Clinical course and left ventricular function in patients with acute myocardial infarction following delayed recanalization of infarct-related artery

International Journal of Cardiology, 41 (1993) 49-57

Clinical course and left ventricular function in patients with acute myocardial infarction following delayed recanalization of infarct-related artery David G. Iosseliani*, Inna I. Inoyatova, Prasanta Kumar Bhattacharya, Eygena I. Yarlikova Department of Emergency and Interventional Cardiology, BakulevS Institute of Cardiovascular Surgery. Leninsky Avenue 8. I 17931 Moscow, Russian Federation

(Received 19 January 1993; revision accepted 22 March 1993)

Abstract The effect of delayed recanalisation of the infarct related artery on clinical course and left ventricular functions was studied in 23 patients with acute myocardial infarction (Group 2). Another 82 patients with acute myocardial infarction served as controls: 48 patients with immediate recanalisation of the infarct related artery following intracoronary thrombolytic therapy (Group 1) and 34 patients with unsuccessful thrombolysis with the artery remaining occluded on repeat angiography (Group 3). Baseline clinical characteristics and left ventricular ejection fractions in the three groups did not differ statistically. Following intracoronary thrombolysis the clinical features and left ventricular functions in the three groups, respectively were as follows: post infarction angina - 45X%, 13.1% and 11.8% ( 1 vs. 2 and 3, P < 0.05); reinfarction - 29.2%, 8.7% and 11.8% (1 vs. 2 and 3, P < 0.05); mortality - O%, 0% and 11.8% (1 and 2 vs. 3; P < 0.05); aneurysm - 16.7%, 21.7% and 52.9% (1 and 2 vs. 3, P < 0.05); heart failure - 20.8%~. 21.7% and 47.1% (1 and 2 vs. 3, P < 0.05). Left ventricular ejection fractions on the second and on days lo- 14 were, respectively, 47.6 + l.l%, 42.8 f 1.1% and 39.2 f 1.6% (1 vs. 2 and 3, P < 0.05) and - 52.1 f l.O%, 48.9 + 1.1% and 44.3 f 1.5% (1 and 2 vs. 3, P < 0.05). Thus following delayed recanalisation of the infarct related artery the clinical course and left ventricular function improved significantly in comparison to patients without recanalisation. Key words: Acute

myocardial

infarction;

Intracoronary

1. Introduction Following the pioneering works of Chazov et al. [l] and Rentrop et al. [2], since the early 198Os, intracoronary thrombolytic therapy has been con-

thrombolytic

therapy;

Delayed

recanalisation

sidered as an established form of therapy in selected groups of patients with acute myocardial infarction. Over the years, a large number of clinical trials [3-161 have shown that successful intracoronary thrombolytic therapy, when carried

* Corresponding author. 0167-5273/93/$06.00 0 1993 Elsevier Scientific Publishers Ireland Ltd. All rights reserved SSDI 0167-5273(93)001753-K

50

D.G. Iosseliani et uL/Int.

out in the first 6 h of onset of symptoms, has some advantages over conventional therapy in the treatment of acute myocardial infarction in terms of improvement in left ventricular functions, in reducing the incidence of reinfarction and in increasing survival. These benefits are believed to occur mainly as a result of restoration of antegrade blood flow through the infarct related artery, which in turn leads to limitation of infarct size by salvaging the jeopardised periinfarct zone, subsequently resulting in restriction of infarct expansion and improved left ventricular remodeling f 17-201. Additionally, several other clinical trials and experimental works [21-251 have shown that thrombolytic therapy, when successful, started well after the conventional 6-h time-window, also leads to improved left ventricular functions and reduced mortality as compared to conventional therapy. This is thought to result from mechanisms other than from limitation of infarct size, because antegrade blood flow through the infarct related artery in these cases occurs well after the infarct zone had undergone irreversible necrosis [20,26-281. Moreover, in several other trials, including one of ours [3,29-313 it was-observed that following intracorona~ thrombolyic therapy, the infarct re-

J. Curdiol. 41 11993)

lated artery which failed to recanalise during the time of thromboIytic therapy, in certain cases (8-27%) is found to be open on repeat coronary an~ography or on autopsy, performed after a few days. Whether this delayed recanalisation has any beneficial effect on the clinical course and prognosis, as well as on the left ventricular functions, is not clear. Our present work was directed towards studying the effects of delayed recanalisation of the infarct related artery on the clinical course and prognosis, as well as on the left ventricular functions, in patients with acute myocardial infarction. 2. Materials and methods 2.1. Patient selection For the present study 105 patients with acute transmural myocardial infarction, who had a totally occluded infarct related artery prior to intracoronary thrombolytic therapy and in whom coronary angiography was repeated prior to discharge from the hospital (mostly at the end of second week) were selected from a total of 277 patients with acute myocardial infarction, who underwent coronary angiography within 6 h of

Total Patients with Emergency Coronary Angiogrephy (n = 277)

Patients with lntracoronary Thrombolytic Therapy (n = 137)

Patients with Repeat Coronary Angiography (n = 105)

Group 1 (+/+I

Group 2 (-I+)

49-57

Group 3 (Controls) W-1

Fig. 1. Plan of patient selection.

W-1

L).G. losseliani et dllnt.

J. Cardid. 41 (1993) 49-57

onset of symptoms with or without subsequent thrombolytic therapy (Fig. 1). All patients were males, aged 37-62 years (mean 51.2+1.3 years). Diagnosis of acute myocardial infarction was made on the basis of (1) typical angina1 chest pain > 30 min, unrelieved by rest or sublingual nitroglycerine, (2) typical electrocardiographic (ECG) changes of acute myocardial infarction, and (3) elevation of creatine phosphokinase and/or its isoenzyme CK-MB. All patients, satisfying these criteria and presenting within 6 h of onset of symptoms, immediately underwent coronary angiography followed by intacoronary thrombolytic therapy, where indicated. Based on the condition of the infarct related artery on the post-thrombolytic and repeat angiograms, the patients were divided into three groups. (1) Successful thrombolysis with maintenance of patency of the infarct related artery on repeat angiography: Group 1 (n = 48). (2) Unsuccessful thrombolysis followed by delayed recanalisation of the infarct related artery on repeat angiography: Group 2 (n = 23). (3) Unsuccessful thrombolytic therapy with persistently occluded infarct related artery on repeat angiography: Group 3 (n = 34). Groups 1 and 3 served as controls.

51

been identified a bolus dose of 200 pg of nitroglycerine was administered through the same catheter to rule out the possibility of coronary spasm mimicking occlusion. Next, a bolus dose of 50 000 Avelesin, units of streptokinase (Streptase, Celiaza) was administered through the catheter, followed by a continuous infusion of 250 000 units of thrombolytic agent through the same catheter with the help of an infusomat over a period of 1.5 h. During this process the infarct related artery was opacified every 15 min to see if recanalisation had taken place. After the full dose of thrombolytic agent had been administered, the infarctrelated artery was again opacified by contrast material. If the part of the artery, distal to the occlusion was not opacified, the thrombolytic procedure was considered unsuccessful. Eiectrocardiography

Electrocardiograms were recorded in the standard 1Zlead manner in all patients on admission, before and immediately after coronary angiography and intracoronary thrombolytic therapy. This was followed by daily recording while the patient remained in the intensive coronary care unit, and thereafter at least three times a week till discharge.

2.2. Coronary angiogra~hy Creatine phosphokinase

Coronary angiography in all studied patients was performed twice: (1) at the time of hospitalisation; and (2) mostly at the second week (in average between lo-14 days). In all the patients coronary angiography was performed by Judkins method [32]. Left ventriculography was done in the 30” right anterior oblique projection. Left coronary artery was viewed in four projections and right coronary artery was viewed in two (45” left anterior oblique and 0” anterio-posterior) projections. Angiograms were read by two observers independently.Acute occlusion was said to be present when an angiographically abrupted coronary artery was seen without collaterals to its distal part. Inrracoronary thrombolytic therapy

After the occluded infarct related artery had

Serum creatine phosphokinase was estimated on admission, prior to cardiac catherisation and thrombolytic therapy, and thereafter every 3 h for the next few days till the serum enzyme levels returned to the normal baseline value of 20.0- 134.0 units/l. Echocardiography

M-mode and two dimensional echocardiographic examinations were carried out in all the patients on admission, after 24-36 h and and again lo-14 days later. Global. left ventricular ejection fraction was calculated by the method of Simpson. Results were analysed using the two tailed Student’s test in order to calculate statistical significance.

D.G. Iosseliani et aL/Inr. J. Cardiol. 41 (IV931 4Y-ST

52

Table 1 Baseline clinical characteristics of the patients studied Characteristic

Mean age (years) Smokers Arterial hypertension Family history of IHD Acute MIa Previous MI Location of infarct Anterior Posterior Mean time to intracoronary

Patient group

f-value

Group 1 (n = 48)

Group 2 (n = 23)

(n = 34)

52.8 zt 1.9 40 (83.3%) 22 (45.8%) 16 (33.3%) 22 (45.8%) 4 (8.3%)

52.0 l 1.2 18 (78. 3%) 8 (34.9%) 6 (26.1%) 10 (43.5%) 2 (8.7%)

51.6 l 1.3 30 (88.2%) IO (29.4%) 12 (35.3%) 14 (41.25%) 4 (11.8%)

NS NS NS NS NS NS

34 (70.8%) 14 (29.2%) 4.7 f 1.2

II (47.8%) I2 (52.2%) 4.3 f 0.9

20 (58.8”/1) 14 (41.2%) 4.6 f 1.2

NS NS NS

Group 3

IHD, ischemic heart disease; MI, myocardial infarction. aAs the first manifestation of ischemic heart disease.

Table 2 Coronary anatomy of the patients studied Characteristic

Patient group Group I (n=48)

Average number of diseased coronary arteries Infarct related artery Left anterior descending Left circumflex Right coronary artery Site of occlusion Proximal third Middle third Distal third Disease type One-vessel Two-vessel Three-vessel “P-value of I and 2 vs. 3. bP-value of I vs. 2.

P-value Group 2 (n = 23)

Group 3 (n = 34)

1.9 f 0.1

I.7 f 0.1

1.9 f 0.1

NS

32 (66.7%)

IO (43.5%)

20 (58.8%)

NS

I6 (33.3%)

38 (79.2%) IO (20.8%)

24 (50.0”/;,) 10 (20.8%) 14 (29.2%)

5 (21.7%) 8 (34.9%)

6 (I 7.6%)) 8 (23.6”W

NS NS

I7 (73.9%) 5 (21.7%) -

28 (82.3%) 4 (11.8%) 2 (5.Y!,)

NS

13 (56.5%) 5 (21.7%) 5 (21.7%)

8 (23.6’%,) 20 (58.8%) 6 (17.6%)

< 0.058, NSb < 0.05”, NSb NS

NS NS

D.G. Iosseliani

et al./lnr.

J. Curdiol.

41 (1993)

53

49-57

3.3. Left ventricular ejection fraction changes The baseline left ventricular ejection fraction in the three groups were similar (42.1 f 1.5%; 41.8 f 1.5% and 41.4 f 1.6%, respectively, P > 0.05). The changes in left ventricular ejection fraction in the different groups are shown in Table 4. Left ventricular ejection fraction, measured 24-36 h later, showed that in Group 1 it rose significantly from the baseline value (42.1 f 1.5% to 47.6 + 1.15, P < 0.05). at the same time in Groups 2 and 3 this change at 24-36 h was statistically not significant (Group 2. 41.8 f 1.5% to 42.8 f 1. lo/o, P > 0.05 and Group 3, 41.4 f 1.6% to 39.2 f 1.6%; P > 0.05). The left ventricular ejection fractions at 24-36 h between Groups 2 and 3 were similar (P > 0.05) while in Group 1 it was significantly higher than in these two groups (P < 0.05). On days 10-14, the left ventricular ejection fraction in both Groups 1 and 2 rose significantly from the respective values at 24-36 h (Group 1, 47.6 f 1.1% to 52.1 f 1.05, P < 0.05; Group 2:42.8 f l.l”/o to 48.9 f 1.1% P < 0.05), while in Group 3 this rise was insigniticant (39.2 f 1.6”/0to44.3 f 1.5% P > 0.05). The mean left ventricular ejection fractions on days lo-14 in Groups 1 and 2 were similar (P > 0.05) and these were significantly higher than the corresponding value in Group 3 (P < 0.05).

3. Results

3.1. Clinical characteristics Baseline clinical characteristics of the patients in the three groups were similar (Table 1). However, analysis of the angiographic data (Table 2) showed that the incidence of single vessel disease was significantly higher in Groups 1 and 2 (54.2% and 56.5%, respectively) as compared to Group 3 (23.6%), (1 and 2 vs. 3, P < 0.05); and the incidence of two-vessel disease was significantly higher in Group 3 (58.8%) as compared to the other two groups (20.8% and 21.7%, respectively), (1 and 2 vs. 3, P < 0.05). The other angiographic characteristics in the three groups were similar. 3.2. Time course of creatine phosphokinase

activit?

in blood

The mean value of creatine phosphokinase in Groups 2 and 3 were respectively, 1723 f 67.3 and 1721 f 88.6 units/l, while in Group 1 this value was much lower (1416 f 83.9 units/l). The time from onset of symptoms to peak creatine phosphokinase value was longer in Groups 2 and 3 (18.3 f 1.4 and 23.1 f 1.8 h, respectively) in comparison to Group 1 (14.5 f 1.2 h). These are shown in Table 3. Further, in Group 1 the mean creatine phosphokinase value rose sharply from 6 h. reaching a sharp peak at 14.5 h and thereafter descended steadily to reach the baseline value by 48 h. On the other hand, in Groups 2 and 3, it rose by 6-9 h, the peak plateaued later (18.3 and 23.1 hours, respectively) and it reached the baseline by the end of the fourth and fifth days, respectively.

Table 3 Peak creatine

phosphokinase

Parameter

Peak CPK level (units/l) Mean time to CPK peak (h) “P-value of 1 vs. 3. bP-value of I vs. 2. cP-value of 2 vs. 3.

(CPK) level and time to creatine Patient

group

Group

1

The clinical course was uncomplicated in a significantly higher number of patients in Groups 1 and 2 (66.7% and 56.5%, respectively) as compared to Group 3 (29.4%); (1 and 2 vs. 3 P < 0.05).

phosphokinase

1.2

peaking

in different

groups f-value

Group

1416.7 + 83.9 14.5 f

3.4. Outcome

2

Group

1723.1 + 67.3 18.3

l

1.4

3

1721.2 zt 88.6 23.1 * I.8

NS <0.05”,

NSh,<

D.G. Iosseliuni et alAnt. J. Cardiol. 41 (1993) 49-57

54

Table 4 Mean left ventricular

ejection

fraction

in the different

groups

during

Left ventricular ejection fraction

Patient

group

(%)

Group

I

Group

Baseline

42.1 f

1.5

41.8

At 24-36 h Days IO-14

47.6 f I.1 52.1 f 1.0

“P-value bP-value

of I vs. 2 and 3. of 2 vs. 3.

‘P-value dP-value

of I and 2 vs. 3. of I vs. 2.

of in-hospital

complications

Characteristic

Number

Uncomplicated clinical course Reinfarction Postinfarction angina Postinfarction aneurysm Congestive heart failure Mortality “P-value of I bP-value of I ‘P-value of 2 dP-value of 2

in the different

and vs. and vs.

2 vs. 3. 2. 3 vs. I. 3.

period P-value

l

2

Group

1.5

41.4 f

42.8 f I.1 48.9 f I.1

Among the complications postinfarction aneurysm and congestive heart failure occurred significantly less in Groups 1 and 2 as compared to Group 3 (aneurysm, 16.7% and 21.7% vs. 52.9% and congestive heart failure, 20.8% and 2 1.7% vs. 47.1%; 1 and 2 vs. 3 P c 0.05 in both instances). While there were no in-hospital deaths in Groups 1 and 2, in Group 3 mortality during the inhospital period was 11.8% (1 and 2 vs. 3, P c 0.05) (Table 5). However, the incidence of postinfarction angina and reinfarction were similar in Groups 2 and 3 (postinfarction angina, 13.1% and l.S%, respectively; reinfarction, 8.7% and 11.8%, respectively) and at the same time significantly lower than in Group 1, where the incidences of

Table 5 Incidence

in-hospital

3

1.6 39.2 f I.6 44.3 f I.5

NSb NSd

postinfarction angina and reinfarction respectively 25.0% and 29.2%.

Our results demonstrated that delayed recanalisation of the infarct related artery after unsuccessful intracoronary thrombolytic therapy took place in 23 out of 105 patients studied (20.1% cases). These findings are in accordance with the results of other workers [29,30], who have also noted delayed recanalisation of the infarct-related artery in 8 to 25% of cases after unsuccessful reperfusion therapy. However, it still remains unclear, whether such delayed recanalisation is the result of

groups

of patients

(%)

P-value

Group 2 (n = 23)

Group 3 (n =34)

32 I4 I2 8 IO

I3 2 3 5 5

IO (29.4) 4 (11.8) 4 (11.8) I8 (52.9) 16 (47.1) 4(11.8)

(56.5) (8.7) (13.1) (21.7) (21.7)

were,

4. Discussion

Group I (n = 48) (66.7) (29.2) (25.0) (16.7) (20.8)

NS <0.05”, <0.05c.

<0.05”, <0.05c, <0.05’. <0.05”. <0.05” <0.05”’

NSb NS” NSd NSb NSb

D.G. losseliuni et al./Inr. J. Cardiol. 41 (1993) 49-57

late effect of the thrombolytic agents or a spontaneous restoration of antegrade blood flow through the infarct-related artery. However, considering the fact that several workers [33-361 have observed a similar phenomenon of spontaneous recanalisation after a variable time (hours or days) following acute myocardial infarction in those patients who did not receive any thrombolytic therapy, we can presume that this delayed recanalisation, as noted by us as well as by others (29,301, occurring after unsuccessful reperfusion therapy, is probably not dependent on thrombolytic therapy. Nevertheless, this aspect is open for further investigations. In our study, although the time to peaking of creatine phosphokinase in the group with delayed recanalisation was shorter than in the group without recanalisation, the peak creatine phosphokinase values in both these groups were very similar. In contrast, in the group with successful thrombolysis the peak creatine phosphokinase level was much lower than in the former two groups. If the peak creatine phosphokinase value is taken as an index of infarct size [37,38], it is evident that in the groups with delayed recanalisation as well as in that without recanalisation, the infarct sizes were similar, i.e., delayed recanalisation of the infarct-related artery fails to limit infarct size; while early recanalisation does lead to limitation of infarct size. Further, in the groups with unsuccessful recanalisation as well as in that with delayed recanalisation the left ventricular ejection fraction, measured 24-36 h after the onset of disease did not change signi~cantly from their respective base-line values; in contrast, in the group with successful recanalisation, the left ventricular ejection fraction rose significantly by 24-36 h from the baseline level. This indicates that infarct size limitation is associated with early improvement in left ventricular function, while failure in infarct limitation is associated with failure in early improvement of left ventricular function. Our results also show that changes in left ventricular ejection fraction by days lo-14 in the groups wjthout recanalisation and with delayed recanalisation were quite different: while in the group with delayed recanalisation it rose signi~cantly to attain a value similar to that in the group with suc-

55

cessful recanalisation (P > 0.05), in the group without recanalisation the left ventricular ejection fraction failed to show any significant increase even by days lo- 14. Further, we have also noted that the course of disease was uneventful in a si~i~cantly higher number of cases in the groups with antegrade blood flow through the infarct related artery, both following acute and delayed recanalisation. These two groups also had significantly lower incidences of post-infarction aneurysm formation and congestive heart failure as compared to the group without antegrade blood flow through the infarct related artery. This can be explained from the fact that following early and successful thrombolysis antegrade blood flow through the infarct related artery protects the myocardium surrounding the infarcted zone from irreversible necrosis for a period of time. However, it is also known that following reperfusion there always remains a significant, if not critical, residual stenosis at the site of previous occlusion. Consequently, the periinfarct zone, supplied by this stenosed artery, remains jeopardised and is prone to ischemia. It results sometimes in incidences of postinfarction angina and/or reinfarction in patients with early successful reperfusion. On the other hand, when thrombolytic therapy is unsuccessful or when recanalisation occurs late, the infarct zone undergoes irreversible necrosis within a variable time interval (about 6 h). If delayed recanalisation takes place after this, there probably no longer remains any significant zone of viable but jeopardised and ischemic periinfarct zone in the vascular bed of the infarct related artery, and hence, the incidence of post infarction angina and/or reinfacrtion is much less. However, the incidences of reinfarction and post-infarction angina were significantly higher in the group with successful reperfusion (Group 1f as compared to the other two groups. Thus it is seen that following defayed recanalisation, the improvement in left ventricular ejection fraction was similar to that as after successful thromboly~ic therapy and reached a value significantly higher than in the group without recanalisation. However, this improvement was slower than in the group with successful reperfu-

D.G. Iosseliuni et al./lnt. J. Cardiol. 41 (19931 49-57

56

sion. This slow response in the improvement of myocardial function may be due to myocardial stunning (271. Secondly, it is also possible that following delayed recanalisation the antegrade blood flow improves the function of the periinfarct zone, although it is unable to restrict the infarct size. The incidence of complications was less after delayed recanalisation or after successful reperfusion therapy, when compared to the group without antegrade blood flow. However, the significantly higher incidences of postinfarction angina and reinfarction following successful reperfusion therapy in comparison to delayed recanalisation suggests that, although early reperfusion salvages myocardium and limits infarct size, the myocardiurn still remains jeopardised and is prone to ischemia. In contrast, following delayed recanalisation, although myocardial salvage do not take place, the susceptibility of the periinfarct zone for ischemia (post infarction angina and/or reinfarction) is significantly reduced.

8

9

10

II

12

13

I4

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I9

20

21

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