Phosphodiesterase-5 Inhibitors Improve Clinical Outcomes, Exercise Capacity and Pulmonary Hemodynamics in Patients With Heart Failure With Reduced Left Ventricular Ejection Fraction: A Meta-Analysis

Vecchis, Renato De; Cesaro, Arturo; Ariano, Carmelina; Giasi, Anna; Cioppa, Carmela

doi:10.14740/jocmr3008w

Cited by 30 publications

(26 citation statements)

References 22 publications

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“…This finding thus supports previous concerns about PH-targeted therapies in HFpEF/HFrEF patients, including PDE5-inhibitors[ 47 ]. Conversely, a recent meta-analysis on PDE5-inhibitors in HFrEF/HFpEF observed a reduction of the composite of death or hospitalisation [ 48 , 49 ], whereas another meta-analysis could not find significant changes in mortality with endothelin receptor antagonists[ 50 ]. However, these meta-analyses mainly included trials of short duration.…”

Section: Discussionmentioning

confidence: 99%

Pulmonary hypertension-targeted therapies in heart failure: A systematic review and meta-analysis

et al. 2018

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BackgroundPulmonary hypertension (PH) due to left heart failure (HF) is the most common form of PH. However, treatment is unclear because there are conflicting results about safety and efficacy of PH-targeted therapies.ObjectivesTo assess the effects of PH-targeted therapy on exercise capacity in HF patients.MethodsMEDLINE, EMBASE and the Cochrane Library were searched from January 1990 to July 2017 for randomized controlled trials comparing PH-targeted therapies to conventional therapy in HF. The primary outcome was to assess the effects on exercise capacity. Secondary outcomes included mortality, hospitalisation, NT-proBNP levels, echocardiographic and hemodynamics parameters and discontinuation rate.Results22 studies were included (n = 5448), including 3, 8 and 11 studies with low, high and unknown risk of bias, respectively. PH-targeted therapies were associated with an improvement of exercise capacity (standardized mean difference 0.29;95%CI:0.08–0.50, p = 0.006). Pre-specified subgroup analyses found that this improvement was predominantly observed in studies evaluating phosphodiesterase-5 inhibitors and prostanoids and in patients with reduced ejection fraction. Moreover, systolic pulmonary artery pressure measured by echocardiography was improved (mean difference: -7.5mmHg; [95%CI]: -14.9,-0.1, p = 0.05), which was also entirely driven by studies evaluating phosphodiesterase-5 inhibitors. However, PH-targeted therapies were associated with an increased treatment discontinuation rates and a potential increase in mortality compared to standard treatment.ConclusionsIn conclusion, PH-targeted therapies and especially phosphodiesterase-5 inhibitors may improve exercise capacity in patients with HF. However, an increase in adverse outcomes was likely. Moreover, most studies were at high or unknown risk of bias, precluding confident conclusions about the effects of PH-targeted therapies.

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Section: Discussionmentioning

confidence: 99%

Pulmonary hypertension-targeted therapies in heart failure: A systematic review and meta-analysis

et al. 2018

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“…In a meta‐analysis assessing the effects of PDE5 inhibitors in patients suffering from PAH due to left chronic heart failure, De Vecchis et al . () found that among patients (>18 years old) with reduced left ventricular ejection fraction, a significant benefit was conferred by PDE5 inhibitors against the risk of the composite endpoint of death and hospitalization. In contrast, patients with preserved left ventricular ejection fraction had no benefit from PDE5 inhibitor treatment.…”

Section: Approved Clinical Applications Of Pde5 Inhibitorsmentioning

confidence: 99%

PDE5 inhibitors – pharmacology and clinical applications 20 years after sildenafil discovery

2018

British J Pharmacology

370

157

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The discovery of the nitric oxide/cGMP pathway was the basis for our understanding of many normal physiological functions and the pathophysiology of several diseases. Since the discovery and introduction of sildenafil, inhibitors of PDE5 have been the first-line therapy for erectile dysfunction (ED). The success of sildenafil in the treatment of ED stimulated research in the field of PDE5 inhibition and led to many new applications, such as treatment of lower urinary symptoms, and pulmonary arterial hypertension, which are now approved indications. However, PDE5 inhibitors have also been used in several other disorders not discussed in this review, and the fields of clinical use are increasing. In the present review, the pharmacological basis of the NO/cGMP pathway and the rationale and clinical use of PDE5 inhibitors in different diseases are discussed.

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“…Recent meta-analyses revealed that PDE5 inhibitors improve pulmonary hemodynamics and clinical outcomes in systolic heart failure patients with pulmonary hypertension [ 25 , 26 ]. The present study demonstrates that RV molecular alterations occur very early during LV pressure-overload before RV systolic pressure increases and that these molecular derangement in the RV are inhibited by sildenafil through mechanisms potentially involving anti-inflammation.…”

Section: Discussionmentioning

confidence: 99%

Sildenafil ameliorates right ventricular early molecular derangement during left ventricular pressure overload

et al. 2018

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Right ventricular (RV) dysfunction following left ventricular (LV) failure is associated with poor prognosis. RV remodeling is thought initiated by the increase in the afterload of RV due to secondary pulmonary hypertension (PH) to impaired LV function; however, RV molecular changes might occur in earlier stages of the disease. cGMP (cyclic guanosine monophosphate)-phosphodiesterase 5 (PDE5) inhibitors, widely used to treat PH through their pulmonary vasorelaxation properties, have shown direct cardiac benefits, but their impacts on the RV in LV diseases are not fully determined. Here we show that RV molecular alterations occur early in the absence of RV hemodynamic changes during LV pressure-overload and are ameliorated by PDE5 inhibition. Two-day moderate LV pressure-overload (transverse aortic constriction) neither altered RV pressure/ function nor RV weight in mice, while it induced only mild LV hypertrophy. Importantly, pathological molecular features were already induced in the RV free wall myocardium, including up-regulation of gene markers for hypertrophy and inflammation, and activation of extracellular signal-regulated kinase (ERK) and calcineurin. Concomitant PDE5 inhibition (sildenafil) prevented induction of such pathological genes and activation of ERK and calcineurin in the RV as well as in the LV. Importantly, dexamethasone also prevented these RV molecular changes, similarly to sildenafil treatment. These results suggest the contributory role of inflammation to the early pathological interventricular interaction between RV and LV. The current study provides the first evidence for the novel early molecular cross-talk between RV and LV, preceding RV hemodynamic changes in LV disease, and supports the therapeutic strategy of enhancing cGMP signaling pathway to treat heart diseases.

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Phosphodiesterase-5 Inhibitors Improve Clinical Outcomes, Exercise Capacity and Pulmonary Hemodynamics in Patients With Heart Failure With Reduced Left Ventricular Ejection Fraction: A Meta-Analysis

Cited by 30 publications

References 22 publications

Pulmonary hypertension-targeted therapies in heart failure: A systematic review and meta-analysis

Pulmonary hypertension-targeted therapies in heart failure: A systematic review and meta-analysis

PDE5 inhibitors – pharmacology and clinical applications 20 years after sildenafil discovery

Sildenafil ameliorates right ventricular early molecular derangement during left ventricular pressure overload

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