Treating Patients on Antiplatelet Therapy
In order to safely and effectively manage this patient population, oral health professionals should be able to recognize the medical indications for which antiplatelets are prescribed and understand their adverse effects.
By Sandra Stramoski, RDH, MSDH, and Anna Matthews, RDH, MS
After reading this course, the participant should be able to:
1. Describe the mechanism of action for antiplatelet medications.
2. Identify the most commonly used antiplatelet therapies.
3. Discuss the implications of antiplatelet therapy on oral health care delivery.
Patients at risk for thromboembolic events—such as those who have
experienced myocardial infarction (MI), stroke, or have recently placed stents—present
new challenges in providing safe and effective oral health care. Antiplatelet
therapy reduces the risk of thromboembolic events dramatically but, at the same
time, raises the likelihood of bleeding events, including perioperative
bleeding associated with medical and dental procedures. Oral health
professionals must be able to recognize the medical indications for which
antiplatelets are prescribed, understand their adverse effects, and be prepared
to manage the growing number of patients in dental settings who are taking
Aspirin was the first oral antiplatelet therapy. In addition to
antiplatelet effects, aspirin provides analgesic, anti-inflammatory, and
antipyretic effects. Aspirin still has a viable place in treating patients with
a variety of vascular disorders and preventing ischemic stroke or MI. New
drugs, called novel oral antiplatelet drugs (NOAPs), are more selective in
targeting the various steps in the hemostasis/coagulation process. The combined
therapeutic and adverse effects of these drugs are additive or synergistic.
MECHANISM OF ACTION
essential participants in the blood coagulation process and in the formation of
fibrin clots. By providing the initial hemostatic plug at the site of vascular
injury, platelets prevent blood loss. But they also participate in the
pathological thromboses that can lead to MI, stroke, and peripheral vascular
thromboses when platelet activation is unwanted. Vessel injury—including
physical damage to the vascular wall, destruction of the endothelium as a
result of disease, and vascular wall irritation following stent placement—are
conditions that may cause platelets to undergo adhesion to the vascular wall,
activation, and aggregation. These platelet changes enhance activation of the
blood coagulation process by providing a surface onto which clotting factors
assemble and by releasing stored clotting factors.1
In a healthy vascular endothelium, several regulatory mechanisms, as well
as numerous required co-factors work in concert to prevent initiation of the
platelet activation and coagulation process.1 Upon vessel injury,
platelets adhere to the vessel wall by interactions with von Willebrand factor
and collagen, causing platelets to change shape and to release adenosine
diphosphate (ADP). The activated platelets also generate thromboxane A2 (TxA2).
Both ADP and TxA2 are agonists that cause further platelet activation and
accumulation of platelets at the injury site. Disruption of the endothelial
layer that serves as a barrier between circulating platelets and the
prothrombotic subendothelial layer leads to exposure of tissue factor, which
catalyzes the coagulation response. This response results in the formation of
thrombin, which further activates platelets and encourages fibrinogen to form
fibrin. The combination of activated platelets and fibrin at the injury site
forms a stable hemostatic plug that arrests bleeding (Figure 1).2
FIGURE 1. The hemostatic process and the role of platelets.
REPRINTED WITH PERMISSION FROM DORSAM RT, KUNAPULI SP. CENTRAL ROLE OF THE P2Y 12 RECEPTOR IN PLATELET ACTIVATION. J
CLIN INVEST. 2004;113:340–345.
Platelets are key players in the blood coagulation cascade. Because
platelets do not have nuclei, they do not have the ability to synthesize new
proteins. Aspirin interferes with the production of TxA2 by blocking its
synthesis from cyclooxygenase 1 (COX-1), thus, preventing platelet activation.1,3 Additionally, the activation of multiple receptors on the platelets'
surface leads to further platelet adhesion and aggregation. The ADP released
following endothelial injury binds to purinergic receptors P2Y1 and P2Y12,
leading to platelet activation. Reversible or irreversible inhibition of either
purinergic receptors by several antiplatelet drugs is sufficient to block
platelet activation (Table 1).1,2,4,5
These potent inhibitors of platelet function have revolutionized
cardiovascular medicine and improved patient outcomes by lowering the risk of
complications, such as restenosis and thrombosis.
Aspirin and Novel Oral
often used synergistically with other antiplatelet agents. Low-dose aspirin (75
mg to 81 mg), used alone or in combination with NOAPs, decreases the risk for
MI events and stroke, and increases short- and long-term survival rates.6 Studies have shown that aspirin offers significant benefits in stroke
prevention. Controversy remains on the preventive use of aspirin in low-risk
patients when a risk of bleeding is present.7,8
Oral health professionals will likely encounter patients taking low-dose
aspirin on a daily basis. Individuals on this regimen typically have a familial
history of heart disease, previous MI and ischemic stroke, or type 2 diabetes.9 Patients taking aspirin without their physician's recommendation should be
advised to consult with their primary care providers.
NOAPs include thienopyridines (ticlopidine, clopidogrel, and prasugrel)
and nonthienopyridines (ticagrelor and vorapaxar). Ticlopidine was the first
thienopyridine introduced in 1991, followed by clopidogrel and prasugrel.
Indications for ticlopidine's use are primary and secondary prevention of
stroke and dual antiplatelet therapy with aspirin for patients undergoing
coronary stent placement.10 It may also be used in place of aspirin
for those who are allergic.
All three drugs in this class are prodrugs, activated after partial
metabolism in the body. They irreversibly inhibit the platelet P2Y12 receptors,
preventing ADP from activating platelets and initiating their aggregation.
Ticlopidine, clopidogrel, and prasugrel are known as ADP receptor antagonists.
Ticlopidine has several adverse effects, with the most serious being
thrombotic thrombocytopenic purpura. This rare but potentially fatal platelet
disorder is characterized by platelet thrombi and possible visible petechial
and purpural lesions on the skin and mucosa. Development of aplastic anemia is
another serious adverse effect. These hematologic effects have encouraged the
more frequent use of its successor, clopidogrel.
Clopidogrel, introduced in 1997, is indicated for secondary prevention of
stroke and MI, and for patients with peripheral artery disease and acute
coronary syndrome.10–12 Clopidogrel is frequently prescribed with
aspirin because it has a synergistic effect in reducing thrombosis after
angioplasty and coronary stent placement, as well as prevention of ischemia in
patients with unstable angina.1 Like ticlopidine, clopidogrel
irreversibly inhibits P2Y12 receptors but is more potent and less likely to
exert adverse hematologic effects.
Genetic variations in clopidogrel metabolism by hepatic drug metabolizers
may prevent transformation to its active form. Clopidogrel now carries a
warning issued by the United States Food and Drug Administration regarding this
concern, as poor metabolism may result in significantly decreased effects.13,14 Like ticlopidine, clopidogrel is associated with thrombocytopenic purpura,
though it is rare.15
Prasugrel is the newest P2Y12 platelet aggregation inhibitor. It is
prescribed for the treatment of acute coronary syndrome, including unstable
angina and nonST-elevation MI, or for patients with ST-elevation MI and for
those who need percutaneous intervention (PCI) (Table 1). PCI, also known
as coronary angioplasty, is used to open blocked coronary arteries and restore
blood flow to the heart muscle. Prasugrel is converted to its activated form
more easily than clopidogrel, and genetic metabolic resistance is not a
concern. Prasugrel is contraindicated for individuals with a history of
transient ischemic attack (TIA) or stroke, or for those older than 75 due to
increased risk of intracranial bleeding.16
Prasugrel may cause significant and sometimes fatal bleeding, and it is
the only medication in its class where medically supervised discontinuation
prior to surgery may be indicated. However, managing the bleeding without
discontinuation, if possible, is preferred.
vorapaxar are nonthienopyridines. Ticagrelor also binds to the P2Y12 receptor
but, unlike thienopyridines, it does not require partial metabolism to exert
its effects. In addition, its platelet binding capabilities are reversible
(Table 1).5 These two features enable ticagrelor to exert a more
rapid onset of action and drug clearance and allow platelets to recover in 72
hours. With the previously described irreversible thienopyridines, platelets
are replaced in 7 days to 10 days. Ticagrelor is most often prescribed twice
daily with low-dose aspirin. It reduces the rate of cardiovascular death in
patients with acute coronary syndrome and post MI, and reduces stent
Individuals taking ticagrelor must keep their aspirin dosage below 100
mg. Drug interactions may also be an issue, with certain agents prescribed in
dentistry, such as some antibiotics and antiviral drugs, potentially impacting
drug effectivenesss and posing a risk of gastrointestinal (GI) bleeding.15
Vorapaxar is unique among the NOAPs because it is a highly selective
antagonist of a specific pathway of platelet aggregation: the
protease-activated receptor-1 (PAR-1 or thrombin). Approved in 2014, vorapaxar
works well in combination with aspirin and P2Y12 receptor antagonists to
further reduce the risk of recurrent thrombosis, particularly recurrent MI.17 It is indicated for the prevention of cardiovascular thrombotic events for
patients with a history of MI or peripheral artery disease. Vorapaxar is
contraindicated for patients with a history of stroke, TIA, intracranial
hemorrhage, and active pathological bleeding.
While platelet inhibition by vorapaxar is considered reversible, it has a
very long half-life (3 days to 8 days). This makes it essentially irreversible
and limits the effectiveness of short-term discontinuation, such as for planned
surgical procedures. Vorapaxar should not be taken concurrently with drugs
metabolized by the same enzymes. In dentistry, these may include some
antivirals and antifungal drugs, as well as carbamazepine (sometimes prescribed
for trigeminal neuralgia).
IMPLICATIONS FOR ORAL HEALTH CARE
concern for patients taking antiplatelet agents in the dental setting is the
possibility of an adverse bleeding event. Secondarily, drug-drug and drug-food
interactions should be assessed. Current research and professional opinion
discourage the discontinuation of oral antiplatelet medications for most dental
procedures.18–21 Oral health professionals must consider patient
characteristics and health history, extent of oral disease, concurrent
medication use, and the type of dental procedure before consulting with the
patient's prescribing physicians regarding antiplatelet therapy and whether any
changes are advised. Sudden discontinuation of these drugs increases the risk
of thromboembolic events, such as stroke or MI. As such, any change or discontinuation
of drug regimen, including aspirin, should be absolutely necessary and
medically supervised. Therefore, any change in or discontinuation of drug
regimen, including aspirin, should be done only when absolutely necessary and
under medical supervision. A systematic review that focused solely on aspirin
use in more than 50,000 subjects concluded discontinuation or noncompliance
with aspirin therapy was associated with a high risk of major cardiac events,
with patients with coronary stents at the greatest risk.22
Patients with recent coronary stent placement of less than 12 months
should not prematurely discontinue dual antiplatelet therapy.23 If
possible, elective dental procedures should be postponed for 1 year. If
postponement is not possible, aspirin therapy should be continued during the
perioperative period to prevent stent thrombosis. Medical consultation is
mandatory in these cases.
Less invasive procedures, such as scaling and root planing and simple
extractions, will not cause enough bleeding to warrant discontinuation of
antiplatelet medications.20,24 Patients on single and dual
antiplatelet therapy may experience prolonged but not clinically significant
bleeding following dental surgery.21 The use of a local anesthetic
with a vasoconstrictor controls bleeding during the procedure and modulates
systemic uptake of the adrenergic agent, and can safely be used for patients
with cardiovascular disease at the recommended cardiac dose.25 Prolonged bleeding (lasting for several hours) after minimally invasive
procedures can be managed with local hemostatic measures and should be reported
to the prescribing physician for follow-up.21,26
Patients who take aspirin should avoid using nonsteroidal
anti-inflammatory drugs (NSAIDs), such as ibuprofen and naproxen. NSAIDs and
aspirin competitively bind to COX-1 and COX-2 enzymes and inhibit
prostaglandin, an enzyme that produces protective mucus in the lining of the GI
tract. This combined GI irritation and antiplatelet effect may cause an
increased risk of GI bleeding. Acetaminophen is a better choice for minor
post-operative pain control in these circumstances.
Interactions caused by co-administration of antiplatelets with inhibitors
or inducers of CYP450 enzymes vary. Prasugrel has negligible concerns and
ticagrelor and vorapaxar may have significant interactions. Common drugs in
this class include antibiotics such metronidazole, erythromycin, and
clarithromycin, in addition to antifungals, including ketoconazole and
fluconazole. These agents either induce or inhibit the desired effects of the
Antiplatelet drugs are increasing patient
quality of life and lifespan. Assessment and elimination of oral infection and
inflammation through prevention, education, and treatment are the first line of
defense in controlling significant bleeding events in the dental setting.
Remaining knowledgeable about cardiovascular diseases, pharmacotherapeutic
agents used for their treatment and prevention, and risks that can contribute
to problematic bleeding associated with oral procedures is important. Using
current and evidence-based practice guidelines is essential when providing care
to patients taking oral antiplatelet drugs.
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- Randomised trial of intravenous streptokinase, oral aspirin, both, or
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- Ridker PM, Cook NR, Lee I-M, et al. A randomized trial of low-dose
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- Morrow DA, Braunwald E, Bonaca MP, et al. Vorapaxar in the secondary
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- Bajkin BV, Vujkov SB, Milekic BR, Vuckovic BA. Risk factors for
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From Dimensions of Dental Hygiene. January 2017;15(1):34-37.