Presenter

Dr. Md. Arifur RahmanMD (Cardiology)

Registrar, CardiologyNational Institute of Cardiovascular Diseases

Role of ARB

Hypertension

in the management of

History of Hypertension

1931- “It is an important compensatory mechanism which should not be tampered with.”

2011Azilsartan,

latest ARB ,USFDA

Why HTN getting so much importance?

Global Mortality 2010: Hypertension is the major risk factor

Adapted from Ezzati et al. Lancet 2012;360:1347-1360.

Attributable mortality in millions (total: 55 861 000)

Developing regionsDeveloped regions

0 87654321

High BPTobacco

High cholesterol

Unsafe sexHigh BMI

Physical inactivityAlcohol

Underweight

7.6 million deaths

Beta-blockersLost its glorious past

Beta-blockers appear to be worse for total mortality

and CV events, stroke and CHD.

Lesser ability to reduce central SBP and pulse

pressure.

Less effective in regressing or delaying OD,

Increase body weight and

Facilitate new-onset diabetes in predisposed patients.

MS in prescriptions

Canada, United States, Austria, Belgium, Czech Republic, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Netherlands, Poland, Portugal, Slovakia, Spain, Switzerland, United Kingdom, Australia, Egypt, Indonesia, Japan (includes hospital data), New Zealand, Pakistan, Philippines, Saudi Arabia, South Africa, Thailand, Turkey, Argentina, Brazil, Colombia, Mexico, Venezuela.

RAAS inhibitors are the cornerstoneof the antihypertensive treatment

Source: IMS. Medical Universe - MAT in prescriptions, 35 countries, 2009

ACEi plain + comb

CCB31%

DIU10%

BB 12%

ARB plain + comb

RAAS inhibitors47%

RAAS Modulators

1.Angiotensin Converting Enzyme Inhibitors• Ramipril• Enalapril• Lisinopril• Perindopril

2. Angiotensin Receptor Blockers• Losartan• Valsartan• Candesartan• Telmisartan• Irbesartan• Olmesartan• Azilsartan

3.Direct Renin Inhibitors• Aliskerin

Development of ARB’s

• Losartan

1986

• Valsartan, Candesartan Irbesartan

1990

• Telmisartan

1991

• Olmesartan

1995

• Azilsatan

2011

Became the first successful Ang II antagonist drug

Valsartan –nonheterocyclic ARBCandesartan – Prodrug have stronger blood pressure lowering effects than and losartan. Irebesartan - longer acting than valsartan & losartan

Telmisartan - longest elimination half-life of the ARBs or about 24 hours

Olmesartan - Newert ARB on the market, marketed in 2002

Azilsartan - Newest ARB on the market, FDA approved 2011

Drug comparison and pharmacokinetics

1. Sankyo Pharma Inc (US). Expanding the Paradigm for Hypertension Management with a New Angiotensin II Receptor Blocker. Benicar® (Olmesartan Medoxomil) [product monograph]. New York: Advantage Communications, 2002.2. Olin BR, ed. Drug Facts and Comparisons. St. Louis: JB Lippincott Co, 2002:514–518. 14

Azilsartan Yes 60 No 11 -- >99 -- 55 45

Key trends in ARBLosartan lower the chance of stroke.

reduce serum uric acid levels.treating nephropathy in patients withT2DM

Valsartan First ARB to receive approval in Heart FailureReverses ventricular remodeling and Improves survival outcome in HF

Telmisartan Highly selective inhibition of the angiotensin II receptor 1 (AT1) longest plasma half-life, largest volume of distribution

Olmesartan Significant mean blood pressure reduction

Azilsartan Highly selective inhibition of the angiotensin II receptor 1 (AT1) longer plasma half-life, larger volume of distribution Powerful 24-hour action, curbing the morning surge in blood pressure compared to other leading ARB’s

ARB in Reducing BP and CV events

Name Patient population

Drugs/follow up

Results

LIFE(Losartan Intervention For Endpoint Reduction in Hypertension Study)

9,193 patients aged 55-80 yr with hypertension and LVH

Losartan, 50-100 mg qd, vs atenolol, 50-100 mg qd

Mean follow-up: 4.8 yr

Losartan decreased the composite end point (cardiovascular mortality, MI, and stroke)significantly more than atenolol for a similar reduction in blood pressure

OPTIMAAL(Optimal Trial In Myocardial Infarction with the Angiotensin Receptor Blocker Losartan)

5,477 European patients aged over 50 with confirmed acute MI and heart failure.

Losartan, 50 mg qd, vs captopril, 50 mg tid

Mean follow-up: 2.7 yr

No significant difference in overall mortality between the groups. The ARB was better tolerated than the ACE inhibitor, with significantly fewer withdrawals due to adverse effects.

16

Renal Protection in Diabetes with ARBs

RENAAL1 (Reduction of Endpoints in NIDDM with the ARB Losartan)

1,513 patients aged 31-70 yr with type 2 diabetes and nephropathy

Losartan, 50-100 mg qd, vs placebo in addition to 'conventional‘ antihypertensives such as beta blockers

Mean follow-up: 3.4 yr

Losartan reduced the occurrence of proteinuria, doubling of serum creatinine concentration and end-stage renal disease by 35%, 25% and 28% respectively.

MARVAL2

(MicroAlbuminuria Reduction with VALsartan)

332 patients aged 35-75 yr with type 2 diabetes and microalbuminuria

Valsartan, 80-160 mg/day, vs amlodipine, 5-10 mg/day

Follow-up: 24 wk

Valsartan improved the urinary albumin excretion rate significantly more than amlodipine and restored normal albumin excretion in significantly more patients

1. Brenner BM, Cooper ME, de Zeeuw D et al . Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345: 861-9. 17

Up to 20% increase in serum creatinine may sometimes occur when

antihypertensive therapy—particularly RAS blockers—but this should

not be taken as a sign of progressive renal deterioration.

Ref-Cardiovascular disease and mortality in a community-based cohort with mild renal insufficiency. Kidney Int 2009;56:2214–2219.

RAS blocker and Renal function

CKD is classified according to eGFR, Calculated by

Modification of diet in renal disease’ (MDRD) formula

Cockcroft-Gault formula

CKD EPI demiology Collaboration (CKD-EPI)- require age, sex,

ethnicity and serum creatinine.

These formulae help to detect mild impairment of renal function

when serum creatinine values are still within the normal range.

Follow-up

Approximately 4–12 weeks - SBP ≥120 mm Hg, GFR ≥60 mL/min/1.73

m2, change in GFR is <15%, and serum potassium ≤4.5 mEq/L.

If SBP <120 mm Hg, GFR <60 mL/min/1.73 m2, change in GFR is ≥15%,

or serum potassium >4.5 mEq/L, follow-up measurements should be at

shorter intervals.

In most cases, the ACE inhibitor or ARB should be continued, despite

mild decreases in GFR and increases in serum potassium

The combination of an ACEi with an ARB had some extra blood pressure

lowering but

had more side effects such as hyperkalemia, hypotension and renal

impairment and did not improve patient outcomes compared to ACEi or ARB alone.

Combination reduce urine protein levels but did not reduce cardiovascular

outcomes and did increase adverse renal outcomes such as acute dialysis.

ACEi , ARB combination

ONTARGET: The ONgoing Telmisartan Alone and in combination with

Ramipril Global Endpoint Trial

•In 20 prospective trials, ACEIs were associated with a statistically

significant 13% reduction in all-cause mortality as compared with

control therapy (RR: 0.87, 95%CI: 0.78-0.98, P=0.02).

•ARBs did not give a significant decrease in the risk of major CV

events (RR: 0.94, 95%CI: 0.85-1.01, P=0.07). There were no significant

effects of ARBs on myocardial infarction (RR: 0.89, 95%CI: 0.74-1.07,

P=0.22) or stroke (RR: 1.00, 95%CI: 0.89-1.12, P=0.94).

Ref: ACE inhibitors and ARBs differentially affect CV morbidity and mortality 15-4-2014 • Cheng J et al., JAMA Intern Med. 2014

Impact on all cause mortality of ACE I and ARB

The effect of treatment on all-cause mortality was significant with ACE inhibitors (p = 0.004), but not with ARBs (p = 0.68).

All-cause mortality in ACEI and ARB hypertension trials.

Differences in receptor binding between ARBs are reflected in marked

differences in antihypertensive efficacy.

Agents such Telmisartan, Azilsartan, Olmesartan produces a greater

reduction in BP, higher response rate and a longer duration of action.

Due to their good tolerability, less side effects patients compliance is

good resulting better outcome for hypertensive patients.

Take home message