Early intravenous thrombolytic therapy for acute myocardial infarction in patients with prior coronary artery bypass grafts

BRIEF REPORTS

The present study suggeststhat oral treatment with dipyridamole and aspirin during the first 10 days after an anterior wall AM1 does not reduce the development of LV thrombi despiteevidenceof significant platelet inhibitory effect as shown by the prolongation of the bleeding time. Based on sample size calculations, we initially planned to enter 40 subjects, since a trial of that size would have been adequateto demonstrate a reduction in thrombus developmentfrom the 40%rate expectedin the placebo group1-7to 10%in the treatment group12with a 5% significance level and a power of 80%. We cannot explain the unusually high prevalence of thrombi in the treatment group. At baseline, there were no significant differences between the treatment and placebo groups, and peak aspartate aminotransferasewas also similar in the 2 groups. The study was stopped becausethe incidenceof 8 thrombi in the treatment group meant that no therapeutic efficacy could be shown even if the planned total of 40 subjects were entered. On day 1 there were no significant differencesin coagulation variables between patients who ultimately developed LV thrombi and those who did not. Thus, early measurementof thesevariables doesnot appear useful as a predictor of thrombus development.Later in their hospital course, patients who developed thrombi had increasedfibrinogen and von Willebrand antigen, and fibrinogen degradation products were detectable in 9 of 11 patients. Theseabnormalities suggesta low level of intravascular consumption, probably due to the LV thrombus. Patients with thrombi also had a significant reduction in platelet count. Activated platelets are removed from the circulating blood. The reduction in platelet count in patients with LV thrombi may therefore be due in part to removal of activated platelets from the circulation. We conclude that treatment with aspirin plus dipyridamole begun within 12 hours of onset of AM1 does not prevent LV thrombus formation in patients with AMI. LV thrombi are associatedwith changesin coagulation variables.

1. Asinger RW, Mike11FL, ElspsrgerJ, Hodges M. Incidenceof left ventricular thrombosis after acute transmural myocardial infarction. N Engl J Med 1981:306:297-302. 2. Friedman MJ, Carlson K, Marcus FI, WoolfendenJM. Clinical correlationsin

patients with acute myocardial infarction and left ventricular thrombusdetected by two-dimensional echocardiography.Am J Med 1982;72;894-898. 3. Keating EC, Gross SA, Schlamowitz RA, GlassmanJ, Mazur JH, Pitt WA, Miller D. Mural thrombi in myocardial infarctions. Am JMed 1983;74:989-995. 4. Bneichou M, Aubry J, Larbi MB, Romani A, Chiche G, Egre A, Djiane P, Bory M, Serradimigni A. Detection descaillots intra-ventriculaires gauchesa la phaseaigue de l’insarctus du myocardepar l’echocardiogolgraphiebi dimensionnelle: a propos de 103 cas. Arch Ma1 Coeur Vaiss 1983;76:1012-1019. 5. Visser CA, Kan G, Lie KI, Durrer D. Left ventricular thrombus following acute myocardial infarction: a prospectiveserial echocardiographicstudy of 96 patients. Eur Heart J 1983;4:333-337. 6. JohannessenK-A, Nordrehaug JE, van der Lippe G. Left ventricular thrombosis and cerebral vascular accident in acute myocardial infarction. Br Heart J 1984:51:553-556. 7. Weinreich DJ, Burke JF, Pauletto FJ. Left ventricular mural thrombi complicating acute myocardial infarction. Ann Intern Med 1984;100:789-794.

6. JohannessenK-A, Nordrehaug JE, van der Lippe G, Vollset SC. Risk factors for embolisation in patients with left ventricular thrombi and acute myocardial infarction. Br Heart J, in press. 9. JohannessenK-A. Peripheral emboli from left ventricular thrombi of different echocardiographicappearancein acute myocardial infarction. Arch Intern Med 1987:147:641-644.

10. Verheught FW, Lindenfeld J, Kirch DL, SteelePP. Left ventricular platelet deposition after acute myocardial infarction. Br Heart J 1984;52;490-496. 11. Stratton JR, Ritchie JL, Hamilton GW, HammermeisterKE, Harker LA. Left ventricular thrombi: in viva detection with indium-111 platelet imaging and two-dimensional echocardiography.Am J Cardiol 1981;47:874-881. 12. Stratton JR, Ritchie JL. The effects of antithrombotic drugsin patientswith left ventricular thrombi: assessmentwith indium-111 platelet imaging and twodimensional echocardiography.Circulation 1984;69:561-568. 13. Aspirin Myocardial Infaction Study ResearchGroup 1980.A randomized controlled trial of aspirin in personsrecoveredfrom myocardial infarction. JAMA 1980;243:661-669.

14. Ezekowitz MD, Smith EO, Cox AC, Taylor FB. Failure of aspirin to prevent incorporation of indium-1 11labelledplateletsinto cardiacthrombi in man.Imcet 1981;2:440-443.

15. Moncada S, Korbut R. Dipyridamole and other phosphodiesterase inhibitors act as antithrombotic agents by potentiating endogenousprostacyclin. Imeet 1978:1:1286-1289.

16. Roth GJ, Stanford N, Majerus PW. Acetylation of prostaglandinsynthaseby aspirin. Proc Nat Acad Sci USA 1975;72:3073. 17. JohannessenK-A, Nordrehaug JE, van der Lippe G. IncreasedOccurrenceof left ventricular thrombi during early treatment with timolol in patientswith acute myocardial infarction. Circulation 1987;1:151-155. 16. Nordrehaug JE, JohannessenK-A, van der Lippe G. Usefulnessof high-dose anticoagulantsin preventingleft ventricular thrombusin acutemyccardial infarction. Am J Cardiol 1985;55:1491-1493. 19. Ivy AC, Nelson D, BuchetG. Standardizationof certain factors in cutaneous venostasisbleeding time technique.J Lab Clin Med 1941;26:1812.

Early Intravenous Thrombolytic Therapy for Acute Myocardial Infarction in Patients with Prior Coronary Artery Bypass Grafts Neal S. Kleiman, MD, David A. Berman, and Robert Roberts, MD

BA,

William R. Gaston,

MD,

W. Richard Cashion,

MD,

ty.536Most published trials have excluded patients with previous coronary artery bypass grafting, primarily becauseof difficulty in identifying the infarct-related corofibrinolytic agents to restore coronary arterial patency,’ nary artery. However, the yearly rate of myocardial inimprove left ventricular function2-4 and reduce mortali- farction is approximately 3%after coronary artery bypass surgery,‘land asthe number of patientswith bypassgrafts From the Baylor College of Medicine, Department of Medicine, Diviincreasesand the population with bypassgrafts in place sion of Cardiology, and the Methodist Hospital, 6535 Fannin, Mail Station F-905, Houston, Texas 77030.Manuscript received August 15, ages,an increasing number of AMIs in this group can be 1988; revised manuscript received September 26, 1988, and accepted anticipated. No published data exist concerning intravenous thrombolytic therapy in thesepatients. We report 5 September 30. reatment of acute myocardial infarction (AMI) T with intravenous thrombolytic agentsis gaining wide acceptance as a result of the demonstrated ability of

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THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 63

TABLE I Characteristics

of Treated

Patients

I

Pt

&e (yrs)

Date of CABG

Native Artery Grafted

Dose of &PA (mg)

Time from AMI to Angio

LVEF (%) (Simpson’s Rule)

ECG Leads ST-Segment Elevation

Resolution of ECG Changes

Postthrombolytic Management

1 2 3 4 5

64 55 63 63 54

1980 1981 1982 1979 1982

LAD LAD Right Right IAD

100 loo 100 100 100

3 days 1 day 3 hours 12 hours 9 days

67 33 67 26 40

wJ4

+

Vlr v2

+

III, aVF II, Ill, aVF

+ -I 0

Repeat CABG PTCA Repeat CABG Repeat CABG Medical

h-V4

AMI = acute myocardial infarction; CABG = coronary artery bypass graft; LAD = left anterior descending; transluminal coronary angioplasty; ti-PA = recombinant tissue plasminogen activator; + = yes; 0 = no.

LVEF = left ventricular

ejection

fraction;

PTCA = percutaneous

casesof successfulthrombolysis using recombinant tissue plasminogenactivator (rt-PA) in patients who had previously undergone coronary bypass surgery. Pertinent clinical data are listed in Table I. Twovessel coronary artery disease was present in patient no. 3; the other patients had 3-vessel disease. Cine frames of the infarct graft of the first 4 patients are shown in Figures 1 through 4. Patient no. 3 died of respiratory failure postoperatively. The other 4 patients were asymptomatic at the time of hospital discharge. Recurrent angina and angiographic restenosis of the graft occurred in patient no. 2 after 6 months. A left ventriculogram performed at this time revealed substantial improvement in ejection fraction compared with the initial study and repeat coronary angioplasty was performed successfully.

Thesecasesrepresentthe first 5 consecutivepatients with saphenousvein bypassgrafts and AM1 treated with intravenous rt-PA at our institution since December 1987.Other investigatorss9 have reported successfulreperfusion of occluded saphenousvein coronary bypass grafts using selective intracoronary infusions of both streptokinaseand urokinase. Intravenous therapy is con-

FIGURE 1. Saphenous vein graft in patient 1 to the left anterior descending coronary artery 3 days after infusion. subtotal occlusion is present.

FIGURE 2. Saphenous vein graft to the left anterior descenaling coronary artery in patient two 24 hours after r&PA infusion. There is a high grade stenosis in its midsection that is suspicious for a filling defect.

FIGURE 3. Saphenous vein graft to the right coronary artery in patient three 3 hours after completion of infusion. There is a high grade, irregular appearing lesion with a filling defect present.

THE AMERICAN

JOURNAL

OF CARDIOLOGY

JANUARY

1, 1989

BRIEF REPORTS

in patients 3 and 4 was responsiblefor the inferior infarctions, both experienceddramatic symptomatic improvement and both had patent right coronary artery grafts with angiographic appearances suggestive of recent thrombosis. Although we do not know the rate at which either spontaneousor drug-induced reperfusionoccursin saphenousvein bypassgraft occlusion,thesecasesdemonstrate that pharmacologic recanalization doesoccur. We thus recommendthat patients presentingwith AMI who have had previousbypasssurgerybe consideredfor early intravenous thrombolytic therapy.

FIGURE 4. Saphenous vein graft to the right coronary artery in patient 4 performed at 12 hours after the &PA infusion. There is a high grade stenosis present in the proximal segment.

siderably less complex than prolonged intracoronary infusion and can be instituted more rapidly. In fact, treatment in 3 of our caseswas begun in a community hospital and the patients were then referred to the tertiary center. The needto institute treatment immediately5 precluded angiographic documentation of total graft occlusion; however,all 5 patients presentedwith ST-segment elevation and prolonged chest pain. Further, there is no reason to believethat the well-documented phenomenonof complete thrombotic occlusion seenin native vessels’should not be operative in bypassgrafts. Although clinical signs are not reliable predictors of patency, 3 of these patients did experience complete resolution of pain and ST-segment elevation, which are the most specific clinical markers reported.lOWhile it might be argued that the occlusion of circumflex rather than right coronary grafts seen

1. ChesebroJH, Knatterud G, Roberts R, Borer J, Cohen LS, Dalen J, Dodge HT. Francis CK, Hillis D, Ludbrook P, Markis JE, Mueller H, PassamaniER, Powers ER, Rao AK, Robertson T, Ross A, Ryan TJ, Sobel BE, Willerson J, Williams DO, Zaret BL, Braunwald E. Thrombolysis in Myocardial Infarction (TIMI) Trial, Phase I: a comparison between intravenous tissue plasminogen activator and intravenous streptokinase.Circulation 1987;76:142-154. 2. White HD, Norris RM, Brown MA, Takayama M, Maslowski A, BassNM, Ormiston JA, Whitlock T. Effect of intravenousstreptokinaseon left ventricular function and early survival after acute myocardial infarction. iV Engl J Med 1987;317:8SO-855. 3. Guerci AD, Gerstenblith G, Brinker JA, Chandra NC, Gottlieb SO, Bahr RD,

WeissJL, Shapiro EP, Flaherty JT, Bush DE, Chew PH, ottlieb SH, Halperin HR, Ouyang P, Walford GD, Bell WR, Fatterpaker AK, LFewellyn M, Top01EJ, Healy B, Siu CO, Becker LC, Weisfeldt ML. A randomizedtrial of intravenous tissue plasminogen activator for acute myocardial infarction with subsequent randomizaton to elective coronary angioplasty. N Engl J Med 1987;317:16131618.

4. O’Rourke M, Baron D, Kcough A, Kelly R, Nelson G, BarnesC, Raftos J, Graham K, Hillman K, Newman H, Healey J, Woolridge J, Rivers J, White H, Whitlock R, Norris R. Limitation of myocardial infarction by early infusion of recombinant tissue type plasminogenactivator. Circulation 1988;77:131 l-l 325. 5. Gruppo Italian0 per lo Studio della Streptcchinasi nell ‘Infarto Miocardico (GISSI). Long-term effects of intravenous thrombolysis in acute myocardial infarction: final report of the GISSI Study. Lmcet1987;2:872-874. 6. AIMS Trial Study Group. Effect of intravenous APSAC on mortality after acute myocardial infarction: preliminary report of a placebo-controlledclinical trial. Lancet 1988:1:545-549. 7. Coronary Artery Surgery Study (CASS) Principal Investigators and Their Associates.A randomized trial of coronary artery bypass.Quality of life in patients randomly assignedto treatment groups. Circulation 1983,68:952-956. 6. Rentrop P, Blanke H, Karsch KR, Kostering H, Oster H, Leitz H. Recanalization of an acutely occludedaortocoronary bypassby intragraft fibrinolysis. Circulation 1980,62:1123-1127.

9. Smuckler Al, Rufty AJ Jr, Headley RN, Welbourne R. Thrombolysis in an aortocoronary saphenousvein graft. Cathet Cardiouasc Diagn 1982;8:507-512. 10. Kircher BJ, Top01EJ, O’Neill WW, Pitt B. Prediction of infarct coronary artery recanalization after intravenous thrombolytic therapy. Am J Cardiol 1987;59:513-515.

Effect of Felodipine on Hyperventilation-Induced in Variant Angina Pectoris

Ischemic Attacks

Diego Ardissino, MD, Stefano Savonitto, MD, Paola Zanini, MD, Stefano De Servi, MD, Paolo Barberis, MD, Giuse Cavallotti, MD, Giuseppe Specchia, MD, and Carlo Montemartini, MD t is not easy to document the efficacy of a new Ichemic antianginal drug in vasospasticangina becausethe isattacks may occur sporadically and long-term clinical observation is not always convenient. For this reason, provocative tests, originally developed for diagnostic purposes,have been used for evaluating and comFrom the Divisione di Cardiologia, Istituto di Ricovero e Cura a Carattere Scientifico, Policlinico S. Matteo, Universita’ degli Studi di Pavia, 27100 Pavia, Italy. Manuscript received July 19, 1988; revised manuscript received and accepted November 3, 1988.

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THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 63

paring the efficacy of different drugs and for confirming the spontaneousremissionof the vasospasticdisease.The hyperventilation test has proved to be a useful and safe procedurein this regard.1-3This study assessed the efficacy of felodipine, a new dihydropyridine calcium antagonist, in preventing hyperventilation-induced ischemic attacks in patients with variant angina. Fourteen men ages 45 to 67 years (mean 57) were selected for study from those admitted to our clinic between April 1987 and April I988 after they fulfilled the