COMPARATIVE EVALUATION OF RISK FACTORS, TREATMENT PROFILE AND CLINICAL OUTCOMES OF HEART FAILURE PATIENTS

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1 INTERNATIONAL JOURNAL OF RESEARCH IN PHARMACY AND CHEMISTRY Available online at Research Article COMPARATIVE EVALUATION OF RISK FACTORS, TREATMENT PROFILE AND CLINICAL OUTCOMES OF HEART FAILURE PATIENTS Slowk Kalidas Prajapati 1*, P Sam. Daniel 1 and Parloop A. Bhatt 2 1Shri Sarvajanik Pharmacy College, Mehsana, Gujarat, India. 2L. M. College of Pharmacy, Ahmedabad, Gujarat, India *Corresponding Author: shlok.praj77@gmail.com ABSTRACT This study compares the efficacy of drugs with and Spironolactone with Eplerenone on the clinical outcome (LVEF) of Heart Failure patients. Among the guideline of Heart Failure the effectiveness of different drugs or class of drugs is different so this study helps us in understanding the nature drugs or class of drugs. The RALES trial demonstrated that spironolactone improved the prognosis of patients with heart failure (HF). However, it is unknown whether the discharge use of spironolactone is associated with better long-term outcomes among hospitalized systolic HF patients in routine clinical practice. This study examined the effects of spironolactone use at discharge on clinical outcome (LVEF) by comparing with outcomes in patients with similar class of drugs eplerenone. Same comparison was done for and and LVEF was compared. Along with LVEF, blood pressure was also compared. A retrospective cohort study using population-based administrative databases in CIMS hospital Ahmedabad from August 29 January 211. Each individual was observed before treatment and after 1 year of treatment. Total 732 HF patients were selected according to inclusion criteria from that 443HF patients were in group I comparison [ (n=318) with (n=125)] and 289 HF patients were in group II comparison [Spironolactone (n=216) with eplerenone (n=73)]. The outcome measures were blood pressure and LVEF. In group I ( and ) comparison both shown effective in reducing the BP and Improving the LVEF but the improve the LVEF better than.in group II comparison(spironolactone with eplerenone).the spironolactone was shown significant improvement in LVEF compare to eplerenone and change in BP was almost the same. In group I, shown better improvement in LVEF than but in BP no significant change was observed. In group II spironolactone shown significant change in improvement of LVEF than eplerenone and no identical change in BP was shown. Keywords: Heart Failure, Echocardiography, LVEF, BP. 741

2 INTODUCTION Heart failure is a clinical syndrome that can result from any disorder that impairs the ability of the ventricle to fill with or eject blood, thus rendering the heart unable to pump blood at a rate sufficient to meet the metabolic demands of the body. Heart failure is the final common pathway for numerous cardiac disorders, including those affecting the pericardium, heart valves, and myocardium. Diseases that adversely affect ventricular diastole (filling), ventricular systole (contraction), or both can lead to heart failure. The most common causes of heart failure are coronary heart disease (CHD), high blood pressure, and diabetes. Treating these problems can prevent or improve heart failure [1].The diagnosis of heart failure is confirmed based on Complete blood count, Chest x-ray, ECG, Echocardiography. The treatment guideline for the heart failure is,, aldosterone antagonist, Beta-blocker 1. Previous studies show that and provide powerful risk reduction in patients with heart failure and left ventricular dysfunction 2,3,4.Results from the randomized clinical trial RALES demonstrated that spironolactone significantly improved outcomes in patients with severe HF 5. In the EPHESUS, eplerenone, a selective aldosterone antagonist with less adverse effects than spironolactone, reduced the relative risk of death during a mean follow-up of 16 months when added to conventional treatment including ACE inhibitor or and β- blocker 6.At the present time, it is unknown if patients with diabetes, hypertension and heart failure who are intolerant of can get similar vascular benefits with an or not so the comparison of and was performed in the present study also the comparison of aldosterone antagonist agent eplerenone and spironolactone was performed and shown for their individual effect on clinical outcome (LVEF) of heart failure patients. The result of this present study will add the knowledge to existing knowledge of medical science. METHODS Study Population Retrospective, Single centric study involving patient with Heart failure at Care Institute of Medical Science (CIMS), Ahmedabad, From August 29 to January 211. A retrospective clinical analysis of 732 Heart Failure patients data was screened from 142 Heart Failure Patients based on echocardiography diagnosed and inclusion criteria study of protocol at CIMS hospital, Ahmedabad. From 732 HF patients 443 HF patients were in group I comparison that was (n=318) Compare with (n=125) and 289 HF Patients were in group II comparison that was Spironolactone (n=216) compare with Eplerenone (n=73). Parameters like treatment (Pharmacotherapy) and outcomes analyzed. The risk factors of cardiac failure and other co-morbid conditions recorded. Outcomes measures Number of co-morbidities as a risk factor for heart failure,change in SBP,DBP,Change in cardiac output (LVEF) measure in various categories of Drugs treatment. Statistical Analysis All analyses were performed utilizing graphpad prism software version 5.4, Continuous baseline and outcome variables are given as mean value ± SD (standard deviation) while discrete variables are given as absolute values and percentages, Comparison between continuous variables was performed using unpaired student t test while discrete variables were compared using a conventional chi-square test, A p value.5 was indicative of significance. RESULTS From 142 HF patients 732 HF patients who had Heart Failure and have LVEF < 55% were screened according to inclusion criteria of the study protocol for the comparison of the HF drugs. The baseline characteristic and prevalence of risk factors in 732 HF patients are shown in Table 1. From the table 1 in single risk factors the hypertension was 11.48%,diabetes was 1.11%, obesity 6.42%, F.CVD 6.97% and smoking was 6.15%.where as in the double risk factors HD was 5.33%,DO was 5.87%,HO was 2.46%,SO was 2.6% and others shown in table 1. In three risk factors HDO was 3.55%,STA was 3.28%,HFO was 2.87% and others as shown in table 1. The >3 risk factor was 6.83% and 6.69% HF patients had no risk factors. The mean age of the 732 HF patients was 55.82(Mean ±SD) and BMI was 24.54(Mean ±SD). Table 1 and Figure 1 shows that the prevelance of single and double risk factors 742

3 are more prominent in HF patients compared to more than two risk factors. In the 732 HF patients 443 HF patients were in group I comparison that is (n=318) Compare with (n=125) and 289 HF Patients were in group II comparison that is Spironolactone (n=216) Compare with Eplerenone (n=73). A clinical baseline characteristic of group I of both drugs ( and ) is shown in Table 2. Both these drugs were almost similar with regard to age, sex, presence of Medical history. The mean heart rate and the mean systolic blood pressure were similar in both the drugs. The medical history had almost same in both the drugs. In The hypertension was 54.4 % where as in hypertension was 53.6 %, diabetes mellitus in was 43.8 % and in was 44 %, F.CVD was 26.1 % in and in was 26.4 %, obesity in was 3.5 % and in was 31.2 % so in all that the medical history of both the drugs are almost same as shown in Figure 2. The use of concomitant medications during the follow-up period of 1 year is shown in Figure 3 Aspirin was 9.88 in and in 87.2%, Beta blocker was and 86.4% in and, Digoxin was 87.1% and 85.6 in and respectively and all other remaining drugs given as concomitants were almost the same so it can t affect the result of the present comparison study much so minimize the effect of the concomitants drugs on the results. In group I comparison among users 44% started on perindopril (4mg OD), 35% started on ramipril (2.5mg BD), 15% started on enalapril (2.5mg BD) and the remaining 6% started on other ACE inhibitors. Among users 26% started on losartan (25mg BD), 46% started on valsartan (4mg BD), and 28% started on telmisartan (4mg OD). The mean value and SD of SBP I and SBP II was ±12.74 and 12.78±16.43 in and in was SBP I ±12.53 and SBP II 119.9±14.6 The and both drugs decreased the SBP from before treatment and after one year treatment of and. The p value of systolic blood pressure of the and is shown significant as in Table 3, but the significant of p value shown only in DBP of and not in. The mean decreased of SBP in and graphically present in figure 4. Both of this drugs shown significant value of the p as both of this drugs are effective in reducing the systolic blood pressure and so effectively use in Heart failure. The mean percentage change of SBP by and is shown in figure 5. the was reduce mean % whereas reduce mean % so from the mean % of and there was no much difference was obtained from both drugs so both are effective in reducing in SBP. The mean value and SD of for the LVEF I and LVEF II were 29.64±6.69 and 31.64±7.31 and the mean and SD of for the LVEF I and LVEF II were 29.7±7.73 and 32±9.18 respectively. Both and had shown significant value of p as shown in Table 4 so both drugs are effective in increasing LVEF as clinical outcomes and so both effectively use in heart failure. The mean change of LVEF from before treatment to after 1 year of treatment with and is shown in figure 6. The mean percentage improvement of LVEF from before treatment to after 1 year of treatment with the comparative drugs ( and ) is shown in figure 7 from the mean percentage of improvement it can say that the was shown maximum improvement in LVEF than. The had 1.7 mean % improvement whereas had 6.74 mean % of improvement so is more effective in improving the clinical outcome (LVEF) than. A clinical baseline characteristic of group II of both drugs (Spironolactone and Eplerenone) is shown in Table 5. Both these drugs were almost similar with regard to age, sex, presence of Medical history. The mean heart rate and the mean systolic blood pressure were similar in both the drugs. In Eplerenone and Spironolactone comparison the dose of eplerenone was 25mg OD and spironolactone dose was 25mg OD. The medical history had almost same in both the drugs. In Spironolactone hypertension was 49.53% and in Eplerenone was 46.57%, Diabetes mellitus in Spironolactone was and in Eplerenone was 36.98%,F.CVD in Spironolactone was 18.98% and in Eplerenone was 19.17% all other medical history is shown in Table 5 so in all that the medical history of both the drugs are almost same as shown in Figure 8. The use of concomitant medications during the follow-up period of 1 year is shown in Figure 9.The use of was 39.35% and 39.72% in spironolactone and eplerenone, Use of was 8.33% and 9.58% in spironolactone 743

4 and eplerenone respectively. The Betablockers in Spironolactone was 63.42% and in Eplerenone was 64.38%, The digoxin in Spironolactone was 83.33% and in Eplerenone was 86.3%, Diuretics in Spironolactone was 1.64% and in Eplerenone was 12.32% and all other remaining drugs given as concomitants were almost the same so it can t affect the result of the present comparison study much so minimize the effect of the concomitants drugs on the results. In group II comparison the eplerenone dose was 25mg OD and spironolactone dose was 25mg OD. The mean value and SD of SBP I and SBP II were ±12.17 and ±15.22 in Spironolactone and in Eplerenone was SBP I ±12.58 and SBP II ± The Spironolactone and Eplerenone both drugs decreased the SBP from before treatment and after one year treatment of Spironolactone and Eplerenone as shown in Figure 1. The p value of systolic blood pressure of the Spironolactone and Eplerenone is shown significant as shown in Table 6, but the significant of p value was not shown in DBP of Spironolactone and not in Eplerenone.so both of these drugs are effectively useful in heart failure. The mean percentage change of SBP by Spironolactone and Eplerenone is shown in figure 11.The % mean reduction of SBP was 8.92(%) in Spironolactone whereas Eplerenone reduce 6.8 % mean as shown in figure 11. so from the mean % of Spironolactone and Eplerenone there was slightly difference was obtained from both drugs so both are effective in reducing in SBP. The Mean and SD of LVEF I and LVEF II was 28.65±6.71, 3.84±7.41 respectively in Spironolactone and in Eplerenone there were 29.93±7.53, 3.79±6.62 in LVEF I and LVEF II respectively shown in table 7. The difference between before treatment and after one year of treatment was significant in spironolactone. From the figure 12 the difference is shown between LVEF I and LVEF II. The p value was significant in spironolactone compare to eplerenone so from this comparative study the spironolactone shown positive improvement of clinical outcome (LVEF) than eplerenone. The percentage mean change of the LVEF was shown high in spironolactone than in eplerenone. The figure 13 shows clear that improvement of % mean change of LVEF was higher in spironolactone than eplerenone. DISCUSSION In the present study there was two groups in group I comparison of drugs and and in group II comparison of drugs Spironolactone and Eplerenone was done. Inhibition of the renin-angiotensin system, with angiotensin converting enzyme inhibitors () and angiotensin receptor blockers (s) has emerged as a cornerstone in the prevention and treatment of cardiovascular diseases. and provide powerful risk reduction in patients with heart failure and left ventricular dysfunction 2,3,4. To our knowledge, this study represents the comparative evaluation of and. In our comparative study of drugs and the results shows that both drugs shown their beneficial effect in reduction of blood pressure and improving the clinical outcome as a LVEF and both drugs shows significant p value between before and after 1 year treatment interval but the shows better improvement in increasing the LVEF as 1.7 % mean improvement than compare to the as 6.74 % mean improvement. In reduction of SBP, reduced % mean and reduced 12.14% mean so in reduction of SBP both drugs shown almost similar effect. The comparison of aldosterone antagonist s drugs spironolactone and eplerenone was done. Results from the randomized clinical trial RALES demonstrated that spironolactone significantly improved outcomes in patients with severe HF 5. In the EPHESUS, eplerenone, a selective aldosterone antagonist with less adverse effects than spironolactone, reduced the relative risk of death during a mean follow-up of 16 months when added to conventional treatment including ACE inhibitor or and β-blocker 6.In present comparative study (spironolactone and eplerenone) the effect of spironolactone on clinical outcome as LVEF of heart failure shown significant p value between before treatment and after 1 year of treatment whereas in the eplerenone the p value did not shown significant between before and after 1 year of treatment. The % mean improvement of LVEF in spironolactone was 7.64% mean whereas in eplerenone was a 2.87 % mean so from the results of our study the long term treatment of 1 year with spironolactone shown better improvement of clinical outcome (LVEF) than compare to the eplerenone. 744

5 CONCLUSION This study shows that in group I comparison ( with ), and shown improvement in LVEF of HF patients but the percentage mean improvement of LVEF was high in than and no significant change was observed in BP of users and users so in condition of patients intolerant both drugs can use as alternative to each other s and for better improvement of LVEF can use. In group II comparison (spironolactone with eplerenone), spironolactone shown significant improvement of LVEF in HF patients than eplerenone and no identical change in BP was shown so spironolactone used at discharge medications can improve the clinical outcomes (LVEF) of HF patients than eplerenone. This study shows that it is possible to implement a new treatment strategy which shown better improvement in clinical outcomes (LVEF) in comparison within the class of drugs and with other class of drugs. Although in long term studies with a larger population size are required to confirm the long term benefits of class of drugs and within the class of drugs in heart failure patients. Table 1: Baseline characteristics and Prevalence of Risk Factors Sr no. Characteristic Total(n=732) % 1 Age* 732(55.82±1.46) 2 BMI* 732(24.54±4.93) 3 Gender Male Female Single Risk Factor Hypertension Diabetes F.CVD Obesity Smoking Double Risk Factor HD DO HO SO DS DF FO ST Other combination Three risk factor HDO STA HFO HST STO >3 Risk Factor combination 8 No Risk Factor *Values are mean ± SD HD=hypertension+diabetes,DO=diabetes+obesity, HO=hypertension+obesity, SO=smoking+obesity,DS=diabetes+smoking, DF=diabetes+F.CVD,FO=F.CVD+obesity, ST=smoking+diabetes, HDO=hypertension+diabetes+obesity,STA=smoking+tobacco+alcohol, HFO=hypertension+F.CVD+obesity, HST=hypertension+smoking+tobacco, STO=smoking+tobacco+obesity. 745

6 Table 2: Characteristics of Cohort Groups of and (No. of HF Patients n= 443) Sr no. Characteristic (n=318) (n=125) P 1 Age(years)* 55.23± ± Gender Male 268(84.27%) 96(76.8%).64 Female 5(15.72%) 29(23.2%) 3 BMI* 24.64± ± Blood pressure(mm Hg)* SBP(mm Hg)* ± ± DBP(mm Hg)* 72.1± ± Heart Rate (beat/min)* 73.14± ± Medical History (%) Hypertension 173(54.4%) 67(53.6%).87 Diabetes mellitus 137(43.8%) 55(44%).86 Family history of CVD 86(26.1%) 33(26.4%).89 Obesity 97(3.5%) 39(31.2%).88 Smoking 76(23.89%) 29(23.2%).87 Tabacco 61(19.18%) 25(2%).84 7 Concomitant Drugs Use Aspirin 289(9.88%) 19(87.2%).24 Anticoagulants 247(77.67%) 93(74.4%).46 Antiarrhythmic 81(25.47%) 29(23.2%).61 Beta-blockers 267(83.96%) 18(86.4%).43 Calcium channel blocker 189(59.43%) 71(56.8%).61 Digoxin 277(87.1%) 17(85.6%).67 Diuretics 29(91.19%) 117(93.6%).4 Lipid lowering agents(statins) 217(68.23%) 83(66.4%).7 * Values are mean ± SD Table 3: Effect of and Influence on Systolic Blood Pressure and Diastolic Blood Pressure BP Mean (mmhg) (n=318) SD P value MEAN (mmhg) (n=125) SD P value SBPI SBP II % Change % Change DBP I DBP II % Change -.68 % Change Table 4: Clinical Outcome (LVEF) of and Parameter (n=318) (n=125) Left ventricular Ejection Fraction MEAN SD P MEAN SD P LVEF I LVEF II % Change

7 Table 5: Characteristics of Cohort Groups of Spironolactone and Eplerenone (No. of HF Patients n= 289) Sr Spironolacton Eplerenone Patients Characteristic no. e (n=216) (n=73) P value 1 Age(years) 55.76± ± Gender.27 Male Female BMI 24.11± ± Blood pressure SBP(mm Hg) ± ± DBP(mm Hg) 73.15± ± Heart Rate (beat/min) 74.14± ± Medical History (%) Hypertension 17(49.53%) 34(46.57%).66 Diabetes mellitus 86(39.81%) 27(36.98%).66 Family history of CVD 41(18.98%) 14(19.17%).97 Obesity 61(28.24%) 22(3.73%).75 Smoking 35(16.2%) 13(17.8%).76 Tabacco 2(9.25%) 8(1.9%).67 6 Concomitant Drugs Use 85(39.35%) 29(39.72%).95 18(8.33%) 7(9.58%).74 Aspirin 191(88.42%) 64(87.67%).86 Anticoagulants 132(61.11%) 46(63%).77 Antiarrhythmic 36(16.6%) 13(17.8%).82 Beta-blockers 137(63.42%) 47(64.38%).88 Calcium channel blocker 119(55.9%) 39(53.42%).82 Digoxin 18(83.33%) 63(86.3%).54 Diuretics 23(1.64%) 9(12.32%).69 Lipid lowering agents(statins) 132(61.11%) 46(63.1%).77 Table 6: Effect of Spironolactone and Eplerenone influence on Systolic blood pressure and Diastolic blood pressure Spironolactone Eplerenone P BP MEAN SD MEAN SD P value value SBP I(Pretreatment).1.1 SBP II(Post treatment) % Mean change -8.92% -6.82% DBP I (Pretreatment).4.51 DBP II (Post treatment) % Mean change -.95% -1.18% Table 7: Clinical outcome (LVEF) of Spironolactone and Eplerenone Parameter Spironolactone Eplerenone Left ventricular MEAN SD P MEAN SD P Ejection Fraction LVEF I LVEF II % change

8 14% Prevelance of Risk Factors (%) 7% 7% 31% 41% Single Risk Factors Double Risk Factors Fig. 1: Distribution of Risk Factors Three risk factors % of HF patients 1 5 Medical history Fig. 2: Previous Medical History of and drugs % of HF patients Aspirin Anticoagula Antiarrhyth Beta-blockers Calcium Digoxin Diuretics lipid Concomitant medication Fig. 3: Comparison of concomitant medication of and Mean SBP change (mmhg) * * SBP 1 SBP 2 Fig. 4: Mean change of systolic blood pressure in and (* p <.5) 748

9 ACE I % SBP change % SBP change Fig. 5: Mean percentage change of systolic blood pressure in and Mean change of LVEF (%) * * LVEF 1 LVEF 2 Fig. 6: Mean change of LVEF in and (*p<.5) Mean % of LVEF change Mean Percentage of LVEF change (%) Drugs 1.7 Fig. 7: Mean Percentage Improvement LVEF in and 749

10 % of HF patients 5 Spironolactone Eplerenone Medical history Fig. 8: Previous Medical History of Spironolactone and Eplerenone % of medication Aspirin Anticoagul Antiarrhyt Beta- Calcium Digoxin Diuretics Lipid Spironolactone Eplerenone Concomitant medication Fig. 9: Comparison of Concomitant Medication of Spironolactone and Eplrenone Mean SBP (mmhg) * * SBP 1 SBP 2 Spironolactone Eplerenone Fig. 1: Mean (±SD) change of systolic blood pressure of spironolactone and eplerenone(*p<.5) [Before treatment and After 1 year of treatment] 75

11 % Mean of SBP change % Mean of SBP change -8-1 Fig. 11: Mean Percentage Change of Systolic Blood Pressure in Spironolactone and Eplerenone Mean LVEF (%) * LVEF 1 LVEF 2 Spironolactone Eplerenone Fig. 12: Mean change of LVEF in Spironolactone and Eplerenone (*p<.5) [Before treatment and after 1 year of treatment] 1 5 % Mean change of LVEF % Mean change of LVEF Fig. 13: % Mean change of LVEF in Spironolactone and Eplerenone [Before treatment and after 1 year of treatment] 751

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