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We have evaluated the fibrinogen/fibrin fragment E antigen assay as a diagnostic test in patients with clinically suspected venous thrombosis by comparing the results of this assay with venography in 272 patients. The result of the fragment E antigen assay was elevated in 79 of 80 patients with positive venograms for recent venous thrombosis (sensitivity 99%) and within the normal range in 161 of 192 patients with normal venograms (specificity 84%). The fragment E assay was also evaluated in 130 medical and surgical controls without evidence of venous thrombosis by leg scanning and the test was found to be relatively nonspecific. However, in the patient group under study, a correct clinical diagnosis of no thrombosis, based on a normal fragment E result, was made in 161 of 162 cases (negative predictive value of 99%). Therefore, a normal test result effectively excludes a diagnosis of venous thrombosis in clinically symptomatic patients. The assay, as currently performed, is technically demanding and takes 24 hr to complete. Therefore, it will have to be simplified before it can be applied to clinical practice.

Acute deep-vein thrombosis is usually treated with intravenous heparin for a number of days, then with oral anticoagulants for weeks to months. We have compared adjusted-dose warfarin sodium with fixed low-dose subcutaneous heparin in the prevention of recurrent deep-vein thrombosis. Sixty-eight patients with acute deep-vein thrombosis confirmed by venography were treated with intravenous heparin and then randomized to secondary prophylaxis. Nine of 35 patients receiving subcutaneous heparin, but none of 33 receiving warfarin sodium, had new episodes of objectively documented venous thromboembolism (P = 0.001). Seven patients on warfarin sodium experienced bleeding complications (of which four were major), as compared with no patients receiving subcutaneous heparin (P less than 0.005). Thus, adjusted-dose warfarin sodium is more effective than low-dose subcutaneous heparin in preventing recurrent venous thromboembolism, but its use is accompanied by a significant risk of bleeding.

Differing opinions about the value of ventilation-perfusion lung scanning have created controversy concerning the correct approach to the diagnosis of pulmonary embolism. In a prospective study of 305 consecutive patients with clinically suspected pulmonary embolism and abnormal perfusion lung scans, we evaluated the role of ventilation-perfusion lung scanning, pulmonary angiography, and objective testing for venous thrombosis in the diagnostic process. Segmental or greater perfusion defects with ventilation mismatch have a high probability (86 percent) of pulmonary embolism. Contrary to current clinical practice, however, the approach of ruling against pulmonary embolism by a "low probability" scan pattern is incorrect, even with an improved technique for ventilation imaging; the frequency of pulmonary embolism in these patients ranged from 25 to 40 percent. Objective testing for venous thrombosis provides a practical alternative to performing pulmonary angiography in the diagnostic work-up; by providing an endpoint for commencing anticoagulant therapy, a positive result obviates the need for further testing in 20 to 30 percent of patients.

Venography remains the standard method for the diagnosis of deep venous thrombosis but it is invasive and frequently causes discomfort. A randomised double-blind study was performed to determine the efficacy of lidocaine in reducing pain and discomfort associated with venography. Sixty patients undergoing ascending venography received 40 mg of lidocaine (2 ml of 2% lidocaine mixed with 50 ml of contrast medium) in one leg and saline in the other. Assessment of pain was by a standard questionnaire administered by an investigator unaware of the sequence of administration of lidocaine or saline placebo. Twenty-four patients reported no difference in pain or discomfort between the two limbs. Of the 36 patients experiencing an overall difference in pain between the two legs, 12 reported more pain in the leg receiving lidocaine and 24 reported more pain in the leg receiving saline (p = 0.023). There were no significant side effects attributable to lidocaine. These results indicate that lidocaine is beneficial in reducing pain and discomfort associated with venography.

Impedance plethysmography using the cuff technique has been compared with venography in 346 consecutive patients with suspected venous thromboembolism. The limbs were classified according to the venographic results as no thrombosis, proximal (popliteal, femoral, or iliac) vein thrombosis, and calf thrombosis. A discriminant analysis was performed. The impedance plethysmographic result was normal in 386 of 397 limbs which were normal on venography, a specificity of 97%, and abnormal in 124 of 133 limbs which showed proximal vein thrombosis, a sensitivity of 93%. Seventy-three of 88 limbs with calf vein thrombi and a normal impedance plethysmographic result. The sensitivity in 29 limbs with asymptomatic proximal vein thrombosis was 83%. Impedance plethysmography is an accurate method for detecting proximal vein thrombosis but has limitations which include the possibility of false positive results due to arterial insufficiency and muscle tension.

Recurrent venous thrombosis presents a diagnostic challenge. Venography, impedance plethysmography and fibrinogen leg scanning all have potential limitations, and their role in this context has not been evaluated. We performed a prospective cohort study evaluating impedance plethysmography and leg scanning, plus venography, using outcome on long-term follow-up as the end point in 270 patients with clinically suspected recurrent deep-vein thrombosis. Anticoagulant treatment was withheld in the 181 patients negative by noninvasive testing and was given in patients positive by impedance plethysmography if leg scanning was positive or if intraluminal filling defects were detected by venography. The validity of this approach was tested by long-term follow-up. Three of 181 patients (1.7%) negative by noninvasive testing had a recurrence, compared with 18 of 89 (20%) with positive findings (p less than 0.001). Our objective diagnostic approach has high clinical utility; an objective rationale for withholding or giving treatment was established in 95% of patients.

We investigated the hypothesis that the diagnostic accuracy of impedance plethysmography (IPG) for thrombosis of the popliteal or more proximal veins increases with enhanced venous filling. Venous filling was increased by prolonging cuff occlusion and by sequential testing. IPG and vengography were performed on 169 legs with and 317 legs without proximal vein thrombosis. The sensitivity and specificity of IPG rose significantly with increased venous filling. Changes in venous filling were associated with corresponding changes in emptying in normal legs, but not those with proximal vein thrombosis, so that the regression lines relating venous filling and emptying in normal and abnormal legs diverged significantly (P less than 0.001). If the IPG sequence had been terminated after only a single 45 second occlusion time test, sensitivity would have deteriorated by 10% and specificity by 20%. These observations indicate that the accuracy of IPG can be significantly enhanced if optimal venous filling is obtained.

Intravenous heparin is the initial treatment of choice for most patients with acute pulmonary embolism or proximal deep vein thrombosis. The primary objective of initial heparin therapy in such patients is to prevent recurrent venous thromboembolism. The efficacy of intravenous heparin for this purpose has been established by randomized clinical trials in patients with pulmonary embolism, and more recently, in patients with proximal vein thrombosis. Heparin is given as an initial intravenous bolus of 5000 units, followed by a maintenance dose of 30,000-40,000 units per 24 h by continuous intravenous infusion. A recent randomized trial in patients with proximal vein thrombosis indicates that failure to achieve an adequate anticoagulant response (APTT greater than 1.5 times control) is associated with a high risk (25%) of recurrent venous thromboembolism. Intravenous heparin administered in doses that prolong the activated partial thromboplastin time (APTT) to 1.5 or more times the control value is highly effective, and associated with a low frequency (2%) of recurrent venous thromboembolism. Heparin is continued for 7-10 days, overlapped with warfarin sodium during the last 4-5 days. Multiple randomized clinical trials indicate that this approach is highly effective. An alternative approach is to commence heparin and oral anticoagulants together at the time of diagnosis, and to discontinue heparin on the fourth or fifth day. A recent randomized trial in patients with submassive venous thrombosis or pulmonary embolism suggests that 4-5 days of initial heparin therapy is effective and safe, but this approach must be evaluated by further randomized trials before it is recommended for patients with extensive proximal vein thrombosis.(ABSTRACT TRUNCATED AT 250 WORDS)

We have previously reported that long-term therapy with warfarin is effective for preventing recurrent venous thromboembolism in patients with proximal-vein thrombosis but that there is an appreciable risk of hemorrhage. To determine whether that risk could be reduced without a loss of effectiveness, we randomly allocated 96 patients with proximal-vein thrombosis to a group receiving less intense anticoagulant therapy, with a mean prothrombin time of 26.9 seconds using the Manchester comparative reagent (corresponding Simplastin time, 15 seconds), or a group given more intense therapy, with a mean Simplastin time of 19.4 seconds (corresponding prothrombin time 41 seconds with the Manchester comparative reagent) (P less than 0.001). Two of 47 patients (4 per cent) in the less intensely treated group had hemorrhagic complications, as compared with 11 of 49 patients (22 per cent) in the more intensely anticoagulated group (P = 0.015 by the two-tailed test). This difference was due to minor bleeding episodes. The frequency of recurrent venous thromboembolism was low in both groups (2 per cent). Our findings indicate that less intense anticoagulant therapy is associated with a low frequency of recurrent venous thromboembolism (2 per cent) and a reduced risk of hemorrhage.

The clinical diagnosis of venous thrombosis lacks sensitivity and specificity. Venography is recognized as the diagnostic reference standard but is invasive and associated with patient morbidity.125I-fibrinogen leg scanning is sensitive to calf vein thrombosis but is relatively insensitive to femoral vein thrombosis and does not detect iliac vein thrombosis. This test is most useful as a screening test in high-risk medical and surgical patients. The test may be falsely positive at the site of hematoma, and because of this, it has serious limitations in patients undergoing knee and hip surgery. Leg scanning also has limitations when used to diagnose patients with suspected venous thrombosis because it may take up to 72 hours to obtain a positive result. Impedance plethysmography (IPG), a noninvasive technique, is sensitive and specific for thrombosis involving the popliteal, femoral, and iliac veins. Combined with125Ifibrinogen leg scanning, this test has considerable potential as a screening test in patients undergoing hip surgery. The combined use of IPG and leg scanning has also been shown to be highly accurate for the diagnosis of clinically suspected venous thrombosis, and this approach offers a less invasive alternative to venography in these patients. The Doppler ultrasound flowmeter, like the IPG, is sensitive to popliteal and more proximal vein thrombosis but is relatively insensitive to calf vein thrombosis. The interpretation of the results of this test is more subjective and much more dependent upon the expertise of the examiner than is the IPG. A number of other techniques, including image scanning, and themography, are under investigation but require further evaluation before they can be recommended in the management of patients with venous thromboembolism.

Venous thrombi are intravascular deposits composed predominantly of fibrin and red blood cells with a variable platelet and leukocyte component. They frequently arise in large venous sinuses in the calf, in valve cusp pockets either in the deep veins of the calf or thigh or in venous segments that have been exposed to direct trauma. Venous thrombosis can be produced experimentally by a combination of stasis and systemic hypercoagulability or by stasis and endothelial damage. Thrombosis is augmented if the fibrinolytic mechanism is inhibited or defective. A number of clinical conditions and laboratory abnormalities are associated with and predispose to venous thrombosis and, in many of these, it is possible to identify one or more of the thrombogenic factors discussed. Venous thromboembolism (venous thrombosis and pulmonary embolism) is a serious and potentially fatal disorder that usually complicates the course of sick hospitalized patients, but occasionally affects ambulant and otherwise healthy individuals. Screening studies with iodine-125 fibrinogen leg scanning, impedance plethysmography and perfusion lung scanning have shown that the majority of venous thrombi and pulmonary emboli that occur in hospitalized patients are small and asymptomatic, and it is likely that most are clinically insignificant. In bedridden patients, most thrombi commence in the calf and are asymptomatic. When a calf vein thrombus extends into the proximal venous segment, the risk of clinically significant pulmonary embolism increases. Less is known about the incidence and clinical significance in a nonhospital population; although asymptomatic disease occurs, its frequency is unknown. In contrast to the patients with asymptomatic venous thrombosis, symptomatic patients with venous thrombosis usually have large occulsive thrombi localized in their proximal veins.

The clinical diagnosis of pulmonary embolism is highly nonspecific because none of the symptoms or signs of pulmonary embolism is unique and all may be caused by other cardiorespiratory disorders. Thus, objective testing is mandatory to either confirm or exclude a diagnosis of pulmonary embolism. Based on current available information, a diagnostic approach for the management of clinically suspected pulmonary embolism is proposed. After a history and physical examination, electrocardiogram and chest X-ray film, all patients should undergo perfusion lung scanning. The finding of a normal perfusion lung scan rules out clinically significant pulmonary embolism, and anticoagulant therapy is withheld. The management of patients with an abnormal perfusion lung scan is more complex. If this scan demonstrates one or more segmental (or greater) perfusion defects, ventilation lung scanning should be performed because the probability of pulmonary embolism is markedly increased if a mismatch is found, with a high probability scan (positive predictive value 86 %) providing an end point for commencing anticoagulant therapy in the majority of patients. In an abnormal ventilationperfusion study, the presence of a ventilation-perfusion match does not rule out the possibility of pulmonary embolism, and further objective testing is required in these patients with nonhigh probability scans. Similarly, in patients with small perfusion defects (one or more subsegmental defects) or indeterminate lung scan findings (in which the perfusion scan defects correspond to a defect on a chest X-ray film), the predictive values obtained from these ventilation-perfusion scan patterns are not sufficiently high or low to confirm or exclude the presence of pulmonary embolism. Alternative approaches are available that would reduce the need for pulmonary angiography in patients with abnormal but nonhigh probability ventilationperfusion lung scans. In these patients, venography or impedance plethysmography could be performed as the next step of the diagnostic evaluation. If the presence of deep vein thrombosis is confirmed by these tests, anticoagulant therapy can be commenced without the need to perform pulmonary angiography. If the tests are negative, pulmonary angiography is required to confirm the presence or absence of pulmonary embolism because a negative venogram occurs in up to 30% of patients with pulmonary embolism by angiography and, therefore, may not be used to exclude venous thromboembolism. Other approaches (for example, serial impedance plethysmography) are being explored in selected patients.

The clinical diagnosis of venous thrombosis is highly non-specific. The reason for this is that none of the symptoms or signs of venous thrombosis is unique to this condition--that is, each can be caused by nonthrombotic disorders. Objective testing to confirm or exclude the diagnosis of venous thrombosis, then, is mandatory in patients with clinically suspected deep vein thrombosis.

The clinical diagnosis of venous thrombosis is inaccurate because the clinical findings are both insensitive and nonspecific. The sensitivity of clinical diagnosis is low because many potentially dangerous venous thrombi are clinically silent. The specificity of clinical diagnosis is low because the symptoms or signs of venous thrombosis all can be caused by nonthrombotic disorders. For these reasons, a practical approach for the diagnosis of venous thrombosis is important. A current approach to the diagnosis of clinically suspected venous thrombosis favors the use of impedance plethysmography over Doppler ultrasonography as the main test for this disorder. This is because impedance plethysmography is precise and objective, whereas the interpretation of Doppler ultrasonography is subjective and requires considerable skill and experience to form reliable diagnoses. The use of serial impedance plethysmography has been evaluated recently in a prospective study. The rationale of repeated impedance plethysmography evaluation is based on the premise that calf vein thrombi are only clinically important when they extend into the proximal veins, at which point detection with impedance plethysmography is possible. Therefore, by performing repeated examinations with impedance plethysmography in patients with clinically suspected venous thrombosis, it is possible to identify patients with extending calf vein thrombosis who can be treated appropriately. Impedance plethysmography is performed immediately on referral; if it is positive in the absence of clinical conditions that are known to produce falsely positive results, the diagnosis of venous thrombosis is established, and the patient is treated accordingly. If the result of the initial impedance plethysmography evaluation is negative, anticoagulant therapy is withheld, and impedance plethysmography is repeated the following day, again on day 5 to 7 and on day 10 to 14. If impedance plethysmography becomes positive during this time, a diagnosis of venous thrombosis is made and anticoagulant therapy is commenced. Positive impedance plethysmography in the presence of conditions known to produce a false positive result (for example, congestive cardiac failure) should be confirmed by venography. If noninvasive tests for the diagnosis of venous thrombosis are not available, a clinical suspicion of venous thrombosis should be objectively confirmed or excluded by performing ascending venography.

The optimal method of venous thrombosis prophylaxis in patients with stroke is uncertain. ORG 10172 is a low molecular weight heparinoid consisting principally of heparan and dermatan sulphates. In animal studies, ORG 10172 is as effective as unfractionated heparin in preventing venous thrombosis but produces less bleeding. There have been a limited number of descriptive studies on its use in humans, but to date randomized efficacy trials of ORG 10172 in the prevention of venous thrombosis have not been reported. A double blind randomized trial was carried out to compare ORG 10172 with placebo in the prevention of deep vein thrombosis in patients with thrombotic stroke. Seventy-five patients were randomized to receive ORG 10172 (50 patients) in a loading dose of 1,000 anti-Xa units intravenously followed by 750 anti-Xa units subcutaneously 12 hourly or placebo (25 patients). Prophylaxis was commenced within 7 days of stroke onset, continued for 14 days or until discharge from hospital, if earlier. Venous thrombosis surveillance was carried out with 125-1 fibrinogen leg scanning and impedance plethysmography. Venous thrombosis was confirmed by venography which occurred in 2 of 50 (4%) in the ORG 10172 group and 7 of 25 (28%) in the placebo group (p=0.005). The corresponding rates for proximal vein thrombosis were 0% and 16%, respectively (p=0.01). There was one major haemorrhage in the treated group and one minor haemorrhage in the placebo group. The anti-factor Xa levels (units/ml; mean ± SE) gradually rose from 0.18 ± 0.001 and 0.06 ± 0.01 six and 12 hours after injection on the first day to 0.24 ± 0.02 and 0.12 ± 0.01 after 11 days treatment. The results of this study indicate that ORG 10172 heparinoid is effective prophylaxis against deep vein thrombosis in patients with acute thrombotic stroke.

Initial therapy with intravenous heparin, followed by long-term anticoagulant therapy for three months or more, is the treatment of choice for most patients with acute venous thrombosis. Inferior vena caval interruption, using a transvenously inserted filter, is the management of choice for preventing pulmonary embolism in patients in whom anticoagulant therapy is contraindicated, and in the very rare patient in whom anticoagulant therapy is ineffective. The role of thrombolytic therapy has not been completely resolved. It was hoped that thrombolytic therapy would minimize or prevent the post-phlebitic syndrome; unfortunately, this may not be the case because the critical factor in the development of the post-phlebitic syndrome appears to be venous valve damage, which occurs early in the formation of venous thrombosis. Thrombolytic therapy should be considered in selected patients with acute massive venous thrombosis (eg. the patient with phlegmasia cerulea dolens).Intravenous heparin administered in doses which prolong the activated partial thromboplastin time (APTT) to 1.5 to 2 times control is highly effective and is associated with a low frequency (2%) of recurrent venous thromboembolism. A recent randomized trial (1) in patients with proximal-vein thrombosis indicates that failure to achieve an adequate anticoagulant response (APTT > 1.5 times control) is associated with a high risk (20%) of recurrent venous thromboembolism. Therefore, sufficient heparin should be administered to maintain the APTT above 1.5 times the control value.Intravenous heparin is continued for 7 to 10 days, overlapped with oral anticoagulant therapy for 4 to 5 days before heparin is stopped. Multiple randomized clinical trials in patients with proximal-vein thrombosis indicate that when heparin is administered for 7 to 10 days, followed by adequate long-term anticoagulant therapy, the frequency of recurrent venous thromboembolism is very low (2%). An alternative approach is to commence heparin and oral anticoagulants together at the time of diagnosis, and to discontinue heparin on the fourth or fifth day. If this latter approach is effective, it would avoid 4 to 5 days of unnecessary hospitalization in many patients, and would markedly reduce the cost of initial heparin therapy. A recent randomized trial (2) in patients with submassive venous thromboembolism suggests that 4 to 5 days of initial heparin therapy is effective and safe, but this approach must be evaluated by further randomized clinical trials before it is routinely recommended.Recent clinical trials indicate that inadequate long-term therapy in patients with proximal-vein thrombosis results in a high frequency (40-50%) of recurrent venous thromboembolism and is cost-ineffective because of the diagnostic and treatment costs of recurrent venous thromboembolism (3). The risk of recurrence is markedly reduced to 2% by adequate long-term anticoagulant therapy with warfarin sodium or adjusted subcutaneous heparin; both of these approaches are markedly more cost-effective than inadequate long-term therapy (3). Oral anticoagulant therapy with warfarin sodium for three months (or longer in selected patients), is less expensive than adjusted subcutaneous heparin and is preferred in most patients with acute proximal-vein thrombosis. The risk of bleeding associated with oral anticoagulant therapy can be reduced to less than 5%, without loss of effectiveness for preventing recurrent venous thromboembolism, by adjusting the dose of warfarin sodium to achieve a less intense anticoagulant effect (PT 1.25 to 1.5 times control using a rabbit brain thromboplastin such as Simplastin or Dade-C, corresponding to an INR of 2.0 to 3.0). Less intense warfarin sodium therapy is the most cost-effective of the alternative long-term anticoagulant regimens (3). Adjusted dose subcutaneous heparin is an effective and safe alternative to warfarin sodium; although slightly more expensive, it is the long-term regimen of choice in pregnant patients, and in patients returning to geographically remote areas lacking the facilities for anticoagulant monitoring (in whom the dose is adjusted during the first few days of long-term therapy and then fixed). REFERENCES: (1) Hull R, Raskob G, Hirsh J et al. N Engl J Med 1986;315:1109-1114. (2) Gallus A, Jackaman J, Tillett J et al.Lancet 1986;2:1293-1296. (3) Hull R, Raskob G, Hirsh J, Sackett DL. JAMA 1984;252:235-239.

Patients with venous thrombosis are usually treated with heparin and then with oral anticoagulants. The pattern of practice related to the continued use of oral anticoagulants after the patient with venous thromboembolism is discharged from hospital varies considerably from centre to centre. Some clinicians use no anticoagulants after the patient is discharged, while others treat the patient for up to a year.

After a promising introduction, many diagnostic tests prove with further experience to be very limited in their clinical application. There are two major reasons for inappropriate application of diagnostic tests. Firstly, the evidence for their clinical value is based on basic or experimental studies, the findings of which have been incorrectly equated with hard evidence for their clinical efficacy. Secondly, studies evaluating diagnostic efficacy have frequently failed to include essential design features which are required to adequately assess the sensitivity, specificity and predictive values of the test under evaluation. The diagnostic dilemma of ventilationperfusion lung scanning is a classic example of the failure to adequately assess a diagnostic test. The diagnostic efficacy of ventilation-perfusion lung scanning is currently uncertain and highly controversial because none of the published studies have adequately evaluated this non-invasive approach. To resolve this uncertainty, we have incorporated the six essential criteria for evaluating diagnostic efficacy in a prospective study of ventilation-perfusion lung scanning and pulmonary angiography. These essential criteria are: comparison with pulmonary angiography, the reference test in consecutive patients; entering a broad spectrum of patients with suspected pulmonary embolism; including a large number of patients with varying clinical severity of illness and disease; and patients with a wide variety of co-morbid conditions; avoiding diagnostic suspicion bias by evaluating consecutive patients and by interpreting the test results independently without knowledge of each other or the patient’s condition; and finally testing the clinical validity of negative results by long-term follow-up. The effect of these criteria on the outcome of this trial will be presented.

Impedance plethysmography (IPG) combined with leg scanning is highly sensitive and specific for deep vein thrombosis (DVT) in patients with their first episode of clinically suspected DVT. This approach has not been evaluated in patients with suspected recurrent DVT. In this group of patients venography alone is of limited value in excluding acute DVT in the presence of previous DVT but is useful if constant intraluminal filling defects (ILFD) suggesting acute DVT are present. We have evaluated the clinical utility of IPG plus leg scanning and venography in 132 patients with clinically suspected acute recurrent DVT. If the IPG on referral was negative the patient was leg scanned daily for 72 hours and if both were negative, anticoagulant therapy was witheld. The validity and safety of this approach was tested by 3 months follow-up. If IPG was positive, venography was performed to distinguish ILFD’s from chronic DVT. If ILFD’s were detected, anticoagulant therapy was commenced. If no ILFD’s were detected the patient was leg scanned for 72 hours and if negative treatment was witheld. The clinical utility of this non-invasive approach is demonstrated by the results of this study. Of 132 patients, 82 (62%) were negative by both non-invasive tests and none died, developed pulmonary embolism or recurrent DVT during follow-up. The remaining 50 patients were positive by noninvasive testing; in 31 patients ILFD’s were detected and in 16 venography was indeterminate showing collaterals, absent segments, recanalization or inadequate visualization. The leg scan was positive in 10 of the latter 16 patients. Thus the diagnosis of recurrent acute DVT was established by the presence of ILFD’s or a positive leg scan. In 6 patients with a positive IPG, negative leg scan and indeterminate venogram the diagnosis remained uncertain. In conclusion this combined non-invasive and invasive approach provided definitive management in 126 of 132 patients (95%).

The clinical value of adding impedance plethysmography (IPG) to 125 I-fibrinogen leg scanning was evaluated and compared in 630 patients who had general surgical procedures and 385 patients who had hip surgery. Patients were screened by both tests and venography was performed if either test was positive to determine a) the frequency with which proximal VT, confirmed by venography, was detected by IPG but not by leg scanning, and b) the positive predictive value of these tests used either alone or in combination. Either the IPG or leg scan result was abnormal in 67 of 630 general surgical patients (11%) and in 158 of 385 hip surgery patients (41%). The positive predictive values of the tests in general surgical and hip surgery patients was 79% and 86% respectively for the leg scan alone, 33% and 90% for IPG alone and 87% and 95% when both the leg scan and IPG were positive. The addition of IPG to leg scanning in general surgical patients identified only 1 addition patient with proximal vein thrombosis (0.2%) whereas in hip surgery patients the addition of IPG identified 25 additional patients with proximal vein thrombosis (6%). It is concluded that the addition of IPG to leg scanning is not useful among general surgical patients but is of substantial clinical value in hip surgery patients.

Intermittent sequential pneumatic compression of the calf was evaluated for the prevention of venous thrombosis in a prospective randomized study of 199 patients with intracranial disease. Sequential calf compression was applied for a maximum of 14 days and reduced the frequency of venous thrombosis from 20. 8% in 96 control patients to 7. 8% in 103 patients given prophylaxis, p=0. 01. Sequential calf compression also reduced the frequency of proximal vein thrombosis from 8. 3% in control patients to 2. 9% in patients given prophylaxis, p=0.09. Calf compression was well tolerated by patients and is recommended as a practical form of prophylaxis in these patients.

Venography is the standard method for the diagnosis of venous thrombosis but is invasive and may cause discomfort. We evaluated the combination of impedance plethysmography and 125I-fibrinogen leg scanning as an alternative to venography in 200 symptomatic patients. One or both of these less invasive tests was positive in 81 of 86 patients with positive venograms (sensitivity of 94 per cent) and both were negative in 104 of 114 patients with negative venograms (specificity of 91 per cent). These two tests detected all 60 patients with popliteal or more proximal venous thrombosis and 21 of 26 patients with calf-vein thrombosis. In addition, this approach detected 21 of 22 patients with calf-vein thrombosis with symptoms for eight days or less. These results suggest that the combination of these two less invasive tests can be used as an alternative to venography in selected patients with clinically suspected venous thrombosis. (N Engl J Med 296:1497–1500, 1977)

Until the past decade, physicians were content to base therapeutic decisions on the clinical diagnosis of deep-vein thrombosis. Subsequently, numerous studies demonstrated that clinical diagnosis of this condition is nonspecific. Although many now use objective methods to diagnose venous thrombosis, their relative cost and effectiveness have not been adequately studied. We performed a cost-effectiveness analysis of 516 patients with clinically suspected venous thrombosis who were evaluated by clinical diagnosis, venography, and the less invasive combination of impedance plethysmography and leg scanning. We used this analysis to rank these alternative approaches in terms of both cost and effectiveness. The results indicate that clinical diagnosis is cost ineffective. Venography is cost effective--more so when applied as an outpatient investigation. Impedance plethysmography plus leg scanning is a practical, less invasive alternative to outpatient venography. The cost of inpatient diagnosis is likely to remain the major cost; thus, emphasis should be placed on outpatient diagnostic procedures.

We performed a randomized double-blind trial comparing continuous intravenous heparin with intermittent subcutaneous heparin in the initial treatment of 115 patients with acute proximal deep-vein thrombosis. Intermittent subcutaneous heparin as administered in this trial was inferior to continuous intravenous heparin in preventing recurrent venous thromboembolism. The subcutaneous heparin regimen induced an initial anticoagulant response below the target therapeutic range in the majority of patients and resulted in a high frequency of recurrent venous thromboembolism (11 of 57 patients, 19.3 percent), which was virtually confined to patients with a subtherapeutic anticoagulant response. In contrast, continuous intravenous heparin induced a therapeutic anticoagulant response in the majority of patients and a low frequency of recurrent events (3 of 58 patients, 5.2 percent; P = 0.024); the recurrences were limited to patients with an initial subtherapeutic anticoagulant response. The results of this trial establish the efficacy of intravenous heparin in the treatment of proximal venous thrombosis and suggest a relation between the effectiveness of heparin and the levels of anticoagulation achieved; such a relation could explain the observed failure of the subcutaneous regimen.

Intermittent calf compression (ICC) prevents postoperative venous thrombosis (VT) but has not been previously tested in patients who remain immobilized for prolonged periods. We have evaluated a pulsatile elastic stocking in a randomized trial of 61 patients who underwent elective knee surgery. The stockings were worn for up to 17 days or until patient discharge and did not produce patient discomfort. The patients were well matched for age, sex, type of operation and aspirin use. Bilateral venography was performed on all patients 14–17 days postoperatively or earlier if the 1251-fibrinogen scan became positive. Nineteen of the 29 patients (65.5%) in the control group and 2 of 32 patients (6.3%) in the stocking group developed deep VT (p

Background Deep-vein thrombosis is a potentially life-threatening complication of total hip or knee replacement. There are few data on the effectiveness and safety of warfarin as compared with low-molecular-weight heparin as prophylaxis against this problem. Methods We therefore performed a randomized, double-blind trial in 1436 patients to evaluate the effectiveness and safety of low-molecular-weight heparin (given subcutaneously once daily) as compared with adjusted-dose warfarin to prevent venous thrombosis after hip or knee replacement. Treatment with the drugs was started postoperatively. The primary end point was deep-vein thrombosis as detected by contrast venography (performed a mean of 9.4 days after surgery in each group). Results Among the 1207 patients with interpretable venograms, 231 of 617 patients (37.4 percent) in the warfarin group and 185 of 590 patients (31.4 percent) in the low-molecular-weight-heparin group had deep-vein thrombosis (P = 0.03). The reduction in risk with low-molecular...

Previously, we compared fixed low doses of heparin with adjusted doses of warfarin for the long-term treatment of venous thrombosis; in that study low-dose heparin was ineffective in preventing recurrence in patients with proximal-vein thrombosis. We have now completed a randomized trial comparing adjusted doses of heparin and of warfarin for prevention of recurrent venous thromboembolism in patients with proximal-vein thrombosis. One hundred six consecutive patients with acute proximal-vein thrombosis confirmed by venography were treated with intravenous heparin and then randomized to secondary prophylaxis. Two of 53 patients receiving heparin, as compared with one of 53 receiving warfarin, had new episodes of objectively documented venous thromboembolism. Nine patients taking warfarin had bleeding complications (which were major in three patients), as compared with one patient taking heparin (P = 0.008). Our data indicate that adjusted-dose subcutaneous heparin therapy provides an effective alternative to warfarin sodium and is associated with a lower risk of bleeding.

Hamilton, Ont. Children with suspected venous thromboembolic disease are not uncommonly seen in pediatric referral centres. The only objective test widely accepted In pediatrics for the assessment of deep vein thrombosis (DVT) is venography. Impedance plethysmography (IPG) has been proven safe in adults. We have performed a feasibility study of clinical use of IPC in children with suspected DVT. We studied 14 consecutive patients who presented with pain, swelling or erythema of a lower extremity. Their ages ranged from 7-18 yrs. with a median of 16 yrs and a mean of 15.5 yrs. We performed IPG on both legs using the technique described In adults. Only patients with positive(+) IPG underwent venography. All three patients with +IPG had venogram-confirmed DVT. Deficiencies of proteins CS(2)the use of adult-sized cuffs in small chlldren. It should be possible to overcome the latter by modifying cuff size. We feel a larger experience with the use of IPG in children with symptoms or signs of DVT is required. We conclude that IPG which has been validated in adults, has utility in the diagnosis of venous thromboembolic disease in children.

Inherent contradictions in current diagnostic recommendations for pulmonary embolism have created considerable confusion and controversy. To resolve these contradictions, we did a prospective study of ventilation-perfusion scanning, pulmonary angiography, and venography in consecutive patients with clinically suspected pulmonary embolism and abnormal perfusion scans. Ventilation scanning increased the probability of pulmonary embolism in patients with large perfusion defects and ventilation mismatch, but a ventilation-perfusion match was not helpful in ruling out pulmonary embolism. Small perfusion defects with mismatch had neither sufficiently high nor low probability to be of diagnostic value. The observed frequency of proximal vein thrombosis (19% to 51%) and its association with the range of ventilation-perfusion defects have important implications for management of pulmonary embolism. Pulmonary angiography is required in combination with venography in most patients with perfusion abnormalities because the probability of pulmonary embolism is neither sufficiently high nor low to confirm or exclude pulmonary embolism.

• Pleuritic chest pain is a frequent complaint in patients coming to the emergency room, but the proportion of such patients with pulmonary embolism is uncertain. In a prospective study, we evaluated the diagnostic outcomes in 173 consecutive patients who came to the emergency room with pleuritic chest pain. Pulmonary embolism, as demonstrated by angiography or autopsy, was present in 36 (21%). The need for objective testing is clearly indicated by our finding that the sensitivity (85%) and specificity (37%) of predetermined clinical variables for pulmonary embolism were insufficient to allow a definitive treatment decision. Optimal sensitivity and specificity are obtained by using pulmonary angiography in combination with lung scanning. The proportion of patients requiring angiography is substantially reduced, from 43% to 26%, without significant loss of accuracy, if ventilation imaging and impedance plethysmography are used together with perfusion scanning. ( Arch Intern Med 1988;148:838-844)

Considerable progress has been made over the last 15 years in our understanding of the natural history, diagnosis, and treatment of deep vein thrombosis.1The nonspecificity of clinical diagnosis has been confirmed by several studies,2-5and the reliability of objective tests such as fibrinogen I 125 leg scanning,6venography,7and impedance plethysmography (IPG) has been established for patients who present with their first episode of clinically suspected venous thrombosis.8,9In contrast, relatively few studies have been performed to clarify the diagnostic process in patients with a history of venous thrombosis who have recurrent symptoms of leg pain and swelling.10,11 Until recently, most of these symptomatic patients were considered to have acute recurrent deep vein thrombosis (which is potentially life-threatening) on the basis of their clinical presentation alone. They then received long-term anticoagulant therapy or, in some cases, caval interruption procedures. Some patients experienced the inconvenience of multiple hospital admissions or

Recent data from randomized trials have provided a clear understanding of the effectiveness and safety of differing long-term anticoagulant therapies for proximal vein thrombosis. An issue that has not been addressed is their cost-effectiveness. We have performed a cost-effectiveness analysis to rank alternative approaches for long-term therapy. Less intense oral anticoagulant therapy using warfarin sodium is the most cost-effective approach and is preferred in the majority of patients. ( JAMA 1984;252:235-239)

We have reported previously that low-dose subcutaneous (sc) heparin is less effective than adjusted dose warfarin sodium in the long-term treatment of venous thrombosis as 9 of 35 patients (26%) receiving low dose sc heparin developed acute recurrent venous thromboembolism compared with none of 33 patients receiving warfarin (p=0.001).Seven patients on warfarin suffered bleeding compared with none on low-dose sc heparin (p < 0.005). Using an identical study design, 101 patients with venographically confirmed acute deep vein thrombosis have entered a second trial reported here, comparing higher doses of sc heparin 12 hourly, titrated at the onset (by adjusting the mid interval PTT to 1½ to 2 times control), compared with adjusted dose warfarin (PT 1½ to 2 times control). All patients were treated with full doses of heparin for 14 days and then randomized to either treatment group for a 12 week course. The patients were followed in a special clinic and routinely screened with leg scanning and impedance plethysmography at 3 week intervals and on an emergency basis if they developed recurrent symptoms.During long-term treatment no patient on warfarin or titrated sc heparin developed recurrent venous thromboembolism. On follow-up, after discontinuation of long-term therapy, 4 patients randomized to warfarin and 4 patients randomized to titrated sc heparin developed recurrent deep vein thrombosis confirmed by objective testing. One of 51 patients on titrated sc heparin suffered bleeding compared with 9 of 50 patients on warfarin (p < 0.02).These results suggest that titrated sc heparin is as effective as warfarin for preventing recurrent venous thromboembolism and its use is associated with less bleeding than warfarin.

Because death due to pulmonary embolism is relatively rare following general surgery, many question the need for prophylaxis. In addition, there has been reluctance to apply new interventions whose cost-effectiveness has not been adequately evaluated. A cost-effectiveness analysis based on over 1000 high-risk patients undergoing abdominothoracic surgery, with effectiveness measured in terms of numbers of deaths from pulmonary embolism averted, has shown subcutaneous administration of heparin in low doses starting 2 hours before the operation to be the most cost-effective of several active approaches to prophylaxis. It averted seven of the eight deaths expected without active prophylaxis per 1000 such patients and cost half as much as the traditional approach of intervening only when venous thromboembolism becomes clinically apparent. Intravenous administration of dextran, although effective, was expensive, and leg scanning with iodine-125-labelled fibrinogen was extremely expensive. Intermittent pneumatic compression of the legs was inexpensive, but, as with leg scanning, its effectiveness has not been determined in randomized trials.