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Antithrombotic Drug Therapy in Cardiovascular Disease
of all patients with acute PE, is clearly at high risk of in-hospital death (6,45), particularly during the
first few hours after admission
(46). To date, only one small randomized trial specifically focused on
the benefits of fibrinolysis (SK vs. heparin) in massive PE
(47). This trial was terminated after only
eight patients because of excessively high mortality in the heparin-only group. Overall, meta-analyzed
data from five trials which included patients with massive PE appear to suggest a significant reduction
of death or PE recurrence after fibrinolysis
(48). Despite this weak body of evidence, there is consen-
sus among experts, and in guidelines
(49,50), that fibrinolysis should be administered to patients with
massive PE in the absence of absolute contraindications (Table
18.2). Uncontrolled data also suggest
that fibrinolysis may be a safe and effective alternative to surgery in patients with PE and free-floating
thrombi in the right heart
(51,52).
FIBRINOLYSIS GENERALLY NOT INDICATED IN NON-HIGH-RISK,
NON-MASSIVE PE
A meta-analysis of randomized trials which excluded hypotensive patients with high-risk PE sug-
gested that heparin anticoagulation is sufficient as the initial treatment of PE, and that fibrinolysis
may have no clinical benefits in this setting (48). Nevertheless, several years ago, registry data gener-
ated the hypothesis that the detection of subclinical RV dysfunction in a normotensive patient with
acute PE may help define an elevated, intermediate death risk in the acute phase (5,6). It was further
postulated that these patients may benefit from early fibrinolytic treatment
(15).
IDENTIFYING AN INTERMEDIATE-RISK GROUP AMONG NORMOTENSIVE
PATIENTS WITH PE
A number of echocardiographic findings, including right ventricular enlargement and/or
hypokinesis of the free wall, leftward septal shift, and evidence of pulmonary hypertension, have
been proposed for non-invasive diagnosis of RV dysfunction at the bedside. Several registries
and cohort studies could demonstrate an association between abnormal echocardiographic findings
and a poor in-hospital outcome in terms of PE-related death and complications (7,14,53–55). Still,
the prognostic value of cardiac ultrasound in normotensive patients with PE is not universally
accepted (56). Indeed, the echocardiographic studies published to date were characterized by
high methodological diversity and a number of important limitations
(57). These included, for
example, the lack of standardization of the echocardiographic criteria used for assessing the
function of the right ventricle, the lack of definitive confirmation of PE in some of the patients,
the inclusion of both normotensive and hypotensive patients, and the possible confounding
effects of early fibrinolytic treatment. Further limitations related to cardiac ultrasound itself
include the need for an experienced echocardiographer on a round-the-clock basis and the poor
quality of transthoracic imaging in some individuals, particularly those who are obese, on
mechanical ventilation, or have severe pulmonary emphysema. Moreover, differential diagnosis
between an episode of acute PE and recurrent thromboembolism (chronic thromboembolic pul-
monary hypertension) may be difficult, although some echocardiographic criteria have been
proposed to distinguish between acute and chronic cor pulmonale
(58).
As an alternative to echocardiography, four-chamber views of the heart on computed tomography
may detect RV enlargement as a surrogate marker of RV dysfunction due to PE and predict early
death. In a large retrospective series of 431 patients, it was found that 30-day mortality was 16% in
patientswithRVenlargement,definedasright/leftventriculardimensionratio>0.9onmultidetector-
row chest CT, compared to 7.7% in those without this finding (59). Multivariate analysis revealed that
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Fibrinolysis for Pulmonary Embolism
RV enlargement independently predicted 30-day mortality (hazard ratio, 5.17). Another retrospective
study on 120 patients evaluated the prognostic value of a predefined right/left ventricular short-axis
diameter ratio of 1.0 during 3-month follow-up
(60). The negative predictive value of a small right
ventricle
approached100%,whereasthepositivepredictivevalueofanRV/LVratio>1.0wasrather
low with regard to PE-related mortality (10%) and appeared to be inferior to that of a pulmonary
artery obstruction index of 40% or higher. In fact, a review of the data available to date reveals that
as many as 60% of all patients with PE may have some evidence of RV enlargement on CT scan. It
thus appears that detection of an enlarged right ventricle on CT (and possibly on echocardiography)
may not, by itself, suffice to indicate an elevated death risk and justify fibrinolysis.
Cardiac biomarkers may assist imaging modalities in identifying intermediate-risk patients.
Elevated cardiac troponin I or T levels, a sensitive indicator of myocardial cell damage and micro-
scopic myocardial necrosis, are found in 11–50% of patients with acute PE. A large number of studies,
which were included in recent a meta-analysis (61), could show that cardiac troponin elevation cor-
relates with the presence of RV dysfunction on echocardiography and possesses a high (97–100%)
negative predictive value with regard to death or complication risk in the acute phase. Thus, normal
troponin levels may rule out an adverse outcome in patients with PE. However, the positive predictive
value of these biomarkers is probably low. Consequently, troponin elevation alone does not suffice to
predict early death or complications in patients with acute PE, and it is unlikely that it could, by itself,
identify intermediate-risk patients as potential candidates for fibrinolytic treatment. The natriuretic
peptides BNP and NT-proBNP are characterized by extreme prognostic sensitivity and a negative
prognostic value, which is probably higher than that of the cardiac troponins. On the other hand, they
exhibit a very low specificity and positive prognostic value in the range of 12–25% (62). Furthermore,
appropriate threshold levels for distinguishing between a “positive” and a “negative” BNP or
NT-proBNP test have not yet been prospectively validated. Heart-type fatty acid-binding protein
(H-FABP) is a small cytoplasmatic protein which is abundant in the heart. Following myocardial cell
damage, it diffuses rapidly through the interstitial space and appears in the circulation as early as
90 min after symptom onset, reaching its peak within 6 h. It might provide prognostic information
superior to that of cardiac troponins in acute pulmonary embolism
(63). Finally, very recent data suggest
that the novel biomarker Growth-Differentiation Factor (GDF)-15 is a sensitive global indicator of
poor outcome in acute PE, and that it can assist imaging studies or myocardium-specific biomarkers
in identifying normotensive intermediate-risk patients, as well as those in whom closer long-term
follow-up may help prevent late deaths (64).
At present, the existing evidence appears to support the rationale for further risk stratification of
normotensive patients with confirmed acute PE. Strategies which combine the information provided
by an imaging procedure (echocardiogram or CT) and a biomarker test, preferably troponin I or T,
were reported to identify patients with an up to tenfold elevated death or complication risk compared
to those with absence of RV dysfunction or myocardial injury (62,65,66). The critical, as yet unan-
swered question is, of course, whether this information may have therapeutic implications, particularly
with regard to a possible indication for early fibrinolysis in this patient group.
IS FIBRINOLYSIS INDICATED IN PATIENTS WITH INTERMEDIATE-RISK PE?
A recent randomized trial randomized 256 normotensive patients with sub-massive PE to heparin
vs. rtPA treatment (16). RV dysfunction and/or pulmonary hypertension was diagnosed on the basis
of echocardiography, ECG, and right-heart catheterization. The primary combined end point, in-
hospital death or clinical deterioration requiring escalation of treatment, was significantly reduced
(from 25 to 11%) in the fibrinolysis compared with the heparin group. However, the differences were
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Antithrombotic Drug Therapy in Cardiovascular Disease
entirely due to a more frequent need for secondary (emergency) fibrinolysis in the heparin group
during the hospital stay, while the overall mortality rate was not affected by the type of treatment. A
large multinational trial, initiated in 2007, is currently attempting to resolve the controversy still sur-
rounding the appropriate treatment of the intermediate-risk patient group (ClinicalTrials.gov Identifier:
NCT00639743). This study, which plans to randomize more than 1,000 patients by the end of, is using
the recently validated risk stratification tools described above (RV imaging and cardiac biomarkers)
to diagnose RV dysfunction and myocardial injury in the absence of hypotension and shock.
CONCLUSIONS AND OUTLOOK
Although the diagnostic approach to patients with suspected acute pulmonary embolism has
made significant progress in the past years, the indications for fibrinolytic treatment remain partly
controversial. Fibrinolysis is clearly indicated in high-risk, clinically massive PE, i.e., in patients
with persistent arterial hypotension and shock. Alteplase, given as 100-mg infusion over 2
h, is the
most systematically evaluated fibrinolytic regimen and therefore considered as the treatment of
choice for patients with PE, although regimens using urokinase or streptokinase also were shown
to be efficacious (ClinicalTrials. gov: Identifier: NCT00639743). However, beyond the setting of
high-risk PE, there is increasing awareness of the need for risk stratification of normotensive
patients and the search for an intermediate-risk group. Recent studies suggested that imaging methods
or cardiac biomarkers alone may be insufficient for guiding therapeutic decisions, particularly with
regard to early fibrinolysis versus heparin alone, in normotensive patients with acute non-massive
PE. Instead, the existing evidence appears to support the use of risk assessment algorithms (such as
the one proposed in Fig. 2), which combine the information provided by an imaging procedure (RV
dysfunction on echocardiography or CT) and a biomarker test (RV myocardial injury indicated by
elevated troponin I or T). A large multinational trial is currently investigating whether the indica-
tions for fibrinolysis should be extended to intermediate-risk PE.
PE confirmed,
no hypotension or shock
Troponin
testing
Imaging of RV
(Echocardiography, CT)
Low-risk PE
Biomarker test negative
and
RV normal
Either biomarker positive
or
RV abnormal
Biomarker test positive
and
RV abnormal
Intermediate-risk PE
Fig. 2. Contemporary risk stratification of normotensive patients with acute pulmonary embolism, i.e., excluding high-
risk, clinically massive PE. (Adapted and slightly modified from (69).) RV right ventricle; CT computed tomogaphy.
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Fibrinolysis for Pulmonary Embolism
REFERENCES
1. White RH (2003) The epidemiology of venous thromboembolism. Circulation 107:I4–I8
2.
Cohen AT, Agnelli G, Anderson FA et al (2007) Venous thromboembolism (VTE) in Europe. The number of VTE events
and associated morbidity and mortality. Thromb Haemost 98:756–764
3.
Cohen AT, Edmondson RA, Phillips MJ, Ward VP, Kakkar VV (1996) The changing pattern of venous thromboembolic
disease. Haemostasis 26:65–71
4.
Lindblad B, Sternby NH, Bergqvist D (1991) Incidence of venous thromboembolism verified by necropsy over 30 years.
BMJ 302:709–711
5.
Goldhaber SZ, Visani L, De Rosa M (1999) Acute pulmonary embolism: clinical outcomes in the International
Cooperative Pulmonary Embolism Registry (ICOPER). Lancet 353:1386–1389
6.
Kasper W, Konstantinides S, Geibel A et al (1997) Management strategies and determinants of outcome in acute major
pulmonary embolism: results of a multicenter registry. J Am Coll Cardiol 30:1165–1171
7.
Kasper W, Konstantinides S, Geibel A, Tiede N, Krause T, Just H (1997) Prognostic significance of right ventricular
afterload stress detected by echocardiography in patients with clinically suspected pulmonary embolism. Heart
77:346–349
8.
British Thoracic Society (1992) Optimum duration of anticoagulation for deep-vein thrombosis and pulmonary embo-
lism. Research Committee of the British Thoracic Society. Lancet 340:873–876
9. Carson JL, Kelley MA, Duff A et al (1992) The clinical course of pulmonary embolism. N Engl J Med 326:1240–1245
10.
Konstantinides S (2005) Pulmonary embolism: impact of right ventricular dysfunction. Curr Opin Cardiol
20:496–501
11.
McIntyre KM, Sasahara AA (1974) Determinants of right ventricular function and hemodynamics after pulmonary
embolism. Chest 65:534–543
12. McIntyre KM, Sasahara AA (1971) The hemodynamic response to pulmonary embolism in patients without prior car-
diopulmonary disease. Am J Cardiol 28:288–294
13. Lualdi JC, Goldhaber SZ (1995) Right ventricular dysfunction after acute pulmonary embolism: pathophysiologic fac-
tors, detection, and therapeutic implications. Am Heart J 130:1276–1282
14. Kucher N, Rossi E, De Rosa M, Goldhaber SZ (2005) Prognostic role of echocardiography among patients with acute
pulmonary embolism and a systolic arterial pressure of 90 mm Hg or higher. Arch Intern Med 165:1777–1781
15. Konstantinides S, Geibel A, Olschewski M et al (1997) Association between thrombolytic treatment and the prognosis
of hemodynamically stable patients with major pulmonary embolism: results of a multicenter registry. Circulation
96:882–888
16.
Konstantinides S, Geibel A, Heusel G, Heinrich F, Kasper W (2002) Heparin plus alteplase compared with heparin
alone in patients with submassive pulmonary embolism. N Engl J Med 347:1143–1150
17.
(1973) The urokinase pulmonary embolism trial. A national cooperative study. Circulation 47:II1–II108
18.
Tibbutt DA, Davies JA, Anderson JA et al (1974) Comparison by controlled clinical trial of streptokinase and heparin
in treatment of life-threatening pulmonary embolism. Br Med J 1:343–347
19. Ly B, Arnesen H, Eie H, Hol R (1978) A controlled clinical trial of streptokinase and heparin in the treatment of major
pulmonary embolism. Acta Med Scand 203:465–470
20. Marini C, Di Ricco G, Rossi G, Rindi M, Palla R, Giuntini C (1988) Fibrinolytic effects of urokinase and heparin in
acute pulmonary embolism: a randomized clinical trial. Respiration 54:162–173
21.
Levine M, Hirsh J, Weitz J et al (1990) A randomized trial of a single bolus dosage regimen of recombinant tissue
plasminogen activator in patients with acute pulmonary embolism. Chest 98:1473–1479
22. (1990) Tissue plasminogen activator for the treatment of acute pulmonary embolism. A collaborative study by the
PIOPED Investigators. Chest 97:528–533
23. Dalla-Volta S, Palla A, Santolicandro A et al (1992) PAIMS 2: alteplase combined with heparin versus heparin in the treat-
ment of acute pulmonary embolism. Plasminogen activator Italian multicenter study 2. J Am Coll Cardiol 20:520–526
24. Goldhaber SZ, Haire WD, Feldstein ML et al (1993) Alteplase versus heparin in acute pulmonary embolism: ran-
domised trial assessing right-ventricular function and pulmonary perfusion. Lancet 341:507–511
25. Meneveau N, Seronde MF, Blonde MC et al (2006) Management of unsuccessful thrombolysis in acute massive pulmo-
nary embolism. Chest 129:1043–1050
26. Daniels LB, Parker JA, Patel SR, Grodstein F, Goldhaber SZ (1997) Relation of duration of symptoms with response to
thrombolytic therapy in pulmonary embolism. Am J Cardiol 80:184–188
27. Dalen JE, Banas JS Jr, Brooks HL, Evans GL, Paraskos JA, Dexter L (1969) Resolution rate of acute pulmonary embo-
lism in man. N Engl J Med 280:1194–1199
359
https://t.me/med1917
Antithrombotic Drug Therapy in Cardiovascular Disease
28. Konstantinides S, Tiede N, Geibel A, Olschewski M, Just H, Kasper W (1998) Comparison of alteplase versus heparin
for resolution of major pulmonary embolism. Am J Cardiol 82:966–970
29.
(1974) Urokinase-streptokinase embolism trial. Phase 2 results. A cooperative study. JAMA 229:1606–1613
30.
Meyer G, Sors H, Charbonnier B et al (1992) Effects of intravenous urokinase versus alteplase on total pulmonary
resistance in acute massive pulmonary embolism: a European multicenter double-blind trial. The European Cooperative
Study Group for Pulmonary Embolism [see comments]. J Am Coll Cardiol 19:239–245
31.
Goldhaber SZ, Kessler CM, Heit J et al (1988) Randomised controlled trial of recombinant tissue plasminogen activator
versus urokinase in the treatment of acute pulmonary embolism. Lancet 2:293–298
32.
Meneveau N, Schiele F, Metz D et al (1998) Comparative efficacy of a two-hour regimen of streptokinase versus
alteplase in acute massive pulmonary embolism: immediate clinical and hemodynamic outcome and one-year follow-
up. J Am Coll Cardiol 31:1057–1063
33.
Meneveau N, Schiele F, Vuillemenot A et al (1997) Streptokinase vs alteplase in massive pulmonary embolism. A ran-
domized trial assessing right heart haemodynamics and pulmonary vascular obstruction. Eur Heart J 18:1141–1148
34.
Goldhaber SZ, Agnelli G, Levine MN (1994) Reduced dose bolus alteplase vs conventional alteplase infusion for pul-
monary embolism thrombolysis. An international multicenter randomized trial. The Bolus Alteplase Pulmonary
Embolism Group. Chest 106:718–724
35.
Sors H, Pacouret G, Azarian R, Meyer G, Charbonnier B, Simonneau G (1994) Hemodynamic effects of bolus vs 2-h
infusion of alteplase in acute massive pulmonary embolism. A randomized controlled multicenter trial. Chest
106:712–717
36.
Tebbe U, Graf A, Kamke W et al (1999) Hemodynamic effects of double bolus reteplase versus alteplase infusion in
massive pulmonary embolism. Am Heart J 138:39–44
37.
Kline JA, Hernandez-Nino J, Jones AE (2007) Tenecteplase to treat pulmonary embolism in the emergency department.
J Thromb Thrombolysis 23(2):101–105
38. Verstraete M, Miller GA, Bounameaux H et al (1988) Intravenous and intrapulmonary recombinant tissue-type plas-
minogen activator in the treatment of acute massive pulmonary embolism. Circulation 77:353–360
39. Kanter DS, Mikkola KM, Patel SR, Parker JA, Goldhaber SZ (1997) Thrombolytic therapy for pulmonary embolism.
Frequency of intracranial hemorrhage and associated risk factors. Chest 111:1241–1245
40. Goldhaber SZ, Kessler CM, Heit JA et al (1992) Recombinant tissue-type plasminogen activator versus a novel dosing
regimen of urokinase in acute pulmonary embolism: a randomized controlled multicenter trial. J Am Coll Cardiol
20:24–30
41.
Konstantinides S, Marder VJ (2006) Thrombolysis in venous thromboembolism. In: Colman RW, Marder VJ, Clowes
AW, George JN, Goldhaber SZ (eds) Hemostasis and Thrombosis. Lippincott Williams and Wilkins, Philadelphia, pp
1317–1329
42.
Stein PD, Hull RD, Raskob G (1994) Risks for major bleeding from thrombolytic therapy in patients with acute pulmo-
nary embolism. Consideration of noninvasive management [see comments]. Ann Intern Med 121:313–317
43. Hamel E, Pacouret G, Vincentelli D et al (2001) Thrombolysis or heparin therapy in massive pulmonary embolism with
right ventricular dilation: results from a 128-patient monocenter registry. Chest 120:120–125
44. Meyer G, Gisselbrecht M, Diehl JL, Journois D, Sors H (1998) Incidence and predictors of major hemorrhagic compli-
cations from thrombolytic therapy in patients with massive pulmonary embolism. Am J Med 105:472–477
45. Kucher N, Rossi E, De Rosa M, Goldhaber SZ (2006) Massive pulmonary embolism. Circulation 113:577–582
46. Stein PD, Henry JW (1995) Prevalence of acute pulmonary embolism among patients in a general hospital and at
autopsy. Chest 108:978–981
47.
Jerjes-Sanchez C, Ramírez-Rivera A, de Lourdes G et al (1995) Streptokinase and Heparin versus Heparin Alone in
Massive Pulmonary Embolism: A Randomized Controlled Trial. J Thromb Thrombolysis 2:227–229
48. Wan S, Quinlan DJ, Agnelli G, Eikelboom JW (2004) Thrombolysis compared with heparin for the initial treatment of
pulmonary embolism: a meta-analysis of the randomized controlled trials. Circulation 110:744–749
49. Torbicki A, Perrier A, Konstantinides SV et al. Guidelines on the diagnosis and management of acute pulmonary embo-
lism: The Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of
Cardiology (ESC). Eur Heart J 2008; 29:2276–2315
50. Kearon C, Kahn SR, Agenlli G, Goldhaber S, Raskob GE, Comerota AJ. Antithrombotoc therapy for venous throm-
boembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).
Chest 2008; 133(6 Suppl):454S–545S
51. Rose PS, Punjabi NM, Pearse DB (2002) Treatment of right heart thromboemboli. Chest 121:806–814
52. Chartier L, Bera J, Delomez M et al (1999) Free-floating thrombi in the right heart: diagnosis, management, and prog-
nostic indexes in 38 consecutive patients. Circulation 99:2779–2783
360
https://t.me/med1917
Fibrinolysis for Pulmonary Embolism
53. Vieillard-Baron A, Page B, Augarde R et al (2001) Acute cor pulmonale in massive pulmonary embolism: incidence,
echocardiographic pattern, clinical implications and recovery rate. Intensive Care Med 27:1481–1486
54.
Grifoni S, Olivotto I, Cecchini P et al (2000) Short-term clinical outcome of patients with acute pulmonary embolism,
normal blood pressure, and echocardiographic right ventricular dysfunction. Circulation 101:2817–2822
55.
Ribeiro A, Lindmarker P, Johnsson H, Juhlin-Dannfelt A, Jorfeldt L (1999) Pulmonary embolism: one-year follow-up
with echocardiography Doppler and five-year survival analysis [see comments]. Circulation 99:1325–1330
56.
ten Wolde M, Sohne M, Quak E, Mac Gillavry MR, Buller HR (2004) Prognostic value of echocardiographically
assessed right ventricular dysfunction in patients with pulmonary embolism. Arch Intern Med 164:1685–1689
57.
Sanchez O, Trinquart L, Colombet I et al (2008) Prognostic value of right ventricular dysfunction in patients with
haemodynamically stable pulmonary embolism: a systematic review. Eur Heart J 29(12):1569–1577
58.
Kasper W, Geibel A, Tiede N et al (1993) Distinguishing between acute and subacute massive pulmonary embolism by
conventional and Doppler echocardiography. Br Heart J 70:352–356
59.
Schoepf UJ, Kucher N, Kipfmueller F, Quiroz R, Costello P, Goldhaber SZ (2004) Right ventricular enlargement on
chest computed tomography: a predictor of early death in acute pulmonary embolism. Circulation 110:3276–3280
60.
van der Meer RW, Pattynama PM, van Strijen MJ et al (2005) Right ventricular dysfunction and pulmonary obstruction
index at helical CT: prediction of clinical outcome during 3-month follow-up in patients with acute pulmonary embo-
lism. Radiology 235:798–803
61.
Becattini C, Vedovati MC, Agnelli G (2007) Prognostic value of troponins in acute pulmonary embolism: a meta-
analysis. Circulation 116:427–433
62. Klok FA, Mos IC, Huisman MV. Brain-type natriuretic peptide levels in the prediction of adverse outcome in patients
with pulmonary embolism: a systematic review and meta-analysis. Am J Respir Crit Care Med 2008; 178(4):425–430
63.
Puls M, Dellas C, Lankeit M et al (2007) Heart-type fatty acid-binding protein permits early risk stratification of
pulmonary embolism. Eur Heart J 28:224–229
64. Lankeit M, Kempf T, Dellas C et al (2008) Growth differentiation factor-15 for prognostic assessment of patients with
acute pulmonary embolism. Am J Respir Crit Care Med 177:1018–1025
65. Binder L, Pieske B, Olschewski M et al (2005) N-terminal pro-brain natriuretic peptide or troponin testing followed by
echocardiography for risk stratification of acute pulmonary embolism. Circulation 112:1573–1579
66. Scridon T, Scridon C, Skali H, Alvarez A, Goldhaber SZ, Solomon SD (2005) Prognostic significance of troponin eleva-
tion and right ventricular enlargement in acute pulmonary embolism. Am J Cardiol 96:303–305
67. Van De WF, Ardissino D, Betriu A et al (2003) Management of acute myocardial infarction in patients presenting with
ST-segment elevation. The Task Force on the Management of Acute Myocardial Infarction of the European Society of
Cardiology. Eur Heart J 24:28–66
68.
Meyer G (2007) Thrombolysis. In: Konstantinides SV (ed) Management of acute pulmonary embolism. Humana,
Totowa, pp 125–136
69.
Konstantinides SV (2008) Acute pulmonary embolism revisited: thromboembolic venous disease. Heart 94:795–802
361
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19 Duration of Anticoagulant Therapy After
Venous Thromboembolism
Clive Kearon
Co n t e n t s
Management Of Vitamin K Antagonist Therapy
Antiplatelet Therapy for Treatment of VTE
Recommended Duration of Anticoagulation in Individual Patients
References
Ab s t r A c t Long-term treatment of venous thromboembolism (VTE) primarily focuses on the duration
of anticoagulant therapy, usually with vitamin K antagonists (VKA). The duration of therapy should be
individualized based on the risk of recurrent VTE if treatment is stopped and the risk of bleeding if treat-
ment is continued. The risk of recurrence is low if thrombosis was provoked by a reversible risk factor
such as surgery; 3 months of treatment is usually adequate for such patients. The risk of recurrence is high
if thrombosis was associated active cancer; indefinite anticoagulant therapy, with low-molecular-weight
heparin for at least the first 3 months, is often indicated for such patients. Risk of recurrence is interme-
diate if thrombosis was an unprovoked proximal deep vein thrombosis or pulmonary embolism; indefinite
anticoagulant therapy is often appropriate for such patients. Among patients with unprovoked proximal
deep vein thrombosis or pulmonary embolism, more than one previous episode of VTE, presentation as
pulmonary embolism, male sex, and a positive D-dilmer test 1 month after stopping anticoagulant therapy,
particularly favor indefinite anticoagulant therapy. High risk of bleeding and patient preference favor
treatment for only 3 months. New anticoagulants, that may improve the risk: benefit ratio of anticoagulant
therapy and should reduce the burden of therapy, are expected to be available soon.
Key words:
Deep vein thrombosis; Pulmonary embolism; Anticoagulation; Warfarin; INR; Monitoring
Long-term treatment of venous thromboembolism (VTE) is usually with a vitamin K antagonist
(VKA) and less commonly with a low-molecular weight heparin (LMWH). Long-term therapy has two
goals that overlap in timing: (1) to complete treatment of the acute episode of VTE (predominantly in
the first 3
months); and (2) to prevent new episodes of VTE that are not directly related to the acute
event (predominantly after the first 3 months).
The need for long-term therapy of VTE after an initial 5–10 day course of therapeutic-dose heparin
has been established by trials that have shown that long-term therapy with VKA markedly reduced
recurrent VTE in patients with: (1) symptomatic isolated distal deep vein thrombosis (DVT) com-
From: Contemporary Cardiology: Antithrombotic Drug Therapy in Cardiovascular Disease
Edited by: A.T. Askari and A.M. Lincoff (eds.), DOI 10.1007/978-1-60327-235-3_19
© Humana Press, a part of Springer Science+Business Media, LLC 2010
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Antithrombotic Drug Therapy in Cardiovascular Disease
pared with controls who did not receive long-term therapy (0/23 vs. 8/28 [29%] at 3 months; p < 0.01)
(1); and (2) proximal DVT compared with low dose (5,000 U twice daily) subcutaneous heparin (0/17
vs. 9/19 [47%] at 3
months; p < 0.001) (2). High rates of recurrent VTE in patients who are only
treated for 4 or 6
weeks with VKA compared to those treated for 3 or 6 months further supports the
need for long-term therapy (see below)
(3–5).
MANAGEMENT OF VITAMIN K ANTAGONIST THERAPY
Initiation of VKA
Studies have shown that about 5 days of heparin therapy (VKA started on first or second day) was
as effective as 10–14
days of heparin therapy (VKA started after about 5 days), and thus, established
that VKA could be started the same day as heparin
(6,7). Two trials in hospitalized patients showed
that starting warfarin at a dose of 5
mg, compared with 10 mg, is associated with less excessive anti-
coagulation and does not meaningfully delay onset of anticoagulation
(8,9). However, a similar study
in outpatients with acute VTE found that starting with 10
mg of warfarin was superior to starting with
5
mg (10). Observational studies have shown that lower VKA maintenance doses are required in older
patients, women, and those with impaired nutrition and vitamin K deficiency
(11,12). Thus, these data
suggest that warfarin can usually be started at a first dose of 10
mg in younger (e.g., less than 60 years)
and healthy outpatients, and at a first dose of 5
mg in older and hospitalized patients. Nomograms, to
guide the first days of warfarin dosing, were published from previous studies
(9,10).
Long-Term Monitoring and Adjustment of VKA
Many factors modify the anticoagulant response to VKA therapy and, therefore, there are marked
differences in VKA dosing required to achieve an International Normalized Ratio (INR) of 2.0–3.0,
both among patients and in the same patient over time (11). Consequently, VKA dosing needs to be
adjusted in response to ongoing INR measurements in order to maximize the time a patient is in the
target INR range. Good anticoagulant control is important as: (1) subtherapeutic anticoagulation
(particularly below INR 1.5) increases recurrent VTE, (2) supratherapeutic anticoagulation (particu-
larly over INR 5.0) increases bleeding, and (3) poor anticoagulant control increases the burden of
anticoagulant therapy and discourages patients and healthcare providers from continuing VKA therapy
when it is indicated
(11). Principles and management strategies that facilitate optimal long-term
anticoagulation are summarized in Table
1.
Optimal Intensity of Vitamin K Antagonist Therapy
VKA inhibits two enzymes (vitamin K epoxide reductase and vitamin K reductase) that convert
vitamin K epoxide, via vitamin K, to hydroquinone (vitamin KH
2
). Subsequently, hydroquinone defi-
ciency results in defective carboxylation, and reduced functional levels of coagulation factors II, VII,
IX, and X, thereby achieving anticoagulation. The degree, or intensity, of resultant anticoagulation is
measured as a prothrombin time ratio, usually expressed in a standardized form as the INR (11). Hull
and colleagues established that acute treatment of VTE (i.e., first 3 months) with a target INR of 2.5
(range 2.0–3.0) was as effective but caused less bleeding than treatment with a target INR of 3.5
(range 3.0–4.0) (13). In patients with an antiphospholipid antibody and mostly VTE, two studies have
shown that targeting an INR of 2.5 is as effective as targeting an INR of 3.5 (14,15).
The observation in two trials (3,16) that there were no episodes of recurrent VTE among patients
who remained on extended-duration VKA targeted an INR of ~2.5 (3,16) (Table 3) suggesting that
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Duration of Anticoagulant Therapy After Venous Thromboembolism
lowering the intensity of anticoagulation to a target INR of ~1.75 after the first 3 months of conven-
tional intensity therapy might reduce bleeding without loss of efficacy. When this hypothesis was
subsequently tested in a double-blind trial of patients with unprovoked VTE, the lower intensity of
anticoagulation was less effective in preventing recurrent VTE (intention-to-treat analysis: 1.9% vs.
0.7% per patient-year; hazard ratio 2.8 [95% CI 1.1–7.0]) and was associated with the same fre-
quency of major bleeding (1.1% vs. 0.9% per patient-year; hazard ratio 1.2 [95% CI 0.4–3.0]) as
conventional intensity therapy (Table 3) (17). As discussed later in this chapter, after the first
3 months of conventional intensity VKA therapy, low intensity anticoagulation (target INR of 1.75)
has been shown to reduce the risk of recurrent VTE by about two-thirds and is compatible with a
less frequent INR testing (e.g., about 2 months) than is usual with conventional intensity anticoagu-
lation (Table 3) (18).
Based on these studies, a target INR of 2.5 (range 2.0–3.0) is recommended as the optimal intensity
of anticoagulation for both acute and long-term treatment of VTE.
Table 1
Principles and recommendations for maintenance of vitamin K antagonist therapy
Interval between INR measurements
• Graduallyincreaseintervalfromevery2–3daysinthefirstweektoevery2–4weeks(e.g.,after6weeks)
(11).
• Decreaseintervalbetweentestingifthepatientbecomesillorifamedicationisaddedorstopped(11,116).
• DecreaseintervalifINRresultsbecomeunstable.
Dosing of warfarin
• Averagedailywarfarindoseisabout6mgatage50andabout3.5mgatage80(12).
• Ifwarfarinmaintenancedoseneedstobeincreasedordecreased,stepsof10%areusuallysuitable.Thiscan
be done by calculating the total dose of warfarin given in the preceding week, and adjusting the next week(s)
total dose by 10%; this often translates into a change in the total week’s dose of 2.5–5.0 mg of warfarin (11).
• IfINR>5.0,1or2dosesofwarfarinshouldbewithheldinadditiontoreducingthemaintenanceofwarfa-
rindose.IfINR>5.0,thepatienthasariskofbleeding,orINR>10.0,1–2.5mgoforalvitaminKshould
also be given (11,117,118).
Method of anticoagulant monitoring
• AsystematicprocessformonitoringVKAshouldbeusedthatincludespatienteducation,andexplicit
patient and healthcare provider responsibility for each stage of the process (e.g., patient attends a desig-
nated laboratory for INR testing; INR results are communicated to healthcare providers at pre-specified
time (e.g., same or following day); INR results are recorded in the patient’s anticoagulation record; VKA
dose is selected; VKA dose and timing of next INR measurement are communicated to the patient)
(11).
• UseofadedicatedanticoagulantservicecanimprovedeliveryofVKAtherapy(11).
• Self-testing,orself-dosing,isappropriateinselectedwelleducatedandmotivatedpatients(11,119).
• Computerprogramscanfacilitateselectionofwarfarindose,trackingofINRandVKAdosing,andcom-
munication of VKA dosing to patients (e.g., via mail) (11).
Interruption of VKA
• After1month,andparticularlyafter3months,ofVKAtherapyforVTE,shortinterruptionsofVKA(e.g.,
£5 days) are well tolerated (i.e., associated with a low risk of recurrence) provided patients have not under-
gone a procedure that is associated with VTE (11,62).
• PatientswhohavehadaprocedurethatisassociatedwithVTE(e.g.,surgerywithgeneralanesthetic)
should receive supplemental VTE prophylaxis (e.g., a heparin preparation) until their INR increases, or is
expected to have increased (e.g., ~3 days), to above INR 1.5 (11,120).
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Antithrombotic Drug Therapy in Cardiovascular Disease
Duration of Anticoagulant Therapy
Anticoagulant therapy for VTE should be continued until: (1) its benefits (reduction of recurrent
VTE) no longer clearly outweigh its risks (increase in bleeding); or (2) the patient prefers to stop
treatment even if continuing treatment is beneficial. In patients with an average risk of bleeding
while on anticoagulant therapy, therefore, the decision to stop or continue therapy is dominated by
the risk of recurrent VTE if treatment is stopped. Current evidence suggests that the risk of recur-
rence after stopping therapy is largely determined by two factors: (1) whether the acute episode of
VTE has been effectively treated, and (2) the patient’s intrinsic risk of having a new episode of VTE
(i.e., not arising directly from the episode of thrombosis for which patients have been receiving treat-
ment). If therapy is stopped before the acute episode of thrombosis is adequately treated, the risk of
recurrent VTE will be higher than if treatment was stopped after a longer course of anticoagulation.
If patients have a persistently high intrinsic risk for thrombosis, even if the acute episode of throm-
bosis has effectively been treated, they will have a high risk of recurrence once anticoagulant
therapy is stopped; if this risk is high enough relative to the patient’s increased risk of bleeding on
anticoagulants, indefinite therapy will be indicated. As patients’ intrinsic risk of recurrent VTE has
influenced the enrolling of patients in trials that have compared durations of anticoagulant therapy
and needs to be considered in the interpretation of these studies, risk factors for recurrent VTE in
individual patients will be considered before reviewing the studies that have compared different
durations of VKA in patients with VTE.
Patient Related Risk Factors for Recurrent VTE After Stopping Anticoagulant Therapy
Cancer
Cancer is associated with about a threefold increased risk of recurrent VTE both during (19–
23)
and after (22,24–26) anticoagulant therapy, and among patients with cancer, the risk of recur-
rence is about threefold higher in those with metastatic disease
(23) (Table 2). The risk of
recurrent VTE after stopping anticoagulant therapy is expected to be high (i.e., 10–20% in the
first year) in cancer patients, particularly if there is progressive or metastatic disease, poor
mobility, or ongoing chemotherapy
(25–27). The risk of recurrence is uncertain, and likely to be
lower, if the cancer has responded to therapy, or if the initial VTE was provoked by an additional
reversible risk factor, such as surgery or chemotherapy (see below). Because cancer is considered
to be such a strong risk factor for recurrent VTE, there is widespread agreement that most
patients with VTE and cancer require long-term anticoagulant therapy and these patients have
been excluded from the randomized trials that have compared different durations of anticoagu-
lant therapy.
Reversibility of Risk Factors for VTE
It has become clear that patients with VTE provoked by a major reversible risk factor, such as
surgery, have a low risk of recurrence (i.e., about 3% in the first year) after 3 or more months of anti-
coagulant therapy, whereas the risk is high (i.e., about 10% in the first year) in patients with an unpro-
voked (also termed “idiopathic”) VTE and in those with a persistent risk for thrombosis (Table
2)
(4,5,18,26–31). If VTE was provoked by a minor reversible risk factor, such as leg trauma, estrogen
therapy, or prolonged air travel (e.g., a flight of over 8 h), there is an intermediate risk of recurrent
VTE after stopping anticoagulant therapy (i.e., approximately 5% in the first year) (25,31,32).
Because of this difference in the risk of recurrence, many recent trials selectively enrolled patients
with unprovoked VTE and compared longer durations of therapy (16–18,33–35), or enrolled patients
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