Phosphodiesterase type 5 inhibitors and guanylate cyclase stimulators
Nitric oxide (NO) is a vasodilator which inhibits platelet activation and has antiproliferative effects in vascular smooth muscle. Its effects are mediated through cylic GMP.Cylic GMP is degraded by phosphodiesterase type-5 (PDE-5). PDE-5 inhibitors slow the degradation of cyclic GMP and increase the levels of nitric oxide. There are three currently available; sildenafil, tadalafil and vardenafil. Guanylate cyclase stimulators act by enhancing cyclic GMP production and there is one currently available, Riociguat. Table 3 below summarises the evidence for the PDE-5i and riociguat.
See web table VIB in 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension – web addenda
Sildenafil
Sildenafil is a potent inhibitor of phosphodiesterase type 5. Three RCTs have shown improvement in exercise capacity, symptoms, functional class and haemodynamics.22 An RCT studying dual therapy of sidenafil with epoprostenol showed improvements after 12 weeks in 6MWD and time to clinical worsening. All deaths occured in the placebo group. Sildenafil is licensed for use at 20 mg tds only.
Side effects of sildenafil include headache, flushing, epistaxis, indigestion, diarrhoea and myalgia. It is contra-indicated in patients who have previously had gastrointestinal haemorrhage. Sildenafil is contraindicated in any patient taking nitrates.
Tadalafil
Tadalafil is an oral selective PDE-5 inhibitor.. One RCT has showna favourable effect on symptoms, exercise capacity, haemodynamics and time to clinical worsening at 40mg once daily at 12 weeks.23
Side effects (see SPC) include headache, dyspepsia, flushing, and nasal congestion. It is contra-indicated in certain groups of patients with cardiovascular disease, in those who are using any form of organic nitrate, and in patients with non-arteritic anterior ischaemic optic neuropathy.
Vardenafil
Vardenafil is an oral selective PDE-5 inhibitor. One RCT has shown improvements in exercise capacity, haemodynamics and time to clinical worsening. It has a similar side effect profile to sildenafil.
Riociguat
Riociguat is an oral, soluble guanylate cyclase stimulator. While is enhances cGMP production, animal studies have also shown anti-proliferative and anti-remodelling properties. One RCT has shown an improvement in exercise capacity, haemodynamic, functional class and time to clinical worsening in treatment naive patients. Patients already on therapy with ERAs or prostanoids showed an improvement in exercise capacity. Syncope is the most common side effect and combination with a PDE-5i is contraindicated due to hypotension.
Learning points
- Endothelial dysfunction occurs in PH, with reduced availability of NO (and hence a tendency to vasoconstriction)
- Drugs which augment NO availability, such as PDE-5 inhibitors and soluble guanylate cyclase stimulators, can improve symptoms
Endothelin receptor antagonists
Endothelin-1 binds to endothelin receptors type A and B in the pulmonary vascular smooth muscle and exerts vasoconstrictor and mitogenic effects. Activation of the endothelin system has a prominent role in the pathogenesis of PAH. Three ERAs are currently available and include Ambrisentan, Bosentan and Macitentan. The main adverse effect is liver toxicity and patients require monthly liver function tests. Furthermore, there is a risk of teratogenicity and falling haemoglobin levels so monthly pregnancy tests in women of child-bearing age and three monthly haemoglobin testing is required. Data from clinical trials show no obvious clinical difference between endothelin A blockers and combined endothelin A and B receptor blockers (see table 4).
See web table VIA in 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension – web addenda
Ambrisentan
Ambrisentan preferentially binds with endothelin receptor type A. It improves symptoms, exercise capacity, haemodynamics and time to clinical worsening in patients with IPAH, PAH due to connective tissue disease and PAH associated with HIV infection. The incidence of abnormal liver function tests is 0.8–3% and peripheral oedema has also been reported.
Bosentan
Bosentan is a dual endothelin receptor antagonist. Bosentan improves exercise capacity, functional class, cardiac index and other haemodynamic indices, echocardiographic and Doppler variables and reduces time to clinical worsening. It has been evaluated in IPAH, CTD associated and Eisenmenger syndrome. Dose dependent increases in aminotransferases occurs in approximately 10% of cases and is reversible.
Long-term survival data28 indicate that first-line therapy with bosentan, with the addition of other therapy or change to other therapy as needed, resulted in survival estimates of 96% at one year and 89% at two years. Some 85% and 70%, respectively, were alive and on bosentan therapy alone at the end of one and two years.
Compared with placebo, in patients with Eisenmenger syndrome bosentan reduced pulmonary vascular resistance and mPAP and increased exercise capacity without worsening oxygen saturation.
Bosentan also appears to give improvements in patients with PAH associated with HIV infection
Macitentan
Macitentan is a dual endothelin receptor antagonist and the most recent ERA. It has been evaluated in one RCT and significantly reduced the composite endpoint of morbidity and mortality among patients with PAH and increased exercise capacity. No liver toxitiy was shown but 4.3% of patients had a reduction in Hb to <8 g/dl.
Learning points
- Endothelin is a potent vasoconstrictor
- Endothelin receptor antagonists are drugs that block the action of endothelin and improve pulmonary vascular remodelling
Combination therapy in pulmonary hypertension
Combination therapy is standard practice for other forms of cardiovascular disease such as heart failure and hypertension. Pulmonary hypertension is another disease that involves multiple molecular pathways: the option of targeting multiple pathways in this condition in order to maximise efficacy is appealing, especially since many patients have a suboptimal response or develop tolerance to an initial therapeutic regimen.6
Drug therapy is administered with the intention of patients reaching clinical efficacy targets created for individual patients. Combination therapy may be given sequentially or upfront. Sequential combination therapy is the most widely used strategy; monotherapy is initiated, and then on follow up, failure to achieve certain goals after the peak effect of the drug should have been reached triggers the addition of a second and then a third drug.. These goals include reaching or maintaining WHO FC I or II and the near-normalisation of resting cardiac index and/or NT-proBNP plasma levels. Tables 5 and 6 below outline the recommendations for drug monotherapy (initial therapy) and then sequential combination therapy. Further details regarding the evidence behind combination therapy is beyond the scope of this module and is outlined in further reading.
See table 19 in 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension
See table 21 in 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension
The rationale for upfront combination is based on the poor prognosis of PAH which is comparable to many malignancies. Tables 7 and 8 below summarise the recommendations and evidence in regards to initial drug combination therapy. While BREATHE-2 was a negative RCT, the most recent, multi-centre, multi-national, blinded, placebo-controlled trial which compared first line monotherapy with tadalafil or ambrisentan with upfront combination therapy with tadalafil and ambrisentan in de novo WHO FC II and III PAH patients showed a 50% reduction in events in the combination group. Improvements were observed in exercise capacity, rate of satisfactory clinical response and NT pro BNP levels. As this study has shown that initial combination therapy was superior to initial monotherapy in delaying clinical failure, a higher grade of recommendation has been given to this initial combination.
See table 20 in 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension
See web table VID in 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension – web addenda
The approach of waiting until the patient deteriorates to add a second drug is inappropriate because clinical deterioration in a patient with PAH is difficult to recover.
Patients entering clinical trials in the current era tend to have milder symptoms and walk further at baseline. This is leading to the use of primary end points such as time to clinical worsening and its variants, which are favoured by regulatory authorities because this is a clinical rather than a surrogate measurement. Increased duration of trials beyond the typical 12–16 weeks of monotherapy trials as well as changes in trial design are likely to yield more useful data about clinical outcomes. Time to clinical worsening is an end point which combines mortality, hospitalization for PAH and various measures of clinical deterioration usually including WHO functional class and 6MWT distance.
Learning points
- Patients at low and intermediate risk can be treated with either initial monotherapy or initial combination therapy
- In the case of initial monotherapy, no evidence-based first-line monotherapy can be proposed so the choice of drug depends on patient and drug factors and physician experience
- In high risk patients, initial combination therapy including IV prostacylin analogues, particularly epoprostenol should be considered
- Experience with combination therapy is increasing
- Therapy should be tailored to achieve/maintain certain goals before clinical deterioration
