Journal of Clinical Medicine Research, ISSN 1918-3003 print, 1918-3011 online, Open Access
Article copyright, the authors; Journal compilation copyright, J Clin Med Res and Elmer Press Inc
Journal website http://www.jocmr.org

Original Article

Volume 9, Number 6, June 2017, pages 488-498

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

Figures

Figure 1.
Figure 1. Flow diagram for meta-analysis according to PRISMA statement.
Figure 2.
Figure 2. Deaths/hospitalizations of HF.
Figure 3.
Figure 3. Adverse events in patients with CHF.
Figure 4.
Figure 4. Peak VO2 in CHF.
Figure 5.
Figure 5. The 6MWT in patients with CHF.
Figure 6.
Figure 6. LVEF in HFREF and HFPEF patients under treatment with PDE5i.
Figure 7.
Figure 7. E/e’ ratio in HFREF and HFPEF patients.
Figure 8.
Figure 8. Pulmonary pressures in CHF patients.
Figure 9.
Figure 9. PVR during therapy with PDE5i.

Tables

Table 1. Baseline Features of Included RCTs
 
Amin et al (2013) [7]Andersen et al ( 2013) [8]Behling et al (2008) [9]Guazzi et al (Circ Heart Fail 2011) [10]Guazzi et al (Circulation 2011) [11]Guazzi et al (2012) [112]Guazzi et al (2007) [13]Hoendermis et al (2015) [14]Katz et al (2005) [15]Kim et al (2015) [16]Lewis et al (2008) [17]Lewis et al (2007) [3]Redfield et al (2013) [18]Webster et al (2004) [19]
†Sub-analysis of Lewis et al. CHF: chronic heart failure; HFREF: heart failure with reduced left ventricular ejection fraction; HFPEF: heart failure with preserved left ventricular ejection fraction; PH: pulmonary hypertension; EOB: exercise oscillatory breathing; MI: myocardial infarction; NYHA: New York Heart Association; PDE5i: phosphodiesterase type 5 inhibitor; CPET: cardiopulmonary exercise test; echo-: echocardiography; FMD: flow-mediated dilatation; BNP: B-type natriuretic peptide; QoL: quality of life; BP: blood pressure; 6MWT: six-minute walking test; CMRI: cardiac magnetic resonance imaging.
Subjects randomized
(n; PDE5i/placebo)		53/5335/3511/823/2222/2216/1623/2321/2260/7221/2015/1517/17113/10335/35
Drug nameSildenafilSildenafilSildenafilSildenafilSildenafilSildenafilSildenafilSildenafilSildenafilUdenafilSildenafilSildenafilSildenafilSildenafil
Drug dosage25 mg bid for first 2 weeks; 50 mg tid for next 10 weeks40 mg tid50 mg tid50 mg tid50 mg tid50 mg tid50 mg bid20 mg tid for first 2 weeks; 60 mg tid for next 10 weeks25/50/100 mg50 mg bid for first 4 weeks; 100 mg bid for next 8 weeks25 - 75 mg tid25 - 75 mg tid20 mg tid for first 12 weeks; 60 mg tid for next 12 weeks50 mg once daily
Inclusion criteriaHFREFDiastolic dysfunction after MIHFREFHFREFHFPEF with PHHFREF with PH and EOBHFREFHFPEF with PHCHF (HFREF) with EDHFREFHFREF with PH†HFREF with PHHFPEFCHF (HFREF)
  NYHAII-III-I-IIIII-IIIII-IVIII-IVII-IIIII-IIII-IIIII-IVII-IVII-IVII-IVII-III
  LVEF< 35%≥ 45%≤ 40%< 40%≥ 50%< 45%≤ 45%≥ 45%≤ 40%≤ 40%< 40%< 40%≥ 50%-
Follow-up duration (months)32112121263333361.5
Outcome measuresBP, NYHA, 6MWTEcho-, cardiac cath, CPET, 6MWTEcho-, CPET, FMDEcho-, CPET, BNP, QoLEcho-, cardiac cath, QoLCPET, cardiac cathEcho-, CPET, FMDCardiac cath, CPET, Echo-International index of erectile functionEcho-, CPETCardiac cath, CPET, ventriculo-graphyCPET: peak VO2Echo-, CMRI, CPET, 6MWTInternational index of erectile function

 

Table 2. Different Impact of PDE5 Inhibitors According to Pulmonary Hemodynamics
 
Amin et al (2013) [7]Andersen et al (2013) [8]Behling (2008) [9]Guazzi et al (Circ Heart Fail 2011) [10]Guazzi et al (Circulation 2011) [11]Guazzi et al (2012) [12]Guazzi et al (2007) [13]Hoendermis et al (2015) [14]Kim et al (2015) [16]Lewis et al (2008) [17]Lewis et al (2007) [3]Redfield et al ( 2013) [18]
Improvement in exercise capacity was evaluated based on the changes in peak VO2 and VE/VCO2 slope evidenced by cardiopulmonary exercise test, or based on 6MWT. Improvement in LV function was evaluated based on the changes in LVEF. Reduction in pulmonary pressures was evaluated based on the changes in mPAP, PCWP and PVR by means of cardiac cath, or using PASP derived from echocardiogram. *Converted from echocardiographic PASP by the following equation: mPAP (mm Hg) = (0.61 × PASP (mm Hg)) + 2 mm Hg [5]. †Sub-analysis of Lewis et al, 2007. HFREF: heart failure with reduced left ventricular ejection fraction; HFPEF: heart failure with preserved left ventricular ejection fraction; PH: pulmonary hypertension; EOB: exercise oscillatory breathing; MI: myocardial infarction; mPAP: mean pulmonary arterial pressure; dPAP: diastolic pulmonary arterial pressure; PCWP: pulmonary capillary wedge pressure; TPG: transpulmonary gradient; DPG: diastolic pulmonary gradient; PVR: pulmonary vascular resistance; N/A: not applicable.
Inclusion criteriaHFREFDiastolic dysfunction after MIHFREFHFREFHFPEF with PHHFREF with PH and EOBHFREFHFPEF with PHHFREFHFREF with PH†HFREF with PHHFPEF
Pulmonary hemodynamic parameters
mPAP (mm Hg; PDE5i/placebo)-19/2036.2/39.8*24.6/25.2*39/3735/3422.7/21.5*35/3527/28.2*30/3330/3327/27*
dPAP (mm Hg; PDE5i/placebo)-14/15--31.6/29.7--20/21----
PCWP (mm Hg; PDE5i/placebo)-43082--22/21.921/20-19.9/20.8-18/1918/19-
TPG (mm Hg; PDE5i/placebo)-7/7--16.2/14.515.2/14.7-13/13-12/1412/14-
DPG (mm Hg; PDE5i/placebo)-2/2--9.6/7.8-2/-1----
PVR (dyn·s/cm5; PDE5i/placebo)-207/220--310.4/261.6360/354-207/203-340/360340/360-
Features of combined post- and pre-capillary PH (DPG ≥ 7 mm Hg; PVR > 3 WU (> 240 dyn·s/cm5))Not investigatedNoNot investigatedNot investigatedYesYesNoMainly no (Cpc-PH in 12%)Not investigatedYesYesNot investigated
Outcomes
  Exercise capacityNo changeNo changeImprovedImprovedN/AImprovedImprovedNo changeImprovedImprovedImprovedNo change
  LV functionN/AImprovedNo changeImprovedImprovedImprovedImprovedNo changeImprovedN/AImprovedNo change
  Pulmonary pressureN/ANo changeReducedReducedReducedReducedReducedNo changeReducedReducedReducedNo change