- Email: [email protected]
Prognosis in acute pulmonary embolism
technique that has such promise for cytopathologists and for women. *Fré A F Kreuger, Marjolein van Ballegooijen, Heleen Doornewaard *Department of Health Promotion, Municipal Health Service of R o t t e r d a m ,R o t t e r d a m ,P O Box 70032, 3000LP, Netherlands; Department of Public Health, Erasmus University, Rotterdam; and Department of Pathology, Utrecht University 1
Solomon HM, Frist S. PAPNET testing for HSILs: the few cell/small cell challenge. Acta Cytol 1998; 4 2 : 253–59. 2 Editorial. The screening muddle. Lancet 1998; 3 5 1 : 459. 3 Doorneward H, van den Tweel JG, van der Graaf Y. Evaluation of semi-automated cervical screening: a comparision of sensitivity and specificity of semi-automated and manual screening (in Dutch).Utrecht,Netherlands:Departments of Pathology and Epidemiology, Utrecht University, 1998. 4 Raffle AE. New tests in cervical screening. Lancet 1998; 3 5 1 : 297.
Prognosis in acute pulmonary embolism See page 1386
Pulmonary embolism is a potentially fatal disease. In a study published 39 years ago in The Lancet, Barritt and Jordan reported that anticoagulant therapy reduces mortality in patients with a clinical diagnosis of pulmonary embolism.1 Currently, most patients presenting with “submassive” pulmonary embolism are treated with an initial course of intravenous unfractionated heparin or subcutaneous low-molecularweight heparin, followed by at least 3–6 months of oral anticogulant therapy. Although most clinicians agree that thrombolytic therapy is indicated in pulmonary embolism associated with shock, its role in patients with submassive pulmonary embolism remains controversial. Some clinicians have suggested that the indications for thrombolysis should be expanded to include haemodynamically stable patients with echo-
cardiographic evidence of impaired right-ventricular dysfunction.2,3 Others, however, argue that the potential benefits of thrombolytic therapy in this subset of patients are likely to be offset by an increase in major bleeding.4 Information about the risk of death from fatal pulmonary embolism in treated patients presenting with acute pulmonary embolism is provided by three recent studies (panel). Two are prospective trials that included only patients with documented submassive pulmonary embolism, whereas the third, the International Cooperative Pulmonary Embolism Registry (ICOPER) study, published in this issue of The Lancet, included all patients judged to have pulmonary embolism. In the Columbus study, six (2·2%) of the 271 patients presenting with pulmonary embolism developed fatal pulmonary embolism during 12 weeks of follow-up, and an additional five died suddenly of undetermined causes that may have included pulmonary embolism (11 of 271 or 4·1%).5 In the THÉSÉE study, the 90-day mortality rate was 4·2%.6 Six of 612 patients (1·0%) died of certain or highly probable pulmonary embolism, and five others died of unknown causes that may have included pulmonary embolism (11 of 612 or 1·8%). On the basis of the results of these two trials, mortality seems to be low in patients with submassive pulmonary embolism receiving adequate anticoagulant therapy. By contrast, in the ICOPER cohort of 2454 consecutive patients with acute pulmonary embolism, the 3-month mortality rate was 17·5%, with 45·1% of deaths ascribed to pulmonary embolism. Several factors could be responsible for the discrepancy in mortality rates between the two randomised trials and the ICOPER study. Both the Columbus and THÉSÉE studies excluded patients
Characteristics of Columbus, THÉSÉE, and ICOPER studies Study Columbus
Inclusion criteria Consecutive patients with acute symptomatic PE confirmed by: High probability lung scan or Pulmonary angiogram or Objective diagnosis of deep-vein thrombosis in the presence of nondiagnostic lung scan
Exclusion criteria Therapeutic anticoagulation for >24 h Thrombolytic therapy planned Anticoagulant therapy contraindicated Gastrointestinal bleeding within 14 days Surgery within 3 days Stroke within 10 days Platelets <100 000/µL Weight <35 kg Age <18 years Documented pregnancy or inadequate contraception Inaccessible for follow-up
Fatal PE (%) 2·2%
THÉSÉE
Consecutive patients >18 years of age with acute symptomatic PE confirmed by: High probability lung scan or Pulmonary angiogram or anticoagulant therapy Objective diagnosis of deep-vein thrombosis in the presence of non-diagnostic lung scan
Therapeutic anticoagulation for >24 h Massive PE requiring thrombolytic therapy, embolectomy, or inferior vena caval interruption Active bleeding or disorders contraindicating Life expectancy <3 months Severe hepatic renal failure Documented pregnancy Non-compliance likely
1·0%
ICOPER
All patients with asymptomatic or symptomatic acute PE who had the diagnosis established by the attending physician within 31 days of symptom onset Major PE first discovered at necropsy
None
7·9%
THE LANCET • Vol 353 • April 24, 1999
1375
judged to require thrombolytic therapy. The THÉSÉE trial also excluded patients needing inferior vena caval interruption or pulmonary embolectomy and those judged to have a life-expectancy of less than 3 months. However, 28% of patients in the THÉSÉE study had clinical features compatible with major pulmonary embolism, including cyanosis (13%), syncope (9%), acute right-ventricular failure (15%), and shock (2%). Despite these poor prognostic signs, adequate anticoagulant therapy alone proved to be very effective. ICOPER probably included a larger proportion of patients with massive pulmonary embolism than the other two studies, which would account for the higher mortality. Certain characteristics of the registry, however, may limit the validity of the results. First, the inclusion of 61 patients with fatal pulmonary embolism diagnosed only at necropsy leads to a biased estimate of the risk of death in patients presenting with acute pulmonary embolism. Even if patients diagnosed with pulmonary embolism only at necropsy are excluded, the 3-month mortality rate is 15·4%. Second, only 86% of ICOPER patients had their pulmonary embolism confirmed by objective testing. The paper does not specify how the remainder of patients were diagnosed, and it is possible that a proportion had other disorders not likely to respond to therapy for pulmonary embolism. Finally, there was no assessment of adequacy of treatment, which raises the possibility that therapy could have been suboptimum in some, which would have increased the likelihood of fatal pulmonary embolism. The ICOPER investigators suggest that the performance of a readily available test, echocardiography, may permit selection of patients at increased risk of death who might benefit from more aggressive therapy. However, as the investigators acknowledge, their data are not definitive. The study does, however, highlight the need for randomised comparison of thrombolytic therapy and anticoagulant therapy alone in patients presenting with clinically submassive pulmonary embolism and right-ventricular dysfunction. Until then, patients with submassive pulmonary embolism should continue to be treated with adequate doses of anticoagulants, and thrombolytic therapy should be reserved for those with massive embolism. Jack Hirsh, Shannon M Bates Hamilton Civic Hospitals Research Centre, Hamilton, Ontario L8V 1C3, Canada 1 Barritt DW, Jordan SC. Anticoagulant drugs in the treatment of pulmonary embolism: a controlled trial. Lancet 1 9 6 0 ;i : 1309–12. 2 Goldhaber SZ, Haire WD, Feldstein ML, et al. Altepase versus heparin in acute pulmonary embolism: randomised trial assessing right-ventricular dysfunction and pulmonary perfusion. Lancet 1993; 3 4 1 : 507–11. 3 Ribeiro A, Lindmarker P, Juhlin-Dannfelt A, Johnsson H, Jorfeldt L. Echocardiography doppler in pulmonary embolism: right ventricular dysfunction as a predictor of mortality rate. Am Heart J 1997; 1 3 4 : 479–87. 4 Dalen JE, Alpert JS, Hirsh J. Thrombolytic therapy for pulmonary embolism. Arch Intern Med 1997; 1 5 7 : 2550–56. 5 The Columbus Investigators. Low-molecular-weight heparin in the treatment of patients with venous thromboembolism. N Engl J Med 1997; 3 3 7 : 657–62. 6 Simonneau G, Sors H, Charbonnier B, et al. A comparison of lowmolecular-weight heparin with unfractionated heparin for acute pulmonary embolism. N Engl J Med 1997; 3 3 7 : 663–69.
1376
Flies and the elimination of blinding trachoma See page 1401
The aggressive flies that assault the eyes, nose, and mouth in villages with endemic trachoma seem to be an obvious vector for this blinding eye disease.1 In Africa and Asia these flies are primarily Musca sorbens, which efficiently transfer infectious nasal and ocular discharges from person to person.2,3 In this issue of The Lancet, Paul Emerson and his colleagues address the neglected role of fly suppression in efforts to eliminate blindness caused by trachoma. They found that the prevalence of inflammatory trachoma in villages that were frequently sprayed was significantly lower than that in control villages. Because trachoma is so successfully treated with oral azithromycin, will the allocation of resources to fly control be cost-effective? The World Health Organization estimates that trachoma has blinded 6 million people, or 15·5% of the 38 million blind in the world, that it has produced painful inturned eyelashes in 11 million more, and that active infectious trachoma affects 150 million children.4,5 The new developments that now make the elimination of trachomatous blindness a realistic goal include a simplified system of trachoma assessment to target localities needing antibiotic and surgical intervention;6 azithromycin, an erythromycin derivative, effective as a single oral dose against infectious trachoma;7-9 DNA amplification techniques to detect the causative Chlamydia trachomatis and thus identify high-risk groups for antibiotic treatment;10 and behavioural research, including clinical trials on the modification of health-related behaviours to control infectious trachoma.11 WHO has had a programme in trachoma control since its inception, and in 1997 it launched a concerted effort to control trachomatous blindness by forming a consortium, the “Global Elimination of Trachoma by 2020” (GET 2020), which includes non-governmental development agencies, donor organisations, technical experts, and WHO staff. This campaign is based on the SAFE strategy: Surgery for inturned eyelids; Antibiotic treatment (either oral azithromycin or local tetracycline) to entire communities to reduce prevalence rates of C trachomatis; Face washing and improved hygiene of young children; and Environmental improvement with safer water and disposal of animal and human waste. Recently the Edna McConnell Clark Foundation and Pfizer Inc announced the formation of the International Trachoma Initiative, an organisation to provide support and distribute azithromycin to the national programmes of trachoma control in five countries—Ghana, Mali, Morocco, Tanzania, and Vietnam.12 Although azithromycin treatment is a significant advance in trachoma control, the regression of trachoma in many regions of the world has occurred with economic development and the accompanying improvements in the standard of living.13 The currently recommended use of azithromycin for trachoma is a single dose administered as community-wide (mass) treatment. In three African countries such mass treatment effectively reduced the rates of chlamydial eye infection for 1 year.14 As yet there are no guidelines for the frequency of retreatment with azithromycin or for targeted treatment (eg, to children under 10). C trachomatis has not developed antibiotic resistance, but the use of any antibiotic on this scale will
THE LANCET • Vol 353 • April 24, 1999
Solomon HM, Frist S. PAPNET testing for HSILs: the few cell/small cell challenge. Acta Cytol 1998; 4 2 : 253–59. 2 Editorial. The screening muddle. Lancet 1998; 3 5 1 : 459. 3 Doorneward H, van den Tweel JG, van der Graaf Y. Evaluation of semi-automated cervical screening: a comparision of sensitivity and specificity of semi-automated and manual screening (in Dutch).Utrecht,Netherlands:Departments of Pathology and Epidemiology, Utrecht University, 1998. 4 Raffle AE. New tests in cervical screening. Lancet 1998; 3 5 1 : 297.
Prognosis in acute pulmonary embolism See page 1386
Pulmonary embolism is a potentially fatal disease. In a study published 39 years ago in The Lancet, Barritt and Jordan reported that anticoagulant therapy reduces mortality in patients with a clinical diagnosis of pulmonary embolism.1 Currently, most patients presenting with “submassive” pulmonary embolism are treated with an initial course of intravenous unfractionated heparin or subcutaneous low-molecularweight heparin, followed by at least 3–6 months of oral anticogulant therapy. Although most clinicians agree that thrombolytic therapy is indicated in pulmonary embolism associated with shock, its role in patients with submassive pulmonary embolism remains controversial. Some clinicians have suggested that the indications for thrombolysis should be expanded to include haemodynamically stable patients with echo-
cardiographic evidence of impaired right-ventricular dysfunction.2,3 Others, however, argue that the potential benefits of thrombolytic therapy in this subset of patients are likely to be offset by an increase in major bleeding.4 Information about the risk of death from fatal pulmonary embolism in treated patients presenting with acute pulmonary embolism is provided by three recent studies (panel). Two are prospective trials that included only patients with documented submassive pulmonary embolism, whereas the third, the International Cooperative Pulmonary Embolism Registry (ICOPER) study, published in this issue of The Lancet, included all patients judged to have pulmonary embolism. In the Columbus study, six (2·2%) of the 271 patients presenting with pulmonary embolism developed fatal pulmonary embolism during 12 weeks of follow-up, and an additional five died suddenly of undetermined causes that may have included pulmonary embolism (11 of 271 or 4·1%).5 In the THÉSÉE study, the 90-day mortality rate was 4·2%.6 Six of 612 patients (1·0%) died of certain or highly probable pulmonary embolism, and five others died of unknown causes that may have included pulmonary embolism (11 of 612 or 1·8%). On the basis of the results of these two trials, mortality seems to be low in patients with submassive pulmonary embolism receiving adequate anticoagulant therapy. By contrast, in the ICOPER cohort of 2454 consecutive patients with acute pulmonary embolism, the 3-month mortality rate was 17·5%, with 45·1% of deaths ascribed to pulmonary embolism. Several factors could be responsible for the discrepancy in mortality rates between the two randomised trials and the ICOPER study. Both the Columbus and THÉSÉE studies excluded patients
Characteristics of Columbus, THÉSÉE, and ICOPER studies Study Columbus
Inclusion criteria Consecutive patients with acute symptomatic PE confirmed by: High probability lung scan or Pulmonary angiogram or Objective diagnosis of deep-vein thrombosis in the presence of nondiagnostic lung scan
Exclusion criteria Therapeutic anticoagulation for >24 h Thrombolytic therapy planned Anticoagulant therapy contraindicated Gastrointestinal bleeding within 14 days Surgery within 3 days Stroke within 10 days Platelets <100 000/µL Weight <35 kg Age <18 years Documented pregnancy or inadequate contraception Inaccessible for follow-up
Fatal PE (%) 2·2%
THÉSÉE
Consecutive patients >18 years of age with acute symptomatic PE confirmed by: High probability lung scan or Pulmonary angiogram or anticoagulant therapy Objective diagnosis of deep-vein thrombosis in the presence of non-diagnostic lung scan
Therapeutic anticoagulation for >24 h Massive PE requiring thrombolytic therapy, embolectomy, or inferior vena caval interruption Active bleeding or disorders contraindicating Life expectancy <3 months Severe hepatic renal failure Documented pregnancy Non-compliance likely
1·0%
ICOPER
All patients with asymptomatic or symptomatic acute PE who had the diagnosis established by the attending physician within 31 days of symptom onset Major PE first discovered at necropsy
None
7·9%
THE LANCET • Vol 353 • April 24, 1999
1375
judged to require thrombolytic therapy. The THÉSÉE trial also excluded patients needing inferior vena caval interruption or pulmonary embolectomy and those judged to have a life-expectancy of less than 3 months. However, 28% of patients in the THÉSÉE study had clinical features compatible with major pulmonary embolism, including cyanosis (13%), syncope (9%), acute right-ventricular failure (15%), and shock (2%). Despite these poor prognostic signs, adequate anticoagulant therapy alone proved to be very effective. ICOPER probably included a larger proportion of patients with massive pulmonary embolism than the other two studies, which would account for the higher mortality. Certain characteristics of the registry, however, may limit the validity of the results. First, the inclusion of 61 patients with fatal pulmonary embolism diagnosed only at necropsy leads to a biased estimate of the risk of death in patients presenting with acute pulmonary embolism. Even if patients diagnosed with pulmonary embolism only at necropsy are excluded, the 3-month mortality rate is 15·4%. Second, only 86% of ICOPER patients had their pulmonary embolism confirmed by objective testing. The paper does not specify how the remainder of patients were diagnosed, and it is possible that a proportion had other disorders not likely to respond to therapy for pulmonary embolism. Finally, there was no assessment of adequacy of treatment, which raises the possibility that therapy could have been suboptimum in some, which would have increased the likelihood of fatal pulmonary embolism. The ICOPER investigators suggest that the performance of a readily available test, echocardiography, may permit selection of patients at increased risk of death who might benefit from more aggressive therapy. However, as the investigators acknowledge, their data are not definitive. The study does, however, highlight the need for randomised comparison of thrombolytic therapy and anticoagulant therapy alone in patients presenting with clinically submassive pulmonary embolism and right-ventricular dysfunction. Until then, patients with submassive pulmonary embolism should continue to be treated with adequate doses of anticoagulants, and thrombolytic therapy should be reserved for those with massive embolism. Jack Hirsh, Shannon M Bates Hamilton Civic Hospitals Research Centre, Hamilton, Ontario L8V 1C3, Canada 1 Barritt DW, Jordan SC. Anticoagulant drugs in the treatment of pulmonary embolism: a controlled trial. Lancet 1 9 6 0 ;i : 1309–12. 2 Goldhaber SZ, Haire WD, Feldstein ML, et al. Altepase versus heparin in acute pulmonary embolism: randomised trial assessing right-ventricular dysfunction and pulmonary perfusion. Lancet 1993; 3 4 1 : 507–11. 3 Ribeiro A, Lindmarker P, Juhlin-Dannfelt A, Johnsson H, Jorfeldt L. Echocardiography doppler in pulmonary embolism: right ventricular dysfunction as a predictor of mortality rate. Am Heart J 1997; 1 3 4 : 479–87. 4 Dalen JE, Alpert JS, Hirsh J. Thrombolytic therapy for pulmonary embolism. Arch Intern Med 1997; 1 5 7 : 2550–56. 5 The Columbus Investigators. Low-molecular-weight heparin in the treatment of patients with venous thromboembolism. N Engl J Med 1997; 3 3 7 : 657–62. 6 Simonneau G, Sors H, Charbonnier B, et al. A comparison of lowmolecular-weight heparin with unfractionated heparin for acute pulmonary embolism. N Engl J Med 1997; 3 3 7 : 663–69.
1376
Flies and the elimination of blinding trachoma See page 1401
The aggressive flies that assault the eyes, nose, and mouth in villages with endemic trachoma seem to be an obvious vector for this blinding eye disease.1 In Africa and Asia these flies are primarily Musca sorbens, which efficiently transfer infectious nasal and ocular discharges from person to person.2,3 In this issue of The Lancet, Paul Emerson and his colleagues address the neglected role of fly suppression in efforts to eliminate blindness caused by trachoma. They found that the prevalence of inflammatory trachoma in villages that were frequently sprayed was significantly lower than that in control villages. Because trachoma is so successfully treated with oral azithromycin, will the allocation of resources to fly control be cost-effective? The World Health Organization estimates that trachoma has blinded 6 million people, or 15·5% of the 38 million blind in the world, that it has produced painful inturned eyelashes in 11 million more, and that active infectious trachoma affects 150 million children.4,5 The new developments that now make the elimination of trachomatous blindness a realistic goal include a simplified system of trachoma assessment to target localities needing antibiotic and surgical intervention;6 azithromycin, an erythromycin derivative, effective as a single oral dose against infectious trachoma;7-9 DNA amplification techniques to detect the causative Chlamydia trachomatis and thus identify high-risk groups for antibiotic treatment;10 and behavioural research, including clinical trials on the modification of health-related behaviours to control infectious trachoma.11 WHO has had a programme in trachoma control since its inception, and in 1997 it launched a concerted effort to control trachomatous blindness by forming a consortium, the “Global Elimination of Trachoma by 2020” (GET 2020), which includes non-governmental development agencies, donor organisations, technical experts, and WHO staff. This campaign is based on the SAFE strategy: Surgery for inturned eyelids; Antibiotic treatment (either oral azithromycin or local tetracycline) to entire communities to reduce prevalence rates of C trachomatis; Face washing and improved hygiene of young children; and Environmental improvement with safer water and disposal of animal and human waste. Recently the Edna McConnell Clark Foundation and Pfizer Inc announced the formation of the International Trachoma Initiative, an organisation to provide support and distribute azithromycin to the national programmes of trachoma control in five countries—Ghana, Mali, Morocco, Tanzania, and Vietnam.12 Although azithromycin treatment is a significant advance in trachoma control, the regression of trachoma in many regions of the world has occurred with economic development and the accompanying improvements in the standard of living.13 The currently recommended use of azithromycin for trachoma is a single dose administered as community-wide (mass) treatment. In three African countries such mass treatment effectively reduced the rates of chlamydial eye infection for 1 year.14 As yet there are no guidelines for the frequency of retreatment with azithromycin or for targeted treatment (eg, to children under 10). C trachomatis has not developed antibiotic resistance, but the use of any antibiotic on this scale will
THE LANCET • Vol 353 • April 24, 1999