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Urine Test Predicts Vein Clot Risk

TUESDAY, May -- A higher-than-normal level of the protein albumin in urine indicates an increased risk of dangerous blood clots in the deep veins of the lungs and legs, a Dutch study finds.

These venous thromboembolisms (VTEs) include deep vein thrombosis (DVT), a clotting in the lower extremities which gained recent notoriety when it occurred in passengers on long-haul flights. These clots can become dangerous if they travel to the lungs to produce a pulmonary embolism.

But the presence of albumin in urine might warn of VTE risk, the new study found.

"Microalbuminuria is a known risk factor for arterial conditions such as myocardial infarction [heart attack] and stroke," noted Bakhtawar K. Mahmoodi, a medical student at the University of Groningen who is lead author of a report in the May 6 issue of the Journal of the American Medical Association. "Now it is also found to be a risk factor for venous thromboembolism. This is the first time it has shown to be a risk factor for VTE."

Tests to detect albumin and other proteins in the urine now are commonly done to help assess the risk of problems caused by damage to the arteries, which carry blood from the heart. Those tests now generally are done in people in people known to be at risk because of conditions including diabetes and high blood pressure. Those conditions can reduce the function of kidneys, which remove proteins from the blood.

This latest study indicates that such a urine test could also help assess the risk of problems in the veins, which carry blood back to the heart, said Dr. Ron T. Gansevoort, an associate professor of nephrology at Groningen, who oversaw the research.

The report was based on an ongoing study designed to include all adult residents of Groningen. It included data on almost 8,600 adults, 129 of whom had venous clots during the study period of more than eight years -- an average incidence of 0.14 percent per year.

The incidence of such clots was 40 percent higher for people with slightly elevated urine levels of albumin and more than twice as high for people with more elevated levels than for those with normal levels, after adjustment for known risk factors such as diabetes, the researchers found.

The report is one of several that have demonstrated a possible value of urine tests to help determine the risk of cardiovascular disease. A German research group reported recently that a urine test looking for fragments of a different protein, collagen, might help detect an increased risk of heart disease.

And in 2007, physicians at Brigham and Women's Hospital in Boston found that high levels of albumin in urine of people with stable cardiovascular disease indicated an increased risk of death.

Studies have shown that high urine levels of albumin have a greater association with arterial condition than with venous problems, Gansevoort said. "There are two sides to the coin," he said. "One is how often you find the problems. The incidence of arterial problems is twice as high than for venous problems."

"Then, how serious is an arterial problem against a venous problem? If you have a myocardial infarction or a stroke, it is more serious than a venous thrombosis on a leg. But pulmonary [lung] emboli are very important problems," he said.

The new study does not indicate a need for using urine tests as a mass screening method, Gansevoort said. "But if someone comes into my clinic who I suspect might have venous thrombosis or embolism, possibly with a family history, I might add a test for microalbuminuria. If there is shortness of breath showing that there might be a pulmonary embolism, I can use a test for microalbuminuria in diagnosis."

WHO says Blood Clot risk doubles after 4-hour travel:

June 29, 2007 01:42:25 AM PST

The chances of developing deep vein thrombosis double after traveling for four hours or more, the World Health Organization (WHO) said on Friday in a study estimating one in 6,000 long-haul passengers is at risk.

Tall people whose legs are jammed in economy class and the very short whose feet do not touch the ground are particularly vulnerable to potentially dangerous blood clots linked to immobility during travel, the United Nations agency said.

The obese, women on birth control pills and those with blood clotting disorders are also more susceptible, as are frequent travelers and those who take very long journeys.

"There is an increased risk of venous thromboembolism during travel where the passenger is seated and immobile over four hours, whether in a plane, train, bus or car," said Catherine Le Gales-Camus, WHO assistant director-general for non-communicable disease and mental health.

"What causes the risk is immobility," she told a news conference. "The risk is not only true for people flying."

Without regular muscle contractions, blood starts to pool in the legs and can create conditions for a clot, or thrombus, to develop in deep veins. Thrombosis can be symptom-free or trigger cramps, soreness and swelling in affected areas.

It is most dangerous in cases where blood clots travel through the body to the lung, blocking blood flow. Such pulmonary embolism, characterized by chest pain and breathing difficulties, can be fatal if untreated.

About 2 billion people travel by air each year and many more take overland trips where they sit still for prolonged periods.

Health experts said the overall prevalence of deep vein thrombosis is relatively low, noting that the 1 in 6,000 ratio includes those with small or asymptomatic clots.

Still, it means an average of one person is affected for every 20 long-haul flights carrying 300 passengers.

To reduce the chance of developing blood clots, WHO special advisor Shanthi Mendis said travelers should exercise their calf muscles with up-and-down movements of the feet and ankle joints, and leave their seats for a few minutes when possible.

Mendis cautioned air passengers against taking sleeping pills or drinking too much alcohol. People should also avoid wearing tight clothing that can constrain circulation, she said.

Newer birth control pills raise clot risk, group warns

Last Updated: Tuesday, February 6, 2007 | 12:17 PM ET

Some newer, low-dose birth control pills double the risk of potentially dangerous blood clots compared with older contraceptives and should be banned, a U.S. consumer group says.

Public Citizen filed a petition with the U.S. Food and Drug Administration on Tuesday to stop the sale of birth control pills containing a type of progestin called desogestrel.

"By banning third-generation oral contraceptives, the FDA will potentially save hundreds of young women a year from developing venous thrombosis and its disabling and sometimes fatal consequences," the petition read.

The newer contraceptives may lead to about 30 blood clots per 100,000 users, compared with 15 clots per 100,000 people taking "second generation" pills that contain estrogen and progestin.

In the U.S., the newer pills include a warning about the increased risk.

Several pharmaceutical companies sell third-generation oral contraceptives, including Johnson & Johnson's Ortho-Cept. Health Canada has approved sales of Ortho-Cept.

Public Citizen said there is no evidence that desogestrel pills offer improved clinical benefits.

"FDA will carefully review the petition," said agency spokeswoman Susan Cruzan

Volume 345:165-169 July 19, 2001 Number 3

Three Months versus One Year of Oral Anticoagulant Therapy for Idiopathic Deep Venous Thrombosis

Giancarlo Agnelli, M.D., Paolo Prandoni, M.D., Ph.D., Maria Gabriella Santamaria, M.D., Paola Bagatella, M.D., Alfonso Iorio, M.D., Mario Bazzan, M.D., Marco Moia, M.D., Giuliana Guazzaloca, M.D., Adriano Bertoldi, M.D., Cristina Tomasi, M.D., Gianluigi Scannapieco, M.D., Alessandra Ascani, M.D., Sabina Villalta, M.D., Michela Frulla, M.D., Laura Mosena, M.D., Antonio Girolami, M.D., Antonella Vaccarino, M.D., Adriano Alatri, M.D., Gualtiero Palareti, M.D., Mario Marchesi, M.D., Giovanni Battista Ambrosio, M.D., Roberto Parisi, M.D., Silvia Doria, M.D., Luigi Steidl, M.D., Fabio Ambrosini, M.D., Mauro Silingardi, M.D., Angelo Ghirarduzzi, M.D., Ido Iori, M.D., Walter Ageno, M.D., and the Warfarin Optimal Duration Italian Trial Investigators

ABSTRACT

Background In patients with idiopathic deep venous thrombosis, continuing anticoagulant therapy beyond three months is associated with a reduced incidence of recurrent thrombosis during the period of therapy. Whether this benefit persists after anticoagulant therapy is discontinued is controversial.

Methods Patients with a first episode of idiopathic proximal deep venous thrombosis who had completed three months of oral anticoagulant therapy were randomly assigned to the discontinuation of oral anticoagulants or to their continuation for nine additional months. The primary study outcome was recurrence of symptomatic, objectively confirmed venous thromboembolism during at least two years of follow-up.

Results The primary intention-to-treat analysis showed that of 134 patients assigned to continued oral anticoagulant therapy, 21 had a recurrence of venous thromboembolism (15.7 percent; average follow-up, 37.8 months), as compared with 21 of 133 patients assigned to the discontinuation of oral anticoagulant therapy (15.8 percent; average follow-up, 37.2 months), resulting in a relative risk of 0.99 (95 percent confidence interval, 0.57 to 1.73). During the initial nine months after randomization (after all patients received three months of therapy), 1 patient had a recurrence while receiving oral anticoagulant therapy (0.7 percent), as compared with 11 of the patients assigned to the discontinuation of oral anticoagulant therapy (8.3 percent, P=0.003). The incidence of recurrence after the discontinuation of treatment was 5.1 percent per patient-year in patients in whom oral anticoagulant therapy was discontinued after 3 months and 5.0 percent per patient-year in patients who received an additional 9 months of oral anticoagulant therapy. None of the recurrences were fatal. Four patients had nonfatal major bleeding during the extended period of anticoagulant therapy (3.0 percent).

Conclusions In patients with idiopathic deep venous thrombosis, the clinical benefit associated with extending the duration of anticoagulant therapy to one year is not maintained after the therapy is discontinued.

The optimal duration of treatment with oral anticoagulant agents after deep venous thrombosis reflects a balance between the risk of recurrence when treatment is discontinued and the risk of bleeding resulting from continued anticoagulant therapy.1,2,3 The risk of recurrent thromboembolism after the discontinuation of anticoagulant therapy is highly dependent on patient-specific risk factors.4,5,6,7 Patients who have thrombosis in the absence of known risk factors (i.e., who have idiopathic venous thrombosis) or in association with persistent risk factors (such as cancer and thrombophilia) are at higher risk of recurrence than patients with thrombosis associated with time-limited, reversible risk factors.4,5,6,7 In this last group of patients, oral anticoagulant therapy can be limited to three months after the elimination of the risk factor. More prolonged courses of anticoagulant therapy are recommended for patients in whom thrombosis is associated with persistent risk factors2; in addition, on the basis of the results of two recent, adequately designed studies, longer therapy should be considered for patients with idiopathic thrombosis.5,8

In the more recent of the two studies, Kearon et al. randomly assigned patients with idiopathic venous thromboembolism who had received three months of oral anticoagulant therapy to the discontinuation of anticoagulant therapy or its continuation for two additional years.8 The study was terminated early because of the impressive reduction in the risk of recurrence of thromboembolic events during therapy in the group of patients assigned to continued anticoagulant therapy. Whether the advantage observed in patients in whom therapy is continued for an extended period is maintained after that therapy has been stopped remains unclear.

We conducted a multicenter, randomized trial to evaluate the long-term clinical benefit of extending to one year the three-month course of oral anticoagulant therapy after a first episode of idiopathic proximal deep venous thrombosis. The primary outcome of the study was the symptomatic, objectively confirmed recurrence of venous thromboembolism during at least two years of follow-up.

Methods

Patients

Consecutive patients ranging from 15 to 85 years old with a first episode of symptomatic idiopathic proximal deep venous thrombosis, as demonstrated on compression ultrasonography or venography, were eligible for the study, provided that they had completed three uninterrupted months of oral anticoagulant therapy without having a recurrence of thromboembolism or bleeding. Idiopathic deep venous thrombosis was defined as thrombosis occurring in the absence of known cancer, known thrombophilia, prolonged immobilization (i.e., lasting more than seven days) from any cause, recent trauma or surgery (i.e., within the previous three months), pregnancy, recent childbirth, or the use of oral contraceptives. Systematic screening for occult cancer or thrombophilia was not performed before patients were enrolled in the study. Patients who required prolonged anticoagulant therapy for reasons other than venous thromboembolism were excluded from the study, as were patients with major psychiatric disorders, patients with a life expectancy shorter than two years, those who could not return for the follow-up visits, and those who declined to participate. The study protocol was approved by the institutional review boards of the participating hospitals; all patients gave written informed consent.

Study Design and Interventions

The Warfarin Optimal Duration Italian Trial was a randomized, multicenter, open trial with independent, blinded assessment of the outcome events. The study was designed to evaluate the clinical benefit of extending to one year the three-month course of oral anticoagulant therapy after a first episode of idiopathic proximal deep venous thrombosis. After three months of therapy with warfarin (in 97 percent of the cases) or acenocoumarol, patients were randomly assigned to discontinue oral anticoagulant therapy or to continue it for nine additional months.

The dose of warfarin or other oral anticoagulant was adjusted to achieve a target international normalized ratio (INR) between 2.0 and 3.0. The therapy was monitored in anticoagulant clinics associated with the 10 study centers, all in Italy.

Outcome Measures

The primary outcome of the study was the recurrence of symptomatic, objectively confirmed deep venous thromboembolism during a follow-up period of at least two years. The criteria for the diagnosis of recurrent deep venous thrombosis were positive results on compression ultrasonography or venography in the contralateral leg; an intraluminal filling defect in the ipsilateral leg that was visible on a venogram; or the finding on ultrasonography of a newly noncompressible venous segment in the ipsilateral leg. The criteria for the diagnosis of pulmonary embolism were a diagnostic pulmonary angiogram, a ventilation–perfusion lung scan indicating a high probability of pulmonary embolism, or an indeterminate lung scan with a high degree of clinical suspicion of pulmonary embolism in a patient with an objectively diagnosed asymptomatic recurrence of deep venous thrombosis.

Bleeding was defined as major if it was clinically overt and associated with either a decrease in the hemoglobin level of at least 2 g per deciliter or the need for the transfusion of 2 or more units of red cells; if it was retroperitoneal or intracranial; or if it warranted the permanent discontinuation of the study drug. Deaths were classified as the result of pulmonary embolism, bleeding, or another identifiable cause or as unexplained.

All suspected outcome events (recurrent thromboembolism and bleeding episodes) and all deaths were reviewed centrally, for both the interim and final analyses, by an independent, external adjudication committee whose members were unaware of the treatment-group assignments.

Follow-up

Patients were instructed to return for follow-up visits at 3, 6, and 12 months after randomization and every 6 months thereafter until the completion of the study. Patients were asked to return to the study center immediately if symptoms developed that were suggestive of recurrent venous thromboembolism or bleeding. For all patients who died during the follow-up period, the date and cause of death were documented. We attempted to gain permission for autopsies of all patients in whom a pulmonary embolism could not be excluded as the cause of death.

Statistical Analysis

The primary analysis of efficacy was a comparison of the rates of symptomatic, objectively confirmed recurrence of venous thromboembolism in the two treatment groups during a follow-up period of at least two years after randomization. The primary analysis was performed on an intention-to-treat basis. However, since some patients discontinued oral anticoagulant therapy before its scheduled completion, continued to use the anticoagulant after its scheduled completion, or resumed its use after the scheduled interruption, a per-protocol analysis including only the patients who completed treatment according to the study protocol was also performed.

On the basis of the results of previous studies, it was assumed that the rate of recurrence of venous thromboembolism would be 15 percent over two years of postrandomization follow-up in patients assigned to the discontinuation of oral anticoagulant therapy.5,6 We also assumed that the prolongation of oral anticoagulant therapy by nine months would produce a 50 percent reduction in the risk of recurrence. Given these assumptions, we needed 246 patients in each group to detect a difference of this magnitude between groups with a power of 80 percent and a type I error rate of 5 percent. In order to avoid the exposure of the study patients to an ineffective or dangerous therapeutic regimen, one prespecified interim analysis of efficacy and safety was planned after the randomization of the first 246 patients. The following criteria for stopping the trial were defined a priori: an overall rate of recurrence of thromboembolic events lower than 7.5 percent; an unequivocal reduction in the rate of recurrent venous thromboembolism in the patients assigned to continued therapy (P<0.001 by a one-sided test); a risk of recurrence in the continued-therapy group that was less than 25 percent lower than that in the group assigned to discontinue therapy, in the presence of the expected rate of events (15±2.5 percent) in the latter group; or a rate of major bleeding higher than 5 percent in the continued-therapy group.

The cumulative hazard of recurrent venous thromboembolism was calculated according to the Kaplan–Meier life-table method.9 Rates of recurrence in the two groups were compared with the use of the log-rank test.10

Results

Patients

The recruitment of patients began in January 1995 and was stopped in June 1998 after the inclusion of 267 patients, when the results of the interim analysis were available and showed a difference of less than 25 percent in the risk of recurrence. At that time, thromboembolic events had recurred in 16 of the 123 patients assigned to the discontinuation of oral anticoagulant therapy (13.0 percent) and in 15 of the 123 patients assigned to the continuation of oral anticoagulant therapy (12.2 percent), corresponding to a difference in risk of 6.2 percent. Follow-up was continued until the last enrolled patient completed two years of follow-up.

At the time of randomization, 290 consecutive patients met the criteria for inclusion, among whom 23 also met one of the criteria for exclusion. The reasons for the exclusion of patients were contraindications to long-term anticoagulant therapy (in eight patients), other indications for long-term anticoagulant therapy (in six patients), declining to give consent (in six patients), and inability to return for follow-up visits (in three patients). Therefore, 267 patients were enrolled in the study, 133 in the group assigned to discontinue oral anticoagulant therapy and 134 in the group assigned to continue therapy.

The base-line characteristics of the patients in the two treatment groups were similar. The average age was 67.7±7.3 years among the patients assigned to discontinue therapy and 66.8±6.7 years among those assigned to continue therapy; men accounted for 61.2 percent of the patients assigned to discontinue therapy and 54.5 percent of those assigned to continue therapy. Approximately 20 percent of patients in both groups received low-molecular-weight heparin as an initial treatment; the remaining patients received intravenous unfractionated heparin. Four patients declined to continue oral anticoagulant therapy after randomization. Oral anticoagulant therapy was prematurely and permanently discontinued in nine patients assigned to the continuation of therapy. Oral anticoagulant therapy was prolonged beyond its scheduled cessation in two patients assigned to discontinue therapy and was resumed after the scheduled cessation in five patients assigned to discontinue therapy. On the basis of the linear interpolation of INR results between tests, we estimate that the INR was between 2.0 and 3.0 for an average of 81 percent of the time during the nine months of extended anticoagulant therapy. During the follow-up period, cancer was newly diagnosed in five patients — three assigned to continue therapy and two to discontinue therapy (1.9 percent of the total cohort; lung cancer in two patients and bladder cancer, breast cancer, and prostate cancer in one patient each).

Recurrent Venous Thromboembolism

The primary intention-to-treat analysis showed that of the 134 patients assigned to continue therapy, 21 had recurrent venous thromboembolism (15.7 percent; average follow-up, 37.8 months), as did 21 of the 133 patients assigned to discontinue therapy (15.8 percent; average follow-up, 37.2 months), resulting in a relative risk of 0.99 (95 percent confidence interval, 0.57 to 1.73). The features of the recurrences are shown in Table 1. All episodes of recurrent venous thromboembolism were idiopathic, and none were fatal. The average time to recurrence was 11.2 months from randomization in the patients assigned to discontinue therapy and 16.0 months from randomization in those assigned to continue therapy. The cumulative hazard of recurrent venous thromboembolism in the two groups according to the intention-to-treat analysis is shown in Figure 1 (log-rank statistic=0.02, P=0.88). Of the 115 patients assigned to continue therapy who were included in the per-protocol analysis, 18 had a recurrence of venous thromboembolism (15.7 percent), as compared with 21 of the 126 patients assigned to discontinue therapy who were included in this analysis (16.7 percent), resulting in a relative risk of 0.94 (95 percent confidence interval, 0.54 to 1.67).

An intention-to-treat analysis showed that the risk of recurrence during the first nine months of follow-up was lower among the patients assigned to continue therapy (4 patients; 3.0 percent; 4.6 percent per patient-year) than in those assigned to discontinue therapy (11 patients; 8.3 percent; 12.3 percent per patient-year; relative risk, as compared with patients assigned to discontinue therapy, 0.36; 95 percent confidence interval, 0.12 to 1.11). Three patients assigned to continue therapy who had recurrent thromboembolism during the initial nine-month study period had prematurely interrupted oral anticoagulant therapy (two voluntarily and one because of major bleeding). Thus, only one patient had a recurrence while receiving active oral anticoagulant therapy (0.7 percent; 1.2 percent per patient-year; relative risk as compared with patients assigned to discontinue therapy, 0.09; 95 percent confidence interval, 0.02 to 0.69; P=0.003).

The incidence of recurrence after the discontinuation of therapy was 5.1 percent per patient-year among the patients assigned to discontinue therapy (95 percent confidence interval, 3.2 to 7.5 percent; 21 events; average interval since discontinuation, 37.2 months) and 5.0 percent per patient-year in those assigned to continue therapy (95 percent confidence interval, 3.1 to 7.8 percent; 17 events; average interval since discontinuation, 29.4 months).

Bleeding Complications

Four patients (3.0 percent) assigned to continue therapy had nonfatal episodes of major bleeding while receiving oral anticoagulant therapy (melena in three patients and menorrhagia in one patient). None of these patients had an INR above the therapeutic range at the time of the episode. Two fatal episodes of bleeding occurred in patients assigned to discontinue therapy (1.5 percent) — one intracranial, 1 month after the discontinuation of oral anticoagulant therapy, and the other gastrointestinal, 12 months after discontinuation.

Deaths

Fourteen patients (5.2 percent) died during the study period. Seven patients assigned to discontinue therapy died — three from myocardial infarction, two from heart failure, one from intracranial bleeding, and one from gastrointestinal bleeding. Seven patients assigned to continue therapy died — three from myocardial infarction, three from cancer, and one from respiratory failure.

Cumulative Adverse Outcomes

A total of 28 patients assigned to discontinue therapy (21.1 percent) had at least one adverse outcome (a symptomatic, objectively confirmed recurrence of venous thromboembolism, major bleeding, or death), as compared with 31 patients assigned to continue therapy (23.1 percent) (Table 2). No adverse events occurred in patients in whom therapy was extended or resumed after its scheduled interruption or in any of the four patients who declined to continue therapy after randomization.

Table 2. Adverse Outcomes According to Treatment Group.

Discussion

Kearon et al.8 showed that the rate of recurrence of venous thromboembolism in patients with idiopathic deep venous thrombosis who were assigned to receive extended anticoagulant therapy was lower while they were receiving that therapy than the rate of recurrence in patients assigned to discontinue anticoagulant therapy. The results of our study show that the clinical benefit achieved during therapy when the three-month course of oral anticoagulant therapy is extended to one year is not maintained after the discontinuation of therapy. Approximately two thirds of the recurrences of thromboembolic events in both treatment groups occurred during the first year after the discontinuation of oral anticoagulant therapy. These findings suggest that prolonging anticoagulant therapy beyond three months in patients with idiopathic deep venous thrombosis simply delays recurrence until anticoagulant therapy is stopped, rather than reducing the risk of recurrence.

Despite the fact that patients with a high risk of bleeding were excluded from this study and that oral anticoagulant therapy was monitored closely, 3 percent of patients had major bleeding during the nine months of extended oral anticoagulant therapy, a percentage consistent with the rate of bleeding events in previous studies.5,8

The results of this study apply only to patients with idiopathic deep venous thrombosis as defined by the study protocol. Patients with known permanent or temporary risk factors were excluded from this study, but systematic screening for thrombophilia and cancer was not performed. Our findings are likely to apply to the large majority of patients with a first episode of apparently spontaneous deep venous thrombosis, since they are currently not systematically screened for occult cancer and thrombophilia. Differences in the definition of idiopathic venous thromboembolism and in the duration of anticoagulant therapy could help explain the differences between the outcome in our study and those in other studies.5,8

As in some previous studies, all recurrent thromboembolic events were idiopathic,8 and more than half involved the initially unaffected leg.11 The idiopathic nature of the recurrences suggests that these events could be prevented by continuous anticoagulant therapy, but not by intermittent prophylaxis limited to the times when temporary risk factors for deep venous thrombosis are present. The recurrences in the contralateral leg suggest that a persistent underlying hypercoagulable state, rather than residual anatomical changes, accounts for the high risk of recurrence in patients with idiopathic venous thrombosis who have stopped oral anticoagulant therapy.12

Our study was not a double-blind trial. However, its findings are likely to be valid, since a number of measures were taken to avoid bias. These were the enrollment of consecutive patients, central randomization, follow-up of all patients who underwent randomization, the central adjudication of all outcome events by a committee unaware of the treatment assignments, the assessment of recurrences of venous thromboembolism and bleeding events on the basis of predetermined objective criteria, and the inclusion in the study analysis of all patients randomly assigned to treatment groups.

With respect to the primary a priori hypothesis, this study shows that 15 percent of patients with presumed idiopathic proximal deep venous thrombosis will probably have a recurrence in the first two to three years after the discontinuation of anticoagulant therapy. We confirmed that during extended oral anticoagulant therapy, the rate of recurrence is negligible in patients who actually continue therapy. The administration of oral anticoagulants indefinitely could extend the initial benefit, but such therapy carries the risk of bleeding and is inconvenient. Anticoagulant therapy of indefinite duration could be made safer by reducing the doses of oral anticoagulants after an initial period of treatment with the full dose. The development of oral antithrombotic agents that have an improved safety profile and do not require laboratory monitoring could certainly pave the way toward extending therapy indefinitely. Patients with presumed idiopathic deep venous thrombosis could be further categorized in order to identify those at high risk for recurrence after the discontinuation of anticoagulant therapy.

Studies assessing both the strategy of extending low-dose anticoagulant therapy indefinitely and that of improving risk stratification among patients with idiopathic venous thromboembolism have recently begun or been planned. The results of these studies will probably define the optimal long-term treatment for patients with idiopathic deep venous thrombosis.

Presented in part at the 20th Congress of the International Society of Thrombosis and Haemostasis, Washington, D.C., August 20, 1999.

We are indebted to Jack Hirsh for his scientific advice; to Paolo Reboldi and Giuseppe Airoldi for their contribution to the management of the data and the statistical analyses; to Eva Tikotin for editorial assistance; to the nursing and laboratory staff of the participating centers for their enthusiastic cooperation; and to the patients included in the study for their trust and support.

Source Information

From the Sezione di Medicina Interna e Cardiovascolare, Dipartimento di Medicina Interna, Università di Perugia, Perugia (G.A., M.G.S., A.I.); the Istituto di Clinica Medica II, Università di Padova, Padua (P.P., P.B.); the Istituto di Ematologia, Università di Torino, Turin (M.B.); the Centro Emofilia e Trombosi, Istituto di Ricovero e Cura a Carattere Scientifico Ospedale Maggiore, Milan (M.M.); the Divisione di Angiologia, Policlinico S. Orsola-Malpighi, Bologna (G.G.); the Divisione di Chirurgia Vascolare, Ospedale S. Chiara, Trento (A.B.); the Divisione di Medicina, Ospedale Civile, Bolzano (C.T.); the Divisione Medica I, Ospedale S. Giovanni e Paolo, Venice (G.S.), and the Dipartimento di Medicina Interna e Terapia Medica, Università di Varese, Varese (W.A.) — all in Italy.

Other authors were Alessandra Ascani, M.D. (Università di Perugia, Perugia); Sabina Villalta, M.D., Michela Frulla, M.D., Laura Mosena, M.D., Antonio Girolami, M.D. (Università di Padova, Padua); Antonella Vaccarino, M.D. (Università di Torino, Turin); Adriano Alatri, M.D. (Università di Milano, Milan); Gualtiero Palareti, M.D. (Policlinico S. Orsola-Malpighi, Bologna); Mario Marchesi, M.D. (Ospedale Civile, Bolzano); Giovanni Battista Ambrosio, M.D., Roberto Parisi, M.D., Silvia Doria, M.D. (Ospedale S. Giovanni e Paolo, Venice); Luigi Steidl, M.D., Fabio Ambrosini, M.D. (Università di Varese, Varese); Mauro Silingardi, M.D., Angelo Ghirarduzzi, M.D., and Ido Iori, M.D. (Arcispedale S. Maria Nuova, Reggio Emilia).

Address reprint requests to Professor Agnelli at the Sezione di Medicina Interna e Cardiovascolare, Dipartimento di Medicina Interna, Università di Perugia, Via Enrico dal Pozzo, 06123 Perugia, Italy, or at agnellig@unipg.it.

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Schafer AI. Venous thrombosis as a chronic disease. N Engl J Med 1999;340:955-956.[Full Text]

"Obesity Strongly Linked to Pulmonary Embolism and Deep Venous Thrombosis"

NEW YORK, NY -- September 9, 2005 -- Obesity is a risk factor for venous thromboembolic disease in men as well as women, particularly those under age 40 years, according to results from an extensive study published in the September issue of The American Journal of Medicine. Since 1927, obesity has been thought to be a risk factor for fatal pulmonary embolism (PE). Because of the high proportion of obesity in the general population, previous studies have not determined whether obesity is an independent risk factor for PE or deep venous thrombosis (DVT). The new findings, published in the September issue of The American Journal of Medicine, was conducted by researchers from St. Joseph Mercy Oakland Hospital, Pontiac, Michigan; Wayne State University, Detroit, Michigan; and Oakland University, Rochester, Michigan. They analyzed over 20 years of patient records compiled by the National Hospital Discharge Survey (NHDS) to further investigate the potential risk of obesity in venous thromboembolism. The NHDS is comprehensive in its scope including data on patients of all races and ages obtained annually from 181,000 to 307,000 sampled patient abstracts from 400 to 494 non-Federal short-stay hospitals in 50 states and the District of Columbia. There were more than 12,000,000 obese patients and almost 700,000,000 non-obese patients in the sampled data. The relative risk of DVT, comparing obese patients with non-obese patients, was 2.50. The relative risk of PE was 2.21. Obese females had a greater relative risk for DVT than obese males, 2.75 versus 2.02. Obesity had the greatest impact on patients aged less than 40 years, in whom the relative risk for PE in obese patients was 5.19 and the relative risk for DVT was 5.20. In females aged less than 40 years, the relative risk for DVT comparing obese with non-obese patients was 6.10. In males less than 40 years of age, the relative risk for DVT was 3.71. Paul D. Stein, MD, writes "Now that we know with certainty that obesity is a risk factor for PE, particularly in men and women under age 40, the presence of obesity may alert physicians to a possibility of the diagnosis. The diagnosis of PE is frequently missed even though PE is the third most common acute cardiovascular disease after myocardial infarction and stroke." REFERENCES: Stein PD, et al. Obesity as a risk factor in venous thromboembolism. The American Journal of Medicine, Volume 118, Number 9 (September 2005). SOURCE: Elsevier Health Sciences

New Anticoagulants for Treatment of Venous Thromboembolism

Jeffrey I. Weitz, MD, FRCP(C), FACP, FCCP(Circulation. 2004;110:I-19 – I-26.)

Treatment of Venous Thromboembolism

From McMaster University and Henderson Research Centre, Hamilton, Ontario, Canada.

Correspondence to Dr Jeffrey I. Weitz, Henderson Research Centre, 711 Concession Street, Hamilton, Ontario, Canada, L8V 1C3. E-mail jweitz@thrombosis.hhscr.org

Treatment of venous thromboembolism (VTE) usually starts with concomitant administration of heparin or low-molecular-weight heparin (LMWH) and a vitamin K antagonist. The parenteral anticoagulant, which is given for at least 5 days, is stopped once the vitamin K antagonist produces a therapeutic level of anticoagulation. Although the introduction of LMWH has simplified the initial treatment of VTE, problems remain. LMWH must be given by daily subcutaneous (SC) injection and vitamin K antagonists require routine coagulation monitoring, which is inconvenient for patients and physicians. Recently, 3 new anticoagulants have been introduced in an attempt to overcome these limitations. These include fondaparinux and idraparinux, synthetic analogs of the pentasaccharide sequence that mediates the interaction of heparin and LMWH with antithrombin, and ximelagatran, an orally active inhibitor of thrombin. These agents produce a predictable anticoagulant response; thus, routine coagulation monitoring is unnecessary. Because they do not bind to platelets or platelet factor 4, fondaparinux and idraparinux do not cause heparin-induced thrombocytopenia (HIT). Unlike vitamin K antagonists, ximelagatran has a rapid onset of action, thereby obviating the need for concomitant administration of a parenteral anticoagulant when starting treatment. The lack of an antidote for these new agents is a drawback, particularly for idraparinux, which has a long half-life.

Fighting lethal flights with a new seat; [Daily Edition]

NICKY BLACKBURN. Jerusalem Post. Jerusalem: Jul 23, 2004. pg. 16

For some years, inventor Arnold Jonas commuted once a month between the United States and Israel. It was an exhausting process and Jonas - an Israeli who moved to the US - hated the long and cramped 20-hour journeys. During the flight he would keep changing positions to try to find a comfortable position for his stiff legs and knees.

"It was painful, unpleasant, and most of the time I was just stuck in my seat," says Jonas, a jovial 60-year- old who bears a distinct resemblance to actor Bob Hoskins. "I'd watch other passengers and see how they moved from position to position. None of them were comfortable. Everyone was suffering. It was awful for all of us."

With little else to do on these flights, Jonas - a former journalist - began to think about how he could make the trip more comfortable. He started experimenting, bringing pieces of wood covered in fabric for comfort to support his legs and lift them further off the ground. Gradually an idea began to form in his mind. Today that idea has reached fruition, and Jonas has developed a new airplane seat, called NewSit, that could help transform flying into both a more comfortable and far safer experience.

These days, there is increasing awareness that air travel, aside from being a deeply uncomfortable experience especially for those in economy class, can be dangerous for your health. According to statistics from the US Department of Health, every year, in the US alone, about one million people suffer from deep vein thrombosis (DVT), or blood clots, as a result of flying, and one thousand people die. Worldwide studies show that 10 percent of passengers develop some level of blood clots, and those on Trans- Atlantic flights are especially at risk. Just a few weeks ago, a 50-year- old Israeli woman died of a blood clot in Tel Aviv's Tel Hashomer hospital, 12 hours after arriving by plane from New York.

"More people die from DVT every year than from AIDS or breast cancer combined," says Jonas, quoting figures from Aventis Pharmaceuticals.

DVT is a formation of a blood clot in one of the deep veins of the body, usually in the legs. It occurs mostly in people who have been immobile for long periods, such as sitting for long periods on a flight. Blood passing through the deepest veins in the calf or thigh, begins to flow more slowly and a clot can occur. Once this clot reaches the heart or the brain, the damage is caused. The phenomenon is often called "economy class syndrome," though business flyers also die of DVT.

EVERYONE ON a flight is at risk of DVT, including children, but some passengers have a higher risk than others. Smokers, drinkers, the obese, people with heart disease, pregnant women, women on birth control, people over 40, even post-surgical patients, all have a greater chance of developing a blood clot.

DVT can occur as late as two weeks after a flight. Jonas admits that it is highly likely that many deaths from DVT are not correctly attributed because patients do not think to mention a recent flight to their physician.

The main reason flights are so lethal is that passengers are often effectively stuck in their seats for hours. Many airlines today recommend that passengers get up and walk around for a few minutes every half an hour to improve their blood circulation. In most cases, however, this is extremely difficult to accomplish. There is no space to walk. Passengers in center seats do not want to repeatedly disturb their neighbors by asking them to let them pass, and in turbulence or bad weather conditions, pilots will often insist that passengers remain seated at all times.

The result is that passengers sit for many hours without moving their legs at all.

The NewSit is exactly the same size as a usual economy class seat, but it is made in two parts. With the push of a button, the front quarter of the seat rises up, lifting the passenger's legs off the floor, and enabling him to move them in two directions - forwards and back, and up and down. The passenger can decide whether he wants to do these movements individually, or at the same time. This swinging movement increases blood circulation, helping to prevent the formation of blood clots.

At the same time it also provides a more comfortable sitting and sleeping option for passengers. Today when air travelers tilt their chairs back to go to sleep, their feet remain in the same position on the floor, which puts pressure on their legs and spine. By lifting their feet from the floor, the NewSit offers a far more natural sleeping position.

In addition, the seat offers more comfort to tall people, who currently suffer terribly from the cramped seating. The front part of the seat rises to a maximum of 10cm, and increases leg room.

JONAS BEGAN working on his NewSit five years ago. He was awarded the US patent earlier this year, and expects to get a European patent soon. Last year, Jonas built a prototype of the seat in the garage of his former US home. A series of tests and examinations, including a comparative sitting test, were then carried out at California State University at Fullerton, in California. Results were good, according to Jonas.

Dr. Hanan Lobel, a doctor who carried out the tests said:"It is my opinion that NewSit is bound to create a revolution in travel conditions, making it more healthy and comfortable."

Jonas, who is retired, first went public with the seat at an expo for aircraft interiors in Hamburg last year. He was invited to take part in the show at the last minute after a cancellation and had just two weeks to prepare. The response was encouraging and Jonas met a number of the world's leading air seat manufacturers. Jonas then took part in a show in Paris, after a French company invited him to join its booth, and again managed to attract a great deal of attention.

Since then NewSit has received a great deal of media attention, particularly in the US. Every day, Jonas receives dozens of e- mails from around the world, offering investment or representation.

In January this year, Jonas returned to Israel after a 20-year sojourn, and began a series of meetings with some of the leading airlines in the world. Interest in the product is running high, and one large airline operator is now examining the product with a view to possibly introducing the seats to certain sections of its aircraft.

Today, economy class seats cost airline companies about $2,500, while business seats can cost up to $10,000. The NewSit costs just $600 more per seat, says Jonas.

"If the airline charges passengers $50 extra for these seats per journey, they can make back their investment in 12 days," he says.

The prototype seat, which until a few days ago, was sitting in the living room of Jonas's home in Hod Hasharon, is now undergoing tests at a number of Israeli hospitals. Initial results of ultrasound tests show that blood circulation rises dramatically when a passenger swings his legs on the seat. These tests are likely to be completed sometime over the next few months.

THE AIRLINE industry is a tough and competitive one to enter. There are only six or seven aircraft seat manufacturers in the world, and as Jonas admits, airlines are very reluctant to make any major changes to seating.

"Airline chairs have not changed for years. Some may be slightly larger, or more comfortable than others, but it is basically the same design," says Jonas. "This is a totally new idea, and that makes it harder for the airlines to accept."

In addition, he adds, airlines still do not want to admit that DVT is caused by long-haul flights.

On the other hand, however, airlines today are being hit by lawsuits filed by thousands of passengers who have suffered DVT after a flight.

This could potentially cost the airliners millions of dollars in compensation, and will force them to look for alternatives that could prevent this condition occurring in passengers. Recently, Jonas was invited to offer information about his new seat to lawyers in the US as part of a DVT case against an airliner.

In the meantime, Jonas has to make some tough decisions. Now is the time to take his seat to the next stage of development, and Jonas must decide whether to approach aircraft seat manufacturers and form some kind of partnership, or whether to set up his own company to manufacture the seats himself. The latter route is undoubtedly the hardest, but it is also an exciting option.

Up to now, Jonas has funded development of the seat alone, but he is now looking for investors who might help him take the innovation to the next stage.

"This could be an excellent opportunity for someone looking for a new business to develop," says Jonas.

He already has other applications up his sleeve. The design of the chair is good for anyone who sits for prolonged periods, like the handicapped - who currently take drugs to prevent clots forming, the elderly, people undergoing physiotherapy, or workers who sit for many hours in front of the computer. It can also be adapted for public transport, tour buses, or cinemas and theaters.

"This idea can go in many directions," says Jonas.

Jonas has also just completed development of a special shorter airline seat for children, which allows them to bend their knees. He has already applied for a patent for this idea.

This is a crucial time for Jonas and his airline seat, and he knows it.

"It's like drilling for oil," he says. "We have all the positive signs that we are about to hit the jackpot. The soil is wet with oil, and we can almost taste it, but we still need to do a bit more drilling before the well starts to gush.

"Anything could happen now. It's a gamble. I'm investing everything I've got in terms of time and attention. Now all I need is a little bit of luck. Luck is also part of the game."

[Illustration]

Photo; Caption: Arnold Jonas's NewSit is the same size as a usual economy class seat, but its swinging movement increases blood circulation, helping to prevent the formation of blood clots.

Reproduced with permission of the copyright owner. Further reproduction or distribution is prohibited without permission.

Treatment of DVT WITH LOVENOX

Traditionally, a patient diagnosed with DVT has been hospitalized for treatment, which includes intravenous heparin and monitoring of the aPTT. The patient remains hospitalized until warfarin is administered to achieve an INR between 2.0 and 3.0. Such management usually results in a three- to seven-day hospital stay.2

Recent randomized, controlled trials demonstrate the efficacy of low-molecular-weight heparin in the treatment of DVT, both in the hospital13-16 and in an outpatient setting.17,18 Results of each of these studies demonstrated no advantage to standard intravenous heparin over low-molecular-weight heparin in terms of recurrent thromboembolism or major bleeding complications (Table 1). Patients who received twice-daily injections of low-molecular-weight heparin spent fewer days in the hospital and, in the studies where low-molecular-weight heparin was administered in the outpatient setting, many patients did not require hospitalization at all.17,18 Furthermore, social functioning and physical activity were better in the group receiving low-molecular-weight heparin.18 The dosage of low-molecular-weight heparin depends on the specific agent used (Table 2).

Cost analysis was incomplete in these trials; however, elimination of even a single hospital day by use of low-molecular-weight heparin would be likely to yield a savings. In our community, the cost of low-molecular-weight heparin ranges from approximately $100 to $150 per day. The average cost of treating a patient with uncomplicated DVT is reduced by approximately $5,000 to $8,000 when using low-molecular-weight heparin instead of standard heparin therapy. It is likely that additional studies will yield important information on the cost savings of treatment with low-molecular-weight heparin.

Patients with a first episode of proximal DVT and no risk factors for bleeding complications (e.g., active peptic ulcer disease, thrombocytopenia, liver disease, other coagulopathy) are good candidates for initial therapy with low-molecular-weight heparin. The Physicians' Desk Reference19 does not yet list low-molecular-weight heparin as an indicated use in the treatment of DVT; hence, this suggested treatment represents an off-label use. Because several subsets of patients were excluded from the low-molecular-weight heparin trials, treatment with low-molecular-weight heparin in these patients cannot be recommended at this time (Table 3).

Several recent articles have reported the safety and efficacy of low-molecular-weight heparin in the treatment of pulmonary embolism.20,21 Because pulmonary embolism is sometimes suspected in patients with DVT, appropriate treatment is essential. Treatment with low-molecular-weight heparin may still be considered in patients with DVT and suspected pulmonary embolus. Physicians should become familiar with the absolute and relative contraindications of the specific brand of low-molecular-weight heparin they choose to use.

Appropriate patients may be taught to self-administer low-molecular-weight heparin or, if needed, a visiting nurse or a family member can give the injections. Warfarin is started on the first or second day of therapy with low-molecular-weight heparin and, once the INR is between 2.0 and 3.0, the low-molecular-weight heparin is discontinued (Figure 1).

As with any illness, patients benefit from education about the potential consequences of both their disease and its treatment. Close physician follow-up is advised when treating patients with low-molecular-weight heparin.

WHO SHOULD NOT USE LOW MOLECULAR WEIGHT HEPARIN

TABLE 3

Subsets of Patients Excluded from Controlled Trials of LMW Heparin in DVT*

• Previous history of DVT:

--Ipsilaterally15

--Ipsilaterally in the past two years12

--Two or more episodes, either extremity16

--Any venous thromboembolism in the past two years17

• Pregnancy12-17

• Renal or hepatic insufficiency13,15

• Active bleeding13-16

• Surgery in the previous five15 to seven14 days

• Protein C,13,16 antithrombin III or protein S deficiency16 (hypercoagulable state)

• Inability to undergo outpatient treatment16

• Noncompliance16

• Other relative contraindications:

--Thrombocytopenia

--Coagulopathy

--Active peptic ulcer disease

LMW=low-molecular-weight; DVT=deep venous thrombosis.

*--Currently evidence is insufficient to support the routine use of low-molecular-weight heparin in the treatment of DVT in these patients.

Information from references 12 through 17.

LOVENOX® (enoxaparin sodium) Injection

Lovenox® (enoxaparin sodium) Injection is a unique chemical entity in a class of antithrombotic agents known as low-molecular-weight heparins (LMWH). Lovenox was approved in the United States and Canada in 1993, and it has been available in Europe since 1987. Outside of the US, Lovenox is also known under the brand names, Clexane® and Klexane®.

The No. 1 selling low-molecular-weight heparin in the world, Lovenox is obtained by alkaline degradation of heparin benzyl ester and is about one-third the molecular size of unfractionated heparin. Numerous clinical studies have demonstrated that Lovenox is a safe and effective way to reduce the risk of deep vein thrombosis (DVT) in a wide range of patient populations, and is the only LMWH that is more effective than unfractionated heparin in the treatment of unstable angina and non-Q-wave myocardial infarction when administered concomitantly with aspirin. This has been demonstrated by more than 14 years of safety and efficacy and by the treatment of 82 million patients in 96 countries.

RANGE OF INDICATIONS

Lovenox is the only low-molecular-weight heparin in the United States approved by the Food and Drug Administration for all of the following uses:

Prophylaxis of deep-vein thrombosis, which may lead to pulmonary embolism:

in medical patients who are at risk for thromboembolic complications due to severely restricted mobility* during acute illness;

in patients undergoing abdominal surgery who are at risk for thromboembolic complications;

in patients undergoing hip replacement surgery, during and following hospitalization;

in patients undergoing knee replacement surgery.

Prophylaxis of ischemic complications of unstable angina and non-Q-wave myocardial infarction, when concurrently administered with aspirin.

Inpatient treatment of acute deep-vein thrombosis with or without pulmonary embolism, when administered in conjunction with warfarin sodium.

Outpatient treatment of acute deep-vein thrombosis without pulmonary embolism when administered with warfarin sodium.

* Defined as walking distance of <10 meters for < 3 days

STRONG SAFETY AND EFFICACY PROFILE

With numerous national and international clinical studies demonstrating its safety and efficacy, Lovenox is the most widely studied LMWH. Fourteen years of experience has proven Lovenox to be safe and effective in the prevention and treatment of venous and arterial thrombosis. Some of the key studies show that:

In Deep-Vein Thrombosis:

Lovenox is comparable to and as safe as unfractionated heparin in the prophylaxis of DVT in patients undergoing total knee replacement and total hip replacement surgeries (C.W. Colwell, 1995)1.

After surgery, Lovenox administered once-daily is as effective as unfractionated heparin in the prophylaxis of DVT in patients undergoing elective hip replacement surgery (T.E. Spiro, 1994)2.

Hospitalized acutely ill medical (non-surgical) patients are at significant risk for venous thromboembolic events (deep-vein thrombosis or pulmonary embolism), and prophylaxis with Lovenox significantly reduces the risk across a range of patient categories. (M.M. Samama, 1999)3

UA/NQMI:

Lovenox with aspirin is more effective than and as safe as unfractionated heparin in reducing the incidence of death and myocardial infarction in patients with UA/NQMI (ESSENCE: M. Cohen, 1998; TIMI 11b: E.M. Antman, 1999 )4, 5

ADMINISTRATION

Lovenox has been shown to have a more predictable anticoagulant effect than unfractionated heparin

Unlike unfractionated heparin, Lovenox does not routinely require monitoring of blood clotting times

Appropriate patients may be able to administer the Lovenox injection in the comfort of their own homes.

IMPORTANT SAFETY INFORMATION

LOVENOX® (enoxaparin sodium) Injection cannot be used interchangeably with other low-molecular-weight heparins or unfractionated heparin, as they differ in their manufacturing process, molecular weight distribution, anti-Xa and anti-IIa activities, units and dosage.

When epidural/spinal anesthesia or spinal puncture is employed, patients anticoagulated or scheduled to be anticoagulated with low-molecular-weight heparins or heparinoids are at risk of developing an epidural or spinal hematoma, which can result in long-term or permanent paralysis.

The risk of these events is increased by the use of postoperative indwelling epidural catheters or by the concomitant use of drugs affecting hemostasis. Patients should be frequently monitored for signs and symptoms of neurological impairment. (See boxed WARNING.)

As with other anticoagulants, use with extreme caution in patients with conditions that increase the risk of hemorrhage. Unless otherwise indicated, agents that may affect hemostasis should be discontinued prior to LOVENOX therapy. Bleeding can occur at any site during LOVENOX therapy. An unexplained fall in hematocrit or blood pressure should lead to a search for a bleeding site. (See WARNINGS.)

Thromobocytopenia can occur with LOVENOX. In patients with a history of heparin-induced thrombocytopenia, LOVENOX should be used with extreme caution. Thrombocytopenia of any degree should be monitored closely. If the platelet count falls below 100,000/mm3, LOVENOX should be discontinued. Cases of heparin-induced thrombocytopenia have been observed in clinical practice. (See WARNINGS.)

The use of LOVENOX is not recommended for thromboprophylaxis in patients with prosthetic heart valves. (See WARNINGS.)

LOVENOX is contraindicated in patients with hypersensitivity to enoxaparin sodium, heparin, or pork products, and in patients with active major bleeding.

Click here for full prescribing information, including boxed WARNING.

For more information, please visit www.lovenox.com.

1Colwell CW Efficacy and Safety of Enoxaparin Versus Unfractionated Heparin for Prevention of Deep Venous Thrombosis after Elective Knee Arthroplasty. Scripps Clinic and Research Foundation, 1995.

2Spiro TE. Efficacy and safety of enoxaparin to prevent venous thrombosis after hip replacement surgery. Ann Int Med 1994;121:81-89.

3Samama MM et al. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. N Engl J Med 1999;341:793-800.

4Cohen M. et al. Low-molecular-weight heparins in non-ST-segment elevation ischemia: The ESSENCE Trial. American Journal of Cardiology 1998:vol. 82(5B).

5Antman EM et al. Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-Q-wave myocardial infarction: Results of the thrombolysis in myocardial infarction (TIMI) IIB trial. Circulation 1999;100:1593-1601.

LOVENOX® (enoxaparin sodium) Injection

Pulmonary Embolism

Pulmonary embolism is the sudden blocking of an artery of the lung (pulmonary artery) by an embolus--usually a blood clot (thrombus).

The functions of the arteries of the lungs are to carry enough blood containing oxygen and nutrients to keep the lung tissue healthy and to carry carbon dioxide to the lungs for removal from the body (see Section 4, Chapter 38). However, when a large artery to the lung is blocked by an embolus, the amount of blood supplied may be insufficient, eventually causing lung tissue to die.

About 10% of people with pulmonary embolism suffer some lung tissue death (called pulmonary infarction). Sometimes the body breaks up small clots quickly, keeping damage to a minimum. Large clots take much longer to disintegrate, so more damage is done. Large clots may cause sudden death by blocking so much of the lung arteries that the oxygen supply to the body is inadequate to sustain life or by placing an excessive strain on the heart.

The prevalence of pulmonary embolism in people admitted to the hospital is about 1%. When an autopsy is performed, pulmonary embolism is often unexpectedly found to be the cause of death in about 5% of people.

Causes

The most common type of embolus that travels to the lungs is a blood clot, usually one that forms in a leg or pelvic vein (see Section 3, Chapter 36) when blood flow slows down or stops, as may occur in the leg veins when a person stays in one position for a long time. People who have been on prolonged bed rest and those sitting for long time periods without moving around (as may happen during air travel) are at particular risk. When the person starts moving again, the clot can break loose. Far less often, blood clots form in the veins of the arms or in the right side of the heart. Once a clot breaks free into the bloodstream, it usually travels to the lungs.

Another type of embolus may form from fat, which can escape into the blood from the bone marrow when a bone is fractured. An embolus also may form from amniotic fluid being forced into the pelvic veins during childbirth. However, both fat and amniotic fluid emboli are rare. If they form, they usually lodge in small vessels such as the arterioles and capillaries of the lung, where they generally cause less damage than blood clots. However, if many of these smaller vessels become obstructed, acute respiratory distress syndrome (see Section 4, Chapter 56) or pulmonary hypertension (see Section 4, Chapter 54) may develop; both of these conditions can lead to respiratory failure, heart failure, and shock.

Cancerous tumor fragments may break free into the circulation to form emboli, which, if they are numerous, can cause pulmonary hypertension as the cancer spreads throughout the lungs.

Air bubbles may form an emboli and cause pulmonary embolism after a vein has been exposed to large amounts of air, as may occur during intravenous infusion of drugs, nutrients, or fluid. Air emboli may also form when a vein is being operated on (such as when a blood clot is being removed) or when a person is being resuscitated (because of the force of chest compressions). An additional risk is when a person dives underwater; the risk depends on how deep the person dives and how fast he ascends to the surface of the water (see Section 24, Chapter 295).

Symptoms

Symptoms depend on the extent that the pulmonary artery is blocked and on the person's overall health. For example, people who have another disease such as chronic obstructive pulmonary disease or coronary artery disease may have more disabling symptoms.

Small emboli may not cause any symptoms, but most emboli cause shortness of breath, which comes on very quickly. Shortness of breath may be the only symptom, especially if pulmonary infarction does not develop. Often, the breathing is very rapid, and the person may feel anxious or restless and appear to have an anxiety attack. Larger emboli commonly cause sharp pain in the chest, especially when the person inhales; the pain is called pleuritic chest pain.

In some people, the first symptoms of pulmonary embolism may be light-headedness, fainting, or seizures. These symptoms usually result from a sudden decrease in the heart's ability to deliver enough oxygen-rich blood to the brain and other organs. Irregular heartbeats may also occur. People with obstruction of one or more large pulmonary arteries may have a blue skin color (cyanosis) and can die suddenly.

The symptoms of pulmonary embolism usually develop abruptly, whereas the symptoms of pulmonary infarction develop over the following hours. If pulmonary infarction occurs, the person experiences coughing that may produce blood-stained sputum, sharp chest pain when the person breathes in, and in some cases, fever. Symptoms of infarction often last several days but usually become milder every day.

In people who have recurring episodes of small pulmonary emboli, symptoms such as chronic shortness of breath, swelling of the ankles or legs, and weakness tend to develop progressively over weeks, months, or years.

Diagnosis

A doctor suspects pulmonary embolism based on the person's symptoms and predisposing factors, such as a recent surgery or a prolonged period of bed rest. A large pulmonary embolism may be relatively easy for a doctor to diagnose, especially when there are obvious preconditions, such as signs of a blood clot in a leg. Certain procedures are often needed to confirm the diagnosis. Even with these procedures, however, many emboli can be quite subtle and difficult for doctors to diagnose conclusively.

A chest x-ray may reveal subtle changes in the blood vessel patterns after embolism and signs of pulmonary infarction. However, the results are often normal, and even when they are abnormal, they rarely enable the doctor to establish the diagnosis with certainty.

An electrocardiogram may show abnormalities, but often these abnormalities are transient and can only support the possibility of pulmonary embolism.

A lung perfusion scan is one of the best tests for diagnosing pulmonary embolism. A tiny amount of radioactive substance is injected into a vein and travels to the lungs, where it outlines the blood supply (perfusion) of the lung. Areas without normal blood supply appear dark on the scan because no radioactive particles can reach them. Normal scan results indicate that the person does not have a significant blood vessel obstruction. Abnormal scan results support the possibility of pulmonary embolism but may also reflect conditions other than pulmonary embolism, such as obstructive lung disease (for example, emphysema, which can result in decreased blood flow to areas where lung tissue has been damaged).

Usually, the perfusion scan is coupled with a lung ventilation scan. The person inhales a harmless gas containing a trace amount of radioactive material, which is distributed throughout the small air sacs of the lungs (alveoli). The areas where carbon dioxide is being released and oxygen taken up can then be seen on a scanner. By comparing this scan to the pattern of blood supply shown on the perfusion scan, a doctor can usually determine whether a person has had a pulmonary embolism by a mismatch between ventilation and blood perfusion.

Pulmonary angiography (see Section 4, Chapter 39) is an accurate means of diagnosing pulmonary embolism, but it poses some risk and is more uncomfortable than the other tests. It is usually performed only if the other tests fail to demonstrate a conclusive diagnosis of a pulmonary embolism. In an x-ray procedure, a radiopaque dye is injected into the pulmonary arteries. A pulmonary embolism shows up as blockage in an artery. A certain type of computed tomography (CT) called CT angiography is another accurate test. CT angiography can be used if pulmonary angiography is not available or if the person should not undergo this test for some reason.

Additional tests, such as an ultrasound to examine the legs for blood clots in the veins, may be performed to find out where the embolus originally developed. A blood test (D-dimer test) can provide additional support of the diagnosis. A normal test result can help to exclude pulmonary embolism as the cause of a person's symptoms.

Prevention

Given the danger of pulmonary embolism and the limitations of treatment, doctors try to prevent blood clots from forming in the veins of people at risk of pulmonary embolism. In general, a person who is prone to clotting should try to be active and move around as much as possible. For example, when traveling on an airplane for a long period, the person should try to get up and move around every two hours.

For people who have undergone surgery--especially older people--the risk of clot formation can be reduced by the following measures: wearing compression elastic stockings, doing leg exercises, and getting out of bed and becoming active as soon as possible. For people who cannot move their legs, intermittent air compression devices can provide rhythmic external pressure to keep blood moving in the legs and thighs. However, these devices alone are inadequate to prevent clot formation in people who have undergone hip or knee surgery.

Anticoagulant drugs are given. Heparin is the most widely used therapy for reducing the likelihood of clots forming in calf veins after any type of major surgery, especially surgery for the legs (see Section 14, Chapter 173). Hospitalized people at high risk of developing pulmonary embolism (such as those with heart failure, an acute myocardial infarction, chronic lung disease, obesity, a stroke or other neurologic problem or who have had clots in the past) benefit from small doses of heparin even if they are not undergoing surgery. Small doses are injected just under the skin shortly before the operation and ideally until the person is up and walking again. Low-dose heparin does not increase the frequency of major bleeding complications, but heparin can increase minor oozing of blood from wounds. Low-dose heparin can also be used for operations involving the spine or brain.

A different form of heparin, called low-molecular-weight heparin, is equally or even more effective in preventing clots than the use of traditional heparin. Low-molecular-weight heparin is also injected just under the skin and is usually continued until the risk of developing clots has passed.

Warfarin, an anticoagulant given by mouth, may be given when a person has undergone certain kinds of surgery that are particularly likely to result in clots, such as surgery for a hip fracture or a joint replacement. Warfarin therapy may need to be continued for several weeks or months. Low-molecular-weight heparin is also effective for people in this situation.

Treatment

Treatment of pulmonary embolism begins with the administration of oxygen and, if necessary, analgesics to relieve pain. Anticoagulant drugs such as heparin are given to prevent existing blood clots from enlarging and additional clots from forming. Heparin is given intravenously to achieve a rapid effect, and doctors carefully regulate the dose. Doctors strive to achieve a full effect within the first 24 hours of treatment. Otherwise, the person is at high risk of more pulmonary emboli, and new clots or enlargement of existing clots in leg and pelvic veins. Low-molecular-weight heparin is probably equally effective to traditional heparin and does not require the blood test monitoring that conventional heparin requires. Warfarin, which also inhibits clotting but takes longer to start working, is given next. Because warfarin is taken by mouth, it can be used long-term. Heparin and warfarin are given together for 5 to 7 days, until blood tests show that the warfarin is effectively preventing clotting. Then, the heparin is discontinued.

How long anticoagulants are given depends on the person's situation. If pulmonary embolism is caused by a temporary predisposing factor, such as surgery, treatment is given for 2 to 3 months. If the cause is some longer-term problem, such as prolonged bed rest, treatment usually is given for 3 to 6 months, but sometimes it must continue indefinitely. For example, people who have recurrent pulmonary embolism, often due to a hereditary predisposition to clotting, usually take anticoagulants indefinitely. While taking warfarin, the person periodically has to have a blood test to determine if the dose needs to be adjusted. Changes in diet and many other drugs may affect the magnitude of anticoagulation by this drug. If excessive anticoagulation occurs, severe bleeding in a number of body organs can develop.

Thrombolytic therapy is used for people who appear to be in danger of dying of pulmonary embolism. Thrombolytic drugs such as streptokinase or tissue plasminogen activator (TPA) break up and dissolve the clot. However, these drugs cannot be given to people who have had surgery in the preceding 2 weeks, are pregnant, have had a recent stroke, or tend to bleed excessively. Surgery may be needed to save someone with severe embolism; removal of the embolus from the pulmonary artery may be lifesaving. Surgery is also used to remove long-standing pulmonary artery clots that cause persistent shortness of breath and pulmonary hypertension.

A filter can be surgically placed in the main vein in the abdomen that drains blood from the legs and pelvis to the right side of the heart (see Section 3, Chapter 36). Such a filter can be used if emboli recur despite anticoagulant treatment or if anticoagulants cannot be used or cause significant bleeding. Because clots generally originate in the legs or pelvis, this filter usually prevents them from being carried into the pulmonary artery.

For emboli that form from fat or amniotic fluid, oxygen therapy and use of a ventilator may be needed. In addition, because emboli that develop from amniotic fluid may stimulate the formation of blood clots (coagulation), agents such as cryoprecipitate are sometimes needed to block certain key steps in the formation of these clots (such as the development of fibrin deposits in the circulation).

Prognosis

About half of the people with untreated pulmonary embolism will have another embolism. As many as half of these recurrences may be fatal. Anticoagulant treatment can reduce the rate of recurrence to about 1 in 20 people; only about 1 in 5 of these people will die of pulmonary embolism. The likelihood of dying depends on the size of the embolus, the size and number of pulmonary arteries blocked, and the person's overall health status. Anyone with a serious heart or lung problem is at greater risk of dying from pulmonary embolism. A person with normal heart and lung function usually survives unless the embolus blocks half or more of the pulmonary vessels. If death occurs from pulmonary embolism, it usually occurs rapidly, often within 1 to 2 hours.

An air embolism can cause death, but only if the amount of air that reaches the heart and pulmonary arteries is large. Death occurs with a large air embolus not only because blood flow to much of the lungs is blocked but also because the heart cannot effectively pump blood.