Angiotensin Receptor Blockers in the Management of Hypertension: A Real-World Perspective and Current Recommendations

References

• Forouzanfar MH, Alexander L, Anderson HR, et al.; GBD 2013 Risk Factors Collaborators. Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks in 188 countries, 1990‐2013: a systematic analysis for the global burden of disease study 2013. Lancet. 2015;386(10010):2287‐2323.
   Web of Science ®Google Scholar
• Ettehad D, Emdin CA, Kiran A, et al. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. Lancet. 2016;387(10022):957–967. doi:10.1016/S0140-6736(15)01225-8
   PubMed Web of Science ®Google Scholar
• Rahimi K, Bidel Z, Nazarzadeh M, et al.; Blood Pressure Lowering Treatment Trialists’ Collaboration. Pharmacological blood pressure lowering for primary and secondary prevention of cardiovascular disease across different levels of blood pressure: an individual participant-level data meta-analysis. Lancet. 2021;397(10285):1625–1636. doi:10.1016/S0140-6736(21)00590-0.
   PubMed Web of Science ®Google Scholar
• Katsanos AH, Filippatou A, Manios E, et al. Blood pressure reduction and secondary stroke prevention: a systematic review and metaregression analysis of randomized clinical trials. Hypertension. 2017;69(1):171‐179. doi:10.1161/HYPERTENSIONAHA.116.08485
   PubMed Web of Science ®Google Scholar
• Williams B, Mancia G, Spiering W, et al. ESC scientific document group. 2018 ESC/ESH guidelines for the management of arterial hypertension. Eur Heart J. 2018;39(33):3021–3104. doi:10.1093/eurheartj/ehy339
   PubMed Web of Science ®Google Scholar
• Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/ AHA/ AAPA/ ABC/ ACPM/ AGS/ APhA/ ASH/ ASPC/ NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines. J Am Coll Cardiol. 2018;71(19):e127–e248. doi:10.1016/j.jacc.2017.11.006
   PubMed Web of Science ®Google Scholar
• Volpe M, Gallo G, Battistoni A, Tocci G. Implications of guidelines for hypertension management in Europe. Circ Res. 2019;124(7):972–974. doi:10.1161/CIRCRESAHA.119.314724
   PubMed Web of Science ®Google Scholar
• Burnier M. Angiotensin II type 1 receptor blockers. Circulation. 2001;103:904–912. doi:10.1161/01.CIR.103.6.904
   PubMed Web of Science ®Google Scholar
• Burnier M, Vuignier Y, Wuerzner G. State-of-the-art treatment of hypertension: established and new drugs. Eur Heart J. 2014;35(9):557–562. doi:10.1093/eurheartj/eht465
   PubMed Web of Science ®Google Scholar
• Schmieder RE. Mechanisms for the clinical benefits of angiotensin II receptor blockers. Am J Hypertens. 2005;18(5 Pt 1):720–730. doi:10.1016/j.amjhyper.2004.11.032
   PubMed Web of Science ®Google Scholar
• Messerli FH, Bangalore S, Bavishi C, Rimoldi SF. Angiotensin-converting enzyme inhibitors in hypertension: to use or not to use? J Am Coll Cardiol. 2018;71(13):1474–1482. doi:10.1016/j.jacc.2018.01.058
   PubMed Web of Science ®Google Scholar
• Boehm M, Nabel EG. Angiotensin-converting enzyme 2 – a new cardiac regulator. N Engl J Med. 2002;347(22):1795–1797. doi:10.1056/NEJMcibr022472
   PubMed Web of Science ®Google Scholar
• Taddei S, Bortolotto L. Unraveling the pivotal role of bradykinin in ACE inhibitor activity. Am J Cardiovasc Drugs. 2016;16(5):309–321. doi:10.1007/s40256-016-0173-4
   PubMed Web of Science ®Google Scholar
• 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;20:579–586. doi:10.1016/j.amjhyper.2006.12.010
   PubMed Web of Science ®Google Scholar
• Oparil S. Newly emerging pharmacologic differences in angiotensin II receptor blockers. Am J Hypertens. 2000;13(1 Pt 2):18S–24S. doi:10.1016/S0895-7061(99)00250-2
   PubMed Web of Science ®Google Scholar
• Abraham HM, White CM, White WB. The comparative efficacy and safety of the angiotensin receptor blockers in the management of hypertension and other cardiovascular diseases. Drug Saf. 2015;38(1):33–54. doi:10.1007/s40264-014-0239-7
   PubMed Web of Science ®Google Scholar
• Gitt AK, Bramlage P, Potthoff SA, et al.; EARLY Registry Group. Azilsartan compared to ACE inhibitors in anti-hypertensive therapy: one-year outcomes of the observational EARLY registry. BMC Cardiovasc Disord. 2016;8(16):56. doi:10.1186/s12872-016-0222-6.
   Web of Science ®Google Scholar
• Ruilope L, Schaefer A. The fixed-dose combination of olmesartan/amlodipine was superior in central aortic blood pressure reduction compared with perindopril/amlodipine: a randomized, double-blind trial in patients with hypertension. Adv Ther. 2013;30(12):1086–1099. doi:10.1007/s12325-013-0076-6
   PubMed Web of Science ®Google Scholar
• Law MR, Wald NJ, Morris JK, Jordan RE. Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials. BMJ. 2003;326(7404):1427. doi:10.1136/bmj.326.7404.1427
   PubMed Web of Science ®Google Scholar
• Malacco E, Omboni S, Volpe M, Auteri A, Zanchetti A; ESPORT Study Group. Antihypertensive efficacy and safety of olmesartan medoxomil and ramipril in elderly patients with mild to moderate essential hypertension: the ESPORT study. J Hypertens. 2010;28(11):2342–2350. doi:10.1097/HJH.0b013e32833e116b
   PubMedGoogle Scholar
• Chrysant SG, Weber MA, Wang AC, Hinman DJ. Evaluation of antihypertensive therapy with the combination of olmesartan medoxomil and hydrochlorothiazide. Am J Hypertens. 2004;17(3):252–259. doi:10.1016/j.amjhyper.2003.11.003
   PubMed Web of Science ®Google Scholar
• Kereiakes DJ, Maa JF, Shojaee A, Dubiel R. Effect of an olmesartan medoxomil-based treatment algorithm on systolic blood pressure in patients with stage 1 or 2 hypertension: a randomized, double-blind, placebo-controlled study. Am J Cardiovasc Drugs. 2010;10(4):239–246. doi:10.2165/11538630-000000000-00000
   PubMed Web of Science ®Google Scholar
• Kereiakes DJ, Neutel J, Stoakes KA, et al. The effects of an olmesartan medoxomil-based treatment algorithm on 24-h blood pressure levels in elderly patients aged 65 and older. J Clin Hypertens. 2009;11(8):411–421. doi:10.1111/j.1751-7176.2009.00147.x
   PubMed Web of Science ®Google Scholar
• Sellin L, Stegbauer J, Laeis P, Rump LC. Adding hydrochlorothiazide to olmesartan dose dependently improves 24-h blood pressure and response rates in mild-to-moderate hypertension. J Hypertens. 2005;23(11):2083–2092. doi:10.1097/01.hjh.0000186022.74245.01
   PubMed Web of Science ®Google Scholar
• Punzi H, Neutel JM, Kereiakes DJ, et al. Efficacy of amlodipine and olmesartan medoxomil in patients with hypertension: the AZOR trial evaluating blood pressure reductions and control (AZTEC) study. Ther Adv Cardiovasc Dis. 2010;4(4):209–221.
   PubMedGoogle Scholar
• Chrysant SG, Melino M, Karki S, Lee J, Heyrman R. The combination of olmesartan medoxomil and amlodipine besylate in controlling high blood pressure: COACH, a randomized, double blind, placebo-controlled, 8-week factorial efficacy and safety study. Clin Ther. 2008;30(4):587–604. doi:10.1016/j.clinthera.2008.04.002
   PubMed Web of Science ®Google Scholar
• Volpe M, Brommer P, Haag U, Miele C. Efficacy and tolerability of olmesartan medoxomil combined with amlodipine in patients with moderate to severe hypertension after amlodipine monotherapy: a randomized, double-blind, parallel-group, multicentre study. Clin Drug Investig. 2009;29(1):11–25. doi:10.2165/0044011-200929010-00002
   PubMed Web of Science ®Google Scholar
• Volpe M, Gallo G, Tocci G. New approach to blood pressure control: triple combination pill. Trends Cardiovasc Med. 2020;30(2):72–77. doi:10.1016/j.tcm.2019.03.002
   PubMed Web of Science ®Google Scholar
• Lindholm LH, Ibsen H, Dahlöf B, et al.; LIFE Study Group. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002;359(9311):1004–1010. doi:10.1016/S0140-6736(02)08090-X
   PubMed Web of Science ®Google Scholar
• Schrader J, Lüders S, Kulschewski A, et al.; MOSES Study Group. Morbidity and mortality after stroke, eprosartan compared with nitrendipine for secondary prevention: principal results of a prospective randomized controlled study (MOSES). Stroke. 2005;36(6):1218–1226. doi:10.1161/01.STR.0000166048.35740.a9.
   PubMed Web of Science ®Google Scholar
• Volpe M, Savoia C. New treatment options in the management of hypertension: appraising the potential role of azilsartan medoxomil. Integr Blood Press Control. 2012;5:19–25. doi:10.2147/IBPC.S13784
   PubMedGoogle Scholar
• Kajiya T, Ho C, Wang J, Vilardi R, Kurtz W. Molecular and cellular effects of azilsartan: a new generation angiotensin II receptor blocker. J Hypertens. 2011;29:2476–2483. doi:10.1097/HJH.0b013e32834c46fd
   PubMed Web of Science ®Google Scholar
• Zhao M, Li Y, Wang J, et al. Azilsartan treatment improves insulin sensitivity in obese spontaneously hypertensive Koletsky rats. Diabetes Obes Metab. 2011;13(12):1123–1129. doi:10.1111/j.1463-1326.2011.01471.x
   PubMed Web of Science ®Google Scholar
• Kusumoto K, Igata H, Ojima M, et al. Antihypertensive, insulin sensitizing and renoprotective effects of a novel, potent and long-acting angiotensin II type 1 receptor blocker, azilsartan medoxomil, in rat and dog models. Eur J Pharmacol. 2011;669:84–93.
   PubMed Web of Science ®Google Scholar
• Haller H, Ito S, Izzo JL Jr, et al. ROADMAP Trial Investigators. Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes. N Engl J Med. 2011;364(10):907–917. doi:10.1056/NEJMoa1007994
   PubMed Web of Science ®Google Scholar
• Parving HH, Lehnert H, Bröchner-Mortensen J, Gomis R, Andersen S, Arner P; Irbesartan in patients with type 2 diabetes and microalbuminuria study group. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001;345(12):870–878. doi:10.1056/NEJMoa011489
   PubMed Web of Science ®Google Scholar
• Brenner BM, Cooper ME, de Zeeuw D, et al.; RENAAL Study Investigators. The losartan renal protection study–rationale, study design and baseline characteristics of RENAAL (reduction of endpoints in NIDDM with the angiotensin II antagonist losartan). J Renin Angiotensin Aldosterone Syst. 2000;1(4):328–335. doi:10.3317/jraas.2000.062.
   PubMedGoogle Scholar
• Lewis EJ, Hunsicker LG, Clarke WR, et al.; Collaborative Study Group. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345(12):851–860. doi:10.1056/NEJMoa011303.
   PubMed Web of Science ®Google Scholar
• Miao Y, Ottenbros SA, Laverman GD, et al. Effect of a reduction in uric acid on renal outcomes during losartan treatment: a post hoc analysis of the reduction of endpoints in non-insulin-dependent diabetes mellitus with the angiotensin II antagonist losartan trial. Hypertension. 2011;58(1):2–7. doi:10.1161/HYPERTENSIONAHA.111.171488
   PubMed Web of Science ®Google Scholar
• Koh KK, Chung WJ, Ahn JY, et al. Angiotensin II type 1 receptor blockers reduce tissue factor activity and plasminogen activator inhibitor type-1 antigen in hypertensive patients: a randomized, double-blind, placebo-controlled study. Atherosclerosis. 2004;177(1):155–160. doi:10.1016/j.atherosclerosis.2004.07.008
   PubMed Web of Science ®Google Scholar
• Bryniarski P, Nazimek K, Marcinkiewicz J. Immunomodulatory activity of the most commonly used antihypertensive drugs-angiotensin converting enzyme inhibitors and angiotensin ii receptor blockers. Int J Mol Sci. 2022;23(3):1772. doi:10.3390/ijms23031772
   PubMed Web of Science ®Google Scholar
• Verdecchia P, Sleight P, Mancia G, et al.; ONTARGET/TRANSCEND Investigators. Effects of telmisartan, ramipril, and their combination on left ventricular hypertrophy in individuals at high vascular risk in the ongoing telmisartan alone and in combination with ramipril global end point trial and the telmisartan randomized assessment study in ACE intolerant subjects with cardiovascular disease. Circulation. 2009;120(14):1380–1389. doi:10.1161/CIRCULATIONAHA.109.865774.
   PubMed Web of Science ®Google Scholar
• Bangalore S, Kumar S, Wetterslev J, Messerli FH. Angiotensin receptor blockers and risk of myocardial infarction: meta-analyses and trial sequential analyses of 147 020 patients from randomised trials. BMJ. 2011;342:d2234. doi:10.1136/bmj.d2234
   PubMed Web of Science ®Google Scholar
• Pitt B, Segal R, Martinez FA, et al. Randomised trial of losartan versus captopril in patients over 65 with heart failure (evaluation of losartan in the elderly study, ELITE). Lancet. 1997;349(9054):747–752. doi:10.1016/S0140-6736(97)01187-2
   PubMed Web of Science ®Google Scholar
• Pitt S, Poole-Wilson PA, Segal R, et al. Randomised trial of losartan versus captopril on mortality in patients with symptomatic heart failure: the losartan heart failure survival study – ELITE II. Lancet. 2000;355:1582–1587. doi:10.1016/S0140-6736(00)02213-3
   PubMed Web of Science ®Google Scholar
• Cohn JN, Tognoni G, Glazer RD, Spormann D, Hester A. Rationale and design of the valsartan heart failure trial: a large multinational trial to assess the effects of valsartan, an angiotensin-receptor blocker, on morbidity and mortality in chronic congestive heart failure. J Card Fail. 1999;5(2):155–160. doi:10.1016/S1071-9164(99)90038-6
   PubMed Web of Science ®Google Scholar
• Young JB, Dunlap ME, Pfeffer MA, et al.; Candesartan in heart failure assessment of reduction in mortality and morbidity (CHARM) investigators and committees. Mortality and morbidity reduction with Candesartan in patients with chronic heart failure and left ventricular systolic dysfunction: results of the CHARM low-left ventricular ejection fraction trials. Circulation. 2004;110(17):2618–2626. doi:10.1161/01.CIR.0000146819.43235.A9
   PubMed Web of Science ®Google Scholar
• Dickstein K, Kjekshus J; OPTIMAAL Steering, Committee of the OPTIMAAL study group. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Optimal trial in myocardial infarction with angiotensin ii antagonist losartan. Lancet. 2002;360(9335):752–760. doi:10.1016/s0140-6736(02)09895-1
   PubMed Web of Science ®Google Scholar
• Pfeffer MA, McMurray JJ, Velazquez EJ, et al.; Valsartan in Acute Myocardial Infarction Trial Investigators. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med. 2003;349(20):1893–1906. doi:10.1056/NEJMoa032292.
   PubMed Web of Science ®Google Scholar
• Klingbeil AU, Schneider M, Martus P, Messerli FH, Schmieder RE. A meta-analysis of the effects of treatment on left ventricular mass in essential hypertension. Am J Med. 2003;115(1):41–46. doi:10.1016/S0002-9343(03)00158-X
   PubMed Web of Science ®Google Scholar
• Xu R, Sun S, Huo Y, et al. Effects of ACEIs versus ARBs on proteinuria or albuminuria in primary hypertension: a meta-analysis of randomized trials. Medicine. 2015;94(39):e1560. doi:10.1097/MD.0000000000001560
   PubMed Web of Science ®Google Scholar
• Savarese G, Costanzo P, Cleland JG, et al. A meta-analysis reporting effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in patients without heart failure. J Am Coll Cardiol. 2013;61:131–142. doi:10.1016/j.jacc.2012.10.011
   PubMed Web of Science ®Google Scholar
• Li EC, Heran BS, Wright JM. Angiotensin converting enzyme (ACE) inhibitors versus angiotensin receptor blockers for primary hypertension. Cochrane Database Syst Rev. 2014;2014(8):CD009096.
   PubMedGoogle Scholar
• Potier L, Roussel R, Elbez Y, et al.; REACH Registry Investigators*. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in high vascular risk. Heart. 2017;103(17):1339–1346. doi:10.1136/heartjnl-2016-310705.
   PubMed Web of Science ®Google Scholar
• Bangalore S, Fakheri R, Toklu B, Ogedegbe G, Weintraub H, Messerli FH. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in patients without heart failure? Insights from 254,301 patients from randomized trials. Mayo Clin Proc. 2016;91(1):51–60. doi:10.1016/j.mayocp.2015.10.019
   PubMed Web of Science ®Google Scholar
• Ricci F, Di Castelnuovo A, Savarese G, Perrone Filardi P, De Caterina R. ACE-inhibitors versus angiotensin receptor blockers for prevention of events in cardiovascular patients without heart failure - A network meta-analysis. Int J Cardiol. 2016;15(217):128–134. doi:10.1016/j.ijcard.2016.04.132
   Web of Science ®Google Scholar
• 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;78(3):591–603. doi:10.1161/HYPERTENSIONAHA.120.16667
   PubMed Web of Science ®Google Scholar
• Thomopoulos C, Parati G, Zanchetti A. Effects of blood-pressure-lowering treatment in hypertension: discontinuations for adverse events attributed to different classes of antihypertensive drugs: meta-analyses of randomized trials. J Hypertens. 2016;34:1921–1932. doi:10.1097/HJH.0000000000001052
   PubMed Web of Science ®Google Scholar
• Toh S, Reichman ME, Houstoun M, et al. Comparative risk for angioedema associated with the use of drugs that target the renin-angiotensin-aldosterone system. Arch Intern Med. 2012;172(20):1582–1589. doi:10.1001/2013.jamainternmed.34
   PubMedGoogle Scholar
• Bangalore S, Kumar S, Kjeldsen SE, et al. Antihypertensive drugs and risk of cancer: network meta-analyses and trial sequential analyses of 324,168 participants from randomised trials. Lancet Oncol. 2011;12(1):65–82. doi:10.1016/S1470-2045(10)70260-6
   PubMed Web of Science ®Google Scholar
• Angiotensin receptor blockers: impact on costs of care. Am J Manag Care. 2005;11(13 Suppl):S400–S403.
   PubMed Web of Science ®Google Scholar
• Hofmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181:271.e8–280.e8. doi:10.1016/j.cell.2020.02.052
   Web of Science ®Google Scholar
• Savoia C, Arrabito E, Parente R, et al. Mas receptor activation contributes to the improvement of nitric oxide bioavailability and vascular remodeling during chronic AT1R (angiotensin type-1 receptor) blockade in experimental hypertension. Hypertension. 2020;76:1753–1761. doi:10.1161/HYPERTENSIONAHA.120.15527
   PubMed Web of Science ®Google Scholar
• Gallo G, Calvez V, Savoia C. Hypertension and COVID-19: current evidence and perspectives. High Blood Press Cardiovasc Prev. 2022;29(2):115–123. doi:10.1007/s40292-022-00506-9
   PubMed Web of Science ®Google Scholar
• Sattar Y, Mukuntharaj P, Zghouzi M, et al. Safety and efficacy of renin-angiotensin-aldosterone system inhibitors in COVID-19 population. High Blood Press Cardiovasc Prev. 2021;28(4):405–416. doi:10.1007/s40292-021-00462-w
   PubMed Web of Science ®Google Scholar
• Mancusi C, Grassi G, Borghi C, et al.; SARS-RAS Investigator Group. Clinical characteristics and outcomes of patients with COVID-19 infection: the results of the SARS-RAS study of the Italian society of hypertension. High Blood Press Cardiovasc Prev. 2021;28(1):5–11. doi:10.1007/s40292-020-00429-3.
   PubMed Web of Science ®Google Scholar
• Rubattu S, Gallo G, Volpe M. A contemporary view of natriuretic peptides in the SARS-CoV-2 era. Front Physiol. 2021;16(12):643721. doi:10.3389/fphys.2021.643721
   Web of Science ®Google Scholar
• Rubattu S, Gallo G, Volpe M. Sacubitril/valsartan: potential impact of ARNi “Beyond the Wall” of ACE2 on treatment and prognosis of heart failure patients with coronavirus disease-19. Front Cardiovasc Med. 2020;27(7):616564. doi:10.3389/fcvm.2020.616564
   Web of Science ®Google Scholar
• Lopes RD, Macedo AVS, de Barros E Silva PGM, et al.; BRACE CORONA Investigators. Effect of discontinuing vs continuing angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on days alive and out of the hospital in patients admitted with COVID-19: a randomized clinical trial. JAMA. 2021;325(3):254–264. doi:10.1001/jama.2020.25864.
   PubMed Web of Science ®Google Scholar
• Duarte M, Pelorosso F, Nicolosi LN, et al. Telmisartan for treatment of Covid-19 patients: an open multicenter randomized clinical trial. EClinicalMedicine. 2021;37:100962. doi:10.1016/j.eclinm.2021.100962
   PubMedGoogle Scholar
• The Task Force for the management of COVID-19 of the European Society of Cardiology. ESC guidance for the diagnosis and management of cardiovascular disease during the COVID-19 pandemic: part 2—care pathways, treatment, and follow-up. Eur Heart J. 2021. doi:10.1093/eurheartj/ehab697
   Web of Science ®Google Scholar
• Arai T, Yasuda Y, Takaya T, et al. Angiotensin-converting enzyme inhibitors, angiotensin-II receptor antagonists, and pneumonia in elderly hypertensive patients with stroke. Chest. 2001;119:660–661. doi:10.1378/chest.119.2.660
   PubMed Web of Science ®Google Scholar
• Harada J, Sekizawa K. Angiotensin-converting enzyme inhibitors and pneumonia in elderly patients with intracerebral hemorrhage. J Am Geriatr Soc. 2006;54:175–176. doi:10.1111/j.1532-5415.2005.00575_8.x
   PubMed Web of Science ®Google Scholar
• Liu CL, Shau WY, Wu CS, Lai MS. Angiotensin-converting enzyme inhibitor/angiotensin II receptor blockers and pneumonia risk among stroke patients. J Hypertens. 2012;30:2223–2229. doi:10.1097/HJH.0b013e328357a87a
   PubMed Web of Science ®Google Scholar