NEWS & OPINION
New studies on IFIS prompt ASCRS/AAO educational update for prescribing physicians
by David F. Chang, MD
Two new studies on intraoperative floppy iris syndrome (IFIS) that I was involved with will be published this month, and they have prompted a renewed joint effort by ASCRS and AAO to educate prescribing physicians about the potential adverse effects of systemic α1-antagonists on cataract surgery. The first study (Chang DF, Campbell JR, Colin J, Schweitzer C. Prospective masked comparison of intraoperative floppy iris syndrome severity with tamsulosin versus alfuzosin. Ophthalmology 2014;121 (April):829–834) adds to the mounting evidence that tamsulosin creates a higher risk of severe IFIS compared to non-selective α1-antagonists.
Of the α1 receptor subtypes, the α1-A receptor predominates in both the iris dilator and prostatic smooth muscle. Among α1-antagonists prescribed for benign prostatic hyperplasia (BPH), only tamsulosin and silodosin are subtype selective and demonstrate the highest affinity for the α1-A receptor. Such receptor uroselectivity reduces the risk of postural hypotension due to blockade of the α1-B receptors in vascular smooth muscle. All of the α1-antagonists can impair pupil dilation and cause IFIS. However, a number of prospective and retrospective studies have suggested that the frequency and severity of IFIS is greater in patients taking tamsulosin compared to the non-selective α1-antagonists, such as terazosin, doxazosin, and alfuzosin.1,2 A 2011 meta-analysis of 17 published studies reported that tamsulosin had a 40-fold higher pooled odds ratio for IFIS compared to alfuzosin and terazosin.2 In vitro experiments demonstrated that tamsulosin is a much stronger antagonist of rabbit iris dilator muscle contraction than alfuzosin.3 Finally, a 2008 survey of ASCRS members indicated that 90% of respondents (with enough personal experience) felt that IFIS was more common with tamsulosin than with non-selective α1-antagonists.4
Because many of the prior studies were retrospective and not masked, my co-investigators and I decided to conduct a multicenter prospective, masked, controlled comparison of tamsulosin and alfuzosin—the two α1-antagonists with the fewest reported cardiovascular adverse events. Undoubtedly one of the reasons that tamsulosin became the most prescribed treatment for BPH was its theoretical uroselectivity and reduced incidence of postural hypotension. Although it is a non-selective α1-antagonist, alfuzosin is often referred to as "clinically uroselective." The reduction in postural hypotension with alfuzosin is not due to receptor specificity, but rather to pill reformulation to slow release of the molecule in the GI tract. The study was conducted in France, where alfuzosin is more commonly prescribed than in most other countries. Sanofi Aventis, the manufacturer of alfuzosin (Uroxatral), is a French pharmaceutical company. Eight study surgeons from four sites enrolled 113 consecutive patients taking either tamsulosin or alfuzosin. Each time a study patient was enrolled, a control patient with no prior history of α1-antagonist use was enrolled by the same cataract surgeon on the same day. All 226 cases were videotaped and two masked ophthalmologists (John Campbell, MD, and myself) then graded every video for the presence and severity of IFIS. Severe IFIS—defined as iris billowing and prolapse with ≥2 mm of pupil constriction—was more common with either α1-antagonist compared to control eyes. However, severe IFIS was noted in 34.3% (24/70) of the tamsulosin eyes and 16.3% (7/43) of the alfuzosin eyes (P<0.05). Therefore, if an α1-antagonist with a lower risk of cardiovascular side effects is indicated, patients with cataracts may want to try alfuzosin first.
Unfortunately for cataract surgeons, tamsulosin continues to be the most frequently prescribed medication for BPH, and its use will surely rise now that it is generic in the United States. As an alternative to α1-antagonists, 5-α reductase inhibitors (dutasteride and finasteride) are also effective and approved as medical monotherapy of BPH. However, a large multinational randomized trial demonstrated that the combination of dutasteride and tamsulosin was superior to either drug alone in the prevention of BPH progression.5 Ophthalmologists must therefore recognize that Jalyn is the brand name for this specific drug combination. Finally, silodosin (Rapaflo) is the most recent α1- antagonist to be approved for BPH and most resembles tamsulosin in its α1-A receptor subtype specificity.
The second study (Doss EL, Potter MB, Chang DF. Primary care physicians still lack awareness of IFIS. J Cataract Refract Surg 2014;40 (April):685–686) was a survey of primary care physicians from the University of California, San Francisco (UCSF) designed to assess their α1-antagonist prescribing patterns and their awareness of IFIS. A brief questionnaire was emailed to 350 healthcare providers in the UCSF Collaborative Research Network and 133 responded. Forty percent initiate BPH medical treatment at least twice a month. Overall, only 35% were aware that α1-antagonists can cause cataract surgical complications; only half (17%) factored this into treatment considerations. Less than 10% inquire about a history of cataract prior to initiating α1-antagonist treatment, and only 31% regularly advise patients to inform their ophthalmologist about taking these drugs. Most respondents (96%) desired more information on this topic. Based on the new information from these two studies, the ASCRS Cataract Clinical Committee decided that a renewed effort to educate prescribing physicians treating BPH should be initiated. We have collaborated with AAO in writing a joint educational document that was formally issued in April. This new document updates the 2008 joint ASCRS/AAO IFIS educational statement, which asked prescribing physicians to consider 1) involving the ophthalmologist prior to initiating α1-antagonists in patients with known cataracts and 2) reminding patients taking systemic α1-antagonists to report this medication history prior to having any eye surgery. The newly issued educational statement states, "Patients with symptomatic cataracts may wish to consider cataract surgery prior to initiating non-emergent α1-antagonist therapy. Because tamsulosin is associated with the highest risk of IFIS, patients with cataracts may wish to consider a non-selective α1-antagonist as initial treatment." We have communicated with the American Academy of Family Physicians, the American College of Physicians, and the American Urological Association who will each help to disseminate this information to their respective memberships. In addition, this document is a concise, referenced summary that ophthalmologists can share with prescribing doctors in their communities on an individual basis. It can be downloaded from the ASCRS website, www.ascrs.org.
1. Chang DF, Braga-Mele R, Mamalis N, et al. ASCRS white paper: clinical review of intraoperative floppy-iris syndrome. J Cataract Refract Surg 2008;34:2153–2162.
2. Chatziralli IP, Sergentanis TN. Risk factors for intraoperative floppy iris syndrome: A meta-analysis. Ophthalmology 2011; 118:730–735.
3. Palea S, Chang DF, Rekik M, et al. Comparative effect of alfuzosin and tamsulosin on the contractile response of isolated rabbit prostatic and iris dilator smooth muscles. Possible model for intraoperative floppy iris syndrome. J Cataract Refract Surg 2008; 34: 489–496.
4. Chang DF, Braga-Mele R, Mamalis N, et al. Clinical experience with intraoperative floppy-iris syndrome. Results of the 2008 ASCRS member survey. J Cataract Refract Surg 2008; 34:1201–1209.
5. Roehrborn, CG, Siami P, Barkin J, et al. The effects of combination therapy with dutasteride and tamsulosin on clinical outcomes in men with symptomatic benign prostatic hyperplasia: 4-year results from the CombAT study. Eur. Urol. 2010; 57:123–131.