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.

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)

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 <140/90 mmHg was achieved in 93% of patients. By the end of the study, all patients reached BP control. The pulse BP (PBP), which reflects peripheral vessel elasticity and patency and myocardial functioning, decreased by 30.3% (р<0.001).

PBP > 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<0.001). There was also a trend of VEGF reduction. (20)

A significant reduction in sVCAM-1 level after 6 months of treatment along with the achievement of the target BP level demonstrates improvement in endothelial function in the study subjects. The question of whether the improvement in endothelial function is due to a reduction in BP during the treatment or pleiotropic effects of the SPC components is a subject for discussion. However, the improvement of endothelial function is a direct indicator of the organ-protective effect of the drug. Apart from achieving BP control and a significant reduction in PBP, the therapy with a triple SPC of perindopril/indapamide/amlodipine also improved the vascular endothelial state by significantly lowering sVCAM-1. (18) Furthermore, increased patient adherence and improved overall quality of life were also observed during the therapy with the SPC of perindopril/indapamide/amlodipine. (20)

Further information on the action of double and triple SPCs of perindopril/amlodipine (Dalneva^®) 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)

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)