Reduced infarct size in nonreperfused myocardial infarction by combined infusion of isosorbide dinitrate and streptokinase The value of thrombolytic therapy in myocardial infarction is well established, while any beneficial effect of adjunct therapy is more uncertain. In a double-blind, randomized, parallel-group study the effect of combined intravenous infusions of streptokinase and isosorbide dinitrate (ISDN) on enzyme-estimated infarct size was investigated. One hundred consecutive patients with strong clinical and electrocardiographic suspicion of myocardial infarction, admitted to the coronary care unit within 8 hours after the onset of symptoms, were given a streptokinase infusion of 1.5 million units for 1 hour and a titrated dose of ISDN or placebo for 48 hours. From isoenzyme B of creatine kinase (CK-B) values measured every 4 hours, the infarct size was calculated and the possible presence of reperfusion was evaluated. The infarct size in patients receiving ISDN infusion was reduced (p = 0.04, one-sided test) compared with placebo. By subdividing the patients according to whether or not reperfusion had occurred, the infarct size appeared to be similar following ISDN and placebo in patients with reperfusion (419 versus 369 U/L), whereas the infarct size in patients not reperfused was markedly reduced after treatment with ISDN (223 versus 1320 U/L, p = 0.003). In conclusion, the present study demonstrates that the infarct size may be reduced by other means than reperfusion and it supports the use of combined infusion of thrombolytic agents and nitrates in patients with suspected myocardial infarction. (AM HEART J 1992;124:1139.)

Per Hildebrandt, MD, PhD, Christian Torp-Pedersen, MD, PhD, Tomas Joen, MD, Elsebeth Iversen, MD, Gunnar Jensen, MD, Dorthe Jeppesen, MD, Thomas Melchior, MD, Hans-J#rgen Schytten, MD, Vibeke Ringsdal, MD, Jytte Jensen, MD, Frank Steensgaard-Hansen, MD, J$rgen Granborg, MD, Christian Hassager, MD, Marija Weiss, MD, and Wolfgang Ermer, MD Hellerup,

Denmark,

and Monheim,

Germany

Following the completion of several major clinical studies, the value of thrombolytic treatment in patients with acute myocardial infarction (MI) has been well estab1ished.l Infarct size2 as well as mortality rate3. 4 are reduced. Before the thrombolytic era, several drugs were tested for their ability to reduce infarct size. 5-7 Among these, nitrates were shown to reduce infarct size, as estimated by serial determinations of the MB isoenzyme of creatine kinase,“1° and a recent meta-analysis of the studies employing nitrates suggested an improvement in survival.ll From the Departments of Cardiology Hospital: and the International Medical Monheim. Received

for publication

Nov.

and Clinical Department,

6. 1991; accepted

May

Reprint requests: Per Hildebrandt, MD, Department tofte Hospital. Niels Andersens vej 65, 2900 Hellerup, 4/1/40562

Chemistry, Glostrup Schwarz Pharma AG,

Following the established use of thrombolytic agents, two new questions arise: (1) Is it possible to gain further improvement by combining thrombolysis with other drug intervention? and (2) Is it possible to reduce the infarct size in patients in whom thrombolysis has not succeeded? To approach these questions, we performed a randomized, double-blind and placebo-controlled study on the effect of intravenous isosorbide dinitrate (ISDN) on infarct size as estimated by serial determinations of the B isoenzyme of creatine kinase (CK-B) in a group of patients receiving thrombolysis within 8 hours of suspected MI. The patients were further subdivided as to whether reperfusion was likely achieved or not.

8, 1992. of Cardiology, Denmark.

Gen-

METHODS Patients. In accordance with available data,s a sample size of 100 patients was chosen to ensure at least 90 % power 1139

1140

Hildebrandt

et al.

American

Table I. Initial clinical data and data related to the infusion in the 99 patients included in the study (median and 95th percentiles) ISDN

Placebo

Initial clinical data No. 50 Age (yr) 64 (48.81) Male sex Anterior location of infarction Pain prior to 2 (l-6) admission (hr) Pain prior to ISDN 4 (2-8) infusion (hr) Previous AM1 26 5 Previous angina 36’;) History of 20T hypertension History of diabetes 6 “i mellitus History of hyper12’; cholesteremia Infusion data Duration of 48 (24-48) infusion (hr) Max dose rate 6 (2-10) (mg/hr) Total dose (mg) 240 (16-480) Premature 9”; discontinuation Side effects of 16”~’ streptokinase Use of oral 16 ‘;> nitroglycerin ISDN,

Isosorbide

dinitrate;

AMI,

49 62 (43-81)

Both

p

99 63 (44-81) 71”; 4.5 “i

0.36 0.16 0.49

2 (l-6)

2 (l-6)

0.83

4 (2-8)

4 (2-8)

0.84

24 “,m 33 ‘7 16”~

0.29 0.32 0.30

12 “i

9’r

0.28

6’;

9“c

0.31

18 (7-48)

48 (7-48)

0.24

5 (2-10)

5 (‘L-10)

0.94

192 (90-480) 16 5

222 (21.480)0.77 12’; 0.32

13’
4% of total creatine kinasell), 90 patients (44 receiving ISDN and 46 receiving placebo) were considered to have acute MI, whereas nine patients (six receiving ISDN and three receiving placebo) were not considered to have acute MI. Two patients died during the infusion (both receiving placebo) and a total of six patients died during hospitalization (two receiving ISDN and four receiving placebo). As judged by kl and the time to peak CK-B, ISDN had no apparent influence on reperfusion. Median kl

November

1142

Table

Hildebrandt

et al.

American

1992

Heart JOurnal

III. Other indicators of illness registered in the 99 study patients End

point

+ReplISDN

Nitrate therapy during infusion Development of clinical shock Heart failure at discharge Digoxin therapy at discharge ACE inhibition at discharge Nitrate therapy at discharge Ca blocker therapy at discharge Hospital mortality @-blocker at discharge Angina after 1 month Development of a Q wave Morphine consumption during infusion Furosemide dose at discharge (mg) ACE, Angiotensin-converting

enzyme;

Ca, calcium;

(mg)

+ Replplbo

12’1 5 ‘;’ 23’,> 3’,# 13’r 3’,, 18’,, 5’;. 5’r 41 (ii 61’< 12 25

other abbreviations

16’, 6’, .38 “L 21’; 12 1’; 9’, 9’r 9’, 12°C. 39”; 67°C 15 34 as in Tables

was 0.24 in the placebo group and 0.31 in the ISDN group (p = 0.89), and the median time to peak CK-B was 11 hours in both groups (p = 0.84). Excluding patients without a significant rise in CK-B did not influence the results. Treatment with ISDN resulted in an overall trend toward a smaller infarct size than placebo infusion (Table II). However, the reduction was only significant using a one-tailed test. The median difference was 142 U/L (95% confidence interval, -8 to 386). Table II and Fig. 1 also show the infarct size (Co) in the patients subdivided according to likely reperfusion (kl > 0.185). ISDN had no influence on the infarct size in patients experiencing reperfusion. However, in patients without reperfusion, infarct size was significantly reduced after treatment with ISDN (p = 0.0075). The median difference in infarct size between patients treated with ISDN and placebo was 1003 U/L (95% confidence interval, 522 to 1508). The discriminative value of kl was not critical; using a higher kl value of 0.21 resulted in 35 patients classified without reperfusion, but the difference in infarct size remained large (p = 0.008). In addition, omitting patients without significant increases in CK-B did not change the result (p = 0.008). Similarly, no difference was observed in the group of patients who were probably reperfused when these modifications were made in the calculations. Using the method of time to peak CK-B for evaluating reperfusion, 10 patients in the placebo group and 12 in the ISDN group were apparently not reperfused. The difference in infarct size, however, remained significant (p = 0.047). Table III provides secondary information. The p value indicates whether any difference was observed between the four groups (Chi square, nonparametric one-way analysis of variance). It appears that the

_-.. -ReplISDN 33