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Editor(s)-In-Chief: The APEX Trial Investigators, C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]

Overview

There have been various trials and studies since the discovery of PE. These trials and studies have guided are knowledge about the disease and are approach to diagnosis and treatment of pulmonary embolism. The major trials and studies which have caused the most impact are mentioned in this chapter.

Trials assessing diagnosis

1. PIOPED (Prospective Investigation in Pulmonary Embolism Diagnosis) (1989).[1]

(ClinicalTrials.gov number, NCT00000566).

  • Patient enrollment: 1493
  • Inclusion criteria: Occlusion of a lobar artery or at least two segmental arteries evident at angiography. Risk factors, signs, symptoms or laboratory findings which were unexplained and suggestive of acute pulmonary embolism
  • Purpose : To evaluate the sensitivity and specificity of two major, widely used technologies, radionuclear imaging (ventilation-perfusion scanning) and pulmonary angiography, for the diagnosis of pulmonary embolism.
  • Result: Almost all patients with pulmonary embolism had abnormal scans of high, intermediate, or low probability, but so did most without pulmonary embolism (sensitivity, 98%; specificity, 10%). Of 116 patients with high-probability scans and definitive angiograms, 102 (88%) had pulmonary embolism, but only a minority with pulmonary embolism had high-probability scans (sensitivity, 41%; specificity, 97%). Of 322 with intermediate-probability scans and definitive angiograms, 105 (33%) had pulmonary embolism.

2. PIOPED II (Prospective Investigation in Pulmonary Embolism Diagnosis II). (2004) [2][3]

(ClinicalTrials.gov number, NCT00007085).

  • Patient enrollment: 824
  • Inclusion criteria: 1) Age ≥ 18 years; 2) suspected diagnosis of acute PE; 3) Able to give informed consent; 4) Willing to undergo VQ lung scan, spiral CT, venous compression ultrasound of the lower limbs (U/S), and digital subtraction angiography (DSA).
  • Purpose : It was designed to assess the efficacy of the spiral computed tomographic pulmonary angiogram in patients suspected of having acute pulmonary embolism (PE).
  • Result: In patients with suspected pulmonary embolism, multidetector CTA-CTV has a higher diagnostic sensitivity than does CTA alone, with similar specificity. The predictive value of either CTA or CTA-CTV is high with a concordant clinical assessment, but additional testing is necessary when the clinical probability is inconsistent with the imaging results.
  • Comparison with PIOPED: In contrast to the original PIOPED study, which used contrast pulmonary angiography as the primary reference test for PE, PIOPED II used composite reference test for venous thromboembolism that was based on the ventilation/perfusion lung scan, venous compression ultrasound of the lower extremities, digital subtraction pulmonary angiography, and contrast venography in various combinations to establish the PE status of the patient. New criteria for ventilation/perfusion lung scan diagnosis were developed for PIOPED II.

3. PIOPED III (Prospective Investigation of Pulmonary Embolism Diagnosis III) (2010).[4]

(ClinicalTrials.gov number, NCT00241826).

  • Patient enrolled: 818
  • Inclusion criteria: 1) Age≥ 18 years; 2)Had been hospitalized or in the emergency department with diagnosed or excluded pulmonary embolism.
  • Purpose :The purpose of this study is to determine the diagnostic accuracy of gadolinium-enhanced magnetic resonance angiography (Gd-MRA) of the pulmonary arteries in combination with magnetic resonance venography (MRV) of the veins of the thighs in patients with clinically suspected acute pulmonary embolism (PE).
  • Result: Magnetic resonance angiography, averaged across centers, was technically inadequate in 25% of patients (92 of 371). The proportion of technically inadequate images ranged from 11% to 52% at various centers. Including patients with technically inadequate images, magnetic resonance angiography identified 57% (59 of 104) with pulmonary embolism. Technically adequate magnetic resonance angiography had a sensitivity of 78% and a specificity of 99%. Technically adequate magnetic resonance angiography and venography had a sensitivity of 92% and a specificity of 96%, but 52% of patients (194 of 370) had technically inadequate results.
  • Conclusion: Magnetic resonance pulmonary angiography should be considered only at centers that routinely perform it well and only for patients for whom standard tests are contraindicated. Magnetic resonance pulmonary angiography and magnetic resonance venography combined have a higher sensitivity than magnetic resonance pulmonary angiography alone in patients with technically adequate images, but it is more difficult to obtain technically adequate images with the 2 procedures

Trials assessing prophylaxis

MEDNOX (Prophylaxis in MEdical Patients with ENoxaparin) (1999). [5]

  • Patient enrollment: 1102
  • Inclusion criteria: Medical patients >40 years of age with a projected hospital stay of at least six days, no prolonged immobilization, and one of the following illnesses: class III or IV heart failure, acute respiratory failure not requiring mechanical ventilation, acute infection without shock, acute rheumatic or musculoskeletal disorder, or inflammatory bowel disease. Patients with any but the first two diagnoses also had to have a clinical risk factor for thromboembolism, including age >75, cancer, previous venous thromboembolism, obesity, varicose veins, hormone therapy, or chronic heart or respiratory failure.
  • Purpose:This randomized, double-blind, multicenter study compared two daily doses of subcutaneous enoxaparin with placebo for prevention of thromboembolism in patients hospitalized for acute medical illnesses.
  • Result: The primary outcome could be assessed in 866 patients. The incidence of venous thromboembolism was significantly lower in the group that received 40 mg of enoxaparin (5.5 percent [16 of 291 patients]) than in the group that received placebo (14.9 percent [43 of 288 patients]) (relative risk, 0.37; 97.6 percent confidence interval, 0.22 to 0.63; P< 0.001). The benefit observed with 40 mg of enoxaparin was maintained at three months. There was no significant difference in the incidence of venous thromboembolism between the group that received 20 mg of enoxaparin (43 of 287 patients [15.0 percent]) and the placebo group. The incidence of adverse effects did not differ significantly between the placebo group and either enoxaparin group. By day 110, 50 patients had died in the placebo group (13.9 percent), 51 had died in the 20-mg group (14.7 percent), and 41 had died in the 40-mg group (11.4 percent); the differences were not significant.

Trial assessing prevention of VTE

PREVENT Randomized, placebo-controlled trial of dalteparin for the prevention of venous thromboembolismin acutely ill medical patients. (2004) [6]

  • Patient enrollment: 3706
  • Inclusion criteria: Patients were considered for inclusion if they were ≥40 years of age with an acute medical condition requiring a projected hospitalization of ≥4 days and had ≤3 days of prior immobilization.Inclusion criteria were acute congestive heart failure, acute respiratory failure that did not require ventilatory support, infection without septic shock, acute rheumatologic disorders, or inflammatory bowel disease. Except for congestive heart or acute respiratory failure, patients had to have ≥1 additional risk factors for venous thromboembolism: age ≥75 years, cancer, previous venous thromboembolism, obesity, varicose veins and/or chronic venous insufficiency, hormone replacement therapy, history of chronic heart failure, chronic respiratory failure, or myeloproliferative syndrome.
  • Purpose: Tto assess the efficacy and safety of dalteparin in the prevention of venous thromboembolism in acutely ill medical patients.
  • Result: The incidence of venous thromboembolism was reduced from 4.96% (73 of 1473 patients) in the placebo group to 2.77% (42 of 1518 patients) in the dalteparin group, an absolute risk reduction of 2.19% or a relative risk reduction of 45% (relative risk, 0.55; 95% CI, 0.38 to 0.80; P=0.0015). The observed benefit was maintained at 90 days. The overall incidence of major bleeding was low but higher in the dalteparin group (9 patients; 0.49%) compared with the placebo group (3 patients; 0.16%).
  • Conclusion: Dalteparin 5000 IU once daily halved the rate of venous thromboembolism with a low risk of bleeding.

Trials assessing treatment

Trials assessing the role of anticoagulant in treatment

Anticoagulant drugs in the treatment of pulmonary embolism: A controlled trial (1960). [7]

  • Patient enrollment: 73
  • Inclusion criteria: Diagnosis of PE with no contraindications to anticoagulants.
  • Purpose:Assessing the role of heparin in treatment.
  • Result: Study concluded that when a patient has had pulmonary embolism, heparin and nicoumalone reduce the risk of death from that embolism. The likelihood of recurrent embolism is also diminished.

Trials assessing the efficacy of Urokinase compared to Heparin alone

UPET (Urokinase in Pulmonary Embolism Trial) (1970). [8] It was the first RCT to assess the role of thrombolytics in PE

  • Patient enrollment: 160 (78 received anticoagulants alone, and 82 received urokinase followed by anticoagulants).
  • Inclusion criteria: Angiographically‐proven pulmonary embolism.
  • Purpose :. To determine whether abnormalities, produced by the presence of obstructing emboli in the pulmonary circulation, and measured by lung scanning, pulmonary arteriography,and hemodynamic factors are returned toward normal more rapidly with a urokinase regimen as compared to anticoagulant therapy alone.
  • Results : The degree of improvement in patient receiving Urokinase was significantly greater, however, the serial perfusion scan done beyond 24 hours showed that the difference progressively decreased, such that no difference was found at 5 or 14 days or at 3, 6, or 12 months.

Trial comparing Low-molecular-weight Heparin With Standard Heparin

Treatment of acute venous thromboembolism with low molecular weight heparin (Fragmin) (1989) [9]

  • Patient enrollment: 194.
  • Inclusion criteria: All patients with clinical symptoms of deep venous thrombosis of the leg, axillary vein thrombosis, or pulmonary embolism were eligible for the study.
  • Purpose : To determine the safety and efficacy of low molecular weight heparin (Fragmin) compared with standard heparin as the initial treatment of acute venous thromboembolism.
  • Methods : Ninety-eight patients received continuous intravenous heparin, and 96 patients received Fragmin for 5-10 days. Doses were adjusted to maintain anti-Xa levels between 0.3 and 0.6 unit/ml for patients with a high risk for a bleeding complication and between 0.4 and 0.9 unit/ml for patients with a low risk for bleeding. Treatment was stopped when a therapeutic level of anticoagulation (INR > 3.5) was reached with coumarins.
  • Results : Thirteen patients in the heparin group and 10 patients in the Fragmin group had a major bleeding complication. The incidence of major and minor bleeding complications combined decreased from 48.9% to 38.5% (95% confidence interval for the difference, -3.5% to +24.2%), corresponding with a relative bleeding risk reduction of 21.2%. There were no significant differences in efficacy as defined by new high-probability defects on repeat ventilation-perfusion scintigraphy of the lung in 80 patients: six of 46 patients in the heparin group and 3 of 34 patients in the Fragmin group had new defects (95% confidence interval for the difference, -9.4% to +17.8%).
  • Conclusion : Low molecular weight heparin (Fragmin) given in adjusted, continuous, and intravenous doses is safe and effective as initial treatment of acute venous thromboembolism compared with heparin. There is a trend in risk reduction for bleeding in favor of low molecular weight heparin, a trend, however, that is smaller than expected compared with animal studies.

Trial comparing Low-molecular-weight Heparin With Unfractionated Heparin

THESEE (A comparison of low-molecular-weight heparin with unfractionated heparin for acute pulmonary embolism). (1997) [10]

  • Patient enrollment: 612 patients (Mean Patient Age: 67 years % Female: 55 )
  • Inclusion criteria: Individuals over the age of 18 who presented with acute pulmonary embolism documented by pulmonary angiography, high probability ventilation-perfusion imaging, or by intermediate probability ventilation-perfusion imaging and a deep venous thrombosis diagnosed by venography or ultrasound were eligible.
  • Purpose: The goal of this study was to assess the safety and efficacy of anticoagulation with tinzaparin, a low-molecular-weight heparin (LMWH), compared to unfractionated heparin among patients with acute symptomatic pulmonary embolism.
  • Result: Initial subcutaneous therapy with the low-molecular-weight heparin tinzaparin appeared to be as effective and safe as intravenous unfractionated heparin in patients with acute pulmonary embolism.

Trials assessing the efficacy of LMWH in reducing mortality in acutely ill patients

1. Subcutaneous enoxaparin once or twice daily compared with intravenous unfractionated heparin for treatment of venous thromboembolic disease. (2001) [11]

  • Patient enrollment: 900 (74 hospitals in 16 countries.)
  • Inclusion criteria: Symptomatic lower-extremity deep venous thrombosis, and with confirmed pulmonary embolism.
  • Purpose: To determine whether subcutaneous enoxaparin administered once or twice daily is as effective as continuously infused unfractionated heparin in acute symptomatic venous thromboembolic disease.
  • Result: Equivalent efficacy was seen in the heparin group and both enoxaparin groups. Symptomatic venous thromboembolism recurred in 12 of 290 patients receiving unfractionated heparin (4.1%), 13 of 298 patients receiving once-daily enoxaparin (4.4%), and 9 of 312 patients receiving twice-daily enoxaparin (2.9%). Compared with unfractionated heparin, the treatment difference was 0.2% (95% CI, -3.04% to 3.49%) for once-dailyenoxaparin and -1.2% (CI, -4.2% to 1.7%) for twice-daily enoxaparin. Incidence of major hemorrhage did not differ among the three treatment groups. Major hemorrhage occurred in 6 of 290 patients (2.1%) in the unfractionated heparin group, 5 of 298 patients (1.7%) in the once-daily enoxaparingroup, and 4 of 312 patients (1.3%) in the twice-daily enoxaparin group.
  • Conclusion: Subcutaneous enoxaparin once or twice daily is as effective and safe as dose-adjusted, continuously infused unfractionated heparin in the prevention of recurrent symptomatic venous thromboembolic disease.

2. LIFENOX (Study to Evaluate the Mortality Reduction of Enoxaparin in Hospitalized Acutely Ill Medical Receiving Enoxaparin) (2011).[12]

(ClinicalTrials.gov number, NCT00622648).

  • Patient enrollment: 8307
  • Inclusion criteria: Age ≥ 40 years and hospitalization for acute decompensated heart failure, severe systemic infection with at least one risk factor for venous thromboembolism, or active cancer.
  • Purpose: To asses the effect of subcutaneous enoxaparin (40 mg daily) as compared with placebo--both administered for 10±4 days in patients who were wearing elastic stockings with graduated compression--on the rate of death from any cause among hospitalized, acutely ill medical patients at participating sites in China, India, Korea, Malaysia, Mexico, the Philippines, and Tunisia.
  • Result: Enoxaparin plus elastic stockings with graduated compression, failed to show any reduction in the rate of death from any cause among hospitalized, acutely ill medical patients, when compared to elastic stockings with graduated compression alone.

Trial assessing the role of aspirin in reducing the in-hospital morbidity due to VTE in high-risk patients undergoing major surgery

(PEP) Pulmonary Embolism Prevention Trial (2000) [13]

  • Patient enrollment: 17,444 (Mean 79 year, % Female: 79)
  • Inclusion criteria: Patients with a femoral-neck fracture or other fracture of the proximal femur in all participating countries. In New Zealand, patients undergoing elective hip or knee arthroplasty were also eligible. The fundamental eligibility criterion was the treating physicians’s uncertainty as to the balance of benefits and risks of low-dose aspirin for the particular patient.
  • Purpose: To assess the role of Aspirin in reducing the in-hospital morbidity due to VTE. Previous trials of antiplatelet therapy for the prevention of venous thromboembolism have individually been inconclusive, the aim of this large randomised placebo-controlled trial was to confirm or refute these apparent benefits.
  • Result: Among the patients with hip fracture, allocation to aspirin produced proportional reductions in pulmonary embolism of 43% (95% CI 18-60; p=0.002) and in symptomatic deep-vein thrombosis of 29% (3-48; p=0.03).

Trial assessing the efficacy of oral Rivaroxaban for the treatment of symptomatic pulmonary embolism

EINSTEIN PE (2012) [14]

  • Patient enrollment: 4832
  • Inclusion criteria: Patients who had acute symptomatic pulmonary embolism with or without deep-vein thrombosis.
  • Purpose: A fixed-dose regimen of rivaroxaban, an oral factor Xa inhibitor, has been shown to be as effective as standard anticoagulant therapy for the treatment of deep-vein thrombosis, without the need for laboratory monitoring. This approach may also simplify the treatment of pulmonary embolism.
  • Result: Rivaroxaban was noninferior to standard therapy (noninferiority margin, 2.0; P=0.003) for the primary efficacy outcome, with 50 events in the rivaroxaban group (2.1%) versus 44 events in the standard-therapy group (1.8%) (hazard ratio, 1.12; 95% confidence interval [CI], 0.75 to 1.68). The principal safety outcome occurred in 10.3% of patients in the rivaroxaban group and 11.4% of those in the standard-therapy group (hazard ratio, 0.90; 95% CI, 0.76 to 1.07; P=0.23). Major bleeding was observed in 26 patients (1.1%) in the rivaroxaban group and 52 patients (2.2%) in the standard-therapy group (hazard ratio, 0.49; 95% CI, 0.31 to 0.79; P=0.003). Rates of other adverse events were similar in the two groups.

Registries documenting outcome of PE patients

Study assessing the efficacy of Thrombolysis

MAPPET (Management Strategy and Prognosis of Pulmonary Embolism Registry) (1997).[15]

  • Patient enrollment: 1001
  • Inclusion criteria: Based on the clinical findings at presentation and the results of electrocardiographic, echocardiographic, nuclear imaging and cardiac catheterization studies.
  • Purpose: Study investigated current management strategies as well as the clinical course of acute major pulmonary embolism.
  • Result: Echocardiography was the most frequently performed diagnostic procedure (74%). Lung scan or pulmonary angiography were performed in 79% of clinically stable patients but much less frequently in those with circulatory collapse at presentation (32%, p < 0.001). Thrombolytic agents were given to 478 patients (48%), often despite the presence of contraindications (193 [40%] of 478). The frequency of initial thrombolysis was significantly higher in clinically unstable than in normotensive patients (57% vs. 22%, p < 0.001). Overall in-hospital mortality rate ranged from 8.1% in the group of stable patients to 25% in those presenting with cardiogenic shock and to 65% in patients necessitating cardiopulmonary resuscitation. Major bleeding was reported in 92 patients (9.2%), but cerebral bleeding was uncommon (0.5%). Finally, recurrent pulmonary embolism occurred in 172 patients (17%).

Study assessing the factors causing death

ICOPER (International Cooperative Pulmonary Embolism Registry) (1999).[16]

  • Patient enrollment: 2454
  • Inclusion criteria: 2110 (86.0%) patients had PE proven by necropsy, high-probability lung scan, pulmonary angiography, or venous ultrasonography plus high clinical suspicion; ICOPER accepted without independent review diagnoses and interpretation of imaging provided by participating centres; 3-month follow-up was completed in 98.0% of patients.
  • Purpose: Aim of identifying factors associated with death.
  • Result: The overall crude mortality rate at 3 months was 17.4% (426 of 2454 deaths, including 52 patients lost to follow-up): 179 of 397 (45.1%) deaths were ascribed to PE and 70 of 397 (17.6%) to cancer, and no information on the cause of death was available for 29 patients. On multiple-regression modelling, age over 70 years (hazard ratio 1.6 [95% CI 1.1-2.3]), cancer (2.3 [1.5-3.5]), congestive heart failure (2.4 [1.5-3.7]), chronic obstructive pulmonary disease (1.8 [1.2-2.7]), systolic arterial hypotension (2.9 [1.7-5.0]), tachypnoea (2.0 [1.2-3.2]), and right-ventricular hypokinesis on echocardiography (2.0 [1.3-2.9]) were identified as significant prognostic factors.

Latest/Ongoing Trials

Trial evaluating the safety of withholding anticoagulation in subsegmental PE patients

A Multicenter Prospective Cohort Management Study to Evaluate the Safety of Withholding Anticoagulation in Patients With Subsegmental PE Who Have a Negative Serial Bilateral Lower Extremity Ultrasound (SSPE) [3]

(ClinicalTrials.gov number, NCT01455818).

  • Estimated patient enrollment: 300 (Still recruiting)
  • Inclusion criteria: Consecutive out-patients with symptomatic, isolated SSPE (any number), that are newly diagnosed by CTPA, will be eligible to participate in the study.
  • Purpose: The investigators plan to follow 270 patients with small blood clots in their lungs for 90 days. These patients will not be treated with blood thinners but will be followed closely with other non-invasive tests to avoid progression or recurrence of blood clots.
  • Study Type: Observational
  • Study Design: Observational Model:Cohort, Time Perspective:Prospective.

References

  1. ↑ "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 (20): 2753–9. 1990. PMID 2332918. |access-date= requires |url= (help)
  2. ↑ Gottschalk A, Stein PD, Goodman LR, Sostman HD (2002). "Overview of Prospective Investigation of Pulmonary Embolism Diagnosis II". Semin Nucl Med. 32 (3): 173–82. doi:10.1053/snuc.2002.124177. PMID 12105798. Retrieved 2012-01-10. Unknown parameter |month= ignored (help)
  3. ↑ Stein PD, Fowler SE, Goodman LR, Gottschalk A, Hales CA, Hull RD, Leeper KV, Popovich J, Quinn DA, Sos TA, Sostman HD, Tapson VF, Wakefield TW, Weg JG, Woodard PK (2006). "Multidetector computed tomography for acute pulmonary embolism". N. Engl. J. Med. 354 (22): 2317–27. doi:10.1056/NEJMoa052367. PMID 16738268. Retrieved 2012-04-28. Unknown parameter |month= ignored (help)
  4. ↑ Stein PD, Chenevert TL, Fowler SE, Goodman LR, Gottschalk A, Hales CA, Hull RD, Jablonski KA, Leeper KV, Naidich DP, Sak DJ, Sostman HD, Tapson VF, Weg JG, Woodard PK (2010). "Gadolinium-enhanced magnetic resonance angiography for pulmonary embolism: a multicenter prospective study (PIOPED III)". Ann. Intern. Med. 152 (7): 434–43, W142–3. doi:10.1059/0003-4819-152-7-201004060-00008. PMC 3138428. PMID 20368649. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)
  5. ↑ Samama MM, Cohen AT, Darmon JY, Desjardins L, Eldor A, Janbon C, Leizorovicz A, Nguyen H, Olsson CG, Turpie AG, Weisslinger N (1999). "A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group". N. Engl. J. Med. 341 (11): 793–800. doi:10.1056/NEJM199909093411103. PMID 10477777. Retrieved 2012-05-02. Unknown parameter |month= ignored (help)
  6. ↑ Leizorovicz A, Cohen AT, Turpie AG, Olsson CG, Vaitkus PT, Goldhaber SZ (2004). "Randomized, placebo-controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients". Circulation. 110 (7): 874–9. doi:10.1161/01.CIR.0000138928.83266.24. PMID 15289368. Retrieved 2012-05-02. Unknown parameter |month= ignored (help)
  7. ↑ BARRITT DW, JORDAN SC (1960). "Anticoagulant drugs in the treatment of pulmonary embolism. A controlled trial". Lancet. 1 (7138): 1309–12. PMID 13797091. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)
  8. ↑ {Ч{cite journal |author= |title=Urokinase pulmonary embolism trial. Phase 1 results: a cooperative study |journal=JAMA |volume=214 |issue=12 |pages=2163–72 |year=1970 |month=December |pmid=5536580 |doi= |url= |accessdate=2012-04-27}}
  9. ↑ Albada J, Nieuwenhuis HK, Sixma JJ (1989). "Treatment of acute venous thromboembolism with low molecular weight heparin (Fragmin). Results of a double-blind randomized study". Circulation. 80 (4): 935–40. PMID 2551537. Retrieved 2012-05-02. Unknown parameter |month= ignored (help)
  10. ↑ Simonneau G, Sors H, Charbonnier B, Page Y, Laaban JP, Azarian R, Laurent M, Hirsch JL, Ferrari E, Bosson JL, Mottier D, Beau B (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 (10): 663–9. doi:10.1056/NEJM199709043371002. PMID 9278462. Retrieved 2012-04-27. Unknown parameter |month= ignored (help)
  11. ↑ Merli G, Spiro TE, Olsson CG, Abildgaard U, Davidson BL, Eldor A, Elias D, Grigg A, Musset D, Rodgers GM, Trowbridge AA, Yusen RD, Zawilska K (2001). "Subcutaneous enoxaparin once or twice daily compared with intravenous unfractionated heparin for treatment of venous thromboembolic disease". Ann. Intern. Med. 134 (3): 191–202. PMID 11177331. Retrieved 2012-05-02. Unknown parameter |month= ignored (help)
  12. ↑ Kakkar AK, Cimminiello C, Goldhaber SZ, Parakh R, Wang C, Bergmann JF (2011). "Low-molecular-weight heparin and mortality in acutely ill medical patients". N. Engl. J. Med. 365 (26): 2463–72. doi:10.1056/NEJMoa1111288 url=http://www.nejm.org/doi/abs/10.1056/NEJMoa1111288?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed Check |doi= value (help). PMID 22204723. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)
  13. ↑ "Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial". Lancet. 355 (9212): 1295–302. 2000. PMID 10776741. Retrieved 2012-04-28. Unknown parameter |month= ignored (help)
  14. ↑ Büller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, Minar E, Chlumsky J, Verhamme P, Wells P, Agnelli G, Cohen A, Berkowitz SD, Bounameaux H, Davidson BL, Misselwitz F, Gallus AS, Raskob GE, Schellong S, Segers A (2012). "Oral rivaroxaban for the treatment of symptomatic pulmonary embolism". N. Engl. J. Med. 366 (14): 1287–97. doi:10.1056/NEJMoa1113572. PMID 22449293. Retrieved 2012-04-28. Unknown parameter |month= ignored (help)
  15. ↑ Kasper W, Konstantinides S, Geibel A, Olschewski M, Heinrich F, Grosser KD; et al. (1997). "Management strategies and determinants of outcome in acute major pulmonary embolism: results of a multicenter registry". J Am Coll Cardiol. 30 (5): 1165–71. PMID 9350909.
  16. ↑ Goldhaber SZ, Visani L, De Rosa M (1999). "Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER)". Lancet. 353 (9162): 1386–9. PMID 10227218. Retrieved 2012-01-13. Unknown parameter |month= ignored (help)

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