Authors

• Sonja Frančula-Zaninović — Dom Zdravlja Zagreb-Centar, Zagreb, Hrvatska

Abstract

The prevalence of arterial hypertension (AH) is still high. Hypertension is the most important changeable cardiovascular (CV) risk factor and is significantly associated with high morbidity and mortality from cardiovascular and cerebrovascular (CBV) diseases. AH thus represents a significant healthcare problem. It is multifactorial, and the treatment approach is based on combination treatment. Combination treatment consist of two or more antihypertensives of different groups with different mechanisms, which results in faster achievement of target blood pressure (BP) values. According to the guidelines for the treatment of arterial hypertension published by the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC), it is recommended to introduce the combination therapy already in the first stage of the disease as the first line of treatment in case of high CV risk and comorbidity or in case of failed treatment with a single medication. Unfortunately, prescribing multiple tablets to be taken during the day reduces treatment adherence. The goal of modern AH treatment is to use fixed-dose combinations of antihypertensives with complementary and synergistic effects in order to achieve the most effective treatment. Management of BP is significantly improved even at smaller doses of the active components in the combination, which also reduces the incidence of side-effects. Receiving a treatment which is effective, does not burden the patient, and is taken once per day significantly increases patient adherence. The ultimate goal of such successful treatment of AH is the reduction of CV and CBV morbidity and mortality. According to the ESH/ESC guidelines for the treatment of hypertension, the optimal combination is that of three groups of antihypertensives: renin-angiotensin-aldosterone system inhibitors, calcium channel antagonists, and diuretics.

Keywords

arterial hypertension, fixed antihypertensive combinations, adherence

DOI

Full Text

## Introduction Arterial hypertension (AH) is the most important changeable risk factor for cardiovascular (CV) and cerebrovascular (CBV) morbidity and mortality. It is one of the most significant public health problems (64 million disability adjusted life years (DALY); 4.4%) (1). In addition to CV and CBV diseases, AH is also a risk factor for the development of chronic kidney diseases (2). According to the EH-UH study, the prevalence of AH in Croatia is 37.5%. 59% of hypertensive patients receive antihypertensive therapy, and only 19.4% achieve good blood pressure (BP) management (1). The American Heart Association has estimated that the annual economic cost of CV diseases conditioned by AH will grow to approximately 200 billion US dollars by 2030 (3, 4). Despite the growing number of antihypertensive drugs and their availability, AH control for treated patients is still relatively poor. In most countries, about half of such patients who receive treatment still do not achieve BP control (5). ## The significance of blood pressure control Many clinical studies and meta-analyses have shown that better BP control reduces CV and CVB morbidity and mortality (6, 7). The clinical studies VALUE, ACCOMPLISH, and Syst-Eur have demonstrated that early diagnosis and treatment of AH lead to a reduction in the incidence of myocardial infarction, stroke, and CV morbidity and mortality (3, 8-10). Approximately 50% of hypertensive patients require 2 or more antihypertensives, and at least 25% require a triple combination of drugs to achieve target BP values (3, 11). ALLHAT, INVEST, SCOPE, HOT, MDRD, and AASK are examples of clinical trials demonstrating that combined antihypertensive therapy is necessary in most patients (3). Consequently, the 2007 guidelines of the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC) for AH treatment were the first time treatment with antihypertensive combinations was included in the first line of treatment for isolated systolic hypertension, rapidly progressive hypertension, and for patients with BP <140/90 mmHg, with the goal of preventing damage to target organs (diabetics, chronic parenchymal renal disease) (11, 12). According to the latest ESH/ESC guidelines from 2013, the treatment of choice for AH depends on BP values, estimated CV risk, comorbidities, damage to target organs, and age; treatment can be started with one or with a combination of 2 antihypertensives (13). The first stage of AH is the most common. Approximately 2/3 coronary deaths associated with hypertension happen in patients with stage 1 AH (14). It is this group of patients that represents a significant public health issue. This was confirmed by the MRFIT study, which followed 122 086 hypertonic patients. During 15 years of follow-up, 6 293 patients died due to coronary heart disease (14). Damage to target organs, cardiac remodeling, reduced stroke volume, and elevated heart frequency can occur even in stage 1 AH and in pre-hypertension. Timely AH treatment and the earliest possible achievement of target BP values is thus of the utmost importance (14). In this early stage of the disease, most patients feel well, do not report subjective difficulties, do not consider themselves sick, and are often hard to convince of the necessity of treatment (14). The ESH/ESC guidelines recommend combined treatment in stage 1 AH in cases of high CV risk and in stage 2 and 3 AH (13). This type of treatment offers multiple advantages: it has less side-effects and is thus better tolerated, the time searching for effective treatment is reduced for high BP values, and fixed combinations simplify the treatment (intake once per day) and usually have a lower price than the individual components. This increases patient adherence to treatment, which leads to faster and better BP control (12, 15). Treatment adherence is very important in AH. It is influenced by a number of factors: the number of tablets to be taken per day, forgetfulness, the appearance of side-effects, and cooperation with the physician. According to some meta-analyses, significantly better adherence is achieved by prescribing fixed doses of antihypertensives than by free combinations of individual antihypertensives (3). Better adherence leads to better BP control, reduced CV and CVB morbidity, reduced sick days and hospitalization for CV and CVB, and consequently a reduced economic burden (3). The rational approach to combined antihypertensive therapy entails choosing drugs that have a complementary, but different mechanism of action. According to ESH/ESC guidelines for the treatment of AH, the highest recommendation goes to the combination of renin-angiotensin-aldosterone system (RAAS) inhibitors, diuretics, and calcium channel antagonists (13). The ACCOMPLISH study demonstrated the effectiveness of treatment with fixed-dose combinations of two antihypertensives (amlodipine – a calcium channel antagonist –and benazepril – an ACE inhibitor) and their superiority in comparison with the combination of benazepril and hydrochlorothiazide in hypertensive patients with high cardiovascular risk (10, 15). In the ADVANCE study, patients with type 2 diabetes receiving a fixed dose of perindopril (ACE inhibitor) and indapamide (diuretic) had an 18% reduction in CV events and a 21% reduction in renal events (15, 16). ## The significance of combined therapy Combined therapy comprises two types of treatment: prescribing different medications separately or prescribing fixed combinations of different drugs in a single tablet. Taking a fixed combination simplifies the treatment regimen (usually once per day), which is especially important in elderly patients and in patients taking multiple medications due to comorbidity. According to the ESH/ESC (13) guidelines, combined treatment should satisfy the following conditions: - Complementary mechanisms of action. - The antihypertensive effect should be larger than that of each component individually. - The combination should have better tolerability. - The complementary mechanisms of action can reduce the side-effects of the individual drugs. Treatment with drug combinations leads to greater BP reduction and more rapid achievement of target BP values and reduces the risk of CV events and mortality. Fixed-dose combinations reduce the number of tablets in daily treatment and improve patient compliance as well as the level of BP control (13). In addition to the additive effect, combination treatment should also achieve more effective treatment with lower doses of the individual component drugs, more rapidly achieve target BP, and provide better tolerability (reduced incidence of side-effects). Desirable combinations should have a complementary and synergistic effect. ACE inhibitors have a protective effect on endothelial function and the atherosclerosis process which achieves renal and CV protection (clinical trials ADVANCE, ASCOT, EUROPA, PREAMI, PEPCHF, PROGRESS, HOPE), reduce damage to target organs, and reduce morbidity and mortality (17). In the EUROPA study, after a year of receiving perindopril, there was a reduction in inflammatory processes, endothelial cell apoptosis, and a normalization in the bradykinin/angiotensin II ratio. Perindopril has a high lipophilicity, high affinity for tissue ACE, and a trough-to-peak ratio of 75-100% (18). Consequently, perindopril guarantees 24-hour BP control, delays progression of atherosclerosis, alleviates endothelial dysfunction, and has an antithrombotic and anti-inflammatory effect (19). Perindopril thus contributes to better treatment for hypertensive and CV patients. Calcium channel antagonists are a heterogeneous group of antihypertensives. The most commonly prescribed is amlodipine, which belongs to the dihydropyridine group. Reducing calcium flow to cells leads to vasodilatation of the peripheral and coronary arteries and arterioles. It does not have a large negative inotropic effect and does not affect atrioventricular conduction. It has anti-atherosclerotic and anti-oxidative properties as well as a long-lasting antihypertensive effect (18, 20). The combination of perindopril and amlodipine was examined in the ASCOT study, and the results showed that this combination is well-tolerated, significantly reduces BP, and reduces CV events in comparison with a fixed combination of beta blockers and thiazide (21). Even today, diuretics are still equal to other groups of antihypertensives. Thiazide diuretics are the ones most commonly used in AH treatment, mostly in combination with other groups of antihypertensives. They are especially recommended in the treatment of elderly patients with isolated systolic hypertension and hypertensive patients with heart failure (22). They improve filtration, absorption, and secretion of electrolytes in the kidneys and have a vasodilatory effect. Indapamide stands out due to a number of advantages: in addition to the above-mentioned effects, it inhibits calcium in the blood vessel walls (vasodilatation and a reduction in peripheral resistance), which provides an additional reduction in BP (22). It is metabolically neutral, has a cardioprotective effect, reduces total mortality, provides 24-hour BP control, and has a low incidence of side-effects (23-25). In the PROGRESS clinical trial, the combination of indapamide and perindopril reduced stroke risk by 43% in comparison with the placebo group (26). As an initial treatment for AH, this combination reduces CV and CBV outcomes in comparison with monotherapy (27). Antihypertensive combinations are the basis of modern AH treatment. Every fourth patient receives 3 antihypertensives with the goal of controlling BP (13). However, taking multiple tablets per day leads to poorer patient adherence to treatment. Fixed antihypertensive combinations achieve excellent treatment adherence due to the reduction in the number of tablets, better tolerability, and better effectiveness, all of which motivate the patient to adhere to the treatment. The above-mentioned perindopril, amlodipine, and indapamide are examples of drugs where their fixed combination has excellent pharmacodynamics due to different, but complementary mechanisms of action, and the synergic effect on BP is present over 24-hours for all three components in the combination. This fixed combination also has excellent tolerability: perindopril reduced edema that can be cause by amlodipine; amlodipine reduces the incidence of cough caused by perindopril; indapamide has beneficial effects on metabolic parameters (glucose, lipids). This fixed triple combination confirmed its excellent efficacy and safety in the PETRA prospective, observational, open label clinical trial (**Figure 1**) (28). The study monitored the effectiveness of BP control over 3 months in 11 209 hypertonic patients of both sexes who received a fixed-dose triple-combination of perindopril/indapamide/amlodipine once per day. The dose was adjusted to the pressure (BP was measured in the clinic, at home, and with 24-hour ambulatory BP measurement). Before the introduction of this combination, the patients had been receiving dual combined therapy. The monitored secondary outcomes of the treatment were: safety, tolerability, and laboratory parameters. The results showed significant reduction in BP: 73% of patients with previously uncontrolled BP achieved target values. Metabolic parameters also improved (reduced glucose and blood lipids). This combination also demonstrated excellent tolerability: side-effects manifested in only 0.5% of patients (ankle edema, dry cough, tachycardia, dizziness, hypotension) (28). FIGURE 1. The results of PETRA study. Adapted from Abraham G. The antihypertensive efficacy of the triple fixed combination of perindopril, indapamide and amlodipine: The results of PETRA study. Adv Ther 2017. Only 50% of the general population in developed countries adheres to chronic treatment, and 70% of the drugs that are picked up are never even taken (29). Multiple factors determine adherence to treatment: age, sex, level of education, forgetfulness, dose frequency, the number of prescribed medications, and inadequate cooperation with the physician. Adherence can be improved by providing patients with better education and information, but one of the most important measures that can improve adherence and patient compliance to treatment is introducing fixed drug combinations. Fixed antihypertensive combinations reduce poor compliance by 24%. The best adherence is achieved by prescribing a single dose per day (29). ## Conclusion According to current studies, 94% of newly-diagnosed hypertensive patients should initiate treatment with a combination of two antihypertensives. Combined therapy with three antihypertensives with a complementary effect is invaluable in the treatment of approximately 30% of these patients in order to achieve good BP pressure and reduce target organ damage. Combined therapy is the basis of modern AH treatment, and the choice of antihypertensives depends on hemodynamic and metabolic criteria. In order to achieve the best possible compliance and adherence to treatment, the number of tablets in daily therapy and the incidence of side-effects should be reduced, while increasing the efficacy and effectiveness of the treatment and reducing treatment costs. Our experience so far has demonstrated that the fixed-dose combination of three antihypertensives, perindopril/indapamide/amlodipine, achieves all these goals. This is also the combination recommended by the most recent ESH/ESC guidelines for the treatment of AH. The PETRA observational clinical trial has demonstrated that this fixed combination in different doses of active ingredients rapidly achieves target BP values in patients with unregulated AH, shows good tolerability, is metabolically neutral, and significantly increased treatment adherence.

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