JACC Vol. 16. No. 3 September 1990541-4
on, the use of thrQmbo~yt~c grarion of newly formed left nsequent risk of early cerebral
d ofcases occurr occurrence
of st
risk subgroup (7) in which y has shown variable abil-
ity to reduce formation (g-11) and enhance resolution (5) of s, as well as reduce the occurrence of embolic ,121and death (8). ~~fortu~ate~y,prophylact therapy for myocardial ~~~arctiQn has been complicated by central to 0.14% of patients tr the characteristics of stroke have occurred in the thrombolytic era. First, the repop’ed rate C$ woke cotnplkarittg myocardial
infarction
has decreased.
In
with streptokinase (13-U), anisoylated tokinase activator complex (APSAC) (16) and recombinant tissue-type plasminogen activator (r&PA)(17,W. the incidence rate of stroke in the treated groups ranged from 0.4% to 1.1% (mean 0.9%) and, in the control groups, ranged from 0.0% to 1.0% (mean 0.9%), respectively (13-20). Although this reduction in the incidence of stroke may result from improved general treatment of high risk patients. the de-
*Editorials published in Journnl qf tlta A~~~~ricar~ Collr~c of Crrrtiiolog reflect the views of the authors and do not necessxily represent the views of JACC or the American College of Cardiology. From the Departments of Neurology and Medicine, Uni! :rci!y of Maryland School of Medicine, Baltimore. Maryland. Addre s for reorints: Gary D. Plotnick. MD. Division of Cardiology. Departrneit of Medicine, University of Maryland Hospital, 22 South Greene Street, Baltimore. Maryland 21201. 01990 by the American
College ot :‘..:-L nlogy
Beof the hemorr
with 100 mg of rt-PA bemorrbage (p < 0.01) relation is confounded exclusion of p: Ants with blood or history of acute cerebrovascula
the loccalior! and titnirag of of interest irow p~~e~4o~~e~~ola~ic arid ~echa~l~.~~ic viewpoints. As many as 70% cerebral lobes (cortical and they are frequently ( ultiple (37).This d~str~butior~ is most atypical for hypertensive hemorrhages. although acute hypertension may play 3.contribatory role in some 07351097/90/$3.50
542
SLOAN AND PLOTNICK EDITORIAL COMMENT
cases. This pattern is typical for coagulopathy-induced as well as other nonhypertensive causes of intracerebral hemorrhage (39). Intracerebral hemorrhage has frequently been reported to occur during (30,31,35) and usually 524 h (13+19,20,29,35,36) after infusion of the fibrinolytic agent. Although isolated case reports of intracerebral hemorrhage have been associated with severe hypofibrinogenemia (31,34),several studies (30,38,40)have shown a poor correlation between the existence of a lytic state and intracerebral bleeding. The presence of a markedly prolonged activated partial thromboplastin time and a higher dose per body weight (for example, women with smaller body size) may have contributed to intracerebral bleeding in some cases (24,30,31,34,37,39).Other disease processes. such as cerebral congophilic amyloid angiopathy or undefined preexisting vascular lesions in the brain, may be unmasked by thrombolytic therapy protocols and lead to brain hemorrhages (2434-37). Detailed neurodiagnostic evaluation and pathologic data on this critical point are virtually nonexistent; in only one case has histologic examination of brain tissue from the wall of an intracerebral hematoma been performed, the result of which was normal (34). Prognosis. In addition, the prognosis of patients with myocardial infarction who have cerebrovascular events after thrombolytic therapy may be improving (14-16,19,20, 29-31,34,37). The overall mortality rate ranges between 28% (20) and 43% (14,15). Whereas the mortality rate in patients with intracerebral hemorrhage may be as high as 70% (13,17,20,30,31,34-37),more recent studies suggest that the acute mortality rate has been reduced to 44% (37) and 52% (35,36).This reduction may reflect more careful patient selection, better control of the dosage of the fibrinolytic agent and concomitant therapies, and in some instances, aggressive medical or surgical management, or both. The present study. In this issue of the Journal, O’Connor et al. (41) report on the occurrence of ischemic stroke and intracranial hemorrhage complicating the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) I, II and III trials. Thirteen (1.8%)of 708 patients treated with various doses of &PA or urokinase, or both, had a stroke: 4 strokes (0.6%) were hemorrhagic and 9 (1.3%) were ischemic, of which 8 were cardioembolic. Only the occurrence of a large anterior myocardial infarction (with ejection fraction ~45%) was a predictor of ischcmic stroke (p = O.OOlS). This finding is not surprising. No prespecified risk factor was helpful in predictingthe occurrence of hemorrhagic stroke, Depressed level Of consciousness and large lesions on the computed tomographic (CT) scan with midline shift were more common in the patients with hemorrhagic stroke. The mortality rate for ischemic and hemorrhagic strokes was 11% and 25%. respectively. This study is important in that it pools the stroke experi-
JACC “JoI. 16. No. 3 September J990:541-4
ence in three large thrombolyt~ctherapy trials with systematic evaluation and follow-up of stroke patients. AltRough the incidence of cerebrovascu!ar events is somew than in recently published series (13- PS,l9,20), reflec?the small number of patients enrolled in th wellas the careful, prospective recognition and evaluation of cases by a dedicated neurologist. By contrast, the mortality rates are quite low, which may be because of excellent patient care or exclusion of patients at high risk of death, or a combination of these. It is clear that dev of a change in Bevel of consciousness, headache, focal neurologicsymptoms or seizures during or soon after thro boiytic therapy should be viewed witb a high index of suspicion and that CT scanning must be performed immediately to distinguish among intracranial hemorrhage, cerebral infarction and the effects of severe cardiac dysfunction or concomitant myocardial infarction therapy, or both. The present study ;41) has two weaknesses. First, as the authors state, the small number of obscrvatioiis prcchide statistically meaningful assessment of predictors for intracerebral hemorrhage, including aspirin use and degree of hypofibrinogenemia, which would influence the bleeding time and activated partial tbrombo~lasti~ time values. Moreover, it is not clear that the bleeding times, fibrinogen levels and activated partial thromboplastin times for the stroke patients are different from those patients without a cerebrovascuiar complication. The contribution of heparin therapy to the occurrence of intracerebral hemorrhage is incompletely understood (24). Second, the precise site, the occurrence of blood pressure fluctuations and the temporal profile of illness in the paGents with hemorrhagic c’trokewere not clear. Nonetheless, the authors have made a valuable contribution by describing a method to obtain a better understanding of the risk of specific cerebrovascuiar complicationsof thrombolytic therapy for myocardial infarction. Implications. It is hoped that future studies will apply similar methodologies to gain insights islto risk factors for ischemic and hemorrhagic stroke in this setting. Although it may not be possible to totally eliminate the occurrence of stroke after thrombolytic therapy for myocardiai infarction, neurodiagnostic evaluation and pathologic description of adequate numbers of cases of cerebral infarction and intracerebral hemorrhage and associated factors may permit delineation of their mechanisms and suggest appropriate preventive measures. It IS clearly important to be able to distinguish parenchymatous intracerebral hemorrhage from cerebral infarction with hemorrhagic transformation as their appearance on the CT scan may be identical (29,32). We urge investigators in ongoing large thrombolytic therapy trials to work closely with neurologists and neuropathologists to facilitate the realization of this objective. Only ti:pp can we begin to make a significantimpact on the burden of neurologic mortality and morbidity in patients successfully
JACC Vol. 16, No. 3 September 1990:54t-4
itctiVator given up ii0 4 hours after onset of myocardial infarction. Lancet l988:l:!O3-7. 19. IS6S-2(Second Internaoonal Sludy of Infarct Survival). Randomized trial of inlrirvenoms\lreprokina\e. oral a+irin. both or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-?. Lam-et 1988;2: 349-60. I. Thompson PL. Robinson JS. Stroke after acute myocardial relation to infarct size. Br Med J 1978:2:457-Y.
2. Komrad MS. Coffey CE. Coffey MS. McKinnis R. Massey EW. Califf RM. Myocardial infarction and stroke. Neurology 1984;34: 1403-Y. 3. Weinrich DJ, Burke JF. complicaling acute myocar 94. 4. Joh:mnesscn K-A. Nordrehaug osis and cerebrovascular rt J 1984:51:553-6.
letto FJ. Left ventricular
6. Olsson CG. Skene AM. von der Lippe 6. Jensen 6. ~arn~too JR. Trial of tissue plasminogen activator for mortality reduction in acute myocardial infarc:ion: Anglo-Scandinavian Study of EarlyThrombolysis (ASSETI. Ldncet 1988:?:5?5-30.
infarction:
!I.
Tiefenbrunn risk. JAMA
22.
eld AC, Gore JM. Paraskos 5. et al. impact of thrombolytic therapy on li ventricular mural thrombi in acute myocardial infarcrron. Am J Cardiol lY88:62:3lO-l.
mural thrombi
JE. von der Eippe G. Left ventricular accident in acute myocardial infarction.
EC. Gross SA. Schlamowitz RA. et al. Mural thrombi in myotxdtal ‘nfarctions: prospective evaluation by two-dimensional echocardiography. Am J Med 1983:74:989-95. 6. Frieaman MJ. Carlson K. arcur Fl. Wcolfendsn JM. Clinical corrclations in patients witb acute mgocardial infxclion and left ventricular thrombosis detected by two.dimensional echocardiography. Am J Med 1982:72:894-8.
AJ. Ludbrook PA. Coronary l98Y:!Al:2107-8.
thrombolysis:
it’s worth the
23. Lupi 6. Domenicucci S. Chiarella F. Bellotti P. Vecchio C. Influence of thrombolytic treatment followed by full dose anticodgulation of the frequency of left ventricular thrombi in acute myocardial infarction. Am J Cardiol 1989:64:58X-90. 24. Cohen D. Coronary thrombolysis: streptokinase or recombinant type pla5minopen activator’? Ann Intern Med lY90;112:529-38.
tissur-
25. Cranston RE. Wolfson MA. uchsbaum HW. Feinberg W A. Plasminogen activator and cerebral mfarction (letter). Ann Intern Med 1988:108:766.
7. Johannessen K-A. Nordrehaug JE. van der Lilape 6. Vollset SE. Risk factors for embolisation in patients with left ventricular tbrombi and acute myocardial infarction. Br Heart J 1988:60:104-10.
26. Stafford PJ. Strachan CJL. Vincent R. Chamberlain DA. Multiple microemboli after disintegration of clot during thrombolysis for acute myocardial infarction. Br Med J 1969:299: 1310-2.
8. The SCATI (Studio sulla Calciparana nellAngina e nella Trombosi ventriculonre nell’lnfartol Group. Randomized controlled trial of subcutaneous calcium-beparin in acute myocardial infarction. Lancet 1989:?: 182-6.
27. Braunwald E. Kndtterud GL. Passamani ER. Robertson TL. Announcement of protocol change in thrombolysis in myocardial infarction irial (letter). J Am Call Cardiol 1987:9:467.
9. Turpie AGG, Robinson JG, Doylt DJ. et al. Comparison oflugh dose with low-dose subcutaneous heparin to prevent left ventricular wall mural thrombus in patients with acute transmural anterior myocardial infarction. N Engl J Med 1989:320:352-7. IO. Davis MJE, Ireland MA. ERect ofearly anticoagulation on the frequency of left ventricular thromhi ..fter anterior wall acute myocardial infarction. Am J Cardioi 1986;57: 1244-7.
I I. Hart RG. Prevention and treatment of cardioembolic stroke. In: Furlan AJ, ed. The Hear: and Stroke. Berlin: Springer-Verlag.
1987:17-36.
28. Brdunwald E. Knatterud GL. Passamaai E, Robertson TL. Solomon R. Update from the Thrombolysic in Myocudial Infarction trial (letter). J Am Coil Cardiol 1987:10:970. 29. Passamdni E. H&es M. erman M, et al. The Thrombolysis in Myocardial Infarction tTIMIl Phase II Pilot Study: tissue plasminogen activator followed by :ercutaneous transluminal coronary angioplasty. J Am Coil Cardiol 19Xi:lOt\uppl Bl:515-64B. 30. Ca!iff PM, Topo! Et. George BS. et al. Hemrrrhagic complications associated with the u%e of intravenous tissue plasminogen activator in treatment of acute myocardial infarction. Am J Med 1988;85:353-9.
12. Report of The Working Party, Medical Research Council. Assessment of short-term anticoagulant administration after cardiac infarction. Br Med J 1%9:1:3?5-42.
31. Carlson S. Aldrich MS. Greenberg HS. Top01 EJ. lntracerebral hemorrhage complicating intravenous tissue plasminogen activator treatment Arch Neurol 198X:45:1070-3.
13. Schrlader R. Neuhaus K-L, Leizorovicz A, Linderer T. Tebbe U. for the ISAM Study Group. A prospective placebo-controlled double-blind multicenter trial of intravenous streptokinase (ISAM): Long-term mortality and morbidity in acute myocardial infarction. J Am Coll Cardiol 1987:9: 197-203.
32. Sloan MA. del Zoppo GJ. Brott TG. Thrombolysis and stroke. In: Julian DG. Norris RM. Kiibler W. Swan HJ. Collen D, Verstraete M. eds. Thrombolysis in Cardiovascular Disease. New York: Marcel-Dekker. 1989:361-80.
14. Rovelli F, Devita C, Feruglio GA, Lotto A, Selvini A. Tognini G and GISSI Investigators. GISSI trial: early results and late follow-up. J Am Coll Cardiol l987:IO(suppl B):33B-9B. 15. Maggioni AP. Farnia ML, Franzosi MG, for the GlSSl Group. Stroke in the GI5SI trial (abstr). Circulaiion 1989;8O(suppl Ill:lI-350. 16. AIMS Trial Study Group. Effect of intravenous APSAC on mortality after acute myocardial infarction: preliminary report of a placebo-controlled clinical trial. Lancet 1988;1:545-9. 17. Van der Werf F. Arnold AER. for tke European Cooperative Study Group for Recombinant Tissue-Type Plasminogen Activator (r&PA). Effect of intravenous tissue plasminogen activator on infarc? size. left ventricular function, and survival in patients with acute myocardial infarction. Br Med J 1988;297:i374-9, 18. National Heart Fgandation of Australia Coronary Thrombolysis Group. Coronary thrombolysis and myocardial salvage by tissue plasminogen
33. The TIM1 Study Group. Comparison of invasive and consrrvative strategies after treatment with intravenous tissue plasminogen activator in acute myocardil infarction. N Engl J Med 1987;320:618-27. 34. Kase CS. O’Neal AM. Fisher M. Girgis GN, Ordia JI. Intracranial hemorrhage after use of tissue plasminogen activat’ tr for coronary thrombolysis. Ann lnterq Med 199O:l l2:!7-21. 35. Sloan MA, Price TR, Randall AM. Solomon RE. T rrin ML and the TIM1 Investigators. lntracerebral hemorrhage after rt-P/i and heparin for acute mvocardial infarction: the TIMI II oilot and randomized trial combined ---, experience (abstr). Stroke 1990;2l(suppll:182. 36. Gore J, Sloan hi. Price T. et al. and the TIM1 Investigators. Intracranial hemorrhage after rl-PA and heparin for acute myocardial infarction: the TIM1 Ii pilot and randomized trial combined ex:xricxc (obstr). J Am Coil Cardiol 1990:15(suppl At:I5A. 37. Kase CS. Pessin MS. Zivin JA. dell Zoppo GJ. !+lan AJ and the rt-PA Acute Stroke Study Group. Intracranial hemorrhage following thrombol-
544
JACC Vol.16.No. 3
SLOANANDPLOTNICK EDITORIALCOMMENT
September
ysis with tissue plasminogen activator (abstrl. Neurology 191. 38. Aldrich MS. Sherman SA. Greenberg HS. Cerebrovascular of streptokinase infusion. JAMA 1985:253: 1777-9. 39. Kase CS. lntracerebral 9986;97:5!?0-5.
hemorrhage:
nonhypertensive
1990:4Ots~ppl9: complications causes. Stroke
40.Rao AK. Pratt C. Berke A, et al. Thrombolysis in Myocardial Infarction
1990549-4
(TIM19 Phase I: hemorrhagic manifestations and changes in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase. J Am Co8 Cardiol 9988. l9:l-91. 49. O’Connor CM. Califf RM. Massey EW, et al. Stroke and acute myocar_ dial infarction in the thrombolytic era: clinical correlates and long-term prognosis. 3 Am Coll Cardiol 99!70;16:533-40.
on, the use of thrQmbo~yt~c grarion of newly formed left nsequent risk of early cerebral
d ofcases occurr occurrence
of st
risk subgroup (7) in which y has shown variable abil-
ity to reduce formation (g-11) and enhance resolution (5) of s, as well as reduce the occurrence of embolic ,121and death (8). ~~fortu~ate~y,prophylact therapy for myocardial ~~~arctiQn has been complicated by central to 0.14% of patients tr the characteristics of stroke have occurred in the thrombolytic era. First, the repop’ed rate C$ woke cotnplkarittg myocardial
infarction
has decreased.
In
with streptokinase (13-U), anisoylated tokinase activator complex (APSAC) (16) and recombinant tissue-type plasminogen activator (r&PA)(17,W. the incidence rate of stroke in the treated groups ranged from 0.4% to 1.1% (mean 0.9%) and, in the control groups, ranged from 0.0% to 1.0% (mean 0.9%), respectively (13-20). Although this reduction in the incidence of stroke may result from improved general treatment of high risk patients. the de-
*Editorials published in Journnl qf tlta A~~~~ricar~ Collr~c of Crrrtiiolog reflect the views of the authors and do not necessxily represent the views of JACC or the American College of Cardiology. From the Departments of Neurology and Medicine, Uni! :rci!y of Maryland School of Medicine, Baltimore. Maryland. Addre s for reorints: Gary D. Plotnick. MD. Division of Cardiology. Departrneit of Medicine, University of Maryland Hospital, 22 South Greene Street, Baltimore. Maryland 21201. 01990 by the American
College ot :‘..:-L nlogy
Beof the hemorr
with 100 mg of rt-PA bemorrbage (p < 0.01) relation is confounded exclusion of p: Ants with blood or history of acute cerebrovascula
the loccalior! and titnirag of of interest irow p~~e~4o~~e~~ola~ic arid ~echa~l~.~~ic viewpoints. As many as 70% cerebral lobes (cortical and they are frequently ( ultiple (37).This d~str~butior~ is most atypical for hypertensive hemorrhages. although acute hypertension may play 3.contribatory role in some 07351097/90/$3.50
542
SLOAN AND PLOTNICK EDITORIAL COMMENT
cases. This pattern is typical for coagulopathy-induced as well as other nonhypertensive causes of intracerebral hemorrhage (39). Intracerebral hemorrhage has frequently been reported to occur during (30,31,35) and usually 524 h (13+19,20,29,35,36) after infusion of the fibrinolytic agent. Although isolated case reports of intracerebral hemorrhage have been associated with severe hypofibrinogenemia (31,34),several studies (30,38,40)have shown a poor correlation between the existence of a lytic state and intracerebral bleeding. The presence of a markedly prolonged activated partial thromboplastin time and a higher dose per body weight (for example, women with smaller body size) may have contributed to intracerebral bleeding in some cases (24,30,31,34,37,39).Other disease processes. such as cerebral congophilic amyloid angiopathy or undefined preexisting vascular lesions in the brain, may be unmasked by thrombolytic therapy protocols and lead to brain hemorrhages (2434-37). Detailed neurodiagnostic evaluation and pathologic data on this critical point are virtually nonexistent; in only one case has histologic examination of brain tissue from the wall of an intracerebral hematoma been performed, the result of which was normal (34). Prognosis. In addition, the prognosis of patients with myocardial infarction who have cerebrovascular events after thrombolytic therapy may be improving (14-16,19,20, 29-31,34,37). The overall mortality rate ranges between 28% (20) and 43% (14,15). Whereas the mortality rate in patients with intracerebral hemorrhage may be as high as 70% (13,17,20,30,31,34-37),more recent studies suggest that the acute mortality rate has been reduced to 44% (37) and 52% (35,36).This reduction may reflect more careful patient selection, better control of the dosage of the fibrinolytic agent and concomitant therapies, and in some instances, aggressive medical or surgical management, or both. The present study. In this issue of the Journal, O’Connor et al. (41) report on the occurrence of ischemic stroke and intracranial hemorrhage complicating the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) I, II and III trials. Thirteen (1.8%)of 708 patients treated with various doses of &PA or urokinase, or both, had a stroke: 4 strokes (0.6%) were hemorrhagic and 9 (1.3%) were ischemic, of which 8 were cardioembolic. Only the occurrence of a large anterior myocardial infarction (with ejection fraction ~45%) was a predictor of ischcmic stroke (p = O.OOlS). This finding is not surprising. No prespecified risk factor was helpful in predictingthe occurrence of hemorrhagic stroke, Depressed level Of consciousness and large lesions on the computed tomographic (CT) scan with midline shift were more common in the patients with hemorrhagic stroke. The mortality rate for ischemic and hemorrhagic strokes was 11% and 25%. respectively. This study is important in that it pools the stroke experi-
JACC “JoI. 16. No. 3 September J990:541-4
ence in three large thrombolyt~ctherapy trials with systematic evaluation and follow-up of stroke patients. AltRough the incidence of cerebrovascu!ar events is somew than in recently published series (13- PS,l9,20), reflec?the small number of patients enrolled in th wellas the careful, prospective recognition and evaluation of cases by a dedicated neurologist. By contrast, the mortality rates are quite low, which may be because of excellent patient care or exclusion of patients at high risk of death, or a combination of these. It is clear that dev of a change in Bevel of consciousness, headache, focal neurologicsymptoms or seizures during or soon after thro boiytic therapy should be viewed witb a high index of suspicion and that CT scanning must be performed immediately to distinguish among intracranial hemorrhage, cerebral infarction and the effects of severe cardiac dysfunction or concomitant myocardial infarction therapy, or both. The present study ;41) has two weaknesses. First, as the authors state, the small number of obscrvatioiis prcchide statistically meaningful assessment of predictors for intracerebral hemorrhage, including aspirin use and degree of hypofibrinogenemia, which would influence the bleeding time and activated partial tbrombo~lasti~ time values. Moreover, it is not clear that the bleeding times, fibrinogen levels and activated partial thromboplastin times for the stroke patients are different from those patients without a cerebrovascuiar complication. The contribution of heparin therapy to the occurrence of intracerebral hemorrhage is incompletely understood (24). Second, the precise site, the occurrence of blood pressure fluctuations and the temporal profile of illness in the paGents with hemorrhagic c’trokewere not clear. Nonetheless, the authors have made a valuable contribution by describing a method to obtain a better understanding of the risk of specific cerebrovascuiar complicationsof thrombolytic therapy for myocardial infarction. Implications. It is hoped that future studies will apply similar methodologies to gain insights islto risk factors for ischemic and hemorrhagic stroke in this setting. Although it may not be possible to totally eliminate the occurrence of stroke after thrombolytic therapy for myocardiai infarction, neurodiagnostic evaluation and pathologic description of adequate numbers of cases of cerebral infarction and intracerebral hemorrhage and associated factors may permit delineation of their mechanisms and suggest appropriate preventive measures. It IS clearly important to be able to distinguish parenchymatous intracerebral hemorrhage from cerebral infarction with hemorrhagic transformation as their appearance on the CT scan may be identical (29,32). We urge investigators in ongoing large thrombolytic therapy trials to work closely with neurologists and neuropathologists to facilitate the realization of this objective. Only ti:pp can we begin to make a significantimpact on the burden of neurologic mortality and morbidity in patients successfully
JACC Vol. 16, No. 3 September 1990:54t-4
itctiVator given up ii0 4 hours after onset of myocardial infarction. Lancet l988:l:!O3-7. 19. IS6S-2(Second Internaoonal Sludy of Infarct Survival). Randomized trial of inlrirvenoms\lreprokina\e. oral a+irin. both or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-?. Lam-et 1988;2: 349-60. I. Thompson PL. Robinson JS. Stroke after acute myocardial relation to infarct size. Br Med J 1978:2:457-Y.
2. Komrad MS. Coffey CE. Coffey MS. McKinnis R. Massey EW. Califf RM. Myocardial infarction and stroke. Neurology 1984;34: 1403-Y. 3. Weinrich DJ, Burke JF. complicaling acute myocar 94. 4. Joh:mnesscn K-A. Nordrehaug osis and cerebrovascular rt J 1984:51:553-6.
letto FJ. Left ventricular
6. Olsson CG. Skene AM. von der Lippe 6. Jensen 6. ~arn~too JR. Trial of tissue plasminogen activator for mortality reduction in acute myocardial infarc:ion: Anglo-Scandinavian Study of EarlyThrombolysis (ASSETI. Ldncet 1988:?:5?5-30.
infarction:
!I.
Tiefenbrunn risk. JAMA
22.
eld AC, Gore JM. Paraskos 5. et al. impact of thrombolytic therapy on li ventricular mural thrombi in acute myocardial infarcrron. Am J Cardiol lY88:62:3lO-l.
mural thrombi
JE. von der Eippe G. Left ventricular accident in acute myocardial infarction.
EC. Gross SA. Schlamowitz RA. et al. Mural thrombi in myotxdtal ‘nfarctions: prospective evaluation by two-dimensional echocardiography. Am J Med 1983:74:989-95. 6. Frieaman MJ. Carlson K. arcur Fl. Wcolfendsn JM. Clinical corrclations in patients witb acute mgocardial infxclion and left ventricular thrombosis detected by two.dimensional echocardiography. Am J Med 1982:72:894-8.
AJ. Ludbrook PA. Coronary l98Y:!Al:2107-8.
thrombolysis:
it’s worth the
23. Lupi 6. Domenicucci S. Chiarella F. Bellotti P. Vecchio C. Influence of thrombolytic treatment followed by full dose anticodgulation of the frequency of left ventricular thrombi in acute myocardial infarction. Am J Cardiol 1989:64:58X-90. 24. Cohen D. Coronary thrombolysis: streptokinase or recombinant type pla5minopen activator’? Ann Intern Med lY90;112:529-38.
tissur-
25. Cranston RE. Wolfson MA. uchsbaum HW. Feinberg W A. Plasminogen activator and cerebral mfarction (letter). Ann Intern Med 1988:108:766.
7. Johannessen K-A. Nordrehaug JE. van der Lilape 6. Vollset SE. Risk factors for embolisation in patients with left ventricular tbrombi and acute myocardial infarction. Br Heart J 1988:60:104-10.
26. Stafford PJ. Strachan CJL. Vincent R. Chamberlain DA. Multiple microemboli after disintegration of clot during thrombolysis for acute myocardial infarction. Br Med J 1969:299: 1310-2.
8. The SCATI (Studio sulla Calciparana nellAngina e nella Trombosi ventriculonre nell’lnfartol Group. Randomized controlled trial of subcutaneous calcium-beparin in acute myocardial infarction. Lancet 1989:?: 182-6.
27. Braunwald E. Kndtterud GL. Passamani ER. Robertson TL. Announcement of protocol change in thrombolysis in myocardial infarction irial (letter). J Am Call Cardiol 1987:9:467.
9. Turpie AGG, Robinson JG, Doylt DJ. et al. Comparison oflugh dose with low-dose subcutaneous heparin to prevent left ventricular wall mural thrombus in patients with acute transmural anterior myocardial infarction. N Engl J Med 1989:320:352-7. IO. Davis MJE, Ireland MA. ERect ofearly anticoagulation on the frequency of left ventricular thromhi ..fter anterior wall acute myocardial infarction. Am J Cardioi 1986;57: 1244-7.
I I. Hart RG. Prevention and treatment of cardioembolic stroke. In: Furlan AJ, ed. The Hear: and Stroke. Berlin: Springer-Verlag.
1987:17-36.
28. Brdunwald E. Knatterud GL. Passamaai E, Robertson TL. Solomon R. Update from the Thrombolysic in Myocudial Infarction trial (letter). J Am Coil Cardiol 1987:10:970. 29. Passamdni E. H&es M. erman M, et al. The Thrombolysis in Myocardial Infarction tTIMIl Phase II Pilot Study: tissue plasminogen activator followed by :ercutaneous transluminal coronary angioplasty. J Am Coil Cardiol 19Xi:lOt\uppl Bl:515-64B. 30. Ca!iff PM, Topo! Et. George BS. et al. Hemrrrhagic complications associated with the u%e of intravenous tissue plasminogen activator in treatment of acute myocardial infarction. Am J Med 1988;85:353-9.
12. Report of The Working Party, Medical Research Council. Assessment of short-term anticoagulant administration after cardiac infarction. Br Med J 1%9:1:3?5-42.
31. Carlson S. Aldrich MS. Greenberg HS. Top01 EJ. lntracerebral hemorrhage complicating intravenous tissue plasminogen activator treatment Arch Neurol 198X:45:1070-3.
13. Schrlader R. Neuhaus K-L, Leizorovicz A, Linderer T. Tebbe U. for the ISAM Study Group. A prospective placebo-controlled double-blind multicenter trial of intravenous streptokinase (ISAM): Long-term mortality and morbidity in acute myocardial infarction. J Am Coll Cardiol 1987:9: 197-203.
32. Sloan MA. del Zoppo GJ. Brott TG. Thrombolysis and stroke. In: Julian DG. Norris RM. Kiibler W. Swan HJ. Collen D, Verstraete M. eds. Thrombolysis in Cardiovascular Disease. New York: Marcel-Dekker. 1989:361-80.
14. Rovelli F, Devita C, Feruglio GA, Lotto A, Selvini A. Tognini G and GISSI Investigators. GISSI trial: early results and late follow-up. J Am Coll Cardiol l987:IO(suppl B):33B-9B. 15. Maggioni AP. Farnia ML, Franzosi MG, for the GlSSl Group. Stroke in the GI5SI trial (abstr). Circulaiion 1989;8O(suppl Ill:lI-350. 16. AIMS Trial Study Group. Effect of intravenous APSAC on mortality after acute myocardial infarction: preliminary report of a placebo-controlled clinical trial. Lancet 1988;1:545-9. 17. Van der Werf F. Arnold AER. for tke European Cooperative Study Group for Recombinant Tissue-Type Plasminogen Activator (r&PA). Effect of intravenous tissue plasminogen activator on infarc? size. left ventricular function, and survival in patients with acute myocardial infarction. Br Med J 1988;297:i374-9, 18. National Heart Fgandation of Australia Coronary Thrombolysis Group. Coronary thrombolysis and myocardial salvage by tissue plasminogen
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