Benefit vs Risk of Extended Anticoagulation After Pulmonary Embolism

Andrew Shorr, MD, MPH


November 04, 2015

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This is Andy Shorr from Georgetown University in Washington, DC, with a pulmonary and critical care literature update. Today I want to discuss results of the PADIS-PE study, reported by Couturaud and colleagues[1] in the July 7, 2015 issue of JAMA.

Pulmonary embolism (PE) is a major issue for pulmonary and critical care specialists. One of the most challenging questions is how long to continue anticoagulation for patients with a first unprovoked PE. In general, the usual duration of anticoagulation for those patients is 6 months, and then you stop it; however, a number of studies[2,3,4] have shown that extending the duration of anticoagulation up to 24 months can reduce the rate of subsequent PE, albeit at the cost of some bleeding complications. Overall mortality rates are similar in those trials, but those studies are small and underpowered in terms of looking at mortality. In addition, if you stop the anticoagulation at month 24, what happens at month 25? That outcome is unestablished and was the focus of the PADIS-PE study.

The Study Design

The study enrolled patients who had already received 6 months of anticoagulation for a first unprovoked PE and randomly assigned them to receive placebo or 18 more months of anticoagulation with warfarin to reach a goal international normalized ratio (INR) of 2-3. The primary endpoint during that period was a composite of major bleeding and recurrent venous thromboembolic events. At the end of the 24-month treatment period, patients were followed for a subsequent 24 months with no anticoagulation, for a median of about 41 months in all. Thus, the study comprised three separate phases: a 6-month treatment-mandatory period for everyone; a period of active treatment vs placebo randomization; and finally a no-treatment period with observation and follow-up.

The study included about 360 patients, with each arm comprising about 180 patients who were well-matched for risk factors, comorbidities, age, etc., and excellent attention to follow-up. These investigators should be commended for this; during a study that goes on for nearly 4 years in which follow-up is essential, it is extremely easy to lose patients to follow-up, but these authors lost very few patients to follow-up. Remember that a loss of one or two patients or one or two deaths on either side can really skew the results of a study like this.

Study Results

When you break out the details of the study, the results are not surprising. During the 18 months of anticoagulation in one arm and placebo in the other, the rate of recurrent venous thromboembolism (VTE) in the active treatment arm was reduced substantially from 25 events in the placebo arm to about 6 in the active treatment arm. That comes at the price, of course, of more major bleeding. There was one major bleed in the placebo arm vs four in the active treatment arm; none of the major bleeds were fatal.

Thus, if you continue anticoagulation for 2 years with an INR goal of 2-3, the bleeding risk is manageable, but remember that this was in the setting of a study with very close attention to detail and very selective patients. The extended anticoagulation period definitely reduced the rate of recurrent PE. Also important is that for these patients who had a PE, the recurrent VTE was a PE, not a deep vein thrombosis. The type of recurrence seems to line up with the initial event, so if you present with a PE, the recurrence tends to be a PE.

Results After Extended Follow-up

During the extended follow-up to 41 months, after anticoagulation and placebo were stopped, the primary endpoint of major bleeding combined with recurrent VTE began to come together. By the end of 41 months, the rate of major bleeding and the rate of recurrent PE in both study arms was equivalent. Once you have stopped the anticoagulation in a patient with unprovoked PE, not surprisingly, the rate of major bleeding decreases as the rate of recurrent VTE increases. It is during that first 6 months after stopping anticoagulation, whether it is stopped early, after the first 6 months of anticoagulation, or late, after a total of 24 months of anticoagulation, that the risk for VTE goes up. About half of the total risk over the entire 42 month follow-up period occurred during the first 6 months after anticoagulation was discontinued. This suggests that perhaps life-long anticoagulation is something we need to consider in these patients with first unprovoked VTE. Perhaps we need to consider that although these patients may not have an identified hypercoagulable state, they do have one, but it simply does not have a name, or we do not have a test that can measure it.

Overall, whether anticoagulation lasted 24 months or 6 months, there was no difference in mortality, but in a 360-patient study, I would not expect to see a difference. This study was not powered to answer the question about the mortality tradeoff.

I believe that this study does suggest that we need to re-evaluate the risk/benefit equation when it comes to anticoagulation. In the era of the new novel oral anticoagulant agents with a much smaller bleeding risk, we may want to consider extended anticoagulation. We have extended anticoagulation in the AMPLIFY trial[5] with apixaban, which suggested a benefit of extended treatment vs discontinuation. With these safer agents, we should conduct larger trials to answer this question.

The PADIS-PE trial did not adjust for or deal with the issue of exposure to aspirin; we certainly know that after a first unprovoked PE, after the cessation of full-strength anticoagulation with warfarin, aspirin does provide some small but not marginal benefit. That was not allowed in this trial, and therefore we cannot say what happens if these people are on aspirin following the warfarin. Aspirin is recommended by the International Society on Thrombosis and Haemostasis for patients who have had first unprovoked PE, have finished their anticoagulation with full-strength warfarin, and do not have a contraindication.[6]

This is a thought-provoking trial that provides useful new information about the duration of the anticoagulation for first unprovoked PE, a very common and serious disease. The results suggest that we need to do larger trials with longer periods of follow-up to answer this question.

This is Andy Shorr from Washington, DC.


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