Page 2407 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 146 Acute Coronary Syndromes 2149

significantly reduce death or reinfarction compared with placebo or half-life of 17 hours, which enables once-daily administration and
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no heparin, but increased bleeding. However, these trials were produces an even more predictable anticoagulant effect than LMWH
underpowered to demonstrate a benefit of heparin. Definitive data and does not appear to cause heparin-induced thrombocytopenia.
concerning the efficacy of heparin in STEMI patients treated with Protamine sulfate has no effect on the anticoagulant activity of
fibrinolysis come from a metaanalysis of 26 trials involving 73,000 fondaparinux.
patients, in which heparin, given either intravenously or subcutane- Fondaparinux has been evaluated in patients with ACS in three
ously, reduced mortality and reinfarction compared with placebo or large phase III randomized controlled trials. The OASIS-6 trial evalu-
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no heparin. Consistent benefits were evident in a subset of five ated fondaparinux in 12,092 STEMI patients treated with single or
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trials in which patients also received aspirin; heparin compared dual antiplatelet therapy and fibrinolytic therapy. Compared with
with placebo or no heparin reduced both mortality (8.6% vs. 9.1%; placebo or heparin, fondaparinux (2.5 mg/day) reduced the risk of
p = .03) and reinfarction (3.0% vs. 3.3%; p = .04). reinfarction or death (9.7% vs. 11.2%; p = .008) with consistent
Short-term heparin therapy is also beneficial when added to effects in patients with or without an indication for heparin therapy
aspirin in patients with NSTE ACS. A meta-analysis of six trials and in patients who received aspirin alone or the combination of
involving 1353 patients demonstrated that compared with placebo aspirin and clopidogrel. Fondaparinux did not increase major bleed-
or no heparin, up to 7 days of IV heparin reduced death or MI (4.5% ing. However, fondaparinux was associated with no benefit and a
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vs. 7.4%; p = .045) with a nonsignificant excess of major bleeding. trend for harm in patients undergoing primary PCI.
Heparin has not been rigorously evaluated in ACS patients undergo- The OASIS-5 trial evaluated fondaparinux in 20,078 patients
ing PCI but is routinely used in this setting. with NSTE ACS treated with aspirin with or without clopidogrel.
Fondaparinux (2.5 mg once daily) and enoxaparin (1 mg/kg twice a
day) given for a mean of 6 days were associated with similar rates of
Low-Molecular-Weight Heparin the primary outcome of refractory ischemic, MI, or death at 9 days
(5.8% vs. 5.7%), but there was a lower rate of major bleeding with
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LMWH is derived from heparin by enzymatic or chemical methods, fondaparinux (2.2% vs. 4.1%; p < .001). At 30 days, fondaparinux
yielding shorter polysaccharide chains that produce a more predict- was associated with a reduced rate of death compared with enoxaparin
able anticoagulant effect than heparin and a lower propensity for (2.9% vs. 3.5%; p = .02), which appeared to be explained primarily
heparin-induced thrombocytopenia. LMWH is given in fixed weight- by the lower rate of bleeding. In 6238 invasively managed patients,
adjusted doses without routine coagulation monitoring. The antico- fondaparinux and enoxaparin were associated with similar rates of the
agulant effects of LMWH can be partially reversed with protamine primary outcome but fondaparinux was associated with a small excess
sulfate. of catheter-related thrombosis (0.9% vs. 0.4%) and a reduction in
The CREATE trial (n = 15,570) was the largest of four trials that major bleeding (2.4% vs. 5.1%; p < .00001). The risk of catheter
evaluated the efficacy and safety of various LMWH preparations in thrombosis was largely prevented by the administration of heparin at
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patients with STEMI also treated with aspirin and fibrinolysis. the time of intervention.
Approximately half of patients in the CREATE trial were treated with The FUTURA OASIS-8 (Fondaparinux Trial With Unfraction-
dual antiplatelet therapy. The pooled data (n = 16,943) demonstrated ated Heparin During Revascularization in Acute Coronary Syndromes)
that compared with placebo, initial LMWH continued for up to 7 study compared the effect of standard-dose heparin (85 units/kg bolus
days reduced the risk of reinfarction (1.6% vs. 2.2%; p < .05) and with additional boluses based on an activated clotting time dosing
death (7.8% vs. 8.7%; p < .05) at the cost of an increase in major algorithm) with reduced-dose heparin (50 units/kg without activated
bleeding (1.1% vs. 0.4%; p < .05). clotting time adjustment) on the primary outcome, a composite of
Most of the trials comparing LMWH with heparin for the treat- bleeding or major vascular site access complications, in 2026 patients
ment of STEMI tested enoxaparin. Pooled data from eight trials with NSTE ACS who were treated with fondaparinux and scheduled
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involving 27,758 patients demonstrated that compared with heparin, to undergo PCI within 72 hours. The incidences of the primary
initial LMWH reduced the risk of MI (2.1% vs. 3.9%; p < .05) with outcome and of catheter-related thrombosis were similar in the two
similar rates of death (5.3% vs. 5.8%) at the cost of an increase in heparin dose groups, but death, MI, or target vessel revascularization
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major bleeding (2.2% vs. 1.6%). Consistent results were evident at occurred more often in the low-dose group. These data support the
30 days. use of standard-dose heparin in patients with NSTE ACS who are
The FRISC-1 (Fragmin during Instability in Coronary Artery treated with fondaparinux and scheduled to undergo PCI.
Disease 1) trial evaluated the efficacy and safety of dalteparin in
patients with NSTE ACS. Pooled data from FRISC-1 (n = 1539)
and a second much smaller phase II study demonstrated that com- Bivalirudin
pared with placebo or no LMWH, LMWH reduced the risk of MI
or death (1.6% vs. 5.2%; p < .0001) with no significant increase in Bivalirudin is an IV direct thrombin inhibitor that binds thrombin
major bleeding. and prevents it from interacting and its substrates. Bivalirudin has a
Multiple trials have compared LMWH with heparin in patients short half-life of only 25 minutes after IV injection, making the lack
with NSTE ACS. A pooled analysis of five trials involving 12,171 of an antidote less problematic than it is for longer-acting anticoagu-
patients demonstrated that LMWH and heparin were associated with lants. It is about 20% renally cleared, and the half-life is prolonged
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similar rates of MI or death (2.2% vs. 2.3%) and major bleeding. in patients with renal impairment. Bivalirudin does not cause
A subsequent meta-analysis involving 21,946 patients with NSTE heparin-induced thrombocytopenia.
ACS demonstrated that compared with heparin, enoxaparin reduced The efficacy and safety of direct thrombin inhibitors in ACS
the risk of death or MI (10.1% vs. 11.0%; p < .05) with no increase patients and those undergoing PCI was examined in the Direct
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in major bleeding. The latter meta-analysis included some trials that Thrombin Inhibitor Trialists’ Collaboration metaanalysis involving
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did not involve the use of GP IIb/IIIa inhibitors and other in which data from 11 trials and 35,970 patients. The pooled data indicated
they were widely used. The proportion of patients who underwent a significant benefit of direct thrombin inhibitors (including bivali-
an invasive management strategy also varied among the trials. rudin) compared with heparin for the prevention of MI or death.
Clopidogrel and GP IIb/IIIa inhibitors were not used in the trials
included in this meta-analysis.
Fondaparinux The HORIZONS AMI (Harmonizing Outcomes with Revascu-
larization and Stents in Acute Myocardial Infarction) trial evaluated
Fondaparinux is a synthetic pentasaccharide that contains the essen- the use of bivalirudin in 3602 STEMI patients undergoing PCI who
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tial five-sugar chain that binds antithrombin with high affinity and were treated with the combination of aspirin and clopidogrel.
enhances the rate at which it inhibits factor Xa. Fondaparinux has a Compared with heparin plus GP IIb/IIIa, bivalirudin plus provisional