Comparison of effects of thrombolytic therapy on left ventricular function in patients over with...

CORONARY ARTERY DISEASE The

American Jouyal

01 2udiolog~

MAY 1, 1991, VOL. 67, NO. 11

Comparison of Effects of Thrombolytic Therapy on Left Ventricular Function in Patients Over with Those Under 60 Years of Age Harvey White, MB, David Cross, MB, Margaret Scott, and Robin Norris, MD

This study examined the effect of age on left ventricular (LV) function, assessed by contrast ventriculography 3 weeks after a first acute myocardial infarction in 312 patients who received thrombolytic therapy within 4 hours of the onset of infarction and in 63 patients who received placebo. Streptokinase was given to 166 patients and recombinant tissue-type plasminogen activator @t-PA) to 124. Patients were divided into 2 age groups: <60 years (n = 244) and 260 years (n = 151). Thrombolytic therapy improved ejection fraction in both age groups: from 54 f 13 to 59 f 11% (p = 0.021) in the younger group and from 50 f 14 to 57 f 13% (p = 0.004) in the older group. Ejection fraction was identical in streptokinase- and &PA-treated patients. Multifactor analysis of variance revealed that younger age and thrombolytic therapy were independently associated with improved ejection fraction. Thrombolytic therapy also reduced end-systolic volume (p = 0.001) by 14 ml in the elderly and 9 ml in the younger group. Mi- nor bleeding complications were more frequent in the elderly and 3 serious hemorrhages occurred in patients 160 years. These findings re- veal that thrombolysis improves LV function in all age groups studied. Decause increasing age is independently associated with a lower ejection fraction after acute myocardial infarction, thrombolytic therapy may confer greater bene- fits in older patients.

(Am J Cardiol 1991;67:913-918)

From the Green Lane Hospital, Auckland, New Zealand. This study was supported in part by grants from the Medical Research Council of New Zealand, Auckland, and the National Heart Foundation of New Zealand, Auckland. Manuscript received October 22, 1990; revised manuscript received and accepted January 2, 1991.

Address for reprints: Harvey White, MB, Cardiovascular Research Unit, Green Lane Hospital, Auckland, New Zealand.

M ortality after acute myocardial infarction is higher in elderly patients than in young patients.‘m3 Elderly patients also have a higher

incidence of cardiac rupture,4 congestive heart failure and cardiogenic shock. l-3 The greater incidence of complications may relate to a number of factors, in- cluding previous myocardial infarction, more severe coronary artery disease, a higher frequency of systemic hypertension and impaired healing. Large controlled trials of thrombolytic therapy have shown that elderly patients benefit from the same percent reduction in mortality as younger patients.5-8 However, because the elderly have a higher mortality untreated, the absolute mortality benefit is greater than in younger patients.

Left ventricular (LV) function has consistently been shown to be the major prognostic factor after recovery from myocardial infarction, both before and since the advent of thrombolytic therapy.9-11 Placebo-controlled studies of thrombolytic therapy have generally shown preservation of LV function. 1 2-2o To determine whether thrombolytic therapy has differing effects on LV function in older compared with younger patients, we examined the effects of age and thrombolytic therapy on ejection fraction and end-systolic volume, assessed by contrast ventriculography 3 weeks after a first myocardial infarction.

METHODS Patients: The study group comprised patients en-

rolled in 2 trials of thrombolytic therapy.‘*T2r All patients presented with a first myocardial infarction and were randomized within 4 hours of the onset of typical ischemic chest pain of 230 minutes’ duration. Electro- cardiographic criteria for inclusion were ST-segment elevation of >l mm in the limb leads or leads V4 to Vg, or 2 mm of ST elevation in leads Vr to V3. Changes were required in >2 contiguous leads. Patients were excluded from randomization if they had a known hemorrhagic diathesis, previous stroke, peptic ulcer-

THE AMERICAN JOURNAL OF CARDIOLOGY MAY 1, 1991 913

ation within 6 months, previous genitourinary bleeding, were taking anticoagulants, were hypertensive (200 mm Hg systolic), or had undergone recent (within 2 weeks) surgery or trauma. Patients with cardiogenic shock were not excluded. Patients were divided into 2 groups, 1 aged <60 years and the other 60 to 70 years. This empiric division was prospectively defined before data analysis and chosen to produce groups of compa- rable size. These studies were approved by the ethics committees of the 4 participating hospitals.

Procedure: Thrombolytic therapy or placebo was administered in a double-blind manner. Placebo or 1.5 million U of streptokinase was infused over 30 minutes and a lo-mg bolus followed by 90 mg of recombinant tissue-type plasminogen activator (rt-PA) or placebo was infused over 3 hours. Aspirin (50 mg/day) and dipyridamole (400 mg/day) were begun on admission. Heparin was infused 30 minutes after commencement of the blinded infusion at 1,000 U/hour and continued for 48 hours. The dose was adjusted to keep the activat- ed partial thromboplastin time between 90 and 110 sec- onds.

Cardiac catheterization was performed 3 weeks after infarction. Earlier catheterization was performed only if patients had severe postinfarction angina uncon- trollable by medical management. Coronary artery disease was assessed by a scoring system based on stenoses and the amount of myocardium supplied.9 Myocardial score counts both occluded and patent arteries and is scored out of 15. A score of 5 approximates l-vessel disease and a score of 10 approximates 2-vessel disease. Stenosis score is the amount of myocardium supplied by coronary arteries with 250% diameter stenoses. Pa- tency of the infarct-related artery was classified according to Thrombolysis in Myocardial Infarction (TIMI) criteria.22 Ventricular volumes and ejection fractions were calculated from the right anterior oblique ventric- ulogram by a modified area-length method.9 All anal- yses were made by experienced cardiac radiologists blinded to treatment allocation.

Statistical considerations: Continuous variables are expressed as mean f standard deviation. Univariate comparison of continuous variables is by 1 -way analysis of variance and categorical variables are compared by the chi-square test with Yates correction for continuity in 2 X 2 tables. All p values reported are 2-tailed.

The relations between the 2 primary classifying variables (age <60 or 260 years; active thrombolytic therapy or placebo) and the dependent variables of LV volume and ejection fraction were assessed by multifactor analysis of variance. In view of the differing baseline characteristics of patients in the 2 age groups, all baseline characteristics examined (sex, site of infarction,

914 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 67

body surface area, history of hypertension, diabetes mellitus, claudication or angina, cigarette smoking, and prior treatment with p blockers and calcium antagonists) were entered into a stepwise variable selection multiple linear regression model, and those variables associated with a particular dependent variable entered as covariates in the final multifactor analysis of variance and covariance. Age was entered as both a continuous and dichotomous variable. All possible 2-way interac- tions were examined.

RESULTS Four-hundred forty-two patients with a first infarc-

tion were entered into the 2 thrombolytic trials.‘4,22 Two-hundred sixty-four were aged <60 years and 178 260 years. The thrombolytic agent was streptokinase in 214 patients, rt-PA in 135, and 93 received placebo. Left ventriculograms were available for analysis from 395 patients (89%). Twenty-six patients died before cardiac catheterization could be performed, 19 declined to have cardiac catheterization, and 2 ventriculograms were technically inadequate. The mean age of the patients without adequate ventriculography was 58 f 10 years and 27 patients were 260 years of age.

Baseline characteristics of patients with ventriculograms are listed in Table I. Important differences exist- ed between the 2 age groups. Older patients were more frequently female, had smaller body surface areas and were less likely to smoke cigarettes.

Findings at cardiac catheterization: Table II lists cardiac catheterization findings for patients aged <60 and 260 years receiving thrombolytic therapy or placebo. Multifactor analysis of variance revealed that both younger age (p = 0.04) and thrombolytic therapy (p = 0.0001) were independently associated with improved ejection fraction. Although the absolute benefit in ejection fraction with thrombolytic therapy was greater in older patients (7.5 vs 4.3%), there was not a statistically significant interaction between age and thrombolytic therapy (p = 0.38). The only baseline variable significantly associated with ejection fraction was the site of infarction (anterior worse than inferior, p <O.OOOl). Correction for this covariate did not alter the relations among age, thrombolytic therapy and ejection fraction. The mean ejection fraction was identical in patients receiving streptokinase and i-t-PA.

Thrombolytic therapy significantly reduced end-systolic volume (p = 0.001 ), an effect observed in both age groups. There was no relation between age and end-systolic volume on univariate or multivariate analysis. Of the other baseline characteristics, lower body surface area and inferior rather than anterior infarction were both associated with a lower end-systolic volume

TABLE I Baseline Characteristics at Three-Week Ventriculography

Age -330 years

Placebo Active

Age 60 to 70years

Placebo Active p Value”

i(%) F (%)

Age W Past history (%)

Hypertension+ Diabetes mellitus Claudication Angina*

Smoking5 (3 blockers’1 Calcium antagonists’ Infarct location

Anterior (%) Inferior (%)

Body surface area (ma)

48 85 83 196 71 35 72 116 0.010 15 17 29 28 0.010 5ozk7 51i6 64f3 64&3

33 22 31 26 6 10 6 13 6 2 11 5

13 12 17 21 0.058 50 70 51 46 0.001 25 10 23 18

4 4 6 4

33 38 37 33 67 62 63 67 1.9f0.2 1.9f0.2 1.8iO.2 1.8zkO.2 O.OOl

*All patientsaged <6Ovs all >60years. + Hlstory of treated hypertension *Angina for >3 months before Infarct. § Cigarette, pipe or cigar smoker at time of admission. ’ Taking drug regularly before admission

TABLE II Left Ventricular Function at Three-Week Catheterization

Age <60 years

Active (n = 196)

Placebo (n=43) p Value

Age >60 Years

Active (n= 116)

Placebo (n = 35)

p Value

Ejection fraction (%) 59ill 54f 13 0.02 57*13 50514 0.01 End-systolic volume (ml) 639~28 72f45 0.08 59k31 74f44 0.02 End-diastolicvolume (ml) 150f46 149 f 60 0.94 134k 45 142 f 53 0.37 Infarct artery patency” 72% 52% 0.01 74% 57% 0.09 Stenosis score 6.4 f 4.2 7.2 f 4.6 0.26 8.6 f 4.2 7.7 f 3.7 0.28

* Patency of the infarct-related artery according to Thrombolysis in Myocardial Infarction criteria: O-l = occluded, 2-3 = patent

(p <O.OOOl in both cases). Correction for these covariates did not alter the relations among age, thrombolytic therapy and end-systolic volume.

End-diastolic volume was not affected by thrombolytic therapy. On univariate testing, older age was associated with smaller LV end-diastolic volumes (<60 vs 260 years, p = 0.005, as continuous variable r = -0.18, p = 0.0003). Older patients were, however, more frequently female and were also significantly smaller. Body surface area was positively correlated with end-diastolic volume (r = 0.42, p <O.OOOOl ) and, after correction for this covariate, neither age (p = 0.36) nor any other baseline variable was associated with end-diastolic volume.

Older patients had more extensive coronary artery disease as assessed by our scoring system. There was no difference in the incidence of a patent infarct-related artery in younger and older patients, but myocardial score was 8.7 f 2.5 in patients aged 160 years and 7.6

f 2.8 in patients aged <60 (p <O.OOOl). Stenosis score (reflecting the extent of myocardium supplied by ste- notic vessels) was also higher in the older age group (8.4 f 4.1 vs 6.5 f 4.3; p <O.OOl).

Hemorrhage and allergy: All major hemorrhagic events occurred in patients aged 160 years. Two patients (0.5%) died of intracerebral bleeding after thrombolytic therapy. One patient developed intracere- bra1 bleeding at multiple sites 13 hours after t-t-PA therapy and another patient who initially received streptokinase had an intracerebellar hemorrhage several hours after receiving rt-PA for threatened reinfarction 8 days later. One further patient required splenectomy for a subcapsular hematoma after t-t-PA. Minor hemorrhage occurred in 32 patients, with gastrointestinal bleeding (blood-streaked vomitus or melena) in 4%j he- maturia in 0.6%, and cutaneous or soft-tissue bleeding in 4.6%. Minor bleeding occurred more frequently in the elderly (14.5 vs 5.6%, p = 0.009).


TABLE III Age and Risk of Early Death After Thrombolytic Therapy

Absolute Mortality Reduction

Control Agent Per Thousand

Study Age Patients (follow-up) (yr) n % n % Treated

GISSI-I5 (21 days) Streptokinase

<65 3,784 8% 3,824 6% 20 66-75 1,442 18% 1,444 17% 15 a75 623 33% 592 29% 42

ISIS-2’j (1 month) Streptokinase

<60 3,856 6% 3,864 4% 16 60-69 3,023 14% 3,033 11% 38 870 1,716 22% 1,695 18% 34

Streptokinase and Aspirin

<60 1,924 6% 1,938 4% 25 60-69 1,524 16% 1,500 9% 70 370 852 24% 854 16% 80

ASSET7 (1 month) rt-PA

<55 745 4% 748 4% 6 56-65 896 8% 963 6% 14 66-75 852 16% 827 11% 58

AIMS* (30 days) APSAC

<60 379 6% 372 4d 21 60-70 254 21% 252 10% 114

SuperscrIpt numerals refer to reference Ilst. AIMS = APSAC Interventnnal Mortality Study; APSAC = anisoylated plasmlnogen

streptokinse activator complex; ASSET = Anglo-Scandinavian Study of Early Throm- bolytic Therapy; GISSI-1 = Gruppo ltaliano per lo Studio della Streptochwsl nell’ln- farcto miocardio; ISIS-2 = Second International Study of Infarct Survival; rt-PA = recombinant tissue-type plasmrwgen aciivator.

Minor allergic reactions (rash or fever and rigors) occurred in 3.3% of patients receiving streptokinase. No anaphylactic reactions or severe delayed reactions were observed.

Mortality and reinfarction: Twenty-five patients died within 30 days of the index infarction, 17 (4.9%) after thrombolytic therapy and 8 (8.6%) in the placebo group. The mortality in patients aged (60 years was 4.5%, compared with 7.3% in patients 260 (p = 0.31).

Reinfarction occurred within 30 days of index infarction in 25 patients. The incidence was similar in patients aged <60 (5.7%) and 260 years (5.6%).

Angioplasty and surgery: Fifteen patients (3.4%) underwent coronary angioplasty or bypass surgery within 30 days of thrombolytic therapy, with identical intervention rates in both age groups.

DISCUSSION This study evaluated the effects of age and throm-

bolytic therapy on LV function after a first myocardial infarction. Thrombolytic therapy significantly improved

LV ejection fraction, by 4.3% in younger patients and 7.5% in older patients. Multivariate analysis revealed that older age was independently associated with lower ejection fraction. End-systolic volume was also reduced in elderly patients who received thrombolytic therapy, and we have previously shown that end-systolic volume is a more important prognostic factor than ejection fraction after myocardial infarction.g A limitation of the current study is that patients >70 years of age were not included.

Age is an important prognostic factor after myocardial infarction.lm3 In the Worcester Heart Attack Study,23 the overall hospital mortality was 5% for patients aged <55 years, 7.9% for those aged 55 to 64 years, 16.1% for those aged 65 to 74 years, and 32.1% for those aged 275 years. The elderly also have an increased incidence of complications after myocardial infarction. ’ m4 Possible causes include a higher prevalence of systemic hypertension, diabetes mellitus and preex- isting angina in the elderly.3 Elderly patients in our study had more extensive coronary artery disease, which may impair noninfarct zone contractility. Elderly patients may also have relatively more LV dysfunction due to impaired healing.

Most thrombolytic trials in patients with acute myocardial infarction have restricted randomization on the basis of age because of concern about the possibility of an increased risk of hemorrhage in the elderly, based on experience of the bleeding complications of heparin24 and an increase of major hemorrhage in elderly women receiving streptokinase in an early observational study.25 However, 2 large trials of intravenous streptokinase, the Gruppo Italian0 per lo Studio della Strepto- chinasi nell’Infarto Miocardio5 (GISSI-I ) and the Sec- ond International Study of Infarct Survival (ISIS-2)6 had no age limit. In GISSI-1, 35% of patients were aged 265 years and 10.4% 275 years and, in ISIS-2, 3,411 patients aged 270 years were randomized. Hem- orrhagic complications were not increased in the elderly in either tria1.5,26

Information on hemorrhagic complications with rt- PA in the elderly is available from the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) and TIMI28 trials, although both restricted entry to patients aged <76 years. Both studies entailed early cardiac catheterization, and bleeding was largely related to arterial puncture sites. Multiple regression analysis was used to determine risk factors for hemorrhagic complications in the TAM1 tria1,27 in which 150 mg of rt-PA was administered. Factors associated with increased bleeding risk were invasive procedures (angioplasty or balloon pump insertion), female gender, smaller size


and older age. In the TIM1 tria1,28 factors associated with increased bleeding risk were dose of rt-PA per kilogram of body weight, age and elevated diastolic blood pressure. These results suggest that hemorrhagic complications might be reduced by adjusting rt-PA dose for body weight.

The GISSI-2 and international study group trials29 demonstrated an excess of stroke in the elderly and in patients receiving rt-PA rather than streptokinase. The difference between rt-PA and streptokinase was mainly due to a higher incidence of stroke in patients aged 270 years receiving rt-PA (2.7%) compared with streptokinase ( 1.6%). The incidence of hemorrhagic complications in various age groups has not been reported.

Table III lists the mortality and the absolute mortality reduction in 4 large controlled trials of thrombolytic therapy. The relative benefit of thrombolysis is similar in all age groups but, because of the high mortality of elderly patients in the control groups (16 to 33%), the absolute mortality benefit is much greater in older patients. The difference in absolute mortality benefit between younger and older age groups ranges from two- fold to tenfold. In the ISIS-2 study,6 aspirin further reduced mortality in the treatment group, particularly in patients aged 260 years, without increasing the risk of hemorrhage or stroke. There has been no random: ized study of the effect on mortality of aspirin in con- junction with rt-PA.

Our study shows that thrombolytic therapy is at least as effective in preserving LV function in elderly patients as it is in younger patients. Limitation of LV damage should enable the quality of life of those surviv- ing infarction to be maintained, and also enhance long- term survival. Advanced age alone should not be con- sidered a contraindication to thrombolytic therapy.

Acknowledgment: We would like to thank the phy- sicians who collaborated in this study: Nigel Bass, BM, Michael Brown, MB, Peter Brand& MB, Edward Clarke, MB, Hamish Hart, MB, Andrew Maslowski, MB, John Mercer, MB, Kevin O’Brien, MB, John Or- miston, MB, John Rivers, MB, Norman Sharpe, MB, Morimasa Takayama, MD, Toby Whitlock, MB. We would also like to thank the nurses who helped care for the patients, Barbara Williams for assistance in data collection, and Carol Caunter and Anna Breckon for secretarial assistance.

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