Authors

• Alenka Kmecl — Krka, d. d., Novo mesto, Slovenia — ORCID: 0000-0001-8800-226X
• Breda Barbič-Žagar — Krka, d. d., Novo mesto, Slovenia — ORCID: 0000-0002-1173-7361
• Polona Knavs Vrhunec — Krka, d. d., Novo mesto, Slovenia — ORCID: 0000-0002-8474-1820

Abstract

Summary: High blood pressure has been identified as the leading risk factor, among 67 studied, for death and disability. Blood pressure control is still far from what would be necessary to reduce the cardiovascular risk. The treatment of hypertensive patients remains a challenging issue in daily clinical practice. The reduction in cardiovascular events with perindopril supports the concept of cardiovascular protective effects of perindopril beyond blood pressure lowering. Effective blood pressure control, as demonstrated in clinical studies with Krka’s perindopril and its fixed-dose combinations with indapamide and amlodipine, together with good tolerability and convenient once-daily dosing, have a positive impact on patients’ adherence to the treatment – which is a crucial step towards reaching the blood pressure targets.

Keywords

perindopril, hypertension, blood pressure, efficacy, safety, adherence

DOI

Full Text

## Introduction High blood pressure has been identified as the leading risk factor, among 67 studied, for death and disability. (1) Blood pressure (BP) control is still far from what would be necessary to reduce the cardiovascular risk. (2) Clinical trials have shown that treatment of hypertension reduces the risk of cardiovascular disease outcomes, including incident stroke (by 35 to 40%), myocardial infarction (by 15 to 25%), and heart failure (by up to 64%). (1) On the global level, BP normalization to below 140/90 mmHg is achieved in no more than 50% of hypertensive patients. (2) This suggests that despite comprehensive guidelines and numerous clinical trials, the treatment of hypertensive patients remains a challenging issue in daily clinical practice. (2) When optimizing the efficacy of antihypertensive treatment, the crucial goals are: (2) - BP normalization lasting 24 hours; - prevention/regression of target organ damage; - reduction of cardiovascular events. ## Effects of perindopril are not limited to blood pressure reduction Perindopril is a long-acting once-daily lipophilic ACE inhibitor with a pronounced 24-hour BP lowering effect. (2, 3) Perindopril has greater documented vascular penetration than other medicines of the same class and the best documented efficacy with respect to several parameters assessing vascular dysfunction or structural alterations in different segments of the arterial tree. (2) It exhibits high affinity for the tissue angiotensin-converting enzyme and organ-protective effects, especially when used in higher dosages. (2) Improvement in the angiotensin II-bradykinin balance, achieved by perindopril, has a number of beneficial effects on the cardiovascular system, including antihypertensive and antiatherosclerotic effects. (3) Large morbidity-mortality clinical studies, such as EUROPA and PROGRESS, have shown that antihypertensive treatment with perindopril reduces or prevents cardiovascular disease in a wide range of patients. (3) The reduction in cardiovascular events was higher than could have been expected from the observed reduction in BP achieved with perindopril. These findings suggest specific anti-atherosclerotic and anti-inflammatory effects, as well as effects on endothelium dysfunction. (3) The outcomes of these and other clinical studies support the concept of cardiovascular protective effects of perindopril beyond blood pressure lowering. (3) ## Blood pressure normalization with Krka’s perindopril The efficacy and safety of treatment with Krka’s perindopril (4) or the fixed-dose combination of perindopril and indapamide were assessed in 4,574 patients with mild to moderate arterial hypertension (mean age 62±12.3 years; 49% of male and 51% of female patients). There were 1,726 (37.7%) patients who had not been treated for hypertension before inclusion in the study. Among the 2,848 patients who had previous antihypertensive therapy, 81.4% had been treated with other ACE inhibitors. After 4 months of treatment, a statistically significant reduction in both SBP and DBP was observed in the patient population. The mean decrease in systolic blood pressure (SBP) was 22.8 mmHg (from 157.5 to 134.7 mmHg; mean relative reduction 14.7%) and in diastolic blood pressure (DBP) 10.4 mmHg (from 91.8 to 81.4 mmHg; mean relative reduction 11.3%). At the end of the study, 80% of the patients had a normalized BP of 140/90 mmHg or lower. The changes in SBP and DBP values are shown in **Figure 1**. Figure 1. The number of patients with substantially lowered blood pressure increased already in the first month after introduction of perindopril or perindopril/indapamide therapy. The majority of patients moved into the controlled blood pressure zone, which was even more obvious after 4 months of treatment. The most commonly used doses were Perineva* 4 mg and Co-Perineva* 4 mg/1.25 mg. In most patients, no adjustment of dosage was necessary during the study duration. The treatment with Krka’s perindopril and the fixed-dose combination of perindopril and indapamide was associated with an excellent adherence: 72.5% of the patients completely adhered to the treatment protocol and took all prescribed doses, 17.5% of the patients forgot to take the medicine once and only 9.6% forgot to take it twice. This can also be attributed to good tolerability of the study medicine, since 97% of the patients had no adverse reactions. During the study approximately half of the patients regularly monitored and recorded their home BP values. The BP levels were significantly reduced (p <0.0001) in both groups of patients. In the self-monitoring group, the mean SBP reduction was 25.6 mmHg and the mean DBP reduction 11.8 mmHg. In the group without self-monitoring, the mean SBP reduction was 23.2 mmHg and the mean DBP reduction 11.1 mmHg. The differences in SBP and DBP reduction between both groups were statistically significant. From the above results it can be concluded that patients’ self-monitoring of BP could also have contributed to good rates of BP normalization. ## Fixed-dose combination of perindopril and amlodipine for patients with higher blood pressure levels and additional risk factors The efficacy of perindopril in the treatment of hypertension has been documented in several large-scale clinical studies, particularly in combination with the calcium antagonist amlodipine or the diuretic indapamide, showing beneficial effects in reducing cardiovascular events and mortality. (5) Perindopril in the fixed-dose combination with amlodipine or indapamide is highly effective for both BP control and cardiovascular prevention, (5) which is especially important in patients with additional cardiovascular risk factors. (6) A total number of 3,821 patients with arterial hypertension were included in the non-interventional clinical study COMPLIANT. (7) Of these, 88% had additional cardiovascular risk factors. Dyslipidemia as the most frequent risk factor was present in 55% of the patients, followed by abdominal obesity in 45% of the patients. A 33% portion of the patients had 2 additional risk factors apart of hypertension, and 26% had 3 or more additional risk factors. The population included 752 (20%) patients who had no antihypertensive therapy prior to inclusion. Among 3069 (80%) patients who had been previously treated for hypertension, the majority had therapy with RAAS inhibitors (n=2497), mainly ACE inhibitors, and calcium antagonists (n=849), the rest of the patients (n=1257) received other antihypertensive therapies. At inclusion, the patients were prescribed Krka’s fixed-dose combination of perindopril and amlodipine; Dalneva* 4 mg/5 mg was prescribed to 55% of the patients. At the end of the study, 37% of the patients still had the same dose. The higher dose of perindopril, 8 mg, has been introduced in 42% of the patients at the beginning of the study. During the study, the dose could be adjusted if necessary, so by the end of the study 55% of the patients received the higher dose of perindopril (**Table 1**). In case of dose adjustment, physicians mostly decided to prescribe higher doses of both active ingredients. ### Table 1: Dosing of Krka’s fixed-dose combination of perindopril and amlodipine during the study. At the end of the study, 37% of the patients were still treated with perindopril/amlodipine 4 mg/5 mg. The higher dose of perindopril, 8 mg, which offers better blood pressure reduction and organ protection, was not taken advantage of to an optimal extent. After four months of treatment, the BP levels were statistically significantly reduced in all patients, irrespectively of the initial stage of hypertension. By the end of the study the patients had an average BP level of 135.7/81.3 mmHg (**Figure 2**). Figure 2. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were statistically significantly reduced already after the first month of treatment with Krka’s fixed-dose combination of perindopril and amlodipine. After 4 months, the patients reached an average SBP of 135.7 mmHg and an average DBP of 81.3 mmHg. The introduction of Krka’s fixed-dose combination of perindopril and amlodipine resulted in further BP reduction if compared to previous therapies, including 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 (**Figure 3**). Figure 3. Blood pressure was further reduced after introduction of the fixed dose combination of perindopril and amlodipine in patients previously treated with other antihypertensive drugs. ACEI = ACE inhibitor; CCB = calcium channel blockers; D = diuretic; BP = blood pressure; SBP = systolic blood pressure; DBP = diastolica blood pressure. Treatment with Krka’s fixed-dose combination of perindopril and amlodipine was well tolerated: 94% of the patients experienced no adverse reactions. The most common treatment-related adverse events observed during the study were peripheral edema (3.2%), cough (0.8%) and erythema (0.5%). Hypotension was observed in 10 (0.3%) patients. In the physicians’ opinion, adherence to treatment increased from 90.6% of adherent patients after 1 month to 94.5% after 4 months. The patients evaluated themselves as adherent in an even higher number, reaching 98.3% after 4 months of treatment with Krka’s fixed-dose combination of perindopril and amlodipine. ## Conclusion The clinical efficacy of perindopril was demonstrated, as well as its safety and good tolerability. (5) The higher dosage is suggested for a greater BP control and cardiovascular protection in hypertensive patients. (5) The combination therapy is an important option for effective BP control in clinical practice, and perindopril in the fixed-dose combination with the diuretic indapamide and the calcium antagonist amlodipine is highly effective in both BP control and cardiovascular prevention. (5) The results of clinical studies with Krka’s perindopril and its combinations with indapamide and amlodipine demonstrate that can effectively be applied in hypertension management. (4, 7) The good tolerability profile of these medicines and convenient once-daily dosing have a positive impact on patients’ adherence to the treatment (4, 7) – which is a crucial step towards reaching the blood pressure targets. (8)

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