Effects of Phosphodiesterase-5 Inhibitors in Patients with Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-Analysis

Figures & data

Figure 1. PRISMA flow chart summarising results of the literature search.

Table 1. Summary characteristics of included studies.

Study (author & year)	Region	Study design	Trial period	Patients number (males)	Mean age		PDE-5 inhibitor	Dose	Control	Mean 6MWD (m)		mPAP (mmHg)		mPASP (mmHg)		PaO2 (mmHg)		PaCO2 (mmHg)
					Test	Control				Test	Control	Test	Control	Test	Control	Test	Control	Test	Control
Lederer et al. (2012) [19]	USA	Double-blind, 2-period crossover RCT	9 weeks	10 (8)	66 ± 4	66 ± 4	Sildenafil	25mg TDS	Placebo	458 ± 62.82	466 ± 49.02	–	–	–	–	73 ± 5.23	77 ± 4.08	42 ± 2.82	40 ± 2.20
Vitulo et al. (2016) [20]	Italy	Parallel-group RCT	16 weeks	28 (21)	66.4 ± 6.5	64.1 ± 11.0	Sildenafil	20mg TDS	Placebo	237.3 ± 102.67	297.3 ± 101.19	35.49 ± 9.67	36.70 ± 9.01	–	–	69.05 ± 13.83	70.24 ± 12.65	42.22 ± 6.58	41.24 ± 6.39
Goudie et al. (2014) [21]	Scotland (UK)	Double blind, parallel-group RCT	12 weeks	120 (82)	68 ± 8	70 ± 7	Tadalafil	10mg OD	Placebo	15.5 ± 32.24*	15.0 ± 32.26*	26.6 ± 5.2	30.8 ± 7.5	–	–	–	–	–	–
Shrestha et al. (2017) [22]	Nepal	Parallel-group RCT	4 weeks	61 (28)	63.75 ± 5.99	64.93 ± 3.74	Sildenafil	25mg TDS	Standard optimal COPD therapy	250.2 ± 74.1	196.27 ± 75.12	–	–	66.03 ± 19.62	63.84 ± 5.82	–	–	–	–
Rao et al. (2010) [23]	India	Double blind, parallel-group RCT	12 weeks	37 (males not stated)	60.7 ± 8.5	63.6 ± 6.7	Sildenafil	20mg TDS	Placebo	191 ± 127*	39 ± 87*	41 ± 8	44 ± 12	–	–	–	–	–	–
Blanco et al. (2013) [24]	Spain	Double blind, parallel group RCT	12 weeks	60 (54)	66 ± 8	65 ± 8	Sildenafil	20mg TDS	Placebo	23 (−12 − 40)**	21 (−12 − 40)**	–	–	–	–	64.5 (61.4–71.7)**	63.0 (56.8–72.7)**
Holverda et al. (2008) [25]	Netherlands	Parallel-group RCT	not stated	18 (11)	66 ± 9	66 ± 9	Sildenafil	50mg	Placebo	–	–	–	–	–	–	69.01 ± 14.25	69.01 ± 13.50	37.50 ± 6.75	36.75 ± 5.25
Rafiei et al. (2012) [26]	Iran	Double-blind, parallel-group RCT	1 week	40 (19)	48.8 ± 1.3	49.8 ± 1.4	Sildenafil	20mg BD	Placebo	–	–	–	–	–	–	–	–	42 ± 6.2	43 ± 6.4
Salem et al. (2013) [27]	Egypt	Parallel-group RCT	6 weeks	40 (18)	57 ± 8	55 ± 7	Sildenafil	25mg or 50 mg TDS	Placebo	–	–	–	–	43 ± 4	53 ± 7	–	–	–	–

Mean ± SD, unless otherwise stated.

RCT, randomised controlled trial; PDE-5 inhibitor, phosphodiesterase-5 inhibitor; 6MWD, 6-minute walk distance; mPAP, mean pulmonary artery pressure;  mPASP, mean pulmonary arterial systolic pressure; PaO₂, partial pressure of oxygen; PaCO₂, partial pressure of carbon dioxide.

*Mean change reported.

**Median (95% confidence interval).

Figure 2. Risk of bias graph: review authors’ judgements about each risk of bias item presented as percentages across all included studies.

Table 2. Risk of bias summary: review authors’ judgements about each risk of bias item for each included study.

	Random sequence generation	Allocation concealment	Blinding of participants and personnel	Blinding of outcome assessments	Incomplete outcome data	Selective reporting	Other bias
Blanco et al. (2013) [24]	+	+	?	?	?	+	+
Goudie et al. (2014) [21]	+	+	+	+	?	+	+
Holverda et al. (2008) [25]	?	+	?	?	+	−	?
Lederer et al. (2012) [19]	+	+	+	+	?	+	+
Rafiei et al. (2012) [26]	+	+	+	?	+	+	+
Salem et al. (2013) [27]	+	+	?	?	+	+	+
Shrestha et al. (2017) [22]	+	−	−	−	?	?	+
Vitulo et al. (2016) [20]	+	+	?	?	+	+	+
Rao et al. (2010) [23]	+	+	+	?	+	+	+

+, low risk; −, high risk; ?, unclear risk.

Figure 3. 6-minute walk distance (6MWD) outcome with phosphodiesterase-5 inhibitor treatment versus control in COPD patients. SD, standard difference; IV, inverse variance; CI, confidence interval; df, degree of freedom.

Figure 4. Mean pulmonary artery pressure (mPAP) outcome with phosphodiesterase-5 inhibitor treatment versus control in COPD patients. SD, standard difference; IV, inverse variance; CI, confidence interval; df, degree of freedom.

Table 3. Summary of adverse events reported in treatment and control groups.

Study	Treatment group		Control group		Types of adverse reaction experienced across both groups
	Adverse event	Number of patients	Adverse event	Number of patients
Rao et al. (2010) [23]	Epigastric discomfort	1	Acute exacerbation	1	Headache—most common Other adverse effects included were epigastric pain or discomfort, headache, paraesthesia, and numbness.
Lederer et al. (2012) [19]	At least one adverse event	9	Two adverse events	1	Dyspnoea; abdominal pain; blurry vision; headache; pleuritic pain; nasal congestion; upper respiratory tract infection; epistaxis; rib pain; facial flushing; back pain; dizziness.
Salem et al. (2013) [27]	None reported		None reported		No severe adverse events were reported.
Blanco et al. (2013) [24]	At least one adverse event	16	At least one adverse event	16	COPD exacerbation (most common) and headache. Adverse event occurring once in the placebo group included arrhythmia; blurred vision; epistaxis; diastolic hypertension; hypotension; psychiatric disorders; depression. Adverse event occurring in the sildenafil group included angina pectoris; dizziness; somnolence; gastritis; peripheral oedema; palpebral oedema; rhinorrhoea.
	Exacerbations leading to discontinuation	4	Exacerbations leading to discontinuation	2
	Exacerbations leading to hospitalisation	3	Exacerbations leading to hospitalisation	2
	Headache	2	Headache	1
	COPD exacerbations	10	COPD exacerbations	11
Goudie et al. (2014) [21]	COPD exacerbations	22	COPD exacerbations	27	Headache; dyspepsia; facial flushing; transient ischaemic attack; two deaths due to ruptured abdominal aortic aneurysm and pneumonia.
	Hospitalised	3	Hospitalised	4
	Dyspepsia	19	Headache	5
	Headache	17	Dyspepsia	5
	Facial flushing	2
	Transient ischaemic attack	1
	Deaths (due to ruptured abdominal aortic aneurysm and pneumonia)	2
Vitulo et al. (2016) [20]	Mild to moderate adverse event	5	None reported		Headache, diarrhoea, flushing, limb pain, dyspnoea, myalgia, and peripheral oedema.
Shrestha et al. (2017) [22]	None reported		None reported		One or more episodes of syncope; flushing (most common minor symptom); diarrhoea, tremor.

Figure 5. Headache adverse effect outcome in phosphodiesterase-5 inhibitor treatment versus control in COPD patients. SD, standard difference; IV, inverse variance; CI, confidence interval; df, degree of freedom.

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