Review
Novel anticoagulants for stroke prevention in atrial fibrillation: safety issues in the elderly Expert Rev. Clin. Pharmacol. 6(6), 677–689 (2013)
Anton Strunets1, Mahek Mirza1, Jasbir Sra2 and Arshad Jahangir*1 1 Center for Integrative Research on Cardiovascular Aging (CIRCA), Aurora University of Wisconsin Medical Group, Aurora Health Care, 3033 South 27th Street, Milwaukee, WI, USA 2 Aurora Cardiovascular Services, Aurora Sinai/Aurora St Luke’s Medical Centers, University of Wisconsin School of Medicine and Public Health, Milwaukee, WI, USA *Author for correspondence: Tel.: +1 414 649 7597 [email protected]
Vitamin K antagonists (VKAs) are the most widely used anticoagulants for stroke prevention in patients with atrial fibrillation (AF). Recently, the US FDA approved three novel anticoagulants that work through inhibition of coagulation cascade independent of Vitamin K-dependent enzymatic reactions and, therefore, should have less food–drug interactions. Since AF is a disease of the aging heart, it is important to assess safety and efficacy of these new anticoagulants in elderly patients. We reviewed age-related changes in pharmacokinetics and pharmacodynamics observed with senescence and the effects of these changes on novel anticoagulants, known and anticipated drug and food interactions, and challenges related to bleeding complications and temporary discontinuation prior to surgery or interventional procedure. Although advantageous to VKA in age groups represented in trials, there are lack of data on VKA usage in older–elderly patients; additional research and post-marketing analysis in older–elderly patients are needed. KEYWORDS: atrial fibrillation • apixaban • bleeding • dabigatran • drug–drug interaction • elderly • novel anticoagulants • rivaroxaban • stroke • warfarin
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, posing significant risk of morbidity and mortality related to thromboembolism-triggered stroke, with an annual cost to the health care system exceeding $15 billion [1–4]. A disease of the aging heart, with a 100-fold higher prevalence in octogenarians (8–10%) compared with young and middle-aged adults (30 ml/min; caution is advised in patients with CrCl 15–29 ml/min, especially if drugs that may increase rivaroxaban plasma concentration are concomitantly used; rivaroxaban use is not recommended when CrCl is 50% bioavailability when taken orally, with peak plasma concentration of 3–4 h. Absorption of apixaban in the gastrointestinal tract is not affected by food [47]. It is taken twice daily with half-life of 10–14 h. Liver metabolism is partly dependent on CYP3A4 and partly independent [48]. More than 70% of the administered dose is recovered in feces and about 25% in urine (FIGURE 3) [48]. In elderly patients, a change in distribution and elimination phase of AUC is >30% greater than in younger subjects, with a marginal increase in women as compared with men. The apixaban efficacy in various age subgroups was analyzed in the ARISTOTLE trial and found to be superior to VKA in those >75 years [49]. Drug interactions
In experimental models based on human liver, oxidative metabolism of apixaban was primarily catalyzed by CYP3A4/5, with minor involvement of CYP1A2 and CYP2J2 [50]. These suggest the possibility of interaction with other drugs that are substrates or inducers of CYP3A4/5 (TABLE 4) including antihypertensives, antiarrhythmics and antibiotics commonly used in the elderly. Combined administration of apixaban with ketoconazole, a strong inhibitor of CYP3A4 and P-gp, resulted in 1.6-fold increase in mean maximum concentration; therefore, the use of apixaban is not recommended with ‘azole’ antifungals. Diltiazem hydrochloride, a moderate CYP3A4 and P-gp inhibitor (TABLES 3 & 4) widely used in the elderly for rate control of AF www.expert-reviews.com
Extrinsic pathway
XI
TTP889
Review
and/or hypertension, resulted in a 40% increase in mean apixaban AUC and 30% increase in maximum plasma apixaban concentration. The simultaneous use of apixaban with other strong CYP3A4 and P-gp inducers (TABLE 4) has potential to reduce plasma concentration of apixaban and should be used with caution [51]. Atenolol and digoxin showed no clinically significant pharmacokinetic interactions with apixaban. Effects of body weight & gender
Due to multiple elimination pathways, apixaban pharmacokinetics are not significantly altered by patient age, sex, race or ethnicity. Renal clearance of the drug seemed to be unaffected by the weight variations, and there was a linear relationship between plasma antifactor Xa activity and apixaban plasma concentration independent of body weight. It was suggested that weight alone is unlikely to require adjustment of apixaban dose in the absence of other factors contributing to medication metabolism and elimination [52]. Effects of age & renal impairment
The median age of patients in the ARISTOTLE trial comparing apixaban to warfarin in patients with AF was 70 years (interquartile range 63–76 years) [53]. In patients >65 years, apixaban was better than warfarin in reducing the primary efficacy outcome of stroke and systemic embolism. For bleeding risk, interaction with diabetes and moderate to severe renal impairment indicated better outcomes. Compared to warfarin, the rates of stroke, death and major bleeding were reduced by 681
Review
Strunets, Mirza, Sra & Jahangir
Apixaban
Rivaroxaban
Dabigatran
Being a univalent direct thrombin inhibitor, it binds to the active site inactivating both fibrin-bound and fibrin-free thromDuodenum Duodenum Duodenum P-gp P-gp P-gp bin. In contrast, indirect thrombin inhibitors such as heparin and low-molecDabigatran etexilate (bioavailability: 3–7%) ular-weight heparin have no effect on enterase-mediated Apixaban fibrin-bound thrombin. In theory, the Rivaroxaban hydrolysis (bioavailability: 50%) (bioavailability: ability to inhibit fibrin-bound thrombin without food - 66% presents an advantage over the heparins No with food > 80%) Cyp150 since bound thrombin can continue to trigger thrombus expansion. Inhibition of thrombin by dabigatran stops conversion Dabigatran Cyp3A4 Cyp3A4 Cyp2J2 of fibrinogen to fibrin, positive feedback amplification of coagulation activation, P-gp No crosslinking of fibrin monomers, platelet Cyp150 activation and inhibition of fibrinolysis. Half-life Half-life Half-life 11–13h 8–15h Dabigatran etexilate is rapidly absorbed 14–17h following oral administration and hydro~65% ~35% ~20% ~80% ~73% ~27% lyzed to active form by esterases in the stool urine stool urine stool urine gut, plasma and liver. High oral doses are required to achieve adequate plasma conFigure 3. Potential pharmacokinetic interaction sites for new anticoagulants. The bioavailability of an anticoagulant is affected by interaction with drugs modulating the activ- centrations, as absolute bioavailability of ity of P-glycoprotein (P-gp) listed in TABLE 3. Intestinal P-gp is involved in transport of all three dabigatran is only 6.5% (FIGURE 3) [58]. drugs and, for rivaroxaban, P-gp in the kidneys also is involved. Dabigatran etexilate underAnticoagulation effect achieved is proporgoes hydrolysis by esterases to active dabigatran. Cytochrome Cyp3A4 is mainly involved in tionate to plasma concentration and metabolism of rivaroxaban and, to a lesser extent, apixaban, with minimal impact on dabipeaks within 0.5–2 h of oral gatran. Drugs affecting Cyp3A4 (TABLE 4) can alter clearance of these agents. For dabigatran, administration (TABLE 2) [58–60]. In healthy renal excretion is the main route of elimination and therefore creatinine clearance becomes volunteers, steady-state concentrations are an important factor. The elimination half-life in the elderly is indicated. achieved 72 h after administration [58]. Patients with active liver disease were apixaban, regardless of renal functions, with the greatest relative excluded from the RE-LY trial [61] and its use in elderly with reduction in major bleeding seen in patients with impaired advanced hepatic impairment should be avoided. renal functions [54]. Transformation of dabigatran etexilate to dabigatran is completed in the liver and approximately one-fifth of the drug is conjugated with glucuronic acid and removed via the Dabigatran biliary system (FIGURE 3) [62]. The active form of the drug is not Pharmacodynamics & pharmacokinetic basics of dabigatran metabolized by cytochrome P450 enzymes, but it is a subDabigatran etexilate is a low-molecular-weight prodrug that strate of the P-gp efflux transporter (FIGURE 3). The mean dabiexhibits no pharmacological activity after oral administration gatran half-life in healthy volunteers following a single dose and requires conversion to the active form dabigatran, a com- is 8 h and increases to 12–14 h after multiple doses (TABLE 2) petitive and reversible direct thrombin inhibitor (FIGURE 2) [55–57]. [58–60,63]. In an older population, the half-life was slightly A
B
C
Table 3. Drugs effecting P-glycoprotein (not all-inclusive). P-glycoprotein substrates
P-glycoprotein modulators
Cardiovascular drugs Digoxin, dipyridamole, diltiazem, losartan, quinidine, tacrolimus, apixaban, rivaroxaban, dabigatran Psychotropic agents Tricyclic antidepressants, phenothiazines, paroxetine, resperidone Antineoplastic agents Actinomycin D, daunorubicin, doxorubicin, etoposide, mitomycin, paclitaxel, taxol, vinblastine, vincristine Other agents Cyclosporine, colchicine, steroids, aldosterone, dexamethasone, protease inhibitors, 99mTc-SESTAMIBI, rifampicin, St John’s wort
Inhibitors Amiloride, amiodarone, captopril, carvedilol, diltiazem, dipyridamole, doxazocin, dronedarone, felodipine, nifedipine, propranolol, propafenone, quinidine, ranolazine, spironalactone, verapamil, statins, azithromycin, cefoperazone, ceftriaxone, clarithromycin, conivaptan, cortisol, cyclosporine, erythromycin, haloperidol, itraconazole, ketoconazole, paroxetine, phenothiazines, ritonavir and lopinavir tacrolimus, tamoxifen, tricyclic antidepressants Inducers carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampin, St John’s wort, tipranavir/ritonavir
682
Expert Rev. Clin. Pharmacol. 6(6), (2013)
Novel anticoagulants in the elderly
Review
Table 4. Drugs affecting cytochrome P450 enzymes involved in anticoagulant metabolism (not all-inclusive). CYP enzymes (anticoagulant metabolized)
Strong inhibitors ‡fivefold " in AUC or >80% # in CL
CYP2C9 (warfarin)
Moderate inhibitors ‡2 but 80 years [67], the likelihood of bleeding complications is greater in the elderly. In patients with a CrCl of 683
Review
Strunets, Mirza, Sra & Jahangir
24 h, which increases the risk of bleeding [64,68]. The recommended dose for renal clearance for CrCl 15–30 ml/min is 75 mg twice daily and not defined for CrCl 200 ng/ml dabigatran plasma concentration or diluted thrombin time >65 s are associated with an increased risk of bleeding. For rivaroxaban and apixaban, a point-of-care-determined INR is unreliable for the evaluation of factor Xa inhibitory activity. Antifactor Xa ‘chromogenic assays’ that assess plasma concentrations of the factor Xa inhibitors are available, but data on bleeding risk or risk for thromboembolism are not available. Regular monitoring of renal function in elderly patients receiving novel anticoagulants, particularly dabigatran, or in any patient following an event or condition that may affect renal function, is recommended [69]. Renal function should be monitored every 6 months in the elderly and the dose adapted to respective changes in renal function. For dabigatran, a lower dose (75 mg twice daily) for patients with severe renal insufficiency (CrCl 15–30 ml/min) was approved by the FDA based on pharmacokinetic simulations; however, outcome data for the new anticoagulants in patients with CrCL 48 h after the procedure. On resumption, maximal anticoagulation effect is accomplished within 2–4 h of ingestion. Management of overdose or emergent reversal of anticoagulant effect
One of the main concerns and limitations of novel anticoagulants is the lack of readily available antidote or reliable method of reversing the effects of coagulation cascade blockade. The management of overdose of new anticoagulants or conditions that increase plasma levels (renal insufficiency, P-gp and CYP3A4 inhibitors) depends on whether active bleeding is present. Since the plasma half-life of these drugs is short (TABLE 2), a waitful watching approach can be considered in most nonbleeding cases, with restoration of normal hemostasis expected within 12–24 h after the last dose [70]. Administration of fresh frozen plasma that works for warfarin may not be effective because of the plasma abundance of the drug that can block newly administered coagulation factors. Ex vivo studies using a recombinant monoclonal antibody targeting dabigatran and reconstituted factor Xa are under way and may result in a method of rapid and specific reversal of anticoagulation effect in critically ill patients in need of emergency hemostasis [71,72].
Review
At this time, nonspecific procoagulants, such as prothrombin complex concentrate (PCC) and recombinant factor VIIa, are available for managements of major bleeding or rapid reversal in case of emergency invasive procedures or life-threatening bleeding [73]. The studies supporting the use of these nonspecific emergency agents to reverse the coagulation effect of novel anticoagulants are lacking and specific geriatric doses are not defined. The use of these agents is associated with significantly increased risk of spontaneous thromboembolic complications and, therefore, should be reserved for emergency situations [74,75]. In healthy volunteers exposed to therapeutic doses of rivaroxaban, PCC administration resulted in rapid normalization of coagulation parameters, whereas administration of PCC to patients medicated with dabigatran had no significant effect [76,77]. The experience with use of nonspecific prothrombotic agents to reverse the effects of novel anticoagulants is limited and strong prothrombotic side effects versus benefits must be carefully balanced [18]. Expert commentary
The use of anticoagulation to prevent stroke is an important issue in elderly patients with AF. Although there is general concern about increased risk of bleeding in the aged, anticoagulation for prevention of stroke is more effective in elderly patients >65 years than those 65 years with or without risk factors. Lowest adequate intensity of anticoagulation possible to minimize bleeding complications in the elderly must be balanced with its effectiveness in prevention of thromboembolic complications. Until recently, warfarin was the only available FDA-approved option for stroke prevention in patients with nonvalvular AF, and the emergence of new pharmaceutical agents is an important step forward in reducing inconvenience with frequent monitoring of anticoagulation and food–drug interactions with the use of VKA, thus improving patient quality of life and outcomes. Novel
Table 5. Timing of interruption before surgery or invasive procedure. Calculated creatinine clearance (ml/min)
Half-life (h; range)
Timing of last dose before surgery Standard risk of bleeding†
High risk of bleeding‡
Dabigatran >80
13 (11–22)
‡1 day
‡2 days
>50 to 80
15 (12–34)
‡36 h
‡3 days
>30 to 50
18 (13–23)
‡2 days
‡4 days
30
27 (22–35)
Not indicated
Not indicated
>30
12 (11–13)
‡1 day
‡2 days
15–30
Unknown
‡36 h
‡2 days
Novel anticoagulants for stroke prevention in atrial fibrillation: safety issues in the elderly Expert Rev. Clin. Pharmacol. 6(6), 677–689 (2013)
Anton Strunets1, Mahek Mirza1, Jasbir Sra2 and Arshad Jahangir*1 1 Center for Integrative Research on Cardiovascular Aging (CIRCA), Aurora University of Wisconsin Medical Group, Aurora Health Care, 3033 South 27th Street, Milwaukee, WI, USA 2 Aurora Cardiovascular Services, Aurora Sinai/Aurora St Luke’s Medical Centers, University of Wisconsin School of Medicine and Public Health, Milwaukee, WI, USA *Author for correspondence: Tel.: +1 414 649 7597 [email protected]
Vitamin K antagonists (VKAs) are the most widely used anticoagulants for stroke prevention in patients with atrial fibrillation (AF). Recently, the US FDA approved three novel anticoagulants that work through inhibition of coagulation cascade independent of Vitamin K-dependent enzymatic reactions and, therefore, should have less food–drug interactions. Since AF is a disease of the aging heart, it is important to assess safety and efficacy of these new anticoagulants in elderly patients. We reviewed age-related changes in pharmacokinetics and pharmacodynamics observed with senescence and the effects of these changes on novel anticoagulants, known and anticipated drug and food interactions, and challenges related to bleeding complications and temporary discontinuation prior to surgery or interventional procedure. Although advantageous to VKA in age groups represented in trials, there are lack of data on VKA usage in older–elderly patients; additional research and post-marketing analysis in older–elderly patients are needed. KEYWORDS: atrial fibrillation • apixaban • bleeding • dabigatran • drug–drug interaction • elderly • novel anticoagulants • rivaroxaban • stroke • warfarin
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, posing significant risk of morbidity and mortality related to thromboembolism-triggered stroke, with an annual cost to the health care system exceeding $15 billion [1–4]. A disease of the aging heart, with a 100-fold higher prevalence in octogenarians (8–10%) compared with young and middle-aged adults (30 ml/min; caution is advised in patients with CrCl 15–29 ml/min, especially if drugs that may increase rivaroxaban plasma concentration are concomitantly used; rivaroxaban use is not recommended when CrCl is 50% bioavailability when taken orally, with peak plasma concentration of 3–4 h. Absorption of apixaban in the gastrointestinal tract is not affected by food [47]. It is taken twice daily with half-life of 10–14 h. Liver metabolism is partly dependent on CYP3A4 and partly independent [48]. More than 70% of the administered dose is recovered in feces and about 25% in urine (FIGURE 3) [48]. In elderly patients, a change in distribution and elimination phase of AUC is >30% greater than in younger subjects, with a marginal increase in women as compared with men. The apixaban efficacy in various age subgroups was analyzed in the ARISTOTLE trial and found to be superior to VKA in those >75 years [49]. Drug interactions
In experimental models based on human liver, oxidative metabolism of apixaban was primarily catalyzed by CYP3A4/5, with minor involvement of CYP1A2 and CYP2J2 [50]. These suggest the possibility of interaction with other drugs that are substrates or inducers of CYP3A4/5 (TABLE 4) including antihypertensives, antiarrhythmics and antibiotics commonly used in the elderly. Combined administration of apixaban with ketoconazole, a strong inhibitor of CYP3A4 and P-gp, resulted in 1.6-fold increase in mean maximum concentration; therefore, the use of apixaban is not recommended with ‘azole’ antifungals. Diltiazem hydrochloride, a moderate CYP3A4 and P-gp inhibitor (TABLES 3 & 4) widely used in the elderly for rate control of AF www.expert-reviews.com
Extrinsic pathway
XI
TTP889
Review
and/or hypertension, resulted in a 40% increase in mean apixaban AUC and 30% increase in maximum plasma apixaban concentration. The simultaneous use of apixaban with other strong CYP3A4 and P-gp inducers (TABLE 4) has potential to reduce plasma concentration of apixaban and should be used with caution [51]. Atenolol and digoxin showed no clinically significant pharmacokinetic interactions with apixaban. Effects of body weight & gender
Due to multiple elimination pathways, apixaban pharmacokinetics are not significantly altered by patient age, sex, race or ethnicity. Renal clearance of the drug seemed to be unaffected by the weight variations, and there was a linear relationship between plasma antifactor Xa activity and apixaban plasma concentration independent of body weight. It was suggested that weight alone is unlikely to require adjustment of apixaban dose in the absence of other factors contributing to medication metabolism and elimination [52]. Effects of age & renal impairment
The median age of patients in the ARISTOTLE trial comparing apixaban to warfarin in patients with AF was 70 years (interquartile range 63–76 years) [53]. In patients >65 years, apixaban was better than warfarin in reducing the primary efficacy outcome of stroke and systemic embolism. For bleeding risk, interaction with diabetes and moderate to severe renal impairment indicated better outcomes. Compared to warfarin, the rates of stroke, death and major bleeding were reduced by 681
Review
Strunets, Mirza, Sra & Jahangir
Apixaban
Rivaroxaban
Dabigatran
Being a univalent direct thrombin inhibitor, it binds to the active site inactivating both fibrin-bound and fibrin-free thromDuodenum Duodenum Duodenum P-gp P-gp P-gp bin. In contrast, indirect thrombin inhibitors such as heparin and low-molecDabigatran etexilate (bioavailability: 3–7%) ular-weight heparin have no effect on enterase-mediated Apixaban fibrin-bound thrombin. In theory, the Rivaroxaban hydrolysis (bioavailability: 50%) (bioavailability: ability to inhibit fibrin-bound thrombin without food - 66% presents an advantage over the heparins No with food > 80%) Cyp150 since bound thrombin can continue to trigger thrombus expansion. Inhibition of thrombin by dabigatran stops conversion Dabigatran Cyp3A4 Cyp3A4 Cyp2J2 of fibrinogen to fibrin, positive feedback amplification of coagulation activation, P-gp No crosslinking of fibrin monomers, platelet Cyp150 activation and inhibition of fibrinolysis. Half-life Half-life Half-life 11–13h 8–15h Dabigatran etexilate is rapidly absorbed 14–17h following oral administration and hydro~65% ~35% ~20% ~80% ~73% ~27% lyzed to active form by esterases in the stool urine stool urine stool urine gut, plasma and liver. High oral doses are required to achieve adequate plasma conFigure 3. Potential pharmacokinetic interaction sites for new anticoagulants. The bioavailability of an anticoagulant is affected by interaction with drugs modulating the activ- centrations, as absolute bioavailability of ity of P-glycoprotein (P-gp) listed in TABLE 3. Intestinal P-gp is involved in transport of all three dabigatran is only 6.5% (FIGURE 3) [58]. drugs and, for rivaroxaban, P-gp in the kidneys also is involved. Dabigatran etexilate underAnticoagulation effect achieved is proporgoes hydrolysis by esterases to active dabigatran. Cytochrome Cyp3A4 is mainly involved in tionate to plasma concentration and metabolism of rivaroxaban and, to a lesser extent, apixaban, with minimal impact on dabipeaks within 0.5–2 h of oral gatran. Drugs affecting Cyp3A4 (TABLE 4) can alter clearance of these agents. For dabigatran, administration (TABLE 2) [58–60]. In healthy renal excretion is the main route of elimination and therefore creatinine clearance becomes volunteers, steady-state concentrations are an important factor. The elimination half-life in the elderly is indicated. achieved 72 h after administration [58]. Patients with active liver disease were apixaban, regardless of renal functions, with the greatest relative excluded from the RE-LY trial [61] and its use in elderly with reduction in major bleeding seen in patients with impaired advanced hepatic impairment should be avoided. renal functions [54]. Transformation of dabigatran etexilate to dabigatran is completed in the liver and approximately one-fifth of the drug is conjugated with glucuronic acid and removed via the Dabigatran biliary system (FIGURE 3) [62]. The active form of the drug is not Pharmacodynamics & pharmacokinetic basics of dabigatran metabolized by cytochrome P450 enzymes, but it is a subDabigatran etexilate is a low-molecular-weight prodrug that strate of the P-gp efflux transporter (FIGURE 3). The mean dabiexhibits no pharmacological activity after oral administration gatran half-life in healthy volunteers following a single dose and requires conversion to the active form dabigatran, a com- is 8 h and increases to 12–14 h after multiple doses (TABLE 2) petitive and reversible direct thrombin inhibitor (FIGURE 2) [55–57]. [58–60,63]. In an older population, the half-life was slightly A
B
C
Table 3. Drugs effecting P-glycoprotein (not all-inclusive). P-glycoprotein substrates
P-glycoprotein modulators
Cardiovascular drugs Digoxin, dipyridamole, diltiazem, losartan, quinidine, tacrolimus, apixaban, rivaroxaban, dabigatran Psychotropic agents Tricyclic antidepressants, phenothiazines, paroxetine, resperidone Antineoplastic agents Actinomycin D, daunorubicin, doxorubicin, etoposide, mitomycin, paclitaxel, taxol, vinblastine, vincristine Other agents Cyclosporine, colchicine, steroids, aldosterone, dexamethasone, protease inhibitors, 99mTc-SESTAMIBI, rifampicin, St John’s wort
Inhibitors Amiloride, amiodarone, captopril, carvedilol, diltiazem, dipyridamole, doxazocin, dronedarone, felodipine, nifedipine, propranolol, propafenone, quinidine, ranolazine, spironalactone, verapamil, statins, azithromycin, cefoperazone, ceftriaxone, clarithromycin, conivaptan, cortisol, cyclosporine, erythromycin, haloperidol, itraconazole, ketoconazole, paroxetine, phenothiazines, ritonavir and lopinavir tacrolimus, tamoxifen, tricyclic antidepressants Inducers carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampin, St John’s wort, tipranavir/ritonavir
682
Expert Rev. Clin. Pharmacol. 6(6), (2013)
Novel anticoagulants in the elderly
Review
Table 4. Drugs affecting cytochrome P450 enzymes involved in anticoagulant metabolism (not all-inclusive). CYP enzymes (anticoagulant metabolized)
Strong inhibitors ‡fivefold " in AUC or >80% # in CL
CYP2C9 (warfarin)
Moderate inhibitors ‡2 but 80 years [67], the likelihood of bleeding complications is greater in the elderly. In patients with a CrCl of 683
Review
Strunets, Mirza, Sra & Jahangir
24 h, which increases the risk of bleeding [64,68]. The recommended dose for renal clearance for CrCl 15–30 ml/min is 75 mg twice daily and not defined for CrCl 200 ng/ml dabigatran plasma concentration or diluted thrombin time >65 s are associated with an increased risk of bleeding. For rivaroxaban and apixaban, a point-of-care-determined INR is unreliable for the evaluation of factor Xa inhibitory activity. Antifactor Xa ‘chromogenic assays’ that assess plasma concentrations of the factor Xa inhibitors are available, but data on bleeding risk or risk for thromboembolism are not available. Regular monitoring of renal function in elderly patients receiving novel anticoagulants, particularly dabigatran, or in any patient following an event or condition that may affect renal function, is recommended [69]. Renal function should be monitored every 6 months in the elderly and the dose adapted to respective changes in renal function. For dabigatran, a lower dose (75 mg twice daily) for patients with severe renal insufficiency (CrCl 15–30 ml/min) was approved by the FDA based on pharmacokinetic simulations; however, outcome data for the new anticoagulants in patients with CrCL 48 h after the procedure. On resumption, maximal anticoagulation effect is accomplished within 2–4 h of ingestion. Management of overdose or emergent reversal of anticoagulant effect
One of the main concerns and limitations of novel anticoagulants is the lack of readily available antidote or reliable method of reversing the effects of coagulation cascade blockade. The management of overdose of new anticoagulants or conditions that increase plasma levels (renal insufficiency, P-gp and CYP3A4 inhibitors) depends on whether active bleeding is present. Since the plasma half-life of these drugs is short (TABLE 2), a waitful watching approach can be considered in most nonbleeding cases, with restoration of normal hemostasis expected within 12–24 h after the last dose [70]. Administration of fresh frozen plasma that works for warfarin may not be effective because of the plasma abundance of the drug that can block newly administered coagulation factors. Ex vivo studies using a recombinant monoclonal antibody targeting dabigatran and reconstituted factor Xa are under way and may result in a method of rapid and specific reversal of anticoagulation effect in critically ill patients in need of emergency hemostasis [71,72].
Review
At this time, nonspecific procoagulants, such as prothrombin complex concentrate (PCC) and recombinant factor VIIa, are available for managements of major bleeding or rapid reversal in case of emergency invasive procedures or life-threatening bleeding [73]. The studies supporting the use of these nonspecific emergency agents to reverse the coagulation effect of novel anticoagulants are lacking and specific geriatric doses are not defined. The use of these agents is associated with significantly increased risk of spontaneous thromboembolic complications and, therefore, should be reserved for emergency situations [74,75]. In healthy volunteers exposed to therapeutic doses of rivaroxaban, PCC administration resulted in rapid normalization of coagulation parameters, whereas administration of PCC to patients medicated with dabigatran had no significant effect [76,77]. The experience with use of nonspecific prothrombotic agents to reverse the effects of novel anticoagulants is limited and strong prothrombotic side effects versus benefits must be carefully balanced [18]. Expert commentary
The use of anticoagulation to prevent stroke is an important issue in elderly patients with AF. Although there is general concern about increased risk of bleeding in the aged, anticoagulation for prevention of stroke is more effective in elderly patients >65 years than those 65 years with or without risk factors. Lowest adequate intensity of anticoagulation possible to minimize bleeding complications in the elderly must be balanced with its effectiveness in prevention of thromboembolic complications. Until recently, warfarin was the only available FDA-approved option for stroke prevention in patients with nonvalvular AF, and the emergence of new pharmaceutical agents is an important step forward in reducing inconvenience with frequent monitoring of anticoagulation and food–drug interactions with the use of VKA, thus improving patient quality of life and outcomes. Novel
Table 5. Timing of interruption before surgery or invasive procedure. Calculated creatinine clearance (ml/min)
Half-life (h; range)
Timing of last dose before surgery Standard risk of bleeding†
High risk of bleeding‡
Dabigatran >80
13 (11–22)
‡1 day
‡2 days
>50 to 80
15 (12–34)
‡36 h
‡3 days
>30 to 50
18 (13–23)
‡2 days
‡4 days
30
27 (22–35)
Not indicated
Not indicated
>30
12 (11–13)
‡1 day
‡2 days
15–30
Unknown
‡36 h
‡2 days
