Designing Thrombolytic Agents: Focus on Safety and Efficacy Dksir6
COlktI,
Thrombolytk therapy for evolving acute myocard&l InfarctIon (AH) reduces Infarct size, preservesventrkularfunctlon,andreducesmortalRy. intravenous streptokhmse lscommonly foHowedbyapprdmately5O%patencyofcoronaryarterleswRhln9Omlnutesandbyreductlon ofmortalRyby2S%.RewnWmnttlssueplasmlnugen activator @t-PA)ls more potent for coronary arterial thrombdyds , praduclng both more rapldandmorefrequentrecanallzatkn(approxlmately7S%patencyat9Omlnutes)wRhadoseof I.00 mg given over 3 houra Side effects (mainly assodatedwRhtheuseofstreptdcl-WI nase and &PA are not markedly dmerent. 7hat thehlghereffkacyofrt-PAwouldtrandatelntoa laqgerreductlonofmortalRylssuggestedbythe resuRsofseveralsmalltrlalsbutrenlalnstobe codirmedIn~comparatlvecllnkal trials. 7hls question has not been adsquately answered by ths recent lntematknal rt-PA/streptokhmse mortalRy trial and the Intematlonal Study on brhwct Survival (lSlS-3) study, because otconcemswRhrespecttotbsroleofconJuncthfehWwenousheparlnadmlnktr8tknandthe dose of rt=PA used In lSlS-3. All available thrombolytkagentsstlllhaveslgnmcantsho~, lncMlngtheneedforlargedosestobemaxlmally efklent, a Ilmlted flbrln spe#kRy, and a slgnlfkant assodated bwtedency. New developmsntstowardbnprovedeffkacyandflbrlMpecwRyofthrombolytkagentsllicluds the use of mutants of r&-PA,chhnerk rt-PA or slngle chain uroklnaw plasmlnogen activator molecules, and antibody-targeted thrombolytk agenk.Someoftheseartlfklalplasmlnogenactlvatorshavea&tolO4oklInweasedpotency (thrombolytk actlvRy par unR dose), but whether they are safe enough to be clbikally useful remalns to bs es&WMed. The conJunctlve use of From the Center for Thrombosis and Vascular Research, University of Leuven, Belgium Address for reprints: DBsik Collen, MD, PhD, Center for Thrombosis and Vascular Research, K.U. Leuven, Campus Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium.
MD, PhD
antkoagulantsandantlplateMagentswRh thelreffkacyto thrombolytkagentslncreaws an extent that monothwapywlth a pV actlvatoraknelsnolongertenable.Reparlnand effkhtforaccderaaspMn=-Wmalerately tlonoflyslsandprewntknofreodudn,but arerelatlvelysafe. More sekdlve thrembk lnhlbRorsandant@lateletagentsaremorepotent, butthelrsafetyremalnstobeconRrmd.ContlnuedlnvesUgaWnlnthlsareawlllprovldenewlnslghtsandpromoteprogresstowardthededopmentoftheldeal thrombdytictherapY9 coronaryarteCharacterbedbymaxbnbedstablS rlal thronWly& wRh mhdmal bkedlq& (Am J Cardlol l992~7lA-SlA)
T
he beneficial effects of thrombolytic therapy for thromboembolic diseases are now well established and the side effects are in general less serious than was initially anticipated. This has resulted in a continuously expanding use of thrombolytic therapy, particularly in patients with evolving myocardial infarction. The limited efficacy and the occasional life-threatening side effects of current therapeutic schemes, however, remain a matter of concern and warrant further investigation into improved agents and strategies. Many aspects of the risk-benefit ratio of thrombolytic therapy are reviewed in the other articles in this supplement. Here, the focus is on safety and efficacy of thrombolytic strategies in terms of the dosing, duration, and nature of the thrombolytic agents used, the interactive effects of conjunctive antithrombotic agents, and the baseline characteristics of the patient. The available data from clinical trials will be reviewed and extrapolated to potential improvements with experimental agents or combinations. Although safety encompasses many adverse reactions, including arrhythmia and allergic reactions, this review will focus on bleeding side effects, and more particularly on intracerebral bleeding and ischemic stroke. The present experience obtained in randomized clinical trials with thrombolytic therapy, in which at A SYMPOSIUM: SAFETY OF THROMBOLYTIC AGENTS
7i.A
+ + +
+ +
* + ? ? +(>24h) +(>24h)
-
+ + ? ?
Aspirin
-c (SC 4 h)
?(sc4h)
f (SC 12 h) f (SC 12 h) f (SC 4 h)
+ + + +
+ (24 h) + (24 h)
+ + ? ? ? ? ?
Heparin
?
(4.2)* (4.6)* -
0.9 0.9 -
0.6
0.9 -
-
-
-
-
-
-
1.4
-
-
t-PA
-
-
0.7 0.5 0.5 0.4
-? --
0.5
-
-
-
-
0.2
-
-
?
Placebo SK
1.0
-
0.3 -
-
-
-
APSAC
Major Bleeding (%)
ICE ICE (Stroke) ICE (stroke) ICB (stroke) ICB (stroke) ICB ICB (stroke) ICB (stroke) (Stroke) (Stroke) ICB (stroke) ICB (stroke) ICB (stroke) ICB (stroke) ProbXB (stroke) Prob.lCB (stroke) Prob.lCB (stroke)
Definition SK
-
-
(0.5)
-
-
0.3(1.1)
0.3 (0.9)
-
-
-
0 0 0.5 (0.9) 0.2 (1.1) 0.0 (0.9) 0.1 (0.8) 0.1 0.1 (1.0) -
Placebo ._
-
(1.1)
0.6 (1.5)
-
0.7 (1.5)
-
0.4 (0.8) 0.6 (1.4) 0.4 (1.3)
-
-
-
-
-
-
-
-
1
-
APSAC
-
-
-
1
t-PA
0.3(1.1)
Neurologic Events (%)
-
-
-
-
9.8 12.2
-
-
13.0 -
7.1 -
Placebo
4.7 5.2 -
-
7.2
-
-
-
-
inAcute
10.6
6.4 -
-
-
_
_
-
-
t-PA APSAC
8.9 10.5 10.3 --
8.5
-
-
-_
--_ -
-_
10.7 --
-
6.3
SK
Early Mortality (%I
days days days days 35 days 35 days 35 days 30 days 30 days 30 days 3Odays 42 days 42 days Hospital (M 9 d) Hospital (M 9 d) 35days 35 days 35days
21 21 21 21
End Point
&enb
‘Bleedmg and hematologic event rates represent data obtained with 100 mg rt-PA in this highly invasive study. amDut,=dutepbse; AIMS = APSAC Intervention Mortahty Study; Alt = $teplase; APSAC = anisoylated plasminogen-streptokinase activator complex; ASA = aspirin; ASSET = Anglo-Scandinavian Study of Earfy Thmmblysis; Cons = B GISSI-1 = Gruppu ltallano per lo Sb@o della Streptochmasl nel! lnfarto Miocardico; GISSI-2 Gruppo Italian0 per lo Studio della Soprawivenza nell’ lnfarto Miocardico; ICB = intracranial bleeding; lnv = invasive app-h; ~SAM = f,-,h-strepdduMse Myocardial Infarction; ISIS = lnternabonal Study on Infarct Swwal; Plac = placebo; Prob = pmbable; SK = streptokinase; TIMI = Thrombolysis in Myocardial Infarction; t-PA = alteplase or duteplase.
Plac: 882 SK: 859 GISSI-1’ Plac: 5852 SK: 5860 Plac: 4238 ISIS-23 SK: 8490 SK + ASA: 4239 ASSET4 Plac: 2493 Alt: 2512 AIM!? Plac: 502 APSAC:502 TIMI-II6 Cons: 1626 Inv: 1636 GISSI-2/lnternationaI SK: 10,396 Study Group7 Alt: 10,372 ISIS-38 SK: 13,000 Dut: 13,000 APSAC:13,000
ISAM’
Study
Patient No.
Adjunctive Therapy
TABLE 1 Major Bleeding, Neurologic Events and Early Mortality in Large (> 500 Patients per Group) Controlled Clinical Trials with Intravenous Throml)ojfiic
least 500 patients were allocated to each group, are summarized in Table I. In aggregate, the placebocontrolled studies have demonstrated that thrombolytic therapy with streptokinase,1-3recombinant tissue plasminogen activator (rt-PA)4 or anisoylated plasminogen streptokinase activator complex (APSAC)’ reduces mortality; and that the mortality benefit is achieved with acceptable frequencies of side effects. However, because of their simple design, these studies provide little or no information on the mechanisms by which clinical benefit is achieved. The only 2 mega-trials performed to date that have compared the efficacy for mortality reduction of different thrombolytic agents in patients with acute myocardial infarction (AMI) have shown no difference in early mortality and, if anything, a higher intracerebral bleeding rate with the “high tech” rt-PA and APSAC than with the “low tech” streptokinase.7Y8 The argument could end here with the conclusion that more efficient thrombolytic agents do not confer better clinical outcome, but are associated with higher toxicity than the combination of streptokinase and aspirin, as was established by the Second International Study on Infarct Survival (ISIS-2). However, significant questions concerning the design and monitoring of the comparative mega-trials persist, which have been totally overlooked during the recent wide dissemination of the ISIS-3 results. It would, therefore, seem appropriate to analyze critically the available data before discussing potential further improvements of thrombolytic agents and strategies. CURRENT STATUS OF lHROMROLYllC THERAPY OF ACUTE MYOCAROIAL INFARCTION
The recognition that thrombosis within the infarct-related coronary artery plays a major role in the pathogenesis of AMI, and the observation that early administration of thrombolytic agents results in recanalization of occluded coronary arteries, have provided the basis for the development of thrombolytic therapy in AMI. The hypothesis underlying this form of treatment is that coronary artery occlusion leads to ischemia and cell death, resulting in ventricular dysfunction and reduced life expectancy, and that timely recanalization, within a time window that allows salvage of ischemit myocardium, reduces infarct size, preserves myocardial function, and reduces early and late mortality. The most rational treatment of patients with AM1 is therefore likely to be thrombolytic therapy with agents or combinations that produce stable coronary artery recanalization as frequently
and as rapidly as possible, but with acceptable safety. Late opening of an occluded coronary artery may have some beneficial effect by limiting left ventricular remodeling, improving the electrical stability of the heart, or providing collateral vesselsto viable myocardium.g Further, adjunctive therapy with anticoagulant and/or antiplatelet agents clearly contributes to the efficacy of thrombolysis. Comparathfedfkacyofsbv@Mmeand rt-PA: Comparative studies between streptokinase and rt-PA have shown a difference in efficacy for early coronary artery recanalization”; this conclusion has been supported by results of several noncomparative studies with similar design and end points (for references, see Collen”). Coronary artery patency is present in approximately 22% of patients within 90 minutes after the start of placebo infusion (usually including heparin and occasionally aspirin), probably around 35% after 2U8 hours, and around 65% after l-3 weeks. Streptokinase administration is associated with around 53% patency at 90 minutes and 75% after l-3 weeks, whereas rt-PA, in combination with intravenous heparin, is associated with 75% patency at 90 minutes, 85% at 24-48 hours and 81% at l-3 weeks.‘* This analysis may be somewhat biased in favor of placebo as a result of higher early mortality in placebo-treated patients than in patients given thrombolytic agents. It is, however, difficult to imagine from these data that late patency would be the primary determinant of clinical outcome. Early patency, measured around 90 minutes after the start of therapy, is significantly increased over placebo (22%) with either streptokinase (53%) or rt-PA (75%) whereas the efficacy for coronary recanalization with rt-PA is about 50% higher than with streptokinase. Nevertheless, comparative studies between streptokinase and rt-PA have not shown a difference in preservation of left ventricular function,‘3*‘4 in combined clinical outcome,” or in survival.7’8 This lack of correlation between initial efficacy and clinical outcome may have several explanations. First, initial recanalization obviously needs to be sustained in order to convey benefit. In the absence of adequate anticoagulation, the higher initial efficacy of rt-PA indeed appears to be offset by more frequent reocclusion, as demonstrated in several recent trials with angiographic end points (Table II). Whereas heparin did not appear to affect patency at 90 minutes,16its omission markedly reduced the patency rates measured at 7-24 hours,*’ 48-72 hours (mean 55 hours)” or at 48-120 A SYMPOSIUM: SAFETY OF THROMBOLYTIC AGENTS
73A
TABLE II Influence of Heparin on Coronary Patency Following Alteplase infusion End point (Time after Start of Therapy) Heparin With
Without
Study
90 min
Top01et al,161989 Hsia et al,” 1990 Bleich et al,181990 ECSG,” 1991 Top01et al,161989 Hsia et al,]’ 1990 Bleich et al,lB 1989 ECSG,” 1991 P
79% (50/63)
7-14 hr
48-72 hr
4B-120 hr
? No ?
82% (82/100)
71% (30/42) 83% (214/258) 79% (54168) 52% (48/93) 43% (18/42) 0.83
COlktI,
Thrombolytk therapy for evolving acute myocard&l InfarctIon (AH) reduces Infarct size, preservesventrkularfunctlon,andreducesmortalRy. intravenous streptokhmse lscommonly foHowedbyapprdmately5O%patencyofcoronaryarterleswRhln9Omlnutesandbyreductlon ofmortalRyby2S%.RewnWmnttlssueplasmlnugen activator @t-PA)ls more potent for coronary arterial thrombdyds , praduclng both more rapldandmorefrequentrecanallzatkn(approxlmately7S%patencyat9Omlnutes)wRhadoseof I.00 mg given over 3 houra Side effects (mainly assodatedwRhtheuseofstreptdcl-WI nase and &PA are not markedly dmerent. 7hat thehlghereffkacyofrt-PAwouldtrandatelntoa laqgerreductlonofmortalRylssuggestedbythe resuRsofseveralsmalltrlalsbutrenlalnstobe codirmedIn~comparatlvecllnkal trials. 7hls question has not been adsquately answered by ths recent lntematknal rt-PA/streptokhmse mortalRy trial and the Intematlonal Study on brhwct Survival (lSlS-3) study, because otconcemswRhrespecttotbsroleofconJuncthfehWwenousheparlnadmlnktr8tknandthe dose of rt=PA used In lSlS-3. All available thrombolytkagentsstlllhaveslgnmcantsho~, lncMlngtheneedforlargedosestobemaxlmally efklent, a Ilmlted flbrln spe#kRy, and a slgnlfkant assodated bwtedency. New developmsntstowardbnprovedeffkacyandflbrlMpecwRyofthrombolytkagentsllicluds the use of mutants of r&-PA,chhnerk rt-PA or slngle chain uroklnaw plasmlnogen activator molecules, and antibody-targeted thrombolytk agenk.Someoftheseartlfklalplasmlnogenactlvatorshavea&tolO4oklInweasedpotency (thrombolytk actlvRy par unR dose), but whether they are safe enough to be clbikally useful remalns to bs es&WMed. The conJunctlve use of From the Center for Thrombosis and Vascular Research, University of Leuven, Belgium Address for reprints: DBsik Collen, MD, PhD, Center for Thrombosis and Vascular Research, K.U. Leuven, Campus Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium.
MD, PhD
antkoagulantsandantlplateMagentswRh thelreffkacyto thrombolytkagentslncreaws an extent that monothwapywlth a pV actlvatoraknelsnolongertenable.Reparlnand effkhtforaccderaaspMn=-Wmalerately tlonoflyslsandprewntknofreodudn,but arerelatlvelysafe. More sekdlve thrembk lnhlbRorsandant@lateletagentsaremorepotent, butthelrsafetyremalnstobeconRrmd.ContlnuedlnvesUgaWnlnthlsareawlllprovldenewlnslghtsandpromoteprogresstowardthededopmentoftheldeal thrombdytictherapY9 coronaryarteCharacterbedbymaxbnbedstablS rlal thronWly& wRh mhdmal bkedlq& (Am J Cardlol l992~7lA-SlA)
T
he beneficial effects of thrombolytic therapy for thromboembolic diseases are now well established and the side effects are in general less serious than was initially anticipated. This has resulted in a continuously expanding use of thrombolytic therapy, particularly in patients with evolving myocardial infarction. The limited efficacy and the occasional life-threatening side effects of current therapeutic schemes, however, remain a matter of concern and warrant further investigation into improved agents and strategies. Many aspects of the risk-benefit ratio of thrombolytic therapy are reviewed in the other articles in this supplement. Here, the focus is on safety and efficacy of thrombolytic strategies in terms of the dosing, duration, and nature of the thrombolytic agents used, the interactive effects of conjunctive antithrombotic agents, and the baseline characteristics of the patient. The available data from clinical trials will be reviewed and extrapolated to potential improvements with experimental agents or combinations. Although safety encompasses many adverse reactions, including arrhythmia and allergic reactions, this review will focus on bleeding side effects, and more particularly on intracerebral bleeding and ischemic stroke. The present experience obtained in randomized clinical trials with thrombolytic therapy, in which at A SYMPOSIUM: SAFETY OF THROMBOLYTIC AGENTS
7i.A
+ + +
+ +
* + ? ? +(>24h) +(>24h)
-
+ + ? ?
Aspirin
-c (SC 4 h)
?(sc4h)
f (SC 12 h) f (SC 12 h) f (SC 4 h)
+ + + +
+ (24 h) + (24 h)
+ + ? ? ? ? ?
Heparin
?
(4.2)* (4.6)* -
0.9 0.9 -
0.6
0.9 -
-
-
-
-
-
-
1.4
-
-
t-PA
-
-
0.7 0.5 0.5 0.4
-? --
0.5
-
-
-
-
0.2
-
-
?
Placebo SK
1.0
-
0.3 -
-
-
-
APSAC
Major Bleeding (%)
ICE ICE (Stroke) ICE (stroke) ICB (stroke) ICB (stroke) ICB ICB (stroke) ICB (stroke) (Stroke) (Stroke) ICB (stroke) ICB (stroke) ICB (stroke) ICB (stroke) ProbXB (stroke) Prob.lCB (stroke) Prob.lCB (stroke)
Definition SK
-
-
(0.5)
-
-
0.3(1.1)
0.3 (0.9)
-
-
-
0 0 0.5 (0.9) 0.2 (1.1) 0.0 (0.9) 0.1 (0.8) 0.1 0.1 (1.0) -
Placebo ._
-
(1.1)
0.6 (1.5)
-
0.7 (1.5)
-
0.4 (0.8) 0.6 (1.4) 0.4 (1.3)
-
-
-
-
-
-
-
-
1
-
APSAC
-
-
-
1
t-PA
0.3(1.1)
Neurologic Events (%)
-
-
-
-
9.8 12.2
-
-
13.0 -
7.1 -
Placebo
4.7 5.2 -
-
7.2
-
-
-
-
inAcute
10.6
6.4 -
-
-
_
_
-
-
t-PA APSAC
8.9 10.5 10.3 --
8.5
-
-
-_
--_ -
-_
10.7 --
-
6.3
SK
Early Mortality (%I
days days days days 35 days 35 days 35 days 30 days 30 days 30 days 3Odays 42 days 42 days Hospital (M 9 d) Hospital (M 9 d) 35days 35 days 35days
21 21 21 21
End Point
&enb
‘Bleedmg and hematologic event rates represent data obtained with 100 mg rt-PA in this highly invasive study. amDut,=dutepbse; AIMS = APSAC Intervention Mortahty Study; Alt = $teplase; APSAC = anisoylated plasminogen-streptokinase activator complex; ASA = aspirin; ASSET = Anglo-Scandinavian Study of Earfy Thmmblysis; Cons = B GISSI-1 = Gruppu ltallano per lo Sb@o della Streptochmasl nel! lnfarto Miocardico; GISSI-2 Gruppo Italian0 per lo Studio della Soprawivenza nell’ lnfarto Miocardico; ICB = intracranial bleeding; lnv = invasive app-h; ~SAM = f,-,h-strepdduMse Myocardial Infarction; ISIS = lnternabonal Study on Infarct Swwal; Plac = placebo; Prob = pmbable; SK = streptokinase; TIMI = Thrombolysis in Myocardial Infarction; t-PA = alteplase or duteplase.
Plac: 882 SK: 859 GISSI-1’ Plac: 5852 SK: 5860 Plac: 4238 ISIS-23 SK: 8490 SK + ASA: 4239 ASSET4 Plac: 2493 Alt: 2512 AIM!? Plac: 502 APSAC:502 TIMI-II6 Cons: 1626 Inv: 1636 GISSI-2/lnternationaI SK: 10,396 Study Group7 Alt: 10,372 ISIS-38 SK: 13,000 Dut: 13,000 APSAC:13,000
ISAM’
Study
Patient No.
Adjunctive Therapy
TABLE 1 Major Bleeding, Neurologic Events and Early Mortality in Large (> 500 Patients per Group) Controlled Clinical Trials with Intravenous Throml)ojfiic
least 500 patients were allocated to each group, are summarized in Table I. In aggregate, the placebocontrolled studies have demonstrated that thrombolytic therapy with streptokinase,1-3recombinant tissue plasminogen activator (rt-PA)4 or anisoylated plasminogen streptokinase activator complex (APSAC)’ reduces mortality; and that the mortality benefit is achieved with acceptable frequencies of side effects. However, because of their simple design, these studies provide little or no information on the mechanisms by which clinical benefit is achieved. The only 2 mega-trials performed to date that have compared the efficacy for mortality reduction of different thrombolytic agents in patients with acute myocardial infarction (AMI) have shown no difference in early mortality and, if anything, a higher intracerebral bleeding rate with the “high tech” rt-PA and APSAC than with the “low tech” streptokinase.7Y8 The argument could end here with the conclusion that more efficient thrombolytic agents do not confer better clinical outcome, but are associated with higher toxicity than the combination of streptokinase and aspirin, as was established by the Second International Study on Infarct Survival (ISIS-2). However, significant questions concerning the design and monitoring of the comparative mega-trials persist, which have been totally overlooked during the recent wide dissemination of the ISIS-3 results. It would, therefore, seem appropriate to analyze critically the available data before discussing potential further improvements of thrombolytic agents and strategies. CURRENT STATUS OF lHROMROLYllC THERAPY OF ACUTE MYOCAROIAL INFARCTION
The recognition that thrombosis within the infarct-related coronary artery plays a major role in the pathogenesis of AMI, and the observation that early administration of thrombolytic agents results in recanalization of occluded coronary arteries, have provided the basis for the development of thrombolytic therapy in AMI. The hypothesis underlying this form of treatment is that coronary artery occlusion leads to ischemia and cell death, resulting in ventricular dysfunction and reduced life expectancy, and that timely recanalization, within a time window that allows salvage of ischemit myocardium, reduces infarct size, preserves myocardial function, and reduces early and late mortality. The most rational treatment of patients with AM1 is therefore likely to be thrombolytic therapy with agents or combinations that produce stable coronary artery recanalization as frequently
and as rapidly as possible, but with acceptable safety. Late opening of an occluded coronary artery may have some beneficial effect by limiting left ventricular remodeling, improving the electrical stability of the heart, or providing collateral vesselsto viable myocardium.g Further, adjunctive therapy with anticoagulant and/or antiplatelet agents clearly contributes to the efficacy of thrombolysis. Comparathfedfkacyofsbv@Mmeand rt-PA: Comparative studies between streptokinase and rt-PA have shown a difference in efficacy for early coronary artery recanalization”; this conclusion has been supported by results of several noncomparative studies with similar design and end points (for references, see Collen”). Coronary artery patency is present in approximately 22% of patients within 90 minutes after the start of placebo infusion (usually including heparin and occasionally aspirin), probably around 35% after 2U8 hours, and around 65% after l-3 weeks. Streptokinase administration is associated with around 53% patency at 90 minutes and 75% after l-3 weeks, whereas rt-PA, in combination with intravenous heparin, is associated with 75% patency at 90 minutes, 85% at 24-48 hours and 81% at l-3 weeks.‘* This analysis may be somewhat biased in favor of placebo as a result of higher early mortality in placebo-treated patients than in patients given thrombolytic agents. It is, however, difficult to imagine from these data that late patency would be the primary determinant of clinical outcome. Early patency, measured around 90 minutes after the start of therapy, is significantly increased over placebo (22%) with either streptokinase (53%) or rt-PA (75%) whereas the efficacy for coronary recanalization with rt-PA is about 50% higher than with streptokinase. Nevertheless, comparative studies between streptokinase and rt-PA have not shown a difference in preservation of left ventricular function,‘3*‘4 in combined clinical outcome,” or in survival.7’8 This lack of correlation between initial efficacy and clinical outcome may have several explanations. First, initial recanalization obviously needs to be sustained in order to convey benefit. In the absence of adequate anticoagulation, the higher initial efficacy of rt-PA indeed appears to be offset by more frequent reocclusion, as demonstrated in several recent trials with angiographic end points (Table II). Whereas heparin did not appear to affect patency at 90 minutes,16its omission markedly reduced the patency rates measured at 7-24 hours,*’ 48-72 hours (mean 55 hours)” or at 48-120 A SYMPOSIUM: SAFETY OF THROMBOLYTIC AGENTS
73A
TABLE II Influence of Heparin on Coronary Patency Following Alteplase infusion End point (Time after Start of Therapy) Heparin With
Without
Study
90 min
Top01et al,161989 Hsia et al,” 1990 Bleich et al,181990 ECSG,” 1991 Top01et al,161989 Hsia et al,]’ 1990 Bleich et al,lB 1989 ECSG,” 1991 P
79% (50/63)
7-14 hr
48-72 hr
4B-120 hr
? No ?
82% (82/100)
71% (30/42) 83% (214/258) 79% (54168) 52% (48/93) 43% (18/42) 0.83
