Indapamide/Perindopril-Teva, 1.25 mg+5 mg, film-coated tablets, 30 pcs.: instructions for use, reviews and analogues, prices in pharmacies. Buy and deliver to the nearest pharmacy or home in

Indapamide/Perindopril-Teva, 1.25 mg+5 mg, film-coated tablets, 30 pcs.

Undesirable combination of drugs.

Lithium preparations.

With the simultaneous use of lithium preparations and ACE inhibitors, a reversible increase in the content of lithium in the blood plasma and associated toxic effects may occur. Additional use of thiazide diuretics may further increase lithium levels and increase the risk of toxicity. The simultaneous use of a combination of perindopril and indapamide with lithium preparations is not recommended. In the case of such therapy, regular monitoring of the lithium content in the blood plasma is necessary.

A combination of drugs that requires special attention.

Baclofen.

When used simultaneously with baclofen, the antihypertensive effect may be enhanced. Blood pressure and renal function should be monitored and, if necessary, dose adjustment of antihypertensive drugs is required.

Combination of drugs requiring attention.

Tricyclic antidepressants, antipsychotic drugs (neuroleptics).

Drugs in these classes enhance the antihypertensive effect and increase the risk of orthostatic hypotension (additive effect).

Glucocorticosteroids (GCS), tetracosactide.

It is possible to reduce the antihypertensive effect (retention of fluid and sodium ions as a result of the action of corticosteroids).

Other antihypertensive drugs.

The antihypertensive effect may be enhanced.

Perindopril.

Simultaneous use is contraindicated.

Aliskiren.

Patients with diabetes mellitus or impaired renal function (GFR less than 60 ml/min) are at increased risk of hyperkalemia, deterioration of renal function, and increased incidence of cardiovascular morbidity and mortality.

Undesirable combination of drugs.

Aliskiren.

In patients without diabetes mellitus or renal impairment, there may be an increased risk of hyperkalemia, worsening renal function, and increased incidence of cardiovascular morbidity and mortality.

Potassium-sparing diuretics (amiloride, spironolactone, eplerenone, triamterene, both in monotherapy and as part of combination therapy) and potassium supplements.

ACE inhibitors reduce diuretic-induced potassium loss. Potassium-sparing diuretics (eg, spironolactone, eplerenone, triamterene, or amiloride) or potassium-containing salt substitutes may cause significant increases in plasma potassium levels, including death. If simultaneous use of an ACE inhibitor and the above drugs is necessary (in case of confirmed hypokalemia), caution should be exercised and regular monitoring of potassium levels in the blood plasma and ECG parameters should be carried out.

A combination of drugs that requires special attention.

Oral hypoglycemic drugs (sulfonylureas) and insulin.

The following effects have been reported for captopril and enalapril. ACE inhibitors may enhance the hypoglycemic effect of insulin and sulfonylureas in patients with diabetes mellitus. The development of hypoglycemia is very rare (due to an increase in glucose tolerance and a decrease in the need for insulin).

Nonsteroidal anti-inflammatory drugs (NSAIDs), including high doses of acetylsalicylic acid (more than 3 g/day).

The simultaneous use of ACE inhibitors and NSAIDs (acetylsalicylic acid in a dose that has an anti-inflammatory effect, cyclooxygenase-2 inhibitors and non-selective NSAIDs) may lead to a decrease in the antihypertensive effect. Concomitant use of ACE inhibitors and NSAIDs may lead to deterioration of renal function, including the development of acute renal failure and an increase in serum potassium, especially in patients with reduced renal function. Caution should be exercised when using this combination, especially in elderly patients. Patients need to compensate for fluid loss and regularly monitor kidney function, both at the beginning of treatment and throughout the treatment process.

Allopurinol, cytostatic and immunosuppressive drugs, GCS (for systemic use) and procainamide.

Concomitant use with ACE inhibitors may be accompanied by an increased risk of leukopenia.

Preparations for general anesthesia.

The simultaneous use of ACE inhibitors and general anesthesia may lead to an increase in the antihypertensive effect.

Diuretics (thiazide and loop).

The use of diuretics in high doses can lead to hypovolemia, and the addition of perindopril to therapy can lead to arterial hypotension.

Gold preparations.

When using ACE inhibitors, including perindopril, in patients receiving intravenous gold (sodium aurothiomalate), reactions similar to those that occur when using nitrates (redness of the skin, nausea, vomiting, arterial hypotension) may rarely develop.

Double blockade of the RAAS.

The literature has reported that in patients with established atherosclerotic disease, heart failure, or diabetes mellitus with end-organ damage, concomitant therapy with an ACE inhibitor and an ARB II is associated with a higher incidence of hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure). ) compared to the use of only one drug that affects the RAAS. Dual blockade (for example, when combining an ACE inhibitor with an ARB II) should be limited to selected cases with careful monitoring of renal function, potassium levels and blood pressure.

Ectramustine.

Concomitant use may result in an increased risk of adverse effects such as angioedema.

Gliptins (lipagliptin, saxagliptin, sitagliptin, vitagliptin).

Concomitant use with ACE inhibitors may increase the risk of angioedema due to inhibition of dipeptidyl peptidase IV (DPP-IV) activity by gliptin.

Sympathomimetics.

Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors. When using such a combination, the effectiveness of ACE inhibitors should be regularly assessed.

Indapamide.

A combination of drugs that requires special attention.

Drugs that can cause aritis.

Due to the fact that there is a risk of developing hypokalemia, caution should be exercised when using indapamide simultaneously with drugs that can cause arrhythmias, for example, class IA antiarrhythmic drugs (quinidine, hydroquinidine, disopyramide), class III antiarrhythmic drugs (amiodarone, dofetilide, ibutilide, bretylium tosylate), sotalol, some antipsychotics (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine), benzamides (amisulpride, sulpiride, sultopride, tiapride), butyrophenones (droperidol, haloperidol), other antipsychotics (pimozide), other drugs such as bepridil , cisapride, difemanil methyl sulfate, erythromycin IV, halofantrine, mizolastine, moxifloxacin, pentamidine, sparfloxacin, vincamine IV, methadone, astemizole, terfenadine. Plasma potassium levels should be monitored and, if necessary, adjusted, and the QT interval monitored .

Medicines that can cause hypokalemia.

Amphotericin B (iv), gluco- and mineralocorticosteroids (for systemic use), tetracosactide. laxatives that stimulate gastrointestinal motility increase the risk of hypokalemia (additive effect). It is necessary to monitor the potassium content in the blood plasma and, if necessary, correct it. Particular attention should be paid to patients concomitantly receiving cardiac glycosides. Laxatives that do not stimulate gastrointestinal motility should be used.

Cardiac glycosides.

Hypokalemia enhances the toxic effect of cardiac glycosides. With the simultaneous use of indapamide and cardiac glycosides, the potassium content in the blood plasma and ECG readings should be monitored and therapy should be adjusted if necessary.

Combination of drugs requiring attention.

Metformin.

Functional renal failure, which can occur while taking diuretics, especially loop diuretics, when used simultaneously with metformin, increases the risk of developing lactic acidosis. Metformin should not be used if the plasma creatinine concentration exceeds 15 mg/l (135 µmol/l) in men and 12 mg/l (110 µmol/l) in women.

Iodine-containing radiopaque agents.

Dehydration while taking diuretics increases the risk of developing acute renal failure, especially when using high doses of iodinated contrast agents. Before using iodinated contrast agents, patients need to compensate for fluid loss.

Calcium salts.

With simultaneous use, hypercalcemia may develop due to decreased calcium excretion by the kidneys.

Cyclosporine.

It is possible to increase the concentration of creatinine in the blood plasma without changing the concentration of cyclosporine, even with normal fluid and sodium levels.

PERINDOPRIL PLUS INDAPAMIDE

special instructions

Perindopril PLUS Indapamide
The simultaneous use of Perindopril PLUS Indapamide with lithium preparations is not recommended.

Therapy with Perindopril PLUS Indapamide is contraindicated in patients with severe renal failure (creatinine clearance less than 30 ml/min). In some patients with arterial hypertension without previous renal impairment, symptoms of acute renal failure may occur during therapy with Perindopril PLUS Indapamide. In this case, treatment with Perindopril PLUS Indapamide should be discontinued. In the future, you can resume combination therapy using low doses of Perindopril PLUS Indapamide, or use perindopril and indapamide in monotherapy. Such patients require regular monitoring of potassium levels and creatinine concentrations in the blood serum every 2 weeks after the start of therapy and every subsequent 2 months of therapy with Perindopril PLUS Indapamide.

Acute renal failure often develops in patients with severe chronic heart failure or underlying renal impairment, incl. with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney. Taking the drug Perindopril PLUS Indapamide is not recommended for patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney.

Hyponatremia is associated with a risk of a sudden decrease in blood pressure (especially in patients with bilateral renal artery stenosis or arterial stenosis of a single functioning kidney). Therefore, during dynamic monitoring of patients, attention should be paid to possible symptoms of dehydration and a decrease in plasma electrolytes, for example, after prolonged diarrhea or vomiting. Such patients require regular monitoring of plasma electrolytes.

With a pronounced decrease in blood pressure, intravenous administration of 0.9% sodium chloride solution may be required.

Transient arterial hypotension is not a contraindication for further continuation of therapy. After restoration of blood volume and blood pressure, you can resume therapy with Perindopril PLUS Indapamide, using low doses of the drug, or using perindopril and indapamide in monotherapy.

The combined use of perindopril and indapamide does not prevent the development of hypokalemia, especially in patients with diabetes mellitus or renal failure. As in the case of the combined use of antihypertensive drugs and a diuretic, regular monitoring of potassium levels in the blood plasma is necessary.

Perindopril

In patients taking ACE inhibitors, cases of neutropenia/agranulocytosis, thrombocytopenia and anemia may develop. In patients with normal renal function in the absence of other complications, neutropenia rarely develops and resolves spontaneously after discontinuation of ACE inhibitors.

Perindopril should be used with extreme caution in patients with connective tissue diseases and concomitantly receiving immunosuppressive therapy, allopurinol or procainamide, especially with existing renal impairment. Such patients may develop a severe infection that does not respond to intensive antibiotic therapy. If perindopril is prescribed, it is recommended to periodically monitor the number of leukocytes in the blood. The patient should be warned that if any signs of an infectious disease appear (sore throat, fever), consult a doctor immediately.

When taking ACE inhibitors, incl. perindopril, in rare cases, the development of angioedema of the face, lips, tongue, uvula, and/or larynx may occur. If these symptoms appear, the drug should be stopped immediately. The patient's condition should be monitored until signs of edema completely disappear.

If angioedema affects only the face and lips, its symptoms usually resolve on their own, or antihistamines can be used to treat symptoms. Angioedema, accompanied by swelling of the tongue or larynx, can lead to airway obstruction and death.

If symptoms of angioedema appear, you should immediately administer subcutaneous epinephrine (adrenaline) at a dilution of 1:1000 (0.3 or 0.5 ml) and/or ensure airway patency.

Patients with a history of angioedema not associated with taking ACE inhibitors may have an increased risk of developing it when taking drugs of this group. In patients of the Negroid race, angioedema develops more often than in patients of other races.

In rare cases, angioedema of the intestine develops during therapy with ACE inhibitors. In this case, patients experience abdominal pain as an isolated symptom or in combination with nausea and vomiting, in some cases without previous angioedema of the face and with normal C-1-esterase levels. The diagnosis is made using computed tomography of the abdominal cavity, ultrasound, or at the time of surgery. Symptoms disappear after stopping ACE inhibitors. In patients with abdominal pain receiving ACE inhibitors, the possibility of developing angioedema of the intestine must be taken into account when making a differential diagnosis. There are isolated reports of the development of prolonged, life-threatening anaphylactoid reactions in patients receiving ACE inhibitors during desensitizing therapy with hymenoptera venom (bees, wasps). ACE inhibitors should be used with caution in patients prone to allergic reactions undergoing desensitization procedures. Prescription of an ACE inhibitor should be avoided in patients receiving immunotherapy with hymenoptera venom. However, the development of anaphylactoid reactions can be avoided by temporarily discontinuing the ACE inhibitor at least 24 hours before the start of the desensitization procedure.

In rare cases, life-threatening anaphylactoid reactions may occur in patients receiving ACE inhibitors during LDL apheresis using dextran sulfate. To prevent an anaphylactoid reaction, ACE inhibitor therapy should be discontinued before each LDL apheresis procedure using high-flux membranes.

Anaphylactoid reactions have been reported in patients receiving ACE inhibitors during hemodialysis using high-flux membranes (eg, AN69®). Therefore, it is advisable to use a different type of membrane or use an antihypertensive drug of a different pharmacotherapeutic group.

During therapy with an ACE inhibitor, a dry cough may occur, which disappears after discontinuation of drugs in this group. If a dry cough appears, you should be aware of the possible connection of this symptom with taking an ACE inhibitor. If the doctor believes that ACE inhibitor therapy is necessary for the patient, Perindopril PLUS Indapamide can be continued.

In liver cirrhosis, accompanied by edema and ascites, arterial hypotension, chronic heart failure, significant activation of the renin-angiotensin-aldosterone system (RAAS) is possible, especially with severe hypovolemia and a decrease in the content of electrolytes in the blood plasma (against the background of a salt-free diet or long-term use of diuretics).

The use of an ACE inhibitor causes blockade of the RAAS, and therefore a sharp decrease in blood pressure and/or an increase in serum creatinine is possible, indicating the development of acute renal failure, which is more often observed when taking the first dose of Perindopril PLUS Indapamide or during the first 2 weeks of therapy.

When prescribing Perindopril PLUS Indapamide to patients with diabetes mellitus receiving oral hypoglycemic agents or insulin, blood glucose concentrations should be regularly monitored during the first month of therapy.

Perindopril (like other ACE inhibitors) has a less pronounced antihypertensive effect in patients of the Negroid race compared to representatives of other races.

The use of ACE inhibitors in patients undergoing surgery under general anesthesia can lead to a significant decrease in blood pressure, especially when using general anesthetic agents that have an antihypertensive effect.

It is recommended to stop taking ACE inhibitors, incl. perindopril, 12 hours before surgery, warning the anesthesiologist about the use of ACE inhibitors.

ACE inhibitors should be used with caution in patients with left ventricular outflow tract obstruction and with aortic and/or mitral stenosis and HOCM (hypertrophic obstructive cardiomyopathy).

In rare cases, while taking ACE inhibitors, cholestatic jaundice occurs, with the progression of which fulminant liver necrosis develops, sometimes with a fatal outcome. If jaundice or a significant increase in the activity of liver transaminases occurs while taking ACE inhibitors, Perindopril PLUS Indapamide should be discontinued.

In patients after kidney transplantation or in patients on hemodialysis, anemia may develop.

During treatment with ACE inhibitors, incl. and perindopril may develop hyperkalemia. Risk factors for hyperkalemia are renal failure, old age, diabetes mellitus, some concomitant conditions (decrease in blood volume, acute heart failure in the stage of decompensation, metabolic acidosis), simultaneous use of potassium-sparing diuretics (such as spironolactone, eplerenone, triamterene, amiloride), as well as drugs potassium or potassium-containing substitutes for table salt and the use of other drugs that increase the content of potassium in the blood plasma (for example, heparin). Hyperkalemia can cause serious heart rhythm problems, sometimes fatal. The combined use of the drugs listed above is not recommended; if their use is necessary, therapy should be carried out with extreme caution.

Indapamide

There are reports of cases of increased photosensitivity while taking thiazide and thiazide-like diuretics. If a photosensitivity reaction develops while taking Perindopril PLUS Indapamide, treatment should be discontinued. If it is necessary to resume the use of Perindopril PLUS Indapamide, you should protect exposed skin from direct exposure to sunlight and artificial ultraviolet rays.

Before starting treatment with Perindopril PLUS Indapamide, it is necessary to determine the sodium content in the blood plasma and, while taking the drug, regularly monitor electrolytes in the blood plasma (especially in elderly patients). All diuretics can cause hyponatremia, leading to serious complications.

Therapy with thiazide and thiazide-like diuretics is associated with a risk of developing hypokalemia (less than 3.4 mmol/l) in elderly patients, malnourished patients, patients with liver cirrhosis, patients with peripheral edema, ascites, coronary artery disease, and chronic heart failure. Hypokalemia in these patients increases the toxic effect of cardiac glycosides and increases the risk of developing arrhythmia. The high-risk group includes patients with an increased QT interval on the ECG. Hypokalemia, like bradycardia, contributes to the development of severe cardiac arrhythmias, especially ventricular arrhythmias, which can be fatal. In all the described cases, regular monitoring of potassium levels in the blood plasma is necessary. The first determination of potassium in the blood plasma should be carried out within the first week of starting therapy with Perindopril PLUS Indapamide.

Thiazide and thiazide-like diuretics reduce the excretion of calcium by the kidneys, leading to a slight and temporary increase in calcium levels in the blood plasma. Severe hypercalcemia may be a consequence of latent hyperparathyroidism. Before studying the function of the parathyroid glands, you should stop taking the drug Perindopril PLUS Indapamide.

Glucose concentrations should be monitored in patients with diabetes mellitus.

In patients with increased concentrations of uric acid in the blood plasma during therapy with Perindopril PLUS Indapamide, the frequency of exacerbations of gout may increase.

Hypovolemia as a result of a decrease in blood volume or hyponatremia caused by taking diuretics at the beginning of treatment with Perindopril PLUS Indapamide can lead to a decrease in glomerular filtration rate and be accompanied by an increase in creatinine and urea in the blood plasma.

Indapamide may give a false-positive reaction during doping control.

Use in pediatrics

The drug Perindopril PLUS Indapamide is contraindicated in children and adolescents under 18 years of age due to the lack of data on the effectiveness and safety of its use.

Every year, stroke causes the death of 5 million people. More than 15 million more patients who have suffered this severe vascular complication survive, but every third of them becomes disabled [1,2]. In addition, they have a very high risk of recurrent stroke: it has been established that within 5 years after the first stroke or dynamic cerebrovascular accident (DCVA), it develops in at least every sixth patient [3]. Due to these circumstances, the search for effective and safe methods for preventing recurrent stroke becomes a priority.

Currently, in order to prevent recurrent stroke and other severe vascular disorders in patients who have suffered an ischemic stroke or DVM, antiplatelet therapy is widely used, reducing the risk of these complications by 15-20% [4,5]. In some limited categories of patients, carotid endarterectomy (for carotid artery stenosis) and anticoagulant therapy (for atrial fibrillation) are used to prevent recurrent stroke; for patients who have suffered a hemorrhagic stroke, there are generally no methods for preventing recurrent stroke with proven effectiveness [6].

Observational studies indicate that the risk of primary ischemic or hemorrhagic stroke directly depends on the degree of increase in blood pressure (BP) [7]. There is less data on the relationship between blood pressure and recurrent stroke. Some epidemiological studies suggest that arterial hypertension (AH) is associated with an increased risk of recurrent stroke [8,9], while others deny the existence of such a relationship [10]. To a large extent, this contradiction may be due to the fact that the most severe cerebrovascular disorders with a poor prognosis often lead to a decrease in blood pressure [11]. However, a prognostic relationship between increased blood pressure and the risk of recurrent stroke apparently still exists. This is evidenced by the results of a large study, which included 2435 clinically stable patients with a history of limited ischemic stroke or DCI [12]. In this category of patients, each decrease in systolic blood pressure is 10 mm Hg. was associated with a 28% reduction in the risk of recurrent stroke.

Systematic reviews of randomized trials of the effectiveness of antihypertensive drugs in patients with hypertension indicate that a constant decrease in diastolic blood pressure by 5-6 mm Hg. reduces the risk of primary stroke by approximately one third [13,14]. However, no significant differences were found in the effectiveness of representatives of the main classes of antihypertensive drugs. Several randomized trials have provided antihypertensive therapy to patients with cerebrovascular disease, most of whom had suffered ischemic stroke. A meta-analysis of the data obtained (2742 patients) demonstrated that in this population, a decrease in systolic and systolic blood pressure of 6-8 and 3-4 mmHg. accordingly, is associated with a reduction in the incidence of recurrent stroke by approximately 20% [15]. The effectiveness of antihypertensive therapy in terms of preventing secondary stroke is also evidenced by the preliminary results of a large study (5665 patients) in which the diuretic indapamide was used [16].

Promising results regarding the prevention of recurrent stroke were also obtained with the use of the angiotensin-converting enzyme (ACE) inhibitor ramipril in the large-scale randomized HOPE trial [17]. There is reason to believe that the high therapeutic effectiveness of ACE inhibitors, in terms of preventing vascular accidents, is due not only to their hypotensive effect, but also to the blockade of a number of adverse effects of angiotensin II that are not directly related to an increase in blood pressure. This is why the recently published results of the randomized, placebo-controlled PROGRESS trial [6], in which another ACE inhibitor, perindopril (Prestarium; Servier), was used to prevent secondary stroke, is of great clinical interest. Of particular value to this study is the inclusion of not only patients with hypertension, but also normal blood pressure levels.

Objectives and nature of research progress

The aim of the study was to evaluate the effect of flexible antihypertensive therapy, including the ACE inhibitor perindopril and the diuretic indapamide (Arifan; Servier), on the risk of stroke and other major vascular outcomes in patients with a previous history of stroke or cerebrovascular accident. 172 clinical centers from 10 countries took part in it. In each of them, the study received ethical committee approval.

The criteria for inclusion of patients in the study were stroke (ischemic or hemorrhagic) or stroke within 5 years before the start of the study, clinically stable condition, absence of heart failure and no contraindications to the use of perindopril or indapamide, including previously observed intolerance. Blood pressure level was not considered as an inclusion or exclusion criterion.

Randomization was preceded by a 4-week period during which all patients received perindopril (initially 2 mg per day, then 4 mg). 1016 (14%) of 7121 potential participants were not included in the study due to observed side effects of perindopril or according to their own decision. Thus, PROGRESS included 6105 patients.

Among them, 30% were women, 39% were people of Asian origin; the average age of the patients was 64 years. The vast majority of patients had a history of ischemic (71%) and hemorrhagic (11%) stroke. Diabetes mellitus and coronary heart disease were diagnosed in 12.5% and 16% of study participants, respectively. The mean blood pressure was 147/86 mm Hg. Hypertension (systolic blood pressure > 160 mm Hg or diastolic blood pressure > 90 mm Hg) was observed in 48% of patients during the initial examination.

Based on the results of randomization, study participants were divided into groups of active antihypertensive therapy (3051 patients) or placebo (3054 patients). Active antihypertensive therapy included perindopril (4 mg/day) in combination with indapamide (2.5 mg/day), except in Japan, where the dose was 2 mg/day. All patients in the active antihypertensive therapy group received perindopril, and inapamide was added to it in the absence of contraindications at the discretion of the responsible physician, mainly based on blood pressure levels. In the second group, patients received 1 or 2 placebo tablets, respectively. As a result, 1,770 patients received perindopril plus indapamide (combination therapy) and 1,774 patients received double placebo. One perindopril or one placebo tablet was prescribed to 1281 or 1280 patients, respectively. Inclusion of patients in the study did not exclude their use of other antihypertensive drugs, which were taken by half of the patients, and antiplatelet therapy, which was received by the majority of study participants. The planned duration of treatment was 4.5 years.

The primary outcome assessed in the PROGRESS study was the development of any stroke (fatal or nonfatal, ischemic or hemorrhagic). Secondary endpoints included: fatal or disabling stroke; severe vascular outcomes (non-fatal stroke or myocardial infarction, any vascular death, including sudden); general and specific mortality; need for hospitalization.

Results of the study progress

The average duration of follow-up for patients in the PROGRESS study was 3.9 years (11,893 person-years in the active antihypertensive therapy group and 11,889 person-years in the placebo group). The rate of early treatment discontinuation for any reason, including patient death and unmotivated refusal of therapy, in the active antihypertensive therapy and placebo groups was approximately the same - 23% and 21%. In general, the treatment was well tolerated by patients, but in the group of active antihypertensive therapy, cough and hypotension were more often noted, which became the reason for its early termination.

Under the influence of active antihypertensive therapy, blood pressure decreased by an average of 9.0/4.0 mm Hg. compared to the placebo group. This difference between groups was maintained at approximately the same level throughout the entire observation period. With the combined use of perindopril and indapamide, the hypotensive effect was significantly more pronounced than when taking an ACE inhibitor alone - a decrease in blood pressure by 12.3/5.0 and 4.9/2.8 mmHg. respectively. Only minor differences were noted in the magnitude of the reduction in blood pressure in hypertensive and normotensive patients - 9.5/3.9 and 8.8/4.2 mmHg. respectively.

The most important result of the study was the discovery of a pronounced positive effect of the therapy on the risk of recurrent stroke, i.e. evidence of the feasibility of its use as a means of secondary prevention. If in the placebo group during the observation period stroke developed in 420 patients (14%), then in the active antihypertensive therapy group - only in 307 (10%). Thus, the relative risk reduction as a result of treatment was 28% (p

The overall incidence of severe vascular outcomes was also affected by the active antihypertensive therapy used in the PROGRESS study. While 604 such events were observed in the placebo group, only 458 were observed among patients who received active treatment (a relative risk reduction of 26%). The annual incidence of these outcomes in the active antihypertensive therapy and placebo groups was 4.1% and 5.5%. Particularly noticeable under the influence of treatment was the decrease in the incidence of non-fatal myocardial infarction (relative risk reduction by 38%). At the same time, the differences between the groups in overall and vascular mortality were minimal. The relative risk of death due to stroke decreased under the influence of active antihypertensive therapy by 16%.

During the observation period, 44% of patients in the placebo group were hospitalized. In the group of active antihypertensive therapy, this figure was 41% (relative risk reduction by 9%). The average length of hospital stay decreased under the influence of treatment by 2.5 days.

The effects of antihypertensive therapy on the incidence of stroke and other major vascular outcomes were slightly greater in patients with hypertension. However, no significant differences were found between the subgroups of hypertensive and normotensive study participants.

There were significant differences in the effectiveness of antihypertensive therapy between subgroups of patients receiving combination treatment (perindopril + indapamide) and perindopril alone. Combination therapy was associated with a very large reduction in the relative risk of recurrent stroke overall (by 43%) and each stroke type compared with the double placebo subgroup. Thus, the relative risk of fatal or disabling stroke decreased by 46%, ischemic by 36% and hemorrhagic by 76%. In contrast, perindopril alone had little effect on the overall incidence of stroke compared with the placebo alone (5% relative risk reduction).

A similar picture was observed for the other outcomes assessed. Specifically, in the combination therapy subgroup, the relative risk of major vascular outcomes (combined) was reduced by 40%, nonfatal myocardial infarction by 42%, and vascular death by 28%. Perindopril alone reduced the pooled relative risk of major vascular outcomes by only 4%. The difference between the effects of combination therapy and perindopril on the risk of stroke and any major vascular outcome was statistically significant (p

Discussion and conclusions

The randomized, placebo-controlled PROGRESS trial demonstrated that in patients who had suffered a stroke or stroke, antihypertensive therapy, including the ACE inhibitor perindopril (all patients) and the diuretic indapamide (58% of patients), reduced blood pressure by an average of 9/4 mm Hg. . and reduced the risk of recurrent stroke by more than a quarter. At the same time, the risk of fatal or disabling and hemorrhagic stroke was especially significantly reduced. The risk of the latter decreased by 2 times. It is also important that the ongoing antihypertensive therapy reduced the incidence of stroke not only in hypertension, but also in patients classified as normotensive. It should, however, be noted that the threshold indicator used in the PROGRESS study was an increase in systolic blood pressure (160 mm Hg) by 20 mm Hg. higher than what is currently generally accepted [18,19], i.e. many patients classified as normotensive at randomization should obviously be considered to have hypertension. The effect of antihypertensive therapy on the risk of recurrent stroke also did not depend on the nature of the previous cerebrovascular accident, the time elapsed since its development, and the ethnicity of the patients (Western or Eastern population). In addition to reducing the risk of stroke, antihypertensive therapy reduced the overall risk of severe vascular outcomes to almost the same extent.

Thus, the main results of the PROGRESS study generally correspond to the data obtained in earlier randomized trials [12,15,16], are close to those expected at the achieved level of the hypotensive effect and confirm the positive effect of lowering blood pressure on the risk of recurrent stroke, as well as the existence of a direct relationship between the risk of stroke and blood pressure levels. From this point of view, the discovered fact of the positive effect of active antihypertensive therapy on the risk of stroke in normotensive patients is very important. This is contrary to the results of some observational studies indicating an inverse relationship between the risk of recurrent stroke and blood pressure levels in the absence of hypertension [20]. The reason for this contradiction obviously lies in the systematic errors characteristic of observational studies, which can influence not only the magnitude, but also the direction of the effect [21].

Another result of the PROGRESS study is of great practical importance. The active antihypertensive therapy used in it reduced the total risk of severe vascular outcomes by 26%, incl. non-fatal myocardial infarction - by 38%. This reduction is almost 2 times greater than would be expected based on the results of earlier studies in which antihypertensive therapy was based mainly on the use of diuretics and beta-blockers [13]. However, the magnitude of this effect was consistent with that observed in the HOPE study and other large trials of ACE inhibitors [14,22]. It follows that the high effectiveness of antihypertensive therapy against severe, primarily coronary, vascular outcomes, found in the PROGRESS study, is primarily due to its constituent perindopril.

It was found that a particularly pronounced drop in the risk of recurrent stroke (of any kind) and major vascular outcomes was observed in the subgroup of patients who received active antihypertensive therapy, which included a combination of perindopril with indapamide and reduced systolic/diastolic blood pressure by an average of 12.3/5.0 mm Hg (see table). When using combination therapy, the incidence of severe (fatal disabling) stroke decreased by almost 2 times, and hemorrhagic stroke by 4 times. The total incidence of main vascular outcomes decreased by 2/5. This reduction in the risk of recurrent stroke and other severe vascular outcomes was fully consistent with that expected for this hypotensive effect (the forecast is based on the results of a meta-analysis of 27 clinical trials, including more than 136 thousand participants) [23]. In contrast, in the subgroup of patients receiving perindopril alone (BP reduction by 4.9/2.8 mm Hg), antihypertensive therapy did not lead to a significant reduction in the risk of severe vascular outcomes, including stroke. This difference in the magnitude of the therapeutic effect between the subgroups of combination therapy and perindopril is obviously associated primarily with a significant (more than 2-fold) difference in the magnitude of the achieved hypotensive effect. Another reason may be the rather random assignment of indapamide to participants in the PROGRESS trial, which was not randomized.

In general, the results of the PROGRESS study are of significant interest for practical healthcare. Considering the large number of patients included in the study and its multicenter nature, as well as the duration of observation, the data obtained directly confirm the need for active antihypertensive therapy as part of secondary prevention of stroke, regardless of blood pressure levels. Analysis of the study results indicates that in patients with cerebrovascular disease, antihypertensive therapy, including perindopril and indapamide, effectively prevents the development of severe coronary outcomes. It is estimated that its administration for 5 years will prevent one fatal or severe non-fatal vascular outcome in 11 patients. In terms of effectiveness as a means of secondary prevention, this combination is at least as effective as antiplatelet drugs [4,5] and statins [24,25]. In addition, it is well tolerated and highly safe, with virtually no difference from placebo in terms of withdrawal rates.

Thus, the combination antihypertensive therapy used in the PROGRESS study, including perindopril and indapamide, can be recommended to a wide range of patients who have had a stroke or cerebrovascular accident in order to prevent recurrent stroke and other severe vascular outcomes, regardless of the level of blood pressure and duration of cerebrovascular episodes. After an acute stroke or a stroke, the decision to prescribe such treatment should be made at the time the patient is discharged from the hospital or at his first visit to the doctor after discharge.

Indapril

Perindopril, indapamide

The use of the drug Indapril is not accompanied by a significant reduction in the frequency of side effects (see section “Side Effects”). When initiating therapy with two antihypertensive drugs that the patient has not previously received, an increased risk of idiosyncrasy cannot be excluded. Careful monitoring of the patient can minimize this risk.

Lithium preparations

The simultaneous use of a combination of perindopril and indapamide with lithium preparations is not recommended (see section “Interaction with other drugs”).

Renal dysfunction

Therapy is contraindicated in patients with severe renal failure (creatinine clearance less than 30 ml/min). In some patients with hypertension without previous obvious renal impairment, laboratory signs of functional renal failure may appear during therapy. In this case, treatment should be stopped. In the future, you can resume combination therapy using low doses of drugs, or use drugs in monotherapy.

Such patients require regular monitoring of serum potassium and creatinine levels - 2 weeks after the start of therapy and every 2 months thereafter. Renal failure most often occurs in patients with severe chronic heart failure or underlying renal impairment, including stenosis of one or two renal arteries.

As a rule, the use of perindopril and indapamide is not recommended for patients with bilateral renal artery stenosis or stenosis of a single functioning kidney.

Arterial hypotension and water-electrolyte imbalance

Hyponatremia is associated with a risk of sudden development of arterial hypotension (especially in patients with stenosis of one or two renal arteries). Therefore, during dynamic monitoring of patients, attention should be paid to possible symptoms of dehydration and decreased levels of electrolytes in the blood plasma, for example, after diarrhea or vomiting. Such patients require regular monitoring of plasma electrolyte levels.

In case of severe arterial hypotension, intravenous administration of 0.9% sodium chloride solution may be required.

Transient arterial hypotension is not a contraindication for continued therapy. After restoration of circulating blood volume and blood pressure, therapy can be resumed using drugs in monotherapy.

Potassium level

Excipients

It should be taken into account that the excipients of the drug include lactose monohydrate. The drug should not be prescribed to patients with hereditary galactose intolerance, lactase deficiency and glucose-galactose malabsorption.

Perindopril

Neutropenia/agranulocytosis

The risk of developing neutropenia while taking ACE inhibitors is dose-dependent and depends on the drug taken and the presence of concomitant diseases. Neutropenia rarely occurs in patients without concomitant diseases, however, the risk increases in patients with impaired renal function, especially against the background of systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma).

After discontinuation of ACE inhibitors, clinical signs of neutropenia disappear on their own.

Perindopril should be used with extreme caution in patients with diffuse connective tissue diseases, while taking immunosuppressive drugs, allopurinol or procainamide, and when used together, especially in patients with underlying renal impairment. Some patients developed severe infections, in some cases resistant to intensive antibiotic therapy. When prescribing perindopril to such patients, it is recommended to periodically monitor the number of leukocytes in the blood. Patients should report any signs of infectious diseases (eg, sore throat, fever) to their doctor.

Hypersensitivity/angioedema (Quincke's edema)

When taking ACE inhibitors, including perindopril, in rare cases, the development of angioedema of the face, extremities, lips, tongue, glottis and/or larynx may occur. If symptoms appear, perindopril should be discontinued immediately and the patient should be observed until signs of edema completely disappear. If the swelling affects only the face and lips, it usually resolves on its own, although antihistamines may be used to treat symptoms.

Angioedema, accompanied by swelling of the larynx, can be fatal. Swelling of the tongue, glottis, or larynx can lead to airway obstruction. If such symptoms appear, you should immediately administer epinephrine (adrenaline) subcutaneously at a dilution of 1:1000 (0.3 or 0.5 ml) and/or ensure airway patency.

Patients with a history of angioedema not associated with taking ACE inhibitors may have an increased risk of developing it when taking drugs of this group (see section “Contraindications”).

Anaphylactoid reactions during desensitization

There are isolated reports of the development of long-term, life-threatening anaphylactoid reactions in patients receiving ACE inhibitors during desensitizing therapy with the venom of hymenoptera insects (bees, wasps).

ACE inhibitors should be used with caution in patients prone to allergic reactions undergoing desensitization procedures. Prescription of an ACE inhibitor should be avoided in patients receiving immunotherapy with hymenoptera venom. However, anaphylactoid reaction can be avoided by temporarily discontinuing ACE inhibitors at least 24 hours before the procedure.

Anaphylactoid reactions during LDL apheresis

In rare cases, life-threatening anaphylactoid reactions may occur in patients receiving ACE inhibitors during low-density lipoprotein (LDL) apheresis using dextran sulfate. To prevent an anaphylactoid reaction, ACE inhibitor therapy should be temporarily discontinued before each apheresis procedure.

Hemodialysis

Potassium-sparing diuretics and potassium supplements

As a rule, the combined use of perindopril and potassium-sparing diuretics, as well as potassium preparations and potassium-containing salt substitutes is not recommended (see section “Interaction with other drugs”).

Cough

During therapy with an ACE inhibitor, a dry cough may occur. The cough persists for a long time while taking drugs of this group and disappears after their discontinuation. If a patient develops a dry cough, one should be aware of the possible connection of this symptom with taking an ACE inhibitor. If the attending physician believes that ACE inhibitor therapy is necessary for the patient, the drug may be continued.

Children and teenagers

Indapril should not be prescribed to children and adolescents under the age of 18 years due to the lack of data on the effectiveness and safety of the use of perindopril as monotherapy or as part of combination therapy in patients in this age group.

Risk of arterial hypotension and/or renal failure (in patients with chronic heart failure, fluid and electrolyte imbalance, etc.)

In some pathological conditions, significant activation of the renin-angiotensin-aldosterone system may be observed, especially with severe hypovolemia and a decrease in the level of plasma electrolytes (against the background of a salt-free diet or long-term use of diuretics), in patients with initially low blood pressure, stenosis of one or two kidneys arteries, chronic heart failure or cirrhosis of the liver with the presence of edema and ascites.

The use of an ACE inhibitor causes a blockade of this system and therefore may be accompanied by a sharp decrease in blood pressure and/or an increase in the level of creatinine in the blood plasma, indicating the development of functional renal failure. These phenomena are more often observed when taking the first dose of the drug or during the first two weeks of therapy. Sometimes these conditions develop acutely and during other periods of therapy. In such cases, when resuming therapy, it is recommended to use the drug at a lower dose and gradually increase the dose.

Elderly patients

Before starting to take the drug, it is necessary to assess the functional activity of the kidneys and the concentration of potassium in the blood plasma. At the beginning of therapy, the dose of the drug is selected taking into account the degree of reduction in blood pressure, especially in the case of dehydration and loss of electrolytes. Such measures help to avoid a sharp decrease in blood pressure.

Atherosclerosis

The risk of arterial hypotension exists in all patients, however, special care should be taken when using the drug in patients with coronary heart disease and cerebrovascular insufficiency. In such patients, treatment should be started with low doses.

Patients with renovascular hypertension

The treatment method for renovascular hypertension is revascularization. However, the use of ACE inhibitors has a beneficial effect in patients both awaiting surgery and in cases where such surgery cannot be performed.

In patients with diagnosed or suspected renal artery stenosis, treatment should begin with lower doses of perindopril and indapamide. Some patients may develop functional renal failure, which disappears when the drug is discontinued.

Other risk groups

In persons with chronic heart failure (functional class IV according to the NYHA classification) and patients with insulin-dependent diabetes mellitus (risk of spontaneous increase in potassium concentration), treatment should begin with lower doses of perindopril and indapamide and under constant medical supervision. Patients with arterial hypertension and coronary heart disease should not stop taking beta-blockers: ACE inhibitors should be used together with beta-blockers.

Patients with diabetes mellitus

When prescribing the drug to patients with diabetes mellitus receiving oral hypoglycemic agents or insulin, blood glucose levels should be carefully monitored during the first month of therapy.

Ethnic differences

Perindopril, like other ACE inhibitors, apparently has a less pronounced hypotensive effect in patients of the Negroid race compared to representatives of other races. Perhaps this difference is due to the fact that patients with arterial hypertension of the Negroid race more often have low renin activity.

Surgery / General anesthesia

The use of ACE inhibitors in patients undergoing surgery using general anesthesia can lead to a significant decrease in blood pressure, especially when using general anesthesia agents that have a hypotensive effect. It is recommended to stop taking long-acting ACE inhibitors, including perindopril, 12 hours before surgery.

Aortic stenosis / Mitral stenosis / Hypertrophic cardiomyopathy

ACE inhibitors should be prescribed with caution to patients with left ventricular outflow obstruction.

Liver failure

In rare cases, cholestatic jaundice occurs while taking ACE inhibitors. As this syndrome progresses, fulminant liver necrosis develops, sometimes with death. The mechanism of development of this syndrome is unclear. If jaundice occurs while taking ACE inhibitors, the patient should consult a doctor. If there is a significant increase in the activity of liver enzymes while taking ACE inhibitors, you should stop taking the drug (see section “Side Effects”).

Anemia

Anemia can develop in patients after kidney transplantation or in patients on hemodialysis. In this case, the decrease in hemoglobin concentration is greater, the higher its initial value: This effect is apparently not dose-dependent, but may be associated with the mechanism of action of ACE inhibitors.

Hyperkalemia

Hyperkalemia may develop during treatment with ACE inhibitors, including perindopril. Risk factors for hyperkalemia are renal failure, impaired renal function, old age, diabetes mellitus, some concomitant conditions (dehydration, acute decompensation of heart failure, metabolic acidosis), concomitant use of potassium-sparing diuretics (such as spironolactone, eplerenone, triamterene, amiloride), as well as drugs potassium or potassium-containing substitutes for table salt, as well as the use of other drugs that increase the level of potassium in the blood plasma (for example, heparin). The use of potassium supplements, potassium-sparing diuretics, potassium-sparing table salt substitutes can lead to a significant increase in potassium levels in the blood, especially in patients with reduced renal function. Hyperkalemia can cause serious, sometimes fatal, abnormal heart rhythms. If combined use of the above drugs is necessary, treatment should be carried out with caution, against the background of regular monitoring of potassium levels in the blood serum (see section “Interaction with other drugs”).

Indapamide

When thiazide and thiazide-like diuretics are prescribed to patients with impaired liver function, hepatic encephalopathy may develop. In this case, diuretics should be stopped immediately.

Photosensitivity

While taking thiazide and thiazide-like diuretics, cases of photosensitivity reactions have been reported (see section "Side effects"). If photosensitivity reactions develop while taking the drug, treatment should be discontinued. If it is necessary to continue diuretic therapy, it is recommended to protect the skin from exposure to sunlight and artificial UV rays.

Water and electrolyte balance

Content of sodium ions in blood plasma

Before starting treatment, it is necessary to determine the content of sodium ions in the blood plasma. While taking the drug, this indicator should be regularly monitored. All diuretics can cause hyponatremia, which sometimes leads to serious complications. Hyponatremia at the initial stage may not be accompanied by clinical symptoms, so regular laboratory monitoring is necessary. More frequent monitoring of sodium ion levels is indicated for patients with liver cirrhosis and the elderly (see sections “Side effects” and “Overdose”).

Content of potassium ions in blood plasma

Therapy with thiazide and thiazide-like diuretics is associated with a risk of hypokalemia. Hypokalemia (less than 3.4 mmol/l) should be avoided in the following high-risk patients: elderly patients, debilitated patients or those receiving concomitant drug therapy, patients with liver cirrhosis, peripheral edema or ascites, coronary artery disease, heart failure. Hypokalemia in these patients enhances the toxic effect of cardiac glycosides and increases the risk of developing arrhythmias.

The high-risk group also includes patients with an increased QT interval, and it does not matter whether this increase is caused by congenital causes or the effect of drugs.

Hypokalemia, like bradycardia, contributes to the development of severe cardiac arrhythmias, especially arrhythmias, which can be fatal. In all the cases described above, more regular monitoring of the content of potassium ions in the blood plasma is necessary. The first measurement of potassium ion concentration should be carried out within the first week from the start of therapy.

If hypokalemia is detected, appropriate treatment should be prescribed.

Content of calcium ions in blood plasma

Thiazide and thiazide-like diuretics reduce the excretion of calcium ions by the kidneys, leading to a slight and temporary increase in the concentration of calcium in the blood plasma. Severe hypercalcemia may be a consequence of previously undiagnosed hyperparathyroidism. Before studying the function of the parathyroid glands, you should stop taking diuretic drugs.

Plasma glucose levels

It is necessary to monitor blood glucose levels in patients with diabetes mellitus, especially in the presence of hypokalemia.

Uric acid

In patients with elevated levels of uric acid in the blood plasma during therapy, the frequency of gout attacks may increase.

Diuretics and kidney function

Thiazide and thiazide-like diuretics are fully effective only in patients with normal or slightly impaired renal function (plasma creatinine in adults below 25 mg/mol or 220 µmol/l). In elderly patients, creatinine clearance is calculated taking into account age, body weight and gender. At the beginning of treatment with diuretics, patients due to hypovolemia and hyponatremia may experience a temporary decrease in glomerular filtration rate and an increase in the concentration of urea and creatinine in the blood plasma. This transient functional renal failure is not dangerous for patients with unchanged renal function, but its severity may increase in patients with renal failure.

Athletes

Indapamide may give a positive reaction during doping control.

Dual blockade of the renin-angiotensin-aldosterone system

Dual blockade of the renin-angiotensin-aldosterone system is associated with an increased risk of hypotension, hyperkalemia and renal dysfunction (including acute renal failure) compared with monotherapy. Dual blockade of the RAAS using ACE inhibitors, ARB II or Aliskiren cannot be recommended for any patient, especially patients with diabetic nephropathy.

In some cases, when the combined use of ACE inhibitors or ARB II is absolutely indicated, careful supervision by a specialist and mandatory monitoring of renal function, water and electrolyte balance, and blood pressure are necessary. This applies to the use of candesartan or valsartan as adjunctive therapy to ACE inhibitors in patients with chronic heart failure. Carrying out double blockade of the RAAS under the careful supervision of a specialist and mandatory monitoring of renal function, water-electrolyte balance and blood pressure is possible in patients with chronic heart failure with intolerance to aldosterone antagonists (spironolactone), who have persistence of symptoms of chronic heart failure, despite other adequate therapy.