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angiotensin II receptor antagonist (ARB)

Indications: 1) hypertension - ARBs that cross the blood-brain barrier may be linked to less memory decline - ARBs that cross the blood-brain barrier are telmisartan & candesartan [33] 2) an ACE inhibitor is indicated, but not tolerated a) heart failure [21,26] - left ventricular systolic dysfunction - ARBs reduce risk of heart failure in patients with diabetes mellitus by 30% [23] b) left ventricular hypertrophy [22] c) diabetes mellitus* - diabetic nephropathy d) nondiabetic proteinuric nephropathy [22] e) stroke prevention [2], no benefit for stroke prevention [23] f) migraine prophylaxis# [4] g) ARBs have similar cardiovascular outcomes vs ACE inhibitors with fewer adverse effects [34] 3) ischemic stroke risk reduction - diminished risk of cognitive decline likely through diminished risk of ischemic stroke [14] - no benefit for stroke prevention [23] 4) myocardial infarction - ARB as beneficial as ACE inhibitor after STEMI in patients with preserved LV systolic function [25] - less effective than ACE inhibitors for cardiovascular risk reduction [23] 5) 22% lower risk for colorectal cancer within 3 years of negative colonoscopy [32] * No reduction in mortality. [8] # only candesartan shown to have beneficial effects [4] Contraindications: 1) pregnancy, trimesters 2 & 3, probably 1 as well [13,28] - teratogenic in 1st trimester [21] - fetal or neonatal renal failure in 2nd & 3rd trimesters [21] 2) question of safety in lactation [21] 3) angioedema with ACE inhibitor* [3,7] 4) hypovolemia * 8% of patients with angioedema from ACE inhibitor will experience angioedema with ARB [7] Monitor: - serum potassium & serum creatinine at baseline & 2-3 weeks after initiation of ARB [21] - serum creatinine & serum urea nitrogen every 6 months* - serum electrolytes every 6 months* * hold ARB if serum potassium >= 5.5 meq/L * cut dose of ARB in 1/2 or hold if serum creatinine increases by > 30% [21,24] Adverse effects: 1) well tolerated 2) similar to placebo 3) reduced incidence of cough relative to ACE inhibitors 4) urticaria & angioedema (rare) 5) increased renal fibrosis? [9] 6) no increased risk of myocardial infarction in high-risk patients [11] 7) hyperkalemia, may not be a problem with losartan 8) no increase in risk of cancer [16] 9) risk of contrast nephropathy [18] 10) may decrease GFR & increase serum creatinine in patients with renal perfusion maintained by increased angiotensin-2 [21] 11) increases in serum creatinine after the start of ACE inhibitor or ARB is associated with adverse cardiorenal outcomes, even below the guideline recommended threshold of a 30% increase for stopping treatment [29] 12) <2% with serum creatinine increases of >=30% after starting ARB - these patients with increased risk for - end-stage renal disease (RR=3.4) - myocardial infarction (RR=1.5) - heart failure (RR=1.4) - all-cause mortality (RR=1.8) [29] 13) increase in adverse events seen (hospitalizations & emergency department visits) after switching from brand name to generic drug (17%) [30] * nitrosamines NDEA & NMBA found in certain lots of losartan & valsartan (2018) * FDA list nitrosamine-free ARBs [31] Drug interactions: 1) use in cominbation ACE inhibitor: risks exceed benefits 2) ARBs potentiate the effect of diuretics via hypertrophy of the loop of Henle. Laboratory: - plasma renin should be high [21] - if not, suspect hyperaldosteronism, check plasma aldosterone/renin Mechanism of action: 1) antagonism of angiotensin II receptor type 1 but not type 2 [9] - activation of angiotensin II receptor type 2 in the brain may provide some cognitive protection [19] 2) comparable to ACE inhibitors in antihypertensive efficacy 3) benficial effects on symptoms & hemodynamic/neurohumoral surrogate markers in patients with heart failure 4) antiproteinuric effect; may not prevent microalbuminuria or its progression to proteinuria in diabetic nephropathy 5) no inhibitory effect on angiotensin converting enzyme (ACE) 6) do not inhibit breakdown of bradykinin 7) reduced antihypertensive effect in African Americans (similar to ACE inhibitors) 8) may slow progression of atherosclerosis [2] 9) may improve insulin sensitivity [10] 10) may slow progression to end-stage-renal-disease [12] 11) may upregulate Klotho [27]

Interactions

drug interactions drug adverse effects (more general classes) monitor with ARBs

Related

ACE inhibitors vs angiotensin receptor blockers (ARB) angiotensin II (Giapreza) angiotensin II receptor type 2 & 4-stimulating antihypertensive angiotensin-2 receptor angiotensin-converting enzyme (ACE) inhibitor CHARM program (clinical trials) combination of ACE inhibitor/angiotension 2 receptor antagonist

Specific

azilsartan (Edarbi) candesartan (Atacand) eprosartan (Teveten) irbesartan (Avapro) losartan (Cozaar) olmesartan (Benicar) sparsentan (Filspari) telmisartan (Micardis) valsartan (Diovan)

General

receptor antagonist renin-angiotensin-aldosterone system inhibitor (RAAS inhibitor)

Properties

References

  1. Kaiser Permanente Northern California Regional Drug Formulary, Update 9/99
  2. Prescriber's Letter 9(4):19 2002
  3. Prescriber's Letter 9(11):61 2002
  4. Journal Watch 23(4):34, 2003 Tronvik E et al, JAMA 289:65, 2003
  5. Prescriber's Letter 10(10):59 2003
  6. Journal Watch 23(21):165, 2003
  7. Prescriber's Letter 11(7):37 2004
  8. Journal Watch 24(23):173, 2004 Strippoli GF, Craig M, Deeks JJ, Schena FP, Craig JC. Effects of angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists on mortality and renal outcomes in diabetic nephropathy: systematic review. BMJ. 2004 Oct 9;329(7470):828. Epub 2004 Sep 30. Review. PMID: 15459003 http://bmj.bmjjournals.com/cgi/content/full/329/7470/828
  9. Prescriber's Letter 12(6): 2005 Comparison of Outcomes Between Angiotensin-Converting Enzyme Inhibitors and Angiotensin-Receptor Blockers Detail-Document#: 210613 (subscription needed) http://www.prescribersletter.com
  10. Prescriber's Letter 12(7): 2005 Evidence for Preventing Type 2 Diabetes Detail-Document#: 210707 (subscription needed) http://www.prescribersletter.com
  11. Demers C, McMurray JJ, Swedberg K, Pfeffer MA, Granger CB, Olofsson B, McKelvie RS, Ostergren J, Michelson EL, Johansson PA, Wang D, Yusuf S; CHARM Investigators. Impact of candesartan on nonfatal myocardial infarction and cardiovascular death in patients with heart failure. JAMA. 2005 Oct 12;294(14):1794-8. PMID: 16219883 - McDonald MA, Simpson SH, Ezekowitz JA, Gyenes G, Tsuyuki RT. Angiotensin receptor blockers and risk of myocardial infarction: systematic review. BMJ. 2005 Oct 15;331(7521):873. Epub 2005 Sep 23. Review. PMID: 16183653
  12. Casas JP, Chua W, Loukogeorgakis S, Vallance P, Smeeth L, Hingorani AD, MacAllister RJ. Effect of inhibitors of the renin-angiotensin system and other antihypertensive drugs on renal outcomes: systematic review and meta-analysis. Lancet. 2005 Dec 10;366(9502):2026-33. Review. PMID: 16338452
  13. FDA Medwatch http://www.fda.gov/medwatch/safety/2006/safety06.htm#Angiotensin
  14. Li NC et al Use of angiotensin receptor blockers and risk of dementia in a predominantly male population: prospective cohort analysis BMJ 2010;340:b5465 PMID: 20068258 http://www.bmj.com/cgi/content/full/340/jan12_1/b5465
  15. Prescriber's Letter Comparison of Angiotensin Receptor Blockers Detail-Document#: 210613 (subscription needed) http://www.prescribersletter.com - Prescriber's Letter 17(3): 2010 CHART: Comparison of Angiotensin Receptor Blockers CHART: Angiotensin Receptor Blocker (ARB) Antihypertensive Dose Comparison CHART: Target Doses of Heart Failure Medications Detail-Document#: 260301 (subscription needed) http://www.prescribersletter.com
  16. Sipahi I et al Angiotensin-receptor blockade and risk of cancer: meta-analysis of randomised controlled trials Lancet Oncol. 2010 Jul;11(7):627-36. Epub 2010 Jun 11. PMID: 20542468 doi:10.1016/S1470-2045(10)70106-6 http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2810%2970106-6/abstract - FDA MedWatch, 07/15/2010 Angiotensin Receptor Blockers (ARBs): Ongoing Safety Review for Cancer Risk http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm219185.htm - FDA Drug Safety Communication: 06/02/2011 No increase in risk of cancer with certain blood pressure drugs- Angiotensin Receptor Blockers (ARBs) http://www.fda.gov/Drugs/DrugSafety/ucm257516.htm - Bhaskaran K et al. Angiotensin receptor blockers and risk of cancer: Cohort study among people receiving antihypertensive drugs in UK General Practice Research Database. BMJ 2012 Apr 24; 344:e2697 PMID: 22531797
  17. Prescriber's Letter 18(4): 2011 Comparison of Angiotensin Receptor Blockers Detail-Document#: 270403 (subscription needed) http://www.prescribersletter.com
  18. Rim MY et al. The effect of renin-angiotensin-aldosterone system blockade on contrast-induced acute kidney injury: A propensity-matched study. Am J Kidney Dis 2012 Oct; 60:576. PMID: 22658321
  19. Hajjar I et al Effect of antihypertensive therapy on cognitive function in early executive cognitive impairment: a double-blind randomized clinical trial. Arch Intern Med. 2012 Mar 12;172(5):442-4 PMID: 22412114
  20. Taylor AA, Siragy H, Nesbitt S. Angiotensin receptor blockers: pharmacology, efficacy, and safety. J Clin Hypertens (Greenwich). 2011 Sep;13(9):677-86. PMID: 21896150
  21. Medical Knowledge Self Assessment Program (MKSAP) 16, 17, 18, 19. American College of Physicians, Philadelphia 2012, 2015, 2018, 2021.
  22. Deprecated Reference
  23. Cheng J, Zhang W, Zhang X et al Effect of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers on All-Cause Mortality, Cardiovascular Deaths, and Cardiovascular Events in Patients With Diabetes MellitusA Meta-analysis. JAMA Intern Med. Published online March 31, 2014 PMID: 24687000 http://archinte.jamanetwork.com/article.aspx?articleid=1847572
  24. Prescriber's Letter 21(6): 2014 Safe Use of ACE Inhibitors or ARBs Detail-Document#: 300618 (subscription needed) http://www.prescribersletter.com
  25. Yang JH et al Angiotensin receptor blocker in patients with ST segment elevation myocardial infarction with preserved left ventricular systolic function: prospective cohort study. BMJ 2014;349:g6650 PMID: 25398372 http://www.bmj.com/content/349/bmj.g6650
  26. Heran BS, Musini VM, Bassett K, Taylor RS, Wright JM Angiotensin receptor blockers for heart failure. Cochrane Database Syst Rev. 2012 Apr 18;4:CD003040 PMID: 22513909
  27. Yoon HE1, Ghee JY, Piao S et al Angiotensin II blockade upregulates the expression of Klotho, the anti-ageing gene, in an experimental model of chronic cyclosporine nephropathy. Nephrol Dial Transplant. 2011 Mar;26(3):800-13 PMID: 20813770
  28. Bullo M, Tschumi S, Bucher BS et al Pregnancy outcome following exposure to angiotennists: a systematic review. Hypertension. 2012 Aug;60(2):444-50. Review. PMID: 22753220 Free Article
  29. Schmidt M et al Serum creatinine elevation after renin-angiotensin system blockade and long term cardiorenal risks: cohort study. BMJ 2017;356:j791 PMID: 28279964 Free full text http://www.bmj.com/content/356/bmj.j791
  30. Leclerc J, Blais C, Rochette L, Hamel D, Guenette L, Poirier P. Impact of the Commercialization of Three Generic Angiotensin II Receptor Blockers on Adverse Events in Quebec, Canada. A Population-Based Time Series Analysis. Circulation: Cardiovascular Quality and Outcomes. 2017; 10:e003891. Published October 3, 2017 PMID: 28974512 http://circoutcomes.ahajournals.org/content/10/10/e003891 - Alter DA When Do We Decide That Generic and Brand-Name Drugs Are Clinically Equivalent? Perfecting Decisions With Imperfect Evidence. Circulation: Cardiovascular Quality and Outcomes. 2017; 10:e004158. Published October 3, 2017 PMID: 28974513 http://circoutcomes.ahajournals.org/content/10/10/e004158
  31. FDA Statement. April 4, 2019 Statement from FDA Commissioner Scott Gottlieb, M.D., and Janet Woodcock, M.D., director of the Center for Drug Evaluation and Research on the agency's list of known nitrosamine-free valsartan and ARB class medicines, as part of agency's ongoing efforts to resolve ongoing safety issue. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm635251.htm - FDA Drug Safety and Availability. FDA's Assessment of Currently Marketed ARB drug product. https://www.fda.gov/Drugs/DrugSafety/ucm634620.htm
  32. Nelson R Antihypertensives Linked to Reduced Risk of Colorectal Cancer Medscape - Jul 06, 2020. https://www.medscape.com/viewarticle/933438 - Cheung KS, Chan EW, Seto WK et al ACE (Angiotensin-Converting Enzyme) Inhibitors/Angiotensin Receptor Blockers Are Associated With Lower Colorectal Cancer Risk. Hypertension. July 6, 2020 PMID: 32623923 https://www.ahajournals.org/doi/10.1161/HYPERTENSIONAHA.120.15317
  33. Pass W Memory benefit seen with antihypertensives crossing blood-brain barrier. Internal Medicine News. 2021. June 21. https://www.mdedge.com/internalmedicine/article/241878/neurology/memory-benefit-seen-antihypertensives-crossing-blood-brain
  34. Chen R, Suchard MA, Krumholz HM et al. Comparative first-line effectiveness and safety of ACE (angiotensin- converting enzyme) inhibitors and angiotensin receptor blockers: A multinational cohort study. Hypertension 2021 Sep; 78:591. PMID: 34304580 PMCID: PMC8363588 (available on 2022-09-01) https://www.ahajournals.org/doi/10.1161/HYPERTENSIONAHA.120.16667

Component-of

angiotensin receptor neprilysin inhibitor (ARNI) combination of ACE inhibitor/angiotension 2 receptor antagonist