Pulmonary arterial hypertension (PAH) has an estimated prevalence of 15–25 cases/million population.1 This chronic, progressive disease is defined by a mean pulmonary arterial pressure >25mmHg in conjunction with normal pulmonary capillary wedge pressure <15mmHg.2 The disease is characterized by increased vascular resistance of the pulmonary microvasculature, ultimately resulting in right ventricular overload, right heart failure, and death.3
Severity of PAH is graded by the New York Heart Association functional classifications (NYHA FC, see Table 1), a modification of the original classification by the World Health Organization (WHO);4 symptomatic severity has long since been recognized to be related to prognosis.5 Not only is PAH a rapidly evolving disease, but it is also asymptomatic in the early stages. As such, approximately 75% of patients present with NYHA FC III and marked functional impairment at diagnosis.1 PAH is classified as idiopathic (IPAH), familial (FPAH), or occurring in association with other conditions or risk factors.6
These subgroups share similar clinical and pathological features, but the precise etiology of PAH remains unknown. This article will consider the treatments available in PAH, the increasing use of combination therapies, and the implications of resulting drug–drug interactions (DDIs) in PAH, with a special focus on endothelin receptor antagonists (ERAs).
Current Management of Pulmonary Arterial Hypertension
Treatment of PAH can be non-specific or disease-specific (see Table 2). Anticoagulants are commonly used as conventional therapy in PAH, despite the fact that there has been no evidence from prospective, randomized, placebo-controlled studies in support of this approach. Studies that support the use of anticoagulants have largely been retrospective or non-randomized, with small study numbers of patients with IPAH.7,8 A target international normalized ratio (INR) for oral anticoagulation of between 1.5 and 2.5 is recommended.9
Diuretics and low-sodium diets are able to relieve hypervolemia and the associated symptoms, but it is not known whether this approach reduces the burden of right ventricular overload and improves prognosis. Digoxin has also been used as PAH therapy due to its ability to increase cardiac output, but doubts regarding its long-term efficacy have restricted its use to cases of PAH associated with atrial fibrillation.10 The vasodilatory activity of calcium-channel blockers can be used in a minority of PAH patients to counteract vasoconstriction, which was originally assumed to be the underlying cause of PAH. Favorable response rates to an acute vasodilator are achieved in fewer than 10% of patients, only half of whom are able to maintain long-term responses.11
Studies of the underlying molecular mechanism in PAH have allowed the development of disease-specific therapies in the three established molecular pathways of PAH pathophysiology: the prostacyclin pathway, the nitric oxide (NO) pathway, and the endothelin (ET) pathway.
Prostacyclin Pathway and Prostanoids
Prostacyclin is a metabolite of arachidonic acid produced by the vascular endothelium and acts as a potent pulmonary and systemic vasodilator through the effects of the secondary messenger cyclic adenosine monophosphate (cAMP).12,13 Prostacyclin also has antiproliferative properties and inhibitory effects on platelet aggregation. Deficiencies of prostacyclin due to reduced expression of prostacyclin synthase in PAH led to the development of prostanoid replacement therapy, of which there are three prostacyclin analogs available on the market (see Table 2). Although effective in improving exercise capacity, cardiopulmonary hemodynamics, and symptoms,14–18 the short half-lives of these drugs mean that drug delivery is via continuous intravenous (IV) or subcutaneous (SC) administration, which can cause infection from venous catheters and site pain, respectively, or frequent inhalation therapy.19
Nitric Oxide Pathway and Phosphodiesterase Inhibitors
NO has potent pulmonary vasodilatory effects and inhibits platelet activation and vascular smooth-muscle cell proliferation; vasodilation is achieved by activation of the soluble guanylate cyclase by NO and production of the second messenger cyclic guanosine monophosphate (cGMP).20 However, increased expression of phosphodiesterase-5 (PDE5) in the lungs in PAH leads to enhanced cGMP degradation.
Therefore, selective inhibition of PDE5 by sildenafil blocks cGMP degradation in the pulmonary vasculature, leading to increased vasodilatory activity of endogenous NO.21 Sildenafil has also been shown to improve the six-minute walk distance (6MWD), hemodynamic variables, and NYHA FC.21
Endothelin Pathway and Endothelin Receptor Antagonists
Levels of ET-1, a potent vasoconstrictor and smooth-muscle mitogen, are elevated in the plasma and lung tissue of patients with PAH.22 The effects of ET are mediated by two ET receptor isoforms: ET type A (ETA) and ET type B (ETB). Activation of ETA receptors mediates vasoconstriction and cellular proliferation of pulmonary vascular smooth-muscle cells; in normal pulmonary vasculature, ETB receptors mediate vasodilation primarily through clearance of ET-1 circulating in the vascular beds of the lungs and kidneys, and increased production of prostacyclin and NO.23 Bosentan is a non-selective (dual) ERA; ambrisentan and sitaxentan are specific antagonists of the ETA receptor. Currently, there is no clear evidence suggesting that receptor selectivity confers any advantage in terms of the clinical efficacy of these drugs.
Large-scale clinical studies have shown that ERAs have proven efficacy in mediating vasoconstriction in PAH. In the Bosentan Randomized Trial of Endothelin Antagonised Therapy (BREATHE-1), patients receiving bosentan exhibited improvements in FC and exercise capacity as measured by 6MWD and prolonged time to clinical worsening compared with patients receiving placebo.24 The Sitaxentan to Relieve Impaired Exercise (STRIDE-1) trial showed that patients receiving sitaxentan benefited in terms of improvements of 6MWD, NYHA FC, and pulmonary hemodynamics.25 The Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo- Controlled, Multicenter, Efficacy Study 1 and 2 (ARIES-1 and ARIES-2) found that patients who were randomized to the ambrisentan groups had significant improvements in increased 6MWD, time to clinical worsening, FC, Borg dyspnea score, and quality of life score.26 The ERAs are associated with hepatoxicity requiring monthly liver function testing; bosentan and sitaxentan have both been found to induce a dose-dependent increase in hepatic transaminase levels to more than three times the upper limit of normal (ULN) in 11 and 5% of patients, respectively.24,27
Clinical trials have found a lower incidence of acute hepatotoxicity with ambrisentan, with fewer than 3% of patients experiencing elevations in hepatic aminotransferases more than three times ULN.28–30 This lower incidence of liver function abnormalities has been attributed to the fact that, unlike the other ERAs, ambrisentan does not inhibit the bile salt export pump (BSEP) in the liver.31–33
Combination Therapy and Drug–Drug Interactions
With disease-specific therapeutic strategies targeting the multiple pathophysiological pathways and mechanisms of PAH, it is possible that the addition of one agent to another could confer additive or synergistic benefits. Patients can receive disease-specific agents alongside general background therapies, but continued disease progression may eventually lead patients to require a combination of disease-specific therapies in order to effectively manage the disease. The European Society of Cardiology (ESC) advocates such an approach for patients with advanced disease who are not responsive to or exhibit deterioration with first-line treatment.34 The Registry to EValuate Early And Long-term PAH Disease Management (REVEAL) showed that combination therapy is frequently used to treat PAH in the US, with 36% of patients undergoing dual combination and 9% receiving triple combination.35
Combination therapy can provide benefits for patients with PAH, addressing more than one of the disease mechanisms and perhaps even allowing for dose reductions and lowered risk for side effects due to enhanced efficacy.36 However, combination therapy also presents the risk for DDIs, which can compromise disease efficacy or increase the incidence or severity of adverse effects, thereby negatively affecting the health of the patient. Furthermore, the aging population means an increase in the proportion of elderly patients with PAH,1,37 many of whom will also require concomitant drug therapy for the prevention or treatment of other age-related diseases, such as diabetes and hypertension.38 PAH is also frequently associated with other comorbidities that require concomitant medical treatments, such as scleroderma, HIV, and congenital heart disease.39–41
Studies have shown favorable outcomes in patients receiving combination therapy; sildenafil plus IV epoprostenol conferred improvements in 6MWD and hemodynamic parameters over placebo, with a significant reduction in the number of patients exhibiting clinical worsening, and improved survival.42
Significant improvements were achieved in 6MWD, NYHA FC, and post-inhalation hemodynamic parameters in patients with IPAH or associated PAH with NYHA FC III who received the combination of bosentan and iloprost over those who received bosentan and placebo,43 although another study found no significant change in 6MWD upon addition of iloprost to bosentan.44
Other studies have documented encouraging results with additional benefits upon sequential addition of bosentan or sildenafil to prostanoids.45–48 The combination of the orally available bosentan and sildenafil has also provided an interesting outcome; patients with mild PAH (WHO FC II) who received this combination were shown to experience decreased pulmonary vascular resistance, but no improvements in 6MWD.49 Other studies have reported improved 6MWD and NYHA FC in patients with IPAH.50,51 However, there are pharmacological interactions affecting the metabolism and efficacy of these drugs. Currently, there are no long-term data available concerning combination therapy.
DDIs are a result of one medicine altering the pharmacokinetics or pharmacodynamics of another. The most notable DDI is that involving the cytochrome (CYP) P450 oxidases, where modulation of the various CYP isozymes of this enzyme system by one drug can invariably effect the metabolism of another. A number of P450 isozymes with important roles in drug metabolism have been identified; approximately 90% of drug metabolisms by the CYP system can be accounted for by CYP1A2, CYP2C19, CYP2C9, CYP2D6, CYP2E1, and CYP3A4.52–54 Of the highly expressed CYP3A family, CYP3A4 is the most abundant isoform expressed in the liver and gut,55 while CYP2D6 and the CYP2C family are also responsible for metabolizing a majority of other clinically relevant drugs.56 Drug pharmacokinetics can be influenced by the rate of absorption, the distribution into bodily areas, biotransformation, and clearance rates; additional variables of age, genetics, and disease mean that DDIs can present in myriad ways in clinical practice. These DDIs can be subtle and go unnoticed unless there is reason to suspect a DDI. Therapeutic ranges of drugs are generally designated such that the lower spectrum is approximately equal to the concentration at which half of the greatest possible therapeutic effect is achieved, while the higher end of the spectrum will limit the number of toxicities to 5–10% of patients.57
DDIs can then be problematic if the affected drug has a narrow therapeutic window as—in the case of warfarin58—minute changes in plasma concentration could lead to sub-therapeutic effects or toxicity. Furthermore, DDIs are associated with substantial financial effects on healthcare resources; investigations into potential DDIs can prolong the duration and rate of hospitalization, increase the need for therapeutic monitoring, and require extensive laboratory and clinical testing.59,60
Drug–Drug Interactions with Endothelin Receptor Antagonists
A number of cytochrome P450 pathways are involved in the metabolism of the ERAs and PDE-5 inhibitor sildenafil (see Table 3). However, ambrisentan, a non-sulphonamide, propanoic-acid-based ERA, is principally metabolized through hepatic glucuronidation, with a minor route through the cytochrome P450 system. These characteristics confer a low risk for DDIs with ambrisentan.31 Drug-induced inhibition of cytochrome isozymes can potentially increase the plasma concentration of the drug, whereas induction would decrease the plasma concentration. The DDIs associated with ERAs are of special interest because many of these interactions are with medications that are taken alongside intercurrent illnesses or conditions (see Table 4).36 The use of some of these drugs is associated with potential DDIS: bosentan is an inducer of hepatic CYP isozymes, and sitaxentan inhibits hepatic CYP isozymes.36 Some of these potential clinically significant DDIs are identified in Table 5.
Bosentan and sitaxentan are known to compromise the level and therefore the efficacy of CYP3A4 substrates, including cyclosporin, oral estrogens, and simvastatin. Strong CYP3A4 inhibitors such as ketoconazole and cyclosporine increase plasma levels of bosentan; the combination of cyclosporine with bosentan or sitaxentan is contraindicated and cautioned with ambrisentan.31,61,62 Although metabolized by CYP3A4, studies suggest a lack of inductive effect for ambrisentan on the CYP3A4 isozyme.31 Furthermore, ambrisentan does not appear to interact with the commonly used PAH therapies of sildenafil, a CYP3A4 substrate, and warfarin, a CYP2C9 substrate.28,63,64 Co-administration of bosentan and sildenafil induces a two-fold increase in sildenafil clearance,65 while increasing bosentan levels by about 50%.36,65,66
The resultant decreased dose of sildenafil could lead to a lack of effect (especially in the indicated dose of 20mg twice a day), while increased bosentan plasma concentration can cause hepatic toxicity. Small but not clinically significant elevations of sildenafil have been observed when co-administered with sitaxentan and ambrisentan separately.67–69 Induction of CYP2C9 by bosentan or inhibition by sitaxentan can modify warfarin metabolism and alter the bioavailability of the drug,25,27,36,70,71 which has considerable implications for patients with PAH who use warfarin as background therapy. Indeed, an up to 80% reduction of warfarin was necessary in clinical trials with sitaxentan to prevent over-anticoagulation and account for potential bleeding.27 Close INR monitoring is recommended when introducing these ERAs. The combination of ambrisentan and warfarin in healthy volunteers and PAH patients did not cause any clinically relevant changes in coagulation, INR, or pharmacokinetics of either drug.64
Pregnancy in women with PAH is associated with an increased risk for maternal mortality of 30–50%.72 Therefore, women of child-bearing age are encouraged to use both hormonal and mechanical contraception.34 However, co-administration of PAH drugs can compromise the reliability of hormonal contraceptives. Failure of contraception is possible with bosentan co-administration owing to partial metabolism of estrogens and progestogens by CYP3A4 and CYP2C9. Conversely, sitaxentan increases estrogen levels and can increase contraceptive-associated side effects, such as the risk for thromboembolism, particularly in women who smoke. The combination of ambrisentan and the combined oral contraceptive pill (COCP) did not cause any clinically relevant changes in either component of the COCP.31 All three ERAs are contraindicated in pregnancy owing to their teratogenic profiles.31,61,62 To control hypercholesterolemia and prevent cardiovascular disease, simvastatin is commonly prescribed. Comorbidities present in the aging PAH patient population mean that many of these patients may also require simvastatin therapy. However, co-administration of bosentan and simvastatin significantly reduces the plasma concentration of simvastatin; there was no effect on the plasma concentration of bosentan.71 Patients receiving bosentan in addition to simvastatin therefore need careful monitoring of cholesterol levels and subsequent dose adjustments.
Antiviral drugs used in the treatment of HIV also present potential problems if co-administered with PAH therapies. The HIV protease inhibitors ritonavir and saquinovir are known inhibitors of CYP3A4, which could interfere with the metabolism of CYP450 isozymes and, thus, bosentan, sitaxentan, and ambrisentan. However, DDI studies with antiviral drugs have not been performed.73
The Outlook for Pulmonary Arterial Hypertension Management
The aging PAH patient population presents a number of complications. Not only are patients older at diagnosis, but they are also more likely to suffer from both disease- and age-related comorbidities, necessitating the use of safe and effective PAH therapies in addition to medications that are required for intercurrent illnesses. Indeed, the use of combination therapy is on the rise, and there is a need for PAH therapies that produce minimal DDIs.
It is important to address the matter of DDIs, and their potential to perturb the achievement of therapeutic goals. There are various benefits of reducing DDIs: increased treatment efficacy, enhanced ability to implement combination therapies, and reductions in complications and investigations to allow healthcare resources to be better spent. Although monotherapy in PAH has undergone great medical advances in recent years, patients with PAH still experience poor quality of life and survival, prompting physicians to attempt combination therapies. The limited data available concerning combinations of bosentan or sildenafil plus prostanoids are encouraging, but there is clearly a need for further studies in order to evaluate the role of other combinations of classes of therapies targeting different pathways of PAH: it is necessary to conduct such studies to ascertain which combinations are beneficial and which have the potential for adverse DDIs.
Current data have shown that each of the ERAs has different safety profiles and DDIs. Although each of the ERAs requires monthly liver test monitoring, ambrisentan has demonstrated the least liver toxicity. Head-to-head studies comparing ambrisentan directly with other standard therapies would help to define the role of this drug in treating PAH. As yet, there are no such studies that directly compare the efficacy and side-effect profile and incidence between ERAs; any conferred advantage of one agent over the other in PAH is only speculative.
However, ambrisentan offers a clinically important advantage compared with other ERAs in that there is a lack of any significant drug interactions with warfarin and sildenafil, thus potentially improving patient safety for the population of PAH patients requiring multiple therapies.