Strike out stroke arh

RYAN J PUNAMBOLAM MD FRCPC NEUROLOGY

ARHCC !

May 21 2014

56 P&T®

In patients with AF, dabigatran 150 mg is taken twice daily with or without food. A reduced dose of 75 mg is recommended if the patient’s creatinine clearance (CrCl) is 15 to 30 mL/minute, as calculated with the Cockcroft–Gault formula using actual body weight (see Table 1). Clearance is primarily renal, and the drug is a substrate of permeability glycoprotein (P-gp). The use of dabigatran with P-gp inducers (such as rifampin) should be avoided. The combination of renal impairment and P-gp inhibition has a greater tendency to achieve undesirable concentrations when compared with each factor separately.12–14,26

For patients with moderate renal impairment (a CrCl of 30–50 mL/minute) who are concomitantly taking P-gp inhibitors such as dronedarone (Multaq, Sanofi) or systemic ketocon-azole, a reduced dose of 75 mg is recommended. Approval of the 75-mg dose was based on pharmacokinetic modeling data.14,26 The clinical efficacy of the reduced dose regimen has not been studied.7,10–14 Significant adverse effects occurring with dabigatran at a rate exceeding 15% include dyspepsia and gastritis-like symptoms.14

Routine monitoring of anticoagulation activity is not neces-sary if dabigatran is administered according to the manu-facturer’s recommendations. Dabigatran prolongs thrombin clotting time (TCT), prothrombin time (PT), activated partial thromboplastin time (aPTT), and ecarin clotting time (ECT). TCT, aPTT, and ECT can be used to estimate the drug’s serum concentration. However, the degree of aPTT elevation is not linearly correlated with the dabigatran concentration, and it is particularly inaccurate at higher concentrations of the drug.14,17

A boxed warning cautions against interruptions in dabigatran therapy to avoid an increased risk of stroke resulting from the drug’s short half-life. Therefore, withholding dabigatran for 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

hemodialysis can be considered for reversing life-threatening bleeding.27–30

Clinical Trials and Efficacy In the Randomized Evaluation of Long-Term Anticoagulation

Therapy trial (RE-LY), patients older than 65 years of age with AF received blinded doses of dabigatran 110 mg or 150 mg twice daily to establish non-inferiority versus unblinded, dose-adjust-ed warfarin. Study participants (n = 18,133) were observed for up to 2 years (Table 3).31–35 Two independent investigators who were blinded to treatment assignments confirmed the detection of events from hospital records to minimize potential reporting bias from unblinded INR monitoring. The mean CHADS2 score was 2.1 (see Table 3).32

The incidence of stroke and systemic embolism was similar between dabigatran 110 mg and warfarin (1.54% vs. 1.71% per year, respectively). The relative risk (RR) was 0.9 with a 95% con-fidence interval (CI) of 0.74 to 1.1 (P < 0.001 for non-inferiority).

The higher dose of dabigatran (150 mg twice daily) was associated with a significant reduction in stroke and systemic embolism compared with warfarin (1.11% per year; RR, 0.65%; 95% CI, 0.52–0.81; P < 0.001 for non-inferiority and superiority). Dabigatran 150 mg was associated with a lower incidence of both ischemic stroke (hazard ratio [HR], 0.75; 95% CI, 0.58–0.97) and hemorrhagic stroke (HR, 0.26; 95% CI, 0.14–0.49).

The primary safety outcome (major bleeding) for dabigatran 150 mg and 110 mg was 3.32% (P = 0.32) and 2.87% (P = 0.003) per year, respectively, compared with 3.57% per year with war-farin. The incidence of gastrointestinal bleeding was higher in the dabigatran 150-mg treatment arm compared with the warfarin arm, (1.5% vs. 1.02% annually respectively; RR, 1.5; 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 PM

Disclosures

• Speaker Fees from Bayer, Sanofi-Aventis, Allergan, Tribute Pharmaceuticals, Boehringer-Ingelheim

S124 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 ChinaIn 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

On the basis of current demographic and population-level vascu-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

LimitationsAs 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.

ConclusionsStroke 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

The Burden of Stroke in the United StatesStroke continues to present a significant public health challenge for the United States. Stroke is a leading cause of adult disabil-ity1; race-ethnic and geographic disparities in stroke incidence and outcomes have remained stubbornly persistent,2 and the total number of deaths from stroke is projected to increase in the coming decades as the population ages.3 However, there is also reason for optimism. During the last 40 years, there has been a >60% decline in the age-adjusted mortality rate from stroke in the United States,4 and stroke has recently moved from its prior position as the third leading cause of death to become the fourth leading cause of death overall.5

Although there are multiple factors to help to explain this trend, improvements in blood pressure control at the population level are likely to be playing a major role. During the last few decades, each successive national health survey has recorded improvements in population systolic blood pressure and hypertension control. For example, the median systolic blood pressure among aged 60 to 74 years in 1960–1962 was ≈150 mm Hg.6 In subsequent surveys, the median systolic blood pres-sure has consistently declined and by the 1988–1991 National Health and Nutrition Examination Survey III, the median sys-tolic blood pressure had decreased to 130 mm Hg.6

Improvements in blood pressure have been particularly pro-nounced among those with very high blood pressure, which confers a disproportionately higher risk for stroke. For instance, during the same period, the 90th percentile for systolic blood pres-sure decreased from >190 mm Hg to <160 mm Hg.6 This pattern of improved hypertension control has also been demonstrated in other high-income countries, which have experienced a 42% decrease in stroke incidence overall during the past 40 years.7

The Ongoing Global Epidemic of StrokeFrom the global prospective, the outlook for stroke is quite dis-tinct. The conventional wisdom is that heart disease and stroke are primarily diseases of the developed world, although in point of fact most of the burden of cardiovascular disease and stroke is borne by countries in the developing world.8,9 Stroke continues to be the second leading cause of death worldwide (second only to cardiovascular disease) and accounts for ≈1 in 10 deaths or 5.7 million deaths a year.10 This mortality burden has come with a more than doubling of the stroke incidence in low- and middle-income countries 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 100 000 compared with a rate of 32 per 100 000 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

Received November 6, 2012; accepted April 4, 2013.From the Departments of Neurology (A.S.K., S.C.J.) and Epidemiology and Biostatistics (S.C.J.), University of California, San Francisco, CA.Correspondence to Anthony S. Kim, MD, MAS, Department of Neurology, University of California, San Francisco, 675 Nelson Rising Lane, Room

411B, San Francisco, CA 94158. E-mail [email protected](Stroke. 2013;44[suppl 1]:S123-S125.)© 2013 American Heart Association, Inc.

Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.111.000067

STR

Stroke

0039-2499

10.1161/STROKEAHA.111.000067

202944

Kim and Johnston The Global Stroke Epidemic

01

June

2013

00

00

00

00

© 2013 American Heart Association, Inc.

2013

8

Saritha SalveThe 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 ChinaIn 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

On the basis of current demographic and population-level vascu-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

LimitationsAs 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.

ConclusionsStroke 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

Stroke Types and Incidence

Ischemic stroke 85-88%

Hemorrhagic stroke 12-15%

Other 5%

Cryptogenic 30%

Cardiogenicembolism

20%

Small vessel disease

“lacunes” 25%

Atherosclerotic cerebrovascular

disease 20%

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 million individuals.

Zone of Infarction

Embolism

“Hemorrhagic Conversion”

Reperfusion

Embolism breaks up, entering into one branch

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

CARDIOEMBOLIC STROKES:

CLINICAL FEATURES

• Abrupt onset (vs. stuttering)

• LOC

• Aphasia without motor deficit

• Concurrent embolism to other organs

• Hemanopia without hemiparesis

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

Preadmission medications in patients with known atrial fibrillation who were admitted with acute ischemic stroke (high-risk cohort, n=597).

Warfarin Has a Narrow Therapeutic WindowRelationship 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.!

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

% o

f elig

ible

pat

ient

s re

ceiv

ing

war

farin!

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"

• 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

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.

•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

Bleeding Risk ManagementAddress 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

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

the reduction of stroke/SSE (ischemic and hemorrhagic, anddriven by hemorrhagic).6 Interestingly, all 3 NOACs wereassociated with less intracranial bleeding compared withwarfarin 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 NOACClearance

The extent of renal excretion is an important distinguish-ing feature of NOACs. Up to 80% of circulating dabigatran iseliminated renally, whereas only 33% and 25% of unchangedrivaroxaban and apixaban is cleared by the kidney.7-9 After150 mg administration, total dabigatran area under theconcentration curve (AUC) was increased by 1.5-, 3.1-, and6.3-fold in individuals with mild, moderate, and severe renalimpairment, respectively, compared with healthy individuals,leading to increased terminal half-life (t1/2b) to 15, 18, and27 hours.10 For rivaroxaban, subjects with mild, moderate,and severe impairment exhibited an increase in AUC of 44%,52%, and 65%, respectively.11 The coagulation parameterprothrombin time (PT) was affected in a similar fashion.For apixaban, though no changes were observed in apixabananti-FXa activity, overall AUC increased by 16%, 29%, and44% in individuals with mild, moderate, and severe renalimpairment compared with individuals with normal renalfunction.12

Importance of Drug Metabolism and TransportProcesses for NOACs

Dabigatran etexilate is the prodrug of dabigatran, anda substrate of efflux transporter P-glycoprotein (P-gp) (enco-ded by ABCB1), with an absolute bioavailability of only6.5%.13,14 Bioavailable dabigatran etexilate is convertedentirely to dabigatran by nonspecific ubiquitously expressed

carboxylesterases in the enterocytes, portal circulation, andhepatocytes.7,13,15 Very recently, a genome-wide subanalysisof the RE-LY trial demonstrated that a single-nucleotidepolymorphism (SNP) in the carboxyesterase 1 gene (CES1;rs2244613) attenuated dabigatran formation leading to lowertrough concentrations and the ABCB1 SNP rs4148738 andCES1 SNP rs8192935 were associated with higher and lowerpeak dabigatran concentrations, respectively.16 Rivaroxaban’sbioavailability is dose-dependent; the absolute bioavailabilityof 10 mg rivaroxaban ranged from 80% to 100%, andbioavailability of 20 mg in fasting conditions was 66%.17

Coadministration of 15 or 20 mg rivaroxaban with foodincreased the AUC by 39%.18 The low bioavailability infasting conditions might result in risk of inadequate anti-coagulation and thus, rivaroxaban should be administeredwith food. Apixaban’s absolute bioavailability is 50% and notaffected by food intake.9

Dabigatran is not metabolized by the cytochrome P450(CYP) isoenzymes; rather, it is conjugated to acylglucur-onides.19 In patients with moderate hepatic impairment, thebioconversion from prodrug to dabigatran was slightly slowerwhen compared with healthy subjects although the AUCand extent of dabigatran glucuronidation was unchanged.20

Conversely, rivaroxaban and apixaban are both subject toCYP-mediated metabolism whereby CYP3A4/5 and CYP2J2accounts for clearance of two-thirds of rivaroxaban,8,21 andapixaban metabolism is predominantly driven by CYP3A4/5.22 Patients with mild (Child-Pugh A) hepatic impairmentshowed no difference in rivaroxaban PK and PD.23 However,patients with moderate (Child-Pugh B) hepatic impairmentexhibited reduced clearance of rivaroxaban. Therefore, rivar-oxaban is not recommended in patients with moderate orsevere (Child-Pugh C) hepatic impairment. The PK and anti-FXa activity of 5 mg apixaban was not altered in subjects witheither mild or moderate liver impairment when comparedwith healthy individuals.12

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.

S26 Canadian Journal of CardiologyVolume 29 2013

Therapy (RE-LY) trial (open-label; n ¼ 18,133), 150 mgdabigatran twice daily (BID) was associated with lower ratesof stroke/SSE, achieving superiority, but a similar rate ofmajor bleeding and 110 mg BID was associated with similarrates of stroke/SSE but fewer bleeds compared with warfarin.3

Rivaroxaban and apixaban are the first and second oral directFXa inhibitors approved for AF.4 In the Rivaroxaban OnceDaily Oral Direct Factor Xa Inhibition Compared With

Vitamin K Antagonist for Prevention of Stroke and EmbolismTrial in Atrial Fibrillation (ROCKET-AF) trial (double-blin-ded, n ¼ 14,264), rivaroxaban was noninferior to warfarinand 20 mg rivaroxaban once daily (OD) resulted in similarrates of stroke/SSE and major bleeding.5 In the Apixaban forReduction in Stroke and Other ThromboemboLic Eventsin Atrial Fibrillation (ARISTOTLE) trial (double-blinded;n ¼ 18, 201), 5 mg BID apixaban was superior to warfarin in

Table 1. Comparison of pharmacokinetic features of warfarin, dabigatran, rivaroxaban and apixaban

Parameter Warfarin Dabigatran Rivaroxaban Apixaban

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 inhibitionof clotting factor synthesis

Fast Fast Fast

Offset of action Long Short Short ShortAbsorption Rapid Rapid, acid-dependent Rapid RapidBioavailability (%) 100 6.5 80* 50tmax (h) 2.0-4.0 1.0-3.0 2.5-4.0 1.0-3.0Vd (L) 10 60-70 50-55 21Protein binding (%) 99 35 95 87t1/2b (h) 40 12-17 9-13 8-15Renal excretion None 80 33 25Fecal excretion None 20 28 50-70CL/F (L/h) 0.35 70-140 10 5Accumulation in plasma Dependent on CYP2C9

metabolic efficiencyNone None 1.3-1.9

Food effect No effect on absorption;dietary vitamin Kinfluence on PD

Delayed absorption withfood with no influenceon bioavailability

Delayed absorption with foodwith increased bioavailability

None

Age Yes, lower CL/F as ageincreases

Yes, lower CL/F as ageincreases

None Yes, lower CL/F as ageincreases

Body weight Yes, higher dose forincreased weight

None None Yes, higher exposure with lowbody weight (< 60 kg)

Sex Yes, lower CL/F in women Yes, lower CL/F in women None Yes, higher exposure in womenEthnicity Lower dose in Asian

patients; higher dose inAfrican-American patients

None Lower dose in Japanesepatients

None

Drug transporter None P-gp P-gp, BCRP P-gp, BCRPCYP-mediated metabolism CYP2C9, CYP3A4,

CYP2C19, CYP1A2None CYP3A4/5, CYP2J2 (equal) CYP3A4/5, CYP2J2 (minor),

CYP1A2 (minor)Drug-drug interactions Many; affecting metabolism Potent P-gp inhibitors;

affecting absorptionPotent CYP3A4 and P-gp

inhibitors; affectingabsorption, metabolism,and excretion

Potent CYP3A4 and P-gpinhibitors; affectingabsorption, metabolism,and excretion

Dosing for AF Variable (0.5-16 mg OD) 150, 110 mg BID 20, 15 mg OD 5, 2.5 mg BIDCoagulation measurement INR TT > Hemoclot > ECT >

aPTTanti-FXa > PT anti-FXa

AF, atrial fibrillation; aPTT, activated partial thromboplastin test; BCRP, breast cancer resistance protein; BID, twice daily; CL/F, apparent clearance; CYP,cytochrom P450 isozymes; ECT, ecarin clotting time; INR, international normalized ratio; OD, once daily; PD, pharmacodynamic characteristics; P-gp,P-glycoprotein; PT, prothrombin time; t1/2b, terminal half-life; tmax, time to maximum plasma concentration; TT, thrombin time; Vd, volume of distribution;VKOR, vitamin K epoxide reductase enzyme.

* Bioavailability is dependent on dose (more than 10 mg) and food intake. Thus, rivaroxaban doses greater than 10 mg OD should be administered with food.However, 10 mg rivaroxaban is only licensed for prophylaxis of thromboembolism after elective hip or knee surgery.

of clinical variables such as age, renal function, dosing interval, anddrug metabolism (CYP3A4) and transport (P-glycoprotein), we mightbe able to better predict the risk for sub- and supratherapeutic anti-coagulation response and individualize OAC selection and dosing.

pharmacodynamiques de chacun des m!edicaments compos!es, etfournissons des directives sur la s!election et le dosage des 3 NACOrelatifs à la warfarine lorsque le traitement par ACO des patients ayantune FA est envisag!e. Essentiellement, nous montrons que par unemeilleure compr!ehension de l’effet des variables cliniques commel’âge, le fonctionnement r!enal, l’intervalle posologique ainsi que lem!etabolisme (CYP3A4) et le transport (glycoprot!eine P) dum!edicament, nous pouvons être capables de mieux pr!edire le risquede r!eponse au traitement anticoagulant sous-th!erapeutique et supra-th!erapeutique, et d’individualiser la s!election et le dosage de l’ACO.

Gong and Kim S25Pharmacokinetics of New Oral Anticoagulants










Fast Fast Fast






None









None























Fast Fast Fast






None









None























Fast Fast Fast






None









None























Fast Fast Fast






None









None























Fast Fast Fast






None









None













Gong and Kim S25Pharmacokinetics of New Oral AnticoagulantsTherapy (RE-LY) trial (open-label; n ¼ 18,133), 150 mg

dabigatran twice daily (BID) was associated with lower ratesof stroke/SSE, achieving superiority, but a similar rate ofmajor bleeding and 110 mg BID was associated with similarrates of stroke/SSE but fewer bleeds compared with warfarin.3









Fast Fast Fast






None









None























Fast Fast Fast






None









None























Fast Fast Fast






None









None














ReviewImportance 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

aDivision of Clinical Pharmacology, Department of Medicine, University of Western Ontario, London, Ontario, CanadabDepartment of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada

ABSTRACTWarfarin has been the mainstay oral anticoagulant (OAC) medicationprescribed 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 monitoringand dose titration. These limitations have prompted the clinicaldevelopment of new OACs (NOACs) that directly target the coagulationcascade with rapid onset/offset of action, lower risk for drug-druginteractions, 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 ofthese NOACs has been characterized, differences in their pharmaco-kinetic and pharmacodynamic profiles have become a significantconsideration in terms of drug selection and dosing. In this review, weoutline key pharmacokinetic and pharmacodynamic features of eachcompound and provide guidance on selection and dosing of the 3NOACs relative to warfarin when considering OAC therapy for AFpatients. Importantly, we show that by better understanding the effect

R!ESUM!ELa warfarine a !et!e le pilier des anticoagulants oraux (ACO) prescrit pourla pr!evention de l’accident vasculaire c!er!ebral chez les patients ayantune fibrillation auriculaire (FA). Cependant, le traitement par la war-farine est difficile en raison de la variabilit!e interindividuelle marqu!eede la dose et de la r!eponse, ce qui rend n!ecessaire une surveillancefr!equente et un r!eglage posologique. Ces limites ont suscit!e led!eveloppement clinique de nouveaux ACO (NACO) qui ciblent directe-ment la cascade de coagulation par un d!elai d’action rapide et unedur!ee d’action, un plus faible risque d’interactions m!edicamenteuseset une r!eponse plus pr!evisible. R!ecemment, 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 solutionde rechange au traitement par la warfarine. Tandis que l’efficacit!e del’anticoagulation de ces NACO a !et!e !etablie, les diff!erences dans leursprofils pharmacocin!etiques et pharmacodynamiques sont devenuesune pr!eoccupation importante en ce qui a trait à la s!election dum!edicament et du dosage. Dans cette revue, nous exposons lesgrandes lignes des principales caract!eristiques pharmacocin!etiques et

Atrial fibrillation (AF) is associated with a 5-fold increasein risk of disabling stroke.1 Therefore, antithrombotic therapyis required for stroke and systemic embolism (SSE) prophy-laxis. Until recently, the vitamin K antagonist warfarin wasthe 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 oflimitations including delayed onset of action, large interindi-vidual variability in response, unpredictable pharmacokineticcharacteristics (PK), drug-drug interactions, and polymor-phisms in genes affecting metabolism and pharmacodynamic(PD) characteristics. Intensive monitoring using internationalnormalized 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 sufficientlywide therapeutic window to allow for fixed-dose administra-tion without the need for routine response monitoring.NOACs directly inhibit the coagulation pathway, either FXaor thrombin, for rapid onset of antithrombotic effects. ThePK and pharmacology of these NOACs are distinct from thatof warfarin (Table 1, Fig. 1). In the present review, we willhighlight the PK and PD features of the 3 NOACs that haverecently been approved for stroke prevention in AF patientsand provide NOAC selection and dosing recommendationsbased on their PK-PD profiles.

Clinical Outcomes Data Comparing NOACs WithWarfarin

Dabigatran etexilate is the first oral direct thrombininhibitor to be approved for its clinical use in AF patients.2 Inthe 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: [email protected] page S32 for disclosure information.

0828-282X/$ - see front matter ! 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

















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.

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

between apixaban plasma concentrations and anti-FXa activitywas confirmed in elective hip/knee replacement patients.12

It is important to keep in mind that the sensitivityand precision of different reagents and instruments used forthese coagulation assays is yet to be established. Furthervalidation of these coagulation assays in measuring NOACanticoagulation response is required in the real-world clinicalsetting. Moreover, is it evident that variability in NOACplasma exposure will have a significant effect on anti-coagulation efficacy considering the direct PK-PD relationshipand its association with clinical outcomes; thus, quantifyingNOAC plasma concentration is likely the most reliableassessment of response and bleeding risk.

Selecting the Right OACAlthough the NOACs have shown efficacy similar or

greater than warfarin, it is unlikely that they will fully replacewarfarin. The interindividual variability in exposure/responseof NOACs and bleeding risk associated with anticoagulationtherapy remains a pertinent issue. Indeed, even in a clinicaltrial setting with stringent enrollment criteria, the 1-dose-fits-all dosing regimen strategy did not appear successful forNOACs, likely due to the various clinical covariates thatsignificantly affected extent of drug exposure and response(Fig. 2).41,44-47 Moreover, dabigatran and rivaroxaban useoutside of the clinical trial setting has recently been noted toexhibit large interindividual variability in concentration andresponse.47,48 The same trend is likely to be observed withapixaban as its clinical use increases.

Nevertheless, the emergence of multiple NOACs hasmeant greater therapeutic options for treating physicians.However, we are now starting to face the question of how toselect the most appropriate NOAC for individual patients.Factors to be assessed for deciding the right anticoagulantinclude 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-statedabigatran 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 ofvarious clinical variables and a genetic variation in the carboxylester-ase 1 (CES1) gene on dabigatran concentration based on known areaunder the concentration curve (AUC) change.44 The shaded arearepresents Ctrough dabigatran concentrations associated withincreased antithrombotic efficacy and decreased major bleeding riskaccording 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 20mg once daily administration is represented by the dashed black line(digitized from Mueck et al.).45 Coloured solid lines represent thepredicted effect of various clinical variables on rivaroxaban concen-tration based on known AUC change.45 Although the optimal plasmaCtrough of rivaroxaban has not been well defined as of yet, the shadedarea represents the 5%-95% confidence interval of Ctrough observed inthe Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared

With Vitamin K Antagonist for Prevention of Stroke and Embolism Trialin Atrial Fibrillation (ROCKET-AF) trial and the dashed line representsthe average Ctrough. (C) Predicted mean steady-state apixaban plasmaconcentrations after 5 mg twice-daily administration is represented bythe dashed black line (digitized from Leil et al.).46 Coloured solid linesrepresent the predicted effect of various clinical variables on apixabanconcentration based on known AUC change.12 The shaded arearepresents the population pharmacokinetics model predicted 5%-95%confidence interval of Ctrough in atrial fibrillation patients. Of note, theeffect of P-gp inhibition on dabigatran plasma concentration curveshown here was in the presence of the P-gp inhibitor verapamil. Theeffect of P-gp/CYP3A4 inhibition on rivaroxaban and apixaban plasmaconcentration curves shown here was in the presence of the P-gp/CYP3A4 inhibitor ketoconazole. P-gp/CYP3A4 was induced by rifam-picin for dabigatran, rivaroxaban, and apixaban. AF, atrial fibrillation;CrCl, creatinine clearance; Ctrough, trough plasma concentration; CYP,cytochrome P450; P-gp, P-glycoprotein; SNP, single-nucleotide poly-morphism.Disclaimer: We note that although the observed and expected plasmaconcentrations of rivaroxaban and apixaban, respectively, are shownhere, the relationship and interpretation of these concentrations toclinical events/outcomes remains to be seen as more data becomeavailable.


between apixaban plasma concentrations and anti-FXa activitywas confirmed in elective hip/knee replacement patients.12

It is important to keep in mind that the sensitivityand precision of different reagents and instruments used forthese coagulation assays is yet to be established. Furthervalidation of these coagulation assays in measuring NOACanticoagulation response is required in the real-world clinicalsetting. Moreover, is it evident that variability in NOACplasma exposure will have a significant effect on anti-coagulation efficacy considering the direct PK-PD relationshipand its association with clinical outcomes; thus, quantifyingNOAC plasma concentration is likely the most reliableassessment of response and bleeding risk.

Selecting the Right OACAlthough the NOACs have shown efficacy similar or

greater than warfarin, it is unlikely that they will fully replacewarfarin. The interindividual variability in exposure/responseof NOACs and bleeding risk associated with anticoagulationtherapy remains a pertinent issue. Indeed, even in a clinicaltrial setting with stringent enrollment criteria, the 1-dose-fits-all dosing regimen strategy did not appear successful forNOACs, likely due to the various clinical covariates thatsignificantly affected extent of drug exposure and response(Fig. 2).41,44-47 Moreover, dabigatran and rivaroxaban useoutside of the clinical trial setting has recently been noted toexhibit large interindividual variability in concentration andresponse.47,48 The same trend is likely to be observed withapixaban as its clinical use increases.

Nevertheless, the emergence of multiple NOACs hasmeant greater therapeutic options for treating physicians.However, we are now starting to face the question of how toselect the most appropriate NOAC for individual patients.Factors to be assessed for deciding the right anticoagulantinclude 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-statedabigatran 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 ofvarious clinical variables and a genetic variation in the carboxylester-ase 1 (CES1) gene on dabigatran concentration based on known areaunder the concentration curve (AUC) change.44 The shaded arearepresents Ctrough dabigatran concentrations associated withincreased antithrombotic efficacy and decreased major bleeding riskaccording 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 20mg once daily administration is represented by the dashed black line(digitized from Mueck et al.).45 Coloured solid lines represent thepredicted effect of various clinical variables on rivaroxaban concen-tration based on known AUC change.45 Although the optimal plasmaCtrough of rivaroxaban has not been well defined as of yet, the shadedarea represents the 5%-95% confidence interval of Ctrough observed inthe Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared

With Vitamin K Antagonist for Prevention of Stroke and Embolism Trialin Atrial Fibrillation (ROCKET-AF) trial and the dashed line representsthe average Ctrough. (C) Predicted mean steady-state apixaban plasmaconcentrations after 5 mg twice-daily administration is represented bythe dashed black line (digitized from Leil et al.).46 Coloured solid linesrepresent the predicted effect of various clinical variables on apixabanconcentration based on known AUC change.12 The shaded arearepresents the population pharmacokinetics model predicted 5%-95%confidence interval of Ctrough in atrial fibrillation patients. Of note, theeffect of P-gp inhibition on dabigatran plasma concentration curveshown here was in the presence of the P-gp inhibitor verapamil. Theeffect of P-gp/CYP3A4 inhibition on rivaroxaban and apixaban plasmaconcentration curves shown here was in the presence of the P-gp/CYP3A4 inhibitor ketoconazole. P-gp/CYP3A4 was induced by rifam-picin for dabigatran, rivaroxaban, and apixaban. AF, atrial fibrillation;CrCl, creatinine clearance; Ctrough, trough plasma concentration; CYP,cytochrome P450; P-gp, P-glycoprotein; SNP, single-nucleotide poly-morphism.Disclaimer: We note that although the observed and expected plasmaconcentrations of rivaroxaban and apixaban, respectively, are shownhere, the relationship and interpretation of these concentrations toclinical events/outcomes remains to be seen as more data becomeavailable.


































56 P&T®

In patients with AF, dabigatran 150 mg is taken twice daily with or without food. A reduced dose of 75 mg is recommended if the patient’s creatinine clearance (CrCl) is 15 to 30 mL/minute, as calculated with the Cockcroft–Gault formula using actual body weight (see Table 1). Clearance is primarily renal, and the drug is a substrate of permeability glycoprotein (P-gp). The use of dabigatran with P-gp inducers (such as rifampin) should be avoided. The combination of renal impairment and P-gp inhibition has a greater tendency to achieve undesirable concentrations when compared with each factor separately.12–14,26

For patients with moderate renal impairment (a CrCl of 30–50 mL/minute) who are concomitantly taking P-gp inhibitors such as dronedarone (Multaq, Sanofi) or systemic ketocon-azole, a reduced dose of 75 mg is recommended. Approval of the 75-mg dose was based on pharmacokinetic modeling data.14,26 The clinical efficacy of the reduced dose regimen has not been studied.7,10–14 Significant adverse effects occurring with dabigatran at a rate exceeding 15% include dyspepsia and gastritis-like symptoms.14

Routine monitoring of anticoagulation activity is not neces-sary if dabigatran is administered according to the manu-facturer’s recommendations. Dabigatran prolongs thrombin clotting time (TCT), prothrombin time (PT), activated partial thromboplastin time (aPTT), and ecarin clotting time (ECT). TCT, aPTT, and ECT can be used to estimate the drug’s serum concentration. However, the degree of aPTT elevation is not linearly correlated with the dabigatran concentration, and it is particularly inaccurate at higher concentrations of the drug.14,17

A boxed warning cautions against interruptions in dabigatran therapy to avoid an increased risk of stroke resulting from the drug’s short half-life. Therefore, withholding dabigatran for 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

hemodialysis can be considered for reversing life-threatening bleeding.27–30

Clinical Trials and Efficacy In the Randomized Evaluation of Long-Term Anticoagulation

Therapy trial (RE-LY), patients older than 65 years of age with AF received blinded doses of dabigatran 110 mg or 150 mg twice daily to establish non-inferiority versus unblinded, dose-adjust-ed warfarin. Study participants (n = 18,133) were observed for up to 2 years (Table 3).31–35 Two independent investigators who were blinded to treatment assignments confirmed the detection of events from hospital records to minimize potential reporting bias from unblinded INR monitoring. The mean CHADS2 score was 2.1 (see Table 3).32

The incidence of stroke and systemic embolism was similar between dabigatran 110 mg and warfarin (1.54% vs. 1.71% per year, respectively). The relative risk (RR) was 0.9 with a 95% con-fidence interval (CI) of 0.74 to 1.1 (P < 0.001 for non-inferiority).

The higher dose of dabigatran (150 mg twice daily) was associated with a significant reduction in stroke and systemic embolism compared with warfarin (1.11% per year; RR, 0.65%; 95% CI, 0.52–0.81; P < 0.001 for non-inferiority and superiority). Dabigatran 150 mg was associated with a lower incidence of both ischemic stroke (hazard ratio [HR], 0.75; 95% CI, 0.58–0.97) and hemorrhagic stroke (HR, 0.26; 95% CI, 0.14–0.49).

The primary safety outcome (major bleeding) for dabigatran 150 mg and 110 mg was 3.32% (P = 0.32) and 2.87% (P = 0.003) per year, respectively, compared with 3.57% per year with war-farin. The incidence of gastrointestinal bleeding was higher in the dabigatran 150-mg treatment arm compared with the warfarin arm, (1.5% vs. 1.02% annually respectively; RR, 1.5; 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 PM54 P&T®

ABSTRACTAtrial fibrillation (AF) is the most common cardiac arrhyth-

mia in the U.S. Anticoagulation is recommended for stroke prevention in AF patients with intermediate-to-high stroke risk (i.e., patients with a CHADS2 score of 1 or greater). Warfarin was previously the only option for oral anticoagulation in these patients, but three new oral anticoagulants have become avail-able as alternatives for warfarin in patients with nonvalvular AF. The advantages of the newer agents include a rapid onset, predictable pharmacokinetics, and no need for routine anti-coagulation monitoring.

Dabigatran (Pradaxa) and apixaban (Eliquis) have demonstrated improved efficacy compared with warfarin. Rivaroxaban (Xarelto) was non-inferior to warfarin for stroke prevention in AF. Apixaban demonstrated a reduced incidence of major bleeding compared with warfarin and a reduction in all-cause mortality.

Limitations to the use of the new oral anticoagulants include the lack of a reversal agent; an inability to use the therapies in specific patient populations (such as those with severe renal or hepatic impairment); limited experience with drug–drug and drug–disease interactions; and a lack of available coagulation tests to quantify their effects. Although the newer agents have higher acquisition costs, the benefits of cost savings may be derived from the potential for decreasing the incidence of hemorrhagic stroke and intracranial bleeding and reducing the need for anticoagulation monitoring. Benefits and risks should be carefully weighed before these agents are prescribed for patients presenting with new-onset AF.

Atrial fibrillation (AF) is the most common cardiac arrhyth-mia in U.S.1 The incidence and prevalence of AF increase with age.2 The number of people affected by AF is projected to exceed 12 million by 2050.3 The lifetime risk of AF in patients 40 years of age and older is estimated at 25%.3,4 Stroke is a major complication associated with AF, which contributes to the mor-bidity and mortality associated with the disease. Patients with AF have a four-fold to five-fold increased risk of stroke. This risk varies among patient populations, according to age, sex, and the presence of comorbid disease states (e.g., diabetes, hypertension, congestive heart failure, and vascular disease).3,5,6

Anticoagulation is recommended for stroke prevention for intermediate-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

Dr. Shafeeq is Assistant Clinical Professor in the College of Pharmacy and Health Sciences at St. John’s University in Queens, New York, 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.


54 P&T®


















P&T® 57

significant differences in the incidence of thrombosis, bleeding, and death between groups. Patients in the home-monitoring group included those taking warfarin for reasons other than AF. The TTR for home monitoring was 61.9%, which was slightly lower than TTR values in RE-LY.38

A secondary (facility-level) analysis of the RE-LY trial com-pared the efficacy of dabigatran versus warfarin. Study centers were stratified based on mean TTR quartiles (<57.1%, 57.1% to 65.5%, 65.5% to 72.6%, and >72.6%). Dabigatran 150 mg twice daily demonstrated a lower risk of stroke or systemic embo-lism across all quartiles of TTR. Meanwhile, rates of stroke or systemic embolism increased with lower-center TTR in the warfarin group. Fewer hemorrhagic strokes were noted in both dabigatran arms.37

Seven studies reported an estimated cost benefit of dabi-gatran over warfarin. Two studies from the United Kingdom, published in 2011, and one Danish study, published in 2012, demonstrated a beneficial incremental cost-effectiveness ratio (ICER) of dabigatran over warfarin with data from the RE-LY trial.39–41 The ICER describes the additional cost of using dabi-gatran over warfarin in order to see an improvement in one quality-adjusted life year (QALY), which is the easiest approach for estimating quality-of-life benefits. A wide range of ICERs have been reported for dabigatran, compared with warfarin, in European studies: $7,350 in patients younger than age 80; $12,300 for patients 80 years of age or older; and $35,800 for patients with CHADS2 scores of 3 or higher.39,40

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

more benefit with decreasing TTR on warfarin therapy. Cost-effectiveness was most sensitive to monthly costs of recurrent stroke , intracerebral hemorrhage (ICH), or both; the initial age of the cohort; the relative risk of stroke; the cost of dabigatran; and the TTR. Based on a willingness-to-pay threshold of $50,000 per QALY, dabigatran 150 mg was deemed to be cost-effective in the target population of patients 70 years of age and older with nonvalvular AF, prior stroke, or transient ischemic attack, and with no contraindications to anticoagulation. Notable excep-tions in which no cost–benefit was seen applied to patients 81 years of age and older, a TTR with warfarin greater than 73%, and monthly costs of dabigatran exceeding $320.

In another U.S. analysis, dabigatran was generally considered to be cost-effective as an alternative to warfarin, but it appeared to be less cost-effective when daily dabigatran costs exceeded $13.70 for the high dose (150 mg) in patients 65 years of age and older.45

Medicare Part D currently provides coverage for dabigatran. The wholesale cost of dabigatran 150 mg twice daily, according to Red Book, is $10 per day, which may support warfarin as a more economical option, especially for patients paying out of pocket.46 The cost-effectiveness analysis comparing dabigatran with the other new oral anticoagulants is discussed on page 62.47

Factor Xa enables the conversion of prothrombin to throm-bin, which is involved in the formation of clots. Rivaroxaban 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% warfarin1.54% dabigatran 110 mg 1.11% dabigatran 150 mga,b

2.4% warfarin2.1% rivaroxaban

1.6% warfarin1.27% apixabana,b

Safety

Major bleeding 3.57% warfarin2.87% dabigatran 110 mga

3.32% dabigatran 150 mg


3.09% warfarin2.13% apixabana

Intracranial hemorrhage (%/year) 0.74% warfarin0.23% dabigatran 110 mga

0.3% dabigatran 150 mga

0.7% warfarin0.5% rivaroxabana

0.8% warfarin0.33% apixaban

Myocardial Infarction 0.64% warfarin0.82% dabigatran 110 mg 0.81% dabigatran 150 mg


0.61% warfarin0.53% apixaban

a P < 0.05. b Superiority.Data from Connelly et al., Granger et al., and Patel et al.32–35


54 P&T®


















54 P&T®


















Avai lable onl ine at www.sc iencedirect .com

journal homepage: www.elsevier .com/ locate / jva l

Cost-Effectiveness of New Oral Anticoagulants Compared with Warfarinin Preventing Stroke and Other Cardiovascular Events in Patients withAtrial FibrillationDoug 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,!

1Faculty of Medicine, Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Canada; 2Applied Health Economic Research Unit,Ottawa, Canada; 3University of Ottawa Heart Institute, Ottawa, Canada; 4Canadian Agency for Drugs and Technologies in Health Ottawa, Canada;5Department 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 warfarinin patients with nonvalvular atrial fibrillation. Secondary objectivesrelated to assessing the cost-effectiveness of new oral anticoagu-lants stratified by center-specific time in therapeutic range, age, andCHADS2 score. Methods: Cost-effectiveness was assessed by theincremental cost per quality-adjusted life-year (QALY) gained. Anal-ysis used a Markov cohort model that followed patients frominitiation of pharmacotherapy to death. Transition probabilitieswere obtained from a concurrent network meta-analysis. Utilityvalues and costs were obtained from published data. Numerousdeterministic sensitivity analyses and probabilistic analysis wereconducted. Results: The incremental cost per QALY gained fordabigatran 150 mg versus warfarin was $20,797. Apixaban producedequal QALYs at a higher cost. Dabigatran 110 mg and rivaroxabanwere 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, apatient’s CHADS2 score, and patient age, with either dabigatran 150mg or apixaban being optimal. Conclusions: Results were highlysensitive to patient characteristics. Rivaroxaban and dabigatran 110mg were unlikely to be cost-effective. For different characteristics,apixaban or dabigatran 150 mg were optimal. Thus, the choicebetween these two options may come down to the price of apixabanand further evidence on the impact of major and minor bleeds withdabigatran.Keywords: anticoagulants, atrial fibrillation, cardiovascular, cost-effectiveness, warfarin.

Copyright & 2013, International Society for Pharmacoeconomics andOutcomes 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 riskof death and have higher annual rates of mortality [1,2]. AF andstroke are more common among the elderly [3,4].

Preventing events such as stroke is an important part ofmanaging patients with AF. Antithrombotic strategies forpatients 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 withAF but are associated with some drawbacks, including a need forlaboratory monitoring, an increased risk of bleeding complica-tions, and several food and drug interactions [5,6]. Recently, anumber of new oral anticoagulants (NOACs) have been approved,including dabigatran, a direct thrombin inhibitor, and the directfactor Xa inhibitors, rivaroxaban and apixaban.

While dabigatran, apixaban, and rivaroxaban have been dem-onstrated to be effective in preventing stroke/systemic embolismin patients with AF, the comparative cost-effectiveness of theseNOACs is not clear. Currently, treatment with warfarin includingregular international normalized ratio monitoring costs less than$300 per annum. The new anticoagulants examined in this studycost more than $1100 per annum. Thus, the cost-effectiveness ofthese agents will depend on the balance between the increasedbenefits in terms of stroke prevention, the effect on bleedingrates, and the increased drug costs [7–11]. This analysis is the firstsystematic, independent analysis of the cost-effectiveness of allthree NOACs in comparison to warfarin in patients withnonvalvular AF.

This study involved incorporating data from a concurrentsystematic review into an economic model of NOAC use inCanada [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: [email protected].

* Address correspondence to: George A. Wells, Cardiovascular Research Methods Centre, University of Ottawa Heart Institute, 40 RuskinStreet, Ottawa, ON, Canada K1Y 4W7.

VA L U E I N H E A L T H 1 6 ( 2 0 1 3 ) 4 9 8 – 5 0 6

Avai lable onl ine at www.sc iencedirect .com

journal homepage: www.elsevier .com/ locate / jva l

Cost-Effectiveness of New Oral Anticoagulants Compared with Warfarinin Preventing Stroke and Other Cardiovascular Events in Patients withAtrial FibrillationDoug 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,!

1Faculty of Medicine, Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Canada; 2Applied Health Economic Research Unit,Ottawa, Canada; 3University of Ottawa Heart Institute, Ottawa, Canada; 4Canadian Agency for Drugs and Technologies in Health Ottawa, Canada;5Department 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 warfarinin patients with nonvalvular atrial fibrillation. Secondary objectivesrelated to assessing the cost-effectiveness of new oral anticoagu-lants stratified by center-specific time in therapeutic range, age, andCHADS2 score. Methods: Cost-effectiveness was assessed by theincremental cost per quality-adjusted life-year (QALY) gained. Anal-ysis used a Markov cohort model that followed patients frominitiation of pharmacotherapy to death. Transition probabilitieswere obtained from a concurrent network meta-analysis. Utilityvalues and costs were obtained from published data. Numerousdeterministic sensitivity analyses and probabilistic analysis wereconducted. Results: The incremental cost per QALY gained fordabigatran 150 mg versus warfarin was $20,797. Apixaban producedequal QALYs at a higher cost. Dabigatran 110 mg and rivaroxabanwere 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, apatient’s CHADS2 score, and patient age, with either dabigatran 150mg or apixaban being optimal. Conclusions: Results were highlysensitive to patient characteristics. Rivaroxaban and dabigatran 110mg were unlikely to be cost-effective. For different characteristics,apixaban or dabigatran 150 mg were optimal. Thus, the choicebetween these two options may come down to the price of apixabanand further evidence on the impact of major and minor bleeds withdabigatran.Keywords: anticoagulants, atrial fibrillation, cardiovascular, cost-effectiveness, warfarin.

Copyright & 2013, International Society for Pharmacoeconomics andOutcomes 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 riskof death and have higher annual rates of mortality [1,2]. AF andstroke are more common among the elderly [3,4].

Preventing events such as stroke is an important part ofmanaging patients with AF. Antithrombotic strategies forpatients 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 withAF but are associated with some drawbacks, including a need forlaboratory monitoring, an increased risk of bleeding complica-tions, and several food and drug interactions [5,6]. Recently, anumber of new oral anticoagulants (NOACs) have been approved,including dabigatran, a direct thrombin inhibitor, and the directfactor Xa inhibitors, rivaroxaban and apixaban.

While dabigatran, apixaban, and rivaroxaban have been dem-onstrated to be effective in preventing stroke/systemic embolismin patients with AF, the comparative cost-effectiveness of theseNOACs is not clear. Currently, treatment with warfarin includingregular international normalized ratio monitoring costs less than$300 per annum. The new anticoagulants examined in this studycost more than $1100 per annum. Thus, the cost-effectiveness ofthese agents will depend on the balance between the increasedbenefits in terms of stroke prevention, the effect on bleedingrates, and the increased drug costs [7–11]. This analysis is the firstsystematic, independent analysis of the cost-effectiveness of allthree NOACs in comparison to warfarin in patients withnonvalvular AF.

This study involved incorporating data from a concurrentsystematic review into an economic model of NOAC use inCanada [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: [email protected].

* Address correspondence to: George A. Wells, Cardiovascular Research Methods Centre, University of Ottawa Heart Institute, 40 RuskinStreet, Ottawa, ON, Canada K1Y 4W7.

VA L U E I N H E A L T H 1 6 ( 2 0 1 3 ) 4 9 8 – 5 0 6

major clinical trials). A cycle length of 3 months was adopted,with sensitivity analysis using cycle lengths of 1 month, 6months, and 1 year. Future events were discounted at a rate of5% per annum, with sensitivity analysis using rates of 0% and 3%.

Efficacy, Safety, and Adverse Events

The baseline estimates for the annual rates of clinical events onwarfarin and the probability that events were fatal were obtainedfrom the RE-LY RCT (Table 1) [14]. Sensitivity analysis adoptedwarfarin event rates from other major RCTs to assess the impacton results. No differences in event fatality rates between treat-ments were assumed. For incorporation into the economicmodel, transition probabilities for the duration of cycle lengthwere obtained by using standard methodology.

The estimate for the transition probability for each event fordabigatran, apixaban, and rivaroxaban was derived by using theodds ratio for each treatment obtained from a network meta-analysis. A detailed description of the methods and results of thenetwork meta-analysis are available elsewhere [12]. Based on theavailable results, the following events were modeled to vary byanticoagulant: stroke, MI, major bleeds, and ICH. In addition, themodel incorporated the same risks of minor bleeds, PE, and TIAfor all anticoagulants. Sensitivity analyses were conducted incor-porating the relative risks of minor bleeds and nonvasculardeaths.

Utility Values

Utility values were based on whether the patients experienced anevent (MI, stroke, PE, TIA, ICH, and extracranial hemorrhage) inthe 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 ontreatment. 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 byusing the Bank of Canada Inflation Calculator [34]. Drug costswere obtained from the Ontario Drug Benefit formulary or fromthe drug manufacturer [27]. Because no drug costs were availablefor apixaban at the time of the analysis, the costs were assumedto equal the drug costs for dabigatran. For each drug therapy,annual drug treatment costs include a $7 prescription fee (every 3months) and an 8% pharmacist’s markup. For warfarin, an addi-tional cost of international normalized ratio monitoring wasadded [28]. The costs of events and any associated long-term

care were obtained from the most recently available Canadiansources (Table 1) [11,29–32,35]. In sensitivity analyses, costs wereincreased and decreased by 50%.

Deterministic Sensitivity Analysis

A wide range of univariate sensitivity analyses were conducted totest the effect of changes in underlying parameter values andassumptions within the models. An Online Appendix in Supple-mental Materials found at doi: 10.1016/j.jval.2013.01.009 detailsthe range and results of these analyses.

Threshold Analysis

Threshold analysis was conducted to assess the value of aparameter required to lead to change in the interpretation ofthe base result. This was based on assuming a willingness-to-payvalue of $50,000 for a QALY. Analysis was conducted for param-eters for which there was limited information: that is, the price ofapixaban and the consequences of minor and major bleeds withdabigatran.

Probabilistic Sensitivity Analysis

Probabilistic sensitivity analysis was conducted by using a MonteCarlo simulation [29]. For the Monte Carlo simulation, probabilitydistributions related to natural history parameters, relative risksand odds ratios, costs, and utilities were incorporated into theanalysis. Analysis adopted standard methods for defining uncer-tainty around parameters (Table 1). Estimates of incrementalcosts 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 outcomeestimates was obtained. Cost-effectiveness acceptability curvesthat present the probability that each treatment is optimal givendifferent values of willingness to pay for an additional QALY werederived [36].

Analysis of Variability

Stratified analyses were conducted to assess the sensitivity of theresults to changes in the underlying patient population. Stratifiedanalyses incorporated, where possible, different warfarin-relatedevent rates based on the patient profile and available data. Inaddition, where possible, different estimates of the relativetreatment effect of the newer oral anticoagulants compared withwarfarin were included. Analyses were conducted to stratifypatient 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 6.480Dabigatran 150 mg 21,486 6.617 20,797 20,797

Dominated therapiesApixaban 21,966 6.617 24,312 Dominated by dabigatran 150 mgRivaroxaban 22,016 6.541 55,757 Dominated by dabigatran 150 mg and apixabanDabigatran 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 thetreatment.ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-year.

VA L U E I N H E A L T H 1 6 ( 2 0 1 3 ) 4 9 8 – 5 0 6502

These criteria relate to the degree of stroke risk for patientsreceiving warfarin.

Results

Base-Case Analysis

Treatment with dabigatran 110 mg ($22,804) is more costly thanwith rivaroxaban ($22,016), apixaban ($21,966), dabigatran 150 mg($21,486), and warfarin ($18,620). For dabigatran 150 mg, treat-ment costs were the greatest component of costs (Table 2). For allother treatments, stroke-related costs were the greatest costcomponent.

Dabigatran 150 mg and apixaban were the most effectivetreatments in terms of QALYs (6.617). Dabigatran 110 mg (6.543)and rivaroxaban (6.541) also produce more QALYs than warfarinbut fewer than dabigatran 150 mg and apixaban.

The incremental cost per QALY gained (ICUR) for dabigatran150 mg versus warfarin was $20,797. Because dabigatran 110 mg,apixaban, and rivaroxaban were more expensive and producedless or equal QALYs, they were all dominated by dabigatran150 mg.

Deterministic Sensitivity Analysis

The Online Appendix provides the results of the detailed uni-variate sensitivity analysis. The interpretation of the results wasgenerally robust with the exception of the following.

Results were sensitive to the drug costs of apixaban. With a10% reduction in the price of apixaban, apixaban would be cost-effective assuming a maximum willingness-to-pay value of atleast $18,077 for a QALY. If the cost of apixaban was reduced by20% to $2.56 per tablet, apixaban would be cost-effective assum-ing a maximum willingness-to-pay value of at least $11,742 fora QALY.

Results were very sensitive to the time horizon adopted. Witha time horizon of 10 years, the ICUR for dabigatran versus that forwarfarin was $50,455. With a time horizon of 2 years (the typicalduration of the RCTs considered within the network meta-analysis), apixaban produced more QALYs than did dabigatran150 mg but the ICUR compared with that for warfarin was$362,797.

If the relative effects of treatments on nonvascular deathswere included, rivaroxaban would be optimal as the ICUR forrivaroxaban versus that for warfarin was $8278.

If treatment discontinuations not related to vascular eventswere included in the analysis, apixaban produced more QALYs

than did dabigatran 150 mg with an ICUR compared with that ofwarfarin of $21,911.

In the analysis comparing switching patients from dabigatran150 mg to dabigatran 110 mg at age 80 years to staying ondabigatran, staying on dabigatran 150 mg was more cost-effective.

If patients had a previous major stroke, the incremental costper QALY for all treatments relative to warfarin increased; theICUR for dabigatran 150 mg versus that for warfarin was $144,801.

Threshold Analyses

Threshold analysis assumed a willingness-to-pay value of$50,000 per QALY gained.

If the cost and disutility associated with major and minorbleeds for dabigatran were 38% higher than estimated, apixabanwould be cost-effective. Apixaban would be more cost-effectivethan dabigatran 150 mg if the price of apixaban was less than$3.01 per tablet. Rivaroxaban would be cost-effective if the pricewas lowered to $1.10 per tablet.

Probabilistic Sensitivity Analysis

The probabilistic sensitivity analysis highlights the uncertaintyaround conclusions relating to cost-effectiveness (Fig. 2). At awillingness-to-pay value of $50,000 for a QALY, dabigatran 150 mgwas the optimal treatment in 50.8% of the replications, apixabanin 44.1%, rivaroxaban in 2.1%, dabigatran 110 mg in 1.6%, andwarfarin in 1.4%. Results were similar for all values of l from$40,000 to $100,000.

Analysis of Variability

Table 3 provides detailed results of the analysis by variability.Results were very sensitive to patient’s baseline CHADS2 score.Based on a threshold of $50,000 per QALY gained, dabigatran 150mg was optimal if the CHADS2 score was less than 2 or more than2 with previous minor stroke. Apixaban would be optimal if theCHADS2 score was 2 or more with no previous stroke.

Based on a threshold of $50,000, dabigatran 150 mg wasoptimal for patients aged younger than 60 and 70 years andapixaban was optimal for those aged 80 years.

In centers in which the TTR was less than 66%, dabigatran 150mg would be optimal based on a threshold of $50,000. In centersin which the TTR was 66% or more, apixaban would be optimal.

Discussion

In the base-case analysis, dabigatran 150 mg was likely to be theoptimal treatment choice assuming that a decision maker waswilling to pay at least $20,797 per QALY. However, the conclusionsare uncertain given that apixaban was associated with equalQALYs at only a slightly higher cost. The results of the proba-bilistic analysis illustrate this further in that the probability thatdabigatran was optimal was no higher than 51%. Results wereinsensitive to many of the parameter assumptions within themodel except for the cost of apixaban and the costs andconsequences from minor and major bleeds with dabigatran.

The results need to be placed in context with recent studies inthis area. Five separate analyses of the cost-effectiveness ofdabigatran versus warfarin in patients with nonvalvular AF havebeen published [7–11,37]. All studies were heavily reliant onclinical data from the RE-LY clinical trial and adopted Markovmodels of similar format. No studies of the cost-effectiveness ofrivaroxaban or apixaban in this population have been published.Similar to our study, a UK study funded by the Medical ResearchCouncil found that dabigatran would not be cost-effective incenters in which patients achieved good therapeutic control

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

$0 $20,000 $40,000 $60,000 $80,000 $100,000

Prob

abili

ty T

reat

men

t is

Op!

mal

Threshold Value for a QALY

Warfarin Dabigatran 150mg Rivaroxaban Apixaban Dabigatran 110mg

Fig. 2 – Cost-effectiveness Acceptability Curve.

VA L U E I N H E A L T H 1 6 ( 2 0 1 3 ) 4 9 8 – 5 0 6 503

AVERROES Study

28

Apixaban Event rate

(%/year)

ASA Event rate (%/year)

Apixaban vs ASA

P ValueStroke or systemic embolism

1.62 3.63 <0.001

Ischemic stroke 1.37 3.11 <0.001Hemorrhagic stroke

0.19 0.28 0.45

Major bleeding 1.41 0.92 0.07

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-gp29

well as cost considerations following an extensive discussion on risks andbenefits of both therapies.

If NOACs are chosen, we recommend either dabigatran, apixaban orrivaroxaban in patients aged b75 years and with no upper gastrointes-tinal history (i.e., dyspepsia, gastroesophageal reflux), prior MI/ACS,renal dysfunction or HAS-BLED ≥ 3. In patients who prefer once-dailydrugs, rivaroxaban should be prescribed.

In patients with one or more of the above concomitant conditions,our recommendation is either apixaban or rivaroxaban (with the properdose-adjustments when indicated). However, rivaroxaban is not pro-posed if patients have a prior history of gastrointestinal bleeding,which has been shown to be a strong predictor for major bleeding inpatient treated with this agent [105].

In patients ≥75 years old with none of the concomitant charac-teristics listed in our algorithm, we still recommend either apixaban

or rivaroxaban, whereas in the presence of one or more of the condi-tions listed above,we recommendonly apixaban due to its better effica-cy/safety balance in elderly patients who often have concomitant renalfailure and are at high risk of bleeding, especially gastrointestinal.

In patients who refuse oral anticoagulation and are at a low riskof bleeding, the recommendation is aspirin plus clopidogrel and, lesseffectively, aspirin alone.

6. Cost-effectiveness

Given the high burden of AF-related stroke and that NOACs canmoreeffectively prevent stroke than warfarin, albeit at a higher drug cost,there is a need for a systematic evaluation of the costs and benefits ofthese new agents due to the lack of clear indications on this issue bycurrent guidelines [1,10,35].

Non-Valvular AF

TTR ≥ 70% for 6 monthsdespite compliance/adherence

Yes

Continue on Warfarinor 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 NOACsif good compliance/adherence

Yes

NoNo antithrombotic therapy

CHA2DS2-VASc ≥ 1

No

Yes No

Age < 75 yrs Age ≥ 75 yrs

Upper GI historyPrior MI/ACS

CrCl 30-60 mL/minHAS-BLED ≥ 3

either Apixabanor Dabigatran

or Rivaroxaban

either Apixabanor Rivaroxaban

Yes for 1 or more

Upper GI historyPrior MI/ACS

CrCl 30-60 mL/minHAS-BLED ≥ 3

Yes for 1 or more

either Apixabanor Rivaroxaban

Apixaban

Aspirin plus clopidogrel, or, less effectively, aspirin alone may be considered only when patients at low risk of bleeding refuse any oral anticoagulation.

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

Fig. 1. An evidence-based algorithm for the management of oral anticoagulation in patients with non-valvular atrial fibrillation utilized at the authors' current institutions. TTR, time intherapeutic range with international normalized ratio (INR) between 2 and 3; AF, atrial fibrillation; NOAC, newer oral anticoagulant; CHA2DS2-VASc (Congestive heart failure, Hypertension,Age ≥ 75 years [doubled], Diabetes mellitus, prior Stroke/TIA [doubled], Vascular disease (myocardial infarction, complex aortic plaque, and peripheral artery disease), Age 65–74 years andSex category [female sex]) score is ameasure of the risk of stroke, the score is calculated by summing all the points for a given patient; SAMe-TT2R2 (Sex female, Age b 60 years,Medical history,Treatment, Tobacco use [doubled] and Race [doubled]) score is a measure for predicting the quality of INR control, the score is calculated by summing all the points for a given patient; GI,gastrointestinal;MI,myocardial infarction; ACS, acute coronary syndromes; CrCl, creatinine clearance;HAS-BLED (Hypertension,Abnormal renal or liver function [1 point each], Stroke, Bleedinghistory or predisposition, Labile INR [TTR b 60%], Elderly [N65 years], and Drugs or alcohol abuse [1 point each; includes antiplatelets or anti-inflammatory drugs]) score is ameasure to stratifythe risk of bleeding, the score is calculated by summing all the points for a given patient.

10 S. Rosanio et al. / International Journal of Cardiology xxx (2014) xxx–xxx

Please cite this article as: Rosanio S, et al, Pharmacology, benefits, unaddressed questions, and pragmatic issues of the newer oral anticoagulantsfor stroke prophylaxis in non..., Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.179

Review

Pharmacology, benefits, unaddressed questions, and pragmatic issues ofthe newer oral anticoagulants for stroke prophylaxis in non-valvularatrial 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 ba Department of Internal Medicine, Division of Cardiology, University of North Texas Health Science Center, Fort Worth, TX, United Statesb 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 2013Received in revised form 6 March 2014Accepted 17 April 2014Available online xxxx

Keywords:Atrial fibrillationStrokeDabigatranRivaroxabanApixabanEdoxaban

This systematic review aims to provide an update on pharmacology, efficacy and safety of the newer oral directthrombin and factor Xa inhibitors, which have emerged for the first time in ~60 years as cogent alternatives towarfarin for stroke prophylaxis in non-valvular atrial fibrillation. We also discuss on four of the most commonclinical 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 coronarystenting; and 4) patients planning to receive AF ablation with the use of pulmonary vein isolation. New aspectspresented in current guidelines are covered andwe also propose an evidence-based anticoagulationmanagementalgorithm.

© 2014 Elsevier Ireland Ltd. All rights reserved.

1. Introduction

Non-valvular atrial fibrillation (AF) in the absence of rheumaticmitral stenosis or a prosthetic heart valve is themost common sustainedcardiac rhythm disorder worldwide, occurring in 1 to 2% of the generalpopulation [1,2]. AF affects over 2 million people in the US and over6 million across the European Union and occurs more frequently inthe elderly [1,2]. As such, the prevalence of AF is projected to doublein 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 cardioembolicand one-third being atherothrombotic [4].

Atrial fibrillation-related strokes are more likely to be massive, areoften fatal or associated with long-term disability and exhibit highrecurrence rates compared to strokes of other etiologies [5]. Due tothe nature of these events, strokes represent amajor public health prob-lem with a huge economic burden. In the US, the estimated direct andindirect costs of stroke were $34.3 billion in 2008 [6].

The long-term risk of stroke in AF depends on the clinical predictorscollectively assessed in the CHADS2 scoring scheme inwhich Congestiveheart failure, Hypertension, Age ≥ 75 years and Diabetes mellitus areeach assigned one point or two points for a history of Stroke/transientischemic attack [TIA] or CHA2DS2-VASc, which considers additional riskfactors, such as vascular disease (myocardial infarction [MI], complexaortic 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 Societyof Cardiology guidelines recommend that all patients with AF and aCHADS2 or CHA2DS2-VASc score ≥ 1 should be on long-term oralanticoagulation [1,10].

Warfarin, the most prescribed oral anticoagulant acts by loweringthe serum levels of vitamin K-dependent pro-coagulant proteins andis highly effective for the prevention of AF-related stroke, resulting ina 64% risk reduction compared to placebo and a 37% risk reduction com-pared with antiplatelet therapy [11]. However, warfarin has severaldrawbacks (slow onset and offset of action; narrow therapeutic range[international normalized ratio, INR of 2.0–3.0] that requires regularmonitoring; several interactionswith food, alcohol, and drugs; potentialethnic, genetic, and age-related variations in dose response; and highbleeding risk [0.3–0.5%/yr]), which have resulted in its suboptimal usein clinical practice and promoted the search for more convenient andsafer oral anticoagulants [12–18].

International Journal of Cardiology xxx (2014) xxx–xxx

⁎ Corresponding author at: Department of Internal Medicine, Division of Cardiology,855 Montgomery Street, PCC Room 315, Fort Worth, TX 76107, United States. Tel.: +1 817735 7624x2072 (office); fax: +1 817 735 2748.

E-mail address: [email protected] (S. Rosanio).

IJCA-18080; No of Pages 13

http://dx.doi.org/10.1016/j.ijcard.2014.04.1790167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.

Contents lists available at ScienceDirect

International Journal of Cardiology

j ourna l homepage: www.e lsev ie r .com/ locate / i j ca rd


Review

Pharmacology, benefits, unaddressed questions, and pragmatic issues ofthe newer oral anticoagulants for stroke prophylaxis in non-valvularatrial 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 ba Department of Internal Medicine, Division of Cardiology, University of North Texas Health Science Center, Fort Worth, TX, United Statesb 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 2013Received in revised form 6 March 2014Accepted 17 April 2014Available online xxxx

Keywords:Atrial fibrillationStrokeDabigatranRivaroxabanApixabanEdoxaban

This systematic review aims to provide an update on pharmacology, efficacy and safety of the newer oral directthrombin and factor Xa inhibitors, which have emerged for the first time in ~60 years as cogent alternatives towarfarin for stroke prophylaxis in non-valvular atrial fibrillation. We also discuss on four of the most commonclinical 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 coronarystenting; and 4) patients planning to receive AF ablation with the use of pulmonary vein isolation. New aspectspresented in current guidelines are covered andwe also propose an evidence-based anticoagulationmanagementalgorithm.

© 2014 Elsevier Ireland Ltd. All rights reserved.

1. Introduction

Non-valvular atrial fibrillation (AF) in the absence of rheumaticmitral stenosis or a prosthetic heart valve is themost common sustainedcardiac rhythm disorder worldwide, occurring in 1 to 2% of the generalpopulation [1,2]. AF affects over 2 million people in the US and over6 million across the European Union and occurs more frequently inthe elderly [1,2]. As such, the prevalence of AF is projected to doublein 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 cardioembolicand one-third being atherothrombotic [4].

Atrial fibrillation-related strokes are more likely to be massive, areoften fatal or associated with long-term disability and exhibit highrecurrence rates compared to strokes of other etiologies [5]. Due tothe nature of these events, strokes represent amajor public health prob-lem with a huge economic burden. In the US, the estimated direct andindirect costs of stroke were $34.3 billion in 2008 [6].

The long-term risk of stroke in AF depends on the clinical predictorscollectively assessed in the CHADS2 scoring scheme inwhich Congestiveheart failure, Hypertension, Age ≥ 75 years and Diabetes mellitus areeach assigned one point or two points for a history of Stroke/transientischemic attack [TIA] or CHA2DS2-VASc, which considers additional riskfactors, such as vascular disease (myocardial infarction [MI], complexaortic 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 Societyof Cardiology guidelines recommend that all patients with AF and aCHADS2 or CHA2DS2-VASc score ≥ 1 should be on long-term oralanticoagulation [1,10].

Warfarin, the most prescribed oral anticoagulant acts by loweringthe serum levels of vitamin K-dependent pro-coagulant proteins andis highly effective for the prevention of AF-related stroke, resulting ina 64% risk reduction compared to placebo and a 37% risk reduction com-pared with antiplatelet therapy [11]. However, warfarin has severaldrawbacks (slow onset and offset of action; narrow therapeutic range[international normalized ratio, INR of 2.0–3.0] that requires regularmonitoring; several interactionswith food, alcohol, and drugs; potentialethnic, genetic, and age-related variations in dose response; and highbleeding risk [0.3–0.5%/yr]), which have resulted in its suboptimal usein clinical practice and promoted the search for more convenient andsafer oral anticoagulants [12–18].

International Journal of Cardiology xxx (2014) xxx–xxx

⁎ Corresponding author at: Department of Internal Medicine, Division of Cardiology,855 Montgomery Street, PCC Room 315, Fort Worth, TX 76107, United States. Tel.: +1 817735 7624x2072 (office); fax: +1 817 735 2748.

E-mail address: [email protected] (S. Rosanio).

IJCA-18080; No of Pages 13

http://dx.doi.org/10.1016/j.ijcard.2014.04.1790167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.

Contents lists available at ScienceDirect

International Journal of Cardiology

j ourna l homepage: www.e lsev ie r .com/ locate / i j ca rd


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

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.

Coumadin Dabigatran 150 Rivaroxaban Apixaban

STROKE

ICH

GIB NNH 100/2yrs NNH 100/2yrs

REVERSAL

MI

D/C Dyspepsia

RENAL CrCl<30 CrCl<30 CrCl<15

COST

MONITORING

Health & Medicine

Strike out stroke arh