JACC Vol. 19 . No-i April 1992:892-7
992
Editorial Comment a 24-t, basis with immediate access for the patient with acute infarction . Even if further rand --mized trials show an advan-
Improved Early Infarct-Related Vessel Patency After Thromholytic Therapy*
tage for this strategy, it is unlikely (hat, given the logistic didlCUlties associated with its use, we will achieve a major improvement in ventricular function and sarival in large numbers of patients with acute r .^.socardial infarction . 'fhepresentsstudy . The recent rudy by Neuhaus nt al . 19)
BERTRAM PITT, MD, FACC
demonstrating an improved early tvdency rat, of >90th with front-loaded rt-PA, infusing 10u mg of ti-PA over 90 min
Arrrr
Arbor,
Michigan
without an apparent increase in bleeding risk, is therefore of great interest and has important therapeutic potential .
The major
goal
Should this strategy result in an improved cony and susof reperfusion strategies in patients with tained potency rate there would he a lesser impetus to pursue
acute myocardial infarction is to achieve patency of the the strategy of rescue angioplasty and a lesser justification infarct-related artery . Improvement in ventricular function for early coronary arteriography . The strategy of direct and survival are related to initial and continued potency of this artery . The greater initial patency of the infarct-related artery after intravenous recombinant tissue-type plasminogen activator (r(-PA) compared with that achieved with intravenous streptokinase in the Thrombolysis in Myocardial Infarction (TIM[) trial (I) led to the selection of rt-PA as the thrombolytic agent of choice in the United States . With current intravenous thrombolytic strategies, the highest potency rate achieved is 75% . Early use of intrave-
coronary angioplasty without thrombolytic therapy might also lose some of its appeal it early administration of front-loaded rt-PA achieves a high rate of initial and sustained potency of the infarct-related artery . The study by Neuhaus dial. (10) in this issue of the Journal is therefore of importance in giving us some initial perspective on the potential of the front-loaded re-PA regimen to achieve and maintain patency of the infarct-related artery in comparison
nous heparin and the use ofcombined thrombolytic regimens
with intravenous APSAC . Neuhaus et al . (l0) show that
have failed to break through this ceiling (2-4), which may be
front-loaded it-PA achieved a 90-min palency rate of 84 .4%
a result of several factors. These include complexity of the
versus 70 .3% for intravenous APSAC . However, because of
atherosclerotic plaque with intramural plaque hemorrhage (5),
ongoing platelet deposition into the thrombus with
resistance to thrombolysis iii1 as well as inadequate thrombolytic effectiveness or dose of the chosen thrombolytic agent . The failure of current intravenous thmmbulylie strategies to achieve a higher patency rate of the infarct-related artery has led to several adjunctive and alternative strategies for reperfusion, Rescue angioplasty for patients with failed
a higher reocclusion rate with front-loaded n-PA, at l4 to 21 days the two regimens had a similar patency rate . The greater initial palency rate with the front-loaded rt-PA regimen was associated with a significantly lower in-hospital mortality rate. The finding in this study that initial infarctvessel patency is associated with improved survival lends encouragement to the development of combined thrombulytic strategies (I l) and further use of adjunctive strategies with antithrombin or antihbrin platelet agents such as hirudi n
intravenous thrombolysis has been evaluated in several trials
or antagonists to the glycoprotein Ilbillla platelet receptor
(7) . However, initial results have been disappointing because
(12-14). These agents have the potential to achieve even
of a relatively high rate of complications including death .
greater initial patency as suggested by initial animal studies
The failure of rescue angioplasty may be related to platelet
(13) . If the high rate of reocclusion associated with rt-PA, as
activation, particularly aftcrrt-PA and mechanical trauma to
documented in this study (10), could be reduced by adjunc-
the residual thrombus, resulting in reocclusion . Several
tive autipla€elet therapy, one might expect even greater
investigators (8) have achieved a high patency rate by using direct coronary angioplasty without intravenous thrum-
benefit for survival since reocclusion is associated with a loss of functional recovery and an increase in mortality (15) .
hntytic therapy ("direct" angioplasty) . A patency rate of
Implications. One should, however, be cautious in adopt-
>90% has been achieved with a relatively low complication
ing the strategy of front-loaded rt-PA before seeing the
rate with this strategy . Although feasible, this strategy has
results of far larger prospective randomized trials demon-
only limited applicability because of the limited availability
strating its safety and ei'hcacy over a longer period of title .
of angioplasty facilities and laboratories willing to operate on
The greater early patency of the infarct-related vessel with standard n-PA dosing regimens than with intravenous streptokinase (I) did not result in improved survival when these
.fl'Ed, togah published in Jmvnnl ofrhe Ameriraa nftege of Cardiology ,he news or the authors and do not eececserity represent the views or JACC nr the American College of Cardiology . From the University of Michigan Medical Center, Ann Art- Michigan Address for reprints : nenrnm Pill . !,t0. Taubuni Medical Center . Ann Arbor. Michigan 48109, ttwe by the Amedenn Cullegc art -iiovsy
agents were compared in the GISSI-2 (16) and ISIS-3 (17) trials . Although there has been criticism of both of these trials relating to their delayed subcutaneous heparin regimens, one would have expected that intravenous n-PA in these trials should have achieved greater initial patency of uaJs-touvusai55 .Ua
JAMV.1, 19. Na April 1972 :692-3
Eatnoo.IAI. r: sI 4r 5J
o .ianinaen activator and in-c- as ,'rcprnhina,r clinical hndinps ihraaph hn,pirat dematge . Circolanon 1987 ;7t :14 =`_4 . Torn) F3 . Groan BS . Ke,nikc DJ, et d . A mvJamiad controlled trial vim,-r- state plarrarce_en activatnramde :dy'mtrneeanns heparin
the infarct-related artery, al least in comparison with intravenous streptokina a . The tack o : early intravenous heparin in these trials would be expected to have a greater influence on reoeelusion than on initial patency . Because Neuhaus et al . (10) suggest that early rather i .ran late palcttc5 i, importance in improving survival, one would have expected improved survival
ISIS-3
in
the r:-PA arm
of
the
GISSI-2 (161
o aril al enfarctron. Cvcula :ien 19h9 ;9
,.
231-M1.
el E .tcodemted.combined.rtsJarieethranroarrc dvnc nratpgec for-soap myocardial iofaruioo . Con, Opin Cardiol 19911 :5 :
and 4- Topd El. r_ultR Rbi Gave. Pte;, c z1- Coronary .meual rhrombolysis
trials (17), at least in comparison with intravenous
strepokinase . Whether trial design or factors other ihnn infarct-vessel patency account for the failure of rt-PA to demonstrate improved survival despite its early patency advantage remains to he determined . .A far larger noinber of patients, in the range of 10 .0(0 per treatment arm. will also be needed to be studied before we can assess the effect of front-loaded rt-PA or any other regimen on the incidence of
;" nnh combined infusion ofrecambinam llatet ;pt *,-Moo 'cm and urrki.adtr in patems wait scale myoardial "T-lion . Circulation t9shrn7'11002 . 5 kkharcson 6C. Allen DC, Monon P. Mvnagh JO, Scott ME. O'Keefe tin Falhelogieehangen .3Cm mlrmenuesslnptokinaschcmrnudmerµht p~dilrr1, with aaL4 myocardial'.nfcal tx attar[ i isssr1- ;sa-6 b6 iaw JK . Gala I IK. 7iskird A.A, n,' . I?i:.c.nnal srnsitiaity of prYth,a' cyte-rich and plaakt-rkh unettal thrombi to Ipso with remrrhiscnl ,r-PA: a retohk eaptznation I., rvr s crcc ao coronar y thrombolysis, csulatiue uk9:i9:9co_6 .
major bleeding, which is approximately IV, with standard thrombolytic regimens (17) . Although there was a lower incidence of bleeding mooned in the trial by Neuhaus el a!. (10),
with front-loaded
en-PA
Clam with APSAC- as the
7 Torc 10 Cal.0 RM, Ccearge BS . et h . A nvdamrced treat of immedia :m versus delayed tactile anpoplasty aftcr tmmlxnnto tissue P . -'.p. n decor msaxrrliel infarction N Enrl J Stud 198? :117 :581-8. a . Hanzlerr 00 • Rutherford BD . McCon hav DR. er al. Pmemaneoas translnmirxl emonary anpiryrlaay->,Ihand wnhmd thromholynr therapy
authors point out, this difference may be due to the use of early intravenous heparin, which may not be necessary with intravenous
APSAC
given the lower incidence
of
reocclu-
Sion associated with its use . Conclusions. Thus, whi .a it appears that we cat achieve improved early patency by front-loaded r0--PA and
could
likely achieve even better initial and sustained patency by
for rrealn and A .11. nnacardial infantici- Am 14 .1 3 1983Jrp .9G973. 9, Veuhaas KL . Feuerer W . Jeep Teebe a- et al . Improved Mrovehnl}sic allh a i relOad dose repines of recumbi .tent tisme-type plasminosen -WT. J Am Call ( t%6 .did 1989;14.: . Neuhaus K L . inn Es- R . felt, C, et al . Improved thrombatteis in J-11) .are olyoemdial infarction with front-lasdud admtnrstnalron of ahcp!ssc
the addition of adjunctive antiplatelet therapy, we still have
resuhs of the n-PA-APSAC Parency Suedy ITAPal . J Am C,11 Cereal 1990:19:68.0-91 .
much to learn concerning the dose of thrombolytic therapy
11 He, . M • CheubraJH . Funny WJ, Bailey KR, Badinmn L . FactT V.
as well as the addition and timing of heparin and other adjunctive therapies. Neuhaus et al . (10) have given us hope for improved survival by improved early infarct vessel patency. To achieve the full potential of the thrombolytic era we will need to further explore this and other dosing regimens of thrombolytic agents with new adjunctive therapies. Clearly we have much to learn . The
GISSI 2 (16) and ISIS-3
(17) trials mark the end of one phase of our exploration for the optimal reperfusion strategy . The next phase is just beginning . Although it is premature to predict which thrombolvtic agent will he the agent of choice, it is not too early to predict that we will achieve greater early and sustained patency with improved functional recovery and survival by further careful study
of strategies now
12 . MinketliM,SapJ,SrvieC,etal.Evaluanenoftheinhibitionbyhepavn and hirvdin of eaagulaoine activator daring el-PA induced tbmmbolysie . Blood 1969 :74:107530. It . Colter BS. Felts 1D• Smith SR, Sadder LE . rock[ R. Abolirion of in vo plaldet thrombus formation in prirnoes with monabnal amibadtra to the platelet GP Ilblllla receptor : eutrelicmn with bleeding time . platelet aggregarice and blockade or GP knits receptors . C'rcalotion r989at 1766-74. 14. Gold HK, Colter BS, Yasuda T . et a1 . Radial cud sustained coronary amen, recarlalization 01b a comb, rd bolus in)eceien of recombinant dsmeayprplasminoSc, mlivalorandmonosOineiae'liplateletGP11WIIle canine pr0Paratie,. Circulation 19pp:7T6?B-71$. Ohman EM . Caaff RM . Tepal EL et al . Consegaences of reocclusin futievilg successful reperf tekir lherepy in arose myocardial Infarction .
under develnptnent
and in or soon to be in clinical trial .
References !.
Efrccen of thrombin inhibition on the de .elepncan of acute plarekllhienbin deposition dmirpangtoplasty in ptg5 . hepann vents recombrnanl fin ;din, a specific thrombin inhibitor . Circulation 1989 :79:657-d5 .
ChesebroJO,KnalleruiC,Roberts it,etal .ThromholymmMyocard,al Infarction (TIMn lal • Pnose 1:1 almpaneon between inttnvenoas ttsaae
Cinulafion 1990:At:761A1 . 16. Gntppo Irrtienn per In Sludia Delta 3npeneeiarneu 9d1'Infiono
Min-
cardicp: GISS4L a factorial ruedomized vial of alteplase arenas srreptakioam emu be pear core® en hepeva cornea 12490 r->atienls with scale myamdiat adareaot- Lancer 199m336bs-71 . I7. SchetdtS .etcd.ISIS-3,ImplinuonsroeAmeriranpactice :medicalpor•N dlswssion . Cmdinyuc Rey Rm 1991 :12:37-6d .
992
Editorial Comment a 24-t, basis with immediate access for the patient with acute infarction . Even if further rand --mized trials show an advan-
Improved Early Infarct-Related Vessel Patency After Thromholytic Therapy*
tage for this strategy, it is unlikely (hat, given the logistic didlCUlties associated with its use, we will achieve a major improvement in ventricular function and sarival in large numbers of patients with acute r .^.socardial infarction . 'fhepresentsstudy . The recent rudy by Neuhaus nt al . 19)
BERTRAM PITT, MD, FACC
demonstrating an improved early tvdency rat, of >90th with front-loaded rt-PA, infusing 10u mg of ti-PA over 90 min
Arrrr
Arbor,
Michigan
without an apparent increase in bleeding risk, is therefore of great interest and has important therapeutic potential .
The major
goal
Should this strategy result in an improved cony and susof reperfusion strategies in patients with tained potency rate there would he a lesser impetus to pursue
acute myocardial infarction is to achieve patency of the the strategy of rescue angioplasty and a lesser justification infarct-related artery . Improvement in ventricular function for early coronary arteriography . The strategy of direct and survival are related to initial and continued potency of this artery . The greater initial patency of the infarct-related artery after intravenous recombinant tissue-type plasminogen activator (r(-PA) compared with that achieved with intravenous streptokinase in the Thrombolysis in Myocardial Infarction (TIM[) trial (I) led to the selection of rt-PA as the thrombolytic agent of choice in the United States . With current intravenous thrombolytic strategies, the highest potency rate achieved is 75% . Early use of intrave-
coronary angioplasty without thrombolytic therapy might also lose some of its appeal it early administration of front-loaded rt-PA achieves a high rate of initial and sustained potency of the infarct-related artery . The study by Neuhaus dial. (10) in this issue of the Journal is therefore of importance in giving us some initial perspective on the potential of the front-loaded re-PA regimen to achieve and maintain patency of the infarct-related artery in comparison
nous heparin and the use ofcombined thrombolytic regimens
with intravenous APSAC . Neuhaus et al . (l0) show that
have failed to break through this ceiling (2-4), which may be
front-loaded it-PA achieved a 90-min palency rate of 84 .4%
a result of several factors. These include complexity of the
versus 70 .3% for intravenous APSAC . However, because of
atherosclerotic plaque with intramural plaque hemorrhage (5),
ongoing platelet deposition into the thrombus with
resistance to thrombolysis iii1 as well as inadequate thrombolytic effectiveness or dose of the chosen thrombolytic agent . The failure of current intravenous thmmbulylie strategies to achieve a higher patency rate of the infarct-related artery has led to several adjunctive and alternative strategies for reperfusion, Rescue angioplasty for patients with failed
a higher reocclusion rate with front-loaded n-PA, at l4 to 21 days the two regimens had a similar patency rate . The greater initial palency rate with the front-loaded rt-PA regimen was associated with a significantly lower in-hospital mortality rate. The finding in this study that initial infarctvessel patency is associated with improved survival lends encouragement to the development of combined thrombulytic strategies (I l) and further use of adjunctive strategies with antithrombin or antihbrin platelet agents such as hirudi n
intravenous thrombolysis has been evaluated in several trials
or antagonists to the glycoprotein Ilbillla platelet receptor
(7) . However, initial results have been disappointing because
(12-14). These agents have the potential to achieve even
of a relatively high rate of complications including death .
greater initial patency as suggested by initial animal studies
The failure of rescue angioplasty may be related to platelet
(13) . If the high rate of reocclusion associated with rt-PA, as
activation, particularly aftcrrt-PA and mechanical trauma to
documented in this study (10), could be reduced by adjunc-
the residual thrombus, resulting in reocclusion . Several
tive autipla€elet therapy, one might expect even greater
investigators (8) have achieved a high patency rate by using direct coronary angioplasty without intravenous thrum-
benefit for survival since reocclusion is associated with a loss of functional recovery and an increase in mortality (15) .
hntytic therapy ("direct" angioplasty) . A patency rate of
Implications. One should, however, be cautious in adopt-
>90% has been achieved with a relatively low complication
ing the strategy of front-loaded rt-PA before seeing the
rate with this strategy . Although feasible, this strategy has
results of far larger prospective randomized trials demon-
only limited applicability because of the limited availability
strating its safety and ei'hcacy over a longer period of title .
of angioplasty facilities and laboratories willing to operate on
The greater early patency of the infarct-related vessel with standard n-PA dosing regimens than with intravenous streptokinase (I) did not result in improved survival when these
.fl'Ed, togah published in Jmvnnl ofrhe Ameriraa nftege of Cardiology ,he news or the authors and do not eececserity represent the views or JACC nr the American College of Cardiology . From the University of Michigan Medical Center, Ann Art- Michigan Address for reprints : nenrnm Pill . !,t0. Taubuni Medical Center . Ann Arbor. Michigan 48109, ttwe by the Amedenn Cullegc art -iiovsy
agents were compared in the GISSI-2 (16) and ISIS-3 (17) trials . Although there has been criticism of both of these trials relating to their delayed subcutaneous heparin regimens, one would have expected that intravenous n-PA in these trials should have achieved greater initial patency of uaJs-touvusai55 .Ua
JAMV.1, 19. Na April 1972 :692-3
Eatnoo.IAI. r: sI 4r 5J
o .ianinaen activator and in-c- as ,'rcprnhina,r clinical hndinps ihraaph hn,pirat dematge . Circolanon 1987 ;7t :14 =`_4 . Torn) F3 . Groan BS . Ke,nikc DJ, et d . A mvJamiad controlled trial vim,-r- state plarrarce_en activatnramde :dy'mtrneeanns heparin
the infarct-related artery, al least in comparison with intravenous streptokina a . The tack o : early intravenous heparin in these trials would be expected to have a greater influence on reoeelusion than on initial patency . Because Neuhaus et al . (10) suggest that early rather i .ran late palcttc5 i, importance in improving survival, one would have expected improved survival
ISIS-3
in
the r:-PA arm
of
the
GISSI-2 (161
o aril al enfarctron. Cvcula :ien 19h9 ;9
,.
231-M1.
el E .tcodemted.combined.rtsJarieethranroarrc dvnc nratpgec for-soap myocardial iofaruioo . Con, Opin Cardiol 19911 :5 :
and 4- Topd El. r_ultR Rbi Gave. Pte;, c z1- Coronary .meual rhrombolysis
trials (17), at least in comparison with intravenous
strepokinase . Whether trial design or factors other ihnn infarct-vessel patency account for the failure of rt-PA to demonstrate improved survival despite its early patency advantage remains to he determined . .A far larger noinber of patients, in the range of 10 .0(0 per treatment arm. will also be needed to be studied before we can assess the effect of front-loaded rt-PA or any other regimen on the incidence of
;" nnh combined infusion ofrecambinam llatet ;pt *,-Moo 'cm and urrki.adtr in patems wait scale myoardial "T-lion . Circulation t9shrn7'11002 . 5 kkharcson 6C. Allen DC, Monon P. Mvnagh JO, Scott ME. O'Keefe tin Falhelogieehangen .3Cm mlrmenuesslnptokinaschcmrnudmerµht p~dilrr1, with aaL4 myocardial'.nfcal tx attar[ i isssr1- ;sa-6 b6 iaw JK . Gala I IK. 7iskird A.A, n,' . I?i:.c.nnal srnsitiaity of prYth,a' cyte-rich and plaakt-rkh unettal thrombi to Ipso with remrrhiscnl ,r-PA: a retohk eaptznation I., rvr s crcc ao coronar y thrombolysis, csulatiue uk9:i9:9co_6 .
major bleeding, which is approximately IV, with standard thrombolytic regimens (17) . Although there was a lower incidence of bleeding mooned in the trial by Neuhaus el a!. (10),
with front-loaded
en-PA
Clam with APSAC- as the
7 Torc 10 Cal.0 RM, Ccearge BS . et h . A nvdamrced treat of immedia :m versus delayed tactile anpoplasty aftcr tmmlxnnto tissue P . -'.p. n decor msaxrrliel infarction N Enrl J Stud 198? :117 :581-8. a . Hanzlerr 00 • Rutherford BD . McCon hav DR. er al. Pmemaneoas translnmirxl emonary anpiryrlaay->,Ihand wnhmd thromholynr therapy
authors point out, this difference may be due to the use of early intravenous heparin, which may not be necessary with intravenous
APSAC
given the lower incidence
of
reocclu-
Sion associated with its use . Conclusions. Thus, whi .a it appears that we cat achieve improved early patency by front-loaded r0--PA and
could
likely achieve even better initial and sustained patency by
for rrealn and A .11. nnacardial infantici- Am 14 .1 3 1983Jrp .9G973. 9, Veuhaas KL . Feuerer W . Jeep Teebe a- et al . Improved Mrovehnl}sic allh a i relOad dose repines of recumbi .tent tisme-type plasminosen -WT. J Am Call ( t%6 .did 1989;14.: . Neuhaus K L . inn Es- R . felt, C, et al . Improved thrombatteis in J-11) .are olyoemdial infarction with front-lasdud admtnrstnalron of ahcp!ssc
the addition of adjunctive antiplatelet therapy, we still have
resuhs of the n-PA-APSAC Parency Suedy ITAPal . J Am C,11 Cereal 1990:19:68.0-91 .
much to learn concerning the dose of thrombolytic therapy
11 He, . M • CheubraJH . Funny WJ, Bailey KR, Badinmn L . FactT V.
as well as the addition and timing of heparin and other adjunctive therapies. Neuhaus et al . (10) have given us hope for improved survival by improved early infarct vessel patency. To achieve the full potential of the thrombolytic era we will need to further explore this and other dosing regimens of thrombolytic agents with new adjunctive therapies. Clearly we have much to learn . The
GISSI 2 (16) and ISIS-3
(17) trials mark the end of one phase of our exploration for the optimal reperfusion strategy . The next phase is just beginning . Although it is premature to predict which thrombolvtic agent will he the agent of choice, it is not too early to predict that we will achieve greater early and sustained patency with improved functional recovery and survival by further careful study
of strategies now
12 . MinketliM,SapJ,SrvieC,etal.Evaluanenoftheinhibitionbyhepavn and hirvdin of eaagulaoine activator daring el-PA induced tbmmbolysie . Blood 1969 :74:107530. It . Colter BS. Felts 1D• Smith SR, Sadder LE . rock[ R. Abolirion of in vo plaldet thrombus formation in prirnoes with monabnal amibadtra to the platelet GP Ilblllla receptor : eutrelicmn with bleeding time . platelet aggregarice and blockade or GP knits receptors . C'rcalotion r989at 1766-74. 14. Gold HK, Colter BS, Yasuda T . et a1 . Radial cud sustained coronary amen, recarlalization 01b a comb, rd bolus in)eceien of recombinant dsmeayprplasminoSc, mlivalorandmonosOineiae'liplateletGP11WIIle canine pr0Paratie,. Circulation 19pp:7T6?B-71$. Ohman EM . Caaff RM . Tepal EL et al . Consegaences of reocclusin futievilg successful reperf tekir lherepy in arose myocardial Infarction .
under develnptnent
and in or soon to be in clinical trial .
References !.
Efrccen of thrombin inhibition on the de .elepncan of acute plarekllhienbin deposition dmirpangtoplasty in ptg5 . hepann vents recombrnanl fin ;din, a specific thrombin inhibitor . Circulation 1989 :79:657-d5 .
ChesebroJO,KnalleruiC,Roberts it,etal .ThromholymmMyocard,al Infarction (TIMn lal • Pnose 1:1 almpaneon between inttnvenoas ttsaae
Cinulafion 1990:At:761A1 . 16. Gntppo Irrtienn per In Sludia Delta 3npeneeiarneu 9d1'Infiono
Min-
cardicp: GISS4L a factorial ruedomized vial of alteplase arenas srreptakioam emu be pear core® en hepeva cornea 12490 r->atienls with scale myamdiat adareaot- Lancer 199m336bs-71 . I7. SchetdtS .etcd.ISIS-3,ImplinuonsroeAmeriranpactice :medicalpor•N dlswssion . Cmdinyuc Rey Rm 1991 :12:37-6d .
