Authors

• Tina Kuhar — Krka, d. d., Novo mesto, Slovenija — ORCID: 0000-0002-2590-4802
• Alenka Kmecl — Krka, d. d., Novo mesto, Slovenija — ORCID: 0000-0001-8800-226X
• Mateja Grošelj — Krka, d. d., Novo mesto, Slovenija — ORCID: 0000-0002-4035-7691
• Breda Barbič-Žagar — Krka, d. d., Novo mesto, Slovenija — ORCID: 0000-0002-1173-7361

Abstract

Endothelial dysfunction is the earliest vascular abnormality and it is involved in all stages of the cardiovascular continuum. Antihypertensive compounds should ideally have additional endothelial protective properties beyond their ability to reduce blood pressure. Among angiotensin-converting enzyme inhibitors, perindopril appears to have the greatest endothelial protective effects. Amlodipine is well known for its atheroprotective effect. Clinical evidence has shown that perindopril and amlodipine could individually interrupt and slow the progression of cardiovascular disease with long-term beneficial effects of treatment on mortality. The effect is enhanced and broadened if both agents are used together. Early prescription of perindopril and amlodipine appears to be important, as most of the treatment benefits of both agents occur in the early or middle stages of the cardiovascular continuum. Clinical evidence also supports the beneficial effect on the vascular endothelium offered by the triple combination of perindopril and amlodipine with indapamide.

Keywords

perindopril, amlodipine, endothelial dysfunction, cardiovascular continuum

DOI

Full Text

## Introduction The functional integrity of the endothelium is essential for vascular health. In addition to maintaining a delicate balance between vasodilation and vasoconstriction, the endothelium has numerous other roles crucial for sustaining vascular homeostasis. (1) In the presence of cardiovascular (CV) risk factors, especially hypertension, hypercholesterolemia, diabetes, and smoking, the endothelium undergoes functional and structural alterations that result in it losing its cardioprotective role and becoming proatherosclerotic. (1) Endothelial dysfunction is the earliest vascular abnormality. (1) It is involved in all stages of the CV continuum and is a reliable prognostic indicator of CV events. (1) The possibility of ameliorating impaired endothelial function may be an important target for antihypertensive therapy. (2) The blood pressure (BP) lowering effect per se is not sufficient to reverse endothelial dysfunction. (2) Outcome studies have established the association of ameliorated endothelial dysfunction with improved hard endpoints in morbidity and mortality. (3) Antihypertensive drugs should ideally have additional endothelial protective properties beyond their ability to reduce BP. (2) Many studies provide convincing evidence that angiotensin-converting-enzyme inhibitors (ACEIs) can restore endothelial function. (2, 4) Among ACEIs, perindopril appears to have the greatest endothelium protective effects and has demonstrated efficacy in a number of markers of endothelial dysfunction including arterial stiffness and progression of atherosclerosis. ## From endothelial dysfunction to cardiovascular events Vascular endothelium is now viewed as an organ whose normal functioning is crucial to maintaining vascular health, and whose dysfunction is key in the initiation, progression, and clinical complications of vascular disease. (5) Once endothelial dysfunction is present, it predisposes the vessel to inflammatory response, including vascular remodeling, formation of atherosclerotic lesions in arteries, and finally plaque rupture and thrombus formation. (3, 6) Endothelial dysfunction is regarded as the first phase of atherosclerosis and is present long before atherosclerotic plaques or even CV events. There is evidence that it marks a stage of atherosclerotic progression but, conversely, its role as a marker also holds true in the reverse direction: lifestyle changes and drugs such as ACEIs measurably improve endothelial dysfunction. (6) The beneficial vascular effects of perindopril, including improvement of endothelial function, have been widely studied and recognized. (1, 7, 8) On the other hand, amlodipine is well known for its atheroprotective effect. (9, 10) A less frequently mentioned fact is that amlodipine therapy also improves endothelial function in patients with hypertension. (11, 12).By attenuating the deleterious effects of cardiovascular disease (CVD) at multiple stages of the CV continuum on top of lowering BP, perindopril and amlodipine could interrupt and slow the progression of CVD – as has been shown by the ASCOT study in which the antihypertensive and vascular effects of both agents have translated into real-life clinical benefits. (8) The ASCOT study clarified the role of ACE inhibition in the reduction of CV events in patients with hypertension without CVD. In the BP-lowering arm of the trial, patients (n = 19,257) at moderate CV risk were randomized to amlodipine 5-10 mg with the addition of perindopril 4-8 mg as required or atenolol with the addition of diuretic as required. ASCOT was stopped prematurely (after a median of 5.5 years) because the patients in the amlodipine/perindopril group showed an 11% reduction in all-cause mortality (p = 0.0247) compared with the atenolol/diuretic regimen. The mean BP in the amlodipine/perindopril group was 2.7/1.9 mmHg lower than in the beta-blocker/diuretic group – a difference which could not entirely account for the difference in outcome. (1) The CAFE sub-study (n = 2,199) evaluated the effects of the two ASCOT treatment regimens on central aortic pressure. Both treatment approaches produced similar reductions in brachial BP, but the central aortic BP and central aortic pulse pressure were reduced significantly more with amlodipine/perindopril vs. the atenolol/diuretic regimen (24.3 and 23.0 mmHg, respectively, both p = 0.0001), which correlated with reductions in CV events or procedures. (1, 13) These agents may have complimentary effects on endothelial function and vasodilation that improve CV outcomes that cannot be predicted only by changes in the brachial arterial BP. (13) These findings suggest that amlodipine/perindopril therapy disrupts the pathophysiological continuum, slowing the progression of CVD in hypertensive patients. (1) The long-term beneficial effects of treatment with amlodipine/perindopril on mortality have been additionally confirmed by the results of the ASCOT Legacy study in which the participants from the original ASCOT study were followed for a median of 16 years. (1) In the participants from the non-lipid-lowering arm group (n = 3,975), there were fewer CV deaths among the patients assigned to amlodipine/perindopril-based treatment compared with atenolol/diuretic-based treatment (adjusted hazard ratio 0.79, 0.67-0.93, p = 0.0046). (1) Perindopril and amlodipine are both able to slow the progression of CVD. (8) The preventive capability of both agents is extended over various stages of the CV continuum. Both counteract the disruption of myocardial oxygen supply and demand: perindopril by increasing the coronary reserve and maximizing the coronary blood flow, and amlodipine by decreasing coronary vascular resistance. Both are able to reduce left ventricular hypertrophy and myocardial ischemia. Coronary thrombosis and myocardial infarction are inhibited by both perindopril and amlodipine. (8) A single pill combination (SPC) of perindopril/amlodipine offers a faster response, better BP reduction, BP control, and adherence than either of both agents in monotherapy. The combination is likely to be more effective on outcomes, even though it acts on the same number of the CV continuum stages as perindopril or amlodipine alone. In addition, early concomitant prescription of perindopril and amlodipine appears important, as most of the treatment benefits of both agents occur in the early or middle stages of the CV continuum. (8) In the beginning of May, a novel low-dose SPC of perindopril and amlodipine (2.85 mg/2.5 mg) was launched in Croatia, indicated for the start of hypertension therapy. (14) As stated in the 2018 ESC/ESH guidelines for the management of arterial hypertension, the concept of initiating therapy with a two-drug combination for most patients with hypertension is likely to have a major effect on clinical practice and the speed and quality of BP control. (15) ## When two agents are not enough to control blood pressure Studies suggest that a two-drug combination therapy will control BP in approximately two-thirds of patients. For patients whose BP is not controlled by a two-drug combination therapy, the logical option is to increase treatment to a three-drug combination therapy: usually a renin-angiotensin system blocker, a calcium channel blocker, and a diuretic. (15) When the combination of amlodipine and perindopril is not enough for reaching BP control, a triple SPC with the addition of indapamide is a valuable treatment option. The metabolically neutral diuretic indapamide itself exerts beneficial effects on target organs, as it reduces left ventricular hypertrophy and microalbuminuria, the risk for stroke, and total mortality. Furthermore, it has been shown that indapamide has no effect on lipid metabolism (triglycerides, LDL-cholesterol, and HDL-cholesterol) and on carbohydrate metabolism, making it a suitable choice for a wide variety of patients also when used in combinations. (16-19) As for perindopril and amlodipine, there is also clinical evidence supporting the beneficial effect on the vascular endothelium offered by the triple combination of these two drugs with indapamide. In the clinical study by Chukayeva (20) and colleagues, the patients (n = 44) who did not reach their BP targets with the previous combined therapy were upgraded to a treatment with the SPC of perindopril/amlodipine/indapamide (Co-Dalneva®; **Table 1**). A month after the upgrade of therapy, 47.7% of patients reached the target BP level, whereas after 3 months BP 60 mm Hg (in elderly) is a sign of subclinical target organ damage. Achieving the normal level of PBP demonstrates the organ-protective activity of the drug. Vascular endothelium is an independent link in the regulation of vascular tone. The change in endothelial function was indirectly assessed using inflammation markers and molecular-biological markers of neoangiogenesis, such as the vascular endothelial adhesion molecule and the vascular endothelial growth factor. The peripheral blood concentration of the soluble form of vascular endothelial growth factor (sVCAM-1) increases only with a pathological activation of the endothelium. Change in expression of sVСАМ-1 can therefore be used to evaluate the change in the endothelial condition. (20) **Table 2** shows changes in the markers of inflammation (СRP, IL-6, IL-10) after 6 months of treatment with the SPC of perindopril/amlodipine/indapamide. The levels of the sVCAM-1 endothelial dysfunction marker decreased significantly (from 1063.5±442.4 to 898.67±433.5 ng/mL, р®) and perindopril/indapamide/amlodipine (Co-Dalneva®) on BP reduction and vascular health are expected from the international, prospective, interventional study PRECIOUS. The study was conducted in 7 countries – Croatia, Slovenia, Serbia, Hungary, Poland, Russia, and Armenia – not only with the aim of assessing the efficacy and safety of the these SPCs in continuous 24-hour BP control but also establishing the correlation between 24-hour central and peripheral BP. The results of interim analysis are available at the moment, presenting the data of 103 patients. They show that the dual SPC of perindopril/amlodipine and the triple SPC of perindopril/indapamide/amlodipine reduce BP effectively, leading to high rates of BP control achieved in a short time with a good safety profile and a very high level of treatment adherence. (21) ## Conclusion Due to their pleiotropic effects, perindopril and amlodipine with or without indapamide represent a valuable treatment option, slowing the progression of CVD with long-term beneficial effects of treatment on mortality. (1, 8) Early prescription of perindopril and amlodipine appears important, as most of the treatment benefits of both drugs occur in the early or middle stages of the CV continuum. (8) The combination of both is likely to be more effective on outcomes, especially in form of a SPC. (8, 15) As stated in the 2018 ESC/ESH guidelines for the management of arterial hypertension, the concept of initiating therapy with a two-drug combination for most patients with hypertension is likely to have a major effect on clinical practice and the speed and quality of BP control. (15) The novel SPC, Predalneva® (perindopril 2.85 mg/amlodipine 2.5 mg), which is also indicated for the initial therapy of hypertension, (14) is an additional extension of Krka’s wide portfolio of perindopril-based drugs in Croatia. (22) When the combination of amlodipine and perindopril is not enough for reaching BP control, a triple SPC with the addition of the metabolically neutral diuretic indapamide is a logical choice due to its proven protective advantages and suitability in a wide variety of patients. (15, 20, 21, 23-28) Krka’s perindopril-based drugs have consistently demonstrated their effectiveness and safety in clinical studies with around 90,000 included patients. (20, 21, 28-34) Physicians in Croatia can now select among 15 alternatives enabling individualized therapy in patients with different needs. (22)

Literature

1. Ancion A, Tridetti J, Nguyen Trung ML, Oury C, Lancellotti P. A Review of the Role of Bradykinin and Nitric Oxide in the Cardioprotective Action of Angiotensin-Converting Enzyme Inhibitors: Focus on Perindopril. Cardiol Ther. 2019 December;8(2):179–91. https://doi.org/10.1007/s40119-019-00150-w
2. Virdis A, Ghiadoni L, Taddei S. Effects of antihypertensive treatment on endothelial function. Curr Hypertens Rep. 2011 August;13(4):276–81. https://doi.org/10.1007/s11906-011-0207-x
3. Barthelmes J, Nägele MP, Ludovici V, Ruschitzka F, Sudano I, Flammer AJ. Endothelial dysfunction in cardiovascular disease and Flammer syndrome-similarities and differences. EPMA J. 2017 June 6;8(2):99–109. https://doi.org/10.1007/s13167-017-0099-1
4. Barrios V, Escobar C. Complementary mechanisms of action and rationale for the fixed combination of perindopril and indapamide in treating hypertension - update on clinical utility. Integr Blood Press Control. 2010;3:11–9. https://doi.org/10.2147/IBPC.S6636
5. Cahill PA, Redmond EM. Vascular endothelium - Gatekeeper of vessel health. Atherosclerosis. 2016 May;248:97–109. https://doi.org/10.1016/j.atherosclerosis.2016.03.007
6. Badimon L, Padró T, Vilahur G. Atherosclerosis, platelets and thrombosis in acute ischaemic heart disease. Eur Heart J Acute Cardiovasc Care. 2012 April;1(1):60–74. https://doi.org/10.1177/2048872612441582
7. Dinicolantonio JJ, Lavie CJ, O’Keefe JH. Not all angiotensin-converting enzyme inhibitors are equal: focus on ramipril and perindopril. Postgrad Med. 2013 July;125(4):154–68. https://doi.org/10.3810/pgm.2013.07.2687
8. Borghi C, Morbini M, Cicero AF. Combination therapy in the extended cardiovascular continuum: a focus on perindopril and amlodipine. J Cardiovasc Med (Hagerstown). 2015 May;16(5):390–9. https://doi.org/10.2459/JCM.0000000000000240
9. Mason RP, Marche P, Hintze TH. Novel vascular biology of third-generation L-type calcium channel antagonists: ancillary actions of amlodipine. Arterioscler Thromb Vasc Biol. 2003 December;23(12):2155–63. https://doi.org/10.1161/01.ATV.0000097770.66965.2A
10. Nayler WG. The antiatherogenic effects of amlodipine: promise of preclinical data. J Hum Hypertens. 1992 Dec;6 Suppl 1:S19-23. https://pubmed.ncbi.nlm.nih.gov/1284082/
11. Koh KK, Han SH, Ahn JY, Chung WJ, Lee Y, Shin EK. Amlodipine improves endothelial function and metabolic parameters in patients with hypertension. Int J Cardiol. 2009 March 20;133(1):23–31. https://doi.org/10.1016/j.ijcard.2007.11.058
12. He Y, Si D, Yang C, Ni L, Li B, Ding M, et al. The effects of amlodipine and S(-)-amlodipine on vascular endothelial function in patients with hypertension. Am J Hypertens. 2014 January;27(1):27–31. https://doi.org/10.1093/ajh/hpt138
13. Mason RP, Jacob RF, Corbalan JJ, Kaliszan R, Malinski T. Amlodipine increased endothelial nitric oxide and decreased nitroxidative stress disproportionately to blood pressure changes. Am J Hypertens. 2014 March;27(3):482–8. https://doi.org/10.1093/ajh/hpt202
14. Krka, tovarna zdravil, d. d., Novo mesto. Predalneva. Available from: (May 29, 2020). https://www.krka.biz/hr/lijekovi-i-drugi-proizvodi/lijekovi-na-recept/predalneva/14221/
15. Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J. 2018 September 1;39(33):3021–104. https://doi.org/10.1093/eurheartj/ehy339
16. Krka, tovarna zdravil, d. d., Novo mesto. Co-Dalneva. (May 29, 2020). https://www.krka.biz/hr/lijekovi-i-drugi-proizvodi/lijekovi-na-recept/co-dalneva/12804/
17. Beckett NS, Peters R, Fletcher AE, Staessen JA, Liu L, Dumitrascu D, et al. Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008 May 1;358(18):1887–98. https://doi.org/10.1056/NEJMoa0801369
18. Gosse P, Sheridan DJ, Zannad F, Dubourg O, Guéret P, Karpov Y, et al. Regression of left ventricular hypertrophy in hypertensive patients treated with indapamide SR 1.5 mg versus enalapril 20 mg: the LIVE study. J Hypertens. 2000 October;18(10):1465–75. https://doi.org/10.1097/00004872-200018100-00015
19. Farsang C. Efficacy and tolerability of fixed-dose combination of perindopril/indapamide in type 2 diabetes mellitus: PICASSO trial. Adv Ther. 2014 March;31(3):333–44. https://doi.org/10.1007/s12325-014-0107-y
20. Chukaeva II, Spiryakina YG, Glibko KV, Orlov DA, Bayramova AS, Logunova IY. Achievement of the main goals of therapy by using of a triple fixed combination of amlodipine, indapamide and perindopril (Co-Dalneva®) in patients with arterial hypertension. Systemic Hypertension. 2017;14(2):36-40. Available from: (May 29, 2020). https://syst-hypertension.ru/2075-082X/article/view/29182/pdf
21. Gaciong Z, Brguljan-Hitij J. The Efficacy and Safety of Single-Pill Combination of Perindopril/Amlodipine and Single-Pill Combination of Perindopril/Indapamide/Amlodipine in Patients with Newly Diagnosed and Uncontrolled Hypertension. Interim data from the PRECIOUS study. 2020 [cited 2020 May 19]. https://www.krka.biz/en/for-professional-public/kmf/prescription-pharmaceuticals/cardiovascular-diseases/precious-press/#
22. Hrvatski zavod za zdravstveno osiguranje. Objavljene liste lijekova. Available from: (May 29, 2020). https://www.hzzo.hr/zdravstveni-sustav-rh/trazilica-za-lijekove-s-vazecih-lista/
23. Chalmers J, Arima H, Woodward M, Mancia G, Poulter N, Hirakawa Y, et al. Effects of combination of perindopril, indapamide, and calcium channel blockers in patients with type 2 diabetes mellitus: results from the Action In Diabetes and Vascular Disease: Preterax and Diamicron Controlled Evaluation (ADVANCE) trial. Hypertension. 2014 February;63(2):259–64. https://doi.org/10.1161/HYPERTENSIONAHA.113.02252
24. Tóth K. PIANIST Investigators. Antihypertensive efficacy of triple combination perindopril/indapamide plus amlodipine in high-risk hypertensives: results of the PIANIST study (Perindopril-Indapamide plus AmlodipiNe in high rISk hyperTensive patients). Am J Cardiovasc Drugs. 2014 April;14(2):137–45. https://doi.org/10.1007/s40256-014-0067-2
25. Páll D, Szántó I, Szabó Z. Triple combination therapy in hypertension: the antihypertensive efficacy of treatment with perindopril, amlodipine, and indapamide SR. Clin Drug Investig. 2014 October;34(10):701–8. https://doi.org/10.1007/s40261-014-0223-0
26. 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 July;34(7):1753–63. https://doi.org/10.1007/s12325-017-0572-1
27. Tsioufis K, Douma S, Kallistratos MS, Manolis AJ. Effectiveness and Adherence to Treatment with Perindopril/Indapamide/Amlodipine Single-Pill Combination in a Greek Population with Hypertension. Clin Drug Investig. 2019 April;39(4):385–93. https://doi.org/10.1007/s40261-019-00761-0
28. Kislyak OA, Chukaeva II, Vygodin VA. Modern Recommendations and Real Clinical Practice: the Results of the SILA Study. Rational Pharmacotherapy in Cardiology. 2019;15(2):166–73. (In Russ.). https://doi.org/10.20996/1819-6446-2019-15-2-166-173
29. Final report. Postmarketing surveillance study of the efficacy and safety of perindopril (Prenessa®) or perindopril and indapamide (Co-Prenessa®) in the treatment of arterial hypertension. Data on file. Krka, d.d., Novo mesto, Slovenia, 2010.
30. Final report. Non-interventional follow-up of efficacy and safety of treatment with fixed-dose combination of perindopril and amlodipine (Amlessa®) in patients with arterial hypertension and the impact of additional risk factors for cardiovascular diseases on patient compliance (COMPLIANT). Data on file. Krka, d.d., Novo mesto, Slovenia, 2016.
31. Kopač J, Grošelj M, Barbič-Žagar B. Contribution of Krka’s Raas-acting Medicines in the Treatment of Hypertension: 25 Years of Clinical experience. Cardiol Croat. 2014;9(11-12):570–7. https://doi.org/10.15836/ccar.2014.570
32. Drapkina OM. Combination therapy of high-risk patients in real clinical practice. Results of synergy study. Part 1. Antihypertensive branch. Rational Pharmacotherapy in Cardiology. 2017;13(2):155–63. (In Russ.). https://doi.org/10.20996/1819-6446-2017-13-2-155-163
33. Napalkov DA. Russian Trial ALGORITHM: Implementation of Combined Antihypertensive and Hypolipidemic Treatment for Clinical Efficacy Achievement in Routine Clinical Practice. Rational Pharmacotherapy in Cardiology. 2019;15(6):779–88. (In Russ.). https://doi.org/10.20996/1819-6446-2019-15-6-779-788
34. Final report „Spremljanje doseganja ciljnih vrednosti krvnega tlaka pri bolnikih z novoodkrito arterijsko hipertenzijo v ambulanti družinske medicine po vključitvi diplomirane medicinske sestre v strokovni tim – PERFORM“ (KPASES 03/2017 – PERFORM/SI). 2019 Data on file; Krka d. d., Novo mesto.