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==Trials assessing diagnosis== | ==Trials assessing diagnosis== | ||
1. '''PIOPED''' (Prospective Investigation in Pulmonary Embolism Diagnosis) (1989).<ref name="pmid2332918">{{cite journal |author= |title=Value of the ventilation/perfusion scan in acute pulmonary embolism. Results of the prospective investigation of pulmonary embolism diagnosis (PIOPED). The PIOPED Investigators |journal=JAMA |volume=263 |issue=20 |pages=2753–9 |year=1990 |pmid=2332918 |doi= |url= |accessdate=2012-01-10}}</ref> | 1. '''PIOPED''' (Prospective Investigation in Pulmonary Embolism Diagnosis) (1989).<ref name="pmid2332918">{{cite journal |author=|title=Value of the ventilation/perfusion scan in acute pulmonary embolism. Results of the prospective investigation of pulmonary embolism diagnosis (PIOPED). The PIOPED Investigators |journal=JAMA |volume=263 |issue=20 |pages=2753–9 |year=1990 |pmid=2332918|doi= |url= |accessdate=2012-01-10}}</ref> | ||
(ClinicalTrials.gov number, NCT00000566). | (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. | * '''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) ( | 2. '''PIOPED II '''(Prospective Investigation in Pulmonary Embolism Diagnosis II). (2004) <ref name="pmid12105798">{{cite journal |author=Gottschalk A, Stein PD, Goodman LR, Sostman HD |title=Overview of Prospective Investigation of Pulmonary Embolism Diagnosis II |journal=Semin Nucl Med |volume=32 |issue=3 |pages=173–82 |year=2002 |month=July |pmid=12105798|doi=10.1053/snuc.2002.124177 |url=http://linkinghub.elsevier.com/retrieve/pii/S0001-2998(02)80003-4|accessdate=2012-01-10}}</ref><ref name="pmid16738268">{{cite journal |author=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 |title=Multidetector computed tomography for acute pulmonary embolism |journal=N. Engl. J. Med. |volume=354 |issue=22 |pages=2317–27 |year=2006|month=June |pmid=16738268 |doi=10.1056/NEJMoa052367 |url=http://dx.doi.org/10.1056/NEJMoa052367 |accessdate=2012-04-28}}</ref> | ||
(ClinicalTrials.gov number, NCT00007085). | (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). | * '''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. | * '''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). <ref name="pmid20368649">{{cite journal |author=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|title=Gadolinium-enhanced magnetic resonance angiography for pulmonary embolism: a multicenter prospective study (PIOPED III)|journal=Ann. Intern. Med. |volume=152 |issue=7 |pages=434–43, W142–3 |year=2010 |month=April |pmid=20368649 |pmc=3138428|doi=10.1059/0003-4819-152-7-201004060-00008 |url= |accessdate=2012-01-10}}</ref> | 3. '''PIOPED III '''(Prospective Investigation of Pulmonary Embolism Diagnosis III) (2010).<ref name="pmid20368649">{{cite journal|author=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|title=Gadolinium-enhanced magnetic resonance angiography for pulmonary embolism: a multicenter prospective study (PIOPED III)|journal=Ann. Intern. Med. |volume=152 |issue=7 |pages=434–43, W142–3 |year=2010|month=April |pmid=20368649 |pmc=3138428|doi=10.1059/0003-4819-152-7-201004060-00008 |url= |accessdate=2012-01-10}}</ref> | ||
(ClinicalTrials.gov number, NCT00241826). | (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).''' | * '''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 treatment== | ==Trials assessing treatment== | ||
Revision as of 16:40, 28 April 2012
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Pulmonary Embolism Microchapters |
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Pulmonary Embolism Assessment of Probability of Subsequent VTE and Risk Scores |
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Trials |
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Case Studies |
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Pulmonary embolism landmark trials On the Web |
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Directions to Hospitals Treating Pulmonary embolism landmark trials |
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Risk calculators and risk factors for Pulmonary embolism landmark trials |
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 treatment
Trials assessing the role of anticoagulant in treatment
Anticoagulant drugs in the treatment of pulmonary embolism: A controlled trial (1960). [5]
- 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). [6] 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 Unfractionated Heparin
THESEE (A comparison of low-molecular-weight heparin with unfractionated heparin for acute pulmonary embolism). (1997) [7]
- 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
LIFENOX (Study to Evaluate the Mortality Reduction of Enoxaparin in Hospitalized Acutely Ill Medical Receiving Enoxaparin) (2011).[8]
(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) [9]
- 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).
Registries documenting outcome of PE patients
Study assessing the efficacy of Thrombolysis
MAPPET (Management Strategy and Prognosis of Pulmonary Embolism Registry) (1997).[10]
- 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).[11]
- 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
- ↑ "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) - ↑ 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) - ↑ 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) - ↑ 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) - ↑ 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) - ↑ {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}}
- ↑ 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) - ↑ 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) - ↑ "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) - ↑ 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.
- ↑ 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)