coagulation specialty clinics.4 Prospective randomizedstudies are needed to determine if warfarin therapy dis-continuation rates are lower or more clinically appro-priate when patients are treated at anticoagulation clin-ics, but perhaps underuse of anticoagulation clinics inthe study by Gomes et al2 contributed to the high re-ported discontinuation rates.

Gomes and colleagues2 state that

These findings highlight the importance of considering re-cent, real-world estimates of warfarin therapy persistence, par-ticularly when comparing warfarin with newer anticoagulantsthat also carry a risk of hemorrhage yet require no routine moni-toring.

This suggests that persistence rates of newer anticoagu-lants might exceed that of warfarin therapy. However, inthe Randomized Evaluation of Long-Term Anticoagula-tion Therapy (RE-LY) trial, which compared the use of adirect thrombin inhibitor vs warfarin in patients with AF,the discontinuation rate of dabigatran therapy exceeded thatof warfarin after 1 and 2 years of study follow-up.9 In theRivaroxaban Once Daily Oral Direct Factor Xa InhibitionCompared with Vitamin K Antagonism for Prevention ofStroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) comparing rivaroxaban vs warfarin in patients with AF,rivaroxaban therapy discontinuation occurred at a slightlyhigher rate than warfarin (24% vs 22%), although the sta-tistical significance of this difference was not reported.10

Thus, the extent to which warfarin-related therapy chal-lenges and anticoagulation monitoring are bothersomeenough to have an impact on patient- and health care pro-vider–initiated therapy discontinuation vs newer nonmoni-tored anticoagulation therapies is yet to be fully deter-mined. Although further evaluation is needed, neweranticoagulation discontinuation rates may resemble or couldpossibly even exceed warfarin therapy discontinuation ratesin populations with AF.

In the context of other studies evaluating warfarintherapy persistence and discontinuation in patients withAF, the findings of Gomes and colleagues2 point to sev-eral key considerations. First, their findings highlight theimportance of evaluating appropriateness of anticoagu-lation-related patient and medical decision making. De-finitively establishing the long-term safety of newer an-ticoagulants in real-world settings and determining ifanticoagulation persistence improves when patients aretreated at anticoagulation clinics could indicate if devel-oping anticoagulation clinic infrastructure is warrantedin an era of increasing use of newer anticoagulants re-quiring less rigorous monitoring. Finally, the current lit-erature indicates that discontinuation rates may at leastbe similar or perhaps even higher with newer anticoagu-lants vs warfarin. Therefore, even with the use of neweranticoagulants, an emphasis on the appropriateness ofcontinuation and precise patient adherence will con-tinue to be important themes associated with anticoagu-lation.

Published Online: October 22, 2012. doi:10.1001/2013.jamainternmed.616

Author Affiliations: Department of Clinical Pharmacy andOutcomes Sciences, South Carolina College of Phar-macy, University of South Carolina Campus, Columbia(Dr Maxwell); and South Carolina and the Hollings Can-cer Center, Charleston (Dr Bennett).Correspondence: Dr Bennett, South Carolina College ofPharmacy, University of South Carolina Campus, 715Sumter St, Columbia, SC 29208 (bennettc@sccp.sc.edu).Financial Disclosure: None reported.Funding/Support: Funding sources for this study in-clude The Doris Levkoff Meddin Program on Medica-tion Safety and Efficacy and the South Carolina Smart StateCenter for Medication Safety and Efficacy.

1. Go AS, Hylek EM, Chang Y, et al. Anticoagulation therapy for stroke pre-vention in atrial fibrillation: how well do randomized trials translate intoclinical practice? JAMA. 2003;290(20):2685-2692.

2. Gomes T, Mamdani MM, Holbrook AM, Paterson JM, Juurlink DN. Persis-tence with therapy among patients treated with warfarin for atrial fibrilla-tion [published online October 22, 2012]. Arch Intern Med. 2012;172(21):1687-1689.

3. Fang MC, Go AS, Chang Y, et al. Warfarin discontinuation after starting war-farin for atrial fibrillation. Circ Cardiovasc Qual Outcomes. 2010;3(6):624-631.

4. Gallagher AM, Rietbrock S, Plumb J, van Staa TP. Initiation and persistenceof warfarin or aspirin in patients with chronic atrial fibrillation in generalpractice: do the appropriate patients receive stroke prophylaxis? J ThrombHaemost. 2008;6(9):1500-1506.

5. Song X, Sander SD, Varker H, Amin A. Patterns and predictors of use of war-farin and other common long-term medications in patients with atrialfibrillation. Am J Cardiovasc Drugs. 2012;12(4):245-253.

6. Hylek EM, Evans-Molina C, Shea C, Henault LE, Regan S. Major hemor-rhage and tolerability of warfarin in the first year of therapy among elderlypatients with atrial fibrillation. Circulation. 2007;115(21):2689-2696.

7. Kneeland PP, Fang MC. Current issues in patient adherence and persis-tence: focus on anticoagulants for the treatment and prevention ofthromboembolism. Patient Prefer Adherence. 2010;4:51-60.

8. Pengo V, Pegoraro C, Cucchini U, Iliceto S. Worldwide management of oralanticoagulant therapy: the ISAM study. J Thromb Thrombolysis. 2006;21(1):73-77.

9. Connolly SJ, Ezekowitz MD, Yusuf S, et al; RE-LY Steering Committee andInvestigators. Dabigatran versus warfarin in patients with atrial fibrillation.N Engl J Med. 2009;361(12):1139-1151.

10. Patel MR, Mahaffey KW, Garg J, et al; ROCKET AF Investigators. Rivaroxa-ban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-891.

COMMENTS AND OPINIONS

Lactobacilli vs Antibiotics to PreventRecurrent Urinary Tract Infections:An Inconclusive, Not Inferior, Outcome

T he timely report on preventive treatments for re-current urinary tract infections (UTIs), Beere-poot et al1(p711) concluded that oral lactobacilli,

when compared with trimethoprim-sulfamethoxazole,“did not meet the noninferiority criteria.”1(p711) Al-though this phraseology is technically correct, its mean-ing is somewhat opaque, and others have misunder-stood the study to demonstrate that lactobacilli “wereinferior to”2 or “not as effective as”3 antibiotic prophy-laxis. Greater clarity may have been achieved by follow-ing the example of the Consolidated Standards of Re-porting Trials (CONSORT) Group and declaring the data“inconclusive,” since the 95% confidence interval for be-

Whitney Maxwell, PharmD, BCPSCharles L. Bennett, MD, PhD, MPP

ARCH INTERN MED/ VOL 172 (NO. 21), NOV 26, 2012 WWW.ARCHINTERNMED.COM1690

©2012 American Medical Association. All rights reserved.

Downloaded From: http://archinte.jamanetwork.com/ by a University of Texas at Austin User on 09/01/2013

tween-treatment difference in number of symptomaticUTIs overlapped the noninferiority margin.4

In absolute terms, the 10% noninferiority margin rep-resented only 0.29 symptomatic UTIs per person per year.Further discussion of whether this is a clinically mean-ingful threshold, either from an individual or popula-tional standpoint, would be welcomed.

Author Affiliation: Division of Urology, Ann and Rob-ert H. Lurie Children’s Hospital of Chicago, Chicago, Il-linois.Correspondence: Dr Faasse, Division of Urology, Annand Robert H. Lurie Children’s Hospital of Chicago, 225E Chicago Ave, Chicago, IL 60611 (mfaasse@sbcglobal.net).Conflict of Interest Disclosures: None reported.

1. Beerepoot MAJ, ter Riet G, Nys S, et al. Lactobacilli vs antibiotics to preventurinary tract infections: a randomized, double-blind, noninferiority trial inpostmenopausal women. Arch Intern Med. 2012;172(9):704-712.

2. Trautner BW, Gupta K. The advantages of second best: preventing recurrentcystitis while sparing the microbiome. Arch Intern Med. 2012;172(9):712-714.

3. Garcia J. Lactobacillus prophylaxis less helpful than antibiotics for UTI. http://www.medscape.com/viewarticle/763769. Accessed May 20, 2012.

4. Piaggio G, Elbourne DR, Altman DG, Pocock SJ, Evans SJW; CONSORT Group.Reporting of noninferiority and equivalence randomized trials: an extensionof the CONSORT statement. JAMA. 2006;295(10):1152-1160.

In reply

We thank Dr Faasse for his thoughtful comments. We agreethat it would have been clearer to use the term “inconclu-sive” instead of the one we used.

As far as we are aware, there are no validated rules todetermine noninferiority margins. Nor can there be, sincealmost every clinical situation has its own peculiarities. Whatconstitutes a clinically acceptable difference is ultimately amatter of judgment and may vary across patients, physi-cians, investigators, regulators, or payers.1 It is striking butperhaps not surprising that in trial registrations of nonin-feriority trials, the noninferiority margins are very often ab-sent.2 A rational approach to planning noninferiority trialswould involve performing a cost-utility analysis to derivethe noninferiority margins before embarking on the trial.Such analyses could incorporate the different opinions of thevarious stakeholders.

Our choice of a 10% noninferiority margin was a fairlyintuitive mix of weighing pros and cons of lactobacilli pro-phylaxis. As pros, we considered less antimicrobial resis-tance and the fact that women are motivated to avoid anti-biotics; as cons, lower effectiveness and slightly highercosts.

The difficulties of weighing these factors are com-pounded by the fact that the antimicrobial resistance ratesmaterialize at the societal level, whereas the other factorshave actual meaning for the women themselves. An eco-nomic evaluation of our trial is currently under way.

Author Affiliations: Division of Infectious Diseases, De-partment of Internal Medicine (Drs Beerepoot and Geer-lings), Department of General Practice (Dr ter Riet), Aca-demic Medical Center, Amsterdam, the Netherlands.Correspondence: Dr Geerlings, Division of Infectious Dis-eases, Department of Internal Medicine, Academic Medi-cal Center, Amsterdam, Meibergdreef 9, 1105 AZ Am-sterdam, the Netherlands (s.e.geerlings@amc.uva.nl).Conflict of Interest Disclosures: None reported.

1. Kaul S, Diamond GA, Weintraub WS. Trials and tribulations of non-inferiority: the ximelagatran experience. J Am Coll Cardiol. 2005;46(11):1986-1995.

2. Dekkers OM, Soonawala D, Vandenbroucke JP, Egger M. Reporting of non-inferiority trials was incomplete in trial registries. J Clin Epidemiol. 2011;64(9):1034-1038.

There Is Nothing Personal

I oannidis1 nicely addressed key challenges of “per-sonal” genetic prediction for common diseases. Ex-pectations are huge in this domain. I argue that some

of these expectations may be favored by the term per-sonal and that it would be better to use the term strati-fied.2-4

Patient’s characteristics such as age, sex, lifestyle, so-cioeconomic status, biomarkers, past environmental ex-posure, or genetic variants can help identify groups orstrata of patients who are more (or less) likely to de-velop a disease or respond to a treatment.3 Such charac-teristics can improve our ability to estimate the prob-ability of getting a common disease. Nevertheless,probability is a group property and should not be con-founded with individual determinism. At the individuallevel, either you get or do not get the disease; there is noprobability. Suppose there are 2 patients with exactly thesame characteristics, including genetic makeup, and thesecharacteristics are predictive of getting a disease. These2 patients are in the same risk stratum, which is associ-ated with a given—and sometimes quantifiable—likelihood of getting the disease. Still, 1 of these 2 pa-tients could get the disease and not the other, and it isnot possible to know a priori which one will be afflictedeventually.

Inference of the risk associated with the characteris-tics of these patients is to the corresponding group or stra-tum level, not to the personal or individual level wherenear-random events occur.2 Prediction can be strong atstratum level and poor at individual level, especially forremote outcomes (eg, common chronic diseases requir-ing years to occur) compared with imminent outcomes(eg, death in critically ill patients).5 There is nothing per-sonal—bad luck, chance, or randomness is at work,2,6 andrandomness gets cancelled out at a stratum level, not atan individual level.

Author Affiliation: Institute of Social and Preventive Medi-cine, University Hospital of Lausanne, Lausanne, Swit-zerland.

Mark Adrian Faasse, MD

Marielle Beerepoot, MDGerben ter Riet, MD, PhDSuzanne E. Geerlings, MD, PhD

Arnaud Chiolero, MD, PhD

ARCH INTERN MED/ VOL 172 (NO. 21), NOV 26, 2012 WWW.ARCHINTERNMED.COM1691

©2012 American Medical Association. All rights reserved.

Downloaded From: http://archinte.jamanetwork.com/ by a University of Texas at Austin User on 09/01/2013