Is sildenafil indicated in dogs with pulmonary arterial hypertension secondary to left-sided congestive failure? (spoiler alert….it’s not)
Pulmonary arterial hypertension (PAH) secondary to left-sided heart disease is categorised as type II in human medicine and is usually described as ‘post-capillary’. To some extent PAH may arise by transfer of hydrostatic pressure back through the pulmonary capillary bed. If elevations in pulmonary artery pressure are simply proportionate to changes in the pulmonary veins then the PAH is described as ‘isolated post-capillary pulmonary hypertension’. Superimposed upon this are usually secondary structural changes in pulmonary arterioles which produce a disproportionate PAH catchily-termed ‘‘post-capillary pulmonary hypertension with a pre-capillary component’.
If it were not for secondary pre-capillary changes then it might be expected that optimal PAH treatment would coincide with optimal control of left-sided congestive failure. However, since it appears that this is not the commonest scenario in dogs (or people) there would appear to be an option, at least theoretically, to target the secondary pre-capillary changes with therapeutic agents.
It is our impression that some UK clinicians do prescribe sildenafil to dogs with type II PAH. It’s worth a look at the evidence.
There’s precious little dog-specific evidence out there….and, as usual, it’s small numbers and contentious inclusion criteria all the way. That’s not to criticise those involved: there just aren’t the resources available to investigate to the same depth as in human medicine.
J Vet Intern Med. 2007 Nov-Dec;21(6):1258-64.
Sildenafil citrate therapy in 22 dogs with pulmonary hypertension.
Kellum HB, Stepien RL.
https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1939-1676.2007.tb01947.x
Only 9/22 of these dogs had moderate to severe left atrial enlargement suggesting type II (although coexistence of other pathologies was not excluded). The study was retrospective, non-blinded and uncontrolled. Although it is suggested that clinical status improved in these 9 dogs there would appear to be plenty of scope for placebo effect or chance. No changes in objective physical parameters, diagnostic measurements or survival were documented. As such, it probably doesn’t help us an awful lot.
So, the human data:
Curr Cardiol Rev. 2015 Feb; 11(1): 73–79.
Pulmonary Hypertension: Types and Treatments
Lisa J Rose-Jones*,1 and Vallerie V Mclaughlin
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4347212/#R53
This 2015 article is a good starting point. To quote the relevant paragraph:
‘The 2009 PH Consensus document notes that if after optimal treatment of the etiology of PVH, the TPG and PVR remain elevated in the setting of a normal or only minimally elevated PCWP, that PAH specific therapy may offer clinical benefit [1]. However, traditional PAH therapies have been employed in the PVH population with variable success. ERA trials in systolic heart failure have reported early exacerbations of heart failure secondary to fluid retention [48]. Prostacyclin has been shown to improve cardiac index and decrease PVR in advanced heart failure, but create a strong trend toward increased mortality [49]. PDE-5 inhibitors may be a potential therapy for PVH. A growing body of evidence, in both experimental models and human studies, has shown that NO-dependent pulmonary vasodilatation is impaired in heart failure [50, 51]. Sildenafil (50 mg three times daily) administered in a randomized controlled trial of 44 patients with heart failure with preserved ejection fraction and PH demonstrated a substantial improvement in pulmonary pressures , RV function, LV diastolic function, and quality of life over a one year follow up [52]. However, the recently published RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure) trial failed to demonstrate a significant benefit of sildenafil on clinical outcomes or exercise capacity [53]. Of note, this study did not require the presence of PH. Small studies of patients with systolic heart failure and PVH have demonstrated safety, improved hemodynamics, and increased exercise capacity with PDE-5 inhibitor use [54, 55]. Sildenafil 50 mg three times daily randomized to 45 NYHA class II/III patients with systolic heart failure on a stable heart failure regimen resulted in a significant increase in ejection fraction, 29.5% to 36.3%, p< 0.01, LV end diastolic dimensions, and LV mass index at 1 year compared to placebo [55]. The effect of PDE-5 inhibitors on cardiovascular outcomes including mortality will be the focus of the multicenter PITCH-HF trial (PDE5 Inhibition with Tadalafil Changes Outcomes in Heart Failure) in patients with LVEF< 40% and secondary PH. The body of evidence for PDE-5 inhibitor use is growing, but further research is needed.’
Sadly, the vaunted PITCH-HF trial was stopped: possibly due to practical issues rather than drug issues.
https://www.mdedge.com/ecardiologynews/article/80494/heart-failure/pitch-called-balk
Another review article published shortly thereafter….
Pulmonary hypertension in heart failure:
Measurable, but how meaningful?
John J. Ryan, MD, and James C. Fang, MD
http://www.jhltonline.org/article/S1053-2498(14)01283-2/pdf
…concurs that, whatever the effect of specific treatment on pulmonary arterial pressures, there is no evidence of clinical or survival benefit.
By 2016 we’re no further on with specific therapies:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4800173/
Left ventricular heart failure and pulmonary hypertension
Stephan Rosenkranz, J. Simon R. Gibbs, Rolf Wachter, Teresa De Marco, Anton Vonk-Noordegraaf, Jean-Luc Vachiéry
Eur Heart J. 2016 Mar 21; 37(12): 942–954
But it’s interesting to note this comment from that paper:
‘the CHAMPION trial has shown that consideration of the PAP (assessed by an implantable device) as an additional treatment target profoundly reduced the rate of HF-associated hospitalizations in both HFpEF and HFrEF.56,57 Of note, reductions of PAP were not achieved by targeted PAH drugs in this trial, but by optimized HF treatment including adjustment of diuretics.’
By 2017 we are at:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5331483/
Pulmonary Hypertension
Marius M. Hoeper, Hossein-Ardeschir Ghofrani, Ekkehard Grünig, Hans Klose, Horst Olschewski, Stephan Rosenkranz
Dtsch Arztebl Int. 2017 Feb; 114(5): 73–84
…who say:
‘None of the drugs licensed for the treatment of pulmonary arterial hypertension (etable 1) have any proven effect in patients with pulmonary hypertension on the basis of left heart disease or lung disease, so their use cannot be recommended in these indications. The randomized controlled multicenter studies conducted to test the action of drugs for pulmonary arterial hypertension in these groups of patients have all been negative, i.e., there was no sign of efficacy or the drug was actually harmful (17– 21). The potential risk entailed in using drugs for pulmonary arterial hypertension in patients with left heart disease or lung disease was emphasized by the recent discontinuation of a phase-II study of riociguat in patients with pulmonary hypertension based on fibrotic lung disease owing to signs of an elevated risk of mortality in the riociguat group (RISE-IIP, clinicaltrial.gov NCT02138825).’
With a rider that:
‘The occasional patients with simultaneous left heart or lung disease and severe pulmonary (arterial) hypertension in whom the underlying disease does not explain the extent of pulmonary hypertension or right heart overload constitute an exception to the recommendation not to use pulmonary arterial hypertension drugs.’
And finally, in 2018 -last month in fact!:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5997828/
Front Med (Lausanne). 2018; 5: 174.
Published online 2018 Jun 6
Pathophysiology and Diagnosis of Pulmonary Hypertension Due to Left Heart Disease
Athanasios Charalampopoulos,* Robert Lewis, Peter Hickey, Charlotte Durrington, Charlie Elliot, Robin Condliffe, Ian Sabroe, and David G. Kiely
‘Up to now, no pulmonary vasodilator treatment has proven to be efficacious in PH-LHD. Some of the PAH drugs have even been detrimental when given in patients with LHD. Hence, it is apparent that the accurate identification of the major driver of PH in each patient is essential. …… A better understanding of pathophysiology and further clinical trials are required to clarify whether Cpc-PH is a distinct clinical entity or part of a spectrum of PH phenotypes and identify potential treatments for the future.’
As far as I’m concerned there doesn’t appear to be any evidence base for treating pulmonary hypertension in dogs with left-sided CHF with anything other than conventional congestive failure management.
