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340 Anticoagulation Therapy
https://t.me/med1917
Duration of Use of Anticoagulants in VTE
See Table 13-10 for therapy duration recommendations.
TABLE 13-10: ACCP Recommended Duration of Anticoagulation
Therapy
Indication* Length of Therapy ACCP Evidence Grade
Provoked proximal DVT or PE
Provoked isolated distal DVT
First unprovoked proximal DVT or PE with
high bleeding risk
Second unprovoked VTE, high bleeding risk
First unprovoked isolated distal
DVT, or PE
Evaluate for risk–benefit of extended
therapy at 3 months
First unprovoked proximal DVT or PE Extended therapy 2B (low bleeding risk)
Second unprovoked VTE Extended therapy 1B (low bleeding risk)
DVT of leg or PE with active cancer Extended therapy 1B (low bleeding risk)
*See Table 13-3 provoking risk factors and Table 13-11 for bleeding risk stratification; see Table
13-12 for risk factors helpful in determining length of therapy in patient with unprovoked VTE.
†
Isolated DVT without severe symptoms can be managed by serial imaging for 2 weeks;
anticoagulate if clot extends proximally.
4
†
†
, proximal
3 months 1B
2C
1B
2B
At least 3 months 1B
1B
2B (moderate bleeding
risk)
2B (moderate bleeding
risk)
2B (high bleeding risk)
TABLE 13-11: ACCP Bleeding Risk Stratification for VTE
Risk factors for
bleeding on
anticoagulation
therapy
Low risk 0 risk factors
Moderate risk 1 risk factor
High risk ≥2 risk factors
Source: Adapted from the 2016 Antithrombotic Therapy for VTE Disease CHEST Guideline and
Expert Panel Report.
4
Age >65, previous bleeding, active malignancy, renal failure, liver
failure, thrombocytopenia, previous stroke, diabetes mellitus, anemia,
antiplatelet therapy, poor warfarin control, reduced functional capacity,
recent surgery/intervention, frequent falls, alcohol abuse, nonsteroidal
anti-inflammatory medications
VENOUS THROMBOEMBOLISM TREATMENT 341
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• Determining the duration of therapy:
The length and duration of anticoagulation
should be regularly reassessed at least
annually, considering that the risk for overall
VTE recurrence is 7% within the first year
and 40% within 5 years.
In general, the long-term risks of
35
anticoagulant use (bleeding) must be weighed
against the risk of repeat thrombosis when
deciding the optimal length of therapy.
The role of thrombophilia assessment to
help guide the length of therapy decision is
controversial.
A positive d-dimer at the time of warfarin
discontinuation or shortly thereafter has been
shown in clinical trials to identify patients
at higher risk for developing recurrent VTE,
particularly in women.
36
The risk for recurrence is not the same
between men and women, with women
having a 45% lower risk of recurrent VTE
than men.
Patients that stop anticoagulation after
37
a provoked VTE should consider aspirin
therapy; aspirin does help prevent recurrent
VTE (less effective than anticoagulation),
and secondary prevention therapies for
arterial disease may have been stopped
because the patient was placed on
anticoagulation.
Risk Factors to Determine Length of Anticoagulation
Therapy
The patient characteristics and comorbidities in Table 13-12 are important
to recognize when determining the length of anticoagulation therapy. For
example, patients with known antiphospholipid antibody syndrome are high
risk for recurrent VTE and may benefit from a longer course of therapy.
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TABLE 13-12: Positive and Negative Risk Factors for Recurrent
VTE to Help Determine Length of Therapy to Prevent
Recurrent VTE
Risk Factor Relative Risk
Antiphospholipid antibody syndrome 2
Male gender 1.6
Hereditary thrombophilia 1.5
Residual thrombosis in proximal veins 1.5
Two or more prior VTE 1.5
Asian descent 0.8
Isolated calf thrombosis (vs. proximal DVT) 0.5
34,35
Negative D-dimer 1 month after VKA
discontinuation
0.4
THROMBOPHILIA TESTING
Patients diagnosed with VTE, accompanied with the characteristics below,
may be referred for thrombophilia testing as it could be helpful in determining length of therapy.
Indications When Hereditary Hypercoagulability Tests
May Be Useful to Guide Therapy*
•
VTE before the age of 40
•
Strong family history of VTE
•
Thrombosis at an atypical anatomical site
•
Large PE
•
Neonatal purpura fulminans or warfarin skin necrosis
•
Multiple VTEs
•
Recurrent pregnancy losses, stillbirth
*These tests can be deferred until after a 3–6 month anticoagulant course
of therapy, as initial anticoagulation management is unlikely to change with
regard to the results of testing.
See Figure 13-10 for proposed treatment duration when thrombophilia
testing information is available.
VENOUS THROMBOEMBOLISM TREATMENT 343
Protein C deficiency
Protein S deficiency
Antithrombin deficiency
ky platelet syndrome
Greater than one abnor
Indefinite Anticoagulatio
n
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Homocycystinemia
(consider indefinite
vitamin
3–6 mo Anticoagulatio
supplementation)
Thromboembolism
Treatment duration
algorithm in inherited
hypercoaguable states
Malignancy
(anticoagulate until
malignancy eradicated)
Indeterminate Anticoagulation
Prothrombin G20210A
Factor V Leiden heterozygote
Elevated factor VIII levels
Variable Anticoagulation
n
Uncommon hypercoaguable
stic
Antiphospholipid antibody syndrome
(indefinite anticoagulation unless 6 mo
of persistent negative antibodies)
3–6 mo anticoagulation
Use prophylaxis in high-risk scenarios
Lifelong anticoagulation
Ye s
No
Spontaneous or
recurrent thrombosis
disorder
mality
FIGURE 13-10. Proposed Treatment Algorithm When Thrombophilia Information Is Known
Source: Adapted with permission from Thomas RH. Hypercoagulability syndromes. Arch Intern Med. 2001;161(20):2433–2439.
344 Anticoagulation Therapy
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SUMMARY
The management of VTE continues to evolve. Since the last edition of this
text, DOACs have supplanted VKA therapy as the preferred first-line therapy
for initial and secondary treatment for most patients, although their use in
special patient populations (e.g., patients with cancer and genetic thrombophilia) requires further study. Ongoing clinical trials in cancer-associated
VTE patients will help clarify the role of DOACs in this important patient
population. The data on the use of fibrinolytics continue to evolve yet remain
unclear in patients without massive PE. Careful consideration is needed on
the use of fibrinolytics in patients with submassive PE, where the risk–benefit
needs to be thoroughly reviewed in each patient. The duration of VTE treatment also continues to evolve. When determining the medication choice and
duration of treatment, you should consider patient-specific characteristics
that influence both recurrent VTE risk and major bleeding along with patient
preference. All clinicians should closely monitor this quickly changing literature and be sure to individualize all patient treatment decisions.
REFERENCES AND KEY ARTICLES*
1. Centers for Disease Control and Prevention. National Vital Statistics Reports. Deaths:
Final Data for 2012. http://www.cdc.gov/nchs/data/nvsr/nvsr63/nvsr63_09.pdf.
Accessed August 3, 2017.
2.
Goldhaber SZ. Deep Venous thrombosis and pulmonary thromboembolism. In: Kasper
D, Fauci A, Hauser S, et al., eds. Harrison’s Principles of Internal Medicine. 19th ed.
New York, NY: McGraw-Hill; 2014.
Kucher N. Deep-vein thrombosis of the upper extremity. N Engl J Med. 2011;364:861-
3.
869.
*4. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST
Guideline. Chest. 2016;149:315-352.
*5. Konstantinides SV, Torbicki A, Agnelli G, et al. 2014 ESC Guidelines on the diagnosis
and management of acute pulmonary embolism: The Task Force for the Diagnosis
and Management of Acute Pulmonary Embolism of the European Society of
Cardiology (ESC) Endorsed by the European Respiratory Society (ERS). Eur Heart J.
2014;35:3033-3069, 3069a-3069k.
6. Wells PS, Anderson DR, Bormanis J, et al. Value of assessment of pretest probability of
deep-vein thrombosis in clinical management. Lancet. 1997;350(9094):1795-1798.
7. Wikimedia. https://upload.wikimedia.org/wikipedia/en/e/ea/SADDLE_PE.JPG.
8. Wikicommons. https://commons.wikimedia.org/wiki/File:Pulmonary_embolism_
scintigraphy_PLoS.png).
9. Wells PS, Anderson DR, Rodger M, et al. Derivation of a simple clinical model to
categorize patients probability of pulmonary embolism: increasing the models utility
with the SimpliRED D-dimer. Thromb Haemost. 2000;83(3):416-420.
10. Gibson NS, Sohne M, Kruip MJ, et al. Further validation and simplification of the Wells
clinical decision rule in pulmonary embolism. Thromb Haemost. 2008;99:229-234.
VENOUS THROMBOEMBOLISM TREATMENT 345
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11. Aujesky D, Obrosky DS, Stone RA, et al. Derivation and validation of a prognostic
model for pulmonary embolism. Am J Respir Crit Care Med. 2005;172:1041-1046.
12. Jimenez D, Aujesky D, Moores L, et al. Simplification of the pulmonary embolism
severity index for prognostication in patients with acute symptomatic pulmonary
embolism. Arch Intern Med. 2010;170:1383-1389.
Vedantham S, Piazza G, Sista AK, Goldenburg NA. Guidance on the use of thrombolytic
*13.
therapy for the treatment of venous thromboembolism. J Thromb Thrombolysis.
2016;41:68-80.
Eight-year follow-up of patients with permanent vena cava filters in the prevention of
14.
pulmonary embolism: the PREPIC (Prevention du Risque d’Embolie Pulmonaire par
Interruption Cave) randomized study. Circulation. 2005;112(3):416-422.
15.
Mismetti P, Laporte S, Pellerin O, et al. Effect of retrievable inferior vena cava filter
plus anticoagulation vs anticoagulation alone on risk of recurrent pulmonary embolism.
A randomized clinical trial. JAMA. 2015;313(16):1627-1635.
Stein PD, Matta F, Keyes DC, et al. Impact of vena cava filters on in-hospital case
16.
fatality rate from pulmonary embolism. Am J Med. 2012;125(5):478-484.
17. Isogai T, Yasunaga H, Matsui H, et al. Effectiveness of inferior vena cava filters on
mortality as an adjuvant to antithrombotic therapy. Am J Med. 2015;128(3):312.e23-
321.e31.
18.
Lyman GH, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis
and treatment in patients with cancer: American Society of Clinical Oncology clinical
practice guideline update. J Clin Oncol. 2013;31(17):2189.
National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in
19.
Oncology. Cancer-Associated Venous Thromboembolic Disease. Version 2.2014. http://
www.nccn.org. Published August 11, 2015; accessed August 3, 2017.
20.
Lee AY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a coumarin
for the prevention of recurrent venous thromboembolism in patients with cancer. N
Engl J Med. 2003;349(2):146-153.
21. Wu C, Lee AYY. Novel or non-vitamin k antagonist oral anticoagulants and the
treatment of cancer-associated thrombosis. Semin Thromb Hemost. 2015;41:237-243.
22. Vedovati MC, Germini F, Agnelli G, et al. Direct oral anticoagulants in patients with
VTE and cancer: a systematic review and meta-analysis. Chest. 2015; 147:475-483.
*23. Schulman S, Kakkar AK, Goldhaber SZ, et al.; RE-COVER II Trial Investigators.
Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled
analysis. Circulation. 2014;129:764-772.
*24. Büller HR, Prins MH, Lensin AW, et al; EINSTEIN–PE Investigators. Oral
rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med.
2012;366:1287-1297.
*25. Prins MH, Lensing AW, Bauersachs R, et al. Oral rivaroxaban versus standard therapy
for the treatment of symptomatic venous thromboembolism: a pooled analysis of the
EINSTEIN-DVT and PE randomized studies. Thromb J. 2013;11:21.
*26. Agnelli G, Buller HR, Cohen A, et al; AMPLIFY Investigators. Oral apixaban for the
treatment of acute venous thromboembolism. N Engl J Med. 2013;369:799-808.
*27. Büller HR, Décousus H, Grosso MA, et al.; Hokusai-VTE Investigators. Edoxaban
versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J
Med. 2013;9:1406-1415.
346 Anticoagulation Therapy
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28. Kubitza D, Becka M, Zuehlsdorf M, et al. Body weight has limited influence on the
safety, tolerability, pharmacokinetics or pharmacodynamics of rivaroxaban (bay 59-
7939) in healthy subjects. J Clin Pharmacol. 2007;47:218-226.
Upreti VV, Wang J, Barrett YC, et al. Effect of extreme body weight on the
29.
pharmacokinetics, pharmacodynamics, safety and tolerability of apixaban in healthy
subjects. Br J Clin Pharmacol. 2013;76:908-916.
Lisenfeld KH, Lehr T, Dansirikul C, et al. Population pharmacokinetic analysis of
30.
the oral thrombin inhibitor dabigatran etexilate in patients with non valvular atrial
fibrillation from the RE-LY trial. J Thromb Haemost. 2011;11:2168-2175.
*31.
Weitz JI, Lensing WA, Prins MH, et al.; EINSTEIN-CHOICE Investigators.
Rivaroxaban or aspirin for extended treatment of venous thromboembolism. N Engl J
Med. 2017;376:1211-1222.
32.
Kearon C, Ginsberg JS, Kovacs MJ, et al. Comparison of low-intensity warfarin therapy
with conventional-intensity warfarin therapy for long-term prevention of recurrent
venous thromboembolism. N Engl J Med. 2003;349(7):631-639.
Ridker PM, Goldhaber SZ, Danielson E, et al. Long-term, low-intensity warfarin
33.
therapy for the prevention of recurrent venous thromboembolism. N Engl J Med. Apr
10 2003;348(15):1425-1434.
34.
Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease:
Antithrombotic Therapy and Prevention of Thrombosis. 9th ed.: American College
of Chest Physicians Evidence-based Clinical Practice Guidelines. Chest. 2012
Feb;141(suppl 2):e419S-494S.
35. Prandoni P, Noventa F, Ghirarduzzi A, et al. The risk of recurrent venous
thromboembolism after discontinuing anticoagulation in patients with acute proximal
deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1,626
patients. Haematologica. 2007;92(2):199-205.
36. Baglin T, Palmer CR, Luddington R, et al. Unprovoked recurrent venous thrombosis:
prediction by D-dimer and clinical risk factors. J Thromb Haemost. 2008;6:577-582.
37. McRae S, Tran H, Schulman S, et al. Effect of patient’s sex on risk of recurrent venous
thromboembolism: a metaanalysis. Lancet. 2006;368:371-378.
38. Thomas RH. Hypercoagulability syndromes. Arch Intern Med. 2001;161(20):2433-
2439.
14
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Chapter
ATRIAL FIBRILLATION
Daniel M. Witt
INTRODUCTION
Atrial fibrillation (AF) is a common cardiac rhythm disorder. Although AF rarely
causes life-threatening hemodynamic compromise, it is an important independent
risk factor for cardiogenic embolic stroke and systemic arterial thromboembolism.1
Approximately 90% of AF thromboembolic complications are stroke related, while
the remaining 10% are systemic embolism (see Table 14-1 for more information on
classifications). The following contribute to thromboembolic risk associated with AF:
•
Stasis or turbulence of blood flow within the left atrial appendage leads to thrombus
formation.
•
Dysfunction of vascular endothelium predisposes to local or systemic hypercoagulability.
•
Conversion to normal sinus rhythm (NSR)—spontaneous or intentional—may dislodge
any existing left atrial thrombi.
MORBIDITY AND MORTALITY ASSOCIATED
WITH AF
•
Nonvalvular AF is associated with a 5-fold increased risk of stroke.
•
The annual risk for nonfatal stroke in untreated AF patients varies between 0.8% and
9.6% (average ~5%) depending on concurrent individual risk factors.
•
Attributable stroke risk in AF increases with age:
1.5% for patients 50–59 years
23% for patients 80–89 years
•
AF-related strokes tend to be more severe than non-AF-related strokes.
Data from high-quality, randomized controlled clinical trials overwhelmingly
demonstrates that long-term, adjusted-dose anticoagulation therapy with vitamin
K-antagonists (e.g., warfarin) or direct-acting oral anticoagulants (DOACs) (e.g.,
dabigatran, rivaroxaban, apixaban, edoxaban) virtually eliminates the stroke risk
associated with AF.
preventing AF-related stroke, only about half of patients who could benefit receive
anticoagulation therapy.3 Increasing age, perceived bleeding risk, and the innate
complexity of managing anticoagulation therapy are some reasons underlying why
clinicians and patients with AF opt against anticoagulation therapy.
1,2
3
1
Despite the proven efficacy of anticoagulation therapy in
347
348 Anticoagulation Therapy
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TABLE 14-1: Classification of Atrial Fibrillation
Paroxysmal AF Terminates spontaneously or with intervention within 7 days (may
Persistent AF Continuously sustained for >7 days
Long-standing
persistent AF
Permanent AF When patient and clinician jointly decide to stop further attempts to
Nonvalvular AF AF in the absence of rheumatic mitral stenosis, a mechanical or
a
Attitude may change as symptoms, efficacy of therapeutic interventions, and patient–clinician
preferences evolve over time.
AF: atrial fibrillation
recur)
Continuously sustained for >12 months
restore/maintain sinus rhythm (a therapeutic attitude not related to
inherent pathophysiologic attributes of AF)
bioprosthetic heart valve, or mitral valve repair
1
a
TREATMENT OVERVIEW
Rate versus Rhythm Control
•
Evidence from randomized clinical trials indicates that cardioversion of AF to
normal sinus rhythm (rhythm control) is not necessary nor preferable to allowing
AF to continue while controlling ventricular response rate with AV node blockade
(rate control) with concurrent anticoagulation in those with high enough risk to
justify therapy.
4,5
The AFFIRM trial found no difference in mortality or stroke rate
between patients assigned to one strategy or the other.
The RACE trial (patients had persistent AF post failed cardioversion)
4
found rate control not inferior to rhythm control for prevention of
death and morbidity.
Rate- or rhythm-control strategies do not seem to affect quality of
5
life significantly or differently.
Ischemic events occurred with similar frequency with either a rhythm
or rate control strategy, especially when warfarin was discontinued
or when anticoagulation was subtherapeutic.
In younger individuals, a combined rate and rhythm approach may
minimize the risk of related heart failure.
Whether a rate or rhythm control strategy is employed, AF patients
with thromboembolic risk factors should probably receive chronic
anticoagulation.
1
ATRIAL FIBRILLATION 349
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Antithrombotic Therapy for Stroke Prevention in
Nonvalvular AF
See Figure 14-1.
•
Patients with valvular AF are at high stroke risk and should receive anticoagulation therapy.
•
Decisions regarding antithrombotic therapy for patients with nonvalvular AF
should be based on shared decision making, discussion of risks of stroke and
bleeding (including risk for falls), and patient’s preferences.
•
Aspirin provides little protection against stroke in AF and is markedly inferior to
warfarin (International Normalized Ratio [INR] 2–3) or DOAC therapy.
•
Adjusted-dose warfarin for stroke prevention is significantly better than clopidogrel plus aspirin, and clopidogrel plus aspirin is superior to aspirin alone.
•
Apixaban for stroke prevention is significantly better than aspirin without
increased bleeding risk.
•
For patients with stable coronary artery disease, adding aspirin to warfarin
6
therapy increases the risk of major bleeding and does not provide further protec
tion against ischemic stroke in patients with AF.
•
Patients with AF and mechanical heart valve replacement should be treated with
2
warfarin with the target INR determined by the location (mitral vs. aortic) and
type of valve (bi-leaflet versus older valve types).
Adding low-dose aspirin (50–100 mg/day) to warfarin therapy has
1
been suggested for patients with mechanical valves who are at
low risk for bleeding.
Dabigatran is contraindicated for use in patients with mechanical
7
heart valves (safety and efficacy information is lacking for rivar
oxaban, apixaban, and edoxaban and mechanical heart valves).
Data examining DOAC use in patients with bioprosthetic heart
valves are limited, and use is not currently recommended.
•
The need for ongoing anticoagulation therapy should be reevaluated at periodic
intervals.
•
The key decision in AF stroke risk reduction is whether to use oral antico-
5
agulation (warfarin or DOAC therapy)—Antiplatelet therapy with aspirin or
clopidogrel plus aspirin should be considered only when oral anticoagulation
is not an option due to either very low stroke risk or contraindications to oral
anticoagulation therapy (e.g., bleeding risk, inability to comply with the require
ments of therapy).
1,2
1
1,2
1
-
-
1
-
Nonvalvular AF Stroke Risk Stratification Tools and
Consensus Panel Treatment Guidelines
•
Warfarin or DOAC therapy is highly effective at reducing the risk for stroke
associated with nonvalvular AF.
However, anticoagulation therapy is associated with increased
bleeding risk—most importantly the risk for intracranial hemorrhage.
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