Other Adverse Effects. Adverse effects other than hemorrhage are uncommon. Possible undesired responses include skin necrosis, alopecia, urticaria, dermatitis, fever, GI disturbances, and red-orange discoloration of urine, which must not be confused with hematuria. Long-term warfarin use (more than 12 months) may weaken bones and thereby increase the risk of fractures.
Drug Interactions
General Considerations. Warfarin is subject to a large number of clinically significant adverse interactions—perhaps more than any other drug. As a result of interactions, anti- coagulant effects may be reduced to the point of permitting thrombosis, or they may be increased to the point of causing hemorrhage. Patients must be informed about the potential for hazardous interactions and instructed to avoid all drugs not specifically approved by the prescriber. This prohibition includes prescription drugs and over-the-counter products.
Interactions between warfarin and other drugs are shown in Table 52.4. As indicated, the interactants fall into three major categories: (1) drugs that increase anticoagulant effects, (2) drugs that promote bleeding, and (3) drugs that decrease anticoagulant effects. The major mechanisms by which anti- coagulant effects can be increased are (1) displacement of warfarin from plasma albumin, (2) inhibition of the hepatic enzymes that degrade warfarin, and (3) decreased synthesis of clotting factors. The major mechanisms for decreasing anticoagulant effects are (1) acceleration of warfarin degradation through induction of hepatic drug-metabolizing enzymes, (2) increased synthesis of clotting factors, and (3) inhibition of warfarin absorption. Mechanisms by which drugs can promote bleeding, and thereby complicate anticoagulant therapy, include (1) inhibition of platelet aggregation, (2) inhibition of clotting factors, and (3) generation of GI ulcers.
The existence of an interaction between warfarin and another drug does not absolutely preclude using the combination. The interaction does mean, however, that the combination must be used with due caution. The potential for harm is greatest when an interacting drug is being added to or withdrawn from the regimen. At these times, PT must be monitored, and the dosage of warfarin adjusted to compensate for the impact of removing or adding an interacting drug.
Specific Interacting Drugs. Of the many drugs listed in Table 52.4, a few are especially likely to produce interactions of clinical significance. Four are discussed here.
Heparin. The interaction of heparin with warfarin is obvious: Being an anticoagulant itself, heparin directly increases the bleeding tendencies brought on by warfarin. Yet because onset of a therapeutic INR when starting warfarin therapy may take a few days, heparin is often administered alongside warfarin during this time. Combined therapy with heparin plus warfarin must be performed with care.
Aspirin. Aspirin inhibits platelet aggregation. By blocking aggregation, aspirin can suppress formation of the platelet plug that initiates hemostasis. To make matters worse, aspirin can act directly on the GI tract to cause ulcers, thereby initiating bleeding. Therefore, when the antifibrin effects of warfarin are coupled with the antiplatelet and ulcerogenic effects of aspirin, the potential for hemorrhage is significant. Accordingly, patients should be warned specifically against using any product that contains aspirin, unless the provider has prescribed aspirin therapy. Drugs similar to aspirin (e.g., indomethacin, ibuprofen) should be avoided as well.
Nonaspirin Antiplatelet Drugs. Like aspirin, other anti- platelet drugs can increase the risk of bleeding with warfarin.
bleeding (from excessive anticoagulation) and thrombosis (from insufficient anticoagulation). The CoaguChek meter costs about
$1300 and the ProTime meter costs about $2700 to $3500.
Each test costs about $10.
Adverse Effects
Hemorrhage. Bleeding is the major complication of warfarin therapy. Hemorrhage can occur at any site. Patients should be monitored closely for signs of bleeding (reduced blood pressure, increased heart rate, bruises, petechiae, hema- tomas, red or black stools, cloudy or discolored urine, pelvic pain, headache, and lumbar pain). If bleeding develops, warfarin should be discontinued. Severe overdose can be treated with vitamin K (discussed later). Patients should be encouraged to carry identification (e.g., Medic Alert bracelet) to inform emergency personnel of warfarin use. Of note, compared with warfarin, the newer oral anticoagulants—apixaban, rivaroxaban, edoxaban, and dabigatran—pose a significantly lower risk of serious bleeds.
Several measures can reduce the risk of bleeding. Candidates for treatment must be carefully screened for risk factors (see Warnings and Contraindications). INR must be measured frequently. A variety of drugs can potentiate warfarin’s effects (see Drug Interactions later in this section), and hence must be used with care. Patients should be given detailed verbal and written instructions regarding signs of bleeding, dosage size and timing, and scheduling of INR tests. When a patient is incapable of accurate self-medication, a responsible individual must supervise treatment. Patients should be advised to make a record of each dose, rather than relying on memory. A soft toothbrush can reduce gingival bleeding. An electric razor can reduce cuts from shaving.
Warfarin intensifies bleeding during surgery. Accordingly, surgeons must be informed of warfarin use. Patients anticipat- ing elective procedures should discontinue warfarin several days before the appointment. If an emergency procedure must be performed, injection of vitamin K can help suppress bleeding.
Does warfarin increase bleeding during dental surgery? Yes, but not that much. Accordingly, most patients needn’t inter- rupt warfarin for dental procedures, including dental surgery.
However, it is important that the INR be in the target range.
Fetal Hemorrhage and Teratogenesis From Use During Pregnancy. Warfarin can cross the placenta and affect the developing fetus. Fetal hemorrhage and death have occurred.
In addition, warfarin can cause gross malformations, central nervous system (CNS) defects, and optic atrophy. Accordingly, warfarin is classified in U.S. Food and Drug Administration (FDA) Pregnancy Risk Category Xb: The risks to the developing fetus outweigh any possible benefits of treatment. Women of childbearing age should be informed about the potential for teratogenesis and advised to postpone pregnancy. If pregnancy occurs, the possibility of termination should be discussed.
If an anticoagulant is needed during pregnancy, heparin or LMW heparin, which does not cross the placenta, should be employed.
Use During Lactation. Warfarin enters breast milk. Women should be advised against breast-feeding.
bAs of 2020, the FDA will no longer use Pregnancy Risk Categories. Please refer to Chapter 9 for more information.
CHAPTER 52 Anticoagulant, Antiplatelet, and Thrombolytic Drugs
acetaminophen can increase the risk of bleeding: Compared with nonusers of acetaminophen, those who take just 4 regular- strength tablets a day for a week are 10 times more likely to have a dangerously high INR. Unlike aspirin, which promotes bleeding by inhibiting platelet aggregation, acetaminophen is believed to inhibit warfarin degradation, thereby raising warfarin levels. At this time, the interaction between acetaminophen and warfarin has not been proven. Nonetheless, when the drugs are combined, the INR should be monitored closely.
Other Notable Interactions. Several drugs, including phenobarbital, carbamazepine, and rifampin, are powerful inducers of hepatic drug-metabolizing enzymes. As a result, these drugs can accelerate warfarin degradation, thereby decreasing anticoagulant effects. Accordingly, if one of these drugs is added to the regimen, warfarin dosage must be increased. Of equal importance, when an inducer is withdrawn, causing rates of drug metabolism to decline, a compensatory decrease in warfarin dosage must be made.
Intravaginal miconazole can intensify the anticoagulant effects of war- farin. (Miconazole is the antifungal agent found in Monistat brand vaginal suppositories and cream, used for vaginal candidiasis [yeast infection].) One woman using the combination reported bruising, bleeding gums, and a nosebleed. We have long known that systemic miconazole (as well as other azole antifungal agents) can inhibit the metabolism of warfarin and can thereby cause warfarin levels to rise. Apparently, intravaginal miconazole can be absorbed in amounts sufficient to do the same. Because of this interaction, women taking warfarin should not use intravaginal miconazole. If the drugs must be used concurrently, anticoagulation should be monitored closely and warfarin dosage reduced as indicated.
Like the azole antifungal agents, cimetidine (a drug for ulcers) and disulfiram (a drug for alcoholism) can inhibit warfarin metabolism and can thereby increase anticoagulant effects.
Vitamin K increases clotting factor synthesis and can thereby decrease anticoagulant effects.
Sulfonamide antibacterial drugs can displace warfarin from albumin and thereby increase anticoagulant effects.
Leflunomide [Arava], a drug for arthritis, can significantly increase the INR in just a few days, probably by inhibiting warfarin degradation. Case reports suggest that two other antiarthritic agents—glucosamine and chondroitin—may also potentiate warfarin action.
Warnings and Contraindications
Like heparin, warfarin is contraindicated for patients with severe thrombocytopenia or uncontrollable bleeding and for patients undergoing lumbar puncture, regional anesthesia, or surgery of the eye, brain, or spinal cord. Also like heparin, warfarin must be used with extreme caution in patients at high risk of bleeding, including those with hemophilia, increased capillary permeability, dissecting aneurysm, GI ulcers, and severe hypertension, and in women anticipating abortion. In addition, warfarin is contraindicated in the presence of vitamin K deficiency, liver disease, and alcoholism—conditions that can disrupt hepatic synthesis of clotting factors. Warfarin is also contraindicated during pregnancy and lactation.
Vitamin K1 for Warfarin Overdose
The effects of warfarin overdose can be overcome with vitamin K1 (phytonadione). Vitamin K1 antagonizes warfarin’s actions and can thereby reverse warfarin-induced inhibition of clotting factor synthesis. (Vitamin K3—menadione—has no effect on warfarin action.)
Vitamin K may be given orally or IV; subQ administration is less effective and should be avoided. Intravenous vitamin K acts faster than oral vitamin K, but can cause severe ana- phylactoid reactions, characterized by flushing, hypotension, and cardiovascular collapse. To reduce this risk, vitamin K should be diluted and infused slowly.
As a rule, small doses—2.5 mg PO or 0.5 to 1 mg IV—are preferred. Large doses (e.g., 10 mg PO) can cause prolonged Accordingly, these drugs (e.g., clopidogrel, dipyridamole,
ticlopidine, abciximab) should be used with caution.
Acetaminophen. In the past, acetaminophen was consid- ered safe for patients on warfarin. In fact, acetaminophen was routinely recommended as an aspirin substitute for patients who needed a mild analgesic. Now, however, it appears that
Drug Category
Mechanism of Interaction
Representative Interacting Drugs Drugs that
increase the effects of warfarin
Displacement of warfarin from albumin
Aspirin and other salicylates Sulfonamides Inhibition of
warfarin degradation
Acetaminophen Amiodarone
Azole antifungal agents Cimetidine
Disulfiram Leflunomide Trimethoprim-
sulfamethoxazole Decreased
synthesis of clotting factors
Certain parenteral cephalosporins, including cefoperazone and cefamandole Drugs that
promote bleeding
Inhibition of platelet aggregation
Abciximab Aspirin and other
salicylates Cilostazol Clopidogrel Dipyridamole Eptifibatide Prasugrel Ticagrelor Ticlopidine Tirofiban Inhibition of
clotting factors and/or thrombin
Antimetabolites Apixaban Argatroban Bivalirudin Dabigatran Desirudin Fondaparinux Heparins Rivaroxaban Promotion of
ulcer formation Aspirin Glucocorticoids Indomethacin Phenylbutazone Drugs that
decrease the effects of warfarin
Induction of drug- metabolizing enzymes
Carbamazepine Phenobarbital Phenytoin Rifampin Promotion of
clotting factor synthesis
Oral contraceptives Vitamin K1
Reduction of warfarin absorption
Cholestyramine Colestipol
TABLE 52.4 ■ Interactions Between Warfarin and Other Drugs
range from 2 to 10 mg/day, are determined by the target INR value. For most patients, dosage should be adjusted to produce an INR between 2 and 3.
Genetics and Dosage Adjustment. Patients with variant genes that code for VKORC1 and CYP2C9 are at increased risk of warfarin-induced bleeding, and hence require reduced doses. As noted previously, VKORC1 is the target enzyme that warfarin inhibits, and CYP2C9 is the enzyme that metabo- lizes warfarin. Variations in VKORC1 increase the enzyme’s sensitivity to inhibition by warfarin, and variations in CYP2C9 delay warfarin breakdown. With either variation, effects of warfarin are increased. To reduce the risk of bleeding, the FDA now recommends—but does not require—that patients undergo genetic testing for these variants. Dosage reductions based on this information can be determined using the calculator at www.warfarindosing.org.
Preparations
Warfarin sodium [Coumadin, Jantoven] is available in tablets (1, 2, 2.5, 3, 4, 5, 6, 7.5, and 10 mg) for oral use. In addition, warfarin is available in a formula- tion for parenteral dosing, which is not commonly done.
Direct Thrombin Inhibitors
The anticoagulants discussed in this section work by direct inhibition of thrombin. Hence, they differ from the heparin- like anticoagulants, which inhibit thrombin indirectly (by enhancing the activity of antithrombin). One of the direct thrombin inhibitors—dabigatran—is administered PO; another—
desirudin—is administered subQ; and two others—bivalirudin and argatroban—are administered by continuous IV infusion.
Only the subQ and PO drugs are suitable for outpatient use.
Dabigatran Etexilate
Dabigatran etexilate [Pradaxa, Pradax ] is an oral prodrug that undergoes rapid conversion to dabigatran, a reversible, direct thrombin inhibitor. Compared with warfarin—our oldest oral anticoagulant—dabigatran has five major advantages: rapid onset; no need to monitor anticoagulation; few drug-food interactions; lower risk of major bleeding; and, since responses are predictable, the same dose can be used for all patients, regardless of age or weight. Contrasts between dabigatran and warfarin are shown in Table 52.6.
Mechanism of Action. Dabigatran is a direct, reversible inhibitor of thrombin. The drug binds with and inhibits thrombin that is free in the blood, as well as thrombin that is bound to clots. In contrast, heparin inhibits only free thrombin. By inhibiting thrombin, dabigatran (1) prevents the conversion of fibrinogen into fibrin and (2) prevents the activation of factor XIII, and thereby prevents the conversion of soluble fibrin into insoluble fibrin.
Therapeutic Use
Atrial Fibrillation. In the United States, dabigatran is approved for the treatment of DVT and PE, as well as for prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Approval was based on the RE-LY trial, in which over 18,000 patients were randomized to receive either dabigatran (110 or 150 mg twice daily) or warfarin (dosage adjusted to produce an INR of 2 to 3). At the lower dabigatran dose (110 mg twice daily), the incidence of bleeding with dabigatran was less than with warfarin, but protection against stroke was less too. By contrast, at the higher dose (150 mg twice daily), the incidence of bleeding with dabigatran resistance to warfarin, thereby hampering restoration of
anticoagulation once bleeding is under control.
If vitamin K fails to control bleeding, levels of clotting factors can be raised quickly by infusing fresh whole blood, fresh-frozen plasma, or plasma concentrates of vitamin K–
dependent clotting factors.
What About Dietary Vitamin K?
Like medicinal vitamin K, dietary vitamin K can reduce the anticoagulant effects of warfarin. Dietary sources include mayonnaise, canola oil, soybean oil, and green leafy vegetables.
Must patients avoid these foods? No. But they should keep intake of vitamin K constant. If vitamin K intake does increase, then warfarin dosage should be increased as well. Conversely, if vitamin K intake decreases, the warfarin dosage should decrease too.
Contrasts Between Warfarin and Heparin
Although heparin and warfarin are both anticoagulants, they differ in important ways (Table 52.5). Whereas warfarin is given orally, heparin is given by injection. Although both drugs decrease fibrin formation, they do so by different mechanisms:
heparin inactivates thrombin and factor Xa, whereas warfarin inhibits synthesis of clotting factors. Heparin and warfarin differ with respect to time course of action: effects of heparin begin and fade rapidly, whereas effects of warfarin begin slowly but persist several days. Different tests are used to monitor therapy. Changes in aPTT are used to monitor heparin treatment;
changes in PT are used to monitor warfarin. Finally, these drugs differ with respect to management of overdose. Protamine is given to counteract heparin; vitamin K1 is given to counteract warfarin.
Dosage
Basic Considerations. Dosage requirements for warfarin vary widely among individuals, and hence dosage must be tailored to each patient. Traditionally, dosage adjustments have been done empirically (i.e., by trial and error). Dosing is usually begun at 2 to 5 mg/day. Maintenance dosages, which typically
Heparin Warfarin
Mechanism
of action Activates antithrombin, which then inactivates thrombin and factor Xa
Inhibits synthesis of vitamin K–dependent clotting factors, including prothrombin and factor X
Route IV or subQ PO
Onset Rapid (minutes) Slow (hours) Duration Brief (hours) Prolonged (days) Monitoring aPTT or anti-Xa
heparin assay PT (INR)a Antidote for
overdose Protamine Vitamin K1
TABLE 52.5 ■ Contrasts Between Heparin and Warfarin
aPTT, Activated partial thromboplastin time; PT, prothrombin time.
aTest results are reported as an INR (international normalized ratio).
CHAPTER 52 Anticoagulant, Antiplatelet, and Thrombolytic Drugs
absorption.) Plasma levels peak about 1 hour after dosing in the absence of food, and 3 hours after dosing in the presence of food. In the blood, plasma esterases rapidly convert dabigatran etexilate to dabigatran, the drug’s active form. Protein binding in blood is low (about 35%). Dabigatran is not metabolized by hepatic enzymes. Elimination is primarily renal. The half-life is 13 hours in patients with normal renal function (CrCl 50 mL/
min or higher), and it increases to 18 hours in patients with moderate renal impairment (CrCl 30 to 50 mL/min).
Adverse Effects
Bleeding. Like all other anticoagulants, dabigatran can cause bleeding. In the RE-LY trial, about 17% of patients taking 150 mg of dabigatran twice daily experienced bleeding of any intensity, and 3% experienced major bleeding. Patients who develop pathologic bleeding should stop taking the drug.
Compared with warfarin, dabigatran is safer, posing a much lower risk of hemorrhagic stroke and other major bleeds.
Because dabigatran is not highly protein bound, dialysis can remove much of the drug (about 60% over 2 to 3 hours).
equaled that with warfarin, but the incidence of stroke or embolism was significantly lower. On the basis of these results, the FDA concluded that, for patients with atrial fibrillation, the benefit/risk profile of dabigatran was better at 150 mg twice daily than at 110 mg twice daily, and hence they approved the higher dose for these patients.
Knee or Hip Replacement. Dabigatran is approved for prevention of VTE following knee or hip replacement surgery.
The dosage is 220 mg once daily, following an initial dose of 110 mg.
DVT/PE Treatment. In 2014, the FDA approved dabigatran for the treatment of DVT and PE in patients who have been treated with a parenteral anticoagulant for 5 to 10 days, and to reduce the risk of recurrent DVT and PE in patients who have been previously treated. The dose for treatment is 150 mg twice daily.
Pharmacokinetics. Dabigatran etexilate is well absorbed from the GI tract, both in the presence and absence of food.
(Food delays absorption but does not reduce the extent of Warfarin [Coumadin] Rivaroxaban
[Xarelto] Apixaban
[Eliquis] Edoxaban
[Savaysa] Dabigatran Etexilate [Pradaxa, Pradax ] Mechanism Decreased synthesis of
vitamin K–
dependent clotting factors
Inhibition of factor Xa Inhibition of
factor Xa Inhibition of
factor Xa Direct inhibition of thrombin
Indications
Atrial fibrillation Yes Yes Yes Yes Yes
Heart valve
replacement Yes No No No No
Knee or hip
replacement Yes Yes No No Yes
Onset Delayed (days) Rapid (hours) Rapid (hours) Rapid (hours) Rapid (hours)
Duration Prolonged Short Short Short Short
Antidote available Yes (oral/parenteral
vitamin K) No No No No
Drug-food
interactions Many Few Few Few Few
INR testing needed Yes No No No No
Dosage Adjusted based on
INR Fixed Fixed Fixed Fixed
Doses/day One One Two One Two
Clinical experience Extensive Limited Limited Limited Limited
Advantages,
summary Decades of clinical experience Precise dosage timing
not critical, owing to long duration Antidote available for
overdose
Rapid onset Fixed dosage No blood tests needed Less bleeding and
hemorrhagic stroke Few drug-food
interactions
Same as
rivaroxaban Same as
rivaroxaban Same as rivaroxaban
Disadvantages,
summary Delayed onset Blood tests required No fixed dosage Many drug-food
interactions
Dosing on time is important, owing to short duration No antidote to
overdose Limited clinical
experience
Same as
rivaroxaban Same as
rivaroxaban Same as rivaroxaban plus GI disturbances are common TABLE 52.6 ■ Properties of Oral Anticoagulants
Hirudin Analogs Bivalirudin
Actions and Use. Bivalirudin [Angiomax], an IV direct thrombin inhibitor, has actions like those of dabigatran. The drug is a synthetic 20–amino acid peptide that is chemically related to hirudin, an anticoagulant isolated from the saliva of leeches.
Bivalirudin is given in combination with aspirin, clopidogrel, or prasugrel to prevent clot formation in patients undergoing coronary angioplasty. At this time, the standard therapy for these patients is aspirin combined with a platelet GP IIb/IIIa inhibitor combined with low-dose, unfractionated heparin.
Bivalirudin, an alternative to heparin in this regimen, has been studied in combination with aspirin, as well as GP IIb/IIIa inhibitors. In one trial—the Hirulog Angioplasty Study—bivalirudin plus aspirin was compared with heparin plus aspirin. Bivalirudin was at least as effective as heparin at preventing ischemic complications (MI, abrupt vessel closure, death), and caused fewer bleeding complications. In a subgroup of patients—those with postinfarction angina—bivalirudin was significantly more effective than heparin.
Adverse Effects. The most common side effects are back pain, nausea, hypotension, and headache. Other relatively common effects (incidence greater than 5%) include vomiting, abdominal pain, pelvic pain, anxiety, nervousness, insomnia, bradycardia, and fever.
Bleeding is the effect of greatest concern. However, compared with heparin, bivalirudin causes fewer incidents of major bleeding (3.7% vs. 9.3%), and fewer patients require transfusions (2% vs. 5.7%). Coadministration of bivalirudin with heparin, warfarin, or thrombolytic drugs increases the risk of bleeding.
Pharmacokinetics. With IV dosing, anticoagulation begins immediately.
Drug levels are maintained by continuous infusion. Bivalirudin is eliminated primarily by renal excretion and partly by proteolytic cleavage. The half-life is short (25 minutes) in patients with normal renal function, but may be longer in patients with renal impairment. Coagulation returns to baseline about 1 hour after stopping the infusion. Anticoagulation can be monitored by measuring activated clotting time.
Comparison With Heparin. Bivalirudin is just as effective as heparin and has several advantages: It works independently of antithrombin, inhibits clot-bound thrombin as well as free thrombin, and causes less bleeding and fewer ischemic events. However, the drug has one disadvantage: Bivalirudin is more expensive than heparin. One single-use vial, good for a full course of treatment, costs about $1000, compared with $10 for an equivalent course of heparin. However, the manufacturer estimates that reductions in bleeding and ischemic complications would save, on average, $1000 per patient, which would offset the greater cost of bivalirudin. The bottom line? Bivalirudin works as well as heparin, is safer, and may be equally cost effective—and hence is considered an attractive alternative to heparin for use during angioplasty.
Preparations, Dosage, and Administration. Bivalirudin [Angiomax]
is supplied as a lyophilized powder (250 mg) for reconstitution in sterile water. Dosing consists of an initial IV bolus (0.75 mg/kg) followed by continu- ous infusion (1.75 mg/kg/hr) for the duration of the procedure, and up to 4 hours after. If necessary, bivalirudin may be infused for up to 20 additional hours at a rate of 0.2 mg/kg/hr. Treatment should begin just before angioplasty.
Dosage should be reduced in patients with severe renal impairment. All patients should take aspirin (300 to 325 mg).
Desirudin. Desirudin [Iprivask] is a direct thrombin inhibitor similar to bivalirudin. However, unlike bivalirudin, which is given by IV infusion, desirudin is given by subQ injection. Desirudin is indicated for prevention of DVT in patients undergoing elective hip replacement surgery. In clinical trials, patients experienced fewer thromboembolic events than those given unfractionated heparin or enoxaparin, an LMW heparin.
Desirudin is completely absorbed following subQ injection, achieving peak plasma levels in 1 to 3 hours. Elimination is primarily by renal excretion and partly by proteolytic cleavage. In patients with normal renal function, the elimination half-life is 2 to 3 hours. By contrast, in those with severe renal impairment, the half-life is greatly prolonged (up to 12 hours).
As with other anticoagulants, hemorrhage is the adverse effect of greatest concern. In clinical trials, the incidence of hemorrhage was 30% in the desirudin group, compared with 33% in the enoxaparin group and 20% in the heparin group. Less serious effects include wound secretion, injection-site mass, anemia, nausea, and deep thrombophlebitis.
In patients undergoing spinal or epidural anesthesia, desirudin may cause spinal or epidural hematoma, which can result in long-term or even permanent paralysis. Hematoma risk is increased by the use of other drugs that impair hemostasis (e.g., nonsteroidal anti-inflammatory drugs [NSAIDs], antiplatelet drugs, warfarin, heparin). Patients should be monitored for signs of neurologic impairment and given immediate treatment if they develop.
Because dabigatran is eliminated primarily in the urine, maintaining adequate diuresis is important.
Owing to bleeding risk, dabigatran should be stopped before elective surgery. For patients with normal renal function (CrCl 50 mL/min or higher), dosing should stop 1 or 2 days before surgery. For patients with renal impairment (CrCl below 50 mL/
min), dosing should stop 3 to 5 days before surgery.
Gastrointestinal Disturbances. About 35% of patients experience dyspepsia (abdominal pain, bloating, nausea, vomit- ing) and/or gastritis-like symptoms (esophagitis, gastroesopha- geal reflux disease, gastric hemorrhage, erosive gastritis, hemorrhagic gastritis, GI ulcer). Symptoms of dyspepsia can be reduced by taking dabigatran with food and by using an acid-suppressing drug (proton pump inhibitor or histamine2
receptor blocker). If these measures don’t help, patients may try a switch to warfarin, which carries a much lower risk of adverse GI effects.
Drug Interactions. Dabigatran is not metabolized by hepatic P450 enzymes, nor is it an inhibitor or inducer of these enzymes. Accordingly, dabigatran does not have metabolic interactions with other drugs.
Dabigatran etexilate is a substrate for intestinal P-glycoprotein, the transporter protein that can pump dabigatran and other drugs back into the intestine. Drugs that inhibit P-glycoprotein can increase dabigatran absorption and blood levels, and drugs that induce P-glycoprotein can decrease dabigatran absorption and blood levels. Combined use with a P-glycoprotein inhibitor (e.g., ketoconazole, amiodarone, verapamil, quinidine) could cause bleeding from excessive dabigatran levels, and hence these combinations should be avoided. Combined use with a P-glycoprotein inducer appears to be safe, even though it might reduce beneficial effects somewhat.
Bleeding risk is increased by other drugs that impair hemostasis.
Preparations, Dosage, Administration, and Storage
Preparations. Dabigatran etexilate [Pradaxa] is available in three strengths:
75-, 110-, and 150-mg capsules.
Administration. Dosing may be done with or without food. Patients should swallow the capsules intact. If the capsules are crushed, chewed, or opened, absorption will be increased by 75%, thereby posing a risk of bleeding.
Dosage for Atrial Fibrillation. The usual dosage is 150 mg twice daily. If a dose is missed, it should be taken as soon as possible on the same day. However, if the missed dose cannot be taken at least 6 hours before the next scheduled dose, the missed dose should be skipped.
In patients with significant renal impairment (CrCl 15 to 30 mL/min), the dosage is 75 mg twice a day. For patients with greater renal impairment (CrCl below 15 mL/min), no dosing recommendation can be made.
Switching From Warfarin to Dabigatran. Discontinue warfarin, wait until the INR falls below 2, and then start dabigatran.
Switching From Dabigatran to Warfarin. Because onset of warfarin’s effects is delayed, warfarin should be started before stopping dabigatran, based on CrCl as follows:
• CrCl above 50 mL/min—start warfarin 3 days before stopping dabigatran.
• CrCl 31 to 50 mL—start warfarin 2 days before stopping dabigatran.
• CrCl 15 to 30 mL—start warfarin 1 day before stopping dabigatran.
• CrCl below 15 mL/min—no recommendation can be made.
Storage. Dabigatran is unstable, especially when exposed to moisture.
To maintain efficacy, the drug must be stored in the manufacturer-supplied bottle, which has a desiccant cap. Patients should open just one bottle at a time and should not distribute dabigatran to any other container, such as a weekly pill organizer. Current labeling says that once the bottle is opened, dabigatran should be used within 30 days. However, recent evidence indicates that dabigatran capsules maintain efficacy for 4 months, provided they are stored in the original container—away from excessive moisture, heat, and cold—with the cap tightly closed after each use.
CHAPTER 52 Anticoagulant, Antiplatelet, and Thrombolytic Drugs
atrial fibrillation (i.e., patients with atrial fibrillation who do not have a prosthetic heart valve or hemodynamically significant valve disease). Rivaroxaban was at least as effective as warfarin and carried the same risk of major hemorrhagic events of all kinds—but had a lower risk for intracranial bleeds and fatal bleeds.
Pharmacokinetics. Rivaroxaban is administered orally, and bioavailability is high (80% to 90%). Plasma levels peak 2 to 4 hours after dosing. Protein binding in blood is substantial (92% to 95%). Rivaroxaban undergoes partial metabolism by CYP3A4 (the 3A4 isoenzyme of cytochrome P450) and is a substrate for P-glycoprotein, an efflux transporter that helps remove rivaroxaban from the body. Rivaroxaban is eliminated in the urine (36% as unchanged drug) and feces (7% as unchanged drug), with a half-life of 5 to 9 hours. In patients with renal impairment or hepatic impairment, rivaroxaban levels may accumulate.
Adverse Effects
Bleeding. Bleeding is the most common adverse effect and can occur at any site. Patients have experienced epidural hematoma, as well as major intracranial, retinal, adrenal, and GI bleeds. Some people have died. Bleeding risk is increased by other drugs that impede hemostasis. How does rivaroxaban compare with warfarin? The risk of hemorrhagic stroke and other major bleeds is significantly lower with rivaroxaban.
In the event of overdose, we have no specific antidote to reverse this drug’s anticoagulant effects. However we can prevent further absorption of ingested rivaroxaban with activated charcoal (see Chapter 109). Treatment with several agents—
recombinant factor VIIa, prothrombin complex concentrate (PCC), or activated PCC—can be considered. Preliminary studies of PCC have been promising, but more testing must be completed. Because rivaroxaban is highly protein bound, dialysis is unlikely to remove it from the blood.
Spinal/Epidural Hematoma. Like all other anticoagulants, rivaroxaban poses a risk of spinal or epidural hematoma in patients undergoing spinal puncture or epidural anesthesia.
Prolonged or permanent paralysis can result. Rivaroxaban should be discontinued at least 18 hours before removing an epidural catheter; once the catheter is out, another 6 hours should elapse before rivaroxaban is restarted. If a traumatic puncture occurs, rivaroxaban should be delayed for at least 24 hours. Anticoagulant-related spinal/epidural hematoma is discussed further earlier in this chapter (see Adverse Effects under Heparin).
Drug Interactions. Levels of rivaroxaban can be altered by drugs that inhibit or induce CYP3A4 and P-glycoprotein.
Specifically, in patients with normal renal function, drugs that inhibit CYP3A4 strongly and also inhibit P-glycoprotein (e.g., ketoconazole, itraconazole, ritonavir) can raise rivaroxaban levels enough to increase the risk of bleeding. Similarly, in patients with renal impairment, drugs that inhibit CYP3A4 moderately and also inhibit P-glycoprotein (e.g., amiodarone, dronedarone, quinidine, diltiazem, verapamil, ranolazine, macro- lide antibiotics) can raise rivaroxaban levels enough to increase the risk of bleeding. Conversely, drugs that induce CYP3A4 strongly and also induce P-glycoprotein (e.g., carbamazepine, phenytoin, rifampin, St. John’s wort) may reduce rivaroxaban levels enough to increase the risk of thrombotic events. Of note, rivaroxaban itself does not inhibit or induce cytochrome P450 enzymes or P-glycoprotein, and hence is unlikely to alter the effects of other drugs.
Desirudin [Iprivask] is supplied as a lyophilized powder (15 mg) in single-use vials. Immediately after reconstitution (with 0.5 mL of 3% mannitol in sterile water), the drug is administered by deep subQ injection into the thigh or abdominal wall. For patients with normal renal function, the dosage is 15 mg every 12 hours, beginning 5 to 15 minutes before hip surgery (but after induction of regional block anesthesia, if used). For patients with moderate renal impairment (CrCl 30 to 50 mL/min), dosage is reduced to 5 mg every 12 hours. For those with severe renal impairment (CrCl below 30 mL/min), dosage is reduced to 1.7 mg every 12 hours. For all patients, the usual duration of treatment is 9 to 12 days.
Argatroban. Like bivalirudin, argatroban is an IV anticoagulant that works by direct inhibition of thrombin. The drug is indicated for prophylaxis and treatment of thrombosis in patients with HIT. In clinical trials, argatroban reduced development of new thrombosis and permitted restoration of platelet counts. Like other anticoagulants, argatroban poses a risk of hemorrhage.
About 12% of patients experience hematuria. Allergic reactions (dyspnea, cough, rash), which develop in 10% of patients, occur almost exclusively in those receiving either thrombolytic drugs (e.g., alteplase) or contrast media for coronary angioplasty. Argatroban has a short half-life (about 45 minutes), owing to rapid metabolism by the liver. Treatment is monitored by measuring the aPTT. When infusion of argatroban is discontinued, the aPTT returns to baseline in 2 to 4 hours.
Argatroban is supplied in 2.5-mL single-dose vials (100 mg/mL) intended for dilution followed by continuous IV infusion. Dosage depends on the setting as follows:
• For prophylaxis and treatment of thrombosis in patients with HIT and normal liver function (but who are not undergoing percutaneous coronary intervention [PCI])—The initial infusion rate is 2 mcg/kg/min. In patients with liver dysfunction, the initial rate is only 0.5 mcg/kg/min.
Dosage is adjusted to maintain the aPTT at 1.5 to 3 times the baseline value.
• For prevention of thrombosis in patients with or at risk of HIT who are undergoing PCI—Give an IV bolus (350 mcg/kg) followed by continuous IV infusion (25 mcg/kg/min). Adjust the infusion rate (and perhaps give a second IV bolus) to achieve the desired activated clotting time.
Direct Factor Xa Inhibitors
Rivaroxaban
Actions and Uses. Rivaroxaban [Xarelto] is an oral anticoagulant that causes selective inhibition of factor Xa (activated factor X). Unlike fondaparinux (previously discussed), which acts indirectly, rivaroxaban binds directly with the active center of factor Xa and thereby inhibits production of thrombin. Compared with warfarin, our oldest oral anticoagu- lant, rivaroxaban has several advantages: rapid onset, fixed dosage, lower bleeding risk, few drug interactions, and no need for INR monitoring. Rivaroxaban has three approved uses: (1) prevention of DVT and PE following total hip or knee replacement surgery, (2) prevention of stroke in patients with atrial fibrillation, and (3) treatment of DVT and PE unrelated to orthopedic surgery. Contrasts with warfarin are shown in Table 52.6.
Clinical Trials
Knee and Hip Replacement Patients. In a series of trials known as RECORD (Regulation of Coagulation in Orthopedic Surgery to Prevent Deep Vein Thrombosis and Pulmonary Embolism), rivaroxaban was compared with enoxaparin (an LMW heparin) in patients who had undergone hip or knee replacement surgery. Patients who received rivaroxaban (10 mg once daily) were much less likely to experience DVT, VTE, PE, or death, compared with patients who received enoxaparin (40 mg once daily or 30 mg twice daily). With both drugs, the incidence of major bleeding episodes was low (0.2%).
Nonvalvular Atrial Fibrillation Patients. In a trial known as ROCKET AF, rivaroxaban was compared with warfarin for preventing stroke in patients with nonvalvular
is increased by other drugs that impede hemostasis. How does apixaban compare with warfarin? The risk of hemorrhagic stroke and other major bleeds is significantly lower with apixaban.
In the event of overdose, we have no specific antidote to reverse this drug’s anticoagulant effects. Treatment with several agents—recombinant factor VIIa, PCC, or activated PCC—can be considered, but testing has not been completed.
Like rivaroxaban, apixaban is highly protein bound. Dialysis is unlikely to remove it from the blood.
Drug Interactions. Levels of rivaroxaban can be altered by drugs that inhibit or induce CYP3A4 and P-glycoprotein.
Specifically, in patients with normal renal function, drugs that inhibit CYP3A4 strongly and also inhibit P-glycoprotein (e.g., ketoconazole, itraconazole, ritonavir) can raise apixaban levels enough to increase the risk of bleeding. Conversely, drugs that induce CYP3A4 strongly and also induce P-glycoprotein (e.g., carbamazepine, phenytoin, rifampin, St. John’s wort) may reduce apixaban levels enough to increase the risk of thrombotic events.
Precautions
Renal Impairment. Renal impairment can delay excretion of apixaban, increasing the risk of bleeding. In patients with renal impairment, defined as a serum creatinine level greater than or equal to 1.5 mg/dL, apixaban dosing is decreased.
Pregnancy. Studies of apixaban in pregnant patients are lacking. The drug may increase the risk of hemorrhage during pregnancy and delivery. Apixaban is classified in FDA Pregnancy Risk Category B.d
Preparations, Dosage, and Administration. Apixaban [Eliquis] is supplied in tablets (2.5 and 5 mg). The recommended dose for most patients with atrial fibrillation is 5 mg taken orally twice daily. In patients with renal impairment, dosing is decreased to 2.5 mg twice daily.
For the treatment of DVT, the dose is doubled to 10 mg twice daily. For prophylaxis after orthopedic surgery, the dose is only 2.5 mg twice daily.
Edoxaban
Edoxaban [Savaysa] is a newer oral anticoagulant that also causes selective inhibition of factor Xa. Edoxaban has two approved uses: (1) prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation and (2) treatment of DVT/PE. Because it is a novel oral anticoagulant, like apixaban and rivaroxaban, edoxaban causes adverse effects and has drug interactions similar to these drugs.
Preparations, Dosage, and Administration. Edoxaban is available in 15-, 30-, and 60-mg tablets. The suggested dose for patients with atrial fibrillation is 60 mg orally daily. Treatment for DVT and PE is weight based.
For patients who weigh less than 60 kg, the dose is 30 mg daily. For patients who weigh more than 60 kg, this dose is doubled to 60 mg daily. As with the other NOACs, doses should be decreased in patients with renal impairment.
Antithrombin
As discussed earlier, antithrombin (AT) is an endogenous compound that sup- presses coagulation, primarily by inhibiting thrombin and factor Xa. Clinically, AT is used to prevent thrombosis in patients with inherited AT deficiency.
Currently, we have two AT preparations, marketed as ATryn and Thrombate III. ATryn is made by recombinant DNA technology; Thrombate III is made by extraction from human plasma. Nonetheless, the actions of both products are the same: suppression of coagulation mediated by thrombin and factor Xa.
Recombinant Human Antithrombin
Production. Recombinant human AT (rhAT), sold as ATryn, is produced in goats that have been given the DNA sequence for human AT, along with genetic instructions that cause the AT to be expressed into their milk. The
Owing to the risk of bleeding, rivaroxaban should not be combined with other anticoagulants. Concurrent use with antiplatelet drugs and fibrinolytics should be done with caution.
Precautions
Renal Impairment. Renal impairment can delay excretion of rivaroxaban and can thereby increase the risk of bleeding.
Accordingly, rivaroxaban should be avoided in patients with severe renal impairment, indicated by a CrCl below 30 mL/
min. In patients with moderate renal impairment (CrCl 30 to 50 mL/min), rivaroxaban should be used with caution. If renal failure develops during treatment, rivaroxaban should be discontinued.
Hepatic Impairment. In clinical trials, rivaroxaban levels and anticoagulation were excessive in patients with moderate hepatic impairment. Accordingly, in patients with moderate or severe hepatic impairment, rivaroxaban should not be used.
Pregnancy. Rivaroxaban appears unsafe in pregnancy. The drug increases the risk of pregnancy-related hemorrhage and may have detrimental effects on the fetus. When pregnant rabbits were given high doses (10 mg/kg or more) during organogenesis, rivaroxaban increased fetal resorption, decreased fetal weight, and decreased the number of live fetuses. However, dosing of rats and rabbits early in pregnancy was not associated with gross fetal malformations. Rivaroxaban is classified in FDA Pregnancy Risk Category Cc, and should be used only if the benefits are deemed to outweigh the risks to the mother and fetus.
Preparations, Dosage, and Administration. Rivaroxaban [Xarelto]
is supplied in tablets (10, 15, and 20 mg). Whether dosing is done with food depends on the setting, as discussed later.
Prevention of DVT. The recommended dosage is 10 mg once a day, with or without food, starting 6 to 10 hours after knee or hip replacement surgery. If a dose is missed, it should be taken as soon as possible, and the next dose should be taken as originally scheduled. Treatment duration is 12 days following knee replacement and 35 days following hip replacement.
Nonvalvular Atrial Fibrillation. Dosing is done once a day with the evening meal. For patients with normal renal function, the dosage is 20 mg once daily, and for patients with moderate renal impairment, the dosage is 15 mg once daily. Patients with severe renal impairment should not use this drug.
Treatment of DVT/PE. Dosing is started at 15 mg twice daily for the first 21 days, and then increased to 20 mg daily. Doses should be taken at approximately the same time each day.
Apixaban
Actions and Uses. Apixaban [Eliquis] is an additional oral anticoagulant that causes selective inhibition of factor Xa. Apixaban inhibits free and clot-bound factor Xa, as well as prothrombinase activity. Apixaban has three approved uses:
(1) prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, (2) treatment of DVT/PE, and (3) prophylaxis of DVT in patients undergoing hip or knee replacement.
Pharmacokinetics. Apixaban is administered orally, and bioavailability is moderate (~50%). Plasma levels peak 2 to 4 hours after dosing. Protein binding in blood is substantial (87%). Apixaban undergoes partial metabolism by CYP3A4.
Apixaban is eliminated in the urine and feces, with a half- life of 12 hours after repeated dosing. In patients with renal impairment, apixaban levels may accumulate.
Adverse Effects
Bleeding. As with rivaroxaban, bleeding is the most common adverse effect and can occur at any site. Bleeding risk
cAs of 2020, the FDA will no longer use Pregnancy Risk Categories. Please refer to Chapter 9 for more information.
dAs of 2020, the FDA will no longer use Pregnancy Risk Categories. Please refer to Chapter 9 for more information.
CHAPTER 52 Anticoagulant, Antiplatelet, and Thrombolytic Drugs
share the same indication (prevention of thromboembolic events associated with surgery or childbirth in patients with inherited AT deficiency), both pose a risk of hemorrhage, both increase the anticoagulant effects of heparin, and both are given by IV infusion. The drugs differ primarily in that plasma-derived AT carries a risk of hepatitis C and other infections, whereas rhAT does not.
Thrombate III is supplied as a powder (500 and 1000 units) in single-use vials and must be reconstituted with sterile water before use. As with rhAT, dosage is based on AT activity and body weight.
ANTIPLATELET DRUGS
Antiplatelet drugs suppress platelet aggregation. Since a platelet core constitutes the bulk of an arterial thrombus, the principal indication for the antiplatelet drugs is prevention of thrombosis in arteries. In contrast, the principal indication for antico- agulants (e.g., heparin, warfarin) is prevention of thrombosis in veins.
There are three major groups of antiplatelet drugs: aspirin (a
“group” with one member), P2Y12 ADP receptor antagonists, and GP IIb/IIIa receptor antagonists. As indicated in Fig. 52.1, aspirin and the P2Y12 ADP receptor antagonists affect only one pathway in platelet activation, and hence their antiplatelet effects are limited. In contrast, the GP IIb/IIIa antagonists block the final common step in platelet activation, and hence have powerful antiplatelet effects. Properties of the major classes of antiplatelet drugs are shown in Table 52.7.
Aspirin
The basic pharmacology of aspirin is discussed in Chapter 71.
Consideration here is limited to aspirin’s role in preventing arterial thrombosis.
Mechanism of Antiplatelet Action
Aspirin suppresses platelet aggregation by causing irreversible inhibition of cyclooxygenase, an enzyme required by platelets to synthesize TXA2. As noted, TXA2 is one of the factors that can promote platelet activation. In addition to activating platelets, TXA2 acts on vascular smooth muscle to promote vasoconstriction. Both actions promote hemostasis. By inhibit- ing cyclooxygenase, aspirin suppresses both TXA2-mediated
rhAT produced in goats is nearly identical to endogenous AT: Both compounds have the same sequence of amino acids, but they have different patterns of glycosylation. (Glycosylation refers to sugar derivatives attached to the amino acid backbone of rhAT.) rhAT is the first drug produced in transgenic animals to be approved for use in the United States.
Therapeutic Use. rhAT is approved for prevention of perioperative or peripartum thromboembolic events in patients with inherited AT deficiency, a disorder that puts these people at high risk of VTE. In fact, to protect against thromboembolism, these people typically require lifelong therapy with an anticoagulant, usually warfarin. During surgery or childbirth, the risk of thrombosis increases. However, there is also an obvious increase in the risk of serious bleeding. Accordingly, when patients with hereditary AT deficiency are facing childbirth or surgery, anticoagulant therapy is usually discontinued—
reducing the risk of bleeding, but increasing the risk of thrombosis. To reduce that risk of thrombosis, rhAT is given until anticoagulant therapy can be safely resumed. In clinical trials, rhAT prevented thromboembolism associated with childbirth or surgery in 30 of 31 patients with inherited AT deficiency.
Adverse Effects. The principal concern is hemorrhage. To minimize risk, AT activity should be monitored, and if it rises too high, the rhAT dosage should be reduced. In addition to causing outright hemorrhage, rhAT may cause hematoma, hematuria, and hemarthrosis. Infusion-site reactions are common.
Because rhAt is derived from goats’ milk, there is a risk of hypersensitivity reactions. Accordingly, patients should be closely observed during the infusion period. If signs of a hypersensitivity reaction develop (e.g., hives, generalized urticaria, wheezing, hypotension), rhAT should be discontinued immediately.
Interaction With Heparin. As discussed earlier, heparin produces its anticoagulant effects by enhancing the actions of AT. Accordingly, if rhAT is given to a patient taking heparin, anticoagulation will be greatly increased, thereby posing a risk of bleeding. Accordingly, if heparin is used with rhAT, tests for anticoagulation should be performed often, especially during the first hours following the initiation or termination of rhAT use.
Comparison With Plasma-Derived AT. rhAT has two advantages over plasma-derived AT. First, supplies of rhAT are more abundant because supplies are not limited by the availability of human volunteers. Second, rhAT is safer because plasma-derived AT carries a risk of infection, especially hepatitis C, whereas rhAT carries no such risk.
Preparations, Dosage, and Administration. rhAT [ATryn] is supplied as a powder (1750 units) in single-use vials for reconstitution with 10 mL of sterile water, followed by further dilution before IV infusion. Treatment consists of a 15-minute loading infusion followed immediately by a continuous maintenance infusion. The loading infusion should begin before delivery or 24 hours before surgery, and should continue until normal maintenance coagulation can be re-established. Dosage size is based on the patient’s AT activity and body weight. The goal is to maintain AT activity between 80%
and 120% of normal. During the maintenance infusion, AT activity should be monitored periodically, and the dosage adjusted accordingly.
Plasma-Derived Antithrombin
Plasma-derived AT [Thrombate III] is made by extraction from the plasma of human volunteers. Thrombate III is like rhAT in most regards: Both drugs
Aspirin, a Cyclooxygenase Inhibitor
P2Y12 Adenosine Diphosphate (ADP) Receptor Blockers
Protease-Activated Receptor-1 (PAR-1) Antagonists
Glycoprotein (GP) IIb/IIIa Receptor Blockers Representative drug Aspirin Clopidogrel [Plavix] Vorapaxar [Zontivity] Tirofiban [Aggrastat]
Mechanism of
antiplatelet action Irreversibly inhibits cyclooxygenase, and thereby blocks synthesis of TXA2
Irreversibly blocks
receptors for ADPa Reversibly blocks the protease-activated receptor-1 (PAR-1) expressed on platelets
Reversibly blocks receptors for GP IIb/IIIa
Route PO PO PO IV infusion
Duration of effects Effects persist 7–10 days
after the last dose Effects persist 7–10 days after the last dosea
Effects persist 7–10 days
after the last dose Effects stop within 4 hr of stopping the infusion
Cost $3/month $87/month $320/month $1000/course
TABLE 52.7 ■ Properties of the Major Classes of Antiplatelet Drugs
aThe ADP receptor blocker ticagrelor [Brilinta] causes reversible ADP receptor blockade, so effects wear off faster than with clopidogrel.
TXA2, Thromboxane A2.
Dosing
Dosage for preventing cardiovascular events should be low.
Maximal inhibition of platelet cyclooxygenase, and hence maximal effects on platelet function, can be produced in a few days by taking 81 mg/day. Dosages above 81 mg/day offer no increase in benefits, but do increase the risk of GI bleeding and stroke. Accordingly, for chronic therapy, a dosage of 81 mg/
day is probably adequate. A higher dosage (e.g., 325 mg/day) is indicated for initial treatment of an acute event, such as MI, to establish full antiplatelet effects rapidly—after which 81 mg/
day can be taken for maintenance.
P2Y
12Adenosine Diphosphate Receptor Antagonists
Drugs in this class block P2Y12 ADP receptors on the platelet surface, preventing ADP-stimulated aggregation (see Fig. 52.1).
Three P2Y12 ADP receptor antagonists are available. Two of them—clopidogrel and prasugrel—cause irreversible receptor blockade, and the third—ticagrelor—causes reversible receptor blockade. Clopidogrel, prasugrel, and ticagrelor are used for secondary prevention of atherothrombotic events in patients with acute coronary syndromes (ACS), defined as unstable angina or MI. All three drugs are taken orally and can cause serious bleeding.
Clopidogrel
Clopidogrel [Plavix] is an oral antiplatelet drug with effects much like those of aspirin. The drug is taken to prevent stenosis of coronary stents and for secondary prevention of MI, ischemic stroke, and other vascular events.
Antiplatelet Actions. Clopidogrel blocks P2Y12 ADP receptors on platelets and thereby prevents ADP-stimulated platelet aggregation. As with aspirin, antiplatelet effects are irreversible, and hence persist for the life of the platelet. Effects begin 2 hours after the first dose and plateau after 3 to 7 days of treatment. At the recommended dosage, platelet aggregation is inhibited by 40% to 60%. Platelet function and bleeding time return to baseline 7 to 10 days after the last dose.
Pharmacokinetics. Clopidogrel is rapidly absorbed from the GI tract, both in the presence and absence of food. Bioavail- ability is about 50%. Clopidogrel is a prodrug that undergoes metabolism to its active form, primarily by hepatic CYP2C19 (the 2C19 isoenzyme of cytochrome P450). People with variant forms of the CYP2C19 gene are poor metabolizers of clopidogrel, and hence may not benefit adequately from the drug.
Therapeutic Use. Clopidogrel is used widely to prevent blockage of coronary artery stents and to reduce thrombotic events—MI, ischemic stroke, and vascular death—in patients with ACS and in those with atherosclerosis documented by recent MI, recent stroke, or established peripheral arterial disease. In patients with ACS, clopidogrel should always be combined with aspirin (75 to 325 mg once daily).
Clopidogrel should not be used in poor metabolizers. As noted, people with variant forms of the CYP2C19 gene cannot reliably convert clopidogrel to its active form. When treated with standard dosages of clopidogrel, these poor metabolizers exhibit a higher rate of cardiovascular events compared with normal metabolizers. Poor metabolizers can be identified by testing a blood or saliva sample for CYP2C19 variants, or by vasoconstriction and platelet aggregation, thereby reducing
the risk of arterial thrombosis. Because inhibition of cyclo- oxygenase by aspirin is irreversible and because platelets lack the machinery to synthesize new cyclooxygenase, the effects of a single dose of aspirin persist for the life of the platelet (7 to 10 days).
In addition to inhibiting the synthesis of TXA2, aspirin can inhibit synthesis of prostacyclin by the blood vessel wall. Since prostacyclin has effects that are exactly opposite to those of TXA2—namely, suppression of platelet aggregation and promo- tion of vasodilation—suppression of prostacyclin synthesis can partially offset the beneficial effects of aspirin therapy.
Fortunately, aspirin is able to inhibit synthesis of TXA2 at doses that are lower than those needed to inhibit synthesis of prostacyclin. Accordingly, if we keep the dosage of aspirin low (325 mg/day or less), we can minimize inhibition of prostacyclin production while maintaining inhibition of TXA2 production.
Indications for Antiplatelet Therapy
Antiplatelet therapy with aspirin has multiple indications of proven efficacy:
• Ischemic stroke (to reduce the risk of death and nonfatal stroke)
• TIAs (to reduce the risk of death and nonfatal stroke)
• Chronic stable angina (to reduce the risk of MI and sudden death)
• Unstable angina (to reduce the combined risk of death and nonfatal MI)
• Coronary stenting (to prevent reocclusion)
• Acute MI (to reduce the risk of vascular mortality)
• Previous MI (to reduce the combined risk of death and nonfatal MI)
• Primary prevention of MI (to prevent a first MI in men and in women age 65 and older)
In all of these situations, prophylactic therapy with aspirin can reduce morbidity, and possibly mortality. Primary prevention of MI is discussed next.
Primary Prevention of MI. In 2009, the U.S. Preventive Services Task Force (USPSTF) issued updated guidelines on the use of aspirin for primary prevention of MI. The USPSTF recommends the use of aspirin for men ages 45 to 79 years and women ages 55 to 79 years when the potential benefit of a reduction in MI outweighs the potential harm of an increase in GI hemorrhage. Cardiovascular risk is based on five factors—age, gender, cholesterol levels, blood pressure, and smoking status—and can be calculated using an online risk assessment tool, such as those at www.med-decisions.com.
Although the optimal aspirin dosage for primary prevention is unknown, low doses (e.g., 81 mg/day) appear as effective as higher ones.
Adverse Effects
Even in low doses, aspirin increases the risk of GI bleeding and hemorrhagic stroke. Among middle-aged people taking aspirin for 5 years, the estimated rate of major GI bleeding episodes is 2 to 4 per 1000 patients, and the rate of hemorrhagic stroke is 0 to 2 episodes per 1000 patients. Use of enteric-coated or buffered aspirin may not reduce the risk of GI bleeding.
Benefits of treatment must be weighed against bleeding risks.
If GI bleeding occurs, adding a proton pump inhibitor (e.g., omeprazole [Prilosec]) to reduce gastric acidity can help.
