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Article of the Week: NSAID use and ED risk

Every Week the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video from Mr. Darshan Patel, discussing his paper.

If you only have time to read one article this week, it should be this one.

Non-steroidal anti-inflammatory drug (NSAID) use is not associated with erectile dysfunction risk: results from the Prostate Cancer Prevention Trial

 

Darshan P. Patel, Jeannette M. Schenk*, Amy Darke, Jeremy B. Myers, William O. Brant and James M. Hotaling

 

Division of Urology, University of Utah, Salt Lake City, UT, *Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA, and SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

 

Objective

To evaluate the associations of non-steroidal anti-inflammatory drug (NSAID) use with risk of erectile dysfunction (ED), considering the indications for NSAID use.

Patients and Methods

We analysed data from 4 726 men in the placebo arm of the Prostate Cancer Prevention Trial (PCPT) without evidence of ED at baseline. Incident ED was defined as mild/moderate (decrease in normal function) or severe (absence of function). Proportional hazards models were used to estimate the covariate-adjusted associations of NSAID-related medical conditions and time-dependent NSAID use with ED risk.

AOTWMar3

Results

Arthritis (hazard ratio [HR] 1.56), chronic musculoskeletal pain (HR 1.35), general musculoskeletal complaints (HR 1.36), headaches (HR 1.44), sciatica (HR 1.50) and atherosclerotic disease (HR 1.60) were all significantly associated with an increased risk of mild/moderate ED, while only general musculoskeletal complaints (HR 1.22), headaches (HR 1.47) and atherosclerotic disease (HR 1.60) were associated with an increased risk of severe ED. Non-aspirin NSAID use was associated with an increased risk of mild/moderate ED (HR 1.16; P = 0.02) and aspirin use was associated with an increased risk of severe ED (HR 1.16; P = 0.03, respectively). The associations of NSAID use with ED risk were attenuated after controlling for indications for NSAID use.

Conclusions

The modest associations of NSAID use with ED risk in the present cohort were probably attributable to confounding indications for NSAID use. NSAID use was not associated with ED risk.

Editorial: PCPT May Exculpate COX Blockers in Erectile Dysfunction

NSAIDs are one of the most commonly used medications classes in the USA. Despite their ubiquity, they remain controversial. The withdrawal of the selective cyclooxygenase (COX)-2 inhibitor Rofecoxib in 2004 was a low point, culminating in a >$4.85 billion dollar (American dollars) settlement by Merck Pharmaceuticals. More recently, in July 2015 the USA Food and Drug Administration (FDA) strengthened a ‘black box warning’ (warning that appears on the package insert) on all NSAIDs for increased risks of heart attack, stroke, and heart failure (www.fda.gov/drugs/drugsafety). Given common vascular pathways in erectile dysfunction (ED) and heart disease, detrimental effects on sexual health have long been suspected as well. This month’s issue of BJUI provides a new perspective on this relationship and may help exculpate these common drugs [1].

It is thought that the cardiovascular risk of NSAIDs arises from inhibition of the COX-arachidonic acid synthesis pathway, which produces important mediators (e.g. eicosanoids like prostacyclin and various prostaglandin subtypes) for inflammation, vascular tone, and vascular permeability [2]. Given that many of the same chemical mediators affect erectile physiology, it is not surprising that a previous study of 80 966 men showed an association between NSAID use and ED after accounting for age, race, and comorbidities [3].

In ‘Non-steroidal anti-inflammatory drug use not associated with erectile dysfunction risk …’, Patel et al. [1] show that this risk may not be what it once seemed. They assess the risk of developing ED for men in the placebo arm of the Prostate Cancer Prevention Trial (PCPT) after first reported NSAID use. There is a small but statistically significant and consistent relationship between initiation of NSAID use and ED. Curiously, the association of NSAIDs with ED disappeared once they controlled for the indications for NSAID use such as arthritis, chronic pain, headaches, and cardiovascular disease. This finding makes sense: common indications for NSAIDs, like arthritis, headaches, and chronic musculoskeletal pain, may indicate an underlying sedentary lifestyle or chronic inflammatory conditions, both imputed in ED [4]. As such, this study design provides key epidemiological inference on the causal links between inflammation, lifestyle, and ED. It may be these factors, not NSAIDs themselves, which account for the previously shown association with ED.

With that said, epidemiological assessment of eicosanoid-mediated effects on ED may require further study. For example, NSAID-mediated downregulation of endothelial signalling molecules could produce a short-lived, but clinically significant effect on cavernosal blood supply. Alternatively, ED may only arise in the setting of chronic downregulation of affected pathways. Epidemiological studies characterising the relationship between NSAID use and ED should therefore assess the amount and duration of NSAIDs use, as well as the quality and timing of erections relative to use. Basic research may also help elucidate this relationship. Earlier studies have assessed cavernosal endothelial concentrations of these same vascular mediators in diabetic animal models [5]. In a similar fashion in vivo assessment of COX-derived mediators using animal models could further characterise the vascular pathways involved in erection and the effects of NSAID use.

Patel et al. [1] add a valuable contribution to the study of NSAIDs and ED. Their finding that NSAID-induced effects on ED disappear when controlling for the indications of NSAID, may support the inflammatory hypothesis of ED. But as others have noted, there is an intrinsic difficulty in retrospectively assessing the complex, multifactorial causes of sexual dysfunction [6]. Future studies on the amount and timing of NSAID use, paired with biochemical studies of vascular mediators in the cavernosal endothelium in NSAID users, may allow for even more nuanced characterisation of the effects of COX inhibition on erectile function. While logistically challenging, such studies could provide the key evidence for assessing the vascular pathways underlying ED and their relationship with NSAIDs.

Alexander P. Cole, Jeffrey J. Leow, and Quoc-Dien Trinh
Center for Surgery and Public Health, Division of Urology, Brigham and Womens Hospital, Harvard Medical School, Boston, MA, USA

 

References

 

1 Patel DP, Schenk JM, Darke A, Myers JB, Brant WO, Hotaling JMNon-steroidal anti-inammatory drug use not associated with erectile dysfunction risk: results from the Prostate Cancer Prevention Trial. BJU Int 2016; 117: 5006

 

2 Antman EM, DeMets D, Loscalzo J. Cyclooxygenase inhibition and cardiovascular risk. Circulation 2005; 112: 75970

 

3 Gleason JM, Slezak JM, Jung H et al. Regular nonsteroidal anti- inammatory drug use and erectile dysfunction. J Urol 2011; 185: 138893

 

4 Vlachopoulos C, Rokkas K, Ioakeimidis N, Stefanadis C.Inammation, metabolic syndrome, erectile dysfunction, and coronary artery disease: common links. Eur Urol 2007; 52: 1590600

 

5 Sullivan M, Thompson CS, Mikhailidis DP, Morgan RJ, Angelini GDJeremy JY. Differential alterations of prostacyclin, cyclic AMP and cyclic GMP formation in the corpus cavernosum of the diabetic rabbit. Br Urol 1998; 82: 57884

 

6 Lombardi G, Musco S, Kessler TM, Li Marzi V, Lanciotti MDel Popolo G. Management of sexual dysfunction due to central nervous system disorders: a systematic review. BJU Int 2015; 115(Suppl.6): 4756

 

Video: NSAID use is not associated with erectile dysfunction risk

Non-steroidal anti-inflammatory drug (NSAID) use is not associated with erectile dysfunction risk: results from the Prostate Cancer Prevention Trial

Darshan P. Patel, Jeannette M. Schenk*, Amy Darke, Jeremy B. Myers, William O. Brant and James M. Hotaling

 

Division of Urology, University of Utah, Salt Lake City, UT, *Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA, and SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

 

Objective

To evaluate the associations of non-steroidal anti-inflammatory drug (NSAID) use with risk of erectile dysfunction (ED), considering the indications for NSAID use.

Patients and Methods

We analysed data from 4 726 men in the placebo arm of the Prostate Cancer Prevention Trial (PCPT) without evidence of ED at baseline. Incident ED was defined as mild/moderate (decrease in normal function) or severe (absence of function). Proportional hazards models were used to estimate the covariate-adjusted associations of NSAID-related medical conditions and time-dependent NSAID use with ED risk.

AOTWMar3

Results

Arthritis (hazard ratio [HR] 1.56), chronic musculoskeletal pain (HR 1.35), general musculoskeletal complaints (HR 1.36), headaches (HR 1.44), sciatica (HR 1.50) and atherosclerotic disease (HR 1.60) were all significantly associated with an increased risk of mild/moderate ED, while only general musculoskeletal complaints (HR 1.22), headaches (HR 1.47) and atherosclerotic disease (HR 1.60) were associated with an increased risk of severe ED. Non-aspirin NSAID use was associated with an increased risk of mild/moderate ED (HR 1.16; P = 0.02) and aspirin use was associated with an increased risk of severe ED (HR 1.16; P = 0.03, respectively). The associations of NSAID use with ED risk were attenuated after controlling for indications for NSAID use.

Conclusions

The modest associations of NSAID use with ED risk in the present cohort were probably attributable to confounding indications for NSAID use. NSAID use was not associated with ED risk.

Article of the week: RP is safe in patients taking aspirin

Every week the Editor-in-Chief selects the Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video from Mr. Sami-Ramzi Leyh-Bannurah discussing his paper.

If you only have time to read one article this week, it should be this one.

Open and robot-assisted radical retropubic prostatectomy in men receiving ongoing low-dose aspirin medication: revisiting an old paradigm?

Sami-Ramzi Leyh-Bannurah, Jens Hansen, Hendrik Isbarn, Thomas Steuber, Pierre Tennstedt, Uwe Michl, Thorsten Schlomm*, Alexander Haese, Hans Heinzer, Hartwig Huland, Markus Graefen and Lars Budäus

Martini Clinic, Prostate Cancer Center at University Hospital Hamburg-Eppendorf, and *Department of Urology, Section for Translational Prostate Cancer Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Read the full article
OBJECTIVE

• To assess blood loss, transfusion rates and 90-day complication rates in patients receiving ongoing 100 mg/day aspirin medication and undergoing open radical prostatectomy (RP) or robot-assisted RP (RARP).

PATIENTS AND METHODS

• Between February 2010 and August 2011, 2061 open RPs and 400 RARPs were performed. All patients received low-molecular-weight heparin for thrombembolism prophylaxis. Aspirin intake during surgery was recorded in 137 patients (5.5%).

• Descriptive statistics and multivariable analyses after propensity-score matching for balancing potential differences in patients with and without aspirin medication were used to assess the risk of blood loss above the median in patients undergoing open RP or RARP.

RESULTS

• The median blood loss in the open RP cohort with and without aspirin medication was 750 and 700 mL, respectively, and in the RARP cohort it was 200 and 150 mL, respectively. Within the same cohorts, transfusions were administered in 21 and 8% and 0 and 1% of patients, respectively.

• The 90-day complication rates in patients with ongoing aspirin medication were 5.8, 4.4, 7.3 and 0% for Clavien grades I, II, III and IV complications, respectively.

• In multivariable analyses and after propensity-score matching, prostate volume (odds ratio 1.03; 95% CI 1.02–1.04; P < 0.01) but not ongoing aspirin medication achieved independent predictor status for the risk of blood loss above the median.

CONCLUSIONS

• Major surgery such as open RP and RARP can be safely performed in patients with ongoing aspirin medication without greater blood loss.

• Higher 90-day complication rates were not detected in such patients.

• Differences in transfusion rates between the groups receiving and not receiving ongoing aspirin medication may be explained by a higher proportion of patients with coronary artery disease in the group receiving ongoing aspirin mediciation. This comorbidity may result in a higher peri-operative threshold for allogenic blood transfusion.

Editorial: Perioperative aspirin: To give or not to give?

As the population ages and life expectancy increases, one may safely assume that more men will be diagnosed with diseases of the elderly such as prostate cancer. In the USA, it is estimated that the number of older adults (≥65 years old) will double between 2010 and 2030, contributing to a 45% increase in cancer incidence [1]. Also, it is likely that these older patients will present with multiple comorbidities, commonly described as ‘multimorbidity’ in the contemporary medical literature, including chronic cardiac and pulmonary conditions requiring multidisciplinary medical management.

Hence, the present study by Leyh-Bannurah et al. [2] examining the peri-operative use of aspirin in patients undergoing radical prostatectomy (RP) is a timely and important contribution, and may very well influence our clinical decision-making regarding the perioperative management of the anti-coagulated patient. Their results show that perioperative continuation of aspirin made no difference in peri and postoperative outcomes following RP. Previous studies have assessed the effect of aspirin continuation in patients undergoing minimally invasive RP, but the present study is the first to evaluate the effect of aspirin continuation in patients undergoing minimally invasive and open RP at a high-volume tertiary centre. Studies from other surgical specialties evaluating the role of anti-platelet therapy and its timing before surgery have shown conflicting results. The study by Park et al. [3], looking at discontinuation of aspirin for ≥7 days vs <7 days before surgery in patients undergoing lumbar spinal fusion, found that aspirin discontinued only 3–7 days before surgery significantly increased the risk of intraoperative bleeding. Alghamdi et al. [4] found similar results in patients undergoing coronary artery bypass grafting. In contrast, the study by Wolf et al. [5] showed that continuation of aspirin up to the day of the surgery did not increase the risk of bleeding, transfusion or other adverse outcomes in patients undergoing pancreatectomy. Similarly, Khudairy et al. [6] assessed the use of clopidogrel and its discontinuation time in hip fracture repair, and found that whether it was stopped ≥1 week or <1 week before surgery did not make any difference to the risk of bleeding or peri-operative complications. Nonetheless, the evidence provided by the present study by Leyh-Bannurah et al. is important, as the risk of bleeding seems to be procedure-specific, depending on the nature and source of potential bleeding (primarily arterial vs primarily venous). The lack of information, however, regarding cardiovascular morbidities in their patient population is an important limitation of their study; as such factors may influence perioperative decision-making, including the threshold for transfusion.

Read the full article

Akshay Sood and Quoc-Dien Trinh*
VUI Center for Outcomes Research, Analytics and Evaluation, Henry Ford Health System, Detroit, MI, and *Division of Urologic Surgery and Center for Surgery and Public Health, Brigham and Women’s Hospital/Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

References

  1. Lamb A. Fast Facts: prostate cancer, seventh edition. BJU Int 2012; 110: E157
  2. Park JH, Ahn Y, Choi BS et al. Antithrombotic effects of aspirin on 1- or 2-level lumbar spinal fusion surgery: a comparison between 2 groups discontinuing aspirin use before and after 7 days prior to surgery. Spine 2013; 38: 1561–1565
  3. Alghamdi AA, Moussa F, Fremes SE. Does the use of preoperative aspirin increase the risk of bleeding in patients undergoing coronary artery bypass grafting surgery? Systematic review and meta-analysis. J Cardiac Surg 2007; 22: 247–256
  4. Wolf AM, Pucci MJ, Gabale SD et al. Safety of perioperative aspirin therapy in pancreatic operations. Surgery 2014; 155: 39–46
  5. Al Khudairy A, Al-Hadeedi O, Sayana MK, Galvin R, Quinlan JF. Withholding clopidogrel for 3 to 6 versus 7 days or more before surgery in hip fracture patients. J Orthop Surg 2013; 21: 146–150

Video: Effect of peri-operative aspirin medication in open or robot-assisted RP

Open and robot-assisted radical retropubic prostatectomy in men receiving ongoing low-dose aspirin medication: revisiting an old paradigm?

Sami-Ramzi Leyh-Bannurah, Jens Hansen, Hendrik Isbarn, Thomas Steuber, Pierre Tennstedt, Uwe Michl, Thorsten Schlomm*, Alexander Haese, Hans Heinzer, Hartwig Huland, Markus Graefen and Lars Budäus

Martini Clinic, Prostate Cancer Center at University Hospital Hamburg-Eppendorf, and *Department of Urology, Section for Translational Prostate Cancer Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Read the full article
OBJECTIVE

• To assess blood loss, transfusion rates and 90-day complication rates in patients receiving ongoing 100 mg/day aspirin medication and undergoing open radical prostatectomy (RP) or robot-assisted RP (RARP).

PATIENTS AND METHODS

• Between February 2010 and August 2011, 2061 open RPs and 400 RARPs were performed. All patients received low-molecular-weight heparin for thrombembolism prophylaxis. Aspirin intake during surgery was recorded in 137 patients (5.5%).

• Descriptive statistics and multivariable analyses after propensity-score matching for balancing potential differences in patients with and without aspirin medication were used to assess the risk of blood loss above the median in patients undergoing open RP or RARP.

RESULTS

• The median blood loss in the open RP cohort with and without aspirin medication was 750 and 700 mL, respectively, and in the RARP cohort it was 200 and 150 mL, respectively. Within the same cohorts, transfusions were administered in 21 and 8% and 0 and 1% of patients, respectively.

• The 90-day complication rates in patients with ongoing aspirin medication were 5.8, 4.4, 7.3 and 0% for Clavien grades I, II, III and IV complications, respectively.

• In multivariable analyses and after propensity-score matching, prostate volume (odds ratio 1.03; 95% CI 1.02–1.04; P < 0.01) but not ongoing aspirin medication achieved independent predictor status for the risk of blood loss above the median.

CONCLUSIONS

• Major surgery such as open RP and RARP can be safely performed in patients with ongoing aspirin medication without greater blood loss.

• Higher 90-day complication rates were not detected in such patients.

• Differences in transfusion rates between the groups receiving and not receiving ongoing aspirin medication may be explained by a higher proportion of patients with coronary artery disease in the group receiving ongoing aspirin mediciation. This comorbidity may result in a higher peri-operative threshold for allogenic blood transfusion.

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