JACC Vol. 16. No. 3 September 1990563-8

Since the ~u~rodu~~~o nary angioplasty more unchallenged position disease. Advances in experience and technical skill of the practitioners have improved initial success rates. Simultaneo rates have substantially decreased (2-5). closure of the dilated vessel occurring in c procedure is still one of the main hazards of the operation (2-5). Coronary angioplasty generally results in disruption of the fibrous cap of the coronary artery plaque (63. During

From the Division of Cardiology and Division of Haematology and Oncology, Hannover Medical School. Hannover. Federal Republic of Germany. This study was supptied by a grant from Sandoz Stiftung fiir Therapeutische Forschung, Niirnberg. Federal Republic of Germany. Manuscript received October 23. 1989: revised manuscript received February 22, 1990, accepted March 14. 1990. : Dietrich C. Gulba. MD. MSc, Divisiun of Cardiology, Hannover Medical School, Konstanty-Gutschow-Strasse 8. D-3000 Hannover 61 I Federal Republic of Germany. OW!Ktby the American Colkge of Cardiology

me of early woun deling of the coronary stenosis occurs as e of the orga~iza~ioi~ :? this thrombotic leading to improved vessel geometry in the m cases. Abrupt closure of rhe coronary artery, be closely related to the angioplasty proce concomitant antithrombotic therapy with he ed by overshooting of the rin, vessel reclosure may be uite reasonable, therefore, thrombus growth (4,6). It see that thrombolysis together with low pressure redilations may improve the early success rate of coronary angiop~asty. The present study was designed to determine I) whether coronary artery a plasty and 2) whether th remains patent or tends to cause the pivotal role of thr

undergoing

combined

thrombolysis

and redilation. 073%Kt97/90/$3.50

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JACC Vol. 16. No. 3 September 1990:563-8

GULBA ET AL. THROMBOLYSIS IN THROMBOTIC OCCLUSIONS DURING ANGIOPLASTY

Table 1.

PatientCharacterislics Patients Screened (Feb. 1987~July 1988)

Patients (nr.) Gender (femNmale) Palients excluded before study entry* Dilated vessels (RCA/LCx/LAD/muldple) AEe (Yr) Height (cm) Weight (kg)

Padents Undergoing Thrombolysis for Abrupt Occlusion (Feb. 1987~July 1988)

Patients Undergoing Thrombolysis With Coagulation Analysis (May 1987~July 1988)

565

27

21

761489

4123 -

3118

51 lOl/68/278/67 56.4 + 8.9 172.5 + 8.7 75.9 r 10.4

914/14155.8 + 13.3

7/3/11158.3 r 8.9

175.1 r 5.9

174.8 f. 6.1

80.7 + 8.6

78.9 r 8.7

*For technical reasons such as bypass graft angioplasty or coronary stenosis not passed with the guide wire or = left aalerior descending coronary artery; LCx = left

with the balloon catheter. Data are mean values 2 SD. LA circumflex coronary artery: RCA = right coronary artery.

Selectionof patients. Patients were selected from a of 565 consecutive patients who underwent coronary plasty for severe (>70%) coronary artery stenosi February 1987 through July 1988. All patients were pretreated with 500 mg of oral aspirin, oral nitrates and a calcium channei blocker. Only those patients were selected for study entry who after angioplasty had abrupt closure of the vessel while they were still in the catheterization laboratory. Patients in whom it was not possible to advance the catheter over the stenosis were excluded from study. Patients were also excluded for the following reasons: 1) multiple vessel angioplasty, 2) angioplasty of a bypass graft. 3) unstable circulatory conditions, 4) history of recent gastrointestinal bleeding, 5) history of cerebrovascular accident, 6) known bleeding tendency, and 7) all other contraindications to thrombolytic therapy. Patients were also excluded if a large intimal dissection with a clearly visible intimalflap was angiographicallyidentifiedto have obviously caused the vessel closure. Before the patients were entered into the study, witnessed oral consent was obtained from all patients. The protocol was approved before the study by our institutional ethical committee. Study patients(Table1). From February 1987through July 1988, 565 patients underwent coronary angioplasty. Fifty-one patients were not entered into the study because their stenosis was not crossed, a bypass graft was dilated or one of the other exclusion criteria for study entry was present; 67 additional patients (11.9%) were excluded for multiple vessel dilations. Twenty-seven (6%)of the remaining 447 patients had acute thrombotic coronary occlusion during the angioplasty procedure. These 27 patients underwent combined intracoronarylintravenous thrombo!ysis combined with repeat low pressure balloon inflations. Beginning May 1987,detailed coagulation and fibrinolysisanalyses were performed (21 of the 27 patients). Two additional

patients (0.5%)suffered acute coronary occlusion obviously resulting from the presence of a coronary flap; they bot cy aortocoronary bypass grafting. la&y. This was perfo guiding catheter, stee 5F monorail balloon catheter positioned th groin. Before the procedure was started, 10 tionated heparin was administered intraven Four electrocardiographic (ECG) leads (including one epicardial lead) as well as aortic and pulmonary wedge pressures were coot~~~o~s~ymonitore . A~g~op~astywas performed with balloon inflation pressures ranging from 3 to 12 atm. All procedures were carried out with surgical standby. diagnosis of acute thrombotic closure was based on the following criteria: 1) a slowly progressing structure surrounded by contrast medium that finally completely obstructed the coronary bed, or 2) an intraluminal fillingdefect clearly visible on the fluoroscopic image of the angiogram that finally led to complete obstruction of the vessel lumen. Both criteria were accompanied by grade 0 or 1 flow according to the grading scale introduced by the Thrombolysis in MyocardialInfarction (TIMI) investigators (11). Thrombolytic therapy. After thrombotic vessel occlusion had been diagnosed, an intracoronary injection of 5,000 to 10,000IU unfractionated heparin (Liquemin, Hoffman LaRoche AC) was given in doses of 5,000 IU through the guiding catheter (Fig. 1) and redilation was performed with balloon pressures of 2 to 4 atm. The balloon catheter was then removed and thrombolytic therapy commenced with the least possible time delay. Thrombolysis wus smwd with intracoronary administration of 20 mg single chain, recombinant tissue-type inogen activator (&PA) (Actilyse, Dr. Karl Thomae, GmbH) infused over a 5 min period through the guiding catheter and was then continued with a 60 min intravenous infusion of 50

JACC Vol. 16. No. 3 September l99O:S63-8

acute thrombotlc coronary OCClUSlOn

5 -10000IE heparin i.c. bolus

~~~~~~ B. Study design. d = day: i-c. = ~~~r~~~r~fl~~r~~IE = internationai units; i.v. = intravenous: PKA = perc~ntaneous tra~s~Mm~~a1coronary angioptasty: t = time: TAT = thrombin-

mg. This regimen was selected in actor

~rn~~~ys~s, the guide wire was IcJ in place. As soon as the patients reported recurrence & chest pain, an additional injection of contrast If the vessel had reoccluded, the angio od cell counts atm. As soon as reopening of the vess the angioplasty catheter was again I indicated, this proce had been achieved o evident. Final angioplasty failure was okays assumed if lastirzg patency was not achieved within 60 rnin afiler rhe start of thrombo~ysis. Degenclling on the estimated amount of myocardium at risk, patients then either un bypass grafting or the vessel was left occ treated in the coronary care unit until c had returned to normal. In case of persistent patency of the vessel, an additional intracoronary injection of 5,000 1U heparin was administered through the guiding catheter and the catheter was then removed, with the arterial and venous catheter sheaths left in place. The patients were then transferred to the coronary care unit, where they were followed up for 24 h and the KG and cardiac enzyme leve repeatedly monitored. Coronary angiography was repeated 24 to 34 h later (Fig. 1). Until reexamination all patients were given a continuous infusion of 1,250 W/h heparin through the catheter sheaths. In addition, patients were given an intravenous daily infusion of 75 mg intravenous nitrates, 30

ter or the need for a blood transfusion

were

of ~-2 U of

Statistical evaluations were formed with Fisher’s exact test and Fisher’s t test. values ~0.05 were regarded as statistically sig reported p valves are two sided and not adjusted testing.

per-

Dersion.In 22

occlusion

closely related to angioplasty, the vessel was patent at (FiP. 2). Two discharge from the cat~eteri~a~~on lab gef cy bypass of the remanding 5 patients underwe grafting. In these two patients thrombolysis was ~~tagoaized by giving I million klU aprotinin as an intravenous over a 5 min period foollowed by a continuous intrav infusion of B million klU/h aprotinin. patients the hazards of an emergency considered higher than the risk from t infarction. These patients were treated conventionally in the

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GULBA ET AL. THROMBOLYSIS IN THROMBOTIC OCCLUSIONS DURING ANGIOPLASTY

Figure 2. Results of treatment in 27 patients with coronary thrombosis after angioplasty. Abbreviations as

in FigureI.

intensive care unit. All three patients developed cardiac enzyme or ECG signs, or both, of a small or moderate myocardial infarction. Follow-up angiography 24 to 36 h after angioplasty was performed in all 22patients in whom the vessel was patent at

discharge from the catheterization laboratory. Reocclusion of the dilated vessel was revealed in 12patients (54.5%)(Fig. 2), 11 of whom demonstrated cardiac enzyme or ECG signs, or both, of a small or moderate myocardial infarction. Only 5 of the 12 early vessel closures were accompanied by symptoms suggestive of myocardial reinfarction. However, seven of the 10remainingpatients with a persistently patent vessel at follow-up angiography also demonstrated cardiac enzyme signs of a small myocardial infarction. Adverse effects. One patient undergoing emergency bypass operation went into cardiogenic shock during the an-

gioplasty procedure. In this patient tbrombo~ysis was stopped with aprotinin as described, an diately underwent an emergency bypass 0 small myocardial infarction during the complications were observed in 10 patients were related to the puncture site in ni one patient had massive gum bleeding as well as hematemesis after thrombolysis was co None of the patients with bleeding com~~icati0~s blood transfusion. time was ~ro~0~~edto rombolysis, resulting in an average prolongation of 181? 5.5s before and 181? at 120 min into thrombolysis. In the 21 patients in wh detailed coagulation and fibrinolysisanalysis was perfor plasminogenand alpha*-antiplasminlevels decreased to 71 2 44% (p < 0.05) and 51 +. 47.5% (p < 0.05) of the baseline values, respectively. Simultanecdusly, average fibrin0 levels dropped to 94 + 32%of the baseline vahies ( whereas D-dimer levels-the specific split products linked fibrin-increased from 594 zz 789 to &liter (p < 0.01). When the patients were cl ing to clinical course (successful treatment vessel patency versus nonreopening plus early reocclusion), no significant differences were revealed between the two groups of patients. Thrombin-antith group of 21 patients

complex levels in the tot from9.1

5 13.6to11.6+ 12 Ccglliter(Fig. 3). When the patients were separated into two groups according to clinical course, the values for the thrombin-antithrombin-Ill complex levels between these two groups of patients were significantly different. Patients with successful thrombolysis and persistent patency demon-

Figure 3. Thrombin-antithrombin-III

complex (TAT)levels (&liter) in 27 patients with thrombotic occlusion during coronary angioplasty. Abbreviations as in Figure 1. to 6 3

6il

120mm standard range

e persistent patency at 24-36 h follow up

; 0 Persistent occlusion;

o reocclusion at 24-36 h follow up

atients with abru

combined regimen of i~tracoro~a sis together with repeat mild pre patency rate X30% was achieve catheterization laboratory.

e l~tervent~on. high thrombin activities at the

In recent studies in patients with

more, the thrombi~antithrombin-III complex levels measured 2 h after the start of thrombolysis were predictive of the short-term clinical course of the patients (9). With a view toward elucidating the role of the clotting an ed detailed investigationsof fibrinolytic syste her p~asm~r~ogcn,alpha,the hemostatic in, fibrinogen nor -dimer levels were related to the clinical course samples had not been collected in the presence of specific t-t-PAinhibitors, in vitro lysis was not completely precluded. Hence, there remains some uncertainty as to whether the

the coronary thrombus and thus may further enhance appositional thrombus growth. Hence, repeated balloon inflations, as performed in this study, may interfere with the local

abolished. In two thirds of the patients with abrupt throm-

568

JACC Vol. 16, MO. 3

GULBA ET AL.

THROMBOLYSIS IN THROMBOTIC OCCLUSIONS DURING ANGIOPLASTY

botic closure of the coronary artery closely related to

angioplasty, the current concepts for anticoagulationfait to abolish the local procoagulant activities. Thus, local thrombin release is continuously increased and becomes finally detectable even in venous blood. In these patients each measure undertaken, such as repeat balloon inflationsor the administration of thrombolytic agents, may promote rather than prevent the precipitation of additional thrombotic material. Conclusions. In this study, pretreatment of patients with aspirin and high dose intravenous heparin frequently failed to control the intensifying procoagulant activities causing thrombotic occlusion of the dilated coronary artery. It seems highly unlikely, therefore, that administering more heparin than was given in this study will accomplish therapeutic success. Hence, until stronger thrumbin inhibitors like hirudin (21) or stronger platelet inhibitors like glycoprotein IIbiIIIa platelet receptor inhibitors (22) are available for routine clinical use, the combination of thrombolytic agents with repeat balloon inflations should only be considered as an intermediate therapy. Because of the high reocclusion rate of >50% during the first 36 h of clinicalfollow-up, even those patients in whom reopening of the vessel can be achieved should at the present time undergo immediate aortocoronary bypass grafting. We hope that in the near future, a prospective variable may be derived from thrombin-antithrombin-III complex measurements upon which an individual decision for immediate bypass operation can be based. ces 1. Gruenlzig AR. Henning A. Siegenthaler WE, Nonoperative dilatation of coronary artery stenosis: percutaneous transluminal coronary angioplasty. N Engl J Med 1979;301:61-8. 2. Holmes DR Jr, Holubkov R, Vlietstra RE. et al. Comparison of complications during percutaneoustransluminal coronary angioplasty from 1977 to 1981 and from 1985 to 1986: the National Heart. Lung. and Blood Institute Percutaneous Transluminal Coronary Angioplrity Registry. 3 Am Call Cardiol 1988;12:1149-55. 3. King SE. Percutaneous transluminal coronary angioplasty: the second decade. Am J Cardiol 1988;62:2K-6K.

September

1

:563-R

6. Haudenschild CC. Pathogenesis of restenosis. Z Kardiol 1989;78(suppl 31:28-34. 7. Dgber C, Jungbluth A. Rumpelt H-J. Erbel R. Meyer J. Thoenes W. Morphology of the coronary arteries after combined tbrombolysis and percutaneous transluminal coronary angioplasty for acute myocardial infarction. Am 3 Cardiot 1986;58:698-703. 8. Eisenberg PR, Sherman L, Rich M, et at. importance of continued activation of thrombin reflected bv fibrinowotide A to the efficacy of thrombolysis. J Am Coil Cardlol 1986:7:125’-62. 9. Gulba DC, Barthels M. Reil G-H, Licktlen PR. Thrombinlantithrombin111 complex level as early predictor of reocclusion after successful thrombolysis (letter). Lancet 19882:97. IO. Rapold HJ. Kuemmerli H, Weiss aeberh A. Monitoring of fibrin generation during thrombolytic therapy of acute myocardial infarction with recombinant tissue-type plasminogen activator. Circulation 1989;79:980-9. II. Williams DO. Borer J. Braunwald E, et al. Intravenous recombinant tissue-type plasminogen activator in patients with acute myocardial infarction: a report from the NHLBl Tbrombolysis in Myocardial Infarction trial. Circulation 1986;73:338-46. 12. Friberger P. Kniis M. Gustavson S. Aurell L. Claeson G. Methods for determination of plasmin, antiplasmin and plasminogen by means of substrate S-2251. Haemostasis 1978;7:138-45. 13. Bang NO. Beller FK. Deutsch E. Mammen EF, eds. Thrombosis and Bleeding Disorders. Stuttgart: Thieme Verlag, 1971:233-4. 14. Sliitzer KE. Amiral J, Spanuth E. Neue Methoden zur spezifischen Bestimmung von Fibrinspaltprodukten (D-Dimere). Lab Med 1988:12: 51-9. IS. Pelzer H. Schwarz A. Heimburger N. Determination of human thrombinantithrombin 111complex in plasma with an enzyme-linked immunosorbent assay. Thromb Haemostas 1988:59:101-6. 16. Suryapranala H. de Feyter PJ, Serruys PW. Coronary angioplasty in patients with unstdbte angina pectoris: is there a role for thrombolysis? J Am Co11Cardiol 1988:I2tsuppl Ak69A-77A. 17. Francis CW. Markham RE. Barlow GH, Florack TM. Dobrzvnski DM. Marder VJ. Thrombin activity of fibrin thrombi and sol&e plasmic derivatives, J Lab Clin Med 1983;102:220-30. 18. Seitz R. Blanke H. PnIlorius G, Strauer B-E, Egbting R. increasedthrombin activity during thrombolysis. Thromb Haemoslas 1988$9:541-2. 19. Barthels M. Mdller. W. Gulba DC. Bohn U. Oestereich CH, Poliwoda H. Elevated levels of thrombin-antithrombin complex in plasma in vitro and in vivo after addition of pro-urokinase-urokinase (abstr). Blut 1989;58: 116. 20. Owen 1. Friedman KD. Grossman BA, Wilkins C, Berke AD. Powers ER. Thrombolytic therapy with tissue plasminogen activator or streptokinase induces transient thrombin activity. Blood 1988;72:616-20.

4. Simoons ML. Reoclusionlrestenosis after coronary artery bypass surgery, percutaneous transluminal coronary angioplasty and thrombolysis. 2 Karriiol 1989;78(suppI3):35-41.

21. Heras M. Chesebro JH. Penny WJ, Bailey KR. Badimon L, Fuster V. Effects of thrombin inhibition on the development of acute plateletlhrombus deposition during angioplasty in pigs: heparin versus recombinant hirudin. a specific thrombin inhibitor. Circulation 1989:79:657-65.

5. Rupprecht H-J, &bet R. Bfennecke R, et al. Aktuelle Komplikations-rate der purkutanen translumina!en Koronamngioplastie bei stabiler und instabiler Angina. Dtsch Med Wochenschr 1988;i 13:409-13.

22. Caller BS, Scudder LE. Inhibition of dog platelet function by in vivo infusion of F(ab’l2 fragments nf a monoclonal antibody IO the platelet glycoprotein Ilb/llla receptor. Blood 1985:66:1456-9.