Oral Rivaroxaban for
Symptomatic Venous
Thromboembolism
Background
 Tx ↓ risk of recurrence from 25% to 3%
during first 6-12 months of therapy
 Risk after tx ends: 5-10% during first
year
 Standard: Parenteral heparin initially +
Vit K antagonist
 Annual risk of major bleeding after first
year 1-2%
Background
 Monitoring challenging for outpatients
 Solution: oral anticoagulant without
monitoring
 Rivaroxaban: Direct factor Xa
inhibitor
Methods: Acute DVT
 Design: Randomized, open label,
event driven, non-inferiority study
 P: Pts with acute, symptomatic DVT
 I: Rivaroxaban
 C: Enoxaparin + Vit K antagonist
 O: Symptomatic, recurrent VT
Acute DVT: Inclusion Criteria
 Legal age for consent
 Acute, symptomatic objectively
confirmed proximal DVT, without
symptomatic PE
Acute DVT: Exclusion Criteria
 If therapeutic doses of LMWH,
fondaparinux or UFH received for >48
hours or >1 dose of a VKA before
randomization
 Treated with thrombectomy, vena cava
filter or a fibrinolytic agent for the
current episode of thrombosis
 Any CIs
Methods: Acute DVT
 Duration of tx: determined by the treating
physician
 15 mg BID X 3 wks
 20 mg OD for 3,6 or 12 months
 Standard: SC enoxaparin ( 1mg/kg BID)
 Warfarin or acenocoumarol started within
48 hrs of randomization
Methods: Continued Tx Study
 Design: Randomized, double-blind (subject,
caregiver,investigator, outcomes assessor),
event-driven superiority study
 P: Pts with DVT or PE treated x 6-12 months
with a Vit K antagonist or rivaroxaban
 I: Rivaroxaban 20 mg OD
 C: Placebo
 O: Symptomatic, Recurrent VT
Continued Tx Study: Inclusion
Criteria
 Objectively confirmed symptomatic DVT
or PE
 Treated X 6-12 months with
acenocoumarol or warfarin or
rivaroxaban
 If there was equipoise with respect to
the need for continued anticoagulation
Exclusion criteria for both studies
 Another indication for Vit K antagonist
 CrCl< 30ml/min
 Clinically significant liver disease (acute hepatitis,
chronic active hepatitis, or cirrhosis) or an ALT>3
ULN
 Bacterial endocarditis
 Active bleeding or a high risk of bleeding
Exclusion Criteria for both studies

CI anticoagulant treatment

SBP >180 mm Hg or DBP>110 mm Hg

Childbearing potential without proper contraception
measures

Pregnancy or breast feeding

Concomitant use of strong P-450 3A4 inhibitors or inducers

Participation in another experimental pharmacotherapeutic
program within 30 days before screening

Life expectancy <3 months
Methods
 Continued Tx: Rivaroxaban 20 mg OD
or matching placebo for 6 or 12
months
 Both studies: NSAID & antiplatelet
use discouraged
 If indicated ASA (up to 100 mg),
clopidogrel (75 mg) or both allowed
Outcome assessments
 1⁰ efficacy outcome: Symptomatic,
recurrent VT
 Acute DVT Study:
 Principal safety outcome: Clinically relevant
bleeding = composite of major or clinically
relevant nonmajor bleeding
 Continued Treatment Study:
 Major bleeding
Outcome assessments
 Predefined 2⁰ outcome:
 All-cause mortality
 Vascular events (ACS, ischemic stroke,
TIA or SE)
 Net clinical benefit (composite of primary
efficacy outcome +major bleeding)
Statistical Analysis: Acute DVT
 Event driven, Non-inferiority Study
 Assumption: equal efficacy in 2 study groups
 A total of 88 events would provide a power of 90%
to demonstrate that rivaroxaban is non inferior to
standard therapy
 Margin = 2.0, corresponds to maintenance of at
least 50% of the proven efficacy of standard tx
Statistical Analysis: Continued Tx
 Event driven, superiority study
 Assumption: 70% RR with
rivaroxaban
 30 events, power of 90%
Results: Acute DVT
Efficacy
Rivaroxaban Enoxaparin- HR (95% CI) P value
(1731)
VKA (1718)
Recurrent 36(2.1)
VTE
51(3.0)
0.68(0.441.04)
<0.001
Net
clinical
benefit
73(4.2)
0.67(0.470.95)
0.03
51(2.9)
Principal safety outcome: 8.1% in each group
No difference in safety outcomes and total deaths
Results: Continued Treatment
Efficacy
Rivaroxaban
(602)
Placebo
(594)
HR (95% CI)
P
value
Recurrent 8(1.3)
VTE
42(7.1)
0.18(0.090.39)
<0.00
1
Net
clinical
benefit
42(7.1)
0.28 (0.15- <0.0
0.53)
01
12(2.0)
 Nonfatal major bleed 0.7% in
rivaroxaban group vs. none (P=0.11)
CASP SR Checklist
 Did the study ask a clearly focused question? Yes
 Was this a randomized controlled trial (RCT) and was it
appropriately so? The first study is open label but
the second one is RCT. Yes
 Were participants appropriately allocated to
intervention and control groups? Yes
 Were participants, staff and study personnel ‘blind’ to
participants’ study group? Outcomes Assessor
blinded
 Were all of the participants who entered the trial
accounted for at its conclusion? Yes
CASP SR Checklist

Were the participants in all groups followed up and data
collected in the same way? Yes

Did the study have enough participants to minimize the
play of chance? Yes

How are the results presented and what is the main result?

How precise are these results?

Were all important outcomes considered so the results can
be applied?
Limitations
 Blinding: no protection from bias
Suspected cases higher in rivaroxaban
group
 Margin of 2.0 = at least 50% of proven efficacy
of standard therapy. Acceptable?
 On-treatment & per-protocol analyses similar to
ITT but data not shown
Limitations
 Safety: Bleeding events included in the
analyses if occurred during tx or within 2
days after d/c
 Compliance
 Serious events not defined
 Results of non-inferiority trial not as
credible as a superiority trial
Implications to practice
 Dose needs to be studied more
 Single-drug approach to short-term & continued tx of
VT
 Option in patients not willing to do INR monitoring
 Reversal of bleeding: no specific antidote, general
hemostatic measures
 Activated charcoal within 2 hours of dose
 Highly protein bound not dialyzable