John Mandrola, MD

Twitter thread coming on what @adamcifu @VPrasadMDMPH @AndrewFoy82 and I think is the BEST approach to pt care. This is ... The Case for Being a Medical Conservative. amjmed.com/article/S0002-… Thanks to the @amjmed for publishing this.

@djc795 @EricTopol You could have worse afflictions

@EricTopol As someone who has had 4 kidney stones, the solution for me is indirect forced hydration via caffeine addiction. Never had a stone during the periods of my life when I’ve been caffeine addicted.

If you've had a kidney stone, you've been advised that the most important thing to prevent another bout is to increase hydration. Now a randomized trial of hydration in over 1600 participants showed no benefit, despite evidence of increase during volume. thelancet.com/journals/lance…

I’m full time in EP with about 75-80% average RVU productivity. For me, prior auth is a rare bimomthly thing. 95% resolved by sending complete chart. Maybe I am a outlier

Shocked I am about the explosion of detailed critical appraisal that emerges when trial results upend a common practice. Grin. Double grin.

@TaiebPhil @kaulcsmc @AndrewFoy82 — interesting how robust critical appraisal is when trials go the “wrong” way. All the above points can easily be rebutted.

Here are my reservations on the CLOSURE-AF findings: I would have no difficulty accepting a trial showing that LAAO is inferior to medical therapy. But if a trial fails, the reason for that failure should make clinical sense — whether due to lower efficacy for stroke prevention or a lack of meaningful bleeding reduction. What I struggle with is the reflex to blindly accept evidence uncritically when it appears to contradict clinical logic so directly. A few points stand out: 1. The medical arm does not reflect true high-bleeding-risk practice. More than 85% of patients in the medical therapy arm were treated with DOACs or even more intensive antithrombotic regimens. That is difficult to reconcile with the population the trial is supposed to represent: patients at truly high bleeding risk or with contraindications to anticoagulation. Are we really supposed to believe that this group experienced fewer bleeding events than patients in the device arm, most of whom were on SAPT or no antithrombotic therapy after 3–6 months? 2. Crossover was substantial. Thirty-two patients crossed over to the medical arm, representing about 7% of the trial population. That is not trivial and complicates interpretation. 3. Procedural safety was unexpectedly poor. A periprocedural complication rate of 6.2% is strikingly high — more than 3 to 4 times higher than what has been reported in contemporary practice, including SURPASS (~1.3%) and even randomized data such as Amulet IDE. A periprocedural mortality rate of 1.2% is frankly alarming. For so-called expert centers, this is difficult to ignore. The 4.3% rate of periprocedural bleeding is also difficult to accept as representative of modern LAAO practice. In experienced hands, venous access with a 12–14 Fr sheath — especially when closed with ProGlide or even a figure-of-8 stitch — should rarely lead to clinically significant bleeding in patients who are not anticoagulated. It is also notable that no meaningful subanalysis was presented by device type, despite prior signals suggesting differences in procedural safety between platforms. 4. The bleeding signal may actually favor LAAO over time. Bleeding beyond 3–6 months was lower in the device arm than in the medical arm. That is exactly what one would expect biologically. LAAO exchanges an upfront procedural risk for a lower cumulative long-term bleeding burden. If so, the benefit should become more apparent with longer follow-up and the benefits might still appear after longer follow-up. In addition, this makes the loss to follow-up particularly important. As roughly 25% of patients were lost to follow-up after the first 6 months, that creates a meaningful bias against demonstrating the long-term advantage of LAAO. 5. The excess in cardiovascular death also raises mechanistic questions. The device arm showed more cardiac arrests and more MIs. But what is the plausible mechanism? A device-related embolic explanation seems unlikely given that ischemic stroke rates were similar between groups, and strokes account for the vast majority of AF-related systemic embolic events. A more plausible explanation would be procedural factors — air embolism, tamponade, thromboembolism — but if that is the case, then the issue is again procedural quality, not a true indictment of the LAAO strategy itself. I am very interested to see the results of CHAMPION-AF. This may end up being a situation similar to COAPT vs MITRA-FR: same concept, very different trial signals, and a very different interpretation once the dust settles. When data contradict common sense, the answer is not to abandon common sense immediately — it is to examine the data more carefully. #Cardiology #CardioTwitter #EPeeps #Afib #LAAO #StrokePrevention #ClinicalTrials #MedTwitter #StructuralHeart @NEJM @DFCapodanno @drjohnm @AsherElad @escardio

@kaulcsmc @JenaValve Does a “single arm” study count as a trial?

@drjohnm @JenaValve ALIGN-AR trial thelancet.com/journals/lance…

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Well past time for that. Trial would be stopped early for harm or futility in LAAC arm. #ResistTheUrge #HurryUpAndDoLess in the frail.

It’s even worse when you consider the priors, which are extremely dubious

Brilliant post 👇🏻 “What seems to be missed in this accumulation of arguments is straightforward: the burden of proof lies with LAAO, not with the control arm. The issue is the strength of the evidence supporting LAAO, not medical therapy, which remains the reference standard.”

Tomorrow I will have expanded coverage on the This Week in Cardiology (TWIC) podcast of CLOSURE, as well as some context for the upcoming CHAMPION trial to be presented at #ACC26 It will be crucial to be fully informed on CHAMPION's design before the results are presented

Translate: They remember the PREVAIL that did not show inferiority in the primary outcome of efficacy (composite of stroke, systemic embolism [SE], and cardiovascular/unexplained death), but in the coprimario (stroke or SE >7 days' postrandomization). In the FDA evaluation it did not pass.

PROTECT did not pass muster at FDA. This document is in the public realm but it’s not in the journals. In the journals, PROTECT looks like a positive trial; it clearly was not. Cc @AndrewFoy82

A deathly blow to left atrial appendage closure (LAAC)? In the CLOSURE-AF trial including 912 patients with AF at high risk for stroke and bleeding, LAAC was significantly worse than DOAC or other medical Rx nejm.org/doi/full/10.10… @NEJM

and it's inferior to the "why do we need higher evidentiary standards for FDA approval", this is the reason rather than asking the company to prove whether something is better, we approve drugs and devices and then sometimes* learn if it does or does not after many people receive it enormous wealth transfer at the expense of these patients and society at large *narrator: many things are never properly evaluated even after FDA approval

Another sobering result showing that the burden of proof for an invasive preventive strategy should be high. Kudos to @drjohnm, who has been saying this for years.

Finally getting some closure @IngoEitel nejm.org/doi/full/10.10…

@grok is pretty good at this trial’s appraisal

Perfect timing—and a bit of a cruel twist, one might say. In a week, CHAMPION-AF may tell a different story, but the long-awaited CLOSURE-AF, now out in @NEJM, makes for a tough week ahead for those supporting left atrial appendage closure. nejm.org/doi/full/10.10…

@cellisvandyep @drjohnm How is CHAMPION more important? PEP at 3y combines efficacy & safety endpoint, which typically but not always, is biased towards NI. It uses NI margin as risk difference which is typically permissive for NI. It excludes periprocedural bleeding which is biased against DOAC. BIASED

@drjohnm @AndrewFoy82 @MRuzieh Totally agree— esp with B and C. We often underestimate the bleeding risk of even SAPT in elderly pts. And Apixiban is a damn good OAC.