Universidad del Valle, Calle 4B 36-00, Universidad del Valle, Sede San Fernando.
Tamsulosin treatment for benign prostatic hyperplasia and risk of severe hypotension in men aged 40-85 years in the United States: risk window analyses using between and within patient methodology
Data of unpublished studies raises a major concern about the true safety and effectiveness of tamsulosin in patients with lower urinary tract symptoms (Supplementary Table). At least 78.4% (98/124) of tamsulosin registries identified in ClinicalTrials.gov and WHO ICTRP are unpublished. The amount hidden data could be significantly higher considering that 71.8% of tamsulosin study records were retrospectively registered. The median time of follow-up in the twenty-six published registries of tamsulosin was 6 weeks (interquartile range 2-12 weeks). Only five of the published tamsulosin registries included cardiovascular variables as primary or secondary outcomes. It is surprising that only two of the twenty-six published studies reported those outcomes.
The majority of tamsulosin clinical trials excluded patients with cardiovascular risk factors during the enrollment. Moreover, the internal and external validity of tamsulosin clinical trials could not be appropriately determined, the reporting quality of the majority of the studies is very poor according to the CONSORT criteria. The sample size (n=383567) and median time of follow-up (6 weeks, interquartile range 5-50 weeks) of the study by Bird and colleagues is clearly superior to the registered (published and unpublished) previous studies of tamsulosin.1
The association of severe hypotension with tamsulosin in the study by Bird and colleagues is also a good opportunity to review the evidence against the existence of uroselective α blockers:
1. There are no significant pharmacodynamic differences between prazosin and tamsulosin considering the inhibition constants (Pki) of both drugs in prostate (α1A/D) and blood vessels (α1B).2
2. Evidence of cardiovascular effects after the administration of tamsulosin in different animal models.3-6
4. Case reports describing the association of tamsulosin with severe hypotension during general anesthesia.7
3. Evidence obtained in passive orthostasis test performed to patients receiving α blockers.8,9
5. Association of tamsulosin with severe hypotension in the study by Bird and colleagues.1
The available scientific evidence supports the association of tamsulosin with serious adverse cardiovascular drug reactions, probably more than any other pharmacological effect attributed to this drug. I urge doctors to reconsider the use of tamsulosin as a first line treatment in patients with lower urinary tract symptoms. Evidence of other “uroselective” alpha blockers (i.e., alfuzosin and silodosin) and phosphodiesterase type-5 inhibitors (i.e., sildenafil, tadalafil, and vardenafil) supporting their use in patients with benign prostatic hyperplasia is also significantly biased by unpublished research. The availability of tamsulosin without prescription (over the counter) in the United Kingdom needs to be seriously reconsidered.
The flowchart detailing the selection process of registries analyzed in this letter is shown in the Supplementary Figure.
Raw-data is available at the following URL: http://goo.gl/1CqK5w. This database complies with the terms and conditions of ClinicalTrials.gov (available at:http://clinicaltrials.gov/ct2/about-site/terms-conditions) and the WHO ICTRP (available at: http://www.who.int/ictrp/search/download/en/) for using downloaded data.
1. Bird ST, Delaney JAC, Brophy JM, et al. Tamsulosin treatment for benign prostatic hyperplasia and risk of severe hypotension in men aged 40-85 years in the United States: risk window analyses using between and within patient methodology. BMJ 2013;347:f6320.
2. Perez D, Hébert T, Cotecchia S, et al. Adrenoceptors. Last modified on 21/03/2014. Accessed on 16/05/2014. IUPHAR database (IUPHAR-DB),http://www.iuphar-db.org/DATABASE/FamilyMenuForward?familyId=4.
3. Van der Graaf PH, Shankley NP, Black JW. Analysis of the effects of alpha 1-adrenoceptor antagonists on noradrenaline-mediated contraction of rat small mesenteric artery. Br J Pharmacol 1996;118:1308–16.
4. Kenny BA, Miller AM, Williamson IJ, et al. Evaluation of the pharmacological selectivity profile of alpha 1 adrenoceptor antagonists at prostatic alpha 1 adrenoceptors: binding, functional and in vivo studies. Br J Pharmacol 1996;118:871–8.
5. Kenny BA, Naylor AM, Carter AJ, et al. Effect of alpha 1 adrenoceptor antagonists on prostatic pressure and blood pressure in the anesthetized dog. Urology 1994;44:52–7.
6. Akiyama K, Hora M, Yamagishi R, et al. Effects of KMD-3213, a uroselective alpha 1A-adrenoceptor antagonist, on the tilt-induced blood pressure response in normotensive rats. Jpn J Pharmacol 2002;90:131–7.
7. Kumar D, Khan FA. Tamsulosin-induced severe hypotension during general anesthesia: a case report. J Med Case Rep 2010;4:365.
8. Nieminen T, Ylitalo R, Kööbi T, et al. Effects of adrenoceptor blocking drugs on cardiovascular responsiveness to passive orthostasis: a placebo-controlled double-blind study. Arzneimittelforschung 2005;55:205–11.
9. Nieminen T, Ylitalo R, Kööbi T, et al. The vasodilatory effect of alfuzosin and tamsulosin in passive orthostasis: a randomised, double-blind, placebo-controlled study. Eur Urol 2005;47:340–5.
Competing interests: 1. I was one of the evaluators of this article during the open peer-review process of the BMJ. 2. I am the author of the linked editorial to this research article (doi: 10.1136/bmj.f6492). 3. One unpublished clinical trial described in a previous rapid response: http://www.bmj.com/content/347/bmj.f6449/rr/690626