When a Medicine Works but Overall Benefit is Minimal to None
The study of the week explores bleeding reversal agents--an excellent way to learn the necessity of evidence-based medicine
The story of reversal agents for anticoagulants exposes many of the complexities of treating human beings. I like the story and I think you will too.
Some background, then to the ANNEXA-I study.
The new anticoagulants are called direct acting oral anticoagulants or DOACs. Rivaroxaban (Xarelto) and apixaban (Eliquis) are the two most popular. These drugs surpassed the old one, warfarin, because of convenience, efficacy and safety.
One hang-up with some patients is the lack of reversal agent. Warfarin can be easily reversed with two available agents. DOAC reversal has been more challenging.
I always reassure patients that trials including 64k patients comparing DOACs to warfarin showed benefit for the new drugs—and there was no reversal. So, on average, the lack of reversal was not important.
Yet there are patients who take these drugs who develop a serious bleed. Having a safe reversal agent would be an advance.
The most difficult bleed is intracranial bleeding, because there is no place for the blood to go, and it can rapidly increase intracranial pressure—which is deadly.
A total of 263 patients who had intracranial bleeding were randomized to receive the reversal drug andexanet and 267 received usual care.
The authors chose a composite primary endpoint of three things: hemostatic efficacy as defined by expansion of the hematoma by 35% or less, an increase in the stroke scale called NIHSS by less than 7 points (0-42 scale), and no receipt of rescue therapy (like surgical drainage).
Before I go on, I should say that most of these are surrogate endpoints. Being alive and functional are what most patients care about.
These were 78-year-old patients about 42% were female. Most had smaller hematomas and decent function. Patients with large hematomas and poor neurologic function were excluded.
About 85% of the usual care arm received something called prothrombin complex concentrate—which is a mixture of blood products used to reverse anticoagulants, but it is not specifically an antidote for the DOAC agent.
Results
Efficacy: For the chosen surrogate endpoints, andexanet worked. The overall hemostatic efficacy was superior in the andexanet group (67% vs 53%). The absolute risk increase was 13 percentage points, and the p-value was 0.003.
The composite was driven mostly by better outcomes in the hematoma expansion arm. More in the andexanet group had less than 35% expansion (77% vs 65%). For the other two components (NIHSS and no receipt of rescue) the rates were fairly similar in both arms.
Success, then, right? The drug worked?
The Achilles heal of reversal agents is blood clotting. While they may stop the bleeding in one site, the reversal agent can activate clotting elsewhere.
Terrible analogy coning, but forgive me: Blood clotting in the body (medical term-hemostatic balance) is like a dance. Your blood dances between being thin enough not to clot and thick enough to clot when an injury occurs.
Safety: There were more thrombotic (clot-related) events in the andexanet arm vs usual care. It was 10.3% vs 5.6%. That’s nearly 2-fold more. Ischemic stroke occurred in 6.5% receiving andexanet vs 1.5% receiving usual care (difference, 5.0 percentage points; 95% CI, 1.5 to 8.8). MI occurred 4.2% vs 1.5%. There were no significant differences in overall death.
There were also similar numbers of patients in both arms (28 vs 31%) who had acceptable neurologic functioning at one month.
Discussion and Learning Points
The first point is that this trial beautifully shows how we must always have comparisons for reversal agents. Reversing the bleeding is not enough. You have to show that the reversal agent improves outcomes without bad things, like clotting events. And, ultimately, patients care most about being alive and neurologically well.
In this trial, the reversal agent did its job. It reduced expansion of the bleeding in the brain. But there was a cost: 5 more clotting events, 5 more strokes, 3 more heart attacks.
At 30 days, there was no difference in death, nor the number who had acceptable neurologic functioning.
The projected cost of andexanet is ≈ $22,000. These authors write that projected cost of andexanet alone would exceed the entire hospital reimbursement in 74% of patients by a median of $7604.
The final point, and the reason I love this topic, is that it shows how complex the human body is.
The Cartesian thinkers who see therapeutics as being able to fix one aspect of the body—as if it were a car—fail miserably.
Drugs, procedures and surgeries designed to target one problem (here bleeding) always have off-target effects. This is exactly why new treatments need to be tested in proper randomized controlled trials.
JMM
If you like our work here at Sensible Medicine, please consider being a supporter. We aim to be a place were neutral, non-conflicted medical education takes place.
I don’t know if H.L. Mencken ever had to be anti-coagulated, but he did give humanity this one wisecrack that should perhaps be chiseled in stone over the front door of every hospital: "For every complex problem there is a solution that is simple, straightforward, and wrong".
If we're talking about drugs that work but produce no benefit - how about statins? They do a great job of lowering cholesterol but have virtually no effect on all-cause mortality. Somehow though that doesn't affect most docs' religious devotion to them.