Age, outcomes, and treatment effects of fibrinolytic and antithrombotic combinations: Findings from Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT)-3 and ASSENT-3

Age, outcomes, and treatment effects of fibrinolyticand antithrombotic combinations: Findings fromAssessment of the Safety and Efficacy of a NewThrombolytic (ASSENT)-3 and ASSENT-3 PLUSPeter R. Sinnaeve, MD, PhD,a Yao Huang, PhD,b Kris Bogaerts, PhD,a Alec Vahanian, MD, PhD,c

Jennifer Adgey, MD, PhD,d Paul W. Armstrong, MD,e Lars Wallentin, MD,f Frans J. Van de Werf, MD, PhD,a

Christopher B. Granger, MD,b on behalf of the ASSENT-3 and ASSENT-3 PLUS investigators Leuven, Belgium;Durham, NC; Paris, France; Belfast, Northern Ireland; Alberta, Edmonton, Canada; and Uppsala, Sweden

Background Elderly patients with acute myocardial infarction are at particularly high risk for death and bleedingcomplications. The efficacy and safety of antithrombotic strategies in these patients remain unclear.

Methods To provide more insight into the risk and benefit of antithrombotic strategies in the elderly, we examinedpatients from the ASSENT-3 and ASSENT-3 PLUS trials with STEMI who were treated with tenecteplase (TNK) andunfractionated heparin (UFH) or enoxaparin, or half-dose TNK with abciximab and reduced-dose UFH.

Results Older patients had a higher risk profile, and lower use of concomitant therapies and revascularizationprocedures. We found an interaction between age and treatment effect for the efficacy end point ( P = .0007) and theefficacy plus safety end point ( P b .0001). Younger patients (b65 years) had a lower risk of the composite efficacy plus safetyend point with enoxaparin (relative risk [RR] 0.84, 95% CI 0.74-0.94) or abciximab (RR 0.79, 95% CI 0.69-0.90) comparedwith UFH. In patients N65 years of age, the benefit of enoxaparin appeared to be offset by an increased risk of bleedingcomplications. The risk of the efficacy plus safety end point tended to be higher in elderly patients receiving abciximab andhalf-dose TNK (RR 1.18, 95% CI 0.91-1.51 for 76-85 years of age and RR 1.48, 95% CI 0.88-2.49 for N85 years of age).

Conclusions Although TNK with either enoxaparin or abciximab appeared to be more effective than withstandard UHF in younger patients, these combinations tended to be less effective and even may be unsafe in the elderly.Development of new combination strategies and dosing schemes of fibrinolytics and antithrombotics with improvedefficacy and safety in the elderly remains a high priority. (Am Heart J 2006;152:684.e12684.e9.)

Patients N75 years of age constitute 6% of the US

population, but they represent over half of all deaths

after a myocardial infarction (MI). Increasing age is

indeed the most important adverse prognostic factor

after an MI.1,2 Demographic risk factors such as female

sex, low body weight, anterior wall infarction and

previous MI, Killip class III to IV, and hypertension tend

be more prevalent in the elderly population, which in

part explains their poorer outcome.3-8 Elderly patients

From the aDepartment of Cardiology, University Hospital Gasthuisberg, Leuven, Belgium,bDuke Clinical Research Center, Durham, NC, cCardiology Department, Bichat Hospital,

Paris, France, dRegional Medical Cardiology Centre, Royal Victoria Hospital, Belfast,

Northern Ireland, eDepartment of Cardiology, University of Alberta, Edmonton, Canada,

and fDepartment of Cardiology University Hospital, Uppsala, Sweden.

Submitted October 5, 2005; accepted July 3, 2006.

Reprint requests: Peter R. Sinnaeve, MD, PhD, Department of Cardiology, University

Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium.

E-mail: [email protected]

0002-8703/$ - see front matter

n 2006, Mosby, Inc. All rights reserved.

doi:10.1016/j.ahj.2006.07.005

are also more likely to have adverse events,

especially intracranial hemorrhage (ICH) and other

major bleeding complications.8 Thus, the elderly present

an important challenge to the clinician: they are both in

greatest need of more effective antithrombotic therapy

and at greatest risk of complications from the therapy.

More aggressive antithrombotic therapies have been

introduced in an effort to decrease the rate of recurrent

ischemia and reinfarction after thrombolysis in patients

with ST-elevation MI. Glycoprotein IIb/IIIa inhibitors

have been combined with reduced-dose lytics to offset

the increased risk of bleeding complications, especially

in the elderly.9-12 In the ASSENT-3 trial, conjunctive

therapy with enoxaparin and full-dose TNK, or abcix-

imab and half-dose TNK reduced the composite end

point of death, reinfarction, and refractory angina

compared with unfractionated heparin (UFH) in patients

treated with TNK (relative risk 0.74, 95% CI 0.63-0.87 for

enoxaparin and relative risk 0.72, 95% CI 0.61-84 for

abciximab, respectively).12 Based on dividing age by

Figure 1

Design and therapies in ASSENT-3 and ASSENT-3 PLUS.

Table I. Baseline characteristics

VVVVVVVVVVVVVVVVVVVVVVVVVVVVV__65 y (n = 4777) 66-75 y (n = 1925) 76-85 y (n = 905) NNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNN85 y (n = 145)

Age (y) 53 F 8 70 F 3 80 F 3 88 F 2Female (%) 15.8 30.6 43.5 52.4Weight (kg) 81 F 16 76 F 13 72 F 13 67 F 13Diabetes (%) 14.9 22.2 20.4 16.0Time from symptom to start of TNK-tPA (h)

Mean 2.8 F 2.1 3.0 F 1.6 3.1 F 1.6 3.4 F 1.5Median (25th, 75th) 2.5 (1.7, 3.6) 2.7 (1.9, 4.0) 2.8 (1.9, 4.1) 3.1 (2.2, 4.5)

Time from symptom to admission (h)Mean 2.5 F 1.7 2.8 F 1.6 2.8 F 1.6 3.1 F 1.5Median (25th, 75th) 2.3 (1.5, 3.5) 2.5 (1.6, 3.7) 2.5 (1.7, 3.8) 2.8 (2.0, 4.2)

Heart rate (beat/min) 75 F 17 74 F 18 74 F 19 81 F 21Systolic BP (mm Hg) 132 F 22 134 F 24 135 F 25 132 F 26Killip III/IV (%) 0.7/0.3 1.8/0.8 2.4/0.8 4.7/1.6Anterior wall MI (%) 38.6 42.6 45.1 49.3Previous MI (%) 12.2 16.4 17.4 22.8Previous PCI (%) 6.8 6.2 4.7 2.8Previous CABG (%) 2.3 4.2 3.5 1.4Length of hospitalization (d)

Mean 8.7 F 5.6 10.9 F 7.2 13.3 F 9.0 14.3 F 10.0Median (25th, 75th) 7 (5, 10) 9 (6, 13) 10 (6, 17) 10 (6, 27)

tPA, Tissue plasminogen activator; BP, blood pressure; PCI, percutaneous coronary intervention; CABG, coronary artery bypass graft.

American Heart Journal

October 2006684.e2 Sinnaeve et al

V75 versus N75 years, the treatment effect was similar

according to age for enoxaparin, but less effective or

perhaps even harmful for abciximab in the older

patients. In the prehospital arm of the ASSENT-3 trial

(ASSENT-3 PLUS), a reduction in the composite efficacy

end point (14.2% vs 17.4%) and efficacy plus safety end

point (18.3% vs 20.3%) was observed in the enoxaparin

group, none of them significant.13 There was no effect

on both end points in patients N75 years of age, but

enoxaparin was associated with significantly higher risk

of ICH in the elderly.

In the present study, we aim to describe in more detail

the elderly in ASSENT-3, ASSENT-3 PLUS, and in pooled

populations from both trials, and to provide additional

Table III. Outcome according to age (%)

VVVVVVVVVVVVVVVVVVVVVVVVVVVVV__65 y 66-75 y 76-85 y NNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNN85 y P

Mortality (30-d) 2.9 7.5 17.3 24.1 b.0001Mortality (1 y) 4.5 11.3 23.2 32.7 b.000130-d stroke 0.25 0.99 0.99 4.83 b.0001Inhospital ICH 0.61 1.56 2.21 2.07 b.0001Inhospital major bleed 1.9 4.0 7.3 11.0 b.0001Inhospital transfusion 2.8 5.7 10.2 16.7 b.000112-h aPTT above

target8.9 11.3 16.3 15.6 b.0001

CKN 3� ULN 72 64 58 49 b.0001CK-MBN 3� ULN 63 63 58 52 .0005Serious Pulmonary

edema1.8 4.0 5.4 9.0 b.001

Cardiogenic shock 0.3 0.8 0.8 1.6 .004

ULN, Upper limit of normal.

Table II. Concomitant medication and procedures

VVVVVVVVVVVVVVVVVVVVVVVVVVVVV__65 y 66-75 y 76-85 y NNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNNN85 y P

Inhospital medicationh-Blocker (%) 87.9 82.3 77.4 73.8 b.001ACE inhibitor (%) 59.6 66.0 65.5 55.7 b.001Statin (%) 59.7 52.3 45.1 17.4 b.001Aspirin (%)* 97.4 95.9 95.7 95.2 .0014

Inhospital proceduresAngiogram (%) 51.9 49.5 35.8 17.4 b.001PCI (%) 36.9 30.4 23.7 11.8 b.001CABG (%) 3.9 5.1 4.3 1.4 .0385

*Within 12 hours or upon randomization.

Table IV. Effects of antithrombotic treatments on outcome (%) (ASSENT-3 and ASSENT-3 PLUS combined)

Age UFH (n = 2859) Enoxaparin (n = 2858) P

Efficacy (30-d mortality, inhospital reinfarction,inhospital refractory ischemia)

V65 9.3 (161/1723) 6.8 (120/1752) .00766-75 12.9 (94/729) 11.6 (80/689) .46576-85 21.6 (76/352) 20.2 (73/362) .639N85 27.5 (14/51) 28.0 (14/50) .951

Efficacy and safety (30-d mortality, inhospitalreinfarction, inhospital refractory ischemia,ICH, or major bleeding)

V65 10.9 (188/1722) 8.3 (146/1751) .01066-75 15.9 (116/728) 16.5 (114/689) .75576-85 26.1 (92/352) 26.5 (96/362) .908N85 29.4 (15/51) 36.0 (18/50) .480

Death (30-d) V65 3.0 (51/1723) 2.6 (46/1752) .55066-75 7.1 (52/729) 7.5 (52/689) .76576-85 16.2 (57/352) 16.3 (59/16.3) .970N85 21.6 (11/51) 26.0 (13/50) .601

Reinfarction V65 4.8 (82/1726) 2.7 (47/1755) .00166-75 3.3 (24/729) 2.9 (20/690) .66976-85 7.1 (25/352) 3.9 (14/362) .057N85 5.9 (3/51) 2.0 (1/50) .617*

Refractory ischemia V65 6.6 (114/1726) 4.3 (76/1755) .00366-75 6.2 (45/729) 4.8 (33/690) .25176-85 6.5 (23/352) 5.0 (18/362) .370N85 5.9 (3/51) 4.0 (2/50) 1.000*

Intracranial hemorrhage V65 0.6 (10/1726) 0.7 (13/1755) .55766-75 1.9 (14/729) 1.3 (9/690) .35876-85 0.6 (2/352) 3.6 (13/362) .005N85 2.0 (1/51) 2.0 (1/50) 1.000*

Major bleeding V65 1.7 (30/1724) 1.5 (26/1754) .54666-75 2.6 (19/728) 5.2 (36/690) .01176-85 4.8 (17/352) 7.2 (26/362) .186N85 2.0 (1/51) 14.0 (7/50) .031*

*Fisher exact test.

American Heart Journal

Volume 152, Number 4Sinnaeve et al 684.e3

insight on the risk and benefit of novel antithrombotic

regimens according to age.

MethodsPatients

In the ASSENT-3 trial, 6095 patients with acute MI were

randomized to 1 of 3 regimens: full-dose weight-adjusted

tenecteplase (TNK) and enoxaparin, half-dose weight-adjusted

TNK plus weight-adjusted reduced-dose UFH and abciximab,

and full-dose TNK and weight-adjusted UFH. In the prehospital

ASSENT-3 PLUS arm, 1639 patients were randomized to full-

dose weight-adjusted TNK and enoxaparin, or weight-adjusted

TNK plus weight-adjusted reduced-dose UFH. Patients

z18 years of age presenting with typical chest pain within

6 hours of symptom onset and with ST-segment elevation were

eligible. Details of the protocol and treatment regimens have

Table V. Effects of antithrombotic treatments on outcome (%) (ASSENT-3 only)

Age UFH (n = 2038) Enoxaparin (n = 2040) Abciximab (n = 2017) P

Efficacy (30-d mortality, reinfarction,inhospital refractory ischemia)

V65 9.3 (117/1261) 7.0 (90/1282) 5.7 (73/1282) .00266-75 13.2 (67/506) 10.2 (50/492) 11.2 (56/501) .29976-85 23.4 (56/239) 18.7 (43/230) 24.7 (47/190) .279N85 18.8 (6/32) 27.3 (9/33) 32.6 (14/43) .410

Efficacy and safety (30-d mortality,inhospital reinfarction, inhospitalrefractory ischemia, ICH, or major bleeding)

V65 10.6 (133/1260) 8.2 (105/1282) 7.6 (97/1282) .01966-75 16.2 (82/505) 14.6 (72/492) 15.4 (77/500) .78276-85 26.8 (64/239) 24.3 (56/230) 34.2 (65/190) .070N85 21.9 (7/32) 27.3 (9/33) 46.5 (20/43) .055

Death (30-d) V65 3.0 (38/1261) 2.7 (34/1282) 3.0 (39/1282) .80766-75 8.1 (41/506) 6.9 (34/492) 8.2 (41/501) .70376-85 16.7 (40/239) 14.3 (33/230) 21.6 (41/190) .143N85 9.4 (3/32) 24.2 (8/33) 25.6 (11/43) .182

Death (1-y)* V65 4.2 4.2 4.9 .64666-75 10.3 10.8 12.3 .68076-85 21.5 19.7 26.5 .455N85 19.1 45.5 32.6 .294

Reinfarction V65 4.3 (54/1261) 2.6 (33/1284) 1.4 (18/1282) b.00166-75 3.0 (15/506) 2.8 (14/493) 3.6 (18/501) .76576-85 5.9 (14/239) 2.6 (6/230) 3.2 (6/190) .157N85 9.4 (3/32) 0.0 (0/33) 2.3 (1/43) .140y

Refractory ischemia V65 6.5 (82/1261) 4.4 (57/1284) 2.9 (37/1282) b.00166-75 5.7 (29/506) 4.3 (21/493) 3.2 (37/1282) .14376-85 7.5 (18/239) 6.1 (14/230) 3.7 (7/190) .243N85 9.4 (3/32) 3.0 (1/33) 9.3 (4/43) .591*

Intracranial hemorrhage V65 0.4 (5/1261) 0.5 (6/1284) 0.5 (6/1282) .95366-75 2.4 (12/506) 1.6 (8/493) 1.4 (7/501) .47676-85 0.4 (1/239) 1.3 (3/230) 2.6 (5/190) .136*N85 3.1 (1/32) 3.0 (1/33) 2.3 (1/43) 1.000*

Major bleeding V65 1.6 (20/1259) 1.5 (19/1284) 2.6 (33/1282) .08166-75 2.6 (13/505) 4.9 (24/493) 4.4 (22/500) .14376-85 4.2 (10/239) 7.4 (17/230) 12.1 (23/190) .009N85 3.1 (1/32) 6.1 (2/33) 18.6 (8/43) .093*

*Estimates from Kaplan-Meier analysis.yFisher exact test.

American Heart Journal

October 2006684.e4 Sinnaeve et al

been reported in the primary manuscripts and summarized in

Figure 1.12,13 Only long-term follow-up data from the main arm

of the study was used to report 1-year mortality rates.

End pointsThe primary end points were the composites of 30-day

mortality, inhospital reinfarction, or inhospital refractory

ischemia (primary efficacy end point), and the above plus

inhospital ICH or inhospital major noncerebral bleeding

(primary efficacy plus safety end point). All stroke cases were

reviewed by members of a stroke review committee who were

unaware of treatment assignment. There was no central

adjudication for the end points of reinfarction, refractory

ischemia, and bleeding complications. However, definitions

were provided to the investigators who, in addition, had to

confirm the occurrence of these end points on a special form.

Statistical methodsDiscrete variables are summarized with frequencies and

percentages; continuous variables are described as median

with 25th and 75th percentiles. The relationship of age and

mortality was evaluated with the use of a logistic regression

model. Treatment effects were evaluated according to age

subgroups using v2 test, and testing was done for interaction

of treatment effect and age. The age categories used in this

study were not prespecified per protocol. Kaplan-Meier

curves for mortality, efficacy, and efficacy plus safety were

calculated to show the treatment effects across the different

age groups. Although we considered P b .05 to be nominally

statistically significant, the results should be interpreted with

caution given the multiple comparisons and exploratory

nature of these analyses. The combined ASSENT-3 and

ASSENT-3 PLUS analysis in elderly patients was not prespeci-

fied per protocol.

ResultsPatients N75 years of age represented 15.7% of the

study population (n = 1050). Ninety-five patients were

between 86 and 90 years of age and 13 were N90 years

of age. The oldest patient was 95 years of age at the

time of randomization. Baseline characteristics accord-

ing to age group are shown in Table I. Older patients

had a higher risk profile: they included more female

patients and patients with a lower body weight, more

patients with anterior wall MI, or presenting with

Figure 2

A, Risk ratios and 95% CI for the risk composite efficacy end point (death, reinfarction, and refractory angina), and efficacy and safety end point(efficacy plus ICH and noncerebral major bleeding complications) in patients treated with enoxaparin versus UFH. B, Risk ratios and 95% CI forthe risk composite efficacy end point (death, reinfarction, and refractory angina), and efficacy and safety end point (efficacy plus ICH andnoncerebral major bleeding complications) in patients treated with abciximab versus UFH (results from ASSENT-3 and ASSENT-3 PLUS).

American Heart Journal

Volume 152, Number 4Sinnaeve et al 684.e5

Killip class III to IV. Older patients were more likely to

have had a previous MI. They also had longer delays

between onset of symptoms and treatment initiation

and longer hospitalizations.

Elderly patients also generally received less evidence-

based concomitant therapies (Table II). Especially

statins were used less frequently in patients N75 years

of age. In contrast, aspirin use was very high across

all age groups. The use of angiotensin-converting

enzyme (ACE) inhibitors was also more equally distrib-

uted across different age groups. Both angiography

and revascularization procedures were less common

with increasing age (Table II), except for bypass

surgery, which was most common in the 66- to 75-year

age group.

Thirty-day and 1-year mortality rates increased mark-

edly with advancing age (Table III). Thirty-day mortality

in patients aged N75 years was 18.2% compared with

Figure 3

Composite efficacy (panel A) and efficacy plus safety (panel B) end points as a function of age.

American Heart Journal

October 2006684.e6 Sinnaeve et al

4.2% in patients b75 years of age. Total and hemorrhagic

stroke rates also increased with age, as were major

bleeding complications and the need for transfusion.

Target activated partial thromboplastin times (aPTTs)

after 12 hours were more frequently above target limit in

patients N75 years of age. Total creatine kinase (CK) and

the CK-MB fraction tended to decrease with age.

Furthermore, elderly patients were more likely to

develop postinfarction complications, including much

higher rates of serious pulmonary edema and cardio-

genic shock (Table III).

Tables IV and V summarize composite individual end

points for patients per age category receiving different

antithrombotic therapies. Risk ratios are shown in

Figure 2, A and B (results from the 2 study arms

combined). In patients b65 years of age, both enox-

aparin and abciximab were clearly superior to UFH with

respect to the efficacy and efficacy plus safety end

points. When taking the 2 study arms together, enox-

aparin is not better than UFH in patients N65 years of

age, however, as shown by the composite efficacy plus

safety end point. Enoxaparin reduces ischemic compli-

cations after MI in all age groups, but this benefit is

offset by an age-dependent increase in major bleeding

complications. The rate of ICHs was especially high in

elderly receiving enoxaparin, which was mainly driven

by an excess of ICH in ASSENT-3 PLUS. Abciximab

tended to be less efficient or safe than UFH in patients

N75 years of age. In patients N75 years of age, major

bleeding complications were also more common with

abciximab than with conventional UFH.

Event curves as a function of age are shown in

Figure 3, A (efficacy) and Figure 3, B (efficacy plus

safety). We found a significant interaction between age

and treatment effect for the efficacy end point ( P =

.0007) and the efficacy plus safety end point ( P b

.0001). Enoxaparin and abciximab tended to be better

than UFH up to the age of 65 years for both primary end

points. Enoxaparin and abciximab were associated with

an age-dependent increase in both primary end points,

American Heart Journal

Volume 152, Number 4Sinnaeve et al 684.e7

an effect that was less pronounced for UFH. This

resulted in a crossover point at 75 years of age, after

which UFH tends to be more effective and safe than

enoxaparin or abciximab.

DiscussionWe have evaluated the effects of different antithrom-

botic strategies in combination with TNK on the elderly

in ASSENT-3 and ASSENT-3 PLUS. The present study

confirms findings from previous studies that mortality

increases dramatically with age after fibrinolysis for

acute MI.4,8 Enoxaparin with full-dose TNK appears to

be equally effective as UFH, but this benefit is offset by

an age-dependent increase in major bleeding complica-

tions and especially ICHs. Abciximab in combination

with half-dose TNK also appears to be less effective than

UFH in elderly patients. Moreover, ICH and major

bleeding rates are higher with abciximab in patients

N75 years of age.

When given with full-dose TNK, enoxaparin compared

favorably to UFH over all age categories except for the

very old as indicated by the efficacy end point. This

benefit seems to be offset largely by an increase in major

bleeding complications. The combination of abciximab

with half-dose TNK was significantly less effective and

safe than UFH in patients aged N75 years, in contrast

with the promising low efficacy plus safety end point

rate compared with UFH in younger patients. Similar

results have been observed in GUSTO-V with half-dose

reteplase and abciximab.11 Abciximab plus half-dose

reteplase also reduced nonfatal ischemic events post-

infarction in GUSTO-V in the overall population, but not

in patients N75 years of age.11 In contrast, abciximab

was also shown to be superior to placebo in elderly

patients (N65 years) with acute MI treated with primary

stenting.14 The reason why combination therapy is less

safe even when combining with half-dose lytics in

ASSENT-3 and GUSTO-V remains unclear.

Major noncerebral bleeding complications in the

elderly were modestly higher with enoxaparin and

markedly higher with abciximab compared with UFH.

Although a stricter and more conservative heparin

dosing scheme was used compared with that in GUSTO-

I, aPTT levels also tended to be more frequently above

target limits in patients N75 years of age, which might in

part be responsible for some of the bleedings. The

reason for over-anticoagulation in the elderly remains

unclear, but might reflect changes in pharmacokinetics

with age. It also demonstrates that anticoagulation

monitoring needs to be improved in these patients.

Finally, it remains difficult to determine the real impact

of abciximab on outcome in the elderly.15 An increased

risk of bleeding complications in the elderly might be

associated with a higher incidence of anemia, which

might precipitate reinfarction.

In elderly patients, inappropriately high levels of

enoxaparin may cause an increased risk of bleeding

complications when combined with fibrinolysis. Never-

theless, when using a weight-adjusted dose of enoxa-

parin, only severely decreased renal function, but not

age, appears to affect anti-Xa levels independently.16 In

ASSENT-3 and ASSENT-3 PLUS, patients with impaired

renal function (creatinine N2.5 mg/dL for men or

N2.0 mg/dL for women) were excluded. Still, impaired

renal function tends to occur more frequently in the

elderly, which might indirectly lead to inappropriately

high levels of enoxaparin causing an increased risk of

bleeding complications. On the other hand, decreased

renal function was not found to be associated with a

higher incidence of bleeding complications with enox-

aparin in patients treated with fibrinolysis in the

CLARITY study, although no patients N75 years of age

were included.17 In the ExTRACT study, which com-

pared enoxaparin with UFH in patients with STEMI

receiving fibrinolysis, patients N75 years of age received

no bolus and a reduced maintenance dose of enoxaparin

(0.75 mg/kg BID). Although the exact impact of this

dose on bleeding complications in the elderly has not

yet been reported by the authors, no significant

interaction between treatment and age was observed for

the primary efficacy end point.18 Interestingly, when

dose reduction of enoxaparin (65%) was left to the

discretion of the physician in a study of unselected

patients with acute coronary syndrome, elderly subjects

had more frequently suboptimal anti-Xa levels, which

was associated with worse outcome.19

Elderly patients had a higher risk of ICH. Comparable

to rates in GUSTO-I and GUSTO-V.8,11 Intracranial

hemorrhage rate is N3 times as frequent in patients

N75 years of age compared with those b65 years of age.

Intracranial hemorrhage is more frequent in elderly

patients receiving enoxaparin or abciximab. Neverthe-

less, the ASSENT-3 study was underpowered to demon-

strate any difference in ICH between treatments.

Because of the very small number of events, there is also

considerable variation in ICH rate in different treatment

and age groups.

As in previous trials, elderly patients tended to receive

less evidence-based co-therapy. Aspirin, h-blockers and

statins were less frequently given to older patients. The

lower percentage of patients N75 years of age receiving

aspirin in ASSENT-3 and ASSENT-3 PLUS might reflect

the hesitance of some investigators to add aspirin to

more aggressive antithrombotic treatment, especially in

the elderly. In this respect, a similar rationale has led the

investigators in another trial comparing enoxaparin with

UFH in ST-elevation MI to withhold aspirin until after the

study period.20 In contrast, ACE inhibitors were pre-

scribed more frequently in patients between 65 and

85 years of age, perhaps reflecting the higher incidence

of heart failure in the elderly. We did not record

American Heart Journal

October 2006684.e8 Sinnaeve et al

contraindications against evidence-based therapies,

which might in part explain less frequent use in

elderly. Nevertheless, previous studies have reported a

similar underuse of proven drugs despite adjustments

for contraindications.21

Angiography and revascularization procedures were

markedly less common in patients N75 years of age. In

the second NRMI-2 registry, 63% of patients N70 years of

age had a cardiac catheterization compared with 85% of

those b49 years of age.22 In contrast, only 20% of

patients N75 years of age underwent a cardiac catheter-

ization during their hospital stay in a population of

192311 Medicare patients.23 Because mortality after an

acute MI in the elderly is markedly higher than in

younger patients, the reason for withholding angiogra-

phy or revascularization in older patients remains

unclear, but is probably multifactorial. Elderly patients

are more likely to have more extensive coronary

lesions.8,24 Investigators might also be apprehensive in

performing angiography or percutaneous coronary in-

tervention in elderly patients receiving low-molecular-

weight heparin or glycoprotein IIb/IIIa antagonists.

This study has some potential limitations. The overall

sample size is too small to comment on mortality

differences between treatment groups. In addition, some

of the subgroups might also be too small to draw

conclusions, especially in the very old. Furthermore,

clinical trials generally enroll lower-risk patients when

compared with those treated in daily practice. There-

fore, the elderly in ASSENT-3 and ASSENT-3 PLUS may

have relatively lower rates of complications than the

general elderly population.

In conclusion, the present analysis confirms that

elderly patients represent a high-risk population and are

at increased risk of death and major bleeding complica-

tions. Although the combination of half-dose fibrinolytic

agent plus abciximab is a safe and effective therapeutic

option in patients b65 years of age with an acute MI,

data from ASSENT-3 and ASSENT-3 PLUS suggest that

half-dose fibrinolytic and abciximab might be unsafe and

even less effective in the elderly. Enoxaparin as

adjunctive therapy to TNK appears to be at least as

effective as UFH except in the very elderly, but the risk

of major bleeding complications in full dosing is

unacceptably high in patients N75 years of age. Devel-

opment of new dosing schemes or treatment combina-

tions with improved efficacy and safety in the elderly

remains a high priority.

PR Sinnaeve is a Clinical Investigator of the Fund for

Scientific Research—Flanders (Belgium).

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