THERAPY AND PREVENTION
THROMBOLYSIS
Factors influencing probability of reperfusion with
intracoronary ostial infusion of thrombolytic agent
in patients with acute myocardial infarction
MICHAEL P. TENDERA, M.D.,* W. BARTON CAMPBELL, M.D., STANLEY N. TENNANT, M.D.,
WAYNE A. RAY, PH.D.
AND
Downloaded from http://circ.ahajournals.org/ by guest on July 12, 2017
ABSTRACT A multivariate logistic regression equation was used to evaluate variables related to
successful intracoronary thrombolytic therapy. One hundred seventeen patients with a totally occluded
infarct-related artery were randomly given ostial infusions of urokinase or streptokinase in a blinded
study. The opening rate was 57%. The agent used and time from onset of symptoms to beginning of
treatment did not significantly influence opening rate (p > .25). The site of occlusion was a strong
predictor of opening rate (p = .0004). The anterior descending coronary artery was successfully
opened more frequently than the left circumflex or right coronary artery (p = .012). Presence of
collaterals adversely affected the recanalization rate in all groups (p = .0004). These variables had an
additive effect on the probability of opening. Patients with proximal anterior descending occlusion and
no collaterals had a 90% recanalization rate, while those with distal occlusions in vessels other than the
anterior descending and with collaterals had only a 24% chance for reperfusion. Thus location of
occlusion and presence or absence of collaterals may strongly influence opening rates.
Circulation 71, No. 1, 124-128, 1985.
INTRACORONARY thrombolysis is a frequent therapeutic approach for patients in the early phase of acute
myocardial infarction. Protocols vary widely among
institutions. Important variables include dose and rate
of infusion, type of thrombolytic agent, and use of
subselective technique. Patient characteristics may
also be expected to influence opening rates. Reported
reperfusion rates range from 54% to 95%.'-"' In our
previous series of 80 patients the opening rate was
60%.12
The objective of this study was to evaluate the influence on myocardial thrombolysis of the following variables: (1) the artery involved, (2) location of the
thrombus, (3) presence or absence of collateral flow to
the obstructed artery, and (4) time from onset of symptoms to beginning of the infusion. Previous analysis
demonstrated that the thrombolytic agent used did not
influence opening rates.'2
From the Saint Thomas Hospital and Vanderbilt University School of
Medicine, Nashville.
Address for correspondence: W. Barton Campbell, M.D., Department of Cardiology, Saint Thomas Hospital, Box 380, Nashville, TN
37202.
Received April 9, 1984; revision accepted Oct. 11, 1984.
*Present address: 2nd. Department of Cardiology, Silesian Medical
School, Zabrze, Poland 41-800.
124
Methods
The study group comprised 1 17 consecutive patients (99 men
and 18 women), ages 36 to 80 years (57 + 10, mean ± SD)
who met the entry criteria. All patients had (1) onset of chest
pain less than 12 hr before the beginning of infusion, (2) ST
segment changes suggesting acute myocardial injury, (3) angiographically documented complete occlusion of the infarct related artery, and (4) no specific contraindications to thrombolytic
therapy.
After informed consent was obtained, patients with complete
occlusions were given intracoronary urokinase (Abbokinase) or
streptokinase (Streptase) at doses of 6000 or 2000 U/min, respectively, in a previously described randomized double-blind
fashion. 12 Time elapsed from the onset of chest pain to beginning of the infusion varied between 30 min and 590 min (281 ±+
102, mean ± SD). The infusion was carried out with a standard
Judkins catheter placed in the ostium of the right or left coronary
artery according to the site of the occlusion. The effect of therapy was assessed angiographically every 15 min and infusion
time was limited to 120 min.
The occlusion was considered proximal if located before the
first diagonal branch in left anterior descending artery (LAD),
the first obtuse marginal branch in the left circumflex artery
(LCX), and the acute marginal branch in the right coronary
artery (RCA). Other obstructions were defined as distal. Collaterals were regarded as present if the infarct-related artery distal
to occlusion was opacified after injection of the contrast material in the contralateral coronary vessel. No attempt was made to
quantify collateralization. The result of thrombolytic therapy
was assessed at the end of infusion. Only those patients displaying patency of the previously closed coronary artery at comple-
CIRCULATION
THERAPY AND PREVENTION-THROMBOLYSIS
Downloaded from http://circ.ahajournals.org/ by guest on July 12, 2017
tion of the infusion were considered to have had successful
openings.
Statistical analysis. Stepwise multivariate logistic regression was used to analyze the relationship between variables that
characterized the occlusion and probability of reperfusion.'3
The rationale for this analysis is twofold. First, this multivariate
analysis assesses the independent impact of each variable on
rates of thrombolysis, controlling for the effects of other variables. Second, it provides a predictive equation with which probability of reperfusion for a subgroup of patients with a specific
type of occlusion can be estimated. The concordance of predicted probabilities with actual reperfusion rates is a measure of the
variability in opening rates explained by the characteristics of
the occlusions in the multivariate analysis.
The initial model began with an equation that contained five
variables: thrombolytic agent, time, location, involved artery,
and presence or absence of collaterals and interaction among
these variables. The significance of each variable was tested
with a likelihood ratio test. 13 Variables were eliminated from the
model in a stepwise fashion until all that remained were significant at the p = .2 level. The combined significance of the final
variables in the equation (excluding the constant term) was
tested with a likelihood ratio test.
In the stratified analysis of the effect of collateralization, the
significance of the direction of within-subgroup differences was
tested with probabilities from the binomial distribution.
Results
In 66 of 117 patients (57%) thrombolytic therapy
achieved a successful recanalization of the previously
occluded vessel.
Selection of variables associated with reperfusion. No
significant interactions between the variables characterizing the occlusions were found (p > .25). The
thrombolytic agent used was not significantly associated with reperfusion (59% opening for streptokinase vs
52% for urokinase; p > .025) nor was time from onset
of pain to start of the thrombolytic therapy (268 + 99
min, mean + SD, for patients with opening vs 294 ±
98 min for those with no opening; p > .25). Moreover,
there was no significant distinction between the RCA
and LCX (46% openings for RCA, 36% for LCX; p >
.25). Hence, the final variables selected as significantly predictive of reperfusion were site of occlusion
(proximal vs distal), artery (LAD vs RCA or LCX),
and absence or presence of collaterals.
Site of occlusion. The strongest predictor of reperfusion was site of occlusion (p = .0004). Arteries with
proximal occlusions recanalized 74% of the time (45/
61) vs 38% (21/56) for distal occlusions (figure 1).
Artery occluded. The artery occluded was a strong
predictor of successful reperfusion (p = .012). The
LAD was recanalized in 74% of the patients (35/47) as
opposed to 44% (31/70) for the RCA or LCX (figure
2).
Collaterals. Presence of collaterals decreased the rate
of opening (p = .17) (figure 3). Although the signifiVol. 71, No. 1, January 1985
cance given by the multivariate logistic regression
analysis was borderline, the reperfusion rates were
consistently lower for patients with collaterals in each
of eight patient groups defined by location, artery, and
collateralization (p = .004) (figure 4). This result indicates a small, yet definite effect of collaterals.
Combined efect. Taken together, these three variables had a strong cumulative effect on reperfusion rates
(p = .0002) (figure 4). The highest rates were for
proximal occlusion of the LAD without collaterals
(90%). For distal occlusions of the RCA or LCX with
collaterals to the distal portion of the thrombosed vessel, the reperfusion rate was 24%.
Predictive equation. The multivariate logistic equation predicted well the reperfusion rates in subgroups
n=61
n=56
PROXIMAL
D STAL
Lp=00004
SITE OF OCCLUSION
D SUCCESSFUL
OPENING
DNNO OPENING
FIGURE 1. Opening rates: proximal
vs
distal occlusion.
125
TENDERA et al.
Downloaded from http://circ.ahajournals.org/ by guest on July 12, 2017
n= 47
n = I1
n=59
LAD
LCX
RCA
Lp=00~~12
for this series of patients, the observed occlusion characteristics predict well the outcome of thrombolytic
therapy. However, we did not test the predictive power
of the equation in a separate series of patients.
The higher probability of proximal thrombolysis
may be related to local availability of the thrombolytic
agent and/or plasminogen. With a distal occlusion,
penetration of the thrombolytic solution to the clot may
be decreased by a "cul-de-sac" phenomenon, producing an area of stagnant blood proximal to the thrombus2
and/or runoff through patent branches originating
proximal to the obstruction.6 7', 14 The importance of
delivering thrombolytic agent in proximity to the
thrombus has been previously emphasized.2 6. 7
The variation in opening rates of occluded arteries is
poorly understood. Weinstein,"' summarizing the ex-
1
ARTERY OCCLUDED
D
SUCCESSFUL OPENING
D
NO OPENING
FIGURE 2. Opening rates: LAD, LCX. and RCA.
of patients (p = .0002) (figure 4). For this series of
patients the equation was:
exp(Z)
1 + exp(Z)
where Z
1.287 + 1.182XA + 1.514XL +
0.651 XC, with XA = 1 for LAD, XA = 0 for RCA or
1 for proximal, XL = 0 for distal locaLCX, XL
XC
1
for no collaterals, and XC = 0 for
tion,
present collaterals. 14 For example, the predicted rate in
the most successful subgroup was 89% (observed
90%), and 22% in the least successful subgroup (observed 24%) (table 1).
Discussion
Close concordance of the observed reperfusion rates
with those predicted by the logistic model shows that
126
COLLATERALS COLLATERALS
ABSENT
PRESENT
L p =0.17
COLLATERALS
D
SUCCESSFUL OPENING
D
NO OPENING
FIGURE 3. Opening rates: angiographically demonstrable collateral
flow vs no angiographically demonstrable collateral flow.
CIRCULATION
THERAPY AND PREVENTION-THROMBOLYSIS
REPERFUSION RATES BY PATIENT GROUPOBSERVED AND PREDICTED
00
80
D
OBSERVED
D
PREDICTED
t&j
K
IR
60
40
EI1I7
20
Downloaded from http://circ.ahajournals.org/ by guest on July 12, 2017
-
PAT/ENT GROUP
LEGEND
LAD= LEFT ANTERIOR DESCENDING
COL = COLLATERALS
FIGURE 4. Opening rate variation in patient
collaterals.
groups
compared with opening rate predicted by regression equation. COL
perience of several centers, noted opening rates for the
LAD, LCX, and RCA of 79%, 80%, and 78%. Merx
et al.'5 and Cowley and Gold6 found recanalization
rates for the LAD and RCA to be similar, but higher
than for the LCX. However, these studies included
patients with incomplete occlusions, and in some, subselective coronary infusion was used. Our results were
similar to the recent findings of Berte et al. 16 and Giambartolomei et al.'7
We can offer only hypotheses as to the reasons for
these differences. With ostially perfused LCX occlusions there is always a considerable runoff of the
TABLE 1
Observed and predicted probability of coronary artery opening
with thrombolytic therapy in subgroups according to location of
occlusion, artery involved, and presence or absence of collaterals
Probability of
opening
Location
Artery
Proximal LAD
LCX or RCA
Distal
LAD
LCX or RCA
Collaterals
No
Yes
No
Yes
No
Yes
No
Yes
Vol. 71, No. 1, January 1985
n
19
9
17
16
12
7
16
21
Observed Predicted
.895
.778
.706
.563
.667
.429
.417
.238
.887
.804
.706
.557
.633
.474
.346
.216
=
thrombolytic agent through the LAD. The left Judkins
catheter may selectively direct flow to the LAD. The
RCA would appear to have the least runoff of thrombolytic solution proximal to the occlusion. As noted by
Ganz et al. ,2 a column of stagnant blood proximal to
the thrombus is common in the RCA. Both the RCA
and LCX may have less motion than the LAD because
of their location in the atrioventricular groove.
Although collateral flow may prolong myocardial
viability and improve the functional result of reperfusion, 1-21 the tendency of collaterals to decrease the
likelihood of recanalization has not been previously
described.
Absence of collateral flow should allow a greater
pressure gradient across the thrombus. Angiographically inapparent perfusion in or around the thrombus
resulting in enhanced permeation of the thrombolytic
agent is a possible result. An alternative explanation
may be that the mechanism of occlusion is influenced
by collateral flow, resulting in a more prolonged process with a relatively smaller zone of thrombus in the
occluded artery.
In multivariate analysis with time treated as a continuous value, time was not a predictor of opening.
This corroborates the observation of Lee et al.23 24 that
although older thrombi may require higher doses and
more time to dissolve, opening rates are similar.
127
TENDERA et al.
Our analysis suggests stratification of candidates for
thrombolytic therapy according to reperfusion probability. This probability is high (86%) for proximal
LAD occlusions. When the thrombus is present in the
proximal portion of the RCA or LCX or in the distal
segment of LAD, probability of successful opening is
intermediate (64%, 60%, and 58%) but still in a range
presented in the literature. 1` Distal occlusions of the
LCX and RCA are associated with a low probability of
reperfusion. Presence of collateral flow consistently
diminishes the likelihood of opening in all subgroups.
11.
12.
13.
14.
We thank Dr. Henry S. Jennings Ill for review of the
manuscript and Mrs. Marjorie Stratton for preparation of
the manuscript.
15.
References
16.
Downloaded from http://circ.ahajournals.org/ by guest on July 12, 2017
1. Reduto LA, Smalling RW, Freund GG, Gould KL: Intracoronary
infusion of streptokinase in patients with acute myocardial infarction: effects of reperfusion on left ventricular performance. Am J
Cardiol 48: 403, 1981
2. Ganz W, Buchbinder N, Marcus H, Mondkar A, Maddahi J, Charuzi Y, O'Connor L, Shell W, Fishbein MC, Kass R, Miyamoto A,
Swan HJC: Intracoronary thrombolysis in evolving myocardial
infarction. Am Heart J 101: 4, 1981
3. Ganz W, Ninomiya K, Hashida J, Fishbein MC, Buchbinder N,
Marcus H, Mondkar A, Maddahi J, Shah PK, Berman D. Charuzi
Y, Geft I, Shell W, Swan HJC: Intracoronary thrombolysis in acute
myocardial infarction: experimental background and clinical experience. Am Heart J 102: 1145, 1981
4. Ganz W, Geft I, Maddahi J, Berman D, Charuzi Y, Shah PK.
Swan HJC: Nonsurgical reperfusion in evolving myocardial infarction. J Am Coll Cardiol 1: 1247, 1983
5. Rentrop P: Mortality and functional changes after intracoronary
streptokinase infusion. Circulation 66 (suppl Il): II-335, 1982
(abst)
6. Cowley ML, Gold HK: Use of intracoronary streptokinase in acute
myocardial infarction. Mod Concepts Cardiovasc Dis 51: 97, 1982
7. Cowley MJ: Methodologic aspects of intracoronary thrombolysis:
drugs, dosage and duration. Circulation 68 (suppl I): 1-90. 1983
8. Fioretti P, Serruys PW, van den Brand M, Hooghoudt T. Fels PW,
Simoons ML, Meltzer L. Hugenholtz PG: Incidence of recurrent
myocardial ischemia after intracoronary fibrinolysis in acute myocardial infarction. Am J Cardiol 49: 974, 1982 (abst)
9. Kahja F, Walton JA Jr, Brymer JF, Lo E, Osterberger L, O Neil
WW, Colfer HT, Weiss R, Lee T, Kurian T, Goldberg AD, Pitt B:
Intracoronary fibrinolytic therapy in acute myocardial infarction:
report of a prospective randomized trial. N Engl J Med 308: 1305,
1983
10. Anderson JL, Marshall HW. Bray BE, Lutz JR, Frederick PR,
Yanowitz FG, Datz FL. Klausner SC. Hagan AD: A randomized
128
17.
18.
19.
20.
21.
22.
23.
24.
trial of intracoronary streptokinase in the treatment of acute myocardial infarction. N Engl J Med 308: 1312, 1983
Weinstein J: The international registry to support approval of intracoronary streptokinase thrombolysis in the treatment of myocardial
infarction: assessment of safety and efficacy. Circulation 68 (suppl
I): 1-61, 1983
Tennant SN, Dixon J, Venable TC, Page HL, Roach A, Kaiser
AB, Frederiksen RT, Tacogue L, Kaplan P, Babu NS, Anderson
EE, Wooten E, Breinig JB, Campbell WB: Intracoronary thrombolysis in acute myocardial infarction: comparison of the efficacy of
urokinase to streptokinase. Circulation 69: 756, 1984
Engelman L: Stepwise logistic regression. In Dixon WJ, editor:
BMDP statistical software. Berkeley, 1983, University of California Press, pp 330-344
Braunwald E: Thrombolytic therapy in patients with acute myocardial infarction: summary and comments. Circulation 68(suppl I): 167, 1983
Merx W, Doerr R, Rentrop KP, Blanke H, Darsch KR, Mathey
DG, Kremer P, Rutsch W, Schmutzler J: Evaluation of the effectiveness of intracoronary streptokinase infusion in acute myocardial infarction: postprocedure management and hospital course in
204 patients. Am Heart J 102: 1181, 1981
Berte LE, Jutzy KR, Alderman EL, Miller RG, Friedman JP,
Creger WP, Eliastam M: Randomized comparison of intravenous
and intracoronary streptokinase early post myocardial infarction.
Circulation 68(suppl III): 111-1 19, 1983 (abst)
Giambartolomei A, Esente P, Gensini G, Dator C: Acute recanalization of the right coronary artery: description of the new technique
of catheterization. Circulation 68(suppl IIi): 111-208, 1983 (abst)
Schaper W, Pasyk S: Influence of collateral flow on the ischemic
tolerance of the heart following acute and subacute coronary occlusion. Circulation 53(suppl I): 1-57, 1976
Jennings RB. Reiner KA: Factors involved in salvaging ischemic
myocardium: effect of reperfusion of arterial blood. Circulation
68(suppl I): 1-25, 1983
Rentrop P, Blanke H, Karsch KR, Rutsch W, Schartl M. Merx W,
Doerr R, Mathey D, Kuck K: Changes in left ventricular function
after intracoronary streptokinase infusion in clinically evolving
myocardial infarction. Am Heart J 102: 1188, 1981
Mehmel HC, Schwarz F, Schuler G, Maurer W, Tillmans H,
Senges J, Kuebler W: The functional result of intracoronary streptokinase therapy after myocardial infarction may be determined by
collaterals. Circulation 64(suppl IV): IV-194, 1981 (abst)
Schwarz F, Schuler G, Katus H, Mehmel HC, von Olshausen K,
Hoffman M, Herrmann HJ, Kuebler W: Intracoronary thrombolysis in acute myocardial infarction: correlations among serum enzyme, scintigraphic and hemodynamic findings. Am J Cardiol 50:
32. 1982
Lee G, Amsterdam EA, Low R, Joye JA, Kimchi A, DeMaria AN,
Mason DT: Efficacy of percutaneous transluminal coronary recanalization utilizing streptokinase thrombolysis in patients with acute
myocardial infarction. Am Heart J 102: 1159, 1981
Lee G, Joye JA, Amsterdam EA, Low R, DeMaris AN, Krieg P.
Mason DT: Determinants of beneficial coronary streptokinase therapy in acute myocardial infarction: success and rapidity of thrombolysis depends on minimal time from symptom onset to treatment.
Am J Cardiol 49: 973, 1983 (abst)
CIRCULATION
Factors influencing probability of reperfusion with intracoronary ostial infusion of
thrombolytic agent in patients with acute myocardial infarction.
M P Tendera, W B Campbell, S N Tennant and W A Ray
Downloaded from http://circ.ahajournals.org/ by guest on July 12, 2017
Circulation. 1985;71:124-128
doi: 10.1161/01.CIR.71.1.124
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1985 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539
The online version of this article, along with updated information and services, is located on
the World Wide Web at:
http://circ.ahajournals.org/content/71/1/124
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally
published in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the
Editorial Office. Once the online version of the published article for which permission is being requested is
located, click Request Permissions in the middle column of the Web page under Services. Further
information about this process is available in the Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Circulation is online at:
http://circ.ahajournals.org//subscriptions/