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Antithrombotic Drug Therapy in Cardiovascular Disease
treated with anticoagulation alone is <10% while the mortality directly due to PE after proper treatment
with anticoagulation is 2%
(25). A review of thrombolytic therapy for the treatment of acute PE esti-
mates that with a 6.7% death rate from treatment with heparin therapy alone, a study sample of 1,000
patients is needed to have an 80% power to detect a 50% reduction in mortality
(76). There have been
no large randomized controlled trials on this subject to date, but a recent Cochrane meta-analysis
(77)
including 679 patients in eight trials comparing thrombolytic agents (streptokinase, urokinase, or rt-PA)
followed by heparin to heparin alone or heparin plus placebo for the treatment of PE showed no
statistically significant difference in overall mortality (OR 0.89; 95% CI 0.45–1.78), recurrence of PE
(OR 0.63, 95% CI 0.33–1.20), major hemorrhagic events (OR 1.61; 95% CI 0.91–2.86), or minor
hemorrhagic events (OR 1.98; 95% CI 0.68–5.75). Patients who received thrombolytics did have
improved hemodynamic, echocardiographic, V/Q scan, and angiographic outcomes compared to patients
who received heparin alone, but this did not translate to improved mortality. Similarly, of 108
patients in ICOPER with massive PE, 33 patients who received thrombolysis received no mortality
benefit at 90 days (HR 0.79 [95% CI 0.44–1.43]). The overall 90-day mortality rates were 46.3%
(95% CI 31.0–64.8%) with thrombolysis, 55.1% (95% CI 44.3–66.7%) without thrombolysis (78).
Very few studies have been performed regarding the use of thrombolytics in patients with submas-
sive PE who have evidence of right ventricular dysfunction but who are hemodynamically stable.
There has been one such randomized controlled trial of 101 hemodynamically stable patients who
were given rt-PA followed by heparin or heparin alone and followed with echocardiography at 3 and
24 h after administration. There was a statistically significant improvement in right ventricular wall
motion at both 3 and 24
h in the rt-PA group compared to the heparin only group (OR 2.90, 95% CI
0.98–8.6 at 3
h; OR 3.20, 95% CI 1.20–8.57 at 24 h). Worsening of right ventricular motion was seen
in 2% of patients in the rt-PA group and 17% of patients in the heparin only group at 24
h (p = 0.005).
There was also a significant decrease in right ventricular end-diastolic area in the rt-PA group but not
in the heparin only group (79).
Only one study has investigated the effect of systemic versus intrapulmonary thrombolytic therapy
for the treatment of PE (80). This multicenter study included 34 patients with angiographically proven
PE who were randomly assigned to intravenous or intrapulmonary rt-PA in addition to heparin therapy.
There were similar decreases in the severity of embolism determined by angiography and in mean
pulmonary artery pressures among the two groups leading the authors to conclude that inpulmonary
infusion of rt-PA has no benefit over intravenous injection of rt-PA for the treatment of acute PE.
Based on the data available, the 8th ACCP guidelines (25) recommend against the use of systemic
thrombolytic therapy in most patients with PE (Grade 1B), but suggest the use of systemic thrombo-
lytic therapy in patients who are hemodynamically unstable (Grade 1B). The guidelines further
suggest that catheter-directed local thrombolytic therapy not be administered (Grade 1C). The
recommended dose for streptokinase for the treatment of PE is 250,000 IU as a loading dose followed
by a 100,000 IU/h infusion for 24 h. The dose of rt-PA is a 100 mg infusion given over 2 h (Table 5).
Urokinase is not available in the United States. Heparin therapy should be started following the infu-
sion of thrombolytic therapy.
Pulmonary thromboembolectomy is a complex surgical procedure with an associated mortality of
5–24% (81–84). It is generally offered to symptomatic patients with hemodynamic or ventilatory
defects at rest or exercise who have thrombotic material in the main, lobar, or proximal segmental
arteries. The only absolute contraindication to the procedure is severe underlying lung disease, and
the major complications after surgery are bleeding, reperfusion pulmonary edema, and persistent
pulmonary hypertension. Most patients have improvement in NYHA functional class (III or IV before
surgery to I or II after surgery) (85) and in their hemodynamic parameters including mean pulmonary
artery pressure and pulmonary vascular resistance (86). A recent retrospective study involving 47
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Venous Thromboembolism
patients described outcomes of surgical pulmonary embolectomy performed for massive PE (hypoten-
sion present) and submassive PE (right ventricular dysfunction but normal blood pressure) (n
= 15).
The operative mortality was 6%, and overall survival was 86% at 1 year and 83% at 3 years
(81). A
similar study involving 13 patients, 9 with submassive PE, described an 8% in-hospital mortality
(87).
Thus, with progressively decreasing operative morality rates, surgical pulmonary embolectomy may
become a viable option for submassive PE to prevent future right ventricular failure, but randomized
controlled studies are needed to determine the benefit of surgery over contemporary medical therapy.
Currently, pulmonary embolectomy is not recommended for most patients with PE. It is generally
reserved for patients with massive PE who are hemodynamically unstable despite maximal medical
therapy, including anticoagulation and thrombolytic therapy, or for patients who have a contraindica-
tion to thrombolytic therapy or whose critical status does not allow for sufficient time for infusion of
thrombolytics (25). The ACCP guidelines recommend lifelong treatment with a vitamin K antagonist
(VKA) following surgery, and IVC filter placement before or at the time of pulmonary thromboem-
bolectomy is also suggested (25).
REFERENCES
1. Snow V, Qaseem A, Barry P et al (2007) Management of venous thromboembolism: a clinical practice guideline
from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med
146:204–210
2. Silverstein MD, Heit JA, Mohr DN, Petterson TM, O’Fallon WM, Melton LJ 3rd (1998) Trends in the incidence of deep
vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 158:585–593
3. Kyrle PA, Minar E, Bialonczyk C, Hirschl M, Weltermann A, Eichinger S (2004) The risk of recurrent venous throm-
boembolism in men and women. N Engl J Med 350:2558–2563
4. Prandoni P, Bilora F, Marchiori A et al (2003) An association between atherosclerosis and venous thrombosis. N Engl
J Med 348:1435–1441
5. Geerts WH, Berggrist D, Heit JA et al (2008) Prevention of venous thromboembolism: the Seventh ACCP Conference
on Antithrombotic and Thrombolytic Therapy. Chest 133:3815–4535
6. Lindblad B, Eriksson A, Bergqvist D (1991) Autopsy-verified pulmonary embolism in a surgical department: analysis
of the period from 1951 to 1988. Br J Surg 78:849–852
7. Sandler DA, Martin JF (1989) Autopsy proven pulmonary embolism in hospital patients: are we detecting enough deep
vein thrombosis? J R Soc Med 82:203–205
8. Anderson FA Jr, Wheeler HB, Goldberg RJ et al (1991) A population-based perspective of the hospital incidence and
case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch Intern Med
151:933–938
Table 5
Thrombolytic Regimens for the Treatment of Acute PE
Medication Dose
Contraindications to
thrombolytic Agents
Streptokinase (Not recommended
for use if streptokinase has been
used previously)
250,000 IU as a loading dose
over 30 min followed by a
100,000 IU/h infusion for 24 h
Active internal bleeding
Recent (within 2 months)
cerebrovascular accident,
intracranial or intraspinal
surgery
Recombinant tissue-type
plasminogen activator (rt-PA)
100-mg infusion given over 2
h
Intracranial neoplasm,
arteriovenous malformation,
or aneurysm
Severe uncontrolled hypertension
347
https://t.me/med1917
Antithrombotic Drug Therapy in Cardiovascular Disease
9. Cohen AT, Tapson VF, Bergmann JF et al (2008) Venous thromboembolism risk and prophylaxis in the acute hospital
care setting (ENDORSE study): a multinational cross-sectional study. Lancet 371:387–394
10. Geerts WH, Heit JA, Clagett GP et al (2001) Prevention of venous thromboembolism. Chest 119:132S–175S
11. (1975) Prevention of fatal postoperative pulmonary embolism by low doses of heparin. An international multicentre
trial. Lancet 2:45–51.
12. Sagar S, Massey J, Sanderson JM (1975) Low-dose heparin prophylaxis against fatal pulmonary embolism. Br Med J
4:257–259
13. Halkin H, Goldberg J, Modan M, Modan B (1982) Reduction of mortality in general medical in-patients by low-dose
heparin prophylaxis. Ann Intern Med 96:561–565
14. Collins R, Scrimgeour A, Yusuf S, Peto R (1988) Reduction in fatal pulmonary embolism and venous thrombosis by
perioperative administration of subcutaneous heparin. Overview of results of randomized trials in general, orthopedic,
and urologic surgery. N Engl J Med 318:1162–1173
15. Shojania KG, Duncan BW, McDonald KM, Wachter RM, Markowitz AJ (2001) Making health care safer: a critical
analysis of patient safety practices. Evid Rep Technol Assess (Summ) 43:i–x, 1–668
16. Lindblad B, Sternby NH, Bergqvist D (1991) Incidence of venous thromboembolism verified by necropsy over 30 years.
BMJ 302:709–711
17. Heit JA, Mohr DN, Silverstein MD, Petterson TM, O’Fallon WM, Melton LJ 3rd (2000) Predictors of recurrence after
deep vein thrombosis and pulmonary embolism: a population-based cohort study. Arch Intern Med 160:761–768
18. Fedullo PF, Auger WR, Kerr KM, Rubin LJ (2001) Chronic thromboembolic pulmonary hypertension. N Engl J Med
345:1465–1472
19. Pengo V, Lensing AW, Prins MH et al (2004) Incidence of chronic thromboembolic pulmonary hypertension after pul-
monary embolism. N Engl J Med 350:2257–2264
20. Moser KM, Bloor CM (1993) Pulmonary vascular lesions occurring in patients with chronic major vessel thromboem-
bolic pulmonary hypertension. Chest 103:685–692
21. Kim H, Yung GL, Marsh JJ et al (2000) Pulmonary vascular remodeling distal to pulmonary artery ligation is accom-
panied by upregulation of endothelin receptors and nitric oxide synthase. Exp Lung Res 26:287–301
22. Riedel M, Stanek V, Widimsky J, Prerovsky I (1982) Longterm follow-up of patients with pulmonary thromboembo-
lism. Late prognosis and evolution of hemodynamic and respiratory data. Chest 81:151–158
23. Kahn SR, Ginsberg JS (2002) The post-thrombotic syndrome: current knowledge, controversies, and directions for
future research. Blood Rev 16:155–165
24. Puggioni A, Kalra M, Gloviczki P (2005) Practical aspects of the postthrombotic syndrome. Dis Mon 51:166–175
25. Kesron C, Kahn SR, Agnell G et al (2008) Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP
Conference on Antithrombotic and Thrombolytic Therapy. Chest 133:4545–5455
26. Sandler DA, Martin JF, Duncan JS et al (1984) Diagnosis of deep-vein thrombosis: comparison of clinical evaluation,
ultrasound, plethysmography, and venoscan with X-ray venogram. Lancet 2:716–719
27. Wells PS, Anderson DR, Bormanis J et al (1997) Value of assessment of pretest probability of deep-vein thrombosis in
clinical management. Lancet 350:1795–1798
28. Wells PS, Anderson DR, Rodger M et al (2003) Evaluation of D-dimer in the diagnosis of suspected deep-vein throm-
bosis. N Engl J Med 349:1227–1235
29. Tamariz LJ, Eng J, Segal JB et al (2004) Usefulness of clinical prediction rules for the diagnosis of venous thromboem-
bolism: a systematic review. Am J Med 117:676–684
30. Wells PS, Owen C, Doucette S, Fergusson D, Tran H (2006) Does this patient have deep vein thrombosis? JAMA
295:199–207
31. Lensing AW, Prandoni P, Brandjes D et al (1989) Detection of deep-vein thrombosis by real-time B-mode ultrasonog-
raphy. N Engl J Med 320:342–345
32. Mattos MA, Londrey GL, Leutz DW et al (1992) Color-flow duplex scanning for the surveillance and diagnosis of acute
deep venous thrombosis. J Vasc Surg 15:366–375 discussion 375-6
33. Birdwell BG, Raskob GE, Whitsett TL et al (2000) Predictive value of compression ultrasonography for deep vein thrombosis
in symptomatic outpatients: clinical implications of the site of vein noncompressibility. Arch Intern Med 160:309–313
34. Kearon C, Ginsberg JS, Julian JA et al (2006) Comparison of fixed-dose weight-adjusted unfractionated heparin and
low-molecular-weight heparin for acute treatment of venous thromboembolism. JAMA 296:935–942
35. Lee AY, Levine MN, Baker RI et al (2003) Low-molecular-weight heparin versus a coumarin for the prevention of
recurrent venous thromboembolism in patients with cancer. N Engl J Med 349:146–153
36. Lensing AW, Prins MH, Davidson BL, Hirsh J (1995) Treatment of deep venous thrombosis with low-molecular-weight
heparins. A meta-analysis. Arch Intern Med 155:601–607
348
https://t.me/med1917
Venous Thromboembolism
37. Dolovich LR, Ginsberg JS, Douketis JD, Holbrook AM, Cheah G (2000) A meta-analysis comparing low-molecular-weight
heparins with unfractionated heparin in the treatment of venous thromboembolism: examining some unanswered questions
regarding location of treatment, product type, and dosing frequency. Arch Intern Med 160:181–188
38. Levine M, Gent M, Hirsh J et al (1996) A comparison of low-molecular-weight heparin administered primarily at home with
unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med 334:677–681
39. Koopman MM, Prandoni P, Piovella F et al (1996) Treatment of venous thrombosis with intravenous unfractionated
heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at
home. The Tasman Study Group. N Engl J Med 334:682–687
40. Buller HR, Davidson BL, Decousus H et al (2004) Fondaparinux or enoxaparin for the initial treatment of symptomatic
deep venous thrombosis: a randomized trial. Ann Intern Med 140:867–873
41. Buller HR, Davidson BL, Decousus H et al (2003) Subcutaneous fondaparinux versus intravenous unfractionated
heparin in the initial treatment of pulmonary embolism. N Engl J Med 349:1695–1702
42. U.S. Food and Drug Administration. Prescribing Information, Arixtra (fondaparinux sodium) Injection 2005;
GlaxoSmithKline, Research Triangle Park, NC 27709
43. Kaufman JA, Kinney TB, Streiff MB et al (2006) Guidelines for the use of retrievable and convertible vena cava filters: report
from the Society of Interventional Radiology multidisciplinary consensus conference. J Vasc Interv Radiol 17:449–459
44. Heit JA (2005) Venous thromboembolism: disease burden, outcomes and risk factors. J Thromb Haemost 3:1611–1617
45. 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
46. Benotti JR, Dalen JE (1984) The natural history of pulmonary embolism. Clin Chest Med 5:403–410
47. Moser KM, LeMoine JR (1981) Is embolic risk conditioned by location of deep venous thrombosis? Ann Intern Med
94:439–444
48. Wells PS, Anderson DR, Rodger M et al (2000) Derivation of a simple clinical model to categorize patients probability
of pulmonary embolism: increasing the models utility with the SimpliRED D-dimer. Thromb Haemost 83:416–420
49. van Belle A, Buller HR, Huisman MV et al (2006) Effectiveness of managing suspected pulmonary embolism using an
algorithm combining clinical probability, D-dimer testing, and computed tomography. JAMA 295:172–179
50. Stein PD, Fowler SE, Goodman LR et al (2006) Multidetector computed tomography for acute pulmonary embolism.
N Engl J Med 354:2317–2327
51. Moores LK, Jackson WL Jr, Shorr AF, Jackson JL (2004) Meta-analysis: outcomes in patients with suspected pulmo-
nary embolism managed with computed tomographic pulmonary angiography. Ann Intern Med 141:866–874
52. van Beek EJ, Brouwerst EM, Song B, Stein PD, Oudkerk M (2001) Clinical validity of a normal pulmonary angiogram
in patients with suspected pulmonary embolism – a critical review. Clin Radiol 56:838–842
53. Stein PD, Woodard PK, Weg JG et al (2006) Diagnostic pathways in acute pulmonary embolism: recommendations of
the PIOPED II investigators. Am J Med 119:1048–1055
54. Blum A, Bellou A, Guillemin F, Douek P, Laprevote-Heully MC, Wahl D (2005) Performance of magnetic resonance
angiography in suspected acute pulmonary embolism. Thromb Haemost 93:503–511
55. (1990) Value of the ventilation/perfusion scan in acute pulmonary embolism. Results of the prospective investigation of
pulmonary embolism diagnosis (PIOPED). The PIOPED Investigators. JAMA 263:2753–2759
56. Elliott CG, Goldhaber SZ, Visani L, DeRosa M (2000) Chest radiographs in acute pulmonary embolism. Results from
the International Cooperative Pulmonary Embolism Registry. Chest 118:33–38
57. Worsley DF, Alavi A, Aronchick JM, Chen JT, Greenspan RH, Ravin CE (1993) Chest radiographic findings in patients
with acute pulmonary embolism: observations from the PIOPED Study. Radiology 189:133–136
58. Stein PD, Dalen JE, McIntyre KM, Sasahara AA, Wenger NK, Willis PW 3rd (1975) The electrocardiogram in acute
pulmonary embolism. Prog Cardiovasc Dis 17:247–257
59. Sreeram N, Cheriex EC, Smeets JL, Gorgels AP, Wellens HJ (1994) Value of the 12-lead electrocardiogram at hospital
admission in the diagnosis of pulmonary embolism. Am J Cardiol 73:298–303
60. Goldhaber SZ (2002) Echocardiography in the management of pulmonary embolism. Ann Intern Med 136:691–700
61. 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
62. Kasper W, Konstantinides S, Geibel A, Tiede N, Krause T, Just H (1997) Prognostic significance of right ventricular after-
load stress detected by echocardiography in patients with clinically suspected pulmonary embolism. Heart 77:346–349
63. Ribeiro A, Lindmarker P, Juhlin-Dannfelt A, Johnsson H, Jorfeldt L (1997) Echocardiography Doppler in pulmonary
embolism: right ventricular dysfunction as a predictor of mortality rate. Am Heart J 134:479–487
64. 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
349
https://t.me/med1917
Antithrombotic Drug Therapy in Cardiovascular Disease
65. Konstantinides S, Geibel A, Olschewski M et al (2002) Importance of cardiac troponins I and T in risk stratification of
patients with acute pulmonary embolism. Circulation 106:1263–1268
66. Becattini C, Vedovati MC, Agnelli G (2007) Prognostic value of troponins in acute pulmonary embolism: a meta-
analysis. Circulation 116:427–433
67. Scridon T, Scridon C, Skali H, Alvarez A, Goldhaber SZ, Solomon SD (2005) Prognostic significance of troponin
elevation and right ventricular enlargement in acute pulmonary embolism. Am J Cardiol 96:303–305
68. ten Wolde M, Tulevski II, Mulder JW et al (2003) Brain natriuretic peptide as a predictor of adverse outcome in patients
with pulmonary embolism. Circulation 107:2082–2084
69. Hull RD, Raskob GE, Brant RF et al (2000) Low-molecular-weight heparin vs heparin in the treatment of patients with
pulmonary embolism. American-Canadian Thrombosis Study Group. Arch Intern Med 160:229–236
70. Simonneau G, Sors H, Charbonnier B et al (1997) A comparison of low-molecular-weight heparin with unfractionated
heparin for acute pulmonary embolism. The THESEE Study Group. Tinzaparine ou Heparine Standard: Evaluations
dans l’Embolie Pulmonaire. N Engl J Med 337:663–669
71. Food and Drug Administration. Arixtra (fondaparinux sodium) Label Information NDA 21-345/S-010. http://www.fda.
gov/cder/foi/label/2005/021345s010lbl.pdf
2005
72. Urokinase pulmonary embolism trial (1970) Phase 1 results: a cooperative study. Jama 214:2163–2172
73. Urokinase-streptokinase embolism trial. Phase 2 results. A cooperative study. Jama 1974;299:1606–13.
74. 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
75. Meneveau N, Schiele F, Vuillemenot A et al (1997) Streptokinase vs alteplase in massive pulmonary embolism. A randomized
trial assessing right heart haemodynamics and pulmonary vascular obstruction. Eur Heart J 18:1141–1148
76. Anderson DR, Levine MN (1992) Thrombolytic therapy for the treatment of acute pulmonary embolism. CMAJ
146:1317–1324
77. Dong B, Jirong Y, Liu G, Wang Q, Wu T. Thrombolytic therapy for pulmonary embolism. Cochrane Database Syst Rev
2006:CD004437
78. Kucher N, Rossi E, De Rosa M, Goldhaber SZ (2006) Massive pulmonary embolism. Circulation 113:577–582
79. Goldhaber SZ, Haire WD, Feldstein ML et al (1993) Alteplase versus heparin in acute pulmonary embolism: randomised
trial assessing right-ventricular function and pulmonary perfusion. Lancet 341:507–511
80. Verstraete M, Miller GA, Bounameaux H et al (1988) Intravenous and intrapulmonary recombinant tissue-type
plasminogen activator in the treatment of acute massive pulmonary embolism. Circulation 77:353–360
81. Leacche M, Unic D, Goldhaber SZ et al (2005) Modern surgical treatment of massive pulmonary embolism: results in 47
consecutive patients after rapid diagnosis and aggressive surgical approach. J Thorac Cardiovasc Surg 129:1018–1023
82. Jamieson SW, Kapelanski DP (2000) Pulmonary endarterectomy. Curr Probl Surg 37:165–252
83. Miller WT Jr, Osiason AW, Langlotz CP, Palevsky HI (1998) Reperfusion edema after thromboendarterectomy: radio-
graphic patterns of disease. J Thorac Imaging 13:178–183
84. Rubens F, Wells P, Bencze S, Bourke M (2000) Surgical treatment of chronic thromboembolic pulmonary hypertension.
Can Respir J 7:49–57
85. Moser KM, Daily PO, Peterson K et al (1987) Thromboendarterectomy for chronic, major-vessel thromboembolic
pulmonary hypertension. Immediate and long-term results in 42 patients. Ann Intern Med 107:560–565
86. D’Armini AM, Cattadori B, Monterosso C et al (2000) Pulmonary thromboendarterectomy in patients with chronic
thromboembolic pulmonary hypertension: hemodynamic characteristics and changes. Eur J Cardiothorac Surg 18:696–701
discussion 701-2
87. Yalamanchili K, Fleisher AG, Lehrman SG et al (2004) Open pulmonary embolectomy for treatment of major pulmonary
embolism. Ann Thorac Surg 77:819–823 discussion 823
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18 Fibrinolysis for Pulmonary Embolism
Stavros V. Konstantinides
Co n t e n t s
Angiographic And Hemodynamic Benefits Of Fibrinolysis
Fibrinolytic Agents And Regimens For Pe
Hemorrhagic Complications And Contraindications To Fibrinolysis
Clinical Benefits Of Fibrinolysis In Pe: Need For Severity-Adjusted
Management Strategies
Fibrinolysis Indicated In High-Risk, Clinically Massive Pe
Fibrinolysis Generally Not Indicated In Non-High-Risk, Non-Massive Pe
Identifying An Intermediate-Risk Group Among Normotensive
PatientsWith Pe
Is Fibrinolysis Indicated In Patients With IntErmediate-Risk Pe?
Conclusions And Outlook
References
Abstract Morbidity and mortality associated with pulmonary embolism (PE) remain high despite
important advances in cardiovascular diagnosis and treatment. It is generally estimated that 10%
of all patients with PE die during the acute phase of the disease. Overall, 1% of patients admitted
to the hospital die of acute PE, and 10% of all hospital deaths are PE-related. Fibrinolytic therapy
remains the treatment of choice for those patients at the highest risk of mortality without obvious
contraindications. While a consensus opinion exists regarding the management of patients with
PE and associated hypotension, controversy surrounds the use of fibrinolysis for the management
of normotensive patients with non-massive PE. There is increasing awareness of the need for risk
stratification of normotensive patients and the search for an intermediate-risk group. The use of
imaging methods to assess for right ventricular dysfunction and the use of cardiac biomarkers may
identify the patient with non-massive PE who will benefit from fibrinolysis. Ongoing investiga-
tion will hopefully facilitate further risk stratification of patients with PE in order to provide them
with optimal therapies which will improve their overall outcome.
Key words: Alteplase; Fibrinolysis; Heparin; PE; Streptokinase
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_18
© Humana Press, a part of Springer Science+Business Media, LLC 2010
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Antithrombotic Drug Therapy in Cardiovascular Disease
Morbidity and mortality associated with pulmonary embolism (PE) remain high despite important
advances in cardiovascular diagnosis and treatment. The annual incidence rate of venous thromboem-
bolism has been estimated at 100–150 cases per 100,000 population per year, with approximately one
third of these patients presenting with acute PE and two thirds with deep vein thrombosis
(1). It is gener-
ally estimated that 10% of all patients with PE die during the acute phase of the disease. Overall, 1% of
patients admitted to the hospital die of acute PE, and 10% of all hospital deaths are PE-related
(2–4).
Acute PE covers a wide spectrum of clinical severity, and the mortality rates during the acute, in-
hospital phase vary from less than 1% to well over 50% in different studies
(5–9). It is now widely
acknowledged that the principal clinical factor which determines disease severity, and thus the diagnostic
and therapeutic approach to a patient with suspected acute PE, is the presence or absence of acute right
ventricular (RV) dysfunction
(10). Increased pulmonary artery pressure occurs in 60–70% of patients who
have PE and roughly correlates with the anatomic severity of thromboembolic obstruction
(11,12). In
addition, vasoconstrictive factors released from the thrombus and reaction to hypoxia contribute to the
increase in pulmonary vascular resistance. Moreover, pre-existing cardiac or pulmonary disease may
exacerbate the hemodynamic impact of an acute thromboembolic event. RV dysfunction, i.e., dilation and
hypokinesis, results from the interplay of these factors and may initiate a vicious circle of increased myo-
cardial oxygen demand, myocardial ischemia or infarction, and left ventricular preload reduction
(13).
According to the current definition, high-risk, clinically massive PE indicates overt RV failure
which results in refractory arterial hypotension and shock (commonly defined as systolic blood pres-
sure <90
mmHg, or a pressure drop ³40 mmHg from baseline for at least 15 min). This condition
accounts for almost 5% of all cases of acute PE and is associated with a high risk of in-hospital death,
particularly during the first few hours after admission. On the other hand, in the absence of overt
hemodynamic instability (non-high-risk or non-massive PE), patients are generally thought to have a
favorable clinical outcome provided that the disease is diagnosed correctly and anticoagulation can
be instituted without delay. While consensus exists that fibrinolysis is the treatment of choice in hypo-
tensive patients with high-risk PE, controversy persists regarding the potential clinical benefits of this
therapy in selected normotensive patients. Registry data suggests that subclinical RV dysfunction in
a normotensive patient with acute PE might indicate an elevated risk of death in the acute phase
(5,6,14) and therefore, possibly the need for early fibrinolytic treatment (15). These observations were
supported by the results of a large multicenter trial
(16).
This chapter summarizes our current state of knowledge on the benefits and risks of fibrinolysis in
acute PE. It particularly focuses on the recent attempts at risk stratification of normotensive patients
with acute PE and the emerging strategies of severity-adjusted treatment beyond arterial hypotension
and cardiogenic shock.
ANGIOGRAPHIC AND HEMODYNAMIC BENEFITS OF FIBRINOLYSIS
In 1971, Miller et al. observed that streptokinase infusion over 72 h resulted in a significant reduc-
tion of systolic pulmonary artery pressure, total pulmonary resistance, and the angiographic index of
PE severity. In comparison, conventional heparin anticoagulation had no appreciable effect on these
parameters during the first 3 days. Subsequently, a number of randomized trials performed since the
early 1970s (17–24) confirmed that fibrinolytic therapy rapidly resolves thromboembolic obstruction
and exerts beneficial effects on hemodynamic indicators of cardiac function. For example, in the
Urokinase Pulmonary Embolism Trial (UPET), which enrolled 160 patients and still remains one of
the largest randomized fibrinolysis trials in acute PE, urokinase (bolus injection followed by infusion
over 24
h) was superior to heparin alone in resolving pulmonary artery thrombi, and in some patients
this effect appeared to result in clinical stabilization and reversal of cardiogenic shock (17). Another
early study reported an 80% increase in cardiac index and a 40% decrease in pulmonary artery pressure
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(PAP) after 72 h of streptokinase (SK) treatment (18). In a more recent trial, follow-up angiograms
revealed that 100
mg of recombinant tissue plasminogen activator (alteplase; rtPA) induced a 12%
decrease in vascular obstruction at the end of the 2-h infusion period, whereas no change was observed
in patients receiving heparin
(23). The effect of rtPA was associated with a 30% reduction in mean PAP
and a 15% increase in cardiac index. Goldhaber et
al. demonstrated a rapid improvement in RV func-
tion (on 24-h echocardiographic follow-up) and an absence of PE recurrence in patients with echocar-
diographic indicators of RV pressure overload and dysfunction who received alteplase (100
mg
infusion over 2
h) compared to those who received heparin alone (24). Pathognomonic echocardio-
graphic findings were present in 54% of the patients and patients with a normally functioning right
ventricle were not excluded. Registry data suggest that as many as 92% of treated patients can be clas-
sified as responders to fibrinolysis on the basis of clinical and echocardiographic improvement within
the first 36 h (25). The greatest benefit is observed when treatment is initiated within 48 h of symptom
onset
(19), but fibrinolysis can still be useful in patients who have had symptoms for 6–14 days (26).
The hemodynamic benefits of fibrinolysis are prompt and significant compared to those of heparin,
but they do not extend beyond the first few days after the initiation of treatment. In an early observation
study, Dalen et
al. reported that heparin anticoagulation alone (without fibrinolysis) was capable of
reversing pulmonary artery hypertension in most patients, even though improvement required 3
weeks or even longer (27). Trials which directly compared fibrinolytic and heparin treatment and
included follow-up studies indeed showed that, 1 week after treatment, the improvement in the sever-
ity of vascular obstruction (17,23) and the reversal of RV dysfunction (28) no longer differed between
fibrinolysis-treated and heparin-treated patients. It thus follows that fibrinolysis needs to be consid-
ered only in those cases in which a high risk of early (i.e., within the first few hours or days after
presentation) PE-related death is anticipated.
FIBRINOLYTIC AGENTS AND REGIMENS FOR PE
Validated regimens of the approved fibrinolytic agents SK, UK, and rtPA are shown in Table 1.
Heparin should not be infused concurrently with streptokinase or urokinase, while its use during
alteplase administration is optional.
It is frequently debated whether all fibrinolytic agents and regimens are equally effective. In this
regard, the USPET study documented comparable efficacy of urokinase (UK) and SK infused over a
period of 12–24
h (29). In more recent randomized comparison trials (30,31), 100 mg of rtPA infused
over 2
h led to faster angiographic and hemodynamic improvement compared to UK infused over 12
or 24 h at the rate of 4,400 U/kg/h. However, the results no longer differed at the end of the UK infusion.
Similarly, the 2-h infusion of rtPA appeared to be superior over a 12-h SK infusion (at 100,000 U/h),
Table 1
Validated and approved fibrinolytic regimens for pulmonary embolism
Streptokinase 250,000 IU as a loading dose over 30 min, followed by 100,000 IU/h over
12–24 h
a
Alternative dosing: 1.5 million IU over 2 h
Urokinase 4,400 IU/kg as a loading dose over 10 min, followed by 4,400 IU/Kg/h over
12–24 h
a, b
Alternative dosing: three million IU over 2 h
rtPA 100 mg over 2 h
a
Accelerated dosing: 0.6 mg/kg over 15 min
a
FDA-approved regimen
b
Urokinase available in European countries, not in the United States
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but no difference was observed when the same SK dosage was given over 2 h (32,33). Furthermore,
two trials that compared the 2-h, 100-mg rtPA regimen with a short infusion (over 15
min) of 0.6 mg/
kg rtPA reported a slightly faster improvement with the 2-h regimen at the cost of slightly (non-sig-
nificantly) higher bleeding rates (34,35).
In summary, it can be stated that the fibrinolytic regimens tested to date are more or less comparable
with regard to efficacy (Fig. 1), but long infusion periods of SK or UK should generally be avoided.
Recently, satisfactory hemodynamic results were obtained with double-bolus reteplase given as
two injections (10 U) 30 min apart (36), although this agent has not yet officially been approved for
PE. Preliminary uncontrolled data also appear to support the efficacy and safety of tenecteplase, an
agent given by one single rapid bolus injection, in acute PE (37). Tenecteplase is currently being
tested in a large randomized multinational trial. On the other hand, direct infusion of a fibrinolytic
agent (e.g., rtPA) via a catheter in the pulmonary artery does not offer any advantages over systemic
intravenous fibrinolysis
(38). This latter approach may be considered in combination with interventional
recanalization procedures such as catheter aspiration of thrombi in the pulmonary vessels, but is oth-
erwise not recommended, as it also carries an increased risk of bleeding at the puncture site.
HEMORRHAGIC COMPLICATIONS AND CONTRAINDICATIONS TO
FIBRINOLYSIS
Fibrinolytic therapy carries a significant bleeding risk. Data from controlled trials (16,17,21,23,29–
31,35,38–40) indicate a 13% cumulative rate of major bleeding and a 1.8% rate of intracranial/fatal
hemorrhage (41). Despite this, major hemorrhage has been uncommon in the most recent (and largest)
trials (16,24), a fact which is in agreement with the observation that fibrinolysis-related bleeding rates
are lower when non-invasive imaging methods are used to diagnose PE (42). Non-invasive diagnostic
strategies have increasingly been adopted over the past 10 years thanks to the technical advances in
computed tomographic (CT) pulmonary angiography. On the other hand, data from retrospective
cohort studies and registries suggest a 36% incidence of major bleeding events and a 4% rate of intrac-
ranial/fatal hemorrhage (5,6,43,44). These rates may be exaggerated, as registries include patients who
received fibrinolysis despite the presence of formal contraindications (Table 2). At the same time however,
40
50
60
70
80
90
100
012345678910 11 12
Ho urs
TPR (% form initial value)
tP A 100 mg/2h
SK 100 000 UI/h, 12 h
SK 1.500 000 UI/2 h
UK 4400 UI /kg/h, 12 h
tP A 0.6 mg/k g, 15 mi n
Fig. 1. Reduction of total pulmonary vascular resistance in response to different fibrinolytic regimens evaluated in
prospective randomized studies. (Adapted from (68).) TPR total pulmonary resistance; t PA tissue type plasminogen
activator; SK streptokinase; UK urokinase.
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it can be argued that registry data are more realistic (and thus more alarming) with regard to the true
risks of fibrinolytic treatment, as they reflect everyday clinical practice. In any case, these results highlight
the critical importance of carefully defining the indications for fibrinolysis in acute PE, particularly
in patients who appear hemodynamically stable at presentation.
CLINICAL BENEFITS OF FIBRINOLYSIS IN PE: NEED FOR SEVERITY-ADJUSTED
MANAGEMENT STRATEGIES
Despite its unequivocal angiographic and hemodynamic benefits, at least during the first days after
initiation of treatment, the (presumed) favorable effects of fibrinolysis on the clinical outcome of
patients with PE could not be convincingly demonstrated. This partly relies on the fact that the vast
majority of fibrinolysis trials in PE neither were designed nor had the statistical power to address
clinical end points. Even the most recent and largest of these trials failed to show a survival benefit
(16,24), possibly because they included “low-risk” patients whose mortality rate in the acute phase
could not (and did not need to) be further reduced by immediate recanalization.
In weighing the risks against the benefits of fibrinolysis and thus the indications for this type of
treatment in PE, it is necessary to distinguish between hypotensive, hemodynamically unstable
patients with clinically massive PE, and normotensive patients with non-massive PE. Furthermore,
within the latter group, the crucial issue is to determine which, if any, patients necessitate prompt
relief of pulmonary vascular obstruction and reversal of RV dysfunction.
FIBRINOLYSIS INDICATED IN HIGH-RISK, CLINICALLY MASSIVE PE
Patients with clinically massive PE are those presenting with cardiogenic shock and/or persistent
arterial hypotension, generally defined as systolic blood pressure <90 mmHg or a pressure drop of at
least 40 mmHg for at least 15 min. This patient group with overt RV failure, representing almost 5%
Table 2
Formal contraindications to fibrinolytic therapy as defined by the
European Society of Cardiology, Task Force on the Management of
Acute Myocardial Infarction (67)
Absolute contraindications
• Hemorrhagicstrokeorstrokeofunknownoriginatanytime
• Ischemicstrokeinpreceding6months
• Centralnervoussystemdamageorneoplasms
• Recentmajortrauma/surgery/headinjury(withinpreceding3weeks)
• Gastro-intestinalbleedingwithinthelastmonth
• Knownbleeding
Relative contraindications
• Transientischemicattackinpreceding6months
• Oralanticoagulanttherapy
• Pregnancyorwithin1weekpostpartum
• Non-compressiblepunctures
• Traumaticresuscitation
• Refractoryhypertension(systolicbloodpressure>180mmHg)
• Advancedliverdisease
• Infectiveendocarditis
• Activepepticulcer
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