Clinical effects of combined treatment by optimal dose of furosemide and spironolactone on diastolic heart failure in elderly patients

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1 890 Clinicl effects of combined tretment by optiml dose of furosemide nd spironolctone on distolic hert filure in elderly ptients ZHI HAO CHEN 1,2*, YU RONG JIANG 1,2*, JIA QIN PENG 1,2, JIA WANG DING 1,2, SONG LI 1,2, JIAN YANG 1,2, HUI WU 1,2 nd JUN YANG 1,2 1 Deprtment of Crdiology, The First College of Clinicl Medicl Sciences; 2 Institute of Crdiovsculr Diseses, Chin Three Gorges University, Yichng, Hubei , P.R. Chin Received November 20, 2015; Accepted December 30, 2015 DOI: /etm Abstrct. Distolic hert filure (DHF) is chrcterized by symptoms including reduced ventriculr relxtion nd complince, resulting in congestion of pulmonry nd systemic circultion. The curtive effects of regulr crdic gents re ineffective. Thus, new gents re required to tret chronic crdic filure. The im of the present study ws to exmine the clinicl effects of the combined tretment by optiml dose of furosemide (20 mg/dy) nd spironolctone (40 mg/dy) on elderly ptients with distolic hert filure (DHF) [New York Hert Assocition (NYHA) 1 2 grde]. A totl of 93 ptients dignosed with DHF between Februry, 2013 nd Februry, 2014 were enrolled in the present study. The ptients were rndomly divided into the furosemide group (20 mg/dy, n=27), optiml dose group (20 mg/dy furosemide+40 mg/dy spirolctone, n=36), nd lrge dose group (40 mg/dy furosemide+100 mg/dy spirolctone, n=30). Following tretment for one month, comprison nd nlysis of the NYHA clss, left ventriculr ejection frction (LVEF) nd left ventriculr end distolic dimeter (LVEDD), left ventriculr wll segmentl motion mong the three groups were performed. The re hospitliztion rte of hert filure nd incidence of electrolyte disorder mong the three groups ws compred nd their differences nlysed. Compred with pretretment, the NYHA clssifictions of the three groups fter tretment were reduced nd differences were sttisticlly significnt (P<0.05). By contrst, for the NYHA clssifiction fter tretment there ws no sttisticl significnce (P>0.05). Compred Correspondence to: Dr Jun Yng, Deprtment of Crdiology, The First College of Clinicl Medicl Sciences, Chin Three Gorges University, 183 Yiling Rod, Yichng, Hubei , P.R. Chin E mil: zhihochen008@163.com * Contributed eqully Key words: furosemide, spironolctone, elderly, distolic hert filure, left ventriculr ejection frction, left ventriculr end distolic dimeter, electrolyte with pretretment, LVEF of the optiml dose group incresed, LVEDD decresed, nd the verge systolic myocrdil pek velocity nd erly distolic myocrdil pek velocity of ventriculr wll motion were reduced, with differences being sttisticlly significnt (P<0.05). By contrst, in the furosemide nd lrge dose groups no sttisticl significnce ws identified before nd fter the tretment (P>0.05). Improvement of the optiml dose group following tretment ws more significnt thn the remining two groups, nd differences were sttisticlly significnt (P<0.05). The re hospitliztion rte of hert filure nd incidence of electrolyte disorder in the optiml dose group following tretment were significntly less thn the other two groups, nd differences were sttisticlly significnt (P<0.05). In conclusion, the optiml dose (20 mg/dy furosemide+40 mg/dy spirolctone) significntly improved the clinicl symptoms of elderly DHF ptients (NYHA 1 2 grde) nd meliorted their long term prognosis. Introduction Distolic hert filure (DHF) is syndrome chrcterized by symptoms including norml ventriculr systolic functions, nd reduction of ventriculr relxtion nd complince, which leding to n increse in ventriculr filling volume nd filling pressure, thereby resulting in congestion of pulmonry nd systemic circultion (1). Elderly individuls hve higher incidence of hypertension, coronry hert disese nd dibetics s well s higher proportion of DHF in the erly stges. Previous findings hve shown tht the proportion of DHF on elderly ptients ws 56.4%, which ws higher thn tht of systolic hert filure (SHF) (2). The curtive effects of regulr crdic gents, vsculr diltion drugs, hydrgogue, nd neuroendocrine ntgonists in treting DHF re inferior to SHF. Furosemide is type of diuretic drugs tht is used long term. Although it did not reduce the deth rte, furosemide significntly improved clinicl symptoms s well s curtive effects (3). In the guidelines issued by Europe nd Americ in 2012, spirolctone ws considered I drug nd smll dose ws recommended for the tretment of chronic crdic filure (4). In ddition, its nti ventriculr remodeling effect ws comprble to ngiotensin converting

2 CHEN et l: COMBINED TREATMENT ON DIASTOLIC HEART FAILURE IN ELDERLY PATIENTS 891 enzyme inhibitor (ACEI) drugs (4). However, dt for the effect of the clinicl ppliction of these two types of drugs re not vilble. Consequently, in this study we nlyzed the clinicl effects of the combined tretment by optiml dose of furosemide (20 mg/dy) nd spironolctone (40 mg/dy) to elderly ptients with DHF [New York Hert Assocition (NYHA) 1 2 grde] to provide new pproch for clinicl tretment. Mterils nd methods Generl mterils. A totl of 93 ptients tht were dignosed with DHF t the Deprtment of Crdiology t the Yichng Centrl People's Hospitl between Februry, 2013 nd Februry, 2014 were enrolled in the study. Of the 93 ptients, 49 cses were mle nd 44 cses femle, ged yers, with n verge of 75.8±6.6 yers nd course of disese of 2 13 yers, with n verge of 7.2±1.5 yers. Of the 93 ptients 28 cses were hypertensive, 16 cses hd dibetes, 31 cses hd coronry hert disese nd 9 cses hd cerebrl infrction. The dignosis of DHF ws confirmed by the Europen Society of Crdiology (2012) dignostic criteri: i) ptients were ccompnied with obvious crdic filure clinicl performnce; ii) ptients whose left ventriculr systolic functions were impired; nd iii) ptients whose left ventriculr systolic functions were norml nd LVEF >50%. The exclusion criteri for the study were: i) ptients with dilted crdio myopthy, rheumtic vlvulr hert disese, serious myocrditis nd other crdic orgnic diseses; ii) ptients with severe heptic renl dysfunction, peptic ulcer nd other severe digestive trct diseses s well s mlignnt electrolyte disorder; nd iii) ptients with severe rrhythmi, chronic obstructive pulmonry disese, pernicious nemi nd ptients tht declined inclusion for the study. Approvl for the study ws obtined from the Ethics Committee of the Centrl People's Hospitl of Yichng. Informed consent ws provided by the ptients nd their reltives. The ptients were rndomly divided into the furosemide group (20 mg/dy, n=27); optiml dose group (20 mg/dy furosemide+40 mg/dy spirolctone, n=36); nd lrge dose group (40 mg/dy furosemide+100 mg/dy spirolctone, n=30). Differences with regrd to ge, gender, disese course nd complictions betweent the three groups were not sttisticlly significnt (P>0.05). Experimentl method. Prior to tretment, the ptients were required to ccept disese ssessment to dignose cuse of hert filure. For the ptients with severe myocrdil ischemi, revsculriztion tretment ws pplied nd bsic drugs included clcium ion ntgonists, ACEI drugs nd β blockers. As for ptients with complictions such s hypertension nd dibetics, proper ntihypertensive nd hypoglycemic therpy were pplied. After tretment for 1 month, the NYHA clssifiction, left ventriculr ejection frction (LVEF), left ventriculr end distolic dimeter (LVEDD), nd left ventriculr wll segmentl motion were compred for the three groups nd the differences nlyzed. The re hospitliztion rte of hert filure nd incidence of electrolyte disorder for the three groups were compred nd the differences nlyzed. Echocrdiogrphy exmintion ws performed s per the suggestion of the Americn Society of Echocrdiogrphy (5). MyLb 50 (Esote, Shnghi, Chin) ws used nd the trnsducer frequency ws set t MHz, the section on left ventriculr long xis ws produced nd M mode ultrsonogrphy ws used to generte the end distole t 1 cm under the vlvul bicuspidlis. Subsequently, the LVEDDs were observed, section ws mde on stndrd picl 4 chmber nd the nteroposterior (A P dimeter) nd superoinferior dimeters of the left trium were mesured. The Simpson double method ws employed to observe nd mesure the volume of the left trium nd clculte the LVEF. Doppler imging ws pplied to tissues to mesure the motion velocity spectrum of the mitrl ring long the long xis crdic muscle tissues in the inferior wll, side wll, ventriculr septum nd front wll. Sttisticl nlysis. The sttisticl softwre pckge SPSS 18.0 (SPSS, Inc., Chicgo, IL, USA) ws used to process the dt. Mesurement dt were presented s mens ± stndrd devition. Anlysis of vrince ws used for comprisons between groups. Enumertion dt were presented s cse or percentge. The χ 2 test ws used for comprisons between groups. P<0.05 ws considered to indicte sttisticlly significnt difference. Results Comprisons of NYHA clssifiction, LVEF nd LVEDD for the there groups of ptients. Comprisons of the differences between NYHA clssifiction, LVEF nd LVEDD were crried out for the three groups prior to tretment. No sttisticl significnce ws identified (F=0.524, P=0.307, F=0.526, P=0.331, F=0.347, P=0.625, P>0.05). By contrst, the NYHA clssifictions of the three groups fter tretment s compred to the pretretment vlues were reduced nd differences were sttisticlly significnt (furosemide group: 1.2±0.4 vs. 1.6±0.3, t=4.967, P=0.038; optiml dose group: 1.3±0.5 vs. 1.8±0.4, t=5.124, P=0.036; lrge dose group: 1.3±0.6 vs. 1.7±0.5, t=4.768, P=0.039; P<0.05). Differences in the NYHA clssifiction for the three groups fter tretment were not sttisticlly significnt (F=0.639, P=0.812, P>0.05). Compred with pretretment, LVEF of the optiml dose group incresed, LVEDD decresed nd the differences were sttisticlly significnt [(63.8±2.1) vs. (55.7±1.5)%, t=5.124, P=0.036; (56.9±2.3) vs. (63.4±1.5) mm, t=5.524, P=0.034; P<0.05)] wheres comprisons in the remining two groups prior to nd following tretment were not sttisticlly significnt (LVEF: furosemide group: t=0.624, P=0.332; lrge dose group: t=0.754, P=0.421; LVEDD: furosemide group: t=0.421, P=0.213; lrge dose group: t=0.724, P=0.632; P>0.05). Improvement of the optiml dose group following tretment ws more significnt thn the remining two groups nd differences were sttisticlly significnt (F=5.526, P=0.027, F=5.938, P=0.023) (P<0.05; Tble I). Comprisons on ventriculr wll motion for the three groups of ptients. Differences on the verge systolic myocrdil pek velocity (Sm) nd erly distolic myocrdil pek velocity (Em) for the three groups prior to tretment were

3 892 Tble I. Comprisons of the NYHA clssifiction, LVEF nd LVEDD for the three groups of ptients. NYHA clssifiction LVEF, % LVEDD, mm Group Pretretment Post-tretment Pretretment Post-tretment Pretretment Post-tretment Furosemide 1.6± ± ± ± ± ±2.1 Optiml dose 1.8± ± ± ± ± ±2.3 Lrge dose 1.7± ± ± ± ± ±1.8 F-vlue P-vlue P<0.05 sttisticlly significnt. NYHA, New York Hert Assocition; LVEF, left ventriculr ejection frction; LVEDD, left ventriculr end distolic dimeter. Tble II. Comprisons of ventriculr wll motion for the three groups of ptients. Averge Sm, cm/sec Averge Em, cm/sec Group Pretretment Post-tretment Pretretment Post-tretment Furosemide 12.3± ± ± ±1.4 Optiml dose 13.5± ± ± ±1.5 Lrge dose 12.6± ± ± ±1.3 F-vlue P-vlue P<0.05 sttisticlly significnt. Sm, systolic myocrdil pek velocity; Em, erly distolic myocrdil pek velocity. Tble III. Comprisons of the re-hospitliztion rte of hert filure nd incidence of electrolyte disorder for the three groups of ptients [cse (%)]. Group Cse Re-hospitliztion rte of hert filure Incidence of electrolyte disorder Furosemide 27 7 (25.9) 4 (14.8) Optiml dose 36 5 (13.9) 3 (8.3) Lrge dose 30 6 (20.0) 4 (13.3) χ 2 test P-vlue <0.001 <0.001 P<0.05 sttisticlly significnt. not sttisticlly significnt (F=0.634, P=0.103, F=0.653, P=0.417; P>0.05). Compred with pretretment, the verge Sm nd Em in the optiml group following tretment were gretly reduced nd differences were sttisticlly significnt (t=6.124, P=0.015, t=6.302, P=0.018; P<0.05). Comprisons in the remining two groups prior to nd following tretment were not sttisticlly significnt (verge Sm: furosemide group: t=0.825, P=0.424; lrge dose group: t=0.937, P=0.632; verge Em: furosemide group: t=0.535, P=0.257; lrge dose group: t=0.627, P=0.439; P>0.05). Improvement of the optiml dose group following tretment ws more significnt thn the furosemide nd lrge dose groups nd differences were sttisticlly significnt (P<0.05; Tble II). Comprisons of the re hospitliztion rte of hert filure nd incidence of electrolyte disorder for the three groups of ptients. The re hospitliztion rte of hert filure nd incidence of electrolyte disorder in the optiml dose group following tretment were significntly less thn the furosemide nd lrge dose groups nd differences were sttisticlly significnt (X 2 =6.159, P=0.046, X 2 =6.910, P=0.032) (P<0.05; Tble III). Discussion DHF is chronic congestive hert filure chrcterized by reduced ventriculr relxtion nd complince (2). It is cliniclly independent disese tht usully occurs prior to SHF.

4 CHEN et l: COMBINED TREATMENT ON DIASTOLIC HEART FAILURE IN ELDERLY PATIENTS 893 Clinicl studies hve shown tht DHF ptients ccount for lmost 50% of the totl hert filure ptients nd the mjority of these ptients re elderly individuls. DHF hs seriously ffected qulity of life of the elderly (6). In the clinicl set up, most of the tretment experience ws from SHFs nd tretment on DHF minly consisted of SHFs. However, internl mechnisms of the two diseses were mrkedly different, thus, their curtive effects re notbly different (7). There is different frme of reference regrding the ppliction of diuretic furosemide nd spirolctone. In one study, in which ptients were initilly dministered smll dose of furosemide, suggested their seprte use (8). The dose ws grdully incresed nd spirolctone ws dministered only to prevent electrolyte disturbnces. Although this first line tretment ws sfe, the course of tretment ws conducted over long period of time. Results of tht study showed tht short term curtive effects were not significnt, long distnce nti ventriculr remodeling effects were wek, symptoms of hert filure occurred repetedly, the condition of the disese ws grdully excerbted resulting in poor prognosis (9,10). Other studies recommended dministering tretment with lrge dose of furosemide nd spirolctone to intensify the diuretic effects. Lrge dose tretment (40 mg/dy furosemide+100 mg/dy spirolctone) my exhibit improved diuretic efficcy in liver cirrhosis nd scites. However, this type of tretment my result in severe complictions, such s circulting hypovolemi nd electrolyte disturbnce in elderly DHF ptients. Additionlly, its nti ventriculr remodeling effects were mrkedly wek, nd in the short term, this my led to deteriortion of the ptients' condition. Consequently, its ppliction ws limited cliniclly (11-13). In the present study, we hve nlyzed the clinicl effects of the combined tretment by optiml dose of furosemide (20 mg/dy) nd spironolctone (40 mg/dy) on elderly ptients with DHF (NYHA 1 2 grde). The results showed sttisclly significnt decrese in NYHA clssifictions of the three groups following tretment. Additionlly, when compred with pretretment, LVEF of the optiml dose group incresed, LVEDD decresed, nd the verge Sm nd Em of the ventriculr wll motion were reduced. The differences were sttisticlly significnt while comprisons in the furosemide nd lrge dose groups prior to nd following tretment were not sttisticlly significnt. Improvement of the optiml dose group following tretment ws more significnt thn the remining two groups nd differences were sttisticlly significnt. The re hospitliztion hert filure rte nd incidence of electrolyte disorder in the optiml dose group following tretment were significntly less thn the remining two groups nd differences were sttisticlly significnt. LVEF nd LVEDD were used s sensitive indictors of ventriculr remodeling. Furosemide, s loop diuretic, my be used to improve fluid retention in the short term nd eliminte sodium nd potssium, nd its disturbnces on kidney, blood ft nd blood sugr were reltively wek (14). A review of the literture (12,13) hs shown tht 20 mg ws the optiml dose for diuresis on ptients with light nd moderte crdic filure nd long term tretment ws sfe nd effective. ACEI drugs my ntgonize stimultion of the renin ngiotension ldosterone system in hert filure ptients in compensted stge nd reduce the level of ldosterone. However, recent studies hve identified tht even tolerble dose of ACEI drugs my not reduce the level of ldosterone to stisfctory levels. This my be becuse produce nd metbolism of ldosterone hd bypssing wys. Therefore, the direct receptor ntgonist of ldosterone nd spirolctone, ws ble to produce fvorble effects. Findings from the EMPHASIS HF test hve confirmed tht the ldosterone receptor ntgonist, eplerenone, improved the clinicl prognosis of ptients with NYHA SHF (15). The pproprite dose of furosemide nd ldosterone my lso significntly improve the motion extent, speed nd hrmony of the left ventriculr wll nd is fvorble for the tretment of hert filures complicted by interventriculr hert block nd intrventriculr conduction dely. Relevnt studies (16) hve lso shown tht smll dose of spirolctone significntly reduces the proportion of hert filure ptients required to ccept crdic resynchroniztion therpy, significntly improve their long term survivl rte, nd reduce the extensive economic burden. Although the number of smples in the present study were reltively limited, we concluded tht the optiml dose (20 mg/dy furosemide+40 mg/dy spirolctone) significntly improved the clinicl symptoms of DHF in elderly ptients (NYHA 1 2 grde) nd hve good prognosis. References 1. 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