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Highlights and Final Remarks
Highlights and Final Remarks* Antonio Palla, MD, FCCP; and Carlo Giuntini MD, FCCP
(Chest 1995; 107:56S-57S)
to its high frequency and potential lethality, pulmonary embolism (PE) may be considered an illness of social relevance. Venous thromboembolism accounts for approximately 300,000 hospitalizations and 50,000 deaths per year in the United States; 1 likewise, in Italy, as many as 50,000 new cases per year and an overall short-term case fatality of 11.4% are reported. 2 Venous thromboembolism is the third most common cardiovascular disease after acute ischemic syndromes and stroke. Although recent advances have been made in understanding the epidemiology, diagnosis, and treatment, PE is still largely undetected and untreated;3-5 as a consequence, the mortality rate has not changed in the last three decades.6-9 To improve detection, a better knowledge of pathology, epidemiology, and clinical presentation of, and diagnostic approach to PE are essential. While the pathologic diagnosis is commonly thought to be definitive, even the pathologist may face difficulties in providing reliable estimates of the occurrence of PE, as shown by Wagenvoort (see page lOS). This is due to seasonal variation in incidence, disappearance of emboli by thrombolysis, large variation in size of emboli, and the difficulty in differentiating embolized vs formed in situ thrombi. Detection of the site of origin in the deep veins of the legs, morphology and degree of organization of emboli, and presence of pulmonary infarction or hemorrhage may help the pathologist. However, the diagnosis of PE must be pursued during life. Thus, Morpurgo and Schmid (see page l8S) showed us that often a fatal embolus is relatively small but hardly tolerated by patients affected by cardiopulmonary disease. Moreover, the origin of thrombi may be demonstrated in only 53% of cases; the most frequent site is the region of the inferior vena cava. The great majority of emboli are multiple, located in the right lung and in the lower lobes. Most importantly, emboli are usually of different ages, which suggests that an early diagnosis may prevent death. Early diagnosis, nevertheless, is possible only when ~e
*From the Istituto di Fisiolo~ia Clinica, CNR, and Istituto di Clinica Medica II, Universita di Pisa, Italy. Supported in part with funds from the Ministry of the University and of the Scientific and Technological Research, Rome, Italy. Reprint requests: Dr. Palla, Istituto Clinica Medica II , Via Roma, 67, 56126 Pisa, Italy
565
epidemiologic and clinical aspects of PE are known. The article by Giuntini and coworkers (see page 3S) pointed out three essential points. First, the hospital medical staff and general practitioners may be trained to increase their clinical suspicion of PE if'a referral center for the diagnosis is present and active in the area. Indeed, the number of patients sent with the suspicion of PE has increased progressively in the diagnostic unit in Pisa from about 40 in 1969 to around 380 in 1990, without a decline in a priori probability for patients to be affected by PE. Second, a remarkable number of patients referred with the suspicion of PE (40%) are affected by idiopathic PE (ie, without apparent risk factors). In this group, primary prevention is not feasible, and early diagnosis is the only way to save patients. Third, there is a close association between idiopathic PE and subsequent development of clinically overt cancer (9% of patients). Idiopathic PE also implicates a significantly shorter survival of these patients, mostly for causes of death that reflect increased predisposition to thrombogenesis. Clinical assessment is essential for both raising the suspicion and making an early diagnosis of PE, as shown by Palla and coworkers (see page 21S). Manganelli et al (see page 25S) pointed out that a reliable and consistent pattern of PE is hard to define. However, clinical assessment, mostly if associated with characteristic findings of ECG, chest radiography, and arterial blood gas data, proves most useful to enroll in a rather accurate and not overwhelming measure in the majority of patients for definitive diagnosis. Definitive diagnosis of PE can be made by pulmonary arteriography. In this respect, the PISA-PED group (see page 33S) has shown that PE may be diagnosed noninvasively in most patients and angiography is necessary in only 21 % of patients who show discordant clinical and perfusion scan evaluation . However performed, the diagnosis of PE must be followed by treatment. Indeed, several therapeutic options exist, such as fibrinolytics, traditional and new anticoagulants, and pure thrombin inhibitors. Goldhaber (see page 45S) reports on a number of recent clinical trials that have shown that thrombolytics are definitely effective and do not necessitate infusion directly into the pulmonary circulation, as Final Remarks (Palla, Giuntini)
thought only few years ago; moreover, present fibrinolytic therapy is relatively safe and, therefore, does not require special laboratory tests for monitoring. As a consequence, fibrinolytic treatment is also economic. Finally, it may be employed until2 weeks after the acute embolization, which notably increases the number of patients who possibly benefit. It seems, therefore, that time has come for a large trial that focuses on reduction of mortality , recurrence of PE, and chronic thromboembolic pulmonary hypertension in patients treated with fibrinolytics . With respect to anticoagulation, Agnelli (see page 39S) stated that unfractioned heparin is the drug of choice for prophylaxis and short-term treatment of PE, while oral anticoagulants are mostly used for prophylaxis in high-risk patients and in long-term treatment of PE. In high-risk patients, prophylaxis with low molecular weight heparin or adjusted doses of unfractioned heparin is recommended . In treating patients with PE, the administration of heparin as a bolus IV dose followed by an IV infusion for 7 to 10 days is still the treatment of choice. However, new drugs, such as low molecular weight heparin and pure thrombin inhibitors, such as hirudin, may improve the efficacy of heparin, since they do not specifically bind to plasma proteins, such as fibrinogen, factor VIII, etc. Despite the availability of diagnostic and therapeutic options, some patients with PE continue to have undetected or simply untreated conditions. Therefore, a rare but serious complication of PE may occur, ie, pulmonary hypertension secondary to unresolved emboli. In this regard, the French experience with pulmonary thromboendarterectomy and lung transplantation reported by Simonneau and coworkers (see page 52S) is of great importance. One third of these patients had no history of deep vein thrombosis or PE; only one third had evidence of a coagulation disorder, mostly the presence of lupus anticoagulant. Results of thromboendarterectomy were a dramatic functional and hemodynamic improvement in most patients. Lung transplantation yielded a survival of six of eight patients at the follow-up from 5 months to 5 years. The numerous articles recently published in the medical literature, the several trials on diagnosis and treatment sponsored by prestigious medical institu-
tions, such as the National Institutes of Health, the state-of-the-art review prepared under the auspices of the World Health Organization and the International Society and Federation of Cardiology Task Force, are evidence of a novel interest in this challenging area of venous thromboembolism. Much has been done and more will be accomplished in the future in order to improve prevention, diagnosis, and treatment of PE with the final goal of reducing mortality and recurrence. The number of patients in whom the diagnosis is being made at autopsy is still disproportionally high for a potentially treatable disease such as PE. This symposium, held in Florence under the auspices of the European Respiratory Society, aimed at focusing on the most recent developments in epidemiology, pathology, diagnosis, and treatment of PE. It seems to us that this aim has been fulfilled . The acknowledgments are to be shared among the symposium participants for their reports: Boerhinger Ingelheim Italia for the generous support; American College of Chest Physicians and European Respiratory Society for sponsoring this educational symposium; and Professor Dario Olivieri for including the Symposium into the annual meeting of the Society. REFERENCES
1 Goldhaber SZ. Thrombolysis for pulmonary embolism. Prog Cardiovasc Dis 1991; 34:113-34 2 Di Ricco G, Melillo E, Rindi M, e tal. Prognosi a breve termine dell'embolia polmonare. G Ita) Cardiol1988; 18:578-84 3 Morpurgo M, Schmid C. Clinico-pathological correlations in pulmonary embolism: a posteriori evaluation. Prog Respir Res 1980; 13:8-15 4 Modan B, Sharon E, Jelin N. Factors contributing to the incorrect diagnosis of pulmonary embolic disease. Chest 1972; 62: 388-93 5 Goldhaber SZ, Hennekens CH, Evans DA, et al. Factors influencing the correct antemortem diagnosis of major pulmonary embolism. Am J Med 1982; 73:822-26 6 Bergqvist D, Fredin H. Pulmonary embolism and mortality in patients with fractured hips: a prospective consecutive series. Eur J Surg 1991 ; 157:571-74 7 Bergqvist D, Lindblad. A 30-year survey of pulmonary embolism verified at autopsy: an analysis of 1,274 surgical patients. Br J Surg 1985; 72:105-08 8 Lilienfeld DE, ChanE, Ehland J, et al. Mortality from pulmonary embolism in the United States: 1962 to 1984. Chest 1990; 98:1067-72 9 Lilienfeld DE, Godbold JH, Burke GL, et al. Hospitalization and case fatality for pulmonary embolism in the twin cities: 1979-1984. Am Heart J 1990; 120:392-95
CHEST / 107 / 1 I JANUARY, 1995/ Supplement
575
(Chest 1995; 107:56S-57S)
to its high frequency and potential lethality, pulmonary embolism (PE) may be considered an illness of social relevance. Venous thromboembolism accounts for approximately 300,000 hospitalizations and 50,000 deaths per year in the United States; 1 likewise, in Italy, as many as 50,000 new cases per year and an overall short-term case fatality of 11.4% are reported. 2 Venous thromboembolism is the third most common cardiovascular disease after acute ischemic syndromes and stroke. Although recent advances have been made in understanding the epidemiology, diagnosis, and treatment, PE is still largely undetected and untreated;3-5 as a consequence, the mortality rate has not changed in the last three decades.6-9 To improve detection, a better knowledge of pathology, epidemiology, and clinical presentation of, and diagnostic approach to PE are essential. While the pathologic diagnosis is commonly thought to be definitive, even the pathologist may face difficulties in providing reliable estimates of the occurrence of PE, as shown by Wagenvoort (see page lOS). This is due to seasonal variation in incidence, disappearance of emboli by thrombolysis, large variation in size of emboli, and the difficulty in differentiating embolized vs formed in situ thrombi. Detection of the site of origin in the deep veins of the legs, morphology and degree of organization of emboli, and presence of pulmonary infarction or hemorrhage may help the pathologist. However, the diagnosis of PE must be pursued during life. Thus, Morpurgo and Schmid (see page l8S) showed us that often a fatal embolus is relatively small but hardly tolerated by patients affected by cardiopulmonary disease. Moreover, the origin of thrombi may be demonstrated in only 53% of cases; the most frequent site is the region of the inferior vena cava. The great majority of emboli are multiple, located in the right lung and in the lower lobes. Most importantly, emboli are usually of different ages, which suggests that an early diagnosis may prevent death. Early diagnosis, nevertheless, is possible only when ~e
*From the Istituto di Fisiolo~ia Clinica, CNR, and Istituto di Clinica Medica II, Universita di Pisa, Italy. Supported in part with funds from the Ministry of the University and of the Scientific and Technological Research, Rome, Italy. Reprint requests: Dr. Palla, Istituto Clinica Medica II , Via Roma, 67, 56126 Pisa, Italy
565
epidemiologic and clinical aspects of PE are known. The article by Giuntini and coworkers (see page 3S) pointed out three essential points. First, the hospital medical staff and general practitioners may be trained to increase their clinical suspicion of PE if'a referral center for the diagnosis is present and active in the area. Indeed, the number of patients sent with the suspicion of PE has increased progressively in the diagnostic unit in Pisa from about 40 in 1969 to around 380 in 1990, without a decline in a priori probability for patients to be affected by PE. Second, a remarkable number of patients referred with the suspicion of PE (40%) are affected by idiopathic PE (ie, without apparent risk factors). In this group, primary prevention is not feasible, and early diagnosis is the only way to save patients. Third, there is a close association between idiopathic PE and subsequent development of clinically overt cancer (9% of patients). Idiopathic PE also implicates a significantly shorter survival of these patients, mostly for causes of death that reflect increased predisposition to thrombogenesis. Clinical assessment is essential for both raising the suspicion and making an early diagnosis of PE, as shown by Palla and coworkers (see page 21S). Manganelli et al (see page 25S) pointed out that a reliable and consistent pattern of PE is hard to define. However, clinical assessment, mostly if associated with characteristic findings of ECG, chest radiography, and arterial blood gas data, proves most useful to enroll in a rather accurate and not overwhelming measure in the majority of patients for definitive diagnosis. Definitive diagnosis of PE can be made by pulmonary arteriography. In this respect, the PISA-PED group (see page 33S) has shown that PE may be diagnosed noninvasively in most patients and angiography is necessary in only 21 % of patients who show discordant clinical and perfusion scan evaluation . However performed, the diagnosis of PE must be followed by treatment. Indeed, several therapeutic options exist, such as fibrinolytics, traditional and new anticoagulants, and pure thrombin inhibitors. Goldhaber (see page 45S) reports on a number of recent clinical trials that have shown that thrombolytics are definitely effective and do not necessitate infusion directly into the pulmonary circulation, as Final Remarks (Palla, Giuntini)
thought only few years ago; moreover, present fibrinolytic therapy is relatively safe and, therefore, does not require special laboratory tests for monitoring. As a consequence, fibrinolytic treatment is also economic. Finally, it may be employed until2 weeks after the acute embolization, which notably increases the number of patients who possibly benefit. It seems, therefore, that time has come for a large trial that focuses on reduction of mortality , recurrence of PE, and chronic thromboembolic pulmonary hypertension in patients treated with fibrinolytics . With respect to anticoagulation, Agnelli (see page 39S) stated that unfractioned heparin is the drug of choice for prophylaxis and short-term treatment of PE, while oral anticoagulants are mostly used for prophylaxis in high-risk patients and in long-term treatment of PE. In high-risk patients, prophylaxis with low molecular weight heparin or adjusted doses of unfractioned heparin is recommended . In treating patients with PE, the administration of heparin as a bolus IV dose followed by an IV infusion for 7 to 10 days is still the treatment of choice. However, new drugs, such as low molecular weight heparin and pure thrombin inhibitors, such as hirudin, may improve the efficacy of heparin, since they do not specifically bind to plasma proteins, such as fibrinogen, factor VIII, etc. Despite the availability of diagnostic and therapeutic options, some patients with PE continue to have undetected or simply untreated conditions. Therefore, a rare but serious complication of PE may occur, ie, pulmonary hypertension secondary to unresolved emboli. In this regard, the French experience with pulmonary thromboendarterectomy and lung transplantation reported by Simonneau and coworkers (see page 52S) is of great importance. One third of these patients had no history of deep vein thrombosis or PE; only one third had evidence of a coagulation disorder, mostly the presence of lupus anticoagulant. Results of thromboendarterectomy were a dramatic functional and hemodynamic improvement in most patients. Lung transplantation yielded a survival of six of eight patients at the follow-up from 5 months to 5 years. The numerous articles recently published in the medical literature, the several trials on diagnosis and treatment sponsored by prestigious medical institu-
tions, such as the National Institutes of Health, the state-of-the-art review prepared under the auspices of the World Health Organization and the International Society and Federation of Cardiology Task Force, are evidence of a novel interest in this challenging area of venous thromboembolism. Much has been done and more will be accomplished in the future in order to improve prevention, diagnosis, and treatment of PE with the final goal of reducing mortality and recurrence. The number of patients in whom the diagnosis is being made at autopsy is still disproportionally high for a potentially treatable disease such as PE. This symposium, held in Florence under the auspices of the European Respiratory Society, aimed at focusing on the most recent developments in epidemiology, pathology, diagnosis, and treatment of PE. It seems to us that this aim has been fulfilled . The acknowledgments are to be shared among the symposium participants for their reports: Boerhinger Ingelheim Italia for the generous support; American College of Chest Physicians and European Respiratory Society for sponsoring this educational symposium; and Professor Dario Olivieri for including the Symposium into the annual meeting of the Society. REFERENCES
1 Goldhaber SZ. Thrombolysis for pulmonary embolism. Prog Cardiovasc Dis 1991; 34:113-34 2 Di Ricco G, Melillo E, Rindi M, e tal. Prognosi a breve termine dell'embolia polmonare. G Ita) Cardiol1988; 18:578-84 3 Morpurgo M, Schmid C. Clinico-pathological correlations in pulmonary embolism: a posteriori evaluation. Prog Respir Res 1980; 13:8-15 4 Modan B, Sharon E, Jelin N. Factors contributing to the incorrect diagnosis of pulmonary embolic disease. Chest 1972; 62: 388-93 5 Goldhaber SZ, Hennekens CH, Evans DA, et al. Factors influencing the correct antemortem diagnosis of major pulmonary embolism. Am J Med 1982; 73:822-26 6 Bergqvist D, Fredin H. Pulmonary embolism and mortality in patients with fractured hips: a prospective consecutive series. Eur J Surg 1991 ; 157:571-74 7 Bergqvist D, Lindblad. A 30-year survey of pulmonary embolism verified at autopsy: an analysis of 1,274 surgical patients. Br J Surg 1985; 72:105-08 8 Lilienfeld DE, ChanE, Ehland J, et al. Mortality from pulmonary embolism in the United States: 1962 to 1984. Chest 1990; 98:1067-72 9 Lilienfeld DE, Godbold JH, Burke GL, et al. Hospitalization and case fatality for pulmonary embolism in the twin cities: 1979-1984. Am Heart J 1990; 120:392-95
CHEST / 107 / 1 I JANUARY, 1995/ Supplement
575