Randomized Controlled Trial of Sildenafil for Preventing Recurrent Ischemic Priapism in Sickle Cell Disease

Abstract

BACKGROUND

Successful preventive therapy for ischemic priapism, a disorder of penile erection with major physical and psychologic consequences, is limited. We conducted a randomized, double-blind, placebo-controlled clinical trial to assess the efficacy and safety of sildenafil by a systematic dosing protocol to prevent recurrent ischemic priapism associated with sickle cell disease.

METHODS

Thirteen patients with sickle cell disease reporting priapism recurrences at least twice weekly were randomized to receive sildenafil 50 mg or placebo daily, unassociated with sleep or sexual activity, for 8 weeks, followed by open-label use of this sildenafil regimen for an additional 8 weeks.

RESULTS

Priapism frequency reduction by 50% did not differ between sildenafil and placebo groups by intention-to-treat or per protocol analyses (P = 1.0). However, during open-label assessment, 5 of 8 patients (62.5%) by intention-to-treat analysis and 2 of 3 patients (66.7%) by per protocol analysis met this primary efficacy outcome. No significant differences were found between study groups in rates of adverse effects, although major priapism episodes were decreased 4-fold in patients monitored “on-treatment.”

CONCLUSIONS

Sildenafil use by systematic dosing may offer a strategy to prevent recurrent ischemic priapism in patients with sickle cell disease.

Priapism is a clinical disorder characterized by prolonged penile erection in the absence of sexual arousal or desire.^1,2 Its ischemic form, presenting as a single, major episode, or recurrence, is associated with penile pain, erectile tissue destruction and loss, and permanent erectile inability.^2,3 Ischemic priapism occurs in several population groups, most notably in individuals with sickle cell disease (sickle cell disease), among whom as many as 40% are affected.^4–6

Treatments for this disorder are lacking, in large part because the disorder is clinically misunderstood and ideal medical interventions are undeveloped.⁷ Major scientific progress in this field in recent years has advanced understanding of the pathophysiology, in particular derangements in molecular effector pathways mediating penile erection.⁸ On the basis of evidence that aberrant activity of the nitric oxide (nitrergic) signal transduction pathway is a molecular mechanism for this disorder,^9,10 nitrergic-regulatory phosphodiesterase type 5 inhibitors have been preliminarily investigated in uncontrolled pilot studies suggesting feasibility and potential efficacy to prevent priapism.^11,12 We conducted a randomized, controlled trial to evaluate the benefit of the phosphodiesterase type 5 inhibitor sildenafil via an investigational protocol to prevent recurrent ischemic priapism in patients with sickle cell disease.

METHODS

Patients

Patients with sickle cell disease (confirmed SS or SC hemoglobinopathy), aged 14 to 45 years, were recruited from regional hematology and urology clinics. Inclusion criteria were occurrences of at least 2 self-reported priapism episodes per week and ability to provide written informed consent or assent. Exclusion criteria were estimated glomerular filtration rate <50 mL/min, clinical cirrhosis, pulmonary hypertension based on echocardiography, alcohol use exceeding 2 standard drinks daily, or formal contraindications for using phosphodiesterase type 5 inhibitor therapy.¹³ The study was approved by the Institutional Review Board (#NA_00017554) and the Food and Drug Administration (IND 075673) and registered at www.ClinicalTrials.gov as NCT00940901.

Study Design

This was a single-center, 2-phase, double-blind, placebo-controlled, parallel-group study conducted prospectively from June 2008 to November 2012. After baseline evaluation, consisting of clinical history, physical examination, routine serologic testing, and completion of study-specific instruments (Priapism/Sexual Activity Log and Priapism Questionnaire), patients were randomized in a 1:1 allocation to enter an 8-week double-blind phase (phase 1) consisting of daily sildenafil 50 mg or placebo (Pfizer Inc, New York, NY). The subsequent 8-week open-label phase (phase 2) of sildenafil 50 mg once daily was offered to all participants. Participants were instructed to take the medication in the morning a few hours after awakening and without sexual stimulation.^11,12 Patients were monitored by biweekly nurse coordinator phone calls (to record progress and medication changes and to document adverse event occurrences and adherence to study drug) and by in-clinic evaluations every 4 weeks (which included repeat administration of study instruments). A Data Safety and Monitoring Board performed quarterly reviews with assessments of trial progress, clinical outcomes, and occurrence of adverse events.

Outcomes and Statistical Analysis

The primary efficacy outcome was a 50% reduction (1-tier decrease) in priapism episodes biweekly from the baseline of each respective trial phase. Secondary outcomes included subjective improvements in episode frequency and duration and decrease in the median number of biweekly episodes of priapism in each phase. A simple tiered scoring system was devised, with the assignment of a numeric value to a priapism recurrence range as follows: 0 = no episodes, 1 = 1 to 2 episodes, 2 = 3 to 4 episodes, 3 = 5 to 8 episodes, 4 = 9 to 16 episodes, 5 = >16 episodes.

An a priori sample size of 24 patients in each group was calculated on the basis of a 50% reduction from a baseline mean frequency of 5.9 ± 5.0 priapism episodes per individual (Johns Hopkins Hospital historical data), considering a statistical power of 80% and an alpha error of 0.05. Last observation carried forward was used to determine the final priapism episode range at the completion of each study phase. Identical methods were applied for both intention-to-treat and per protocol analyses. We defined protocol adherence as 60% of expected drug-regimen use.

Baseline scores were compared between treatment groups using the Wilcoxon rank-sum test. Repeated evaluations for each patient were analyzed using a linear mixed model. Categoric outcomes were compared using the Fisher exact test. Data were analyzed using SAS version 9.2 (SAS Institute, Inc, Cary, NC). A P value <.05 was considered statistically significant.

RESULTS

Among 110 patients with sickle cell disease evaluated with recurrent ischemic priapism, 13 were enrolled and entered in phase 1. Baseline demographic and clinical characteristics are shown in Table 1. No significant differences were found between randomized treatment groups. After 5 patients were lost to follow-up, 8 remaining patients participated in phase 2; 1 patient was lost to follow-up thereafter.

Table 1.

Baseline Characteristics

	Placebo (n = 7)	Sildenafil (n = 6)	P Value
Age, y ± SD	23.0 ± 8.7	21.7 ± 5.3	.75
Hypertension, no. (%)	1 (14.3)	2 (33.3)	.56
Stroke, no. (%)	3 (42.9)	1 (16.7)	.56
Avascular necrosis, no. (%)	1 (14.3)	0 (0)	1.00
Acute chest syndrome, no. (%)	1 (14.3)	2 (33.3)	.56
Asthma, no. (%)	2 (28.6)	2 (33.3)	1.00
Smoker, no. (%)	1 (14.3)	2 (33.3)	.56
Alcohol use, no. (%)	3 (42.9)	3 (50)	1.00

no = number; SD = Standard Deviation.

At the end of phase 1, no significant differences were found between groups regarding decreases in episodes by score tier, that is, 3 of 6 patients (50%) in the sildenafil group and 3 of 7 patients (42.9%) in the placebo group by intention-to-treat analysis (P = 1.0) and 1 of 3 patients (33.3%) and 2 of 4 patients (50%), respectively, by per protocol analysis (P = 1.0; Table 2, Figure 1A). Likewise, no significant differences were found for decreased priapism frequency or duration (Table 2) or decreased median weekly change in priapism episode score (data not shown) between groups by both analyses. At the end of phase 2, 5 of 8 patients (62.5%) by intention-to-treat analysis and 2 of 3 patients (66.7%) by per protocol analysis had a decrease in episode tier (Table 2, Figure 1B). Approximately one third of patients reported decreased priapism frequency or duration during this phase by either analysis (Table 2).

Table 2.

Priapism Episode Range, Frequency, and Duration Proportions Between Groups by Intention-to-Treat and Per-Protocol Analysis

Intention-to-Treat
		Episode Range		Frequency		Duration
		Decrease no. (%)	P Value	Decrease no. (%)	P Value	Decrease no. (%)	P Value
End of Double-Blind Phase	Placebo group (n = 7)	3 (42.9)	1.00	2 (28.6)	1.00	1 (14.3)	.56
	Sildenafil group (n = 6)	3 (50.0)		1 (16.7)		2 (33.0)
End of Open-Label Phase	Former placebo group (n = 4)	3 (75.0)	.55*	2 (25.0)	.58*	0 (0.0)	1.00*
	Former sildenafil group (n = 4)	2 (50.0)	1.00*	1 (12.5)	1.00*	1 (12.5)	1.00*
	All (n = 8)	5 (62.5)		3 (37.5)		1 (12.5)
Per-Protocol
		Episode Range		Frequency		Duration
		Decrease no. (%)	P Value	Decrease no. (%)	P Value	Decrease no. (%)	P Value
End of Double-Blind Phase	Placebo group (n = 4)	2 (50.0)	1.00	2 (50.0)	.43	1 (25.0)	1.00
	Sildenafil group (n = 3)	1 (33.3)		0 (0.0)		1 (33.3)
End of Open-Label Phase	All (n = 3)	2 (66.7)		1 (33.3)		1 (33.3)

Figure 1.

(A) Difference in patient episode scores at the end of phase 1 from the initial baseline. (B) Difference in patient episode scores at the end of phase 2 from the reset baseline. Decreasing scores indicate improvement in reported episode score. *Patients meeting protocol adherence. Pt = patient.

Adverse effects of sildenafil therapy were infrequent and transient, consistent with those associated previously with phosphodiesterase type 5 inhibitor use^13,14; no significant differences were found between sildenafil and placebo groups (Table 3). Seven of 13 patients (53.8%) were hospitalized 14 times during the course of the study, among whom 10 visits by 6 patients were related to major priapism episodes. Of note, of the 10 priapism-related visits, 2 (20%) occurred in patients actively on sildenafil therapy, whereas the remaining 8 (80%) were associated with placebo use or nonadherence to the therapeutic regimen.

Table 3.

Adverse Events

Adverse Effects	Sildenafil Group (n = 6), n (%)	Placebo Group (n = 7), n (%)		P Value
Headache	0	0		1
Flushing	2 (33.3)	0		.19
Nasal Congestion	0	0		1
Abnormal vision	0	2 (33.3)		.46
Dyspepsia	1 (16.7)	0		.46
Myalgia	0	0		1
Hypotension	0	0		1
Major Adverse Events	Sildenafil Adherent	Sildenafil Nonadherent	Placebo	Total Events
Priapism	2	5	3	10
Vaso-occlusive crisis	0	2	1	3
Asthma attack	0	0	1	1

DISCUSSION

Our study is the first randomized, double-blind, placebo-controlled clinical trial of a therapy directed toward preventing recurrent ischemic priapism in patients with sickle cell disease. Although the efficacy of systematic sildenafil compared with placebo was not definitively demonstrated, the findings from this trial do not exclude clinical benefit and provide additional support for the safety of this therapy for those with priapism. A reduction in priapism episodes was observed in the majority of patients participating in the open-label phase. It also is notable that major priapism episodes were observed 4 times less often in patients assigned and adherent to sildenafil therapy, compared with those who were not assigned or adherent to the prescribed regimen.

We acknowledge numerous challenges associated with conducting this trial. A primary challenge was the difficulty in assessing recurrent ischemic priapism, which presents heterogeneously and is not standardly quantified.¹⁵ We were strict in our definition of the problem, in terms of frequency thresholds for study inclusion criteria and for evaluating response to therapy; however, this stringency resulted in the exclusion of many individuals with varied presentations of recurrent ischemic priapism and possibly limited determinations of therapeutic success. The nature of this disorder also presented obstacles, in that patients with sickle cell disease often are unaware of the health threat of recurrent ischemic priapism or demote it relative to other adverse health problems related to their disease.^16,17 Furthermore, the difficulty in successfully performing a controlled clinical trial for priapism in patients with sickle cell disease¹⁸ has been documented. We also encountered lack of acceptance for and actual fear of priapism risk in using this therapy by patients and their guardians, who had recognized the study treatment involved a highly advertised erectogenic drug.¹³ Despite our extensive counseling that treatment with sildenafil per study protocol was unlikely to increase priapism, this notion certainly contributed to difficult enrollment and to the low rate of study completion.

Our sildenafil protocol to control recurrent ischemic priapism is rational. This therapeutic strategy has been shown to reverse the priapism phenotype in sickle cell disease transgenic mice,¹⁹ restoring nitrergic balance and counteracting oxidative stress mechanisms that have been described in the erectile tissue of these animals,^9,19–24 as well as that of humans with sickle cell disease.²⁵

Study Limitations

Conclusive statements regarding the success of this therapy are certainly restrained. Limitations of our study include its small sample size, performance at a single clinical center, potential patient recall bias, and use of unvalidated assessment tools. We also did not ascertain the psychologic benefits²⁶ of our intervention or the possible effect²⁷ of our attention to this distressing problem among all study participants.

CONCLUSIONS

Our observations suggest that further studies in this arena are warranted; however, given demanding specifications for using phosphodiesterase type 5 inhibitors in this context, along with patient concerns about increased risk of priapism and expense, alternative therapeutic prospects with nitrergic restorative effects may become preferred.^7,21 Further clinical trials in this nascent field should be informed by this investigation, which offers insights into aspects of clinical trial methodology for recurrent ischemic priapism interventions, including participant inclusion criteria and study end points.

CLINICAL SIGNIFICANCE.

• Adherence to a sildenafil dosing regimen is critical because 66.7% of adherent patients demonstrated a 50% reduction in priapism episode frequency during the open-label phase.

• Four-fold fewer priapism-related hospital visits occurred among patients adherent to therapy than those who were nonadherent or receiving placebo, suggesting a potential benefit in reducing the occurrence of major episodes.

• No significant differences regarding adverse effects of sildenafil therapy were found between the sildenafil and placebo groups.