CTEPH Requires Careful, Targeted Counseling

Although rare, chronic thromboembolic pulmonary arterial hypertension (CTEPH) is of growing interest to specialty pharmacists and that interest is galvanized by the fact that without treatment, this disease is often fatal within 2 years, and until recently, there were no FDA-approved pharmacologic treatments. Now the approximately 5% of individuals who develop this progressive disease following a venous thromboembolism have a pharmacologic option.

Previously, the only treatment was surgical (pulmonary endarterectomy), which has the potential to be curative but is contraindicated in patients who have unreachable disease or significant comorbidities and/or advanced age. Additionally, up to one-third of patients have residual pulmonary hypertension following surgery. Some patients were treated offlabel with pulmonary arterial hypertension (PAH) therapies, the only alternative for nonoperable or recurrent CTEPH at the time. Since 2013, however, riociguat has been available following accelerated FDA approval.

At the Asembia Specialty Pharmacy Summit 2019, Dustin Fraidenburg, MD, discussed this new targeted treatment and its novel mechanism of action. He noted that patients who develop CTEPH experience a chronic increase in right ventricular afterload. Subsequently, they develop increased wall thickness and cell size that initially stimulates adaptive remodeling that improves function. Over time, however, the right ventricle fails and the patient develops cardiac hypertrophy, dilatation, reduced cardiac contractility, and myocardial fibrosis.

Large emboli, recurrent pulmonary embolism, and insufficient anticoagulation are risk factors for CTEPH. Approximately 40% of patients are inoperable, and all patients—inoperable or operable—require lifelong anticoagulation. Fraidenburg covered off-label use of the medications approved for PAH, stressing that these are used because of the overlapping pathophysiology between CTEPH and PAH.

Fraidenburg also discussed riociguat and its propensity to address the underlying pathophysiology associated with CTEPH. An advantage of this treatment is that it is administered by mouth and its adverse effects tend to be mild. Many drugs used to treat PAH must be infused intravenously. It is teratogenic; therefore, it has a boxed warning and risk evaluation and mitigation strategy (REMS) program. It also interacts with numerous drugs, including strong CYP inhibitors and nitrates. Pharmacists should take note that smokers can expect to have plasma riociguat concentrations that are 50% lower than nonsmokers’ and may require higher doses.

Rebekah H. Anguiano, PharmD, BCPS, BCACP, addressed unique concerns for specialty pharmacists. She reviewed the numerous counseling points and dosing, drug interactions, contraindications, and REMS programs for teratogenicity. She stressed that adherence counseling is critical. The only FDA-approved drug, riociguat, is titrated based on tolerability and taken 3 times daily. If 3 days or more are missed, then it must be retitrated.

She also noted that off-label use of macitentan requires clear counseling. It is teratogenic and therefore also has a REMS program to reduce the risk of pregnancy. Female patients of reproductive potential must have baseline and ongoing monthly pregnancy tests and continuously use effective contraception. Anguiano emphasized that patients with CTEPH need annual flu vaccines and counseling about lifelong adherence to anticoagulation and, if they smoke, tobacco cessation.

Anguiano added that specialty pharmacists can have a tremendous impact on patients with CTEPH. Pharmacists can help their health care organizations create algorithms for diagnosing this deadly disease and ensure that patients are referred to pulmonary hypertension expert centers for evaluation and appropriate pharmacologic treatment when indicated.