Definitely, the addition of small doses of rivaroxaban to the current antiplatelet treatment for PAD is an impressive and promising treatment regimen that might give additional protection against cardiovascular death in severe cases of this group of patients. However, there are still questions about the results of the main studies that presented this effect, mainly the COMPASS trial. In particular, one could mention the following:

When compared against aspirin, the combination of rivaroxaban 2.5 mg twice daily plus aspirin reduced the rate of the composite primary outcome (death, stroke, MI) by 1.3% but with the cost of 1.2% increase of major bleeding. This was downplayed by the authors of the COMPASS trial because fatal bleeding was not increased. 

In plain numbers, a gain of 1.3% means that more than 98% of people who take the drug combination (ASA+rivaroxaban) get the same result as those who take aspirin alone, this meaning that establishing as standard this treatment regimen would be useless for the great majority of patients. Definitely, a careful subgroup analysis is necessary in order to find these small groups of PAD patients that might benefit from this treatment.

The comparison of the combination therapy in COMPASS trial was against aspirin which, today, is not the first-line antiplatelet treatment in PAD patients. We do know, since the long 1995 and the CAPRIE trial, that clopidogrel should be preferred over aspirin in PAD patients, and this is part of the existing guidelines (2017, ESC-ESVS). According to the well-known CAPRIE trial subgroup analysis in PAD patients, clopidogrel offered an absolute reduction of 1.15% against aspirin (RRR 23.8%) similar to the 1.3% offered by the combo ASA-Riva treatment. Obviously, in 2020, clopidogrel is the antiplatelet regimen that should be compared to any other antithrombotic/antiplatelet treatment in PAD patients and not aspirin.

The comparison of dual treatment (antiplatelet + warfarin in therapeutic dosage) against aspirin has been previously examined (WAVE trial, NEJM 2007) with disappointing results. In particular, in patients with PAD the combination of treatment was not more effective than antiplatelet therapy alone in preventing major cardiovascular complications and was associated with an increase in life-threatening bleeding. This meant that the addition of an anticoagulant medication was not definitely a per se bonus on treatment. A potential different effect of anti-Xa agent might be considered, but this needs further investigation.

Finally, as the authors of COMPASS mention, “trials that are stopped early for efficacy” (as did the COMPASS trial) “may overestimate the treatment effect”.

I think that as long the combo treatment (ASA+Riva) has not broadly been accepted as a standard treatment in the existing guidelines, this should be presented with serious caution and attention as a potential treatment regimen. Otherwise, we could be considered as proponents of an expensive twice-daily drug with not clearly proved benefits and harms, in patients who already receive a great bunch of other medications.   

3 Comments

  1. Other issues:
    1. The COMPASS trial included patients with carotid artery disease in about 25% of included patients. Those patients either had a history of carotid intervention or an asymptomatic stenosis greater than 50%. This means that we are talking about probably asymptomatic patients with moderate to severe carotid stenosis. If the combined treatment ASA+Riva is accepted for the PAD based on the COMPASS trial why isn’t it an accepted treatment for the asymptomatic (or symptomatic) carotid stenosis?

  2. 2. The amputation rates at 3 years post is ranges between 0.5% and 1.2%. I wonder what sort of PAD has that low amputation rate? Definitely, not the critical ischemia, and I believe neither has the intermittent claudication.

  3. Bayer and Johnson & Johnson Settle Lawsuits Over Xarelto, a Blood Thinner, for $775 Million. The settlement resolves about 25,000 lawsuits, which claimed the companies failed to warn about deadly bleeding episodes caused by the drug.

    https://www.nytimes.com/2019/03/25/health/xarelto-blood-thinner-lawsuit-settlement.html

Leave a Reply