Angiotensin II type 1 receptor antagonists in the treatment of hypertension in elderly patients: focus on patient outcomes

Figures & data

Figure 1 Schematic illustration of the RAAS and the main pathways by which RAAS regulates cardiovascular function.^148,149

Abbreviations: ACE, angiotensin-converting enzyme; ACEIs, angiotensin-converting enzyme inhibitors; ARBs, angiotensin receptor blockers; CNS, central nervous system; NE, norepinephrine; RAAS, renin–angiotensin–aldosterone system; RSN, renal sympathetic nerve; ROS, reactive oxygen species.

Table 1 Major clinical trials of angiotensin II type 1 receptor antagonists in the elderly

Study	Patients	Treatment groups	Primary outcome	Results
Comparison with ACEIs
ONTARGET^Citation71	25,620 patients at high risk of coronary, peripheral, or CBV events; mean age 66.4 years	Telmisartan 80 mg/day^a Ramipril 10 mg/day^a Telmisartan 80 mg/day + ramipril 10 mg/day^a	Composite of death from cardiovascular causes, MI, stroke, or hospitalization for HF	Telmisartan 16.7%, ramipril 16.5% RR 1.01 (P = 0.01) Telmisartan + ramipril 16.3% RR 0.99 (P < 0.001)
VALIANT^Citation70	14,703 patients with AMI and clinical HF or EF ≤ 35%; mean age 65 years	Valsartan 247 mg/day^a Captopril 117 mg/day^a Valsartan 116 mg/day + captopril 107 mg/day^a	Mortality from any cause	Valsartan 19.9%, captopril 19.5% HR 1.00 (0.90, 1.1; P = 0.98) Valsartan + captopril 19.3% HR 0.98 (0.89, 1.09; P = 0.73)
OPTIMAAL^Citation69	5477 patients with AMI and HF; mean age 67.4 years	Losartan 45 mg/day^a Captopril 44 mg tid^a	All-cause mortality	Losartan 18%, captopril 16% RR 1.13 (0.99, 1.28; P = 0.07)
ELITE II^Citation62	3152 patients NYHA class II–IV HF, EF ≤ 40%; mean age 71.5 years	Losartan 50 mg/day Captopril 50 mg tid	All-cause mortality, sudden death, or resuscitated arrest	Losartan 17.7%, captopril 15.9% HR 1.13 (0.95, 1.35; P = 0.16)
ELITE^Citation61	722 ACEI naive patients, NYHA class II–IV HF, EF ≤ 40%; mean age 73.5 years	Losartan 42.6 mg/day^a Captopril 122.7 mg/day^a	Tolerability measure of a persisting increase in serum creatinine of 26.5 μmol/L or more (≥ 0.3 mg/dL) on therapy	Losartan 4.8%, captopril 8.7% RR 0.46 (0.05, 0.69; P = 0.035)
Comparison with placebo
TRANSCEND^Citation72	5926 patients at high risk of coronary, peripheral, or CBV events; mean age 66.9 years	Telmisartan 80 mg/day Placebo	Composite of cardiovascular death, MI, stroke, or hospitalization for HF	Telmisartan 15.7%, placebo 17%, HR 0.92 (0.95; P = 0.216)
CHARMPRESERVED^Citation68	3023 patients with CHF (NYHA II–IV) EF > 40%, mean age 67.1 years	Candesartan 4–32 mg/day Placebo	Cardiovascular death or admission to hospital for CHF	Candesartan 11.2%, placebo 11.3%, AHR 0.95 (0.76, 1.18; P = 0.635)
CHARMALTERNATIVE^Citation66	2028 patients with CHF (NYHA II–IV), EF ≤ 40%, mean age 66.5 years	Candesartan 4–32 mg/day Placebo	Composite of cardiovascular death or hospital admission for CHF	Candesartan 26%, placebo 29%, AHR 0.83 (0.70, 0.99; P = 0.033)
Val-HeFTSUBGROUP^Citation60	366 patients with CHF (NYHA II–IV), EF < 40%, LVIDD > 2.9 cm/m^2; mean age 67.2 years	Valsartan 40–160 mg bid Placebo	Time to death and time to composite endpoint of first mortality or morbidity, defined as death, sudden death with resuscitation, hospital admission for HF, or administration of intravenous inotropic or vasodilator drugs for ≥ 4 h without hospital admission	Valsartan 17.3%, placebo 27.1% RR 0.67 (0.64, 1.06; P = 0.017)
Addition of AT1 receptor antagonist to ACEIs
CHARMADDED^Citation67	2548 patients with CHF (NYHA II–IV), EF ≤ 40%; mean age 64 years	Candesartan 4–32 mg/day Placebo	Composite of cardiovascular death or hospital admission for CHF	Candesartan 23.7%, placebo 27.3% RR 0.83 (0.71, 0.97; P = 0.021)
Val-HeFT^Citation63	5010 patients with CHF (NYHA II–IV), EF < 40%, LVIDD > 2.9 cm/m^2; mean age 62.7 years	Valsartan 254 mg/day^a Placebo	Mortality and the combined endpoint of mortality and morbidity, defined as the incidence of cardiac arrest with resuscitation, hospitalization for HF, or receipt of intravenous inotropic or vasodilator therapy for at least 4 h	Valsartan 19.7%, placebo 19.4% RR 1.02 (0.88, 1.18; P = 0.80)

Note:

a Mean daily dose.

Abbreviations: ACEIs, angiotensin-converting enzyme inhibitors; AHR, adjusted hazard ratio; AMI, acute myocardial infarction; bid, twice daily; CBV, cardiopulmonary blood volume; CHARM, Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity; CHF, congestive heart failure; EF, ejection fraction; ELITE, Evaluation of Losartan in the Elderly; HF, heart failure; HR, hazard ratio; LVIDD, left ventricular internal diastolic diameter; MI, myocardial infarction; NYHA, New York Heart Association; ONTARGET, The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial; RR, risk ratio; OPTIMAAL, Optimal Trial in Myocardial Infarction With Angiotensin II Antagonist Losartan; tid, three times daily; TRANSCEND, The Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease; Val-HeFT, Valsartan in Heart Failure Trial; VALIANT, Valsartan in Acute Myocardial Infarction Trial.

Table 2 Pharmacology and pharmacokinetics of ARBs

Drug	Candesartan^Citation132	Eprosartan^Citation141^–^Citation144	Irbesartan^Citation99,Citation145,Citation146	Losartan^Citation52	Olmesartan^Citation147	Telmisartan^Citation107,Citation129,Citation130	Valsartan^Citation100,Citation131
Dosage (mg/day)	8–32	400–800	150–300	25–100	20–40	20–80	80–320
Tmax (h)	3–5	1–3	1.5–2	1–2	1–3	0.5–1	2–4
Half-life (h)	5–9	5–9	11–15	1–3	10–15	20–38	6–9
Vd (L)	0.13	13	53–93	34	17	500–2000	17
Protein binding (%)	>99	98	90–96	>99	99	>99.5	94–97
Metabolism	CYP2C9	2% glucuronide	<20% CYP2C9	14% CYP2C9	None	Glucuronide	10% oxidative
Excretion: renal vs fecal (%)	33–67	7–90	20–80	40–60	35–50	2–98	13–83
Bioavailability (%)	15	13	60–80	33	26–29	40–60	10–35
Active metabolite	Candesartan	No	No	E-3174	Olmesartan	No	No
Receptor antagonism type	Noncompetitive	Competitive	Noncompetitive	Both	Competitive	Noncompetitive	Noncompetitive
Drug interactions	None	None	None	None	None	Digoxin	None

Abbreviations: ARBs, angiotensin receptor blockers; T_max, time to reach peak maximum concentration following drug administration; V_d, volume of distribution.

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