Initial combination therapy with macitentan and tadalal in pulmonary arterial hypertension: a retrospective cohort study

Purpose: Initial combination therapy with ambrisentan and tadalal has been demonstrated superior to either agent alone in pulmonary arterial hypertension (PAH). More recently, the OPTIMA trial showed ecacy of another combination of endothelin receptor antagonist and phosphodiesterase 5-inhibitor, macitentan and tadalal, as initial therapy for PAH. The objective of this study was to assess the effectiveness, tolerability, and safety of macitentan and tadalal in a real-world clinical setting. Methods: This single centre, retrospective cohort study identied adult patients newly diagnosed with PAH between January 2014 and December 2017 who were started on macitentan and tadalal. Patients were retrospectively followed for one year. Effectiveness was evaluated via change from baseline in disease risk prole based on a validated score incorporating World Health Organization functional class, 6-minute walk distance (6MWD), B-type natriuretic peptide (BNP), and hemodynamics on follow-up right heart catheterization. Secondary endpoints included change in 6MWD, BNP, and hemodynamic variables. Drug tolerability and adverse events were assessed. Results: The cohort included 46 patients, 8 of whom (17%) did not tolerate and discontinued either macitentan or tadalal. Median time to follow-up was 161 days (IQR 72). 42% of patients with an initially moderate or high risk disease prole improved to low risk. Secondary endpoints showed a reduction in the geometric mean of pulmonary vascular resistance of 45% (95% CI 29, 57%) and improvement in 6MWD of 88m (95% CI 27, 148m). Conclusion: In a real-world setting, macitentan and tadalal as initial combination therapy for PAH was well tolerated and yielded clinical benet.


Background
Pulmonary arterial hypertension (PAH) is a disease characterized by vascular remodelling leading to progressive elevation of pulmonary vascular resistance, right heart failure and death [1]. While there is no cure to the proliferative pulmonary arteriopathy, three mechanistically different pathways are known that may be targeted pharmacologically to delay disease progression [2]. The AMBITION trial demonstrated that, in treatment-naïve patients, upfront combination therapy targeting two such pathways via ambrisentan (an endothelin receptor antagonist, ERA) and tadala l (a phosphodiesterase type 5 inhibitor, PDE-5i) was superior to either drug as monotherapy, with most of this bene t derived from a lower rate of hospitalization for worsening PAH [3,4].
Based in part on these ndings, initial combination therapy with ERA/PDE-5i has become a recommended treatment strategy in patients newly diagnosed with PAH, although the interchangeability of different ERA/PDE5-i agents is not certain [5,6]. Macitentan is a relatively newer ERA with higher biochemical antagonistic potency, longer half-life and suggested improved adverse effect pro le compared to ambrisentan [7]. Most recently, the prospective OPTIMA trial showed macitentan and tadala l were well tolerated and resulted in a 47% reduction in the geometric mean of pulmonary vascular resistance after 16 weeks of therapy compared to baseline [8].
While the OPTIMA trial demonstrated the relative e cacy of macitentan and tadala l, we sought to add to this experience by assessing the effectiveness of macitentan and tadala l in a real-world clinical setting over longer follow-up and with particular focus on improvement in validated, guideline-based disease risk category [5].

Methods
We conducted a single-centre, retrospective cohort study. Consecutive patients referred to the Pulmonary Hypertension Program at the Toronto General Hospital between January 2014 and December 2017 were eligible for inclusion. A manual chart review identi ed patients started on upfront combination therapy with macitentan and tadala l. Patient records were reviewed for treatment effect, safety, and tolerability of macitentan and tadala l over one year of follow-up. The study was approved by the institutional Ethics Board (UHN17-5845).

Inclusion and Exclusion Criteria
Individuals aged 18 years and older were included if they were newly diagnosed with PAH in the previous 6 months and started on macitentan and tadala l within 6 weeks of one another. Full doses consisted of macitentan 10mg and tadala l 40mg daily. PAH etiologies included idiopathic, heritable, and PAH associated with anorexigen use, connective tissue disease (CTD), congenital heart disease, or human immunode ciency virus infection. A diagnosis of PAH was established by right heart catheterization (RHC) demonstrating mean pulmonary arterial pressure (mPAP) of ≥25mm Hg , pulmonary capillary wedge pressure (PCWP) ≤15mm Hg , and pulmonary vascular resistance (PVR) of ≥3 Wood Units (WU).
Exclusion criteria consisted of PAH secondary to portopulmonary hypertension, concurrent therapy with a prostacyclin, or any prior PAH-speci c therapy.

Effectiveness
Treatment effects of macitentan and tadala l were assessed in all individuals who received at least one dose of each drug, similar to an intention-to-treat analysis. Effectiveness was evaluated over one year of follow-up based on the 2015 European Society of Cardiology (ESC)/European Respiratory Society (ERS) risk assessment table for prognostication in PAH [5]. We examined change in World Health Organization . For three patients who expired during the one-year study, highest risk categories were imputed on follow-up. Overall risk pro les at baseline and follow-up were calculated by taking the mean value among all prognostic variables rounded to the nearest integer. The primary endpoint was percentage of patients improving to the low overall risk category following treatment with macitentan and tadala l. Secondary endpoints were changes in WHO FC, 6MWD, BNP, and hemodynamic variables on follow-up RHC. For the three patients who expired, the worst value recorded in the study was imputed for each variable on follow-up. For all other individuals, each patient's baseline data was imputed on followup wherever the latter was missing (Table S1).

Tolerability and Safety
Safety endpoints assessed were the occurrence of hypotension (systolic blood pressure <85mm Hg or diastolic blood pressure <50mm Hg ), edema (new or worsening peripheral edema), headache, anemia (hemoglobin decline ≥15g/L from baseline to an absolute value <100g/L) or liver enzyme elevation (transaminases greater than 3 times the upper limit of normal) within one year of follow-up. Tolerability endpoints included agent discontinuation as well as reason for and time to discontinuation.

Statistics
Simple descriptive statistics were used to express patient characteristics and the primary endpoint. Change in categorical variables before and after treatment was assessed using a Chi squared/Fisher's exact test, as appropriate. Secondary endpoints consisting of change in continuous variables were estimated by simple linear regression; BNP, PVR, and CI data were lognormally distributed and the ratio of geometric means at baseline and follow-up was used to assess change.

Results
Between January 2014 and December 2017, 46 patients newly diagnosed with PAH were started on combination therapy with macitentan and tadala l, receiving at least one dose of each medication. Demographic data and disease etiology are presented in Table 1. The median age was 56 years and 85% of patients were female. The etiology of PAH was relatively evenly divided between idiopathic PAH (50%) and PAH associated with connective tissue disease (43%), most commonly scleroderma (26%).  (7) Systemic lupus erythematosus 2 (4)

Effectiveness
Cohort composition by overall risk category at baseline and follow-up is shown in Figure 1. The median time from start of therapy to follow-up and reassessment via RHC was 161 days (IQR 72). Forty-three of 46 patients (93%) were at high or intermediate risk at baseline, of whom 18 patients (42%) met the primary endpoint and improved to low risk category on follow-up. Three patients died within 6 months of starting treatment: 2 were initially at moderate risk and did not tolerate macitentan, discontinuing the drug within one week of initiation, and 1 was initially high risk and remained so despite dual therapy. All 3 individuals who died were women with scleroderma aged >65 years.
Changes in PAH prognostic variables at baseline and follow-up are described in Table 2 analysis was restricted to the subset of patients who tolerated and did not discontinue macitentan or tadala l (Table S2). Change in risk category for individual PAH prognostic variables as per 2015 ESC/ERS guidelines are shown in Table S3. Adverse events and drug discontinuations are summarized in Table 3. In total, 8 of 46 patients (5 macitentan and 3 tadala l; 17% total) discontinued therapy due to an adverse effect or intolerance. Baseline characteristics of individuals who discontinued either macitentan or tadala l are shown in Table  S4. Of these 8 patients, 2 expired within one year due to progressive disease, having only tolerated tadala l monotherapy. Two other patients who discontinued macitentan or tadala l went on with monotherapy; the remaining 4 had the ERA or PDE-5i substituted with a different drug of the same class.
The most common adverse events associated with combination therapy were headache and edema, occurring in 50% and 30% of individuals, respectively. Headache occurred within days of starting therapy, resulting in discontinuation of tadala l in 2 individuals (4%). A further 4 cases required transient stopping and gradual re-introduction of tadala l. Edema led to discontinuation of macitentan in 3 cases (7%), of which two patients required admission to hospital for intravenous diuresis.
Anemia occurred in 6 cases (13%) between 20 to 171 days of starting macitentan. Three of these cases were complicated by superimposed confounding factors felt to be the primary drivers of the anemia. One case required red blood cell transfusion, but anemia did not lead to discontinuation of macitentan in any of the 6 cases. Transaminitis greater than 3 times the upper limit of normal occurred in one patient 22 days after initiation of macitentan, reaching an ALT of 230 IU and AST of 456 IU from previously normal baseline values. Macitentan was discontinued and the patient was later started on ambrisentan without recurrence of transaminitis.
An additional 2 patients discontinued PAH therapy due to other adverse effects. One patient elected to stop tadala l 18 days from initiation due to signi cant epistaxis, though this was also in the setting of a supratherapeutic INR of 5 and felt unlikely to be related to tadala l. In another case, macitentan was discontinued within 8 days due to unremitting nausea and decreased appetite, possibly confounded by worsening PAH.

Discussion
Our study describes a Canadian experience with macitentan and tadala l as initial therapy for newly diagnosed PAH. Among this cohort, a majority of individuals (83%) tolerated macitentan and tadala l, and 42% of patients with initially moderate or high risk disease improved to low risk based on a validated prognostic score composed of WHO functional class, 6MWD, BNP, and hemodynamic parameters [5,9]. These ndings provide real-world effectiveness data supporting the use of this particular ERA/PDE5-i combination, which has only been speci cally studied in one previous trial [8].
While the AMBITION trial demonstrated that initial combination therapy with ambrisentan and tadala l reduced the composite endpoint of death or worsening PAH compared to either drug in monotherapy [3], generalizability to all ERA/PDE-5i combinations is not guaranteed. Indirect data from the SERAPHIN trial suggests bene t of macitentan and PDE-5i. The addition of macitentan to background PDE-5i therapy (62% of trial patients) in this study reduced the primary endpoint of morbidity and mortality by 38%, similar to those not on background therapy [10]. However, of those individuals on background therapy, most were on sildena l and had been stabilized on this drug for at least 3 months, limiting the information that can be extrapolated regarding the particular combination of macitentan and tadala l [11]. This led to the French OPTIMA trial designed speci cally to examine macitentan and tadala l in newly diagnosed PAH over 16 weeks [8]. This prospective, open-label, single-arm, multicentre trial enrolled 46 patients and found treatment with macitentan and tadala l led to a 47% reduction in the geometric mean of PVR and 36m improvement in 6MWD [8]. Only 2 individuals discontinued drug therapy before 16 weeks due to either a revision in etiology of PAH or an adverse event.
Our ndings con rm the results of the OPTIMA trial outside of the rigorous trial setting. Speci cally, we observed a near-identical reduction in PVR of 45%, as well as an improvement in 6MWD of 88m. Compared to OPTIMA, we found more individuals discontinued either macitentan or tadala l due to adverse effects (17% compared to 4%). While the lower number of discontinuations in OPTIMA likely re ects selection bias in the highly motivated patients who took part in the trial, the current study continues to suggest that this combination is well-tolerated in most individuals with relatively minor adverse effects. We observed headache considerably more frequently in the current study compared to OPTIMA (50% vs 24%), while instances of edema, anemia, and transaminitis were similar (30% vs 28%, 13 vs 13%, 2% vs 2%, respectively). All adverse effects were comparable to previous major trials [3,10], and there were no cases of treatment discontinuation due to anemia or transaminitis.
The current study has several strengths, including a real-world setting, lengthy follow-up time of one year that exceeds most trials in PAH, and application of the validated ESC/ERC prognostic score for assessing response to therapy and low-risk disease status as a primary outcome. This prognostic score has been independently validated in three studies [12][13][14] and constitutes an endpoint that is increasingly recognized and clinically relevant to long-term outcomes in PAH [9]. Furthermore, follow-up assessment of hemodynamics on RHC was available for a vast majority of individuals in the current study, demonstrating meaningful improvement in physiologic variables shown to be directly related to improved clinical outcomes [15]. Although a retrospective trial design, analysis was conducted as intention-to-treat and missing data was handled as conservatively as possible, either carrying forward baseline values or imputing the worst value observed across the entire study for those patients who died. This lends credibility to the signi cant bene cial effect observed. The limitations of the study include its retrospective nature, small number of participants, lack of control group, and possible bias in clinician selection of those individuals to start on dual oral therapy. While the study was restricted to a single Canadian centre, the close agreement of the current results with the French OPTIMA trial is reassuring with regards to the generalizability of the ndings.

Conclusions
Our retrospective analysis suggests that macitentan and tadala l are a viable ERA/PDE-5i combination in a real-world setting. Drug tolerability remained high and 42% of individuals who started as intermediate or high risk had improved to a low risk pro le, which has been associated with excellent 5-year transplantfree survival. However, approximately 60% remained intermediate or high risk, highlighting the limitations of initial oral combination therapy.

Declarations
Funding: This research did not receive any speci c grant from funding agencies in the public, commercial or not-for-pro t sectors.
Con icts of interest: The authors declare that they have no competing interests.
Availability of data and materials: The datasets generated and/or analysed during the current study are not publicly available but are available from the corresponding author on request.