Results of a Randomized, Double-Blind, Multicenter, Placebo-Controlled, Parallel-Group Study of the Efficacy and Safety of Mexidol in Prolonged Sequential Therapy of Patients in the Acute and Early Recovery Stages of Hemispheric Stroke (the EPICA study)

Author:
L. V. Stakhovskaya1, N. A. Shamalov1, D. R. Khasanova2, E. V. Mel’nikova3, A. S. Agaf’ina4, K. V. Golikov5, E. I. Bogdanov6, A. A. Yakupova6, L. V. Roshkovskaya7, L. V. Lukinykh8, T. M. Lokshtanova9, I. E. Poverennova10, and L. A. Shchepankevich11

1 Research Institute of Cerebrovascular Pathology and Stroke, Pirogov Russian National Research Medical University, Russian Ministry of Health, Moscow, Russia; e-mail: lstakh@mail.ru.

2 Interregional Clinical Diagnostic Center, Kazan, Russia.

3 St. Petersburg City Clinical Hospital No. 26, St. Petersburg, Russia.

4 St. Petersburg City Clinical Hospital No. 40 of the Resort Administrative District, St. Petersburg, Russia.

5 St. Petersburg City General Hospital No. 2, St. Petersburg, Russia.

6 Kazan Sate Medical University, Russian Ministry of Health, Kazan, Russia.

7 Nikolaevskaya Hospital, St. Petersburg, Russia.

8 Vsevolzhsk Clinical Interregional Hospital, Leningradskaya Oblast, Russia.

9 Pirogov City Clinical Hospital No. 1, Samara, Russia.

10 Seredavin Samara Regional Clinical Hospital, Samara, Russia.

11 Research Institute of Experimental and Clinical Medicine, Novosibirsk, Russia.

Summary:
Objectives. To assess the effi cacy and safety of prolonged sequential therapy with Mexidol in patients with hemispheric ischemic stroke (IS) in the acute and early recovery phases. Materials and methods. A randomized, double-blind, multicenter, placebo-controlled, parallel-group study included 151 patients (62 men and 89 women) was performed in which 150 patients (62 men and 88 women) aged 40–79 years were randomized. Simple randomization was used to defi ne two groups: patients of group 1 received Mexidol therapy at a dose of 500 mg/day by intravenous infusion for 10 days followed by oral doses of 1 tablet (125 mg) three times a day for eight weeks. Patients of group 2 received placebo by the same protocol. The duration of involvement in the trial was 67–71 days. Results. At the end of treatment, mean scores on the modified Rankin scale (mRS) were lower in group 1 than group 2 (p = 0.04). Decreases in mean mRS scores (at visits 1–5) were more marked in group 1 (p = 0.023). The proportion of patients achieving recovery corresponding to 0–2 points on the mRS (at visit 5) was signifi cantly greater in group 1 (p = 0.039). Testing on the National Institutes of Health Stroke Scale at visit 5 gave a signifi cantly lower score in group 1 (p = 0.035). Decreases in scores on the National Institutes of Health Stroke Scale at the end of treatment relative to the baseline level in patients with diabetes mellitus were more marked in group 1 (p = 0.038). In group 1, the total population and the subpopulation of patients with diabetes mellitus showed more marked improvements in quality of life, which was apparent by visit 2. The proportion of patients without diffi culty mobilizing was signifi cantly greater in group 1 (p = 0.022). There were no signifi cant differences in the frequencies of adverse events in patients of the two groups. Conclusions. Use of Mexidol in the acute and early recovery phases of IS is recommended. Keywords: acute cerebrovascular accident, Mexidol, ethylmethylhydroxypyridine succinate, effi cacy and safety, ischemic stroke, acute phase, early recovery phase, EPICA.


The efficacy of ethylmethylhydroxypyridine in the rehabilitation treatment of poststroke patients

Author:
O.V. M.V. ZHURAVLEVA1,2, A.B. PROKOFIEV1,2, V.V. ARKHIPOV1, S.YU. SEREBROVA1,2, G.I. GORODETSKAY1,2, O.A. DEMIDOVA1

1 Research center for examination of medical devices, Moscow, Russia

2 Sechenov First Moscow state medical University (Sechenov University), Moscow, Russia

Summary:
The analysis of the clinical efficacy and safety of ethylmethylhydroxypyridine succinate (mexidol) in the complex of rehabilitation measures in patients after ischemic stroke (IS) shows that course treatment with mexidol improves the recovery of neurological functions, decreases neurological deficit, cognitive disorders, including memory impairment, and manifestations of asthenic syndrome, increases the level of social adaptation and improves the psycho-emotional state of patients, reduces spasticity, increases motor and speech activity, praxis, reliably eliminates the ignoring syndrome. There is a decrease in the level of total cholesterol and low-density b-lipoproteins in the blood, and decrease in the severity of hypercoagulation. The results of the studies have convincingly shown the efficacy of mexidol at all stages of rehabilitation treatment of patients with IS.
Keywords: ethylmethylhydroxypyridine succinate, mexidol, rehabilitation, recovery, stroke.


Efficacy and safety of the drug Mexidol forte 250 as part of long-term sequential therapy in patients with carotid stroke

Author:
I.A. STRELNIKOVA1, A.A. SVETKINA1,2, O.V. ANDROFAGINA1

1 Samara Regional Clinical Hospital named after V.D. Seredavina, Samara, Russia;

2 Samara State Medical University, Samara, Russia

Summary:
Objective. To evaluate an effect of long-term sequential therapy with mexidol and mexidol forte on the functional outcome of patients with carotid ischemic stroke. Material and methods. The study included 50 patients with newly developed carotid stroke, hospitalized in the stroke unit on the first day from the onset of the disease. Patients of the main group (n=25) received mexidol in a dose of 500 mg intravenously once a day for 14 days, then mexidol forte 250 in tabs 250 mg 3 times a day for 60 days. Patients of the comparison group (n=25) received standard basic therapy. The significance of intergroup differences was assessed using the Mann—Whitney test, Fisher’s exact test, and relative risk (OR) calculation. Differences were considered significant at a level of p<0,05. Results. After 14 days of therapy, both groups of patients showed a positive trend compared to baseline. At the same time, patients of the mexidol group had a higher MoCA score (U=173,5, p=0,006), a lower score when performing tasks on dynamic praxis (U=214,0, p=0,028) and optical spatial disturbances (U=170,5, p=0,003), better memorization strength (181,5, p = 0,006) and better performance on abstraction MOCA subtest (U=200,5, p=0,014). By the 74th day, the absence of moderate cognitive impairment (MoCA> 26 points) was diagnosed in 17 patients (68%) of the main group and 14 patients (56%) of the comparison group. No significant differences were found. Moreover, patients of the main group had a significantly lower NIHSS score (U=124,0, p<0,001) and a lower degree of disability: a total mRS score 0—2 was achieved in 19 (76%) patients of the main group and only in 12 (48%) patients of the comparison group (OR=3,34, F=0,07, p<0,05). Also, patients receiving long-term sequential therapy with mexidol and mexidol forte 250 had milder spatial disorders than patients of the comparison group. Conclusion. Consecutive treatment with mexidol and mexidol forte 250 in the acute and early recovery periods of ischemic stroke positively affects the regression of local neurological symptoms, increases the likelihood of achieving independence in everyday life by 3,34 times, and reduces the severity of optical-spatial, neurodynamic and memory impairments.
Keywords: ischemic stroke, mexidol, mexidol forte 250, cognitive impairment, functional outcome.


Review of clinical guidelines for the treatment and prevention of ischemic stroke

Author:
A.I. FEDIN, K.R. BADALYAN

Pirogov Russian National Research Medical University, Russian Ministry of Health, Moscow, Russia

Summary:
One of the leading causes of death, disability and severe maladaptation of patients is ischemic stroke, which accounts for about 80% of all types of acute cerebrovascular accidents. At the same time, approximately 2/3 of the patients show residual effects of cerebral circulation disorders of varying severity. Currently, the problem of ischemic stroke attracts great attention and international and domestic recommendations developed for the prevention, treatment and rehabilitation of stroke patients are one of the aspects of work in this area. The article provides an overview of the latest clinical guidelines for the early management of patients with acute ischemic stroke of the American Heart Association and the American Stroke Association, as well as features of stroke therapy and prevention in Russia, Europe and USA. Keywords: ischemic stroke, clinical guidelines, therapy of ischemic stroke.


Pharmacoeconomic analysis of the neuroprotective medicines in the treatment of ischemic stroke

Author:
R.I. YAGUDINA1, A.YU. KULIKOV1, V.A. KRYLOV1, E.YU. SOLOVIEVA2, A.I. FEDIN2

1Sechenov First Moscow State Medical University, Ministry of Health of Russia, Moscow, Russia;
2Pirogov Russian National Research Medical University N.I.Pirogov Russian National Research Medical University of the Ministry of Health
of Russia, Moscow, Russia

Summary:
Objective. To perform a pharmacoeconomic analysis of the most frequently prescribed neuroprotective medicines for treating patients with mild ischemic stroke in the acute and early rehabilitation periods in the Russian Federation. Material and methods. Three medical technologies were compared: ethylmethylhydroxypyridine succinate (mexidol), inosine + nicotinamide + riboflavin + succinic acid (cytoflavin) and a deproteinized hemoderivate of the blood of calves (actovegin). Cost minimization analysis, budget impact analysis and sensitivity analysis were performed based on the indirect comparison results. Results. Efficacy analysis shows that mentioned above medicines have the same efficacy: mean difference mexidol is 0,2 (CI min 0,25; max 0,65), cytoflavin — 0,61 (CI min 0,23; max 0,99), actovegin 0,2 (CI min 0,18; max 0,22). The cost minimization analysis for the Russian Federation shows that mexidol therapy is associated with the lowest costs, while savings are observed both in the evaluation of total costs and separate components: intravenous ampoules and tablet forms. The savings in comparison with cytoflavin and actovegin are 231 RUB and 12,872 RUB, respectively. These savings will be enough to treat five patients with ischemic stroke (IS) with mexidol. Moreover, oral mexidol therapy is cheaper than the same dosage forms of cytoflavin and actovegin by 481 RUB and 3,164 RUB, respectively. This is an advantage for the treatment of population at the outpatient stage. Budget impact analysis has shown that the budget for the medicines for treating IS at the current distribution between treatment regimens, is estimated at 1.99 BN RUB. The increase in the proportion of patients receiving mexidol by 10% reduces total costs to 1.75 BN RUB, which is 240 M RUB less than current costs. With these savings 85 thousand patients with IS could be treated. The sensitivity analysis reveals that the result of the cost minimization analysis and the budget impact analysis remain stable when both the amount of the population and the cost of 1 mg of mexidol vary from –10% to + 10%. Conclusions. Mexidol has the same efficacy as alternatives. However mexidol is superior to cytoflavin and actovegin in terms of cost minimization analysis. The savings from one course of alternatives will cover costs of treatment of five patients with IS using mexidol. The increase in the proportion of patients receiving mexidol is associated with savings, which allows us to consider mexidol therapy of mild IS as budget-saving in the Russian Federation. Keywords: pharmacoeconomics, indirect comparison, cost minimization analysis, budget impact analysis, neuroprotectors, ischemic stroke.


Evaluation of blood rheology by patients with acute ischemic stroke with Mexidol administration

Author:
D.M. PLOTNIKOV1, M.N. STEGMEIER1, O.I. ALIEV2

1 Department of Neurology and Neurosurgery, Siberian State Medical University, Tomsk, Russia;
2 Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia

Summary:
Objective. To study rheological properties of blood in patients with acute ischemic stroke treated with mexidol. Material and methods. Sixty patients with acute stroke, including 32 patients who received mexidol (500 mg/IV/20 days) and 28 people who received magnesium sulfate (2000 mg/IV/20 days) were examined. The control group included 20 people without a cardiovascular pathology. Blood rheology (viscosity of whole blood, plasma viscosity, hematocrit, aggregation and deformability of erythrocytes, fibrinogen level) was evaluated in patients three times: for the first 12 hours, 3—5 days and 18—20 days after hospitalization. Results. Hyperviscosity syndrome was observed in all patients with stroke. A significant decrease in blood viscosity was found in patients treated with mexidol: in the 3–5th day at low shear rates and in the 18—20th day at 3—100 s–1 shear rates. Significant differences in hematocrit (p=0.026) and fibrinogen levels (p=0.017) in patients treated with different drugs were found in the 18—20th day of the disease. Higher erythrocyte deformability index was recorded in patients treated with mexidol in the 3—5th day at shear rates of 90 and 890 s–1, in the 18—20th day at shear rates of 90—360 s–1. Conclusion. The study confirms the impact of mexidol on the fluidity of blood during the acute cerebral ischemia and shows its efficacy in reducing blood viscosity, decreasing the level of hematocrit and fibrinogen, increasing the deformability of erythrocytes.
Keywords: acute ischemic stroke, rheological parameters of blood, blood viscosity, erythrocytes deformability, mexidol (ethylmethylhydroxypyridine succinate), treatment of stroke.


Effect of mexidol on the efficiency of intravenous thrombolytic therapy for ischemic stroke during the therapeutic window

Author:
Knni K.S., Dyomin T.V., Adeeva L.B.
Interregional Clinical and Diagnostic Center, Kazan, Russia 12A, Karbyshev St., Kazan, Republic of Tatarstan 420101

Summary:
Objective: to evaluate the effect of intravenous mexidol on the efficiency of intravenous thrombolytic therapy (TLT) during the therapeutic window. Patients and methods. The retrospective study enrolled 123 patients with ischemic stroke (IS) who had undergone intravenous TLT in the vascular centers of the Republic of Tatarstan. The National Institutes of Health Stroke Scale (NIHSS) was used to assess the time course of changes in their neurological status. According to the baseline severity of a neurological deficit, all the patients were divided into three subgroups: 1) mild IS (<8 NIHSS scores at admission); 2) moderate IS (>8 scores); and 3) severe IS (<16 scores). All the patients underwent X-ray computed tomography at admission, at 24 hours after TLT, and in case of worsening of their health status. Results. The prehospital use of mexidol followed by TLT in patients with IS had a positive effect on the regression of neurological deficit regardless of the severity of the disease. There were significant differences in the degree of regression of neurological deficit according to NIHSS at 24 hours and 10 days after hospital admission in patients with severe IS, who received intravenous mexidol at the prehospital stage and who did not take this drug before TLT. The pre-TLT use of mexidol contributed to higher regression of neurological deficit. There was a lower frequency of hemorrhagic transformations in the patients who used mexidol at the prehospital stage versus those who did not. Conclusion. The findings demonstrate the positive effect of mexidol on the efficiency and safety of TLT in patients with IS.

Keywords: ethylmethylhydroxypyridine succinate; intravenous thrombolytic therapy; ischemic stroke; neuroprotective therapy.


Assessment of the efficacy of mexidol in the combination with hyperbaric oxygen in acute ischemic stroke

Author:
N.S. KULAI, E.YU. KOVALCHUK.
Saint-Petersburg I.I. Dzhanelidze research institute of emergency medicine, Saint-Petersburg, Russia.

Summary:
Objective. To study the efficacy of mexidol in the combination with hyperbaric oxygenation (HBO) in comparison with the standard HBO sessions in patients with acute ischemic stroke. Material and methods. One hundred and twelve patients were examined. In the main group, 48 patients underwent HBO and received treatment with mexidol. The control group consisted of 64 people who underwent the standard HBO sessions only. Results and conclusion. The use of combination therapy (HBO+mexidol) leads to the significantly more rapid normalization of acute phase indices which are correlated with neurological deficit reduction.

Keywords: ischemic stroke, hyperbaric oxygen therapy, mexidol.


An influence of submaximal (submineximal) doses of mexidol on oxidant stress and inflammation in the acute period of ischemic stroke

Author:
A.R. GODUNOVA, A.A. RAKHIMOVA, O.I. LEONTYEVA, I.G. TALIPOVA, R.M. YAKHIN, SH.G. MUSIN.
Emergency Hospital, Naberezhnye Chelny, Russia.

Summary:
Objective. To study an effect of submaximal doses of mexidol on the dynamics of biochemical markers of inflammation and damage to brain tissue in the acute period of ischemic stroke. Material and methods. A total of 60 patients admitted in the first 6h after disease onset with a verified ischemic stroke (7-9 points on the ASPECT scale) were enrolled in the study. Thirty patients in the study group received submaximal doses of mexidol: 750 mg infusion dropwise in 250 ml of 0.9% NaCl solution for 6 days. Thirty patients of the control group received standard therapy. Biomarkers and neurological status were evaluated within 60 minutes from the time of admission to the hospital and after 6 days. Results and conclusion. In both groups, the changes in CRP, IL-6, and fibrinogen did not contribute to the efficacy of mexidol. The brain natriuretic peptide (BNP) biomarker, plasma-A-associated pregnancy (PAPP-A) biomarker, average NIHSS score and mean cerebroasthenia score on the MFI-20 scale in the study group were significantly reduced compared to the control group. This study indicates a decrease in oxidative stress and signs of inflammation, a reduction of the severity of neurological deficit and an increase in physical activity of patients treated with submaximal doses of mexidol. Given the activation time of the damaged antioxidant system of the body, the recommended period of treatment is 3 months.

Keywords: antioxidant stress, inflammation, acute period, ischemic stroke, mexidol.


Modern strategies of protection of hypoxic-ischemic brain damage

Author:
S.N. YANISHEVSKY, N.V. TSYGAN, S.YU. GOLOKHVASTOV, R.V. ANDREEV, I.V. LITVINENKO, O.S. KARPOVA, V.A. YAKOVLEVA.
Kirov Military Medical Academy, St. Petersburg, Russia.

Summary:
Nowadays, there are two complementary approaches to treatment of patients with ischemic stroke: reperfusion and neuroprotection. The main purpose of neuroprotection is to intervene ischemic cascade at every stage of the pathological process and thus avoid the death of nerve cells and expand the therapeutic window for reperfusion therapy. The use of drugs with neurotrophic, antioxidant and neuroregenerative effects is pathogenically explained at all stages of post stroke rehabilitation. Ethylmethylhydroxypyridine succinate (mexidol) is a derivative of succinic acid with antihypoxic, membrane protective, nootropic, anticonvulsant and sedative action. The majority of researchers confirmed the positive effect of mexidol expressed as the marked regression of neurological deficit and wider opportunities for further early rehabilitation. The results of the randomized double blind multicenter placebo-controlled, parallel-group trial of the efficacy and safety of prolonged sequential therapy with mexidol in the acute and early recovery stages of hemispheric ischemic stroke (EPICA) were published in 2017. The results of the study showed the best positive dynamics of neurological function recovery in case of timely treatment with mexidol with the following two month therapy. The safety of the long-term use of mexidol was confirmed.

Keywords: stroke, acute period, neuroprotection, succinate, efficacy of treatment, safety of therapy.