EFFECTS OF FIXED COMBINATION OF LISINOPRIL PLUS HYDROCHLOROTHIAZIDE ON REGRESSION OF LEFT VENTRICULAR HYPERTROPHY IN PATIENTS WITH ESSENTIAL HYPERTENSION : AN OPENED , MULTI-CENTRE , PROSPECTIVE CLINICAL TRIAL

The aim of this trial was to examine the effects of antihypertensive fixed combination of lisinopril plus hydrochlorothiazide (Lopril H, Bosnalijek dd, Bosnia and Herzegovina) on regression of left ventricular hypertrophy in patients with essential arterial hypertension. We included 297 patients in our trial, aged 54.65+/-9.6 years, with treated or untreated hypertension and with high risk of cardiac events, in an opened trial of therapy based on lisinopril plus hydrochlorothiazide. Patients from five European countries were followed up for a period of 12 weeks. Duration of treatment was 12 weeks. We adjusted daily doses of lisinopril plus hydrochlorothiazide after every clinical examination and recorded adverse effects of drugs. In the beginning and after 12 weeks of treatment, 277 patients (93.2%) underwent 2-dimensional echocardiography and there were 186 patients evaluated for efficacy of treatment on left ventricular hypertrophy (LVH). We recorded a regression of index mass LVH (168.56 vs 161.51 g/m2, P<0.0001), and regression was something more in women vs men. We recorded average reduction of left ventricular mass index for patients with LVH (N=186) by 7.05 g/m2 (4.18%) in all patients, by 6.73 g/m2 (3.93%) in men and 7.27 g/m2 (4,37%) in women. The proportion of patients who attained a regression of left ventricular mass tended to be greater in men (54.55% vs 53.21%). This research has proved regression of LVH in more than 53% patients after using fixed combination of lisinopril plus hydrochlorothiazide.


Introduction
Left ventricular (LV) hypertrophy is a strong predictor of cardiovascular morbidity and mortality in the general population, and particularly in patients with hypertension.Regression of LV hypertrophy by antihypertensive therapy appears to reduce the risk for developing cardiovascular complications.Consequently, reversal of LVH is an important goal of antihypertensive therapy.Angiotensin converting enzyme (ACE) inhibitors reduce LV mass to a greater extent than other antihypertensive drug classes, when equivalent levels of blood pressure reduction are achieved.Th is provides strong evidence for the role of the renin-angiotensin-aldosterone system in the development or maintenance of LV hypertrophy.
The aim of this trial was to examine influence of fixed combination lisinopril plus hydrochlorothiazide (Lopril H, Bosnalijek dd, Bosnia and Herzegovina) on regression of left ventricular hypertrophy in patients with essential arterial hypertension.

Patients and Methods
The trial was open, multi-centre, prospective, clinical trial lasting  weeks per patient.Totally  subjects with essential hypertension were included in the trial, both genders aged  to  years.Total duration of the trial per patient was  weeks.Th e following examinations and measuring were performed prior to including into trial: Blood pressure and pulse Echocardiography (of heart obligatory LVMI -left ventricle mass index) Average age of all patients included into trial was ,±, years, and  women and  men were included into trial.On the basis of initial results of echocardiography we found  patients with left ventricular hypertrophy.Average duration of illness for all patients was around ,±, years.
In addition to high blood pressure, increased body weight (body mass index ,-, ) was present in  women and , men, and obesity (body mass index above ) was present in , women and  men, so that completely , women and , men had optimal body weight.

Abstract
Th e aim of this trial was to examine the eff ects of antihypertensive fi xed combination of lisinopril plus hydrochlorothiazide (Lopril H, Bosnalijek dd, Bosnia and Herzegovina) on regression of left ventricular hypertrophy in patients with essential arterial hypertension.We included  patients in our trial, aged ,±, years, with treated or untreated hypertension and with high risk of cardiac events, in an opened trial of therapy based on lisinopril plus hydrochlorothiazide.Patients from fi ve European countries were followed up for a period of  weeks.Duration of treatment was  weeks.We adjusted daily doses of lisinopril plus hydrochlorothiazide after every clinical examination and recorded adverse eff ects of drugs.In the beginning and after  weeks of treatment,  patients (,) underwent -dimensional echocardiography and there were  patients evaluated for effi cacy of treatment on left ventricular hypertrophy (LVH).We recorded a regression of index mass LVH (, vs , g/m  , P<,), and regression was something more in women vs men.We recorded average reduction of left ventricular mass index for patients with LVH (N=) by , g/m  (,) in all patients, by , g/m  (,) in men and , g/m  (,) in women.Th e proportion of patients who attained a regression of left ventricular mass tended to be greater in men (, vs ,).Th is research has proved regression of LVH in more than  patients after using fi xed combination of lisinopril plus hydrochlorothiazide.
KEY WORDS: essential hypertension, left ventricular hypertrophy, lisinopril, hydrochlorthiazide As an estimate of signifi cance of diff erences between the average measuring, signifi cance was taken of P<,.

Methods
Th e study was done in compliance with Guidelines for Good Clinical Practice and Helsinki Declaration of the World Medical Association and all patients provided written informed consent before the beginning of the study.This -week opened prospective clinical trial was done at  centres in fi ve European countries.After  weeks of washout period for patients receiving antihypertensive medications, patients entered the study.Patients were followed up for period of  weeks and duration of treatment was  weeks.We adjusted daily doses of lisinopril plus hydrochlorothiazide (Lopril H, Bosnalijek dd, Bosnia and Herzegovina) after every clinical examination and recorded adverse eff ects of drugs.LVH was documented by echocardiogram (Devereux criteria [LV mass index ≥ g/m  for men and≥ g/ m  for women]) ().

Results
Total number of  patients (ITT) were included in the trial,  patients completely fi nalised the trial (by trial protocol, PP, ,), and for  patients we did not make analyses of echocardiography (,).Reasons for giving up the trial are not related to side-eff ects of drugs, nor intolerance to medicines, but they are linked to patients' non-cooperation in the trial (e.g.irregular coming to control check-ups and irregular administration of therapy).We made analysis of blood pressure for all included patients (n=) in the trial, and average lowering was accomplished for sys/dia BP ,mmHg/,mmHg, or by ,/,.Analysis of results has shown that we obtained the best results in medication's eff ect on the systolic blood pressure, where lowering was accomplished in all the groups from , to ,, while differences between baseline and fi nal values of diastolic blood pressure by groups were from , to ,.Treatment with  ).We recorded average reduction of left ventricular mass index for patients with LVH (N=) by , g/ m (,) in all patients, by , g/m (,) in men and , g/m (,) in women.The proportion of patients who attained a regression of left ventricular mass tended to be greater in men (, vs ,).This research has proved regression of LVH in more than  patients after using fixed combination of lisinopril plus hydrochlorothiazide.

Discussion
LV hypertrophy is an important determinant of cardiovascular morbidity and mortality (,), and reduc-tion of LV hypertrophy with antihypertensive therapy reduces the number of cardiovascular events (,).One of the most important prognostic factors in hypertension is electrocardiographic or echocardio- Posterior wall thickness at end diastole PWTd (mm) 11. graphic left ventricular hypertrophy, with the latter already present in as many as  of patients with newly diagnosed hypertension.In a multicenter observational study of hypertensive patients with no prior history of cardiovascular or renal disease, echocardiographic left ventricular hypertrophy at baseline was accompanied by a three-fold increase in the cumulative -year incidence of cardiovascular events ().Because of the firmly established prognostic significance of left ventricular hypertrophy, numerous studies have examined the ability of antihypertensive therapy to cause regression of left ventricular hypertrophy.Meta-analyses estimate that left ventricular mass can be reduced by  to  with an ACE inhibitor, ARB, or CCB;  with a thiazide diuretic; but only  with a β-blocker.In contrast, in patients undergoing valve replacement for aortic stenosis, nearly complete surgical normalization of systolic load results in a rapid and dramatic  reduction in left ventricular mass.The comparatively disappointing eff ects of the antihypertensive drug trials are likely to be related to the incomplete normalization of systolic load in monotherapy trials ().Despite the impressive body of randomized clinical trial data, it remains to be determined whether even intensive antihypertensive therapy can completely normalize the excessive risks of cardiovascular and renal disease associated with untreated hypertension.In a large hypertensive referral clinic in Gothenburg, Sweden, treatment of hypertension in initially middle-aged men to a goal of / to  mm Hg with diuretics and β-blockers for  years did not completely normalize the risk of myocardial infarction.The persistently elevated risks in the treated patients were related to the existence of associated risk factors, such as cigarette smoking and elevated blood lipid levels, and emphasize the need for global risk reduction and larger reductions in blood pressure.Randomized trials have not yet established whether even lower blood pressure goals than those presently endorsed would produce further reductions in cardiovascular morbidity and mortality and in the risk of end-stage renal disease.Because of their relatively short duration (typically less than  years), randomized trials underestimate the life-time protection against premature disability and death afforded by several decades of antihypertensive therapy in clinical practice.In the Framingham Heart Study, treatment of hypertension for  years in middle-aged adults reduced total cardiovascular mortality by , which is considerably greater than the results of most randomized trials despite the less intense treatment guidelines when therapy was initiated in the s to s ().We used fixed combination of two antihypertensives lisinopril and hydrohlorthiazid (Lopril H, Bosnalijek dd, Bosnia and Herzegovina).The efficacy can be seen in the reduction of systolic and diastolic pressure, and this research has proved regression of LVH in more than  patients after using fixed combination of lisinopril plus hydrochlorothiazide.

Conclusion
Th is research has proved good effi cacy and tolerability of fi xed combination of lisinopril plus hydrochlorothiazide (Lopril H, Bosnalijek dd, Bosnia and Herzegovina) and in more than  patients recorded regression of left ventricular hypertrophy.Separate Th is trial is supported by pharmaceutical company Bosnalijek dd, Jukićeva , Sarajevo, Bosnia and Herzegovina.
analyses were made in statistical programme MedCalc for Windows, version ... (MedCalc Software, Mariakerke, Belgium).Results are shown through the usual descriptive statistics and paired samples T-test.

TABLE 1 .
Baseline characteristics and risk factors of the patients VJEKOSLAV GERC ET AL.: EFFECTS OF FIXED COMBINATION OF LISINOPRIL PLUS HYDROCHLOROTHIAZIDE ON REGRESSION OF LEFT VENTRICULAR HYPERTROPHY IN PATIENTS WITH ESSENTIAL HYPERTENSION: AN OPENED, MULTICENTRE, PROSPECTIVE CLINICAL TRIAL

Table  ;
GERC ET AL.: EFFECTS OF FIXED COMBINATION OF LISINOPRIL PLUS HYDROCHLOROTHIAZIDE ON REGRESSION OF LEFT VENTRICULAR HYPERTROPHY IN PATIENTS WITH ESSENTIAL HYPERTENSION: AN OPENED, MULTICENTRE, PROSPECTIVE CLINICAL TRIAL Figure VJEKOSLAV

TABLE 4 .
Echocardiography results of men with LVH included in trial (n=77) Legend: SD -standard deviation, *p<0,05.VJEKOSLAV GERC ET AL.: EFFECTS OF FIXED COMBINATION OF LISINOPRIL PLUS HYDROCHLOROTHIAZIDE ON REGRESSION OF LEFT VENTRICULAR HYPERTROPHY IN PATIENTS WITH ESSENTIAL HYPERTENSION: AN OPENED, MULTICENTRE, PROSPECTIVE CLINICAL TRIAL
VJEKOSLAV GERC ET AL.: EFFECTS OF FIXED COMBINATION OF LISINOPRIL PLUS HYDROCHLOROTHIAZIDE ON REGRESSION OF LEFT VENTRICULAR HYPERTROPHY IN PATIENTS WITH ESSENTIAL HYPERTENSION: AN OPENED, MULTICENTRE, PROSPECTIVE CLINICAL TRIAL