Indications for and utilization of angiotensin receptor II blockers in patients at high cardiovascular risk

Figures & data

Figure 1 Scheme of the renin-angiotensin system.

Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blockers; NO, nitric oxide; SNS, sympathetic nervous system; tPA, tissue plasminogen activator; AT₁, angiotensin II type 1 receptor; AT₂, angiotensin II type 2 receptor.

Table 1 Comparative pharmacokinetic properties of angiotensin II receptor blockers^43,128

Drug	tmax(h)	Bioavailability (%)	t½ (h)	Vd (L)	Interaction with food	Elimination (feces/urine)
Losartan	1 (3–4)*	33	2 (4–6)*	34 (12)*	No	60/35
Valsartan	2	23	7	17	No	83/13
Irbesartan	1–2	60–80	12–20	53–93	No	80/20
Candesartan	3–5	42	9–13	0.13 L/kg	No	67/33
Eprosartan	2–6	13	5–7	308	No	90/10
Telmisartan	1	43	24	500	No	>98% fecal
Olmesartan	1.4–2.8	26^†	11.8–14.7	14.7–19.7	No	35%–49% urinary recovery rate^‡
Azilsartan	1.5–3	60	11	16	No	55/42

Notes:

* Values in parentheses are for EXP 3174, the active metabolite of losartan;

† olmesartan medoxomil;

‡ intravenous olmesartan.

Abbreviations: PK, pharmacokinetic; ARB, angiotensin II receptor blocker; t_½, terminal elimination half-life; t_max, time to maximum plasma concentration; V_d, volume of distribution.

Table 2 Patient characteristics and findings from selected outcomes trials of angiotensin II receptor blockers in patients at different stages of the cardiovascular and renal disease continua^{17–20,22,25–27,67–78}

Study	Patient characteristics	Treatments	Primary outcomes
Studies in patients with hypertension and other complications
LIFE^Citation22	Patients aged 55–80 years, with essential hypertension and LVH; n = 9193	Losartan- or atenolol-based antihypertensive regimen; mean follow-up: 4.8 years	Significant reduction in composite endpoint of CV death, MI, or stroke with losartan-based regimen versus atenolol-based regimen
VALUE^Citation74	Patients aged ≥50 years, with hypertension and a high risk of cardiac events based on the presence qualifying risk factors; n = 15,313	Valsartan- or amlodipine-based antihypertensive regimen; mean follow-up: 4.2 years	No significant difference between treatments for the composite endpoint of cardiac morbidity and mortality. Amlodipine demonstrated superior efficacy compared with valsartan on the incidence of MI, which was most likely a BP-related effect
The Kyoto Heart Study^Citation75	Patients aged ≥20 years, with uncontrolled hypertension and high CV risks; n = 3031	Valsartan- or non-ARB-based antihypertensive regimen; median follow-up 3.27 years	Significant reduction in the composite endpoint of fatal and nonfatal CV events with the valsartan-based regimen versus the non-ARB-based regimen. Relatively soft endpoints driving the results and the open-label design have been a source of criticism
IRMA2^Citation20	Patients aged 30–70 years, with T2DM, hypertension and persistent microalbuminuria; n = 590	Irbesartan or placebo on a background of antihypertensive treatment; median follow-up 2.0 years	Significant reduction in the primary endpoint of a UAE rate >200 μg/min that was 30% higher than baseline with irbesartan vs placebo. Findings confirmed in a substudy using 24-hour ABPM^Citation61
RENAAL^Citation21	Patients aged 31–70 years, with T2DM, hypertension and diabetic nephropathy; n = 1513	Losartan or placebo on a background of antihypertensive treatment; mean follow-up 3.4 years	Significant reduction in the primary composite endpoint of a doubling of the baseline serum creatinine concentration, the development of ESRD, or all-cause mortality with losartan vs placebo (−16%)
IDNT^Citation19	Patients aged 30–70 years, with T2DM, hypertension and diabetic nephropathy; n = 1715	Irbesartan or amlodipine or placebo on a background of antihypertensive treatment; mean follow-up 2.6 years	Significant reduction in the primary composite endpoint of a doubling of the baseline serum creatinine concentration, the development of ESRD or all-cause mortality with irbesartan vs amlodipine (−23%) and with irbesartan vs placebo (−20%)
DETAIL^®^Citation24	Patients aged 35–80 years, with T2DM, mild to moderate hypertension and early nephropathy; n = 250	Telmisartan or enalapril on a background of antihypertensive treatment; mean/median follow-up not available	Equivalent reduction in the primary endpoint of the change in the GFR from baseline during 5 years of treatment with telmisartan vs enalapril
AMADEO^®^Citation27	Patients aged 21–80 years, with T2DM, hypertension, or on antihypertensive drugs and overt nephropathy; n = 860	Telmisartan or losartan on a background of antihypertensive treatment mean follow-up 0.89 years	Significant reduction in the primary endpoint of the difference in the urinary albumin to creatinine ratio from baseline to week 52 with telmisartan vs losartan despite similar BP reductions in the 2 groups
VIVALDI^®^Citation77	Patients aged 30–80 years, with T2DM, hypertension and overt nephropathy; n = 885	Telmisartan or valsartan on a background of antihypertensive treatment mean/median follow-up not available	Equivalent reductions in the primary endpoint of the change from baseline in the 24-hour proteinuria after 12 months for telmisartan and valsartan. Greater renoprotection was seen in those patients with better BP control
Studies in high-risk patients with a broad range of risk factors
ONTARGET^Citation28	High-risk patients aged ≥55 years, with coronary, peripheral, or cerebrovascular disease or diabetes with end-organ damage; n = 25,620	Telmisartan-, ramipril- or telmisartan plus ramipril-based antihypertensive regimens; median follow-up 4.7 years	Telmisartan was equivalent to ramipril for the primary composite endpoint of CV death, MI, stroke, or hospitalization due to HF, but it was associated with less angioedema and better treatment adherence. The combination was associated with more adverse events without an increase in efficacy
TRANSCEND^Citation29	High-risk patients aged ≥55 years, with coronary, peripheral, or cerebrovascular disease or diabetes with end-organ damage, and intolerant to ACE inhibitors; n = 5926	Telmisartan regimen or placebo-based regimen (on a background of other antihypertensive agents); median follow-up 4.7 years	Equivalent reduction in the primary composite endpoint of CV death, MI, stroke, or hospitalization for HF with telmisartan vs placebo. Significant reduction in the secondary composite endpoint of CV death, MI, or stroke with telmisartan (13%; HR 0.87) vs placebo (14.8%)
ROADMAP^Citation93	High-risk patients with type 2 diabetes and at least one additional cardiovascular risk factor, but no evidence of renal dysfunction; n = 4447	Olmesartan regimen or placebo-based regimen (on a background of other antihypertensive agents); median follow-up 3.2 years	No significant difference on the primary (time to first onset of microalbuminuria) or secondary (composite of CV complications or death from CV causes). A significant excess of CV mortality seen in the olmesartan arm
Studies in high-risk patients with HF
VALIANT^Citation78	Patients aged ≥18 years, with HF or left ventricular systolic dysfunction, or both, and prior MI; n = 14,703	Valsartan monotherapy, captopril monotherapy, or valsartan plus captopril on a background of antihypertensive treatment; median follow-up 2.1 years	Equivalent efficacy for the primary endpoint of all-cause mortality for all three groups. The valsartan plus captopril group had the most drug-related adverse events
Val-HEFT^Citation79	Patients aged ≥18 years, with chronic HF and left ventricular systolic dysfunction; n = 5010	Valsartan monotherapy or placebo on a background of antihypertensive treatment, which was ACE inhibitors in 93% of patients; mean follow-up 1.9 years	Equivalent efficacy for the primary endpoint of all-cause mortality for the 2 groups. Significant reduction in the composite endpoint of mortality and morbidity with the valsartan-based regimen vs the placebo-based regimen, and this was driven by a 24% reduction in the rate of adjudicated hospitalizations for worsening HF
OPTIMAAL^Citation80	Patients aged ≥50 years, with HF or left ventricular systolic dysfunction, and acute MI; n = 5477	Losartan monotherapy or captopril monotherapy on a background of antihypertensive treatment; mean follow-up 2.7 years	Trend for superior efficacy in the captopril group compared with the losartan group for the endpoint of all-cause mortality. Losartan was significantly better tolerated than captopril, being associated with significantly fewer discontinuations
ELITE II^Citation81	Patients aged ≥60 years, with HF and left ventricular systolic dysfunction; n = 3152	Losartan monotherapy or captopril monotherapy on a background of antihypertensive treatment; median follow-up 1.5 years	Equivalent efficacy for the primary endpoint of all-cause mortality for the 2 groups. Losartan was significantly better tolerated than captopril, being associated with significantly fewer discontinuations
HEAAL^Citation82	Patients aged ≥18 years, with HF, left ventricular systolic dysfunction and known intolerance to ACE inhibitors; n = 3846	Losartan 50 mg/day vs 150 mg/day on a background of antihypertensive treatment; median follow-up 4.7 years	Significant reduction in the primary composite endpoint of all-cause mortality and hospital admission for HF with the higher-dose losartan group compared with the lower-dose losartan group. There was no significant difference in the rate of treatment discontinuation between the doses
CHARM-Overall^Citation83	Patients aged ≥18 years, with HF with/without left ventricular systolic dysfunction; n = 7601	Candesartan or placebo on a background of antihypertensive treatment; median follow-up 3.1 years	Significant reduction in the primary endpoint of all-cause mortality with candesartan vs placebo
CHARM-Preserved^Citation84	Patients aged ≥18 years, with HF with preserved left ventricular systolic function (ejection fraction >40%); n = 3023	Candesartan or placebo on a background of antihypertensive treatment; median follow-up 3.0 years	Nonsignificant reduction in the primary composite endpoint of CV death or hospital admission for HF with candesartan vs placebo; the reduction was driven by significantly fewer candesartan-treated patients being hospitalized or HF
I-PRESERVE^Citation85	Patients aged ≥60 years, with HF with preserved left ventricular systolic function (ejection fraction ≥45%); n = 4128	Irbesartan or placebo on a background of antihypertensive treatment; mean follow-up 4.1 years	No significant difference in the primary composite endpoint of all-cause mortality and hospitalization for a CV event with irbesartan vs placebo

Abbreviations: ABPM, ambulatory blood pressure monitoring; ACE, angiotensin-converting enzyme; AMADEO^®, A trial to compare telMisartan 40 mg titrated to 80 mg versus losArtan 50 mg titrated to 100 mg in hypertensive type 2 DiabEtic patients with Overt nephropathy; ARB, angiotensin II receptor blocker; BP, blood pressure; CHARM, Candesartan in Heart failure Assessment of Reduction in Mortality and Morbidity; CV, cardiovascular; DETAIL^®, Diabetics Exposed to Telmisartan And enalaprIL; ELITE-II, Evaluation of Losartan In The Elderly-II; ESRD, end-stage renal disease; GFR, glomerular filtration rate; HEAAL, Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure; HF, heart failure; HR, hazard ratio; IDNT, Irbesartan Type II Diabetic Nephropathy Trial; I-PRESERVE, Irbesartan in HF with preserved EF; IRMA-2, IRbesartan in patients with type 2 diabetes and MicroAlbuminuria; LIFE, Losartan Intervention For Endpoint Reduction in Hypertension; LVH, left ventricular hypertrophy; MI, myocardial infarction; OPTIMAAL, OPtimal Therapy In Myocardial infarction with the Angiotensin II Antagonist Losartan; RENAAL, Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan; T2DM, type 2 diabetes mellitus; UAE, urinary albumin excretion; Val-HEFT, Valsartan in Heart Failure Trial; VALIANT, VALsartan in Acute myocardial iNfarcTion; VALUE, Valsartan Antihypertensive Long-term Use Evaluation; VIVALDI^®, A trial to inVestigate the efficacy of telmIsartan versus VALsartan in hypertensive type 2 DIabetic patients with overt nephropathy.

Table 3 Indications for the eight currently available angiotensin receptor blockers

	Azilsartan	Candesartan	Eprosartan	Irbesartan	Losartan	Olmesartan	Telmisartan	Valsartan
Hypertension	•	•	•	•	•	•	•	•
Hypertension and type 2 diabetic renal disease				•	•
Prevention of stroke in hypertension and LVH					•
CV high risk
T2DM with target organ damage   Atherothrombotic							•
CV disease, for example:
Coronary heart disease							•
Peripheral arterial disease							•
Stroke							•
Heart failure or left ventricular dysfunction		•			•			•

Abbreviations: CV, cardiovascular; HF, heart failure; LVH, left ventricular hypertrophy; T2DM, type 2 diabetes mellitus.

KurtzTWPravenecMMolecule-specific effects of angiotensin II-receptor blockers independent of the renin-angiotensin systemAm J Hypertens200821885285918535538

 PubMed Web of Science ®Google Scholar

VolpeMMorgantiAExecutive Committee of the Italian Society of Hypertension2010 position paper of the Italian Society of Hypertension (SIIA): angiotensin receptor blockers and risk of cancerHigh Blood Press Cardiovasc Prev2011181374021612311

 PubMedGoogle Scholar

YusufSSleightPPogueJBoschJDaviesRDagenaisGEffects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study InvestigatorsN Engl J Med2000342314515310639539

 PubMed Web of Science ®Google Scholar

ParvingHHLehnertHBröchner-MortensenJGomisRAndersenSArnerPIrbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study GroupThe effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetesN Engl J Med20013451287087811565519

 PubMed Web of Science ®Google Scholar

DahlöfBDevereuxRBKjeldsenSELIFE Study GroupCardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenololLancet20023599311995100311937178

 PubMed Web of Science ®Google Scholar

PoulterNRWedelHDahlöfBASCOT InvestigatorsRole of blood pressure and other variables in the differential cardiovascular event rates noted in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA)Lancet2005366948990791316154017

 PubMed Web of Science ®Google Scholar

BakrisGBurgessEWeirMDavidaiGKovalSAMADEO Study InvestigatorsTelmisartan is more effective than losartan in reducing proteinuria in patients with diabetic nephropathyKidney Int200874336436918496508

 PubMed Web of Science ®Google Scholar

GilesTDOparilSSilfaniTNWangAWalkerJFComparison of increasing doses of olmesartan medoxomil, losartan potassium, and valsartan in patients with essential hypertensionJ Clin Hypertens (Greenwich)20079318719517341994

 PubMedGoogle Scholar

PfefferMAMcMurrayJJVelazquezEJValsartan in Acute Myocardial Infarction Trial InvestigatorsValsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or bothN Engl J Med2003349201893190614610160

 PubMed Web of Science ®Google Scholar

JuliusSKjeldsenSEWeberMVALUE Trial GroupOutcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trialLancet200436394262022203115207952

 PubMed Web of Science ®Google Scholar

SawadaTYamadaHDahlöfBMatsubaraHKyoto Heart Study GroupEffects of valsartan on morbidity and mortality in uncontrolled hypertensive patients with high cardiovascular risks: Kyoto Heart StudyEur Heart J200930202461246919723695

 PubMed Web of Science ®Google Scholar

AldermanMAiyerKJUric acid: role in cardiovascular disease and effects of losartanCurr Med Res Opin200420336937915025846

 PubMed Web of Science ®Google Scholar

BrennerBMCooperMEde ZeeuwDRENAAL Study InvestigatorsEffects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathyN Engl J Med20013451286186911565518

 PubMed Web of Science ®Google Scholar

LewisEJHunsickerLGClarkeWRCollaborative Study GroupRenoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetesN Engl J Med20013451285186011565517

 PubMed Web of Science ®Google Scholar

BarnettAHBainSCBouterPDiabetics Exposed to Telmisartan and Enalapril Study GroupAngiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathyN Engl J Med2004351191952196115516696

 PubMed Web of Science ®Google Scholar

GalleJSchwedhelmEPinnettiSBögerRHWannerCVIVALDI investigatorsAntiproteinuric effects of angiotensin receptor blockers: telmisartan versus valsartan in hypertensive patients with type 2 diabetes mellitus and overt nephropathyNephrol Dial Transplant200823103174318318450829

 PubMed Web of Science ®Google Scholar

ONTARGET InvestigatorsYusufSTeoKKPogueJTelmisartan, ramipril, or both in patients at high risk for vascular eventsN Engl J Med2008358151547155918378520

 PubMed Web of Science ®Google Scholar

YusufSTeoKAndersonCTelmisartan Randomised Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (TRANSCEND) InvestigatorsEffects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trialLancet200837296441174118318757085

 PubMed Web of Science ®Google Scholar

HallerHItoSIzzoJLROADMAP Trial InvestigatorsOlmesartan for the delay or prevention of microalbuminuria in Type 2 diabetesN Engl J Med20113641090791721388309

 PubMed Web of Science ®Google Scholar

CohnJNTognoniGValsartan Heart Failure Trial InvestigatorsA randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failureN Engl J Med2001345231667167511759645

 PubMed Web of Science ®Google Scholar

DicksteinKKjekshusJOPTIMAAL Steering Committee of the OPTIMAAL Study GroupEffects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist LosartanLancet2002360933575276012241832

 PubMed Web of Science ®Google Scholar

PittBPoole-WilsonPASegalREffect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial – the Losartan Heart Failure Survival Study ELITE IILancet200035592151582158710821361

 PubMed Web of Science ®Google Scholar

KonstamMANeatonJDDicksteinKHEAAL InvestigatorsEffects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trialLancet200937497041840184819922995

 PubMed Web of Science ®Google Scholar

PfefferMASwedbergKGrangerCBCHARM Investigators and CommitteesEffects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programmeLancet2003362938675976613678868

 PubMed Web of Science ®Google Scholar

YusufSPfefferMASwedbergKCHARM Investigators and CommitteesEffects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved TrialLancet2003362938677778113678871

 PubMed Web of Science ®Google Scholar

MassieBMCarsonPEMcMurrayJJI-PRESERVE InvestigatorsIrbesartan in patients with heart failure and preserved ejection fractionN Engl J Med2008359232456246719001508

 PubMed Web of Science ®Google Scholar