Dose Selection for Clinical Development in the Treatment of Hypertension: The Aprocitentan Case and Lessons from the Past
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Jan 30, 2024
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Abstract
Dose selection plays a critical role in the clinical development of a drug. This current review highlights the lessons learned from previous dose finding studies (DFSs) of antihypertensive drugs and from the recent example of aprocitentan, a novel endothelin receptor antagonist for the treatment of resistant hypertension. Based on these, the authors provide 10 key recommendations for an efficient DFS for a new antihypertensive medication. These recommendations respect critical comments repeatedly made by the U.S. Food and Drug Administration (FDA) Division of Cardiology and Nephrology over the last 5 decades and go beyond the more limited recommendations made in the 2016 Committee for Medicinal Products for Human Use (CHMP) guideline on the development of new antihypertensive medications. The added value of a dose-response modelling approach enriches prior regulatory advice on DFSs.
Article Details
How to Cite
M, Bellet et al.
Dose Selection for Clinical Development in the Treatment of Hypertension: The Aprocitentan Case and Lessons from the Past.
Medical Research Archives, [S.l.], v. 12, n. 1, jan. 2024.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/4962>. Date accessed: 21 dec. 2024.
doi: https://doi.org/10.18103/mra.v12i1.4962.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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2. CPMP/ICH/378/95. ICH E4 Dose response information to support drug registration. 1994. https://www.ema.europa.eu/en/ich-e4-dose-response-information-support-drug-registration-scientific-guideline
3. Bretz F, Dette H, Pinheiro JC. Practical considerations for optimal designs in clinical dose finding studies. Stat Med. Mar 30 2010;29(7-8):731-42. doi:10.1002/sim.3802
4. Sacks LV, Shamsuddin HH, Yasinskaya YI, Bouri K, Lanthier ML, Sherman RE. Scientific and regulatory reasons for delay and denial of FDA approval of initial applications for new drugs, 2000-2012. JAMA. 2014;311(4):378-84. doi:10.1001/jama.2013.282542.
5. Cross J, Lee H, Westelinck A, Nelson J, Grudzinskas C, Peck C. Postmarketing drug dosage changes of 499 FDA-approved new molecular entities, 1980-1999. Pharmacoepidemiol Drug Saf. 2002;11:439-46.
6. Desai M, Stockbridge N, Temple R. Blood pressure as an example of a biomarker that functions as a surrogate. Aaps j. Mar 10 2006;8(1):E146-52. doi:10.1208/aapsj080117
7. FDA Guidance document; Hypertension Indication: Drug Labeling for Cardiovascular Outcome Claims. 2011. . https://www.fda.gov/regulatory-information/search-fda-guidance-documents/hypertension-indication-drug-labeling-cardiovascular-outcome-claims
8. Nejad SH, Azzam O, Schlaich MP. Dual Endothelin Antagonism with Aprocitentan as a Novel Therapeutic Approach for Resistant Hypertension. Current Hypertension Reports 2023;25:343-352.
9. Materson BJ, Oster JR, Michael UF, et al. Dose response to chlorthalidone in patients with mild hypertension. Efficacy of a lower dose. Clin Pharmacol Ther 1978;24(2):192-198
10. Tweeddale MG, Ogilvie RI, Ruedy J. Antihypertensive and biochemical effects of chlorthalidone. Clinical Pharmacology & Therapeutics. 1977;22(5)(1):519-527.
11. Multiple risk factor intervention trial. Risk factor changes and mortality results. Multiple Risk Factor Intervention Trial Research Group. Jama. Sep 24 1982;248(12):1465-77.
12. Siscovick DS, Raghunathan TE, Psaty BM, et al. Diuretic therapy for hypertension and the risk of primary cardiac arrest. NEJM. 1994;330:1852-1857
13. Gavras H, Brunner HR, Turini GA, et al. Antihypertensive Effect of the Oral Angiotensin Converting-Enzyme Inhibitor SQ 14225 in Man. NEJM. 1978;298(18):991-995. doi:10.1056/NEJM19780504298180
14. Frohlich ED, Cooper RA, Lewis EJ. Review of the overall experience of captopril in hypertension. Arch Intern Med. 1984;144(7):1441-4
15. Materson BJ, Freis ED, Anderson S, Taguchi J. Low-dose captopril for the treatment of mild to moderate hypertension. Hypertension. 1983;5(2): 139-44. doi:doi:10.1161/01.HYP.5.5_Pt_2.III139
16. Goa KL, Wagstaff AJ. Losartan Potassium: A Review of its Pharmacology, Clinical Efficacy and Tolerability in the Management of Hypertension. Drugs. 1996;51, 820–845
17. Aliskiren (Rasilez), EPAR smpc. First published 2009, last update 2016. https://www.ema.europa.eu/en/documents/product-information/rasilez-epar-product-information_en.pdf
18. Trensz F, Bortolamiol C, Kramberg M, et al. Pharmacological Characterization of Aprocitentan, a Dual Endothelin Receptor Antagonist, Alone and in Combination with Blockers of the Renin Angiotensin System, in Two Models of Experimental Hypertension. J Pharmacol Exp Ther. Mar 2019;368(3):462-473. doi:10.1124/jpet.118.253864
19. Verweij P, Danaietash P, Flamion B, Ménard J, Bellet M. Randomized Dose-Response Study of the New Dual Endothelin Receptor Antagonist Aprocitentan in Hypertension. Hypertension. Apr 2020;75(4):956-965. doi:10.1161/hypertensionaha.119.14504
20. Bretz F, Pinheiro JC, Branson M. Combining multiple comparisons and modeling techniques in dose-response studies. Biometrics. Sep 2005;61(3):738-48. doi:10.1111/j.1541-0420.2005.00344.x
21. Calhoun DA, White WB, Krum H, et al. Effects of a novel aldosterone synthase inhibitor for treatment of primary hypertension: results of a randomized, double-blind, placebo- and active-controlled phase 2 trial. Circulation. Nov 1 2011;124(18):1945-55. doi:10.1161/circulationaha.111.029892
22. FDA. Request for Qualification of MCP-Mod as an efficient statistical methodology for model-based design and analysis of Phase II dose finding studies under model uncertainty. 2015. . https://www.fda.gov/media/99313/download
23. EMA/CHMP/SAWP/757052/2013. Qualification Opinion of MCP-Mod as an efficient statistical methodology for model-based design and analysis of Phase II dose finding studies under model uncertainty. 2014. https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/qualification-opinion-mcp-mod-efficient-statistical-methodology-model-based-design-analysis-phase-ii_en.pdf
24. Bornkamp B, Pinheiro J, Bretz F, Sandig L, Thomas M. DoseFinding: Planning and Analyzing Dose Finding Experiments. 1.1-1.
25. Schlaich MP, Bellet M, Weber MA, et al. Dual endothelin antagonist aprocitentan for resistant hypertension (PRECISION): a multicentre, blinded, randomised, parallel-group, phase 3 trial. Lancet. Dec 3 2022;400(10367):1927-1937. doi:10.1016/s0140-6736(22)02034-7
26. Gueneau de Mussy P, Sidharta PN, Wuerzner G, et al. Effects of the Dual Endothelin Receptor Antagonist Aprocitentan on Body Weight and Fluid Homeostasis in Healthy Subjects on a High Sodium Diet. Clin Pharmacol Ther. Mar 2021;109(3):746-753. doi:10.1002/cpt.2043
27. Brewster LM, van Montfrans GA, J K. Systematic review: antihypertensive drug therapy in black patients. Ann Intern Med. Oct 19 2004;141(8):614-27. doi:10.7326/0003-4819-141-8-200410190-00009
28. Huang SM, Bhattaram A, Mehrotra N, Wang Y. Is this the dose for you?: the role of modeling. Clin Pharmacol Ther. Feb 2013;93(2):159-62. doi:10.1038/clpt.2012.228
29. Johnston GD. Dose-response relationships with antihypertensive drugs. Pharmacol Ther. 1992;55(1):53-93. doi:10.1016/0163-7258(92)90029-y
30. Temple R. Difficulties in Evaluating Positive Control Trials Proc Am Statist Assoc (Biopharmaceutical Sect). 1983:1-7.
31. Menard J, Bellet M, Brunner HR. Hypertension: Pathophysiology, diagnosis, and management. vol Chapter 148. Clinical development of hypertensive drugs. Second edition, Raven Press Ltd. ; 1995.
32. Temple R. Dose-response and registration of new drugs. Dose response relationships in clinical pharmacology. 1989;pl45–167
33. O'Neill RT, Temple R. The prevention and treatment of missing data in clinical trials: an FDA perspective on the importance of dealing with it. Clin Pharmacol Ther. Mar 2012;91(3):550-4. doi:10.1038/clpt.2011.340
34. Carlsen JE, Kober L, Torp-Pedersen C, Johansen P. Relation between dose of bendrofluazide, antihypertensive effect, and adverse biochemical effects. Bmj. Apr 14 1990;300(6730):975-8. doi:10.1136/bmj.300.6730.975
35. Bulpitt CJ. Randomised Controlled Clinical Trials. Springer; 1983.
36. Myers MG, Lipicky R.J. Assessment of antihypertensive activity in the regulatory setting. Blood Press Monit. Dec 2001;6(6):309-12. doi:10.1097/00126097-200112000-00008
37. DeFelice A, Willard J, Lawrence J, et al. The risks associated with short-term placebo-controlled antihypertensive clinical trials: a descriptive meta-analysis. J Hum Hypertens. Oct 2008;22(10):659-68. doi:10.1038/jhh.2008.51
38. ICH E10 Choice of control group in clinical trials - Scientific guideline. 2001. https://www.ema.europa.eu/en/ich-e10-choice-control-group-clinical-trials-scientific-guideline
39. Gomez HJ, Cirillo VJ, Sromovsky JA, et al. Lisinopril dose-response relationship in essential hypertension. Br J Clin Pharmacol. Oct 1989;28(4):415-20. doi:10.1111/j.1365-2125.1989.tb03521.x
40. Patel HC, Hayward C, Ozdemir BA, et al. Magnitude of blood pressure reduction in the placebo arms of modern hypertension trials: implications for trials of renal denervation. Hypertension. Feb 2015;65(2):401-6. doi:10.1161/hypertensionaha.114.04640
41. Laffin LJ, Rodman D, Luther JM, et al. Aldosterone Synthase Inhibition With Lorundrostat for Uncontrolled Hypertension: The Target-HTN Randomized Clinical Trial. Jama. Sep 26 2023;330(12):1140-1150. doi:10.1001/jama.2023.16029
42. Freeman MW, Halvorsen Y D, Marshall W, et al. Phase 2 Trial of Baxdrostat for Treatment-Resistant Hypertension. N Engl J Med. Feb 2 2023;388(5):395-405. doi:10.1056/NEJMoa2213169
43. Mutti E, Trazzi S, Omboni S, Parati G, G M. Effect of placebo on 24-h non-invasive ambulatory blood pressure. J Hypertens. Apr 1991;9(4):361-4. doi:10.1097/00004872-199104000-00008
44. Center for Drug Evaluation and Research- Aliskiren hemifumarate. 2007 NDA-21985. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021985s000_MedR_P1.pdf
45. 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. Mar 2011;57(3):413-20. doi:10.1161/hypertensionaha.110.163402
46. Myers MG, Valdivieso M, Kiss A. Use of automated office blood pressure measurement to reduce the white coat response. J Hypertens. Apr 2009;27(2):280-6. doi:10.1097/HJH.0b013e328335d091
47. Grassi G, Quarti-Trevano F, Seravalle G, et al. Sympathetic Neural Mechanisms Underlying Attended and Unattended Blood Pressure Measurement. Hypertension. Dec 1 2021;78(4):1126-1133. doi:10.1161/HYPERTENSIONAHA.121.17657
48. Danaietash P, Verweij P, Wang JG, et al. Identifying and treating resistant hypertension in PRECISION: A randomized long-term clinical trial with aprocitentan. J Clin Hypertens (Greenwich). Jul 2022;24(7):804-813. doi:10.1111/jch.14517
49. Mancia G, Verdecchia P. Clinical value of ambulatory blood pressure: evidence and limits. Circ Res. Mar 13 2015;116(6):1034-45. doi:10.1161/circresaha.116.303755
50. Messerli FH, Bangalore S, Schmieder RE. Wilder's principle: pre-treatment value determines post-treatment response. Eur Heart J. Mar 1 2015;36(9):576-9. doi:10.1093/eurheartj/ehu467
51. Lees KR, Squire IB, Reid JL. The clinical pharmacology of ACE inhibitors: evidence for clinically relevant differences? Clin Exp Pharmacol Physiol Suppl. 1992;19:49-53. doi:10.1111/j.1440-1681.1992.tb02810.x
52. EMA/CHMP/ICH/436221/2017. ICH E9 (R1) addendum on estimands and sensitivity analysis in clinical trials to the guideline on statistical principles for clinical trials. 2020. https://www.ema.europa.eu/en/documents/scientific-guideline/ich-e9-r1-addendum-estimands-sensitivity-analysis-clinical-trials-guideline-statistical-principles_en.pdf
53. 4 ECR. Guideline on clinical investigation of medicinal products in the treatment of hypertension. 2016. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-clinical-investigation-medicinal-products-treatment-hypertension-revision-4_en.pdf
54. First-in-class aminopeptidase-A inhibitor fails to reduce treatment-resistant hypertension. 2022. https://sessions.hub.heart.org/aha-22/article/22539144/firstinclass-aminopeptidasea-inhibitor-fails-to-reduce-treatmentresistant-hypertension
55. Ferdinand KC, Balavoine F, Besse B, et al. Efficacy and Safety of Firibastat, A First-in-Class Brain Aminopeptidase A Inhibitor, in Hypertensive Overweight Patients of Multiple Ethnic Origins. Circulation. Jul 9 2019;140(2):138-146. doi:10.1161/circulationaha.119.040070
2. CPMP/ICH/378/95. ICH E4 Dose response information to support drug registration. 1994. https://www.ema.europa.eu/en/ich-e4-dose-response-information-support-drug-registration-scientific-guideline
3. Bretz F, Dette H, Pinheiro JC. Practical considerations for optimal designs in clinical dose finding studies. Stat Med. Mar 30 2010;29(7-8):731-42. doi:10.1002/sim.3802
4. Sacks LV, Shamsuddin HH, Yasinskaya YI, Bouri K, Lanthier ML, Sherman RE. Scientific and regulatory reasons for delay and denial of FDA approval of initial applications for new drugs, 2000-2012. JAMA. 2014;311(4):378-84. doi:10.1001/jama.2013.282542.
5. Cross J, Lee H, Westelinck A, Nelson J, Grudzinskas C, Peck C. Postmarketing drug dosage changes of 499 FDA-approved new molecular entities, 1980-1999. Pharmacoepidemiol Drug Saf. 2002;11:439-46.
6. Desai M, Stockbridge N, Temple R. Blood pressure as an example of a biomarker that functions as a surrogate. Aaps j. Mar 10 2006;8(1):E146-52. doi:10.1208/aapsj080117
7. FDA Guidance document; Hypertension Indication: Drug Labeling for Cardiovascular Outcome Claims. 2011. . https://www.fda.gov/regulatory-information/search-fda-guidance-documents/hypertension-indication-drug-labeling-cardiovascular-outcome-claims
8. Nejad SH, Azzam O, Schlaich MP. Dual Endothelin Antagonism with Aprocitentan as a Novel Therapeutic Approach for Resistant Hypertension. Current Hypertension Reports 2023;25:343-352.
9. Materson BJ, Oster JR, Michael UF, et al. Dose response to chlorthalidone in patients with mild hypertension. Efficacy of a lower dose. Clin Pharmacol Ther 1978;24(2):192-198
10. Tweeddale MG, Ogilvie RI, Ruedy J. Antihypertensive and biochemical effects of chlorthalidone. Clinical Pharmacology & Therapeutics. 1977;22(5)(1):519-527.
11. Multiple risk factor intervention trial. Risk factor changes and mortality results. Multiple Risk Factor Intervention Trial Research Group. Jama. Sep 24 1982;248(12):1465-77.
12. Siscovick DS, Raghunathan TE, Psaty BM, et al. Diuretic therapy for hypertension and the risk of primary cardiac arrest. NEJM. 1994;330:1852-1857
13. Gavras H, Brunner HR, Turini GA, et al. Antihypertensive Effect of the Oral Angiotensin Converting-Enzyme Inhibitor SQ 14225 in Man. NEJM. 1978;298(18):991-995. doi:10.1056/NEJM19780504298180
14. Frohlich ED, Cooper RA, Lewis EJ. Review of the overall experience of captopril in hypertension. Arch Intern Med. 1984;144(7):1441-4
15. Materson BJ, Freis ED, Anderson S, Taguchi J. Low-dose captopril for the treatment of mild to moderate hypertension. Hypertension. 1983;5(2): 139-44. doi:doi:10.1161/01.HYP.5.5_Pt_2.III139
16. Goa KL, Wagstaff AJ. Losartan Potassium: A Review of its Pharmacology, Clinical Efficacy and Tolerability in the Management of Hypertension. Drugs. 1996;51, 820–845
17. Aliskiren (Rasilez), EPAR smpc. First published 2009, last update 2016. https://www.ema.europa.eu/en/documents/product-information/rasilez-epar-product-information_en.pdf
18. Trensz F, Bortolamiol C, Kramberg M, et al. Pharmacological Characterization of Aprocitentan, a Dual Endothelin Receptor Antagonist, Alone and in Combination with Blockers of the Renin Angiotensin System, in Two Models of Experimental Hypertension. J Pharmacol Exp Ther. Mar 2019;368(3):462-473. doi:10.1124/jpet.118.253864
19. Verweij P, Danaietash P, Flamion B, Ménard J, Bellet M. Randomized Dose-Response Study of the New Dual Endothelin Receptor Antagonist Aprocitentan in Hypertension. Hypertension. Apr 2020;75(4):956-965. doi:10.1161/hypertensionaha.119.14504
20. Bretz F, Pinheiro JC, Branson M. Combining multiple comparisons and modeling techniques in dose-response studies. Biometrics. Sep 2005;61(3):738-48. doi:10.1111/j.1541-0420.2005.00344.x
21. Calhoun DA, White WB, Krum H, et al. Effects of a novel aldosterone synthase inhibitor for treatment of primary hypertension: results of a randomized, double-blind, placebo- and active-controlled phase 2 trial. Circulation. Nov 1 2011;124(18):1945-55. doi:10.1161/circulationaha.111.029892
22. FDA. Request for Qualification of MCP-Mod as an efficient statistical methodology for model-based design and analysis of Phase II dose finding studies under model uncertainty. 2015. . https://www.fda.gov/media/99313/download
23. EMA/CHMP/SAWP/757052/2013. Qualification Opinion of MCP-Mod as an efficient statistical methodology for model-based design and analysis of Phase II dose finding studies under model uncertainty. 2014. https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/qualification-opinion-mcp-mod-efficient-statistical-methodology-model-based-design-analysis-phase-ii_en.pdf
24. Bornkamp B, Pinheiro J, Bretz F, Sandig L, Thomas M. DoseFinding: Planning and Analyzing Dose Finding Experiments. 1.1-1.
25. Schlaich MP, Bellet M, Weber MA, et al. Dual endothelin antagonist aprocitentan for resistant hypertension (PRECISION): a multicentre, blinded, randomised, parallel-group, phase 3 trial. Lancet. Dec 3 2022;400(10367):1927-1937. doi:10.1016/s0140-6736(22)02034-7
26. Gueneau de Mussy P, Sidharta PN, Wuerzner G, et al. Effects of the Dual Endothelin Receptor Antagonist Aprocitentan on Body Weight and Fluid Homeostasis in Healthy Subjects on a High Sodium Diet. Clin Pharmacol Ther. Mar 2021;109(3):746-753. doi:10.1002/cpt.2043
27. Brewster LM, van Montfrans GA, J K. Systematic review: antihypertensive drug therapy in black patients. Ann Intern Med. Oct 19 2004;141(8):614-27. doi:10.7326/0003-4819-141-8-200410190-00009
28. Huang SM, Bhattaram A, Mehrotra N, Wang Y. Is this the dose for you?: the role of modeling. Clin Pharmacol Ther. Feb 2013;93(2):159-62. doi:10.1038/clpt.2012.228
29. Johnston GD. Dose-response relationships with antihypertensive drugs. Pharmacol Ther. 1992;55(1):53-93. doi:10.1016/0163-7258(92)90029-y
30. Temple R. Difficulties in Evaluating Positive Control Trials Proc Am Statist Assoc (Biopharmaceutical Sect). 1983:1-7.
31. Menard J, Bellet M, Brunner HR. Hypertension: Pathophysiology, diagnosis, and management. vol Chapter 148. Clinical development of hypertensive drugs. Second edition, Raven Press Ltd. ; 1995.
32. Temple R. Dose-response and registration of new drugs. Dose response relationships in clinical pharmacology. 1989;pl45–167
33. O'Neill RT, Temple R. The prevention and treatment of missing data in clinical trials: an FDA perspective on the importance of dealing with it. Clin Pharmacol Ther. Mar 2012;91(3):550-4. doi:10.1038/clpt.2011.340
34. Carlsen JE, Kober L, Torp-Pedersen C, Johansen P. Relation between dose of bendrofluazide, antihypertensive effect, and adverse biochemical effects. Bmj. Apr 14 1990;300(6730):975-8. doi:10.1136/bmj.300.6730.975
35. Bulpitt CJ. Randomised Controlled Clinical Trials. Springer; 1983.
36. Myers MG, Lipicky R.J. Assessment of antihypertensive activity in the regulatory setting. Blood Press Monit. Dec 2001;6(6):309-12. doi:10.1097/00126097-200112000-00008
37. DeFelice A, Willard J, Lawrence J, et al. The risks associated with short-term placebo-controlled antihypertensive clinical trials: a descriptive meta-analysis. J Hum Hypertens. Oct 2008;22(10):659-68. doi:10.1038/jhh.2008.51
38. ICH E10 Choice of control group in clinical trials - Scientific guideline. 2001. https://www.ema.europa.eu/en/ich-e10-choice-control-group-clinical-trials-scientific-guideline
39. Gomez HJ, Cirillo VJ, Sromovsky JA, et al. Lisinopril dose-response relationship in essential hypertension. Br J Clin Pharmacol. Oct 1989;28(4):415-20. doi:10.1111/j.1365-2125.1989.tb03521.x
40. Patel HC, Hayward C, Ozdemir BA, et al. Magnitude of blood pressure reduction in the placebo arms of modern hypertension trials: implications for trials of renal denervation. Hypertension. Feb 2015;65(2):401-6. doi:10.1161/hypertensionaha.114.04640
41. Laffin LJ, Rodman D, Luther JM, et al. Aldosterone Synthase Inhibition With Lorundrostat for Uncontrolled Hypertension: The Target-HTN Randomized Clinical Trial. Jama. Sep 26 2023;330(12):1140-1150. doi:10.1001/jama.2023.16029
42. Freeman MW, Halvorsen Y D, Marshall W, et al. Phase 2 Trial of Baxdrostat for Treatment-Resistant Hypertension. N Engl J Med. Feb 2 2023;388(5):395-405. doi:10.1056/NEJMoa2213169
43. Mutti E, Trazzi S, Omboni S, Parati G, G M. Effect of placebo on 24-h non-invasive ambulatory blood pressure. J Hypertens. Apr 1991;9(4):361-4. doi:10.1097/00004872-199104000-00008
44. Center for Drug Evaluation and Research- Aliskiren hemifumarate. 2007 NDA-21985. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021985s000_MedR_P1.pdf
45. 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. Mar 2011;57(3):413-20. doi:10.1161/hypertensionaha.110.163402
46. Myers MG, Valdivieso M, Kiss A. Use of automated office blood pressure measurement to reduce the white coat response. J Hypertens. Apr 2009;27(2):280-6. doi:10.1097/HJH.0b013e328335d091
47. Grassi G, Quarti-Trevano F, Seravalle G, et al. Sympathetic Neural Mechanisms Underlying Attended and Unattended Blood Pressure Measurement. Hypertension. Dec 1 2021;78(4):1126-1133. doi:10.1161/HYPERTENSIONAHA.121.17657
48. Danaietash P, Verweij P, Wang JG, et al. Identifying and treating resistant hypertension in PRECISION: A randomized long-term clinical trial with aprocitentan. J Clin Hypertens (Greenwich). Jul 2022;24(7):804-813. doi:10.1111/jch.14517
49. Mancia G, Verdecchia P. Clinical value of ambulatory blood pressure: evidence and limits. Circ Res. Mar 13 2015;116(6):1034-45. doi:10.1161/circresaha.116.303755
50. Messerli FH, Bangalore S, Schmieder RE. Wilder's principle: pre-treatment value determines post-treatment response. Eur Heart J. Mar 1 2015;36(9):576-9. doi:10.1093/eurheartj/ehu467
51. Lees KR, Squire IB, Reid JL. The clinical pharmacology of ACE inhibitors: evidence for clinically relevant differences? Clin Exp Pharmacol Physiol Suppl. 1992;19:49-53. doi:10.1111/j.1440-1681.1992.tb02810.x
52. EMA/CHMP/ICH/436221/2017. ICH E9 (R1) addendum on estimands and sensitivity analysis in clinical trials to the guideline on statistical principles for clinical trials. 2020. https://www.ema.europa.eu/en/documents/scientific-guideline/ich-e9-r1-addendum-estimands-sensitivity-analysis-clinical-trials-guideline-statistical-principles_en.pdf
53. 4 ECR. Guideline on clinical investigation of medicinal products in the treatment of hypertension. 2016. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-clinical-investigation-medicinal-products-treatment-hypertension-revision-4_en.pdf
54. First-in-class aminopeptidase-A inhibitor fails to reduce treatment-resistant hypertension. 2022. https://sessions.hub.heart.org/aha-22/article/22539144/firstinclass-aminopeptidasea-inhibitor-fails-to-reduce-treatmentresistant-hypertension
55. Ferdinand KC, Balavoine F, Besse B, et al. Efficacy and Safety of Firibastat, A First-in-Class Brain Aminopeptidase A Inhibitor, in Hypertensive Overweight Patients of Multiple Ethnic Origins. Circulation. Jul 9 2019;140(2):138-146. doi:10.1161/circulationaha.119.040070