Skip to main content
. 2019 Jan 31;2019(1):CD012621. doi: 10.1002/14651858.CD012621.pub2

Machado 2009.

Methods Multicentre, placebo‐controlled, double‐blind trial
16 weeks duration
Participants Inclusion criteria:
  • Adults and children (aged > 12 years)

  • with sickle cell disease (including, but not limited to SS, SC, SD, or S‐beta zero thalassemia)

  • with doppler‐defined PH (TRV ≥ 2.7 m/s) and 6MWD of 150 to 500 metres (WHO Group 5)

  • Randomised participants were stratified by TRV (2.7 to 2.9 m/s and ≥ 3.0 m/s), and those in upper strata underwent a right‐heart catheterisation (RHC)


Exclusion criteria:
  • Current pregnancy or lactation

  • Stroke within the last 6 weeks

  • Diagnosis of pulmonary embolism within the last 3 months

  • History of retinal detachment or retinal haemorrhage in the last 6 months

  • Non‐arteritic anterior ischaemic optic neuropathy (NAION) in 1 or both eyes

  • History of sustained priapism requiring medical or surgical treatment, unless currently impotent or on transfusion programme within the last 2 years

  • Any unstable (chronic or acute) condition that in the opinion of the investigator will prevent completion of the study

  • People taking nitrate‐based vasodilators, prostacyclin, or endothelin antagonists

  • LVEF < 40% or clinically significant ischaemic, valvular or constrictive heart disease

  • LVEF < 40% or SF < 22%, people in other research studies with investigational drugs (with the exception of hydroxyurea) unless the other trial has been approved by the walk‐PHaSST Executive Committee for co‐participation

  • Acute or chronic impairment (other than dyspnoea), limiting the ability to comply with study requirements (in particular with 6MWT), e.g. angina pectoris, intermittent claudication, symptomatic hip osteonecrosis, tonsillectomies for sleep apnoea within 3 months prior to randomisation

  • People taking potent CYP3A4 inhibitor therapy (e.g. itraconazole, ritonavir, ketoconazole)

  • People who are anticoagulated and have proliferative retinopathy (unless they have had ophthalmologist‐recommended intervention (e.g. phototherapy) or have been cleared by the ophthalmologist to participate in the study)

  • People with systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg


n = 74, with a planned study size of 132
Interventions Oral sildenafil 20 mg 3 times daily for 6 weeks,followed by 40 mg 3 times daily for 4 weeks, followed by 80 mg 3 times daily for 6 weeks, compared to placebo in a similarly uptitrated fashion
Outcomes Primary outcome measures: Change in exercise capacity as assessed by 6MWD
Secondary outcome measures: Change from baseline in PH at week 16 as assessed by tricuspid regurgitant jet velocity, Borg dyspnoea score, (severity is measured on a 10‐point scale with 0 = nothing at all and 10 = maximum severity of breathlessness), BNP levels.
Notes The study was prematurely stopped due to a statistically significant increase in serious adverse events in the sildenafil arm
Published as an abstract only, but also registered on the clinical trial registry: NCT00492531
Publicly funded
Trial conducted at 10 United States and United Kingdom Centers, dates not specified
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk States randomised, but methods not clearly stated
Allocation concealment (selection bias) Low risk Placebo‐controlled
Blinding of participants and personnel (performance bias) 
 All outcomes Low risk States participants and personnel were blinded
Blinding of outcome assessment (detection bias) 
 All outcomes Low risk States investigators were blinded
Incomplete outcome data (attrition bias) 
 All outcomes Low risk Withdrawals and reasons for trial termination clearly described
Selective reporting (reporting bias) Low risk Study was published despite early termination
Other bias Low risk Risk of other bias is unlikely. Although this is an abstract only, further methods were published on the clinical trials registry