First-line treatment of hypertension: critical appraisal of potential role of aliskiren and hydrochlorothiazide in a fixed combination

Figures & data

Table 1 Effects of RAAS blockers and common antihypertensive agents on different RAAS components

Agent	PRC	PRA	Angiotensinogen	Angiotensin I	Angiotensin II	Angiotensin 1–7	Aldosterone
β-blockers	↓	↓	–	↓	↓	↓	↓
Calcium antagonists	↑	↑	↓	↑	↑	↑	↑
Diuretics	↑	↑	↓	↑	↑	↑	↑
ACEi	↑	↑	↓	↑	↓	↑	↓
ARBs	↑	↑	↓	↑	↑	↑	↓
Aliskiren	↑↑	↓	–	↓	↓	↓	↓
Aliskiren-HCTZ	↑↑↑	↓	–	↓	↓	↓	↓

Abbreviations: ACEi, angiotensin-converting-enzyme inhibitors; ARB, angiotensin receptor blocker; HCTZ, hydrochlorothiazide; PRC, plasma renin concentration; PRA, plasma renin activity; RAAS, renin-angiotensin-aldosterone system.

Figure 1 Schematic illustration of the RAAS and the sites of its blocking for existing RAAS blockers. Shown also are the alternative pathways, which are possibly activated through increase of the different components of the RAAS due to the actions of RAAS blocking agents (see also Table 1). Increased renin concentration in the blood can lead to stimulation of the (pro)renin receptor, which leads to intracellular activation of apoptosis, hypertrophy, and fibrosis pathways. Increase of angiotensin II and its metabolites leads to stimulation of alternative receptors which have different effects on vasoconstriction, endothelial function, hypertrophy, and inflammation.

Abbreviations: ACEi, angiotensin-converting-enzyme inhibitor; ARB, angiotensinreceptor blocker; AT-R, angiotensin receptor.

Table 2 Important studies comparing the effects of the aliskiren/hydrochlorothiazide combination with other treatment regimens

Reference	Patients (n)	Regimen	Results
Villamil^Citation31	2776	Ali 75-150-300 HCTZ 6.25-12.5-25 Ali-HCTZ all comb. except 300/6.25	Comparable doses of Ali and HCTZ equally effective in lowering BP, comb; achieved further BP reduction
Jordan^Citation32	489 obese pts already on HCTZ 25 mg	Ali-HCTZ 300/25 Irb-HCTZ 300/25 Aml-HCTZ 10/25 HCTZ 25	All combinations equally effective in lowering BP and better than HCTZ alone; Aml-HCTZ less tolerable due to edema, hypokalemia
Duprez^Citation45	901 elderly pts (>65 years)	Ali 150 → 300 Ramipril 5 → 10 Add-on HCTZ 25 after 12 weeks and Aml 10 mg after 22 weeks, if needed	Ali group achieved target BP with the addition of fewer drugs
Strasser^Citation55	183 pts with severe hypertension (>180/110 mmHg)	Ali 150 → 300 Lis 20 → 40 Add-on HCTZ 25 as needed	Ali and Lis equally effective in lowering BP, HCTZ addon in similar number of pts in both groups needed
Nickenig^Citation46	880 pts unresponsive to Ali 300 alone	Single-pill Ali-HCTZ 300/12.5 or 300/25 versus Ali 300 alone	Single-pill comb more effective in BP lowering than monotherapy, similarly well tolerated
Blumenstein^Citation47	722 pts unresponsive to HCTZ 25 alone	Single-pill Ali-HCTZ 150/25 or 300/25 versus HCTZ 25 alone	Single-pill more efficient in lowering BP than monotherapy, similarly well tolerated, less hypokalemia with the single-pill combination

Note: Arrows indicate uptitration of the drug from the initial to the final dose.

Abbreviations: Ali, aliskiren; Aml, amlodipine; BP, blood pressure; HCTZ, hydrochlorothiazide; Irb, irbesartan; Lis, lisinopril; pts, patients.

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DuprezDAMungerMABothaJKeefeDLCharneyANAliskiren for geriatric lowering of systolic hypertension: A randomized controlled trialJ Hum Hypertens201024960060820033075

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StrasserRHPuigJGFarsangCCroketMLiJvan IngenHA comparison of the tolerability of the direct renin inhibitor aliskiren and lisinopril in patients with severe hypertensionJ Hum Hypertens2007211078078717541390

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NickenigGSimanenkovVLemboGEfficacy of aliskiren/hydrochlorothiazide single-pill combinations in aliskiren non-respondersBlood Press Suppl20082314019203020

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BlumensteinMRomaszkoJCalderonAAntihypertensive efficacy and tolerability of aliskiren/hydrochlorothiazide (HCT) single-pill combinations in patients who are non-responsive to HCT 25 mg aloneCurr Med Res Opin200925490391019245300

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