Azilsartan Medoxomil for Treating Hypertension - Clinical Implications of Recent Trials

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Abstract

Objective: To evaluate the efficacy, safety, and clinical role of azilsartan medoxomil, an angiotensin-II receptor blocker (ARB) that recently gained US Food and Drug Administration approval for lowering of blood pressure (BP) in patients with hypertension. Methods: A systematic review of the literature was performed through October 2011 using the keywords and medical subject headings azilsartan, azilsartan medoxomil, TAK-491, TAK-536, and Edarbi. Citations eligible for inclusion were in vitro or in vivo evaluations of azilsartan medoxomil with no restrictions on patient population or indication used. Data related to the patient populations and outcomes of interest were extracted from each citation. Results: Three trials are available in full publication form, with others available only as abstracts. Azilsartan medoxomil 40 mg and 80 mg daily significantly improves both systolic and diastolic BP from baseline compared with placebo, and the 80 mg dose has greater efficacy than other ARBs, including olmesartan 40 mg daily and valsartan 320 mg daily. Improvements in both 24-hour BP using ambulatory monitoring and clinic BPs, as well as a higher proportion of patients reaching goal, have been seen with azilsartan medoxomil. Additional information shows added BP lowering when azilsartan medoxomil is combined with chlorthalidone. Adverse events are similar with azilsartan medoxomil compared to other ARBs and include headache, dizziness, urinary tract infections, and fatigue. Conclusions: Azilsartan medoxomil is a safe and effective ARB with a unique pharmacologic profile compared with other agents, including slowed angiotensin-II type 1 (AT1) receptor dissociation rates and improved receptor specificity. Studies have shown azilsartan medoxomil 80 mg once daily to reduce BP to a greater extent than valsartan and olmesartan, with similar safety and tolerability.

Acknowledgments: Supported in part by funding from the National Institutes of Health R01 AG022092-06 (PI: Dr White).
Support: The publication costs of this article were supported by Takeda Pharmaceuticals North America. Takeda Pharmaceuticals North America has had no involvement in the content of this article beyond review for factual accuracy. William L Baker, PharmD, BCPS (AQ Cardiology), and William B White, MD, FACP, FAHA, FASH, were fully responsible for all content and editorial decisions and received no financial support or other form of compensation related to the development of the manuscript.

Disclosure
William L Baker, PharmD, BCPS (AQ Cardiology), has no conflicts of interest to declare. William B White, MD, FACP, FAHA, FASH, discloses that his division has received research funding from Takeda Global Research and Development, manufacturer of azilsartan medoxomil, between 2007 and 2009. He is a paid safety consultant to Takeda for chairing the adjudication committee of the febuxostat cardiovascular outcomes study. He chairs the steering committee of the Examination of cardiovascular outcomes: alogliptin versus standard of care in patients with type 2 diabetes mellitus and acute coronary syndrome (EXAMINE) trial assessing the cardiovascular safety of alogliptin.
Correspondence
William L Baker, PharmD, BCPS (AQ Cardiology), Assistant Professor of Pharmacy and Medicine, University of Connecticut Schools of Pharmacy and Medicine, 263 Farmington Avenue, MC2205, Farmington, CT 06030. E: wbaker@uchc.edu
Received date
15 November 2011
Accepted date
20 January 2012
Citation
US Cardiology Volume 9 - Issue 1 - Spring 2012;2012:9(1):16-21
Correspondence
William L Baker, PharmD, BCPS (AQ Cardiology), Assistant Professor of Pharmacy and Medicine, University of Connecticut Schools of Pharmacy and Medicine, 263 Farmington Avenue, MC2205, Farmington, CT 06030. E: wbaker@uchc.edu

Pages

Despite advances in diagnostic and treatment modalities, hypertension remains a prevalent medical condition, affecting over 26 % of the adult population, a number expected to rise to nearly 30 % by the year 2025.1 It is a major risk factor for cardiovascular disease morbidity and mortality, including stroke, heart failure, and renal disease.2,3 Numerous investigations have demonstrated the ability of various pharmacologic treatment regimens to decrease major cardiovascular event rates.4,5 Despite this evidence, adequate control of blood pressure (BP) remains poor.2,6 Pharmacologic agents that attenuate the actions of the renin–angiotensin–aldosterone system (RAAS) comprise one of the most popular antihypertensive strategies for patients with elevated BP.2,7 These include angiotensin-converting enzyme inhibitors (ACEIs), angiotensin-II receptor blockers (ARBs), direct renin inhibitors, and aldosterone antagonists. ARBs attenuate the action of angiotensin-II by binding to and inhibiting the angiotensin-II type 1 (AT1) receptor, inducing a dose-dependent decrease in peripheral resistance, reduction in vascular smooth muscle contraction, and reduced synthesis and effects of aldosterone on the kidney.8 These pharmacologic properties have led to improved outcomes with ARB use across a number of disease states, including coronary heart disease, diabetic patients with kidney disease, and heart failure.9,10
Azilsartan medoxomil (Edarbi™, Takeda Pharmaceuticals America, Inc., Deerfield, IL) is a highly selective ARB and was approved by the US Food and Drug Administration (FDA) (February 2011) for the treatment of adults with hypertension.11 Given the large number of ARBs that are currently available in the US, it is important to understand the pharmacologic and clinical characteristics of azilsartan medoxomil that may differentiate the drug for contemporary hypertension management.

Pharmacology and Pharmacokinetics

Azilsartan medoxomil is a prodrug that is hydrolyzed within the gastrointestinal tract to azilsartan prior to and/or during absorption. It is structurally related to candesartan with the exception of a chemical alteration that increases the lipophilicity of azilsartan medoxomil and potentially improves its oral bioavailability.12 Azilsartan appears to be an insurmountable selective AT1 antagonist with greater potency and a longer-lasting pharmacologic effect compared with other ARBs. Ojima et al. showed that azilsartan is more potent and has more slowly dissociating AT1 antagonist properties compared with other agents in the ARB class.13

Pages

References
  1. Kearney PM, Whelton M, Reynolds K, et al., Global burden of hypertension: analysis of worldwide data, Lancet, 2005;365:217–23.
  2. Chobanian AV, Bakris GL, Black HR, et al., The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report, JAMA, 2003;289:2560–72.
  3. Mancia G, De Backer G, Dominiczak A, et al., 2007 ESH-ESC Practice Guidelines for the Management of Arterial Hypertension: ESH-ESC Task Force on the Management of Arterial Hypertension, J Hypertens, 2007;25:1751–62.
  4. Czernichow S, Zanchetti A, Turnbull F, et al., The effects of blood pressure reduction and of different blood pressure-lowering regimens on major cardiovascular events according to baseline blood pressure: meta-analysis of randomized trials, J Hypertens, 2011;29:4–16.
  5. Turnbull F, Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials, Lancet, 2003;362:1527–35.
  6. Egan BM, Zhao Y, Axon RN, US trends in prevalence, awareness, treatment, and control of hypertension, 1988-2008, JAMA, 2010;303:2043–50.
  7. Elliott WJ, Plauschinat CA, Skrepnek GH, et al., Persistence, adherence, and risk of discontinuation associated with commonly prescribed antihypertensive drug monotherapies, J Am Board Fam Med, 2007;20:72–80.
  8. Burnier M, Angiotensin II type 1 receptor blockers, Circulation, 2001;103:904–12.
  9. Baumhakel M, Bohm M, Cardiovascular outcomes with angiotensin II receptor blockers: clinical implications of recent trials, Vasc Health Risk Manag, 2011;7:391–7.
  10. Verdecchia P, Angeli F, Repaci S, et al., Comparative assessment of angiotensin receptor blockers in different clinical settings, Vasc Health Risk Manag, 2009;5:939–48.
  11. FDA, Edarbi Label. Package insert, 2011.
  12. Kohara Y, Kubo K, Imamiya E, et al., Synthesis and angiotensin II receptor antagonistic activities of benzimidazole derivatives bearing acidic heterocycles as novel tetrazole bioisosteres, J Med Chem, 1996;39:5228–35.
  13. Ojima M, Igata H, Tanaka M, et al., In vitro antagonistic properties of a new angiotensin type 1 receptor blocker, azilsartan, in receptor binding and function studies, J Pharmacol Exp Ther, 2011;336:801–8.
  14. French C, Tarikuz Zaman AKM, Sobel BE, The angiotensin receptor blocker, azilsartan medoxomil (TAK-491), suppresses vascular wall expression of plasminogen activator inhibitor type-I protein potentially facilitating the stabilization of atherosclerotic plaques, J Cardiovasc Pharmacol, 2011;58:143–8.
  15. Iwai M, Chen R, Imura Y, Horiuchi M, TAK-536, a new AT1 receptor blocker, improves glucose intolerance and adipocyte differentiation, Am J Hypertens, 2007;20:579–86.
  16. Ye Y, Keyes KT, Zhang CF, et al., Additive effect of TAK-491, a new angiotensin receptor blocker, and pioglitazone, in reducing myocardial infarct size, Cardiovasc Drugs Ther, 2010;24:107–20.
  17. Zhao M, Li Y, Wang J, et al., Azilsartan treatment improves insulin sensitivity in obese spontaneously hypertensive Koletsky rats, Diabetes Obes Metab, 2011;13:1123–9.
  18. Bakris GL, Sica D, Weber M, et al., The comparative effects of azilsartan medoxomil and olmesartan on ambulatory and clinic blood pressure, J Clin Hypertens (Greenwich), 2011;13:81–8.
  19. Bönner G, Bakris GL, Sica D, et al., Comparison of antihypertensive efficacy of the new angiotensin receptor blocker azilsartan medoxomil with ramipril: Pp.16.112, J Hypertens, 2010;28:e283. doi: 10.1097/01.hjh.0000379038.73342.22.
  20. Cushman WC, Sica D, Bakris GL, Efficacy and safety of azilsartan medoxomil/chlorthalidone vs olmesartan/HCTZ combination in stage 2 systolic HTN. Abstract PO-162, J Clin Hypertens (Greenwich), 2011;13(Suppl. 1):A81.
  21. Sica D, White WB, Weber MA, et al., Comparison of the novel angiotensin II receptor blocker azilsartan medoxomil vs valsartan by ambulatory blood pressure monitoring, J Clin Hypertens (Greenwich), 2011;13:467–72.
  22. Sica D, Bakris GL, White WB, Fixed-dose combination of azilsartan medoxomil/CLD provides superior BP reduction to monotherapies in stage 2 HTN. Abstract PO-182, J Clin Hypertens (Greenwich), 2011; 13(Suppl. 1):A90.
  23. Sica D, Bakris GL, White WB, et al, New angiotensin II receptor blocker azilsartan medoxomil coadministered with chlorthalidone provides potent blood pressure reduction in stage 2 hypertension. Poster 238, Presented at: American Society of Hypertension Annual Scientific Meeting, New York, May 3, 2010.
  24. Weber MA, White WB, Sica D, et al, Antihypertensive efficacy of the new angiotensin receptor blocker azilsartan medoxomil in combination with amlodipine. Abstract PO-241, J Clin Hypertens (Greenwich), 2010;12(Suppl. 1):A115.
  25. White WB, Weber MA, Sica D, et al., Effects of the angiotensin receptor blocker azilsartan medoxomil versus olmesartan and valsartan on ambulatory and clinic blood pressure in patients with stages 1 and 2 hypertension, Hypertension, 2011;57:413–20.
  26. White WB, Relating cardiovascular risk to out-of-office blood pressure and the importance of controlling blood pressure 24 hours a day, Am J Med, 2008;121(8 Suppl.):S2–7.
  27. Dolan E, Stanton AV, Thom S, et al., Ambulatory blood pressure monitoring predicts cardiovascular events in treated hypertensive patients--an Anglo-Scandinavian cardiac outcomes trial substudy, J Hypertens, 2009;27:876–85.
  28. Fagard RH, Thijs L, Staessen JA, et al., Prognostic significance of ambulatory blood pressure in hypertensive patients with history of cardiovascular disease, Blood Press Monit, 2008;13:325–32.
  29. White WB, Advances in ambulatory blood pressure monitoring for the evaluation of antihypertensive therapy. In: White WB (ed.), Blood Pressure Monitoring in Cardiovascular Medicine and Therapeutics, 2nd edn, Totowa, NJ: Springer-Verlag-Humana Press, 2007;437–62.
  30. Campbell P, Ghuman N, Wakefield D, et al., Long-term reproducibility of ambulatory blood pressure is superior to office blood pressure in the very elderly, J Hum Hypertens, 2010;24:749–54.
  31. Mansoor GA, McCabe EJ, White WB, Long-term reproducibility of ambulatory blood pressure, J Hypertens, 1994;12:703–8.
  32. Jamerson K, Weber MA, Bakris GL, et al., Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients, N Engl J Med, 2008;359:2417–28.
  33. Dorsch MP, Gillespie BW, Erickson SR, et al., Chlorthalidone reduces cardiovascular events compared with hydrochlorothiazide: a retrospective cohort analysis, Hypertension, 2011;57:689–94.
  34. Ernst ME, Carter BL, Goerdt CJ, et al., Comparative antihypertensive effects of hydrochlorothiazide and chlorthalidone on ambulatory and office blood pressure, Hypertension, 2006;47:352–8.
  35. Mancia G, Seravalle G, Grassi G, Tolerability and treatment compliance with angiotensin II receptor antagonists, Am J Hypertens, 2003;16:1066–73.
  36. Ross SD, Akhras KS, Zhang S, et al., Discontinuation of antihypertensive drugs due to adverse events: a systematic review and meta-analysis, Pharmacotherapy, 2001;21:940–53.
  37. Conlin PR, Gerth WC, Fox J, et al., Four-year persistence patterns among patients initiating therapy with the angiotensin II receptor antagonist losartan versus other antihypertensive drug classes, Clin Ther, 2001;23:1999–2010.
  38. Pfeffer MA, Swedberg K, Granger CB, et al., Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme, Lancet, 2003;362:759–66.
  39. Yusuf S, Teo K, Anderson C, et al., Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial, Lancet, 2008;372:1174–83.
  40. Yusuf S, Teo KK, Pogue J, et al., Telmisartan, ramipril, or both in patients at high risk for vascular events, N Engl J Med, 2008;358:1547–59.
  41. Saji H, Yamanaka M, Hagiwara A, et al., Losartan and fetal toxic effects, Lancet, 2001;357:363.