Authors

• Teja Prijatelj — Krka, d. d., Novo mesto, Slovenija — ORCID: 0000-0001-9759-2361
• 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

One in three adults suffers from high blood pressure (BP), and the prevalence is expected to rise in the future due to population ageing and unhealthy lifestyles. Despite increased public awareness and access to a variety of antihypertensives, BP control remains an unmet objective. The data suggest that a significant proportion of patients with hypertension are not identified and treated, or despite the therapy do not have BP lowered to the recommended values (below 140/90 mmHg). Recently published extracts from the 2018 European Society of Cardiology and European Society of Hypertension Joint Guidelines for the Management of Arterial Hypertension emphasize that the first objective of treatment should be to lower BP below 140/90 mmHg in all patients. If the treatment is well-tolerated, BP should be targeted to 130/80 mmHg in most patients in order to maximally reduce the risk of cardiovascular events, which is the main goal of hypertension treatment. Some solutions which may help improve the BP control are discussed below.

Keywords

KLJUČNE RIJEČI: arterijska hipertenzija, kontrola vrijednosti arterijskog tlaka, liječenje, perindopril, erbumin

DOI

Full Text

## Introduction Hypertension, which affects every third adult, remains one of the leading causes of mortality, one of the most relevant risk factors for cardiovascular (CV) disease, and a major cause of premature death. (1, 2) Blood pressure (BP) reduction per se is the primary determinant of CV risk reduction. (3) The results of a systematic review and meta-analysis of 123 large-scale BP lowering trials with 613,815 participants provide strong support for lowering BP, i.e. systolic blood pressure, to less than 130 mmHg in terms of reducing the risk of major CV events (**Figure 1**). (4) This is also reflected in the 2018 European Society of Cardiology (ESC) and European Society of Hypertension (ESH) Joint Guidelines for the Management of Arterial Hypertension, which suggest that the first objective of the treatment should be to lower BP below 140/90 mmHg in all patients. If the treatment is well-tolerated, BP should be targeted to 130/80 mmHg in most patients. (5) Despite increased awareness of the importance of lowering BP below 140/90 mmHg, this target remains unmet. An analysis of BP screening results for more than 1.2 million patients included in the May Measurement Month 2017 global action has been published recently. Almost 20% of hypertensive individuals were not receiving any antihypertensive treatment and almost 50% of individuals receiving treatment did not have BP controlled. (6) Early identification of hypertension and its treatment for achieving target values are critically important in the management of every patient with hypertension in order to prevent target organ damage, which may result in CV disease, stroke, and kidney failure. (7-9) FIGURE 1. Results of meta-analysis of 123 large-scale blood pressure (BP) lowering trials with 613,815 participants. The graph shows how much a 10 mm Hg reduction in systolic BP reduced the risk of cardiovascular (CV) disease and death. The 2013 ESH/ESC Hypertension Guidelines (10) recommend the following approaches, which can result in improved overall BP control: - BP measurements at visits not related to hypertension or problems of a CV nature; - Management of grade 1 hypertension; - Initial combination therapy in high-risk patients and in patients with markedly elevated BP; - Therapy simplification by using single-pill combinations (SPCs) in order to decrease pill burden for the patient and improve adherence, which has a determinant role in achieving favorable treatment outcomes; - Therapy upgrade in case of an insufficient BP control. ## Grade 1 hypertension: To treat or not to treat? Hypertension is a progressive CV syndrome arising from complex and interrelated etiologies. Early markers of the syndrome are often present before BP elevation is sustained. (11) Mild BP elevation, i.e. grade 1 hypertension, is the most prevalent form (74%) of hypertension and due to its frequency has a large impact on public health. The prevalence of grade 1 hypertension is so high that despite a relatively low individual risk this type of hypertension accounts for nearly 60% of all coronary deaths. Hypertension starts early and with time BP rises exponentially. Target organ damage, which makes hypertension a major risk factor for CV morbidity and mortality, is observed already in grade 1 hypertension. Early treatment of grade 1 hypertension may prevent vascular damage caused by high BP, thus preventing the development of high-risk hypertension and reducing the incidence of CV events. (12) ## Two-drug combination as initial therapy in most patients More than 80% of patients with hypertension have additional risk factors (e.g. male sex, age, smoking, abnormal lipids and glucose levels, obesity, family history of early CV disease), that make BP difficult to regulate. (10) Regardless of the medication used, a monotherapy can effectively reduce BP in no more than 25% of patients with hypertension. (3, 10) Advantages of using a combination therapy from the beginning are: prompter treatment response, a greater probability of achieving target BP, and lower probability of discouraging patient adherence with many treatment changes. (10) Additionally, an initial combination therapy is associated with 34% risk reduction of CV events and deaths compared with an initial monotherapy and subsequent switch to a combination therapy. (13) The 2018 ESC/ESH Hypertension Guidelines confirmed the strategy of initial treatment with a combination therapy for most patients, where SPCs are a preferred choice as these additionally improve adherence. (5) Krka introduced its perindopril (Perineva®) in 2005 as the first generic perindopril. (14) Two years later, Krka’s SPC with indapamide (Co-Perineva®) followed as the first generic. (15) A clinical study with Perineva and Co-Perineva (16), which included 4,574 patients with mild to moderate hypertension, demonstrated statistically significant reduction in systolic BP (mean reduction of 22.8 mmHg) and diastolic BP (mean reduction of 10.4 mmHg) after four months of treatment. At the end of the study, 78% of patients had a BP of 140/90 mmHg or lower. The treatment was associated with excellent treatment adherence, since 72.5% of the patients completely adhered to the treatment. This can also be attributed to good tolerability, since 97% of the patients had no adverse reactions. Nine out of 10 patients were more than satisfied with the treatment with Perineva and Co-Perineva. ## Uncontrolled blood pressure: Resistant hypertension or a non-adherent patient? Due to multifactorial etiology of hypertension, successful BP control often requires treatment with a combination of molecules acting on different targets. (9) Simultaneous treatment with two antihypertensives from different classes is required in approximately 50% of patients with hypertension, while a triple combination is required in approximately 25% of them in order to achieve long-term BP control. (3, 17) On the other hand, polypharmacy represents a heavy burden for the patients, considering that many of these patients also concomitantly receive medications for other chronic diseases. (18) This results in poor adherence, which is one of the main causes for low BP control. The data show that after one year, about one half of patients with hypertension stop their treatment. (10) The 2018 ESC/ESH Hypertension Guidelines recommend the use of SPCs whenever applicable to simplify the therapy, resulting in faster achievement of the target BP and better adherence to the treatment. (10, 19) Additionally, the treatment with SPCs is better tolerated due to complementary mechanisms of action attributed to molecules combined in a single tablet. (20) In 2011, Krka launched the first generic SPC of perindopril and amlodipine (Dalneva®). (21) Because of its beneficial properties in terms of reducing CV events and mortality, as well as fast and effective BP reduction, the combination of perindopril and amlodipine is among most favored combinations in the treatment of hypertension. (22, 23) A clinical study with Dalneva (COMPLIANT) (24), which included 3,821 patients, demonstrated statistically significant BP reductions after four months in all patients, irrespective of the initial grade of hypertension. By the end of the study, the patients achieved an average BP level of 135.7/81.3 mmHg. Introduction of Dalneva resulted in additional BP reduction compared with previous therapies with an ACE inhibitor, a calcium antagonist, a combination of an ACE inhibitor and a calcium antagonist or a combination of an ACE inhibitor and a diuretic. In 2014, Krka widened its perindopril portfolio with a triple SPC of perindopril, indapamide and amlodipine (Co-Dalneva®) as the first pharmaceutical company to offer such combination in Europe. (2, 25) ## Krka’s perindopril family: Effective and safe treatment for any patient with hypertension Krka’s complex perindopril portfolio includes 15 strengths and allows for an individually-tailored treatment of any hypertension grade. Initiating therapy with perindopril or SPC of perindopril and indapamide makes it possible to subsequently upgrade the therapy in case of insufficient BP control. (26) In more than ten years of clinical use, Krka’s perindopril has consistently demonstrated its effectiveness and safety as a monotherapy and in SPCs in clinical studies with more than 55,000 patients as well as in everyday clinical practice. (14, 16, 24, 27-30) Wide experience and trust have made Krka’s perindopril and its SPCs the most prescribed generic perindopril products in Europe with almost 2.5 million treated patients. (30) ## Perindopril erbumine or perindopril arginine: Which one to choose? The active substance perindopril is chemically bound either to erbumine (with lower molecular weight) or arginine (with higher molecular weight). This is why the 2, 4 and 8 mg dosages of perindopril erbumine differ from the 2.5, 5 and 10 mg dosages of perindopril arginine. However, perindopril erbumine and perindopril arginine provide the same plasma concentrations of the active substance, resulting in the same therapeutic effect. The therapeutic equivalence of the two has been confirmed by bioequivalence studies. The registration of the originator’s perindopril arginine was based on its bioequivalence with perindopril erbumine. (31-35) For own innovative formulation of perindopril erbumine, Krka was awarded a gold recognition and granted patent protection. (36) All major clinical trials in more than 50,000 patients (e.g. EUROPA, PROGRESS, PREAMI, ADVANCE, ASCOT-BPLA, PEP-CHF), which confirmed clinical benefits of perindopril in wide groups of patients, were performed with perindopril erbumine. (37-42) ## Conclusion The majority of CV diseases can be prevented through timely elimination or control of their main risk factors. (43) There is still potential to improve the diagnosis and treatment of hypertension as a dominant modifiable predisposing factor for CV diseases. (2, 6) Even small BP reductions provide significant benefits in reducing risk of experiencing CV complication. (4) The accessibility of advanced antihypertensives, e.g. perindopril, possessing favorable properties (24-hour BP normalization, prevention/regression of target organ damage, reduction of CV events), and SPCs, which improve adherence, might facilitate the achievement of BP targets. (10, 44, 45) Effective BP control and safety, demonstrated in clinical studies, together with positive experiences in daily clinical practice have made Krka’s perindopril the physician’s first choice for generic perindopril in Europe. (14, 16, 24, 27-30)

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