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_4105_Библиотеки_им_академика_М_И_Перельмана
.pdf
118
CHAPTER 8 Antithrombotic Therapy
including a signifi cant increase in the risk of fatal and life-threatening bleeding.
The incidence of intracranial hemorrhage was similar between treatment arms
(0.3 versus 0.3 percent).
40
A post hoc analysis demonstrated that prasugrel
should not be administered to patients with a history of stroke or TIA. The use
of prasugrel in patients over the age of 75 or weighing less than 60 kg should
be carefully considered, and a lower dose of 5 mg daily may be used in such
patients.
41
Following completion of the TRITON-TIMI 38 trial, the Targeted Platelet
Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary
Syndromes (TRILOGY-ACS) trial compared the long-term effi cacy of prasugrel
(10 mg daily) versus clopidogrel (75 mg daily) in 7,243 patients with ACS who
were managed medically without coronary revascularization.
42
A lower mainte-
nance dose of prasugrel 5 mg daily was evaluated in patients over the age of 75
or weighing less than 60 kg. In the topline analysis of 7,243 subjects under the
age of 75, prasugrel did not reduce the risk of CV death, MI, or stroke compared
with clopidogrel over a median follow-up of 17 months (HR 0.91, 95 percent CI
0.79–1.05).
42
Within the subgroup of patients who underwent coronary angiog-
raphy, prasugrel reduced the risk of CV death, MI, or stroke by 23 percent (HR
0.77, 95 percent CI 0.61–0.98) compared with clopidogrel. Rates of severe and
intracranial bleeding were similar across treatment arms. Overall, the results of
the TRILOGY-ACS trial do not support the use of prasugrel in patients who do
not undergo cardiac catheterization or coronary revascularization after ACS.
Ticagrelor
Ticagrelor is a non-thienopyridine that binds reversibly to the P2Y12 recep-
tor and does not require bioactivation. Ticagrelor has been shown to achieve
12.1
3.7
2.4
1.8
9.9
2.5
1.1
2.4
0
2
4
6
8
10
12
14
CV death, non-fatal
MI or non-fatal stroke
Urgent target-vessel
revascularization
Stent thrombosis Non-CABG-related
TIMI major bleeding
Clopidogrel
Prasugrel
Event rate at 15 months (%)
HR 0.81
(95% CI 0.73–0.90)
HR 0.66
(95% CI 0.54–0.81)
HR 0.48
(95% CI 0.36–0.64)
HR 1.32
(95% CI 1.03–1.68)
Figure 8.2 Kaplan-Meier event rates at 15 months and the relative risk (hazard ratio,
95 percent confi dence interval) for prasugrel versus clopidogrel for patients with ACS
undergoing PCI in the TRITON-TIMI 38 trial.
https://t.me/med1917
119
CHAPTER 8 Antithrombotic Therapy
more rapid inhibition of platelet aggregation than a clopidogrel loading dose of
600 mg and has faster offset kinetics.
43
The Platelet Inhibition and Patient Outcomes (PLATO) trial randomized
18,624 subjects with ACS to ticagrelor (180-mg loading dose, 90 mg twice
daily) or clopidogrel (300- to 600-mg loading dose, 75 mg daily) on a back-
ground of aspirin.
43
At 12 months, ticagrelor reduced the risk of vascular death,
MI, or stroke by 16 percent compared with clopidogrel (HR 0.84, 95 percent
CI 0.77–0.92), including a signifi cant reduction in all-cause mortality (4.5 versus
5.9 percent, p < 0.001, Fig. 8.3). Ticagrelor increased the risk of non-CABG-
related major bleeding but did not increase the risk of fatal or CABG-related
major bleeding (Fig. 8.3). Ticagrelor is associated with an increased frequency
of dyspnea and asymptomatic ventricular pauses.
43
A post hoc analysis sug-
gested that ticagrelor should only be used in combination with aspirin doses
of 100 mg daily or less. The ongoing PEGASUS trial is evaluating the effi -
cacy and safety of ticagrelor in patients more than 1 year following an MI
(NCT01225562).
Protease-activated receptor (PAR-1) antagonists
Vorapaxar and atopaxar are novel platelet antagonists that interfere with
thrombin-mediated platelet activation via the platelet protease-activated
receptor (PAR-1). Despite a trend toward effi cacy, vorapaxar did not signifi -
cantly reduce the risk of CV death, MI, stroke, or recurrent ischemia leading to
urgent revascularization in patients after ACS (HR 0.92, 95 percent 0.85–1.01).
44
In contrast, vorapaxar (2.5 mg daily without loading dose) signifi cantly reduced
the risk of CV death, MI, or stroke by 13 percent (HR 0.87, 95 percent CI 0.80–
0.94) over a median of 30 months in 26,449 patients with stable atheroscle-
rotic disease in the Thrombin Receptor Antagonist in Secondary Prevention of
11.7
5.9
2.9
3.8
7.9
9.8
4.5
2.2
4.5
7.4
0
2
4
6
8
10
12
14
Vascular death, MI,
or stroke
Death from
any cause
Stent thrombosis
(definite or probable)
Non-CABG-related
TIMI major bleeding
CABG-related major
bleeding
Clopidogrel
Ticagrelor
Event rate at 12 months (%)
HR 0.84
(95% CI 0.77–0.92)
HR 0.78
(95% CI 0.69–0.89)
HR 0.75
(95% CI 0.59–0.95)
HR 0.95
(95% CI 0.85–1.06)
HR 1.19
(95% CI 1.02–1.38)
Figure 8.3 Kaplan-Meier event rates at 12 months and the relative risk (hazard ratio,
95 percent confi dence interval) for ticagrelor versus clopidogrel for patients with ACS in
the PLATO trial.
https://t.me/med1917
120
CHAPTER 8 Antithrombotic Therapy
Atherothrombotic Ischemic Events (TRA2P-TIMI 50) trial, including a signifi cant
17 percent reduction in the risk of MI.
45
Vorapaxar increased the risk of moder-
ate or severe bleeding, including a signifi cant increase in the risk of intracranial
hemorrhage. In subjects with peripheral arterial disease, vorapaxar reduced the
risk of acute limb ischemia by 42 percent (HR 0.58, 95 percent CI 0.39–0.86).
However, vorapaxar should not be used in patients with a history of TIA or
stroke due to an unacceptable increase in the risk of intracranial hemorrhage.
Atopaxar, a PAR-1 antagonist with a shorter half-life than vorapaxar, has
not been evaluated in phase III testing. In phase II trials, atopaxar demonstrated
favorable trends toward effi cacy, including a signifi cant reduction in Holter-
detected ischemia with a small increase in bleeding in patients with stable coro-
nary artery disease or after ACS.
46–47
GP IIb/IIIa inhibitors
GP IIb/IIIa inhibitors interfere with platelet aggregation by blocking the GP IIb/
IIIa receptor that is expressed on the activated platelet. In turn, this action pre-
vents fi brinogen cross-linking from occurring between platelets via the GP IIb/
IIIa receptor. Abciximab is a humanized monoclonal antibody that targets the
platelet’s GP IIb/IIIa receptor, as well as integrins on endothelial and smooth
muscle cells and leukocytes. In contrast, both eptifi batide and tirofi ban are
intravenous, small-molecule inhibitors that competitively block the GP IIb/IIIa
receptor.
48
The effi cacy of GP IIb/IIIa inhibitors for reducing CV events has been dem-
onstrated in several trials of patients with ACS and those undergoing PCI.
48
In particular, the benefi t of GP IIb/IIIa inhibitors appears to be enhanced in
high-risk patients, including those with elevated biomarkers, those undergoing
PCI, or those with diabetes mellitus.
48
More contemporary trials have aimed
to address the optimal timing of administering these drugs and whether there
is additive benefi t for GP IIb/IIIa receptor inhibitors on a background of dual
antiplatelet therapy. The Early Glycoprotein IIb/IIIa Inhibition in Patients with
NSTE-ACS (EARLY-ACS) trial enrolled 9,492 patients and randomized them
to either early routine administration of eptifi batide or delayed provisional
eptifi batide at the time of PCI.
49
Early administration of eptifi batide did not
reduce the risk of CV events compared with delayed provisional administra-
tion (HR 0.92, 95 percent CI 0.80–1.06), but it increased the risk of TIMI major
bleeding (2.6 versus 1.8 percent, p = 0.02). In the Intracoronary Stenting and
Antithrombotic Regimen–Rapid Early Action for Coronary Treatment (ISAR-
REACT) trial, 2,159 low- to intermediate-risk patients undergoing elective PCI
who all received clopidogrel 600 mg more than 2 hours prior to PCI were
randomized to abciximab or placebo.
50
At the end of follow-up, there was no
difference in the risk of CV events or major bleeding complications between
groups; the abciximab group showed a higher rate of thrombocytopenia. In
contrast, the ISAR-REACT 2 trial enrolled higher-risk patients with non-ST-
elevation ACS (NSTE-ACS) who had been pretreated with clopidogrel 600 mg
and randomized them to abciximab or placebo.
51
In this higher-risk group,
abciximab reduced the risk of 30-day CV events by 25 percent compared with
placebo, but the benefi t appeared to be confi ned to subjects with elevated
biomarkers of myonecrosis.
51
https://t.me/med1917
121
CHAPTER 8 Antithrombotic Therapy
Anticoagulant therapy
Parenteral anticoagulants
Unfractionated heparin
Unfractionated heparin (UFH) is a heterogeneous mixture of glycosamino-
glycans containing a pentasaccharide sequence that binds to antithrombin III
and induces a conformational change that leads to rapid inhibition of thrombin
and Factors Xa, IXa, XIa, and XIIa.
52
Since UFH has been empirically used for
decades in the management of patients with ACS, there are a limited number of
rigorous randomized trials that have evaluated its effi cacy. In a meta-analysis of
six randomized trials of patients with unstable angina, the use of UFH reduced
the risk of death or MI by 33 percent (RR 0.67, 95 percent CI 0.44–1.02) com-
pared with aspirin alone.
52
However, since the dataset included only 1,353 sub-
jects, the results fell short of achieving statistical signifi cance. Limitations to the
use of UFH include the drug’s unpredictable pharmacodynamics and potential
complications, including heparin-induced thrombocytopenia. However, intrave-
nous protamine sulfate is available to rapidly reverse its anticoagulant effects by
binding to UFH to form a stable salt.
Low molecular-weight heparin
Depolymerization of UFH yields the low-molecular-weight fragments that
make up low-molecular-weight heparin (LMWH). LMWH has greater bioavail-
ability, a longer half-life, more consistent pharmacodynamics, and fewer off-
target side effects than UFH.
53
The effi cacy of LMWH (in particular enoxaparin)
compared with UFH has been evaluated in several randomized clinical trials.
54
In a meta-analysis that combined data from six randomized trials that included
21,946 subjects with NSTE-ACS, enoxaparin reduced the risk of death or MI by
9 percent (HR 0.91, 95 percent CI 0.83–0.99) compared with UFH.
54
Mortality
and major bleeding were similar between treatment arms.
However, concerns have been raised regarding the risk of bleeding when
LMWH is used in patients undergoing PCI. In the Superior Yield of the New
Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa inhibitors
(SYNERGY) trial, enoxaparin was non-inferior to UFH in regards to CV out-
comes, but enoxaparin increased the risk of TIMI major bleeding (3.7 versus
2.5 percent, p = 0.028).
55
Outcomes appeared to be worse for subjects who
had been switched between types of anticoagulant therapies around the time
of their PCI.
55
The effi cacy of LMWH was also evaluated in 20,506 patients present-
ing with STEMI and receiving fi brinolytic therapy in the Enoxaparin versus
Unfractionated Heparin with Fibrinolysis for ST-Elevation Myocardial Infarction
(ExTRACT-TIMI 25) trial.
56
A strategy of enoxaparin throughout the index hos-
pitalization reduced the risk of death or MI by 17 percent at 30 days compared
with UFH for 48 hours, but increased the risk of major bleeding.
56
Bivalirudin
Bivalirudin is a parenteral direct thrombin inhibitor that has been evaluated
in patients with ACS and those undergoing PCI. The Acute Catheterization
and Urgent Intervention Triage Strategy (ACUITY) trial was a prospective,
https://t.me/med1917
122
CHAPTER 8 Antithrombotic Therapy
open-label trial that randomized 13,819 patients with moderate- or high-risk
ACS to one of three treatment arms: heparin plus GP IIb/IIIa inhibitor, bivalirudin
plus GP IIb/IIIa inhibitor, or bivalirudin alone.
57
Bivalirudin alone was determined
to be non-inferior to heparin plus GP IIb/IIIa inhibitor with respect to ischemic
events (7.8 versus 7.3 percent, respectively, p = 0.32, Fig. 8.4). Monotherapy
with bivalirudin reduced the risk of major bleeding (3.0 versus 5.7 percent,
p < 0.001) and therefore was superior to the combination of heparin with a GP
IIb/IIIIa inhibitor in regards to the net clinical outcome of ischemic and bleeding
events (10.1 versus 11.7 percent, p = 0.02, Fig. 8.4). Among patients who did
not receive a thienopyridine prior to angiography, ischemic events tended to
be more frequent with bivalirudin monotherapy than with heparin plus a GP
IIb/IIIa inhibitor (RR 1.29; 95 percent CI 1.03–1.63, p for interaction = 0.054).
Consistent fi ndings for bivalirudin have been observed in randomized trials of
patients undergoing PCI
58
and across the spectrum of ACS.
59
The effi cacy of bivalirudin versus heparin with GP IIb/IIIa inhibitor was further
evaluated in 3,602 subjects with STEMI undergoing primary PCI enrolled in the
Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial
Infarction (HORIZONS-AMI) trial. Bivalirudin reduced the risk of 30-day net
adverse events (RR 0.76, 95 percent CI 0.63–0.92), a benefi t that was driven by
a reduction in major bleeding (RR 0.60, 95 percent CI 0.46–0.77).
60
There was
an increased risk of stent thrombosis within 24 hours in the bivalirudin group,
but no signifi cant increase was seen at 30 days. Bivalirudin reduced the risk of
cardiac death (RR 0.62, 95 percent CI 0.40–0.95, p = 0.03) and all-cause death
(RR 0.66, 95 percent CI 0.44–1.00, p = 0.047) at 30 days.
60
11.7
7.3
4.9
5.7
11.8
7.7
5.0
5.3
10.1
7.8
5.4
3.0
0.0
2.0
4.0
6.0
8.0
10.0
12.0
14.0
Net clinical outcome
(composite ischemia
or major bleeding)
Composite ischemia
(death, MI or unplanned
revascularization)
MI Non-CABG-related TIMI
major bleeding
UFH or LMWH +GPI
Bivalirudin + GPI
Bivalirudin alone
Event rate at 30 days (%)
Figure 8.4 The incidence of clinical outcomes at 30 days in the ACUITY trial. The
ACUITY trial was an open-label trial that compared heparin plus a GP IIb/IIIa inhibitor
(GPI), bivalirudin plus a GPI, and bivalirudin alone in patients with moderate- or high-risk
ACS who were undergoing an early invasive strategy.
https://t.me/med1917
123
CHAPTER 8 Antithrombotic Therapy
Fondaparinux
Fondaparinux is a synthetic pentasaccharide Factor Xa inhibitor. The effi cacy
of fondaparinux as an anticoagulant in the setting of NSTE-ACS was evaluated
in the Fifth Organization to Assess Strategies in Acute Ischemic Syndromes
(OASIS-5) trial. The trial randomized 20,078 subjects with NSTE-ACS to fonda-
parinux (2.5 mg SC daily) or enoxaparin (1 mg/kg SC twice daily).
61
Of those
subjects enrolled, 63 percent underwent coronary angiography and 34 percent
underwent PCI for the index event. Fondaparinux was non-inferior to enox-
aparin in regards to the primary effi cacy end point of death, MI, or refractory
ischemia (HR 1.01, 95 percent CI 0.90–1.13) at 9 days. However, fondaparinux
reduced the number of deaths at 30 days (295 versus 352, p = 0.02) and at
180 days (574 versus 638, p = 0.05). This may in part be explained by a reduced
incidence of major bleeding (HR 0.52, 95 percent CI 0.44–0.61) for patients
treated with fondaparinux compared with enoxaparin.
61
Subsequently, fondaparinux was evaluated in 12,092 patients with STEMI
in the OASIS-6 trial.
62
Subjects were randomized to fondaparinux (2.5 mg SC
daily) for 8 days versus usual care (usual care: stratum 1 = placebo in those in
whom UFH was deemed not indicated; stratum 2 = UFH for up to 48 hours).
Fondaparinux reduced the risk of death or reinfarction at 30 days (HR 0.86,
95 percent CI 0.77–0.96) compared with usual care. Although there was a ten-
dency toward fewer bleeds with fondaparinux, this difference was not statisti-
cally signifi cant. Fondaparinux was associated with a reduced risk of death at
day 9 ( p = 0.04), at day 30 ( p = 0.03), and at study end (3 to 6 months, p = 0.03).
Although there was no heterogeneity in regards to effi cacy of fondaparinux
in stratum 1 versus stratum 2, subjects who underwent primary PCI did not
appear to benefi t from fondaparinux. A higher incidence of catheter-related
thrombosis was observed for patients treated with fondaparinux during PCI,
thereby necessitating the use of standard-dose UFH during the procedure if
fondaparinux to is to be used.
62
Oral anticoagulants after ACS
Warfarin inhibits vitamin K epoxide reductase, which catalyzes the conversion of
vitamin K to vitamin KH
2
. In turn, vitamin KH
2
is involved in gamma-carboxylation,
which is required for the biological activity of the vitamin K-dependent coagula-
tion proteins, including Factors II, VII, IX, and X, as well as protein C and S. In a
meta-analysis of ten randomized, controlled trials comparing aspirin monotherapy
to aspirin in combination with warfarin (targeted INR > 2.0), warfarin reduced the
risk of MI by 44 percent, ischemic stroke by 54 percent, and revascularization by
20 percent.
63
However, the addition of warfarin increased the risk of major bleed-
ing by 250 percent, and mortality did not differ between groups.
63
Rivaroxaban is a novel oral Factor Xa inhibitor that has been evaluated for
the treatment and prevention of venous and arterial thrombosis. The Anti-Xa
Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in
Subjects with Acute Coronary Syndrome (ATLAS ACS 2-TIMI 51) trial ran-
domized 15,526 subjects following recent ACS to very low-dose or low-dose
rivaroxaban (2.5 or 5 mg twice daily) versus placebo.
64
Subjects with a history of
stroke or TIA were excluded from participation if they were to be treated with
both aspirin and a thienopyridine. Of those enrolled, 93 percent were treated
https://t.me/med1917
124
CHAPTER 8 Antithrombotic Therapy
with a background of a thienopyridine. After a mean duration of 13.1 months,
rivaroxaban signifi cantly reduced the risk of CV death, MI, or stroke by 16 per-
cent (HR 0.84, 95 percent CI 0.74–0.96), including a signifi cant reduction in the
risk of stent thrombosis (HR 0.69, 95 percent CI 0.51–0.93). Rivaroxaban at a
dose of 2.5 mg twice daily signifi cantly reduced the risk of CV death (2.7 versus
4.1 percent, p = 0.002) and all-cause death (2.9 versus 4.5 percent, p = 0.002).
However, rivaroxaban increased the risk of non-CABG-related major bleeding
and intracranial hemorrhage, without a signifi cant increase in fatal bleeding.
64
In
contrast, anticoagulation with full-dose apixaban, a different Factor Xa inhibitor,
failed to show benefi t in patients after ACS (HR 0.95, 95 percent 0.80–1.11), and
the trial was terminated early due to an increase in fatal and intracranial bleeds.
65
It remains unknown whether the differential effi cacy that was observed for Factor
Xa inhibition after ACS between the rivaroxaban and apixaban trials might be
explained by differences in drug dosing or study populations. However, the differ-
ences in intensity of anticoagulation may offer the most likely explanation.
Future directions
Trials are ongoing to evaluate the benefi t of oral and intravenous anticoagu-
lant therapies with or without different background antiplatelet therapies in
patients after ACS. Additional antiplatelet therapies remain under investigation.
Cangrelor is a direct-acting and reversible intravenous P2Y12 receptor inhibi-
tor that has been studied in the setting of PCI
66,67
or as a bridge to surgery for
patients who require P2Y12 inhibition.
68
Picotamide inhibits TXA
2
synthase and
TXA
2
receptors and has been proposed as an alternative to aspirin.
69
As more
potent or alternate antiplatelet and anticoagulant therapies undergo clinical
evaluation, continued emphasis will need to be placed on achieving the optimal
balance between effi cacy and safety.
References
1. Davi G, Patrono C . Platelet activation and atherothrombosis. N Engl J Med
2007; 357: 2482–2494 .
2. Patrono C, Garcia Rodriguez LA, Landolfi R, Baigent C . Low-dose aspirin for the
prevention of atherothrombosis. N Engl J Med 2005; 353: 2373–2383 .
3. Peto R, Gray R, Collins R, et al . Randomised trial of prophylactic daily aspirin in
British male doctors. Br Med J (Clin Res Ed) 1988; 296: 313–316 .
4. Final report on the aspirin component of the ongoing Physicians’ Health Study.
Steering Committee of the Physicians’ Health Study Research Group. N Engl J
Med 1989; 321: 129–135 .
5. Thrombosis prevention trial: randomised trial of low-intensity oral anticoagula-
tion with warfarin and low-dose aspirin in the primary prevention of ischaemic
heart disease in men at increased risk. The Medical Research Council’s General
Practice Research Framework. Lancet 1998; 351: 233–241 .
6. Hansson L, Zanchetti A, Carruthers SG, et al . Effects of intensive blood-pressure
lowering and low-dose aspirin in patients with hypertension: principal results
of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study
Group. Lancet 1998; 351: 1755–1762 .
https://t.me/med1917
125
CHAPTER 8 Antithrombotic Therapy
7. de Gaetano G . Low-dose aspirin and vitamin E in people at cardiovascular risk:
a randomised trial in general practice. Collaborative Group of the Primary
Prevention Project. Lancet 2001; 357: 89–95 .
8. Ridker PM, Cook NR, Lee IM, et al . A randomized trial of low-dose aspirin
in the primary prevention of cardiovascular disease in women. N Engl J Med
2005; 352: 1293–1304 .
9. Baigent C, Blackwell L, Collins R, et al . Aspirin in the primary and secondary pre-
vention of vascular disease: collaborative meta-analysis of individual participant
data from randomised trials. Lancet 2009; 373: 1849–1860 .
10. Ogawa H, Nakayama M, Morimoto T, et al . Low-dose aspirin for primary pre-
vention of atherosclerotic events in patients with type 2 diabetes: a randomized
controlled trial. JAMA 2008; 300: 2134–2141 .
11. Belch J, MacCuish A, Campbell I, et al . The prevention of progression of arterial
disease and diabetes (POPADAD) trial: factorial randomised placebo controlled
trial of aspirin and antioxidants in patients with diabetes and asymptomatic
peripheral arterial disease. BMJ 2008; 337: a1840 .
12. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group.
Randomised trial of intravenous streptokinase, oral aspirin, both or neither
among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet
1988; ii : 349–360 .
13. Secondary prevention of vascular disease by prolonged antiplatelet
treatment. Antiplatelet Trialists’ Collaboration. Br Med J (Clin Res Ed)
1988; 296: 320–331 .
14. Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of ran-
domised trials of antiplatelet therapy for prevention of death, myocardial infarc-
tion, and stroke in high risk patients. BMJ 2002; 324: 71–86 .
15. Mehta SR, Bassand JP, Chrolavicius S, et al . Dose comparisons of clopidogrel and
aspirin in acute coronary syndromes. N Engl J Med 2010; 363: 930–942 .
16. Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI Guideline
for Percutaneous Coronary Intervention: a report of the American College of
Cardiology Foundation/American Heart Association Task Force on Practice
Guidelines and the Society for Cardiovascular Angiography and Interventions.
Circulation 2011; 124: e574–e651 .
17. Bertrand ME, Rupprecht HJ, Urban P, Gershlick AH, for the CLASSICS
Investigators. Double-blind study of the safety of clopidogrel with and without a
loading dose in combination with aspirin compared with ticlopidine in combina-
tion with aspirin after coronary stenting: the clopidogrel aspirin stent interna-
tional cooperative study (CLASSICS). Circulation 2000; 102: 624–629 .
18. Cadroy Y, Bossavy JP, Thalamas C, et al . Early potent antithrombotic effect with
combined aspirin and a loading dose of clopidogrel on experimental arterial
thrombogenesis in humans. Circulation 2000; 101: 2823–2828 .
19. Bhatt DL, Bertrand ME, Berger PB, et al . Meta-analysis of randomized and reg-
istry comparisons of ticlopidine with clopidogrel after stenting. J Am Coll Cardiol
2002; 39: 9–14 .
20. The Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events
Trial Investigators. Effects of clopidogrel in addition to aspirin in patients
with acute coronary syndromes without ST-segment elevation. N Engl J Med
2001; 345: 494–502 .
21. Sabatine MS, Cannon CP, Gibson CM, et al . Addition of clopidogrel to aspirin
and fi brinolytic therapy for myocardial infarction with ST-segment elevation.
N Engl J Med 2005; 352: 1179–1189 .
https://t.me/med1917
126
CHAPTER 8 Antithrombotic Therapy
22. Chen ZM, Jiang LX, Chen YP, et al . Addition of clopidogrel to aspirin in 45,852
patients with acute myocardial infarction: randomised placebo-controlled trial.
Lancet 2005; 366: 1607–1621 .
23. CAPRIE Steering Committee. A randomised, blinded, trial of clopi-
dogrel versus aspirin in patients at risk of ischemic events (CAPRIE). Lancet
1996; 348: 1329–1339 .
24. Bhatt DL, Fox KA, Hacke W, et al . Clopidogrel and aspirin versus aspirin alone for
the prevention of atherothrombotic events. N Engl J Med 2006; 354: 1706–1717 .
25. Bhatt DL, Flather MD, Hacke W, et al . Patients with prior myocardial infarction,
stroke, or symptomatic peripheral arterial disease in the CHARISMA trial. J Am
Coll Cardiol 2007; 49: 1982–1988 .
26. Mehta SR, Yusuf S, Peters RJ, et al . Effects of pretreatment with clopidogrel
and aspirin followed by long-term therapy in patients undergoing percutaneous
coronary intervention: the PCI-CURE study. Lancet 2001; 358: 527–533 .
27. Steinhubl SR, Berger PB, Mann JT, 3rd, et al . Early and sustained dual oral anti-
platelet therapy following percutaneous coronary intervention: a randomized
controlled trial. JAMA 2002; 288: 2411–2420 .
28. Mehta SR, Tanguay JF, Eikelboom JW, et al . Double-dose versus standard-dose
clopidogrel and high-dose versus low-dose aspirin in individuals undergoing per-
cutaneous coronary intervention for acute coronary syndromes (CURRENT-
OASIS 7): a randomised factorial trial. Lancet 2010; 376: 1233–1243 .
29. Valgimigli M, Campo G, Monti M, et al . Short- versus long-term duration of
dual-antiplatelet therapy after coronary stenting: a randomized multicenter trial.
Circulation 2012; 125: 2015–2026 .
30. Park SJ, Park DW, Kim YH, et al . Duration of dual antiplatelet therapy after
implantation of drug-eluting stents. N Engl J Med 2010; 362: 1374–1382 .
31. Gwon HC, Hahn JY, Park KW, et al . Six-month versus 12-month dual antiplatelet
therapy after implantation of drug-eluting stents: the Effi cacy of Xience/Promus
Versus Cypher to Reduce Late Loss After Stenting (EXCELLENT) randomized,
multicenter study. Circulation 2012; 125: 505–513 .
32. Gurbel PA, Bliden KP, Hiatt BL, O’Connor CM . Clopidogrel for coronary stent-
ing: response variability, drug resistance, and the effect of pretreatment platelet
reactivity. Circulation 2003; 107: 2908–2913 .
33. Price MJ, Berger PB, Teirstein PS, et al . Standard- vs high-dose clopidogrel
based on platelet function testing after percutaneous coronary intervention: the
GRAVITAS randomized trial. JAMA 2011; 305: 1097–1105 .
34. Collet JP, Cuisset T, Range G, et al . Bedside monitoring to adjust antiplatelet
therapy for coronary stenting. N Engl J Med 2012;367(22):2100–2109.
35. Mega JL, Simon T, Collet JP, et al. Reduced-function CYP2C19 genotype and risk
of adverse clinical outcomes among patients treated with clopidogrel predomi-
nantly for PCI: a meta-analysis. JAMA 2010; 304: 1821–1830 .
36. Mega JL, Hochholzer W, Frelinger AL, 3rd, et al. Dosing clopidogrel based on
CYP2C19 genotype and the effect on platelet reactivity in patients with stable
cardiovascular disease. JAMA 2011; 306: 2221–2228 .
37. Gilard M, Arnaud B, Cornily JC, et al. Infl uence of omeprazole on the anti-
platelet action of clopidogrel associated with aspirin: the randomized, dou-
ble-blind OCLA (Omeprazole CLopidogrel Aspirin) study. J Am Coll Cardiol
2008; 51: 256–260 .
38. O’Donoghue ML, Braunwald E, Antman EM, et al. Pharmacodynamic effect and
clinical effi cacy of clopidogrel and prasugrel with or without a proton-pump
inhibitor: an analysis of two randomised trials. Lancet 2009; 374: 989–997 .
https://t.me/med1917
127
CHAPTER 8 Antithrombotic Therapy
39. Bhatt DL, Cryer BL, Contant CF, et al. Clopidogrel with or without omeprazole
in coronary artery disease. N Engl J Med 2010; 363: 1909–1917 .
40. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in
patients with acute coronary syndromes. N Engl J Med 2007; 357: 2001–2015 .
41. Bhatt DL . Intensifying platelet inhibition—navigating between Scylla and
Charybdis. N Engl J Med 2007; 357: 2078–2081 .
42. Roe MT, Armstrong PW, Fox KA, et al. Prasugrel versus clopidogrel for acute cor-
onary syndromes without revascularization. N Engl J Med 2012; 367: 1297–1309 .
43. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients
with acute coronary syndromes. N Engl J Med 2009; 361: 1045–1057 .
44. Tricoci P, Huang Z, Held C, et al. Thrombin-receptor antagonist vorapaxar in
acute coronary syndromes. N Engl J Med 2012;366(1):20–33.
45. Morrow DA, Braunwald E, Bonaca MP, et al. Vorapaxar in the secondary pre-
vention of atherothrombotic events. N Engl J Med 2012; 366: 1404–1413 .
46. O’Donoghue ML, Bhatt DL, Wiviott SD, et al. Safety and tolerability of atopaxar
in the treatment of patients with acute coronary syndromes: the lessons from
antagonizing the cellular effects of Thrombin-Acute Coronary Syndromes Trial.
Circulation 2011; 123: 1843–1853 .
47. Wiviott SD, Flather MD, O’Donoghue ML, et al. Randomized trial of atopaxar in
the treatment of patients with coronary artery disease: the lessons from antago-
nizing the cellular effect of Thrombin-Coronary Artery Disease Trial. Circulation
2011; 123: 1854–1863 .
48. Jneid H, Anderson JL, Wright RS, et al. 2012 ACCF/AHA focused update of the
guideline for the management of patients with unstable angina/non-ST-eleva-
tion myocardial infarction (updating the 2007 guideline and replacing the 2011
focused update): a report of the American College of Cardiology Foundation/
American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol
2012; 60: 645–681 .
49. Giugliano RP, White JA, Bode C, et al. Early versus delayed, provisional eptifi -
batide in acute coronary syndromes. N Engl J Med 2009; 360: 2176–2190 .
50. Kastrati A, Mehilli J, Schuhlen H, et al. A clinical trial of abciximab in elective
percutaneous coronary intervention after pretreatment with clopidogrel. N Engl
J Med 2004; 350: 232–238 .
51. Kastrati A, Mehilli J, Neumann FJ, et al. Abciximab in patients with acute coronary
syndromes undergoing percutaneous coronary intervention after clopidogrel
pretreatment: the ISAR-REACT 2 randomized trial. JAMA 2006; 295: 1531–1538 .
52. Oler A, Whooley MA, Oler J, Grady D . Adding heparin to aspirin reduces the
incidence of myocardial infarction and death in patients with unstable angina.
A meta-analysis. JAMA 1996; 276: 811–815 .
53. Garcia DA, Baglin TP, Weitz JI, Samama MM . Parenteral anticoagulants:
Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American
College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest .
2012; 141: e24S–43S .
54. Petersen JL, Mahaffey KW, Hasselblad V, et al . Effi cacy and bleeding complica-
tions among patients randomized to enoxaparin or unfractionated heparin for
antithrombin therapy in non-ST-segment elevation acute coronary syndromes: a
systematic overview. JAMA 2004; 292: 89–96 .
55. Ferguson JJ, Califf RM, Antman EM, et al. Enoxaparin vs unfractionated hepa-
rin in high-risk patients with non-ST-segment elevation acute coronary syn-
dromes managed with an intended early invasive strategy: primary results of the
SYNERGY randomized trial. JAMA 2004; 292: 45–54 .
https://t.me/med1917
Соседние файлы в папке Библиотека им академика М.И. Перельмана