- Email: [email protected]
Thrombolytic therapy for women with myocardial infarction: Is there a gender gap?
prognosis of a topic of consider-
ment and
n Rf?ferences 27 to 32. visedmanu5cript received July Eric J. Topd, Departmentof Cadiol-
II,9500Euclid Avenue, Cleveland, Ohio
yses during the same period contmdicted these findings(7.8) sted that excess mortality and morbidity in womca or a higher prevalence of may be due ta greater age congestive heart failure (16). reover, in the current era of reperfusion therapy for acute myocardial infarction, the relevance of these early investigations of patients treated before the widespread use of thromboiytic agents is unclear. The major placebo-controlled trials testing efficacy of throm~~~~~isin acute myocardial infarction have de strated equivalent 30% to 50% reductions in death in both men and women with reperfwsiontherapy (H-14), but unadjusted mortzdity rates in women h higher than in men. The reasons f41 prognosis in women in these recent series have not been clarified,although investigators have suggested that women may suffer as a result of more frequent medical comorbidi07351097193L$6Alo
Recwrenl
ischemia
graphic (ECG)leads were considered for entry into
k or recent (=3 months earlier) infarction, cardiogenic ry, active bleeding or refractory stroke, major trauma, s hypertension. A total of 1,619 patients (348 women, 1,271 se criteria and form the basis of this study. me . Intravenous thrombolytic therapy consisted of rt-PA, urokinase, or a combination of these agents. Various dosage strategies were systematicallytested d~r~~~ different phases of the trial. Ali patients received an intravetmus infusion of heparin for at least 48 to 72 b after thrombolysis, intravenous nitroglycerinand lidocaine during the 1st day, unless contraindicated, and oral aspirifi(325mg daily). Coronary angiography and left ventriculography were
support, Inrrucrunial hemorrhage or nonhtmorrhagic ~tmk was diagnosed on the basis of new necrologic deficits
admission and nadir
revascularization, were based on on-site i~te~r~t~ti~~
of
1782
LYNCOFF ET AL. THROMBOLYSlSFORWQMENWITHMYOCARDlALINFARCTlON
Table 2. Angiographic
A& (yrl kxe (k white)
Risk factors (% of pts) HypWlellSMn Dhbeles
mdlilus
Hyperiipidemia Tobacco us6
Men
(n = 1,271)
Women (n = 348)
p VaIue
55.8 I ICI.1
61.0 2 9.7
< O.oool
90.4
86.8
39
5s 21 24 55
Men
15
13 64
Cknrackristics
0.057 < 0.0001 0.015 0.023 0.003
Infarct-related artery V% of pts) LAD LCX RCA Other or unknown No. of vessels with ~50% stenosis (% of pts) 0
1 2 3 Infarct artery patency at vibnrir ~~~~~~~~~~y(% of pts)
films. Cineangiogramswere subsc~u~~t~yforangiographiccore laboratoryat the University of Michiganfor evaluation of infarct-relatedartery patency, icular function by sbservers residual stenosis and left n: aAbs_dutc vessel diameter unaware of treatment assi r-mined and percent stenoscs we
3s 12 44 3
_I__ W0men 33 13 48 6
5
8
48 28 19
4-l 29 Bh
72
715
within the previous 5
other293 men and
uilarfunction and patency after administration of tb the two gender groups.
with men for mortality, reinfarc-
seiine dern~g~~h~cand clinical and f,271 men studied are were older than men by a quently had a history of bYpertension,diabetes mellitus, hypedipidemia, peripheral
In the overall cohort of 1,619 nexus or surgical coronary revascularizapat tisn was performed in I, 138 patients (70.3%) during the hospital period. Women underwent revascularization onty slightlyless frequently than men (Table 3). The proportions af procedures performed on an acute (including patients randomized to immediatecoronary angioplasty in TAM1 urgent or elective basis were comparable in the two gen 271 men and 65 women with ocduded cssels at the time of acute catt._teri.zation, 207 (76%) and 49 (75%), respectively, underwent rescue
and 1I (17%)were treated conservatively because they had anatomy unsuitable fos revascularization or relatively small regions of myocardium at risk.
noninvasive means: age,
recovery of infarct-zone regional wa cklmedrn
1-1 Men
Women
Value
Angiographic oulcome 90
Infarct-related artery patency t‘% of pts)” Lefl ventricular fraction (%)
ejection
Change in ejection fraction t%)t infarct zone regional wall mation
43
52.2 2 11.3
54.4 2 12.;
0.7 ” 8.9
t.3 + 8.5
-2.20
C 1.23
-2.30
graphic factors (acute ejection fraction. vessels) (odds ratio 1.95, 95% CB 1.01 ts 3.79). Iceding
2 1.26
(SD/chord) Change in infarct zone motion (SDlchordlt
0.41 -c 1.00
0.41 + 1.00
Clinical outcome Death (% of pts)
5.4
9.2
0.014
Stroke t% of pts)
I .4
0.01
Reinfarclion
2.6
3.7 6.4
Recurrent ischemia (% of pts)
18.7
25.1
0.1
Heart failure (% of pts)
32.7
33.9
0.67
(% of pts)
Length of hospital stay Idays) Length of KU
stay (days)
12.0 !z 19.0
14.0 ” 25.5
4.4 I 8.7
4.6 2 4.2
0.005
womi3b. AS a consequence, women required ata 0.8 to I mm tramfu54on units than did men
-
*Patency at prcdisctrargc imgiography dcAned w I’ht~bAy~~~ h MYOcardial Infarction (TM) grade 2 or 3 flow. IChange at prcdischarge angiography from initial findings on acute cardiac catheterization. Values presented are mean value ? SD or percent of patients. ICU = intensive care unit; pts = patients,
complicatioons e T
comphcations appeared t0 wotmen,with nearly identicaldecreases in hernato when either the entire patiem treated patients were consid nadir hematocrit values aver than in met-t, reflecting low
did not quite reach statistical significance Wds ratio
LINCQFFETAL. THROMBOLYSISFORWOMENWITHh4YOCARDIALINFARCTlON
~~nst~ti~~ p0sthospitnl stay mortality, reinfarcization rates with 95% confidence intervds at I men and 293 women disyear afler hmpital discharge in I, char@ alive Cmm the hospitalA
Men In = 992)
Walnen In = 2773
IQ.3+ 5.0 34.1 ? 5.2 0.5 + 2.0
10.95 5.5 29.0 2 5.2 1.3 + 2.1
*P=~.~1~.~~u~Vntedaremean value + SD orpercentofpatients.
equivalent to that experienced by administration of streptokinase or rt dial infarction. This current analysis of the TA provides the first demonstration that thmnbolysis also produces comparable benefit in men and women with regard to infarct-related artery patency and recovery of global and regional left ventricular function. Although the efficacy of thrombolytic therapy for acute myocardial infarction appears to be si ilar in both men and women, there is evidence that this tre
dosages is c~~e~t~y u more recent clinical trials (3f ,45,46).
bleeding was not wornen.Changes in hemaeocritvaiues were nearly identical, although nadi
olytic therapy for acute ~~~rc~
reason cited for ineligibilityin this series was age >75 years,
gender as an independent risk factor for increased r~~rt electrical or mechanical cornplicatisns or congestive
1786
LlNCOFF ET AL. THR6MBOtYSIS FOR WOMEN WITH MYOCARDIAL
lNFARCTIBN
f~lufe, In contrast, the gender daerences in in-hospital mortality observed during this current TAMl study were not simifiat after clinical and an&gaphic data were factored into multivariate anaiysis. The influence of gender on reinfatction did remain marginally significantafter multivariate adjustment, an important finding in light of the markedly adverse outcome in patients with reocclusion and reinfarctii3nafter thromklysis (47). The basis for the observed variability in prognosis for women after acute infarction has not been cleariy defined, renccs in baseline characteristics between patients
nt analyses (20,40,41), cardiac ~athete~~at~~~ in 41 patients was associated with equivalent ~urgieal and percutaneous revascularization in women and men in this current report, Thus, this study extends previsus investigationsby demonstratingthe important finding that in the subset of patients with acute infarction eligible for thrsmblytic therapy, gender differences in the m&r clinical end paints of death and reinkrction may be attributable entirely to difkrences in baselineclinical and risk factors if coronary ~e~~~~~~~ and reon are applied in a consistent manner in both men wad women, study has scvcral limitations.
Condusims, Among patients ~~s~~~a~~~ed for ac cardial infarction, wmen are generally older than
with respect ta, restoration
arter
4. Puletti M, Sunsen L, Curione Iv!. E5ba SM. infwrtion: sex-related di!krencrs io progla 63-A.
6. Marrnor A. Gel&man EM, Schechtmnn K, Sobel BE, Roberts R. Recurrent tmyocardial infarction: clinical predictors and prognostic implicalions. Circulation 1982;66z415-21. a. Norris RM. Caughey DE, De)eemingLW. Mercer CJ1 Seoll PJ. Comwy protpnostic index for predicting survival after recovery from acute myucardial infarction. Lancst ~~7~2:4~~$.
W~i~~~~~~ E, Shapiro S, Frank CW. IVqposis of wm3 with newly diagnosed coronary heart disease-a comparison with co~rsc of disease among men. Am J Public Neahh ~973;63:57~-~3” 9. Robinson K, Conroy RM, Mulcahy R, k&key N. Risk factors and innhospitai course of first episode of myocardial infarction or acute coronary insufficiency in women. 3 Am Coil Cardiol MM;1 1:932-6. 8,
points were examined in
10. Dittrich W, Gilpin E, Nicod P, Cali G, Henning N, Ross J. Acute myocardial infarction in women: influence of gender on mortality and proGnostic variables. Am J Cardiol 1988;62: 1-7. 1I j Grup~Italiano per lo Studio dclla Slreptochinasi Nell’infano Miocardico VXSI). Effectiveness of intravenous thrombolytic treatment in acute myocardia! infarction. Lancet 1%6;1:397-401. 12. ISIS-2 (Second International Study of Infarct Survival) Collaboralive Group. Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17.187 cases of suspected acute myocardial infarctioo: ISIS-2. Lancet 1988:2:349-60. 13, Wilcox RG, Blsson CG, Skene AM. et al. Trial of tissue plasminogen nctivatur for mortality reduction in acute myocardial infarction. AngloScandinavian Study of Early Thrombolysis (ASSET). Lancet 1988;2:52530. 14. AIMS Trial Study Group. Effect of intravenous APSAC on mortality after acute myocatdial infarction: preliminary report of a ~~ace~o-co~t~~~~e~ clinical trial. Lancet 1988;1:545-9.
knowledgeof coronary anatomy.
15. Khan SS, Nessim S, Gray R, Czer LS, Chaux A, MatloBJ. Increased mortality of women in coronary artery bypass surgery: evidence for referral bias. Ann Intern Med 1990;112:561-7.
patients forcoronary
a~~~o~ra~by and coronary ~~vasc~~ar~zat~o~ early after ~~yoca~~a~ infarction: is there evidence for geader bias? Ann Hnte:n
B.
21.
2%.
23.
, Delre KM. Aclllc rnsluminal coronary
24.
25 disks and tong-term
feesuits. 9 Am Coil Cardiol 1983; l:383-90.
24 Kennedy JW, Kaiser CC. Fisher LD, et al. Clinical and angiographic predictors ofoperative mortality from the collaborative study in coronary artery surgery. Circulation
1981;63:793-$01.
27 Topd ~~,~~~i~$~,~~o~~e S, eeal.A raadvmtzed trial of im versus delayed elective angioplasty after iutravenous tissue plasminogen .xctivator in acute myacardial infarction. N Et@ J Med 19B7;317:S81-8. 28.Top01 EJ, Cahff RM, George BS, et al. Coronary arterial thrombdysis with combined infusion of recombinant tissue-type plasrninogen activaor and urokinase in patients with acute myosardial infarction. Circulation 1988:77:1100-7. 29.Tapd EJ, George DS, Kereiakcs DJ, et al. A randomized controlled trial itttravenous tissue plasminogen activator and early intravenous hepartm im acute myocardial infarction. Circulation 1989;79:281-6. 30. Califf RM, Topol EJ, Stack RS, et al. Evaluation of combination thromb&tic therapy and timing of cardiac catheterization in acute myocardial rombolyais pnd Angioplasty in Myocardial Ininfarction. Results zed trial. Circtdation 49991;83:J543-56. farction Phase 5 ra
of
dial infarction. A statewide data base [abstract]. 9 Am Coil Cardiot 1992;19 Suppl A:2OA. Varma V ood WP, Bradley EL, urpby PL Alabama Registry of Myocardial lschemia Investigators. Are wornen with acute myocardial infarction managed differently from men [abstract)? J Am Cdl Cardiol 1992;I WOA.
PfefferMA, Moye &A, Brauwdd E, et al. Selectionb thrombolytic therapy in acute myocardiat infarcrion. J 528-32. 43. Maggioni AP. Franzosi MC. Santoro E, e: al. The risk of stroke in patients with acute myocardial infarctnon alter th~orn~o~yt~c dnd antithrombotic treatment. N Engl J Med 1992;327: i-6. 44. De Jaegere P, Arnold AA, Bath AH, Simoons ML. Intracranial rhage io association with thrombolytic therapy: inci predictive factors. 3 Am Coil Ctirdiol 1992;19:289-94. 45. Topol EJ, Agnelli 6. Strategies for administration xlivatur. Mel Biol Med ~~~~;~~2~~-~4,
bernor-
of tissue plasrninogen
46. Smalling RW, Schumacher R, s D, et al. improved ~~farct”~elated arterial patency after high dose ht-adjusted, rapid infusion of tissuetype phsmiaagen activator in myocardial ~~farct~o~~ results of a multicenter randomized trial of two dosage regimens. J Am Coil Cardiol 1990;15:915-21. 47. Qhman FM, Califf RM, Topol El, et al. Consequences of reocchtsion 31. Wall TC, Calif! RM, George l3S, et al. Accelerated plasminogeo activator after successful reperfuaion therapy in acute myocardid infarction. Cirdose regimens far coronary thrombolysis. J Am Call Cardiol 1992;l'): culation 1990;82:781-91. 482-9.
ment and
n Rf?ferences 27 to 32. visedmanu5cript received July Eric J. Topd, Departmentof Cadiol-
II,9500Euclid Avenue, Cleveland, Ohio
yses during the same period contmdicted these findings(7.8) sted that excess mortality and morbidity in womca or a higher prevalence of may be due ta greater age congestive heart failure (16). reover, in the current era of reperfusion therapy for acute myocardial infarction, the relevance of these early investigations of patients treated before the widespread use of thromboiytic agents is unclear. The major placebo-controlled trials testing efficacy of throm~~~~~isin acute myocardial infarction have de strated equivalent 30% to 50% reductions in death in both men and women with reperfwsiontherapy (H-14), but unadjusted mortzdity rates in women h higher than in men. The reasons f41 prognosis in women in these recent series have not been clarified,although investigators have suggested that women may suffer as a result of more frequent medical comorbidi07351097193L$6Alo
Recwrenl
ischemia
graphic (ECG)leads were considered for entry into
k or recent (=3 months earlier) infarction, cardiogenic ry, active bleeding or refractory stroke, major trauma, s hypertension. A total of 1,619 patients (348 women, 1,271 se criteria and form the basis of this study. me . Intravenous thrombolytic therapy consisted of rt-PA, urokinase, or a combination of these agents. Various dosage strategies were systematicallytested d~r~~~ different phases of the trial. Ali patients received an intravetmus infusion of heparin for at least 48 to 72 b after thrombolysis, intravenous nitroglycerinand lidocaine during the 1st day, unless contraindicated, and oral aspirifi(325mg daily). Coronary angiography and left ventriculography were
support, Inrrucrunial hemorrhage or nonhtmorrhagic ~tmk was diagnosed on the basis of new necrologic deficits
admission and nadir
revascularization, were based on on-site i~te~r~t~ti~~
of
1782
LYNCOFF ET AL. THROMBOLYSlSFORWQMENWITHMYOCARDlALINFARCTlON
Table 2. Angiographic
A& (yrl kxe (k white)
Risk factors (% of pts) HypWlellSMn Dhbeles
mdlilus
Hyperiipidemia Tobacco us6
Men
(n = 1,271)
Women (n = 348)
p VaIue
55.8 I ICI.1
61.0 2 9.7
< O.oool
90.4
86.8
39
5s 21 24 55
Men
15
13 64
Cknrackristics
0.057 < 0.0001 0.015 0.023 0.003
Infarct-related artery V% of pts) LAD LCX RCA Other or unknown No. of vessels with ~50% stenosis (% of pts) 0
1 2 3 Infarct artery patency at vibnrir ~~~~~~~~~~y(% of pts)
films. Cineangiogramswere subsc~u~~t~yforangiographiccore laboratoryat the University of Michiganfor evaluation of infarct-relatedartery patency, icular function by sbservers residual stenosis and left n: aAbs_dutc vessel diameter unaware of treatment assi r-mined and percent stenoscs we
3s 12 44 3
_I__ W0men 33 13 48 6
5
8
48 28 19
4-l 29 Bh
72
715
within the previous 5
other293 men and
uilarfunction and patency after administration of tb the two gender groups.
with men for mortality, reinfarc-
seiine dern~g~~h~cand clinical and f,271 men studied are were older than men by a quently had a history of bYpertension,diabetes mellitus, hypedipidemia, peripheral
In the overall cohort of 1,619 nexus or surgical coronary revascularizapat tisn was performed in I, 138 patients (70.3%) during the hospital period. Women underwent revascularization onty slightlyless frequently than men (Table 3). The proportions af procedures performed on an acute (including patients randomized to immediatecoronary angioplasty in TAM1 urgent or elective basis were comparable in the two gen 271 men and 65 women with ocduded cssels at the time of acute catt._teri.zation, 207 (76%) and 49 (75%), respectively, underwent rescue
and 1I (17%)were treated conservatively because they had anatomy unsuitable fos revascularization or relatively small regions of myocardium at risk.
noninvasive means: age,
recovery of infarct-zone regional wa cklmedrn
1-1 Men
Women
Value
Angiographic oulcome 90
Infarct-related artery patency t‘% of pts)” Lefl ventricular fraction (%)
ejection
Change in ejection fraction t%)t infarct zone regional wall mation
43
52.2 2 11.3
54.4 2 12.;
0.7 ” 8.9
t.3 + 8.5
-2.20
C 1.23
-2.30
graphic factors (acute ejection fraction. vessels) (odds ratio 1.95, 95% CB 1.01 ts 3.79). Iceding
2 1.26
(SD/chord) Change in infarct zone motion (SDlchordlt
0.41 -c 1.00
0.41 + 1.00
Clinical outcome Death (% of pts)
5.4
9.2
0.014
Stroke t% of pts)
I .4
0.01
Reinfarclion
2.6
3.7 6.4
Recurrent ischemia (% of pts)
18.7
25.1
0.1
Heart failure (% of pts)
32.7
33.9
0.67
(% of pts)
Length of hospital stay Idays) Length of KU
stay (days)
12.0 !z 19.0
14.0 ” 25.5
4.4 I 8.7
4.6 2 4.2
0.005
womi3b. AS a consequence, women required ata 0.8 to I mm tramfu54on units than did men
-
*Patency at prcdisctrargc imgiography dcAned w I’ht~bAy~~~ h MYOcardial Infarction (TM) grade 2 or 3 flow. IChange at prcdischarge angiography from initial findings on acute cardiac catheterization. Values presented are mean value ? SD or percent of patients. ICU = intensive care unit; pts = patients,
complicatioons e T
comphcations appeared t0 wotmen,with nearly identicaldecreases in hernato when either the entire patiem treated patients were consid nadir hematocrit values aver than in met-t, reflecting low
did not quite reach statistical significance Wds ratio
LINCQFFETAL. THROMBOLYSISFORWOMENWITHh4YOCARDIALINFARCTlON
~~nst~ti~~ p0sthospitnl stay mortality, reinfarcization rates with 95% confidence intervds at I men and 293 women disyear afler hmpital discharge in I, char@ alive Cmm the hospitalA
Men In = 992)
Walnen In = 2773
IQ.3+ 5.0 34.1 ? 5.2 0.5 + 2.0
10.95 5.5 29.0 2 5.2 1.3 + 2.1
*P=~.~1~.~~u~Vntedaremean value + SD orpercentofpatients.
equivalent to that experienced by administration of streptokinase or rt dial infarction. This current analysis of the TA provides the first demonstration that thmnbolysis also produces comparable benefit in men and women with regard to infarct-related artery patency and recovery of global and regional left ventricular function. Although the efficacy of thrombolytic therapy for acute myocardial infarction appears to be si ilar in both men and women, there is evidence that this tre
dosages is c~~e~t~y u more recent clinical trials (3f ,45,46).
bleeding was not wornen.Changes in hemaeocritvaiues were nearly identical, although nadi
olytic therapy for acute ~~~rc~
reason cited for ineligibilityin this series was age >75 years,
gender as an independent risk factor for increased r~~rt electrical or mechanical cornplicatisns or congestive
1786
LlNCOFF ET AL. THR6MBOtYSIS FOR WOMEN WITH MYOCARDIAL
lNFARCTIBN
f~lufe, In contrast, the gender daerences in in-hospital mortality observed during this current TAMl study were not simifiat after clinical and an&gaphic data were factored into multivariate anaiysis. The influence of gender on reinfatction did remain marginally significantafter multivariate adjustment, an important finding in light of the markedly adverse outcome in patients with reocclusion and reinfarctii3nafter thromklysis (47). The basis for the observed variability in prognosis for women after acute infarction has not been cleariy defined, renccs in baseline characteristics between patients
nt analyses (20,40,41), cardiac ~athete~~at~~~ in 41 patients was associated with equivalent ~urgieal and percutaneous revascularization in women and men in this current report, Thus, this study extends previsus investigationsby demonstratingthe important finding that in the subset of patients with acute infarction eligible for thrsmblytic therapy, gender differences in the m&r clinical end paints of death and reinkrction may be attributable entirely to difkrences in baselineclinical and risk factors if coronary ~e~~~~~~~ and reon are applied in a consistent manner in both men wad women, study has scvcral limitations.
Condusims, Among patients ~~s~~~a~~~ed for ac cardial infarction, wmen are generally older than
with respect ta, restoration
arter
4. Puletti M, Sunsen L, Curione Iv!. E5ba SM. infwrtion: sex-related di!krencrs io progla 63-A.
6. Marrnor A. Gel&man EM, Schechtmnn K, Sobel BE, Roberts R. Recurrent tmyocardial infarction: clinical predictors and prognostic implicalions. Circulation 1982;66z415-21. a. Norris RM. Caughey DE, De)eemingLW. Mercer CJ1 Seoll PJ. Comwy protpnostic index for predicting survival after recovery from acute myucardial infarction. Lancst ~~7~2:4~~$.
W~i~~~~~~ E, Shapiro S, Frank CW. IVqposis of wm3 with newly diagnosed coronary heart disease-a comparison with co~rsc of disease among men. Am J Public Neahh ~973;63:57~-~3” 9. Robinson K, Conroy RM, Mulcahy R, k&key N. Risk factors and innhospitai course of first episode of myocardial infarction or acute coronary insufficiency in women. 3 Am Coil Cardiol MM;1 1:932-6. 8,
points were examined in
10. Dittrich W, Gilpin E, Nicod P, Cali G, Henning N, Ross J. Acute myocardial infarction in women: influence of gender on mortality and proGnostic variables. Am J Cardiol 1988;62: 1-7. 1I j Grup~Italiano per lo Studio dclla Slreptochinasi Nell’infano Miocardico VXSI). Effectiveness of intravenous thrombolytic treatment in acute myocardia! infarction. Lancet 1%6;1:397-401. 12. ISIS-2 (Second International Study of Infarct Survival) Collaboralive Group. Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17.187 cases of suspected acute myocardial infarctioo: ISIS-2. Lancet 1988:2:349-60. 13, Wilcox RG, Blsson CG, Skene AM. et al. Trial of tissue plasminogen nctivatur for mortality reduction in acute myocardial infarction. AngloScandinavian Study of Early Thrombolysis (ASSET). Lancet 1988;2:52530. 14. AIMS Trial Study Group. Effect of intravenous APSAC on mortality after acute myocatdial infarction: preliminary report of a ~~ace~o-co~t~~~~e~ clinical trial. Lancet 1988;1:545-9.
knowledgeof coronary anatomy.
15. Khan SS, Nessim S, Gray R, Czer LS, Chaux A, MatloBJ. Increased mortality of women in coronary artery bypass surgery: evidence for referral bias. Ann Intern Med 1990;112:561-7.
patients forcoronary
a~~~o~ra~by and coronary ~~vasc~~ar~zat~o~ early after ~~yoca~~a~ infarction: is there evidence for geader bias? Ann Hnte:n
B.
21.
2%.
23.
, Delre KM. Aclllc rnsluminal coronary
24.
25 disks and tong-term
feesuits. 9 Am Coil Cardiol 1983; l:383-90.
24 Kennedy JW, Kaiser CC. Fisher LD, et al. Clinical and angiographic predictors ofoperative mortality from the collaborative study in coronary artery surgery. Circulation
1981;63:793-$01.
27 Topd ~~,~~~i~$~,~~o~~e S, eeal.A raadvmtzed trial of im versus delayed elective angioplasty after iutravenous tissue plasminogen .xctivator in acute myacardial infarction. N Et@ J Med 19B7;317:S81-8. 28.Top01 EJ, Cahff RM, George BS, et al. Coronary arterial thrombdysis with combined infusion of recombinant tissue-type plasrninogen activaor and urokinase in patients with acute myosardial infarction. Circulation 1988:77:1100-7. 29.Tapd EJ, George DS, Kereiakcs DJ, et al. A randomized controlled trial itttravenous tissue plasminogen activator and early intravenous hepartm im acute myocardial infarction. Circulation 1989;79:281-6. 30. Califf RM, Topol EJ, Stack RS, et al. Evaluation of combination thromb&tic therapy and timing of cardiac catheterization in acute myocardial rombolyais pnd Angioplasty in Myocardial Ininfarction. Results zed trial. Circtdation 49991;83:J543-56. farction Phase 5 ra
of
dial infarction. A statewide data base [abstract]. 9 Am Coil Cardiot 1992;19 Suppl A:2OA. Varma V ood WP, Bradley EL, urpby PL Alabama Registry of Myocardial lschemia Investigators. Are wornen with acute myocardial infarction managed differently from men [abstract)? J Am Cdl Cardiol 1992;I WOA.
PfefferMA, Moye &A, Brauwdd E, et al. Selectionb thrombolytic therapy in acute myocardiat infarcrion. J 528-32. 43. Maggioni AP. Franzosi MC. Santoro E, e: al. The risk of stroke in patients with acute myocardial infarctnon alter th~orn~o~yt~c dnd antithrombotic treatment. N Engl J Med 1992;327: i-6. 44. De Jaegere P, Arnold AA, Bath AH, Simoons ML. Intracranial rhage io association with thrombolytic therapy: inci predictive factors. 3 Am Coil Ctirdiol 1992;19:289-94. 45. Topol EJ, Agnelli 6. Strategies for administration xlivatur. Mel Biol Med ~~~~;~~2~~-~4,
bernor-
of tissue plasrninogen
46. Smalling RW, Schumacher R, s D, et al. improved ~~farct”~elated arterial patency after high dose ht-adjusted, rapid infusion of tissuetype phsmiaagen activator in myocardial ~~farct~o~~ results of a multicenter randomized trial of two dosage regimens. J Am Coil Cardiol 1990;15:915-21. 47. Qhman FM, Califf RM, Topol El, et al. Consequences of reocchtsion 31. Wall TC, Calif! RM, George l3S, et al. Accelerated plasminogeo activator after successful reperfuaion therapy in acute myocardid infarction. Cirdose regimens far coronary thrombolysis. J Am Call Cardiol 1992;l'): culation 1990;82:781-91. 482-9.