Combination Therapy in Pulmonary Arterial Hypertension: Is This the New Standard of Care?

Pulmonary arterial hypertension (PAH) is a rare, progressive, and potentially fatal cardiopulmonary syndrome that imposes a significant burden on patients in terms of morbidity and mortality, and on managed care organizations in terms of resource utilization. The majority of PAH-approved therapies are high-touch, high-management, high-cost treatments dispensed through specialty pharmacies. Current treatment guidelines recommend combination therapy for patients who show inadequate clinical response or who deteriorate on monotherapy. Combination therapies target 2, or sometimes 3, distinct PAH-associated signaling pathways: the endothelin, prostacyclin, and nitric oxide pathways. Registry data suggest that combination therapy is utilized in more than half of patients with PAH in the United States. Evidence supporting the use of combination therapy is provided through clinical trials, retrospective research, registry data, and expert guidelines. Managed care decision makers are charged with making population-based decisions on resource allocation. These decision makers must always consider cost, but must also be aware that clinical evidence suggests that early treatment with combination therapy can significantly reduce disease burden, may reduce hospitalizations, and should be considered when making coverage decisions.

Am J Manag Care. 2015;21:S151-S161Introduction

Pulmonary arterial hypertension (PAH), a subset of pulmonary hypertension conditions, is a rare but potentially fatal cardiopulmonary syndrome characterized by an abnormally high resting mean pulmonary arterial pressure (greater than or equal to 25 mm Hg), increased pulmonary vascular resistance (PVR) (greater than 3 Woods units), and a pulmonary arterial wedge pressure less than or equal to 15 mm Hg. Derangements in the 3 key biologic pathways (endothelin [ET], nitric oxide [NO], and prostacyclin [PGI₂]) in the pulmonary arterioles result in remodeling of the pulmonary vasculature, with progressive right heart dysfunction and, ultimately, right heart failure and death.^1-7 The annual incidence and prevalence of PAH in the United States has been reported as 2.3 and 12.4 cases per million, respectively.⁸ The 1-year incident mortality rate is 15%.^6,9 Recent estimates from REVEAL (Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management) indicate that patients receiving PAH-specific treatment have a median survival of more than 7 years after diagnosis.⁶

The use of combination therapy was confirmed by the REVEAL data, which disclosed that at the time of enrollment, 46% of patients were taking 2 medications for PAH, and nearly 9% were taking 3 medications for PAH.^3,10-12 Additionally, 13 randomized controlled trials (RCTs)—almost half (43%) of major PAH trials— include a group of patients receiving combination therapy with 1 or more approved PAH drugs.³ This is in part due to the ethical implications of conducting placebo-controlled studies with patients deprived of active treatment already proved to deter PAH progression. Recent trials have proved the safety and efficacy of combination therapies, including risk reduction in morbidity and mortality and decreased hospitalization.

Although there is no cure for PAH, there are 12 approved drug therapies to treat the disease. Most of these therapies are dispensed through specialty pharmacies and are high-touch drugs with associated higher costs. Altogether, drug prescriptions dispensed through the specialty channel from 2013 to 2014 increased 5.8%, accounting for a 30.9% increase in spend for specialty medications. These drugs also account for a growing share (31.8% in 2014, up from 27.7% in 2013) of total overall drug spend and are expected to continue along this trajectory. The increases estimated by this trend calculation are likely modest, as roughly half of specialty medication drug costs are billed through the medical benefit and therefore are not included.¹³ The increased use of combination therapy and the increasing specialty drug spend present a challenge for managed care decision makers as they face the task of making decisions to allocate resources for the maximum benefit of their members. This article will provide these decision makers with information and evolving clinical evidence affirming the potential for combination PAH therapy to become the standard of care.

Treatment Pathways in PAH

Currently, 3 pathways are implicated, with others being studied, in the pathologic mechanisms that lead to pulmonary vasoconstriction, inflammation, fibrosis, thrombus in situ, and vasculature remodeling in patients with PAH (Figure 1).^14,15 These pathways include the ET, PGI₂, and NO pathways and are targets for the current drug therapies. Approved PAH therapies include ET receptor antagonists (ERAs), prostacyclin analogues, phosphodiesterase-5 (PDE5) inhibitors, and a soluble guanylate cyclase (sGC) stimulator.^3,7,14,16

ET-1 is a potent vasoconstrictor that induces vasoconstriction, smooth muscle cell proliferation, and fibrosis.¹⁷ ET-1 acts via 2 receptors, ETA and ETB. In patients with PAH, elevated levels of ET-1 are commonly seen in the circulation and in the lungs, making it a natural target for pharmacologic blockade (Table 1).^7,18-29

In patients with PAH, there is often decreased expression of prostacyclin synthase with reduced prostacyclin production in pulmonary artery endothelial cells, which leads to lower cyclic adenosine monophosphate levels, more vasoconstriction, and proliferation of underlying smooth muscle cells.¹⁴ Prostacyclin analogues (Table 1)^18-29 promote vasodilation of the pulmonary and systemic arterial vascular beds, inhibit proliferation of smooth muscle cells, and inhibit platelet aggregation.^{20,23,24,27-29} Supplementation of endogenous prostacyclin production with exogenous prostacyclin analogues has been shown to be an effective treatment for PAH.^{7,23,24,27,29}

Patients with PAH also have low levels of circulating endogenous NO, which may contribute to some of the pathophysiologic processes of the disease. For instance, in the healthy lung, NO stimulates production of cyclic guanosine monophosphate (cGMP), which promotes vasodilation, and may also help inhibit smooth muscle cell proliferation. Low levels of NO may have the opposite effects in patients with PAH.^7,30-32 Expression of PDE5, which rapidly degrades cGMP, has been shown to be upregulated in patients with PAH.^7,31 By blocking PDE5, selective PDE5 inhibitors (Table 1)^7,18-29 prevent the degradation of cGMP.^18,25,31 Lastly, augmentation of sGC activity with an sGC stimulator is an alternative option for targeting the NO pathway since the sGC activator is not limited by low endogenous NO levels.^19,33 Combination therapy, using distinct and complementary mechanisms of action, targets the derangement in multiple key biologic pathways in the pulmonary arterioles to improve PAH symptoms. Thus, combination therapy is a valuable option for management of patients with PAH (Table 1).^7,16,18-29

Trends in Medication Usage and Costs

The IMS Institute for Healthcare Informatics reported that in 2014, US spending on prescription drugs, after many years of slowing growth, saw the largest spending increase since 2001, with the cost rising 13.1% over 2013 to reach $373.9 billion. This increase is attributed not only to a rise in utilization of specialty medicines, but also to innovation. A record-breaking number of FDA marketing approvals has resulted in many new medicines, a large proportion of which occupy specialty therapy areas that include oncology, hepatitis C, and auto-immune diseases, which collectively accounted for $34.7 billion of drug expenditures in 2014. Also in 2014, 10 first-in-class FDA-approved products designated as orphan drugs were launched for rare conditions such as homozygous familial hypercholesterolemia, idiopathic PAH, Gaucher’s disease, and several types of hemophilia, making new, effective drug therapies available to people diagnosed with rare and neglected diseases.³⁴

Because of this continued increase in specialty drug spending, along with the continued growth of an aging population that uses proportionately more prescription drugs, managed care decision makers are tasked with making policy decisions that consider the use of utilization management tools in order to bring high value to their members. Utilization management tools include strategies such as step edits, prior authorization, and restrictions on combination therapy, among others. Before policy and formulary determination, decision makers must carefully consider clinical evidence in the form of RCTs, retrospective research, registry data, and expert guidelines in order to determine the value of a medication and its place in therapy.

Clinical Support for Combination TherapyProceedings From the World Symposium on Pulmonary Hypertension

In 1973, the first World Symposium on Pulmonary Hypertension (WSPH) was held in Geneva, Switzerland, in response to an epidemic of PAH caused by the anorexigenic medication Aminorex.³⁵ Twenty-five years later, at the time of the second WSPH, in Evian, France, there were only 2 effective treatments for PAH: the prostacyclin analogue epoprostenol, and high-dose calcium channel blockers for the relatively few patients who were responsive to acute vasoreactivity testing. The second symposium is widely regarded as the beginning of the modern era of treatment for PAH because it resulted in the creation of the first PAH treatment algorithm.^3,35

At the time of the third WSPH (Venice, Italy) in 2003, 3 classes of PAH-specific drugs (ERAs, prostanoids, and PDE5 inhibitors) were available for treatment of PAH.³⁵ The proceedings of this symposium classified combination therapies as experimental for patients who failed to show improvement or who displayed deteriorated health with earlier treatment. A supplemental publication opined that, provided that additional confirmatory evidence was obtained, combination therapy would in the future become an early-line therapy.^12,36

It was not until 2008 that the fourth WSPH proceedings endorsed the consideration of combination therapy and goal-oriented treatment. Treatment algorithms developed at the fourth (2008) and fifth (2013) WSPHs delineated the role of the PAH-approved therapies described herein, as well as supportive therapies including supplemental oxygen, diuretics, digitalis, and anticoagulants.^3,7 Table 2³ shows the 2013 evidencebased treatment algorithm for initial therapy for PAH with approved drugs. In patients with inadequate clinical response to monotherapy with a PAH-approved therapy, combination therapy is allocated a grade of recommendation I and level of evidence A. For patients in functional class (FC) III or IV, initial combination therapy is allocated a grade of recommendation IIb and level of evidence C (Table 2 and Table 3).³ The current algorithm recommends the sequential introduction of combination therapy. However, data from newer clinical trials may provide evidence supporting use of initial combination therapy for treatment-naïve patients.^3,15 Before the fifth WSPH proceedings were published, providers utilized combination therapy when treatment goals were not met, and a body of clinical trials evidence with combination therapy in PAH has been developed.

Evolving Clinical Evidence

In 2003, BREATHE-2, a small RCT to assess the safety and efficacy of bosentan combined with epoprostenol for patients in FC III & IV, was reported. Results showed a promising but nonsignificant trend toward greater improvement in hemodynamic parameters. PAHassociated serious adverse events were similar for both treatment arms. In the 12-week STEP trial, which was primarily a safety trial with secondary efficacy end points, iloprost was added to patients on stable bosentan therapy. Safety data were consistent with previous trial experience, and comparable efficacy was demonstrated (time to clinical worsening [TTCW], FC, and hemodynamics). Table 4^22,32,37-52 provides study experience with combination therapy trials. A meta-analysis of 6 trials also confirmed the efficacy and safety of combination therapy. Compared with the control group, combination therapy reduced the risk of clinical worsening (relative risk [RR], 0.48; 95% CI, 0.26-0.91; P = 0.023); increased the 6-minute walk distance (6MWD) significantly (22 m); and reduced the mean pulmonary arterial pressure, right atrial pressure, and PVR. The incidence of serious adverse events was not significantly different between combination therapy and monotherapy (RR, 1.17; 95% CI, 0.40-3.42; P = .77).3

A treatment strategy trial involving combination therapy was published by Hoeper and colleagues in 2005. This study assessed a combination of bosentan and sildenafil, and in cases where treatment goals were not reached, the addition of inhaled iloprost. Comparisons with a historical control group suggested a lengthened survival time with combination therapy, but could not definitively confirm that combination therapy was superior to monotherapy. The authors concluded that prospective controlled trials were needed to address this question.⁵³

By 2008, additional RCTs utilizing combination therapy had been conducted (Table 4).^22,32,37-52 PACES was the first PAH combination therapy study of significant size (N = 267). In the PACES trial, the effect of adding oral sildenafil to long-term intravenous (IV) epoprostenol in patients with PAH was studied over the course of the 16-week trial. Patients were randomly assigned to receive placebo or sildenafil titrated up to 80 mg 3 times daily (4 times higher than the FDA-approved dosage). A placebo-adjusted increase from baseline of 28.8 meters (95% CI, 13.9-43.8; P = .001) in the 6MWD was seen in patients in the sildenafil group. The addition of sildenafil to stable long-term IV epoprostenol therapy resulted in improvements in exercise capacity, hemodynamic parameters, TTCW, and quality of life, but not Borg dyspnea score. Increased rates of headache and dyspepsia occurred with the addition of sildenafil.⁴²

A more recent registration trial, PATENT-1, assessed the efficacy and safety of riociguat in PAH patients. The study included both treatment-naïve patients and those treated with an ERA or an oral, inhaled, or subcutaneous prostanoid. A statistically significant improvement in 6MWD was seen both for patients treated with riociguat monotherapy (38 meters from baseline [95% CI, 15-62 meters]) and those on combination treatment (36 meters from baseline [95% CI, 15-56 meters]). Riociguat was well tolerated, with a discontinuation rate of 3% in the 2.5 mg— maximum dose group versus 7% in the placebo group.^32,54

Not all trials with combination therapy have met primary efficacy end points. Two trials, FREEDOM-C and FREEDOM-C2, utilized oral treprostinil added to stable doses of an ERA and/or PDE5 inhibitor. The primary end point, an improvement in 6MWD, was not met with statistical significance in either trial.^45,46

Importantly, some of the more recent trials have moved away from the functional end point, change in 6MWD, to a composite primary end point that more clearly reflects the progression of the disease. In the late 1990s, Dr Bob Temple of the FDA advocated for meaningful end points in clinical trials. He defined meaningful end points as direct measures of how a patient feels, functions, or survives, with function referring to the ability of a patient to carry out normal daily activities.⁵⁵ More recently, in the proceedings of the fifth WSPH, the experts recommended TTCW as an appropriate end point in registration trials and proposed an array of similarly themed clinical end points, including all-cause death, lung transplantation, hospitalization for worsening PAH (including atrial septostomy), initiation of IV therapy due to worsening PAH, worsening of function (ie, worsening FC and exercise capacity), and worsening of PAH symptoms (eg, worsening of at least 2 of the 4 symptoms: dyspnea, chest pain, dizziness/syncope, and fatigue/activity level).⁵⁶

COMPASS-2, a combination trial using sequential therapy with sildenafil and bosentan, was the earliest PAH trial with a primary morbidity/mortality (M/M) end point. COMPASS-2 began in 2006 and ended in 2013 (Table 4).^22,32,37-52 The trial, although important as the first PAH M/M trial, did not reach its primary end point, as the observed risk reduction for patients treated with bosentan as an add-on to sildenafil was not a statistically significant difference at 17% versus placebo (hazard ratio, 0.83; P = .25). No new safety signals were revealed in the long-term trial (median duration, 22.7 months).^47,57

The first completed event-driven RCT with an M/M end point in PAH to show a significant difference between treatment arms was the SERAPHIN trial, in which macitentan (3 mg and 10 mg) was assessed in a long-term trial. The median treatment period of 115 weeks allowed evaluation of the drug on disease progression. Approximately two-thirds of patients were already on a PAH-approved therapy at enrollment (61.4% on a PDE5-type inhibitor and 5.4% on oral or inhaled prostanoid). Macitentan 10 mg significantly reduced the risk of an M/M event by 45% (P <.001) overall (55% for treatment- naïve patients, 38% for patients on combination therapy). The risk of the secondary composite end point of PAH-related death or hospitalization was reduced by 50% (97.5% CI, 0.34-0.75; P <.001).^22,48

Two additional M/M trials utilizing combination therapy have recently been reported. The GRIPHON study assessed the safety and efficacy of an investigational drug, selexipag (ACT-293987), in the largest PAH M/M trial to date (N = 1156), spanning 4.3 years. Eighty percent of patients enrolled were already on a background regimen of 1 or 2 PAH-approved drug therapies (ERA, PDE5). Selexipag decreased the risk of an M/M event versus placebo by 40% (P <.001).^49,50 This effect was consistent for patients on monotherapy and on combination therapy.

Lastly, the event-driven treatment-strategy trial AMBITION assessed the safety and efficacy of initial combination therapy with tadalafil and ambrisentan versus pooled monotherapy in treatment-naïve incident patients. The top line results demonstrated a 50% (P = .0002) risk reduction of clinical failure with initial combination therapy compared with pooled groups of patients taking either medication alone.^51,52 Figure 2^{5,32,45-52,57} contains a timeline of combination therapy trials, and Table 4^22,32,37-52 presents results of recent combination trials.

Concomitant with the growing body of evidence, the FDA has recently acknowledged the role of combination therapy in the labeling for newer PAH therapies. For example, in the prescribing information for 2 new drugs approved in 2013, Adempas (riociguat) and Opsumit (macitentan), the usage statements mention that these agents have demonstrated efficacy in combination with other approved PAH therapy.^19,22

Combination Therapy Use in Other Chronic Conditions

Combination therapy in PAH has followed the pattern of combination therapy in other chronic conditions, where multiple agents targeting distinct pathways have demonstrated efficacy and safety. The evolution of combination therapy in heart failure (HF) is analogous to current trends in PAH treatment. Early trials in HF, such as CONSENSUS, demonstrated the benefit of enalapril monotherapy. Subsequently, the added benefit of enalapril with a background diuretic and digoxin therapy was confirmed in a clinical trial (SOLVD).^58,59 With the addition of beta-blockers, evidenced by positive results in the CIBIS-II and COMET trials, other combinations became standards of care.^60,61 More recently, HF trials have demonstrated the benefit of treatment regimens that include still other agents targeting additional pathways.^62,63 It is now common practice in HF therapy to utilize a combination regimen with several agents targeting different pathways.⁶⁴ Similar patterns are seen in the treatment of other chronic diseases, such as diabetes, systemic hypertension, and cancer.

Conclusion

Combination therapy has the potential to become the standard of care for PAH patients. Experience with combination therapy in the treatment of PAH demonstrated through a decade of clinical trials has shown benefit. Real-world data from the REVEAL registry suggest that combination therapy in PAH has become prevalent in treatment regimens in the United States and that morbidity may have been positively impacted. Recent M/M trials such as SERAPHIN and GRIPHON provide evidence of clinical benefit of combination therapy across a broad spectrum of patients with PAH. Adoption of initial combination therapy could be near, as clinical practice may reflect the initial combination treatment strategy recently demonstrated in AMBITION. The new European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines will be presented and published at the ESC Congress later in 2015, and it is likely that initial combination therapy will be among the recommendations.

Rare and deadly diseases such as PAH that require high-touch, high-management specialty medications remain on the radar as health plans aim to control costs while improving the quality of care for their members. In pursuit of providing the greatest value and benefit to the majority of the PAH patient population, decision makers must be able to assess these specialty medications with the help of clinical evidence from RCTs, retrospective research, registry data, and expert guidelines. They must weigh the benefit of improved outcomes for patients, and reduction in resource-intensive events (morbidity, hospitalization), against the associated costs. This article has provided support for managed care decision makers as they evaluate combination therapy in PAH.Author affiliation: Medstar Heart Institute, Washington, DC (GR); Drug Information Services—California Regions, Kaiser Permanente, Downey, and University of Southern California School of Pharmacy, Los Angeles (GMB); Medical Managed Markets and Health Economics and Outcomes Research, Actelion Pharmaceuticals US, Inc, South San Francisco, CA (CAL, SR).

Funding source: This supplement was sponsored by Actelion Pharmaceuticals US, Inc.

Author disclosures: Dr Lickert and Ms Raspa report employment and stock ownership with Actelion Pharmaceuticals US, Inc. Dr Ruiz reports being on speakers bureaus for Actelion Pharmaceuticals US, Inc, and United Therapeutics. Dr Besinque reports no relationships or financial interests with any entity that would pose a conflict of interest with the subject matter of this supplement.

Authorship information: Concept and design (GR, CAL, SR); analysis and interpretation of data (GMB); drafting of the manuscript (GMB, CAL, SR); critical revision of the manuscript for important intellectual content (GR, GMB, CAL, SR); and supervision (GR).

Address correspondence to: George Ruiz, MD, MBA, Medstar Heart Institute, 110 Irving St NW, Washington, DC 20010. E-mail: george.ruiz@medstar.net.

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