Anticoagulant and Antiplatelet Drugs

Chemistry

Heparin is not a single molecule, but rather a mixture of long polysaccharide chains, with molecular weights that range from 3000 to 30,000. The active region is a unique pentasaccharide (five-sugar) sequence found randomly along the chain. An important feature of heparin’s structure is the presence of many negatively charged groups. Because of these negative charges, heparin is highly polar and hence cannot readily cross membranes.

Mechanism of Anticoagulant Action

Heparin suppresses coagulation by helping antithrombin inactivate clotting factors, primarily thrombin and factor Xa. As shown in Fig. 44.3, binding of heparin to antithrombin produces a conformational change in antithrombin that greatly enhances its ability to inactivate both thrombin and factor Xa. However, the process of inactivating these two clotting factors is distinct. To inactivate thrombin, heparin must simultaneously bind with both thrombin and antithrombin, thereby forming a ternary complex. In contrast, to inactivate factor Xa, heparin binds only with antithrombin; heparin itself does not bind with factor Xa.

By activating antithrombin, and thereby promoting the inactivation of thrombin and factor Xa, heparin ultimately suppresses formation of fibrin. Because fibrin forms the framework of thrombi in veins, heparin is especially useful for prophylaxis of venous thrombosis. Because thrombin and factor Xa are inhibited as soon as they bind with the heparin-antithrombin complex, the anticoagulant effects of heparin develop quickly (within minutes of intravenous [IV] administration). This contrasts with warfarin, whose full effects are not seen for days.

Because of its polarity and large size, heparin is unable to cross membranes, including those of the gastrointestinal (GI) tract. Consequently, heparin cannot be absorbed if given orally and therefore must be given by injection (IV or subcutaneous [subQ]). Because it cannot cross membranes, heparin does not traverse the placenta and does not enter breast milk.

Therapeutic Uses

Heparin is a preferred anticoagulant for use during pregnancy (because it doesn’t cross the placenta) and in situations that require rapid onset of anticoagulant effects, including pulmonary embolism (PE) and massive deep vein thrombosis (DVT). In addition, heparin is used for patients undergoing open heart surgery and renal dialysis; during these procedures, heparin serves to prevent coagulation in devices of extracorporeal circulation (heart-lung machines, dialyzers). Low-dose therapy is used to prevent postoperative venous thrombosis. Heparin may also be useful for treating disseminated intravascular coagulation, a complex disorder in which fibrin clots form throughout the vascular system and in which bleeding tendencies may be present; bleeding can occur because massive fibrin production consumes available supplies of clotting factors. Heparin is also used as an adjunct to thrombolytic therapy of acute myocardial infarction (MI).

All the drugs in this chapter increase the risk for patient bleeding. Bleeding develops in about 10% of patients and is the principal complication of treatment. Hemorrhage can occur at any site and may be fatal. Patients should be monitored closely for signs of blood loss. These include reduced blood pressure, increased heart rate, bruises, petechiae, hematomas, red or black stools, cloudy or discolored urine, pelvic pain (suggesting ovarian hemorrhage), headache or faintness (suggesting cerebral hemorrhage), and lumbar pain (suggesting adrenal hemorrhage). If bleeding develops, heparin should be withdrawn.

The risk for hemorrhage can be decreased in several ways. First, dosage should be carefully controlled so that the activated partial thromboplastin time (see later) does not exceed 2 times the control value. In addition, candidates for heparin therapy should be screened for risk factors (see “Warnings and Contraindications”). Finally, antiplatelet drugs (e.g., aspirin, clopidogrel) should be avoided.

Risk for hematoma is increased by the following:

Patients should be monitored for signs and symptoms of neurologic impairment. If impairment develops, immediate intervention is needed.

Heparin must be used with extreme caution in all patients who have a high likelihood of bleeding. Among these are individuals with hemophilia, increased capillary permeability, dissecting aneurysm, peptic ulcer disease, severe hypertension, or threatened abortion. Heparin must also be used cautiously in patients with severe disease of the liver or kidneys.

Drug Interactions

In heparin-treated patients, platelet aggregation is the major remaining defense against hemorrhage. Aspirin and other drugs that depress platelet function or affect coagulation will weaken this defense and hence must be employed with caution.

Laboratory Monitoring

The objective of anticoagulant therapy is to reduce blood coagulability to a level that is low enough to prevent thrombosis but not so low as to promote spontaneous bleeding. Because heparin levels can be highly variable, achieving this goal is difficult and requires careful control of dosage based on frequent tests of coagulation. The laboratory test employed most commonly is the activated partial thromboplastin time (aPTT). The normal value for the aPTT is 40 seconds. At therapeutic levels, heparin increases the aPTT by a factor of 1.5 to 2, making the aPTT 60 to 80 seconds. Because heparin has a rapid onset and brief duration, if an aPTT value falls outside the therapeutic range, coagulability can be quickly corrected through an adjustment in dosage: if the aPTT is too long (more than 80 seconds), the dosage should be lowered; conversely, if the aPTT is too short (less than 60 seconds), the dosage should be increased. Measurements of aPTTs should be made frequently (every 4–6 hours) during the initial phase of therapy. When an effective dosage has been established, measuring aPTT once a day will suffice.

Heparin is prescribed in units, not in milligrams. The heparin unit is an index of anticoagulant activity. Heparin dosage is titrated on the basis of laboratory monitoring, and hence dosage can be adjusted as needed based on test results.

Heparin is administered by injection only. Two routes are employed: intravenous (either intermittent or continuous) and subcutaneous. Intramuscular injection causes hematoma and must not be done. Heparin is not administered orally because heparin is too large and too polar to permit intestinal absorption.

Dosage varies by indication. Postoperative prophylaxis of thrombosis, for example, requires relatively small doses. In other situations, such as open heart surgery, much larger doses are needed. The dosages given here are for “general anticoagulant therapy.” As a rule, the aPTT should be employed as a guideline for dosage titration; increases in the aPTT of 1.5- to 2-fold are therapeutic. Because heparin is formulated in widely varying concentrations, you must read the label carefully to ensure that dosing is correct.

Production.

LMW heparins are made by depolymerizing unfractionated heparin (i.e., breaking unfractionated heparin into smaller pieces). Molecular weights in LMW preparations range between 1000 and 9000, with a mean of 4000 to 5000. In comparison, molecular weights in unfractionated heparin range between 3000 and 30,000, with a mean of 12,000 to 15,000.

Mechanism of Action.

Anticoagulant activity of LMW heparin is mediated by the same active pentasaccharide sequence that mediates anticoagulant action of unfractionated heparin. However, because LMW heparin molecules are short, they do not have quite the same effect as unfractionated heparin. Specifically, whereas unfractionated heparin is equally good at inactivating factor Xa and thrombin, LMW heparins preferentially inactivate factor Xa, being much less able to inactivate thrombin. Why the difference? To inactivate thrombin, a heparin chain must not only contain the pentasaccharide sequence that activates antithrombin but must also be long enough to provide a binding site for thrombin. This binding site is necessary because inactivation of thrombin requires simultaneous binding of thrombin with heparin and antithrombin (see Fig. 44.3). In contrast to unfractionated heparin chains, most (but not all) LMW heparin chains are too short to allow thrombin binding, and hence LMW heparins are less able to inactivate thrombin.

Therapeutic Use.

LMW heparins are approved for (1) prevention of DVT after abdominal surgery, hip replacement surgery, or knee replacement surgery; (2) treatment of established DVT, with or without PE; and (3) prevention of ischemic complications in patients with unstable angina, non–Q-wave MI, and ST-elevation MI (STEMI). In addition, these drugs have been used extensively off-label to prevent DVT after general surgery and in patients with multiple trauma and acute spinal injury. When used for prophylaxis or treatment of DVT, LMW heparins are at least as effective as unfractionated heparin, and possibly more effective.

Pharmacokinetics.

Compared with unfractionated heparin, LMW heparins have higher bioavailability and longer half-lives. Bioavailability is higher because LMW heparins do not undergo nonspecific binding to proteins and tissues and hence are more available for anticoagulant effects. Half-lives are prolonged (up to 6 times longer than that of unfractionated heparin) because LMW heparins undergo less binding to macrophages and hence undergo slower clearance by the liver. Because of increased bioavailability, plasma levels of LMW heparin are highly predictable. As a result, these drugs can be given using a fixed dosage, with no need for routine monitoring of coagulation. Because of their long half-lives, LMW heparins can be given just once or twice a day.

Administration, Dosing, and Monitoring.

All LMW heparins are administered by subQ injection. Dosage is sometimes based on body weight, depending on indication. Because plasma levels of LMW heparins are predictable for any given dose, these drugs can be employed using a fixed dosage without laboratory monitoring. This contrasts with unfractionated heparin, which requires dosage adjustments on the basis of aPTT measurements. Because LMW heparins have an extended half-life, dosing can be done once or twice daily. For prophylaxis of DVT, dosing is begun in the perioperative period and continued 5 to 10 days.

Adverse Effects and Interactions.

Bleeding is the major adverse effect. However, the incidence of bleeding complications is less than with unfractionated heparin. Despite the potential for bleeding, LMW heparins are considered safe for outpatient use. Like unfractionated heparin, LMW heparins can cause immune-mediated thrombocytopenia. As with unfractionated heparin, overdose with LMW heparins can be treated with protamine sulfate.

Like unfractionated heparin, LMW heparins can cause severe neurologic injury, including permanent paralysis, when given to patients undergoing spinal puncture or spinal or epidural anesthesia. The risk for serious harm is increased by concurrent use of antiplatelet drugs (e.g., aspirin, clopidogrel) or anticoagulants (e.g., warfarin, dabigatran). Patients should be monitored closely for signs of neurologic impairment.

Cost.

LMW heparins cost more than unfractionated heparin (e.g., about $63/day for dalteparin vs. $8/day for unfractionated heparin). However, because LMW heparins can be used at home and don’t require aPTT monitoring, the overall cost of treatment is lower than with unfractionated heparin.

Individual Preparations

In the United States two LMW heparins are available: enoxaparin and dalteparin. Additional LMW heparins are available in other countries. Each preparation is unique, so clinical experience with one may not apply fully to the other.

Therapeutic Use

Fondaparinux is approved for (1) preventing DVT after hip fracture surgery, hip replacement surgery, knee replacement surgery, or abdominal surgery; (2) treating acute PE (in conjunction with warfarin); and (3) treating acute DVT (in conjunction with warfarin). The drug is somewhat more effective than enoxaparin (an LMW heparin) at preventing DVT but may cause slightly more bleeding. Anticoagulation may persist for 2 to 4 days after the last dose. Fondaparinux is administered using a fixed dosage and does not require routine laboratory monitoring.

Pharmacokinetics

Fondaparinux is administered by subQ injection. Bioavailability is 100%. Plasma levels peak 2 hours after dosing. The drug is eliminated by the kidneys with a half-life of 17 to 21 hours. The half-life is increased in patients with renal impairment.

Adverse Effects

As with other anticoagulants, bleeding is the biggest concern. The risk is increased by advancing age and renal impairment. Fondaparinux should be used with caution in patients with moderate renal impairment, defined as creatinine clearance (CrCl) of 30 to 50 mL/minute, and avoided in patients with severe renal impairment, defined as CrCl below 30 mL/minute. The drug should also be avoided for prophylactic use in patients weighing less than 50 kg because low body weight increases bleeding risk. After surgery, at least 6 hours should elapse before starting fondaparinux. Aspirin and other drugs that interfere with hemostasis should be used with caution. In contrast to overdose with heparin or LMW heparins, overdose with fondaparinux cannot be treated with protamine sulfate.

Fondaparinux does not promote immune-mediated HIT, although it still can lower platelet counts. During clinical trials, thrombocytopenia developed in 3% of patients. Platelet counts should be monitored, and if they fall below 100,000/mm³, fondaparinux should be discontinued.

In patients undergoing anesthesia using an epidural or spinal catheter, fondaparinux (as well as other anticoagulants) can cause spinal or epidural hematoma, which can result in permanent paralysis. However, in clinical trials, when fondaparinux was administered no sooner than 2 hours after catheter removal, no hematomas were reported.

Preparations, Dosage, and Administration

Fondaparinux [Arixtra] is available in single-dose, prefilled syringes (2.5, 5, 7.5, and 10 mg). Dosing is done once a day by subQ injection.

For prevention of DVT, the recommended dosage is 2.5 mg once a day, starting 6 to 8 hours after surgery. The usual duration is 5 to 9 days.

For treatment of acute DVT or acute PE, dosage is based on body weight as follows: for patients under 50 kg, 5 mg once daily; for patients 50 to 100 kg, 7.5 mg once daily, and for patients over 100 kg, 10 mg once daily. The usual duration is 5 to 9 days when overlapping with warfarin.

Atrial Fibrillation

As discussed in Chapter 41, atrial fibrillation carries a high risk for stroke secondary to clot formation in the atrium. When people have atrial fibrillation, anticoagulant therapy is given long term to prevent clot formation. Until recently, warfarin was the only oral anticoagulant available and hence has been the reference standard for stroke prevention. However, four novel oral anticoagulants (NOACs)—dabigatran [Pradaxa, Pradax ], apixaban [Eliquis], edoxaban [Savaysa], and rivaroxaban [Xarelto]—which are much easier to use than warfarin, are likely to replace warfarin as the treatment of choice for many patients.

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 defects, and optic atrophy. Accordingly, warfarin is classified in U.S. Food and Drug Administration (FDA) Pregnancy Risk Category X: 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 do not cross the placenta, should be employed.

Use During Lactation

Warfarin enters breast milk. Women should be advised against breastfeeding.

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 for fractures.

Specific Interacting Drugs

Of the many drugs listed in Table 44.4, a few are especially likely to produce interactions of clinical significance. Four are discussed next.

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.)

As a rule, small doses—2.5 mg by oral administration (PO)—are preferred. Large doses (e.g., 10 mg PO) can cause prolonged resistance to warfarin, thereby hampering restoration of anticoagulation after 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. Patients do not need to avoid these foods but instead 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 44.5). 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.

Genetics and Dosage Adjustment

Patients with variant genes that code for VKORC1 and CYP2C9 are at increased risk for warfarin-induced bleeding and hence require reduced doses. As noted earlier, VKORC1 is the target enzyme that warfarin inhibits, and CYP2C9 is the enzyme that metabolizes 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 for 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.

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.

In the United States dabigatran was first approved for prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Approval was based on the RE-LY trial, in which more than 18,000 patients were randomized to receive either dabigatran (110 or 150 mg twice daily) or warfarin (dosage adjusted to produce an INR of 2–3). 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 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.

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 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 increases to 18 hours in patients with moderate renal impairment (CrCl 30–50 mL/min).

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 for hemorrhagic stroke and other major bleeds.

Because dabigatran is not highly protein bound, dialysis can remove much of the drug (about 60% over 2–3 hours). 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.

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.

Dabigatran etexilate [Pradaxa] is available in three strengths: 75, 110, and 150-mg capsules.

Nonvalvular Atrial Fibrillation Patients.

In a trial known as ROCKET AF, rivaroxaban was compared with warfarin for preventing stroke in patients with nonvalvular 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 for major hemorrhagic events of all kinds—but had a lower risk for intracranial bleeds and fatal bleeds.

Spinal or Epidural Hematoma.

Like all other anticoagulants, rivaroxaban poses a risk for 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; after 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 or epidural hematoma was discussed further earlier (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 for 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, macrolide antibiotics) can raise rivaroxaban levels enough to increase the risk for 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 for 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.

Owing to the risk for bleeding, rivaroxaban should not be combined with other anticoagulants. Concurrent use with antiplatelet drugs and fibrinolytics should be done with caution.

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 for 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 C and should be used only if the benefits are deemed to outweigh the risks to the mother and fetus.

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 after knee replacement and 35 days after 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.

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.

As with rivaroxaban, bleeding is the most common adverse effect and can occur at any site. Bleeding risk is increased by other drugs that impede hemostasis. How does apixaban compare with warfarin? The risk for 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 for 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 for thrombotic events.

Renal impairment can delay excretion of apixaban, increasing the risk for 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.

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.

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 <60 kg, the dose is 30 mg daily. For patients >60 kg, this dose is doubled to 60 mg daily. As with the other NOACs, doses should be decreased in patients with renal impairment.

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.

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. Bioavailability 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 (75–325 mg once daily).

Poor metabolizers can be identified by testing a blood or saliva sample for CYP2C19 variants or by simply measuring the platelet response to treatment. Unfortunately, even with this information, the course of action is not clear. Yes, we could give poor metabolizers higher doses—but doses that might be safe and effective have not been established. As an alternative, poor metabolizers could be treated with either prasugrel [Effient] or ticagrelor [Brilinta], two other P2Y₁₂ ADP receptor antagonists discussed later.

Adverse Effects

Clopidogrel is generally well tolerated. Adverse effects are about the same as with aspirin. The most common complaints are abdominal pain, dyspepsia, diarrhea, and rash.

Clopidogrel should be used with caution in patients taking other drugs that promote bleeding (e.g., heparin, warfarin, aspirin, and NSAIDs).

Preparations, Dosage, and Administration

Clopidogrel [Plavix] is available in 75-mg tablets. The usual maintenance dosage is 75 mg once a day, taken with or without food. A 300-mg loading dose may be used for some patients. The optimal duration of treatment is unknown. Dosage needn’t be changed for older-adult patients or those with renal impairment. Patients being treated for ACS should take daily aspirin (75–325 mg). Clopidogrel should be withdrawn 5 days before elective surgery and then resumed as soon as possible.

Clinical Trial

In a trial known as TRITON-TIMI, prasugrel was compared directly with clopidogrel. The trial enrolled more than 13,000 patients with ACS who were scheduled for coronary angioplasty, also known as percutaneous coronary intervention. The goal with both drugs was to prevent thrombotic complications, including stent restenosis. Patients taking prasugrel experienced fewer thrombotic events but more major bleeding.

Pharmacokinetics

Prasugrel is rapidly absorbed after oral dosing, in both the presence and absence of food. Activation takes place in two steps. The process begins with hydrolysis by esterases in the intestine and ends with conversion to the active metabolite in the liver, primarily by CYP3A4 and CYP2B6, two isoenzymes of cytochrome P450. (Note that activation of prasugrel differs from activation of clopidogrel, which is mediated by CYP2C19.) The entire activation process is fast: plasma levels of the active metabolite peak about 30 minutes after dosing. Elimination of the active form is primarily by hepatic metabolism, followed by excretion in the urine and feces. The active metabolite has a half-life of 7 hours. In patients who weigh less than 60 kg, total exposure to the active metabolite is 30% to 40% higher than in heavier patients. Accordingly, these lighter patients may need a dosage reduction.

Adverse Effects

The principal adverse effect is bleeding, which occurs more often with prasugrel than with clopidogrel. According to results of TRITON-TIMI, among patients not undergoing coronary artery bypass surgery (CABG), the incidence of major bleeding was 2.4% with prasugrel versus 1.8% with clopidogrel, and the incidence of life-threatening bleeding was 0.4% versus 0.1%. Among patients who required CABG surgery, the incidence of major bleeding was greatly increased: 18.8% with prasugrel versus 2.7% with clopidogrel. Accordingly, if CABG surgery is anticipated, prasugrel should not be started. Prasugrel should be avoided by patients at increased risk for bleeding, including patients with active pathologic bleeding, patients older than 75 years, and patients with a history of TIAs or stroke. If possible, major bleeding should be managed without discontinuing prasugrel because discontinuation would increase the risk for a thrombotic event.

Rarely, patients experience hypersensitivity reactions, including potentially life-threatening angioedema. Onset may occur within hours of the first dose, or after 5 to 10 days of treatment.

Data from TRITON-TIMI suggest that prasugrel may increase the risk for cancer. Among patients using the drug, there was a 62% increase in the rate of new and worsening solid tumors. However, we don’t know of any plausible mechanism of tumor promotion. The FDA is monitoring for more cancer cases.

Drug Interactions

Other drugs that promote bleeding (e.g., warfarin, heparin, fibrinolytic drugs, chronic NSAIDs) will increase the risk for a serious bleed and hence should be used with great caution. PPIs, which may slow the activation of clopidogrel (by inhibiting CYP2C19), do not prevent the activation of prasugrel. Also, according to the prasugrel package insert, drugs that induce or inhibit CYP3A4 do not have a significant impact on prasugrel activity.

Preparations, Dosage, and Administration

Prasugrel [Effient] is supplied in 5- and 10-mg tablets for oral dosing, with or without food. Treatment consists of a 60-mg loading dose, followed by once-daily 10-mg maintenance doses. For patients who weigh less than 60 kg, maintenance doses may be reduced to 5 mg. All patients should take aspirin daily (80–325 mg).

Clinical Trial

In a trial known as PLATO, ticagrelor was compared directly with clopidogrel in patients with recent-onset ACS (within the previous 24 hours). The trial randomized more than 18,000 patients to receive either ticagrelor (180 mg once followed by 90 mg twice daily) or clopidogrel (300 mg once followed by 75 mg once daily). All patients also took a daily aspirin. Compared with clopidogrel, ticagrelor produced a greater reduction in MI, stroke, stent restenosis, and CV death. Unfortunately, these advantages were offset by a greater risk for hemorrhagic events, including fatal intracranial bleeding.

Pharmacokinetics

Ticagrelor is administered by mouth, and food has little effect on absorption. Plasma levels peak 1.5 hours after dosing. Bioavailability is 36%. Unlike clopidogrel and prasugrel, which are prodrugs, ticagrelor is active as administered. In the liver, CYP3A4 converts much of each dose to an active metabolite. Later, the parent drug and active metabolite undergo inactivation by CYP3A4, followed by excretion in the feces (58%) and urine (26%). The elimination half-life is 7 hours for ticagrelor itself and 9 hours for the active metabolite.

Adverse Effects

The most common adverse effects are bleeding and dyspnea. Other adverse effects include headache, cough, dizziness, nausea, noncardiac chest pain, diarrhea, and bradycardia, including ventricular pauses.

Anticoagulants (e.g., warfarin, heparin, dabigatran), fibrinolytics (e.g., alteplase, reteplase), and antiplatelet drugs (e.g., aspirin, abciximab) will increase the risk for a serious bleed and hence should be used with great caution.

Contraindications and Precautions

Ticagrelor is contraindicated for patients with active pathologic bleeding, a history of ICH, or severe hepatic impairment. In patients with moderate hepatic impairment, ticagrelor should be used with caution (because levels of ticagrelor itself and its active metabolite could become excessive, thereby increasing the risk for bleeding).

Preparations, Dosage, and Administration

Ticagrelor [Brilinta] is supplied in 90-mg tablets for dosing with or without food. After an initial loading dose (180 mg) combined with 325 mg of aspirin, patients take 90 mg twice daily. Daily aspirin (75–100 mg) should be continued as well. Doses for patients taking ticagrelor for secondary prevention of CV events should take 60 mg twice daily.

Mechanism of Action.

PAR-1 mediates the effects of thrombin, and these receptors are located on the surface of platelets. By reversibly antagonizing these receptors, vorapaxar inhibits thrombin-induced and thrombin receptor agonist peptide (TRAP)-induced platelet aggregation. Vorapaxar does not work on ADP receptors.

Pharmacokinetics.

Vorapaxar is well absorbed after oral administration. Antiplatelet effects begin within 1 hour. The drug undergoes extensive hepatic metabolism followed by excretion in the feces. Vorapaxar has a long half-life (8 days). Effects persist for 7 to 10 days after drug withdrawal (i.e., until new platelets have been synthesized).

Adverse Effects

Bleeding.

Like all other antiplatelet drugs, vorapaxar poses a risk for serious bleeding. In the GUSTO study, serious non-CABG bleeding developed in 3% of patients taking vorapaxar. This is similar to the rates seen with ticagrelor in the PLATO trial.

Clinical Trial.

The benefit of combining aspirin and dipyridamole was demonstrated in the second European Stroke Prevention Study (ESPS-2), a randomized controlled trial that enrolled more than 6000 patients who had suffered a prior ischemic stroke or TIA. Some patients took aspirin alone (25 mg twice daily), some took dipyridamole alone (200 mg twice daily), some took both drugs, and some took placebo. After 24 months, the incidence of fatal or nonfatal ischemic stroke was reduced by 16% with dipyridamole alone, 18% with aspirin alone, and 37% with the combination. Unfortunately, ESPS-2 was tainted by scientific scandal (one investigator, who later resigned, was charged with creating and falsifying data). Although all fraudulent data were discarded before publication, some authorities remain skeptical of the results.

Adverse Effects.

The most common adverse effects of the combination are headache, dizziness, and GI disturbances (nausea, vomiting, diarrhea, abdominal pain, dyspepsia). Of course, bleeding is a concern: the product can cause hemorrhage (3.2% vs. 1.5% with placebo), nosebleed (2.4% vs. 1.5%), and purpura (1.4% vs. 0.4%). The aspirin in Aggrenox poses a risk for GI bleeding from peptic ulcers.

Preparations, Dosage, and Administration.

Aggrenox capsules contain 25 mg of aspirin and 200 mg of extended-release dipyridamole. The recommended dosage is 2 capsules a day—1 in the morning and 1 at night. The cost is about $317 a month, compared with $3 a month for aspirin alone. It is important to note that the daily dose of aspirin (50 mg) is lower than the dose recommended to prevent MI (at least 80 mg/day). Accordingly, supplemental aspirin may be needed.

Adverse Effects

Cilostazol causes a variety of untoward effects. The most common is headache (34%). Others include diarrhea, abnormal stools, palpitations, dizziness, and peripheral edema.

Other drugs that inhibit PDE-3 have increased mortality in patients with heart failure. Whether cilostazol represents a risk is unknown. Nonetheless, heart failure is a contraindication to cilostazol use.

Drug and Food Interactions

Cilostazol is metabolized by hepatic CYP3A4, so cilostazol levels can be increased by CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, erythromycin, fluoxetine, fluvoxamine, nefazodone, sertraline, and grapefruit juice). Metabolism of cilostazol can also be inhibited by omeprazole.

Preparations, Dosage, and Administration

Cilostazol [Pletal] is available in 50- and 100-mg tablets. The usual dosage is 100 mg twice daily, taken 30 minutes before or 2 hours after breakfast and the evening meal. Dosage should be reduced to 50 mg twice daily in patients taking omeprazole and drugs or foods that inhibit CYP3A4.