Renin inhibition with aliskiren in hypertension: focus on aliskiren/hydrochlorothiazide combination therapy

Figures & data

Figure 1 Renin-angiotensin-aldosterone system and the sites of blockade. Thick arrows indicate main pathways, thin arrows denote alternative pathways and dashed arrows show sites of blockade.

Abbreviations: ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker; AT-R, angiotensin receptor; DRI, direct renin inhibitor; LVH, left ventricular hypertrophy.

Table 1 Medication effects on RAAS pathway

Medication	PRC	PRA	Angiotensinogen	Ang I	Ang II		Aldosterone
β-Blocker	↓	↓	–	↓	↓	↓	↓
ACE-I	↑	↑	↓	↑	↓	↑	↓
ARB	↑	↑	↓	↑	↑	↑	↓
Aliskiren	↑↑	↓↓	–	↓	↓	↓	↓
HCTZ	↑	↑	↓	↑	↑	↑	↑
Aliskiren/HCTZ combination	↑↑↑	↓	–	–	–	–	–

Abbreviations: ACE-I, angiotensin converting enzyme inhibitor; Ang I, angiotensin I; Ang II, angiotensin II; Ang _1–7, angiotensin _1–7; ARB, angiotensin receptor blocker; HCTZ, hydrochlorothiazide; PRA, plasma renin activity; PRC, plasma renin concentration; ↑, increased; ↓, decreased; –, unchanged or unknown.

Table 2 Studies of aliskiren therapy in hypertension

Reference (Year)	Number of patients	Treatment regimen (drug dose in mg)	Study duration	Change in msSBP/msDBP from baseline (mmHg)	Responder rate (%)	Control rate (%)	Δ in PRA from baseline (%)	Δ in PRC from baseline (%)
Kushiro et al (2006)	455	ALI-75	8 weeks	−8.6/−7.2	47.8	–	–	–
		ALI-150		−8.7/−7.8	48.2	–	–	–
		ALI-300		−14.1/−10.7	63.7	–	–	–
		Placebo		−2.9/−3.3	27.8	–	–	–
Oh et al (2007)	672	ALI-150	8 weeks	−13.0/−10.3	59.3	35.9	−79.5	+51.5
		ALI-300		−14.7/−11.1	63.3	41.6	−81.1	+101.6
		ALI-600		−15.8/−12.5	69.3	46.4	−75.0	+228.5
		Placebo		−3.8/−4.9	36.2	20.3	+19.5	0
Gradman et al (2005)	652	ALI-150	8 weeks	−11.4/−9.3	–	37.8	–	–
		ALI-300		−15.8/−11.8	–	50.0	–	–
		ALI-600		−15.7/−11.5	–	45.7	–	–
		IRB-150		−12.5/−8.9	–	33.8	–	–
		Placebo		−5.3/−6.3	–	20.8	–	–
Stanton et al (2003)	226	ALI-37.5	4 weeks	−4.3/−1.9	–	–	−55	–
		ALI-75		−4.1/−0.2	–	–	−60	–
		ALI-150		−10.0/−2.2	–	–	−77	–
		ALI-300		−11.8/−5.7	–	–	−83	–
		LOS-100		−11.4/−5.5	–		+110
Pool et al (2007)	1123	ALI-75	8 weeks	−12.1/−10.3	59.9	36.2	–	–
		ALI-150		−12.1/−10.3	59.3	30.0	–	–
		ALI-300		−15.0/−12.3	68.0	42.3	–	–
		VAL-80		−11.2/−10.5	55.2	37.9	–	–
		VAL-160		−15.5/−11.0	65.5	46.6	–	–
		VAL-320		−16.5/−11.3	63.3	41.7	–	–
		ALI/VAL-75/80		−14.5/−11.8	75.0	43.3	–	-
		ALI/VAL-150/160		−16.6/−12.1	66.7	36.7	–	–
		ALI/VAL-300/320		−18.0/−12.9	75.9	50.0	–	–
		VAL/HCTZ-160/12.5		−18.9/−13.5	79.9	55.2	–	–
		Placebo		−10.0/−8.6	48.3	27.8	–	–
Verdecchia et al* (2007)	355	ALI-75	8 weeks	−8.4/−4.5	–	24.2	–	–
		ALI-150		−7.1/−3.6	–	–	–	–
		ALI-300		−8.7/−3.9	–	36.2	–	–
		LIS-30		−10.2/−6.3	–	–	–	–
Anderson et al (2008)	842	ALI-150 → ALI-300 (optional HCTZ add on)	26 weeks	−17.9/−12.0	–	61.4	–	–
		RAM-5 → RAM-10 (optional HCTZ addon)		−15.2/−13.2	–	53.1	–	–
Strasser et al (2007)	183	ALI-150 → ALI-300 (optional HCTZ add on)	8 weeks	−20.0/−18.5	81.5	–	–	–
		LIS-20 → LIS-40 (optional HCTZ add on)		−22.3/−20.1	87.9	–	–	–
O’Brien et al* (2007)	67	ALI-150	3 weeks	−10.4/−5.8	–	–	−65	–
		RAM-5		−6.1/−5.9	–	–	+95	–
		RAM/ALI-5/150		−14.0/−8.7	–	–	–	–
		IRB-150		−11.4/−6.5	–	–	+175	–
		IRB/ALI-150/150		−14.8/−8.2	–	–	–	–
		ALI/HCTZ-150/25		−18.4/−10.6	–	–	–	–
Oparil et al (2007)	1797	ALI-150 → ALI-300	4 → 8 weeks	−13.0/−9.0	53	37	−73	+468
		VAL-160 →VAL-320		−12.8/−9.7	55	34	−160	+138
		ALI/VAL-150/160 → 300/320 Placebo		−17.2/−12.2	66	49	−44	+912
				−4.6/−4.1	30	16	−18	+19
Chrysant et al (2008)	601	ALI/VAL-300/320 (optional HCTZ add on)	6 months	−22.3/−14.4	–	73.4	–	–
Uresin et al (2007)	837	ALI-150 → ALI-300	4 → 8 weeks	−14.7/−11.3	–	–	−66	–
		RAM-5 → RAM-10		−12.0/−10.7	–	–	−48	–
		ALI/RAM-5/150 → 10/300		−16.6/−12.8	–	–	–	–
Drummond et al (2007)	545(sub-optimal response to 5 mg of AML)	AML-5	6 weeks	5.0/4.8	45.2	22.6	−9.9	–
		AML-10		9.6/8.0	59.9	37.9	+58.0	–
		AML/ALI-5/150		11.0/8.5	64.2	42.8	−74.4	–
Schmieder et al (2007)	1124	ALI-300	12 months	−17.4/−12.2	–	60	–	–
		HCTZ-25		−14.7/−10.3	–	51	–	–
Villamil et al (2007)	2776	ALI-75	8 weeks	−9.4/−8.7	51.9	29.0	−54.2	+164
		ALI-150		−12.2/−8.9	51.9	to	−65.1	+192
		ALI-300		−15.7/−10.3	63.9	46.7	−57.6	+348
		HCTZ-6.25		−11.0/−9.1	53.6	32.5	+3.5	+10
		HCTZ-12.5		−13.9/−10.1	60.6	to	+44.7	+26
		HCTZ-25		−14.3/−9.4	59.0	37.8	+71.9	+108
		ALI/HCTZ-75/6.25		−14.3/−10.8	61.5	–	−54.5	–
		ALI/HCTZ-75/12.5		−15.6/−11.1	63.5	–	–	–
		ALI/HCTZ-75/25		−17.3/−11.5	70.4	37.4	–	–
		ALI/HCTZ-150/6.25		−15.3/−10.4	58.4	to	–	–
		ALI/HCTZ-150/12.5		−17.6/−11.9	69.6	59.5	−−49.6	–
		ALI/HCTZ-150/25		−19.5/−12.7	71.1	–	–	–
		ALI/HCTZ-300/12.5		−19.8/−13.9	80.6	–	–	–
		ALI/HCTZ-300/25		−21.2/−14.3	76.9	–	−62.3	+1211
		Placebo		−7.5/−6.9	45.8	28.1	+0.7	+30
Sica et al (2006)	1951	ALI-150 (optional ↑ to AL-300 by month 2)	11 months	−17.5/−12.5	–	–	–	–
				(ALI-150)
		ALI-300		−18.8/−13.3	–	–	–	–
				(ALI-300)
		(optional HCTZ add on)		−18.7/−12.1 (ALI/HCTZ-300/25)	–	–	–	–
Jordan et al (2007)	490(sub-optimal response to HCTZ-25)	ALI-150 → ALI/HCTZ-300/25	8 weeks	−15.8/−11.9	73.5	56.6	−45	–
		IRB-150 → IRB//HCTZ-300/25		−15.4/−11.3	70.9	54.7	+536.6	–
		AML-5 → AML/HCTZ-10/25		−13.6/−10.3	68.0	45.1	+195.6	–
		Placebo/HCTZ-25		−8.6/−7.9	59.0	34.2	+46.3	–

* utilized mean 24-hour ambulatory SBP/DBP.

Abbreviations: ALI, aliskiren; AML, amlodipine; HCTZ, hydrochlorothiazide; IRB, irbesartan; LIS, lisinopril; LOS, losartan; msDBP, mean sitting diastolic blood pressure; msSBP, mean sitting systolic blood pressure; PRA, plasma renin activity; PRC, plasma renin concentration; RAM, ramipril; VAL, valsartan; Responder rate, msDBP < 90 mmHg and/or ≥10 mmHg reduction from baseline; Control rate, msSBP/msDBP < 140/90 mmHg.

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