CURRENT THEXAPEUTIC RESEARCH” VOL. 58, NO. 9, SEPTEMBER 1997

LONG-TERM EFFECTS ON LEFT VENTRICULAR FUNCTION AFTER LATE THROMBOLYSIS IN PATIENTS WITH

MYOCARDIAL INFARCTION

ANTONIO LIGUORI,l FERNANDO DI GREGORI0,1~2 MAURIZIO LECCESE,3 ANGELO MONTEMAIWNO; NICOLA DI IESO,’ LUIGI MAN,%,1

AND CLAUDIO NAPOLI’

‘Division of Cardiology-CCU, Pellegrini Hospital, Naples, ‘The Division of Nuclear Medicine, University of Naples, Naples, 3Department of Medicine, Policlinico Casilino,

Rome, and 4Medieal Direction, Pellegrini Hospital-ASL 1, Naples, Italy

ABSTRACT

This open-label, uncontrolled, retrospective study assessed the long-term effects of late thrombolysis on left ventricular (LV) func- tion. We studied 79 patients (62 men and 27 women; mean age, 51 t 6 years) treated with alteplsse (group 1) and 46 patients (33 men and 13 women; mean age, 52 * 8 years) treated with heparin alone (group 2) at their first myocardial infarction (MI). Patients were eligible for the study if they were younger than 62 years, their du- ration of pain was longer than 6 hours, and they had no episodes of angina in the 48 hours preceding their MI. The peak of creatine hinase-muscle and braiu subunits was significantly less in group 1 than group 2 (106 * 67 vs 206 * 102 IU/L). Both LV ejection fraction and wall-motion score were better in thrombolysed patients, and the cumulative frequency of radionuclide defects was higher in these patients during the g-year follow-up. Our study supports the concept that thrombolysis reduces the incidence of long-term post-MI re- sidual ischemia, improving global LV function even when given late after the onset of MI symptoms. Keg worda: thrombolysis, myocar- dial infarction, regional function, left ventricular function, myocar- dial ischemia.

INTRODUCTION

The effects of late coronary reperfusion after myocardial infarction (MI) are still unclear.’ Although the survival benefit from thrombolysis persists with administration up to 12 hours after onset of MI symptoms,2 the most advantageous effects on the 30-day clinical outcome are observed when thrombolysis is begun within 2 hours.3 In patients thrombolysed within 20 hours, we have previously reported preliminarily a reduced long-term mor- tality (up to 4 years) compared with patients treated with heparin alone.4s5

Address correspondence to: Antonio Liguori, MD, Chief, Division of Cardiology-CCU, Pellegrini Hospital, via A. Albino, 15, 80127 Naples, Italy. Received for publication on June 3, 1997, Printed in the U.S.A. Reproduction in whole or part is not permitted.

570 ooll-393xEm3.50

A. LIGUORI ET AL.

In this retrospective study, we investigated the long-term effects of throm- bolysis on left ventricular (LV) function in MI patients.

We studied retrospectively 125 consecutive patients admitted from 1991 to 1993 to the coronary care unit (Pellegrini Hospital, Naples, Italy) with their first MI and treated with alteplase* (tissue plasminogen activator) (group 1, n = 79) or heparin alone (group 2, n = 46). Sixty milligrams of alteplase was infused intravenously (IV) during the first hour: 10 mg was adm~istered as an initial bolus twice at 20-minute intervals followed by 40 mg as a continuous IV infusion. During the subsequent 1.5 hours, an additional 40 mg of alteplase was administered (total dose, 100 mg). Pa- tients were eligible for the study if they were younger than 62 years, their duration of pain was longer than 6 hours, and they had no episodes of angina in the 48 hours preceding their MI. Physicians assessing the re- sponse to therapy were masked as to treatment (thrombolysis or heparin). The efficacy of thrombolysis, in terms of achieved patency, was assessed by using noninvasive criteria: decrease in chest pain, continuous improve- ment by ST segment monitoring,6 and early creatine kinase-muscle and brain subunits (CK-MB) peak of ~20 hours (Hitachi autoanalyzer with a Boehringer Mannheim kit, Mannheim, Germany). Blood samples were ob- tained every 4 hours during the first 24 hours after admission to the hospital to measure the concentrations of CK-MB. These measurements were then assessed every 12 hours for 96 hours (the upper normal value for CK-MB was 10 IU/L>. LV wall motion was assessed by echocardiography through LV end-diastolic and end-systolic silhouettes, as described by Berning and Steensgard-Hansen and Napoli et a1.7*8 Wall motion was scored on a four-point scale (0 = normal, 1 = moderate hypokinetic, 2 = severe hypokinetic, 3 = akinetic). In addition, single photon emission com- puted tomography (SPECT) (Siemens Orbiter 75, Siemens AG, Berlin, Germany) was performed with a single-day protocol and the stress-rest sequence, and ~mTe~~etium hexakis 2-methox~sobutylisonit~le (MIBI) (sgmTc sestamibi) uptake was scored using a four-point grading system.’ The echocardiographic and scintigraphic observations were masked, and the investigators who evaluated LV function and MIBI-SPECT were also masked as to treatment group. All patients gave informed consent for the investigation, which was approved by the Human Study Committee of the Pellegrini Hospital, Naples. Statistical comparisons were made using Stu- dent’s t test for unpaired data with Bonferroni’s correction. Nonp~amet~c statistics were used for grading system results. The between-run and the within-run coefficient variations were less than 10%.

*Trademark Activase” (Cenentech, Inc., South San Francisco, California).

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EFFECTS OF LATE THROMBOLYSIS ON MYOCARDIAL INFARCTION

RESULTS

In group 1, the time of thrombolysis ranged from 6.5 to 16 hours aRer the onset of symptoms; similarly, heparin was administered from 6 to 18 hours. No statistically significant differences were found between groups with respect to clinical characteristics, risk factors, extension of infarct, or drug regimens begun after MI (Table I). In contrast, the peak of CK-MB was significantly less in group 1 than group 2 (P = 0.02, Table I). Four- year mortality in group 1 patients was significantly lower than group 2 (P = 0.05, Table II). However, morbidity and requirement of various medications did not differ significantly between the groups (Table II). In contrast, the cumulative frequency of patients with ST depressions of >1.5 mm at ~100 watts of exercise (11% vs 34%, P c 0.05 vs group 2) and MIBI defects (ischemic and/or scar) were higher in group 2 than group 1 (Table III). Similarly, both global ventricular function (expressed as LV ejection fraction) and wall-motion score were high in thrombolysed patients at each selected period (Table III). In both groups, none of the results correlated significantly with sex, risk factors, or the time of treat- ment after MI. In contrast, age was correlated with both poor LV ejection fraction and high wall-motion score in group 2 (r = .67 and .72, respec- tively; P < 0.01).

Table I. Patient demographic and clinical characteristics. Data are expressed as mean f SD wherever indicated.

Characteristics*

Hypertension ’ ’ Diabetes Hypercholesterolemia Ever smoked Family history for CAD

Previous treatment (%) Calcium channel blockers Nitrates Aspirin Beta-blockers

No. of leads with ST segment elevation Peak of CK-MB (ILVL)

;3 (8.7)

205i102

CAD = coronary artery disease; CK-MB = creatine kinase-muscle and brain subunits. * Data between roups for all characteristics with exce tion of peak of CK-MB are statistically nonsignificant. For peak of CK- 81 B, P = 0.02 versus heparin (group ! ).

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A. LIGUORI ET AL.

Table II. Four-year follow-up of patients admitted with myocardial infarction.

Group 1 (n = 79)

Four-year mortali 7 Return to work (“0)

(%)

MI since discharge (%) Heart failure (%) Stable angina (%)

FZ~)surge (%) Beta-blockers ( 9 Aspirin (%)

O)

Ml = myocardial infarction; PTCA = percutaneous transcoronary angioplasty. * Data between groups for all events with exception of 4-year mortality are statistically nonsignificant. For 4-year mortality, P = 0.05 versus heparin (group 2).

DISCUSSION AND CONCLUSIONS

This study showed that late thrombolysis in MI decreased 4-year mortality and improved LV function; however, as previously reported,475 various morbidity aspects were not affected. The original GUSTO-I trial reported that patients with accelerated thrombolysis did not have significant sur- vival benefit.” These results may be explained by the fact that the timing was not precisely related to the initial coronary occlusion, and also that patients with long times to treatment were generally sicker and thus had a higher expected mortality.3 However, recent data show that earlier myo- cardial reperfusion may account for the smaller infarct size in patients with preinfarction angina,11 suggesting that this benefit may depend on faster thrombolysis, in addition to or instead of myocardial precondition- ing. Our study population did not have episodes of angina in the 48 hours preceding MI; thus ischemic preconditioning is apparently not responsible for the long-term protective effects on LV function.

Table III. Global ventricular function during study in both groups of patients. Data are ex- pressed as mean f SD where applicable.

Period

During Ml At follow-uo Ivl

LVEF (%) Wall-Motion Score*

Group 1 Group 2 Group 1 Group 2

45 f 5 38 f 4 2.2 f 0.9 2.5 * 0.8

% of MIBI Defects

Group 1 Group 2

38 35

E:“,{ 43 f 3 z::

1 1 .o .l f f 55 f 5t

0.3t 0.4t 2.0 1.9 f f 0.3 0.4 tot z: 1 .l f

53 f 3t 0.3t

45 f 3 1 .l 0.3t ::K?: 1::

f 16t :z

LVEF = left ventricular ejection fraction; MIBI = 2-methoxyisobutylisonitrile; Ml = myocardial infarction. * Wall-motion score: 0 = normal; 1 = moderate hypokinetic; 2 = severe hypokinetic; 3 = akinetic. t P < 0.05 versus heparin (group 2).

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EFFECTS OF LATE THROMROLYSIS ON MYOCARDIAL INFARCTION

Although imprecision in measurement (range, 6 to 16 hours) may limit the ability to detect subtle time-dependent treatment with thrombolysis, we found additional relative advantage for late thrombolysis versus hep- arin alone in global ventricular function. Moreover, the retrospective study design may allow for enrollment bias because we used a nonrandomized assignment of patients to treatments. The pathophysiologic mechanisms responsible for the phenomenon, and the specific role of patient age on LV function in group 2 need further exploration. In addition, this study did not determine the incidence of stroke, which would be an important variable to compare in any further investigations. In conclusion, our results support the belief that thrombolysis improves global LV function even when given late after the onset of MI symptoms.

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