When the rubber meets the road: Real

world data on NOACs- a problem or

myth?
Dr. Deepa Suryanarayan, MD FRCPC
Department of Hematology and Thromboembolism
McMaster University

Disclosures
Nothing to declare

Objectives
Brief review of the clinical trial data of Non Vitamin K antagonist oral
anticoagulants (NOACs)
Compare the clinical trial data with the "real world" data
Touch upon some of the "unresolved concerns" and limitations of NOACs
and some solutions that may be forthcoming

The high stakes balancing act of

anticoagulation
Efficacy and safety are equally
important
Imbalance in either one of them
can result in substantial harm

Novel Anticoagulants for Stroke Prevention in Atrial Fibrillation

Dabigatrana

Apixabanc

RE-LY
Reported
September
2009

2009

2010

ARISTOTLE
Reported
September 2011

2011

2012

Rivaroxabanb

ROCKET-AF
Reported
November
2010

a. Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151

b. Patel MR, et al. N Engl J Med. 2011;365:883-891.
c. Granger CB, et al. N Engl J Med. 2011;365:981-992
d. Giugliano RP, et al. N Engl J Med. 2013;369:2093-2104

2013

2014

Edoxaband
ENGAGE
Report
November
2013

VKAs versus NOACs

Dabigatran

Rivaroxaban

Apixaban

Edoxaban

VKA

Mode of action

Direct thrombin
inhibitor

Factor Xa inhibitor

Factor Xa inhibitor

Factor Xa inhibitor

Vitamin K
antagonist

Bioavailability

3-7%

66% without food, 100%

with food

50%

62%

100%

Elimination half
life

12-17 hrs

12 hrs

9-11 hrs

5-9 hrs (young)

11-13 hrs (elderly)

36-42 hrs

Dose in AF

110 mg bid or
150 mg bid

20 mg od

5 mg bid or 2.5 mg
bid

30 mg od or 60 mg
od

INR 2.0-3.0

Dose in VTE

220 mg od or 150
mg qd (prev);
150 mg bid (tx)

10 mg qd(prev); 15 mg bid
then 20 mg od (tx)

2.5 mg bid (prev); 5

mg bid (tx)

60 mg qd(tx)

INR 2.0-3.0

Time to max
inhibition

0.5-2.0 hrs

2-4 hrs

3-4 hrs

9-11 hrs

72-96 hrs

Phase 3 clinical
trial

RE-LY
Recover,
Recover II
REMEDY

ROCKET-AF
EINSTEIN

ARISTOTLE
AMPLIFY

ENGAGE-AF
HOKUSAI-VTE

ACTIVE-W
SPAF

Year of approval
by FDA

For AF- October

2010
For VTE- April
2014

For AF- Nov 2011

For VTE- Nov 2012

For AF- Dec 2012

For VTE- Aug 2014

For AF and VTE- Jan

2015

1964

Heidbuchel H, Verhamme P, Alings M, et al. European Heart Rhythm Association Practical Guide on the use of new oral
anticoagulants in patients with non-valvular atrial fibrillation. Europace. 2013;15:625651.

Decision tree for antithrombotic therapy in patients with non-valvular atrial fibrillation.

Paulus Kirchhof et al. Eur Heart J 2013;34:1471-1474

Potential limitations of NOACs

Short half life Potential for increased risk of stroke or VTE with poor drug
adherence
Limited availability of lab assays Unable to measure anticoagulation
effect, cannot titrate dose, cannot assess cause for failure of therapy,
cannot assess coagulation inhibition in emergent situations such as urgent
surgery or life threatening bleed
Lack of specific antidote
Drug acquisition costs
Use contraindicated or dose reduction required in patients with sever CKD

Granger CB, Armaganijan L V. Newer Oral Anticoagulants Should Be Used as First-Line Agents to Prevent Thromboembolism in Patients
with Atrial Fibrillation and Risk Factors for Stroke or Thromboembolism. Circulation. 2012;125:159164.

Clinical trial vs real world - Efficacy vs

Effectiveness
Clinical trial-safe and protected
environment
Monitoring is not needed

But in the real world!!

Why should we care about any "real

world" data versus clinical trial?
Efficacy (Clinical trial data)

Effectiveness (Real-world data)

Does it work under ideal

circumstances?

Does it work under usual

circumstances?

Controlled clinical trial

environment

Real world clinical practice

Geared to get FDA approval

Drug performance in the real

world

Fixed regimen with highly

motivated patients

Flexible regimen with your regular

day to day clinic patient

Compliance usually high

Low to high compliance

External validity - low to medium

External Validity- Medium to high

Efficacy data

Comparison of the efficacy and safety of new oral

anticoagulants with warfarin in patients with atrial
fibrillation: a meta-analysis of randomized trials

Christian T Ruff , Robert P Giugliano, Eugene Braunwald, Elaine B Hoff man, Naveen Deenadayalu, Michael D Ezekowitz, A John
Camm, Jeffrey I Weitz, Basil S Lewis, Alexander Parkhomenko, Takeshi Yamashita, Elliott M Antman

4 randomized trials 2009-2013

42,411 patients randomized to NOAC, 29272 to warfarin
Primary analysis was on high dosages ( Dabigatran 150 mg, Rivaroxaban
20 mg, Apixaban 5 mg and Edoxaban 60 mg)

Stroke or systemic embolic events in

large NOAC trials vs warfarin

NOACs associated with a RRR of 20% compared to

warfarin

Ruff CT et al., The Lancet, 2014;383:955-62

NOACs versus warfarin- Major bleeding

14% non-significant reduction in major

bleeding with NOACs

Ruff CT et al., The Lancet, 2014;383:955-62

Meta- Analysis: Secondary endpoints

Reduction in hemorrhagic stroke, overall mortality and ICH with

NOACs but increase in GI bleeding
Low dosages: Non-inferior to VKA for primary endpoint, superior
for major bleeding (RR 0.65, 95% CI 0.43-1.0) but higher relative risk
of ischemic stroke (RR 1.28, 95% CI 1.02-1.60)
Ruff CT et al., The Lancet, 2014;383:955-62

The impact of bleeding complications in patients receiving

target-specific oral anticoagulants: a systematic review and
meta-analysis
by Chatree Chai-Adisaksopha, Mark Crowther, Tetsuya Isayama, and Wendy Lim

Blood
Volume 124(15):2450-2458
October 9, 2014

2014 by American Society of Hematology

Major bleeding events comparing target-specific anticoagulants with VAKs.

The absolute risk difference for major bleeding was 0.64%, with an NNT of 156 using
TSOACs compared with VKAs
Chatree Chai-Adisaksopha et al. Blood 2014;124:2450-2458

2014 by American Society of Hematology

Fatal bleeding events comparing TSOACs with VAKs.

The pooled absolute risk reduction was 0.22%,

resulting in an NNT of 454

Chatree Chai-Adisaksopha et al. Blood 2014;124:2450-2458

2014 by American Society of Hematology

Intracranial bleeding events comparing TSOACs with VAKs.

The pooled absolute risk reduction was 0.57%,

resulting in an NNT of 185
Chatree Chai-Adisaksopha et al. Blood 2014;124:2450-2458

2014 by American Society of Hematology

Major GI bleeding events comparing TSOACs with VAKs.

No difference in the risk of GI bleeding between

TSOACs and VKAs

Chatree Chai-Adisaksopha et al. Blood 2014;124:2450-2458

2014 by American Society of Hematology

What do these meta-analysis tell us?

Overall the results appear reassuring for the NOACs
NOACs are associated with significant reduction in major bleeding, fatal
bleeding, intracranial bleeding, clinically relevant non-major bleeding and
total bleeding.
However, results should be interpreted in the context that these analyses
included patients that participated in major randomized trials where the
environment was more controlled.
They may not reflect the true incidence of bleeding in the real day to
day clinical practice world.

What are the sources of this realworld data?

Wide range of research methodologies with very different data sources
-

Patient registries

Existing electronic health records

Routinely collected administrative data

Primary patient level data collection (prospective and retrospective)

Population health surveys

ISPOR Real World Data task force. Using real world data for coverage and payment decisions:
The ISPOR real world data task force report.
Available at: http://www.ispor.org/workpaper/RWD_TF/RWTFManuscript.pdf

Rationale for Registry

Need for data which are considered contemporary, international and
representative
Information on AF patient characteristics, management and outcomes of
AF has limitations
Large patient numbers can detect rare adverse events and study effect of
co morbidities not previously evaluated.
Generalization to clinical practice
Heterogeneous study subjects
Hypothesis generation when an a priori hypothesis is difficult to define
Supportive data for label extensions
Evidence based medicine for outcomes and reimbursement
Cost effective on a per patient basis
Garrison, LP, Neumann, PJ, Erickson, P (2007) Using real-world data for coverage and payment decisions: the ISPOR Real-World Data
Task Force report. Value Health 10: pp. 326-335

Registry based data

VTE registries

A fib Registries

ORBIT-AF :184 sites in US. EnrollmentJune 2010 to Aug 2011

XAMOS: 17,413 patients in 37 countries for

benefit risk assessment of rivaroxaban for VTE
prophylaxis

GLORY: 15,020 patients from 100 hospitals

across 13 countries who underwent elective
primary hip and knee replacement

GARFIELD: 50,000 patients in 34

countries

IMPROVE: International Medical prevention

registry on VTE. Over 15,000 acutely ill medical
patients from 52 hospitals in 12 countries

EURO Heart Survey: 5333 patients in

35 countries. Includes both inpatient
and outpatient

ENDORSE: To evaluate prevalence of VTE risk

and thromboprhylaxis in acute hospital care
setting. 68,183 patients from 32 countries

RIETE:Multidisciplinary project of consecutive

patients with symptomatic DVT or PE- >45,000
patients enrolled till date.

GLORIA-AF: Newly diagnosed

patients. 56,000 patients in nearly 50
countries enrolled

RELY-AF: 15,400 patients in 34

countries. Patients presenting to ER

Dresden Registry
Study design- Prospective registry
Network of more than 230 physicians from private practices and hospitals
Patients aged 18 or above on therapeutic NOAC are eligible to be
included
No exclusion criteria
Patient followed by telephone 30 days after enrollment and quarterly
thereafter
Main effectiveness outcome was annualized rate of the combined
endpoint of stroke, TIA or systemic embolism
Main safety outcome was annualized rate of major bleeding
Beyer-Westendorf J, Frster K, Pannach S, et al. Rates, management and outcome of bleeding complications during rivaroxaban
therapy in daily care: results from the Dresden NOAC registry. Blood. 2014;

Rates, management, and outcome of rivaroxaban bleeding in daily

care: results from the Dresden NOAC registry
by Jan Beyer-Westendorf, Kati Frster, Sven Pannach, Franziska Ebertz, Vera Gelbricht, Christoph
Thieme, Franziska Michalski, Christina Khler, Sebastian Werth, Kurtulus Sahin, Luise Tittl, Ulrike
Hnsel, and Norbert Weiss

Blood
Volume 124(6):955-962
August 7, 2014

2014 by American Society of Hematology

Rates, management and outcome of rivaroxaban

bleeding in daily care: Dresden NOAC registry

Between Oct 2011- Dec 2013, 1776

Rivaroxaban patients were enrolled

42.9% reported 1082 bleeding events

during/within 3 days after last intake of
rivaroxaban (58.9% minor, 35% non-major
clinically relevant, 6.1% major bleeding)

In case of major bleeding, surgical or

interventional treatment was needed in
37.8% and PCC in 9.1%.

Time to event analysis, 100 patients year

rates of major bleeding were 3.1( 95% CI
2.2-4.3) for SPAF and 4.1( 95% CI 2.5-6.4) for
VTE.

In the as treated analysis, case fatality rates

of bleeding leading to hospitalizations were
5.1% and 6.3% at days 30 and 90 days after
bleeding

Jan Beyer-Westendorf et al. Blood 2014;124:955-962

Rates, management and outcome of rivaroxaban

bleeding in daily care: Dresden NOAC registry

Between Oct 2011- Dec 2013, 1776

Rivaroxaban patients were enrolled

42.9% reported 1082 bleeding events

during/within 3 days after last intake of
Bleeding complications
were
frequent
with
rivaroxaban
(58.9%
minor, 35%
non-major
clinically
relevant,
6.1%
major
bleeding)
rivaroxaban but majority were minor. 6% of all

In case
of major
bleeding,events,
surgical orwhich
bleeding eventsare
major
bleeding
interventional treatment was needed in
and PCC in 9.1%.in 60% of events.
can be managed 37.8%
conservatively
Time to
eventPCC
analysis,
100 rarely
patients year
Procoagulant therapy
with
was
rates of major bleeding were 3.1( 95% CI
2.2-4.3) for SPAF and 4.1( 95% CI 2.5-6.4) for
needed.
VTE.

In the as treated analysis, case fatality rates

of bleeding leading to hospitalizations were
5.1% and 6.3% at days 30 and 90 days after
bleeding

Jan Beyer-Westendorf et al. Blood 2014;124:955-962

Effectiveness and safety of Dabigatran therapy in

daily-care patients with AF- Dresden registry

Between Oct 2011 and Feb 2013, 341 dabigatran patients with SPAF were enrolled into the
registry

Patients receiving 110 mg BID were significantly older and had more co morbidities

Mean duration of follow up was 671.2184.9 days

Stroke/TIA/systemic embolism

Safety endpoints

In an ITT, overall rate of main endpoint of

stroke/TIA/systemic embolism was 2.93/100 patients
years and secondary end point of major CV events
5.24/100 patients years

In an on treatment analysis, annual rate of major

bleeding were 2.3/100 patients years and higher in
patients receiving 110 mg BID instead of 150 mg BID
(2.9 VS 1.7/100 patient years, p=0.34)

Event rates were highest in the first 6 months of

treatment and declined over time

Event rates highest in the first 6 months of treatment

and declined over time

In an on treatment analysis main endpoint

occurred at a rate of 1.9/100 patients years for
patients and numerically lower in patients on 150
mg BID vs 110 mg BID (0.9 vs 2.9, p=0.109)

Beyer-Westendorf J et al, Thromb Haemost. 2015 Mar 5:113(6).

All cause mortality rate was 3.8/100 patients years.

Treatment discontinuation rate was 25.8/100
patient years. Highest in the first 6 months of
treatment. Also higher in newly treated with
dabigatran than for patients switched from VKA to
dabigatran (49.2 vs 42.7, p=0.411)

Effectiveness and safety of Dabigatran therapy in

daily-care patients with AF- Dresden registry

Between Oct 2011 and Feb 2013, 341 dabigatran patients with SPAF were enrolled into the
registry

Patients receiving 110 mg BID were significantly older and had more co morbidities

Mean duration of follow up was 671.2184.9 days

Overall higher rates of stroke/systemic embolism

Stroke/TIA/systemic
embolism
with dabigatran
specifically lower
dose. Higher Safety endpoints
In an ITT,with
overalllower
rate of main
endpoint
of
In an on treatment analysis, annual rate of major
rates of bleeding
dose
of dabigatran.?
stroke/TIA/systemic embolism was 2.93/100 patients
bleeding were 2.3/100 patients years and higher in
Selection bias.
years and secondary end point of major CV events
patients receiving 110 mg BID instead of 150 mg BID
5.24/100 patients years

(2.9 VS 1.7/100 patient years, p=0.34)

Event rates were highest in the first 6 months of

treatment and declined over time

Event rates highest in the first 6 months of treatment

and declined over time

In an on treatment analysis main endpoint

occurred at a rate of 1.9/100 patients years for
patients and numerically lower in patients on 150
mg BID vs 110 mg BID (0.9 vs 2.9, p=0.109)

Beyer-Westendorf J et al, Thromb Haemost. 2015 Mar 5:113(6).

All cause mortality rate was 3.8/100 patients years.

Treatment discontinuation rate was 25.8/100
patient years. Highest in the first 6 months of
treatment. Also higher in newly treated with
dabigatran than for patients switched from VKA to
dabigatran (49.2 vs 42.7, p=0.411)

Drug persistence with rivaroxaban therapy in A

FIB- Dresden registry
1204 patients were enrolled (39.3%
switched from VKA and 60.7% newly
treated)
Overall persistence
with rivaroxaban is
high with a
discontinuation
rate of 15% in the
first year treatment.

223 (18.5%) stopped rivaroxaban

during follow up (median 544 days)
translating to a discontinuation rate
of 13.6 /100 patient years.
Common reasons: Bleeding (30%),
other side effects (24.2%) and
diagnosis of stable rhythm
History of CHF (HR 1.43, P=0.009) or
DM (HR 1.39, P=0.018) were
statistically significant baseline risk
factors for discontinuation
Jan Beyer-Westendorf et al. Europace 2015;17:530-538

Peri-interventional management of
NOACs in daily care- Dresden registry
Between 1 October 2011 and 15 May 2013, 2179 patients were enrolled into
the registry.
595 (27.3%) patients underwent 863 surgical or interventional procedures,
which were classified as minimal in 135 (15.6%) cases, minor in 641 (74.3%),
and major in 87 (10.1%)
Patient characteristics overall were comparable between subgroups of
procedures.
Most procedures were performed in patients receiving rivaroxaban (76%),
dabigatran (23.5%) and apixaban (0.5%).
Primary effectiveness outcome was a combination of centrally adjudicated
cardiovascular events, including death. Primary safety outcome was rate of
major bleeding events during the first 30 days.
Beyer-Westendorf J, Gelbricht V, Frster K, et al. Peri-interventional management of novel oral anticoagulants in daily care: Results
from the prospective Dresden NOAC registry. Eur. Heart J. 2014;35:18881896.

Peri-procedure NOACs- Dresden

Results: Peri procedure, 1% of the patients had a major CV event and 1.2% had major bleeding

Rates of the above complications were higher for major procedures ( 5% and 8% respectively)

During the 863 procedures, NOAC was continued in 22%, temporarily stopped for 49% or stopped
with heparin bridging in 29%.

Median time for NOAC interruption was a 3 days.

Major CV event rates were similar for those with or without heparin bridging (1.6% vs 0.8%, p=NS)
but major bleeding was higher with heparin bridging (2.27% vs 0.5%, p=0.01)

On multivariate analysis major procedures were independently associated with major bleeding
(OR 16.8; P<0.001) but heparin bridging was not.

Authors concluded that continuation or brief interruptions in NOAC therapy for most procedures is
safe, but heparin bridging may be useful in selected high risk patients.

Beyer-Westendorf J, Gelbricht V, Frster K, et al. Peri-interventional management of novel oral anticoagulants in daily care: Results
from the prospective Dresden NOAC registry. Eur. Heart J. 2014;35:18881896.

Peri-procedure NOACs- Dresden

Results: Peri procedure, 1% of the patients had a major CV event and 1.2% had major bleeding

Rates of the above complications were higher for major procedures ( 5% and 8% respectively)

During the 863 procedures, NOAC was continued in 22%, temporarily stopped for 49% or stopped
with heparin bridging in 29%.

Median time for NOAC interruption was a 3 days.

Major CV event rates were similar for those with or without heparin bridging (1.6% vs 0.8%, p=NS)

Bridging but
is of
unproven
efficacy
for
prevention
of vs 0.5%, p=0.01)
major
bleeding was
higher with
heparin
bridging (2.27%
VTE with
NOACs and increases bleeding.
On multivariate analysis major procedures were independently associated with major bleeding
(OR 16.8; P<0.001) but heparin bridging was not.

Authors concluded that continuation or brief interruptions in NOAC therapy for most procedures is
safe, but heparin bridging may be useful in selected high risk patients.

Beyer-Westendorf J, Gelbricht V, Frster K, et al. Peri-interventional management of novel oral anticoagulants in daily care: Results
from the prospective Dresden NOAC registry. Eur. Heart J. 2014;35:18881896.

GARFIELD- registry
Ongoing, multicenter, worldwide
study of adults with non valvular AF.
>55,000 patients enrolled as 5
sequential prospective cohorts at
>1000 sites in up to 50 countries.
Data from 10,135 patients from
cohort 1 revealed that at diagnosis,
55.8% patients were given a VKA,
4.5% received a novel factor Xa
inhibitor or DTI.
Use of all antithrombotic drugs was
higher with a CHADS2 score of 2-6
versus those with score 0 or 1.
NOACs use steadily increasing

Kakkar AK, Mueller I, Bassand JP, et al. Risk Profiles and Antithrombotic Treatment of Patients Newly Diagnosed with Atrial Fibrillation at
Risk of Stroke: Perspectives from the International, Observational, Prospective GARFIELD Registry. PLoS One. 2013;8:

ORBIT-AF
National US registry of outpatients with AF GPS, Cardiologists and EPs
Examined 10,094 patients for better informed treatment of AF between
June 2010 to Aug 2011.
Empirical stroke and bleeding risks were assessed by CHADS2 and
Anticoagulation and risk factors in A fib score (ATRIA)
Physicians were asked to categorize their patients stroke and bleeding risk
separately.

Benjamin A. Steinberg et al. Circulation. 2014;129:2005-2012

ORBIT-AF
Categorization of physician-assigned and empirical risk of stroke (A) and bleeding (B).

There was little agreement between provider assessed risk and empirical
scores in AF. These differences may explain the divergence of AC treatment
decisions from guideline recommendations
Benjamin A. Steinberg et al. Circulation. 2014;129:2005-2012

Copyright American Heart Association, Inc. All rights reserved.

ORBIT-AF: Use and associated risks of concomitant

aspirin with oral anticoagulation in NVAF
Patients with ECG-proven AF 18 years of age able to provide informed
consent and follow-up at least every 6 months were eligible
Study population was limited to those on OAC (n=7347)
Primary outcomes were 6 month bleeding, hospitalization, ischemic events
and mortaility
Multivariable logistic regression models were used to assess factors
associated with concomitant ASA therapy
35% of AF patients on OAC also received ASA
Patients receiving both were more likely to be male than female (66% vs
53%; p<0.0001) and had more co morbid illness than those with OAC alone.

Benjamin A. Steinberg et al. Circulation. 2014;129:2005-2012

Unadjusted, 6-month major bleeding rates among high-risk subgroups are shown with
absolute numbers of events per group noted above.

Use of OAC with ASA

was associated with
significantly
increased risk of
bleeding.
We need to carefully
determine if and
when the benefits of
dual therapy
outweighs the risk of
bleeding

Adjusted major bleeding for OAC+ASA: RR 1.53 (1.20-1.96)

Hx for bleeding for OAC+ASA: RR 1.52 (1.17-1.97)
Benjamin A. Steinberg et al. Circulation. 2013;128:721-728
Copyright American Heart Association, Inc. All rights reserved.

FDA Drug Safety Communication:

Dabigatran vs warfarin.
Incidence rates and adjusted HR comparing 134,000 patients, 65 years or
older matched new user cohorts treated with dabigatran 75 mg or 150 mg
or warfarin for NVAF based on 2010-2012 Medicare data.
It found that dabigatran was associated with

a lower risk of ischemic stroke (HR 0.80(0.67-0.96), intracranial hemorrhage(

HR 0.34 (0.26-0.46), and death compared to warfarin (HR 0.86 (0.77-0.96);

an increased risk of major GI bleeding compared to warfarin (HR 1.28 (1.141.44); and

a similar risk for MI compared to warfarin (HR 0.92 (0.78-1.08).

Dabigatran considered to have a favorable benefit to
risk profile

http://www.fda.gov/Drugs/DrugSafety/ucm396470.htm

Brigham and Womens Harvard Medical

School Marketscan/ Database analysis
To address prescribing patterns and real world safety and effectiveness of
NOACs
Data- MarketScan and United Healthcare. October 2010- Dec 2012
Sequentially matched cohort design consisting of 38,378 patients
Followed patients from start of therapy until a switch or discontinuation of
the anticoagulant, an outcome event or disenrollment
Primary outcomes measured were stroke and major hemorrhage
Interim findings showed a 25% RRR in the rate of major hemorrhage (HR
0.75, 95% CI 0.65-0.87) and a 23% RRR in strokes (HR 0.77, 95% ci 0.54-1.09)for
dabigatran compared to warfarin in NVAF.

Seeger J, Bartels D, Huybrechts K et al. Safety and Effectiveness of Dabigatran Relative to Warfarin in Routine Care. Abstract No.
16227. Presented at: American Heart Association Scientific Sessions 2014. November 15-19, 2014, Chicago, Illinois.

DoD Military Heath system Database- Safety and

effectiveness of dabigatran vs warfarin in NVAF

Retrospective cohort study of adult patients diagnosed with AF within 12 months prior to first OAC
treatment and had a first prescription claim for either dabigatran or warfarin between Oct 2010
and July 2012.

Censored when their prescriptions exceeded a 30 day allowable gap, at OAC switch,
disenrollment, death or study end

14,813 dabigatran and 24,500 warfarin patients were propensity score matched based on
baseline demographics and clinical characteristics

HR in the post-PSM dabigatran cohort had lower likelihood of stroke (HR 0.73 (0.55-0.97), P=0.032),
hemorrhagic stroke (HR 0.32(1.14-0.73), P=0.0071), major ICH (HR 0.49(0.30-0.79), p=0.036), major
urogenital bleeding and other bleeding, MI and death than in the warfarin cohort.

The hazard ratio in the post-PSM dabigatran cohort suggests a higher likelihood for major lower GI
bleeding, but a lower likelihood for intracranial, urogenital, and other bleeding than seen with
warfarin

Villines TC. et al. The Comparative Safety and Effectiveness of the Oral Anticoagulant (OAC) Dabigatran versus Warfarin Utilized in a
Large Healthcare System in Non-valvular Atrial Fibrillation (NVAF) Patients. Presented on 17th November at the American Heart
Association Scientific Sessions 2014, Chicago, USA.

Dabigatran and Warfarin in Real World

Danish Registry of Medicinal Product Statistics, a dabigatran-treated group and a 1:2 propensity matched
warfarin-treated group of n = 4978 and n = 8936, respectively

Conclusions
In this "everyday clinical
practice" post-approval
nationwide clinical cohort,
there were similar
stroke/systemic
embolism and major
bleeding rates with
dabigatran (both
doses) compared with
warfarin

Warfarin D150
matched

Dabigatran
150 mg

Warfarin D110
matched

Dabigatran
110 mg

109 / 3626 / 3.0

60 / 1722 / 3. 5

157 / 4333 / 3.6

62 / 2299 / 2.7

8 / 3684 / 0.2

4 / 1758 / 0.2

18 / 4402 / 0.4

6 / 2322 / 0.3

27 / 3680 / 0.7

1 / 1760 / 0.1

42 / 4398 /1.0

6 / 2323 / 0.3

N = 3996

N = 2239

N = 4940

N = 2739

Primary
Stroke
Systemic
embolism
Intracranial
bleeding

Secondary endpoints
Death from
any cause

72 / 3689 / 4.7

52 / 1760 / 3.0

453 / 4411/ 10.3

185/ 2326 / 8.0

GI bleeding

53 / 3661 / 1.5

26 / 1749 / 1.5

90 / 4369 / 2.1

28 / 2311 /1.2

11 / 3684 / 0.3

0 / 1760 / 0

10 / 4408 / 0.2

4 / 2324 / 0.2

104 / 3630 / 2.9

37 / 1744 / 2.2

151 / 4329/ 3.5

65 / 2296 / 2.8

Traumatic intra
cranial
bleeding
Major bleeding

Larsen TB, et al. J Am Coll Cardiol. 2013;61:2264-2273.[42]

Limitations of Registry data

Non randomized data
Variability in definitions, interpretations, abstractions and collection intervals
Selection bias due to non-sequential patients
Perceived diminished value of research evidence than controlled trials
Analysis of observational data sometimes not straight forward and need to
be interpreted in the context of known limitations of observational studies

Garrison, LP, Neumann, PJ, Erickson, P (2007) Using real-world data for coverage and payment decisions: the ISPOR Real-World Data
Task Force report. Value Health 10: pp. 326-335

Adherence is Key to therapeutic

success

Drugs dont work in patients who

dont take them
Dr. C. Everett Koop, M.D

Issue of adherence with warfarin

Initiate
38% of eligible patients
do not receive
anticoagulant therapy

Implement
36% miss >20% of their
doses
4% have >10% extra
openings
Poor adherence has a
significant effect on
anticoagulation control

1. Kakkar et al. PLoS ONE 2013; 8(5): e63479. doi:10.1371/journal/pone.0063479

2. Kimmel et al. Arch Intern Med 2007;167:229-35
3. Gallagher et al. J Thromb Haemost 2008;6:1500-06.

Persist

During the first year, 30%

patients have discontinued
treatment

Extent of Non-Adherence in Clinical

Trials
16,907
participants
from 95
Clinical
Studies

Once-daily vs. twice-daily dosing: predictions for NOAC drugs.

Once daily and twice daily dosing of the same drug and same total daily dose . 15%
missed doses- 15 once daily missed doses vs 30 twice daily missed doses over 100
days.
Bernard Vrijens, and Hein Heidbuchel Europace 2015;17:514-523
Published on behalf of the European Society of Cardiology. All rights reserved. The Author 2015. For permissions
please email: journals.permissions@oup.com.

Current adherence data on

dabigatran
A retrospective study conducted at a Veterans Affairs hospital utilized
medication possession ratio and defined adequate adherence as >80% of
MPR. It found no difference in adherence for dabigatran followed by
pharmacist managed AC clinic.
A pilot study by Schulman et al, found that 12% of patients on dabigatran
had inadequate adherence.
Another larger cohort of 5376 patients with NVAF at Veteran Affairs hospital
found that up to 27.8% had a PDC of <80% meeting the criteria for non
adherence.
All these data have limitations short follow up, variable measures to assess
adherence and under or over representation of particular cohorts.

Suryanarayan D et al. Semin Thromb Hemost.2014 Nov;40(8):852-9.

Dabigatran and Rivaroxaban adherence study- Real world

experience in different clinical settings (DaRivA)
Unpublished preliminary data
To compare adherence between once daily rivoaroxaban and twice daily
dabigatran among patients in different clinical settings.
Study design: Prospective multicenter cohort study (Canada and Sweden)
Adherence calculated from pharmacy refill data along with a validated 8 item
Morinsky Medication adherence scale.
474 patients (median age 73 yrs); 97% had A fib, 3% VTE; 205 patients on dabigatran
and 269 on rivaroxaban
Adherence of >80% seen in 95%, 89% and 99% of patients followed at cardiology
clinics, family medicine and thrombosis clinics.
Medium adherence with mean score of 6.9 (SD1.29) with the MMAS
Conclusion: Overall adherence to both medications was good with no significant
differences between clinical settings.
Suryanarayan D et al, Dabigatran and Rivaroxaban adherence study- real world experience in different clinics and
extended follow up (DARIVA study) ISTH 15ABS-1595.

Other practical limitations of NOACs

Be wary of drug interactions with

NOACs

NOACs and antiretroviral therapy

Ritonavir
Inhibitor of
CYP3A4(stron
g), PGP and
CYP2D6
Inducer of
CYP2C19(stro
ng), CYP2C9
and CYP1A2
(moderate)

Dabigatran

Rivaroxaban

Apixaban

Clinical
Management

Possible AUC
as a result of
inhibition of
PGP

Possible AUC
as a result of
inhibition of
CYP3A4
metabolism

Possible
clinical effect

Suggest using
dabigatran
with
administration
times
separated or
warfarin

Unlikely to be
clinically
relevant if
administration
times are
separated bu
2 hours

Egan G, et al. Ann Pharmacother. 2014 Jun;48(6):734-40

Lab monitoring specifics

Drug

Tests

Test
characteristics

Limitations

Dabigatran

Activated partial
thromboplastin time
(aPTT)
Thrombin time(TT)
Dilute thrombin time
Ecarin clotting time
(ECT)

Prolongs Aptt
TT sensitive, if
dabigatran absent or in
low concentrations
ECT sensitive

aPTT provides a
nonlinear correlation
and dabigatran levels,
influences by other
factors
ECT,TT and dilute
thrombin time
sometimes may not be
readily available

Rivaroxaban

PT
Aptt
Chromogenic antifactor
Xa assay

Prolongs PT
Prolongs aPTT
Chromogenic assay
provides quantitative
effect

PT results may differ with

different thromboplastin
reagents

Apixaban

PT
Chromogenic antifactor
Xa assay

Prolongs PT
Chromogenic assay
provides quantitative
effect

PT not sensitive at low

concentrations

Fenger-Eriksen C. Acta Anaesthesiol Scand 2014;58:651-59.

Samama MM Clin Chem Lab Med 2011;49:761-72.

Safety of NOACs - Remember

Situations increasing hemorrhagic risk
Renal failure
Very elderly
Low body weight
Concurrent medications such as antiplatelets
Drug interactions

REVERSE-AD

Idarucizumab is a selective and specific

monoclonal antibody fragment of dabigatran

Specific high affinity binding to dabigatran

No effect on coagulation tests or platelet

aggregation

aDabi-Fab is not active in the absence of

dabigatran

Fab has shorter half life than full mAb (hrs vs days
for a full mAb)

Phase I: immediate, complete, and sustained

reversal of dabigatran-induced anticoagulation in
healthy humans. Immediate action , TT reversed
after 5 min

Reversal of the anticoagulation effect was

complete and sustained in 7 /9 subjects who
received the 2g dose and in 8/8 subjects who
received the 4g dose

Phase III started on May 2014 ( until July 2017)

Schiele F. Et al Blood 2013;121(18);3554-3562

ANNEXA-A: Phase 3 randomized

controlled trial of Andexanet alfa
Designed to reverse activity of Factor Xa Inhibitors through a well defined MOA
Acts as a Fxa decoy and retains high affinity for all Fxa inhibitors
No known interaction with other coagulation factors except TFPI
Restored hemostasis in an animal model of bleeding
Multiple Phase 2 proof of concept studies
Phase II study: AnXa able to dose-dependently partially reverse the anticoagulant
effects of rivaroxaban 20% (210mg) , 53% (420mg) immediately after infusion
Double-blind placebo controlled trial, bolus dose antagonized anti Xa activity of
apixaban in healthy volunteers
Next phase is to demonstrate whether prolonged reversal can be sustained with
continuous infusion after bolus
ANNEXA-R (Rivaroxaban) also ongoing
Lu G. et al Nature Med 2013;19(4);446-453
Siegal D. et al. Blood 2014;123;1152-1158

Other ongoing reversal agent studies

FRED Observational multicenter cohort study of efficacy and safety of
FEIBA for reversal of dabigatran in major bleeding
UPRATE- Observational multicenter cohort study of PCC for reversal of oral
Fxa inhibitors in major bleeding

New trials that are ongoing

Rivaroxaban for HITT study
RASET- Randomized trial comparing rivaroxaban with placebo for
treatment of symptomatic superficial vein thrombosis
PAUSE Perioperative anticoagulant use for surgery evaluation study

Unanswered questions which need

exploration!
Optimal management of NOACs around time of acute onset ischemic stroke or ICH
Will dose adjusted NOAC therapy augment the established safety and efficacy of
fixed dose unmonitored NOAC therapy? Is that even an issue?
Is there still a role for Fxa inhibitors to be explored for mechanical prosthetic heart
valves?
Are NOACs still the ideal anticoagulants for strong congenital thrombophilia patients
in comparison to warfarin?
?Role of Fxa inhibitors as thromboprophylaxis in cancer patients at risk for VTE
Safety of triple therapy or double therapy with antiplatelet agents and NOACs?
Challenges still remain and its just the beginning!

Is warfarin being outclassed by the

NOACs?

...Not just yet!

Warfarin is still the drug of choice!

Mechanical heart valves
Long term stability with good TTR and patient preference
Patients with or at risk of poor renal function
Questionable patient compliance
Patients with history of GI bleed
Patients who are on drugs which have significant interactions with NOACs

Mark your Calendars!