Nonacute thrombolytic therapy: An adjunct to coronary angioplasty in patients with large intravascular thrombi

Nonacute thrombolytic therapy: An adjunct to coronary angioplasty in patients with large intravascular thrombi The presence of intravascular thrombus can make coronary angioplasty difficult or impossible to perform. To determine if thrombolytic agents could lyse large, nonacute thrombi, we retrospectively analyzed the angiograms of all 14 patients with unstable angina and large intravascular thrombi (>2 cm in length) who were treated with thrombolytic agents at The Johns Hopkins Hospital between October 1987 and April 1989. Twelve patients were treated with intracoronary streptokinase, and two with intravenous tissue plasminogen activator. Coronary arteriography was repeated immediately after treatment and a mean of 1.6 + 0.3 days later. The degree of thromboiysis and change in distal vessel perfusion was evaluated. Thrombolysis was graded as considerable If there was >75% resolution of apparent thrombus, and as complete if no stenosis or only a discrete restdual stenosis was apparent. Fifty-seven percent of patients uitlmately achieved considerable or complete thromboiysis and were able to undergo successful angioplasty. Patients achieving considerable or complete thrombolysis had a 28 + 7% increase in luminai diameter and demonstrated normalization of initially absent distal perfusion, except for the one patient who had normal distal flow prior to treatment. A maximal thrombolytic effect was evident only at the time of “delayed” angiography in all patients who responded to treatment and underwent both follow-up arteriograms. We conclude that thrombolytfc agents can effectively lyse large, nonacute intravascular thrombi, thereby facilitating coronary angioplasty. A full thrombolytic effect does not occur for hours to days after drug administration, and may not become evident unless delayed angiography is performed. (AM HEART J 1989;118:862.)

Howard P. Grill,

MD, and Jeffrey A. Brinker,

MD. Baltimore, Md.

Unstable angina may result from total or partial occlusion of a coronary artery by thrombus. Percutaneous transluminal coronary angioplasty (PTCA) has been frequently and effectively used as a means of revascularization in these cases; however, the presence of a copious amount of clot makes this procedure difficult or even impossible to perform. When angioplasty is attempted in such cases, it may be associated with an increased complication rate. The presence of thrombus at the dilatation site is associated with a high incidence of acute occlusion’ and distal clot embolization.2 Very large thrombi obscure the underlying atherosclerotic lesion and require multiple dilations along the entire length of the clot. Successful thrombolysis, by removing a large volume of thrombus and improving visualization of the underlying lesion, could make such patients significantly better candidates for PTCA. From Received

the Johns

Hopkins

for publication

Medical Jan.

Institutions, 23,1989;

Reprint requests:Howard P. Grill, of Cardiology, 568 Carnegie Bldg., 4/l/14514

662

accepted

Department May

of Cardiology.

22, 1989.

MD, The Johns Hopkins Hospital, 600 N. Wolfe St., Baltimore, MD

Dept. 21205.

Intracoronary streptokinase has been demonstrated to lyse clots up to 2 weeks old.3 It has therefore been our practice to attempt thrombolysis in all cases where PTCA would be the therapy of choice, but is precluded by the presence of large (>2 cm) intravascular thrombi. In order to assess the efficacy of such treatment, we retrospectively evaluated the results of therapy in all 14 such patients who were treated with thrombolytic agents at The Johns Hopkins Hospital between October 1987 and April 1989. METHODS Patient

selection. Between October 1987 and April 1989,14 patients with unstable angina were found at diag-

nostic catheterization to have angiographic evidence of an intravascular thrombus >2 cm in length, and were treated with thrombolytic agents. Patients with acute Q wave myocardial infarction were not included in this analysis, as the efficacy of such therapy has been well established by several large prospective studies. 4-9 Patients with contraindications to thrombolytic therapy including past history of cerebrovascular accident, gastrointestinal bleeding, recent surgery or trauma, bleeding diathesis, severe hypertension, or known sensitivity to streptokinase were not considered for treatment.

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663

I. Clinical characteristics Age (yr),

Patient 1* 2* 3 4 5 6 I 8 9 10 11 12 13 14

51, 68, 65, 44, 68, 47, 57, 48, 56, 55, 32, 38, 61, 46,

M M M M F M M M F M M M M M

ZC streptokinase

Symptom duration

sex

(days) 10 5 3 14 45 I 14 45 10 6 14 I 30 11

F, Female; IC, intracoronary; IV, intravenous; LAD, left anterior graft. *Patient previously reported.lO tTreated with 100 mg intravenous tissue plasminogen activator.

Vessel LAD-VG LAD-VG LCx-VG RCA-VG RCA-LCx-VG RCA-VG RCA RCA LAD-VG RCA RCA LCX RCA-VG RCA descending;

Procedure. Coronary arteriography was performed via the transfemoral approach. Patients were premeditated with oral diazepam and diphenhydramine. Five thousand units of intravenous heparin were given after vascular accesswasobtained, and angiography was performed in the routine fashion using 8F Judkins catheters. Patients who were identified as having large intravascular thrombi (>2 cm in length) and in whomPTCA wasotherwiseconsidered the therapy of choice were treated with thrombolytic agents. Thrombus was angiographically defined as a discrete filling defect either outlined by or stained with residual contrast medium. In one patient (No. 3), an unsuccessful attempt at passingthe thrombus with a guide wire preceded thrombolytic therapy. Of the 14 patients identified in this manner, eight had thrombi within saphenousvein grafts and six had thrombi in native coronary arteries. Eleven patients received 420,000i 44,000U (range 80,000to 500,000U) of intracoronary or intragraft streptokinase infused over 60 minutes via a Harvard pump (Harvard Apparatus Inc., S. Natick, Mass.). One patient received 500,000U of intragraft followed by 650,000U of intravenous streptokinase, and two patients received 100 mg of intravenous tissue plasminogenactivator (t-PA) infused over 3 hours (Table I). Following infusion of intracoronary streptokinase, patients underwent repeat angiography of the treated vessel. For logistical reasons,patients treated with intravenous tPA did not undergo immediate post-treatment angiography. The femoral sheathswere then sewninto place, and an intravenous infusion of heparin wasbegun at a doseof 1000 U/hr. All patients returned to the catheterization laboratory a mean of 1.6 + 0.3 days later (range 0.3 to 4 days) for “delayed” angiography (Table I). In preparation for anticipated angioplasty, patients were treated with aspirin, 325 mg orally daily, and dipyridamole, 75 mg orally three times daily. Angiographic data. All cineangiogramswere evaluated

LCx, left circumflex;

dose (U X 1000)

Time to delayed imaging (days)

500 500 + 650 IV 240 500 80 500 500 300 t t 500 500 500 500 M, male; RCA, right coronary

0.3 1 1 1 1 1 1 4 3 1 3 1 1 3 artery;

U, units; VG, vein

by two experiencedangiographers.Initial clot size wasdetermined to be >2 cm in length by comparisonto the catheter diameter. In all caseswhere thrombus causeda total occlusion,clot sizewasdetermined by clot staining and/or collateral filling of the vessel.Twelve patients had total occulsions,and in eight the clot was able to be definitively sized either by clear staining of the thrombus or by collateral filling demonstrating a “tail” > 2 cm from the point of occlusion. The effect of thrombolysis was assessed in semiquantitative fashion both immediately following therapy and after delayed angiography. Thrombolysis was considered insignificant if there was <25% resolution of the intraluminal filling defect’s apparent volume, considerable if there wasresolution of >75% of the filling defect’s apparent volume, and complete if the entire filling defect had resolvedor if only a discrete localized residual stenosiswas evident. Distal vesselflow wasgraded as normal, slow, or absent. The percent reduction in luminal diameter at the site of the lesion was determined by comparing caliper measurementsof the stenosis in the view in which it appearedmostsevereto the nearestmoreproximal diseasefree portion of the vessel. RESULTS Clinical

characteristics. The clinical characteristics of the 14 patients in the study are displayed in Table I. There were 12 men and 2 women, with a mean age of 53 + 3 years, who were studied 16 -t 4 days after the onset of unstable angina (range 1 to 45 days). Two of these patients (Nos. 1 and 2) have been previously reported.lO Effect of thrombolysis. Eight patients (57%) demonstrated considerable (five patients) or complete (three patients) dissolution of clot. One of these eight patients underwent only one follow-up angiogram,

October

664

Grill

and

Brinker

Table

II. Response to therapy

American

% Stenosis Patient

Pre

Post

1

100 100 100 83 100

100 100

2 3 4

5 6 7 8 9 10

100 100 100 100

Distal

perfusion

Delayed

Prr

Post

100

41

100

64

0 0 0 2 0 0 0 0

0 0 0 '2 0 0 2 0 * *

100

100

86

86 70 100

82 100 * *

78 100 60 100

0

11

100 100

12 13

99 100

99 100

100

0 0

14

100

100

100

0

67 89

100

Distal perfusion 0, No antegrade flow; *Immediate post-treatment angiography

1. slow antegrade not performed

flow; 2, normal (treatment with

0 0

0 0 0 0 flow; Clot intravenous

while the other seven patients underwent both immediate post-treatment and delayed angiography (Table II). Of these seven, all of whom ulitmately achieved significant thrombolysis, five had no improvement immediately following therapy. The other two patients did have a significant early response to treatment, although a maximal thrombolytic effect was not evident until delayed imaging. Of the eight patients demonstrating significant thrombolysis, seven initially had absent distal perfusion that ultimately normalized. The remaining patient had good distal perfusion prior to treatment. Thrombolytic therapy was associated with a 28 * 7 %, increase in luminal diameter in these eight patients, and all were able to undergo successful PTCA. Fig. 1, A through C, demonstrates the initial, the immediate post-treatment, and the delayed results obtained in a patient with considerable thrombolyses. Eight of the 14 thrombi were within saphenous vein grafts. Five of these patients (63 % ) experienced considerable or complete thrombolysis and, if it had been initially abnormal, an improvement in distal perfusion. One patient who did not obtain angiographic improvement had a successful angioplasty after thrombolytic therapy, while prior to therapy a guide wire could not cross the obstruction. Six patients failed to achieve thrombolysis. Two patients, one of whom, as noted above, had an unsuccessful attempt at PTCA prior to treatment, underwent successful PTCA. One patient had a failed PTCA attempt and underwent bypass surgery, while in the other three angioplasty was not attempted because of the large volume of intravascular thrombus present. One of these three patients un-

('lot Deluyed " 0

Posl

Heart

1989 Journal

mobilizatim Iklawd

0 0

0 '2

0

2

0

0 2 0

0 2

”

0

2 0 2 2 0 0

mobilization 0, insignificant; tissue plasminogen activator).

0 0 2. considerable;

3, complete.

derwent bypass surgery, another was not considered a surgical candidate and died shortly thereafter, while a third is presently alive, but symptomatic. DISCUSSION

Successful lytic therapy in patients with large intravascular thrombi could potentially allow PTCA to be performed in those who might otherwise not be angioplasty candidates. In this retrospective study, considerable or complete thrombolysis was demonstrated in 8 of 14 (57 % ) patients with large intravascular clots treated with thrombolytic agents. Although the number of patients studies was small, this success rate approaches that obtained in the setting of acute myocardial infarction4-’ and post-infarction angina.3 Most studies assessing the efficacy of thrombolytic agents have been conducted in the setting of acute myocardial infarction, where it is of utmost importance to achieve thrombolysis within 60 to 90 minutes. Because our patients were not experiencing an acute ischemic event, the time to actual clot lysis was not critical, giving us the opportunity to observe the delayed effects of these agents. None of the seven patients who had serial angiograms and who ultimately demonstrated considerable or complete clot lysis achieved a maximal thrombolytic effect immediately after treatment. Although the exact time duration needed to maximize the effect of therapy is unknown, it would appear prudent to allow 24 hours for continued thrombolysis to occur in patients who are treated in this manner. This time frame is convenient in that the removal of intravascular sheaths may not be necessary, thereby allowing for continu-

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clot lytic therapy pre PTCA

665

Fig. 1. A, Right anterior oblique view of totally occluded left anterior descendingcoronary artery vein graft. 6, Left anterior oblique view demonstrating persistent “staining” of the body of the left anterior descendingcoronary artery graft following native left coronary injections. Arrows denotea long irregular filling defect consistent with thrombus. There was no changein the graft’s appearanceimmediately after streptokinase infusion. C, Right anterior oblique view of the vein graft 24 hours after treatment. The graft is now patent. Arrow denotesa small amount of residual thrombus.

ous systemic anticoagulation and facilitating

“early” PTCA. Since only two patients were treated with tPA, which may have greater efficacy on older clots, this conclusion may only apply to the use of streptokinase. Saphenous vein bypass grafts have a tendency to develop large thrombi that are usually associated with underlying atherosclerotic lesions, although such clots have also been reported in the absence of a significant plaque. lo In this study, five of the eight patients (63%) with large graft thrombi achieved considerable or complete thrombolysis. Thus thrombolytic therapy may be particularly applicable to this group of patients. Given both the subacute nature of our patients’

symptoms and the large size of the thrombi, it is unlikely that their improvement represented spontaneous thrombolysis. Likewise, although our patients were treated with intravenous heparin between the initial catheterization and delayed angiography, it seems improbable that heparin alone could be responsible for the continued improvement observed following treatment. Recent evidenceI demonstrates that prolonged heparin therapy is associated with the mobilization of a large volume of thrombus; however, this occurs over a much longer time period (7+ 2 days) than we provided. Continuous infusion of urokinase lasting up to 5 daysi has also been reported to lyse occlusive thrombi in saphenous vein grafts. However, this technique carries with it the as-

666

Grill and Brinker

sociated risk of a catheter left in the ascending aorta for several days. Because a much shorter course of therapy is necessary, our treatment appears more cost-effective than the use of either heparin or urokinase. There are risks associated with thrombolytic therapy. Recent studies I3214 have demonstrated up to a 25 % incidence of bleeding requiring transfusion with 2 or more units of blood when intravenous thrombolytic agents are used in the setting of acute catheterization. However, this rate appears to be significantly lower when streptokinase is administered via the intracoronary route, presumably because of the lower dose required. 4-7Accepted contraindications to the use of these agents served as exclusion criteria for the protocol, and no bleeding complications occurred. Acute reocclusion occurred during the angioplasty in one patient (No. 12) who had significant thrombolysis. This occlusion was immediately and successfully redilated, with no further evidence of reocclusion. Another potential complication of thrombolytic therapy is distal clot embolization. This complication was not encountered in any of our study patients. However, it did occur in one of a small number of patients that we have treated who had thrombi < 2 cm in length. This study has several limitations. It contains only a small number of patients analyzed in a retrospective fashion. It is the practice at our institution to treat with thrombolytic agents all patients with unstable angina and large thrombi in whom PTCA would otherwise be the therapy of choice. Although there may have been some unknown bias in patient selection, all patients treated during the 19-month time period covered by the study were included. Our semiquantitative assessment of clot size and resolution was based solely on angiographic appearance, which is the only clinically available tool for making such an analysis. Four of the 12 patients with total occlusions did not demonstrate clot staining or a thrombus tail, such as that seen in Fig. 1, B. In these patients, clot size was determined by assuming that the thrombus extended from the occlusion to the point of retrograde collateral filling. In fact, the thrombi may have been < 2 cm long in these patients. However, significant thrombolysis was noted in only two of these four patients (Nos. 10 and 12). While the angiographic distinction of thrombus from atherosclerosis is not absolute, because all our patients had such large thrombi a clinically important response could be assessed even if what was interpreted as residual plaque were partially composed of thrombus. This was apparent in patient No. 4, in whom the severity of the descrete lesion did not change but a large

American

October 1989 Heart Journal

volume of thrombus was mobilized from the vessel distal to the stenosis, allowing successful PTCA to be performed. Finally, one cannot be certain that the age of the thrombus is equivalent to the duration of the patient’s symptoms. Despite these limitations, our data indicate that thrombolytic therapy can be an efficacious adjunct to PTCA in patients with angiographic evidence of intravascular thrombus and unstable angina of up to several weeks’ duration. Such therapy can decrease clot size, improve distal perfusion, decrease percent stenosis, and appears to facilitate PTCA in patients who might otherwise not be candidates. The maximal effect of such therapy is not manifest for hours after treatment. These findings support the need for a larger scale, prospective study to evaluate more carefully the effects of such therapy. We would like to thank ing the manuscript.

Ms. Diane

Agee for her help in prepar-

REFERENCES

1. Mabin TA, Holmes DR Jr, Smith HC, Vliestra RE, Reeder GS, Chesebro JH, Bresnahan JF. Orszulak TA. Intracoronary thrombus: role in coronary occlusion complicating percutaneous transluminal coronary angioplasty. J Am Co11 Cardiol 1985;5:198-202. 2. Cameron J, Buchbinder M, Wexler L, Oesterle SN. Thromboembolic complications of percutaneous transluminal coronary angioplasty for myocardial infarction. Cathet Cardiovasc Diagn 1987;13:100-6. 3 Shapiro E, Brinker JA, Gottlieb SO, Guzman PA, Bulkley BH. Intracoronary thrombolysis 3 to 13 days after acute myocardial infarction for posinfarction angina pectoris. Am J Cardiol 1985;55:1453-8. 4. Kennedy JW, Ritchie JL, Davis KB, Fritz JK. Western Washington randomized rial of intracoronary streptokinase in acute myocardial infarction. N Engl J Med 1983;309:1477-82. 5. Kaja F, Walton JA Jr, Brymer JF, Lo E, Osterberger L, O’Neill W, Colfer HT. Weiss R, Lee T, Kurian T, Goldberg AD, Pitt B, Goldstein S. Intracoronary fibrinolytic therapy in acute myocardial infarction. Report of a prospective randomized trial. N Engl J Med 1983;308:1305-11. 6. Anderson JL, Marshall HW, Bray BE, Lutz JR, Frederick PR, Yanowitz FG, Datz FL, Klausner SC, Hogan AD. A randomized trial of intracoronary streptokinase in the treatment of acute mvocardial infarction. N Enal J Med 1983:308:1312-18. 7. Rogers WJ, Mantle JA, Hood WP J;, Baxley WA,‘Whitlow PL, Reeves RC, Soto B. Prospective randomized trial of intravenous and intracoronary streptokinase in acute myocardial infarction. Circulation 1983;68:1051-61. 8. The TIM1 Study Group. The Thrombolvsis In Myocardial Infarction (TIMI) trial. N Engl J Med 1985;312:932-6. 9. Guerci AD. Gerstenblith GG. Brinker JA. Chandra NC. Gottlieb SO, Bahr RD, Weiss JL: Shapiro EP; Flahertv JT,‘Bush DE. Chew PH, Gottlieb SH, Halperin HR, Ouyang P, Walford GD. Bell WR. Fatternacker AK. Llewellvn M. TODO~ EJ. Healv B, Siu CO, Becker LC, Weisfeldt ML. A randomized trial of intravenous tissue plasminogen activator for acute myocardial infarction with subsequent randomization to elective coromary angioplasty. N Engl J Med 1987;317:1613-18. 10. Grill HP, Brinker JA. Late thrombotic occlusion of saphenous vein grafts: successful recanalization using thrombolytic therapy. Cathet Cardiovasc Diagn 1988;15:252-9. 11. Douglas JS Jr, Lutz JF, Clements SD, Hollman J, Ischinger T. Meier B, Craver B, Craver .JM, dones EL, Wuller JL, Bone DK, -

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Guyton R. Therapy of large intracoronary thrombi in candidates for percutaneous transluminal coronary angioplasty (Abstract). J Am Co11 Cardiol 1988;11:238A. 12. Hartmann J, McKeever L, Teran J, Bufalino V, Marek J, Brown A, Goodwin M, Amirparviz F, Motarjeme A. Prolonged infusion of urokinase for recanalization of chronically occluded aortocoronary bypass grafts. Am J Cardiol1988;61:18991. 13. Chesebro JH, Knatterud G, Roberts R, Borer J, Cohen LS, Dalen J, Dodge HT, Frances CK, Hillis D, Ludbrook P, Markis JE. Mueller H. Passamani ER. Powers ER. Rao AK. Robertson T, Ross A,‘Ryan TJ, SobelBE, Willers& J, Williams DO, Zaret BL, Braunwald E. Thrombolysis In Myocardial Infarc-

clot lytic therapy pre PTCA

tion (TIMI) trial. Phase I. A comparison between intravenous tissue plasminogen activator and intravenous streptokinase. Clinical findings through hospital discharge. Circulation 1987;76:142-54. 14. Top01 EJ, Califf RM, George BS, Keveiakes DJ, Abbottsmith CW, Candela RJ, Leek L, Pitt B, Stack RS, O’Neill WW, and the Thrombolysis and Angioplasty in Myocardial Infarction study group: a randomized trial of immediate versus delayed elective angioplasty after intravenous tissue plasminogen activator in acute myocardial infarction. N Engl J Med 1987; 317581-8.

Combined treatment with vitamins experimental myocardial infarction

E and C in in pigs

The effect of two different combined treatments with vitamin E acetate and vitamin C on infarct size and recovery of regional myocardial function was investigated in ischemic, reperfused porcine hearts. The left anterior descending coronary artery was distally ligated in 30 thoracotomized pigs for 45 minutes followed by 3 days of reperfusion. Infarct size was determined as the ratio of infarcted (tetrazolium stain) to ischemic (dye technique) myocardium. Regional myocardial function was assessed by sonomicrometry. Ten pigs received vitamin E acetate (12 gm intravenously three times for 1 week) before ischemia and vitamin C (4.4 gm intravenously) before reperfusion (therapy A). Another ‘10 pigs were treated with vitamin E acetate (12 gm intraarterially) and vitamin C (4.4 gm intravenously) during ischemia (therapy B). An additional 10 pigs served as a control group. Global hemodynamics dld not differ significantly among the groups before and during ischemia. Mean plasma concentrations of vitamin E amounted to 107 pg/ml in group A, 16 pg/ml in group B, and 0.9 fig/ml in the control group at the onset of reperfusion. Therapy A reduced the size of the infarct from 73 + 12% to 47 f 16% of the region at risk (p < 0.005) and improved regional systolic shortening from 0 +- 7% to 11 + 6% at 3 days after reperfusion (p < 0.01). Therapy B decreased the size of the infarct to 64 -+ 9% of the region at risk (p = 0.05). Regional systolic shortening was not significantly improved by this treatment protocol (p = 0.18). We conclude that therapy A protects the ischemic, reperfused myocardium probably by scavenging free radicals formed during ischemia and/or during reperfusion. Results of this study do not indicate whether these radicals were generated by jeopardized myocytes or by activated inflammatory cells. Therapy B exhibited only borderline protection. These findings show that cell death of ischemic, reperfused myocytes can be reduced by appropriate treatment with pharmacologic doses of vitamin E acetate and vitamin C. (AM HEART J 1989;118:667.)

Hermann H. Klein, MD, Sibylle Pith, PhD, Stefanie Lindert, Klaus Nebendahl, MDvet, Paul Niedmann, MD, and Heinrich Giittingen,

From the Departments of Cardiology, Experimental Clinical Chemistry, University of Giittingen. Supported by a grant from the Deutsche Organprotektion, GBttingen. Received Reprint Robert 4/l/14509

Kreuzer, MD.

West Germany

for publication

Jan. 6, 1989;

Animal

Research,

Forschungsgemeinschaft, accepted

requests: Priv. Doz. Dr. H. H. Klein, Koch Str. 40, 3400 Giittingen, West

May

SFB 330,

8, 1989.

Med. Klinik Germany.

and

der UniversitBt,

In recent years results of studies that use regionally ischemic, reperfused heart preparations have suggested that the inflammatory response,lT 2 the generation of oxygen-free radicals,3-5 and the intracellular uptake of calcium6 are pathobiochemical mechanisms involved in the transition from reversible to irreversible cell damage. However, general accep667