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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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210 Part III / GPIIb/IIIa Blockade for Ischemic Syndromes
While the patients were in hospital, a total of 12 major ischemic events occurred in
seven placebo patients: death (n = 1), myocardial infarction (n = 4), and urgent interven-
tion because of severe recurrent ischaemia (n = 7). One event (a myocardial infarction)
occurred in a patient treated with c7E3 Fab (Table 3; 1 vs 7 patients, p = 0.03) . Three
placebo patients experienced more than one major event. Multivessel disease was present
in five of the seven placebo patients who developed an event, whereas the c7E3 Fab-treated
patient with an event had single-vessel disease. After correction for the imbalance in base-
line characteristics, the difference between the two groups was not statistically significant
Table 1
Baseline Clinical, Electrocardiographic,
and Angiographic Characteristics of Patient Groups
Group c7E3Fab Placebo
Male/female 20/10 24/6
Age (yr); (median, range) 61, 38–73 60, 38–73
Previous infarct 9 16
Within 7 d 6 5
Previous CABG 0 2
Previous PTCA 4 5
Medication prior to qualifying ischemic attack
Heparin 25 27
Aspirin 21 24
Nitrates
Intravenous 24 27
Oral 4 2
β-Blocker 22 24
Calcium channel blocker 15 22
Ischemia-related vessel
Left anterior descending artery 16 14
Left circumflex 8 6
Right coronary artery 6 10
Multivessel disease 6* 15*
Abbreviations: CABG, coronary artery bypass grafting; PTCA, percutaneous transluminal
coronary angioplasty.
*p = < 0.05.
Table 2
Recurrent Ischemia
Ischemia c7E3 Placebo
No. of patients 30 30
Pain + ST-T changes 2 5
Pain − ST-T changes 1 2
Pain, no ECG available 1 0
Silent ST-T changes 5 12
Patients with pain or ST-T changes 9 16
Patients with recurrent ischemia between diagnostic and second angio-
graphy. Multiple episodes and different types of ischemia could occur in
one patient. Episodes of ischemia during angiography or PTCA were not
included.
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Chapter 9 / Abciximab in Therapy-Resistant Unstable Angina: CAPTURE 211
in this pilot study ( p = 0.16). One patient from the placebo group died 26 d after allocation
after a complicated clinical course, including two urgent PTCA procedures, myocardial
infarction, heart failure, intraaortic balloon pump, and severe bleeding.
Q
UALITATIVE EVALUATION OF CORONARY ANGIOGRAMS
TIMI flow grade 3 in culprit arteries, assessed centrally by the Core Laboratory, was
present in 57% and 63% of patients at the first angiogram in the placebo and treatment
groups, respectively. A substantial improvement in coronary blood flow occurred after
treatment in the c7E3 Fab patient group. In the placebo group, a mix of either improve-
ment or deterioration was observed in TIMI flow score (Table 4). Extensive filling defects
in the coronary arteries were rare. Most filling defects were small, although they were
visible in more than one projection and located distally from the culprit lesion. The num-
bers of intracoronary filling defects and total occlusions in the pre- and posttreatment
Table 3
Major Events
c7E3 Fab Placebo
Events (n = 30) (n = 30)
Death 0 1
Myocardial infarction 1 4
Before PTCA 0 1
After PTCA 1 3
Urgent procedure 0 7
PTCA 0 3
CABG 0 3
Stent 0 1
Total events 1 12
Total number of patients with
one or more major events 1 7
Abbreviations: CABG, coronary artery bypass grafting; PTCA, per-
cutaneous transluminal coronary angioplasty.
Table 4
Qualitative Angiographic Data
a
c7E3 Fab Placebo
(n = 30) (n = 30)
Angiography B A B A
TIMI flow
01143
12101
210576
317231920
Improved 6 4
Worsened 0 3
Intracoronary filling defect 5 2 1 1
a
B, before study drug infusion; A, after study drug infusion.
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212 Part III / GPIIb/IIIa Blockade for Ischemic Syndromes
angiograms are presented in Fig. 1. In the placebo group, one new occlusion was observed,
in two cases patency was restored, with thrombotic remnants in one of these two cases.
Three of five coronary clots resolved in the c7E3 group.
Q
UANTITATIVE CORONARY ANGIOGRAPHIC ANALYSIS
Quantitative coronary angiographic data are summarized in Table 5. In one patient with
a very proximal left anterior descending coronary artery lesion, calculation of percentage
diameter stenosis was not possible because the reference diameter could not be ascer-
tained. Plaque area and extent of obstruction could only be calculated in patent coronary
arteries. A significant decrease in percentage diameter stenosis, extent of obstruction,
and plaque area was observed in the c7E3 patients. In the placebo group, similar changes
were observed to a lesser extent, except for the extent of obstruction, which increased in
the placebo group patients. Differences between groups were not significant.
A
NGIOPLASTY PROCEDURE
Angioplasty was performed in all 60 patients. In one patient who received c7E3 Fab,
PTCA was deferred because of a total occlusion owing to a large intracoronary clot at the
second angiogram. He was treated with intracoronary alteplase 50 mg infused over 30 min,
Fig. 1. Qualitative coronary angiographic data of the ischemia-related coronary artery before (B)
and after (A) study drug infusion. ● = totally occluded coronary artery; Q = intracoronary filling
defect; Q= patent coronary artery, without filling defect. The number of patent vessels with no filling
defect in either angiogram is depicted in the bottom line.
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Chapter 9 / Abciximab in Therapy-Resistant Unstable Angina: CAPTURE 213
followed by 50 mg intravenously over 2 h. The next day, the clots were partly resolved,
and PTCA was performed successfully. One other c7E3 Fab patient with a thrombocyto-
sis of unknown origin received alteplase during PTCA because of persistent thrombus
formation. PTCA was completed with success, and the subsequent clinical course was
uncomplicated. The total success rate of the angioplasty procedure was 83% in the c7E3
Fab group and 70% in the placebo group (Table 6).
Capture Trial
The CAPTURE trial was discontinued after the third interim analysis of 1050 patients.
Complete data, fully reviewed by the Clinical Endpoint Committee, were available for
976 patients, and 74 patients were partially reviewed. By that point, 87 (16.4%) of 532
patients in the placebo group and 56 (10.8%) of 518 in the abciximab group had a primary
endpoint (death, myocardial infarction, or urgent intervention within 30 d). Since the p value
for the difference ( p = 0.0064) was below the prespecified stopping criterion ( p = 0.0072),
and since the data were consistent among all subgroups analyzed, the Safety and Efficacy
Monitoring Committee recommended that recruitment should cease. This recommenda-
tion was followed by the Steering Committee, after consultation with regulatory authorities.
Table 5
Quantitative Angiographic Data From the First Angiogram (I) and After Study
Drug Infusion (II) and the Difference Between Both Measurements (II–I)
c7E3 Fab Placebo
No. (n = 30) No. (n = 30)
DS (%)
I3065.7 (8.6) 29 67.7 (16.1)
II 30 62.3 (10.5) 29 65.6 (15.8)
II−I30−3.4 (6.7)* 29 −2.1 (12.4)
MLD (mm)
I300.9 (0.3) 30 0.9 (0.4)
II 30 1.0 (0.3) 30 0.9 (0.4)
II−I300.1 (0.2) 30 0.0 (0.3)
Ext Ob (mm)
I29 7.3 (2.2) 26 7.2 (3.4)
II 29 6.9 (2.1) 26 7.3 (2.9)
II−I29−0.5 (1.2)* 26 0.3 (1.8)
Plq area (mm
2
)
I29 8.2 (3.4) 26 9.1 (6.8)
II 29 7.1 (2.5) 27 8.6 (4.8)
II−I29−1.1 (1.9)* 25 −0.5 (3.3)
AS (%)
I2089.2 (6.7) 21 90.7 (7.9)
II 23 88.3 (8.4) 22 89.6 (10.2)
II–I 19 −1.8 (8.1) 19 −1.3 (6.4)
Abbreviations: DS, diameter stenosis; MLD, minimal lumen diameter; Ext Ob, extent
of the obstruction; Plq area, plaque area; AS, area stenosis.
*p ≤ 0.05 for paired comparison of angiogram I vs II in each patient group. The changes
between patient groups (c7E3 fab vs placebo) did not reach statistical significance. Numbers
in third and fifth columns represent means (SD).
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214 Part III / GPIIb/IIIa Blockade for Ischemic Syndromes
Figure 2 shows the flow of patients through the trial; 1266 patients were enrolled, of
1400 scheduled. Follow-up data were complete for all but one patient (placebo), who
withdrew consent after randomization.
Five other patients in the placebo group did not receive placebo (two refused but
allowed follow-up and three for logistic reasons). Eight patients did not receive abciximab
(one received other therapy, five withdrew consent but allowed follow-up, two for logistic
reasons).
Table 6
Complications and Untoward Events
During and After Coronary Angioplasty
C7E3Fab Placebo
(n = 30) (n = 30)
Mortality 0 1
Myocardial necrosis 1 3
Urgent CABG 0 3
Re-PTCA 0 2
Residual stenosis > 50% 4 6
Number of patients with one or
more untoward events 5 9
Procedural success (%) 83 70
Abbreviations: CABG, coronary artery bypass grafting; PTCA, percu-
taneous transluminal coronary angioplasty.
Fig. 2. Trial profile.
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Chapter 9 / Abciximab in Therapy-Resistant Unstable Angina: CAPTURE 215
The two treatment groups were similar in terms of baseline characteristics (Table 7):
73% were male, 50% had a history of angina, and 41% had had a previous myocardial
infarction. Seventy-two percent of patients were enrolled within 6 h of the first (diagnos-
tic) angiogram, 60% had experienced myocardial ischemia within the 12 h before treat-
ment, and 95% had an ischemic episode after a minimum of 2-h treatment with nitrates
and intravenous heparin. Study drug was started in 1253 patients. It was discontinued early
(before 30 min after PTCA) in 86 patients (45 placebo, 41 abciximab) for various reasons,
including bleeding (1, 9), bypass surgery (5, 1), and stent placement (8, 3). Angioplasty
was attempted in 1241 patients (98%). The procedure was done earlier than planned in
23 patients (1.8%), 14 of whom were in the placebo group (Table 8). According to the inves-
tigators, the procedure was not successful, with a residual stenosis >50%, in 70 patients
Table 7
Baseline Data and Concomitant Medication
Placebo Abciximab
(n = 635) (n = 630)
M/F 459/176 461/169
Mean (SD) age in years 61 (10) 61 (10)
Anthropometry: mean (SD)
Weight (kg) 76 (12) 76 (12)
Height (cm) 170 (9) 170 (9)
Number of patients with [no. (%)]
Angina > 7 d previously
a
322 (51.4) 300 (48.6)
Infarction within previous 7 d 78 (12.3) 88 (14.0)
Infarction 8–30 d 43 (6.8) 53 (8.4)
Infarction > 30 d previously 116 (18.3) 116 (18.4)
Infarction, date not reported 6 (0.9) 7 (1.1)
PTCA 86 (13.5) 84 (13.3)
CABG 21 (3.3) 11 (1.7)
Risk factors [no. (%)]
Diabetes
a
82 (13.0) 95 (15.1)
Hypertension
a
261 (41.4) 271 (43.4)
Current smokers
a
255 (40.8) 235 (37.5)
Medication within 7 d before enrollment [no. (%)]
Aspirin 582 (91.7) 586 (93.0)
Intravenous heparin 634 (99.8) 627 (99.5)
Nitrates 633 (99.7) 627 (99.5)
β-Blockers 392 (61.7) 400 (63.5)
Calcium antagonists 297 (46.8) 286 (45.4)
Medication after enrollment [no. (%)]
Aspirin 608 (95.7) 604 (95.9)
Ticlopidin 25 (3.9) 25 (4.0)
Intravenous heparin 616 (97.0) 613 (97.3)
β-Blockers 395 (62.2) 412 (65.4)
Nitrates 616 (97.0) 613 (97.3)
Calcium antagonists 314 (49.4) 289 (45.9)
a
In a few patients no data were available for these items; percentages calculated for patients in whom these
data were reported.
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216 Part III / GPIIb/IIIa Blockade for Ischemic Syndromes
receiving placebo and in 37 receiving abciximab (11.2 vs 6.0%, p = 0.001). Treatment
with abciximab also resulted in lower rates of urgent repeat PTCA, urgent stent place-
ment, and bypass surgery (Table 9); however, these differences were not statistically
significant.
The primary endpoint (death, myocardial infarction, or urgent intervention within 30
d of enrollment) occurred in 101 (15.9%) patients in the placebo group and 71 (11.3%)
in the abciximab group (p = 0.012; Table 9, Fig. 3). This difference was owing mainly
to a difference in the proportion with myocardial infarction [52 (8.2%) vs 26 (4.1%),
p = 0.002; Table 9].
The findings were consistent in all subgroups studied and were independent of age,
sex, ECG findings at enrollment, and the presence of diabetes, peripheral vascular disease,
or renal dysfunction. Progression to myocardial infarction during the first 18–24 h after
enrollment was rare, despite the inclusion of patients with acute, refractory, unstable
angina. Even so, the frequency of myocardial infarction before PTCA was significantly
lower in patients receiving abciximab than in those receiving placebo (Table 9, p = 0.029).
Most infarcts occurred during or within 24 h of PTCA (p = 0.021, Fig. 4), whereas infarc-
tion rates were low in both groups 2–30 d after PTCA (Table 9). The lower rate of myocar-
dial infarction in patients receiving abciximab than in those receiving placebo was found
for both Q-wave and non-Q-wave infarcts, and independently of the creatine kinase thresh-
old used to define an infarct (Table 9).
Major bleeding complications occurred in only 3.8% of patients, although both major
and minor bleeding events were more common during treatment with abciximab than
during placebo treatment (Table 9).
Table 8
Angiography and PTCA Results
a
Placebo Abciximab
(n = 635) (n = 630)
Artery with culprit lesion
Left anterior descending 383 (60.3) 385 (61.1)
Left circumflex 104 (16.4) 105 (16.7)
Right coronary 144 (22.7) 138 (21.9)
PTCA timing
Urgent (before planned) 14 (2.2) 9 (1.4)
18–26 h
b
613 (96.5) 597 (94.8)
Delayed (>26 h) 8 (1.3) 15 (2.4)
No PTCA 11 (1.7) 13 (2.1)
PTCA result
Attempted 624 617
Succeeded
c
554 (88.8) 580 (94.0)
Failed
c
70 (11.2) 37 (6.0)
a
Data are numbers, with percent in parentheses.
b
Prespecified time window was 18–24 h after enrollment; in 70 patients
procedure was done between 24 and 26 h for logistic reasons.
c
Percentages of those attempted.
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Chapter 9 / Abciximab in Therapy-Resistant Unstable Angina: CAPTURE 217
Table 9
Clinical Events at 30-day Follow-Up
a
Placebo Abciximab
(n = 635) (n = 630) p value
b
Death, infarction, or urgent intervention 101 (15.9) 71 (11.3) 0.012
Death 8 (1.3) 6 (1.0) >0.1
Myocardial infarction
Before PTCA 13 (2.1) 4 (0.6) 0.029
During PTCA (<24 h) 34 (5.5) 16 (2.6) 0.009
After PTCA (2–30 d) 5 (0.9) 6 (1.0) >0.1
Non-Q-wave 36 (5.5)
c
19 (3.0) 0.036
Q-wave 17 (2.7)
c
7 (1.1) 0.067
Peak CK > 5× normal 21 (3.3) 10 (1.6) 0.067
Peak CK > 10× normal 15 (2.6) 5 (0.8) 0.040
All myocardial infarction 52 (8.2) 26 (4.1) 0.002
Myocardial infarction/death 57 (9.0) 30 (4.8) 0.003
Urgent intervention
Urgent PTCA
Before planned time 14 (2.2) 9 (1.4) >0.1
Repeat PTCA 28 (4.4) 19 (3.1) >0.1
Urgent CABG 11 (1.7) 6 (1.0) >0.1
Urgent stent 42 (6.6) 35 (5.6) >0.1
All urgent interventions 69 (10.9) 49 (7.8) 0.054
Nonurgent interventions
Repeat PTCA 16 (2.6) 21 (3.4) >0.1
CABG 9 (1.4) 4 (0.6) >0.1
Stent 47 (7.4) 49 (7.8) >0.1
Stroke 3 (0.5) 1 (0.2) >0.1
Major bleeding
d
Puncture site 9 19 >0.1
Retroperitoneal 0 2 >0.1
Pulmonary 0 1 >0.1
Gastrointestinal 0 3 >0.1
Urogenital 1 0 >0.1
All major bleeding 12 (19) 24 (3.8) 0.043
Minor bleeding
d
13 (2.0) 30 (4.8) 0.008
Transfusion
d
21 (3.4) 44 (7.1) 0.005
Abbreviations: CK, creatine kinase; CABG, coronary artery bypass graft; PTCA, percutaneous translumi-
nal coronary angioplasty.
a
Data are numbers, with percent in parentheses.
b
p values (two-sided) < 0.1 are reported.
c
One patient had both.
d
Excluding those in patients who underwent CABG.
No excess strokes were observed with abciximab. In the placebo group, two patients
had nonhemorrhagic stroke, and one had an intracranial hemorrhage (1, 5, and 7 d after
enrollment, respectively). Stroke occurred in a single patient treated with abciximab (15 d
after enrollment), but the type of stroke could not be determined. Most bleeding compli-
cations occurred at arterial puncture sites. In both treatment groups, bleeding was more
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218 Part III / GPIIb/IIIa Blockade for Ischemic Syndromes
common in patients who received a high dose of heparin during PTCA, and in patients with
low body weight. For patients receiving <100 IU/kg heparin, the bleeding rates were 1.2
and 4.4% in the placebo and abciximab groups, respectively. The corresponding rates were
2.7 and 6.6% in those receiving 100–149 IU/kg and 7.9 and 14.8% in patients receiving
≥150 IU/kg heparin. In logistic regression analysis, both heparin dose per kg (p = 0.0001)
and use of abciximab (p = 0.0008) were significantly related to bleeding risk. By contrast,
the reduction in primary endpoint was related only to use of abciximab (p = 0.016) and
not to heparin dose (p = 0.70).
Thrombocytopenia (platelets <100 × 10
9
/L) occurred in 5.6% of the abciximab group
and 1.3% of the placebo group. Ten patients receiving abciximab had platelet counts <50
× 10/L within 24 h; no placebo recipient had this complication. None of these patients had
bleeding complications. Two patients had platelet counts <20 × 10/L. Treatment with study
drug (abciximab) was discontinued in five patients, who all received platelet transfusions.
Fig. 3. Time course of combined primary endpoint and its major components.
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Chapter 9 / Abciximab in Therapy-Resistant Unstable Angina: CAPTURE 219
Full recovery of platelet counts (to >100 × 10
9
/L) occurred within 24 h in three patients,
within 48 h in three, and within 5 d in three. Follow-up measurements were not available
in one patient.
At follow-up 6 mo later, death or myocardial infarction had occurred in 56 (8.9%)
abciximab-treated patients and 69 (10.9%) placebo recipients (p = 0.19, Fig. 5). Bypass
surgery had been required by 33 (5.2%) and 44 (6.9%), respectively (p = 0.20). PTCA
was needed for similar proportions of patients in both groups, mainly because of restenosis
(Table 10). Also, medication up to 6 mo of follow-up was similar in the two groups (Table
11). At 6 mo, 242 events had occurred in 193 abciximab-treated patients compared with
274 events in 193 placebo recipients. Thus, the number of events per patient was lower
after abciximab (p = 0.067).
Four years postrandomization, follow-up data were obtained in 1157 patients (94% of
all patients alive at 6 mo). Death and myocardial infarction rates were continuously (non-
significantly) lower over a 4-yr period in patients randomized to abciximab (Table 11).
The initial large and significant difference in death or myocardial infarction favoring
abciximab among patients with a positive troponin-T test at randomization (≥0.1 ng/L)
was maintained throughout the 4-yr follow-up period (18a) (Fig. 6). Death or myocardial
infarction at 4 yr occurred in 16.9 and 24.8% of troponin-T-positive patients receiving
abciximab or placebo (p = 0.015). The incidence of these events in troponin-T positive
patients was comparable with that of troponin-T-negative patients receiving abciximab
or placebo.
A high CRP (>10 mg/L) at randomization was predictive of a higher incidence of death
or myocardial infarction at 6 mo (18b). The same difference in outcome related to initial
CRP level was found at 4-yr follow-up (Fig. 7). The mortality at 4 yr was 9.2% for patients
with high CRP values and 3.9% for patients with low values at entrance (p = 0.001). In
contrast to the risk reduction of abciximab in patients with elevated troponin-T levels,
the risk reduction of abciximab was not dependent on CRP levels at randomization.
Fig. 4. Development of myocardial infarction during treatment with abciximab or placebo, before and
in association with PTCA.
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