Efficacy of a fixed triple combination of antihypertensive drugs for the treatment of arterial hypertension in real clinical practice

Attention! The article is addressed to medical specialists

Sujayeva V.A.

Republican Scientific and Practical Center “Cardiology”, Minsk, Belarus

Effectiveness of fixed triple combinations

of anti-hypertensive drugs

in the treatment of hypertension in real clinical practice

Summary. An assessment of the effectiveness of the fixed combination of perindopril/amlodipine/indapamide is presented ( Co Amlessa, Krka, Slovenia) in real clinical practice. We examined 231 patients with arterial hypertension of I-III degrees aged from 26 to 88 years (average 60.7±10.6 years) from among those who were under outpatient observation and treated under the supervision of general practitioners in Minsk in 2016. Of the 231 included in the study, 131 (57%) patients had concomitant diseases, 224 had previously received antihypertensive treatment, but only 10% of them achieved the target blood pressure (BP) level. Use of a triple fixed combination of perindopril/amlodipine/indapamide ( Co-Amlessa, Krka, Slovenia) contributed to achieving the target blood pressure level after 4 weeks - in 79%, after 8 weeks - in 92% of patients with arterial hypertension, previously ineffectively treated. After 4 weeks of taking the drug Ko Amlessa (KRKA, Slovenia) a decrease in SBP was achieved from 160.2±13.5/93.3±8.7 to 135.1±11.7/81.6±7.1 mm Hg. Art. (R<0,05), через 8 недель - до 129,2±10,5/78,6±5,9 мм рт. ст. (р<0,05). У лиц, не достигших целевого уровня АД, исходный уровень САД - 175,4±9,9 мм рт. ст. - был выше, чем в среднем по группе - 160,2±13,5 мм рт. ст. (р<0,05). Через 4 недели в этой группе лиц выявлено значительное снижение САД до 159,2±9,8 мм рт. ст. (р<0,05), через 8 недель - до 153,1±9,6 мм рт. ст. (р<0,05). Фиксированная комбинация периндоприл/амлодипин/индапамид (Co-Amlessa, Krka, Slovenia) has demonstrated high effectiveness for the treatment of arterial hypertension (including in 92% of individuals who received previous antihypertensive therapy but did not achieve the target blood pressure level) in real clinical practice.

Keywords: arterial hypertension, treatment, fixed combinations, amlodipine, perindopril, indapamide.

Medical news. - 2017. - No. 11. - WITH . 19-23.

Summary. Estimate effectiveness of the fixed combination perindoprile/amlodipine/indapamide in real clinical practice. We exanimate 231 outpatients with the arterial hypertension (AH) of the I-III degree aged from 26 up to 88 years (on average 60.7±10.6 years) treated by therapists of Minsk who in 2016. 131 (57%) from 231 included patients had associated diseases, 224 patients already received anti-hypertensive treatment, but the target level of the blood pressure (BP) was reached by only 10%. Use of the triad fixed combination perindoprile/amlodipine/indapamide (WITH o-Amlessa , KRKA, Slovenia) promoted achievement of the BP target level in 4 weeks - at 79%, in 8 weeks - at 92% of patients which were earlier not reached the BP target level despite the carried-out treatment. In 4 weeks ofWITH o-Amlessa therapy we revealed decreasing of BP from 160.2±13.5/93.3±8.7 to 135.1±11.7/81.6±7.1 mm Hg ( R <0.05), and in 8 weeks - to 129.2±10.5/78.6±5.9 mm Hg ( R <0.05). At the persons which didn’t reach the BP target after 8 weeks we found higher initial BP - 175.4±9.9 mm Hg than on average on group - 160.2±13.5 mm Hg, R <0,05. In 4 weeks in group hadn’t reached target level of BP we found significantly lower than initially level of BP - 159.2±9.8 mm Hg ( R <0,05), in 8 weeks mentioned level became lower - 153.1±9.6 mm Hg taped ( R <0.05). The fixed combination perindoprile/amlodipine/indapamide (Co-Amlessa, KRKA, Slovenia) demonstrated high efficiency for treatment of AH (including 92% of the persons who had received previous anti-hypertensive therapy, but didn’t reach target level of BP) in real clinical practice.

Keywords: arterial hypertension, treatment, the fixed combinations, perindoprile, amlodipine, indapamide.

Meditsinskie news. - 2017. - N11. - P. 19-23.

Increased blood pressure (BP) is one of the most common of these modifiable risk factors for the development of cardiovascular diseases (CVD). However, despite the availability of a large number of highly effective antihypertensive drugs, the fight against arterial hypertension (AH) has still not led to the expected success: the target blood pressure level is reached in about 1/3 of treated patients. It has been established that, regardless of the type of drug, monotherapy in achieving target blood pressure levels is effective only in 30-50% of people with hypertension; in most cases, the use of a combination of at least two drugs is required. According to a meta-analysis of more than 40 randomized clinical trials (RCTs), the combination of two drugs from any two classes of antihypertensive drugs increases the degree of blood pressure reduction much more than dose escalation of a single drug.

However, the effectiveness of antihypertension zive drugs in achieving target blood pressure levels, achieved in multicenter studies, does not always take place in practice. This may be due to a number of factors. Thus, RCTs often do not include elderly patients, people with concomitant cardiac and extracardiac pathologies, impaired liver and kidney function, etc. In addition, adherence to treatment in patients included in RCTs is usually significantly higher than in real clinical practice.

One of the directions of modern hypertensiology is the study of the effectiveness of fixed combinations of antihypertensive drugs. Such combinations, as a rule, consist of drugs that have medicinal synergistic effects. An important aspect of using fixed combinations is the possibility of a single dose of drugs, which helps to increase patient adherence to treatment. The downside of using combination drugs is the risk of side effects, and it can sometimes be difficult to determine which component of the combination drug is affected.

This paper presents an estimate Research on the effectiveness of the fixed combination of perindopril/indapamide/amlodipine ( Co-Amlessa, Krka, Slovenia) in real clinical practice. The study included 231 patients with hypertension I - III degrees aged from 26 to 88 years (average 60.7±10.6 years) from among those who were under observation and received outpatient treatment from general practitioners in Minsk in 2016. All patients were prescribed a fixed combination of perindopril/amlodipine/indapamide ( Co-Amlessa, Krka, Slovenia).

According to the requirements for observational studies, the prescription of drug therapy was carried out strictly in accordance with the instructions for medical use of the drug ( Co-Amlessa, Krka, Slovenia), only for registered indications for use and in accordance with accepted clinical practice. The prescription of drug therapy was based only on medical indications and the doctor’s decision, and did not depend on the patient’s wishes.

A risk factor such as smoking occurred in 54 (23%) patients. The duration of hypertension ranged from 1 to 50 years (average 13.4±8.0 years).

Noteworthy is the fact that the majority of patients belonged to the high and very high risk group: more than half of those examined - 131 (57%) - had concomitant diseases. Coronary heart disease (CHD) in the form of stable angina pectoris I - II functional class (FC) according to the Canadian classification was diagnosed in 27 (1 2%) patients, coronary artery disease with a history of rhythm disturbances - in 14 (6%) patients (11 - atrial fibrillation (AF), 3 - extrasystole (ES), requiring constant use of antiarrhythmic drugs). 16 (7%) patients suffered myocardial infarction (MI) before inclusion in the study (from 1993 to 2015), with three having 2 or more MIs. 2 people had previously undergone myocardial revascularization using coronary artery bypass grafting (CABG), and another one had undergone percutaneous coronary intervention (PCI). 10 (4%) patients suffered cerebrovascular accidents/cerebral infarction. Type 2 diabetes mellitus (DM) was detected in 51 (22%) of those included in the study, and another 2 had previously been diagnosed with type 1 DM. 2 patients had metabolic syndrome (MS), 7 had grade 3 obesity (Table 1).

Table 1. Concomitant diseases in patients with arterial hypertension

Disease	Number of patients, abs. (%)
IHD: stable angina pectoris FC I-II
IHD: post-infarction cardiosclerosis
Coronary artery bypass/percutaneous bypass surgery
IHD: atherosclerotic cardiosclerosis with rhythm disturbances
Cerebrovascular accident/cerebral infarction
Diabetes: · 2nd type · 1st type
Metabolic syndrome
Obesity 3 degrees
Respiratory diseases: · bronchial asthma (BA) Chronic obstructive pulmonary disease (COPD)
Chronic kidney disease (CKD)
Pathology of the thyroid gland (TG)
Cancer (skin, breast)
Pathology of the gastrointestinal tract (GIT): Chronic gastropathy/duodenopathy Chronic gastric/duodenal ulcer
Liver pathology: · chronic hepatitis C Gilbert's syndrome · cholelithiasis · chronic cholecystitis
Vein diseases
Joint diseases: · osteoarthritis psoriatic arthritis · rheumatoid arthritis
Chronic heart failure (CHF)
Eye diseases: · cataract · glaucoma

Exclusion criteria from the study: contraindications to the use of perindopril, amlodipine and indapamide, specified in the instructions for them.

At the first visit, the specialist measured blood pressure in the right and left arms using a hand-held aneroid sphygmomanometer with the subject sitting, after a five-minute rest. The analysis included the average BP value from three measurements on each arm. During control examinations, blood pressure was measured on the arm on which higher values ​​were recorded at the first visit: to measure blood pressure, the right arm was chosen in 164 patients, the left arm in 67 patients.

Visit 2 took place 4 weeks later and after inclusion in the study, visit 3 - after another 4 weeks. At each visit, in addition to systolic and diastolic blood pressure (SBP and DBP, respectively), the patient's clinical condition, heart rate (HR), concomitant medications, adherence to treatment, side effects and adverse events were also assessed.

In accordance with the recommendations of the European Society of Cardiology ( European Society of Cardiology - ESC ) and the European Society of Hypertension ( European Society of Hypertension - ESH ) 2013, the SBP value was taken as the target blood pressure level<140 мм рт. ст. и значение ДАД<90 мм рт. ст. (у лиц без СД) и <85 мм рт. ст. - у лиц с СД .

The patient information database was compiled using the standard Excel 2007 program. Statistical data analysis was performed in the STATISTICA 7.0 program (StatSoft Inc.). When analyzing the significance of the differences in the obtained results, the Student's t-test was used. Data are presented as M±SD. Differences in indicators were considered significant at p value<0,05.

At study entry, the majority (224 of 231) of patients were already receiving antihypertensive treatment. The number of medications taken initially varied from 1 to 6 (group average 2.6±1.1). The majority of those examined - 92 (40%) out of 231 - initially took three medications, 62 (27%) - two drugs, 25 (11%) - one drug, 45 (19%) - more than four drugs, another 7 (3% ) patients did not initially receive antihypertensive treatment, although newly diagnosed hypertension occurred in only one of them.

The majority - 167 (72%) of 231 - of those included in the study initially received a drug from the group of angiotensin-converting enzyme inhibitors (ACEIs), 154 (67%) patients received calcium ion antagonists (CA), 157 (68%) - diuretics, 92 (40%) - other antihypertensive drugs.

Of the ACEI group, perindopril was most often prescribed - 54 (32%) out of 167 patients (at a dose of 8 mg - 15 examined, 4 mg - ten, 2 mg - two, 5 mg - 11 and 10 mg - 16 patients). The average dose of perindopril was 6.6±2.2 mg.

Enalapril at a dose of 5-40 mg (average 23.9±12.1 mg) was initially prescribed to 26 (16%) participants included in the study, lisinopril at a dose of 5-40 mg (average 21.2±11.7 mg) - 48 (29%), ramipril at a dose of 2.5-10 mg (average 8.4±2.4 mg) - 37 (22%), other ACE inhibitors (fosinopril and zofenopril) - one patient each.

Thus, initially all patients received ACE inhibitors in average therapeutic dosages.

Of the drugs in the AK group, amlodipine was most often prescribed: this drug in a dose of 5-10 mg (average 6.2 ± 2.1 mg) was received by 136 (88%) of 154 patients when included in the study, lecarnidipine in a dose of 5-10 mg (average 8.9±2.1 mg) was prescribed to 9 (6%) subjects, nifedipine XL at a dose of 30-60 mg (average 41.3±14, 5 mg) - 8 (5%) patients, another patient received a retard form of diltiazem at a daily dose of 360 mg.

Thus, drugs from the AK group were also prescribed in average therapeutic doses.

Of the diuretics, indapamide was most often prescribed: it was received by 116 (74%) of 157 patients examined, and the retard form at a dose of 1.5 mg was prescribed to 11 (9%) of 116 patients, the remaining 105 received indapamide at a dose of 2.5 mg. Hypothiazide at a dose of 12.5-25 mg (average 19.0±6.4 mg) was prescribed to 37 (24%) included in the study, other diuretics (diuver, spironolactone, furosemide) in average therapeutic doses were received by 4 (2% ) patient.

Among other antihypertensive drugs, β-adrenergic blockers (BABs) were most often used - in 91 out of 92 examined. Preference was given to bisoprolol - 40 (44%) of 91 received it; metoprolol, atenolol, betaxolol, carvedilol, nebivolol were prescribed less frequently.

Medicines from the antagonis group angiotensin receptor product II (ARA) 17 patients received losartan, valsartan, irbersartan, 25 patients received moxonidine, a drug from the group of β-adrenergic blockers was prescribed to one patient.

Considering the high incidence of concomitant pathology, 77 of 231 patients were prescribed antiplatelet agents (acetylsalicylic acid at a dose of 75 mg and/or clopidogrel at a dose of 75 mg), warfarin, nonsteroidal antiplatelet agents upon inclusion in the study. other anti-inflammatory drugs, peripheral vasodilators (long-acting nitrates or molsidomine), ivabradine, trimetazidine, hypoglycemic agents, statins, bronchodilators, antiarrhythmic drugs.

Noteworthy is the fact that initially, at the first visit, 54 (23%) of 231 patients were already receiving fixed combinations of antihypertensive drugs: 11 were prescribed a perindopril/amlodipine combination, 9 were prescribed a fixed combination of perindopril/indapamide, 34 were prescribed a triple combination of perindopril/amlodipine /indapamide. However, only 22 (10%) patients had target blood pressure levels at baseline. The mean blood pressure at baseline was: SBP (right arm) 160.2±13.5 mmHg. Art., DBP (right arm) 93.3±8.7 mm Hg. Art., SBP (left arm) 159.6±14.9 mm Hg. Art., DBP (left arm) 93.0±8.4 mm Hg. Art., heart rate 73.0±8.6 beats/min (figure).

At the first visit, the initial therapy was canceled, starting from the third day, all 231 patients were prescribed the drug Ko Amlessa (KRKA, Slovenia), which is a fixed combination of perindopril/amlodipine/indapamide in various doses (Table 2).

Table 2. Use of a fixed combination of perindopril/amlodipine/indapamide (Co-Amlessa, KRKA, Slovenia)

Dose of perindopril/ amlodipine/ indapamide	Number of patients taking the drug at the indicated dose, abs. (%)
	Visit 1	Visit 2 (after 4 weeks)	Visit 3 (after 8 weeks)
4 mg/ 5 mg/ 1.25 mg
4 mg/ 10 mg/ 1.25 mg
8 mg/ 5 mg/ 2.5 mg
8 mg/ 10 mg/ 2.5 mg

During the first 4 weeks of therapy, adverse events developed in 6 patients: 1 - pain in the epigastric region, 1 - excessive (up to 100/60 mm Hg) decrease in blood pressure, another 3 examined with a decrease in blood pressure to 90/60 mmHg Art. dizziness was noted. In this regard, the dose of the drug Ko Amlessa (KRKA, Slovenia) at visit 2 was reduced by 2 times. None of those included in the study required discontinuation of the drug due to poor tolerability.

At visit 2, 6 patients received a dose of the drug Ko Amlessa (KRKA, Slovenia) was reduced due to the achievement of the target blood pressure level. The average SBP value for the group was 135.1±11.7 mm Hg. Art., which is significantly lower than initially - 160.2±13.5 mmHg. Art. (R<0,05). При этом выявлена также тенденция к уменьшению уровня ДАД при отсутствии роста ЧСС (см. рисунок, р>0.05). Absence of reflex tachycardia during drug therapy , which includes AK, is very relevant, since 46 (20%) of those included in the study had concomitant ischemic heart disease (angina pectoris, previous MI or rhythm disturbances).

At the second visit, 183 (79%) patients reached the target blood pressure level, which is significantly more than at visit 1 - 10% (p<0,05). Среди остальных 48 пациентов у 8 (3%) для достижения целевого уровня АД была увеличена в 2 раза доза препарата Ko Amlessa (KRKA, Slovenia), in another 4 people, beta blockers were added to treatment with Co-Amlessa (in 2 - bisoprolol, in 2 - carvedilol).

A differentiated analysis revealed that individuals who did not reach the target blood pressure level had the most severe hypertension - SBP initially was 175.4 ± 9.9 mm Hg. Art. and was higher than the group average - 160.2±13.5 mm Hg. Art. (R<0,05). Среднее ДАД - 92,2±9,2 мм рт. ст. - было сопоставимым со средним показателем в группе - 93,3±8,7 мм рт. ст. (р>0.05). Despite the failure to achieve the target blood pressure level, at visit 2 in this group of more severe patients, a decrease in the level of both SBP and DBP was recorded - to 159.2 ± 9.8 and 88.8 ± 7.3 mm Hg. Art. accordingly, and the level of SBP became significantly lower than at visit 1 (p<0,05).

When conducting analysis using the pairwise linked method, the option It was found that in persons who did not reach the target blood pressure level at visit 2, the decrease in SBP averaged -16.2 ± 13.9 mm Hg. Art. (R<0,05), уменьшение ДАД было менее выраженным и составило -2,8±9,4 мм рт. ст. (р>0,05).

At visit 3, no adverse events were registered in any of the subjects, that is, they were stopped after reducing the dose at visit 2. The average SBP value for the group was 129.2 ± 10.5 mm Hg. Art., that is, not only lower than initially, but also, taking into account the value of the standard quadratic, did not exceed the norm. The DBP level at visit 3 was 78.6±5.9 mm Hg. Art., which is significantly lower than the original (see figure, p<0,05). Прироста ЧСС при этом не наблюдалось (р<0,05).

212 (92%) patients already had the target blood pressure level - significantly more than at baseline (p<0,05). Лишь 19 (8%) из всех включенных в исследование лиц не смогли достичь целевого уровня АД на визите 3.

However, the average SBP level in the group of people who did not reach the target blood pressure level was 153.2±9.6 mm Hg at the third visit. Art., that is, significantly lower than initially (p<0,05). При анализе методом попарно связанных вариант снижение САД в сравнении с визитом 1 составило -22,2±14,4 мм рт. ст. (р<0,05), в сравнении с показателем на визите 2 - -6,6±7,5 мм рт. ст. (р<0,05). Снижение ДАД в сравнении с показателем во время визита 1 составило -5,3±12,2 мм рт. ст. (р>0.05), compared with that during visit 2 - -1.4±7.0 mmHg. Art. (p>0.05).

Similar results on the impact on the level b BP have been demonstrated using the combination of perindopril/indapamide/amlodipine in studies PIANIST, PAINT, ADVANCE.

So, in the study PIANIST the initial blood pressure level was 160.5±13.3/93.8±8.7 mmHg. Art. (comparable with that identified in this work - 160.2±13.5/93.3±8.7 mmHg). After 4 months of taking the combination of perindopril/amlodipine/indapamide, a decrease in blood pressure was achieved to 132.2±8.6/80.0±6.6 mm Hg. Art. (in the present study - up to 129.2±10.5/78.6±5.9 mm Hg after 8 weeks of taking the drug). Blood pressure reduction in the study PIANIST averaged 28.3±13.5/13.8±9.4 mm Hg. Art. (when taking Co-Amlessa - 22.2±14.4/1.4±7.0 mmHg). Target blood pressure level in the study PIANIST reached 72% of patients, in the present study - 92% of those examined.

The PAINT study included 6088 patients aged 62.8±11.3 years with an initial office blood pressure of 158.1±13.0/92.6±8.8 mmHg. Art., comparable to the indicator in the present study. After 4 months, office blood pressure decreased by 26.7±13.3/12.9±9.4 mmHg. Art., that is, the results are consistent with those obtained when taking a fixed antihypertensive combination Ko Amlessa(KRKA, Slovenia).

The ADVANCE (Action in Diabetes and Vascular Disease) study randomized 11,140 patients (5569 to receive a fixed combination of perindopril/indapamide, 5571 to placebo). At baseline, the mean blood pressure level was slightly lower than in the study with the drug Ko Amlessa (KRKA, Slovenia) and was 145/81 mm Hg. Art. Under the influence of a fixed combination of perindopril/indapamide, a decrease in blood pressure to 134.7/74.8 mm Hg was achieved. Art., that is, on average by 5.6/2.2 mm Hg. Art. (R<0,01). Но еще более важным явилось снижение риска смерти от ССЗ на 18% и общей смертнawn by 14%. The authors concluded that routine administration of a fixed combination of perindopril/indapamide in people with type 2 diabetes is well tolerated and improves prognosis. Taking a fixed combination of perindopril/indapamide for 5 years helped save the life of 1 out of 79 treated patients.

J. Chalmers et al. (2014) found that of the 11,140 patients who entered the ADVANCE study, 3,427 people (1,669 from the active treatment group and 1,758 from the placebo group) received AC, the remaining 7,713 patients (3,900 from the active treatment group and 3,813 - both 3 placebo group) did not receive AK. The inclusion of AK in combination therapy of the ACE inhibitor perindopril and the metabolically neutral diuretic indapamide contributed to an even more pronounced effect on prognosis than when using a combination of these two drugs, in particular on cardiovascular death and death from all causes.

Thus, the generic drug Ko Amlessa (KRKA, Slovenia), which is a fixed combination of perindopril/amlodipine/indapamide, demonstrated high effectiveness for the treatment of arterial hypertension (including in 92% of people receiving antihypertensive therapy, but not achieving the target blood pressure level) in real clinical practice. Data obtained on the effect of the drug Ko Amlessa (KRKA, Slovenia) on blood pressure levels are comparable to the results of the PIANIST, PAINT, ADVANCE studies conducted using original drugs.

Conclusions:

1. Use of a triple fixed combination of perindopril/amlodipine/indapamide ( Co-Amlessa, Krka, Slovenia) contributed to achieving the target blood pressure level after 4 weeks - in 79%, after 8 weeks - in 92% of patients with arterial hypertension who had previously received antihypertensive therapy, but did not achieve their goals.

2. Persons receiving antihypertensive treatment, including using fixed combinations of drugs, had a SBP level of 160.2±13.5 mm Hg when included in the study. Art., DBP - 93.3±8.7 mm Hg. Art., which significantly exceeded the generally accepted target level<140/90 мм рт. ст. и свидетельствовало о низкой эффективности проводимого лечения.

3. After 4 weeks of taking the drug Ko Amlessa (KRKA, Slovenia) a reduction in SBP to 135.1±11.7 mm Hg was achieved. Art. (R<0,05), ДАД - до 81,6±7,1 мм рт. ст., а через 8 недель - до 129,2±10,5 и 78,6±5,9 мм рт. ст. соответственно (р<0,05), что свидетельствует о нормализации артериального давления у лиц, ранее достигавших его контроля, несмотря на проводимое лечение.

4. While taking the drug Ko Amlessa (KRKA, Slovenia) it was not possible to achieve the target blood pressure level after 4 weeks in 21% of patients, after 8 weeks - only in 8% of those examined. In this most difficult group of patients to manage, the initial SBP level was 175.4 ± 9.9 mm Hg. Art., that is, it was higher than the group average (p<0,05). Через 4 недели у лиц с резистентной и более выраженной артериальной гипертензией выявлено снижение САД до 159,2±9,8 мм рт. ст. (р<0,05), через 8 недель - до 153,1±9,6 мм рт. ст. (р<0,05), при анализе методом попарно связанных вариант снижение САД составило -16,2±2,3 и -22,2±3,4 мм рт. ст. соответственно (р<0,05).

5. In persons with severe treatment-resistant arterial hypertension, taking the drug Ko Amlessa (KRKA, Slovenia) led to an additional decrease in SBP by 16 mmHg. Art. - after 4 weeks and by 22 mm Hg. Art. - after 8 weeks of use.

6. Fixed combination of perindopril/amlodipine/indapamide ( Co-Amlessa, Krka, Slovenia) has demonstrated high effectiveness for the treatment of arterial hypertension (including in 92% of individuals who received previous antihypertensive therapy but did not achieve the target blood pressure level) in real clinical practice.

L I T E R A T U R A

1. Mancia G., Fagard R., Narkiewicz K., Redon J., et al. // European Heart Journal. - 2013. - Vol.34. - P.2159-2219.

2. Mancia G., De Backer G., Dominiczak A., et al. // J. Hypertens. - 2007. - Vol.25. - P.1105-1187.

3. Wald D.S., Law M., Morris J.K., Bestwick J.P., Wald N.J.//Am. J. Med. - 2009. - Vol.122. - P.290-300.

4. T ó th K . // Am. J. Cardiovasc Drugs. - 2014. - Vol.14, N2. - P.137-145. doi:10.1007/s40256-014-0067-2.

5. Páll D., Szantó I., Szabó Z.// Clin. Drug Investig. - 2014. - Vol.34, N10. - P.701-708.

6. HellerS.R. // Diabetes Care . - 2009 . - Vol. 32 (Suppl. 2). - S357-S361.

7. Chalmers J., Arima H., Woodward M., et al. // Hypertension. - 2014. - Vol.63. - P.259-264.

Medical news. - 2017. - No. 11. - pp. 19-23.

Attention! The article is addressed to medical specialists. Reprinting this article or its fragments on the Internet without a hyperlink to the source is considered a violation of copyright.

Modern fixed

^ G.E. Gendlin, E.I. Emelina

Department of Hospital Therapy No. 2, Faculty of Medicine, Russian State Medical University. N.I. Pirogov

The main goal of therapy for patients with arterial hypertension is to achieve target blood pressure values, for which various combinations of antihypertensive drugs are used. Combination therapy with diuretics and angiotensin-converting enzyme inhibitors has noticeable advantages. A fixed combination of these drugs is Noliprel A, which is a first-line agent in the modern treatment of arterial hypertension.

Key words: arterial hypertension, antihypertensive drugs, perindopril, indapamide, fixed combinations, Noliprel A.

Arterial hypertension (AH) is one of the most common cardiovascular diseases. According to epidemiological studies, more than a third of the adult population of Russia suffers from hypertension. The main goal of therapy for patients with high blood pressure (BP) is to achieve its target values. According to the recommendations adopted by the European Society of Hypertension together with the European Society of Cardiology, the target blood pressure values ​​are less than 140/90 mmHg. Art., and in patients with diabetes mellitus (DM) or kidney damage -<130/80 мм рт. ст. Аналогичные значения рекомендуют эксперты Всероссийского общества кардиологов (ВНОК). Достижение оптимального уровня АД является важнейшей задачей при ведении больного АГ.

Increase in diastolic blood pressure for every 5-6 mm Hg. Art. (or systolic blood pressure by 10 mm Hg) increases the risk of developing coronary heart disease by 20-25%, stroke - by 35-40%, chronic heart disease

Contact information: Gendlin Gennady Efimovich, [email protected]

birth failure - by 50%. In addition, high blood pressure contributes to the development of left ventricular myocardial hypertrophy, which, in turn, doubles the risk of chronic heart failure and coronary heart disease (regardless of blood pressure level) and 4-9 times increases the risk of severe ventricular arrhythmias.

At the same time, an effective reduction in blood pressure in patients is achieved only in 5-10% of cases. This is due to the fact that in practice it is not always possible to control blood pressure when prescribing only one antihypertensive drug (AGD); there are certain difficulties in selecting adequate doses of AHD to reduce blood pressure to target values; patient adherence to the prescribed treatment also plays an important role.

According to the latest recommendations, one of the first-line drugs can be prescribed as initial therapy for mild and moderate hypertension: a diuretic, an angiotensin-converting enzyme (ACE) inhibitor, a β-blocker, a calcium antagonist, an angiotensin receptor antagonist.

Combinations of antihypertensive drugs

well II, and if the blood pressure decreases insufficiently, the dose of antihypertensive drugs can be increased. Meanwhile, essential hypertension is a heterogeneous disease caused by the presence of a large number of factors that contribute to the development of vasoconstriction and the maintenance of elevated blood pressure. The main pathogenetic mechanisms for the development of hypertension are an increase in the activity of the renin-angiotensin-aldosterone system (RAAS), hyperstimulation of the sympathetic nervous system and sodium retention in the body. Monotherapy aimed at correcting only one of the many pathogenetic links of hypertension often does not allow achieving the target blood pressure level. It is not always possible to identify the specific vasoconstrictor mechanism that dominates the pathogenesis of hypertension in each patient, and this partly explains the low effectiveness of treatment with one drug. The results of a number of studies studying the main groups of antihypertensive drugs used as monotherapy have shown that the effectiveness of treating hypertension with one drug is about 50-60%.

In addition, as the dose of antihypertensive drugs increases, the frequency of adverse effects (AEs) increases, and it is not always possible to achieve the target blood pressure level. For example, when using maximum doses of a diuretic as monotherapy, the risk of developing hypokalemia, hyperuricemia and hyperglycemia is quite high, which forces patients to refuse to use these drugs. In addition, during monotherapy with diuretics, counter-regulatory neurohumoral mechanisms are activated, weakening their antihypertensive properties, which requires increasing the dose and contributes to a greater severity of NE. Other NEs are also dose-dependent - cough when using ACE inhibitors, peripheral edema when treated with calcium antagonists. Selection of adequate doses of antihypertensive drugs becomes

a problem at the outpatient stage of treatment, when the doctor is deprived of the opportunity to regularly monitor the patient’s condition.

The choice of antihypertensive drugs for the treatment of elderly patients must be approached with special attention. Numerous studies conducted in patients with isolated systolic hypertension have shown that achieving the target blood pressure level significantly reduces the risk of strokes and coronary complications.

An important factor in the treatment of hypertension is the patient’s adherence to the treatment prescribed by the doctor, because even carefully selected therapy may be ineffective if the drugs are not taken regularly. In this regard, factors such as deterioration in quality of life due to the need to take one or more drugs, adverse effects from the therapy, and the cost of drug treatment play an important role. Violation of recommendations significantly weakens the effect of reducing cardiovascular risk in patients with hypertension, mainly due to unsatisfactory blood pressure control. To improve patients' interest in treatment, several strategies have been proposed: informing about the risk of cardiovascular complications of hypertension, selecting drugs with an optimal balance of effectiveness and tolerability, training patients to independently measure blood pressure, etc.

At the start of hypertension therapy, different tactics for prescribing antihypertensive drugs are used. It is possible to use one AGP, and in the absence of a satisfactory effect, titrate its dose or add a second AGP with a different mechanism of action. A common tactic is to replace one drug with another while maintaining the monotherapy regimen. In recent years, fixed combinations of antihypertensive drugs have been increasingly used as first-choice therapy.

Primary care doctor

Several large randomized controlled trials (SHEP, COOPE, HOT, ALLHAT, INVEST, LIFE, STOP) have demonstrated that 45-93% of patients require antihypertensive therapy with two or more to achieve target blood pressure and reduce end-organ load. drugs. According to the results of Russian studies that studied the possibilities of treating hypertension in an outpatient setting (ARGUS, QUADRIGA, FAGOT, ROSA, EPIGRAF, etc.), the initial level of systolic blood pressure in most patients ranges from 156-178 mm Hg. Art. At the same time, according to multicenter controlled studies, all antihypertensive drugs recommended for use in monotherapy reduce blood pressure approximately equally - on average, only by 11/6 mm Hg. Art. compared to placebo. The need to enhance the antihypertensive effect requires the prescription of combination therapy in most patients with hypertension.

Thus, if previously combinations of antihypertensive drugs were recommended mainly only when monotherapy was ineffective, now combination therapy can be prescribed already at the start of treatment for patients with blood pressure levels more than 160/100 mm Hg. Art. when combined with diabetes, proteinuria or chronic renal failure (VNOK Recommendations, 2008).

The main advantages of combination antihypertensive therapy are summarized in the National Guidelines for the Prevention and Treatment of Hypertension (2008). These include the possibility of adequate blood pressure control as a result of the use of drugs with different mechanisms of action and potentiation of their effects. A combination of two or even three antihypertensive drugs in full dose is recommended for the treatment of patients with stage I hypertension with low and moderate risk of cardiovascular complications when full-dose monotherapy is ineffective. Patients with hypertension

grades 11-111 and in case of high or very high risk, a combination of two drugs in a low dose should be immediately prescribed, and if there is no reduction in blood pressure to the target level, 2 drugs in a full dose or 3 in a low dose. If the target blood pressure is not achieved with this treatment, a combination of three antihypertensive agents at full dose is possible. Co-administration of antihypertensive drugs inhibits counter-regulatory mechanisms that begin to act at the start of antihypertensive therapy. Most often, when rational combinations are used, there is no need to prescribe maximum doses, which reduces the risk of NE. Combination therapy more effectively prevents target organ damage and helps reduce the incidence of cardiovascular complications.

There are two combination therapy regimens: the use of two or more antihypertensive drugs in arbitrary dosages and the use of dosage forms with fixed combinations of drugs. The first mode allows for an individual approach to the selection of doses and frequency of administration, while the second provides simple and convenient dosing, increasing patient adherence to treatment.

A special place among combined antihypertensive drugs is occupied by drugs that use lower doses than for monotherapy. Since the effect of most antihypertensive drugs is limited due to the activation of feedback mechanisms, due to the synergistic action of the components of combined antihypertensive drugs, it is possible to achieve significantly greater success in achieving the target blood pressure level. The combination of two drugs with different points of application prevents compensatory responses, which leads to a more significant decrease in blood pressure. In addition, the rationality of the combination and optimal doses of components reduce the risk of NE.

Currently, domestic and international recommendations allow

Combinations of antihypertensive drugs

the use of many fixed combinations for the initial treatment of hypertension, while primarily fixed combinations of small doses are allowed as first-line drugs. The use of low-dose combinations reduces the number of NEs, reduces the cost of therapy and thereby undoubtedly improves patient adherence to treatment. It is estimated that more than 50% of patients with mild to moderate hypertension require combination therapy. If hypertension is accompanied by diabetes or chronic renal failure, the proportion of such patients is significantly larger, since the target blood pressure level is lower.

In recent years, there has been a tendency to increase the frequency of use of combination antihypertensive therapy. According to the recent PYTHAGORUS III study, the majority of doctors (about 70%) prefer to use combination antihypertensive therapy in the form of free (69%), fixed (43%) and low-dose (29%) combinations.

The following requirements are imposed on fixed combinations of antihypertensive drugs: the presence of a complementary effect, improvement of the hypotensive effect when used together, the ability to provide organ protection, the proximity of the pharmacodynamic and pharmacokinetic parameters of the drugs included in their composition. The main rational combinations of antihypertensive drugs are currently considered to be combinations of a diuretic and an ACE inhibitor (or an angiotensin II receptor antagonist), a diuretic and a β-blocker, a diuretic and a calcium antagonist, a calcium antagonist and an ACE inhibitor (or an angiotensin II receptor antagonist), dihydropyridine calcium antagonist and P-blocker.

Combination therapy with diuretics and ACE inhibitors has noticeable advantages, since with combined

the use of these drugs often achieves a reduction in blood pressure due to complementary effects. The hypotensive effect of ACE inhibitors is primarily associated with a decrease in the production of angiotensin II, so they are especially effective in patients with increased RAAS activity. The antihypertensive effect of diuretics is limited to some extent by reactive hyperreninemia associated with activation of the RAAS, the severity of which is largely neutralized when ACE inhibitors are prescribed. At the same time, the combination of these groups of drugs is effective not only in patients with increased RAAS activity, but also in patients with normo- and even hyporenin forms of hypertension, which is associated with an increase in the activity of ACE inhibitors in the presence of diuretics. The synergy of these groups of drugs leads to an increase in sodium excretion and a decrease in volume load.

When treated with diuretics, especially in high doses, compensatory activation of the RAAS may occur, leading to a decrease in their hypotensive effect. The addition of an ACE inhibitor to treatment neutralizes this negative neurohumoral effect, increasing the likelihood of a patient’s response to treatment by up to 80% compared to diuretic monotherapy. Conversely, diuretics significantly increase the sensitivity of tissues to ACE inhibitors, which allows them to more often achieve a hypotensive effect. In addition, hypokalemia that occurs during treatment with diuretics can be corrected by ACE inhibitors, which can reduce potassium excretion. Also, ACE inhibitors reduce the adverse effects of diuretics on lipid, carbohydrate and purine metabolism. Finally, ACE inhibitors themselves are weak natriuretics, which enhances the effect of diuretics when used in combination. Thus, the combination of a thiazide or thiazide-like diuretic with

Primary care doctor

An ACE inhibitor allows you to achieve the target blood pressure level while taking lower doses of drugs due to their synergistic effect.

A fixed combination of very low doses of a thiazide-like diuretic (indapamide) and an ACE inhibitor (perindopril) is Noliprel. The pharmacokinetic profiles of perindopril and indapamide in the combination preparation do not change, which makes it possible to take it once a day. Undoubtedly, this improves patient adherence to treatment, reducing the number of medications taken and the frequency of their administration.

The high effectiveness of the fixed combination of perindopril/indapamide has been proven in a number of large experimental and clinical studies. The experiment revealed the specific effect of the combination of perindopril/indapamide on the stiffness of large arteries, as well as the nephroprotective properties of the drug: the ability to reduce proteinuria and improve glomerular function.

Among the most important tasks of adequate antihypertensive therapy, it is necessary to note the prevention of strokes. Recent studies have shown that the cerebroprotective effect differs among different groups of antihypertensive drugs. Thiazide and thiazide-like diuretics have demonstrated their effectiveness in primary (MRC and MRCII studies) and secondary (PATS study) stroke prevention. In the prospective placebo-controlled PROGRESS study, the use of combination therapy with perindopril and indapamide significantly reduced the risk of recurrent stroke.

Prevention of vascular complications in patients with type II diabetes mellitus is also a priority task of the healthcare system. ADVANCE is the first and largest study in patients with type II diabetes, which used

combination drugs Noliprel and Noliprel forte. The study included 11,140 patients with type II diabetes (both with hypertension and normal blood pressure) from 20 countries, including Russia. All patients initially received the therapy necessary for diabetes, including antihypertensive drugs.

The results of the ADVANCE study showed that Noliprel and Noliprel forte reduced overall mortality by 14% and cardiovascular mortality by 18% in patients with type II diabetes. In addition, in patients receiving Noliprel or Noliprel forte, the risk of cardiovascular complications is reduced by 14% and the risk of renal complications by 21%. Based on 1 million patients with type II diabetes already receiving drugs for cardiovascular prevention, the planned administration of Noliprel and Noliprel forte for 5 years can additionally prevent 15,000 vascular, 13,300 coronary and 50,000 renal complications and save 13,000 lives.

The results of the ADVANCE study indicate that widespread use of the fixed combination of perindopril and indapamide in patients with type 2 diabetes reduces the risk of death, as well as macro- and microvascular complications, regardless of baseline blood pressure or concomitant therapy typically used in patients with diabetes. The treatments administered in the study were well tolerated and did not require special monitoring or dose titration and are therefore suitable for widespread use in clinical practice.

Having demonstrated its effectiveness, Noliprel has become popular in many countries around the world, however, transportation conditions around the world, with a wide range of temperature and humidity fluctuations, can affect its stability and effectiveness. Therefore, in the context of the globalization of the drug market, there is a need to create a more stable drug with a longer shelf life. Was

Combinations of antihypertensive drugs

Several stable salts of perindopril were studied and a choice was made in favor of the arginine salt, which has the most acceptable combination of stability and hygroscopicity. So, after 10 years of successful use of Noliprel, new drugs appeared - Noliprel A and Noliprel A forte, which contain the arginine salt of perindopril. For all parameters studied, the arginine salt of perindopril demonstrated an advantage over the previously used tert-butylamine salt. In particular, the shelf life of the drug increased from 2 to 3 years, regardless of temperature. The higher stability of the perindopril compound in Noliprel A means that the drug can be used in different climatic zones while maintaining guaranteed effectiveness. This is of great practical importance for Russia, which has 5 climate zones.

The molecular weight of perindopril arginine is almost 25% greater than perindopril tert-butylamine, so to achieve similar plasma concentrations of perindopril arginine, a dose of perindopril arginine 5 mg was proposed instead of perindopril tert-butylamine 4 mg (and 10 mg instead of 8 mg). mg). The pharmacokinetic properties of the two perindopril salts were compared in experimental studies, where similar bioavailability was demonstrated. Their bioequivalence was then studied in an open-label, randomized, crossover pharmacokinetic study, where each group received a single oral dose of perindopril in the form of either arginine salt (10 mg) or tert-butylamine (8 mg). The results revealed complete bioequivalence of these doses of perindopril and no differences in other clinical parameters studied.

Thus, pharmacokinetic studies have shown complete bioequivalence of the new perindopril salt in comparison with the previously used one.

It is important to emphasize that the active metabolite, perindoprilat, is formed in the liver from both arginine and tert-butylamine salts. Therefore, all the beneficial effects previously demonstrated in large-scale studies with perindopril tert-butylamine also apply to perindopril arginine. Accordingly, the data from the STRATHE, REASON, OPTIMAX, PICXEL, PREMIER, ADVANCE studies, as well as the Russian STRATEGY study, which studied Noliprel, are fully applicable to Noliprel A.

In countries where the combination drug Noliprel was registered earlier, Noliprel A has the same indication for use - hypertension. Noliprel A and Noliprel A forte are recommended for use in patients with newly diagnosed or previously untreated hypertension. The new packaging of Nolipre-la A - a container with an adsorbent and a dispenser, is more convenient and practical, which can also have a positive impact on patient adherence to treatment. It should be noted that perindo-pril arginine/indapamide (Noliprel A) was included in the List of Vital and Essential Medicines by the Russian Ministry of Health and Social Development in 2009.

The introduction into clinical practice of fixed combinations of very low doses of antihypertensive drugs will ensure effective blood pressure control in a large number of patients with hypertension and at the same time minimize the risk of NE. Noliprel A meets all modern requirements for a first-choice antihypertensive and can be recommended as initial therapy for patients with hypertension of different age groups, including left ventricular myocardial hypertrophy, mild heart failure, and diabetic nephropathy. Today, Noliprel A is the first and only low-dose combination drug in Russia.

Primary care doctor

with this drug, providing a rational approach to the treatment of patients with hypertension.

Committee of Experts RMOAS/VNOK. National recommendations for the diagnosis and treatment of arterial hypertension // Cardiovascular therapy and prevention. 2008. T. 7. No. 6. App. 2. http://www.cardiosite.ru/recommendations/article.asp?id=6020 (date of access: 06/09/2010).

Kotovskaya Yu.V., Kobalava Zh.D. Combination therapy of arterial hypertension and cerebrovascular disease // Heart. 2005. T. 4. No. 3. P. 142-150.

Lopatin Yu.M. Fixed low-dose combinations of antihypertensive drugs from the position of first-choice drugs for the treatment of arterial hypertension // Heart. 2005. T. 4. No. 3. P. 151-155.

Chazova I.E., Ratova L.G. Combination therapy of arterial hypertension // Heart. T. 4. No. 3. 2005. P. 120-126.

Chazova I.E., Martynyuk T.V., Kolos I.P. First results of the Russian Strategy program in patients with arterial hypertension: assessment of the effectiveness of Noliprel in case of insufficient blood pressure control // Consilium Medicum. 2007. T 9. No. 5. P. 57-69.

Asmar R., London G.M., O'Rourke M.E., Safar M.E. Improvement in blood pressure, arterial stiffness and wave reflections with a very-low-dose perindopril/indapamide combination in hypertensive patient. A comparison with atenolol // Hypertension. 2001. V. 38. P. 922-926.

Dahlof B, Gosse Ph., Gueret P. et al. Perindopril/indapamide combination more effective than enelapril in reducing blood pressure and left ventricular mass: the PICXEL study // J. Hyper-tens. 2005. V. 23. P. 2063-2070.

European Society of Hypertension-European Society of Cardiology guidelines for the management of arterial hypertension, 2003 // J. Hyper-tens. 2003. V. 21. P. 1011-1053.

Contemporary Fixed Combinations of Antihypertensive Drugs G.E. Gendlin and E.I. Emelina

Main goal of antihypertensive therapy is reduction of blood pressure to the recommended level. Combined therapy with ACE inhibitor and diuretic has been shown to provide greater efficacy in lowering blood pressure than achieved with either agent individually. Such efficient fixed combination of diuretic and ACE inhibitor is Noliprel A, which is a first-line drug in contemporary management of arterial hypertension.

Key words: arterial hypertension, antihypertensive drugs, fixed combination, perindopril, indapamide, Noliprel A.

General Medicine

BtPlllHttlM flttlN ISHІІІ Will

Subscription to the magazine continues

“Medicine” -

periodical educational publication of the Russian State Medical University

A subscription can be issued at any post office in Russia and the CIS.

The magazine is published 4 times a year. The cost of a six-month subscription according to the Rospechat agency catalog is 60 rubles, for one issue - 30 rubles. Subscription index 20832.

Peter A. van Zwieten,
Department of Pharmacotherapy,
cardiology and cardiothoracic
Surgery, Academic Medical
Centre, Netherlands

Csaba Farsang, 1st Department
Internal Medicine, St. Imre Hospital,
Budapest, Hungary

Introduction

It has been established that in approximately half of patients with arterial hypertension, the disease can be effectively controlled by prescribing one antihypertensive drug, in combination with compliance with recommendations for the correction of unfavorable lifestyle factors. This means that the remaining 50% of patients may require the use of 2 or more antihypertensive drugs to adequately control blood pressure levels.

It has been suggested that a combination of two or more drugs may be more effective in lowering high blood pressure, and this has been demonstrated in numerous, usually small, clinical studies.

Large randomized intervention trials have specifically examined only a few antihypertensive drug combinations (specifically, a diuretic and a beta-blocker combination). In addition, at present, the use of fixed combinations in one tablet is gaining more and more recognition, since this approach significantly reduces the number of tablets that need to be taken during the day, which, accordingly, improves the patient’s adherence to treatment - the most significant factor in insufficient therapeutic effect in patients with arterial hypertension. The group of drugs with a fixed dose combination has recently been supplemented with drugs with a fixed combination of low doses.

Effective combinations of two antihypertensive drugs of different classes

To date, studies have been conducted on individual combinations of antihypertensive drugs, in which their effectiveness in reducing high blood pressure has been proven. In this chapter we will discuss a number of drug combinations that have shown their effectiveness in lowering blood pressure, in addition, having an effective effect in certain subgroups of patients. Although not all of the combinations presented were studied in large interventional studies conducted in accordance with the principles of evidence-based medicine, we selected these combinations based on the characteristics of the drugs to affect hemodynamic and other parameters. The effectiveness of such combinations is in most cases confirmed by research results.

Thiazide diuretics + β-blockers: the widespread use of this combination for a long time was facilitated by recommendations for its primary use in patients with uncomplicated hypertension who do not have target organ damage. This combination has been studied in several large-scale intervention studies (such as STOP; MRS, ALLHAT) and its effectiveness can now be considered convincingly proven.

Thiazide diuretics + ACE inhibitors: have an effect in patients with hypertension and congestive chronic heart failure (CHF), isolated systolic hypertension (ISH), as well as in elderly patients with arterial hypertension (usually having ISH). This combination in some cases can have a fairly strong antihypertensive effect, and therefore the addition of an ACE inhibitor to a diuretic (or vice versa) should be carried out with caution in order to prevent a too rapid decrease in blood pressure. In addition, both classes of drugs - ACE inhibitors and diuretics - are standard treatments for CHF.

: It has been proven that in the treatment of arterial hypertension in combination with left ventricular hypertrophy, this combination is more effective than the β-blocker + diuretic combination. This combination can be successfully used in patients with ISH, and also has a beneficial effect in patients with arterial hypertension in combination with CHF.

: This combination has not been studied in large intervention studies, but should be considered if the addition of a beta-blocker to diuretic therapy is not possible due to contraindications.

Diuretics + calcium antagonists (dihydropyridines): Dihydropyridine calcium antagonists are strong vasodilators and can be used in combination with diuretics in patients with ISH, most of whom are elderly. Convincing evidence has been obtained that both diuretics and dihydropyridine calcium antagonists are effective in lowering blood pressure in patients with ISH, and also have a protective effect against the development of complications of hypertension.

α-blockers + β-blockers: This combination can be used for malignant hypertension, but the effectiveness of its use has not been sufficiently studied. Malignant hypertension is believed to be caused by sympathetic hyperactivity and its consequences. In this regard, the sympatholytic effect characteristic of both drugs in this combination is a logical rationale for the use of this combination in patients with ISH. In addition, in the case of sympathetic hyperactivity, the use of centrally acting antihypertensive drugs (imidazoline I1 receptor agonists) as well as non-dihydropyridine calcium antagonists may be discussed.

β-blockers + ACE inhibitors: despite the fact that the antihypertensive effect of this combination is less pronounced than the diuretic + β-blocker combination, it can be used in patients with arterial hypertension who have suffered a myocardial infarction (MI), in the presence of coronary heart disease (CHD) and/or CHF.

Calcium antagonists (dihydropyridine series) + β-blockers: this combination can be prescribed in patients with arterial hypertension in the presence of coronary artery disease. These two classes of drugs, in addition to being effective antihypertensive agents, exhibit a pronounced beneficial effect in patients with coronary artery disease. Prescribing a fixed combination of these drugs can improve patient adherence to treatment.

: This combination may be recommended for the treatment of patients with arterial hypertension in the presence of nephropathy, coronary artery disease or documented atherosclerosis. This combination has a pronounced antihypertensive effect. As is known, calcium antagonists have an anti-ischemic effect in ischemic heart disease. ACE inhibitors have proven renoprotective properties, which may be especially useful in patients with diabetic nephropathy.

Calcium antagonists also have antiatherogenic properties, as demonstrated for lacidipine in the ELSA trial, amlodipine in the PREVENT trial, and nifedipine-GITS (long-acting) in the INSIGHT trial. Similar effects were found with ACE inhibitors (SECURE study).

Calcium antagonists (dihydropyridines) + AT1 receptor blockers: The expected beneficial effects of this combination are generally the same as for the combination of calcium antagonists + ACE inhibitors. The renoprotective effect of drugs in diabetic nephropathy (type 2 diabetes) has been convincingly established. Dihydropyridine calcium antagonists and the AT1 receptor blocker losartan have been shown to have a uricosuric effect, which may be especially useful in patients with gout.

: the use of this combination can be discussed if a patient with arterial hypertension has diabetic nephropathy or glomerulonephritis, since the combination of drugs of these two classes has been shown to reduce proteinuria to a greater extent than with monotherapy. Thus, this combination can have a renoprotective effect.

ACE inhibitors + imidazoline receptor agonists: Theoretically, this combination is indicated if it is necessary to simultaneously suppress the activity of both the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system (SNS). Another therapeutic target for drugs that suppress SNS activity (such as moxonidine) is metabolic syndrome, the development of which is thought to be related to some extent to SNS hyperactivity.

Three-drug combinations

Several preliminary notes should be made regarding triple combinations of various antihypertensive drugs.

The drugs in these combinations are combined together only on a theoretical basis, in fact, in the absence of the necessary clinical evidence. The arguments for using the first pair of drugs in a drug combination are the same as for the combinations of 2 drugs of different classes discussed above. Let's look at potentially significant triple drug combinations:

: A very powerful combination that can be used in the treatment of malignant hypertension.

: A potentially beneficial combination in the treatment of patients with hypertension and diabetes mellitus who have ISH or malignant hypertension.

AT1 receptor antagonists + calcium antagonists + diuretics: This triple combination may help achieve target BP levels (<130 и 85 мм рт. ст.) у больных с артериальной гипертонией, имеющих сахарный диабет 2 типа или у больных с ИСГ.

ACE inhibitors + α1-adrenergic receptor antagonists + imidazoline receptor agonists: a potentially beneficial combination in the treatment of patients with arterial hypertension and diabetes mellitus, as well as patients with metabolic syndrome, especially in the presence of contraindications or poor tolerance to beta-blockers.

: a potentially beneficial combination in the treatment of patients with arterial hypertension and coronary heart disease.

Drugs	Potential Applications
β-blockers + diuretics	Uncomplicated arterial hypertension without target organ damage
Diuretics + ACE inhibitors	Arterial hypertension + congestive chronic heart failure (CHF)
Diuretics + AT1 receptor blockers	Isolated systolic hypertension (ISH) + CHF. Possibly with ISH.
Diuretics + imidazoline I1 receptor agonists	If it is not possible to add a β-blocker to a diuretic (due to contraindications)
Diuretics + calcium antagonists (dihydropyridine series)	ISH (usually in elderly patients)
α-blockers + β-blockers	Malignant hypertension
β-blockers + ACE inhibitors	Patients with arterial hypertension who have had a myocardial infarction (secondary prevention), with CHF and/or coronary artery disease
Calcium antagonists + β-blockers
Calcium antagonists + ACE inhibitors	Arterial hypertension + nephropathy, ischemic heart disease or atherosclerosis
Calcium antagonists + AT1 receptor blockers	Arterial hypertension + nephropathy, ischemic heart disease or atherosclerosis (?)
ACE inhibitors + AT1 receptor blockers	Arterial hypertension + nephropathy
ACE inhibitors + imidazoline I1 receptor agonists	Patients with hyperactivity of the RAAS and SNS
Diuretics + β-blockers + calcium antagonists	Malignant arterial hypertension
Diuretics + calcium antagonists + ACE inhibitors	Malignant ISH, arterial hypertension + diabetes mellitus
Diuretics + calcium antagonists + AT1 receptor blockers	Same
ACE inhibitors + α1-blockers + imidazoline I1 receptor agonists	Arterial hypertension + diabetes mellitus. Metabolic syndrome
ACE inhibitors + calcium antagonists + β-blockers	Arterial hypertension + ischemic heart disease

Conclusion

Combination therapy is increasingly recognized as the primary approach in the treatment of patients with hypertension, as a significant proportion of patients have the disease more effectively controlled with two or, in some cases, three antihypertensive drugs.

Preparations with a fixed combination of 2 drugs can simplify the medication regimen and, thus, improve the patient’s adherence to treatment. The choice of drug combination is mainly based on the hemodynamic and metabolic properties of the individual drugs and their combination, with formal evidence of effectiveness not yet available for most possible combinations.

Bibliography

1. Van Zwieten P.A., Farsang C. Interactions between antihypertensive agents and other drugs. ESH Newsletter 2003; 4:No. 17.
2. Guidelines Subcommittee. 1999 World Health Organization International Society of Hypertension Guidelines for the management of hypertension J Hypertens 1999; 17, 151 - 83.
3. The sixth report of the Joint National Committee on prevention, detection, evaluation and treatment of high blood pressure. Arch Intern Med 1997; 157, 2413-6.
4. Dahlof B, Lindholm LH et al. Morbidity and mortality in the Swedish Trial in old patients with hypertension (STOP-Hypertension). Lancet 1991; 338, 1281 - 5.
5. Medical Research Council Working Party. MRC Trial of treatment of mild hyperten-sion. BMJ 1985:291.47-104.
6. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. JAMA 1991; 265, 3255 - 64
7. Staessen J.A., Fagard R. et al. Randomized double blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet 1997; 350, 757 - 64.
8. Menezes F.L., Van Zwieten P.A. Current diagnosis and treatment in heart fail-ure. Publ Lidel, Lisbon 2001, pp. 207 - 22.
9. Burnier M, Brunner HR. Angiotensin II-receptor antagonists. Lancet 200; 355, 637 - 45.
10. Dahlof B., Devereux R.B., Kjeldsen S.E. et al. for the Losartan Intervention for Endpoint reduction (LIFE) study group. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomized trial against atenolol. Lancet 2002; 359:995 - 1003.
11. Kjeldsen S.E., Dahlof B., Devereux R.B. et al. for the Losartan Intervention for Endpoint reduction (LIFE) study group. Benefits of losartan on cardiovascular morbidity and mortality in patients with isolated systolic hypertension and left ventricular hypertrophy: a LIFE substudy. JAMA 2002; 288: 1491 - 8.
12. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic. The Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT). JAMA 2002; 288; 2988 - 97.
13. Pitt B. et al. Effect of amlodipine on the progression of atherosclerosis and the occurrence of clinical events. Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT). Circulation 2000; 102: 1503 - 10.
14. Brown M.J., Palmer C. et al. Morbidity and mortality in patients randomized to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a goal in hypertension treatment (INSIGHT). Lancet 2000; 356: 366 - 72
15. Lohn E.M., Yusuf S. et al. for the SECUREInvestigators. Effects of ramipril and vitamin E on athersclerosis. The Study to Evaluate Carotid Ultrasound changes in patients treated with Ramipril and vitamin E (SECURE). Circulation 2001; 103: 919 - 25.
16. Farsang C., Kaweczka-Jaszcz K. et al. for the Multicentre Study Group. Antihypertensive effects and tolerability of candesartan cilexetil alone and in combination with amlodipine. Clin Drug Invest 2001; 21: 17 - 23.
17. Dahlof B., Hosie J. on behalf of the Swedish/UK study group. Antihypertensive efficacy and tolerability of a new once-daily felodipine-metoprolol combination compared with each component alone. Blood

Combination blood pressure medications are a combination of two or more substances in one drug that is used to treat hypertension. Combination medications for hypertension are used in low doses when monotherapy is ineffective.

Hypertension

Attention! It is strictly prohibited to purchase, use and store combination drugs without prescription. Before using substances, you should consult your doctor.

Fixed drug combinations

Recently, a retrospective cohort study was conducted that included more than 7000 patients with hypertension. A higher incidence of side effects was found in the group of patients receiving a fixed combination of antihypertensive drugs.

The greatest risk of premature discontinuation of treatment was observed in patients without previous therapy. Not all patients adhere to the prescribed treatment, since side effects reduce the quality of life. Efforts should be made to promote adherence to hypertension treatment. First of all, this applies to patients who have not yet been treated. If you plan to start treatment with a combination of antihypertensive drugs, it is recommended to advise the patient about possible side effects.

The pharmaceutical market offers a number of fixed combinations containing two antihypertensive drugs with different mechanisms of action, most of them containing a diuretic. Typically these medications are taken once a day. Patients are prescribed either two minimum-dose tablets or one extended-release tablet. A fixed triple combination of antihypertensive drugs is also being tested around the world.

Important! It is strictly forbidden to take medications without first consulting a doctor. Improper use of medications can significantly harm the patient. If there is a sharp drop in blood pressure due to taking the drug off-label, you need to call an ambulance and take activated charcoal.

Beta blockers and diuretics

This combination of antihypertensive drugs for the treatment of hypertension has been used in clinical practice for more than three decades, but its importance has declined today. The effectiveness of combining diuretics and beta blockers is lower than treatment based on calcium channel blockers or blockers of the renin-angiotensin-aldosterone system (RAAS).

Treatment with a beta-blocker in combination with a diuretic is accompanied by a higher incidence of unwanted side effects.

Adrenergic receptor blocker

Combination of diuretics

Pharmacies sell combinations of thiazide diuretics with potassium-sparing diuretics to compensate for potassium loss. It is worth noting that combining these medications is not recommended. Combinations of diuretics with other classes of drugs are preferable.

RAAS blockers and diuretics

The mechanisms of action of these two groups of drugs are complemented accordingly. RAAS antagonists compensate for the increased plasma renin activity caused by diuretics. Salt release caused by diuretics contributes to the antihypertensive effect of RAAS blockers.

RAAS antagonists suppress the negative effects of diuretics - they compensate for electrolyte imbalance (especially hypokalemia) and metabolic risks (hyperglycemia). ACE inhibitors and sartans are available in fixed combination with diuretics. Hydrochlorothiazide is most often used as a diuretic.

RAAS

The use of a combination of perindopril with indapamide was shown to have a positive effect on diabetics (patients with diabetes mellitus) in the large randomized ADVANCE trial. In this study, the incidence of the primary endpoint (severe macrovascular and microvascular events) decreased by 9% (p = 0.041). Mortality from vascular accidents decreased by 18%.

The combination of sartans with diuretics is also based on evidence-based medicine. A number of studies have been conducted with irbesartan, which is not currently available in some countries.

The addition of a diuretic also proved useful in the study of patients who did not respond to sartan monotherapy (trade names: Losartan, Candesartan). Patients were randomized to receive telmisartan (40 mg daily) and hydrochlorothiazide (12.5 mg daily) or monotherapy. After 12 weeks, there was a significant reduction in blood pressure in patients receiving combination treatment.

Hydrochlorothiazide

Potassium channel blockers and RAAS

Recently, the combination of RAAS blockers with calcium antagonists has been shown to be particularly beneficial. This is mainly due to the cardioprotective and renoprotective effects, which were found to be higher than those of other antihypertensive dual combinations.

RAAS antagonists block sympathetic and RAAS activation initiated by CCBs. The negative sodium balance caused by CCBs contributes to the antihypertensive effect of RAAS blockers. They also reduce the risk of peripheral edema, which is typical for dose-dependent CCBs. Pharmacies sell combinations of CCBs with ACE inhibitors,

The benefits of ACE inhibitors with dihydropyridine-type calcium channel blockers have been shown in small studies. A large international randomized trial found that the most effective combination was perindopril and amlodipine. The relative risk of developing diabetes with this combination is reduced by almost a third.

Another important randomized trial, ACCOMP, demonstrated the superiority of combination therapy in patients with terminal arterial hypertension. The study was stopped early after three years because the combination with amlodipine was statistically significantly more effective in preventing heart attacks. This treatment significantly slowed the progression of nephropathy. In Russia, fixed combinations of ACE inhibitors with felodipine and amlodipine are available.

Most of the data showing the benefits of ACEIs with non-dihydropyridine-type calcium channel blockers are available for combination with verapamil. A recent meta-analysis of 12 studies showed superiority of the combination of trandolapril and verapamil compared with monotherapy. A higher antihypertensive effect of the combination and a decrease in albuminuria were found. The frequency of adverse reactions was the same as with verapamil monotherapy.

Verapamil

These data make the combination of an ACEI with a CCB a preferable alternative, especially in patients with atherosclerosis, metabolic disorders (diabetes, prediabetes, metabolic syndrome) or organ damage (nephropathy).

Other drugs

For patients with hypertension, the most important treatment goal is to reduce the overall risk of cardiovascular disease. According to the Framingham study, 78% of men and 82% of women with hypertension have other CVD risk factors. Approximately half of patients with hypertension suffer from hypercholesterolemia. In Russia, the presence of these two risk factors – hypertension and hypercholesterolemia – was found in 18% of adults over 20 years of age. Approximately 40% of diabetics were diagnosed with hypertension and hypercholesterolemia, and more than half of the respondents were people over 80 years of age.

Such epidemiological data have prompted drug manufacturers to develop fixed combinations of substances from different pharmacotherapeutic groups to influence two different risk factors with one tablet. The first such drug is a combination of a calcium channel blocker with a statin (amlodipine/atorvastatin). The drug is sold in the Russian Federation.

Atorvastatin and amlodipine

Three-component medicine

Triplixam is a three-component drug that contains three antihypertensive drugs: perindopril, amlodipine and indapamide. The combination is indicated for severe forms of hypertension when a diuretic must be added to the combination to achieve a target blood pressure reduction (below 140/90) in the ambulance.

The effectiveness of the drug has been proven by a recent meta-analysis. Triplixam provides highly effective control of hypertension and leads to a significant reduction in overall mortality (by 28% compared with monotherapy).

"Triplixam"

The medication is suitable for the treatment of severe hypertension. Almost all patients who participated in the studies achieved a significant reduction in blood pressure when using the three-component drug.

The drug has a documented 24-hour antihypertensive effect and clear evidence that it is effective in treating hypertension and preventing heart disease. The recommended dose is 1 tablet daily, which significantly increases the convenience of treatment.

The product is available in four basic dose combinations of individual components. This greatly facilitates the selection of the appropriate dose and the possibility of individually increasing the dosage in accordance with the patient’s blood pressure values.

Benefits of combined substances

Fixed combinations make it possible to reduce the number of tablets, which leads to a simplified dosage regimen and a reduction in the frequency of treatment discontinuation. Patients usually accept a reduction in the number of tablets with gratitude.

A meta-analysis of clinical trials involving nearly 11,000 hypertensive patients found that combining two different antihypertensive agents was more effective in lowering systolic blood pressure (SBP) than simply doubling the dose of one blood pressure drug in older adults. Patients are more likely to adhere to treatment with low-cost combination drugs than monotherapy.

Similar results were recently published in a meta-analysis of 17,999 patients with hypertension. The use of antihypertensive drug combinations was associated with better treatment adherence. Patients receiving the combination were compared with patients receiving single-component drugs. A trend towards a significant decrease in blood pressure (about 4.1/3.1 mmHg) and a decrease in the incidence of side effects was observed in the group that took antihypertensive combination drugs.

Table and classification of drugs of various groups

When treating new generation combination medications for high blood pressure, it is of course important not to neglect financial costs.

Perhaps most significant is the positive effect of the combinations on CVD risk, as is clear from the findings of a recent study. In this study, overall cardiovascular risk was reduced in 209,000 hypertensive patients aged 40–79 years. They suffered half as much from coronary and cerebrovascular disorders.

However, there are no data on fixed triple combinations of antihypertensive drugs to improve hypertension control, reduce the incidence of adverse reactions, the cost of treatment and the incidence of CVD.

Disadvantages of this form of drug treatment and possible consequences

A significant disadvantage of combination treatment is considered to be the impossibility of increasing the dosage of each individual substance. Therefore, some doctors prefer to first administer monocomponent drugs to treat severe hypertension, and then (if monotherapy is ineffective) switch to fixed combinations.

Difficulties in increasing the dose become more acute if health conditions deteriorate, such as symptomatic heart failure. To increase dosage, formulations must be developed that contain the individual active ingredients on opposite sides of the tablet, including a drug-free zone that allows separation of the products.

The duration of action of individual components may vary, causing problems with a product typically taken once daily. The use of drugs with a short half-life of the drug can cause a sharp increase in blood pressure.

If the combination drug causes circulatory collapse, you should stop taking it. In some cases, the doctor may switch from combination treatment to monotherapy. The list of medicines is extensive.

For mild hypertension, it is recommended to start with monotherapy. If this type of treatment is ineffective, it is recommended to switch to multicomponent treatment. Your attending physician will help you create a list of medications. Additional information can be found in the Register of Medicines (RMR).

Advice! It is recommended to entrust the combination of medications to a doctor. Some combinations have an excessive hypotensive effect. Before long-term use of any medications, it is recommended to consult a doctor. Careless use of medications can lead to severely low blood pressure.