Clinical and pharmacological effectiveness of combined therapy of arterial hypertension in metabolic syndrome

The dissertation is devoted to the comparative assessment of the clinical and pharmacological effectiveness of two variants of combined antihypertensive therapy in patients with arterial hypertension combined with metabolic syndrome. The objects of the study are free combinations of the angiotensin-converting enzyme inhibitor enalapril with the non-dihydropyridine calcium channel blocker verapamil SR and with the dihydropyridine calcium channel blocker amlodipine. The work examines the effect of therapy on clinical blood pressure and parameters of 24-hour ambulatory monitoring, on structural and functional parameters of the left ventricle and central haemodynamics, on microalbuminuria, as well as on carbohydrate, lipid and purine metabolism. In addition, a pharmacoeconomic analysis of the two variants of combined pharmacotherapy is carried out, with the determination of cost-effectiveness ratios. The practical significance of the study is related to the substantiation of a differentiated choice of a calcium channel blocker for inclusion in combined therapy of arterial hypertension in metabolic syndrome.

Arterial hypertension is the leading cause of cardiovascular morbidity, a predictor of early disability and mortality, and an alarming indicator of social disadvantage [24, 28, 81, 82, 86, 92, 93, 161, 183, 332]. Despite the progress achieved in the study of arterial hypertension and the development of new antihypertensive drugs, in real clinical practice the problem of effective treatment of this disease cannot always be solved [126, 252]. The optimisation of pharmacotherapy of arterial hypertension is one of the key issues in modern cardiology [7, 41, 106, 107, 117, 210, 334]. Of particular relevance is the improvement of antihypertensive therapy in patients with metabolic syndrome who are at high and very high integral risk of cardiovascular complications [64, 143, 152, 159, 177, 186, 207, 217, 235–237, 241, 285–287, 289, 307, 325]. The presence of metabolic disturbances in arterial hypertension determines a high frequency of target organ damage [36, 52, 172, 181, 239, 244, 248, 267, 296, 312, 328], as well as alterations of the 24-hour blood pressure profile [20, 33, 51, 60, 98, 100, 121, 122, 273]. Recent studies demonstrate that the treatment of patients with arterial hypertension in the presence of metabolic syndrome remains a difficult problem to solve.

To reduce the high integral cardiovascular risk in patients with arterial hypertension and metabolic disturbances, combined antihypertensive pharmacotherapy is required [57, 60, 74, 125, 161, 210, 314, 321]. Among the six existing classes of basic antihypertensive drugs, angiotensin-converting enzyme inhibitors and calcium channel blockers currently have the strongest pathogenetic rationale for the treatment of arterial hypertension in metabolic syndrome [57, 60, 162, 214]. At the same time, the effectiveness of combined therapy with angiotensin-converting enzyme inhibitors and calcium channel blockers in patients with metabolic syndrome remains a relevant and insufficiently studied problem.

The best known variant of combined therapy using an angiotensin-converting enzyme inhibitor and a calcium channel blocker is the combination of trandolapril and isoptin SR. The high antihypertensive effectiveness of the combination of trandolapril and isoptin SR was shown in the large-scale INVEST study [274]. However, that study evaluated the effect of trandolapril / isoptin SR only on "hard" primary endpoints (all-cause mortality, incidence of cardiovascular complications) and secondary endpoints (hospitalisation for cardiovascular complications). The fixed-dose combination of trandolapril and isoptin SR — the preparation Tarka — is the most studied in terms of its effect on "surrogate" endpoints in arterial hypertension and type 2 diabetes mellitus, and its effectiveness has been demonstrated in the EDICTA [295] and TRAEVEND [270] studies. Other fixed-dose combinations of angiotensin-converting enzyme inhibitors and calcium channel blockers exist that are not registered in Russia: Lotrel (benazepril + amlodipine), Lexxel (enalapril + felodipine), Teczem (enalapril + diltiazem). At the same time, the use of fixed-dose combinations of medicinal products is not without certain drawbacks: a less flexible dosing regimen and difficulties in interpreting adverse effects [74, 132]. Free combinations allow modification of the dosing schedule in accordance with the individual biological rhythm of blood pressure and separate titration of the dose of each component. It appears relevant to study the pharmacological possibilities of free combinations of an angiotensin-converting enzyme inhibitor with non-dihydropyridine and dihydropyridine calcium channel blockers and their effect on "soft" clinical endpoints in arterial hypertension and metabolic syndrome.

No data are available on the comparative effect of free combinations of angiotensin-converting enzyme inhibitors and various calcium channel blockers on the course of arterial hypertension in the presence of metabolic syndrome, on the most significant parameters of the 24-hour blood pressure profile: hypertensive load, variability, and the circadian rhythm of systolic and diastolic blood pressure. The effect of combined therapy using various calcium channel blockers on pulse blood pressure has not been sufficiently studied. At the same time, it is known that pulse blood pressure values exceeding 53 mm Hg are associated with a more frequent target organ damage and unfavourable outcomes of arterial hypertension [150, 194, 324]. The effect of different combinations of angiotensin-converting enzyme inhibitors with non-dihydropyridine and dihydropyridine calcium channel blockers on heart rate, elevated values of which reflect hyperactivity of the sympathetic nervous system in arterial hypertension and metabolic syndrome, requires clarification [140, 228, 240, 266, 293]. In the few studies conducted in arterial hypertension and metabolic syndrome, no significant change in heart rate has been shown with monotherapy with angiotensin-converting enzyme inhibitors [4, 17, 34, 61, 109], whereas calcium channel blockers exerted different effects on this parameter [32, 44, 58]. At the same time, it has been proven that the probability of developing coronary heart disease and cardiovascular mortality increases with increasing heart rate [199, 200].

One of the requirements for rational antihypertensive therapy is the presence of an organoprotective effect, which is especially relevant in arterial hypertension and metabolic syndrome [57, 63]. The effect of combined therapy with angiotensin-converting enzyme inhibitors and calcium channel blockers on the structural and functional parameters of the left ventricle in patients with arterial hypertension and metabolic syndrome has not been studied, whereas with monotherapy with either angiotensin-converting enzyme inhibitors or calcium channel blockers, conflicting results have been obtained [17, 19, 29, 34]. An important criterion of the effectiveness of antihypertensive therapy is considered to be its effect on microalbuminuria — an early marker of renal damage in arterial hypertension and diabetes mellitus [226, 264]. Studies conducted in arterial hypertension and type 2 diabetes mellitus have demonstrated the superiority of certain combinations of angiotensin-converting enzyme inhibitors with calcium channel blockers over monotherapy with these agents in reducing albuminuria [145, 270, 275, 305]. At the same time, the prevalence and severity of microalbuminuria among patients with arterial hypertension and metabolic syndrome without diabetes mellitus have not been studied. It is necessary to evaluate the nephroprotective effect of combinations of an angiotensin-converting enzyme inhibitor with a non-dihydropyridine and a dihydropyridine calcium channel blocker, which have different effects on renal blood flow [242].

A fundamental requirement for the drugs constituting combined therapy in patients with arterial hypertension and metabolic syndrome is their metabolic neutrality [57, 63]. However, certain metabolic aspects of combined therapy that includes angiotensin-converting enzyme inhibitors and calcium channel blockers remain unstudied. There are no data on the comparative effect of different combinations of an angiotensin-converting enzyme inhibitor and calcium channel blockers on the level of C-peptide, fasting and postprandial glucose levels, blood lipid profile, and uric acid content.

The pharmacoeconomic advantages of different variants of combined therapy using angiotensin-converting enzyme inhibitors and calcium channel blockers of the non-dihydropyridine and dihydropyridine series in arterial hypertension and metabolic syndrome have not been determined. The present study is devoted to the investigation of these issues.

The aim of the work: optimisation of pharmacotherapy of arterial hypertension in patients with metabolic syndrome on the basis of a study of the clinical and pharmacological effectiveness of two variants of combined therapy using an angiotensin-converting enzyme inhibitor with non-dihydropyridine and dihydropyridine calcium channel blockers.

To achieve this aim, the following tasks were set:

1. To study the clinical effectiveness of two variants of combined therapy with enalapril / verapamil SR and enalapril / amlodipine in patients with arterial hypertension in the presence of metabolic syndrome.

2. To investigate the effect of enalapril with verapamil SR and enalapril with amlodipine on the most significant parameters of the 24-hour blood pressure profile in patients with arterial hypertension and metabolic disturbances.

3. To evaluate the effect of combined therapy with enalapril / verapamil SR and enalapril / amlodipine on central haemodynamics and structural and functional parameters of the left ventricle in patients with arterial hypertension and metabolic syndrome.

4. To study the effect of different variants of two-component pharmacotherapy on the level of microalbuminuria in arterial hypertension and metabolic syndrome.

5. To analyse the effect of enalapril / verapamil SR and enalapril / amlodipine on indicators of carbohydrate, lipid and purine metabolism in patients with arterial hypertension and metabolic syndrome.

6. To carry out a pharmacoeconomic analysis of the effectiveness of combinations of enalapril with a non-dihydropyridine and a dihydropyridine calcium channel blocker in arterial hypertension and metabolic syndrome.

The work was carried out at the city and railway centre for the treatment of arterial hypertension (scientific supervisor — Head of the Department of Clinical Pharmacology, Doctor of Medical Sciences, Professor N.B. Sidorenkova). Individual fragments of the work were carried out in the laboratory of haemodynamic studies of the Department of Clinical Pharmacology (Head — A.S. Volkova), the clinical diagnostic laboratory (Head — I.A. Batanina), and the department of functional diagnostics (Head — T.V. Perevozchikova) of the Clinical Hospital at the Barnaul Station (Chief Physician — Candidate of Medical Sciences A.G. Zaltsman).

Scientific novelty of the work. For the first time, a comprehensive assessment was made of the clinical effectiveness of two variants of combined therapy with the angiotensin-converting enzyme inhibitor enalapril with the non-dihydropyridine calcium channel blocker verapamil SR and the dihydropyridine calcium channel blocker amlodipine in patients with arterial hypertension and metabolic syndrome. The studied variants of combined therapy exerted a comparable positive effect on clinical blood pressure and on the main parameters of the 24-hour blood pressure profile (hypertensive load, circadian rhythm).

The pharmacodynamic features of the combinations of enalapril with verapamil SR and enalapril with amlodipine have been identified. The combination of enalapril and verapamil SR statistically significantly reduces pulse blood pressure, the variability of systolic and diastolic blood pressure, and significantly decreases heart rate in patients with arterial hypertension and metabolic syndrome. The combination of enalapril and amlodipine does not exert a statistically significant effect on pulse blood pressure or on the variability of systolic blood pressure and significantly increases heart rate.

For the first time, the effect of the combinations enalapril / verapamil SR and enalapril / amlodipine on the structural and functional parameters of the left ventricle has been studied. An improvement in the diastolic function of the left ventricle was revealed — a decrease in the ratio of the peak velocities of early and late diastolic filling — together with the superiority of enalapril / verapamil SR regarding the effect on left ventricular diastolic dysfunction.

For the first time, the comparative effect of combined therapy with an angiotensin-converting enzyme inhibitor with a non-dihydropyridine and a dihydropyridine calcium channel blocker on microalbuminuria in arterial hypertension and metabolic syndrome was studied, and a decrease in the level of microalbuminuria under the influence of both variants of two-component therapy was demonstrated.

Metabolic neutrality and a decrease in the atherogenic index under the influence of enalapril / verapamil SR and enalapril / amlodipine in patients with arterial hypertension and metabolic syndrome have been demonstrated.

For the first time, a comparative evaluation of the pharmacoeconomic effectiveness of therapy with enalapril with a non-dihydropyridine or dihydropyridine calcium channel blocker in patients with arterial hypertension and metabolic syndrome has been carried out. The pharmacoeconomic advantage of the combination of enalapril with the non-dihydropyridine calcium channel blocker verapamil SR has been revealed, with lower cost-effectiveness ratios in terms of effect on systolic and mean blood pressure, time index, 24-hour blood pressure index, microalbuminuria, left ventricular diastolic function, and atherogenic index.

Practical significance of the work. The high clinical effectiveness of two-component therapy with enalapril / verapamil SR and enalapril / amlodipine has been established: a decrease in the frequency of the main symptoms of arterial hypertension, a reduction in clinical blood pressure, achievement of target blood pressure in 78% and 80% of cases respectively, a favourable effect on the most significant parameters of the 24-hour blood pressure profile, improvement of left ventricular diastolic function, reduction of microalbuminuria and atherogenic index, and the absence of a negative effect on carbohydrate and purine metabolism — which makes it possible to recommend these drug combinations for the treatment of arterial hypertension in patients with metabolic syndrome.

The identified features of the effect of enalapril / verapamil SR and enalapril / amlodipine on pulse blood pressure and heart rate make it possible to make a differentiated choice of different calcium channel blockers for inclusion in combined therapy of arterial hypertension in metabolic syndrome.

Combined therapy with enalapril / verapamil SR in patients with arterial hypertension and metabolic syndrome has pharmacoeconomic advantages over combined therapy with enalapril / amlodipine, with a lower integrative cost-effectiveness ratio.

Implementation into practice. The use of combined antihypertensive pharmacotherapy — enalapril and verapamil SR, as well as enalapril and amlodipine — in patients with arterial hypertension and metabolic syndrome has been implemented at the Cardiology Research Institute of the Tomsk Scientific Centre of the Siberian Branch of the Russian Academy of Medical Sciences, at the Novosibirsk Regional Clinical Hospital, in the specialised department of the Altai Regional Cardiology Dispensary, in the department of emergency cardiology of City Hospital No. 1 of Barnaul, and in the Departmental Clinical Hospital at Barnaul Station. The results of scientific research on combined pharmacotherapy of arterial hypertension in metabolic syndrome are used in the educational process at the Department of Clinical Pharmacology of Altai State Medical University and at the State Cardiology Research Institute of the Tomsk Scientific Centre of the Siberian Branch of the Russian Academy of Medical Sciences in the training of students, residents, postgraduate students and physicians.

Main propositions for defence:

1. Combined pharmacotherapy in the mode of free combination of the angiotensin-converting enzyme inhibitor enalapril with the non-dihydropyridine calcium channel blocker verapamil SR or the dihydropyridine calcium channel blocker amlodipine, with slow separate titration of doses, provides clinical and antihypertensive effectiveness in patients with arterial hypertension and metabolic syndrome.

2. The combination of enalapril with verapamil SR has advantages over the combination of enalapril with amlodipine in terms of its effect on pulse blood pressure, heart rate, and left ventricular diastolic dysfunction. The combination of enalapril with amlodipine has an advantage in achieving target diastolic blood pressure.

3. The use of the combinations enalapril / verapamil SR and enalapril / amlodipine promotes the development of a nephroprotective effect and does not lead to deterioration of indicators of carbohydrate, lipid and purine metabolism in patients with arterial hypertension and metabolic syndrome.

4. The combination enalapril / verapamil SR has pharmacoeconomic advantages over the combination enalapril / amlodipine in patients with metabolic syndrome, with a lower integrative cost-effectiveness ratio.