COMPARISON OF NEW GENERIC AND ORIGINAL RAMIPRIL IN PATIENTS WITH ARTERIAL HYPERTENSION AND HIGH CARDIOVASCULAR RISK

S.Yu. Martsevich, Yu.V. Lukina*, N.A. Dmitrieva, O.V. Lerman, S.N. Tolpygina, A.A. Serazhim, V.P. Voronina, M.A. Maksimova, L.Yu. Drozdova, A.V. Zakharova 1 State Research Center for Preventive Medicine of Rosmedtechnology. Petroverigsky per. 10, Moscow, 101990 Russia 2 Chair of Evidence Based Medicine, Moscow Medical Academy named after I.M.Setchenov. Bolshaya Pirogovskaya ul. 6, Moscow, 119991 Russia

Цель исследования -изучение эффективности нового дженерического препарата рамиприла Хартила ® в сравнении с оригинальным препаратом Тритаце ® у больных эссенциальной АГ 1-2-й степени с высоким сердечнососудистым риском.Также изучалась возможность достижения целевого уровня артериального давления (АД) при отдельном приеме каждого препарата и в ком-The problem of choice of effective and safe drug still remains topical in practical medicine.Nowadays all drugs are divided into two groups: original and generic (copied).Generics make it possible to decrease treatment costs significantly.Due to lower cost generics are available to more number of patients.That is why generic sales increase all over the world.To be registered in Russia equivalence of a generic to an original drug by its quantitative and qualitative structure, physical and chemical properties and equivalence of pharmacokinetic must be estimated.Deviations of these parameters permitted by the Russian legislation lead to registration of drugs with the same international unlicensed name as an original one but with significantly discrepant therapeutic efficacy and safety.That is why comparative studies of new generics and original drugs are of great importance.
The original ramipril in Russia is Tritace (Sanofi-Aventis, France).Several generics of ramipril were launched during the last few years, one of them is Hartil (Egis, Hungary).Comparative study of generic and original ramipril is relevant.Bioequivalence of the original and a generic drug, which is required for registration, must be confirmed in clinical study of generic efficacy and safety.
The aim of our study was to evaluate efficacy of the new ramipril generic Hartil ® in comparison with the original product -Tritace ® in patients with essential HT of 1-2 degree and high cardiovascular risk.Target blood pressure (BP) achievement when taking each drug separately or in combination with calcium channel blocker amlodipine (if necessary) was studied as well.

Patients
Patients with HT of 1-2 degree: 140<sBP<180 mm Hg and/or 90<dBP<110 mm Hg and high risk of cardiovascular complications were selected for the study (sBP -systolic BP, dBP -diastolic BP).High cardiovascular risk was determined by combination of HT with IHD, diabetes, stroke (in history).Patients with secondary HT; severe chronic heart failure (NYHA III-IV); valvular heart diseases; arterial hypotension; myocardial infarction; severe liver and kidney diseases; unstable angina; severe concomitant diseases that

Comparison of new generic and original ramipril in hypertensives / Сравнение нового дженерика и оригинального рамиприла у больных АГ
Рациональная фармакотерапия в кардиологии 2010;6 (1) demand permanent taking of drugs that influence BP, atrioventricular block of II-III degree; sinoatrial block; bradycardia (heart rate <50 beats per min); bronchial asthma; severe peripheral arterial disorders; high sensitivity to any component of examined medicines were not included into the study.

Design of the study
This was an open, randomized, crossover, comparative study.The study protocol was approved by the Ethical committee of the State Research Center for Preventive Medicine.Each patient gave written informed consent to participate in the trial.Fig. 1 shows the plan of the study.
Each patient, that participated in the study received Hartil and Tritace one after another.Succession of drug administration was randomized.Wash out period of 7 days during which patients were not receiving any antihypertensive drugs preceded treatment with each drug.The exception was made for β-blockers in patients after myocardial infarction (in this case the dose was stable during the whole study).In other patients β-blockers were terminated according to the scheme with the following 7-day wash out period.Nitrates in patients with IHD, and "vascular" therapy in stable doses in patients with previous stroke were allowed as well.
Duration of each drug treatment was 6 weeks.Treatment efficacy evaluation and dose correction were made every 2 weeks.If the treatment was not efficient during first two weeks the dose was doubled.According to clinical guidelines of the European Society of Cardiology the target BP for hypertensive patients with high risk is below 130/80 mm Hg [14].If the target BP (<130/80 mm Hg) was not achieved after 4-week treatment with ramipril, amlodipine was added (Cardilopin, Egis, Hungary).
The drugs were administered once a day in the morning.The initial dose of ramipril was 5 mg/d.Amlodipine was prescribed in dose of 5 mg a day.BP (in sitting posi-
Antihypertensive therapy was stopped for 7 days after 6 weeks of treatment with the first randomized drug.Then the other drug of ramipril was administered, and the treatment was conducted according to the same scheme.
ECG was registered at the beginning and at the end of the study.

Individual efficacy analysis
Antihypertensive effect of the studied drugs was evaluated by BP level (change from the base level after 6-week treatment).The drug was considered effective at BP below 130/80 m Hg (target BP achievement in HT patients with high risk).

Statistical analysis
Data were processed with the program package STATISTICA 6.Standard methods of descriptive statistics were applied (means and standard deviations calculation).Parametric (Student's t-test) and nonparametric criteria (χ 2 , Fisher's exact test) were used for data comparison.Data are presented as M±σ (M -mean, σ -standard deviation).Differences were considered significant at p<0,05.

Results
A total of 30 patients were included in the study, but 3 patients withdrew their consents after the screening visit, before randomization, so final analysis included 27 patients.Among those -14 men (52%) and 13 women (48%) aged 45-83 years, the mean age was 65,8±9,0 years old.HT duration ranged from 1 to 40 years with the mean value of 17,3±11,5 years.All the patients had HT of 1-2 degree: 22 patients -degree 1 and 5 patients -degree 2. Sixteen patients had IHD (six of them had previous myocardial infarction and received β-blockers in doses fixed at the first visit), 6 patients had type 2 diabetes, combination of IHD and type 2 diabetes was registered in 4 patients, and 1 patient had previous stroke.
Twenty five patients of 27, included in the statistical analysis, finished the therapy with both drugs entirely.Two patients completed 6-week treatment with only one drug.One of them received Hartil and quitted the study because of a side effect development.The second one completed the course of Tritace treatment and refused to further participation in the study for the reason not connected with the drug therapy.Thus, 26 patients with HT and high risk of cardiovascular complications received 6-week Hartil treatment, and also 26 patients -treatment with Tritace.циента имели сочетание ИБС с СД 2-го типа, 1 пациент перенес мозговой инсульт.
Patients were randomized into two groups: the patients of the first group initially received Hartil, while the patients of the other group -Tritace.No significant differences in age, anthropometric data, hemodynamic parameters and diseases determining high risk were revealed in the groups (Table 1).
Both drugs had moderate antihypertensive effect, which increased at combined therapy.There were no significant differences between the drugs concerning BP level and heart rate.Fig. 2 and 3 show sBP and dBP dynamics compared to baseline at treatment with each drug.

Clinical efficacy (individual analysis)
According to individual analysis, target BP level at 5 mg of original ramipril (Tritace) was achieved in 3 patients.Twenty three patients required doubling the dose, and 5 mg of Cardilopin was added for 16 patients.Hartil in the initial dose (5 mg) was ineffective in high-risk patients, and dose doubling was necessary for all 26 patients.At that, 20 patients besides dose doubling required Cardilopin administration (Fig. 4).
Target BP was reached in 10 patients, who received Hartil and in 13 patients, treated with Tritace.Difference between the drugs was not significant (at comparison of rel-

Treatment safety
Side effects were infrequent at ramipril treatment and were registered in only 4 patients, all the cases -at Hartil therapy, however one of them was connected with Cardilopin treatment (ankles edema).Side effects registered during the study are listed in Table 3.
There were no significant differences in safety indices between the studied drugs (p=0,11; the Fisher's exact test).

Discussion
According to HOPE trial results ACE inhibitor ramipril significantly decreases initially high risk of cardiovascular complications [15].That is why prescription of this drug to patients with HT of 1-2 degree with high risk due to combination of HT with IHD, diabetes or previous stroke is fully justified.According to European Society of Cardiology guidelines [14] the target BP of hypertensive patients with high and very high risk of complications must be below 130/80 mm Hg.
Results of the study show that the target BP in patients with HT of 1-2 degree and high cardiovascular risk can be achieved at ramipril treatment (both original and generic) in doses not less than 10 mg per day.However in most cases monotherapy turns out to be ineffective in such patients and does not allow reaching the target BP.Treatment with the new ramipril generic Hartil in dose of 10 mg/day (monotherapy) resulted in the target BP achievement in less than one third of the patients (27%), and in combination with amlodipine 5 mg -in less than a half of the patients (38,5%).Thus, combined therapy (ramipril and amlodipine) increases treatment efficacy.
These results are in line with a number of large clinical trials data, which showed that antihypertensive monotherapy seldom allows reaching the target BP level, especially in patients with high risk of cardiovascular complications [16][17][18].So, according to ACCOMPLISH trial results, 38% of high-risk patients received three or more antihypertensive drugs at the beginning of the study, at that only 37% of the patients had BP below 140/90 mm Hg [19].That is why in accordance with European Society of Cardiology guidelines [14] combined antihypertensive therapy should be administered to patients with high cardiovascular risk if BP exceeds the target level by more than 20/10 mm Hg.
Hartil therapy demanded addition of amlodipine more often compared to Tritace treatment.Tritace was also more efficient in combined therapy with Cardilopin, which allowed to achieve the target BP in 50% of the patients.However these distinctions between both studied drugs efficacy were not significant.

Conclusion
Therapeutic equivalence of the new generic ramipril Hartil to the original drug Tritace was demonstrated in patients with HT of 1-2 degree and high cardiovascular risk.However efficacy of ramipril monotherapy in hypertensive patients with IHD, diabetes and previous stroke was low.Combined treatment with two antihypertensive drugs was efficient in 40-50% of cases.

Figure 3 .Figure 4 .
Figure 3. dBP change in the course of the treatment (∆ dBP)

Table 1 .
Baseline characteristics of the groups

Table 2 .
The drugs efficacy evaluation (in accordance to visit number)

Table 3 .
Side effects frequency