Glycoprotein IIb/IIIa Inhibitors.
Consequently, platelet transfusion would not be able to absorb excess drug and would not be
GPIs inhibit GP IIb/IIIa receptors on platelets, blocking the binding of fibrinogen to activated
GP IIb/IIIa receptors, which is the final step in platelet aggregation.
These agents must be given with unfractionated heparin (UFH) or a low-molecular-weight
heparin (LMWH) because coadministration of heparin provides improved protection against
persistent platelet activation, thereby improving outcome after percutaneous coronary
intervention however it should be discontinued immediately after PCI to reduce the risk of
major bleeding.
Note that these agents are only available as an IV infusion.
• Use of GPIs has been declining in recent years; patients likely to benefit most are those
receiving PCI for NSTE-ACS (Non-ST elevation-acute coronary syndrome) with elevated
troponin levels and patients with STEMI who have not been preloaded with a P2Y12 inhibitor
and are not being treated with bivalirudin.
Recommended doses are as follows:
✓ Abciximab: 0.25 mg/kg IV bolus given 10–60 minutes before the start of PCI, followed by
0.125 mcg/kg/min (maximum 10 mcg/min) for 12 hours; alternatively, 0.25 mg/kg
intracoronary bolus only.
Abciximab is a chimeric human-murine monoclonal antibody Fab fragment that blocks the GP
IIb/IIIa receptor–fibrinogen binding. It irreversibly binds to the GP IIb/IIIa receptor, with
platelet function recovery occurring over approximately 24 hours after discontinuation of the
infusion.
Due to the strong binding of abciximab to the GP IIb/IIIa receptor, the drug to receptor ration
is approximately 2:1. Therefore, platelet transfusions can absorb the excess abciximab, and
would be effective in management of a major bleeding episode.
✓ Eptifibatide: 180 mcg/kg IV bolus, repeated in 10 minutes, followed by IV infu- sion of 2
mcg/kg/min for 18–24 hours after PCI; reduce infusion dose by 50% if creatinine clearance
(CrCl) is <50 mL/min (0.83 mL/sec).
✓ Tirofiban: 25 mcg/kg IV bolus, then 0.15 mcg/kg/min for up to 18–24 hours after PCI;
reduce infusion dose by 50% if CrCl is ≤60 mL/min (1.0 mL/sec).
Eptifibatide and tirofiban are commonly referred to as “small molecule” as they are peptide
(Eptifibatide) and nonpeptide (tirofiban) inhibitors of the GP IIb/IIIa receptor.
And in comparison to abciximab, they have a much smaller molecular weight. In addition,
these agents have reversibly binds of the GP IIb/IIIa receptor. Therefore, platelet function
recovery occurs in 2 to 4 hours after discontinuation of the infusion. The reversible binding of
the small molecule agents requires that they overwhelm the ability of fibrinogen to bind to
the GP IIb/IIIa receptor with high concentrations and a drug to receptor ratio that is
approximately 500 to 1000:1.
helpful in the management of bleeding with eptifibatide or tirofiban.
- Platelet transfusion is a lifesaving procedure that is carried out to prevent bleeding
or stop ongoing bleeding in patients with low platelet count or functional platelet
disorders
In general:
• GPIs are not beneficial and should not be used in patients with NSTE-ACS undergoing an
ischemia-driven approach. GPIs should also be avoided in patients with STEMI receiving
reperfusion with fibrinolytics because of significant increases in major bleeding and ICH.
• Besides bleeding, GPIs cause significant thrombocytopenia in about 1% of patients
receiving abciximab and 0.5% with eptifibatide and tirofiban.
GPIs are given with heparin because coadministration of heparin provides improved
protection against persistent platelet activation, thereby improving outcome after
percutaneous coronary intervention, however it is important to differentiate GPI-induced
thrombocytopenia from heparin-induced thrombocytopenia (HIT). Thrombocytopenia from a
GP IIb/IIIa inhibitor occurs more rapidly (within hours) and the platelet count nadir is typically
lower (about 20,000) compared to HIT.
Anticoagulants
• Although patients with ACS are typically on at least two antiplatelet agents for a year or
more, a single anticoagulant is usually given for a short time (the initial few days of
hospitalization). UFH can be used across the spectrum of ACS and regardless of the
management strategy.
Unfractionated heparin provides its anticoagulant activity by binding to the endogenous
anticoagulant antithrombin (AT) via a unique pentasaccharide sequence, increasing its
affinity for clotting factor inhibition by 1000-fold.
These UFH–AT complexes can then inhibit clotting factors IXa, Xa, XIa, XIIa, and thrombin,
with most of the impact provided through inhibition of factor Xa and thrombin. Inhibition of
thrombin requires a tertiary binding between the UFH–AT and thrombin molecules. This
requires that the chain length of the inhibitory molecule be at least 18 saccharides long. Since
most UFH molecules are approximately 45-50 saccharides long, UFHs can inhibit factor Xa
and thrombin in an equal 1:1 ratio.
Currently, the recommended dose of UFH is an IV bolus of 60 units/kg (initial maximum total
dose of 4000 units) and an initial infusion rate of 12 units/kg/hr (initial maximum 1000
units/hr). This is the recommended dose regardless of the ACS diagnosis or management
strategy.
***The anticoagulant effect of UFH has significant interpatient variability. This is due to
additional binding of UFH with endothelial cells, plasma protein, and ingestion by
macrophages.
Because of significant interpatient variability in anticoagulant response, therapy must be
monitored with the activated partial thromboplastin time (aPTT) every 6 hours until two
consecutive readings are within the institution’s therapeutic range (1.5–2 times the control
value), then every 24 hours for the duration of UFH therapy. The activated clotting time (ACT)
is monitored during PCI because it can be measured at the bedside with rapid results. Platelet
counts should also be monitored daily or every other day to detect HIT. If HIT is suspected,
discontinue UFH and provide anticoagulation with an IV direct thrombin inhibitor.
CONTRAINDICATION: Active bleeding, history of heparin-induced thrombocytopenia, severe
bleeding risk, recent stroke
ADE: Bleeding, heparin-induced thrombocytopenia
Low-Molecular-Weight Heparins
Similar to UFHs, LMWHs must first bind to AT to provide their anticoagulant activity. LMWHs
are created through chemical or enzymatic depolymerization of UFH molecules and it results
to a mixture of lower molecular weight fragments compared to the larger intact UFH
molecule. LMWHs are heterogeneous compounds about one-third the size of unfractionated
heparin as they are only less than 18 saccharides long.
LMWH’s anticoagulant activity results mostly from inhibition of factor Xa with only the few
larger fragments able to inhibit thrombin. The ratio of factor Xa to thrombin inhibition with a
LMWH is typically 3:1 or 4:1, depending on the process of depolymerization.
Compared to UFHs, LMWHs provide a predicable anticoagulant dose response with no need
for routine therapeutic monitoring.
Anti-Xa monitoring may be helpful would be pediatrics, pregnancy, obesity (greater than 190
kg), and patients with severe renal insufficiency (eg, creatinine clearance [CrCl] less than 30
mL/min [0.5 mL/s]). While pediatric and pregnant patients rarely have ACS, obesity and
severe renal insufficiency are more common in patients with ACS. Since patients with ACS
typically receive anticoagulant therapy for only a few days, the utility of anti-Xa monitoring in
these patients is limited.
The incidence of HIT is lower with LMWHs (<2%) than with UFH (2%–5%), monitoring of
platelet counts is still warranted. Due to 90% cross reactivity between HIT antibodies from
LMWH and UFH, LMWH is not a safe alternative in patients who develop HIT from UFH and
vice versa.
Enoxaparin is the most widely studied agent in ACS and is the only LMWH recommended in
current guidelines. Data support its efficacy in patients with STEMI and NSTE-ACS, regardless
of the perfusion or management strategy used. However, enoxaparin dosing varies across
these different situations. In patients with STEMI receiving reperfusion with fibrinolytics,
enoxaparin demonstrated a significant 17% reduction in death and MI compared to UFH.
Based on clinical trial data, either UFH or enoxaparin is recommended in patients with NSTE-
ACS.
In patients with NSTE-ACS undergoing an ischemia-driven approach, use
of subcutaneous (SC) enoxaparin at 1 mg/kg every 12 hours for up to 3 days is supported by
two clinical trials that demonstrated a significant reduction in MACE compared to IV UFH
without increasing major bleeding.
CONTRAINDICATION: Active bleeding, history of heparin-induced thrombocytopenia, severe
bleeding risk, recent stroke
ADE: Bleeding, heparin-induced thrombocytopenia
Fondaparinux the only available pentasaccharide worldwide and is a synthetic molecule
existing of only the five saccharides. Again, it needs to bind to and potentiate the activity of
AT. And, due to the small size of the molecule, once it binds to AT it can only inhibit factor Xa
and has no activity against thrombin.
Provides a predicable anticoagulant dose response with no need for therapeutic monitoring
(similar to LMWH).
Based on the lack of antibody cross-reactivity, it is reasonable to consider use of
fondaparinux in patients with a history of HIT. Based on the long half- life of fondaparinux,
the SC dose (2.5 mg) is only given once daily. Fondaparinux is contraindicated in patients with
a CrCl of less than 30 mL/min (0.5 mL/s) due to the significant degree of renal elimination
A clinical trial in NSTE-ACS patients receiving either an ischemia-driven or invasive
management strategy demonstrated similar efficacy between fondaparinux and enoxaparin,
with significantly less major bleeding in patients receiving fondaparinux. Fondaparinux can be
considered in patients undergoing an ischemia-driven approach who are at high risk of
bleeding.
***Fondaparinux is not recommended in patients receiving primary PCI for STEMI because of
clinical trial results demonstrating higher rates of catheter-related thrombosis compared to
UFH. In patients with STEMI receiving fibrinolytics, fondaparinux had efficacy and safety
similar to UFH. However, fondaparinux is rarely used in patients with STEMI based on the lack
of superiority to UFH and the benefit shown with enoxaparin over UFH in this population.
CONTRAINDICATION: Active bleeding, history of heparin-induced thrombocytopenia, severe
bleeding risk, recent stroke
ADE: Bleeding
Fibrin-bound thrombin is still enzymatically active, but the large AT–anticoagulant complexes
are unable to gain access and, therefore, exert anticoagulant activity.
Bivalirudin is a direct thrombin inhibitor means bivalirudin does not have to first bind to AT to
provide its anticoagulant effect and because of the lack of AT binding, bivalirudin can inhibit
not only free or soluble thrombin, similar to UFH and LMWH, but also fibrin-bound thrombin.
It is used only in patients with ACS who receive PCI and can be monitored with the ACT in the
catheterization laboratory. Although current guidelines recommend bivalirudin use, UFH is
often used instead because recent trials suggested that bivalirudin does not offer efficacy or
safety benefits over UFH alone in the setting of primary PCI for STEMI.
Bivalirudin has not been evaluated in patients with STEMI receiving reperfusion with
fibrinolytics or in patients with NSTE-ACS undergoing an ischemia-driven approach.

CONTRAINDICATION: Active bleeding, history of heparin-induced thrombocytopenia, severe

bleeding risk, recent stroke

ADE: Bleeding

SECONDARY PREVENTION OF ISCHEMIC EVENTS

For most patients, the initial 24 hours of ACS care are focused on reperfusion (if appropriate),
antithrombotic therapy, and acute supportive measures. After a diagnosis of ACS, patients
are considered to have atherosclerotic cardiovascular disease (ASCVD) and should be treated
aggressively because they are at the highest risk of recurrent MACE. Again remember that
Major adverse cardiac events (MACE) of acute coronary syndrome (ACS) often occur
suddenly resulting in high mortality and morbidity.

Secondary prevention strategies proved to accomplish these goals typically include anti-
ischemic, antiplatelet, lipid- lowering, and antihypertensive therapies (Table 33-8). Specific
pharmacotherapy proved to decrease mortality, HF, reinfarction or stroke, and stent
thrombosis should be initiated prior to hospital discharge in all patients without
contraindications. Medication reconciliation at discharge should include assessment for
DAPT, β-blocker, angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor
blocker (ARB), and statin therapy unless a contraindication exists (Fig. 33-2). In addition,
short-acting NTG should be prescribed as needed for any subsequent episode of acute angina
for patients not taking phosphodiesterase-5 inhibitors. Select patients may also meet criteria
for benefit from an aldosterone antagonist.

In addition to evaluating patients for the use of medications proved to reduce the risk of
MACE or recurrent symptoms of angina, additional interventions may be appropriate to
optimize outcomes and improve safety. Aggressive risk factor modification strategies such as
increased physical activity, dietary modification, weight loss, blood pressure modification,
and smoking cessation should be communicated to all patients, initiated, and continued
indefinitely.

Proton pump inhibitors provide a protective benefit in patients at highest risk for GI bleeding
from DAPT and may be considered for select patients (eg, history of GI bleeding, triple
therapy with DAPT, and an oral anticoagulant with or without a history of GI bleeding).

All patients should refrain from chronic use of nonsteroidal anti-inflammatory drugs with
high degree of cyclo-oxygenase-2 selectivity such as

as they are associated with increased cerebrovascular and cardiovascular events.