Aliskiren and valsartan combination therapy for the management of hypertension

Figures & data

Figure 1 The renin-angiotensin-aldosterone system.

Abbreviations: DRI, direct renin inhibitor; ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; AT, angiotensin II receptor, type1/2; NO, nitric oxide.

Table 1 Outcomes in cardiovascular disease and renal disease with ACE inhibitors or ARBs

Cardiovascular disease
Study	Patients	Daily treatment regimen	Mean follow-up	Main outcome	Risk reduction versus comparator
HOPE^Citation63	9297 patients at high CV risk	Ramipril 10 mg daily versus placebo	5 years	Composite of MI, stroke, or death	↓22%
CONSENSUS^Citation64	235 patients with severe HF	Enalapril 2.5 to 4 mg versus placebo	188 days	Total mortality	↓27%
SOLVD^Citation65	1284 patients with chronic HF	Enalapril 2.5 to 20 mg	41.4 months	Total mortality	↓16%
Val-HeFT^Citation66	5010 patients with HF receiving standard HF therapy	Valsartan 160 mg versus placebo	23 months	Death and disease plus cardiac arrest, HF hospitalization, or need for IV vasodilators	No difference in mortality ↓13% in combined end point
LIFE^Citation67	9193 hypertensive patients with LVH	Losartan 50–100 mg versus atenolol 50–100 mg	4.8 years	Death, MI, stroke	↓13%
CHARM-alternative^Citation68	2028 patients with chronic HF intolerant of ACE inhibitors	Candesartan 32 mg versus placebo	33.7 months	CV death or HF hospitalization	↓23%
Renal disease
Study	Patients	Daily treatment regimen	Mean follow-up	Main outcome	Risk reduction versus comparator	Annual rate of renal function decline (mL/min/1.73 m^2)
RENAAL^Citation19	1513 patients with type 2 diabetes and nephropathy	Losartan 50–100 mg versus placebo	3.4 years	Doubling of SCr, ESRD, or death	16%	Losartan: ↓4.4 Placebo: ↓5.2
IDNT^Citation69	1715 hypertensive patients with type 2 diabetes and nephropathy	Irbesartan 300 mg, amlodipine 10 mg, or placebo	2.6 years	Doubling of SCr, ESRD, or death	20% versus placebo 23% versus amlodipine	Irbesartan: ↓5.5 Amlodipine: ↓6.8 Placebo: ↓6.5

Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; CV, cardiovascular; MI, myocardial infarction; HF, heart failure; IV, intravenous; LVH, left ventricular hypertrophy; SCr, serum creatinine; ESRD, end-stage renal disease.

Table 2 Outcome studies that included combination treatment with ACE inhibitors and ARBs

Cardiovascular disease
Study	Patients	Daily treatment regimen	Mean follow-up	Main outcome	Main findings with combination therapy
VALIANT^Citation70	4909 4909 4885 Acute MI patients with HF/LVD	Valsartan Captopril Both	24.7 months	Death	Combination did not improve survival relative to either monotherapy (19%–20% in each group died) or other key secondary outcomes despite additional BP lowering. The combination group experienced more AEs than either monotherapy group
CHARM-added^Citation71	2548 patients with HF and LVD receiving ACE inhibitor	Candesartan or placebo	41 months	CV death or HF hospitalization	Outcomes experienced by 42% of patients in placebo group and 38% in candesartan group (P = 0.011). Combination produced larger BP reductions but caused more patients to discontinue treatment for AEs (24% versus 18%; P = 0.0003)
Val-HeFT^Citation66	5010 patients with HF	Valsartan 160 mg vs placebo	23 months	Death and death plus cardiac arrest, HF hospitalization, or need for vasodilators	Among the 366 patients who were receiving an ACE inhibitor plus a β-blocker, valsartan adversely affected total risk of death; among the 366 patients not receiving an ACE inhibitor, valsartan ↓ risk for death 33% and composite end point 44% (versus 0% and ↓13% for combined valsartan/ACE inhibitor)
ONTARGET^Citation31	8576 8542 8502 Patients with vascular disease or high-risk diabetes without HF	Ramipril 10 mg Telmisartan 80 mg Both	56 months	Composite of CV death, MI, stroke, or HF hospitalization	Primary outcome occurred to a similar degree in each group (16.3%–16.7% patients) Compared with ramipril, greater rates of hypotensive symptoms with combination (4.8%) (1.7%; P < 0.001) and renal dysfunction (13.5% versus 10.2%; P < 0.001)
Renal outcomes
CALM^Citation72	199 patients with hypertension, type 2 diabetes, and MAU	Candesartan or lisinopril, followed by candesartan, lisinopril, or the combination	12 weeks	Change in UACR and BP	UACR reduced 50% with combination, 24% with candesartan, and 39% with lisinopril (P = 0.04 for combination vs candesartan and >0.20 versus lisinopril BP reduced 25.3/16.3, 14.1/10.4, and 16.7/10.7 mmHg with combination, candesartan and lisinopril (P ≤ 0.005 for either monotherapy versus combination)
IMPROVE^Citation73	405 hypertensive, high risk CV patients with MAU	Ramipril plus irbesartan Ramipril plus placebo	20 weeks	Change in UAER	UAER reduced 46% with combination versus 42% with ramipril/placebo; P = 0.540 AEs similar between groups
ONTARGET^Citation32	8576 8542 8502	Ramipril 10 mg Telmisartan 80 mg Both	56 months	Composite renal outcome of doubling of SCr, ESRD, or death	Main outcome occurred most frequently with combination (14.5%; P = 0.037) versus 13.4% with telmisartan and 13.5% with ramipril eGFR decrease (mL/min/1.73m^2): ramipril, −2.82; telmisartan, −4.12; combination, −6.11; (P < 0.001 comparisons with ramipril) Worse outcomes despite reduced proteinuria with combination therapy Combination had no clear benefit in overt diabetic nephropathy

Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; MI, myocardial infarction; HF, heart failure; LVD, left ventricular dysfunction; BP, blood pressure; AE, adverse event; MAU, microalbuminuria; UACR, urinary albumin/creatinine ratio; CV, cardiovascular; UAER, urinary albumin excretion rate; AEs, adverse events; SCr, serum creatinine; ESRD, end stage renal disease; eGFR, estimated glomerular filtration rate.

Figure 2 Time course of plasma renin activity in normotensive volunteers after administration of aliskiren 300 mg (open circles), valsartan 160 mg (diamonds), aliskiren 150 mg plus valsartan 80 mg (closed circles), and placebo (triangles). Reprinted with permission from Azizi M, Ménard J, Bissery A, et al. Pharmacologic demonstration of the synergistic effects of a combination of the renin inhibitor aliskiren and the AT1 receptor antagonist valsartan on the angiotensin II-renin feedback interruption. J Am Soc Nephrol. 2004;15(12):3126–3133.⁴⁴ Copyright © 2004 American Society of Nephrology.

Notes: A, aliskiren; V, valsartan.

Figure 3 Effects of antihypertensive agents on plasma renin activity in patients with hypertension.^{37,38,45,60–62}

Notes: CCB, calcium channel blocker; HCTZ, hydrochlorothiazide; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; DRI direct renin inhibitor.

Table 3 Laboratory abnormalities occurring during treatment with placebo, aliskiren 300 mg daily, valsartan 320 mg daily, or the combination of aliskiren 300 mg/valsartan 320 mg: results from an 8-week randomized, double-bind, placebo-controlled study and a 6-month, open-label study in patients with hypertension^47,49

Laboratory abnormality	Number (%) of patients
	8-week study^Citation47				6-month, open-label study^Citation49
	Placebo n = 458	Aliskiren n = 437	Valsartan n = 455	Aliskiren/valsartan n = 446	Aliskiren/valsartan n = 396	Aliskiren/valsartan/HCTZ n = 588
Potassium
<3.5 mmol/L	17 (4)	11 (3)	20 (4)	12 (3)	6 (1.5)	13 (6.8)
>5.5 mmol/L	12 (3)	7 (2)	7 (2)	18 (4)	10 (2.5)	2 (1.0)
≥6.5 mmol/L	6 (1)	4 (1)	5 (1)	2 (0.5)	1 (0.3)	0
Creatinine >176.8 μmol/L	0	1 (0.2)	2 (0.4)	4 (0.9)	1 (0.3)	1 (0.5)
Blood urea nitrogen >14.3 mmol/L	0	1 (0.2)	1 (0.2)	0	1 (0.3)	2 (1.0)

Abbreviation: HCTZ, hydrochlorothiazide (up to 25 mg daily).

Table 4 Cardiovascular morbidity and mortality outcome studies with aliskiren in the ASPIRE HIGHER program

Study	Patients	n	Intervention	Primary outcome	Planned follow-up
ALTITUDE	Type 2 diabetes and at high risk for fatal and nonfatal cardiorenal events	8600	Aliskiren 300 mg or placebo on top of conventional treatment (ACE inhibitor or ARB plus others)	Time to first event of CV death, resuscitated sudden death, MI, stroke, unplanned HF hospitalization, ESRD, renal death, doubling of SCr sustained for ≥1 month	4 years
ATMOSPHERE	Chronic HF	7041	Aliskiren 300 mg, enalapril 10 mg, or a combination	Time to first event of CV death or HF hospitalization	4 years
ASTRONAUT	Hospitalized for worsening HF	1782	Aliskiren 300 mg or placebo on top of standard therapy	Time to first occurrence of CV death or HF rehospitalization within 6 months	6 months
APOLLO	Elderly patients with normal to high BP and high CV risk		Study in development

Abbreviations: ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker; CV, cardiovascular; MI, myocardial infarction; HF, heart failure; ESRD, end stage renal disease; SCr, serum creatinine; BP, blood pressure.

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