CHEST Guidelines
2012 Update
Betsy Bryant Shilliday, Pharm.D., CDE, CPP
Bart Scott, MPAS, PA-C
Brittain Fish Erickson, MHS, PA-C
Carrie Palmer, MSN, RN, ANP-BC, CDE
April 4, 2012
http://chestjournal.chestpubs.org/content/141/2_suppl
Objectives
Review recently FDA approved oral
anticoagulants
Highlight some of the changes from the
2008 (AT8) to the 2012 (AT9) CHEST
Guidelines
Grading System
New Oral Agents
Clotting Cascade System
Rivaroxaban
Apixaban
Dabigatran
Dabigatran (Pradaxa®)
Indications:
– Atrial fibrillation
Dosage:
– 150 mg BID
– Adjustments based upon CrCl
CrCl 15-30 ml/min: 75 mg BID
CrCl <15 ml/min: Not recommended
Dosage Forms:
– Capsules: 75, 150 mg
Must store in original container & use w/in 4 months
Dabigatran (Pradaxa®)
Drug Interactions
– P-glycoprotein inducers or inhibitors
Pradaxa® package insert
Switching between Dabigatran &
other anticoagulants
Agent
Action to take
Warfarin
From warfarin: D/C warfarin and start dabigatran when
INR <2.0
To warfarin: Adjust starting time of warfarin based on
CrCl:
≥ 50: start warfarin 3 days before D/C dabigatran
30-50: start warfarin 2 days before D/C dabigatran
15-30: start warfarin 1 day before D/C dabigatran
Parenteral
Anticoagulants
Start dabigatran 0-2 hours before time that the next dose
of parenteral drug was to have been administered, or at
time of discontinuation of continuously adminstered
parenteral drug
Currently taking dabigatran: wait 12 hrs (CrCl ≥30) or 24
hrs (CrCl <30) after last dose of dabigatran before
initiating treatment with parenteral anticoagulant.
Rivaroxaban (Xarelto®)
Indications:
– Atrial Fibrillation
– Prophylaxis (DVT in patients undergoing knee
or hip replacement surgery
Hip replacement: duration of 35 days
Knee replacement: duration of 12 days
Xarelto® package insert
Rivaroxaban (Xarelto®)
Dosage
– Nonvalvular Atrial Fibrillation:
CrCl >50: 20 mg PO once daily with evening meal
CrCl 15-50: 15 mg PO once daily with evening meal
CrCl <15: avoid use
– Prophylaxis of DVT:
10 mg PO once daily with or without food
Take initial dose at least 6-10 hrs after surgery once
hemostasis has been established.
– Hepatic Impairment:
Avoid use in pts with moderate (Child-Pugh B) and severe
(Child-Pugh C) hepatic impairment or with any degree of
hepatic disease associated with coagulopathy
Dosage Forms: 10, 15, 20 mg tablets
Xarelto® package insert
Rivaroxaban (Xarelto®)
Drug Interactions
– CYP 3A4, 3A5
– CYP 2J2
– P-Glycoprotein transporters
– ATP-binding cassette G2 (ABCG2)
transporters
Avoid concomitant use with combined Pgp and strong CYP3A4 inhibitors/inducers
Xarelto® package insert
Apixaban
Still in late-stage clinical development
Proposed indications
– Prevention and treatment of thromboembolic
events
Proposed dosing
– 5, 10, 20 mg once daily
– 2.5, 5, 10, 20 mg BID
Adverse effects: ? LFT elevation
Drug Interactions: 3A4
Warfarin
Dabigatran Rivaroxaban Apixaban
Comparison
of
Anticoagulants
Target
VKORCI
Thrombin
Factor Xa
Factor Xa
Drug
Prodrug
No
Yes
No
No
Bioavailability
>95%
6.5%
80%
66%
Half-life
72-96 hr
9-13 hr
7-11 hr
8-15 hr
Routine
Yes
anticoagulation
monitoring
No
No
No
Dosing
Once daily
Twice daily
Once daily
Twice daily
Renal
elimination
None
80%
67% renal;
33% fecal
25% renal;
75% fecal
Potential drug
interactions
CYP 2C9,
3A4, 1A2
Potent P-gp
inhibitors
Potent
CYP3A4 and
P-gp
inhibitors
Potent
CYP3A4
inhibitors
Antidote
Vitamin K
None
None
J Thromb Haemost. 2011 Jul;9 Suppl 1:12-9
Management of
Anticoagulant Therapy
Dosing of Warfarin
Sufficiently healthy patients to be treated as
outpatients, we suggest initiating warfarin
10mg daily for first 2 days followed by
dosing based on INR rather than starting
with the estimated maintenance dose (2C)
Patients w/ previously stable therapeutic
INRs who present w/ single out-of-range
INR of ≤ 0.5 below or above therapeutic,
continue current dose & repeat INR w/in 1-2
wks (2C); recommend against bridging (2C)
Frequency of INR Monitoring
in patients on Warfarin
3.1. For patients taking VKA therapy
with consistently stable INRs, we
suggest an INR testing frequency of up
to 12 weeks rather than every 4 weeks
(Grade 2B)
Schulman et al
Purpose: Investigate whether
assessment of warfarin dosing q 12 wks is
as safe as q 4 wk
Design: randomized, noninferiority trial
Patients: 250 patients receiving longterm warfarin therapy, whose dose was
unchanged for at least 6 months
– 226 completed study
Schulman S, et al. Ann Intern Med 2011; 155:653-59.
Outcomes
Primary outcome: TTR
Secondary outcomes:
– number of extreme INRs
– changes in maintenance dose
– major bleeding events
– objectively verified VTE and death
Schulman S, et al. Ann Intern Med 2011; 155:653-59.
Results
%TTR:
– 74.1% (SD, 18.8%) 4 wk vs 71.6% (SD,20%)
12 wk (absolute difference, 2.5 percentage
pts; noninferior p=0.020)
Dose changes:
– fewer dose changes in 12 wk grp (37.1% vs
55.6%); absolute difference, 18.5 percentage
pts; p=0.004
Secondary outcomes: no difference
Schulman S, et al. Ann Intern Med 2011; 155:653-59.
Conclusion
Limitations: 12 wk grp had testing and
contact with staff q 4 wks, single center
and surrogate outcomes
Conclusion: 12 wk monitoring safe and
noninferior to q 4 wk
– “A comparison of INR testing, patient contact,
and warfarin dose assessment q 12 wks vs q
4 wks is necessary before INR testing every
12 wks can be routinely recommended for
practice”
Schulman S, et al. Ann Intern Med 2011; 155:653-59.
Who may be a candidate for
q 12 wk monitoring???
Stable patients on same dose of warfarin
for at least 6 months
Well-educated
Empowered patient who is an active
participant of their care
Prevention of VTE
Non-orthopedic Surgery
General, Abdominal and Pelvic surgeries
Risk of VTE
Recommendation
Very low
No mechanical prophylaxis (2C) or pharmacologic (1B)
Low
Mechanical prophylaxis (2C)
Moderate
LMWH or LDUH (2B) or mechanical prophylaxis
(intermittent pneumatic compression) (2C)
High
LMWH or LDUH (1B), add mechanical prophylaxis (2C)
Ab/pelvic cancer
Extended LMWH (4 weeks) (1B)
Cardiothoracic Surgeries
Cardiac
Uncomplicated
Mechanical prophylaxis (2C)
Prolonged hospital stay
Add LMWH or LDUH to mechanical
prophylaxis (2C)
Thoracic
Moderate risk
LMWH/LDUH (2B)
Mechanical prophylaxis (2C)
High risk
LMWH/LDUH (1B), add mechanical
(2C)
Orthopedic Surgery
Total Hip Arthroplasty (THA) or Total
Knee Arthroplasty (TKA)
10-14 days of:
LMWH, fondaparinux, apixaban,
dabigatran, rivaroxaban, LDUH,
adjusted VKA or aspirin (1B)*
Hip Fracture Surgery (HFS)
10-14 days
LMWH, fondaparinux, LDUH, adjusted
VKA or aspirin (1B)*, IPC (2C)
HFS, THA, TKA
LMWH superior to others (2B)
Major orthopedic surgery
Extended prophylaxis – 35 days (2B)
Major orthopedic surgery and decline
injections or IPC
apixaban, dabigatran (or rivaroxaban,
VKA) (1B)
Perioperative Management
Coronary stents on dual therapy: recommend deferring surgery for at least 6
weeks after placement of bare-metal stent and at least 6 months after drugeluting stent (1C)
If surgery is required in this time frame, recommend continuing dual
antiplatelet instead of stopping (2C)
If receiving IV UFH, stop 4-6 hrs before surgery rather than closer to
surgery (2C)
If receiving sc LMWH – last dose 24 hrs before surgery instead of 12 hr
before surgery (2C)
Resumption of LMWH – in high risk bleeding surgery, suggest resuming 4872 hrs after surgery instead of resuming 24 hrs after surgery (2C)
Diagnosis of DVT
Dx of Suspected 1st LE DVT
Low pretest probability – initial testing: D-dimer, compression
ultrasound (CUS) of proximal veins [UNC lab performs combined
modality whole-leg US w/ compression & Doppler from greater
saphenous vein up], venography or whole-leg ultrasound (US).
*D-dimer > proximal CUS (initial) [Grade 2B]
– Neg = don’t treat, pos = treat
Moderate pretest probability – same as above however, I mention
CUS as 9th Chest recommends repeat CUS in 1 week if initial is
negative
– Neg proximal CUS/ pos D-dimer = repeat CUS in 1 week (2B).
High pretest probability – ultrasound or venography for initial
screening (no D-dimer alone) (1B). Neg CUS, then D-dimer or
whole-leg or repeat CUS 1 week (1B) or venography (2B). Neg
CUS and pos D-dimer, then whole-leg or repeat prox CUS 1 (1B)
week or venography (2B).
Dx of Suspected 1st LE DVT
If isolated distal DVT is detected on whole-leg
US, suggest serial testing to rule out proximal
extension over treatment (2C).
– Remarks: Patients with abnormal isolated distal DVT
findings on US who place a high value on avoiding
the inconvenience of repeat testing and a low value
on avoiding treatment of false-positive results are
likely to choose treatment over repeat US. Patients
with severe symptoms and risk factors for extension
as outlined in 9th ed are more likely to benefit from
treatment over repeat US.
Antithrombotic Therapy for VTE
Acute isolated distal DVT w/out sxs or risk factors for
extension – suggest serial imaging for 2 weeks over initial
anticoagulation (2C).
– Remarks: Patients at high risk for bleeding are more likely
to benefit from serial imaging. Patients who place a high
value on avoiding the inconvenience of repeat imaging and
a low value on the inconvenience of treatment and on the
potential for bleeding are likely to choose initial
anticoagulation over serial imaging.
• With sxs or risk factors for extension in isolated distal DVT
– treat (over serial imaging) [2C].
• Distal DVT managed by serial imaging – recommend no
anticoagulation if no extension (1B), suggest
anticoagulation if extension but confined to distal veins
(2C), recommend anticoagulation if extension into proximal
veins (1B).
Duration/Choice of Anticoagulation
DVT/PE and cancer - w/out high bleeding risk, recommend
extended anticoagulation therapy over 3 months of therapy
(1B); with high bleed risk, suggest extended anticoagulant
therapy (2B).
DVT/PE and cancer not treated w/ LMWH (2B
recommendation LMWH over VKA), suggest VKA over
dabigatran or rivaroxaban for long-term therapy(2B).
Remarks: when these guidelines were being prepared (Oct
2011), postmarketing studies of safety were not available.
Given the paucity of currently available data and that new
data are rapidly emerging, we give a weak recommendation in
favor of VKA and LMWH therapy over dabigatran and
rivaroxaban, and we have not made any recommendations in
favor of one of the new agents over the other.
Duration of Anticoagulation
PE/DVT provoked by surgery or non-surgical transient
risk factor – recommend 3 months of anticoagulation over (1)
treatent of longer period (6-12 mo) [1B], (2) extended tx (1B).
Unprovoked PE/DVT – at least 3 months then evaluate
risk-benefit ratio of extended therapy (2B).
Dx of Pregnancy-Related DVT
Suspected DVT in pregnancy – recommend initial testing
w/ prox CUS over whole-leg US (2C), D-dimer (1B), or
venography (1B).
– Initial CUS neg - suggest further testing w/ either serial
prox CUS at day 3 and 7 (1B) or D-dimer at time of
presentation (2B).
– Positive D-dimer - have an additional f/u prox CUS at day
3 and 7 over venography (1B) or whole-leg (2C).
– Suspected isolated iliac DVT in pregnancy and no
evidence on CUS – suggest further testing w/ either
Doppler US (2C), venography (2C) or MRI (2C) over serial
CUS.
Miscellaneous
Superficial vein thrombosis of lower limb of at least
5 cm – suggest prophylactic dose fondaparinux or LMWH for
45 days over no anticoagulation (2B). Fondaparinux 2.5mg
daily over LMWH (2C).
Catheter associated UEDVT and cancer and catheter
is removed – recommend 3 months of anticoagulation over
longer duration of therapy (2C).
Acute symptomatic UEDVT, suggest against the use of
compression sleeves (2C). However in patients who have
PTS of the arm, suggest a trial of compression sleeves (2C).
Miscellaneous
Symptomatic hepatic, portal, mesenteric, and/or
splenic vein thromboses – recommend anticoagulation
(1B) however incidentally detected thromboses, suggest no
anticoagulation over anticoagulation (2C).
Initiating bridge w/ LMWH – suggest once over twicedaily dosing (2C).
Acute VTE – Suggest anticoagulation tx alone over
catheter-directed thrombolysis (CDT) and operative venous
thrombectomy (2C).
Miscellaneous
Acute PE and hypotension – admit for thrombolytics (2C).
Suspected recurrent ipsilateral DVT and abnl US w/out
prior comparison – recommend further testing w/ venography
or D-dimer over serial prox CUS (2B). Neg D-dimer - suggest no
further testing over venography (2C), positive – suggest
venography (if available) over empirical treatment of recurrence
(2C).
– Remarks: patients who place a high value on avoiding the
inconvenience and potential side effects of a venography are
likely to choose treatment over venography.
Acute prox DVT or PE and IVC filter as an alternative to
anticoagulation – suggest a conventional course of
anticoagulation therapy if risk of bleeding resolves (2B).
– Remarks: 9th Chest does not consider that a permanent IVC
filter, of itself, is an indication for extended anticoagulation.
Antithrombotic Therapy for
Atrial Fibrillation
CURRENT USE
Chest 2012;141(2):7S-47S
SAFETY DATA
Use in the Elderly: RELY Trial
Event Rate (%/yr)
Intracranial Bleeding Rates
Risk of intracranial
& extracranial
bleeding ↑ with age
Warfarin
Dabigatran 150 mg
Dabigatran 110 mg
Event Rate (%/yr)
Age
Extracranial Major Bleeding
Rates
Warfarin is
associated with ↑
intracranial
bleeding
In elderly,
dabigatran
associated with ↑
risk of extracranial
bleeding
Age
Circulation. 2011;123(21):2363-72.
Arch Intern Med. 2011;171(14):1285-6.
SAFETY DATA
Use in the Elderly: RELY Trial
Outcome
Relative Risk
110 mg vs. VKA
Relative Risk
150 mg vs. VKA
Stroke/SE
Age < 75 y
Age > 75 y
0.93 (0.70 – 1.22)
0.88 (0.66 – 1.17)
0.63 (0.46 – 0.86)
0.67 (0.49 – 0.90)
Major Bleeding
Age < 75 y
Age > 75 y
0.62 (0.50 – 0.77)
1.01 (0.83 – 1.23)*
0.70 (0.57 – 0.86)
1.18 (0.98 – 1.42)*
Intracranial
Bleeding
Age < 75 y
Age > 75 y
0.22 (0.11 – 0.45)
0.37 (0.21 – 0.64)
0.43 (0.25 – 0.74)
0.42 (0.25 – 0.70)
Extracranial
Bleeding
Age < 75 y
Age > 75 y
0.72 (0.57 – 0.90)
1.20 (0.97 – 1.48)*
0.78 (0.63 – 0.98)
1.39 (1.13 – 1.70)*
GI Bleeding
Age < 75 y
Age > 75 y
0.82 (0.58 – 1.15)
1.39 (1.03 – 1.98)*
1.19 (0.87 – 1.63)
1.79 (1.35 – 2.37)*
*Statistically significant for interaction
Circulation. 2011;123(21):2363-72.
Arch Intern Med. 2011;171(14):1285-6.
SAFETY DATA
Use in the Elderly: RELY Trial
Major Bleeding
At age < 75 years old,
dabigatran 150 mg ↓ stroke
without ↑ bleeding vs.
warfarin.
150 mg vs. VKA
At age > 75 years old,
extracranial & major bleeding
↑ with dabigatran 150 mg vs.
warfarin.
At age > 75 years old,
warfarin should be
considered over dabigatran.
*Statistically significant
for interaction
Circulation. 2011;123(21):2363-72.
Arch Intern Med. 2011;171(14):1285-6.
Antithrombotic and
Thrombolytic Therapy for
Valvular Disease
Bioprosthetic Valves
Transcatheter aortic bioprosthetic valve
– Aspirin (50-100 mg) + clopidogrel (75 mg)
over VKA or no therapy for 3 months post
surgery (2C)
– Aspirin therapy after 3 months (2C)
Mechanical Valves: Language
Change
Bridging:
– Formerly bridge until INR therapeutic x 2
consecutive days
– Now bridge until INR “stable on VKA” (2C)
Concomitant Aspirin:
– Formerly “additional risk factors” (AF, low EF,
hypercoag, atherosclerosis)
– Now “at low risk of bleeding” (1B)
Antithrombotic and
Thrombolytic Therapy for
Ischemic Stroke
Ischemic Stroke
Change in time frame for IV r-tPA
– Formerly within 3 hours of symptom onset
– Now within 4.5 hours of symptoms onset
Evidence grade within 3 hours: 1A
Evidence grade within 4 hours: 2C
Acute ischemic CVA or TIA
– Early aspirin (within 48 hours) preferred over
parenteral anticoagulation (1A)
Acute Ischemic Stroke: VTE
Prophylaxis
LMWH (prophylactic dose) recommended
over UFH (formerly either/or) (2B)
Recommend against compression hose
(2B)
Acute Hemorrhagic Stroke: VTE
Prophylaxis
LMWH or UFH (prophylactic doses)
between days 2-4 (2C)
Suggest against compression hose (2B)
Ischemic Stroke/TIA + AF
Recommend anticoagulation with
dabigatran (2B):
– Over VKA
– Over aspirin + clopidogrel
If unable/unwilling to take anticoagulant
– Combination aspirin + clopidogrel (1B)
History of Primary ICH
Recommend against use of antithrombotic
therapy for the prevention of ischemic
CVA (2C)
Primary and Secondary
Prevention of Cardiovascular
Disease
Primary Prevention
Aspirin 75-100 mg recommended for all
people over the age of 50 without
symptomatic CV disease (2B)
Change in Language: CAD
2008: NSTEMI versus STEMI
2012: Recommendations based on known
CAD, Acute Coronary Syndrome, and MI
Known CAD
Defined as 1 year post event,
revascularization, or ischemia on testing
– Single therapy with aspirin 75-100 mg or
clopidogrel 75 mg(1A)
– Recommend against dual therapy after 1 year
(2B)
First Year After ACS
No intervention
– Dual antiplatelet therapy for 1 year with either
ticagrelor or clopidogrel + aspirin (75-100 mg)
(1B)
– Ticagrelor + aspirin preferred (2B)
Intervention
– Dual antiplatelet therapy for 1 year with either
ticagrelor or clopidogrel or prasugrel + aspirin
(75-100 mg) (1B)
– Ticagrelor + aspirin preferred (2B)
MI + LV Thrombus (or high risk for
thrombus)
First 3 months
– Aspirin 75-100 mg daily + VKA (1B)
9-12 months
– Discontinue VKA
– Dual antiplatelet therapy per ACS guidelines
After 12 months
– Single antiplatelet therapy per ACS guidelines
PCI with Bare Metal Stent
(BMS)
Month 1
– Aspirin 75-325 mg + clopidogrel 75 mg daily
(1A)
Month 2-12
– Aspirin 75-100 mg + clopidogrel 75 mg daily
(2C)
After 12 months
– Single antiplatelet therapy (1B)
PCI with Drug Eluding Stent
(DES)
First 3-6 months
– Aspirin 75-325 mg + clopidogrel (1A)
Month 3-6 to 12 months
– Aspirin 75-100 mg + clopidogrel (2C)
After 12 months
– Single antiplatelet therapy per CAD guidelines
Antithrombotic Therapy in
Pregnancy
Pregnant Patients
LMWH over UFH
Those attempting to become pregnant:
– Perform frequent pregnancy tests &
substitute LMWH for VKAs when pregnancy
is achieved rather than switching to LMWH
while attempting pregnancy (Grade 2C)
Avoid oral direct thrombin (dabigatran) & antiXa (rivaroxaban, apixaban) inhibitors
Where delivery is planned, recommend d/c
LMWH at least 24 h prior to induction
Postpartum
High risk patients in who significant risk
factors persist following deliver extend
prophylaxis (up to 6 wks) after delivery
Those with acute VTE, suggest
anticoagulants be continued for at least 6
wks postpartum, for a minimum of 3
months duration
Breastfeeding: continue use warfarin or
UFH; avoid direct thrombin & anti-Xa
inhibitors
Summary
New oral anticoagulants now available but
are not the “magic bullet”
– Need to be used in the appropriate candidates
– Adjust for renal function
– Not a one size fits all answer
Extended follow-up intervals of INR
monitoring may be okay in certain, stable,
empowered patients
Lots of changes, these are just a few
highlights
Questions?
http://chestjournal.chestpubs.org/content/141/2_suppl