Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_4011_Библиотеки_им_академика_М_И_Перельмана
.pdf
240 Part III / GPIIb/IIIa Blockade for Ischemic Syndromes
(re)infarction, disabling stroke, and major and intermediate bleeding at 30 d; death and
myocardial infarction at 6 mo; and death at 1-yr follow-up. Study group sizes, drug admin-
istration, and in-hospital cardiac procedures are detailed in Table 2. Demographic data
and comparisons with the other 5-P trials are listed in Table 3. Principal safety and out-
come data at 30 d and 6 mo are provided in Table 4. No difference in the composite of
death or nonfatal MI was noted between the control group and any lamifiban group or the
combination of all lamifiban-treated groups at 30 d. At 6-mo follow-up, a difference in
the composite was present. Compared with the control group, three of the four lamifiban-
treated groups had a lower event rate. Specifically, death or nonfatal MI at 6 mo was
lowered 24% by low-dose lamifiban with or without heparin [odds ratio, 0.72; 95% con-
fidence interval (CI), 0.54–0.96; p = 0.027] and 9% by high-dose lamifiban with or with-
out heparin (odds ratio, 0.89; 95% CI, 0.68–1.16; p = 0.450) compared with control.
For uncertain reasons, the event rates diverged after 30 d. Between 30 and 180 d, the rela-
tive increase in myocardial (re)infarction was 36% for the control group, 19% for the high-
dose lamifiban groups, and 15% for the low-dose lamifiban groups. Likewise, the relative
increase in deaths during this time was 131% for the control group, 89% for the high-dose
lamifiban groups, and 77% for the low-dose lamifiban groups. At 1 yr, all-cause mortality
was 8.2, 8.4, and 6.9%, respectively (p = 0.340; Fig. 5). The overall incidences of bleed-
ing complications and stroke are presented in Table 4. There were more bleeding-related
events among those receiving high-dose lamifiban. The rates of major bleeding were 1.8,
0.6, and 0.8% for high-dose lamifiban groups, low-dose lamifiban groups, and control,
respectively (p = 0.058).
An intriguing analysis from the PARAGON A trial was performed to understand better
a potential dose-response relationship. The lamifiban plasma concentration was mea-
sured in 810 lamifiban-treated patients (34), and this was correlated post hoc with clinical
outcome. The lamifiban level at steady state was directly related to the patient’s renal func-
tion, and a middle concentration range (18–42 ng/mL: corresponding to 80–90% GPIIb/
IIIa receptor occupancy) was associated with a 38% reduction in death and MI at 6 mo.
Based on this information, the PARAGON B study was designed (35). In 29 countries,
5225 patients were randomized equally to placebo or to lamifiban. All lamifiban-treated
patients received a 500 µg intravenous bolus. According to the creatinine clearance, esti-
mated by the Cockcroft-Gault formula, patients were separated according to a creatinine
clearance of 30–40, 40–70, or >70 mL/min and received a 1.0, 1.5, or 2.0 µg/min infusion
of lamifiban, respectively (Table 2). All patients received aspirin and heparin. The primary
endpoint of 30-d death, MI, or severe recurrent ischemia occurred in 11.8% of lamifiban-
treated patients and 12.8% of placebo-treated patients (p = 0.329). Thus, despite the achieve-
ment of targeted plasma levels of lamifiban in the treated group, no over-all benefit was
observed.
Tirofiban
Tirofiban (Aggrastat
™
, Merck, White House Station, NJ), a small-molecule, nonpep-
tide GPIIb/IIIa receptor antagonist, was initially studied in unstable angina in a Phase II,
heparin-controlled study of 71 patients (36). Given for up to 48 h, tirofiban (MK-383) was
well tolerated without significant bleeding. An encouraging reduction in the incidence of
refractory angina was observed with tirofiban studied over a dose range of 0.075–0.15 µg/kg/
min. These findings led to the designs of PRISM and PRISM-PLUS, two Phase III tirofiban
https://t.me/med1917
Chapter 10 / Unstable Angina Trials 241
Table 2
Study Designs and Enrollment Details
Design/detail PARAGON A PRISM PRISM-PLUS PURSUIT PARAGON B GUSTO-IV
Enrollment dates 8/95–5/96 3/94–10/96 11/94–9/96 11/95–1/97 2/98–6/99 7/98–4/00
Drug Lamifiban Tirofiban Tirofiban Eptifibatide Lamifiban Abciximab
Patients enrolled
Total 2282 3232 1915 10,948 5225 7800
Treatment groups 755 @ 300 µg + 1616 @ 0.6 µg/kg/min 773 @ 0.4 µg/kg/min 1487 @ 180 µg/kg 2628 @ 500 mg 2590 @ 0.25 mg/kg
(bolus + infusion) 1 µg/min × 30 min + 0.15 × 30 min + 0.1 + 1.3 µg/kg/min + 1.0–2.0 mg/min + 0.125 µg/kg/min
769 @ 750 µg + µg/kg/min µg/kg/min 4722 @ 180 µg/kg 2597 @ placebo × 24 h
5 µg/min 1616 @ placebo 345 @ 0.6 µg/kg/min + 2.0 µg/kg/min 2612 @ 0.25 mg/kg
758 @ placebo × 30 min + 0.15 4739 @ placebo + 0.125 µg/kg/min
µg/kg/min × 48 h
797 @ placebo 2598 @ placebo
Infusion duration (h) 72 46 71 72 72 24 or 48
Heparin Randomized, blinded Randomized, blinded All patients Recommended All patients All patients UFH
aPTT 60–85 s aPTT 1.5–2 × control aPTT 2 × control (open-label) aPTT 50–70 s @ aPTT 50–70 s
aPTT 50–70 s or LMWH
Early drug discontinuation 19 NA 14 36
(%)
PTCA during study (%) 13 21 31 24 28 19
CABG during study (%) 11 17 23 14 15 11
1º Endpoint Death or MI Death, MI, or refractory Death, MI, or refractory Death or MI Death, MI, or Death or MI
ischemia composite ischemia composite severe recurrent
ischemia
Endpoint analysis (d) 30 2 7 30 30 30
Abbreviations: aPTT, activated partial thromboplastin time; CABG, coronary artery bypass graft; LMWH, low-molecular-weight heparin; MI, myocardial infarction; PTCA, percutaneous
transluminal coronary angioplasty; UFH, unfractionated heparin.
https://t.me/med1917
242 Part III / GPIIb/IIIa Blockade for Ischemic Syndromes
studies in unstable angina and non-Q-wave MI (20,21). PRISM began enrollment in March
1994, and patients with accelerating or rest angina within 24 h and any clinical suspicion
for ischemic heart disease were eligible (Table 2). Suspicion for ischemia included ST-
segment or T-wave abnormalities consistent with ischemia; elevated cardiac enzymes;
history of prior percutaneous transluminal coronary angioplasty (PTCA), coronary artery
bypass graft (CABG), or positive stress test; or a known coronary arterial narrowing
≥50%. In PRISM, 3232 patients were randomized to tirofiban (0.6 µg/kg/min bolus fol-
lowed by a 0.15 µg/kg/min infusion) or heparin. The tirofiban loading dose was actually
given as a 30-min infusion, and the subsequent dose infusion was given for up to 47.5 h.
The mean duration of infusion was 46 h, with 12% of infusions stopped early. All patients
were to receive aspirin, and the target prolongation of aPTT among patients receiving hep-
arin was twice the laboratory control value (Table 2). Patient management was prespeci-
fied in that angiography and coronary intervention during the first 48 h were discouraged.
Unlike other GPIIb/IIIa trials in unstable angina, the PRISM primary composite end-
point was at 48 h. The composite included death, MI, and refractory ischemia. The same
endpoints plus rehospitalization for unstable angina were collected at 7 and 30 d. Refrac-
tory ischemia was defined as recurrent angina with (1) ST-T changes lasting for ≥20 min
within a 1-h period despite full medical therapy, or (2) hemodynamic instability. The com-
posite endpoint at 48 h was reduced 36% by tirofiban, with the greatest effect seen in the
reduction of refractory ischemia events. At the time of endpoint ischemia, most patients
were receiving both nitrates and β-blockers. At 7 d, the reduction in the composite endpoint
by tirofiban was attenuated to a nonsignificant 8% lowering. Likewise, at 30-d follow-up,
tirofiban still reduced the composite outcome, but only by 7% (p = 0.34). A similar decay
of benefit or reversal of effect was seen in GUSTO-IV (Fig. 3).
Table 3
Characteristics of Study Groups at Enrollment (%)
PRISM-
Characteristic PARAGON A PRISM PLUS PURSUIT PARAGON B GUSTO-IV
Age (yr) 66 62 63 64 64 65
Female 35 32 33 35 34 37
Diabetes 18 21 23 22 22 22
Hypertension 49 54 54 55 56 52
High cholesterol 42 47 49 42 50 30
Current smoker 23 26 NA 28 29 NA
Prior MI 35 47 43 32 30 31
Prior PTCA 11 15 10 13 14 10
Prior CABG 9 17 15 12 13 9
Presenting ECG
ST depression 52 32 58 50 45 80
ST elevation 6 7 14 14 16 NA
T-wave inversion 54 51 53 52 46 NA
MI at enrollment 36 25 45 45 57
a
59
a
Abbreviations: MI, myocardial infarction; PTCA, percutaneous transluminal coronary angioplasty; CABG,
coronary artery bypass graft surgery; ECG, electrocardiogram; NA, not available.
a
Local laboratory positive troponin.
https://t.me/med1917
Chapter 10 / Unstable Angina Trials 243
Table 4
Clinical Outcome (%)
PARAGON A PRISM PRISM-PLUS PURSUIT PARAGON B GUSTO-IV
Lamifiban Heparin + Eptifibatide Abciximab
Tirofiban tirofiban Tirofiban Lamifiban
1 µg/min 5 µg/min 0.15 0.10 0.15 1.3 2.0 1–2
Characteristic Placebo ± heparin ± heparin Heparin µg/kg/min Heparin µg/kg/min µg/kg/min Placebo µg/kg/min µg/kg/min Placebo µg/kg/min Placebo 24 h 48 h
No. of patients 758 755 769 1616 1616 797 773 345 4739 1487 4722 2597 2628 2598 2590 2612
30-d outcome
Death 2.9 3.0 3.6 3.6 2.3 4.5 3.6 (6.1) 3.7 (3.4) 3.5 3.3 2.9 3.9 3.4 4.3
Nonfatal MI 10.6 9.4 10.9 4.3 4.1 9.2 6.6 (9.0) 13.5 (12.0) 12.6 9.8 8.8 5.1 5.6 5.9
Death or MI
Overall 11.7 10.6 12.0 7.1 5.8 11.9 8.7 (13.6) 15.7 (13.4) 14.2 11.5 10.6 8.0 8.2 9.1
Relative reduction 9 −61827 10 8−3 −14
PTCA patients 9.1 7.2 10.2 5.9 16.8 11.8
Non-PTCA patients 6.2 3.6 7.8 3.6 15.7 14.6 11.0 10.3
6-mo outcome
Death 6.6 5.2 6.8 7.0 6.9 (7.2) 6.2 6.4
Nonfatal MI 14.3 10.8 12.9 10.5 8.3 (10.1) 15.7 14.7
Death or MI 17.9 13.7 16.4 15.3 12.3 (15.9) 19.0 17.8
Relative reduction 23 8 20 8
Major bleeding
b
3.0 3.0 6.0 0.4 0.4 0.8 1.4 1.3 3.0 0.9 1.3 0.3 0.6 1.0
Intracranial hemorrhage 0 0 0.1 0.1 0.1 0 0 0.1 0.1 0.1 0.1 0.04 0.2 0.1
RBC transfusion
c
4.4 4.4 8.7 1.4 2.4 2.8 4.0 1.8 4.4 8.9 10.3 1.5 2.2 2.9
Thrombocytopenia
a
1.1 1.5 1.3 0.1 0.4 0.3 0.5 0.4 0.6 0.5 0.7 1.0 4.7 7.0
Abbreviations: MI, myocardial infarction; PTCA, percutaneous transluminal coronary angioplasty; RBC, red blood cells.
a
Thrombocytopenia defined as platelet count = 50,000/mm
3
. Numbers in parentheses are from discontinued treatment arms and are not contemporaneous; these are listed only for completeness, not direct comparisons.
b
Major bleeding as defined by intracranial hemorrhage or decrease in hemoglobin of 5 g/dL not associated with coronary artery bypass grafting (CABG), except for PARAGON A.
c
Transfusions reported are those not associated with CABG, except for PARAGON A.
https://t.me/med1917
244 Part III / GPIIb/IIIa Blockade for Ischemic Syndromes
The PRISM-PLUS trial started enrollment in November, 1994 and randomized a total
of 1915 patients. Compared with PRISM, patients in PRISM-PLUS were somewhat more
unstable; they were required to have rest angina within 12 h plus electrocardiographic
evidence of ischemia or serologic evidence of infarction. With these criteria, 45% of
PRISM-PLUS patients had an infarction at enrollment compared with 25% in PRISM.
Patients in PRISM-PLUS were randomized to tirofiban alone (0.6 µg/kg/min loading
followed by 0.15 µg/kg/min), heparin, or tirofiban (0.4 mg/kg/min followed by 0.1 mg/
kg/min) plus heparin. All patients were to receive aspirin, and the target prolongation of
aPTT among patients receiving heparin was twice the laboratory control value. Patient
management was prespecified in that angiography and coronary intervention before 48 h
were discouraged, whereas they were encouraged to be performed between 48 and 96 h
while continuing study drug infusion. Endpoint definitions were similar to those in PRISM,
and the primary endpoint was a composite of death, MI, or refractory ischemia at 7 d.
An interim analysis revealed an increase in 7-d mortality among those randomized to
high-dose tirofiban alone. Thus, after 1031 patients had been enrolled in the overall study,
this treatment arm was discontinued. The 7-d mortality rates for the high-dose tirofiban,
heparin, and moderate-dose tirofiban plus heparin groups were 4.6, 1.1, and 1.5%, respec-
tively. The odds ratio for mortality at 7 d with high-dose tirofiban compared with heparin
alone was 4.1 (95% CI, 1.4–12.3; p = 0.012). Although the 7-d, 30-d, and 6-mo rates of death
as well as the death or MI composite were numerically highest for the high-dose tirofiban
group, this difference was only statistically significant for 7-d mortality. Outcome infor-
mation on this group is presented in Table 4 only for listing purposes and cannot be com-
pared with the final data from the other two arms since it is not contemporaneous.
Fig. 5. Kaplan-Meier estimates of the probability of death during 1-yr follow-up in PARAGON with
control compared with lamifiban patients grouped by low and high doses. All-cause mortality was
8.7, 7.3, and 8.9%, respectively (p = 0.320). (From ref. 19, with permission.)
https://t.me/med1917
Chapter 10 / Unstable Angina Trials 245
Fig. 6. Effect of treatment with heparin or tirofiban plus heparin on the composite primary endpoint
at 7 d among various subgroups. Risk ratios <1 favor the subgroup receiving tirofiban plus heparin
[horizontal lines represent the 95% confidence intervals (CI)]. There were no statistically significant
interactions between the assigned treatment and any of the other factors shown except that effects
of tirofiban were particular marked among those already taking β-blockers at enrollment. (From ref.
21, with permission.)
The primary endpoint (7-d death, MI, refractory ischemia) was reduced 28% by tirofi-
ban plus heparin compared with heparin alone (12.9 vs 17.9%, respectively). Impressively,
this reduction in ischemic events was extended similarly to nearly all subgroups (Fig. 6).
https://t.me/med1917
246 Part III / GPIIb/IIIa Blockade for Ischemic Syndromes
Fig. 7. Kaplan-Meier curves showing the cumulative incidence of events among patients randomly
assigned to receive tirofiban plus heparin or tirofiban alone. The top panel is the composite of death,
myocardial infarction, refractory ischemia, or rehospitalization for unstable angina. The bottom panel
is the composite of death or myocardial infarction. p values were computed by Cox regression analysis.
(From ref. 21, with permission.)
Benefit from tirofiban was durable at 30 d, as the composite endpoint including rehospi-
talization for unstable angina was reduced 17% (18.5% vs 22.3%, p = 0.03) (Fig. 7). Con-
sidering the trend in event rate reduction provided by tirofiban, most of the benefit was
present for preventing refractory ischemia and nonfatal MI. Even at 6-mo follow-up, both
of these ischemic endpoints were reduced 21% in comparison with placebo.
Eptifibatide
Eptifibatide, (Integrilin
™
, COR Therapeutics, South San Francisco, CA) a cyclic hepta-
peptide, and competitive inhibitor of the GPIIb/IIIa receptor, was studied in a Phase II
unstable angina trial published by Schulman et al. in 1996 (37). This dose-finding trial ran-
domized 227 patients to a low dose of eptifibatide (45 µg/kg bolus, 0.5 µg/kg/min infu-
sion), “high-dose” eptifiabtide (90 µg/kg bolus, 1.0 µg/kg/min infusion), or placebo. The
study drug was continued for 24–72 h, and all patients received heparin. The efficacy
parameter was the frequency and duration of ischemic episodes as assessed by continu-
https://t.me/med1917
Chapter 10 / Unstable Angina Trials 247
ous electrocardiographic monitoring. A dose-dependent decrease in ischemic episodes
was observed, although this only reached statistical significance in the high-dose group.
During study drug infusion, no increase in bleeding events was noted with eptifibatide, and
following drug cessation, no rebound phenomena occurred. Subsequent studies per-
formed with eptifibatide during percutaneous coronary intervention used relatively higher
doses of bolus plus infusion (135 µg/kg bolus and 0.5–0.75 µg/kg/min infusion). Even
these doses, however, subsequently only inhibited platelet aggregation by 40–60% (38).
The largest unstable angina study involving a GPIIb/IIIa inhibitor was the Platelet IIb/
IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT)
trial (22). Between November 1995 and January 1997, 10,948 patients in 28 countries were
randomized to one of two doses of eptifibatide or placebo (Table 2). All patients random-
ized to eptifibatide received a 180 µg/kg bolus and either a 1.3 µg/kg/min or 2.0 µg/kg/
min infusion for 72 h. After 1487 patients received the moderate-dose infusion (1.3 µg/
kg/min) of eptifibatide, this arm was discontinued since the higher dose arm had a sim-
ilarly acceptable safety profile. Unlike PRISM-PLUS, the discontinued arm in PURSUIT
was part of a prespecified plan, involved dropping the lower dose group, and was done
because of acceptable safety. Except where noted, the following reported data are from
the remaining 9461 patients equally randomized to placebo or high-dose eptifibatide. The
study was designed to emulate although not interfere with the usual clinical treatment for
patients with unstable angina. Hence, it was recommended, although not required, that
all study patients receive oral aspirin and weight-adjusted intravenous heparin. Likewise,
patients could have angiography and revascularization at any time during the study to
conform with the attending physician’s preference.
The primary endpoint was a composite of all-cause mortality and nonfatal MI (or rein-
farction) at 30 d. Secondary endpoints included death and myocardial (re)infarction at
30 d, the composite at 96 h and 7 d, and safety and efficacy outcome in patients undergoing
percutaneous coronary interventions. Demographic data, study drug administration, and
in-hospital cardiac procedures are detailed in Tables 2 and 3. Principal safety and outcome
data at 30 d and 6 mo are provided in Table 4. The outcome information for the discontin-
ued treatment group is presented in Table 4 only for listing purposes and cannot be com-
pared with the final data from the other two arms since it is not contemporaneous. At the
time of enrollment, 45% of patients had a non-Q-wave myocardial infarction. Importantly,
aspirin was used in 93% of patients, and heparin was used in 90%. Coronary angiography
was performed in 60% of patients, and percutaneous coronary revascularization was per-
formed in 24%.
Based on the site investigators’ reports, the primary 30-d endpoint was reached in
10.0% of control patients and 8.0% of those receiving eptifibatide. Following adjudica-
tion by the Clinical Events Committee, the 12–28% relative reduction in events reported
by sites among the four geographic regions was reduced to −7 to 22% (Fig. 8). Not sur-
prisingly, the death rate did not change with adjudication, but rather, the number of patients
considered to have non-Q-wave MI during follow-up was substantially increased. The
study’s overall adverse event rate climbed from 9 to 15% with adjudication of non-Q-wave
MIs by elevated creatine kinase (CK)-MB. The overall study remained positive at 30 d, with
a 10% reduction in death and nonfatal MI (Fig. 9) and a 22% reduction seen in North
America. These data were durable at 6 mo (Table 4).
Irrespective of site report or Clinical Events Committee, geographic region, or early
vs late follow-up, there was an approx 1.5% absolute reduction in death or nonfatal MI.
https://t.me/med1917
248 Part III / GPIIb/IIIa Blockade for Ischemic Syndromes
This benefit was consistent among the subgroups except for women. As seen in Fig. 10,
some of this discrepancy in gender-related outcome may have been geographically influ-
enced by specific practice patterns. For example, early diagnostic catheterization (≤72 h)
was performed in between 5 and 66% of patients according to location (Eastern Europe
vs North America). Not surprisingly, the range of heparin usage (76–97%), early angio-
plasty (4–25%), and early bypass surgery (1–8%) was also associated with these regional
differences.
CLINICAL OUTCOME: PARAGON A AND B,
PRISM, PRISM-PLUS, PURSUIT (5 Ps), AND GUSTO-IV
The study designs of the 5 Ps and GUSTO-IV have many similarities, but also several
important distinctions (Table 2) with regard to endpoint definitions, percentage of patients
with infarction at enrollment, duration of therapy, concomitant use of heparin, use of per-
cutaneous revascularization, and, importantly, timing of the primary endpoint analysis.
Given these similarities and distinctions, several meta-analysis have already been con-
sidered (39–42).
30-Day Mortality
Considering all patients enrolled into the first four ACS trials testing GPIIb/IIIa recep-
tor blockade (Table 2), Kong et al. (41) performed a formal meta-analysis of approx 10,000
patients who were randomized to active therapy. They found that the odds ratio of death
at 30 d was 0.90 (95% CI, 0.76–1.06) with GPIIb/IIIa treatment compared with placebo.
Overall 30-d mortality for these patients was 3.4% compared with 3.7% for the 7910
patients assigned to receive placebo (p = 0.27). The lowest mortality was 2.3% for those
receiving 0.15 µg/kg/min tirofiban in PRISM (36% relative reduction compared with
placebo, p = 0.02) (Fig. 11). Ironically, the highest 30-d mortality among all treatment
groups in all studies was also for 0.15 µg/kg/min tirofiban, in PRISM-PLUS (6.1% among
Fig. 8. Odds ratio for death or myocardial infarction according to the endpoints adjudicated by the Clin-
ical Events Committee and separated according to geographic region in the PURSUIT trial. (Data
from ref. 22.)
https://t.me/med1917
Chapter 10 / Unstable Angina Trials 249
345 patients). Thus, 30-d mortality was reduced with tirofiban in PRISM; however, this was
not evident in any individual study, suggesting that any true reduction in overall mortality
was minor.
Roffi and colleagues (43) also performed a meta-analysis considering mortality among
all six large-scale GPIIb/IIIa inhibitor ACS trials. Their specific interest was in evaluating
outcome among patients with and without diabetes mellitus. Interestingly, they observed
Fig. 9. Kaplan-Meier curves showing the incidence of death or nonfatal myocardial infarction at
30 d. Events were based on endpoints adjudicated by the Clinical Events Committee, and the p value
is based on the log-rank test. (From ref. 22, with permission.)
Fig. 10. Odds ratio for death or myocardial infarction separated according to gender and geographic
region. Women overall showed no benefit from eptifibatide treatment, although this subgroup find-
ing was primarily limited to outside North America. (Data from ref. 22.)
https://t.me/med1917
Соседние файлы в папке Библиотека им академика М.И. Перельмана