BRIEF REPORTS

JAGS 50:343–348, 2002© 2002 by the American Geriatrics Society 0002-8614/02/$15.00

Efficacy of Thrombolysis in Younger and Older Adult Patients Suffering Their First Acute Q-Wave Myocardial Infarction

Claudio Napoli, MD, PhD, FACA,

*

†

Francesco Cacciatore, MD, PhD,

†

Domenico Bonaduce, MD,

*

Franco Rengo, MD,

*

Mario Condorelli, MD, FACA,

*

Antonio Liguori, MD,

‡

and Pasquale Abete, MD, PhD

*

OBJECTIVES:

Advancing age is an independent predictorof increased mortality after acute myocardial infarction(AMI). Several hypotheses have been developed to try toexplain this phenomenon, but data available about the ef-ficacy of thrombolytic therapy in older patients are stillnot conclusive. The goal of this study was to investigatethe efficacy of thrombolysis in adult and older patientswho suffered their first AMI.

DESIGN:

Retrospective cohort study.

SETTING:

A coronary care unit.

PARTICIPANTS:

The sample included 244 younger (aged

�

65, n

�

166) and older (age

�

65, n

�

78) adult patientssuffering their first Q-wave AMI, all receiving thromboly-sis with human-recombinant tissue-type plasmin-ogen acti-vator (100 mg total dose within 2.5 hours of the onset ofAMI.

MEASUREMENTS:

Infarct size was estimated by isoen-zyme creatine kinase–myoglobin (CK-MB) release, mea-suring the area under the curve as a function of time. STelevation, the sum of ST elevation above the baseline, andthe sum of R wave height in precordial leads V

1

–V

6

wereevaluated using 12-lead electrocardiograms. Myocardialreperfusion was calculated when ST-segment elevation de-creased more than 60% with respect to the most abnormalpeak detected.

RESULTS:

CK-MB peak level was significantly smaller inyounger patients than in older ones (

P

�

.01) and was sig-nificantly correlated with increasing age (

P

�

.0001). Areaunder the 36-hour CK-MB curve was lower in younger pa-tients than in older ones (

P

�

.0001) and was well corre-lated with increasing age (

P

�

.01). Reperfusion time wassignificantly shorter in younger patients (

P

�

.05), and age

was significantly correlated with reperfusion time (

P

�

.001).

CONCLUSIONS:

Infarct size was greater and reperfusiontime was longer in older patients than in younger oneswith first Q-wave AMI treated with thrombolysis. Infarctsize and reperfusion time were linearly correlated with in-creasing age. These findings may help explain the increasein mortality due to AMI observed with advancing age.

J Am Geriatr Soc 50:343–348, 2002.

Key words: older; thrombolysis; myocardial infarction

A

dvancing age is an independent predictor of increasedmortality after acute myocardial infarction (AMI).

1–4

Reasons for the high mortality in older patients with AMIare still poorly understood. Several hypotheses have beendeveloped to try to explain this intriguing phenomenon.The frequent presence of comorbidity

5,6

and superimposedcardiac disorders

7

(hypertension, diabetes mellitus, andvalvular heart diseases), together with the age-related re-duction of endogenous protective mechanisms (myocardialischemic preconditioning

8–11

) could put older patients withAMI at an increased risk of mortality.

Another critical factor that needs to be mentioned toexplain the poor prognosis in older patients with AMI isthe therapeutic approach. In particular, the under use ofthrombolytic therapy, even in the absence of discerniblecontraindications, could affect the prognosis of older pa-tients.

12,13

Several randomized placebo-controlled trials us-ing thrombolysis have demonstrated a reduction in short-term mortality in older patients with AMI.

14–16

Althoughthese benefits were found in older patients with AMI, thesepatients are less likely to receive these fibrinolytic drugsduring hospitalization for AMI because of the greater like-lihood that older patients will have contraindications tothrombolysis and the reluctance of physicians to prescribethese drugs for older patients.

17

Furthermore, some studieshave raised some uncertainties about the efficacy ofthrombolysis in older patients.

18–20

In particular, Thie-mann et al.

20

reported a lack of benefit for intravenous

From the *Department of Clinical Medicine, Cardiovascular Science, and Immunology, School of Medicine, Federico II University, Naples, Italy;

†

De-partment of Medicine, University of California, San Diego, California; and

‡

Division of Cardiology-UTIC, Ospedale dei Pellegrini, Naples, Italy.

Address correspondence to Pasquale Abete, MD, PhD, Dipartimento di Medicina Clinica e Scienze Cardiovascolari, Cattedra di Geriatria, Università degli Studi di Napoli “Federico II,” Facoltà di Medicina e Chirurgia, Via Sergio Pansini, 5, 80131 Napoli, Italy.E-mail: p.abete@unina.it

344

NAPOLI ET AL.

FEBRUARY 2002–VOL. 50, NO. 2 JAGS

thrombolysis in patients aged 75 and older with AMI anda statistically significant 38% relative increase in 30-daymortality. Moreover, few data are available about the hy-pothetical age-related difference in the rapidity of coro-nary reperfusion and infarct size in older patients who suf-fered their first AMI treated with thrombolysis.

Thus, the goal of the present study is to investigate thecharacteristics and the efficacy of thrombolysis with human-recombinant tissue-type plasminogen activator in youngerand older adult patients experiencing their first Q-wave AMI.

METHODS

Patients

We retrospectively studied 244 younger (aged

�

65, n

�

166) and older (aged

�

65, n

�

78) patients who sufferedtheir first Q-wave AMI between 1992 and 1997. The oc-currence of AMI was diagnosed if patients had an isoen-zyme creatine kinase–myoglobin (CK-MB) fraction greaterthan 0.05 or any two of the following criteria: chest pain,doubling of total serum CK levels, and electrocardiographicevidence of AMI (

�

1.5 mm in limb leads and

�

2 mm inprecordial leads). Patients were excluded if AMI was asso-ciated with left bundle branch block, valvular heart disease,hypertension, previous cerebral vascular accident, essentialor secondary hypertension, chronic atrial fibrillation, or in-traventricular conduction defects. Patients with cardiogenicshock, coma on arrival, preexisting dementia, and terminalillness were also excluded from the study. Physicians col-lected a detailed clinical history in all studied patients. Inparticular, we collected information on the administration ofcertain therapies affecting myocardial function (

�

-blockers,calcium antagonists, angiotensin-converting enzyme inhibi-tors, and nitrates), dyslipidemias (plasma cholesterol

�

200mg/dl and/or plasma triglycerides

�

200 mg/dl), and smok-ing habits. Angina pectoris lasting less than 30 minutes, 24hours before the AMI, was defined as preinfarction angina.

Thrombolysis

All patients selected in the present study underwent throm-bolysis. Thrombolytic therapy was started with human-recombinant tissue-type plasminogen activator (Alteplase)using the following standard protocol: 60 mg intrave-nously over the first hour, with 10 mg administered as aninitial bolus twice at 20-minute intervals followed by 40mg as a continuous infusion within 1 hour and 40 mg in-travenously during the subsequent 1.5 hours: total dose,100 mg within 2.5 hours of the onset of AMI. Immediatelybefore administration of the thrombolytic agent, aspirin(200 mg) was administered and then was continued on adaily basis (100 mg/day). A 5,000-IU bolus of heparin wasadministered just before thrombolysis, followed by addi-tional heparin during the first 24 hours, adjusted every 6hours to maintain the activated partial thromboplastintime between two and 2.5 times the control value. Efficacyof thrombolysis was defined by the following criteria: con-tinuous ST-segment monitoring, early CK-MB peak (

�

18hours), and sudden decrease in chest pain.

21

Time to reper-fusion was measured blindly with regard to the age of thepatient. As has been well established,

21

myocardial reperfu-sion occurred when ST-segment elevation decreased morethan 60% relative to the most abnormal peak detected.

Electrocardiographic Measurements

A 12-lead electrocardiogram (ECG) was used to record thenumber of leads showing ST elevation, the sum of ST ele-vation above the baseline (

�

ST of precordial leads V1–V6),and the sum of R wave height in precordial leads V1–V6(

�

R),

22

as previously described in detail.

23

Myocardial Infarct Size Determination

Venous blood samples were obtained every 4 hours duringthe first 24 hours after admission to the coronary care unitfor measuring total CK and its MB isoenzyme. The upperlimits of normal range in our laboratory were 150 and12.5 IU/L for plasma CK and MB isoenzyme, respectively.CK and MB isoenzyme values were then evaluated every12 hours until 96 hours, and the time to the CK peak wasmeasured from the onset of AMI symptoms. Infarct sizewas estimated by the method originally described by Grandeet al.,

24

using the peak CK-MB values and the area underthe curve of various concentrations as a function of time,as previously validated.

23

Echocardiographic Analysis

Two-dimensional echocardiographic measurements wereperformed as recommended by the American Society ofEchocardiography, as previously described in detail.

23

Briefly,left ventricular wall motion was evaluated by left ventricu-lar end-diastolic and end-systolic silhouettes. The degreeof hypokinesis was then scored on a 5-point scale (0

�

normal, 1

�

mildly hypokinetic, 2

�

moderately hypoki-netic, 3

�

severely hypokinetic, 4

�

akinetic). The numberof hypokinetic segments was evaluated by a semiquantita-tive analysis performed on the parasternal short axes im-age at mild papillary muscle level. From the center of theleft ventricle, 24 equally spaced segments were drawn tointersect the endocardial outlines for end-diastolic andend-systolic images.

23

All segments that showed an inwardmotion depressed below the normal range in healthy sub-jects used as controls were taken to be hypokinetic.

Statistical Analysis

Two independent investigators analyzed the data in ablinded fashion with respect to knowledge of the age ofpatients. All results are expressed as means

�

standard de-viation. Correlations were determined by linear regressionanalysis. In the comparison between younger and olderpatients, categorical data and continuous variables wereanalyzed by chi-square and Student

t

tests with Bonfer-roni’s correction, respectively. Statistical significance wasaccepted at the 95% confidence level (

P

�

.05).

RESULTS

Table 1 shows the characteristics of the study population.The two groups did not differ in terms of gender or classi-cal risk factors for coronary heart disease. Similarly, therewas no difference in the prior occurrence of preinfarctionangina or drugs used (Table 1). As expected, in-hospitalmortality and heart failure were higher in older than inyounger patients (Table 1). Moreover, left ventricular dys-function was evaluated at 3 days and at 1 week after AMI.Wall motion score was significantly lower in younger pa-tients (3.05

�

0.25 and 2.35

�

0.18 at 3 days and at 1week, respectively) than in older patients (3.57

�

0.20 and

JAGS FEBRUARY 2002–VOL. 50, NO. 2

THROMBOLYSIS IN PATIENTS WITH ACUTE MYOCARDIAL INFARCTION

345

3.10

�

0.15 at 3 days and at 1 week, respectively;

P

�

.001). Similarly, the number of hypokinetic segments were6.5

�

1.5 and 4.2

�

1.0 in the younger group and 7.5

�

0.9 and 7.0

�

1.1 in the older group at 3 days and at 1week, respectively (

P

�

.0001).Continuous ST-segment monitoring showed that val-

ues of ST elevation before thrombolysis were similar be-tween groups. Moreover,

�

ST elevation values were simi-lar between groups before and after thrombolysis (Table2). Before and after thrombolysis,

�

R waves were higherin younger than in older patients, but these differences didnot reach statistical significance (Table 2).

Younger patients have smaller CK peak levels thanolder patients (925

�

188 vs 1,507

�

255 IU/L,

P

�

.01).Similarly, peak CK-MB levels were significantly smaller inyounger (92

�

45 IU/L) than in older patients (207

�

98IU/L,

P

�

.01). Accordingly, age was significantly corre-lated with CK-MB level (y

�

-105.9

4.6x;

r

2

�

0.728;P � .0001). Area under the integrated 36-hour CK-MBcurve was 1,734 � 709 IU/L in younger patients, com-

pared with 3,097 � 739 IU/L in older patients (P � .0001)(Figure 1A). These curves were also different statisticallyat each sampling point at the eighth and the 20th hour(data not shown). Finally, age correlates well with the ex-tent of the 36-hour MB-CK curve (y � 1,437 64.4x;r2 � 0.678; P � .01) (Figure 1B). Cardiac enzymes peakedat different times in the younger group than in the oldergroup (9.6 � 2.2 vs 11.8 � 2.5 hours, respectively, P �.05). More importantly, when considering ECG parame-ters, adult patients had a significantly shorter reperfusiontime (Figure 2A). More importantly, age was well corre-lated with reperfusion time (y � 24.5 0.49x; r2 � 0.784,P � .001) (Figure 2B). The increase of myocardial infarctsize is positively correlated with time to reperfusion in bothyounger (y � 2,373 82.4x; r2 � 0.414; P � .0001) andolder (y � 2,210 87.9x; r2 � 0.253; P � .0001) patients.Moreover, the comparison between the slopes was statisticallysignificant (P � .0001). Indeed, each unit of time to reperfu-sion determined an increase of �82 IU/L CK-MB in youngerpatients and �88 IU/L CK-MB in older patients (Figure 3).

Table 1. Characteristics of the Study Population

VariableYounger(n � 166)

Older(n � 78) P-value

Age (years), mean � standard deviation 49 � 8 70 � 3 .0001Male/Female, n 94/72 46/32 .83*Hypertension, n (%) 86 (40.4) 45 (57.6) .72*Congestive heart failure, n (%) 14 (8.4) 6 (7.6) .94*Noninsulin dependent diabetes mellitus, n (%) 26 (16.8) 11 (14.1) .93*Dislipidemias, n (%) 44 (26.5) 25 (30.7) .60*Family history for coronary heart disease, n (%) 28 (16.8) 15 (19.2) .84*Ever smoked, n (%) 102 (61.4) 57 (73.0) .48*Anterior myocardial infarction, n (%) 91 (54.8) 47 (60.2) .76*Preinfarction angina, n (%) 54 (32.5) 18 (23.0) .32*In-hospital mortality 5 (3.0) 9 (11.5) .01In-hospital heart failure 14 (8.4) 18 (23.0) .005�-blockers, n (%) 7 (4.2) 6 (7.6) .44*Calcium antagonist, n (%) 34 (20.4) 20 (25.6) .57*Nitrates, n (%) 27 (16.2) 19 (24.3) .28*Aspirin, n (%) 24 (14.4) 12 (15.3) .97*

*Nonsignificant.

Table 2. Electrocardiographic Characteristics of the Study Population

Electrocardiogram parameter

Younger(n � 166)

Older(n � 78)

P-Valuemean � standard deviation

Time from onset of continuous chest pain to thrombolytic treatment, minutes 93.1 � 25.6 99.2 � 24.2 .08*Number of leads with ST elevation 3.5 � 0.6 3.4 � 0.6 .22*� ST elevation on admission, mm 10.7 � 3.5 10.8 � 3.8 .84*� ST elevation at the end of thrombolysis, mm 2.5 � 1.9 3.0 � 2.2 .07*� R waves on admission, mm 42.8 � 24.5 36.8 � 21.8 .06*� R waves at the end of thrombolysis, mm 35.8 � 20.4 32.0 � 18.4 .21*

*Nonsignificant.� � sum of.

346 NAPOLI ET AL. FEBRUARY 2002–VOL. 50, NO. 2 JAGS

DISCUSSIONThe present study demonstrates that infarct size is greaterand reperfusion time longer in older than in younger pa-tients who suffered their first Q-wave AMI and weretreated with thrombolysis. Infarct size and reperfusiontime are linearly correlated with increasing age. Interest-ingly, the age-related lack of efficacy of thrombolysis oc-curs despite similar ECG changes in younger and older pa-tients.

In-hospital mortality is three times higher in olderthan in younger patients.3 Indeed, because more than 80%of coronary deaths occur in patients aged 65 and older,advanced age is considered a powerful predictor of in-hos-pital mortality after AMI.1–4 The mechanisms that causethis higher mortality in older patients with AMI are stillpoorly understood. Increased myocardial mass,25 reduceddiastolic relaxation,26 and impairment of cardiac micro-vascular angiogenesis27 might contribute to the poorerprognosis of older patients with Q-wave AMI. Moreover,it has been recently demonstrated that the reduction of theprotective effect of myocardial ischemic preconditioning inolder patients with AMI seems to explain, at least in part,

the increased mortality in these patients.8,9 Notably, thefrequent presence of comorbid conditions in older patientsmight predispose them to more-severe complications andhigher mortality after AMI.6,7 However, Tofler et al.5 havedemonstrated that adverse baseline characteristics do notjustify the increased in-hospital mortality observed in pa-tients aged 65 and older. Finally, the less-aggressive ther-apy, including thrombolytic therapy, in older patients withAMI seems to play a determining role in the age-related in-crease of mortality after AMI.12,13,17,28–31

The number of older patients with clinical characteristicsindicating the appropriateness of thrombolytic therapy de-creases as age increases for several reasons, including a delayin arrival at the emergency room, the presence of ST depres-sion in relation to ST elevation, and, more importantly, theincreased probability of intracranial hemorrhage.12,13,17,32,33

Thus, the underuse of thrombolytic therapy was previ-ously considered one of the most important causes of highmortality in older patients experiencing AMI. Indeed, itwas proposed that thrombolysis with streptokinase or tis-sue plasminogen activator might contribute to decreasedmortality for AMI in older patients.14–16 However, morerecently, it has been found that, after thrombolysis, thereis a nonsignificant 1% absolute reduction in mortality for

Figure 1. Area under the 36-hour isoenzyme creatine kinase–myoglobin fraction curve in younger (�65, n � 166) and older(�65, n � 78) patients (panel A) and its linear correlation withage (panel B).

Figure 2. Time to reperfusion in younger (�65, n � 166) andolder (�65, n � 78) patients (panel A) and its linear correlationwith age (panel B).

JAGS FEBRUARY 2002–VOL. 50, NO. 2 THROMBOLYSIS IN PATIENTS WITH ACUTE MYOCARDIAL INFARCTION 347

patients aged 75 and older in placebo-controlled trials,18

whereas an observational study has shown an increasedrisk of mortality in patients aged 75 and older who under-went thrombolysis.20 Taken together, these findings indi-cate the advantage of primary angioplasty over throm-bolytic therapy in a subgroup analysis of randomizedtrials.19,34 Although primary angioplasty improves out-come after thrombolysis, it does not appear to provide ad-ditional benefits to older patients.35 This latter study sup-ports the concept that incremental adverse effect of agedoes not vary by treatment strategy. Finally, an increase insudden deaths for mechanical rupture in older patientstreated with thrombolytic agents was found.7 In the subsetof patients who died during hospitalization and under-went autopsy, the percentage of patients aged 70 andolder with cardiac rupture was dramatically higher thanthat of those younger than age 60 (86% vs 19%).

In the Global Use of Strategies to Open Occluded Coro-nary Arteries I15,35 and Gruppo Italiano per lo Studio della So-pravvivenza nell’Infarto del miocardio 23 studies, age-relatedincreased mortality was inversely correlated with CK peak.However, although CK-MB peak increase was not correlatedwith advancing age,15,35 in the present study, we used a CK-MB integrated curve, which represents a more accurate index

of myocardial infarct size than the measure of peak CK orCK-MB alone. To date, neither the National Registry ofMyocardial Infarction (NMRI)14 nor the Cooperative Car-diovascular Project20 studies has focused their analysis on therelationship between infarct size, clinical outcomes, and ad-vancing age. Moreover, the limitation of the NRMI study(and of other large community-based studies) is due to limitedclinical data about absolute and relative contraindications tothrombolysis, cardiovascular risk factors, indicators of infarctsize, and information regarding comorbid conditions.14

Why the efficacy of thrombolytic therapy is attenu-ated in older people is not well understood. A possible ex-planation could be the reduction of the overall benefits onmortality by the higher rate of side effects of the throm-bolytic therapy; another possibility is that the aging heartresponds differently than a younger one to acute myocar-dial ischemia36–38 and oxidative stress at reflow.39 Here, weobserved that the relationship between time to reperfusionand infarct size is positively correlated in younger andolder patients. However, the slope of the curve was steeperin older than in younger patients, indicating a greater in-farct size for each unit increase of time to reperfusion. Fur-thermore, the relationship between time to reperfusionand infarct size is better correlated in younger than inolder patients, suggesting that the larger infarct size ob-served in the older group may be due to other factors thantime to reperfusion alone.

Preinfarction angina is considered one of the clinicalequivalents of ischemic preconditioning, the most power-ful endogenous protective mechanism against myocardialischemia.40–42 Indeed, the beneficial effects of preinfarctionangina on infarct size, myocardial stunning, and clinicaloutcome have been reported.23,43,44 It has been demon-strated that reperfusion time was faster and infarct sizewas smaller in patients with preinfarction angina receivingthrombolytic therapy than in those without.45 Thus, it hasbeen proposed that the benefit of preinfarction anginawith respect to infarct size may depend on faster coronarythrombolysis in addition to ischemic preconditioning.45 Inaddition, there is experimental42,46,47 and clinical8–10,42 evi-dence that ischemic preconditioning is reduced in the ag-ing heart. Thus, the age-related reduction of beneficial ef-fects of ischemic preconditioning with aging may explain,at least in part, the poorer efficacy of thrombolysis inolder than in younger patients with AMI.

Although we have established criteria for patient in-clusion before studying the patient record, data from ret-rospective studies should be viewed with caution. In addi-tion, the lower protein stores present in older people mightmask age-related enzyme level studies, and therefore CKrelease in older patients might be underevaluated. How-ever, we have used a more accurate marker of myocardialnecrosis (CK-MB) and the relative 36 hours integratedcurve to measure the infarct size.48

Therefore, thrombolytic therapy during AMI is less ef-ficacious in older than in younger patients because of de-layed reperfusion time and larger infarct size. These find-ings may explain the higher mortality from AMI observedin older people. Further studies are needed to understandthe pathophysiological mechanisms at the molecular level,which might explain the poor therapeutic results of throm-bolysis in older patients.

Figure 3. Relationship between time to reperfusion and area un-der the 36-hour isoenzyme creatine kinase–myoglobin fractioncurve in younger (�65, n � 166) and older and (�65, n � 78)patients.

348 NAPOLI ET AL. FEBRUARY 2002–VOL. 50, NO. 2 JAGS

REFERENCES1. Harris R, Piracha AR. Acute myocardial infarction in the aged: Prognosis

and management. J Am Geriatr Soc 1970;18:893–904.2. Latting CA, Silverman ME. Acute myocardial infarction in hospitalized pa-

tients over age 70. Am Heart J 1980;100:311–318.3. Maggioni PA, Maseri A, Fresco C et al. Age related increase in mortality

among patients with first myocardial infarctions treated with thrombolysis.N Engl J Med 1993;329:1442–1448.

4. Goldberg RJ, McCormick D, Gurwitz JH et al. Age-related trends in short-and long-term survival after acute myocardial infarction: A 20-year popula-tion-based perspective (1975–1995). Am J Cardiol 1998;82:1311–1317.

5. Tofler GH, Muller JE, Stone PH et al. Factors leading to shorter survival af-ter acute myocardial infarction in patients ages 65 to 75 years compared withyounger patients. Am J Cardiol 1988;62:860–867.

6. Vokonas PS, Kannel WB. Diabetes mellitus and coronary heart disease in theelderly. In: Aronow WS, Tresh DD, eds. Clinics in Geriatric Medicine: Coro-nary Artery Disease in the Elderly. Philadelphia, PA: W. B. Saunders Com-pany, 1996, pp 69–78.

7. Waller BF, Roberts WC. Cardiovascular disease in the very elderly. Analysisof 40 necropsy patients aged 90 years or over. Am J Cardiol 1983;51:403–421.

8. Abete P, Ferrara N, Cacciatore F et al. Angina-induced protection againstmyocardial infarction in adult and senescent patients. A loss of precondition-ing mechanism in aging heart? J Am Coll Cardiol 1997;30:947–954.

9. Napoli C, Liguori A, Cacciatore F et al. “Warm-up” phenomenon detectedby electrocardiographic ambulatory monitoring in adult and elderly patients.J Am Geriatr Soc 1999;47:1114–1117.

10. Ishihara M, Sato H, Tateishi H et al. Beneficial effect of prodromal anginapectoris is lost in elderly patients with acute myocardial infarction. Am HeartJ 2000;139:881–888.

11. Longobardi G, Abete P, Ferrara N et al. “Warm-up” phenomenon in adultand elderly patients with coronary artery disease. Further evidence of the lossof “ischemic preconditioning” in the aging heart. J Gerontol A Biol Sci MedSci 2000;55A:M124–M129.

12. Ellerbeck EF, Jenks SF, Radford MJ et al. Quality of care for Medicare pa-tients with acute myocardial infarction: A four-state pilot study from the co-operative cardiovascular projects. JAMA 1995;273:1509–1514.

13. McLaughin TJ, Soumerai SB, Willison DJ et al. Adherence to national con-sensus guidelines for drug treatment of suspected acute myocardial infarc-tion: Evidence for under treatment in women and in the elderly. Arch InternMed 1996;156:799–805.

14. Gurwitz JH, Gore JM, Goldberg RJ et al., for the Participants in the NationalRegistry of Myocardial Infarction. Recent age-related trends in the use ofthrombolytic therapy in patients who have had acute myocardial infarction.Ann Intern Med 1996;124:283–291.

15. White HD, Barbash GI, Califf MR et al. Age and outcome with contempo-rary thrombolytic therapy. Results from the GUSTO-I trial. Circulation1996;94:1826–1833.

16. Ridker PM, Hennekens CH. Age and thrombolytic therapy. Circulation1996;94:1807–1808.

17. Rich MW. Therapy for acute myocardial infarction in older persons. J AmGeriatr Soc 1998;46:1302–1307.

18. Fibrinolytic Therapy Trialists’ (FTT) Collaborative Group. Indications for fi-brinolytic therapy in suspected acute myocardial infarction: Collaborativeoverview of early mortality and major morbidity results from all randomizedtrials of more than 1000 patients. Lancet 1994;343:311–322.

19. Berger AK, Radford MJ, Wang Y et al. Thrombolytic therapy in older pa-tients. J Am Coll Cardiol 2000;36:366–374.

20. Thiemann DR, Coresh J, Schulman SP et al. Lack of benefit for intravenousthrombolysis in patients with myocardial infarction who are older than 75years. Circulation 2000;101:2239–2246.

21. Krucoff MW, Croll MA, Pope JE et al. Continuously updated ST-segment re-covery analysis for myocardial infarct artery patency assessment and its cor-relation with multiple simultaneous early angiographic observations. Am JCardiol 1993;72:145–151.

22. Blanke H, Scherf F, Karsh KR et al. Electrocardiographic changes after strep-tokinase-induced recanalization in patients with acute left anterior descend-ing artery occlusion. Circulation 1983;68:406–412.

23. Napoli C, Liguori A, Chiariello M et al. New-onset angina preceding acute

myocardial infarction is associated with improved contractile recovery afterthrombolysis. Eur Heart J 1998;19:411–419.

24. Grande P, Hansen BF, Christiansen C et al. Estimation of acute myocardial in-farct size in man by serum CK-MB measurements. Circulation 1982;65:756–767.

25. Gerstenblith G, Frederiksen J, Yin FC et al. Echocardiography assessment ofa normal adult aging population. Circulation 1977;56:672–679.

26. Tresh DD, McGough MF. Heart failure with normal systolic function: Acommon disorder in older people. J Am Geriatr Soc 1995;43:1035–1042.

27. Rivard A, Fabre JT, Silver M et al. Age-dependent impairment of angiogene-sis. Circulation 1999;99:111–120.

28. Krumholz HM, Forman DE, Kuntz RE et al. Coronary revascularization af-ter myocardial infarction in the very elderly: Outcomes and long-term fol-low-up. Ann Intern Med 1993;119:1084–1090.

29. Krumholz HM, Radford MJ, Ellerbeck EF et al. Aspirin for secondary pre-vention after acute myocardial infarction in the elderly: Prescribed use andoutcomes. Ann Intern Med 1996;124:292–298.

30. Soumerae ZS, McLoughlin TJ, Spuegelman D et al. Adverse outcomes of un-der use of �-blockers in elderly survivors of acute myocardial infarction.JAMA 1997;177:115–121.

31. Rosenthal GE, Fortinsky RH. Differences in the treatment of patients withacute myocardial infarction according to patient age. Am J Cardiol 1999;83:650–654.

32. Tresch DD. Management of the older patient with acute myocardial infarc-tion: Difference in clinical presentations between older and younger patients.J Am Geriatr Soc 1998;46:1157–1162.

33. Maggioni AP, Franzosi JG, Santoro E et al., on behalf of the GISSI-2 and In-ternational Study Groups. Analysis of the risk of stroke in 20,891 patientswith acute myocardial infarction following thrombolytic and antithrombotictreatment. N Engl J Med 1992;327:1–6.

34. O’Neil WW, de Boer MJ, Gibbons RJ et al. Lessons from the pooled out-come of the PAMI, ZWOLLE and Mayo Clinic randomized trial of primaryangioplasty versus thrombolytic therapy of acute myocardial infarction. J In-vasive Cardiol 1998;10:4A–10A.

35. Holmes DR, White HD, Pieper KS et al. Effect of age on outcome with pri-mary angioplasty versus thrombolysis. J Am Coll Cardiol 1999;33:412–419.

36. Abete P, Cioppa A, Ferrara P et al. Reduced aerobic metabolic efficiency inpostischemic myocardium dysfunction in rats: Role of aging. Gerontology1995;41:187–194.

37. Headrick JP. Aging impairs functional, metabolic, and ionic recovery fromischemia-reperfusion and hypoxia-reoxygenation. J Mol Cell Cardiol 1998;30:1415–1430.

38. Abete P, Cioppa A, Calabrese C et al. Ischemic threshold and myocardialstunning in the aging heart. Exp Gerontol 1999;34:875–884.

39. Abete P, Napoli C, Santoro G et al. Age-related decrease in cardiac toleranceto oxidative stress. J Mol Cell Cardiol 1999;31:227–236.

40. Murry CE, Sennings RB, Reimer KA. Preconditioning with ischemia: A delayof lethal cell injury in ischemic myocardium. Circulation 1986;74:1124–1136.

41. Kloner RA, Bolli R, Marban E et al. Medical and cellular implications ofstunning, hibernation and preconditioning. An NHLBI workshop. Circula-tion 1998;97:1848–1867.

42. Napoli C, Pinto A, Cirino G. Pharmacological modulation, preclinical stud-ies, and new clinical features of myocardial ischemic preconditioning. Phar-macol Ther 2000;88:311–331.

43. Ottani F, Galvani M, Ferrini D et al. Prodromal angina limits infarct size. Arole of ischemic preconditioning. Circulation 1995;91:291–297.

44. Kloner RA, Shook T, Przyklenk K et al. Previous angina alters in-hospitaloutcome in TIMI 4: A clinical correlate to preconditioning? Circulation1995;91:37–47.

45. Andreotti F, Pasceri V, Hackett DR et al. Preinfarction angina as a predictorof more rapid coronary thrombolysis in patients with acute myocardial in-farction. N Engl J Med 1996;334:7–12.

46. Abete P, Ferrara N, Cioppa A et al. Preconditioning does not prevent post-ischemic dysfunction in aging heart. J Am Coll Cardiol 1996;27:1777–1786.

47. Tani M, Suganuma Y, Hasegawa H et al. Changes in ischemic tolerance andeffects of ischemic preconditioning in middle-aged rat hearts. Circulation1997;95:2559–2566.

48. Friesinger GC, Ryan TJ. Coronary heart disease. Stable and unstable syn-dromes. In: Friesinger GC, ed. Cardiovascular Disease in the Elderly. Phila-delphia. PA: Saunders Edition, 1999, pp 93–122.