- Email: [email protected]
D103 Irbesartan versus enalapril in severe hypertension
POSTERS: Antihypertertsive Drug Treatment
AJH-APRIL 1997-VOL. 10, NO. 4, PART 2
D103
D104
IRBESARTANVERSUSENALAPRfLfN SEVERE HYPERTENSION‘~”, 2fM.Flack”>3S.H~~> 3S. Smith,3J. Hwa,and3RA.Reeves*forthe IrbesnrtaoMulticenter Investigators.‘Univde Montr6al,Montreal,Quebec,Canada, ‘BowmanGraySchoolof Medicine,Winston-Salem,NC, 3Bristol-Myers SquibbPharmaceuticalResearchInstitute, Princeton,NJ. [nthis randomized,multicenter,double-blind,parallelstudy, tbe etlcacy andtolerabilityof the novelangiotensinII ATI (IRBE. SR47436:BMS-186295; receDtor . .. antszonistirbewutan BMS/SanofiWinthrop)was comparedto the ACEinhibitor enalaprilin patientswithseateddiastolicbloodpressure(SeDBP) of 115to 130mmHg. Patientswererandomized2:1 to initial, once-dailydosesoflRBE 150mg andenalapril20 mg that were titratedto 300mg and40 mg,respectively.Open-labeladjunctive hypertensivemedications(HCTZ,atenolol,andnifedipine)were addedafterWeek4 ifBP controlwas inadequate.At Week 12, the antihypertensiveeffectof IRBEwas comparableto that of
THE A.SROC”IATION LOS ARTAN-R4hflPRll. IN ESSENTIAI. HYPERTENSION
Priorto-Week12,with IRBE,althoughstatisticallynot significant,reductionsin troughSeDBPoccurredrelatively earlier,feweradjunctiveandhypertensivemedicationsand fewer doseup titrationswereneeded,andtbe incidenceof adverse eventswas slightlylower. Significantlymorecoughoccurred withenalaprilthanwith IRBE(13.1%vs 2.5”A,p = 0,007). In patientswithseverehypertension,an IRBEbasedregimensbows a morefavorabletolerabilityprofilethanan enalaprilbased regimenwhileprovidingat leastequivalentefficacy. Key Words: AI1receptor~tagoni~t,kbes~, enalapril,co”gh, severehypertension,double-blind,comparativestudy
M Bentivogliu, M Buccolieri, E Carluccio, M Mariotti, M Poliimru, S Tommasi, and L Coma. Chair t)f(krdiolow,
University of Perugia, Perrgia, [taly.
1( is
well knownthat the anlihypertcnsivcactivityof ACE-inhibiWs is a( least in part rcla[cdto the inhibitionor bradykiniumctaholism,with subacquenlincrcasc in EDRF and EDHF. On the olbcr hand, ACEinhibition dcxs not interfere on the chymaaepathway, an imponant ACE-indipendcntway of productionof Angiotensin11(A-II) al the [issue level. on the contrary,the A-II antagonists,blocking the AT) receptors,inhibit the A-H producedfrom all sourcos,providinga more completeblockadeof tic cffoct of A-11,but do not have effect on bradykininmctatmlisnl. With the aim to evahmtc howmuch (he inhibitionof A-11prcducedby the chymaae psthway contributes 10 blocd pressure rertuctkm in hypcrtcnsivcstreatedwith ACE-inhibitors,and howmuchthe inhibition of bradykininmetabolismmayfurtherrrshm bloodpressurein patients treatedwith A-11antagonists,we studiedwith ABPMs groupof mild-tomoderak esssntial hypsrtensives(19M, 1lF, mean age 51.0~8.7yam, clinic SBP/DBP 155,2f10,4/105,6~8,8 morHg)in a controlkd single blindstndy.Atler a 4-weeksplacetmpsriod,patientswererandomizedto re.%ivcimsar’tan(L) 25nlgo.d. or Rsmipril(R) 2,5mgo.d. for 4 wreks, and thereaherto receiveL+I?,at the sane dosages,or to doublethe doses ofthe respectivemonoltrerspyfor 4 weeks.DuringtfreIaal4 weeksof lhe studyall the patientsrsccivedthe assmiationL50mgo.d. + R5n]go.d. in the pstientatreatedwith R, the asawiationof L al low dose further reduced24 hours SBP/DBPof 9,8f4,4/6,8f3,9 mrnHg,while, at high doae, the BP rrduction was 19,8f4,3/12,0t5,6 mrnkfg(p=0,0Q5);in patien.strsatsd with L, the associationof R, cauaeda slight rcduc[ionof BP: 3,2~2,5/4,0~3,9nunffg(lowdoae),snrt 7,3+3,4/5,5+3,5mndfg (highdose)(bothn.s.). In conclusion,the incrsasein bradykinincauaedby ACE-inhibitiondrxs pot signiticrmtfyatkt blord preasure in hypertensivealready treated with A-11amtagonis&.s, whema the more rompletc blockade of A-11 rbtained with A-II antagonist cauaes a further reduction of blind presawein hypertensivsaalreadytreatedwith ACE-inhibitors. Key Words:
AT1-sntagoniats,ACE-inhibitora,chymaaepathway, bradykininmetabolism
D105
D106
ADDITIONOF TRANDOLAPRILTO VERAPAMILSR REDUCES LVH INDEPENDENTLYOF EFFECT ON BLOODPRESSURE. L_M&ddu, FH Mesaerli*,andE Nunez,OcbsncrClinicandAltonOchsnerMedicrdFoundation, NewOrlesos,LA. Left ventricularhypwtrophyis a commonsequelaof essentialhyperterraionand majorcardiovsaeulaxrisk factor. Thisarrslysiswaadesignedtocompareeffrctsof vempamilSR aloneandin eombhrafionwithtrrmdolaprilon bloodpressure arrdheartstroetorein patientswithmildto moderateessentiaf byperterraion. Wecomparedreaultaoftwostudir.vperformedin our inatitotion. Veramnrif T-V 14 10 Numb ofpatierm 4H1O 57.4+12 Age(years) 6/4 717 Race(white/black) 7n 713 Sex(maltifernsle)
CARDIOVASCULARAND RENAL EFFECTS OF A TRANDOLAPRILIVERAPAMIL COMBINATION IN M1l.D TO MODERATE ESSENTIALHYPERTENS1ON. FMYllti F.C. Aepfelbaeher,J.E. Nunez,L. Michafewicz, E.D. Frohlich,F.H. Messerli*,OchsnesMedicalInatitotiona, NewOrlearra,LA. We evshratedthe cardiovascularand renal effectsof a combinationof trandolapril(T) srrdverapsmilSR (V) in pstientawith mildto moderateesaentidhypertension.After a 4 weekplaceborun-inphsae, 14patientawith stageI to II essential hypertension were treated with a fixed dose combination(T=2 mg + V=180 mg) once daily for 12 weeks. Cardiovaacolarhemodynmnicsand renalblood flow (RBF)wereassessedby invaaivelymeasuringcardfseoutput (indocyanhregreen),clearanceof 13]1-prrra-aminohippuric acid, srrdplasmavolume(PV) (1261-labeledplaama serum albumin), and performing 2D-guided M-mnde echo. Results(meanf SD):
1.93KL20
BSA(mz) Duration ofrrratment (weeka) Dose (m#d)
12
l%&0,22 12
24/180-360 240-480 15+12A l;+fcA AMAP(mmHg) 4*13 ~~wxaean) 0.37C 0.6B x Dstaare expremedaameat SD, A= pc.@31;B= F.01, c = BSA= pc.05 vs. baselinevalues.T-V=Trsrrdolspdl/Vmpamil,
bndvsorfa.% area.AMAP=cbamehrmeanarterhdpreamre, A HR~changeinheanr’sts,%L~I/nunHg. percentrechwtion oflerlventdcuhrm ass indexprnunHgreductiom ofMAP. By design of the studies, verapamilSR sfone and in combination with trandolapril similarly reduced arterial pressure; however, combination therapy had a more prrmouneedeffeet onletl vehicular mass. ‘flteaerestdfasuggestthat the eombinadonof vempsrrril SR and trandolaprilis effeeffveand well tolrratedin patients withrsamrtiafhypatemaion.‘D3erxiditionof along-actingACE inhibitorsuch as fmrrdolaprilto verspamilleads to a further decreasein left ventricularmaaswhichis independentof the reduetionof mteriafpreasore. Key Words:
Hypmemaion, eombinrdion therspy,letl ventricularh~ophy, trsodolapril,veraparnil
MAP (nmdfg)
Heartmte(trpm) Cardiac output(Umin) ‘fpRindex(unita)
PV (ml/cm) RBF (mUrriirr) RVRindex(uniLs) LVmsasindsx@Arf2)
B@irrs 123*14 72?8
4.8X1.38 28*4 18.9i3.7
Errdofstody — P 108+12 <0.01 NS 6tMll
4.9M1.63 24*5 18.2+3.6
NS NS NS
773*274 NS o.3&t0.11 <0.05 <0.01 131*43 7M1O NS Ejwdmfraction (%) 68+10 mFFs (%) 16.3*3.3 <0,05 14.6*3.O 48*11 <0.05 RWT(k)’ 53*13 ~ meanarredd ~ure: TPR=mtrdpm ~~~~: RVR=renalva.wukwreaistamz; nrFFS=midwaytibelfrmionsl sbOti : RWT=rekrtiWWdt thickness. 777fi89 0.34+0.12 144*46
~esulta demonstrated the combination of T+V provideda redoctionin meanarreriatpreasoreand LV mass while preserving systemic flow and hrcreaaing systolic performanceaa measuredby rrrFFS. ‘llese cardiovascular functionalsod structuralchangesindicatetha~+V is useful for the treatmentof mfldto moderatee.ssentia3 hyperterrsion. Key Words:
Left ventricular hypertrophy; Systemic hemodymamfcs; Renalhemorfynrmdcs.
131A
AJH-APRIL 1997-VOL. 10, NO. 4, PART 2
D103
D104
IRBESARTANVERSUSENALAPRfLfN SEVERE HYPERTENSION‘~”, 2fM.Flack”>3S.H~~> 3S. Smith,3J. Hwa,and3RA.Reeves*forthe IrbesnrtaoMulticenter Investigators.‘Univde Montr6al,Montreal,Quebec,Canada, ‘BowmanGraySchoolof Medicine,Winston-Salem,NC, 3Bristol-Myers SquibbPharmaceuticalResearchInstitute, Princeton,NJ. [nthis randomized,multicenter,double-blind,parallelstudy, tbe etlcacy andtolerabilityof the novelangiotensinII ATI (IRBE. SR47436:BMS-186295; receDtor . .. antszonistirbewutan BMS/SanofiWinthrop)was comparedto the ACEinhibitor enalaprilin patientswithseateddiastolicbloodpressure(SeDBP) of 115to 130mmHg. Patientswererandomized2:1 to initial, once-dailydosesoflRBE 150mg andenalapril20 mg that were titratedto 300mg and40 mg,respectively.Open-labeladjunctive hypertensivemedications(HCTZ,atenolol,andnifedipine)were addedafterWeek4 ifBP controlwas inadequate.At Week 12, the antihypertensiveeffectof IRBEwas comparableto that of
THE A.SROC”IATION LOS ARTAN-R4hflPRll. IN ESSENTIAI. HYPERTENSION
Priorto-Week12,with IRBE,althoughstatisticallynot significant,reductionsin troughSeDBPoccurredrelatively earlier,feweradjunctiveandhypertensivemedicationsand fewer doseup titrationswereneeded,andtbe incidenceof adverse eventswas slightlylower. Significantlymorecoughoccurred withenalaprilthanwith IRBE(13.1%vs 2.5”A,p = 0,007). In patientswithseverehypertension,an IRBEbasedregimensbows a morefavorabletolerabilityprofilethanan enalaprilbased regimenwhileprovidingat leastequivalentefficacy. Key Words: AI1receptor~tagoni~t,kbes~, enalapril,co”gh, severehypertension,double-blind,comparativestudy
M Bentivogliu, M Buccolieri, E Carluccio, M Mariotti, M Poliimru, S Tommasi, and L Coma. Chair t)f(krdiolow,
University of Perugia, Perrgia, [taly.
1( is
well knownthat the anlihypertcnsivcactivityof ACE-inhibiWs is a( least in part rcla[cdto the inhibitionor bradykiniumctaholism,with subacquenlincrcasc in EDRF and EDHF. On the olbcr hand, ACEinhibition dcxs not interfere on the chymaaepathway, an imponant ACE-indipendcntway of productionof Angiotensin11(A-II) al the [issue level. on the contrary,the A-II antagonists,blocking the AT) receptors,inhibit the A-H producedfrom all sourcos,providinga more completeblockadeof tic cffoct of A-11,but do not have effect on bradykininmctatmlisnl. With the aim to evahmtc howmuch (he inhibitionof A-11prcducedby the chymaae psthway contributes 10 blocd pressure rertuctkm in hypcrtcnsivcstreatedwith ACE-inhibitors,and howmuchthe inhibition of bradykininmetabolismmayfurtherrrshm bloodpressurein patients treatedwith A-11antagonists,we studiedwith ABPMs groupof mild-tomoderak esssntial hypsrtensives(19M, 1lF, mean age 51.0~8.7yam, clinic SBP/DBP 155,2f10,4/105,6~8,8 morHg)in a controlkd single blindstndy.Atler a 4-weeksplacetmpsriod,patientswererandomizedto re.%ivcimsar’tan(L) 25nlgo.d. or Rsmipril(R) 2,5mgo.d. for 4 wreks, and thereaherto receiveL+I?,at the sane dosages,or to doublethe doses ofthe respectivemonoltrerspyfor 4 weeks.DuringtfreIaal4 weeksof lhe studyall the patientsrsccivedthe assmiationL50mgo.d. + R5n]go.d. in the pstientatreatedwith R, the asawiationof L al low dose further reduced24 hours SBP/DBPof 9,8f4,4/6,8f3,9 mrnHg,while, at high doae, the BP rrduction was 19,8f4,3/12,0t5,6 mrnkfg(p=0,0Q5);in patien.strsatsd with L, the associationof R, cauaeda slight rcduc[ionof BP: 3,2~2,5/4,0~3,9nunffg(lowdoae),snrt 7,3+3,4/5,5+3,5mndfg (highdose)(bothn.s.). In conclusion,the incrsasein bradykinincauaedby ACE-inhibitiondrxs pot signiticrmtfyatkt blord preasure in hypertensivealready treated with A-11amtagonis&.s, whema the more rompletc blockade of A-11 rbtained with A-II antagonist cauaes a further reduction of blind presawein hypertensivsaalreadytreatedwith ACE-inhibitors. Key Words:
AT1-sntagoniats,ACE-inhibitora,chymaaepathway, bradykininmetabolism
D105
D106
ADDITIONOF TRANDOLAPRILTO VERAPAMILSR REDUCES LVH INDEPENDENTLYOF EFFECT ON BLOODPRESSURE. L_M&ddu, FH Mesaerli*,andE Nunez,OcbsncrClinicandAltonOchsnerMedicrdFoundation, NewOrlesos,LA. Left ventricularhypwtrophyis a commonsequelaof essentialhyperterraionand majorcardiovsaeulaxrisk factor. Thisarrslysiswaadesignedtocompareeffrctsof vempamilSR aloneandin eombhrafionwithtrrmdolaprilon bloodpressure arrdheartstroetorein patientswithmildto moderateessentiaf byperterraion. Wecomparedreaultaoftwostudir.vperformedin our inatitotion. Veramnrif T-V 14 10 Numb ofpatierm 4H1O 57.4+12 Age(years) 6/4 717 Race(white/black) 7n 713 Sex(maltifernsle)
CARDIOVASCULARAND RENAL EFFECTS OF A TRANDOLAPRILIVERAPAMIL COMBINATION IN M1l.D TO MODERATE ESSENTIALHYPERTENS1ON. FMYllti F.C. Aepfelbaeher,J.E. Nunez,L. Michafewicz, E.D. Frohlich,F.H. Messerli*,OchsnesMedicalInatitotiona, NewOrlearra,LA. We evshratedthe cardiovascularand renal effectsof a combinationof trandolapril(T) srrdverapsmilSR (V) in pstientawith mildto moderateesaentidhypertension.After a 4 weekplaceborun-inphsae, 14patientawith stageI to II essential hypertension were treated with a fixed dose combination(T=2 mg + V=180 mg) once daily for 12 weeks. Cardiovaacolarhemodynmnicsand renalblood flow (RBF)wereassessedby invaaivelymeasuringcardfseoutput (indocyanhregreen),clearanceof 13]1-prrra-aminohippuric acid, srrdplasmavolume(PV) (1261-labeledplaama serum albumin), and performing 2D-guided M-mnde echo. Results(meanf SD):
1.93KL20
BSA(mz) Duration ofrrratment (weeka) Dose (m#d)
12
l%&0,22 12
24/180-360 240-480 15+12A l;+fcA AMAP(mmHg) 4*13 ~~wxaean) 0.37C 0.6B x Dstaare expremedaameat SD, A= pc.@31;B= F.01, c = BSA= pc.05 vs. baselinevalues.T-V=Trsrrdolspdl/Vmpamil,
bndvsorfa.% area.AMAP=cbamehrmeanarterhdpreamre, A HR~changeinheanr’sts,%L~I/nunHg. percentrechwtion oflerlventdcuhrm ass indexprnunHgreductiom ofMAP. By design of the studies, verapamilSR sfone and in combination with trandolapril similarly reduced arterial pressure; however, combination therapy had a more prrmouneedeffeet onletl vehicular mass. ‘flteaerestdfasuggestthat the eombinadonof vempsrrril SR and trandolaprilis effeeffveand well tolrratedin patients withrsamrtiafhypatemaion.‘D3erxiditionof along-actingACE inhibitorsuch as fmrrdolaprilto verspamilleads to a further decreasein left ventricularmaaswhichis independentof the reduetionof mteriafpreasore. Key Words:
Hypmemaion, eombinrdion therspy,letl ventricularh~ophy, trsodolapril,veraparnil
MAP (nmdfg)
Heartmte(trpm) Cardiac output(Umin) ‘fpRindex(unita)
PV (ml/cm) RBF (mUrriirr) RVRindex(uniLs) LVmsasindsx@Arf2)
B@irrs 123*14 72?8
4.8X1.38 28*4 18.9i3.7
Errdofstody — P 108+12 <0.01 NS 6tMll
4.9M1.63 24*5 18.2+3.6
NS NS NS
773*274 NS o.3&t0.11 <0.05 <0.01 131*43 7M1O NS Ejwdmfraction (%) 68+10 mFFs (%) 16.3*3.3 <0,05 14.6*3.O 48*11 <0.05 RWT(k)’ 53*13 ~ meanarredd ~ure: TPR=mtrdpm ~~~~: RVR=renalva.wukwreaistamz; nrFFS=midwaytibelfrmionsl sbOti : RWT=rekrtiWWdt thickness. 777fi89 0.34+0.12 144*46
~esulta demonstrated the combination of T+V provideda redoctionin meanarreriatpreasoreand LV mass while preserving systemic flow and hrcreaaing systolic performanceaa measuredby rrrFFS. ‘llese cardiovascular functionalsod structuralchangesindicatetha~+V is useful for the treatmentof mfldto moderatee.ssentia3 hyperterrsion. Key Words:
Left ventricular hypertrophy; Systemic hemodymamfcs; Renalhemorfynrmdcs.
131A