Epidemiology and natural history of venous thromboembolism

Progress in

Cardiovascular Diseases VOL XXXVI, NO 6

MAY/JUNE 1994

Epidemiology and Natural History of Venous Thromboembolism Joseph S. Alpert and James E. Dalen

1975, WE reviewed the natural history and I Nepidemiology of pulmonary embolism (PE). Since then, a great deal has been learned about the pathophysiology, diagnosis, and treatment of venous thromboembolism (VTE). However, less is known about the natural history and epidemiology of this condition because the diagnosis is often based on clinical data that are fraught with uncertainty. Thus, it is still difficult to ascertain the true incidence and case fatality rate of acute VTE, even though PE is listed as one of the monitored causes of death by the National Center for Health Statistics. a Problems in determining the true incidence and lethality of VTE are compounded by the considerable degree of inaccuracy inherent in death certificate assignment of mortality in patients with suspected VTE. 2 Indeed, the clinical diagnosis of PE remains notoriously inaccurate. 3 Even ventilation/perfusion pulmonary scintigraphy is often incorrect in ascertaining the diagnosis of VTE, as was recently reconfirmed by the Prospective Investigation of Pulmonary Embolism Diagnosis study. 4 Therefore, inaccuracies inherent in the clinical, death certificate, and even autopsy diagnosis of VTE continue to confound attempts to estimate incidence/ prevalence and case fatality rates of this common condition. 5 Further complicating this analysis is the fact that, for many patients, VTE is the final event in a prolonged and inevitably fatal illness. 5 Fatal VTE may even be welcomed in such a setting. What the clinician and the clinical scientist would really like to ascertain is the number of patients who have VTE as an acute primary or an important secondary event, ie, how many patients actually require diagnosis and therapy

for VTE. Estimates of the latter number of patients will remain uncertain until an accurate, simple clinical test for the diagnosis of VTE becomes available, thereby making pulmonary angiography unnecessary. EPIDEMIOLOGY OF VENOUS THROMBOEMBOLISM

The previously stated pessimistic statements not withstanding, a number of investigators have attempted to study the epidemiology of deep venous thrombosis (DVT) and PE. In 1967, Hume et al 6 noted that PE was listed as the principal cause of death for 4,981 individuals in England and Wales. For an additional 21,000 persons, PE was said to have been a contributing cause of death. When these numbers were extrapolated to the population of the United States at that time, it was estimated that 88,200 deaths were the result of PE. The problem with statistics such as these is that they rely on the accuracy of death certificate ascertainment of the cause of death. Unfortunately, the inaccuracy of death certificates is well-known, particularly for VTE, as already mentioned. 2 Indeed, VTE rarely develops de novo in a healthy person; rather, it usually accompanies a chronic, debilitating disease such as heart failure or emphysema that makes ascertation of the primary or contributing cause of death particuFrom the Department of Medicine, College of Medicine, University of Arizona Health Sciences Center, Tucson, AZ. Address reprint requests to Joseph S. Alpert, MD, Department of Medicine, College of Medicine, University of Arizona Health Sciences Center, 1501 N Campbell Ave, Rm 6334, Tuscon, AZ 85724. Copyright 9 1994 by W.B. Saunders Company 0033-0620/94/3606-000155.00/0

Progress in Cardiovascular Diseases, Vol XXXVI, No 6 (May/June), 1994: pp 417-422

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larly difficult. Despite these numerous confounding factors, this report will review the available data and attempt to estimate the morbidity and mortality associated with VTE in the United States.

Incidence and Case Fatality Rates of Deep Vein Thrombosis The incidence and case fatality rates for DVT were examined by Anderson et al 7for metropolitan Worcester, MA. The average annual incidence of DVT was 48 cases per 100,000 population. Incidence rates of DVT increased exponentially with age, eg, 17 per 100,000 for ages 40 through 49 and 232 per 100,000 for ages 70 through 79. Because these numbers are derived from hospital discharge diagnoses, they almost certainly represent underreporting of the true incidence of DVT that is often silent, occurring commonly in patients not hospitalized in acute, general hospitals. Thus, bedridden home-care patients and individuals living in nursing homes and rehabilitation facilities are not adequately represented in the Worcester, MA data base, because many of these patients will not be hospitalized despite clinical deterioration. Risk factors for DVT in the study of Anderson et al included malignancy, heart failure, obstructive airways disease, fractures, myocardial infarction, obesity, stroke, surgical interventions, and trauma. Many patients had two or more risk factors for developing DVT. Of patients with DVT, 92% had one or more physical findings that suggested the diagnosis, eg, leg swelling, tenderness, and warmth. This reflects the selection bias of the study (discharge diagnosis), because previous prospective studies of DVT have shown clinical findings in less than 50% of patients with objectively diagnosed DVT.8,9 The in-hospital case fatality rate for DVT was 5%. Case fatality rates increased with age (10% for ages 40 through 59 and 16% for ages greater than 80 years). Prognosis did not differ between men and women. Extrapolating the incidence and case fatality rates of Anderson et al to the entire United States yields approximately 260,000 cases of DVT hospitalized in this country during 1986; therefore, a minimum of 13,000

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deaths occur in the United States each year as a result of DVT.

Incidence and Case Fatality Rates of Pulmonary Embolism Over the years, a number of investigators have sought to estimate the incidence and case fatality rates for acute PE. 2 The problems and the significant errors inherent in such analyses has been emphasized previously. 2 Treffers et al 1~ reviewed the incidence of PE for 56,000 pregnant and postpartum Dutch women during a 28-year period (1952 through 1979). Acute PE occurred in 0.7% of these women with a relatively constant rate of events over the time period studied. Only 3 deaths occurred (case fatality rate, .005%). During a similar period of time (1954 through 1985), Sachs et a111observed slightly lower maternal mortality rates in Massachusetts (3.4 of 100,000 in 1954 through 1957; 1.9 of 100,000 in 1966 through 1969; and 1.2 of 100,000 in 1982 through 1985). Raso et a112examined the epidemiology of PE in the Piedmont region of Italy between 1976 and 1979. They observed a low incidence of PE, 0.02% in a population of approximately 4.5 million individuals. There was a modest increase in the incidence of PE with advancing age, eg, 0.03% for ages 46 through 55 and 0.08% for ages 66 through 75. Laissue et a113 studied mortality rates for acute PE in Switzerland over a 60-year period (1920 through 1980). They observed a steady increase in mortality over this period of time, approximately i per 100,000 in 1920 increasing to approximately 5 per 100,000 in 1980.13Mortality rates increased prominently with age. Zimmerman et a114 examined the mortality rate from acute PE in Cuyahoga County (Cleveland, OH) in previously healthy, nonpregnant individuals. For the years of 1952 through 1969, the crude death rate was 2.16 per 100,000 for men and 3.96 per 100,000 for women. 14 In 1975, Dalen and Alpert 2 estimated that 200,000 individuals died of PE in the United States. Their estimate included patients in acute hospitals, nursing homes, and in the community. 2They calculated that approximately 630,000 episodes of PE occurred in the United States each year. More recent estimates of incidence and mortality rates for acute PE have tended to

NATURAL HISTORY OF PULMONARY EMBOLISM

be slightly lower than the values reported by Dalen and Alpert. For example, Goldhaber and Hennekens 15 noted a 9% decrease in PE case fatality rates during the 1970's; however, the number of individuals diagnosed with acute PE actually increased as compared with the estimates of Dalen and Alpert. Lilienfeld et a116performed an extensive analysis of PE mortality in the United States for the time period from 1962 through 1984. These investigators noted that age-adjusted death rates for PE increased in both men and women between 1962 and 1974, levelled off through 1979, and then decreased during the early 1980's. 16 Mortality from PE increased dramatically with age, eg, case fatality rates were 10 fold higher in individuals older than 85 years compared with those for persons 35 through 39 years of age. Mortality rates for acute PE were similar in white and nonwhite individuals except in middleaged subjects, where mortality rates were higher for nonwhite individuals.16 Similar mortality trends were noted in Canada. a7 In Lilienfeld's analysis, men were at an increased risk of dying from PE when compared with women. 16 However, this observation does not appear to be universal. Indeed, men and women in France and Switzerland have similar PE mortality rates. In the United Kingdom, on the other hand, women have a higher mortality rate compared with that for m e n . 13'18,19 With respect to incidence, Lilienfeld and associates observed a decrease in the US hospital discharge rate for acute PE between 1979 and 1984.20 They suggested that the decrease in PE mortality during the early 1980's was the result of a decreased incidence of the disease rather than a change in case fatality rates. 2~ Possible explanations for the decrease in acute hospital discharge rates for PE include early mobilization after medical/surgical illness, increased use of prophylaxis against DVT, and a decrease in cardiovascular risk factors. However, data reported by Lilienfeld and Godbold 21 suggest that the incidence of acute PE has not changed much since Dalen and Alpert's estimates in the mid-1970's. 2 Anderson et al 7 arrived at somewhat lower figures based on an analysis of acute hospital discharge diagnoses; however, their estimates only involved patients

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in acute, general hospitals in whom the diagnosis of PE had been made. 7 The number of episodes of acute PE in the United States is likely to be considerably larger if one considers undiagnosed cases as well as cases occurring in nursing homes and in the community.2 Geographic distribution and circadian variation in the incidence of acute pulmonary embolism. PE mortality rates are lower in the Pacific and Rocky Mountain regions of the United States compared with those for the rest of the country.21The New England region reports modestly higher mortality rates, whereas the South Atlantic and Central regions report considerably higher PE death rates. Possible explanations for this geographic difference in PE mortality rates include differences in racial and ethnic composition within the regions as well as different climatic conditions and a differing incidence of atherosclerotic risk factors. 21 Circadian distribution of pulmonary embolism. Circadian variations in incidence and mortality of specific diseases can yield clues to underlying pathophysiologic mechanisms. Colantonio et a122 examined the circadian distribution of fatal PE in 178 Italian patients. The maximum incidence of fatal PE occurred between 5 and 11 am (peak, 7:32 am); the minimum incidence occurred between 12 pm and 11 pm. The investigators suggested that increases in sympathetic tone, postural changes, and muscular activity associated with awakening might favor detachment of deep venous thrombus, thereby producing an episode of PE. 22 Frisbie and Sharma 23 confirmed the findings of Colantonio et al. Effect of gender and race on incidence and mortality of pulmonary embolism. As noted earlier, there is apparently considerable variation in PE mortality from country to country and even within different regions of the United States. 16There are also variations in PE mortality between the genders and between whites and nonwhites? 6,2~ In general, mortality is higher for men and nonwhites, although different age groups define different gender and racial disparities. For example, Lilienfeld et al observed similar PE mortality in whites and nonwhites in younger and older individuals, but increased mortality in middle-aged nonwhites. 16,2~ An increased risk of PE mortality is also present in middle-aged and elderly white and nonwhite

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men. Increased risk of fatal PE in men has not been noted in other countries, eg, Switzerland, France, and the United Kingdom. 13,1849 Reasons for these gender and racial variations are unknown. No gender difference for DVT/PE incidence was observed by Anderson et al. 7 NATURAL HISTORY OF VENOUS THROMBOEMBOLISM DVT apparently originates as a platelet nidus, usually in the region of the venous valves of the calf. As noted by Virchow in the 19th century, the triad of circulatory stasis, venous endothelial injury, and blood hypercoagulability contribute to the initiation of DVT. The thrombogenic nature of the platelet nidus activates the clotting cascade, thereby leading to a red thrombus that grows by accretion of fibrin and platelets. 24;25 The body's intrinsic fibrinolytic system is also activated; the forces of thrombogenesis and thrombolysis then compete for predominance. If thrombogenesis is preeminent, then the thrombus propagates. At any time, part or all of the thrombus may become detached from the venous endothelium, resulting in PE. Alternatively, the thrombus may organize and, ultimately, become incorporated into the wall of the vein. Incompetence of the venous valves and a chronic, postphlebitic condition may result. 26 Thrombi that remain localized to the calf Veins have a decreased tendency to embolize compared with thrombi that extend into the veins of the thigh. 26Approximately 20% of cases of DVT of the calf propagate to the thigh veins. 2v,28 Fifty percent of thigh thrombi eventually embolize. 27,:9,3~Organization of deep venous thrombi takes approximately 7 to 10 days. 26 However, normal venous function does not return before a number of weeks have passed; 30% Of treated DVT patients have normal venous function by 3 weeks; 50% are normal by 6 weeks; 60% to 65% are normal at 3 months; and 90% are normal at 1 year? ~ Complete lysis of major DVT occurs in fewer than 20% of cases. 32 However, complete lysis of small calf emboli occurs quite frequently. 28,33 The greatest risk to the life of the patient with acute PE occurs during the initial minutes to hours after the arrival of the embolus in the pulmonary vascular bed. 26 Sudden increases in

right ventricular (RV) afterload can lead to RV dysfunction, a marked decrease in cardiac output, hypotension or frank shock, supraventricular and/or ventricular arrhythmias, syncope, or cardiac arrest. Remodelling and/or fibrinolytic dissolution of the embolus with consequent reopening of the occluded pulmonary vascular segment occurs within minutes to hours to days in many patients. 34-36Thereby, RV afterload is decreased, and hemodynamic stability may be restored. Dalen et a134 performed serial right heart catheterizations and pulmonary angiograms in 15 patients with treated, major PE. Pulmonary arterial pressures decreased towards normal 10 to 21 days after the index episode of PE. 34 However, pulmonary arterial pressures normalized completely in only 1 patient. Minimal angiographic resolution of PE was seen within the first week after an episode of embolism. Moderate to complete resolution was common at 10 to 21 days and increased further at greater than 30 days after the index episode of PE. 34 In the Urokinase Pulmonary Embolism Trial, complete resolution of lung scan defects in treated patients occurred in 36% of instances at 5 days, in 52% at 14 days, in 73% at 3 months, and in 76% at i year. 37 Most patients survive the first hour after an episode of PE; unfortunately, the diagnosis is not considered seriously in the majority of patients. 2 Recurrent episodes of PE are almost certainly present in the majority of patients who succumb to this entity. 2 Carson et a138observed the natural history of 399 patients with documented PE, 94% of whom received therapy (usually conventional anticoagulation) for their embolism. The early fatality rate in these patients was 2.5%, mostly secondary to recurrent PE. Clinically apparent episodes of recurrent PE occurred in 8.3% of patients, 45% of whom died during a 1-year follow-up period. At one year follow-up, 23.8% of the entire group of patients had died, almost all from underlying cardiovascular disease, pul, monary disease, or malignancyY Essentially all of the PE deaths occurred within 2 weeks of diagnosis; PE recurrence usually occurred within 1 week of the initial episode. Prediletto et a139performed serial pulmonary scintigraphy, pulmonary function tests, arterial

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blood gases, and chest x-rays in 33 patients with major, treated PE. All gas exchange variables were abnormal at the time of initial diagnosis. Considerable improvement in perfusion occurred over the first 30 days after the PE. The rate of improvement of gas exchange variables paralleled scintigraphic resolution. 39 Arterial PO2 and ventilatory capacity tended to normalize during the first month, whereas oxygen and CO2 gradients as well as physiologic dead space were often persistently abnormal 6 months after diagnosis. As noted earlier, the late prognosis of acute PE is dependent on progression of underlying cardiac, pulmonary, and oncologic disease. 38 Prognosis from the episode of PE itself is excellent. 38,4~ Paraskos et al4~performed extensive late follow-up evaluations on 60 patients with documented PE. At follow-up, 32% of the

patients had died, almost universally as a result of underlying disease. PE had largely resolved in 88% of patients. Unresolved PE was documented in only 12% of patients. 4~Only 1 patient had suffered recurrent PE. CONCLUSIONS Acute VTE is a life-threatening event that usually occurs in the setting of severe underlying cardiac, pulmonary, and/or oncologic illness. The greatest period of instability in these patients occurs immediately after the episode of PE. Within days to weeks, most treated patients are stable and have largely resolved anglographic, hemodynamic, and gas exchange parameters. Long-term mortality is related to the severity of the underlying illness. Recurrent and/or unresolved PE is uncommon.

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