Inadequately controlled blood pressure is a major risk factor for cardiovascular disease. Poor blood pressure control rates result in disappointing reductions in prevalence of coronary artery disease, in high incidence of congestive heart failure and in even increasing incidence of end-stage renal failure among hypertensive patients. Blood pressure (BP) control thus remains one of the most important issues in the management of hypertension. (1)

The most important patient-related factor resulting in inadequate control of BP is non-adherence to the prescribed antihypertensive therapy. (1, 2) A study in the UK has shown that approximately 20% of newly diagnosed hypertensive patients have discontinued therapy by 6 months and the discontinuation rate has increased to almost 30% by 1 year. Some other analyses showed even worse results. The cost of therapy may be a reason for poor adherence. However, the more decisive factors are too complex treatment regimens and drug tolerability. Changes in therapy, such as adding a new drug, dropping or switching drugs are also associated with decreased adherence. It is beneficial to keep patients taking the initially assigned treatment in the longterm. (2-4)

The recently issued 2013 ESH/ESC Guidelines for the management of arterial hypertension (5) state that physician should pay attention to adverse drug effects which are powerful hindrance to treatment adherence. The advantage of initiating antihypertensive treatment with combination therapy is a smart decision due to a greater probability of early achieving the target BP and a lower probability of discouraging patient adherence with many treatment changes. Patients receiving combination therapy have a lower drop-out rate than patients given monotherapy. Further advantages are the physiological and pharmacological synergies between different classes of agents that may result in a greater BP reduction and cause fewer side effects thus providing larger benefits than a single agent. The 2013 ESH/ESC Guidelines favour the use of fixed dose combinations of two antihypertensive in a single tablet, because reducing the number of tablets which have to be taken daily improves adherence, and consequentially increases the rate of BP control. (5)

A meta-analysis showed that fixed-dose combination therapy resulted in a 26% decrease in non-adherence compared with free-drug component regimens. Complexity of treatment regimen can be reduced with fixed-dose combination that includes components with 24-hour efficacy, allowing for once-daily administration. (2)

Adherence to therapy predicts the outcomes. Better adherence is not associated only with a significantly better BP control, but also results in significantly lower hospitalization rates. Poor adherence on the other hand is associated with an increased risk of complications. An analysis of more than 15,000 patients in the US showed a 15% higher rate of hospitalization in the group of non-adherent patients. (2) Another analysis of 137,000 patients under the age of 65 with diabetes, hypertension, hypercholesterolemia, and congestive heart failure, hospitalization rates and health care costs were significantly lower for patients with high adherence. Cardiovascular events were almost twice as frequent in non-adherent study participants. (4)

The combination of ACE inhibitor and diuretic remains one of the preferred choices for initial as well as maintenance therapy. (3, 5) Of various fixed dose combinations the one of perindopril and indapamide deserves special attention because of the large-scale outcome trials which have been performed with it and because the findings of the clinical trials have also been confirmed in daily clinical practice.

Wide clinical experience has been accumulated with indapamide. This long-acting thiazide-like diuretic lowers BP through two mechanisms: the natriuretic diuretic effect and the vasorelaxant activity. Indapamide corrects the high noradrenaline reactivity and reduces peripheral resistance. It is highly lipophilic and may accumulate in the plasma membrane of vascular smooth muscle cells, reduce transmembrane calcium influx and cause vasodilation. Indapamide is well tolerated and, contrary to the thiazide diuretics, has no adverse impact on glucose and lipid metabolism. Indapamide does not induce development of glucose intolerance and new-onset of diabetes and neither does it cause increase in total cholesterol, LDL-cholesterol and triglyceride levels. (6-10)

The PICASSO trial conducted with combination of perindopril and indapamide in daily clinical practice has shown clinically significant reductions in the levels of total cholesterol LDL-cholesterol, triglycerides, fasting glucose, and uric acid, while the levels of HDL-cholesterol, sodium, and potassium remained unchanged. (10) Beneficial changes in metabolic parameters were primarily attributed to replacement of drugs with unfavourable metabolic profiles, such as HCTZ and beta- blockers. (10) Due to metabolic neutrality indapamide is appropriate also in patients with type 2 diabetes and in elderly. (7)

The combination of perindopril and indapamide effectively lowers BP and has further favourable effects: it improves endothelial dysfunction (as shown by the improved flowmediated dilation) which results in more favourable cardiovascular prognosis; it reduces large artery stiffness (as shown by decreased pulse wave velocity and reduced central blood pressure in the REASON trial); it reduces left ventricular hypertrophy (as shown by regression of the left ventricular mass index in the trials PICXEL and REASON) and decreases urinary albumin excretion. It delays progression of and reverses diabetic nephropathy. (7)

Large outcome trials with combination of perindopril and indapamide have shown the favourable properties and the improved cardiovascular outcomes in hypertensive patients, including the elderly and the high cardiovascular risk patients. The PROGRESS trial showed a highly significant stroke risk reduction of 28% by the active treatment with perindopril indapamide combination or perindopril alone, whereas the risk of fatal and non-fatal stroke was markedly decreased by 43% with combination of perindopril and indapamide. In the ADVANCE trial, the fixed dose combination of perindopril and indapamide reduced the relative risk of cardiovascular mortality by 18%. It also decreased the risk of non-fatal myocardial infarction, non-fatal stroke and new or worsening nephropathy. In a sub-analysis the fixed dose combination decreased the risk of developing micro- and macroalbuminuria by 21% and 31%, respectively. With this combination, simultaneous protection of the kidney and the cardiovascular system has been achieved. The treatment was well tolerated, with 73% and 74% of participants who received active treatment and placebo, respectively, still adherent to therapy after an average of 4.3 years of followup. (9) In the HYVET trial, the combination of perindopril and indapamide reduced the fatal or non-fatal stroke rate by 30% and the cardiovascular mortality by 23% whereas the rate of heart failure was reduced by 64%. (7)

The PRIMUS trial confirmed beneficial action of perindopril and indapamide in daily clinical practice, where this combination effectively reduced the BP rates and pulse pressure in various patients: newly diagnosed patients, the elderly, patients with isolated systolic hypertension, patients with additional, also multiple cardiovascular risk factors, associated cardiovascular conditions or target organ damage and/or type 2 diabetes. 98% of patients responded to treatment, and few adverse events were recorded. No clinically relevant changes in laboratory values were noted. Physicians rated treatment tolerability as good or very good in 90% of patients. (8)

In Croatia, Krka offers the entire perindopril portfolio including the combination of perindopril and indapamide. Co-Perineva® is available in three therapeutic dosages (2 mg / 0.625 mg; 4 mg / 1.25 mg and 8 mg / 2.5 mg) and offers the opportunity of individualized therapy either for start or for continuation of antihypertensive treatment.