Inhibitors of ACE in clinical practice

In recent years, in the clinical practice, ACE inhibitors are increasingly prescribed. And this is quite natural, since the imbalance of the renin-angiotensin system plays an important role in the development of cardiovascular diseases. Throughout the last decade, numerous studies have been conducted in which the clinical efficacy of ACE inhibitors in various cardiovascular diseases has been studied. The results of these studies are reflected in domestic recommendations, according to which an ACE inhibitor should be prescribed to patients with arterial hypertension, heart failure, acute and myocardial infarction and diabetic nephropathy .

ACE inhibitors are one of the most studied classes of antihypertensive drugs, the effectiveness of which, following diuretics and BB, has been proven in large-scale randomized trials with endpoints. The first study of this kind was the CAPPP study, which compared the effectiveness of ACE inhibitors (captopril 50 mg per day) with atenolol and metoprolol (50–100 mg per day) or hydrochlorothiazide (25 mg per day) for 6 years in the treatment of 10985 patients with hypertension There were no differences in the frequency of the combined endpoint (fatal and non-fatal strokes and myocardial infarction, as well as mortality from other cardiovascular causes) between groups of patients who received ACE inhibitors and BB or diuretics.In this study, a more favorable metabolic profile of captopril was also demonstrated compared with BB and diuretic. The incidence of diabetes by the end of the study in the captopril group was 21%. lower than the other group .

A relatively new scope of ACE inhibitors is the prevention of complications and an increase in mortality in patients with high cardiovascular risk. This is explained by the fact that ACE inhibitors are one of the most effective classes of drugs in terms of improving endothelial function. At least two possible mechanisms of the effect of an ACE inhibitor on the endothelial function have been described. It is possible that ACE inhibitors increase the level of tissue bradykinin [37–38], a powerful stimulator of the release of endothelium-dependent relaxation factors: NO, endothelium-dependent hyperpolarization factor and prostacyclin (PGI2). Another mechanism of action of an ACE inhibitor is the blockade of the formation of angiotensin II, which is considered as an inducer of oxidative stress, leading to a decrease in the bioavailability of NO. AII has the opposite effect with respect to NO.Inhibition of ACE can restore the balance between two vasoactive systems . The dual mechanism of ACE inhibitors is to block the formation of angiotensin II and prevent the destruction of bradykinin, which stimulates the synthesis of endothelial NO, causes the antihypertensive, antiproliferative and angioprotective action of these drugs.

The ability of an ACE inhibitor to improve endothelial function and inhibit atherogenesis processes was first demonstrated in a study of TREND (Trial on Reversing Endothelial Dysfunction) [41]. In a randomized trial lasting half a year in the treatment of 129 IHD patients, the effectiveness of quinapril in relation to the restoration of impaired endothelial function of the coronary arteries was examined, which was assessed using a sample with intracoronary acetylcholine during coronaryography. A reduction of 10–20% in the severity of vasoconstrictor reactions after quinapril therapy was found.

In the BANFF Study, a comparative assessment of the correction of endothelial function was performed with 8 weeks of treatment with different classes of antihypertensive drugs (amlodipine, quinapril, enalapril, losartan) in 80 patients with CHD. The majority of the sample were men (80%), the average age was 58 ± 0.9 years. The risk factors were as follows: hypercholesterolemia was in 54% of patients, AH – in 26%, diabetes – in 10%. A history of myocardial infarction was recorded in 47% of patients, 95% of patients underwent coronary angioplasty. In the course of treatment, blood pressure and blood lipid spectrum did not differ significantly, and the endothelium-dependent vasodilation of the brachial artery in patients with risk factors improved only during treatment with quinapril, while amlodipine, enalapril and losartan did not affect endothelial function [42].

The powerful effect of ACE inhibitors on endothelial function is also confirmed by the results of our own research on the advantages of this class of drugs over others in the treatment of smoking patients with hypertension.

Analysis of large-scale studies indicates a decrease in the effectiveness of antihypertensive drugs in the treatment of smoking patients with hypertension. The use of b- blockers allowed to reduce the number of coronary episodes in non-smoking hypertensive patients, while smokers had no such effect . According to the results of the study using Smad in patients with arterial hypertension, it was found that in smoking patients the levels of systolic and diastolic blood pressure, as well as the heart rate, are statistically significantly higher than in non-smoking patients. The authors make the assumption that such results may indicate that patients with hypertension are not treated . . An analysis of the national sample of treated individuals with hypertension in Sweden, which included 4,424 patients, observed in 189 doctors, indicates a decrease in the effectiveness of antihypertensive therapy in smoking patients. The percentage of inadequately treated persons in relation to DBP (≥ 90 mm. Mercury) in the group of smokers is 32.7%, in the group of non-smokers – 25%, p <0.01. The corresponding figures of systolic blood pressure (≥ 140 mm Hg) are 72.8% and 68.9%, p <0.01 . In the Russian multicenter study Prologue in the group of the main treatment (starting therapy with an ACE inhibitor followed by the addition of hydrochlorothiazide and atenolol), the effectiveness of blood pressure reduction in the smoking group was significantly less than in the non-smoking group [46]. The most important reason for reducing the effectiveness of antihypertensive drugs for the treatment of smokers is endothelial dysfunction that develops in this category of patients [47, 48]. Endothelial dysfunction leads to pronounced peripheral vasospasm, which in turn reduces blood flow at the level of microcirculation followed by ischemia of organs and tissues, which leads to the maintenance of high blood pressure. Therefore, it can be assumed that antihypertensive drugs, corrective DE should have an advantage in smoking patients with hypertension. Such classes of drugs primarily include ACE inhibitors. Let us take an example of another study:23 smokers of patients with hypertension (mean age 38 ± 12 years, smoking experience – 21 years, the average number of cigarettes smoked – 19), who had no other risk factors for 8 weeks, received 20 mg of lisinopril and placebo alternately. The treatment with lisinopril showed a significant increase in the blood flow in the forearm in response to the intraarterial administration of acetylcholine. This fact indicates an improvement and endothelial function . There are few studies confirming the effectiveness of an ACE inhibitor in the treatment of smoking patients with hypertension. In the randomized crossover study, the antihypertensive efficacy of enalapril and atenolol was studied in the treatment of male smokers with AH. The ACE inhibitor enalapril in the smoking group was found to be more effective than the b- blocker atenolol .

In the randomized crossover study itself, 30 smoking patients, men aged 35–64 years with mild and moderate essential arterial hypertension, were included. Within 12 weeks, patients received the drug Iruzid, which is a fixed combination of 20 mg of lisinopril and 12.5 mg of hydrochlorothiazide, and a combination of 50 mg of atenolol with 12.5 mg of hydrochlorothiazide. The decrease in systolic blood pressure after Iruzid treatment amounted to an average of 16.6 mm Hg. Art., and diastolic blood pressure – 10.3 mm Hg. Art. The corresponding figures for a decrease in blood pressure during treatment with a combination of atenolol and hydrochlorothiazide are 11, 9, and 7.6 mm Hg. Art. Differences in decreases and systolic
 and diastolic blood pressure is significant (p <0.005). Thus, Iruzid provided a more pronounced decrease in blood pressure in smokers than the combination of 0.15 % atenolol and hydrochlorothiazide. These differences

Patients who reach the combined primary endpoint (myocardial infarction, stroke, cardiovascular death). Ashley reflected in the effect of two strategies of treatment on endothelial hydrochloric function which is evaluated using a cuff test,
 those. assessment of endothelium- dependent vasodilation (EDVD) of the brachial artery using high-resolution ultrasound. Iruzid therapy led to a marked improvement in endothelial function. Against the background of therapy with Iruzid, a significant pronounced increase in EDVD was observed – 7.9% ± 3.0 before treatment and 15.5% ± 2.2 after treatment (p <0.05). During treatment with a combination of atenolol and hydrochlorothiazide, the change in EDVD was statistically insignificant – 8.2% ± 3.4 and 9.6% ± 3.6 (p> 0.05).

The hypothesis of the possibility of preventing complications and death in patients with high cardiovascular risk of ACE inhibitors has been tested in a number of large multi-site studies: HOPE (Heart Outcomes Prevention Evaluation Study), EUROPEA (EURopean trial coronary Arte-ry disease), PEACE (Prevention of events with Anti- ingin-converting Enzyme inhibition). This list stands out as the HOPE study [51], which involved 9297 men and women with confirmed atherosclerosis of various localization (coronary heart disease, peripheral arterial disease, stroke) or diabetes mellitus at least another risk factor (arterial hypertension, cigarette smoking, microalbuminuria, or dyslipidemia). 80% of patients had coronary heart disease,55% – angina, 52% – history of myocardial infarction, 43% – atherosclerosis of the peripheral arteries, 25% – unstable angina in history, and 26% – coronary artery bypass surgery in history, 18% – percutaneous regstrium, and 18% – acute coronary artery bypass graft bypass, in 18% – percutaneous regstrosis, in 18% – acute coronary artery bypass surgery. 11% have a stroke or transient ischemic attack. Almost half of the patients suffered from hypertension and about 40% – type 2 diabetes. Patients were given a placebo or an ACE inhibitor ramipril (with titration of doses from 1.25 to 10 mg) and continued monitoring for an average of 5 years. The primary endpoint (cardiovascular death, MI, or stroke) was recorded in 17.8% of patients in the placebo group and 14.0% of patients in the ramipril group, reflecting a 22% reduction in risk, p <0.001 (Fig. 3). Ramipril therapy led to a decrease in the frequency of the most important components of this end point – MI, MI (Fig. 4.5). Besides,a reduction in total mortality (from 12.2 to 10.4% within 5 years), the need for revascularization, diabetic complications, diabetes, heart failure, progression of angina pectoris, or cardiac insufficiency. An interesting fact is that the decrease in blood pressure in the ramipril group was relatively small (BP is 3/3 mm Hg), so the results of treatment cannot be explained only by antihypertensive drugs. the effect of the drug .

Thus, in this study, the protective role of ramipril was confirmed in terms of preventing the development of complications in patients with high risk. Moreover, the protective effect of ramipril is in no way associated with a decrease in blood pressure.

Additional evidence of the effectiveness of long-term treatment of ACE inhibitors for the purpose of secondary prophylaxis is the results of the EUROPA study [52]. It included 13,655 patients in the low-risk group, without heart failure, who suffered from stable coronary heart disease. For an average of 4.2 years, they were treated with perindopril or placebo. In patients with perindopril, a decrease in the incidence of cardiovascular outcomes (cardiovascular death, myocardial infarction, sudden death) from 10 to 8% was detected, which meant that for the prevention of a single cardiovascular outcome, treatment was necessary for 4 , 2 years in 50 patients. The benefits of ACE inhibitors were comparable in all subgroups of patients.

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