Pulmonary Hypertension Treatment: Tadalafil to Sotatercept

Treatment of pulmonary arterial hypertension starts with a phosphodiesterase 5 inhibitor such as tadalafil, adds an endothelin receptor antagonist such as macitentan within about a week, and escalates to triple therapy with a prostacyclin-pathway drug if the patient does not improve. Sotatercept, an antiproliferative drug, follows when triple therapy fails. Surgery, pulmonary endarterectomy, treats chronic thromboembolic disease.

That sequence is the working protocol of Dr. Biswarup Purkayastha, Consultant – Heart & Lung Transplant and Vascular Surgery, Artemis Hospitals, Gurugram, India, set out for referring doctors with his own starting doses. This article covers when to start treatment, the drug classes and the pathways they act on, how he prescribes and counsels, when to escalate, the evidence and cost of sotatercept, and the place of surgery. The definition, the groups and how the diagnosis is confirmed are covered in pulmonary hypertension diagnosis; the wider picture is in the complete guide to pulmonary hypertension.

When to start pulmonary hypertension treatment

Dr. Purkayastha's threshold is explicit: anyone with a mean pulmonary artery pressure over 20 mmHg and a pulmonary vascular resistance (PVR) of more than 2 Wood units should be started on therapy. At a minimum that means double therapy: a phosphodiesterase 5 inhibitor together with an endothelin receptor antagonist (a drug that blocks endothelin, a hormone that constricts the pulmonary vessels) such as macitentan, ambrisentan or bosentan. A prostacyclin-pathway drug can wait, but double therapy cannot.

Those numbers define pre-capillary pulmonary hypertension, which is why the right heart catheterisation matters before any prescription. The targeted drugs in this article are licensed for group 1 pulmonary arterial hypertension, and riociguat also for inoperable chronic thromboembolic pulmonary hypertension (CTEPH). In pulmonary hypertension caused by left heart disease or lung disease, guidelines direct treatment at the underlying heart or lung condition rather than at these drugs.

Three therapeutic targets in pulmonary hypertension

Asked to name the major pharmacological pathways, Dr. Purkayastha described three things a clinician wants to achieve:

1. Inhibit phosphodiesterase 5, so that the pulmonary vessels relax.
2. Stimulate soluble guanylate cyclase, the enzyme that produces cyclic GMP, so that the back pressure on the right ventricle eases and right ventricular dysfunction improves.
3. Retard smooth muscle proliferation and hypertrophy in the vessel wall.

Blocking that proliferation, he explained, lowers pulmonary arterial pressure quickly and reduces pulmonary vascular resistance. Until recently, the philosophy of treatment was always to stimulate one receptor or another, or one enzyme or another, to dilate the vessels. Nothing acted on the vessel wall itself. Sotatercept changed that: he likens it to a chemotherapeutic drug, because it prevents smooth muscle proliferation in the pulmonary vasculature. That is why he calls it the game changer.

Guidelines conventionally group the established drugs into three pathways: the endothelin pathway (endothelin receptor antagonists), the nitric oxide pathway (phosphodiesterase 5 inhibitors and soluble guanylate cyclase stimulators) and the prostacyclin pathway. Sotatercept, which inhibits activin signalling, adds a fourth, antiproliferative mechanism.

Pulmonary hypertension drug classes

The established targeted drugs fall into four classes.

Prostacyclin-pathway drugs

• Epoprostenol, an intravenous prostacyclin, which in Dr. Purkayastha's account drastically improves exercise capacity.
• Iloprost, an inhaled prostacyclin analogue taken several times a day. The dose has to be adjusted patient by patient; not every patient tolerates the same amount.
• Treprostinil, another prostacyclin analogue.
• Selexipag, an oral prostacyclin (IP) receptor agonist.

Endothelin receptor antagonists (ERAs): bosentan, ambrisentan and macitentan.

Phosphodiesterase 5 (PDE5) inhibitors: sildenafil and tadalafil. Tadalafil is Dr. Purkayastha's preferred drug.

Soluble guanylate cyclase stimulator: riociguat.

Starting doses: tadalafil and macitentan

For a patient with confirmed pulmonary arterial hypertension, his sequence is:

1. Start the PDE5 inhibitor at a low dose. Tadalafil 5 mg once a day for a patient of 60 kg or more; 2.5 mg once a day for a patient under 60 kg.
2. Build the dose up gradually over a week.
3. Add an endothelin receptor antagonist from the second week, either bosentan, ambrisentan or, his preference, macitentan. For an adult of 60 kg or more, his combination is macitentan 10 mg with tadalafil 5 mg once a day.
4. Give the combination early in the morning, during the patient's active hours, to reduce the risk of drug-related hypotension.

His preference for macitentan rests on the trial evidence: it improves the composite outcome and reduces morbidity and mortality events, the episodes of clinical worsening that matter to patients. This was shown in the SERAPHIN trial, in which macitentan 10 mg reduced the risk of the composite of morbidity and mortality events.

These starting doses are his personal practice for initiation. The licensed maintenance dose of tadalafil for pulmonary arterial hypertension is 40 mg once a day, so low starting doses are a step on the way to titration, not the end point.

Side effects and how to counsel patients

Dr. Purkayastha treats side-effect counselling as part of the prescription.

PDE5 inhibitors. Anyone started on a PDE5 inhibitor must be told two things: they may have fainting episodes from low blood pressure, and they may have prolonged erections. For younger men, his team has a counsellor or clinical psychologist sit down with the patient and explain that nothing is wrong with him and that this is part of the treatment. As the dose is built up, tolerance develops: the duration of erections gradually shortens, or patients become less bothered by it and find practical ways to manage, such as looser clothing. His message to patients is simple reassurance that they will be fine. An erection lasting more than four hours (priapism) is a rare but recognised emergency and needs urgent medical attention.

Selexipag. Patients are often reluctant to take it. Its common side effects are headache, diarrhoea, nausea, jaw pain, muscle and limb pain and flushing. It is given orally, 200 micrograms twice a day for most adults; for patients under 50 kg, his team prefers 100 micrograms twice a day. Selexipag is licensed to start at 200 micrograms twice a day and to be increased weekly to the highest tolerated dose, up to 1,600 micrograms twice a day.

Inhaled iloprost. Patients are warned about its recognised side effects: cough, flushing, headache, jaw pain and low blood pressure. Because the dose must be individualised, his team asks patients for constant feedback and adjusts the dose to balance relief of breathlessness against side effects.

When to escalate to triple combination therapy

If the patient remains symptomatic on double therapy, or the mean pulmonary artery pressure rises, the third component is added: an oral or inhaled prostacyclin-pathway drug, most often oral selexipag. Dr. Purkayastha's rule is that an endothelin receptor antagonist plus a PDE5 inhibitor plus a prostacyclin derivative is the first triple therapy that must be tried in every patient before anyone concludes that the disease is not responding. Declaring a patient a non-responder before that point, he says, "you cannot do that".

For a patient who remains symptomatic, the sequence he gave in the Live Discussion is to add an endothelin receptor antagonist, then oral selexipag if symptoms persist, and only then consider sotatercept.

Sotatercept for pulmonary arterial hypertension

Sotatercept is an antiproliferative drug, given as a subcutaneous injection once every three weeks. It is the drug Dr. Purkayastha calls "the magic drug" and "the newer magic drug on the block", because it acts on the remodelled vessel wall rather than only dilating it.

Sotatercept trial results

The trial he described was a double-blind randomised controlled trial against placebo, with an outcome that combined death, lung transplantation and hospitalisation for worsening pulmonary arterial hypertension lasting more than 24 hours. Death or an adverse outcome occurred in 17% of patients on sotatercept against almost 55% on placebo. That difference, in his words, cannot be a statistical artefact or a marginal result in which "it is marginally better than this"; it is a clear-cut indication that sotatercept is a game changer for group 1 pulmonary hypertension.

The US Food and Drug Administration approved sotatercept in March 2024 for adults with pulmonary arterial hypertension (WHO group 1); in the pivotal trials it was added to background therapy. Its recognised adverse effects include a rise in haemoglobin, a fall in platelet count, bleeding and small dilated blood vessels in the skin (telangiectasia), so haemoglobin and platelets are monitored during treatment.

Sotatercept cost and place in the sequence

Sotatercept is very expensive. Dr. Purkayastha put the cost at around US$10,000 a vial. In his treatment sequence, sotatercept deserves a definite trial once triple therapy has failed to produce a response for at least six months to a year.

A case from his clinic

His team is treating a patient referred from overseas who arrived with a right ventricular systolic pressure of 138 mmHg measured at right heart catheterisation. About two weeks into treatment, the patient's pulmonary arterial systolic pressure had come down from 138. "So yes, it may be an answer," he concluded, but only after triple therapy has had its chance.

Pulmonary endarterectomy for CTEPH

For group 4 disease, chronic thromboembolic pulmonary hypertension, the treatment is surgical. Pulmonary endarterectomy is the surgical removal of organised clot from the lining of the pulmonary arteries. Dr. Purkayastha describes it as "an absolute surgeon's joy" that "will nearly break your back". The operation is long and complex:

• the chest is opened and the patient is placed on cardiopulmonary bypass;
• the patient is cooled to 16 degrees;
• the procedure runs to close to 8 to 10 hours;
• both lungs are cleared of the obstructing thromboembolic material.

Pulmonary endarterectomy is the treatment of choice for operable CTEPH under the 2022 ESC/ERS guidelines. For patients whose disease is inoperable, riociguat and balloon pulmonary angioplasty are the established alternatives. CTEPH surgery is, as he puts it, another important aspect of pulmonary hypertension care, and it requires a centre with an experienced surgical and anaesthetic team. Indicative figures for comparable cardiac operations are on the heart surgery cost page. How acute pulmonary embolism is managed, and how unresolved clot leads to endarterectomy, is covered in Dr. Purkayastha's session on pulmonary embolism, from clot retrieval to pulmonary endarterectomy.

The pulmonary hypertension treatment ladder in summary

• Confirm pre-capillary pulmonary hypertension at right heart catheterisation: mean pulmonary artery pressure above 20 mmHg and PVR above 2 Wood units.
• Start tadalafil at 2.5 or 5 mg once a day by body weight, and build up over a week.
• Add an endothelin receptor antagonist from the second week, preferably macitentan 10 mg, given in the morning.
• Escalate to triple therapy with selexipag or another prostacyclin-pathway drug if symptoms or pressures do not improve.
• Consider sotatercept once triple therapy has failed for at least six months to a year.
• Operate on operable CTEPH with pulmonary endarterectomy.
• Counsel at every step, especially on hypotension and prolonged erections.

The dosing and escalation questions doctors raised during the session, including how to handle the erectile effects of PDE5 inhibitors, are collected in the Live Discussion. Dr. Purkayastha's profile is on his doctor page.