Strike out stroke arh

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Strike out stroke arh

  1. 1. RYAN J PUNAMBOLAM MD FRCPC NEUROLOGY ARHCC ! May 21 2014 h AF, dabigatran 150 mg is taken twice daily od. A reduced dose of 75 mg is recommended reatinine clearance (CrCl) is 15 to 30 mL/ ated with the Cockcroft–Gault formula using ht (see Table 1). Clearance is primarily renal, substrate of permeability glycoprotein (P-gp). atran with P-gp inducers (such as rifampin) d. The combination of renal impairment and as a greater tendency to achieve undesirable hen compared with each factor separately.12–14,26 th moderate renal impairment (a CrCl of 30–50 hemodialysis can be considered for revers bleeding.27–30 Clinical Trials and Efficacy In the Randomized Evaluation of Long-Te Therapy trial (RE-LY), patients older than 6 AF received blinded doses of dabigatran 110 daily to establish non-inferiority versus unb ed warfarin. Study participants (n = 18,133 up to 2 years (Table 3).31–35 Two independen were blinded to treatment assignments confi
  2. 2. Disclosures • Speaker Fees from Bayer, Sanofi-Aventis, Allergan,Tribute Pharmaceuticals, Boehringer-Ingelheim
  3. 3. relative burden of stroke compared with heart disease contrib- utes to substantial societal costs since each stroke is associated with upward of 10 times the cost of myocardial infarction.16 Onthebasisofcurrentdemographicandpopulation-levelvascu- lar risk factor trends, current projections are for an unprecedented 50% increase in stroke incidence in China during the next 20 years.17 Although demographic changes do account for some of the Conclusions Stroke is the second leading cause of death worldwide. In the ongoing global epidemic of cardiovascular disease, stroke has emerged as a major cause of preventable death and morbidity, par- ticularly in the developing world where stroke is the predominant subtype of vascular disease. Demographic and vascular risk factor trends suggest that there will be an even greater burden of disease Figure 1. The Global Stroke-Belt. Relative mortality rate from stroke compared with ischemic heart disease, 2004 (based on WHO Global Burden of Disease data).15 S123 Burden of Stroke in the United States tinues to present a significant public health challenge ted States. Stroke is a leading cause of adult disabil- thnic and geographic disparities in stroke incidence mes have remained stubbornly persistent,2 and the er of deaths from stroke is projected to increase in g decades as the population ages.3 However, there is n for optimism. During the last 40 years, there has 0% decline in the age-adjusted mortality rate from he United States,4 and stroke has recently moved ior position as the third leading cause of death to e fourth leading cause of death overall.5 h there are multiple factors to help to explain this ovements in blood pressure control at the population kely to be playing a major role. During the last few ach successive national health survey has recorded ents in population systolic blood pressure and on control. For example, the median systolic blood mong aged 60 to 74 years in 1960–1962 was ≈150 subsequent surveys, the median systolic blood pres- onsistently declined and by the 1988–1991 National Nutrition Examination Survey III, the median sys- pressure had decreased to 130 mmHg.6 ments in blood pressure have been particularly pro- mong those with very high blood pressure, which isproportionately higher risk for stroke. For instance, ame period, the 90th percentile for systolic blood pres- sed from >190 mmHg to <160 mmHg.6 This pattern d hypertension control has also been demonstrated in -income countries, which have experienced a 42% stroke incidence overall during the past 40 years.7 Ongoing Global Epidemic of Stroke lobal prospective, the outlook for stroke is quite dis- conventional wisdom is that heart disease and stroke ly diseases of the developed world, although in point t of the burden of cardiovascular disease and stroke is ountries in the developing world.8,9 Stroke continues to nd leading cause of death worldwide (second only to ular disease) and accounts for ≈1 in 10 deaths or 5.7 ths a year.10 This mortality burden has come with a doubling of the stroke incidence in low- and middle- untries with incidence rates that commonly surpass the incidence rates seen in most high-income countries.7 So not only is the overall disease burden of stroke higher in the developing world but stroke also accounts for a greater relative proportion of total deaths in low- and middle-income countries as well. There is substantial variation in the distribution of stroke burden by geographic region and by country—the level that may be most relevant for policy and program development. These regional and national hot spots constitute a global stroke belt that parallels the well-documented geographic variations of stroke burden within the stroke belt of the southeastern United States.11 The burden of stroke is particularly high in Eastern Europe, North Asia, Central Africa, and the South Pacific with a 10-fold difference in stroke mortality and morbidity rates between the most affected and least affected countries.12 For example, Russia’s standardized stroke mortality rate is 251 per 100000 compared with a rate of 32 per 100000 in the United States.10 The pattern is quite similar for dis- ability adjusted life year loss rates—a measure of overall disease burden that takes into account both years of potential life lost from premature deaths and long-term disability from stroke.12 Once again, the reasons for this geographic variation in the burden of stroke globally are quite complex. However, national income has emerged as a particularly strong predictor of stroke burden.12 The association between lower national income per capita and higher burden of stroke persists even after adjustment for national measures of typical cardiovascular risk factors, such as physical inactivity, hypertension, diabetes mellitus, tobacco use, alcohol use, and dyslipidemia.12 The strong association of stroke with national income is consistent with an overall shift from communicable diseases to noncommunicable diseases, such as heart disease and stroke, with rising income in what has been termed the epidemiological transition.13 Infection, nutrition, and perinatal disease accounted for 34% of deaths in 1990 but are projected to account for just 15% of total deaths in 2020.14 In contrast, the proportion of deaths from cardiovascular diseases, including stroke, is projected to increase from 28% to 34% during that same period.14 A similar geographic pattern is also seen for the burden of ischemic heart disease worldwide which is not surprising given that these 2 forms of vascular disease have overlapping ath- erosclerotic disease mechanisms and have major modifiable risk factors in common. But although ischemic heart disease is the predominant form of vascular disease burden overall, stroke is the predominant form of vascular disease for many Temporal and Geographic Trends in the Global Stroke Epidemic Anthony S. Kim, MD, MAS; S. Claiborne Johnston, MD, PhD November 6, 2012; accepted April 4, 2013. Departments of Neurology (A.S.K., S.C.J.) and Epidemiology and Biostatistics (S.C.J.), University of California, San Francisco, CA. dence to Anthony S. Kim, MD, MAS, Department of Neurology, University of California, San Francisco, 675 Nelson Rising Lane, Room rancisco, CA 94158. E-mail akim@ucsf.edu 013;44[suppl 1]:S123-S125.) merican Heart Association, Inc. available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.111.000067 The Current State and Future of StrokeS124 Stroke June 2013 lower income countries.15 For example, ischemic heart disease mortality rates are slightly higher than stroke mortality rates in North America, Western and Northern Europe, and Australia.15 In contrast, stroke mortality rates are substantially higher than ischemic heart disease mortality rates in much of Africa and Asia (Figure 1). In South Korea and China, for example, 17% to 18% of all deaths are from stroke compared with just 6% to 8% for ischemic heart disease. This concentration of stroke burden in low-income countries and in Asia and Africa sug- gests that a targeted approach for addressing stroke in the developing world may be warranted.10 The Case of China In this global epidemic, the recent experience of China is deserving of special attention. Not only is China an outlier in terms of its substantial absolute stroke burden but also China is an outlier in terms of its high relative burden of stroke com- pared with ischemic heart disease.15 The sobering projections of stroke incidence for the coming decades provide a case study of the current challenges in addressing this epidemic. Stroke is the leading cause of death in China with an esti- mated 2.5 million incident strokes and 1.6 million deaths from stroke each year.16 As previously described, stroke is the pre- dominant form of vascular disease in China. The stroke mortal- ity rate far exceeds the ischemic heart disease mortality rate in a pattern that is shared by many low- and middle-income coun- tries.15 Hemorrhagic strokes also make up a larger proportion of incident strokes as well.17 In fact, the incidence of hemor- rhagic stroke alone exceeds the incidence of myocardial infarc- tion. This pattern of hemorrhage stroke subtypes and a higher relative burden of stroke compared with heart disease contrib- utes to substantial societal costs since each stroke is associated with upward of 10 times the cost of myocardial infarction.16 Onthebasisofcurrentdemographicandpopulation-levelvascu- lar risk factor trends, current projections are for an unprecedented 50% increase in stroke incidence in China during the next 20 years.17 Although demographic changes do account for some of the expected increases in coronary artery disease and stroke incidence, trends in virtually all the major vascular risk factors, including systolic blood pressure, cholesterol, diabetes mellitus, and smok- ing, are unfavorable and will account for a substantial proportion of the expected excess burden of stroke moving forward.17 Mean population body mass index has been increasing for decades; mean cholesterol, mean systolic blood pressure, and mean blood glucose have been steadily increasing since the early 1990s (Figure 2); and the prevalence of smoking has remained persistently high during the past 20 years.18 In contrast, the United States and Japan have seen steady improvements in population-level measures of choles- terol, systolic blood pressure, and smoking prevalence, although obesity and mean body mass index, as well as mean serum glucose continue to trend upward.18 Limitations As we move forward to meet these challenges, the limited avail- ability of high-quality epidemiological data on stroke and the challenge of integrating heterogeneous data sources will con- tinue to make an accurate transnational picture of the global stroke epidemic a challenging task. Country-level analyses do not take into account the joint distribution of risk factors in important subnational groupings (e.g., by region or by urban/ rural area) and may be subject to the ecological fallacy, whereby an inference made at the population level is falsely assumed to apply at the individual level. However, together as a whole, available data do provide a hint of the magnitude and scope of the challenge and will help to inform public health priorities and policy planning moving forward. Conclusions Stroke is the second leading cause of death worldwide. In the ongoing global epidemic of cardiovascular disease, stroke has emerged as a major cause of preventable death and morbidity, par- ticularly in the developing world where stroke is the predominant subtype of vascular disease. Demographic and vascular risk factor trends suggest that there will be an even greater burden of disease Figure 1. The Global Stroke-Belt. Relative mortality rate from stroke compared with ischemic heart disease, 2004 (based on WHO Global Burden of Disease data).15
  4. 4. Stroke Types and Incidence Ischemic stroke 85-88% Hemorrhagic stroke 12-15% Other
 5% Cryptogenic
 30% Cardiogenic
 embolism
 20% Small vessel disease “lacunes” 25% Atherosclerotic cerebrovascular disease 20% 5
  5. 5. Men and women without AF at 40 years of age were determined to have a 26% and 23% likelihood of developing incident AF by 80 years of age. The estimated US prevalence of atrial fibrillation (AF) in the year 2050 ranges from 5.6 million to as high as 15.9 mil- lion individuals.
  6. 6. Zone of Infarction Embolism “Hemorrhagic Conversion” Reperfusion Embolism breaks up, entering into one branch
  7. 7. 70% The Copenhagen stroke study, a prospective community-based study. n=1,197 **In hospital mortality: 72 deaths, n=217 with AF vs. 171 deaths n=968 without AF †Discharge to own home: n=104 with AF vs. 662 deaths n=968 without AF ‡Length of hospital stay: 50.4 days with AF vs. 39.8 days without AF Among patients who had a stroke, those with AF experienced a: increase in in-hospital mortality** 40% decrease in the relative chance of discharge to own home† 20% increase in the length of hospital stay‡ …compared to those without AF AF-Related Strokes Are More Severe than Strokes not Caused by AF 8
  8. 8. CARDIOEMBOLIC STROKES: CLINICAL FEATURES • Abrupt onset (vs. stuttering) • LOC • Aphasia without motor deficit • Concurrent embolism to other organs • Hemanopia without hemiparesis
  9. 9. irregular ! Investigations: EKG - AF Prior Echo - EF 55%, LAE INR 1.6 ! Medications: Ramipril 5 mg/d Coumadin 6 mg/d Metoprolol 25 mg BID 7 ! There is a history of AF for which he is anticoagulated and hypertension
  10. 10. Preadmission medications in patients with known atrial fibrillation who were admitted with acute ischemic stroke (high-risk cohort, n=597).
  11. 11. Warfarin Has a Narrow Therapeutic Window Relationship between clinical events and INR intensity! 1. Hylek EM et al. Ann Intern Med. 1994;120:897-902.! 2. Hylek EM et al. N Engl J Med. 1996;335:540-546.!
  12. 12. 25% 66% 9% 38% 44% 18% 0% 10% 20% 30% 40% 50% 60% 70% < 2.0 2.0 - 3.0 > 3.0 Clinical trial Clinical practice %ofeligiblepatientsreceivingwarfarin! International Normalised Ratio (INR)! 1 2 INR Control: 
 Clinical Trial vs Clinical Practice (TTR) 1.  Kalra L, et al. BMJ 2000;320:1236-1239 ." 2.  Matchar DB, et al. Am J Med 2002; 113:42-51"
  13. 13. • 1 point for Congestive Heart Failure • 1 point for Hypertension (treated or not) • 1 point for Age ≥ 75 years • 1 point for Diabetes Mellitus • 2 points for Prior Stroke or Transient Ischemic Attack (TIA) CHADS2 Score
 (Simple Prediction Tool for Assessing Stroke Risk) CHADS Stroke rate Stroke risk 0 1.9 (1.2 -3.0) Low 1 2.8 (2.0-3.8) Moderate 2 4.0 (3.1-5.1) High 3 5.9 (4.6-7.3) 4 8.5 (6.3 -11.1) 5 12.5 (8.2-17.5) 6 18.2 (10.5-17.4) 15
  14. 14. HAS-BLED Bleeding Score
 (Simple Tool for Assessing Bleeding Risk) Letter Clinical Characteristic* Points Awarded: Score H Hypertension 1 A Abnormal renal or liver function (1 point each) 1 or 2 S Stroke 1 B Bleeding 1 L Labile INRs 1 E Elderly 1 D Drugs or alcohol (1 point each) 1 or 2 *Hypertension - uncontrolled, >160 mm Hg systolic; Abnormal renal/liver function (one point for presence of renal or liver impairment, maximum two points); Stroke (previous history, particularly lacunar); Bleeding history or predisposition (anemia); Labile international normalized ratio (INR) (i.e. therapeutic time in range < 60%); Elderly ( >65 years); Drugs/alcohol concomitantly (antiplatelet agents, nonsteroidal anti-inflammatory drugs; one point for drugs plus one point for alcohol excess, maximum two points). 16 HAS-BLED is based on data from warfarin and applying a risk screening tool based on warfarin to the NOACs must be interpreted with caution.
  15. 15. •Bleeding risk should be assessed in all patients prior to prescribing anticoagulant therapy •Bleeding risk assessment tools, such as HAS-BLED* are available and are highly specific for patients with AF receiving warfarin therapy Bleeding Risk Assessment *In HAS-BLED, major bleeding was defined as fatal or clinically overt bleeding associated with either transfusion of ≥ 2 U of blood or ≥ 20 g/l decrease in hemoglobin or bleeding involving a critical anatomic site other than the brain parenchyma 18 • A high score indicates a higher risk of bleeding but should not preclude the use of an anticoagulant in patients at risk for stroke • The absolute risk of ischemic stroke exceeds that of bleeding when CHADS2 and HAS-BLED scores are equal • A high score often indicates risk factors for bleeding that can be modified, such as discontinuation of NSAIDs and control of hypertension
  16. 16. Bleeding Risk Management Address reversible risk factors: – Falling → provide mobility aid – Hypertension → treat blood pressure to target – Alcohol → encourage abstinence – Labile INR → use NOACs – Drugs → replace NSAIDs with other analgesics, avoid ASA unless clearly indicated for secondary prevention – GI bleeding → use proton pump inhibitors (PPI) Do not withhold anticoagulation unless bleeding risk extreme HIT Global Consulting Services Inc. 19
  17. 17. CCS 2012 Update to AF Guidelines 20 • Dabigatran and apixaban have greater efficacy and rivaroxaban has similar efficacy to warfarin for stroke prevention ! • Dabigatran and rivaroxaban are not more likely to cause major bleeding than warfarin and apixaban is associated with a lower bleeding risk! • All three NOACs have lower intracranial hemorrhage (ICH) rates than warfarin and are much simpler to use! • All the other guidelines (ESC, AHA, ACCF) agree with the CCS guidelines When oral anticoagulant therapy is indicated, most patients should receive dabigatran, rivaroxaban or apixaban rather than warfarin
  18. 18. the reduction of stroke/SSE (ischemic and hemorrhagic, and driven by hemorrhagic).6 Interestingly, all 3 NOACs were associated with less intracranial bleeding compared with warfarin irrespective of time spent in the therapeutic range (TTR) in the warfarin arm. However, more gastrointestinal (GI) bleeding was observed with dabigatran and rivaroxaban. Importance of Renal Function and NOAC Clearance The extent of renal excretion is an important distinguish- ing feature of NOACs. Up to 80% of circulating dabigatran is eliminated renally, whereas only 33% and 25% of unchanged rivaroxaban and apixaban is cleared by the kidney.7-9 After 150 mg administration, total dabigatran area under the concentration curve (AUC) was increased by 1.5-, 3.1-, and 6.3-fold in individuals with mild, moderate, and severe renal carboxylesterases in the enterocytes, portal circulation, and hepatocytes.7,13,15 Very recently, a genome-wide subanalysis of the RE-LY trial demonstrated that a single-nucleotide polymorphism (SNP) in the carboxyesterase 1 gene (CES1; rs2244613) attenuated dabigatran formation leading to lower trough concentrations and the ABCB1 SNP rs4148738 and CES1 SNP rs8192935 were associated with higher and lower peak dabigatran concentrations, respectively.16 Rivaroxaban’s bioavailability is dose-dependent; the absolute bioavailability of 10 mg rivaroxaban ranged from 80% to 100%, and bioavailability of 20 mg in fasting conditions was 66%.17 Coadministration of 15 or 20 mg rivaroxaban with food increased the AUC by 39%.18 The low bioavailability in fasting conditions might result in risk of inadequate anti- coagulation and thus, rivaroxaban should be administered with food. Apixaban’s absolute bioavailability is 50% and not 9 Figure 1. Summary of absorption, metabolism, and excretion of dabigatran, rivaroxaban, and apixaban. BCRP, breast cancer resistance protein; CYP, cytochrome P450; P-gp, P-glycoprotein. , 150 mg ower rates ar rate of ith similar warfarin.3 oral direct ban Once ared With Vitamin K Antagonist for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) trial (double-blin- ded, n ¼ 14,264), rivaroxaban was noninferior to warfarin and 20 mg rivaroxaban once daily (OD) resulted in similar rates of stroke/SSE and major bleeding.5 In the Apixaban for Reduction in Stroke and Other ThromboemboLic Events in Atrial Fibrillation (ARISTOTLE) trial (double-blinded; n ¼ 18, 201), 5 mg BID apixaban was superior to warfarin in farin, dabigatran, rivaroxaban and apixaban Dabigatran Rivaroxaban Apixaban Direct thrombin inhibitor (free or bound), reversible Factor Xa inhibitor (free or bound), reversible Factor Xa inhibitor (free or bound), reversible Fast Fast Fast Short Short Short Rapid, acid-dependent Rapid Rapid 6.5 80* 50 1.0-3.0 2.5-4.0 1.0-3.0 60-70 50-55 21 18,133), 150 mg ed with lower rates t a similar rate of ociated with similar ared with warfarin.3 d second oral direct Rivaroxaban Once n Compared With Vitamin K Antagonist for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) trial (double-blin- ded, n ¼ 14,264), rivaroxaban was noninferior to warfarin and 20 mg rivaroxaban once daily (OD) resulted in similar rates of stroke/SSE and major bleeding.5 In the Apixaban for Reduction in Stroke and Other ThromboemboLic Events in Atrial Fibrillation (ARISTOTLE) trial (double-blinded; n ¼ 18, 201), 5 mg BID apixaban was superior to warfarin in es of warfarin, dabigatran, rivaroxaban and apixaban Dabigatran Rivaroxaban Apixaban Direct thrombin inhibitor (free or bound), reversible Factor Xa inhibitor (free or bound), reversible Factor Xa inhibitor (free or bound), reversible on nthesis Fast Fast Fast Short Short Short Rapid, acid-dependent Rapid Rapid 6.5 80* 50 1.0-3.0 2.5-4.0 1.0-3.0 60-70 50-55 21 35 95 87 12-17 9-13 8-15 80 33 25 20 28 50-70 metabolisme (CYP3A4) et le transport (glycoproteine P) du medicament, nous pouvons être capables de mieux predire le risque de reponse au traitement anticoagulant sous-therapeutique et supra- therapeutique, et d’individualiser la selection et le dosage de l’ACO. Therapy (RE-LY) trial (open-label; n ¼ 18,133), 150 mg dabigatran twice daily (BID) was associated with lower rates of stroke/SSE, achieving superiority, but a similar rate of major bleeding and 110 mg BID was associated with similar rates of stroke/SSE but fewer bleeds compared with warfarin.3 Rivaroxaban and apixaban are the first and second oral direct FXa inhibitors approved for AF.4 In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonist for Prevention Trial in Atrial Fibrillation (ROCKE ded, n ¼ 14,264), rivaroxaban wa and 20 mg rivaroxaban once daily rates of stroke/SSE and major bleed Reduction in Stroke and Other T in Atrial Fibrillation (ARISTOTLE n ¼ 18, 201), 5 mg BID apixaban w Table 1. Comparison of pharmacokinetic features of warfarin, dabigatran, rivaroxaban and apixaban Parameter Warfarin Dabigatran Rivaroxaban Mechanism of action Inhibition of VKOR Direct thrombin inhibitor (free or bound), reversible Factor Xa inhibitor (free or bound), reversible Onset of action Slow, indirect inhibition of clotting factor synthesis Fast Fast Offset of action Long Short Short Absorption Rapid Rapid, acid-dependent Rapid Bioavailability (%) 100 6.5 80* tmax (h) 2.0-4.0 1.0-3.0 2.5-4.0 Vd (L) 10 60-70 50-55 Protein binding (%) 99 35 95 t1/2b (h) 40 12-17 9-13 Renal excretion None 80 33 Fecal excretion None 20 28 CL/F (L/h) 0.35 70-140 10 l’âge, le fonctionnement renal, l’interva metabolisme (CYP3A4) et le transp medicament, nous pouvons être capable de reponse au traitement anticoagulant therapeutique, et d’individualiser la selec n-label; n ¼ 18,133), 150 mg ) was associated with lower rates periority, but a similar rate of BID was associated with similar bleeds compared with warfarin.3 re the first and second oral direct AF.4 In the Rivaroxaban Once Xa Inhibition Compared With Vitamin K Antagonist for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) trial (double-blin- ded, n ¼ 14,264), rivaroxaban was noninferior to warfarin and 20 mg rivaroxaban once daily (OD) resulted in similar rates of stroke/SSE and major bleeding.5 In the Apixaban for Reduction in Stroke and Other ThromboemboLic Events in Atrial Fibrillation (ARISTOTLE) trial (double-blinded; n ¼ 18, 201), 5 mg BID apixaban was superior to warfarin in cokinetic features of warfarin, dabigatran, rivaroxaban and apixaban Warfarin Dabigatran Rivaroxaban Apixaban ition of VKOR Direct thrombin inhibitor (free or bound), reversible Factor Xa inhibitor (free or bound), reversible Factor Xa inhibitor (free or bound), reversible indirect inhibition clotting factor synthesis Fast Fast Fast Short Short Short d Rapid, acid-dependent Rapid Rapid 6.5 80* 50 .0 1.0-3.0 2.5-4.0 1.0-3.0 60-70 50-55 21 35 95 87 12-17 9-13 8-15 80 33 25 20 28 50-70 70-140 10 5 l’âge, le fonctionnement renal, l’intervalle posologique ainsi que le metabolisme (CYP3A4) et le transport (glycoproteine P) du medicament, nous pouvons être capables de mieux predire le risque de reponse au traitement anticoagulant sous-therapeutique et supra- therapeutique, et d’individualiser la selection et le dosage de l’ACO. of stroke/SSE, achieving superiority, but a similar rate of major bleeding and 110 mg BID was associated with similar rates of stroke/SSE but fewer bleeds compared with warfarin.3 Rivaroxaban and apixaban are the first and second oral direct FXa inhibitors approved for AF.4 In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With ded, n ¼ 14,264), ri and 20 mg rivaroxaba rates of stroke/SSE an Reduction in Stroke in Atrial Fibrillation n ¼ 18, 201), 5 mg B Table 1. Comparison of pharmacokinetic features of warfarin, dabigatran, rivaroxaban and apixaban Parameter Warfarin Dabigatran Rivarox Mechanism of action Inhibition of VKOR Direct thrombin inhibitor (free or bound), reversible Factor Xa inhibi (free or bound Onset of action Slow, indirect inhibition of clotting factor synthesis Fast Fast Offset of action Long Short Short Absorption Rapid Rapid, acid-dependent Rapid Bioavailability (%) 100 6.5 80* tmax (h) 2.0-4.0 1.0-3.0 2.5-4.0 Vd (L) 10 60-70 50-55 Protein binding (%) 99 35 95 t1/2b (h) 40 12-17 9-13 Renal excretion None 80 33 Fecal excretion None 20 28 CL/F (L/h) 0.35 70-140 10 Accumulation in plasma Dependent on CYP2C9 metabolic efficiency None None Food effect No effect on absorption; dietary vitamin K influence on PD Delayed absorption with food with no influence on bioavailability Delayed absorpt with increased ial (open-label; n ¼ 18,133), 150 mg y (BID) was associated with lower rates eving superiority, but a similar rate of 110 mg BID was associated with similar ut fewer bleeds compared with warfarin.3 xaban are the first and second oral direct oved for AF.4 In the Rivaroxaban Once Factor Xa Inhibition Compared With Vitamin K Antagonist for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) trial (double-blin- ded, n ¼ 14,264), rivaroxaban was noninferior to warfarin and 20 mg rivaroxaban once daily (OD) resulted in similar rates of stroke/SSE and major bleeding.5 In the Apixaban for Reduction in Stroke and Other ThromboemboLic Events in Atrial Fibrillation (ARISTOTLE) trial (double-blinded; n ¼ 18, 201), 5 mg BID apixaban was superior to warfarin in f pharmacokinetic features of warfarin, dabigatran, rivaroxaban and apixaban Warfarin Dabigatran Rivaroxaban Apixaban Inhibition of VKOR Direct thrombin inhibitor (free or bound), reversible Factor Xa inhibitor (free or bound), reversible Factor Xa inhibitor (free or bound), reversible Slow, indirect inhibition of clotting factor synthesis Fast Fast Fast Long Short Short Short Rapid Rapid, acid-dependent Rapid Rapid 100 6.5 80* 50 2.0-4.0 1.0-3.0 2.5-4.0 1.0-3.0 10 60-70 50-55 21 99 35 95 87 40 12-17 9-13 8-15 None 80 33 25 None 20 28 50-70 0.35 70-140 10 5 Dependent on CYP2C9 metabolic efficiency None None 1.3-1.9 No effect on absorption; dietary vitamin K influence on PD Delayed absorption with food with no influence on bioavailability Delayed absorption with food with increased bioavailability None Yes, lower CL/F as age increases Yes, lower CL/F as age increases None Yes, lower CL/F as age increases Yes, higher dose for increased weight None None Yes, higher exposure with low body weight ( 60 kg) Yes, lower CL/F in women Yes, lower CL/F in women None Yes, higher exposure in women Lower dose in Asian patients; higher dose in African-American patients None Lower dose in Japanese patients None None P-gp P-gp, BCRP P-gp, BCRP Dabigatran Rivaroxaban Apixaban Direct thrombin inhibitor (free or bound), reversible Factor Xa inhibitor (free or bound), reversible Factor Xa inhibitor (free or bound), reversible ion ynthesis Fast Fast Fast Short Short Short Rapid, acid-dependent Rapid Rapid 6.5 80* 50 1.0-3.0 2.5-4.0 1.0-3.0 60-70 50-55 21 35 95 87 12-17 9-13 8-15 80 33 25 20 28 50-70 70-140 10 5 C9 y None None 1.3-1.9 ion; Delayed absorption with food with no influence on bioavailability Delayed absorption with food with increased bioavailability None ge Yes, lower CL/F as age increases None Yes, lower CL/F as age increases None None Yes, higher exposure with low body weight ( 60 kg) women Yes, lower CL/F in women None Yes, higher exposure in women ose in patients None Lower dose in Japanese patients None P-gp P-gp, BCRP P-gp, BCRP A2 None CYP3A4/5, CYP2J2 (equal) CYP3A4/5, CYP2J2 (minor), CYP1A2 (minor) bolism Potent P-gp inhibitors; affecting absorption Potent CYP3A4 and P-gp inhibitors; affecting absorption, metabolism, and excretion Potent CYP3A4 and P-gp inhibitors; affecting absorption, metabolism, and excretion OD) 150, 110 mg BID 20, 15 mg OD 5, 2.5 mg BID TT Hemoclot ECT anti-FXa PT anti-FXa Table 1. Comparison of pharmacokinetic features of warfarin, dabigatran, rivaroxaban and apixaban Parameter Warfarin Dabigatran Rivaroxaban Mechanism of action Inhibition of VKOR Direct thrombin inhibitor (free or bound), reversible Factor Xa inhibitor (free or bound), reversible Fac ( Onset of action Slow, indirect inhibition of clotting factor synthesis Fast Fast Fas Offset of action Long Short Short Sho Absorption Rapid Rapid, acid-dependent Rapid Rap Bioavailability (%) 100 6.5 80* 50 tmax (h) 2.0-4.0 1.0-3.0 2.5-4.0 1.0 Vd (L) 10 60-70 50-55 21 Protein binding (%) 99 35 95 87 t1/2b (h) 40 12-17 9-13 8-1 Renal excretion None 80 33 25 Fecal excretion None 20 28 50- CL/F (L/h) 0.35 70-140 10 5 Accumulation in plasma Dependent on CYP2C9 metabolic efficiency None None 1.3 Food effect No effect on absorption; dietary vitamin K influence on PD Delayed absorption with food with no influence on bioavailability Delayed absorption with food with increased bioavailability No Age Yes, lower CL/F as age increases Yes, lower CL/F as age increases None Yes i Body weight Yes, higher dose for increased weight None None Yes b Sex Yes, lower CL/F in women Yes, lower CL/F in women None Yes Ethnicity Lower dose in Asian patients; higher dose in African-American patients None Lower dose in Japanese patients No Drug transporter None P-gp P-gp, BCRP P-g CYP-mediated metabolism CYP2C9, CYP3A4, CYP2C19, CYP1A2 None CYP3A4/5, CYP2J2 (equal) CY C Drug-drug interactions Many; affecting metabolism Potent P-gp inhibitors; affecting absorption Potent CYP3A4 and P-gp inhibitors; affecting absorption, metabolism, and excretion Pot i a a Dosing for AF Variable (0.5-16 mg OD) 150, 110 mg BID 20, 15 mg OD 5, Coagulation measurement INR TT Hemoclot ECT aPTT anti-FXa PT ant harmacokinetic features of warfarin, dabigatran, rivaroxaban and apixaban Warfarin Dabigatran Rivaroxaban Apixaban Inhibition of VKOR Direct thrombin inhibitor (free or bound), reversible Factor Xa inhibitor (free or bound), reversible Factor Xa inhibitor (free or bound), reversible Slow, indirect inhibition of clotting factor synthesis Fast Fast Fast Long Short Short Short Rapid Rapid, acid-dependent Rapid Rapid 100 6.5 80* 50 2.0-4.0 1.0-3.0 2.5-4.0 1.0-3.0 10 60-70 50-55 21 99 35 95 87 40 12-17 9-13 8-15 None 80 33 25 None 20 28 50-70 0.35 70-140 10 5 Dependent on CYP2C9 metabolic efficiency None None 1.3-1.9 No effect on absorption; dietary vitamin K influence on PD Delayed absorption with food with no influence on bioavailability Delayed absorption with food with increased bioavailability None Yes, lower CL/F as age increases Yes, lower CL/F as age increases None Yes, lower CL/F as age increases Yes, higher dose for increased weight None None Yes, higher exposure with low body weight ( 60 kg) Yes, lower CL/F in women Yes, lower CL/F in women None Yes, higher exposure in women Lower dose in Asian patients; higher dose in African-American patients None Lower dose in Japanese patients None None P-gp P-gp, BCRP P-gp, BCRP CYP2C9, CYP3A4, CYP2C19, CYP1A2 None CYP3A4/5, CYP2J2 (equal) CYP3A4/5, CYP2J2 (minor), CYP1A2 (minor) Many; affecting metabolism Potent P-gp inhibitors; affecting absorption Potent CYP3A4 and P-gp inhibitors; affecting absorption, metabolism, and excretion Potent CYP3A4 and P-gp inhibitors; affecting absorption, metabolism, and excretion Variable (0.5-16 mg OD) 150, 110 mg BID 20, 15 mg OD 5, 2.5 mg BID INR TT Hemoclot ECT aPTT anti-FXa PT anti-FXa Review Importance of Pharmacokinetic Profile and Variability as Determinants of Dose and Response to Dabigatran, Rivaroxaban, and Apixaban Inna Y. Gong, BMSc,a,b and Richard B. Kim, MDa,b a Division of Clinical Pharmacology, Department of Medicine, University of Western Ontario, London, Ontario, Canada b Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada ABSTRACT Warfarin has been the mainstay oral anticoagulant (OAC) medication prescribed for stroke prevention in atrial fibrillation (AF) patients. However, warfarin therapy is challenging because of marked interin- dividual variability in dose and response, requiring frequent monitoring and dose titration. These limitations have prompted the clinical development of new OACs (NOACs) that directly target the coagulation cascade with rapid onset/offset of action, lower risk for drug-drug interactions, and more predictable response. Recently, NOACs dabi- gatran (direct thrombin inhibitor), and rivaroxaban and apixaban (factor Xa [FXa] inhibitors) have gained regulatory approval as alter- native therapies to warfarin. Though the anticoagulation efficacy of these NOACs has been characterized, differences in their pharmaco- kinetic and pharmacodynamic profiles have become a significant consideration in terms of drug selection and dosing. In this review, we outline key pharmacokinetic and pharmacodynamic features of each compound and provide guidance on selection and dosing of the 3 NOACs relative to warfarin when considering OAC therapy for AF patients. Importantly, we show that by better understanding the effect RESUME La warfarine a ete le pilier des anticoagulants oraux (ACO) prescrit pour la prevention de l’accident vasculaire cerebral chez les patients ayant une fibrillation auriculaire (FA). Cependant, le traitement par la war- farine est difficile en raison de la variabilite interindividuelle marquee de la dose et de la reponse, ce qui rend necessaire une surveillance frequente et un reglage posologique. Ces limites ont suscite le developpement clinique de nouveaux ACO (NACO) qui ciblent directe- ment la cascade de coagulation par un delai d’action rapide et une duree d’action, un plus faible risque d’interactions medicamenteuses et une reponse plus previsible. Recemment, les NACO dont le dabi- gatran (inhibiteur direct de la thrombine), le rivaroxaban et l’apixaban (inhibiteurs du facteur Xa) ont obtenu l’homologation à titre de solution de rechange au traitement par la warfarine. Tandis que l’efficacite de l’anticoagulation de ces NACO a ete etablie, les differences dans leurs profils pharmacocinetiques et pharmacodynamiques sont devenues une preoccupation importante en ce qui a trait à la selection du medicament et du dosage. Dans cette revue, nous exposons les grandes lignes des principales caracteristiques pharmacocinetiques et Atrial fibrillation (AF) is associated with a 5-fold increase in risk of disabling stroke.1 Therefore, antithrombotic therapy is required for stroke and systemic embolism (SSE) prophy- laxis. Until recently, the vitamin K antagonist warfarin was the primary choice for long-term oral anticoagulant (OAC) treatment because stroke risk is reduced by 60% in non- valvular AF patients.1 However, warfarin has a number of limitations including delayed onset of action, large interindi- vidual variability in response, unpredictable pharmacokinetic characteristics (PK), drug-drug interactions, and polymor- phisms in genes affecting metabolism and pharmacodynamic (PD) characteristics. Intensive monitoring using international normalized ratio (INR) and frequent dose adjustments are necessary to provide adequate anticoagulation within warfa- rin’s narrow therapeutic window. Significant effort has been made to develop new OACs (NOACs) with direct mechanisms of action with a sufficiently wide therapeutic window to allow for fixed-dose administra- tion without the need for routine response monitoring. NOACs directly inhibit the coagulation pathway, either FXa or thrombin, for rapid onset of antithrombotic effects. The PK and pharmacology of these NOACs are distinct from that of warfarin (Table 1, Fig. 1). In the present review, we will highlight the PK and PD features of the 3 NOACs that have recently been approved for stroke prevention in AF patients and provide NOAC selection and dosing recommendations based on their PK-PD profiles. Clinical Outcomes Data Comparing NOACs With Warfarin Dabigatran etexilate is the first oral direct thrombin inhibitor to be approved for its clinical use in AF patients.2 In the Randomized Evaluation of Long-term Anticoagulation Received for publication February 3, 2013. Accepted April 4, 2013. Corresponding author: Dr Richard B. Kim, University Hospital, 339 Windermere Rd BBL-115, London, Ontario N6A 5A5, Canada. Tel.: þ1-519-663-3553; fax: þ1-519-663-3232. E-mail: Richard.Kim@lhsc.on.ca See page S32 for disclosure information. 0828-282X/$ - see front matter Ó 2013 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cjca.2013.04.002 Canadian Journal of Cardiology 29 (2013) S24eS33 Review Importance of Pharmacokinetic Profile and Variability as Determinants of Dose and Response to Dabigatran, Rivaroxaban, and Apixaban Inna Y. Gong, BMSc,a,b and Richard B. Kim, MDa,b a Division of Clinical Pharmacology, Department of Medicine, University of Western Ontario, London, Ontario, Canada b Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada ABSTRACT Warfarin has been the mainstay oral anticoagulant (OAC) medication prescribed for stroke prevention in atrial fibrillation (AF) patients. However, warfarin therapy is challenging because of marked interin- dividual variability in dose and response, requiring frequent monitoring and dose titration. These limitations have prompted the clinical development of new OACs (NOACs) that directly target the coagulation cascade with rapid onset/offset of action, lower risk for drug-drug interactions, and more predictable response. Recently, NOACs dabi- gatran (direct thrombin inhibitor), and rivaroxaban and apixaban (factor Xa [FXa] inhibitors) have gained regulatory approval as alter- native therapies to warfarin. Though the anticoagulation efficacy of these NOACs has been characterized, differences in their pharmaco- kinetic and pharmacodynamic profiles have become a significant consideration in terms of drug selection and dosing. In this review, we outline key pharmacokinetic and pharmacodynamic features of each compound and provide guidance on selection and dosing of the 3 NOACs relative to warfarin when considering OAC therapy for AF patients. Importantly, we show that by better understanding the effect RESUME La warfarine a ete le pilier des anticoagulants oraux (ACO) prescrit pour la prevention de l’accident vasculaire cerebral chez les patients ayant une fibrillation auriculaire (FA). Cependant, le traitement par la war- farine est difficile en raison de la variabilite interindividuelle marquee de la dose et de la reponse, ce qui rend necessaire une surveillance frequente et un reglage posologique. Ces limites ont suscite le developpement clinique de nouveaux ACO (NACO) qui ciblent directe- ment la cascade de coagulation par un delai d’action rapide et une duree d’action, un plus faible risque d’interactions medicamenteuses et une reponse plus previsible. Recemment, les NACO dont le dabi- gatran (inhibiteur direct de la thrombine), le rivaroxaban et l’apixaban (inhibiteurs du facteur Xa) ont obtenu l’homologation à titre de solution de rechange au traitement par la warfarine. Tandis que l’efficacite de l’anticoagulation de ces NACO a ete etablie, les differences dans leurs profils pharmacocinetiques et pharmacodynamiques sont devenues une preoccupation importante en ce qui a trait à la selection du medicament et du dosage. Dans cette revue, nous exposons les grandes lignes des principales caracteristiques pharmacocinetiques et Atrial fibrillation (AF) is associated with a 5-fold increase in risk of disabling stroke.1 Therefore, antithrombotic therapy is required for stroke and systemic embolism (SSE) prophy- laxis. Until recently, the vitamin K antagonist warfarin was the primary choice for long-term oral anticoagulant (OAC) treatment because stroke risk is reduced by 60% in non- valvular AF patients.1 However, warfarin has a number of limitations including delayed onset of action, large interindi- vidual variability in response, unpredictable pharmacokinetic characteristics (PK), drug-drug interactions, and polymor- phisms in genes affecting metabolism and pharmacodynamic (PD) characteristics. Intensive monitoring using international normalized ratio (INR) and frequent dose adjustments are necessary to provide adequate anticoagulation within warfa- rin’s narrow therapeutic window. Significant effort has been made to develop new OACs (NOACs) with direct mechanisms of action with a sufficiently wide therapeutic window to allow for fixed-dose administra- tion without the need for routine response monitoring. NOACs directly inhibit the coagulation pathway, either FXa or thrombin, for rapid onset of antithrombotic effects. The PK and pharmacology of these NOACs are distinct from that of warfarin (Table 1, Fig. 1). In the present review, we will highlight the PK and PD features of the 3 NOACs that have recently been approved for stroke prevention in AF patients and provide NOAC selection and dosing recommendations based on their PK-PD profiles. Clinical Outcomes Data Comparing NOACs With Warfarin Dabigatran etexilate is the first oral direct thrombin inhibitor to be approved for its clinical use in AF patients.2 In the Randomized Evaluation of Long-term Anticoagulation Received for publication February 3, 2013. Accepted April 4, 2013. Corresponding author: Dr Richard B. Kim, University Hospital, 339 Windermere Rd BBL-115, London, Ontario N6A 5A5, Canada. Tel.: þ1-519-663-3553; fax: þ1-519-663-3232. E-mail: Richard.Kim@lhsc.on.ca See page S32 for disclosure information. 0828-282X/$ - see front matter Ó 2013 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved. Canadian Journal of Cardiology 29 (2013) S24eS33
  19. 19. CCS 2012 Update to AF Guidelines: Renal Function GFR Warfarin Dabigatran Rivoraxaban Apixaban GFR 50 mL/min Dose adjusted for INR 2.0-3.0 150 mg BID or 
 110 mg BID 20 mg daily 5 mg BID GFR 30-49 mL/min Dose adjusted for INR 2.0-3.0 150 mg BID or 
 110 mg BID 15 mg daily 5 mg BID (for GFR 25 ml/min only) Consider 2.5 mg BID GFR 30 mL/min No RCT data Contraindicated No RCT data No RCT data †Consider Apixaban 2.5 mg po bid if GFR ≤ 25 mL/min, especially if age 80 or body weight 60 kg ‡Dose adjusted warfarin has been used, but observational data regarding safety and efficacy is conflicting ¶No published studies support a dose for this level of renal function; product monographs suggest the drug is not recommended for this level of renal function 22 The patient’s eGFR should be regularly reassessed in order to ensure that changes in the NOAC drug or dose correspond to changes in the eGFR.
  20. 20. NOACs: Possible Drug Interactions DABIGATRAN RIVAROXABAN APIXABAN P-gp inhibitors (e.g., ketoconazole, verapamil, quinidine, amiodarone) Potent CYP3A4 and P-gp inhibitors (e.g., ketoconazole, itraconazole, voriconazole, posaconazole, ritonavir) Potent CYP3A4 and P-gp inhibitors (e.g., ketoconazole, itraconazole, voriconazole, posaconazole, ritonavir) P-gp inducers (e.g., carbamazepine, St. John’s Wort) Potent CYP3A4 and P-gp inducers (e.g., rifampicin, and the anticonvulsants phenytoin, carbamazapine, phenobarbitone) Potent CYP3A4 and P-gp inducers (e.g., rifampicin, and the anticonvulsants phenytoin, carbamazapine, phenobarbitone) *P-gp inhibitors may be expected to decrease systemic exposure to dabigatran, rivoraxaban and apixaban †P-gp inducers reduce plasma concentrations of dabigatran, rivaroxaban and apixaban ‡Combined potent CYP3A4 and P-gp inhibitors is expected to increase exposure to rivoraxaban and apixaban ‡‡Combined potent CYP3A4 and P-gp inducers is expected to reduce plasma concentrations of rivaroxaban and apixaban 23
  21. 21. between apixaban plasma concentrations and anti-FXa activity was confirmed in elective hip/knee replacement patients.12 It is important to keep in mind that the sensitivity and precision of different reagents and instruments used for these coagulation assays is yet to be established. Further validation of these coagulation assays in measuring NOAC anticoagulation response is required in the real-world clinical setting. Moreover, is it evident that variability in NOAC plasma exposure will have a significant effect on anti- coagulation efficacy considering the direct PK-PD relationship and its association with clinical outcomes; thus, quantifying NOAC plasma concentration is likely the most reliable assessment of response and bleeding risk. Selecting the Right OAC Although the NOACs have shown efficacy similar or greater than warfarin, it is unlikely that they will fully replace warfarin. The interindividual variability in exposure/response of NOACs and bleeding risk associated with anticoagulation therapy remains a pertinent issue. Indeed, even in a clinical trial setting with stringent enrollment criteria, the 1-dose-fits- all dosing regimen strategy did not appear successful for NOACs, likely due to the various clinical covariates that significantly affected extent of drug exposure and response (Fig. 2).41,44-47 Moreover, dabigatran and rivaroxaban use outside of the clinical trial setting has recently been noted to exhibit large interindividual variability in concentration and response.47,48 The same trend is likely to be observed with apixaban as its clinical use increases. Nevertheless, the emergence of multiple NOACs has meant greater therapeutic options for treating physicians. However, we are now starting to face the question of how to select the most appropriate NOAC for individual patients. Factors to be assessed for deciding the right anticoagulant include patient bleeding risk (Hypertension, Abnormal Renal/ Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly [ 65 Years], Drugs/Alcohol Concomi- tantly [HAS-BLED]) and benefit (Congestive Heart Failure, Figure 2. Plasma concentration profiles of dabigatran, rivaroxaban, and apixaban in atrial fibrillation patients. (A) Mean steady-state dabigatran plasma concentrations after 150 mg twice-daily adminis- With Vitamin K Antagonist for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) trial and the dashed line represents the average Ctrough. (C) Predicted mean steady-state apixaban plasma concentrations after 5 mg twice-daily administration is represented by the dashed black line (digitized from Leil et al.).46 Coloured solid lines represent the predicted effect of various clinical variables on apixaban S28 Canadian Journal of Cardiology Volume 29 2013 e r a m H s F i L L t Figure 2. Plasma concentration profiles of dabigatran, rivaroxaban, and apixaban in atrial fibrillation patients. (A) Mean steady-state dabigatran plasma concentrations after 150 mg twice-daily adminis- tration is represented by the dashed black line (digitized from Dan- sirikul et al.).43 Coloured solid lines represent the predicted effect of various clinical variables and a genetic variation in the carboxylester- ase 1 (CES1) gene on dabigatran concentration based on known area under the concentration curve (AUC) change.44 The shaded area represents Ctrough dabigatran concentrations associated with increased antithrombotic efficacy and decreased major bleeding risk according to population pharmacokinetics modelling of the Random- ized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial data. (B) Mean steady-state rivaroxaban plasma concentrations following 20 mg once daily administration is represented by the dashed black line (digitized from Mueck et al.).45 Coloured solid lines represent the predicted effect of various clinical variables on rivaroxaban concen- tration based on known AUC change.45 Although the optimal plasma Ctrough of rivaroxaban has not been well defined as of yet, the shaded area represents the 5%-95% confidence interval of Ctrough observed in W i t c t r c r c e s e c C p C c m D c h c Review Importance of Pharmacokinetic Profile and Variability as Determinants of Dose and Response to Dabigatran, Rivaroxaban, and Apixaban Inna Y. Gong, BMSc,a,b and Richard B. Kim, MDa,b a Division of Clinical Pharmacology, Department of Medicine, University of Western Ontario, London, Ontario, Canada b Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada ABSTRACT Warfarin has been the mainstay oral anticoagulant (OAC) medication prescribed for stroke prevention in atrial fibrillation (AF) patients. However, warfarin therapy is challenging because of marked interin- dividual variability in dose and response, requiring frequent monitoring and dose titration. These limitations have prompted the clinical development of new OACs (NOACs) that directly target the coagulation cascade with rapid onset/offset of action, lower risk for drug-drug interactions, and more predictable response. Recently, NOACs dabi- gatran (direct thrombin inhibitor), and rivaroxaban and apixaban (factor Xa [FXa] inhibitors) have gained regulatory approval as alter- native therapies to warfarin. Though the anticoagulation efficacy of these NOACs has been characterized, differences in their pharmaco- kinetic and pharmacodynamic profiles have become a significant consideration in terms of drug selection and dosing. In this review, we outline key pharmacokinetic and pharmacodynamic features of each compound and provide guidance on selection and dosing of the 3 NOACs relative to warfarin when considering OAC therapy for AF patients. Importantly, we show that by better understanding the effect RESUME La warfarine a ete le pilier des anticoagulants oraux (ACO) prescrit pour la prevention de l’accident vasculaire cerebral chez les patients ayant une fibrillation auriculaire (FA). Cependant, le traitement par la war- farine est difficile en raison de la variabilite interindividuelle marquee de la dose et de la reponse, ce qui rend necessaire une surveillance frequente et un reglage posologique. Ces limites ont suscite le developpement clinique de nouveaux ACO (NACO) qui ciblent directe- ment la cascade de coagulation par un delai d’action rapide et une duree d’action, un plus faible risque d’interactions medicamenteuses et une reponse plus previsible. Recemment, les NACO dont le dabi- gatran (inhibiteur direct de la thrombine), le rivaroxaban et l’apixaban (inhibiteurs du facteur Xa) ont obtenu l’homologation à titre de solution de rechange au traitement par la warfarine. Tandis que l’efficacite de l’anticoagulation de ces NACO a ete etablie, les differences dans leurs profils pharmacocinetiques et pharmacodynamiques sont devenues une preoccupation importante en ce qui a trait à la selection du medicament et du dosage. Dans cette revue, nous exposons les grandes lignes des principales caracteristiques pharmacocinetiques et Atrial fibrillation (AF) is associated with a 5-fold increase in risk of disabling stroke.1 Therefore, antithrombotic therapy is required for stroke and systemic embolism (SSE) prophy- laxis. Until recently, the vitamin K antagonist warfarin was the primary choice for long-term oral anticoagulant (OAC) treatment because stroke risk is reduced by 60% in non- valvular AF patients.1 However, warfarin has a number of limitations including delayed onset of action, large interindi- vidual variability in response, unpredictable pharmacokinetic characteristics (PK), drug-drug interactions, and polymor- phisms in genes affecting metabolism and pharmacodynamic (PD) characteristics. Intensive monitoring using international normalized ratio (INR) and frequent dose adjustments are necessary to provide adequate anticoagulation within warfa- rin’s narrow therapeutic window. Significant effort has been made to develop new OACs (NOACs) with direct mechanisms of action with a sufficiently wide therapeutic window to allow for fixed-dose administra- tion without the need for routine response monitoring. NOACs directly inhibit the coagulation pathway, either FXa or thrombin, for rapid onset of antithrombotic effects. The PK and pharmacology of these NOACs are distinct from that of warfarin (Table 1, Fig. 1). In the present review, we will highlight the PK and PD features of the 3 NOACs that have recently been approved for stroke prevention in AF patients and provide NOAC selection and dosing recommendations based on their PK-PD profiles. Clinical Outcomes Data Comparing NOACs With Warfarin Dabigatran etexilate is the first oral direct thrombin inhibitor to be approved for its clinical use in AF patients.2 In the Randomized Evaluation of Long-term Anticoagulation Received for publication February 3, 2013. Accepted April 4, 2013. Corresponding author: Dr Richard B. Kim, University Hospital, 339 Windermere Rd BBL-115, London, Ontario N6A 5A5, Canada. Tel.: þ1-519-663-3553; fax: þ1-519-663-3232. E-mail: Richard.Kim@lhsc.on.ca See page S32 for disclosure information. 0828-282X/$ - see front matter Ó 2013 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cjca.2013.04.002 Canadian Journal of Cardiology 29 (2013) S24eS33 Review Importance of Pharmacokinetic Profile and Variability as Determinants of Dose and Response to Dabigatran, Rivaroxaban, and Apixaban Inna Y. Gong, BMSc,a,b and Richard B. Kim, MDa,b a Division of Clinical Pharmacology, Department of Medicine, University of Western Ontario, London, Ontario, Canada b Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada ABSTRACT Warfarin has been the mainstay oral anticoagulant (OAC) medication prescribed for stroke prevention in atrial fibrillation (AF) patients. However, warfarin therapy is challenging because of marked interin- dividual variability in dose and response, requiring frequent monitoring and dose titration. These limitations have prompted the clinical development of new OACs (NOACs) that directly target the coagulation cascade with rapid onset/offset of action, lower risk for drug-drug interactions, and more predictable response. Recently, NOACs dabi- gatran (direct thrombin inhibitor), and rivaroxaban and apixaban (factor Xa [FXa] inhibitors) have gained regulatory approval as alter- native therapies to warfarin. Though the anticoagulation efficacy of these NOACs has been characterized, differences in their pharmaco- kinetic and pharmacodynamic profiles have become a significant consideration in terms of drug selection and dosing. In this review, we outline key pharmacokinetic and pharmacodynamic features of each compound and provide guidance on selection and dosing of the 3 NOACs relative to warfarin when considering OAC therapy for AF patients. Importantly, we show that by better understanding the effect RESUME La warfarine a ete le pilier des anticoagulants oraux (ACO) prescrit pour la prevention de l’accident vasculaire cerebral chez les patients ayant une fibrillation auriculaire (FA). Cependant, le traitement par la war- farine est difficile en raison de la variabilite interindividuelle marquee de la dose et de la reponse, ce qui rend necessaire une surveillance frequente et un reglage posologique. Ces limites ont suscite le developpement clinique de nouveaux ACO (NACO) qui ciblent directe- ment la cascade de coagulation par un delai d’action rapide et une duree d’action, un plus faible risque d’interactions medicamenteuses et une reponse plus previsible. Recemment, les NACO dont le dabi- gatran (inhibiteur direct de la thrombine), le rivaroxaban et l’apixaban (inhibiteurs du facteur Xa) ont obtenu l’homologation à titre de solution de rechange au traitement par la warfarine. Tandis que l’efficacite de l’anticoagulation de ces NACO a ete etablie, les differences dans leurs profils pharmacocinetiques et pharmacodynamiques sont devenues une preoccupation importante en ce qui a trait à la selection du medicament et du dosage. Dans cette revue, nous exposons les grandes lignes des principales caracteristiques pharmacocinetiques et Atrial fibrillation (AF) is associated with a 5-fold increase in risk of disabling stroke.1 Therefore, antithrombotic therapy is required for stroke and systemic embolism (SSE) prophy- laxis. Until recently, the vitamin K antagonist warfarin was the primary choice for long-term oral anticoagulant (OAC) treatment because stroke risk is reduced by 60% in non- valvular AF patients.1 However, warfarin has a number of limitations including delayed onset of action, large interindi- vidual variability in response, unpredictable pharmacokinetic characteristics (PK), drug-drug interactions, and polymor- phisms in genes affecting metabolism and pharmacodynamic (PD) characteristics. Intensive monitoring using international normalized ratio (INR) and frequent dose adjustments are necessary to provide adequate anticoagulation within warfa- rin’s narrow therapeutic window. Significant effort has been made to develop new OACs (NOACs) with direct mechanisms of action with a sufficiently wide therapeutic window to allow for fixed-dose administra- tion without the need for routine response monitoring. NOACs directly inhibit the coagulation pathway, either FXa or thrombin, for rapid onset of antithrombotic effects. The PK and pharmacology of these NOACs are distinct from that of warfarin (Table 1, Fig. 1). In the present review, we will highlight the PK and PD features of the 3 NOACs that have recently been approved for stroke prevention in AF patients and provide NOAC selection and dosing recommendations based on their PK-PD profiles. Clinical Outcomes Data Comparing NOACs With Warfarin Dabigatran etexilate is the first oral direct thrombin inhibitor to be approved for its clinical use in AF patients.2 In the Randomized Evaluation of Long-term Anticoagulation Received for publication February 3, 2013. Accepted April 4, 2013. Corresponding author: Dr Richard B. Kim, University Hospital, 339 Windermere Rd BBL-115, London, Ontario N6A 5A5, Canada. Tel.: þ1-519-663-3553; fax: þ1-519-663-3232. E-mail: Richard.Kim@lhsc.on.ca See page S32 for disclosure information. 0828-282X/$ - see front matter Ó 2013 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved. Canadian Journal of Cardiology 29 (2013) S24eS33
  22. 22. 56 PT® bleeding or invasive surgery should be minimized when pos- sible.14 Dabigatran should be withheld for 1 to 2 days before an invasive procedure in patients with normal renal function and for 3 to 5 days in patients if the CrCl is 50 mL/minute or below.14 TCT and aPTT can be used to determine the residual anticoagulation activity of dabigatran before the procedure.17,27 There is no known reversal agent for dabigatran. Symptomatic management is the primary approach for bleeding because of dabigatran’s relatively short half-life. Recombinant factor VIIa (rFVIIa), prothrombin complex concentrates (PCCs), or 95% CI, 1.19–1.89; P 0.05). Outcomes in the RE-LY trial are summarized in Table 4.32–35 The percentage of time in the therapeutic INR range (TTR) of 2 to 3 in patients receiving warfarin was approximately 64%, which is similar to the 66.4% TTR reported in a meta- regression analysis of warfarin trials published in 2006 and 2010.36,37 Available INR home-monitoring systems may produce higher rates of TTR than conventional INR monitoring in ambu- latory settings.35 An indirect comparison of home monitoring of vitamin K antagonist (VKA) treatment with dabigatran found no ( Study design Randomized, open-label Randomized, double-blind Randomized, double-blind Follow-up period, median 2 years 1.9 years 1.8 years Age, mean 71.5 years 73 years* 70 years Male sex 63.6% 61.3% 64.5% CHADS2 score, mean ± SD32–35 2.1 ± 1.1 3.48 ± 0.94 2.1 ± 1.1 Prior stroke (%) 20.3 54.9 19.2 Prior vitamin K antagonist therapy (%) 50.2 62.3 57.1 Mean TTR (%) 64 55 62 *Median. TTR = time in therapeutic range (for warfarin therapy). Data from Connelly et al.,31–33 Granger et al.,34 and Patel et al.35 PT_1401_Shafeeq_7fin.indd 56 12/27/13 4:23 PT® RACT fibrillation (AF) is the most common cardiac arrhyth- he U.S. Anticoagulation is recommended for stroke on in AF patients with intermediate-to-high stroke risk ients with a CHADS2 score of 1 or greater). Warfarin viously the only option for oral anticoagulation in these but three new oral anticoagulants have become avail- alternatives for warfarin in patients with nonvalvular advantages of the newer agents include a rapid onset, ble pharmacokinetics, and no need for routine anti- ion monitoring. atran (Pradaxa) and apixaban (Eliquis) have dem- ed improved efficacy compared with warfarin. aban (Xarelto) was non-inferior to warfarin for stroke on in AF. Apixaban demonstrated a reduced incidence bleeding compared with warfarin and a reduction in mortality. ations to the use of the new oral anticoagulants include of a reversal agent; an inability to use the therapies in patient populations (such as those with severe renal or mpairment); limited experience with drug–drug and sease interactions; and a lack of available coagulation quantify their effects. Although the newer agents have cquisition costs, the benefits of cost savings may be from the potential for decreasing the incidence of hagic stroke and intracranial bleeding and reducing the anticoagulation monitoring. Benefits and risks should ully weighed before these agents are prescribed for presenting with new-onset AF. fibrillation (AF) is the most common cardiac arrhyth- .S.1 The incidence and prevalence of AF increase with he number of people affected by AF is projected to 12 million by 2050.3 The lifetime risk of AF in patients of age and older is estimated at 25%.3,4 Stroke is a major ation associated with AF, which contributes to the mor- d mortality associated with the disease. Patients with a four-fold to five-fold increased risk of stroke. This es among patient populations, according to age, sex, presence of comorbid disease states (e.g., diabetes, nsion, congestive heart failure, and vascular disease).3,5,6 oagulation is recommended for stroke prevention mediate-risk and high-risk patients (i.e., those with a CHADS2 score of 1 or higher (Congestive Heart failure, Age over 75, Diabetes, and Stroke).5,7–11 The presence of additional risk factors (female sex, age 65–74 years, and vascular dis- ease) should be considered when health care professionals are determining whether patients in the intermediate-risk category should receive anticoagulation.7–11 Previously, warfarin was the only option for oral anticoagulation in these patients. Currently, three oral anticoagulants are approved by the FDA as alternatives to warfarin in patients with AF. Dabigatran (Pradaxa, Boehringer Ingelheim) was the first new oral anti- coagulant approved for stroke prevention in AF, followed by the oral anti–factor Xa inhibitors rivaroxaban (Xarelto, Janssen) and apixaban (Eliquis, Bristol-Myers Squibb/Pfizer). Rivaroxaban is also approved for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), along with prevention of DVT/ PE in patients undergoing knee or hip replacement surgeries.12 Apixaban, the newest anti-Xa inhibitor, was approved for stroke prevention in December 2012.13 None of the new agents are approved for use in patients with AF secondary to valvular heart disease or mechanical heart valves. The labeling for anti-Xa inhibitors does not in- clude any specific wording regarding their use in patients with bioprosthetic heart valves; however, dabigatran is specifically contraindicated in patients with mechanical bioprosthetic heart valves.14 Results were published for a phase 2 dose–validation study comparing dabigatran with warfarin in 252 patients with mechanical heart values. The study was prematurely termi- nated because of an increased incidence of thromboembolic and bleeding events with dabigatran.15 A summary of FDA-approved indications and doses of these oral agents is provided in Table 1.12–14 An ideal oral anticoagulant has a rapid onset and predictable pharmacokinetics with easily quantifiable and reversible thera- peutic effects. Above all, the medication should be efficacious. When compared with warfarin, the new oral anticoagulants have a faster onset and predicable pharmacokinetics (Table 2).12–14 In addition, routine anticoagulation monitoring is not required, and these agents are at least as efficacious as warfarin. Warfarin exerts its anticoagulation effect by inhibiting the synthesis of vitamin K–dependent coagulation factors II, VII, IX, and X. The primary pharmacological effect of warfarin results from the inhibition of factor II or thrombin.16 More frequent monitoring of the International Normalized Ratio (INR) may be required at the initiation of therapy in order to determine the patient’s individual steady-state dose. Inhibition of multiple vitamin K–dependent coagulation Hira Shafeeq, PharmD, BCPS; and Tran H. Tran, PharmD, BCPS eq is Assistant Clinical Professor in the College of Pharmacy th Sciences at St. John’s University in Queens, New York, ical Specialist in the Neurosurgical Intensive Care Unit at ore University Hospital in Manhasset, New York. Dr. Tran is Clinical Professor at the university and Clinical Pharmacy at New York–Presbyterian Hospital/Columbia University Center in New York, New York. Disclosure: The authors report that they have no financial or com- mercial relationships in regard to this article. in.indd 54 12/27/13 4:23 PM 54 PT® the patient’s individual steady-state dose. Inhibition of multiple vitamin K–dependent coagulation and Clinical Specialist in the Neurosurgical Intensive Care Unit at North Shore University Hospital in Manhasset, New York. Dr. Tran is Assistant Clinical Professor at the university and Clinical Pharmacy Manager at New York–Presbyterian Hospital/Columbia University Medical Center in New York, New York. Disclosure: The authors report that they have no financial or com- mercial relationships in regard to this article. PT_1401_Shafeeq_7fin.indd 54 12/27/13 4:23 PM
  23. 23. PT® 57 A retrospective Canadian study also reported a beneficial ICER of dabigatran as $10,440/QALY versus warfarin and $3,962/QALY versus “real-world” prescribing. This analysis incorporated a lower time in the therapeutic range (59%) and more warfarin-eligible patients taking aspirin (11%) or no treat- ment at all (6%).42,43 A U.S. analysis of the RE-LY data found an ICER of $25,000/ QALY, based on a dabigatran cost of $6.75 per day ($210/ month).14,44 In this analysis, the ICER continued to show and apixaban work by binding to the active site of factor Xa to inhibit clot formation independent of cofactor anti-thrombin III. This mechanism differs from that of parenteral factor Xa inhibi- tors, such as fondaparinux (e.g., Arixtra, GlaxoSmithKline).25 Rivaroxaban (Xarelto) was the first oral reversible factor Xa inhibitor approved by the FDA for stroke prevention in nonval- vular AF in November 2011. It is also approved for treatment Stroke/systemic embolism 1.71% warfarin 1.54% dabigatran 110 mg 1.11% dabigatran 150 mga,b 2.4% warfarin 2.1% rivaroxaban 1.6% warfarin 1.27% apixabana,b Safety Major bleeding 3.57% warfarin 2.87% dabigatran 110 mga 3.32% dabigatran 150 mg 3.4% warfarin 3.6% rivaroxaban 3.09% warfarin 2.13% apixabana Intracranial hemorrhage (%/year) 0.74% warfarin 0.23% dabigatran 110 mga 0.3% dabigatran 150 mga 0.7% warfarin 0.5% rivaroxabana 0.8% warfarin 0.33% apixaban Myocardial Infarction 0.64% warfarin 0.82% dabigatran 110 mg 0.81% dabigatran 150 mg 1.1% warfarin 0.9% rivaroxaban 0.61% warfarin 0.53% apixaban a P 0.05. b Superiority. Data from Connelly et al., Granger et al., and Patel et al.32–35 PT_1401_Shafeeq_7fin.indd 57 12/27/13 4:23 PM T® RACT fibrillation (AF) is the most common cardiac arrhyth- he U.S. Anticoagulation is recommended for stroke on in AF patients with intermediate-to-high stroke risk ients with a CHADS2 score of 1 or greater). Warfarin viously the only option for oral anticoagulation in these but three new oral anticoagulants have become avail- alternatives for warfarin in patients with nonvalvular advantages of the newer agents include a rapid onset, ble pharmacokinetics, and no need for routine anti- ion monitoring. atran (Pradaxa) and apixaban (Eliquis) have dem- ed improved efficacy compared with warfarin. aban (Xarelto) was non-inferior to warfarin for stroke on in AF. Apixaban demonstrated a reduced incidence bleeding compared with warfarin and a reduction in mortality. ations to the use of the new oral anticoagulants include of a reversal agent; an inability to use the therapies in patient populations (such as those with severe renal or mpairment); limited experience with drug–drug and sease interactions; and a lack of available coagulation quantify their effects. Although the newer agents have cquisition costs, the benefits of cost savings may be from the potential for decreasing the incidence of hagic stroke and intracranial bleeding and reducing the anticoagulation monitoring. Benefits and risks should ully weighed before these agents are prescribed for presenting with new-onset AF. fibrillation (AF) is the most common cardiac arrhyth- .S.1 The incidence and prevalence of AF increase with he number of people affected by AF is projected to 12 million by 2050.3 The lifetime risk of AF in patients of age and older is estimated at 25%.3,4 Stroke is a major ation associated with AF, which contributes to the mor- d mortality associated with the disease. Patients with a four-fold to five-fold increased risk of stroke. This es among patient populations, according to age, sex, presence of comorbid disease states (e.g., diabetes, nsion, congestive heart failure, and vascular disease).3,5,6 oagulation is recommended for stroke prevention mediate-risk and high-risk patients (i.e., those with a CHADS2 score of 1 or higher (Congestive Heart failure, Age over 75, Diabetes, and Stroke).5,7–11 The presence of additional risk factors (female sex, age 65–74 years, and vascular dis- ease) should be considered when health care professionals are determining whether patients in the intermediate-risk category should receive anticoagulation.7–11 Previously, warfarin was the only option for oral anticoagulation in these patients. Currently, three oral anticoagulants are approved by the FDA as alternatives to warfarin in patients with AF. Dabigatran (Pradaxa, Boehringer Ingelheim) was the first new oral anti- coagulant approved for stroke prevention in AF, followed by the oral anti–factor Xa inhibitors rivaroxaban (Xarelto, Janssen) and apixaban (Eliquis, Bristol-Myers Squibb/Pfizer). Rivaroxaban is also approved for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), along with prevention of DVT/ PE in patients undergoing knee or hip replacement surgeries.12 Apixaban, the newest anti-Xa inhibitor, was approved for stroke prevention in December 2012.13 None of the new agents are approved for use in patients with AF secondary to valvular heart disease or mechanical heart valves. The labeling for anti-Xa inhibitors does not in- clude any specific wording regarding their use in patients with bioprosthetic heart valves; however, dabigatran is specifically contraindicated in patients with mechanical bioprosthetic heart valves.14 Results were published for a phase 2 dose–validation study comparing dabigatran with warfarin in 252 patients with mechanical heart values. The study was prematurely termi- nated because of an increased incidence of thromboembolic and bleeding events with dabigatran.15 A summary of FDA-approved indications and doses of these oral agents is provided in Table 1.12–14 An ideal oral anticoagulant has a rapid onset and predictable pharmacokinetics with easily quantifiable and reversible thera- peutic effects. Above all, the medication should be efficacious. When compared with warfarin, the new oral anticoagulants have a faster onset and predicable pharmacokinetics (Table 2).12–14 In addition, routine anticoagulation monitoring is not required, and these agents are at least as efficacious as warfarin. Warfarin exerts its anticoagulation effect by inhibiting the synthesis of vitamin K–dependent coagulation factors II, VII, IX, and X. The primary pharmacological effect of warfarin results from the inhibition of factor II or thrombin.16 More frequent monitoring of the International Normalized Ratio (INR) may be required at the initiation of therapy in order to determine the patient’s individual steady-state dose. Inhibition of multiple vitamin K–dependent coagulation Hira Shafeeq, PharmD, BCPS; and Tran H. Tran, PharmD, BCPS eq is Assistant Clinical Professor in the College of Pharmacy th Sciences at St. John’s University in Queens, New York, ical Specialist in the Neurosurgical Intensive Care Unit at ore University Hospital in Manhasset, New York. Dr. Tran is Clinical Professor at the university and Clinical Pharmacy at New York–Presbyterian Hospital/Columbia University Center in New York, New York. Disclosure: The authors report that they have no financial or com- mercial relationships in regard to this article. in.indd 54 12/27/13 4:23 PM 54 PT® the patient’s individual steady-state dose. Inhibition of multiple vitamin K–dependent coagulation and Clinical Specialist in the Neurosurgical Intensive Care Unit at North Shore University Hospital in Manhasset, New York. Dr. Tran is Assistant Clinical Professor at the university and Clinical Pharmacy Manager at New York–Presbyterian Hospital/Columbia University Medical Center in New York, New York. Disclosure: The authors report that they have no financial or com- mercial relationships in regard to this article. PT_1401_Shafeeq_7fin.indd 54 12/27/13 4:23 PM
  24. 24. Cost-Effectiveness of New Oral Anticoagulants Compared with Warfarin in Preventing Stroke and Other Cardiovascular Events in Patients with Atrial Fibrillation Doug Coyle, PhD1,2 , Kathryn Coyle, BScPharm, MSc2 , Chris Cameron, MSc1,3 , Karen Lee, MSc4 , Shannon Kelly, BA(Hons)1,3 , Sabine Steiner, MD, MSc5 , George A. Wells, PhD1,3,Ã 1 Faculty of Medicine, Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Canada; 2 Applied Health Economic Research Unit, Ottawa, Canada; 3 University of Ottawa Heart Institute, Ottawa, Canada; 4 Canadian Agency for Drugs and Technologies in Health Ottawa, Canada; 5 Department of Internal Medicine II, Division of Angiology, Medical University Vienna, Vienna, Austria A B S T R A C T Objectives: The primary objective was to assess the cost- effectiveness of new oral anticoagulants compared with warfarin in patients with nonvalvular atrial fibrillation. Secondary objectives related to assessing the cost-effectiveness of new oral anticoagu- lants stratified by center-specific time in therapeutic range, age, and CHADS2 score. Methods: Cost-effectiveness was assessed by the incremental cost per quality-adjusted life-year (QALY) gained. Anal- ysis used a Markov cohort model that followed patients from initiation of pharmacotherapy to death. Transition probabilities were obtained from a concurrent network meta-analysis. Utility values and costs were obtained from published data. Numerous deterministic sensitivity analyses and probabilistic analysis were conducted. Results: The incremental cost per QALY gained for dabigatran 150 mg versus warfarin was $20,797. Apixaban produced equal QALYs at a higher cost. Dabigatran 110 mg and rivaroxaban were dominated by dabigatran 150 mg and apixaban. Results were sensitive to the drug costs of apixaban, the time horizon adopted, and the consequences from major and minor bleeds with dabiga- tran. Results varied by a center’s average time in therapeutic range, a patient’s CHADS2 score, and patient age, with either dabigatran 150 mg or apixaban being optimal. Conclusions: Results were highly sensitive to patient characteristics. Rivaroxaban and dabigatran 110 mg were unlikely to be cost-effective. For different characteristics, apixaban or dabigatran 150 mg were optimal. Thus, the choice between these two options may come down to the price of apixaban and further evidence on the impact of major and minor bleeds with dabigatran. Keywords: anticoagulants, atrial fibrillation, cardiovascular, cost- effectiveness, warfarin. Copyright 2013, International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. Introduction Approximately 250,000 Canadians are affected by atrial fibrilla- tion (AF) [1]. Patients with AF have a substantially increased risk of death and have higher annual rates of mortality [1,2]. AF and stroke are more common among the elderly [3,4]. Preventing events such as stroke is an important part of managing patients with AF. Antithrombotic strategies for patients with AF include anticoagulant drugs, vitamin K antag- onists , such as warfarin, and antiplatelet agents, such as aspirin. Vitamin K antagonists reduce the risk of stroke in patients with AF but are associated with some drawbacks, including a need for laboratory monitoring, an increased risk of bleeding complica- tions, and several food and drug interactions [5,6]. Recently, a number of new oral anticoagulants (NOACs) have been approved, including dabigatran, a direct thrombin inhibitor, and the direct factor Xa inhibitors, rivaroxaban and apixaban. While dabigatran, apixaban, and rivaroxaban have been dem- onstrated to be effective in preventing stroke/systemic embolism in patients with AF, the comparative cost-effectiveness of these NOACs is not clear. Currently, treatment with warfarin including regular international normalized ratio monitoring costs less than $300 per annum. The new anticoagulants examined in this study cost more than $1100 per annum. Thus, the cost-effectiveness of these agents will depend on the balance between the increased benefits in terms of stroke prevention, the effect on bleeding rates, and the increased drug costs [7–11]. This analysis is the first systematic, independent analysis of the cost-effectiveness of all three NOACs in comparison to warfarin in patients with nonvalvular AF. This study involved incorporating data from a concurrent systematic review into an economic model of NOAC use in Canada [12]. The primary objective was to assess the cost- effectiveness of NOACs compared with warfarin—with additional 1098-3015/$36.00 – see front matter Copyright 2013, International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jval.2013.01.009 E-mail: gawells@ottawaheart.ca. * Address correspondence to: George A. Wells, Cardiovascular Research Methods Centre, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON, Canada K1Y 4W7. Available online at www.sciencedirect.com journal homepage: www.elsevier.com/locate/ Cost-Effectiveness of New Oral Anticoagulants Comp in Preventing Stroke and Other Cardiovascular Event Atrial Fibrillation Doug Coyle, PhD1,2 , Kathryn Coyle, BScPharm, MSc2 , Chris Cameron, MSc1,3 , Karen Lee Sabine Steiner, MD, MSc5 , George A. Wells, PhD1,3,Ã 1 Faculty of Medicine, Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, C Ottawa, Canada; 3 University of Ottawa Heart Institute, Ottawa, Canada; 4 Canadian Agency for Drugs and T 5 Department of Internal Medicine II, Division of Angiology, Medical University Vienna, Vienna, Austria A B S T R A C T Objectives: The primary objective was to assess the cost- effectiveness of new oral anticoagulants compared with warfarin in patients with nonvalvular atrial fibrillation. Secondary objectives related to assessing the cost-effectiveness of new oral anticoagu- lants stratified by center-specific time in therapeutic range, age, and CHADS2 score. Methods: Cost-effectiveness was assessed by the incremental cost per quality-adjusted life-year (QALY) gained. Anal- ysis used a Markov cohort model that followed patients from initiation of pharmacotherapy to death. Transition probabilities were obtained from a concurrent network meta-analysis. Utility values and costs were obtained from published data. Numerous sensitive to the drug cos and the consequences fr tran. Results varied by a c patient’s CHADS2 score, a mg or apixaban being o sensitive to patient chara mg were unlikely to be c apixaban or dabigatran between these two option and further evidence on t dabigatran. VA L U E I N H E A L T H 1 6 ( 2 0 1 3 ) 4 9 8 – 5 0 6 warfarin event rates from other major RCTs to assess the impact on results. No differences in event fatality rates between treat- ments were assumed. For incorporation into the economic model, transition probabilities for the duration of cycle length were obtained by using standard methodology. The estimate for the transition probability for each event for dabigatran, apixaban, and rivaroxaban was derived by using the odds ratio for each treatment obtained from a network meta- analysis. A detailed description of the methods and results of the network meta-analysis are available elsewhere [12]. Based on the available results, the following events were modeled to vary by anticoagulant: stroke, MI, major bleeds, and ICH. In addition, the model incorporated the same risks of minor bleeds, PE, and TIA for all anticoagulants. Sensitivity analyses were conducted incor- porating the relative risks of minor bleeds and nonvascular deaths. Utility Values Utility values were based on whether the patients experienced an event (MI, stroke, PE, TIA, ICH, and extracranial hemorrhage) in the current cycle and their event history (previous MI or stroke). Utility values were sourced from published data (Table 1) [7,24–26,33]. Analysis assumed no difference in utility values on treatment. Sensitivity analysis assumed reduced utility on war- farin and other anticoagulants as per previous studies [7,24,25]. Costs Costs for all resources were adjusted to 2011 Canadian dollars by using the Bank of Canada Inflation Calculator [34]. Drug costs were obtained from the Ontario Drug Benefit formulary or from the drug manufacturer [27]. Because no drug costs were available for apixaban at the time of the analysis, the costs were assumed to equal the drug costs for dabigatran. For each drug therapy, annual drug treatment costs include a $7 prescription fee (every 3 months) and an 8% pharmacist’s markup. For warfarin, an addi- tional cost of international normalized ratio monitoring was added [28]. The costs of events and any associated long-term the range and results of these analyses. Threshold Analysis Threshold analysis was conducted to assess the value of a parameter required to lead to change in the interpretation of the base result. This was based on assuming a willingness-to-pay value of $50,000 for a QALY. Analysis was conducted for param- eters for which there was limited information: that is, the price of apixaban and the consequences of minor and major bleeds with dabigatran. Probabilistic Sensitivity Analysis Probabilistic sensitivity analysis was conducted by using a Monte Carlo simulation [29]. For the Monte Carlo simulation, probability distributions related to natural history parameters, relative risks and odds ratios, costs, and utilities were incorporated into the analysis. Analysis adopted standard methods for defining uncer- tainty around parameters (Table 1). Estimates of incremental costs and QALYs were obtained by re-running the model employ- ing values from the related probability distributions. In this study, 5000 replications were conducted; that is, a set of 5000 outcome estimates was obtained. Cost-effectiveness acceptability curves that present the probability that each treatment is optimal given different values of willingness to pay for an additional QALY were derived [36]. Analysis of Variability Stratified analyses were conducted to assess the sensitivity of the results to changes in the underlying patient population. Stratified analyses incorporated, where possible, different warfarin-related event rates based on the patient profile and available data. In addition, where possible, different estimates of the relative treatment effect of the newer oral anticoagulants compared with warfarin were included. Analyses were conducted to stratify patient by three criteria: CHADS2 score, age, and center’s TTR. Table 2 – Base results. Cost ($) QALYs Incremental cost per QALY gained (ICER) ($) vs. warfarin Sequential ICER Warfarin 18,620 6.480 Dabigatran 150 mg 21,486 6.617 20,797 20,797 Dominated therapies Apixaban 21,966 6.617 24,312 Dominated by dabigatran 150 mg Rivaroxaban 22,016 6.541 55,757 Dominated by dabigatran 150 mg and apixaban Dabigatran 110 mg 22,804 6.543 66,354 Dominated by dabigatran 150 mg and apixaban Note. Dominated ¼ more costly and equal or fewer QALYs; Extended dominance ¼ the combination of two other alternatives dominates the treatment. ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-year. were included, rivaroxaban would be optimal as the ICUR for rivaroxaban versus that for warfarin was $8278. If treatment discontinuations not related to vascular events were included in the analysis, apixaban produced more QALYs in which the TTR was 6 Discussion In the base-case analysi optimal treatment choic willing to pay at least $20 are uncertain given tha QALYs at only a slightly bilistic analysis illustrate dabigatran was optimal insensitive to many of model except for the consequences from min The results need to b this area. Five separate dabigatran versus warfa been published [7–11,37 clinical data from the R models of similar forma rivaroxaban or apixaban Similar to our study, a U Council found that dab centers in which patie 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% $0 $20,000 $40,000 $60,000 $80,000 $100,000 ProbabilityTreatmentisOpƟmal Threshold Value for a QALY Warfarin Dabigatran 150mg Rivaroxaban Apixaban Dabigatran 110mg Fig. 2 – Cost-effectiveness Acceptability Curve.
  25. 25. AVERROES Study 28 Apixaban Event rate (%/year) ASA Event rate (%/year) Apixaban vs ASA P Value Stroke or systemic embolism 1.62 3.63 0.001 Ischemic stroke 1.37 3.11 0.001 Hemorrhagic stroke 0.19 0.28 0.45 Major bleeding 1.41 0.92 0.07
  26. 26. Patients Unsuitable for NOAC Agents AF patients for whom the NOACs are not approved for stroke prevention include: ! • Patients with significant valvular heart disease, particularly severe mitral stenosis • Patients with prosthetic valves • Patients with eGFR 30 mL/min • Patients with active bleeding • Patients with hepatic disease (rivaroxaban and apixaban) • Patients with concomitant systemic treatment with strong inhibitors of CYP3A4 and P-gp • Patients with concomitant systemic treatment with strong inducers of CYP3A4 and P-gp 29
  27. 27. Non-Valvular AF TTR ≥ 70% for 6 months despite compliance/adherence Yes Continue on Warfarin or switch to NOACs based on patient’s preference, benefits risks and costs Yes No Male or female 65 yrs + lone AF If NOACs are chosen On Warfarin Switch to NOACs if good compliance/adherence Yes No No antithrombotic therapy CHA2DS2-VASc ≥ 1 No Yes No Age 75 yrs Age ≥ 75 yrs Upper GI history Prior MI/ACS CrCl 30-60 mL/min HAS-BLED ≥ 3 either Apixaban or Dabigatran or Rivaroxaban either Apixaban or Rivaroxaban Yes for 1 or more Upper GI history Prior MI/ACS CrCl 30-60 mL/min HAS-BLED ≥ 3 Yes for 1 or more either Apixaban or Rivaroxaban Apixaban Aspirin plus clopidogrel, or, less effectively, aspirin alone may be considered only when patients at Warfarin therapy or NOACs Decision based on patient’s preference and values following evaluation of benefits, risks and cost SAMe-TT2R2 score0-1 ≥ 2 Warfarin therapy considered NOACs use encouraged No Yes for 1 or more No Yes for 1 or more 10 S. Rosanio et al. / International Journal of Cardiology xxx (2014) xxx–xxx Review Pharmacology, benefits, unaddressed questions, and pragmatic issues of the newer oral anticoagulants for stroke prophylaxis in non-valvular atrial fibrillation and proposal of a management algorithm Salvatore Rosanio a, ⁎, Abdul M. Keylani a , Darrin C. D'Agostino a , Craig M. DeLaughter a , Antonio Vitarelli b a Department of Internal Medicine, Division of Cardiology, University of North Texas Health Science Center, Fort Worth, TX, United States b Cardio-Respiratory Department, La Sapienza University, Rome, Italy a b s t r a c ta r t i c l e i n f o Article history: Received 17 December 2013 Received in revised form 6 March 2014 Accepted 17 April 2014 Available online xxxx Keywords: Atrial fibrillation Stroke Dabigatran Rivaroxaban Apixaban Edoxaban This systematic review aims to provide an update on pharmacology, efficacy and safety of the newer oral direct thrombin and factor Xa inhibitors, which have emerged for the first time in ~60 years as cogent alternatives to warfarin for stroke prophylaxis in non-valvular atrial fibrillation. We also discuss on four of the most common clinical scenarios with several unsolved questions and areas of uncertainty that may play a role in physicians' reluctance to prescribe the newer oral anticoagulants such as 1) patients with renal failure; 2) the elderly; 3) patients presenting with atrial fibrillation and acute coronary syndromes and/or undergoing coronary stenting; and 4) patients planning to receive AF ablation with the use of pulmonary vein isolation. New aspects presented in current guidelines are covered and we also propose an evidence-based anticoagulation management algorithm. © 2014 Elsevier Ireland Ltd. All rights reserved. 1. Introduction Non-valvular atrial fibrillation (AF) in the absence of rheumatic mitral stenosis or a prosthetic heart valve is the most common sustained cardiac rhythm disorder worldwide, occurring in 1 to 2% of the general population [1,2]. AF affects over 2 million people in the US and over 6 million across the European Union and occurs more frequently in the elderly [1,2]. As such, the prevalence of AF is projected to double in the next 50 years as much of the population ages [3]. Approximately one in three patients with AF will develop an ische- mic stroke in their lifetime, with almost two-thirds being cardioembolic and one-third being atherothrombotic [4]. Atrial fibrillation-related strokes are more likely to be massive, are often fatal or associated with long-term disability and exhibit high recurrence rates compared to strokes of other etiologies [5]. Due to the nature of these events, strokes represent a major public health prob- lem with a huge economic burden. In the US, the estimated direct and indirect costs of stroke were $34.3 billion in 2008 [6]. The long-term risk of stroke in AF depends on the clinical predictors collectively assessed in the CHADS2 scoring scheme in which Congestive heart failure, Hypertension, Age ≥ 75 years and Diabetes mellitus are each assigned one point or two points for a history of Stroke/transient ischemic attack [TIA] or CHA2DS2-VASc, which considers additional risk factors, such as vascular disease (myocardial infarction [MI], complex aortic plaque, peripheral artery disease) and sex category (female sex), each of which is awarded one point, including age of 65 to 74 years, and 2 points if age ≥ 75 years [7–9]. The American College of Chest Physicians and European Society of Cardiology guidelines recommend that all patients with AF and a CHADS2 or CHA2DS2-VASc score ≥ 1 should be on long-term oral anticoagulation [1,10]. Warfarin, the most prescribed oral anticoagulant acts by lowering the serum levels of vitamin K-dependent pro-coagulant proteins and is highly effective for the prevention of AF-related stroke, resulting in a 64% risk reduction compared to placebo and a 37% risk reduction com- pared with antiplatelet therapy [11]. However, warfarin has several drawbacks (slow onset and offset of action; narrow therapeutic range [international normalized ratio, INR of 2.0–3.0] that requires regular monitoring; several interactions with food, alcohol, and drugs; potential ethnic, genetic, and age-related variations in dose response; and high bleeding risk [0.3–0.5%/yr]), which have resulted in its suboptimal use in clinical practice and promoted the search for more convenient and safer oral anticoagulants [12–18]. ⁎ Corresponding author at: Department of Internal Medicine, Division of Cardiology, 855 Montgomery Street, PCC Room 315, Fort Worth, TX 76107, United States. Tel.: +1 817 735 7624x2072 (office); fax: +1 817 735 2748. E-mail address: Salvatore.Rosanio@unthsc.edu (S. Rosanio). http://dx.doi.org/10.1016/j.ijcard.2014.04.179 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved. journal homepage: www.elsevier.com/locate/ijcard Please cite this article as: Rosanio S, et al, Pharmacology, benefits, unaddressed questions, and pragmatic issues of the newer oral anticoagulants for stroke prophylaxis in non..., Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.179 ddressed questions, and pragmatic issues of ts for stroke prophylaxis in non-valvular al of a management algorithm ani a , Darrin C. D'Agostino a , Craig M. DeLaughter a , Antonio Vitarelli b ersity of North Texas Health Science Center, Fort Worth, TX, United States e, Italy b s t r a c t is systematic review aims to provide an update on pharmacology, efficacy and safety of the newer oral direct rombin and factor Xa inhibitors, which have emerged for the first time in ~60 years as cogent alternatives to arfarin for stroke prophylaxis in non-valvular atrial fibrillation. We also discuss on four of the most common nical scenarios with several unsolved questions and areas of uncertainty that may play a role in physicians' luctance to prescribe the newer oral anticoagulants such as 1) patients with renal failure; 2) the elderly; patients presenting with atrial fibrillation and acute coronary syndromes and/or undergoing coronary enting; and 4) patients planning to receive AF ablation with the use of pulmonary vein isolation. New aspects esented in current guidelines are covered and we also propose an evidence-based anticoagulation management gorithm. © 2014 Elsevier Ireland Ltd. All rights reserved. International Journal of Cardiology xxx (2014) xxx–xxx Contents lists available at ScienceDirect ernational Journal of Cardiology al homepage: www.elsevier.com/locate/ijcard
  28. 28. RATIONAL PHARMACY Dagbigitran 150 mg BID Rivaroxaban/Apixiban/ Dagbigitran 110 mg BID 80 yrs and normal renal function Previous and significant bleeding Superior to warfarin in reducing ischemic strokes 80 yrs, eGFR 30-50 Very low body weight Dyspepsia, active CAD *from Dr. Ken Butcher, University of Alberta
  29. 29. Summary Three key lessons: 1) Atrial fibrillation is an increasingly important and preventable cause of ischemic stroke. 2) NOACs are associated with reduced ICH, ischemic strokes and systemic embolism compared with warfarin. 3) NOACs are not “prescribe and forget” drugs. Knowledge of the pharmacokinetics, monitoring (including patient compliance, renal function (dabigitran), take with food (rivaroxaban)), and drug- drug interactions will improve real-world safety.
  30. 30. Coumadin Dabigatran 150 Rivaroxaban Apixaban STROKE ICH GIB NNH 100/2yrs NNH 100/2yrs REVERSAL MI D/C Dyspepsia RENAL CrCl30 CrCl30 CrCl15 COST MONITORING

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