Viagra ( Sildenafil )

A randomized double-blind, placebo-controlled, cross-over trial assessing the effect of tadalafil (Cialis) on the cardiovascular response in men with complete spinal cord injury above the sixth thoracic level: A Pilot Study

Double-blind, randomized cross-over placebo-controlled pilot study.

Objectives

To determine the effects of tadalafil on systolic blood pressure (SBP), heart rate (HR), and dizziness of men with American Spinal Injury Association Impairment Scale-A (AIS-A) spinal cord injury (SCI) between cervical-4 (C4) and thoracic-5 (T5) levels.

Setting

Outpatient rehabilitation clinic.

Design

Double-blind, randomized cross-over placebo-controlled pilot study.

Methods

20 males with AIS-A SCI, C4-T5 received either tadalafil 20 mg or placebo for the first arm, and then were crossed-over after 1 week to the second arm. SBP, HR, and Visual Analogue Scale (VAS) for dizziness upon sitting up from lying were measured at baseline and again 1, 2, 4, 12, 22, 29, and 36 h post dose administration. The change in each outcome measure (SBP, HR, VAS dizziness) was observed from pre-dose to each time point. A change in VAS dizziness of 2 cm or greater (scale 0–10 cm) was considered positive.

Results

Conclusions

Tadalafil use in people with SCI above T6 is safe with respect to not causing hypotension; hemodynamic changes that occurred 12–36 h post administration were compensated for by elevations in HR.

Sponsorship

The Manitoba Medical Services Foundation and the Health Sciences Centre Foundation.

Introduction

Erectile dysfunction (ED) is the persistent inability to achieve or maintain an erection sufficient for satisfactory sexual intercourse [1], and is a common issue among males with spinal cord injury (SCI) [2]. Young men comprise the largest population of patients with SCI (60% are 16–30 years old) and males (80%) [3]. Eighty percent of patients with SCI achieve some type of erection, either reflexogenic, psychogenic, or mixed, but is rarely sufficient to have sexual intercourse without medications [4].

The first-line of treatment for ED in men with SCI is oral phosphodiesterase type-5 (PDE-5) inhibitors [5, 6]. The mechanism of action of these medications involves active inhibition of the PDE-5 enzyme, resulting in an increase in cyclic guanosine mono phosphate with subsequent smooth muscle relaxation of the corpora cavernosa of the penis, allowing for blood to enter and erection to occur when stimulation occurs [5]. Sildenafil (Viagra) TM was the first PDE-5 inhibitor available and more recently available are tadalafil (Cialis) TM [7], vardenafil (Levitra) TM , and others. All of these drugs appear to be generally safe and well tolerated, with similar side effects [8, 9]. Sildenafil has a half-life of about 4 h [10], whereas tadalafil has a mean half-life of 17.5 h [11]. With adequate sexual stimulation, significant erectile response has been observed as early as 16 min and as long as 36 h after dosing with tadalafil in about 50% of men with ED [12]. Sildenafil, tadalafil, and vardenafil all have proven efficacy in the literature in men with SCI [13,14,15,16,17,18,19,20,21,22,23,24]. Tadalafil has been shown to improve erectile function over baseline and compared to placebo regardless of the American Spinal Injury Association Impairment Score (AIS) [21]. The improved erectile function experienced with tadalafil in men with SCI has been shown to continue 12–24 h post-dosing [16, 21, 22]. However, despite of all the efficacy studies in men with SCI using tadalafil, no studies have been done to measure cardiovascular responses in this population after dosing with tadalafil.

People with SCI are at risk of developing orthostatic hypotension, especially those with lesions at or above T5, due to decreased resting levels of circulating catecholamines [25, 26], and no significant release of epinephrine or norepinephrine when changing from a lying to a sitting position. The main concern in this population would be the orthostatic hypotension being caused or exacerbated by PDE-5 inhibitors. An earlier study by our group of the shorter-acting PDE-5 inhibitor, sildenafil, revealed that it causes orthostatic hypotension, tachycardia, and dizziness after administration in the SCI population, particularly in those with tetraplegia, and suggested that caution should be used when prescribing sildenafil to persons with SCIs, as blood pressure can drop significantly [27]. Sipski et al. reported similar results, although only trending to significance, likely a false negative due to small sample size [28]. However, due to the longer lasting effect and longer half-life of tadalafil, there is a concern that any side effects may last longer as well. This has recently been confirmed in a study of men that were not spinal cord injured, where it was found that although the side effect prevalence was similar with the various PDE-5 inhibitors, the duration of the side effects was significantly longer with tadalafil (14.9 h) vs. sildenafil (3.9 h) [29].

Therefore, our primary objective in the present study is to assess the effects of administrating tadalafil 20 mg compared to placebo on the systolic blood pressure (SBP) and heart rate (HR) of men with complete American Spinal Injury Association Impairment Scale-A (AIS-A) SCI above the sixth thoracic level (T6), and how long these effects last. The secondary objective is to compare adverse events with the administration of one dose of tadalafil 20 mg vs. placebo, with measuring dizziness on a Visual Analog Scale (VAS) as an adverse event. As there are several previous studies measuring the efficacy of tadalafil in this population, this aspect was not felt to be a knowledge gap, and therefore efficacy of this medication in the SCI population was not studied again in this particular safety study.

Methods

This was a prospective, randomized, double-blind, placebo controlled, cross-over study of male subjects with AIS-A SCI between the fourth cervical (C4) and fifth thoracic (T5) levels. Subjects enrolled had to be 18–70 years old, a minimum of 6 months post SCI, and able and willing to consent to participate. Excluded were subjects who were diabetic, taking nitroglycerin in any form, had ischemic heart disease or a significantly abnormal electrocardiogram, had lower motor neuron dysfunction, were heroin or cocaine users, had a history of adverse reactions to tadalafil or any other PDE-5 inhibitor, or had used any other PDE-5 inhibitor medications within a week before administration of the study medications. This study was approved by the University of Manitoba Research and Ethics board and registered with Clinicaltrials.gov (registration number NCT01067391).

Subjects were randomly assigned to one of two arms in a double-blinded fashion by our pharmacy. Prior to checking these measures the subject was lying flat for at least 10 min, then sat up and measures were done within 1 min. Those assigned to arm 1 received tadalafil first, arm 2 received placebo first. SBP, HR, and dizziness on VAS (range 0–10 cm) were measured. The pill was then given (tadalafil for arm 1, placebo to arm 2), and the measurements repeated hourly for 2 h, then 4 h post-dose.

After the 4 h measurement, the subject went home and repeated all these measures with an automated BP and HR apparatus at 12 h, 22 h, then every 7 h × 2 (to 36 h post-dose). One week later, the subject returned and was crossed-over to the other arm, with the above procedures and measures repeated.

All applicable institutional regulations concerning the ethical use of human volunteers were followed during the course of this research.

Statistical analyses

Sample size calculation was done using G* power software showed that for a moderate effect size 0.5 at 20% type 2 error rate we need to recruit n = 32 participants. The change in each outcome measure (SBP, HR, VAS) was observed with effects of time from pre-dose to each time point. Linear mixed model was used to test our hypothesis and analyze outcomes using SAS program. A change at any time point in the VAS of 2 or greater was considered positive. Significant comparison was made using post hoc pairwise corrections. The level of significance was α < 0.05.

Results

All 20 participants who were enrolled successfully completed the study (Table 1).

SBP did not change from baseline significantly in either group at any time point. (Fig. 1). Sub-analysis of the cervical level group against the thoracic level group also revealed no significant SBP change at each time point. The HR, however, was increased significantly in the tadalafil group at several time points (12 h p < 0.05, 22 h p < 0.05, 29 h p < 0.01, and 36 h p < 0.05) compared to baseline, with no change in the placebo group (Fig. 2).