Updates on diagnosis & management of pulmonary hypertension from 6th WSPH & OPTIMA study
Latest evidence on diagnosis and management of pulmonary hypertension (PH) has led to the development of practical recommendations by a taskforce of the 6th World Symposium on Pulmonary Hypertension (WSPH) in Nice, France, to help improve patient outcomes and identify future research directions. Early initiation of endothelin receptor antagonist (ERA)/phosphodiesterase type-5 (PDE5) inhibitor combination therapy is now recommended based on results of the recently published OPTIMA study, which showed improved outcomes with macitentan/tadalafil combination therapy in patients with newly-diagnosed pulmonary arterial hypertension (PAH).
Insights from 6th WSPH
Major revisions were made to the haemodynamic definition of PH, as well as use of risk stratification tools and treatment recommendations, to reflect latest evidence on diagnosis and management of the condition. [Pulm Ther 2020;6:9-22]
PH mPAP cut-off: Lowered to 20 mm Hg
PH should now be defined as a mean pulmonary artery pressure (mPAP) of >20 mm Hg – a decrease from the previous definition of mPAP ≥25 mm Hg.
This update was based on four studies which suggested that pulmonary pressures >20 mm Hg were associated with worse clinical outcomes. Moreover, several large studies demonstrated worse survival in patients with borderline PH. [Eur Respir J 2018;51:1701197; Am J Respir Crit Care Med 2018;197:509-516; Circulation 2016;133:1240-1248]
While awaiting implications of the new definition of PH to unfold, there continues to be uncertainty about treatment of patients with mPAP >20 mm Hg and ≤25 mm Hg. Further studies are warranted to better define this patient subgroup and compile appropriate management strategies accordingly.
Risk stratification tools
Several well-validated risk stratification tools for PAH were developed to aid treatment selection and treatment response assessment.
The Registry to Evaluate Early and Long-Term PAH Disease management (REVEAL) tool contains 12–14 variables to predict 5-year mortality in patients with PAH. [Chest 2015;148:1043-1054] Meanwhile, the Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA), Swedish PAH Registry (SPAHR), and French Pulmonary Hypertension Network (FPHN) have developed similar tools using data from large registries. [Eur Respir J 2017;50:1700740; Eur Heart J 2018;39:4175-4181; Eur Respir J 2017;50:1700889]
All of these tools have similar efficacy in identifying patients at high risk, and in stratifying patients who are at low, intermediate or high risk of mortality at 1 year. [Eur Respir J 2019;53:1801889]
Treatment algorithm for group 1 PAH
The 6th WSPH taskforce also updated the treatment algorithm for group 1 PAH, recommending vasoreactivity testing only in patients with idiopathic PAH, heritable PAH, and PAH associated with drugs and toxins. (Figure)
Vasoreactive patients should be treated with calcium channel blocker monotherapy, with progressive uptitration under the supervision of a PH expert.
For non-vasoreactive patients with group 1 PAH who are at low or intermediate risk, the taskforce recommends initial oral combination therapy with ERA and PDE5 inhibitor. For high-risk patients, intravenous prostacyclin analogue (IV PCA) (alone or in combination) should be the treatment of choice. Monotherapy should be used only under certain circumstances and should not be a substitute for combination therapy when appropriate.
Patients should be re-evaluated 3–6 months after treatment initiation. Treatment should be continued if a low-risk status is achieved. For patients at intermediate risk after the initial treatment period, escalation to double or triple therapy is recommended. Those at high risk after the initial treatment period should have therapy escalated to maximal medical therapy including IV PCA.
OPTIMA: Macitentan plus tadalafil in newly-diagnosed PAH
The efficacy and safety of combination therapy with the ERA macitentan and PDE5 inhibitor tadalafil were evaluated in newly-diagnosed PAH patients in the OPTIMA study.
OPTIMA was a prospective, multicentre, single-arm, phase IV study that included 46 patients with newly-diagnosed idiopathic, heritable or associated PAH, and a WHO functional class (FC) of II–III. All patients received macitentan 10 mg once daily, in combination with tadalafil 20 mg once daily initially and uptitrated to 40 mg once daily at day 8±3. Treatment was given for 16 weeks or until PAH progression requiring administration of other PAH drugs. [Eur Respir J 2020;56:2000673]
The study’s primary endpoint was change in pulmonary vascular resistance (PVR) from baseline at week 16, as assessed by right heart catheterization. Secondary endpoints included percentage of patients achieving PVR decrease of ≥30 percent from baseline at week 16, change from baseline to week 16 in mean right atrial pressure, mPAP, cardiac index, total pulmonary resistance, mixed venous oxygen saturation, 6-minute walk distance (6MWD), FC, N-terminal pro-brain natriuretic peptide (NT-proBNP), and percentage of patients with improvement/worsening in FC at week 16.
At 16 weeks, PVR was significantly improved by 47 percent compared with baseline (mean, 6.5 vs 11.7 Wood units; geometric mean ratio, 0.53; 95 percent confidence interval [CI], 0.47 to 0.59; p<0.0001). Eighty-seven percent of patients had ≥30 percent decrease in PVR.
Significant improvements were also observed in 6MWD (mean change from baseline, 35.8 m; 95 percent CI, 15.8 to 55.9 m; p=0.0008) and NT-proBNP level (geometric mean ratio, 0.32; 95 percent CI, 0.23 to 0.44; p<0.0001), as well as in mPAP, cardiac index, total pulmonary resistance and mixed venous oxygen saturation. Sixty-three percent of patients had improvements in FC, while no FC worsening was noted.
Collectively, 65.2 percent of patients had an increase in the number of noninvasive low-risk criteria (ie, FC I/II, 6MWD >400 m, NT-proBNP <300 ng/L).
The safety profile of macitentan/tadalafil combination therapy was generally consistent with previous data for macitentan in combination with PDE5 inhibitors. The most frequent adverse events (AEs) were peripheral oedema (28.3 percent), headache (23.9 percent), diarrhoea (19.6 percent), dyspnoea (15.2 percent), anaemia (13.0 percent) and asthenia (13.0 percent). Serious AEs were reported in 28.3 percent of patients. Three patients (6.5 percent) discontinued treatment due to AEs. No new safety signals were observed during long-term follow-up.
The OPTIMA study showed that combination therapy with macitentan plus tadalafil led to significant improvements in haemodynamic parameters, 6MWD, NT-proBNP levels and FC in patients with newly-diagnosed PAH.
In line with recommendations by the 6th WSPH taskforce, results of the OPTIMA study support early use of ERA/PDE5 inhibitor combination therapy in patients with PAH.