In recent years, ARA has made a huge leap forward in terms of conquering new niches for the treatment of hypertension in various clinical situations. If earlier this class of drugs was in the shadow of an ACE inhibitor (their prescription for hypertension was limited mainly by situations related to side effects due to the administration of ACE inhibitors), then at present the niche of their use, as follows from Table 1, extensive. To better understand the possibilities of ARA, it is necessary to recall their mechanism of action. It is known to inhibit the angiotensin II receptor AT1 – conductors of the main negative effects of this hormone – as a result of which, unlike the ACE inhibitor, the synthesis of AII is not disturbed. The negative effects of AII include vasoconstriction, increased secretion of endothelin, stimulation of the synthesis of peroxide radicals, hypertrophy of smooth muscle cells,increased activity of tissue activator inhibitor type 1 plasminogen. Many of these effects are atherogenic. On the other hand, angiotensin II stimulation of unblocked type 2 receptors (AT2) causes effects opposite to those listed above, namely, vasodilatation, increased production of nitric oxide, and stimulation of antiproliferative processes. Thus, ARA have a double positive mechanism of action, which has a powerful anti-thrombogenic potential.
An illustration of the possibilities of ARA is the LIFE study (a study of the effectiveness of losartan in reducing end points in people with arterial hypertension), the results of which were expected with great interest and are likely to be discussed for a long time [8, 59]. In this study, not only was antihypertensive efficacy of ARA proved for the first time in terms of its effect on end points, but other possibilities were also demonstrated.
In a double-blind, randomized, controlled international study, 9193 hypertensive patients aged 55–80 years participated, with left ventricular hypertrophy. The study participants were randomized into 2 groups for the purpose of treatment as initial with either losartan or atenolol. The initial dose of drugs was, respectively, 50 mg of lazan 1 time per day and 50 mg of atenolol 1 time per day. The drugs could be combined with hydrochlorothiazide – 12.5 mg per day and further increase their dose to 100 mg per day in order to achieve the target blood pressure reduction of less than 140/90 mm Hg. Art. Finally, if the maximum doses of the studied drugs in combination with a diuretic did not provide adequate control of blood pressure, then it was allowed to prescribe additional drugs (with the exception of ARA, ACE inhibitors and BB). The duration of the study averaged 4.8 years.
The objective of the study was to study the comparative efficacy of losartan and atenolol in order to reduce the main endpoint, which included a total of MI, MI and cardiovascular mortality. Other endpoints included the incidence of diabetes mellitus, all-cause mortality, regression of left ventricular hypertrophy, the frequency of hospitalizations for angina or heart failure.
In total, 508 cases of a combined endpoint were detected in the losartan group , and 588 in the atenolol group. Thus, compared to atenolol, losartan reduced the frequency of the main endpoint (cardiovascular mortality, MI and MI) by 13% (p <0.021). The frequency of fatal and nonfatal MI in the losartan group was 25% lower than in the atenolol group (p <0.001), despite the fact that the blood pressure in both groups decreased almost the same – by 30/17 mm Hg. in the group of losartan and at 29/17 mm Hg in the group atenolol. However, there were no differences in the incidence of myocardial infarction in both groups. Another important finding is the significantly lower incidence of diabetes in the Losar group – by 25% (p <0.001). In the subgroup of patients with initial diabetes, the frequency of the main endpoint was lower by 24% (p <0.031), and the rate of cardiovascular mortality was 37% (p <0.028) in the losartan group than in the atenolol group. This indicates a beneficial side effect of losartan. Thanks to this study, a new niche for ARA – AG and myocardial hypertrophy has appeared, since it was shown that a significantly more regressive hypertrophied left ventricle was observed in the subgroup of individuals with losartan compared with atenolol. It was also important thatthat the frequency of side effects when using losartan was significantly less than in the atenolol group. As a result, at the end of the study, significantly more patients continued to take losartan than atenolol.
New possibilities in the treatment of such a problematic group of patients as hypertension with concomitant CHF are associated with ARA. As is known, currently in the treatment of hypertension with CHF, an arsenal of drugs is successfully used that can effectively eliminate the symptoms of heart failure and prolong the life of such patients. These classes of drugs, as is known, include ACE inhibitors, BB, diuretics, and cardiac glycosides. For a long time, the ACE inhibitors, considered to be the gold standard for treating CHF, lacked an alternative to blocking the renin-angiotensin system, which is absolutely necessary in CHF. However, there are a number of situations where patients do not tolerate an ACE inhibitor. In addition, for unknown reasons, the effectiveness of ACE inhibitors in women is significantly lower than in men. In these situations, the doctor needs an alternative to an ACE inhibitor.And this alternative appeared due to the data obtained in the CHARM project, which combined three studies. In a placebo-controlled study CHARM-ALTERNATIVE with more than 2000 patients with CHF, the effectiveness of candesartan in the treatment of patients not taking ACE inhibitors due to their intolerance was studied [60]. The results showed that in case of an intolerance to an ACE inhibitor, the use of candesartan reduces the incidence of MTR and mortality from them, and also reduces the frequency of hospitalization due to the progression of CHF (Fig. 7).in the case of an intolerance to an ACE inhibitor, the use of candesartan reduces the incidence of mortality and mortality from them, and also reduces the frequency of hospitalization due to the progression of heart failure (Fig. 7).in the case of an intolerance to an ACE inhibitor, the use of candesartan reduces the incidence of mortality and mortality from them, and also reduces the frequency of hospitalization due to the progression of heart failure (Fig. 7).
In another study, CHARM-ADDED [61], it was found that the addition of candesartan to IAP F and BB in patients with CHF leads to a clinically significant decrease in the incidence of CCO and death from them, as well as hospitalization due to progression CHF .
In both of these studies , the use of candesartan was characterized by good tolerability. It is not unimportant to note that the effectiveness of desa-sartan was almost the same in both men and women. A comparative analysis of the results of the CHARM project and the SOLVD study showed that the effectiveness of candesartan in order to reduce the risk of death from SSO and the frequency of hospitalization due to the progression of CHF is comparable to the effectiveness of the standard ACE enalapril. It is very important for practical physicians to know the dose titration rules. candesartan, which was used in the CHARM project. The starting dose is 4 mg per day once, which with stable blood pressure and the absence of complications, it doubled every 3-5 days until reaching 16 mg per day. The maximum dosage per day is 32 mg. To date, the use of candesartan in the treatment of patients with CHF is the most reasonable, and it can be used on a par with an ACE inhibitor (evidence grade A). This fact is reflected in the latest European and Russian recommendations on the diagnosis and treatment of CHF. Moreover, in the latest European guidelines for the treatment of hypertension, a new niche for the use of ARA has appeared – a concomitant CHF. Of the other representatives of the ARA, it is also recommended to use losartan and valsartan. In the new recommendations for the diagnosis and treatment of hypertension, there is also a very interesting niche for the use of ARA – preventing the development of atrial fibrillation in patients with a history of arrhythmia paroxysms.All of these new APA niches indicate the most important pleiotropic effect of this class – organ protection, not associated with a decrease in blood pressure.