Episode 135: VTE Series - Management of Antiphospholipid Antibody Syndrome
This week, we round out our discussion we started in our prior episode on APLS, this time focusing on management. Stick around until the end to hear Dan and Vivek battle it out about the optimal time to recommend APLS testing for your patients!
If you have not done so already, we highly recommend you check out episode 134 (diagnosis of APLS) prior to jumping into this one!
Once a diagnosis of APLS is established, what agents do we recommend using for anticoagulation?
In general, the preferred agent for anticoagulation is warfarin with a goal INR of 2-3.
Patients can bridge to therapeutic warfarin with either low molecular weight heparin or unfractionated heparin.
If patients with APLS are higher risk of thrombosis, should we target higher INRs?
A few retrospective analyses tried to answer this question
In 2003, there was the first randomized double-blind study by Crowther et. al published in NEJM that attempted to answer this question
Patients assigned patients with a history of venous thrombosis who had positive antiphospholipid antibodies three months apart to a higher intensity arm (INR 3.1-4) vs. a moderate intensity arm (INR 2.0-3.0).
Their primary objective was to show that the higher intensity dose was more effective than the moderate intensity dose.
The results suggested no difference in recurrent thrombosis at a median follow up time of 2.7 years
No differences in major bleeding.
Therefore it was established that moderate intensity warfarin was appropriate.
Are DOACs are okay to use in APLS?
The first trial to look into this was the RAPS trial in 2016.
This was a randomised, controlled, open-label, phase 2/3, non-inferiority trial, done in two UK hospitals, included patients with antiphospholipid syndrome who were taking warfarin for previous venous thromboembolism, with a target international normalised ratio of 2.5.
They randomly assigned patients 1:1 to continue with warfarin or to rivaroxaban (20mg daily).
The authors had developed a surrogate endpoint called endogenous thrombin potential (ETP).
Ultimately, they did not meet their prespecified non-inferiority threshold of 20%, but the data suggested that maybe rivaroxban would be okay.
Follow up was only for 210 days and there were no events in both groups
This did not answer the fundamental question of DOAC vs. warfarin
In 2019, came the TRAPS trial
This was a prospective randomized phase 3 open-label noninferiority study with blinded end point adjudication conducted in 14 centers in Italy in which the study group was comparing warfarin (INR target 2.5) compared to rivaroxaban for patients with a history of thrombosis (objectively proven arterial, venous, and/or biopsy-proven microthrombosis) and triple positive APLS.
This is important. This represents a very high risk patient population.
The primary endpoint was a composite endpoint of thrombosis, major bleeding, and death
Critical appraisal:
The noninferiority margin for these clinical trials are very important and, given the rarity of this disease, a very wide margin accepting a 50% loss in efficacy of warfarin was chosen
This was based on studies that showed the rate of this composite outcome with warfarin was 6% compared to 13% with observation for triple positive APLS patients
The trial was designed to enroll 568 patients with stopping rules for futility with safety analysis
At an interim analysis after only 120 patients were enrolled, the trial was actually stopped prematurely due to worse arterial thrombotic outcomes in patients in the rivaroxaban arm.
At the time of trial discontinuation, there were 59 patients randomized to the rivaroxaban arm and 61 in the warfarin arm.
In the DOAC arm, ischemic stroke occurred in 4 (7%) patients, and myocardial infarction occurred in 3 (5%) patients,
In the warfarin arm, there were no cases of ischemic stroke or myocardial infarction in the warfarin group.
There were no new venous events in either arm.
When did these arterial events occur?
The arterial events occurred mainly within one year of randomization and most occurred at least 200 days after randomization
Two of the events occurred within about 30 days of randomization
Other important patient characteristics:
There were similar numbers of prior venous and arterial events in these patients which shows that it is not driven exclusively by those who had prior arterial events before randomization
Most of these patients had a BMI around 25 suggesting that it was not baseline comorbidities that lead to these events
Major bleeding was not different between the two arms
There were 4 and 2 cases of major bleeding in the rivaroxaban and warfarin groups, respectively (HR, 2.5; 95% CI; 0.5-13.6; P = .3).
So what did we learn: While DOACs may be preventative against venous thromboembolic events, in patients who are high risk, namely triple positive APLS, there are increased risks of arterial thrombotic events on DOACs compared to warfarin
In triple positive patients, warfarin appears to be the better option based on the TRAPS Trial. But what about patients who are not triple positive?
A randomized study at 6 university hospitals in Spain comparing rivaroxban and warfarin helped answer this question
The primary endpoint was a new thrombotic event over 36 weeks rather than a composite endpoint
Again with a very wide non inferiority margin which makes it easier for the DOAC to win
Included both triple positive and lower risk patients
There 190 patients with 95 in each arm with a median follow up time of 3 years
60% of patients were triple positive and 40% were not, with the vast majority of those patients having lupus anticoagulant alone
There were more arterial events in the DOAC arm at 11% vs. 3% and no difference in VTE
There were 11 arterial events in the DOAC arm and 10 of those were ischemic stroke
This was compared to zero stroke events in the warfarin arm
When you look at the subgroup analysis of non-triple positive patients (roughly 40 per arm), there was no difference in thrombotic events between the two groups with 1 event in each arm
This makes you wonder if DOAC is acceptable for patients who are not triple positive but hard to make definitive conclusions on this small subgroup analysis
There is an ongoing trial evaluating the use of apixaban vs. warfarin called ASTRO-APS
The original protocol used apixaban reduced dose of 2.5 mg BID with a very weak justification given concern for bleeding risk
After the TRAPS trial, this was amended in 2017 to 5 mg BID which makes more sense
When is the optimal time to test for APLS (inpatient vs. outpatient)?
The truth is, there is no right answer to this question!
We invite you to listen to our debate at 21:07 to hear Dan and Vivek tackle this topic:
Pros for inpatient:
If a young patient has a new unprovoked thrombotic event, in light of data suggesting warfarin is better as per the studies outlined above, we want to ensure that our patients are being started on the best anticoagulant for APLS; even if studies are transiently positive, we are trying to minimize future event (especially arterial event)
If a patient does not have positive testing, we may be able to spare starting the patient on warfarin
Cons for inpatient:
Risk of false positives
Pros for outpatient:
Most thrombotic events occurred >200 days after initial event, therefore patient likely will not have another recurrent event before they can be seen in outpatient setting
Decreased risk of false positive testing once out of the acute setting
We can always consider warfarin in the inpatient setting and still recommend outpatient testing. Warfarin does not interfere with testing.
Cons for outpatient:
Needing to hold anticoagulation, particularly DOACs, if needing to do testing (remember that lupus anticoagulant cannot be run while on DOACs)
The crew behind the magic:
Show outline: Ronak Mistry
Production and hosts: Ronak Mistry, Vivek Patel, Dan Hausrath
Editing: Resonate Recordings
Shownotes: Ronak Mistry
Social media management: Ronak Mistry
We are proud to partner with HemOnc.org!
Want to learn more about the trials that lead to the regimens discussed today? What about dosing schedules? See links in the show notes for a link to HemOnc.org
Have some extra time and want to make some extra money? Click here to get paid to participate in market research surveys!
