Pulmonary Arterial Hypertension: Combination Therapy in Practice

Marsha Burks; Simone Stickel; Nazzareno Galiè

Disclosures

Am J Cardiovasc Drugs. 2018;18(4):249-257. 

In This Article

Other Considerations for the Use of Combination Therapy

In order to obtain the maximal benefit from combination therapy, the treatment regimen must be tailored to each patient's specific clinical needs, lifestyle and preference. To achieve this, the following general recommendations should be considered when selecting a combination therapy regimen.

Underlying Disease and Comorbid Conditions

The decision on which treatment strategy is most appropriate for each patient is at the discretion of the treating physician and involves the consideration of several factors, including comorbidities and PAH etiology. Patients seen in clinical practice tend to be older, with more comorbid conditions than historical PAH populations.[27] The administration of combination therapy regimens in these patients may be more challenging and should include assessment of potential interactions with existing medications. For example, patients with coronary artery disease (CAD) may be treated with nitrates to relieve the symptoms of angina. As nitrates, PDE-5is and sGC stimulators all induce vasodilation by increasing the endothelial production of NO, co-administration of these drugs can have serious additive hypotensive effects and is formally contraindicated.[28] Despite this, for a PAH patient with co-existing CAD, the benefits of using a PDE-5i or sGC stimulator may outweigh the risk of eliminating nitrates from the patient's treatment options. However, it is essential that this is carefully managed. Patients should be provided with written guidance as to why they cannot receive nitrates, and this information should be clearly documented in the patient's electronic medical record and communicated to cardiologists and referring doctors. Another comorbidity prevalent in older patients is diabetes.[4,6] Many patients with type 2 diabetes are treated with the glucose-lowering drug glyburide [international nonproprietary name (INN), glibenclamide]. However, a drug–drug interaction between glyburide and the ERA bosentan has been reported.[29] Concomitant administration of bosentan and glyburide resulted in reduced plasma levels of both drugs compared with the levels after a single drug was administered.[29] Furthermore, in the REACH-1 trial of patients with chronic heart failure, an increased incidence of elevated liver enzymes was observed in patients receiving both bosentan and glyburide compared with patients receiving bosentan monotherapy.[30] As a result, the co-administration of bosentan and glyburide is contraindicated[16] and diabetic patients treated with glyburide should receive an alternative ERA as part of their PAH combination therapy regimen.

Disease etiology may also influence the selection of drugs used in each patient's treatment regimen. For example, caution must be applied for human immunodeficiency virus patients treated with anti-retroviral drugs that are strong CYP3A4 inhibitors, such as ritonavir and saquinavir, as these can interfere with the metabolism of ERAs and PDE-5is.[2,3,31] Care is needed when managing PAH patients with associated connective tissue disease, who may be receiving immunosuppressive therapies to treat their underlying condition. For example, co-administration of bosentan with the immunosuppressant cyclosporine is contraindicated.[32] It is also important to be mindful that PAH therapies can exacerbate symptoms in certain etiologies. For instance, the use of vasodilators may lead to a greater degree of hypoxia in patients with systemic sclerosis complicated by interstitial lung disease.[33]

Expert Centers and Patient Support Groups

Due to the challenges in administering combination therapy, we recommend that all PAH patients are managed in expert centers. We are aware that some patients may have to travel considerable distances to reach their nearest expert center, which often poses a logistical challenge. However, managing PAH in a specialist setting provides considerable benefit, which is not always achievable with local care. In expert centers, patients receive care from a multidisciplinary team, including specialist healthcare professionals who see similar patients on a daily basis and thus have considerable experience in recognizing and managing side effects, and can ensure optimal timing when initiating PAH therapies in a combination therapy regimen. Specialist nurses should pro-actively contact patients after the initiation of therapies to provide support and to monitor for side effects, particularly during the early stages of treatment when patients are more likely to be experiencing symptoms. In addition, nurses play a key role in managing patients' expectations of their treatment and educating patients and their carers and families to ensure they are fully informed of the benefits and potential challenges associated with combination therapy. In addition to the availability of specialist staff, expert centers are more likely to be associated with, and to advocate for, patient support groups. Such groups are vital as they provide reassurance and first-hand experience of combination therapy from other patients. Initiatives such as these can engage patients and lead to patient activation, which in turn improves patient confidence and therapy adherence.[34]

Adherence to Therapy

Adherence to therapy can be an issue in many chronic diseases that require long-term pharmacological treatment. Our clinical experience suggests that PAH patients are generally adherent with their combination therapy regimen; they understand the severity of their disease and, as a result, are motivated to take their medication. Nevertheless, PAH specialists must be aware that adherence may be reduced as the number of medications to be taken each day increases, particularly if the treatment regimen requires administration of different drugs at different times of the day. This can be due to patient forgetfulness or perhaps because the treatment schedule does not fit with the patient's lifestyle or other commitments. Another reason for reduced adherence could be that patients may not notice short-term effects of occasionally missing a dose of one out a number of drugs and therefore may not appreciate the importance of taking all therapies regularly. The impact of increasing treatment complexity on adherence has been demonstrated in a number of chronic diseases, where the more tablets that are required each day, the lower the adherence.[35,36] However, increasing the complexity of the treatment regimen can also have the opposite effect and can lead to increased adherence. This trend was observed in a study of congestive heart failure patients, which demonstrated that taking medications twice daily or less was associated with reduced adherence compared with more complex treatment regimens.[37] This might be related to a higher level of attention to routine; indeed, having a highly structured daily routine is a strong independent predictor of adherence.[38] In order for PAH patients to receive the maximal benefit from their combination therapy regimen, it is essential that they take their drugs as prescribed. Although the impact of combination therapy on adherence in PAH is unknown, the necessity of educating patients on the importance of adherence to therapy cannot be stressed enough and is a vital role for the specialist nurse. In addition, PAH specialists can provide useful tools and tips to aid adherence, including setting alarms as reminders for taking medication and preparing weekly pillboxes.

Management of Long-term Combination Therapy

PAH patients are surviving longer than ever and may maintain good functional capacity for years, albeit with a continued risk of rapid deterioration and morbidity.[39] This is supported by three recent registry studies, which reported that more than three-quarters of PAH patients with a low-risk status will still be alive 5 years after enrollment.[40–42] As a result, many patients may receive double or triple combination therapy for years. In our opinion, there are no additional considerations that are specific to the longer-term use of PAH therapies in combination, compared with their short-term use. After successful initiation of combination therapy and resolution of any side effects, patients can be managed in the same way as if they were receiving each agent as a monotherapy. This includes assessments every 3–6 months at an expert center with the overall therapeutic aim of achieving a low mortality risk status.[2,3]

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