- Email: [email protected]
Perspective of the pharmaceutical industry on the development of new drugs for heart failure
Perspective ofthe PharmaceuticalIndustry New Drugs for Heart Failure
on the Development of
SOL I. RAJFER, MD, FACC BlueBeu,PenlhQlvan&
expectedto increasefurtheras survivalafterante myocarDe8pite,recunt8dvwcwinthethelapyofp8tiultswitllhe8rt diiialWioaincnasesandthepopul&nages.Inthe Framin&mHeartStudy(2).theprevalenceof heartfailure abledisabiityaada markedly shorMwllife span.Thus,a inuea!A progres&elywithage, illfrom0.8%ill greatlEedBnddiGMrewediesrennains. per8oasbetweeaSOand59yearsofageto9.1%inpersoas Thegenesisafanoveltherapeuticeatityisadau& betweenIaad89yearsdage.Heert~~isalsotbemost procesB,lequM@EcomndtrmdafcoasidaaMe commondiagaostic-felated grouprepoHedin the elderly. TbcGmt#epIathisplwe~isthe~to~-~ Them&rityofpatWswithheartf&retreatedbyphynewdNgtaQet8onthebnsisofthelateat~dii. RapidideiWMmofaleulcba&alsbwtme,modi6edas &iawueca&@wLdasha*mildto-disease; lleededtoobtainthede!dredpotencyand~cbar!#vemhealtfailunacwlmts~aboutl5%oftlletreated ~,isakey&vItynecwsuyforswces&ldtqg patientpoplwoa(3).Depeadiqgootbe~yoftheir dew&mmLllle!#elecM~-thcn~ diSN,a!lIWlm#rtalitynteslWlgefnwnlO%MO%iIl ligonus~cotlleabswceof~wirh_he3ute3ut (2,4S).nuril&t!!ecourseoftheir experiencecc..* my, aaimaltoxidcy.subssqueatly,trialSh~~~to docummttheeelcacyand!J&!tyafthenewchemiadeatity.It which&e&ctediathehi&~oencyofhoqitaladmissions iSimpel&vethBttlEriSk/beWfltI&tilWfthedWgbe&Ilyawio&edwithtidii.Acconliagtodatafionathe &llaed. centefsforDiseasecoatrol,~forhealtfeilure RegWoryappwalisobtaMana~ofl2yeamafter illtheuaited~tripledbetweeatheeiiulyl97osand syntlAs of a sew &emicalentity(1). For every 1QJKNl mid-l980s,~ayewlytatalofapprorrimatelyl~miUioa che&alenti&ssyr&&ed,10enterllmmtrialsancl1~ dmiagthelatlerpefiod.Healt~~theleading Eaia~llclproval(l).~higblevelafliBkiavolvedin CXUlSe~hO6piM-illtheeldetIy(165yelUSof~~. l-nwxuw~aad~is~~ Illtllisgroupofpatiarts,ithasalsobeenidentifiedastbemost thesteepwitddeve&&aaewmedia&m.Ibecurrent canmanreasonlXrWmiGontothehospital(6).Medicwe e&ateofthecosttothe~iudushyforeacb stawc!Srevealtheextentdthe eamamicbmdelltothe Pmdact@iaiqJ~approvali8$231 million(l). aat&inl989tbeaverageha#alstayforp&atswithheart lhilurewaa8da~a1ulcostS4,373(ii~~ perhoqitalstayavenging$715). EeartFaihuwPubKcEedthBurtlen Tbus,heart4irilunisal&WeaWdagdiso&raad, duringthecomseofthedisease,patientsareexposedto HeartlXlureisagrowiagpublichealthproblem.Inthe umsidemblemorbidity.Thereis unquestionable need for Uaited~,iti8estimatadthat~2millionpsaplebave ympUlU&heWtlhilUlEandthat4ooOlNlneWcaSeS~ additional&rapeu&iaterveationstoimpnwethebleak outlookforpatientswithheartGlare. &osedyearly(2~.ThemunberofcaAofheartGlureis 5ilm, a substantial wnberofpatieW stillhaveconsider-
CnrrentplrssidrurMiU~ HeartFailare Taerapeuticappn&esavaiWe~pa&ntswithheart fArearediscussedel8ewhereilltbissupplemeat.These
JM&VVf
No. 4 @upplcmentA) :98AaMA
RAJFER DEVELOPMENT OF DRUGSFOR HEART FAILURE
199A
TabIe1. PhysicianAwareness ofthe Studiesofleft vent&&r Dysfuncticm (WLVD) SGLVDStudyAwarewsa Total (n=266,
unaided (46)
11
m uPware ($1
36 39
GPm
In= 150) 4 27 69
CD
(n= so) 32 36 32
Awamcss ofACE Inhibihmin SCILVD blmoll8ulmenwarrdsGLVD~ Total (n = 81)
Ftgurel. Physicians’~oftheiruscofdipitnlir,angiotcllsincomedog enzymeinhiitors(ACEIs)and dimzticdqs
Gm4 (n=47)
CD (II = 34)
36 26 56 for the Enahpril(4s) 12 13 12 CmoPd (46) katmentofmiId,moderatezmdsevemheartGhn-e.CD=cmdiob unawale ($1 52 62 38 &as;GPRP= garal pmctitionef5 or blily practitioners: IM = iluemalmedicinespeciaIists. slnlrcfz: consumerMustlialResearch ACE = aogbiwmm enzyme;CD = cddogist; GP = ~aml Service,November 1991. practitioimlM=intedmedkim~pcctlist;SOLVD=SPldiesofLdt VentricularFunctionmntmenttrial. Some: UIR Hat FailureSuvey. mober 1991.
therapeuticstrategiesm effectedpredominantlyby primary care physicians, who account for 78% of clinic visits for heartfailure;visits to cardiologistsrepresentonly 18%of the total numberof visits (7). Physicians were queried recently as to their use of digWs, diureticdrugs and an&ten&-converting enzyme inhibitorsfor the treatmentof patientswith heartfailure;the results of this survey appearin Fi 1. In general,cardiologistsstatedthatthey used angiotensin-converting enzyme inhibitorsmore frequentlyand earlierin the course of the disease than did internists and family or general practitioners. The overwhelmingwority of physiciansincluded diureticdrugs as partof the therapeuticarmamentarium for all degreesof heartfailure.The frequentuse ofdiuretic drugs was ako documentedwhen prescriptionswrittenfor patients with heartfkilurewere examiued. However,~20% dhitid pre~criptim~, were written for angiotensin-converting enzyme inhibitors(Fig. 2); cardiologiststended to prescribe these agents more frecluentlythau did primarycare physiChIlS. Given
the beneficial elects reportedaith angiotensinconvertingenzyme inhiiir8 in patientswith heartfailure, F@re 2. Pcrccnt ofinitialprescriptions fordigita&angioknsincopvertiqenzymei&ii (ACEIs)anddiuretic dn@swrItten for patie~tswitbhemtfailunbyprimarycarepbysiciansOand caldi~sts (CD).source:Me, IntenlalMedicine specialists (MS), NationalDiseaseTherapeutk Index.
their actual use by preAbiq physicians would be expected to be much higher than that reported.The slow adoption of highly elkctive new therapeuticapl#oaches could have an adverse impact on the public health. This issue is particularlyrelevantfor the data obtakd in the StudiesofLeft VentricularDysfunction(SOLVD)treatment trial(4). the largestand krgest trialinvolvisg patientswith heartfailure.The results,publishedin the widely readNew I3zgkz~dJournal of Medicine in August 1991(4), demonstratedthat enalapril-wheo addedto conventioaaltherapy consistingof diureticdrugs, digitalisor m other thau angiotensin-convertiqjenxyme inhibW+reduced mortaliiand hospitaladmissionsforheartfailureiupatients With~tiJ’ddtO-83’lU~he?ut hilure.
A survey of physiciansconducted in October1991 revealedthat~wereuaabletorecalltheIreg~tofthe trii kittout assistance(Tab!e!). Even with assistance(that is, aided)the m+ity (59%)were still unawareofthe W trial.Amougphysiciausi5miKar on the SOLVD m withthetrial,<5O%wereabletoidentiQeaa@Wilasthc angiotensin-converting enxyme inhibitorused in the study. These obserWons emphask the need for targekddisseminationofimportanttherapeuticadvances.
conclusion To date, drugdevelopmentin heartfailurehas fd on idenMyingagentsthatmodi@thehemodynamicdeFange mentspresentin these seriou8lyill patients.A greatneed for altermuivedrug developmentstrategies exists. However, progressin genemt@ innovative Wapeutk approaches willbeimpededbytheabseuceofreliableauimalmodels. Nevertheless,the inexoraHedownhill clinicalcourse characteristicofpatient8withheartthihuedemandsv@orous remedk. succe88fldatt&ment ofthis pursuit improved
of
kttizmmOF DRUaS POR HEART FAILURE
JACCVOL~~.NO.~(!BI&~~A) tmobw 1993:198MoM
on the Development of
SOL I. RAJFER, MD, FACC BlueBeu,PenlhQlvan&
expectedto increasefurtheras survivalafterante myocarDe8pite,recunt8dvwcwinthethelapyofp8tiultswitllhe8rt diiialWioaincnasesandthepopul&nages.Inthe Framin&mHeartStudy(2).theprevalenceof heartfailure abledisabiityaada markedly shorMwllife span.Thus,a inuea!A progres&elywithage, illfrom0.8%ill greatlEedBnddiGMrewediesrennains. per8oasbetweeaSOand59yearsofageto9.1%inpersoas Thegenesisafanoveltherapeuticeatityisadau& betweenIaad89yearsdage.Heert~~isalsotbemost procesB,lequM@EcomndtrmdafcoasidaaMe commondiagaostic-felated grouprepoHedin the elderly. TbcGmt#epIathisplwe~isthe~to~-~ Them&rityofpatWswithheartf&retreatedbyphynewdNgtaQet8onthebnsisofthelateat~dii. RapidideiWMmofaleulcba&alsbwtme,modi6edas &iawueca&@wLdasha*mildto-disease; lleededtoobtainthede!dredpotencyand~cbar!#vemhealtfailunacwlmts~aboutl5%oftlletreated ~,isakey&vItynecwsuyforswces&ldtqg patientpoplwoa(3).Depeadiqgootbe~yoftheir dew&mmLllle!#elecM~-thcn~ diSN,a!lIWlm#rtalitynteslWlgefnwnlO%MO%iIl ligonus~cotlleabswceof~wirh_he3ute3ut (2,4S).nuril&t!!ecourseoftheir experiencecc..* my, aaimaltoxidcy.subssqueatly,trialSh~~~to docummttheeelcacyand!J&!tyafthenewchemiadeatity.It which&e&ctediathehi&~oencyofhoqitaladmissions iSimpel&vethBttlEriSk/beWfltI&tilWfthedWgbe&Ilyawio&edwithtidii.Acconliagtodatafionathe &llaed. centefsforDiseasecoatrol,~forhealtfeilure RegWoryappwalisobtaMana~ofl2yeamafter illtheuaited~tripledbetweeatheeiiulyl97osand syntlAs of a sew &emicalentity(1). For every 1QJKNl mid-l980s,~ayewlytatalofapprorrimatelyl~miUioa che&alenti&ssyr&&ed,10enterllmmtrialsancl1~ dmiagthelatlerpefiod.Healt~~theleading Eaia~llclproval(l).~higblevelafliBkiavolvedin CXUlSe~hO6piM-illtheeldetIy(165yelUSof~~. l-nwxuw~aad~is~~ Illtllisgroupofpatiarts,ithasalsobeenidentifiedastbemost thesteepwitddeve&&aaewmedia&m.Ibecurrent canmanreasonlXrWmiGontothehospital(6).Medicwe e&ateofthecosttothe~iudushyforeacb stawc!Srevealtheextentdthe eamamicbmdelltothe Pmdact@iaiqJ~approvali8$231 million(l). aat&inl989tbeaverageha#alstayforp&atswithheart lhilurewaa8da~a1ulcostS4,373(ii~~ perhoqitalstayavenging$715). EeartFaihuwPubKcEedthBurtlen Tbus,heart4irilunisal&WeaWdagdiso&raad, duringthecomseofthedisease,patientsareexposedto HeartlXlureisagrowiagpublichealthproblem.Inthe umsidemblemorbidity.Thereis unquestionable need for Uaited~,iti8estimatadthat~2millionpsaplebave ympUlU&heWtlhilUlEandthat4ooOlNlneWcaSeS~ additional&rapeu&iaterveationstoimpnwethebleak outlookforpatientswithheartGlare. &osedyearly(2~.ThemunberofcaAofheartGlureis 5ilm, a substantial wnberofpatieW stillhaveconsider-
CnrrentplrssidrurMiU~ HeartFailare Taerapeuticappn&esavaiWe~pa&ntswithheart fArearediscussedel8ewhereilltbissupplemeat.These
JM&VVf
No. 4 @upplcmentA) :98AaMA
RAJFER DEVELOPMENT OF DRUGSFOR HEART FAILURE
199A
TabIe1. PhysicianAwareness ofthe Studiesofleft vent&&r Dysfuncticm (WLVD) SGLVDStudyAwarewsa Total (n=266,
unaided (46)
11
m uPware ($1
36 39
GPm
In= 150) 4 27 69
CD
(n= so) 32 36 32
Awamcss ofACE Inhibihmin SCILVD blmoll8ulmenwarrdsGLVD~ Total (n = 81)
Ftgurel. Physicians’~oftheiruscofdipitnlir,angiotcllsincomedog enzymeinhiitors(ACEIs)and dimzticdqs
Gm4 (n=47)
CD (II = 34)
36 26 56 for the Enahpril(4s) 12 13 12 CmoPd (46) katmentofmiId,moderatezmdsevemheartGhn-e.CD=cmdiob unawale ($1 52 62 38 &as;GPRP= garal pmctitionef5 or blily practitioners: IM = iluemalmedicinespeciaIists. slnlrcfz: consumerMustlialResearch ACE = aogbiwmm enzyme;CD = cddogist; GP = ~aml Service,November 1991. practitioimlM=intedmedkim~pcctlist;SOLVD=SPldiesofLdt VentricularFunctionmntmenttrial. Some: UIR Hat FailureSuvey. mober 1991.
therapeuticstrategiesm effectedpredominantlyby primary care physicians, who account for 78% of clinic visits for heartfailure;visits to cardiologistsrepresentonly 18%of the total numberof visits (7). Physicians were queried recently as to their use of digWs, diureticdrugs and an&ten&-converting enzyme inhibitorsfor the treatmentof patientswith heartfailure;the results of this survey appearin Fi 1. In general,cardiologistsstatedthatthey used angiotensin-converting enzyme inhibitorsmore frequentlyand earlierin the course of the disease than did internists and family or general practitioners. The overwhelmingwority of physiciansincluded diureticdrugs as partof the therapeuticarmamentarium for all degreesof heartfailure.The frequentuse ofdiuretic drugs was ako documentedwhen prescriptionswrittenfor patients with heartfkilurewere examiued. However,~20% dhitid pre~criptim~, were written for angiotensin-converting enzyme inhibitors(Fig. 2); cardiologiststended to prescribe these agents more frecluentlythau did primarycare physiChIlS. Given
the beneficial elects reportedaith angiotensinconvertingenzyme inhiiir8 in patientswith heartfailure, F@re 2. Pcrccnt ofinitialprescriptions fordigita&angioknsincopvertiqenzymei&ii (ACEIs)anddiuretic dn@swrItten for patie~tswitbhemtfailunbyprimarycarepbysiciansOand caldi~sts (CD).source:Me, IntenlalMedicine specialists (MS), NationalDiseaseTherapeutk Index.
their actual use by preAbiq physicians would be expected to be much higher than that reported.The slow adoption of highly elkctive new therapeuticapl#oaches could have an adverse impact on the public health. This issue is particularlyrelevantfor the data obtakd in the StudiesofLeft VentricularDysfunction(SOLVD)treatment trial(4). the largestand krgest trialinvolvisg patientswith heartfailure.The results,publishedin the widely readNew I3zgkz~dJournal of Medicine in August 1991(4), demonstratedthat enalapril-wheo addedto conventioaaltherapy consistingof diureticdrugs, digitalisor m other thau angiotensin-convertiqjenxyme inhibW+reduced mortaliiand hospitaladmissionsforheartfailureiupatients With~tiJ’ddtO-83’lU~he?ut hilure.
A survey of physiciansconducted in October1991 revealedthat~wereuaabletorecalltheIreg~tofthe trii kittout assistance(Tab!e!). Even with assistance(that is, aided)the m+ity (59%)were still unawareofthe W trial.Amougphysiciausi5miKar on the SOLVD m withthetrial,<5O%wereabletoidentiQeaa@Wilasthc angiotensin-converting enxyme inhibitorused in the study. These obserWons emphask the need for targekddisseminationofimportanttherapeuticadvances.
conclusion To date, drugdevelopmentin heartfailurehas fd on idenMyingagentsthatmodi@thehemodynamicdeFange mentspresentin these seriou8lyill patients.A greatneed for altermuivedrug developmentstrategies exists. However, progressin genemt@ innovative Wapeutk approaches willbeimpededbytheabseuceofreliableauimalmodels. Nevertheless,the inexoraHedownhill clinicalcourse characteristicofpatient8withheartthihuedemandsv@orous remedk. succe88fldatt&ment ofthis pursuit improved
of
kttizmmOF DRUaS POR HEART FAILURE
JACCVOL~~.NO.~(!BI&~~A) tmobw 1993:198MoM