ARB UPDATES Dr. Shanjida Sultana

MO,Cardiology NHFH&RI

ARB UPDATES

INTRODUCTION• Angiotensin Receptor Blockers(ARB) also known as

Angiotensin II Receptor Antagonists,AT-1 Receptor Antagonists or Sartans are a group of pharmaceuticals which modulate the renin-angiotensin aldosterone system.• In early 1980s it was noted that a series of imidazole 5-acetic

acid derivatives diminished blood pressure responses to Ang II in rats. Based on that finding & further research a nonpeptide AT receptor blocker Losartan was developed. • In 1995 Losartan was approved for clinical use in the United

States and since then six additional ARBs have been approved.

Angiotensin Receptors

• Specific angiotensin receptors have been discovered, grouped and abbreviated as – AT1 and AT2

• They are present on the surface of the target cells

• Most of the physiological actions of angiotensin are mediated via AT1 receptor

• Losartan is the specific AT1 blocker

DIFFERENCE BETWEEN AT1 & AT2 RECEPTORS

All the adverse effects of angiotensin II is mediated by AT1 receptors.

Vasoconstriction Sodium retention Cell growth promotion & connective tissue deposition LDL-C transport increased Increased efferent arteriolar constriction & thus

increasing intra glomerular pressure. This increases proteinuria.

On the other hand when the same angiotensin II stimulates

AT2 receptors the exactly opposite & beneficial effects occurs.

Potential pathogenic properties of Angiotensin II

HEART • Myocardial Hypertrophy• Interstitial fibrosis CORONARY ARTERIES• Endothelial dysfunction• Coronary constriction via release of norepinephrine.• Increased oxidative stress.• Promotion of inflamatory response & Atheroma.• Promotion of LDL cholesterol uptake.

Kidneys• Increased intraglomeruler pressure.• Increased protein leak.• Glomeruler growth & fibrosis.• Increased sodium reabsorption. Adrenals• Increased formation of aldosterone. Coagulation system• Increased fibrinogen level.

Pharmacokinetics• All ARBs are well absorbed after oral administration but

differ slightly in metabolism and pharmacokinetics.• All of the ARBs, except for telmisartan and olmesartan, are

metabolized in some way by the cytochrome P450 enzyme , in liver.

• Telmisartan is metabolized by glucuronidation and olmesartan is excreted as the unchanged drug. Telmisartan is the only ARB that can cross the blood–brain barrier and can therefore inhibit centrally mediated effects of Ang II, contributing to even better blood pressure control .

Indications of ARBs

• Hypertension • Chronic heart failure • Diabetic Nephropathy• Stroke

Use in Hypertension• ARB reduce BP with an astonishing lack of side effects in

comparison to ACEi.• Already regarded as 1st line therapy in hypertension by

the European Guidelines.

Justifiable use of ARBs in HTN are • Losartan (LIFE)• Valsartan (VALUE & JiKei Heart) • Eprosartan (MOSES).

Comparison of ARBs Versus ACE inhibitors Relevant to Use in HypertensionProperty ARB ACE Inhibitor

•Major site of block

•Major claims,basic science

•Side effects

•Compelling indications,modifiedfrom JNC 7

AT-1 receptor

More complete AT-1 block,AT-2 activity increased;latter may be beneficial(not certain)

Generally similar toplacebo; coughunusual; angioedemavery rare but reported

Heart failure, diabetes,chronic renal disease,recurrent stroke

Converting enzyme

Block of two receptors:AT-1, AT-2. Inhibition ofbreakdown of protectiveBradykinin

Dry cough; angioedemahigher in black (1.6%)than nonblack patients(0.6%), enalapril datafrom OCTAVE24

As for ARB plus post-MI,high coronary risk,recurrent stroke (withdiuretic)

Property ARB ACE Inhibitor

•Major clinicalclaims inHypertension

•Outcome trials(death, stroke,coronary events,etc.)

Equal BP reduction toACE-inhibitors, little orno cough, excellenttolerability, well testedin LVH and in diabeticNephropathy

LIFE (losartan better thanatenolol, stroke less,deaths less in diabetics); VALUE (valsartanvs amlodipine; aboutequal); JIKEI-heart(valsartan)

Well tolerated, years ofexperience especiallyin CHF, good quality oflife; used in coronaryprevention trials (HOPE,EUROPA, PEACE)

Enalapril >diuretic,Diuretic >lisinopril inALLHAT

Use in Chronic Heart Failure• ARBs are reasonable alternative for use in heart failure, (ACEi

intolerant patients )• Justification of using ARB in HF is-

1.Benefits of ARBs are bought almost without any costly side effects.

2.The adverse effects of major renin-angiotensin activation in heart failure are mediated by the stimulation of angiotensin II via AT-1 receptor, which the ARBs specifically block.

3.There are other non ACE paths for the generation of pathogenic angiotensin II.

• Recommendation in AHA and ACC,2009: Use of ARBs is recommended in patients with current or previous symptoms of heart failure and reduced LVEF who have an intolerance to ACEi

Use in Chronic Renal Disease, Including Diabetic Nephropathy• ARBs have better supporting documentation for

benefits in type-2 diabetes. • On the other hand, in type 1 diabetes, the ACE

inhibitors have better evidence of benefit. • In proteinuric renal disease, with or without diabetes,

ARBs and ACE inhibitors similarly reduced proteinuria.• A dual approach, targeting both BP and albuminuria, is

required.

Fewer Cases of New Diabetes• In HTN, losartan was associated with fewer cases of new

diabetes than atenolol,• candesartan was associated with fewer cases than

hydrochlorothiazide (HCTZ), • valsartan was associated with fewer cases than amlodipine. • In the NAVIGATOR study of patients with impaired glucose

tolerance and CVD or risk factors, administration of valsartan up to 160 mg daily for 5 years, plus lifestyle modification, reduced the incidence of diabetes by 14% without reducing the rate of CV events.

Use in Stroke• More than 25 years ago Brown hypothesized that

angiotensin II could protect against strokes . Three recent trials support the Brown hypothesis.

• First, in PROGRESS an ACE inhibitor reduced BP but not repeat stroke unless combined with a diuretic.

• Second, an ARB, eprosartan, reduced repeat stroke better than a CCBs.

• Third, losartan gave better protection from stroke in patients with LVH than atenolol in the LIFE study.

Nonissues with ARBs: Myocardial Infarction and Cancer

• The ARB-MI paradox refers to the theoretical and unexpected proposal that ARBs may increase the risk of MI.

• But, there was controversy about the effects on MI of ARBs versus ACE inhibitors

• The controversy has been settled by the large and comprehensive analysis based on 37 randomized clinical trials including 147,020 participants with a total follow-up of 485,166 patient years. This study firmly refutes the claim that ARBs increase the risk of MI .

• ARBs reduce the risk of stroke, heart failure, and new-onset diabetes.

• Another nonissue is the proposal that ARBs are associated with an increased incidence of cancer.

Combinations of ACE Inhibitor–ARB Therapy

• In heart failure1. Addition of ARB, candesartan or valsartan to ACE-

inhibitor therapy is associated with improved outcomes in CHF.

2. In patients with LV systolic dysfunction who remain symptomatic on ACE inhibitors and beta-blockers, ARBs can give added benefit as an alternative to the addition of third-line aldosterone blockers.

• In stroke, Combined ACE inhibitor–ARB therapy provides CV protection in high-risk persons.

• The ONTARGET study tested the effects on highrisk persons of ramipril 10 mg daily compared with telmisartan 80 mg daily and with the combination..

• Telmisartan was not superior to ramipril, despite telmisartan 80 mg reducing BP better over 24 hr than ramipril 10 mg.

• The combination produced unchanged CV outcomes, although it resulted in increased hypotension, syncope, and renal dysfunction. Thus this combination is not the gold standard .

Comparison of ARBs and ACE Inhibitors in Heart Failure, CV Prevention, and StrokeProperty ARB ACE Inhibitor•HF

•Post-MI: Majorstudies

Valsartan reduces hospitalization; candesartan for class 2-4 HF where EF ≤ 40% to reduce CV deaths and hospitalization; may be added to ACEI

VALIANT, valsartan noninferior to captopril in postinfarct heart failure.

Yes, several but not all.

Several large studies, definite protection including LV dysfunction.

Property ARB ACE Inhibitor

•Diabeticnephropathy:Major claims

•Nondiabetic renal disease•Prevention of CV complications (MI,heart failure, stroke, or CV death)

•Prevention ofStroke

Renoprotective in type 2diabetes independentlyof hypertension; slows progress of microalbuminuria.

Decreases proteinuria.

ONTARGET evaluatestelmisartan vs ramipril vscombination in HOPE-like study. TRANSCEND compares telmisartan with placebo.

LIFE, less stroke in LVHtreated by losartan usuallywith diuretic versus atenolol;less repeat stroke withEprosartan in MOSES.

Renoprotective in type 1 diabetes independently of hypertension; slows development of microalbuminuria in diabetics.

Better outcome, REIN,AASK.

HOPE, reduction of this primary end-point by 22%; EUROPA, reduction of MI and combined endpoints.

PROGRESS, less repeat stroke with perindopril only if with diuretic.

Adverse effects• Hyperkalaemia due to potassium retention mediated

by reduction of aldosterone.

• Impairment of renal function. Caution if bilateral renal artery stenosis suspected.

• Dizziness and syncope. Rare but may be precipitated by volume depletion.

• Angioedema – very rare.

Losartan (Cozaar)• The prototype ARB.• Numerous clinical studies to support its efficacy in BP

reduction, diabetic nephropathy and LVH .• For hypertension, the standard start-up dose is 50 mg once

daily, with an increase to 100 mg if needed.• As with all the ARBs, a dose increase is usually less

effective than the addition of a low-dose diuretic in achieving greater BP control.

• When there is volume depletion or liver disease , the starting dose should be only 25 mg.

• In diabetic nephropathy, in the RENAAL study, losartan (50-100 mg daily) reduced ESRD and proteinuria.

• In heart failure, losartan 50 mg daily was disappointing, whereas a higher dose (150 mg daily) gave positive results.

Irbesartan (Avapro)• Terminal half-life of 11-15 hr• Dose: 150-300 mg once daily • In important studies on type 2 diabetic nephropathy,

irbesartan reduced the rate of progression of microalbuminuria to overt proteinuria.

• In the ACTIVE I study on 9000 high-risk patients with atrial fibrillation, irbesartan was added to prior therapy, including an ACE inhibitor in 60%. Irbesartan did not reduce CV events, yet hospitalization was reduced .

Telmisartan (Micardis)• A very long half life of 24 hr• 40 to 80 mg once daily .• In the main ONTARGET study, 25,620 participants were

randomly assigned to ramipril 10 mg a day , telmisartan 80 mg a day , or the combination of both drugs. Telmisartan and ramipril had equal outcomes in patients judged to be at high CVD.

• In the ONTARGET renal study, telmisartan gave equal renoprotection to ramipril, but the combination of these two agents increased major adverse renal outcomes despite decreasing proteinuria.

• In the combined TRANSCEND and ONTARGET populations, in patients at high vascular risk, telmisartan reduced new-onset electrocardiographic LVH by 37%.

ValsartanDose: Oral; 80-320 mg once daily.• no active metabolite.• In the VALIANT trial, valsartan up to 160 mg twice daily was as

effective as captopril up to 50 mg thrice daily in patients at high risk for fatal and nonfatal CV events after MI.

• Valsartan Antihypertensive Long-term Use Evaluation. VALUE: ( Valsartan vs Amlodipine)

Pt with HTN & high cardiovascular risk factors showed no significant mortality benefit but incidence of fatal & non fatal MI was reduced.

Other agents• Eprosartan (Teveten)• Olmesartan (Benicar)

ACE Inhibitors and ARBs: Shared Contraindications and Cautions• Pregnancy all trimesters.• Severe renal failure (caution if creatinine . 2.5-3 mg/dL, 220- 265 mmol/L)• Hyperkalemia requires caution or cessation.• Bilateral renal artery stenosis or equivalent lesions.• Preexisting hypotension.• Severe aortic stenosis or obstructive cardiomyopathy.• Often less effective in black subjects without added diuretic.

Newer ARB• Azilsartan medoxomil: Compared with olmesartan 40 mg daily, azilsartan 80

mg reduced mean systolic blood pressure (SBP) by an additional 2.1 mm Hg

ARBs under development

Several new nonpeptide ARBs are undergoing clinical trials or are at pre-clinical stages of development.

Embusartan Fonsartan Pratosartan Pratosartan has affinity for the AT1receptor about 7

times higher than losartan.