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

Practical Recommendations for Clinical Practice

When patients commence combination therapy, a number of practical measures can be taken to minimize the risk of side effects, monitor safety and tolerability, and effectively manage any side effects that occur.

Initial Combination Therapy

Staggered Initiation. In an initial combination therapy regimen, patients may be more likely to experience side effects if therapies are introduced in close succession. In addition, the concomitant introduction of multiple drugs can make it difficult to identify which drug is causing the side effect.[25] A short delay between initiation of therapies may allow patients to adapt to the vasodilator effects of one drug before another is added, and would make determination of which agent is responsible for the side effect in question more likely. In our European and US expert centers, double initial combination therapy with an ERA and a PDE-5i involves starting the two therapies a few weeks apart, with the aim of establishing patients on the full dose of both treatments within 1 month. This approach is also applied in combination regimens that include a therapy targeting the PGI2 pathway. For high-risk patients who require a parenteral PGI2 therapy immediately after diagnosis, the parenteral drug is initiated as a first step, and an ERA and/or a PDE-5i initiated a few days later.

Up-Titration. Another approach to improve tolerability is to initiate one or both therapies at a lower than recommended dose. For example, in our clinical experience, administration of tadalafil at 20 mg once daily and then increasing after 1 to 2 weeks to 40 mg once daily is often more tolerable than starting at 40 mg once daily as recommended in the summary of product characteristics.[14] Similarly, for patients who experience headaches when starting a PDE-5i shortly after initiation of an IV PGI2 therapy, up-titration of the IV therapy can be delayed until the headache becomes more manageable.

Such an up-titration approach to combination therapy is supported by data from a number of studies. In the AMBITION trial, ambrisentan and tadalafil were started together at low doses (5 and 20 mg, respectively) and up-titrated to 10 and 40 mg over an 8-week period.[11] While the number of AEs was increased in the combination therapy arm, no differences were observed in the rates of discontinuations due to AEs between the combination therapy arm (12%) and the pooled monotherapy arms using this approach (11%).

Similarly, in a retrospective analysis of newly diagnosed patients admitted to expert centers in the French PH Network,[7] patients were initiated on an ERA and a PDE-5i on the same day and then up-titrated according to clinical need and tolerability. However, this study utilized a faster up-titration schedule than AMBITION, with patients achieving their maximal dose within 4 weeks. This treatment regimen was well-tolerated: over a median follow-up of 30 months, only one patient out of 97 discontinued double combination therapy.[7] Further changes to the up-titration schedule have been made in the ongoing OPTIMA study, where patients receive macitentan 10 mg once daily and tadalafil 20 mg once daily on day 1, followed by a step up to tadalafil 40 mg once daily at day 8 (± 3 days).[26]

Need for Regular Patient Monitoring. After starting initial combination therapy, it is essential that patients are followed up on a regular basis to monitor the safety and tolerability of the treatment regimen. For initial double combination therapy with an ERA and a PDE-5i, nurses typically perform a telephone check-up 1 week after initiation of the second drug and an assessment at the clinic 4–6 weeks later. More frequent check-ups are necessary if riociguat is used, as this drug requires careful up-titration to avoid hypotension (systolic blood pressure < 95 mmHg).[19] For example, at several of our centers, nurses perform a weekly telephone check-up and assess the patient in the clinic after 1 month. For all combinations, home visits by a nurse may be required instead of telephone check-ups if there are any problems with the initiation of therapies.

In addition to follow-up assessments performed by healthcare professionals, patients are advised to self-monitor for the development of certain side effects. An example of this is edema, which is a side effect of vasodilator therapies,[14–19] but also a complication of PAH as a result of right heart failure.[2,3] When initiating combination therapy, patients should check their weight daily and report any rapid and significant gain of over 2 kg promptly to their expert center. Such monitoring will ensure that the development of edema is detected at an early stage.

Management of Side Effects. When side effects occur, it is important that they are managed appropriately. For example, therapies that target the ET and NO pathways are associated with headaches and muscle pain. Temporary dose reduction, in particular for PDE-5is and sGC stimulators, may effectively manage these side effects. It is also important to advise patients that some side effects are temporary. Patients should be encouraged to persist with their treatment regimen beyond the first week, as side effects, such as headache and muscle pain, will likely dissipate over time. In the case of development of edema, clarification of whether this phenomenon is due to heart failure or to systemic vasodilation is required. In the first case, edema associated with weight gain should prompt diuretic dose increase and PAH treatment escalation. Of note, many PAH patients have edema at diagnosis as a manifestation of right heart failure. For these patients, diuretic therapy should be prescribed from the outset. In cases of edema as a result of systemic vasodilation, usually no specific measure is necessary beyond reassurance.

These practical recommendations, particularly the benefits associated with staggered initiation of initial combination therapy, are highlighted in a recent case from one of our centers (Figure 1).

Figure 1.

Patient case illustrating the benefits of initial combination therapy for PAH. A 34-year-old female presented with evidence of severe pulmonary hypertension. After being diagnosed with PAH, the patient received initial triple combination therapy with a PDE-5i, an ERA and an intravenous PGI2 analog using a staggered approach to treatment initiation. Significant functional and symptomatic improvements were reported within 2 months following diagnosis. 6MWD 6-min walk distance, ERA endothelin receptor antagonist, FC functional class, I.v. intravenous, PAH pulmonary arterial hypertension, PDE-5i phosphodiesterase type 5 inhibitor, PGI2 prostacyclin, RHC right heart catheterization. Asterisk indicates an intravenous PGI2 analog was initially up-titrated to 8 ng/kg/min in hospital and then further up-titrated by 1 ng/kg/min per week at home until a target dose of 20–25 ng/kg/min was reached. For this patient, an oral therapy targeting the PGI2 pathway could be an alternative option to an intravenous therapy

Sequential Combination Therapy

In clinical practice, many patients receive sequential combination therapy. This typically includes patients who have maintained a low risk status for months or even years on monotherapy or double combination therapy, but who now need to escalate their treatment with the addition of a second or third therapy. For this type of treatment regimen, patients will have adapted to the systemic vasodilator effects of one drug before starting another. As a result, additive side effects are thought to be less likely than with initial combination therapy. In our clinical experience, adding a therapy to an existing treatment regimen generally results in the same side effect profile as when the drug is given to a treatment-naive patient. Consequently, we manage and monitor the introduction of the new therapy in the same way as if it were given as a monotherapy.

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