SAN ANTONIO, TEX—Two important advances in the prevention of venous thromboembolism (VTE) were recently announced. One new study showed that low-dose dalteparin is safe and effective in acutely ill medical patients at high risk for VTE; another demonstrated that long-term administration of low-intensity warfarin markedly lowers the incidence of recurrent VTE without increasing the risk of severe bleeding.

Unfortunately, both studies use the acronym PREVENT, which has caused confusion. Preliminary results of the first study, formally known as the Prospective Evaluation of Dalteparin Efficacy for Prevention of Venous Thromboembolism in Immobilized Patients Trial, were presented at the annual meeting of the Society of Critical Care Medicine (SCCM) in San Antonio.[1] Results of the second study, the Prevention of Recurrent Venous Thromboembolism Trial, were published recently in the New England Journal of Medicine.[2] Both studies were randomized and used placebo controls (see Table 1).

DALTEPARIN TRIAL

In the dalteparin trial, the patients given active treatment had a 45% lower rate of VTE than did the placebo recipients. “This efficacy was maintained at least up to day 90,” stressed Alan Leizorovicz, MD, who presented the trial results at the SCCM meeting. “The treatment was very well tolerated, and the rate of major bleeding was very low with dalteparin,” added Dr. Leizorovicz, who is Director of the Evaluation of Treatments Unit in the Clinical Pharmacology Department at the University Claude Bernard in Lyon, France. The drug did not, however, appear to alter mortality.

The trial was necessary, said Dr. Leizorovicz, because previous studies of unfractionated heparin or low molecular weight heparin thromboprophylaxis in medical patients had serious limitations. For the new trial, the investigators recruited more than 3,700 acutely ill patients at 219 centers in 26 countries. All of the patients had been hospitalized for more than two days for one of several medical conditions that placed them at high risk for VTE—congestive heart failure, acute respiratory failure, or acute severe systemic disease. In addition, they had to have at least one VTE risk factor, such as cancer, be older than 75, or have a history of deep vein thrombosis (DVT) or pulmonary embolism (PE).

The patients were randomized to subcutaneous dalteparin (5,000 U) or placebo once daily for two weeks. The dalteparin dose, which is similar to that given for DVT prevention in high-risk surgical patients, was selected because previous research with enoxaparin had suggested that a lower dose would be ineffective.

TREATMENT EFFICACY

For the final analysis, there were 1,518 patients in the dalteparin group and 1,473 in the placebo cohort. On day 21, the rates of objectively verified symptomatic VTE, asymptomatic proximal DVT, or sudden death (the composite primary end point) were 2.77% in the patients given dalteparin and 4.96% in the placebo recipients.

The significant difference in the primary end point was predominantly due to a marked reduction in the incidence of asymptomatic proximal DVT in the patients given dalteparin (1.79% vs 3.65%). However, dalteparin thromboprophylaxis was also associated with a decreased incidence of symptomatic DVT (0.28% vs 0.63%). No differences were observed in the rates of symptomatic PE or sudden death, which were quite low in both groups.

The effect of dalteparin on VTE incidence was noticeable early during the study, and it continued for at least three months. VTE incidence immediately after treatment was started was 0.16% in the dalteparin group and 0.33% in the placebo cohort; on day 21, it was 0.57% and 0.98%, respectively; and on day 90 (the end of follow up), it was 1.33% and 1.93%, respectively. Furthermore, “the relative benefit [of dalteparin] was the same in all of the subgroups we looked at,” Dr. Leizorovicz noted.

The overall rate of adverse events was comparablein two groups; severe adverse events, including major bleeding and thrombocytopenia, occurred with similar low frequency both groups. By end follow upmortality about 6%

These results are important, Dr. Leizorovicz stressed, because acutely ill medical patients at risk for VTE are a “very large patient population that presently does not receive almost any thromboprophylaxis.”

WARFARIN TRIAL

Another group for whom thromboprophylaxis has been difficult is patients with idiopathic VTE. Such patients are usually given full-dose anticoagulation after the acute event, but this treatment is too risky for long-term administration. The annual rate of severe bleeding associated with prolonged use of full-dose warfarin (5% to 9%) is virtually identical to the annual rate of recurrent VTE (6% to 9%) in untreated patients.

However, a study led by Paul M. Ridker, MD, recently demonstrated that long-term administration of warfarin aimed at a target International Normalized Ratio (INR) between 1.5 and 2.0 lowered the risk of recurrent VTE by 64%. Furthermore, it achieved this reduction without a significant increase in the risk of major hemorrhage. The results were so dramatic that the study was stopped prematurely and publication was expedited (only three months elapsed between the time the study ended and the results were posted on the New England Journal’s Web site).

At the time the study was stopped, 255 patients had been randomized to receive warfarin, and 253 had been given placebo. All patients had had at least one episode of documented VTE and had been treated with full-dose anticoagulation for three months or more. The median duration of full-dose treatment was about 6.5 months in both groups.

Before randomization, all patients participated in a 28-day run-in phase, during which their warfarin doses were titrated to achieve the target INR. Patients were excluded from further study if their warfarin dose could not be adjusted to a stable level or if it exceeded 10 mg/d.

RESULTS EXCEEDED EXPECTATIONS

The study was stopped on December 4, 2002, after an interim analysis showed that the composite primary end point—the incidence of recurrent VTE, major hemorrhage, or death from any cause—was 48% lower in the warfarin group than in the placebo cohort. Not surprisingly, the rates of both major and minor bleeding were higher in the warfarin recipients; however, because the incidence of major bleeding was low in both groups (five in the warfarin recipients; two in the placebo cohort), the difference in incidence was not statistically significant.

Twelve deaths occurred during the study, which lasted 4.5 years; two thirds of these deaths occurred in the placebo group. Two patients given placebo, but none of the warfarin recipients, suffered fatal PEs. The only death resulting from hemorrhagic stroke occurred in a placebo recipient.

The magnitude of the risk reduction achieved with long-term low-intensity warfarin was similar in all subgroups examined, including patients with thrombophilic mutations, such as factor V Leiden or the G20210A prothrombin polymorphism. Because of both the extent of the risk reduction and the applicability of the findings to so many patient subgroups, Dr. Ridker, a Professor of Medicine at Harvard Medical School in Boston, concluded, “[These] results strongly suggest that long-term use of low-intensity warfarin should be considered a new standard of care for the management of venous thrombosis” once full-dose warfarin treatment is stopped.

—Gale Jurasek

References
1. Leizorovicz A. New developments in cutting edge therapeutics. Presented at: annual meeting of Society of Critical Care Medicine. January 31, 2003; San Antonio, Tex.
2. Ridker PM, Goldhaber SZ, Danielson E, et al. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med. 2003;348:1425-1434.

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