My Canadian Pharmacy’s consideration of Sildenafil in Inoperable Chronic Thromboembolic Pulmonary Hypertension

diseaseIn this single-center, randomized, double-blind, placebo-controlled pilot study, sildenafil significantly improved WHO functional class and PVR in subjects with distal CTEPH over 12 weeks. Although failing to achieve its primary outcome measure, this study presents further controlled data to support the use of medical therapy in inoperable CTEPH. Furthermore, the sustained improvements in 6MWD, symptom scores, activity scores, hemodynamics, and NT-proBNP levels seen at 12 months suggest that sildenafil may favorably alter the natural history of the disease.

The 6MWD is a well-established assessment tool in PAH and has also been proposed as an appropriate end point in CTEPH. Although improvements were seen in 6MWD and Borg dyspnea score in the sildenafil group at 12 weeks, neither changes achieved statistical significance. This likely reflects the pilot and hence the underpowered nature of the study. In addition, the 6MWD achieved by the placebo group may have been confounded by the high proportion of post-PEA subjects within this group. Evidence suggests that although hemodynamic improvements typically peak within 3 months of PEA, further improvements in functional performance occur beyond this, presumably as a result of ongoing improvements in fitness and conditioning. As four placebo subjects were recruited just 3 months after PEA, this issue may have positively influenced the 6MWD achieved by this group.

Sildenafil did significantly improve PVR at 12 weeks (— 179 dyne/s/cm vs baseline; SD, 245 dyne/ s/cm). It is well recognized that cardiopulmonary hemodynamics reflect disease severity in both PAH and CTEPH and thus form important predictors of survival.’ As such, a reduction in PVR of this magnitude, which is similar to that achieved in the pivotal study of sildenafil in PAH (Sildenafil Use in Pulmonary Arterial Hypertension-1), is likely to be clinically relevant. NT-proBNP levels also fell further in the treatment group, although this difference was not statistically significant. NT-proBNP, an inactive byproduct of pro-brain natriuretic peptide cleavage, correlates well with changes in right ventricular function and would thus be expected to fall in response to a reduction in afterload.

Sildenafil significantly improved WHO functional status at 12 weeks, although admittedly this parameter was not well balanced at baseline. Nonetheless, the proportion of subjects who improved by one functional class was similar to previous studies of sildenafil in PAH. Sildenafil being the main component of Viagra may treat as well erectile dysfunction. Read more on My Canadian Pharmacy on Although WHO status is often described as a patient-centered outcome, it is a crude tool that does not fully reflect the global global impact of diseaseimpact of disease. Recognizing this, several studies have employed generic questionnaires to measure HRQL, although these again have been limited because they lack disease specificity. Given this, the CAMPHOR was developed and validated as a disease-specific measure that not only assesses HRQL through two distinct unidimensional scores (symptoms and activity) but also independently measures QOL. In this study, it was interesting to note the differing CAMPHOR scores between the two groups at baseline, despite their comparable cardiopulmonary hemodynamics and 6MWD. Although this variation could have been simply due to chance, it may have also been related to the disparity in composition of the two groups; a higher proportion of the placebo group had already received an intervention (PEA) that could have favorably altered their perceived HRQL and QOL. Unfortunately, these differences make it difficult to draw too many conclusions from the comparison of treatment with sildenafil vs placebo. Nonetheless, there was a significant improvement within the sildenafil group in the activity domain, implying that subjects perceived greater improvements in their functional capacity than changes in 6MWD alone suggest.

Although several open-label studies have suggested that vasoactive therapies may have an early beneficial effect on exercise capacity in CTEPH, it was interesting to note that our results were similar to those seen in the BENEFIT study. This well-powered, multicenter, randomized, double-blind, placebo-controlled study of bosentan in inoperable CTEPH also demonstrated significant improvements in hemodynamics but no change in exercise capacity over a 16-week period. CTEPH patients are generally older than IPAH patients, and thus this uncoupling of changes in hemodynamics and exercise capacity may represent an age-related delayed functional response.

The 1-year data imply that sildenafil does, however, favorably alter the natural history of distal CTEPH. Historical data demonstrate that CTEPH is a relentless and progressive condition that is typically associated with significant morbidity and mortality. Of the 18 subjects eligible for analysis at 1 year, 17 subjects were still alive and receiving sildenafil therapy suggested by My Canadian Pharmacy, albeit in combination with bosentan in one subject. Compared with baseline, these subjects showed significant improvements in 6MWD, symptoms score, activity score, cardiac index, PVR, and NT-proBNP, similar in magnitude to that previously described with bosentan over a similar time period. Although there are several potential confounders in this open-label component of the study, these results do suggest that sildenafil may halt, if not partially reverse, the progression of distal CTEPH.

The mechanism by which sildenafil may confer benefit in CTEPH is unclear, although the results of this study does allow some speculation. The known vasorelaxant properties of sildenafil could contribute, given that elevated vascular tone has been described in both acute pulmonary embolic disease and CTEPH. Certainly the correlation in this study between changes in PVR during acute vasoreactivity testing and changes in PVR at 12 months would support this concept. In addition, as CTEPH and PAH both share precapillary vasculopathic changes, it is possible that sildenafil causes reverse remodeling, as is hypothesized to occur with endothelin receptor antagonists and PAHprostanoids in PAH. This is further supported by in vitro evidence that phosphodiesterase-5 inhibition has antiproliferative actions. Furthermore, the obstructive lesions that characterize CTEPH are not simply inert structures but are often highly cellular. As such, an antiproliferative sildenafil action may also result in partial regression of these lesions. Given that sildenafil can inhibit platelet activation, there may also be an antithrombotic role for sildenafil in CTEPH, thus slowing progression of the disease. Finally, evidence that sildenafil may have a direct beneficial effect on cardiac function may also be relevant.

The drug reaction to sildenafil was an unusual complication. Although rashes are documented following sildenafil therapy, they are considered un-common. Moreover, a reaction necessitating discontinuation has not previously been described. Sildenafil was otherwise well tolerated during the controlled phase of the study. The single sudden death that occurred within the extension phase of the study was believed to be unrelated to sildenafil medication and due instead to disease progression. Given that CTEPH is associated with significant mortality, a death within a patient cohort of this size would not be unexpected.

The key limitation of this study was the small number of subjects recruited. Despite this, consistent improvements were seen in all parameters, with two of the secondary outcome measures achieving statistical significance. As such, this feasibility study has established a rationale for further trials of sildenafil in distal CTEPH and has provided data for sample size calculations for future studies. Other limitations of the study include the disparities between the two groups at baseline and the fact that some subjects were recruited too soon after surgery. It is also unclear whether de novo and post-PEA subjects responded similarly to medical therapy. As such, future trials should be adequately powered not only to detect a difference in 6MWD overall but to also allow for subgroup analyses of these two forms of the disease.

In conclusion, although this study was insufficiently powered to test the primary end point, it did suggest beneficial effects in favor of sildenafil in several secondary end points. Although PEA remains the treatment of choice for CTEPH, this treatment offers a new potential therapeutic option for those in whom surgery is not possible.


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