Ž. Europen Journl of Hert Filure 3 2001 351 357 Systemtic review of the impct of bet blockers on mortlity nd hospitl dmissions in hert filure Mrcelo C. Shibt,, Mrcus D. Flther,b, Duolo Wng c Clinicl Trils nd E lution Unit, Royl Brompton nd Hrefield NHS Trust, Sydney Street, SW3 6NP, London, UK b Imperil College of Science Technology nd Medicine, London, UK c London School of Hygiene nd Tropicl Medicine, London, UK Received 4 August 2000; received in revised form 2 Februry 2001; ccepted 12 Februry 2001 Abstrct Hert filure is common condition tht crries high burden of mortlity nd morbidity. Severl rndomised trils hve evluted the effects of bet blockers in hert filure. This pper gives systemtic overview of published rndomised trils of bet blockers in hert filure using stndrd methods. In ll, 22 rndomised controlled trils were identified with totl of 10 480 ptients, nd n verge of 11 months of tretment. The verge ge ws 61 yers nd 4% were femle. Most studies excluded ptients with severe hert filure. Deth rtes in ptients rndomised to receive bet blockers compred to controls were 458 5657 Ž 8.0%. nd 635 4951 Ž 12.8%. respectively, odds rtio 0.63, 95% CI 0.55 0.72, P 0.00001. Similr reductions were observed for hospitl dmissions for worsening hert filure Ž 11.3 vs. 17.1%, respectively, odds rtio 0.63. nd for the composite outcome of deth or hert-filure hospitl dmission Ž 19.4 vs. 26.9%, respectively, odds rtio 0.66.. These results show tht bet blockers reduce the risk of mortlity or the need for hert-filure hospitl dmission by pproximtely one third. Absolute reductions of 5 6% in event rtes were observed over pproximtely 1 yer of tretment period. These importnt benefits should be implemented s priority, since tretment with bet blockers is inexpensive nd hert filure crries high risk of deth nd disbility. Further informtion on the effect of bet blockers in elderly ptients nd women would be helpful. 2001 Europen Society of Crdiology. All rights reserved. Keywords: Bet blocker; Hert filure; Met-nlysis; Rndomised controlled tril; Systemtic review 1. Introduction Hert filure Ž HF. is ssocited with high rtes of mortlity nd morbidity nd is growing public helth problem. It is estimted tht 2 3% of the popultion in developed countries hve hert filure nd the mjority of these re people 65 yers 1,2. Hert filure is lso ssocited with high rtes of hospitl dmission. In the UK, it is estimted tht there re Corresponding uthor. Tel.: 44-20-7351 8827; fx: 44-20- 7351 8829. E-mil ddress: m.shibt@rbh.nthmes.nhs.uk Ž M.C. Shibt.. pproximtely 120 000 hospitl dmissions per yer, nd pproximtely six times this number in the whole of Europe 3. As consequence, the mngement of HF ccounts for between 1 nd 2% of the helthcre budgets in Western Europe nd the United Sttes 4,5. Estblished tretments for HF include ACE inhibitors nd diuretics. The use of bet blockers in HF hs been demonstrted to prevent deteriortion of myocrdil function, reverse the remodelling process, improve bet drenergic response nd reverse dverse effects of neurohormonl ctivtion 6 8. Systemtic reviews of the rndomised trils of bet blockers in hert filure hve shown beneficil effects on mor- 1388-9842 01 $20.00 2001 Europen Society of Crdiology. All rights reserved. Ž. PII: S 1 3 8 8-9 8 4 2 0 1 00144-1
352 ( ) M.C. Shibt et l. Europen Journl of Hert Filure 3 2001 351 357 tlity nd hospitl dmissions, but this evidence did not led to widespred use of these gents 9 13. Two lrge clinicl trils, Crdic Insufficiency Bisoprolol Study Ž CIBIS-II. nd Metoprolol CR XL Rndomised Intervention Tril in Congestive Hert Filure Ž MERIT-HF., hve been published subsequent to these systemtic reviews 14 16. We hve included CIBIS-II nd MERIT-HF in n updted systemtic review to provide more relible estimtes of the effects of bet blockers on mortlity nd hospitl dmissions in ptients with HF. 2. Methods 2.1. Dt identifiction There hve been five previously published metnlyses of bet blockers in hert filure tht hve brodly included the sme trils 9 13. To identify ny more recent trils, we used computerised bibliogrphic serch of the Medline dtbse ŽNtionl Librry of Medicine, Bethesd, Mrylnd. from Jnury 1998 to Jnury 2000, using the key words bet blocker, clinicl trils nd congestive hert filure. We lso hnd-serched bstrct reports from the min crdiology nd hert filure meetings for the period 1996 2000. We included trils tht fulfilled the following criteri: orl bet blocker compred to inctive control, rndomised lloction nd prllel group design. The primry outcome of interest ws mortlity, but we hve lso included informtion bout hospitlistion where vilble. This systemtic review ws restricted to dt published in mnuscript or bstrct form. We lso checked tht the previous met-nlyses hd covered ll rndomised trils published from 1975 up to 1997 by repeting the serch from Jnury 1970 to December 1999. Trils were excluded if they hd cross-over design or if mortlity dt were not vilble. 2.2. Sttisticl nlysis The estimted tretment effect, s the odds rtio of event between ctive tretment to plcebo, ws clculted for the met-nlysis. We excluded trils tht hd no events reported in either tretment group. We clculted pooled odds rtios with both the Mntel Henszel fixed effects model 17 nd the DerSimonin nd Lird rndom effects model 18. In ddition to incorporting vribility within studies, the rndom effects model lso incorportes the vrince of tretment effect mong studies, which gives the mgnitude of heterogeneity of tretment effect. Specil ttention ws pid to test the homogeneity mong different trils when performing the metnlysis. If the homogeneity test is sttisticlly significnt, it suggests tht the pooled effect does not represent ll trils included eqully well, nd the sources of heterogeneity should therefore be ppropritely investigted nd possibly controlled to void potentil bis 19. However, when heterogeneity does not exist, the fixed effects model my be more pproprite 18. The test for heterogeneity is crried out by clculting 2 sttistic. As this sttistic is not very sensitive, we considered the presence of significnt heterogeneity t the 10% level of significnce s evidence tht the rndom effects model would be more pproprite thn the fixed effects model. The results Ž shown lter. demonstrte tht there is no sttisticlly significnt heterogeneity mong the trils included for our three met-nlyses; therefore, we only report the results from the fixed effects model. 3. Results We identified 22 eligible studies 14,15,20 39 ŽT- ble 1.. Two lrge, rndomised clinicl trils were published in 1999 14,15. A totl of 10480 ptients were rndomised, 5507 to ctive tretment nd 4973 to control. We excluded eight trils from the nlysis becuse no deths were recorded in ny of them 22 26,30,31,33. 3.1. Ptient chrcteristics After pooling informtion from ll trils, the verge ge nd ejection frction were 61.6 yers nd 26%, respectively. Approximtely 4% of the ptients were femle. The etiologies of hert filure in these ptients were: coronry rtery disese Ž 52%.; nonischemic dilted crdiomyopthy Ž 33%.; idiopthic dilted crdiomyopthy Ž 14%.; nd hypertrophic crdiomyopthy Ž 0.3%.. The proportion of ptients who presented with NYHA functionl clss I, II, III nd IV were 1.4, 28.3, 63.3 nd 7.2%, respectively. Diuretics, ACE inhibitors, digitlis, nd vsodiltors were prescribed to 91, 91, 62, nd 26% of the ptients, respectively. Averge follow-up cross the studies ws pproximtely 11 months, nd verge complince to tretment t the end of follow-up ws 85%. 3.2. Tril tretment Of the 22 trils, two used bisoprolol, three bucindolol, eight crvedilol, seven metoprolol nd two nebivolol in double-blind, rndomised fshion nd in wide rnge of doses. The proportion of ll ptients treted with the forementioned bet blockers were 31, 2, 23, 42 nd 0.3%, respectively.
( ) M.C. Shibt et l. Europen Journl of Hert Filure 3 2001 351 357 353 Tble 1 Overview of rndomised, double blind, plcebo-controlled clinicl trils of bet blockde in hert filure ptients Tril Design Tretment Men ge FU All-cuse mortlity Mortlity hospitl dmission Ž yers SD. Ž yers. Treted Control Treted Control events totl events totl events totl events totl 20 Anderson RCT Metoprolol 12.5 50 51 13 1.6 5 25 6 25 mg bid Ž 20.0%. Ž 24.0%. 21 Engelmeier RCT, Metoprolol 6.25 100 51 8 0.8 1 9 2 16 double blind mg od over 4 6 weeks Ž 11.1%. Ž 12.5%. 22 Cucchini RCT, Metoprolol 6.25 100 1 12 0 8 single blind mg od Ž 8.3%. 23 Pollock RCT, Bucindolol 12.5 100 56 0.2 0 12 0 7 double blind mg od 24 Woodley RCT, Bucindolol 12.5 100 56 8 0.2 0 29 0 20 double blind mg over 4-6 weeks 25 Lecht RCT, Nebivolol 0.1 0 6 0 6 double blind 26 Wisenbugh RCT, Nebivolol 1 5 mgod 52 11 0.2 1 11 0 13 double blind Ž 9.0%. 27 MDC RCT, Metoprolol 10 150 mg 49 12 1.5 23 194 21 189 48 194 61 189 double blind over 7 weeks Ž 11.8%. Ž 11.1%. Ž 24.7%. Ž 32.2%. 28 Fisher RCT, Metoprolol 6.25 50 63 10 0.5 1 25 2 25 double blind mg bid Ž 4.0%. Ž 8.0%. 29 CIBIS RCT, Bisoprolol 1.25 5 mg 60 1 1.9 53 320 67 321 88 320 115 321 double blind od over 4 weeks Ž 16.5%. Ž 20.8%. Ž 27.5%. Ž 35.8%. 30 Metr RCT, Crvedilol 6.25 25 mg 52 10 0.3 0 20 0 20 double blind Bid 31 Eichorn RCT, Metoprolol 6.25 50 48 11 0.2 0 15 0 9 double blind mg bid 32 Bristow RCT, Bucindolol 12.5, 50 56 2 0.2 4 105 2 34 double blind nd 200 mg Ž 3.8%. Ž 5.8%. 33 Olsen RCT, Crvedilol 6.25 50 or 54 2 0.3 1 36 0 23 4 36 2 23 double blind 100 mg over 4 weeks Ž 2.7%. Ž 11.1%. Ž 8.7%. 34 Krum RCT, Crvedilol 25 mg bid 56 2 0.3 3 33 2 16 8 33 6 16 double blind Ž 9.0%. Ž 12.5%. Ž 24.2%. Ž 37.5%. 35 PRECISE RCT, Crvedilol 25 50 mg 61 11 0.5 6 133 11 145 double blind bid Ž 4.5%. Ž 7.6%. 36 US Crvedilol RCT, Crvedilol 6.25 up to 58 12 0.5 22 696 31 398 110 696 98 398 double blind 25 50 mg bid over Ž 3.2%. Ž 7.8%. Ž 15.8%. Ž 24.6%. 2 10 weeks Crvedilol RCT, Crvedilol 2 70 2 35 37 efficcy double blind Ž 2.8%. Ž 2.7%. 38 Colucci RCT, Crvedilol 12.5 50 mg 55 11 1 2 232 5 134 10 232 12 134 double blind bid over 6 weeks Ž 0.8%. Ž 3.7%. Ž 4.3%. Ž 8.9%. Austrli New RCT, Crvedilol 3.125 25 67 1.6 20 207 26 208 b 104 207 131 208 Zelnd Hert double blind mg bid over Ž 9.6%. Ž 12.5%. Ž 50.2%. Ž 62.5%. 39 Filure Group 2 5 weeks 14 CIBIS II RCT, Bisoprolol 1.25 10 mg 61 1.3 156 1327 228 1320 388 1327 463 1320 double blind over 5 weeks Ž 11.8%. Ž 17.3%. Ž 29.2%. Ž 35.0%. MERIT 15 RCT, Metoprolol 64 9 1 145 1990 217 2001 641 1990 b 767 2001 Tril double blind 12.5 200 mg Ž 7.2%. Ž 11%. Ž 32.2%. Ž 38.3. Crdiovsculr hospitl dmission. b All-cuse hospitl dmission. 3.3. Effect of bet blockde on ll-cuse mortlity The totl number of deths in ll 14 trils 14,15,20,21,27 29,32,34 39 ws 1065. The CIBIS-II nd MERIT-HF studies ccounted for 746 deths Ž 70% of ll deths.. Deths number of ptients rndomised to bet blockers compred to control were 440 5378 Ž 8.2%. nd 622 4642 Ž 13.3%., respectively, odds rtio 0.65, 95% CI 0.57 0.74, P 0.0001ŽFig. 1.. The test for heterogeneity mong the 14 trils ws not significnt: vrince mong studies 0; test for heterogeneity, 2 Ž 13. 8.44, P 0.81. 3.4. Effect of bet blockde on hospitlistion A totl of 1447 hospitlistions due to worsening
354 ( ) M.C. Shibt et l. Europen Journl of Hert Filure 3 2001 351 357 Fig. 1. The figure shows odds rtios nd 95% confidence limits for rndomised trils of bet blockers compred to control on: Ž. mortlity; Ž b. hospitl dmission; nd Ž c. the composite of mortlity or hospitl dmission. The squres or smll verticl lines represent the point estimtes for ech tril nd the horizontl lines the 95% confidence intervls. Arrows indicte tht the 95% confidence intervls lie outside the horizontl scle. The size of the squre is pproximtely proportionl to the sttisticl weight of the tril in the met-nlysis. Trils represented by smll verticl line hve the lowest sttisticl weight. Dimonds represent the pooled estimte nd 95% confidence intervls. Heterogeneity-test P vlues for mortlity, hospitl dmissions nd the composite of mortlity or hospitl dmission were 0.81, 0.95 nd 0.73, respectively. hert filure were obtined from 13 trils 14,15,21,24,27 29,32,34 36,38,39. CIBIS II nd MERIT-HF contributed with 391 nd 494 events respectively, Žtogether representing 61% of the hospitlistions.. Hospitlistions occurred in 613 5301 Ž 11.5%. nd 833 4827 Ž 17.2%. in ctive nd plcebo groups, respectively, OR 0.63, 95% CI 0.56 0.71, P 0.0001, Ž Fig. 1b.. Of the trils, 13 did not show heterogeneity in terms of odds rtio for hospitlistion vri- nce mong studies 0; test for heterogeneity, 2 Ž 12. 5.00, P 0.95. The combined endpoint of ll-cuse mortlity or hospitl dmission for hert filure ws vilble from nine trils 14,15,27,29,33,34,36,38,39. Events ptients rndomised in treted nd control groups were 1071 5035 Ž 21.2%. nd 1327 4610 Ž 28.7%., respectively, OR 0.68, 95% CI 0.61 0.75, P 0.0001 ŽFig. 1c.. There is no significnt heterogeneity mong these nine trils in odds rtio t the level of 10% vrince mong studies 0; test for heterogeneity, 2 Ž. 8 5.22, P 0.73. 4. Discussion Our nlysis shows cler reltive risk reduction in mortlity mong ptients rndomised to bet blocker compred to control of pproximtely 35%. The bso-
( ) M.C. Shibt et l. Europen Journl of Hert Filure 3 2001 351 357 355 lute difference in mortlity rtes ws 5.1%, indicting tht tretment of 20 ptients for pproximtely 12 months would void one deth. The bsolute difference in hospitl dmissions for hert filure ws 5.7%, indicting tht pproximtely 16 ptients should be treted over pproximtely 1 yer to void one dmission. Together, MERIT-HF nd CIBIS II provide dt on pproximtely 65% of the totl ptients rndomised in the 14 trils. In MERIT-HF, s well s in CIBIS II, the risk reduction ws pproximtely one third, nd bsolute risk reductions were 3.9 nd 5.5%, respectively. MERIT-HF nd CIBIS II hve provided substntil extr informtion to strengthen nd extend the findings of the previous met-nlyses. The Bucindolol Evlution Survivl Tril Ž BEST. Žpresented t the Americn Hert Assocition meeting, Atlnt 1999. evluted the effects of bucindolol in 2708 ptients with hert filure NYHA clss III or IV Ž ejection frction 35%. 40. The tril stopped erly fter men follow-up of 24 months with 33% deths in the plcebo group compred to 30% deths in the bucindolol group. There ws no pprent beneficil effect of bucindolol on mortlity. The Crvedilol Prospective Rndomized Cumultive Survivl Tril Ž COPERNICUS. study evluted the effects of crvedilol in 2289 ptients with hert filure nd men ejection frction of 29%. The tril Žpre- sented t the Europen Society of Crdiology meeting, Amsterdm, August 2000. ws stopped erly due to reduction in the risk of deth of 35% in ptients rndomised to crvedilol compred to plcebo Ž130 deths mong 1156 ptients rndomised to crvedilol nd 190 deths mong 1133 in plcebo, OR 65, 95% CI 0.52 0.81, P 0.00014.. If these results re incorported into the systemtic review, the odds rtio for the effect of bet blockers on mortlity would be 0.71, 95% CI 0.64 0.78, P 0.0001. Thus, the inclusion of these recent trils results only hs modest impct on the mgnitude of the tretment effect observed in the systemtic overview of the published trils. In 1995, $3 400 000 000 billion Ž $5153 per dischrge. ws pid to Medicre beneficiries in the United Sttes for congestive hert filure, which is the single most frequent cuse of hospitlistion for people ge 65 nd older 41. The demonstrtion of reduction in hospitl dmissions for ptients with hert filure, using simple intervention such s bet blocker dministrtion, is likely to hve n importnt impct in qulity of life nd helth economics, since hert filure ccounts for lrge proportion of hospitl dmissions due to crdiovsculr disese. Five previous met-nlyses published between 1996 nd 2000 were identified 9 13. These reports did not incorporte the results from MERIT-HF nd CIBIS II. Aggregte proportionl reductions in mortlity observed in the previous met-nlyses were 31, 31, 28, 31 nd 29%, respectively. These reductions re entirely consistent with the results of CIBIS-II nd MERIT-HF. This consistency supports the relibility of the reductions in the risk of mortlity nd hospitl dmissions of pproximtely one third observed in our nlysis. Risk reductions observed with bet blockers in hert filure re mong the lrgest therpeutic benefits observed in importnt clinicl outcomes. Limittions of the current study include those common to ny systemtic review, such s publiction bis, missing dt, retrospective nlyses, heterogeneity between studies, nd inccurte estimtion of risk. The other importnt limittion is the use of tbulr dt Ž i.e. dt obtined from published reports.. This pproch does not llow nlysis of effects of bet blockers in importnt clinicl subgroups, such s the elderly, or those with more dvnced hert filure. A recent systemtic overview of individul ptient dt from more thn 12 000 ptients of the effect of ACE-inhibitors in ptients with left ventriculr dysfunction nd hert filure showed n bsolute reduction of 3.8% on deth or hospitl dmissions in those rndomised to ACE-inhibitors 42. The effect of bet blockers on mortlity in hert filure ptients is comprble nd is dditionl to the effect of ACE-inhibitors. Further rndomised trils of bet blockers in hert filure re being crried out, including Crvedilol or Metoprolol Europen Tril Ž COMET., Crvedilol Post-Infrct Survivl Control in LV Dysfunction Ž CAPRICORN. 43 nd Study of the Effects of Nebivolol Intervention on Outcomes nd Rehospitlistions in Seniors with Hert Filure Ž SENIORS.. The results of these studies will enhnce our knowledge of the effect of bet blockers in different types of ptients with hert filure. 5. Conclusion The effects of bet blockers in reducing mortlity nd the need for hospitl dmission due to HF in brod rnge of ptients re drmtic. These importnt benefits should be implemented s priority, since bet blocker tretment is inexpensive nd HF crries high risk of deth nd disbility. Further informtion on the effect of bet blockers in elderly ptients nd women would be helpful. References 1 Schoecken DD, Arriet MI, Leverton PE. Prevlence nd mortlity rte of congestive hert filure in the United Sttes. J Am Coll Crdiol 1992;20:301 6.
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( ) M.C. Shibt et l. Europen Journl of Hert Filure 3 2001 351 357 357 37 US Crvedilol Hert Filure Study Group. Crvedilol efficcy in severe hert filure. Proceedings of the Crdiorenl Advisory Pnel Meeting of the Food nd Drug Administrtion, 2 My 1996, 1996 Protocol 239. 38 US Crvedilol Hert Filure Study Group, Colucci WS, Pcker M, Bristow MR et l. Crvedilol inhibits clinicl progression in ptients with mild symptoms of hert filure. Circultion 1996;94:2800 6. 39 Austrli New Zelnd Hert Filure Reserch Collbortive Group. Rndomized, plcebo-controlled tril of crvedilol in ptients with congestive hert filure due to ischemic hert disese. Lncet 1997;349:375 80. 40 Anderson JL, Greenberg B, Boden W et l. Design of the bet-blocker evlution survivl tril Ž BEST.. Am J Crdiol 1995;75:1220 3. 41 1998 Hert nd Stroke Sttisticl Updte. Americn Hert Assocition, 1999. 42 Flther MD, Yusuf S, Købe L et l. E. Long-term ACE-inhibitor therpy in ptients with hert filure or left-ventriculr dysfunction: systemtic overview of dt from individul ptients. Lncet 2000;355:1575 81. 43 Drgie HJ. Design nd methodology of the CAPRICORN tril rndomised double blind plcebo controlled study of the impct of crvedilol on morbidity nd mortlity in ptients with left ventriculr dysfunction fter myocrdil infrction. Eur J Hert Fil 2000;2Ž. 3 :325 32.