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ARB in the management of Hypertension

The document discusses the role of Angiotensin Receptor Blockers (ARBs) in managing hypertension, highlighting their efficacy compared to beta-blockers and the development of various ARB medications over time. It emphasizes the significance of hypertension as a major global health risk, the outcomes of several clinical trials, and the importance of renal monitoring when using these medications. Furthermore, the document notes the advantages of ARBs in terms of patient compliance due to better tolerability and reduced side effects.

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Presenter Dr. Md. Arifur Rahman MD (Cardiology) Registrar, Cardiology National 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.”
2011 Azilsartan, 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 regions Developed regions 0 87654321 7.6 million deaths
Beta-blockers Lost 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 cornerstone of the antihypertensive treatment Source: IMS. Medical Universe - MAT in prescriptions, 35 countries, 2009 ACEi plain + combCCB 31% DIU 10% BB 12% ARB plain + comb RAAS inhibitors 47%
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 Losarta n 1986 Valsartan, Candesart an Irbesartan 1990 Telmisart an 1991 Olmesartan1995 Azilsatan2011 Became the first successful Ang II antagonist drug Valsartan – nonheterocyclic ARB Candesartan – 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 ARB Losartan lower the chance of stroke. reduce serum uric acid levels. treating nephropathy in patients withT2DM Valsartan First ARB to receive approval in Heart Failure Reverses 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 (MicroAlbumin uria Reduction with VALsartan) 332 patients aged 35-75 yr with type 2 diabetes and microalbuminuri a 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
ARB in the management of Hypertension