NO (nitric oxide) to priapism with hydroxyurea and tadalafil Free

In this issue of Blood, Idris et al¹ have demonstrated the feasibility of conducting a trial to prevent priapism in male patients with sickle cell anemia and provide data that suggest a benefit for hydroxyurea in reducing the rate of priapism. Clinical complications of sickle cell disease (SCD) are caused by vaso-occlusion with ischemia-reperfusion injury and hemolytic anemia.² Hemolysis is associated not only with anemia and cholelithiasis but also with vasculopathic complications such as stroke, pulmonary hypertension, kidney disease, leg ulcers, and priapism.

Priapism is a common complication of SCD and refers to a persistent penile erection unrelated to sexual desire. Low-flow (also referred to as ischemic) priapism, the most common form of priapism in SCD, may occur at any age but becomes particularly problematic following puberty. Episodes may present as shorter, more frequent episodes (stuttering priapism) or major episodes (lasting >4 hours). An ischemic priapism episode lasting at least 4 hours is a urologic emergency. Low-flow priapism is associated with decreased or absent blood flow in the penile arteries caused by high pressure in the venous sinuses of the corpora cavernosa, which leads to tense rigidity and pain, a type of compartment syndrome. In addition to pain, emotional distress, and decreased quality of life, repeated episodes of ischemia-induced penile tissue damage may result in erectile dysfunction. Despite the substantial morbidity associated with priapism in SCD, available preventive treatments are few, with even fewer adequately powered, controlled studies.

Intravascular hemolysis results in the release of cell-free plasma hemoglobin, heme, and arginase-1 that inactivate the nitric oxide (NO) signaling axis and promote oxidative stress.² NO signaling is a principal mediator of penile erection, causing smooth muscle relaxation in response to parasympathetic nervous system inputs.³ NO in the smooth muscle cells of the cavernosal artery and the sinusoidal space activates guanylate cyclase, with resultant increased cyclic guanosine monophosphate (cGMP), smooth muscle relaxation, vasodilation, and increased penile blood flow. Phosphodiesterases (PDEs) inactivate cGMP, leading to smooth muscle contraction and termination of the erectile response. Increasing evidence now suggests that priapism occurs owing to NO deficiency with PDE-5 dysregulation and uncontrolled signaling.⁴ 

PDE-5 inhibitors may play an important role in the prevention of priapism by reprogramming PDE-5 and NO signaling. Previous trials of secondary prevention of priapism have been limited by their inadequate statistical power, with none of them showing statistically significant reductions in the frequency of stuttering priapism or major priapism events.⁵ A small placebo-controlled study of sildenafil, a PDE-5 inhibitor, found no statistically significant differences in the frequency or duration of priapism episodes after 8 weeks of treatment.⁶ Hydroxyurea is an inducer of fetal hemoglobin (HbF) and NO donor, which is approved for the prevention of acute vaso-occlusive complications of SCD.^7,8 It has previously been suggested for use in patients with frequent or prolonged priapism episodes.⁹ Although priapism was defined as a painful crisis event in the Multicenter Trial of Hydroxyurea, a landmark trial that demonstrated the clinical efficacy of hydroxyurea in decreasing the frequency of vaso-occlusive episodes, the effect of hydroxyurea on the occurrence of priapism was not reported in this trial.^7,10 

Here, the results of a phase 2 randomized, controlled, feasibility trial to compare oral fixed moderate-dose hydroxyurea plus placebo (as usual care) with oral fixed moderate-dose hydroxyurea plus low-dose of the PDE-5 inhibitor, tadalafil (as the experimental arm), are presented. Although the study achieved its primary outcome measures of recruitment, retention, and adherence to therapy, there was no significant difference in the priapism rate between the usual care and the experimental arms. However, post hoc analysis showed significant reductions in the priapism rates for both the usual care and experimental arms when the mean priapism rates during the screening period were compared with the rates during the trial period. In the participants who consented and provided seminal fluid for analysis at baseline, study exit, and 3 months after stopping hydroxyurea, the sperm concentration, progressive and nonprogressive motility, and normal morphology decreased at the study exit, but returned to pretreatment levels after stopping treatment. At the completion of the trial, significant improvements in quality of life were observed in several domains using the priapism-specific (Priapism Impact Profile) and Patient-Reported Outcomes Measurement Information System-29 (PROMIS-29) physical function instruments in both treatment arms, providing further evidence for improved well-being after treatment with hydroxyurea.

Although there was no significant difference in the priapism rate between the usual care and experimental arms, the study was not designed to show a difference between the 2 arms. The finding of a significant reduction of the priapism rate in the post hoc analysis raises several important questions: (1) would escalation of the hydroxyurea dose to the maximum tolerated dose provide additional benefits compared with fixed-dose hydroxyurea; (2) is the benefit of hydroxyurea owing to its NO donor properties or its HbF-inducing effects and subsequent improvement in hemolytic anemia; (3) will novel antisickling agents, which are currently in clinical trials, be beneficial for priapism owing to their effects on hemolysis; and (4) will the combination of hydroxyurea and tadalafil produce additive or synergistic effects in the prevention of priapism in adequately designed studies? Only the conduct of adequately powered prospective (and mechanistic) studies will answer these questions. Finally, the finding of a reversible effect of hydroxyurea on multiple semen analysis parameters provides further evidence that treatment of patients with SCD with hydroxyurea does not result in a permanent decrease in seminal fluid parameters.

Conflict-of-interest disclosure: K.I.A. has received research funding from Novo Nordisk; served on advisory boards for Agios Pharmaceuticals; served as a consultant for Novartis, Pfizer, GSK, and Sanofi; is a member of a data monitoring committee for Vertex Pharmaceuticals; and is a member of the board of trustees for Vitalant.