Arterial hypertension (AH) is one of the most important modifiable risk factors for the occurrence of micro-and macrovascular defects and their consequences. AH is an important public health concern involved in the development of coronary heart disease, heart insufficiency, cerebrovascular disease, and peripheral arterial disease. It is a risk factor and a development factor of chronic kidney disease (CKD) and is one of the main causes of mortality and morbidity in the world. Each year, cardiovascular (CV) diseases account for 45% of all deaths in Europe, which means that they cause 3.9 million deaths. (1) At least 80% of CV events are preventable by effectively controlling the main risk factors.

When starting treatment for AH, total cardiovascular risk (CVR), comorbidities, and adherence should be assessed in each individual patient. It is also very important to rule out any secondary causes of AH and to assess the degree of damage to target organs. CVR can be assessed using the SCORE scoring system, which calculates the 10-year cumulative risk for the first fatal cardiovascular event based on age, sex, smoking status, and systolic blood pressure. To calculate CVR in the Republic of Croatia, we use the SCORE chart for countries with high CVR.

The first line of the therapeutic approach is a non-pharmacological intervention that includes lifestyle changes in the form of reducing salt and alcohol intake, reducing body weight, regular physical activity, and quitting smoking. If appropriate therapeutic goals are not achieved, in most cases it is necessary to introduce antihypertensives or other medicinal products that will reduce CVR, depending on individual patient characteristics, especially in patients with high CVR. According to the 2018 ESC/ESH Guidelines for the Management of AH (issued by the European Society of Cardiology and the European Society of Hypertension), in most patients it is recommended to start treatment with a combination of two different drugs in order to achieve target blood pressure (BP). (2) Monotherapy is recommended only in patients with grade 1 AH and low total CVR or in very old and fragile patients. On the other hand, the use of two different drugs acts on several pathophysiological mechanisms and adequately covers the 24-hour period of effectiveness, i.e., AH control. Due to the lower doses in fixed-dose combinations of two or more different medicinal products, lower frequency of side effects is achieved while effectively achieving target BP values. The recommended medications include those from the classes of angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB), thiazide and thiazide-like diuretics, calcium channel blockers, and beta blockers. In comparison to other antihypertensives, ACEi, which primarily act by inhibiting the RAAS system, are of particular importance. Hyperactivation of the renin-angiotensin-aldosterone system (RAAS) increases BP, consequently causing mechanical strain and damage to blood vessels, which triggers a local inflammatory response. In this way, RAAS increases angiogenesis, vasoconstriction, and the number of free radicals, which contributes to the development of AH and atherosclerosis. The multicentre, prospective, randomized controlled trial Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA) included 19,257 patients with AH and other CV risk factors, and demonstrated that a fixed dose (a single pill) of perindopril and amlodipine effectively reduces both AP and target organ damage. (3) This combination has been proven to prevent major CV events and mortality, and has a better metabolic and safety profile than a fixed-dose combination of a beta-blocker and a thiazide.

Patients with AH often have associated kidney damage, and adequate control reduces the progression of kidney disease and mortality. Achieving target BP in patients with CKD can be challenging. Lifestyle changes are of particular importance, especially in terms of restricting salt (or sodium) intake. According to the KDIGO guidelines, target systolic pressure should be below 120 mmHg in patients with CKD. (4) In the presence of albuminuria, which is a known indicator of impaired renal function, or global microvascular damage, ACEi or angiotensin II receptor antagonists are recommended due to their effect of reducing albuminuria. The combination of RAAS inhibitors and diuretics is one of the recommended first lines of treatment. (2) It is important to emphasize that when an ACEi or ARB is first introduced, the systemic pressure drops, vasoconstriction of efferent kidney arterioles decreases, and, consequently, glomerular filtration decreases as well. In patient monitoring, this mechanism manifests as an increase in the level of serum creatinine due to a decrease in glomerular filtration. It is important to emphasize that the increase in serum creatinine in this context does not represent a new exacerbation of the renal function, but a favorable hemodynamic effect of the drug on the long-term reduction of glomerular load and preservation of residual kidney function. The use of RAAS inhibitors lowers arterial pressure and reduces glomerular hyperfiltration, which, if associated with albuminuria, has also been shown to increase the risk of total and CV mortality equivalent to or even greater than the risk observed for patients with stage 3A or stage 3B CKD without albuminuria. (5) The use of antihypertensive medicinal products is an unavoidable stop in protecting the remaining kidney function. (6) Increased sodium intake resulting in elevated volume load should be treated with diuretics if this cannot be managed through lifestyle changes. The PIANIST study investigated the role of a fixed-dose combination of the ACEi perindopril, the thiazide-like diuretic indapamide, and amlodipine in the treatment of AH. This fixed combination was demonstrated to be safe and effective in achieving target BP values. (7)

AH is closely related to other comorbidities, such as dyslipidemia, and research has shown that it is often neglected in hypertensive patients, especially in those with high CVR. (8) In this context, it is also necessary to mention patients with familial hypercholesterolemia, which is often detected only after their first CV event, and who require multiple uses of combination therapies to reduce their CVR and to achieve low target values of LDL-C. (9) Regardless of the presence of familial hypercholesterolemia, in patients with AH, even a moderate increase in LDL-C significantly increases their total CVR, which is particularly important when considered at the level of the general population. Dyslipidemia plays an important role in the pathogenesis and progression of functional disorders of the vascular endothelium, heart, and kidneys. Dysfunction of the vascular endothelium that occurs as a result of this condition contributes to the development of atherosclerosis and the occurrence of CV adverse events. Statins are essential drugs in the treatment of dyslipidemia. According to the intensity of their LDL-C lowering effect, statins are classified as high-intensity, including atorvastatin and rosuvastatin, and moderate-intensity drugs. The LDL-C reduction capacity of high-intensity statins is approximately 50%. It is important to emphasize that the risk of adverse CV events in cases of simultaneous occurrence of AH and dyslipidemia is greater than the sum of the risks of individual factors. In addition to their lipid-lowering effect, statins exhibit additional pleotropic mechanisms, such as improving endothelial function, reducing C-reactive protein levels, and reducing platelet aggregation. Several clinical studies have shown the benefits of adding statins to antihypertensive therapy in patients with moderate to high CVR. Statin therapy is associated with better AP control in these patients, regardless of the intensity of antihypertensive drugs. (2, 10) Even in cases where AP targets can be achieved with antihypertensive therapy alone, the addition of statins reduces the risk of acute myocardial infarction and cerebrovascular disease. Guidelines recommend initiating treatment with high-intensity statins. If the target LDL-C is not reached, it is recommended to introduce additional medicinal products such as ezetimibe, and then also a proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i).

Bearing in mind the importance of treating all risk factors on the one hand, and the need of simplifying treatment on the other hand, fixed-dose combinations should be used whenever possible.

Patient adherence is necessary for achieving appropriate clinical goals and effects described in controlled clinical studies. One year after staring antihypertensive therapy, only half of the patients still adhere to the prescribed treatment. (11) Poor adherence is associated with a poorer outcome, and it has been shown that patient compliance drops as the number of pills prescribed increases. Patients appear to be less adherent when they have complex therapeutic regimens requiring them to take multiple tablets several times a day. This problem can be overcome by prescribing tablets with fixed-dose combinations. A fixed-dose combination includes a tablet containing two or more active substances. They simplify treatment and are better accepted by patients, thus achieving better patient compliance and, consequently, adequate control of BP and reduction of CV events. (12) Currently, there are a number of approved single-pill combinations of active substances used for the treatment of AH and its associated diseases. In the era of individualized therapy, there is special emphasis on the clinical assessment of risk factors in patients with AH, which is then used to select the most appropriate fixed-dose combination for each patient. (13)

Effective lowering of BP in patients with AH is essential for lowering individual CVR. Control of hypercholesterolemia according to the principle of “the lower the better” reduces the incidence of CV events. Combination therapy is the basis of the modern treatment of AH. Perindopril, an ACEi with a favorable pharmacokinetic profile, and rosuvastatin, a potent HMG-CoA reductase inhibitor, are well-known and well-studied medicinal products used to treat AH and dyslipidemia. They are also known to have an angioprotective effect. Indapamide, a metabolically neutral long-acting diuretic, in addition to potentiating the effect of the ACEi perindopril and reducing the risk of hyperkaliemia, contributes to the antihypertensive effect of this fixed-dose combination with its pleotropic vasodilation effect.

The combination of perindopril, indapamide, and rosuvastatin in a single tablet (Roxiper^®) is the therapy of choice that meets all the modern criteria for the treatment of patients with AH, dyslipidemia, initial impairment of renal function, and increased total CVR, enabling us to reduce the burden of pills that the average hypertensive patient must take every day.