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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_4011_Библиотеки_им_академика_М_И_Перельмана
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370 Part IV / Practical Issues and Future Applications
Controlling Thrombotic Events, (EXCITE); postacute coronary syndromes, Orbofiban in
Patients with Unstable Coronary Syndromes (OPUS-TIMI 16), Sibrafiban Versus Aspirin
to Yield Maximum Protection from Ischemic Heart Events Post Acute Coronary Syn-
dromes (SYMPHONY), and 2nd SYMPHONY; and secondary prevention, Blockade of
the Receptor Against Vascular Occlusion (BRAVO). A sixth Phase III trial called PURPOSE
(Peripheral Arterial Disease Utilization of Roxifiban to Prevent Outcomes of Ischemic
Events) was initiated to study the effects of roxifiban in noncoronary vascular disease—
specifically, patients with peripheral arterial disease. This study was stopped early, but
details of the study design and outcomes have not been published to date.
From data in Phase II studies, moderate levels of platelet aggregation inhibition in 20 µM
ADP were targeted, ranging from a minimum of at least 25% inhibition with low-dose
sibrafiban to as high as 55–80% with the 50-mg twice-daily regimen of orbofiban in
OPUS-TIMI 16 and 60–90% with the 20-mg three times a day regimen in EXCITE. Syste-
matic measurement of platelet aggregation inhibition was not performed in Phase III, and
only SYMPHONY measured plasma concentrations of study drug. In that study >90% of
patients were within the target concentration range using dosing based on weight and serum
creatinine (23,24).
EXCITE
The EXCITE trial was the only Phase III study of the oral GPIIb/IIIa inhibitors speci-
fically for patients undergoing PCI (21). A total of 7232 patients undergoing elective PCI
were randomized in the EXCITE trial to one of two dose regimens of xemilofiban or
aspirin. Patients randomized to the xemilofiban arms received 20 mg of oral xemilofiban
30–90 min prior to the interventional procedure and then either 10 mg three times a day or
20 mg three times a day for 6 mo. All patients in the xemilofiban arms received background
aspirin therapy, and use of ticlopidine (250 mg twice-daily) was allowed for patients receiv-
ing a coronary stent during the interventional procedure. The primary endpoint was a com-
posite of death, myocardial infarction, or revascularization at 6 mo.
OPUS-TIMI 16
OPUS-TIMI 16 randomized 10,302 patients within 72-h of presentation with an acute
coronary syndrome to either aspirin or one of two dose regimens of orbofiban with back-
ground aspirin therapy (22). Patients did not have to be stabilized from their acute presen-
tation prior to randomization. Patients in both orbofiban treatment arms received orbofiban
50 mg twice daily for 30 d. Patients randomized to the 50/50 arm then received 50 mg
twice daily for the remainder of the study treatment period (planned 1 yr), and those ran-
domized to the 50/30 arm received 30 mg twice daily for the remainder of the treatment
period. No dose adjustments were made for renal function. Although planned for 1-yr fol-
low-up, the study was terminated early at 10 mo. The primary endpoint was a composite
of death, MI, ischemia leading to urgent revascularization, ischemia leading to rehospital-
ization, or stroke and was reported at both 30 d and 10 mo.
SYMPHONY
AND 2ND SYMPHONY
SYMPHONY and 2nd SYMPHONY were part of a development plan designed to test
the hypothesis that the more potent long-term platelet aggregation inhibition with an oral
inhibitor of the GPIIb/IIIa receptor would be more effective and better tolerated in secon-
dary prevention than long-term treatment with aspirin (23–25). As a proof of concept, the
SYMPHONY trial randomized 9233 high-risk acute coronary syndrome patients between
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Chapter 17 / Oral Agents 371
Table 3
Phase III trials of Oral Glycoprotein IIb/IIIa Inhibitors
Efficacy Target
Randomized analysis effect
b
Treatment
(no.) (no.) Agent
a
Indication Enrollment (%) duration Primary endpoint
EXCITE 7232 7232 Xemilofiban Elective 30–90 min before 6 mo Death, myocardial
10 mg tid percutaneous percutaneous 40–70 infarction,
20 mg tid coronary coronary 60–90 revascularization
intervention intervention
OPUS-TIMI 16 10,302 10,288 Orbofiban Post-acute Within 72 h Planned Death, myocardial
50/30 coronary 45–65 1 yr infarction, urgent
50/50 syndrome 55–80 revascularization,
rehospitalization,
stroke
SYMPHONY 9233 9169 Sibrafiban Post-acute 12 h to 7 d 90 d Death, myocardial
Low dose coronary ≥25 infarction, severe
High dose syndrome ≥50 recurrent ischemia
2nd SYMPHONY 6671 6637 Sibrafiban Post-acute 12 h to 7 d Planned Death, myocardial
Low dose coronary ≥25 12–18 mo infarction, severe
High dose syndrome ≥50 recurrent ischemia
BRAVO
c
9198 NA Lotrafiban Secondary >14 d (myocardial 60–70 Event driven; Death, myocardial
prevention infarction) ≥6 mo infarction, stroke,
>30 d (stroke) recurrent ischemia,
urgent revascularization
PURPOSE NA NA Roxifiban Peripheral NA NA NA NA
vascular disease
a
Background aspirin in all studies except SYMPHONY; only in low-dose arm of 2nd SYMPHONY.
b
Platelet aggregation inhibition, 20 µM ADP.
c
Study terminated early by Data and Safety Monitoring Committee.
(Adapted from ref. 41.)
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372 Part IV / Practical Issues and Future Applications
12 h and 7 d after presentation with either ST-segment elevation or non-ST-segment ele-
vation MI or unstable angina with documented ST-segment depression to either aspirin
80 mg twice daily or one of two dose regimens of sibrafiban (low- or high-dose) twice daily
without background aspirin therapy for 90 d (23,24).
A unique feature of the SYMPHONY trial was the requirement that patients be stable
without ongoing ischemia or hemodynamic instability and with Killip class <2 for at least
12 h prior to randomization. Furthermore, SYMPHONY was the first of the oral GPIIb/
IIIa inhibitor trials to assign treatment on the basis of estimated renal function. Patients
randomized in the low-dose arm received either 3, 4.5, or 6 mg of sibrafiban twice daily
based on weight and serum creatinine to achieve a target plasma concentration that would
yield at least 25% steady-state platelet aggregation inhibition with 20 µM ADP stimula-
tion. Similarly, patients in the high-dose arm received one of these same dose regimens,
but weight and serum creatinine were used to achieve at least 50% platelet aggregation
inhibition based on Phase II work. The primary endpoint of SYMPHONY was the 90-d
incidence of a composite of death, MI, or severe recurrent ischemia leading to unplanned
or unscheduled revascularization.
2nd SYMPHONY was designed to assess the effects of sibrafiban compared with aspirin
at longer treatment duration (12–18 mo) and also to allow an assessment of sibrafiban with
background aspirin vs aspirin alone and high-dose sibrafiban alone (25). Planned enroll-
ment was 8400 patients randomly assigned to one of three arms: aspirin 80 mg twice daily,
aspirin 80 mg twice daily plus low-dose sibrafiban twice daily based on weight and renal
function, or high-dose sibrafiban twice daily based on weight and renal function. After the
results of SYMPHONY were known, 2nd SYMPHONY was terminated early after enroll-
ing 6671 patients with moderate- to high-risk ACS, stable for at least 12 h and within 7 d
of presentation. Median treatment duration was 90 (36, 139) d, and median duration of fol-
low-up was 95 (65, 158) d. The primary endpoint was the time to a composite of death,
MI, or severe recurrent ischemia leading to unplanned or unscheduled revascularization.
BRAVO
The BRAVO trial was unique in testing an oral GPIIb/IIIa inhibitor in a true long-term
secondary prevention study (26). Furthermore, patients could be entered after either neu-
rologic (stroke or transient ischemic attack) or cardiac vascular events, or if they had doc-
umented multibed vascular disease (peripheral vascular disease with at least one of either
cerebrovascular disease or coronary artery disease). Patients had to have been stable for
at least 14 d after an ACS or 30 d after a stroke or transient ischemic attack. Prior to early
termination, a total of 9198 patients were randomized to either aspirin or lotrafiban [30 or
50 mg based on renal function (27) twice daily for a planned treatment duration of at least
6 mo in all patients. The primary endpoint was the time to a composite of death, MI, stroke,
recurrent ischemia, or urgent revascularization.
Results
The primary efficacy and bleeding results of the published Phase III trials of oral GPIIb/
IIIa inhibitors are summarized in Figs. 2 and 3, respectively (21,22,24,25). Overall, no trial
revealed a benefit of the oral GPIIb/IIIa inhibitor compared with aspirin on its primary
composite endpoint. However, in each trial bleeding was increased in a dose-dependent
fashion among patients treated with the GPIIb/IIIa inhibitor, suggesting that an increased
antiplatelet effect was achieved. A brief summary of key results of individual studies follows.
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Chapter 17 / Oral Agents 373
EXCITE
In EXCITE, there were no significant differences between treatment groups in the 6-mo
primary death, MI, or urgent revascularization composite endpoint (21). However, the
patterns of the component outcomes shown in Fig. 4 were interesting. Although the over-
all event rate was low, among patients treated with xemilofiban 10 mg, mortality was sig-
nificantly increased at 6 mo compared with aspirin-treated patients (1.7% vs 1.0%, p =
0.04) but was not increased among patients treated with xemilofiban 20 mg (1.1% vs 1.0%,
p = 0.68) (21). Similar to trials of intravenous GPIIb/IIIa inhibitors used for PCI, there was
a significant reduction in MI within 24 h post-PCI in both xemilofiban-treated groups
Fig. 2. Primary efficacy results from published Phase III trials of oral GPIIb/IIIa inhibitor trials.
*, Low-dose refers to the arm containing the lower of the two doses of oral agent, as outlined in Table 3.
**, High-dose refers to the arm containing the higher dose of the oral agent. Primary composite end-
points for each trial are listed in Table 3.
Fig. 3. Bleeding outcomes in the published phase III trials of oral GPIIb/IIIa inhibitors. For asterisks ,
see Fig. 2 legend.
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374 Part IV / Practical Issues and Future Applications
compared with aspirin (Fig. 5) (21). However, at 6 mo, the MI rates were similar between
the groups (aspirin, 8.4%; xemilofiban 10 mg, 8.1%; and xemilofiban 20 mg, 7.5%), sug-
gesting that the rates of MI in the xemilofiban groups during longer term treatment were
higher than in the aspirin group.
The EXCITE results raised questions about the administration of an oral agent with a
time to peak antiaggregatory effect of 4 h only 60–90 min prior to PCI. However, the reduc-
tion in MI in the immediate postprocedure period suggests that even for the low-dose arm
this cannot be the full explanation for the failure to realize a treatment benefit from long-term
administration of xemilofiban. The short half-life of xemilofiban and need for frequent
multiple doses coupled with a high peak/trough ratio may, however, have left receptors unoc-
cupied and vulnerable to fibrinogen binding, particularly at the end of a dosing interval or
in situations of missed doses. Subsequent studies have also suggested that xemilofiban has
intrinsic activating properties that could be either proinflammatory, prothrombotic, or both
(28–33). These findings are not consistently reproducible, however, and a recent study has
suggested that even though xemilofiban does possess receptor activating properties, under
conditions more closely approximating physiologic, increased platelet aggregation does
not result (34).
OPUS-TIMI 16
As in EXCITE, within the overall neutral result on the primary endpoint was a finding
of increased mortality, both at 30 d and at 10 mo (22). In fact, the excess mortality observed
in the 50/30 arm (which was statistically significant) resulted in early termination of enroll-
ment in OPUS-TIMI 16 and ultimately early termination of the treatment and follow-up for
all enrolled patients. Final data revealed significantly higher mortality in both orbofiban-
treated groups compared with aspirin-only patients (orbofiban 50/30, 5.1%; orbofiban
50/50, 4.5%; aspirin alone, 3.7%) (Fig. 6). A blinded cause-of-death analysis identified an
excess of death classified as owing to new thrombotic events among both orbofiban groups
compared with the aspirin-only group. Although the data were not statistically significant,
MI alone and death or MI rates were also higher among orbofiban-treated patients (Fig. 6).
Fig. 4. Secondary efficacy endpoints in the EXCITE trial.
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Chapter 17 / Oral Agents 375
A number of subgroup analyses were performed in an attempt to understand the lack
of treatment benefit overall and increased mortality observed among orbofiban-treated
patients in OPUS-TIMI 16 (22). The only subgroup in which there was an associated treat-
ment benefit for orbofiban was the group of patients who underwent PCI for the index ACS
event while on study drug. Patients with particularly adverse effects of treatment included
those with creatinine clearance ≤ 100 mL/min and those who were more unstable at entry,
including Killip class ≥II. These findings raised questions about trial design such as not
Fig. 5. Myocardial infarction occurring within 24 h after percutaneous coronary intervention by ran-
domized treatment assignment in the EXCITE trial. (From ref. 21, with permission.)
Fig. 6. Secondary efficacy endpoints in the OPUS-TIMI 16 trial.
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376 Part IV / Practical Issues and Future Applications
adjusting dose for renal function despite orbofiban’s renal elimination. Finally, the need
for concomitant antithrombin therapy in conjunction with oral GPIIb/IIIa inhibitor ther-
apy was raised by the observation that patients who received either low-molecular-weight
heparin or unfractionated heparin with orbofiban had fewer recurrent ischemic events dur-
ing the first 2 d of treatment than those who did not. This finding was not observed in the
SYMPHONY or 2nd SYMPHONY databases, however (Newby, unpublished data).
As with all first-generation agents, the pharmacokinetic and pharmacodynamic proper-
ties of orbofiban may have contributed to the observed results of the OPUS-TIMI 16 trial
by potentially leaving activated receptors unoccupied and vulnerable to fibrinogen bind-
ing at trough concentrations at the end of dosing intervals. Furthermore, like xemilofiban,
orbofiban has also been shown in some studies, but not all, to have partial activating prop-
erties that could be prothrombotic and/or proinflammatory and contribute to increased
thrombotic events over the course of therapy (28–33,35,36).
Preliminary reports of genotyping for the Pl
A2
polymorphism of the GPIIIa receptor sub-
unit among a subset of OPUS-TIMI 16 patients suggest that patients carrying the Pl
A2
allele
may be less responsive to treatment, whereas Pl
A1/A1
homozygotes have lower event rates
with orbofiban treatment (Fitzgerald, Leuven Symposium, 2000). Finally, in vitro data
in cultured rat cardiomyocytes suggest that orbofiban (and xemilofiban) may have direct
toxic effects resulting from binding proteins other than the GPIIb/IIIa receptor, in this case
procaspase-3, with resultant activation to caspase-3, leading to induction of apoptosis (37,
38). Such an effect could help to explain the observation of greater increases in mortality
than in MI and other ischemic events among patients treated with these agents.
SYMPHONY
AND 2ND SYMPHONY
In SYMPHONY, the effect of sibrafiban at low and high dose (without background
aspirin therapy) on the 90-d composite endpoint of death, MI, or severe recurrent ische-
mia was similar to that of aspirin (24). In this study death was only slightly higher in the
sibrafiban-treated groups (2.0% for both the low- and high-dose sibrafiban groups) com-
pared with aspirin-treated patients (1.8%). However, there was a nonsignificant, but dose-
dependent increase in the MI and the death or MI composite (Fig. 7). Unlike OPUS-TIMI
16, multiple subgroup analyses revealed no subgroups for which there was a statistically
significant treatment interaction.
The major criticism of the SYMPHONY trial design before the results of OPUS-TIMI
16 and EXCITE were known was the lack of background aspirin therapy in the sibrafiban
treatment arms. Although aspirin is a weak antiplatelet agent, it is possible that its inhibi-
tion of platelet activation as well as its antiinflammatory properties could be important even
as background therapy with a more potent aggregation inhibitor. Furthermore, even though
weak, its antiaggregatory effect during periods of low sibrafiban concentration at the end
of dosing intervals or with treatment interruptions could have been important. Ultimately,
the results were similar to those for orbofiban and xemilofiban administered with aspirin,
as would also be shown in 2nd SYMPHONY. Furthermore, the SYMPHONY trial in which
background aspirin was not used, in conjunction with 2nd SYMPHONY, supports the
notion that no adverse treatment interaction between aspirin and the oral GPIIb/IIIa inhib-
itors contributed to the unexpected findings of OPUS-TIMI 16 and EXCITE. Fewer data
are available regarding proinflammatory or prothrombotic properties of sibrafiban, but
no such evidence has been published to date (39).
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Chapter 17 / Oral Agents 377
Despite the addition of aspirin to the low-dose sibrafiban arm of 2nd SYMPHONY,
the results of the study were similar to all previous studies of the oral GPIIb/IIIa inhibitors
(25). There was no effect of sibrafiban therapy at low or high dose on the time to or inci-
dence of the primary triple composite endpoint of death, MI, or severe recurrent ische-
mia. Mortality was increased significantly in the high-dose arm relative to aspirin alone
[2.4% vs 1.3%, odds ratio (OR) 1.83 (1.17–2.88)] and nonsignificantly by 31% in the low-
dose arm (1.7%) compared with the aspirin arm (1.3%). Blinded cause-of-death review
revealed an excess of ischemic event and sudden deaths among high-dose patients. As shown
in Fig. 8, MI was similar in the low-dose sibrafiban and aspirin arms but significantly
higher in the high-dose sibrafiban arm. The composite of death or MI increased in a dose-
dependent fashion, significantly so in the high-dose arm. These results suggest that there
was no additive effect of aspirin with sibrafiban across the spectrum of treatment duration
in 2nd SYMPHONY.
In 2nd SYMPHONY, there was the opportunity to observe event rates after the with-
drawal of study drug at the early termination of the trial (25). No differences in 30-d post-
treatment rates of death, MI, or their composite were observed to suggest rebound events
at treatment interruption.
BRAVO
After the results of the four previous trials were known, BRAVO continued to enroll
patients under the close scrutiny of its Data and Safety Monitoring Committee (DSMC)
for any unfavorable effects on mortality or other thrombotic events. After enrolling 9198
patients, the trial was stopped by its DSMC in December of 2000 when an increase in
mortality of a magnitude similar to that in the other oral agent trials was observed. At the
point of early termination, preliminary data revealed an increase in mortality in the lotrafi-
ban arm (2.7%) relative to placebo (2.0%) that was statistically significant (p = 0.022) (40).
Similar to previous trials, bleeding was also significantly increased in lotrafiban-treated
patients. Although not observed with xemilofiban, orbofiban, or sibrafiban, these prelim-
inary results also suggested that lotrafiban treatment was associated with significantly more
thrombocytopenia. Because the adverse effects were not offset by any beneficial effects,
Fig. 7. Secondary efficacy endpoints in the SYMPHONY trial.
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378 Part IV / Practical Issues and Future Applications
the DSMC recommended early termination, which followed. In the preliminary report,
there were no differences in treatment effect in patients enrolled after an ACS or with
stroke or transient ischemic attack. Data collection was completed, and publication of the
final results is expected.
The preliminary BRAVO results do help to dispel some of the trial design concerns
raised by previous trials. As in the SYMPHONY studies, despite dosing based on renal
function and the requirement for stabilization prior to enrollment, there was no overall
treatment effect in preliminary analysis, and, similarly, higher mortality was observed in
lotrafiban-treated patients as in the GPIIb/IIIa inhibitor-treated groups in the earlier
studies. Additional review of the final data may offer further insights into the failure of
these agents.
SYSTEMATIC OVERVIEWS OF PHASE III TRIALS
Odds ratios with 95% confidence intervals for mortality for the combined oral GPIIb/
IIIa treatment arms compared with aspirin during the primary treatment period in each
oral GPIIb/IIIa inhibitor trial are shown in Fig. 9. As previously noted, mortality was low
overall. In both OPUS and 2nd SYMPHONY, mortality was significantly increased rela-
tive to aspirin control. In EXCITE and SYMPHONY, the point estimates of the odds ratios
favored aspirin treatment but were not statistically significant. Pooled, the odds ratio for
mortality for patients treated with GPIIb/IIIa inhibitors relative to aspirin control was 1.31
(1.12–1.53), p = 0.0001 (41). The pattern of results was not different after stratifying by
background aspirin therapy: for GPIIb/IIIa inhibitor alone vs aspirin (SYMPHONY and
high-dose arm of 2nd SYMPHONY), the pooled odds ratio for mortality was 1.37 (1.00–
1.86), and for GPIIb/IIIa inhibitor plus aspirin vs aspirin it was 1.38 (1.15–1.86) (41).
Blinded cause-of-death reviews were performed in both OPUS and 2nd SYMPHONY and
suggested that much of this mortality excess may have been accounted for by more ische-
mic/thrombotic event deaths in oral GPIIb/IIIa inhibitor-treated patients (22,25).
In another metaanalysis using a uniform 30-d endpoint for analysis, mortality was
similarly increased in GPIIb/IIIa inhibitor-treated patients compared with aspirin-treated
Fig. 8. Secondary efficacy endpoints in the 2nd SYMPHONY trial. *, Low-dose sibrafiban patients
received background aspirin therapy.
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Chapter 17 / Oral Agents 379
patients (42). Although the association of oral GPIIb/IIIa inhibitor treatment with increased
mortality is highly consistent, the relationship of treatment with MI is dependent on tim-
ing and what trials are included (41,42). As discussed, MI within the first 24 h after PCI in
EXCITE was associated with lower rates of MI in both xemilofiban treatment arms. Driven
by inclusion of these endpoint data, a meta-analysis including xemilofiban and assessing at
a 30-d time point reveals no increase in MI associated with treatment with the oral agents
(42). However, in an analysis limited to the post-ACS trial results and using their longer
follow-up periods, a significant increase in MI is observed [OR 1.16 (1.03–1.29)] (41).
The relationship of oral GPIIb/IIIa inhibitor treatment with recurrent ischemia is interest-
ing. When recurrent ischemia is defined by symptoms associated with revascularization,
as it was in EXCITE, SYMPHONY, and 2nd SYMPHONY, treatment with an oral GPIIb/
IIIa inhibitor appears to have a favorable effect on this endpoint relative to aspirin (21–23).
This pattern is also seen in the subset of recurrent ischemia in OPUS that is defined by its
association with a revascularization procedure (22). However, when recurrent ischemia is
defined by other criteria (including rehospitalization or electrocardiographic changes),
a pattern of increased events associated with treatment with these agents relative to aspirin,
and similar to that observed for mortality and MI, is observed (22,24,25). The pathophysio-
logic rationale for this dichotomy of findings is not clear, but these findings tend to argue
against simply a direct toxic effect of these agents as the sole explanation and suggest a
complexity that goes beyond physiologic constructs. It also highlights the pitfalls of depend-
ing on surrogate endpoints alone or as a part of a composite in both Phase II and Phase III
clinical trials.
THE FAILURE OF THE ORAL AGENTS: WHAT WENT WRONG?
Despite more potent platelet aggregation inhibition than aspirin, use of the oral GPIIb/
IIIa inhibitors in Phase III trials has resulted in unexpected excess mortality relative to
aspirin: pooled OR 1.31 (1.12–1.53) (41). Although a number of potential mechanisms have
been postulated to explain the failure of the oral GPIIb/IIIa inhibitors, no single explanation
is completely satisfactory. Furthermore, the favorable results of the recently completed
Fig. 9. Odds ratios with 95% confidence intervals for mortality in published Phase III studies of oral
GPIIb/IIIa antagonists and for a combined analysis of these results. Event rates (%) are shown for
treatment and control arms.
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