Clinical Drug Investigation

, Volume 39, Issue 4, pp 385–393 | Cite as

Effectiveness and Adherence to Treatment with Perindopril/Indapamide/Amlodipine Single-Pill Combination in a Greek Population with Hypertension

  • Kostas Tsioufis
  • Stella Douma
  • Manolis S. KallistratosEmail author
  • Athanasios J. Manolis
Original Research Article



Despite the overwhelming evidence and the established benefits of antihypertensive treatment, adherence to treatment remains low.


To assess the adherence to treatment with a perindopril/indapamide/amlodipine single-pill combination (SPC), its effectiveness on blood pressure (BP) reduction, as well as the safety and tolerability of this SPC over a 4-month treatment period.


This multicenter, non-interventional study prospectively included 2285 hypertensive patients on perindopril/indapamide/amlodipine SPC. The data were recorded at baseline, 1 month, and 4 months.


Of the 2285 hypertensive patients included in the study, 50.5% were at “high/very high risk”. Mean systolic (SBP)/diastolic (DBP) decreased from 162.3 ± 13.3/93.1 ± 9.3 mmHg at baseline to 129.7 ± 8.3/78.6 ± 7.1 mmHg at 4 months (p < 0.001). Patients with higher baseline BP levels showed greater BP reduction. Patients with hypertension stages 1, 2, and 3 showed mean SBP/DBP reductions of 21.5/10.4 mmHg, 34.2/14.7 mmHg, and 51.2/22.5 mmHg, respectively, at study end (p < 0.001). Only 26 patients (1.1%) prematurely discontinued treatment (0.58% due to an adverse reaction or event).


Perindopril/indapamide/amlodipine SPC decreased BP levels rapidly and significantly. The degree of BP reduction was associated with the severity of hypertension and/or with total cardiovascular risk at baseline. Simplifying the drug regimen by using this SPC improved adherence and showed excellent tolerability.


Compliance with Ethical Standards


This study was funded by Servier Hellas.

Conflict of interest

K. Tsioufis, S. Douma, A.J. Manolis, and M.S. Kallistratos received a research grant from Servier Hellas Pharmaceuticals Ltd. Servier Hellas Pharmaceuticals Ltd was not involved in the collection and interpretation of data, in the writing of the manuscript, or in the decision to submit the manuscript for publication. The authors have no other conflicts of interest with regard to the content of this article.

Ethical approval

All procedures in this study were in accordance with the 1964 Helsinki declaration and its amendments, and the Ethics Committee or institutional review board that approved the study.

Informed consent

Written informed consent obtained from patients.


  1. 1.
    Poulter NR, Prabhakaran D, Caulfield M. Hypertension. Lancet. 2015;22(386):801–12.CrossRefGoogle Scholar
  2. 2.
    Kintscher U. The burden of hypertension. EuroIntervention. 2013;9(Suppl R):R12–5. Scholar
  3. 3.
    Yoon SS, Carroll MD, Fryar CD. Hypertension prevalence and control among adults: United States, 2011–2014. NCHS Data Brief. 2015;220:1–8.Google Scholar
  4. 4.
    Okonofua EC, Simpson KN, Jesri A, Rehman SU, Durkalski VL, Egan BM. Therapeutic inertia is an impediment to achieving the Healthy People 2010 blood pressure control goals. Hypertension. 2006;47:345–51.CrossRefGoogle Scholar
  5. 5.
    Márquez PHP, Torres OH, San-José A, Vidal X, Agustí A, Formiga F, et al. Potentially inappropriate antihypertensive prescriptions to elderly patients: results of a prospective, observational study. Drugs Aging. 2017;34:453–66.CrossRefGoogle Scholar
  6. 6.
    Petrák O, Zelinka T, Štrauch B, Rosa J, Šomlóová Z, Indra T, Combination antihypertensive therapy in clinical practice, et al. The analysis of 1254 consecutive patients with uncontrolled hypertension. J Hum Hypertens. 2016;30:35–9.CrossRefGoogle Scholar
  7. 7.
    Al-Ganmi AH, Perry L, Gholizadeh L, Alotaibi AM. Cardiovascular medication adherence among patients with cardiac disease: a systematic review. J Adv Nurs. 2016;72:3001–14.CrossRefGoogle Scholar
  8. 8.
    Frank J. Managing hypertension using combination therapy. Am Fam Physician. 2008;77:1279–86.Google Scholar
  9. 9.
    Thoenes M, Neuberger HR, Volpe M, Khan BV, Kirch W, Böhm M. Antihypertensive drug therapy and blood pressure control in men and women: an international perspective. J Hum Hypertens. 2010;24:336–44.CrossRefGoogle Scholar
  10. 10.
    Cushman W, Ford C, Cutler J, Margolis K, Davis B, Grimm R, et al. Success and predictors of blood pressure control in diverse North American settings: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). J Clin Hypertens (Greenwich). 2002;4:393–404.CrossRefGoogle Scholar
  11. 11.
    Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Böhm M, et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J. 2013;34:2159–219.CrossRefGoogle Scholar
  12. 12.
    Mancia G, Rea F, Cuspidi C, Grassi G, Corrao G. Blood pressure control in hypertension. Pros and cons of available treatment strategies. J Hypertens. 2017;35:225–33.CrossRefGoogle Scholar
  13. 13.
    Ábrahám G, Dézsi CA. The antihypertensive efficacy of the triple fixed combination of perindopril, indapamide, and amlodipine: the results of the PETRA study. Adv Ther. 2017;34:1753–63. Scholar
  14. 14.
    Mourad JJ, Amodeo C, de Champvallins M, Brzozowska-Villatte R, Asmar R, Study coordinators, investigators. Blood pressure-lowering efficacy and safety of perindopril/indapamide/amlodipine single-pill combination in patients with uncontrolled essential hypertension: a multicenter, randomized, double-blind, controlled trial. J Hypertens. 2017;35(7):1481–95. Scholar
  15. 15.
    Yang W, Chang J, Kahler KH, Fellers T, Orloff J, Wu EQ, et al. Evaluation of compliance and health care utilization in patients treated with single pill vs. free combination antihypertensives. Curr Med Res Opin. 2010;26:2065–76.CrossRefGoogle Scholar
  16. 16.
    Bangalore S, Kamalakkannan G, Parkar S, Messerli F. Fixed-dose combinations improve medication compliance: a meta-analysis. Am J Med. 2007;120:713–9.CrossRefGoogle Scholar
  17. 17.
    Brixner D, Jackson K, Sheng X, Nelson R, Keskinaslan A. Assessment of adherence, persistence, and costs among valsartan and hydrochlorothiazide retrospective cohorts in free- and fixed-dose combinations. Curr Med Res Opin. 2008;24:2597–607.CrossRefGoogle Scholar
  18. 18.
    Gupta A, Arshad S, Poulter N. Compliance, safety, and effectiveness of fixed-dose combinations of antihypertensive agents: a metaanalysis. Hypertension. 2010;55:399–407.CrossRefGoogle Scholar
  19. 19.
    Belsey JD. Optimizing adherence in hypertension: a comparison of outcomes and costs using single tablet regimens vs individual component regimens. J Med Econ. 2012;15:897–905.CrossRefGoogle Scholar
  20. 20.
    Vermeire E, Hearnshaw H, Van Royen P, Denekens J. Patient adherence to treatment: three decades of research. A comprehensive review. J Clin Pharm Ther. 2001;26:331–42.CrossRefGoogle Scholar
  21. 21.
    Caban-Martinez AJ, Davila EP, Zhao W, Arheart K, Hooper MW, Byrne M, et al. Disparities in hypertension control advice according to smoking status. Prev Med. 2010;51:302–6.CrossRefGoogle Scholar
  22. 22.
    McCallum L. Hypertension—state of the art 2017. Clin Med (Lond). 2017;17:338–40.CrossRefGoogle Scholar
  23. 23.
    Chung N, Baek S, Chen M-F, Liau CS, Park CG, Park J, et al. 2008 Expert recommendations on the challenges of hypertension in Asia. Int J Clin Pract. 2008;62:1306–12.CrossRefGoogle Scholar
  24. 24.
    Corrao G, Parodi A, Nicotra F, Zambon A, Merlino L, Cesana G, et al. Better compliance to antihypertensive medications reduces cardiovascular risk. J Hypertens. 2011;29:610–8.CrossRefGoogle Scholar
  25. 25.
    Gradman AH, Basile JN, Carter BL, Bakris GL. Combination therapy in hypertension. J Clin Hypertens (Greenwich). 2011;13:146–54.CrossRefGoogle Scholar
  26. 26.
    Byrd JB, Zeng C, Tavel HM, Magid DJ, O’Connor PJ, Margolis KL, et al. Combination therapy as initial treatment for newly diagnosed hypertension. Am Heart J. 2011;162:340–6.CrossRefGoogle Scholar
  27. 27.
    Selak V, Elley CR, Bullen C, Crengle S, Wadham A, Rafter N, et al. Effect of fixed dose combination treatment on adherence and risk factor control among patients at high risk of cardiovascular disease: randomised controlled trial in primary care. BMJ. 2014;27(348):g3318. Scholar
  28. 28.
    Zanchetti A, Thomopoulos C, Parati G. Randomized controlled trials of blood pressure lowering in hypertension: a critical reappraisal. Circ Res. 2015;13(116):1058–73.CrossRefGoogle Scholar
  29. 29.
    Makani H, Bangalore S, Romero J, Wever-Pinzon O, Messerli FH. Effect of renin-angiotensin system blockade on calcium channel blocker-associated peripheral edema. Am J Med. 2011;124:128–35.CrossRefGoogle Scholar
  30. 30.
    Hamdidouche I, Jullien V, Boutouyrie P, Billaud E, Azizi M, Laurent S. Drug adherence in hypertension: from methodological issues to cardiovascular outcomes. J Hypertens. 2017;35:1133–44.CrossRefGoogle Scholar
  31. 31.
    Fogari R, Malamani GD, Zoppi A, Mugellini A, Rinaldi A, Vanasia A, et al. Effect of benazepril addition to amlodipine on ankle oedema and subcutaneous tissue pressure in hypertensive patients. J Hum Hypertens. 2003;17:207–12.CrossRefGoogle Scholar
  32. 32.
    Volpe Massimo, Tocci Giuliano. Rationale for triple fixed-dose combination therapy with an angiotensin II receptor blocker, a calcium channel blocker, and a thiazide diuretic. Vasc Health Risk Manag. 2012;8:371–80. Scholar
  33. 33.
    Heidenreich PA, Fonarow GC. Are registry hospitals different? A comparison of patients admitted to hospitals of a commercial heart failure registry with those from national and community cohorts. Am Heart J. 2006;152:935–9.CrossRefGoogle Scholar
  34. 34.
    Granger CB, Gersh BJ. Clinical trials and registries in cardiovascular disease: competitive or complementary? Eur Heart J. 2010;31:520–1.CrossRefGoogle Scholar
  35. 35.
    Burnier M, Wuerzner G, Struijker-Boudier H, Urquhart J. Measuring, analyzing, and managing drug adherence in resistant hypertension. Hypertension. 2013;62:218–25.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Kostas Tsioufis
    • 1
  • Stella Douma
    • 2
  • Manolis S. Kallistratos
    • 3
    Email author
  • Athanasios J. Manolis
    • 3
  1. 1.1st Cardiology Clinic, “Hippokration” General HospitalNational and Kapodistrian University of AthensAthensGreece
  2. 2.3rd Department of Internal Medicine, “Papageorgiou Hospital”Aristotle University of ThessalonikiThessaloníkiGreece
  3. 3.Cardiology DepartmentAsklepieion General HospitalAthensGreece

Personalised recommendations