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Effectiveness of Perindopril/Indapamide Single-Pill Combination in Uncontrolled Patients with Hypertension: A Pooled Analysis of the FORTISSIMO, FORSAGE, ACES and PICASSO Observational Studies

Abstract

Introduction

Our objective was to determine the effectiveness of a perindopril/indapamide (Per/Ind) single-pill combination (SPC) in a broad range of patient profiles, including subgroups with varying hypertension severity, age and cardiovascular risk profiles.

Methods

Patient data from four large prospective observational studies (FORTISSIMO, FORSAGE, PICASSO, ACES) were pooled. In each study, patients already treated for hypertension were switched to Per/Ind 10/2.5 mg SPC and systolic and diastolic blood pressure (SBP/DBP) measured at the 1-month (M1) and 3-month (M3) visits. Study endpoints included change in SBP and DBP from baseline to M1 and M3 and the percentage of patients achieving BP control (SBP/DBP < 140/90 mmHg for patients without diabetes or < 140/85 mmHg for patients with diabetes).

Results

A total of 16,763 patients were enrolled and received Per/Ind (94% received the full dose of 10/2.5). Mean patient age was 61.4 years (36% were ≥ 65 years old), 57% were women, and 16% had isolated systolic hypertension (ISH). Mean baseline office SBP/DBP was 162/94 mmHg, and mean duration of hypertension was 11 years. Cardiovascular risk factors and comorbid conditions were common in this population. Significant mean reductions in SBP (− 23 mmHg) and DBP (− 11 mmHg) were observed at M1 compared with baseline (P < 0.001), which were maintained at M3 (− 30 mmHg and − 14 mmHg, respectively). At M3, BP control was achieved by 70% of patients (78% for ISH). In patients with SBP ≥ 180 mmHg at baseline (grade III hypertension), the mean SBP/DBP decrease was − 51/− 20 mmHg and 53% achieved BP control. Per/Ind was well tolerated with an overall rate of adverse events of 1.3%, most frequently cough and dizziness at rates of 0.3% and 0.2%, respectively.

Conclusion

In this hypertensive population including difficult-to-control patient subgroups, switching to Per/Ind 10/2.5 mg SPC led to rapid and important reductions in BP. BP control was achieved in 70% of patients overall in an everyday practice context.

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References

  1. 1.

    Rahimi K, Emdin CA, MacMahon S. The epidemiology of blood pressure and its worldwide management. Circ Res. 2015;116:925–36.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  2. 2.

    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;387:957–67.

    PubMed  Article  PubMed Central  Google Scholar 

  3. 3.

    Thomopoulos C, Parati G, Zanchetti A. Effects of blood pressure lowering on outcome incidence in hypertension. 1. Overview, meta-analyses, and metaregression analyses of randomized trials. J Hypertens. 2014;32:2285–95.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  4. 4.

    Brown DW, Giles WH, Greenlund KJ. Blood pressure parameters and risk of fatal stroke, NHANES II mortality study. Am J Hypertens. 2007;20:338–41.

    PubMed  Article  PubMed Central  Google Scholar 

  5. 5.

    Lawes CM, Vander Hoorn S, Rodgers A. Global burden of blood-pressure-related disease, 2001. Lancet. 2008;371:1513–8.

    PubMed  Article  PubMed Central  Google Scholar 

  6. 6.

    Vishram JK, Borglykke A, Andreasen AH, et al. Impact of age on the importance of systolic and diastolic blood pressures for stroke risk: the MOnica, Risk, Genetics, Archiving, and Monograph (MORGAM) project. Hypertension. 2012;60:1117–23.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  7. 7.

    Williams B, Mancia G, Spiering W, et al. 2018 ESC/ESH guidelines for the management of arterial hypertension. Eur Heart J. 2018;39:3021–104.

    PubMed  PubMed Central  Article  Google Scholar 

  8. 8.

    Chow CK, Teo KK, Rangarajan S, et al. Prevalence, awareness, treatment, and control of hypertension in rural and urban communities in high-, middle-, and low-income countries. JAMA. 2013;310:959–68.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  9. 9.

    Wang YR, Alexander GC, Stafford RS. Outpatient hypertension treatment, treatment intensification, and control in Western Europe and the United States. Arch Intern Med. 2007;167:141–7.

    PubMed  Article  PubMed Central  Google Scholar 

  10. 10.

    Beaney T, Burrell LM, Castillo RR, et al. May Measurement Month 2018: a pragmatic global screening campaign to raise awareness of blood pressure by the International Society of Hypertension. Eur Heart J. 2019;40:2006–17.

    PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    Marquez PHP, Torres OH, San-José A, et al. Potentially inappropriate antihypertensive prescriptions to elderly patients: results of a prospective, observational study. Drugs Aging. 2017;34:453–66.

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Petrák O, Zelinka T, Štrauch B, et al. Combination antihypertensive therapy in clinical practice. The analysis of 1254 consecutive patients with uncontrolled hypertension. J Hum Hypertens. 2016;30:35–9.

    PubMed  Article  CAS  Google Scholar 

  13. 13.

    Vrijens B, Vincze G, Kristanto P, Urquhart J, Burnier M. Adherence to prescribed antihypertensive drug treatments: longitudinal study of electronically compiled dosing histories. BMJ. 2008;336:1114–7.

    PubMed  PubMed Central  Article  Google Scholar 

  14. 14.

    Unger T, Borghi C, Charchar F, Khan NA, Poulter NR, et al. 2020 International society of hypertension global hypertension practice guidelines. Hypertension. 2020;75:1334–57.

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    Imbeault B, Vallée M. Single-pill combinations in the treatment of hypertension in adults: beyond convenience. Can J Diabetes. 2018;42:205–8.

    PubMed  Article  Google Scholar 

  16. 16.

    PROGRESS. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack. Lancet. 2001;358:1033–41.

    Article  Google Scholar 

  17. 17.

    Patel A, MacMahon S, ADVANCE Collaborative Group, et al. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet. 2007;370(9590):829–40.

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008;358:1887–98.

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    Myers MG, Asmar R, Leenen FH, Safar M. Fixed low-dose combination therapy in hypertension—a dose response study of perindopril and indapamide. J Hypertens. 2000;18(3):317–25.

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Mogensen CE, Viberti G, Halimi S, et al. Effect of low-dose perindopril/indapamide on albuminuria in diabetes: Preterax in albuminuria regression: PREMIER. Hypertension. 2003;41:1063–71.

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    Dahlöf B, Gosse P, Gueret P, on behalf of the PICXEL Investigators, et al. Perindopril/indapamide combination more effective than enalapril in reducing blood pressure and left ventricular mass: the PICXEL study. J Hypertens. 2005;23:2063–70.

    PubMed  Article  Google Scholar 

  22. 22.

    Karpov YA. The FORTISSIMO program: advantages of fixed full dose combination of perindopril arginine and indapamide in the treatment of poorly controlled arterial hypertension. Kardiologiia. 2013;53:37–43 ((Russian)).

    PubMed  Google Scholar 

  23. 23.

    Glezer MG, Deev AD. How to increase the effectiveness of antihypertensive therapy in clinical practice. Results of the Russian Observational Program FORSAZH. Kardiologiia. 2016;56:18–24 ((Russian)).

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Nadhazi Z, Dezsi CA. The results of ACES (Antihypertensive Combinations’ Long Term Efficacy Comparing Study): analysis of metabolic effects of antihypertensive combination therapies. Clin Drug Investig. 2016;36:819–27.

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Farsang C, Picasso Investigators. Blood pressure and metabolic efficacy of fixed-dose combination of perindopril and indapamide in everyday practice. Blood Press. 2013;22(Suppl 1):3–10.

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Farsang C. Efficacy and tolerability of fixed-dose combination of perindopril/indapamide in type 2 diabetes mellitus: PICASSO trial. Adv Ther. 2014;31:333–44.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. 27.

    Karpov YA. Full-dose perindopril/indapamide in the treatment of difficult-to-control hypertension. The FORTISSIMO Study. Clin Drug Investig. 2017;37:207–17.

    CAS  PubMed  Article  Google Scholar 

  28. 28.

    Dézsi CA, Farsang C, PICASSO Investigators. Efficacy and tolerability of fixed-dose combination perindopril/indapamide in hypertensive patients with a history of stroke or transient ischemic attack: PICASSO trial. Adv Ther. 2018;35:644–54.

    PubMed  Article  CAS  Google Scholar 

  29. 29.

    Dézsi CA, Glezer M, Villatte R, Karpov Y, Farsang C. Effectiveness of perindopril/indapamide single-pill combination in uncontrolled hypertensive patients: a combined analysis of FORTISSIMO, FORSAGE, ACES and PICASSO observational studies. J Hypertens. 2018;36(e-Suppl 3):202.

    Google Scholar 

  30. 30.

    Whelton PK, Carey RM, Aronow WS, et al. 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:e127–248.

    PubMed  Article  PubMed Central  Google Scholar 

  31. 31.

    Beckett NS, Peters R, Tuomilehto J, et al. Immediate and late benefits of treating very elderly people with hypertension: results from active treatment extension to Hypertension in the Very Elderly randomised controlled trial. BMJ. 2012;344:d7541.

    Article  Google Scholar 

  32. 32.

    Unger T, Borghi C, Charchar F, International Society of Hypertension, et al. 2020 International Society of Hypertension Global Hypertension Practice Guidelines. Hypertension. 2020;75:1334–57.

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Roush GC, Abdelfattah R, Song S, Kostis JB, Ernst ME, Sica DA. Hydrochlorothiazide and alternative diuretics versus renin–angiotensin system inhibitors for the regression of left ventricular hypertrophy: a head-to-head meta-analysis. J Hypertens. 2018;36:1247–55.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  34. 34.

    Patney V, Chaudhary K, Whaley-Connell A. Treatment of diabetic kidney disease with hypertension control and renin angiotensin system inhibition. Adv Chronic Kidney Dis. 2018;25:158–65.

    PubMed  Article  PubMed Central  Google Scholar 

  35. 35.

    Wenzel UO, Benndorf R, Lange S. Treatment of arterial hypertension in obese patients. Semin Nephrol. 2013;33:66–74.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  36. 36.

    Carnagarin R, Matthews V, Gregory C, Schlaich MP. Pharmacotherapeutic strategies for treating hypertension in patients with obesity. Expert Opin Pharmacother. 2018;19:643–51.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  37. 37.

    Nedogoda SV, Chumachek EV, Ledyaeva AA, Tsoma VV, Salasyuk AS, Smirnova VO, Hripaeva VJ, Palashkin RV. Optimization of control of blood pressure, metabolic disorders and target organs protection with fixed perindopril and indapamide combination in treated patients with arterial hypertension. Kardiologiia. 2017;57(2):5–11 ((Russian)).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Glezer MG, FORSAGE Investigators. Antihypertensive effectiveness of perindopril arginine and indapamide single-pill combination according to body mass index: findings from the FORSAGE study. Cardiol Ther. 2020;9:139–52.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. 39.

    Fox K, Kwaku M, Burman KD, et al. The EUROPA trial. Lancet. 2003;362:1935–7.

    Article  Google Scholar 

  40. 40.

    Liu L, Wang Z, Gong L, et al. Blood pressure reduction for the secondary prevention of stroke: a Chinese trial and a systematic review of the literature. Hypertens Res. 2009;32:1032–40.

    PubMed  Article  Google Scholar 

  41. 41.

    Cosentino F, Grant PJ, Aboyans V, et al. 2019 ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J. 2020;41:255–323.

    PubMed  PubMed Central  Article  Google Scholar 

  42. 42.

    American Diabetes Association. 10. Cardiovascular disease and risk management: Standards of Medical Care in Diabetes—2019. Diabetes Care. 2019;42(Suppl. 1):S103–23.

    Article  Google Scholar 

  43. 43.

    World Health Organization. Executive Summary. The selection and use of essential medicines 2019. Report of the 22nd WHO Expert Committee on the selection and use of essential medicines. https://apps.who.int/iris/bitstream/handle/10665/325773/WHO-MVP-EMP-IAU-2019.05-eng.pdf?ua=1. Accessed 30 June 2020.

  44. 44.

    Strauss MH, Hall AS. Angiotensin receptor blockers do not reduce risk of myocardial infarction, cardiovascular death, or total mortality: further evidence for the ARB-MI Paradox. Circulation. 2017;135:2088–90.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  45. 45.

    Knuuti J, Wijns W, Saraste A, et al. 2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J. 2020;41:407–77.

    PubMed  Article  PubMed Central  Google Scholar 

  46. 46.

    Choi IS, Park IB, Lee K, et al. Angiotensin-converting enzyme inhibitors provide better long-term survival benefits to patients with AMI than angiotensin II receptor blockers after survival hospital discharge. J Cardiovasc Pharmacol Ther. 2019;24:120–9.

    CAS  Article  Google Scholar 

  47. 47.

    Kim YH, Her AY, Jeong MH, et al. Comparison between beta-blockers with angiotensin-converting enzyme inhibitors and beta-blockers with angiotensin II type I receptor blockers in ST-segment elevation myocardial infarction after successful percutaneous coronary intervention with drug-eluting stents. Cardiovasc Drugs Ther. 2019;33:55–67.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  48. 48.

    Kim YH, Her AY, Shin ES, Jeong MH. Long-term clinical outcome between beta-blocker with ACEI or ARB in patients with NSTEMI who underwent PCI with drug-eluting stents. J Geriatr Cardiol. 2019;16:280–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Ann SH, Strauss MH, Park GM, et al. Comparison between angiotensin-converting enzyme inhibitor and angiotensin receptor blocker after percutaneous coronary intervention. Int J Cardiol. 2020;306:35–41.

    PubMed  Article  PubMed Central  Google Scholar 

  50. 50.

    Kim YH, Her AY, Jeong MH, et al. Comparison of clinical outcomes between angiotensin-converting-enzyme inhibitors and ARBs in patients with acute myocardial infarction with dyslipidemia after a successful stent implantation. Anatol J Cardiol. 2020;23:86–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Olde Engberink RH, Frenkel WJ, Van Den Bogaard B, Brewster LM, Vogt L, van den Born BJ. Effects of thiazide-type and thiazide-like diuretics on cardiovascular events and mortality. Systematic review and meta-analysis. Hypertension. 2015;65:1033–40.

    CAS  PubMed  Article  Google Scholar 

  52. 52.

    Pareek AK, Messerli FH, Chandurkar NB, et al. Efficacy of low-dose chlorthalidone and hydrochlorothiazide as assessed by 24-h ambulatory blood pressure monitoring. J Am Coll Cardiol. 2016;67:379–89.

    CAS  PubMed  Article  Google Scholar 

  53. 53.

    Burnier M, Bakris G, Williams B. Redefining diuretics use in hypertension: why select a thiazide-like diuretic? J Hypertens. 2019;37:1574–86.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. 54.

    Levy BI, Taddei S. Vascular legacy beyond blood pressure control: benefits of perindopril/indapamide combination in hypertensive patients with diabetes. Curr Med Res Opin. 2018;34:1557–70.

    CAS  PubMed  Article  Google Scholar 

  55. 55.

    Chen P, Chaugai S, Zhao F, Wang DW. Cardioprotective effect of thiazide-like diuretics: a meta-analysis. Am J Hypertens. 2015;28(12):1453–63.

    CAS  PubMed  Article  Google Scholar 

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Acknowledgements

We thank the participants of the studies involved.

Funding

FORTISSIMO was sponsored by Servier, France. FORSAGE was sponsored by Servier, Russia. ACES and PICASSO were sponsored by Egis Pharmaceutical Ltd., Hungary. The hypertensive pooled analysis was sponsored by Servier (I.R.I.S.), France. The Journa’s Rapid Service Fee was funded by Servier, France.

Authorship

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Medical Writing and Editorial Assistance

Editorial assistance was provided by Jeremy Grierson, PhD, and Jenny Grice, BSc, and funded by Servier, France.

Prior Presentation

Data from this study have previously been published as an abstract: Dézsi CA et al., Effectiveness of perindopril/indapamide single-pill combination in uncontrolled hypertensive patients: a combined analysis of FORTISSIMO, FORSAGE, ACES and PICASSO observational studies [Abstract A11531]. Journal of Hypertension Vol 36, e-Supplement 3, October 2018.

Disclosures

Csaba András Dézsi has received fees from EGIS Pharmaceutical Ltd., Hungary, as a speaker. Glezer MG has received fees from Servier as a speaker and an investigator. Karpov YA has received fees from Servier as a speaker and an investigator. Brzozowska-Villatte R is a Servier Global Medical Affairs employee. Farsang C has received fees from Servier as a speaker and an investigator.

Compliance with Ethics Guidelines

All diagnostic procedures were performed based on written informed patient consent. The studies were conducted in accordance with the principles of Good Clinical Practice (GCP) and the Declaration of Helsinki. The study protocols were approved by the ethical committees in all participating clinical sites (full list of IRBs included as Supplementary material).

Data Availability

The datasets generated and/or analysed for this study are not publicly available as they include medical records of patients from a secondary source.

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Correspondence to Csaba András Dézsi.

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Dézsi, C.A., Glezer, M., Karpov, Y. et al. Effectiveness of Perindopril/Indapamide Single-Pill Combination in Uncontrolled Patients with Hypertension: A Pooled Analysis of the FORTISSIMO, FORSAGE, ACES and PICASSO Observational Studies. Adv Ther 38, 479–494 (2021). https://doi.org/10.1007/s12325-020-01527-3

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Keywords

  • Angiotensin-converting enzyme inhibitor
  • Blood pressure control
  • Cardiovascular risk
  • Diabetes
  • Hypertension
  • Indapamide
  • Perindopril
  • Single-pill combination
  • Thiazide-like diuretic