ROLE OF BISOPROLOL ADDING TO ANGIOTENSIN CONVERTING ENZYME (ACE) INHIBITOR AND FUROSEMIDE COMBINATION ON THE LEFT VENTRICULAR FUNCTION IN SYSTOLIC HEART FAILURE PATIENTS

ROLE OF BISOPROLOL ADDITION ON ANGIOTENSIN CONVERTING ENZYME (ACE) INHIBITOR AND FUROSEMIDE COMBINATION ON THE LEFT VENTRICULAR FUNCTION IN SYSTOLIC HEART FAILURE PATIENTSEfta Triastuti, M.Farm.Klin., Apt.Study Program of Pharmacy, Faculty of Medicine, Brawijaya UniversityMalang-Indonesia12th Asian Conference on Clinical PharmacyHONG KONGGood afternoon ladies & gentlemen..AssalamualaikumFor the first let me introduce my self. My name is Efta Triastuti, I am a lecturer in study program of pharmacy, faculty of medicine, Brawijaya university, Malang, Indonesia Secondly, I am very grateful to all of you for being here and listening to my research presentation entitled role of bisoprolol addition on angiotensin converting enzyme inhibitor and furosemide combination on the left ventricular function in systolic HF patients. 1Definition HF can be defined as clinical syndromes which are caused by the impairment of heart function and related to various kind of heart diseases.HF syndrome may lead to the reduction of QOL with high morbidity and mortality rate2Background Routinely use of blockerTherapeutic guideline of heart failure from american heart association (AHA), Scottish Intercollegiate Guidelines Network (SIGN), and National Institute for Health and Clinical Excellence (NICE). Based on the result from several studies such as The Cardiac Insufficiency Bisoprolol Study (CIBIS), -Blocker Evaluation of Survival Trial (BEST), Metoprolol Randomised Intervention Trial in congestive heart failure (MERIT-HF), Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with Heart Failure (SENIORS) and Carvedilol Prospective Randomized Cumulative Survival trial (COPERNICUS) Recommend the routinely use of beta blocker for stable heart failure patients. Which found that beta blocker brought many benefits in QOL, morbidity and mortality if given to stable heart failure patients.Bisoprolol, carvedilol or nebivolol should be the beta blocker of first choice for the treatment of patients with chronic heart failure due to left ventricular systolic dysfunction.3 Blocker role on Heart FailureBISOPROLOLHigh 1 affinityLow effect on bronchusNo ISANo MSABeta blocker play role on the surge beta adrenergic activity in HF by block this activity will provide the reduction effect of excess beta adrenergic activity such as vasocontriction, sodium and water retention which lead to increase cardiac load and aggravate hypoperfusion due to inadequate ventricular ejectionOne of beta blocker which is recommended as the first choice therapy in stable HF is bisoprolol.This agent is available in IndonesiaThis agent has many benefits such as high affinity on beta one receptor that will bring lower risk of bronchospasm. This agent also does not have intrinsic sympathomimetic activity that will cause the more reduction in HR and provide the more adequate filling and loading time of left ventricle. Bisoprolol has no membrane stability activity that will provide the minimum effect on the cardiac conductance.4ObjectivesAnalyze Bisoprolol + optimum combination (ACE inhibitor & Furosemide)The aim of this study is to analyze the addition effect of bisoprolol on the optimum combination of ACE inhibitor & furosemide in systolic HF primarily in left ventricular function which affect to the QOL and the reduction of EF5Methods

Dr Saiful Anwar General HospitalCardiovascular Ambulatory ClinicBisoprolol 3 months Followed upChecked baseline Ejection Fraction & Quality of Life Questionnaire scoreChecked endpoint Ejection Fraction & Quality of Life Questionnaire score

1317Stage C Systolic Heart Failure PatientsReceiving Combination of ACE Inhibitor & Furosemide40-80 Years of Age (n=30)Quasi-experimental study used a one group pretest-posttest designAdded onThis was quasi-experimental study used a one group pretest-posttest design.Research was conducted in cardiovascular ambulatory clinic of Dr. Saiful Anwar General Hospital Malang, Indonesia between february 2011 to january 2012. 13 women and 17 men with stage C systolic heart failure who receiving an optimum combinatio of ACE inhibitor and furosemide were recruited Bisoprolol was added on after baseline EF by echocardiography & QOL by Minessota Living with Heart Failure questionnaire measurementThen followed up for 3 monthsAnd checked end point EF & QOL6Inclusion CriteriaInclusion criteria for patient recruitment were:Stage C chronic & stable HFHad EF reductionReceiving optimum combination dose of ACE inhibitor & furosmideFulfill for bisoprolol indication7Exclusion CriteriaWhereas exclusion criteria were:already accepted bisoprolol before recruitmentAcute HF & needed positive inotropic except digoxinComorbid condition which affect to QOL such as MR, AF & cardiogenic shockBradycardia with HR below 60 x per minuteHypotension with systolic pressure below 100 milimeter of mercurySevere asthma8Ejection Fraction

Ejection fraction was measured by 2 expert in operating echocardiography with Simpson method as a gold standard.This method measures the ventricular volume in the end of diastolic phase and systolic phaseThe volume of end diastolic & systolic phase are being used to calculate the EF with this formula9Quality of Life21 questions each contained 6 choice answers based on the symptom frequenciesThe more frequent symptoms the higher questionnaire scoreThe worse heart failure condition & the higher impact on QOLWhile QOL measured by Minnesota Living with HF questionnaire which contain of 21 questions & each question contained 6 choice answers based on the symptom frequenciesThe more frequent symptoms resulted in the higher questionnaire scoreIts mean the worse heart failure condition & the higher impact on QOL10Statistical AnalysisComparison method:Gaussian distribution pair t-test analysisNon-Gaussian distribution Wilcoxon analysisStatistical analysis in this study is to compare mean baseline EF to mean endpoint EF and mean baseline MLHFQ score to mean endpoint MLHFQ score.If the data following Gaussian distribution then the comparison method used pair t test analysisWhile non-Gaussian distribution data were analyzed by Wilcoxon test 11Sample CharacteristicsChi-Square AnalysisSubjects recruitment was held on February to October 2011 & then we conducted sample screening to meet the inclusion & exclusion criteria, recruited subjects with a good adherence only found 30 patients.Comorbid disease, age, & sex were confounding factors that might have contribution to EF & QOLTherefore should be test the contribution by chi-square analysis12Chi-Square Analysis ResultsPercentage (%)P valueSex:MaleFemale 73.326,70.465Age:40 to 50 years old51 to 60 years old61 to 70 years old71 to 80 years old13.3304016,70.141History of previous illness:HypertensionIschemic heart disease + HTDiabetes Mellitus + HT26.753.3200.061P > 0.05 No significant contribution between those factors to EF or QOLChi-square analysis resulted that between sex, age, & history of previous illness had no significant contribution to EF & QOL showed with the P value more than 0.0513Ejection Fraction ResultsEF percentage (%)P valueMean baseline35.20 8.980.000Mean at 3rd months42.80 10.15The bar charts between mean EF percentage versus time of measurements (before & after Bisoprolol addition) showed the mean baseline EF with the red color & mean endpoint EF with blue color.The mean EF did not meet Gaussian distribution, therefore we conducted non-parametric test comparison in one group pretest-posttest design using Wilcoxon analysisWilcoxon test for EF showed that there was significantly difference between baseline EF & endpoint EF with P value lest than 0.00014QOL Questionnaire Score ResultsMean QOL Questionnaire ScoreP valueMean baseline54.93 9.610.000Mean at 3rd months48.27 8.57The bar charts between mean QOL questionnaire score versus time of measurements (before & after Bisoprolol addition) showed the mean baseline QOL questionnaire score with the green color & mean endpoint QOL questionnaire score with orange color.The mean QOL questionnaire score met Gaussian distribution, therefore we conducted parametric test comparison in one group pretest-posttest design using paired t test analysisPaired t test for QOL questionnaire score showed that there was significantly difference between baseline & endpoint QOL questionnaire score with P value lest than 0.00015Discussions Bisoprolol Decrease heart rateCardiac oxygen demand reductionischemic-related symptoms relieveQOL improvementAdequate filling & loading timeIncrease cardiac output by increasing stroke volume though heart rate declineIncrease Ejection Fraction by reduce blood volume which left in the ventricleInhibit renin releaseAldosterone antagonistic effectDecrease water & sodium retentionCardiac load reductionSlow down HF-related cardiomyopathy progressionNo ISA high effect on HR reductionNo MSA minimum effect on cardiac conductanceFrom this results we discussed that the characteristic of bisoprolol in ISA provide the high effect on HR reduction and bisoprolol characteristic in MSA provide the minimum effect on cardiac conductance.Bisoprolol act to decrease HR which provide Cardiac oxygen demand reduction that relieve ischemic-related symptoms & provide QOL improvement, besides the reduction of HR might provide Adequate filling & loading time which resulted in Increase cardiac output by increasing stroke volume though heart rate decline & Increase Ejection Fraction by reduce blood volume which left in the left ventricle.Bisoprolol also has a role to inhibit renin release which might provide Aldosterone antagonistic effect & caused Decrease water & sodium retention that brought to the Cardiac load reduction & Slow down HF-related cardiomyopathy progression

16ConclusionThis prospective study showed that the routine addition of Bisoprolol to ACE inhibitor and furosemide combination may significantly improve ejection fraction and quality of life in systolic heart failure patients (each by P = 0.000; 95% confidence of interval)Based on the result we might conclude that This prospective study showed that the routine addition of Bisoprolol to ACE inhibitor and furosemide combination may significantly improve ejection fraction and quality of life in systolic heart failure patients (each by P = 0.000; 95% confidence of interval) 17Terimakasih This is the end of my presentation. Thank you very much18