ARTICLES

Comparison of vasopeptidase inhibitor, omapatrilat, and on exercise tolerance and morbidity in patients with : IMPRESS randomised trial

.lean L Routeau, Marc A Pfeffer, Duncan ) Stewaft, Debra lsaac, Francois Sestler, Edmund K Kerut, Charles B Pofter, Guy Proulx, Chunlin Qian, Alan J Block. fot the IMPRESS investigators Summant imponart treatment fo. funher improving the prognosis and Eacl€round We aimed to assess in patlents with congestive well being of patients with this disorder. heart iailure whether dual inhibitjon of neutral endopeptidase Lancet 2000: 356: 615-20 and -converting enzyme (ACE) with the lntroduction inhibitor omapatriiat better than ACE va..opeptidase is Congestive hean failure is characterised by chronic inhibition alone with lisinooril on functional capacity and overactivation of sodium-retaining and warer-retaining clinical outcome. neurohormones. Overactivarion of these vasocotrstrictor Methods We did a prospective, randomised, dolble{lind, oeurohumoral rystems also leads to excessive cellular parallel trial of 573 patients with New York Heart Association growth, cardiac Ebrosis, and cellular toxicity.' Attenuating (NYHA) class ll-lv congestive heart tuilure, left-ventricular the effects of these neurohumoral systems has been one of ejection fraction of 40% or less. and receiving an ACE ;nhibitor. rhe most successfirl stmregies in lowering dre roorbidity and Patients were randomly assigned omapatrilat at a daily target monaliry of patients wift congestive heafi failure.l' dose of 40 mg (f=289) or lisincpril at a daiiy target dose of 20 Although the use of angiotensin-convening-en4me (ACE) mC fi=284J for 24 weeks. The primary endpoint was inhibirors and B-blockers has been beneficial in dris respect, improvement ln .naximum exerclse treadmill test (ETl-) at week the oudook of these patiens remains poor. Therefore, new 12. Secondary endpoints inciuded death and comorbid events srraregies to improve outlook need to be developed.l' indicative of worsening hean fairure. Human beings have developed several endogenous qstems overactivadon of Findlngs Week 12 ETT increased similady in the omapatrilat for countering the effects of vasoconsllictor neuroholmones.' grechanisrn is and lisinopril groups (24 us 31 s, p=0.45). The two drugs were One endogenous vasodilaror systems, whicb include natriuretic fairly well tolerated, bL.! there were fewer cardiovascular- peptides, nitdc oxide, and prostaglaldins.' These peptides system serious adverse events in the omapatrilat group than vasodilate and promote diuresis and natriuresis ard lessen in the lisinopril group (20 [7%] ts 34 172%1, p=0 04). There cellular gro*Th.'' In congestive heart failue, endogenous was a suggestjve trend in favour of omapatrilat on the vasodilator s,Etems are activated to try to compensate for combined endpoint of death or admission for worsening heart chronic acrivadoo of vasoconstriclor sodium and water- failure (p=0.052 hazard ratio 0.53 Cl0.27-1, o21) and a {95% retaiiing neurohormones. The vasopepddase inhibitos, a significant benefit of omapatrilat in the composite qf death, new class of pharmaceutical agents, have been shown to admission, or discontinuation of study treatment for worsening heighren activity of endogenous vasodilator qstems and (F0.035; heart failure 0.52 [0.28-0.96]). Omapatrilat reduce production of the vasoconstrictor aagioteasin Il.' irnproved NYHA class more tian lisinopril in patients who had Vasopeptidase ir-hibitors inhibit the activity of neurral (p=0.035), patients NYHA class lll and lV but not if with NYHA eodopeptidase, an erzJrEre rlEt metabolises endogenous class ll were included. vasodilator peptides, such as naEiuretic peptides (atrial, krt€Drstatlon Our findings suggest that omapatrilat could brain, and calcium-activated neutra.l protease), have some advantages over lisinopdl in the treatment of adrenomedullin, and .s Because these inhibirors patients with congestive heart failure. Thus use of belte! redress the imbalance between mdogenous \€scpeptidas€ inhibitors could constitute a potentially vasoconsu'ictor and vasodilalor substances in coagestive bean failue than does ACE iuhibition alone, they could be Gen6Bl Hospital, Unlv66ity o, Divblon of CardloloEy, Toronto more useful in treasnent ofpatieots with the disorder. Torooto, Eaton Nortt 1S12, Toronto MsG 2C4, 0l{, canada Ve did a randomised double-blind trial to compare dre {J L Rouleau ,lo); DMdon of Ca.dlology, Brlgh.m and Wom€n lisi:ropril exercise Hospltal, Hava.d luodlcal School, Boston, MA, USA effects of omapatrilat with those of on (M A Pfeffer MD); Dlvblon ot Cadlolog!,, St Ml.*la6l'a Ho3pttel, roleraoce in patiens with congestive hean hilure. We also tjnlvcrslty of Torofito (D Stewart MDI; Departm€rt ot Cardlology, assessed side-effecs ofthe treatments, effecrs on deadl rate, Foothllls Genoral H6pital, Uflivsrstty ot CalEary, Calg3ry and comorbid eveots for worsening hean failure. (D lssac MD)i Dopartment of Cadlology, Contre rlospltallor do l'Unlvorslts do Monir€alPavlllon Nolreoam., Monllral iletltod3 (F Sestier MD); Hean Cllnlc of Loulslana, Maroro LA, USA Omapatilat (E K Kerut vD); MldAmertca Cardiology Assoclate3, Kansas Clty, Omapatrilat (Br\1S- 186716) is rtre 6rsr of a oew class of MO, tlSA lC B Poner MD); olvblor o, Cardloloet, Montto.l Hea.t cardiovasolar agents terned vasopepddase inhibtors. (G Proulx MD); and Phamacoutlcal lnstttuie, Urlversity ol Mofitreal Omapatilat is an orally active, Iong actin& selecrive, Resoarch lBtttute. BrlstolMylr! Squibb' Pttncelon, NJ. IJSA competitive inhibitor of neutral endopeptidase (NEP; (C Qian Pho. A J tslock Pho) enkephalinase, nepritysin, EC 3.4.24.1 l) and angiotensin Co e3pofld6nce toi lean L Rouleau (e-mail: jtouleau@torhosp,loronto,on.aa) converting enz,me (ACE; EC 3.4.15.1) with similar K,

6t5 THE I-NCET'vol ,56'.{ugusr 19, 2000 ARTICLES

included in previous randomised trials of omapatilat were /.-5 ^H:. excluded. Aogiotensin-receptor antagonists, sodilatom // \- odre! thalr niu"ates, and inoropes other thaJr digoxin were o(-l/\ prohibited duling the study. Finaly, inability to give informed consent, or arry other medical disolder ,ud8cd by l\/) rhe investigator ro limit optimum participation in rhe srudy, were exclusion criteria. "\-.,^N7--..,7N..r, Randomisation and study Ueatment -Hrjl Ma-ximum-exerdon-exercise tolerance tests (ETI) were .4\ -\./,,t COOH undertaten wirh a modiEed Naughton protocol 2l-27 h tLi after adEriristialion of srudy and concomiEnr t-ttt cardiovascular drugs. ETTs had !o be limited by eirher -\-.-- dyspnoea o! fatigue. After inftial qualification and a screening ETT of less than 12 min, patients entered a Figure 1: Chemlcal structure ot o.napattllat placebo lead-in pedod, in which they did a qualiEcation Kivalues. neutml endopeptdase 8.9 iM, ACE 6.0.M. ETT thar had to be 2-12 o;nr, There were no time values for both NEP and ACE (6gure l), As a result, consraints oo the baseline ETT, and ir was done wiftin 9 omapauilat pormtiares multiple e[dogEtrous rasodilatory dals of 6e quali.Sing smdy. Padenls who met all enu'ance peptides including oaEiureric peptides (atrial, brain, and crireria sropped AcE-inhibiror trearmeot and were calcium acrivared neuEal protease), bradykinin, and randomised rhe nex day to active treatment with l0 mg adrenomedullin, while also ilhibiting the geleration of the omapatrilat riuated ro the target dose of 40 mg once daily, vasoconstrictive peptide, angiorensin [I. The chemical or 5 crg lisinopri.l once daily, titrated to 20 mg daily. Forced na-me is [4S-{4d(R*),7ql0aP] i-octahydrc-4-[2-mercap!q' titration to target or maximum tolerated dose was used at I -oxo-3-phenypropyl) amirol -5-oxo=7Il-pyddo [2, ] - weekly intervals for up to 3 weeks. We based the dose of bl [,3]-thiazephe-7-carborylic acid; its strucmre is shown omapatrilat on a previous long-term haemodynamic study in figule l. Omapatrilar has an oral bioavailability of about *rar showed significanr reduclion of pulmooary capillary- ,OYo, it ltrj,ay be given with or without food, its protein wedge pressure wirh 40 mg omapatrilat.o Administration of bind.ing is 8096, and it has a very large volume of concomitzat cardiovascular treau[ent was required on the distribution (1800 L) suggesting tissue penetrarioo. Time momings of titiation visits, but prohibited on the momings to maximurn concentrarion of an oral dose is about 2 h. lts oforher visis. rncluding those to assess exercise aime. effecrive balflife is 14 19 h. This dmg is metabolised ir rhe Assessment of pauents and endpoints liver. Omapatrilat forms disulphide bonds wth endogenous Clinical assessmenB were done weekly until week 3, and rhiols, and is extensively merabolised via S-merhylarion, rhen ar weeks 6, 12, lA, and 24. Full laboratory amide hydrol],sis, S-oxidation, and flucuronidation. There assessmeots were do[e at baseline, and at week l2 and 24, are no substantial conce[Eadons of acrive metabolites of abbreviared laboratory panels were obtained at all other omapauilat in plasma. About 80% of an intravenous and visits after randomisarioo. radioactive dose and 64% of a! oral radioactive dose were The primary endpoint was change in exercise duration recovered in urine, with less than l% excreted as from baselile ro week 12. Secondary endpoiflB were: tbe unchanged dn-rg (data available). Based on bio- combined endpoinr of death and admission for worsening transforsration data i.o viuo and in vivo, c!'tocbrome P450 hearr &ilure, and 6e combined endpoint of death and enzymes do not seem to be iavolved in 6e metabolism of coooolbidity for worsening heart faihre (admission, omapauilat. In-vitro studies show that omapaailat does not disconEinuaEion of srudy treaunenr, emergency-room visir inhibit P450 isoenzrnes CYP-1A2, CYP-344, CYP-2Cg, of dinical need for supplemental diuretic). Additional CYP-2C19, and CYP-2D6. Omapatrilat has no known endpoinc inc.luded NYHA firacriooal class, physicia! and irter"actioo wirh othe! . patient global .uisessment of healt-failure status at 24 Study population week. Safery assessment ttcluded occurence of tleaftreDt- We did the study in I 13 cenaes in ttre USA and Canada. emergent adveEs€ events, as well as clidcal laborarcry The study was approved by central or local-insdrution assesslrrent of raised concenrarions of senrm creatinine review boards. Patiens gave written informed consent. (>1.5 times baseline and >0.8 times limit of nomtal), blood Patiens werc aged at least l8 yea$, with stable (>3 urea niuogen (>2 times baseline and higher &rn upper months) s]'rptomatic heart fiilure (NYI{A tr-I$, limit of qormal), potassium, and liver-frlncdon tesB. A decreased left-ventricular ejection fraction, and receiving a scrious adverse evetrr was deEned as any of; fatal or life stEble (>4 weeb) dose of ACE inhibitors. Patients were tbreatening, peroaoendy disabling prolonging time speDt eligible if &ey had a seated systolic blood pressure of in hospita.l, an imponant medical eveot, congenita.l 90 Em Hg or highe! at raedomisatioa, but no uoconrolled anomaly, caocer, or overdose. hr?erteosioo or hisrory of acute coronary events o! We used equilibrium gated radioouclide veocicu- rerrascularisarioo procedures wirhin 3 mondrs. Patiens with loglaphy in a subset of 75 padenB to measure left seruE poulssiutrc oflcss than 3.5 or mor€ than 5 3 EtEloyL venticular and right ventricular volu.oes and ejecrion or creatinine of more than 221 p.$ollL were excluded as fracdons at baseline aad 24 week. Data were analysed by a were padents wirh transaminases more rhan twice &e uppe! core laboratory at the New England Medical Cerrae.'o limir ofoormal, leucocytes less than 3'0x l0'/L, neutrophils I 16 patienrs parricipared in the [eu$hormooe substudy. ofless than l 5x 10",{- o! platelets of Iess than 120x 10"/L. Before the moming dose of rhe sody drugs, a Yenous p-blockers were allowed ooly if they had been used fo! at camula was inserted into the patieut's anrecubital vein. least 6 monlhs, calcium-charrnel blockels were allowed only After 30 min, during which rhe patiens remained for coouol of atrial Ebrillation, and patiens who had been recumbent, about 28 EIL of blood was wfthdrawn,

616 THE l-rNCE-f . Vol 3t6. August 19,2000 ARTICLES centrifuged at 4"C, and rhe plasma srored at -80"C before omlc.t ih Lbhorl analysis. Plasma atrial natriuretic peptide, loreptrcphrine, {n:2891 {n:284) angiotensin tr, and endorhelin I wele ana.lysed" by a core laboratory at the MonEeal Hea.t Inslilute (Quebec, 227/62 224/& Canada). We measured plasma neulohormones at baselitre, 231 UA and week l2 and 24. 26 24 26 20 Statstical analysis 54.3 (10.7) 63.6 {10.0) We estimated that 532 pa(icipants (266 per gloup) would tl 186 175 at to a 30 s be needed ro provide 80% power ct=0'0i delefi t 100 107 ditrerence at weet 12 between the two treaunent groups 3 2 (SD 120 I. Patiencs who $opped taking study drugs were asked to relum to do ETTS at week l2 and 24, if medicaly 186 (641) 191(67X) rdiooa$ic dirated cadbmyopaor, 73 (2596) 65(23r) so that thc primary test for diference could be appropriate, 10 (3*) 9 (31) done by intention to treat. w'e did a secoodary a-nalysis to 1013$) 12 (4I) tes! for change in exercise performalce from baseline ro 1013*) 7 {31) weeks I 2 and 24 by A-\O!'A, with terms for baseline lvl..!lr,?n dlt (d6 ISDI) exercise dme and treaEnen!. Ttne-lo-event anallses for 5111159) 500{145) Lelr'v€ninc! a, eiecrion nacion (96) 28.4 {7 5) 27.E(7 5) monaliry afld comorbidir-v were based on Cox's Slandrng systoric blood Dressure (mm Hg) 126.6119.7) 725.7117-81 proportiona.l hazard reglession wirh reatment as the only stano ng diasto ic ilood pGssure imm Hg) 76.2 t10.6) 75.8 (10.1) covariant. Ve assessed ceatment difference in NYFIA sta.dng hean rate (bears/min) 79 6112-9) 79.5 (14.8) potassium (nhol/L) !.42 (0.39) 4.42{0.39) fulctional class a! week 24 wirh the Cochran-Mantel- seru!'r Serurn c,eathrne {snol/L) 103.!130.94) 101.7(27.41 Haenszel merhod (A"\OVA statistic, ranl< scores) Elood ul€a n rogen lmmol/LoI!a) 7.71(3.9) 7,4(3.1) coou:olli-ng for baseline class 'ithe last obseryadon was used 'W'e for patiens who withdrew). messured Eeatment 286 (99*) 280199%) difference in neurohumolal concenEations at 12 weeks and An gr or ens in.l lrecepbr antagon r sti 211%) 2 t7\) 231180*) 23118116) weeks a t test before and after log 24 wit}t two-railed srudent 187165%) 197 69.{) transformadon, which resul$ in near normai distribution 79 t27%) 90 324) for neurohumoral concentraEolrs.': 83 129%1 87 i31{) Ca crh{hannel b ocke6 6 12!6) 12 i4*t Results ? 16 parients were enrolled over l0 months a! 113 study sites Table 1: Domogaphy arld baseline condltlons in the USA and Canada (figure 2). The 6rst padenl was enrolled on Sepr 29, 1997, and 6e last completed the final proportioo patienB receiving 40 mg omapaoilat was assessmen! on Feb l, 1999. The lwo treaGnent groups wete of mg was 4o/o; 20 mg similar for baseline and demographic variables (table l). 88%, 20 mg was 870, and l0 was^nd l%. The ACE htribitors were required as presrudy Eeatmentr and lisinopril was 94%, l0 mg was 5%, arrd 5 mg tbroughour dle sludy. rhe doses used in the omapatrilar and the lisinopril group propofiions remained siEila! was similar (16 mg u2l z'r 16 mg I U). Angiotensin-tr- Exercise dwation receptor antagonists had been inadvertendy used in four Ar l2 weeks, Ihere were similar and small increloents in padents ftwo ir] each group). Oltrer concomitant tleatment exercise duration in the two Eeatmeff groups. Adiusted was simila! in the two srudy groups; dir-tetics in 80%, mean change ftom baseline was 24 s (SE 6) for 6e diBoxin in 67%, and. 9-blockers in 30% of rhe study omapatrilat group (n=2?4) and 3l s (6) for tbe lisinopd.l population. Ar the end of the 3-week titration period, the group (265, p=0'45). The week-24 adjusted change ftom baseline was 40 s for patienB given omapatrilat and 48 s for fiose receiving lisinoplil (p=0 5). Safety and tolerabiliv The two EeaBents were well tolerated. Serious adverse eveuts are sr:mmadsed in table 2. There wete fewer patients in rhe omapacilat group than in the lisiropril group wittr at least one of these evenc. Most selious advelse eveqts arose in the cardior,'ascular srstem, and were less ftequent in the omapatrilat group than the lisinopri.l group (20 Uo/"\ tts 34

orn.e.rd.t Lhlm9.il 1lF289) (F284) 2Ot7X) 3/62Al 0{4 2110$) 9 (261i NS 7 {3s%) 12 (4X} NS 13 {4X) 14 (5%} NS Ouers 5 {2() 5 (29() NS 6 {2%) 8 (396} NS 6 (2%) 9 (3%) NS 5 (2$) 2 (0.7X) NS 21tt t 25 (9S) NS 12 t25Ll 93 133*) NS Totd cajcnb f,tt! rl b.rt ur..r.rt 44(151) 60 {21%) NS

Figure 2: Trial profile Table 2: Sgrloua advgrgo eve,rts

THE UNCET. Vol 156 . Ausust 19, 2000 617 ARTICLES

D (n:284) (95* Cr) 7 12.5%l 19 (6.4%) 0.016 no.n ? (296) 10 (4%) .. ns 5 (1.81) 1? 16.r.96) 0.009 oea$ any c.use (31) . NS 6 (2.rq) 10 (3.6%) NS Admissis I 18 (6i) 4 (1%) 6 ,- ris Asoardle aminolranslnase 2to.7xl 210.7%) NS studrdruS ,ilhdrdral (2i) 6 (3%) . NS alanrne am notr.nsferdsa 3 (1.11) 2 t0.7%) tls Eme{€ncy roomi vi3it 4l1r} Suorlem€ntaldiurelic use rl5 {16 ) Comoosc:death or aomissron 1415{) 25t it 0.5210.27-\.021 0.052 Table 3: lncidonco of slg,llllcantly Elevat.d Prs.pscllled comoosr€i dea$, admrssron or 16 16%) 29 (10%) 0.52 (0.28-{.96) 0-035 plasm€ analyseg stody uealnenl oEconlnled Commrte, anyse.t 54119*) 58 (24!O 0-7s (0.52-1.07) 0.113 p=0'04). Other serious adverse events arcse wiih a U2%], lAccioent and ehe.gencl oen€nlnem usts not.esuNng in admrssio.. i'ls=ion' simihr Aequenry in both groups, Plasma concelrtrations of creatinine and blood urea Table 5: Death and comoabld eveltts of wotsonlng hea,t fallurs nirogeD (as prespeci5ed) wete higher rn parients given lisinopril than in those given omapaoilat, but this difference padents give lisinopril rha!1 in drose given omapatrilat was uot significant (table 3). Serum potassium and liver (seven os ten). kss thao half the admissions for hean enzyme conceflEadons did not diEer significanrly beween failure, excluding emergeocy-room visits that did not result glouPs. in admission, arose in patients on omapau:ilar rhan in those adverse events. Table 4 shows the treaurent_emetgent on lisinopril (eighr [3%] us 18 [6%]), T']re two reaEnenr (p=0'039) Diziness G=0 0001) and vision disru6ance groups did oor drfer ald any comorbid event of worsening were mole ftequelt in patietrts given orDapaEilat than congesuve hean failure. The Kaplan-\leier curve for lisinopril. These eveng were generally mild, of shon the clinically imponanr cornposire of 6rst occurrence of duratioo, and not dose-reiated--discontinuation of death or adsfssion for worsening heart failure separated treatsrelt because of these evenls was infrequeot. Patients early, favouring omapaEilat (hazard ratio o'52 [95% CI with systolic blood pressule ofless dlaD 120 mEl Hg and oo 0'27-l o2), p=0 052j Ecure 3). The cumulative eve omapatrilar seemed al highe! risk of hypotension, perhaps curves for death, admission, or discorutruarion of study because of a tDore acute effect of omapatilat on slslolic Eeauneot were, bowever, signifcandy different berween blood pressure. Despite this 6ndrng, syncope as a serious groups with the curves separating between days 30 and 60 advene event (omapatrilat 0 3% os lisinopril l'8%) or an ard continuing ro divelge throughour the 24-week saudy adveGe event (1 7% os 3 2%) occu.rred mo.e ftequendy (0 ;2 [0 28-o 96], p=0 035; figure 3). wi& lisinopril. Diarrhoea was more frequent in parients given omapatrilat (p=0 007), and patieots older than 65 NYHA functional class and other assessments of heart' years seemed predisposed to tbis event. Tbe frequency of failure status cough was similar in rhe two ceamrent groups, despite the At week 24 (or at rbe observation of patieno who did not patients being given AcE-inhibitors before randomisatioo. complere the s!ud.v) omapaEilar t€arErent had led to more Tracheobmnchitis was seen more frequendy with inprovements and less wonening of NYHA class than omapaEilat (p=0 038). One patient receiving lisinopril had lisinopril Eeatment (p=0 059). ln patiena wi& NYTIA compared with nooe on omapatrilar. functional class III or fV at baseline, this difference was sigri.ificalt (figue 4; p=0 035). Pblsicians' and patients' Clinical outcome global assessmens ofhean-failure status at the eud ofstudy All the individual clinical endpoinc related to survival or showed rhar betweeo 640/0 a{td 67% of all participants had any comorbid event for wonenirg heart failurc fqvoured some degree of improvement and 3-47o had worseoed. No omapatrilat (Eble 5). Tbere were stighdy 6wer deaths in consisrenr treatmenr benefit could be distinguished with rlese assessm€nts. Because an overall objective of the on.oitrlEtln:289) ti.inordl(n:264) Eeatment of patiens with congestive heart hilure is to 94 (3396) 52 (18i) prevent clinical events ald imprcve sense of wellbeing we 60 (21S) 54 {19!6) assessed a composite endpoi that includes bo&. For this FatiSue 59 (20%) 53 (19X) 16(1696) 51t18S) endpoint, the patienr's coodition was deeoed to have 38(13%) 59€1Sr wonened if they died, were admitted to hospital, or they 31l (12X) 1515i). tleatment worsening congestive heart (12%) 35{1296) $opped study for !pt€rresprrdtory infectjon 34 global 32 (11%) 26 (996) failure, increase in NfHA class, ot a worsening 31(11*) 40 (14X) zuise$ment. Improvement was judged by dedease in Cougr 30 (104) 31i11r) NYIIA class o! a moderate or striking implovement in 29110'96) 1716%) had a more beneficial effect 29 {10%) 17 (69() global assessmeot. Omapatrilat 29 (10%) 31i1116) on this composite endpoint than tisinopril (p=0 003); f30 28 (10%) 25 {9S) (45%) patie!rs imprceed, 125 (41y.) re-rnaJrLed unchanged, (11*) 27 t916l 30 (12%) with 97 (34%), 136 23 (E%) 31(111) aIld 34 worsened compared 21t7X) (48%) and 51 (18%). 201796) lE (6X) 1816%) 7 0rr R ad i on u c t ide ve ntic u I ogra P hY 17 {6%) 28 (104) Venricular volumes and eiection &actions generally oisturtaice ll|fhm ventrcu ar 16 (6%) 9 (3%) renained stable and did not difier between treatrnent 15 {s%} s (2r). 1315!t) 11i4%) $oups. The mean change in left-venricutar enddiastolic 13 (5%) 7 (3$) volume, which was tbe primary variable, was less tha! 7214%l 6 i2$) 1 mUtrf in each group. kft-veotdcula! ejecrion Faction a $%l 6 r2$) increased abour one unit in each group. l*ft venuicular .p<0.05. and righr venticrrlar volumes and ejection Aacdons differed Table 4: Most commonly aiising treatmo.it4me,gent advollis little beMeen the lwo groups. eventg

vol 356 Ausust I 9, 2000 618 THE l-ru\CEr ' ' ARTICLES

Death, admbsion for hsart taillre, or uol dLcoillnuatlon ol treatmoit -.1 * .0.] o.10

-9 20 -.1 o-l 0.05 10-.1

0JI 0 ffi lmproved Worsened lmproved Worsened 0 30 60 90 \2a 150 omapatrilat lblnop l Tir.e from randomisatlon (days) Figure 4: Chango ln YHA functlonal clasi Change in NYHA tunctional class in patients with NYHA class lll or lv heaft Lisinopnl 284 274 267 255 247 242 35 faiture lrom b€seline to finalvis(. 9 omaoatnl 2a9 2aa 2ao 276 271 265 34 parients with NYIL{ class Itr and IV congestive healt Doelh or admls.rion fo. heart failure lailure are dificult to isolate. Neverdreless mechanisms are 0.15 - probably relared ro thc improl'ed abiliry of omapatrilat to reduce preload and afterload," and its renal effects, which 0maoauiat would rogether be expected to reduce pu.lmooary a.ra-] ._ congestion and ioprove cardiac oulput more tharr ACE inhibitors. Because the reducdoo in the need for supplernenral diuretics wirh omapatrilat was small and ...] almosr enrircly confned to padents receiviag p-blockers, a drureoc effeo seems unlikely to be dre main mechaaism by which omapauilar innuenced morbid events. .] Although all individual clinical endpoinu rclated to 0 30 60 90 720 150 180 sur,/ival or any comorbid event for worsening heart failure 'l'lm6 (cays) from randomisation were improved widr omapatrilat, the number of patielrts Lisinopril 284 275 26A 256 24A 2$ 35 studied was small and the len$h of fotlow-up shoG making omapatril 289 283 2a2 27a 273 267 34 our resu.lts eocouraging but oot defilitive. This surtement is Flgure 3: Doab and congedlve h€a,t Iailurg coriotbulty particulady m]e since multiple comparisons, as we did, Top: Kapta.FMeier enimates of tlre combined endpoints of deati or lower rhe sEeogth of borderline sig8ificart findiqs. or admtssion tor hean failure or admissioal for hean iailure. Bottom: death Nevertheless, our rcsults are consistent with srudies in discontinuatloa ofVeatment for worsening hea( hllur€. cardiodlyopathic hamsters that show longfi survival with omapatrilar than with capropril,'' and studies in rhe dog Plasma neurohomones pacing-overdrive heafi-failure model, in which omaparilat The effects of the wo drugs on oeurohumoral activation improved cardiac and renal fuactioo.'"r" djffered ooly slightly (table 6). Arial uariuretic peptide Our study supports rhe idea that increase of endogenous differed the most, widr a decease over timqwith lisinopril, vasodilator and diuretic subsEnces iD patienrs wirh but an incrtase over dme with omapatdlat. Plasma congestive heart failure could be beneficial aDd consdmtes a norepinephrine increased over time with lisltopril but not potentially imponant reaulent goal for 6lfdre! improviDg wfth omapatrilat and was signilcantly diEerent between the oudook ard wellbei.og of patieIlIs wi6 the disorder. groups at 12 weeks, but only when data ftom narural log Indeed, natriuretic peptides, nitric oxide, and traasformation wete compared. Plasma angiotensin tr plostaglandirs have cardiovascular and rcnal effects that were similar ia the rwo groups but tended to concentrations are in direo opposition to drose of vasoconstlicto! decrease with lisinopril and to ilcrease with omapauilat. The effect of borh drugs oo plasma eodothelin-l was similar. io.!ri'.!tuh (rt) 0.368 {0.049) 0.296 (0.02) DI.qt.aloo 0.477 (0.0941 0.3:)6 (0.027). I! this study of patients wi& stable heart failue, dre 0-521(0.1151 0.352(0'02E) vasopeptidase iDhibitor omapatrilat did Dot i$prove A$d nrtnr.tlc p.rtn.. (rl) erercise tolerance compared with rhe ACE irhibitor 0 039 (0.m1) 0.037 {0@4} 0 032 (0002). 0{39 (0.m4). lisinopril. Exocise tolerance in patients with coogestive 0.02910.003) 0043 {0 006)it hean failue is 6e result of the convergence of numerous peripheral soEe cardiac." IotervenEions Lalotitdn l, (g/L) factors, soEe and 0.022 (0{02) 0.024 (0.003} &at improve esercise tolerance are not necessarily 0.017 (0{021. 0{25 (0.004) associated with improved survival. Interventions that 0.019 (0.002) 0027 (0.004) improve survival, such as p-blocken and ACE inhibilors, BEdrlh (YL) do not imprcve exercise tolerance, or increase toleEnce less 0.002 10{002) 0{02 (0.0002) o.oo3 (0{003) 0oo3 (0 0003} pure vasodilators or positive thar do interve ions such as 0.003 (0.0002) 0{03 (0 0003) inouopic agena, which have less-beoeficial or harofi.rl .0<0.05 iom Das€rne. tp<0.05 vs sLnopilusin6 actuar notminalNe ratu€s and p:0 efec$ oB survi!Et.'''' NY!{A functional class is decided by t r"lues irom natuGl oS lransfomaloi (p<0'05 iot noeoinephn.e and 053 1ot many combined factots, and, theldore, the hdividual alna nau[e(]c oeDtoe). reasons for the greatet imptovement widl omapatrilat iD Table 6: changes ln nouroho,mones ov€t tlmo (moan [sEl)

6 r9 THE UNCEI . Vol 156 ' Ausust 19, 2000 ARTICLES

E Mcdic.l aeulohonnones and would thus be expec(ed to be Co.e radio.ucltde rcnthcutograpny /aboratory-Ncw BItDd Ceoln M Kolstan, , Udclloo, D Kind (r.chrici.D). cardioprotective and renoprotective by a[enuating the coo.d,nating Cenlre-Bristol-Mycts Squibb-A Block, P Chd, L Harvev effects of chlonic overacdvation of vasoconstrictor (SNdy Dileclors), D A!rcG, D Costasliola, G Cuonotta, D Johnlo. oeurohormones.+' In a subset of 19 patients, pulse-wave (cli.icll sc'effists), W Coop.r, C Qian ($.usdci,tB), G S.6uel (dat velocity was lowered more wirh omapatri.lat than wittt tisinopril, suggesting reduced conduit-vessel stiftless as a Cont0butors potentia.l difference cootdbuting to cli[ical outcome." C Qis was Ih. srrEsric.l corull..nr Atl odcr nvdLisltoIs wrotc 3d The improvement associated with the use of omapatrilat d6,gDcd rh. stud-v sd hclpcd io mtcrplE. a.d Eir. 'n. pap6. did flot seem the result of changes in venEicular firnction rhar could be identified by radionuclide veoeiculogaaphy. There were, however, some differences in circulating I Roul.au JL. Th. n.uohMo..l hypoth6is sd thc lraErdt of h.an help explain its bene6cial neurohodnones that could to f.tllt . Con J Catuot t996; 12 (ruppl D: H. effects. Although these changes wele of marginal 2 Thc SOLVD ltrvcstig3to.s. Etrcct of.oalap.n oo suflilal ir p.rictt(! significaoce, because measutements were raken at ahe qtn .cduced left v.llri.alar cjcctiotr fiEcrio and conS6rivc hcolt trough of dosing, overall neurohumoral effects of f.ilu.€. NE slr,\4.d 199I : 325. 291-'J02. 3 Th. Crrdiac llsuficicncy Bisop.olol Srudy tt (CIBIS-fD: a ftndomiscd underestimated. Omapati.lat omapatrilat might have been t!.al- Ias.et 1999', 3S3t 9-13. plasma reduced plasma [orepinephrine and raised atlial 4 Gohlke P, Lirz !r, Schrtlk.B BA, et al. .1'giorensia'conveflins .DzIne naEiurelic peptides more thaJl lisinopril. Since lrarriuretic i.hibirioo imp.oves cadiac tr'.iion. Htg.iu6ion t994; pepddes reduce adrenergic rone," dle effects of omapatlila! 23: 4l l-18. 5 R.Eune w1. BEdykiDD-mcdiarcd .ardiovascular grot ctivc actioG of peptides could lead to ihe decrease in plasma on oarriuredc -\CE iEhibi.o6. Dus5 1997; 54 (suppl5): 59-?0. norepinephrhe. Surprisingily, plasma angiotensin II 6 .\..arus. M, Tak.yama Y, T.nab€ .\, et .l- AEi.l and bBir oaEirrfttic concenEraEons tended to be higher in patieots given p.p.idB iD ddiovascdd di*eg HtP.lvBid 1994i omapatdlat, suggesting rhal greate! ACE inhibition with :3 (suppl t):231-3,r. Gardrer DG, S.,nson M. N.E uedc pAtides. NE lead the diEelences in outcome 7 lrvE E& tl, omapatrilat did not to ,Ud l99a: ,39. 121-28. in srudy. found this 8 Bmen JC Jr. Varopepddlse inhibiriotrr a dev concep. in blood Most patients given omapar.ilat or lisinopril rolerated the p..rsuR manasem.m, Hfau,,@, 1999; 17 (suppl l):S3Hl. Eeatlne well and tiEalion lo rhe target dose was possible 9 lkra6 H, Mcclco DR, .\lehta S, ct,l. Ijng-te rn beneficill hcmod!'n.dic cod n.uohormonal effects of easopeprjdde innibition by 3 weeks. Pariems given omapalrila( and lisinopril had a wrlh omaparrlal D h.a!1fattv. J An Cnll Cddbl t999; 32: 2 (suppl similar incidence of cough, which is consistenr wirh A):1854. previous clinical studies a!1d compatible wirh ar ovel- lo Konstam MA, Kronenberg l4W, Rous.su MF, ei al. Efsls of th€ whelming role of ACE compared with oeuropeptidase in oglot.nsin conv.rons eEym. inrribrror .Mlapril on !h. lonrtlrm v.ntnculu dnaBdon h paricnr! wirh asymptomrdc in rhe lung. Indeed, fie lung D.oscssion of l.fr the meubolism of bradykinin sysrolic dlstuncooo. SOLVD (Srudi$ of kft Vcnulculrr Dvstuncrion) is by far the orgao with the gteatesr concentralion ofACE. Invcsdsato8. C&srrno, 1993i 8t 227i-43 given (].b er al. AailaEon ofneurohucloEl The Ending of fewer patients omapatri.lat 'r/ith 1 I Roulcau I- de Champlain J, M, more renal dererioration than those givefl lisinopri.l, is slsrem! E posunfarcdon lcft vcrEicular dystuncoon. , An Co[ Cadiol l99lj:2:390-98. compatible with a protective effect of naEiuredc pepddes 12 BeEedict CR Joh$toD. DE, Vcinet DH, et al. RElatioo of on glomerular Eltration !are.''n' ncumhumor?l acdvation to cliaicial variabl€s and dcgE. ofr€ntriorlar Our study suggests drat the vasopeptidase inhibitor dlstuncrioo: a Epon tom r.8t3E-t ofSOLvD. r,4, CoI Cqdial 1994; omapatrilat is well tolested and could have some advaatages !3r l410-20. ) N.gariv. ex.rcise 6ialt io hcan hile: r.sult or d..i8n? the ACE inhibiror lisinopril io the treatrnent of 3 Diclstcin K over Ed H.dt J 1998t l9t 174749. arc undenaking a padenrs with congesrive heart failure. Ve 14 Plcklr M, Bnsiow W& Cohn IN, ct a]. Thc cfi.ci of caredilol oa large-scale phase m $udy (4420 patiena) to compare dre dorbidiiy rDd mon lity in pari.nts wilh chrcdc he.n fEilu!: US effects of omapatrilat and enalapri.l in patienrs whh heart .scdnot hcaltb hihre studt sro,lp. N Eryl1 M.n r996i334t r{9-r5. er of dairPtn wfth failue (OVERTURE !dal). I 5 Cob! J, Johnsoo G, Zi.s.h. S, al. A compaisor hldralazinc-isosortidc diniEltc in th! trlaEnc!! of chrodc cor{ltti!€ h..n tuilurc. N E M.d l 99l i 325: l03_l0. Acknowledgments 'rrr 16 DiBia&o Shbct r R, Kosruk v, et al. A compalhoE of oEd Pr,ncipai ln!€st glto/-J L Roulcau. & Eiirhooc, digoxin, ,!d rh€ir combhation in lhe trcatm.o. ofprti.ats Mernbe6 of the IMPRESS nudy 8/oup--{SA--4€orgE F bathcnian, wnh chroAic hcar Eilur.!. N Eryl Md l9a9\ 32Ot 677-43. M Tooton, M Rotrnm, T H.ck, E K,spcr, H Hanley, M Kl.in, J Sn!i6, I al. of ors.l mihinor. L Baruch, T Iaj@rel, R GieAsDa, M !fikor,, B lteld, J Glode, l7 Pack ! M. Calvci IR, Rodchefc RL .. Efect or D Ker.iakcs, P Phillipq M DibGi-Dunlap, Karl T lrcbd, R GEf, C Elsq monality io sevt'. chlonic hcan hiluJ!. N E srr,4,fd 1991; 3251 C YEncaJr, F!"!cis Mcaapa.c, K Klect , N viiay, D Hassr, t468-75. A Nied.rman, C Pepin., T Palk r, R Sicsd, V J Hculy III, Gary V Hdlcr, l8 Trippodo NC, Fox M, MonticeUo TM, Prlchrl BC, Aslad MM. P Chana, M llmbd1 G ToR, P Kili!, K Ad6ns, C Pona, R Pahc, VasoFptidls. iDhibition with omapaEilat imp.ovca caldirc J Plchn, U Elkaylo, K Nad.[laoct, N Bitt t, J Famhaa\ K K@!, g.omcEy dd su.viEl io caldiomyopathic h.e5tc!s mor. L Cooway, G llma!, R Steioran, I Kosti!, V Smnh, M Klapholr, th.ed do(! ACE iohibi.ioo wirh c:ptoptn. I Cqdiooas Phdatd S Cha.ant, U Th3dsdi, J w:lkcr, C Gribian, D Wood, J F.lic.ta, 1999; 34:782-90. K Ssdth, D Forman, S Mchta G Tinmis, R B.Ii4cr, M Drchobl, 19 ThoEl,3 CV,.UcDmid GM, Holz8Ef. HH, ct rl. ChDaic dud B crcenb€rs, L Ycncn, R Vrsht, D Stasrman, M vicario, S Goldnl'n, irhibioon of ,ngolenlin-toEe€ning cEcrrD. ald oeuErl codopQtidasc V l,eimbach, S EltahaE! J Sind, L P.tovich. Canad+-R l,eado, D Isaac, dudoa &. ddelopncn! of lcft v.sEicular dysffmctio! io dq!. , P T S lna, R Roq, R S McKelvi., S Koua, O Pa*er, M F Mat nsi, C,tdiooe PhMd.ol 1998t l2t 9O2- I 2. M J Arlold, l I5is, D Gosffd, D C Phsn.uf, F S6tic!, J L Roul4u, 20 Cavcro PG, l,Lrsuli6 KB, Wilrvcr J, Sclmou AA, Dcbn y NG' D Rupta, A H€ss, lmlic, R Bharslw, S I Smifi, P Talbot Ir, , Brulcit lC rr. Caldionaal actioos ofncuEai odoPcPti&!. inhibitioa VA Gebhaldr, R Orchrd, M B Khouli, T Davi6, J Bedad, Jlrper, in erpclimenrai congestivc hcan f:iluE. Cftslaiin 1990i t2: 196-201. S LpagE, G Ploulx, Y Pesnt, B A Suls€x, C Fonin, G Moc, D Park6, J Th. V Bafftcio, F Bor.t, T E Cuddy, A,\,loris. 21 ,Mitchdl GF, Block AJ, Hanlcy ttr. T.tdifrc, loulcau I- J pllssult- c@rdtna ng conhinee-M Pf.trer (Lschsi!), D Stryait (Canada-chai!); wlopeptids irhibitor, omapsEilai, ha. a EvoEblc, pso.nB 1,idt coog6tjvc F Sesde., D lesc, S Scrirh (CanadiaD rcgiodal cooldiDatoa), M DibEe!, ird.pend.ot ciitcl oo conduit !,cascl stifticss ir hean :999i 100 (suppl l): I-46. J KosEs, C Yancy, R Wnshr (t-is rtsiolll coordinatoB), J L Roulcau hilu.. Cfizblr, (norcpi4hrine). 22 Abl"ffoo BI- Ando S, Nolrrius CF, RonSEn GA, norat rS. Neurohoinone anautical cen6€s-{ Hall (A},iPBNP), P Snors Ef.€t of aEr.l .aErur.ti€ pcpride on musclc sympadl€ric acnvity (angorensin), P Ccmacck (endodelin-l), N Poitras (cenE-al coordinstor), and iE rc0q cooEol io human hcart hihre. Crrdro, Ig99; 99: J L Roulca'i (norepuephrire). l8l0-15.

620 THE LAr\CET. Vol 156 . Ausus. 19,2000 COMMENTARY

Vasopeptidase inhibition and angieoedema

See page 675 Eranufacrurer decided ro withdraw the applicatioB temporarily. one insEnce, possibly two, death resuited ftom a "lr! 'D Angio-oedema is a well-documenred, but m!e, adverse glottidis." sudden oedena evenr in parierlrs taking .\CE irhibitors.€ It occurs in 0 196 to 0'5% of parients taking these drugs, and Elsewhere in today's Lancet, Jean Rouleau and maybe even more comoonly among black patients. It colleagres repon a comparison of omaparrilat with affects about I of 2500 patielts during lhe lust week lisinopril in 573 patients wiLb class II to fV coogesdve of exposure.l' However, sngro-oedema can 6rst appear hean failure (CHF). The iavestigators found no from a few hours !o 8 years after art ACE ilhibitor is diffe.ence berween the two drug classes in che primary 6rst taken (mediao time ro occurtence 6 months in a endpoinr (exercise toleratrce). Howevei, omaparilar teniary referral certer)j unfortunately, a median of l0 conferred more beneht than lisinopril on rhe composite months elapses beween onset of angio_oedema and endpoint of death, hospital sra,v, or discontinuation of withdrawal ofACE inhibitors (range I day to l0 years).' study lor worseling of CHF. The The percenrage of ail angio-oedemas rhat are porenrially invesdgators do not say wh-v .bey chose this primary life-threarening anacks-ie, affecting the lar-vn-\ or endpoint, but they do poin! out rhai interve[tions rhat upper respiratory llact-has been reponcd ro be less improve exercise toleraulce are nor aecessarily associated t\an 20yo, but it may leach 50% among paoents with improved sunival, and vice versa. Although the wrth angio-oedema thar is hereditary in origin or maio obiective in treadng CHF is not just to reduce associared with ACE inhibiriod.' Both rhese Rpes are morbidiry arld mortaliry, bu! also to improve ttle presumably mediared by bradykinh.' Of rhese life- parienr's qualiry of life, the discrepancy belween effects threarening angio-oedemas, the percenlage that ends on primary and secondary endpoints corroborales views fatally ranges ftom less than 57o to 20%.ai Thus, that exercise tolerance is of limited value as a surrogate fatalities caused by angio-oedema associated with ACE- for outcome in CHF. Both drugs were equally well inhibitor rherapy seem ro be exceedingly rare, but rolelsted. Rises i.o serum creariline were three times adequate treaunent could prevenr almost all deaths. less frequent wirh omapatriJar tban with lisinopril, However, since worldwide 35-40 million patients are but more adverse eveors related to vasodilatioo exposed ro ACE in-hibitors, this drug class could still (dizziness, h)?otension) and ro the gasuointesginal account for several hundled deaths per year (eg, tracr (nauservogritiag, diarrhoea, constipation) were 40 000 000 x 0.396 x 20o/o x 5o/o = 1200). Rale instances reponed. Not unexpectedly, few advetse effects specific of angio-oedema bave also been leported with to angiotensin-convening-eo-4rme (ACE) hhibirion angiotensin-receptor in-hibitors, but they rday not be wele leported, since pretreatrrent with ACE inhibirors mediaied by bradykini!.' was an iuclusion criterion. Since most padents reponed in the new-drug Omaparrilat was to be rapidly marketed for applicadon for omapatrilar were exposed to the drug for hypertensioa and CHF, and, because of its seemingly only a shon dme, the 0 7% rare of angio-oedema rDust unique therapeutic features, had been put on rhe fast be coosidered bigh coEpared ,,rith that for angio- track by the US Food and Drug Administration in oedema reiated ro ACE in-hibitors. Angio-oedema Jalruary this year. It aifects rhe cardiovascular system by occurred in 0,3496 of the more than 4000 palients who inhibiting the ACE (and thereby intermpting the - received .aEipril in the HOPE Srudy (more than twice angiotensia-aldostelooe cascade), and by inhibiting the as commonly as in the placebo group),'" and it was fatal oeutral eodopeptidase (NEP) (a.red thereby increasiog in one patient. In the new-drug application angio- the concentration of natriuretic peptides). Both these oedema was more than three times as common whell enzymes also inactivate bradykinin, and ACE inhibitors the starring dose of omapatrilat was 20 mg or more alone have been shown to increase plasma kinir than it was wirh lower doses, which suggests a concentrations.': Bradykinin is probably the mediator of pharmacodynamic rather than an aUergic effect. Because the angio-oedema associated with ACE inhibitors.k any hisrory of angioedema is a sEict exclusion c.iterioo, Plasoa bradykinin coocentratioos can rise more tha! the incidence of a[gioedema may be ulderestimated io tenfold during acute anacks of angio-oedema associated clinical trials. Siuce all patients in Rouleau aDd with a! ACE inhibiror.' In data submined for rhe New colleagues' study had previously bee! exposed to ACE Drug Application of ocrapatriJat, 44 insrances of algio- inhibitors, it is oor surprising thar in the omapatrilat oedema occurred amolrg lrlore rhao 6000 patiems, arrd group tiere was Do case of angio-oedema amoflg 289 four cases were severe enough ro requie inrubation. The patients treated for only 24 weeks. Nevenheless, the FDA raised concem abour this adverse effecr, and the significant diifereace in gasuointestinal side-eEects

608 THE L{NCEr. Vol 356 . Augusr 19, 2000 berween oroapatrilar a[d lisinopril in this study is cardiovas.ular evcuca io hid-n,k p.ricnr!. Thc Hcart Outcohcs disturbing. Diarrhoea, nausea or vomiting, and Pr.v.n.ton Ev.luation Stldy Iov.3tig.io6. NE r/, M.d ?OOOi 342. dyspepsia were twice as comsron with orhapatrilar as t45-53. (75 patients had I I Fiant MM, Gelfaf,d JA, Aikidson ,P. H.r.diEry arsio.d.na: fic with lisinopril repo(s zs 38). Five clini<.lsFdromc rEd rts manag tuenl Ann latcd M.d 1976;A4. serious gastroinresdnal side-effects with omapatrilat, 580-91. compared with rwo with lisinopril. Could it be rhat some l2 Villenhcimer R, Srcdbcrs K. Drc$in8 h.arr-hilure of these patiems had gastroitrtestinal angio-oedema? In paricDls on Savilc Ro*-6ilorcd trcaEnctrr? kn..r 2000i 355: his original descriprion of heredirary angio-neurotic 20t2 \1. oedema, Osler stated, "Associated with the oedema there is almost invariably gasuointestinal disrurbaoce: Ganciclovir rcslstance: a matter of time colic, nausea, vomiting, and sometimes diarrhoea". and titre Episodes of constipation, eveo ileus, have been reponed page with intesdnal a[gio-oedema," and ii Rouleau and See 645 colleagues' study colrsdpadon was also twice as frequen! As the availability of andviral agents for berpeseiruses with omapanilar rhan with lisinopril. increases, so does not only krowledge of their efficacy CHF carries a more serious progaosis tharr essemial but also lhe problems associated with their use. The hlpenension, aod .isk/belrefit ratios of therapeuric developmenr of antiviral resisrance has been of intervenrions must be assessed separately for these two much concern bui resistance of herpes simplex virus indications.'' The sfudy of Rouleau and colleagues (HSD ro aciclovir has been essenrially lesrricred suggests tbat omapatrilat, apart from conferrilg to immunocompromised patielrs and attdbuted to porerdal cardiovascula. beneflrs, may be of advantage rhe high concentrations of virus in rhese padenB and in CHF patients with renal impairment- But as a dual lhe consequent oppo.runir-v for selection of a resistant ACE and NEP in-hibitor, omaparilat also carries a mutant.r Thele bas beeo only ooe report of higher risk of life-threarening angio-oedema than do HSV resrstance to aciclovir in aa immunocompetent ACE inhibitors alone. In the database submined for the padent, and this case may have occurred as a new-drug applicatioo, omapatrilar at doses of 20 mg and result of transmission of aciclovir-resistant virus from above exered a more powerirl anrih]?ertensive effec! an AIDS padelt to an immunocompeteot sexual than did some of the other drug classes. Unfomrnately, contact.l ganciclovir- ar the same doses it also conferred a risk of angio- A similar pamerB is emerging with (CMV), oedema rhat was several times higher than that of ACE resistant cltomegaiovirus which secms to infect inhibitors, For omapat lat, as for any therapy, the immutrocornpromised paden$ who have either profourtd risktenefit rario musr be qualrified before it becomes immuoosuppression with ver)-. high viral "loads" or have generally available. In this cofltext, the temporary undelgooe long periods of therapy. Until the advent o[ withdrawal of the new-drug applicaaion for omapatrilar highly acrive antiretroviral therapy, patients with AIDS were ganciclovir pending furthe! assessment ol i6 safery is commendable. and CMV reriniris rhoughr ro .equire Eeatmenr for the rest of their lives, so the lenrhy F H M aEdJ N (ind thc insututiooi they wolk for) hav! reccived 8lants treament heightened the risk that antiviral-resisuat ald honorria fmm s.vcEl conpani.s '-\ar manufacrur. druBs for thc lrerlment ofcorSesdvc her.l failure o! hpcneosion aDd have held ad strains would develop in rhem. hoc cotrsulrancies for or been on lhe speakers Iist for some orrhesc Initial experience in AIDS pariena suggested that resistance was rare but later studies made it clear rhar ganciclovir resista[ce develops in a slow but plogressive *Franz H Messe i, Jirg Nussberger manner. The filst study showed that ganciclorir- rOchsner Clinic and ALton Ochsner Med cal Foundation, New orleans, resistant virus was shed by abour 8% of patients after 3 LA 70121, USA; a.d Depa(ment of lntemal [,ledicine, University mooths of t!eatmen!.' A second study folmd thar I I % of Hosprtal, Lausanne, Swrtzerrand, patients had a resistant blood or urine isolate at 6 months aIrd 27'5% by 9 months.' Osler W. H.r.dnary ansio-Deurooc o.dema..4- J,Ved Sd 1888i 95: 162-67. Until recendy, there have been only scalered repom P.llacei A, Bt1lmer HR, N$sb.rs.rj. Plasm. kEins incr.a.c after of ganciclovir resistance in transplant recipients. Irr ansiorcnsin-conecnins en4.rn. idibiDon in huma, subj€cts. CI' Sa 1999, Kruger a:rd colleagues reponed that l8 of 148 (Cokh) r994i 81t 567-74. (5 2%) lung-uansplanr lecipients had isolates ftom I Nulsbcr8.r CuSpo M, A.g$tulz C, Cicardi M, Pellacad A, r, blood or bronchoa.lveolar lavage fluid' that exhibited AaostoDi A- Plaso. br.dykidn io arpo.oedema. &r.,' t998i 351: 1693-97. soae degree of ganciclovir resistarce. As reponed by 4 fuoston' A, Cic.rdi },t, Cugno M. ZioBale LC. Gioffrc D. Ajit Limaye and colleagues in today's .Lazc.r, the subsets Nussb.rgerJ. Ang,ocd.n. du. ro egroicnsh-coovcnDs cn4m. of allograft recipients at special risk were CMV- i^hibitots. Irrrno?hdd@ologr 1999 i 14t 2 l-25 - seronegative patieots who received an organ kom a 5 Israili ZH, Hall wD. Coud ed &EloGurcnc .d.rri aso.iar.d CMV-seroposirive donor and those padeats with tie with a.giorcosin-convening cM,Er. Ehibitor rh.rapy: a revi of th.lh.ratue and psllrophyiiology- Ann lnrc M.d 1992t ll7| most complicated tralsplants who required long periods 29442. of intense immunosuppression (eg, kidney/pancreas 6 Sl.t.r EE, Mcr.ill DD, Gu.s! HA, .t rl. Cli,iczl p.ofil. of recipients). On average, the patients in this leport wele qth angocdema $socbr.d aEgio(.os'! coovcftiEg-euym. treated with ganciclovir for a mean of 190 days, which inhibidon. l98E; 260: 967-70. r,4,444 suggested rhat the duration of gaociclovir exposrne is 7 Crossman E, M.sselli FH, N.urcl JM. Ansioteosin II reccpror blockcn: .qual or prcfcr€d subdruica for ACE inbibitoGl .4r, also an imponant fuctot in ttre development of Inrzm ll.d20OOi lsot r9o5-11. resistance. As mendoned by the invesdgatols, these 8 Wcincr JM- Farlurc to r.co8Dis! lhc associatioE of life-tb.r.atening idtially CMv-negative parienrs with CMV-posirive aagio-o.dema and a!9orenlin.conv.dDs c.zyme ilnibior therapy. donors develop higher C.W viral loads thao do initially Aust N Z Md t995t 25t 24142. I CMV-posirive patients, arrd this larger load, coupled 9 Acker CG, Gre.nbcr8 A. Angio.dcEa induced by &e aogiotcBsin II block.r losArrrD. f,I E Al7,Ue.l l995i rlrt 1572. with lengthy Eeatmenr, presumably ilcreases the l0 Yusuf S, SleiShr P, Posuc J, Bosch J, Davies R, Dar.&is c. chance of selection of a resislalt mutanr. The EE cB of ao angioreNiD-convcrdng-eDzlm. ilhibiror, rzmipnl, oE imponance of rhe severiry of immunosuppressioo is

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