Riociguat and Balloon Pulmonary Angioplasty in Inoperable CTEPH: Sequence, Not Substitute
Frank's chronic clot sits too distal for surgery to reach. Whether medication and a catheter procedure compete for the same slot in his treatment, or actually work in sequence, is what divides the room.
Frank M., a 66-year-old man, has spent every summer for the past twenty years restoring an old wooden sailboat with his son, and this past July was the first time in two decades neither of them could get it more than a few hundred yards from the dock — Frank's breathlessness stopping them well short of open water. He had a documented pulmonary embolism eight years ago, treated with six months of anticoagulation and, he was told at the time, resolved. It was not. A ventilation-perfusion scan ordered for his progressive dyspnea this spring showed multiple mismatched segmental defects, and CT pulmonary angiography confirmed chronic, organized thrombus lining both lower-lobe pulmonary arteries — chronic thromboembolic pulmonary hypertension, not a new clot. Right heart catheterization showed a mean pulmonary artery pressure of 41mmHg and pulmonary vascular resistance of 6.5 Wood units — above the 4-Wood-unit floor the randomized trials in this disease used to decide who was sick enough to enrol. He was referred to a CTEPH center for surgical evaluation, and the surgical team's read, based on the distribution of his disease well into the distal, segmental branches on both sides rather than the more proximal, surgically accessible vessels pulmonary endarterectomy is best suited to clear, was that he is not a good operative candidate — not because he couldn't tolerate the surgery, but because the disease itself sits in a place a scalpel can't usefully reach.
That leaves two real, non-surgical paths, and the team disagrees about which comes first. Riociguat, a soluble guanylate cyclase stimulator, was studied in inoperable and persistent CTEPH in CHEST-1 (Ghofrani and colleagues, 2013), improved six-minute walk distance and pulmonary vascular resistance, and remains the only medication carrying a formal indication for this exact population. Balloon pulmonary angioplasty mechanically dilates the same distal, surgically inaccessible vessels riociguat can only reach pharmacologically — and, contrary to how it is usually described, it is not registry-only. Two randomized trials have put it head-to-head against riociguat here. RACE (Jaïs and colleagues, 2022) enrolled treatment-naive patients above 4 Wood units — Frank's own entry ticket — and found resistance at 26 weeks down to 39.9% of baseline with angioplasty against riociguat's 66.7%; MR BPA (Kawakami and colleagues, 2022) ran the same direction on mean pulmonary artery pressure at twelve months. Both also confirmed the cost the registries had flagged: procedural complications, hemoptysis foremost. So nobody here is weighing proven against unproven. Two therapies have each been measured in his own hemodynamic band, and the disagreement is about what the trials measuring them were built to answer — a question about trial design, not about whether either works.
CTEPH center multidisciplinary review
Riociguat carries the formal indication for exactly his situation, established by CHEST-1's improvement in six-minute walk distance and pulmonary vascular resistance. It's non-invasive, it's reversible if it doesn't help, and — this is the part I keep coming back to — its benefit doesn't depend on who happens to be holding the wire. RACE and MR BPA were both run at centers doing this constantly. I am not disputing their numbers. I am asking whether their complication rates come with us when we refer him, and I don't think anybody in this room actually knows.
That's a fair question and it's a different one from the one you opened with, so let's be clear about what we're conceding to each other. Angioplasty is not a registry-only intervention any more. RACE and MR BPA both randomized it head-to-head against riociguat in inoperable CTEPH, and both favored the catheter on the hemodynamic endpoint — RACE had resistance down to 39.9% of baseline at 26 weeks against riociguat's 66.7%.
And RACE enrolled above 4 Wood units. He's at 6.5. That's not a trial I'm stretching toward him — it's a trial that would have taken him. Your transferability worry is real, but notice where it leaves us: it's an argument against referring anyone anywhere for anything operator-dependent, and we refer for endarterectomy on exactly the same kind of center-specific data without blinking. If the objection is that we should send him somewhere good, I agree. If it's that the evidence is thinner on my side, that stopped being true in 2022.
You've both been arguing about which trial to follow, and neither trial asked our question. RACE and MR BPA were designed to compare these therapies. But look at what RACE did after the primary endpoint: it took the patients still above 4 Wood units at 26 weeks and gave them the other therapy — riociguat after the catheter, the catheter after riociguat. A trial that ends by combining its own two arms is telling you the comparison was the wrong frame. So: start riociguat now and refer for a planned angioplasty series, not riociguat instead of angioplasty. One caution about my own reasoning, because I want it on the record — the usual justification for pre-treating, that lowering resistance first reduces reperfusion pulmonary edema, is convention at CTEPH centers and is mechanistically sound, but it has never been randomized. I'm sequencing on the strength of RACE's ancillary design, which is real, and not on the edema argument, which everyone repeats and nobody has tested.
Agreed: start riociguat now, with interventional referral placed for a planned balloon pulmonary angioplasty series once his hemodynamics have had a chance to improve.
Not agreed: how much RACE's and MR BPA's results survive the trip from an expert center to wherever Frank is actually treated. The pulmonary hypertension specialist holds that a procedural effect size is only as good as the operator reproducing it, and would want volume figures from the receiving center before committing. The interventional cardiologist regards that standard as one no procedure has ever met prospectively, endarterectomy included. Both noticed, without resolving it, that the sequencing they did agree on rests on a trial's secondary design choice rather than on anything either trial set out to test — which is a thinner foundation than the confidence in the room reflected.