (EUDRACT: 2008-005432-32, ISRCTN 62554526)
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Citation:Raghuraman RP, Carney C, Mullahy H, Ogunseitan O, Wang D, et al. (2017) Effects of Candesartan versus Amlodipine on Capillary Rarefaction, Pulse Wave Velocity and Central Blood Pressure in Patients with Essential Hypertension. J Non Invasive Vasc Invest 2: 008.
Copyright: © 2017 Tarek F Antonios, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.