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 PLUS

Article Outline

• Abstract
• Methods
  • Patients
  • End points
  • Statistical methods
• Results
• Discussion
• Acknowledgment
• References
• Copyright

Background

Elderly patients with acute myocardial infarction are at particularly high risk for death and bleeding complications. 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 examined patients from the ASSENT-3 and ASSENT-3 PLUS trials with STEMI who were treated with tenecteplase (TNK) and unfractionated 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 revascularization procedures. We found an interaction between age and treatment effect for the efficacy end point (P = .0007) and the efficacy plus safety end point (P < .0001). Younger patients (<65 years) had a lower risk of the composite efficacy plus safety end 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) compared with UFH. In patients >65 years of age, the benefit of enoxaparin appeared to be offset by an increased risk of bleeding complications. The risk of the efficacy plus safety end point tended to be higher in elderly patients receiving abciximab and half-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 >85 years of age).

Conclusions

Although TNK with either enoxaparin or abciximab appeared to be more effective than with standard 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 improved efficacy and safety in the elderly remains a high priority.

Patients >75 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, ⁴, ⁵, ⁶, ⁷, ⁸ Elderly patients 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, ¹⁰, ¹¹, ¹² In the ASSENT-3 trial, conjunctive therapy with enoxaparin and full-dose TNK, or abciximab 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 ≤75 versus >75 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 >75 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 insight on the risk and benefit of novel antithrombotic regimens according to age.

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Methods 

Patients 

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 ≥18 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 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.

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• Figure 1. 

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

End points 

The 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 methods 

Discrete 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 χ² 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 < .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 prespecified per protocol.

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Results 

Patients >75 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 >90 years of age. The oldest patient was 95 years of age at the time of randomization. Baseline characteristics according 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 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.

Table I. Baseline characteristics

	≤65 y (n = 4777)	66-75 y (n = 1925)	76-85 y (n = 905)	>85 y (n = 145)
Age (y)	53 ± 8	70 ± 3	80 ± 3	88 ± 2
Female (%)	15.8	30.6	43.5	52.4
Weight (kg)	81 ± 16	76 ± 13	72 ± 13	67 ± 13
Diabetes (%)	14.9	22.2	20.4	16.0
Time from symptom to start of TNK-tPA (h)
Mean	2.8 ± 2.1	3.0 ± 1.6	3.1 ± 1.6	3.4 ± 1.5
Median (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 ± 1.7	2.8 ± 1.6	2.8 ± 1.6	3.1 ± 1.5
Median (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 ± 17	74 ± 18	74 ± 19	81 ± 21
Systolic BP (mm Hg)	132 ± 22	134 ± 24	135 ± 25	132 ± 26
Killip III/IV (%)	0.7/0.3	1.8/0.8	2.4/0.8	4.7/1.6
Anterior wall MI (%)	38.6	42.6	45.1	49.3
Previous MI (%)	12.2	16.4	17.4	22.8
Previous PCI (%)	6.8	6.2	4.7	2.8
Previous CABG (%)	2.3	4.2	3.5	1.4
Length of hospitalization (d)
Mean	8.7 ± 5.6	10.9 ± 7.2	13.3 ± 9.0	14.3 ± 10.0
Median (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.

Elderly patients also generally received less evidence-based concomitant therapies (Table II). Especially statins were used less frequently in patients >75 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 distributed 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.

Table II. Concomitant medication and procedures

Thirty-day and 1-year mortality rates increased markedly with advancing age (Table III). Thirty-day mortality in patients aged >75 years was 18.2% compared with 4.2% in patients <75 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 >75 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 cardiogenic shock (Table III).

Table III. Outcome according to age (%)

ULN, Upper limit of normal.

Table IV, Table 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 <65 years of age, both enoxaparin 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, enoxaparin is not better than UFH in patients >65 years of age, however, as shown by the composite efficacy plus safety end point. Enoxaparin reduces ischemic complications 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 >75 years of age. In patients >75 years of age, major bleeding complications were also more common with abciximab than with conventional UFH.

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

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

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• 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 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 abciximab versus UFH (results from ASSENT-3 and ASSENT-3 PLUS).

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 < .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, 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.

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• Figure 3. 

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

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Discussion 

We have evaluated the effects of different antithrombotic 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 complications 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 >75 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 >75 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 postinfarction in GUSTO-V in the overall population, but not in patients >75 years of age.¹¹ In contrast, abciximab was also shown to be superior to placebo in elderly patients (>65 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 >75 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. Nevertheless, when using a weight-adjusted dose of enoxaparin, 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 >2.5 mg/dL for men or >2.0 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 enoxaparin in patients treated with fibrinolysis in the CLARITY study, although no patients >75 years of age were included.¹⁷ In the ExTRACT study, which compared enoxaparin with UFH in patients with STEMI receiving fibrinolysis, patients >75 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 >3 times as frequent in patients >75 years of age compared with those <65 years of age. Intracranial hemorrhage is more frequent in elderly patients receiving enoxaparin or abciximab. Nevertheless, the ASSENT-3 study was underpowered to demonstrate 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, β-blockers and statins were less frequently given to older patients. The lower percentage of patients >75 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 prescribed 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 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 >75 years of age. In the second NRMI-2 registry, 63% of patients >70 years of age had a cardiac catheterization compared with 85% of those <49 years of age.²² In contrast, only 20% of patients >75 years of age underwent a cardiac catheterization 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 angiography 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 intervention 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. Therefore, 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 complications. Although the combination of half-dose fibrinolytic agent plus abciximab is a safe and effective therapeutic option in patients <65 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 >75 years of age. Development of new dosing schemes or treatment combinations with improved efficacy and safety in the elderly remains a high priority.

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PR Sinnaeve is a Clinical Investigator of the Fund for Scientific Research—Flanders (Belgium).

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