Letters
is important to note that the mean INR change that we identified remained small, with only about 1 in 10 patients prescribed these agents having a follow-up INR of 5.0 or greater. Catherine S. Riggs, PharmD Thomas Delate, PhD Nathan P. Clark, PharmD Author Affiliations: Department of Clinical Pharmacy, Kaiser Permanente, Colorado, Aurora (Riggs, Delate, Clark); Department of Clinical Pharmacy, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Denver (Delate, Clark). Corresponding Author: Nathan P. Clark, PharmD, Department of Clinical Pharmacy, Kaiser Permanente, 16601 E Centretech Pkwy, Aurora, CO 80011 ([email protected]) Conflict of Interest Disclosures: None reported. 1. Clark NP, Delate T, Riggs CS, et al; Warfarin-Associated Research Projects and Other Endeavors Consortium. Warfarin interactions with antibiotics in the ambulatory care setting. JAMA Intern Med. 2014;174(3):409-416.
Gabapentin Treatment for Alcohol Dependence To the Editor New treatments—both pharmacologic and nonpharmacologic—for one of the most devastating substance abuse disorders, alcoholism, are direly needed. We were therefore delighted to read an article reporting on a trial of gabapentin as a treatment option for alcohol dependence.1 Unfortunately, this article does not clarify whether gabapentin increases the proportion of abstinent patients or those without heavy drinking. While the research protocol had stipulated a sample size of 150 patients randomized to 1 treatment and 1 placebo control group, the same number of patients was split among 3 groups: 2 active treatment and 1 placebo control group (clinicaltrials.gov identifier: NCT00391716). The authors calculated their sample size based on an acamprosate trial from a different setting.2 Consequently, it seems that the odds ratio for one of the co-primary end points, abstinence, compares the higher dosage group, gabapentin 1800 mg/d, with placebo and was not statistically different (odds ratio, 4.8; 95% CI, 0.9-35.0). This fact is obscured by the article’s focus on a linear dose effect, with a P value below .05 from an extended Mantel-Haenszel χ2 test for linear association. In contrast, no P values were reported for the prespecified analysis. We believe that outcomes should not be selectively reported, and clinical trials should either adhere to their preregistered protocol or explain why they differed from it. Therefore, this present trial should be regarded as a dose-ranging study but not as a pivotal trial, which provides proof with traditional frequentist inference. Benjamin P. Geisler, MD, MPH Arnab Ghosh, MD, MA Author Affiliations: Department of Medicine, NYU School of Medicine, New York, New York. Corresponding Author: Benjamin P. Geisler, MD, MPH, NYU School of Medicine, 564 First Ave, 17E, New York, NY 10016 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Mason BJ, Quello S, Goodell V, Shadan F, Kyle M, Begovic A. Gabapentin treatment for alcohol dependence: a randomized clinical trial. JAMA Intern Med. 2014;174(1):70-77.
jamainternalmedicine.com
2. Pelc I, Verbanck P, Le Bon O, Gavrilovic M, Lion K, Lehert P. Efficacy and safety of acamprosate in the treatment of detoxified alcohol-dependent patients: a 90-day placebo-controlled dose-finding study. Br J Psychiatry. 1997; 171:73-77.
In Reply We are delighted to learn of Geisler and Ghosh’s interest in treating alcohol dependence and welcome the opportunity to address some of their misunderstandings about our report of a randomized clinical trial of gabapentin for the treatment of alcohol dependence.1 Contrary to their concern that ours was initially a 2-arm trial, our original protocol in fact specified a 3-arm dose-ranging design (gabapentin, 1800, 900, and 0 mg/d) and was reviewed as such by the National Institute on Alcohol Abuse and Alcoholism (NIAAA), the Scripps institutional review board, and the JAMA Internal Medicine (JAMA-IM) statistical reviewer (per JAMA-IM’s requirement that the original protocol be included with a clinical trial submission), and the clinicaltrials.gov link referenced by the authors specifies “dose ranging.” The authors also questioned the basis of our power analysis; no relevant gabapentin data were available in 2003, when the study was designed, so we used data from a dose-ranging trial of acamprosate, the most pharmacologically similar alcoholism treatment to gabapentin.2 Again, this was found acceptable across all the aforementioned levels of review. Given our dose-ranging design, testing for a linear dose-effect was the primary goal of the study and was significant, as reported in the article for all outcomes: abstinence, no heavy drinking, drinking quantity and frequency, γ-glutamyltransferase, craving, sleep, and mood. As noted by Schwenk,3 “The positive effects of gabapentin were dose-responsive, which suggest a biological basis for the benefits, and the improvement certainly justifies larger studies in more-typical patients.” With the linear dose response confirmed, we reported comparisons for gabapentin, 1800 mg, vs placebo: the rate of abstinence was 4 times greater (χ2 = 4.3, P = .04) and the rate of no heavy drinking doubled (χ2 = 5.3, P = .02). The numbers needed to treat (8 for abstinence and 5 for no heavy drinking) associated with gabapentin for these outcomes are equivalent or superior to those reported in a recent meta-analysis of clinical trials involving US Food and Drug Administration–approved treatments.4 Moreover, gabapentin was uniquely associated with significant improvements in mood and sleep. Geisler and Ghosh chose to disregard the a priori dose-ranging analytic plan and focus on a less robust odds ratio measure from a (statistically significant) comparison between 1 dosage group and the placebo group on a single outcome to support their negative conclusion. This highly selective use of data to craft a negative argument is misleading and can lead to an erroneous conclusion not supported by the full data set. Finally, we did not claim that ours was a pivotal trial, which refers to a trial intended to provide evidence for drugmarketing approval, but rather stated that “[l]arger studies in more diverse populations of patients with alcohol dependence are needed to replicate and extend these findings.”1(p76) The array of findings we present are solid evidence that gabapentin has clinically and statistically significant effects on drinking behavior and symptoms of early abstinence in alcoJAMA Internal Medicine July 2014 Volume 174, Number 7
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a Ndsu Library Periodicals User on 05/27/2015
1201
Letters
hol dependence, which bode well for developing a potential medication to relieve a significant amount of human suffering and cost to our health care system.
Author Affiliation: Department of Family and Social Medicine, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York.
Barbara J. Mason, PhD Vivian Goodell, MPH Farhad Shadan, MD, PhD
Conflict of Interest Disclosures: None reported. 1. Schiff GD, Puopolo AL, Huben-Kearney A, et al. Primary care closed claims experience of Massachusetts malpractice insurers. JAMA Intern Med. 2013;173 (22):2063-2068.
Author Affiliations: The Scripps Research Institute, Pearson Center for Alcoholism and Addiction, Research, La Jolla, California (Mason, Goodell, Shadan); Scripps Clinic and Scripps Green Hospital, La Jolla, California (Shadan). Corresponding Author: Barbara J. Mason, PhD, Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, 10550 N Torrey Pines Rd, TPC-5, La Jolla, CA 92037 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Mason BJ, Quello S, Goodell V, Shadan F, Kyle M, Begovic A. Gabapentin treatment for alcohol dependence: a randomized clinical trial. JAMA Intern Med. 2014;174(1):70-77. 2. Pelc I, Verbanck P, Le Bon O, Gavrilovic M, Lion K, Lehert P. Efficacy and safety of acamprosate in the treatment of detoxified alcohol-dependent patients: a 90-day placebo-controlled dose-finding study. Br J Psychiatry. 1997; 171:73-77. 3. Schwenk TL. Gabapentin improves rates of abstinence in alcohol-dependent patients. NEJM Journal Watch. November 21, 2013. http://www.jwatch.org /na32870/2013/11/21/gabapentin-improves-rates-abstinence-alcohol -dependent. Accessed March 7, 2014. 4. Maisel NC, Blodgett JC, Wilbourne PL, Humphreys K, Finney JW. Meta-analysis of naltrexone and acamprosate for treating alcohol use disorders: when are these medications most helpful? Addiction. 2013;108(2):275-293.
We Have Strict Statutes and Most Biting Laws To the Editor In their recent article, Schiff and colleagues1 computed the rate of malpractice claims filed against adult primary care physicians (PCPs) in Massachusetts. They found an annual rate of 3.3% (roughly 110 cases per year for 3305 physicians), noting that the rate was remarkably stable over the 5-year study period. A lawsuit rate of 3.3% per year may not seem like much. (Hyman and Sage2 proclaimed it a relatively “modest rate” in their Invited Commentary on the article by Schiff et al.1) But annual rates convey a false sense of well-being. A more meaningful indicator of risk is the career likelihood of a malpractice claim. Using the following binomial probability formula: 1 – (1 – λ)t, where λ is the annual risk of suit (eg, Schiff and coauthors’ rate of 0.033) and t is the duration of a medical career (eg, 40 years), I calculate that the probability of a Massachusetts PCP being sued at least once during his or her career as 74%. The binomial rests on a few assumptions: the annual risk of suit is the same each year, all PCPs face the same risk, and the risk to physicians each year is independent to what happened to them in any earlier year. While it is anticipated that reality will depart to some extent from the probability model, a 74% chance of suit, even as a first approximation, suggests that many PCPs will feel pressure to practice medicine defensively. A noteworthy contribution, then, is the authors’ identification of the breakdowns points in the process of care that most often result in legal liability. Rebecca Arden Harris, MD 1202
Corresponding Author: Rebecca Arden Harris, MD, 654 Lindley Rd, Glenside, PA 19038 ([email protected]).
2. Hyman DA, Sage WM. Medical malpractice in the outpatient setting: through a glass, darkly. JAMA Intern Med. 2013;173(22):2069-2070.
In Reply We thank Dr Harris for acknowledging the importance of malpractice risk that primary care physicians (and, we would add, their patients) painfully face, particularly the significant burden that the 3.3% annual rate translates to as it cumulatively accrues over a physician’s career. Dr Harris’ calculations, as well our findings, are consistent with other reported data.1,2 Aside from emphasis on the high statistical lifetime likelihood that a primary care physician might be sued, the author points out the value of the “identification of the breakdowns in care,” as well as raising the potential for resulting “defensive” medical practices. The Agency for Healthcare Research and Quality–funded PROMISES (Proactive Reduction of Outpatient Malpractice: Improving Safety, Efficiency, and Satisfaction) project, under whose auspices the Massachusetts insurers pooled the data we analyzed, specifically aimed to lower such risk by preventing failures and dropped balls in targeted areas of test result, referral, and medication management, as well as overarching communication breakdowns. However, we would point out that based on the literature and our work with participating Massachusetts primary care offices, practicing “defensive medicine” by ordering more tests and referrals can also add risks if health care practitioners do not reliably follow up and act on those results and referral recommendations. We hope that whatever added anxieties and stresses of malpractice "biting laws" Dr Harris invokes can also positively motivate and guide efforts to significantly improve primary care office systems. Toward that end, the PROMISES project has developed and made freely available a series of videos and guides on how to ensure safer and more reliable systems.3 Finally, regarding the need to practice more defensively, we also note the importance of being less defensive. Practitioners, particularly primary care physicians, need to build and maintain the trust of their patients, even when things go wrong. Thus candor, honest disclosure, willingness to modestly recognize that patients’ criticisms and concerns can both help us become better physicians and help in reducing malpractice suits and risks. Among the resources we have developed are a guide and video interview with Lucian Leape, MD, which give practical advice about how to share errors with patients and families.4,5 Gordon D. Schiff, MD Madeleine Biondolillo, MD Author Affiliations: Division of General Internal Medicine and Primary Care, Brigham and Women’s Hospital, Boston, Massachusetts (Schiff); Department of Medicine, Harvard Medical School, Boston, Massachusetts (Schiff); Bureau of
JAMA Internal Medicine July 2014 Volume 174, Number 7
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a Ndsu Library Periodicals User on 05/27/2015
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is important to note that the mean INR change that we identified remained small, with only about 1 in 10 patients prescribed these agents having a follow-up INR of 5.0 or greater. Catherine S. Riggs, PharmD Thomas Delate, PhD Nathan P. Clark, PharmD Author Affiliations: Department of Clinical Pharmacy, Kaiser Permanente, Colorado, Aurora (Riggs, Delate, Clark); Department of Clinical Pharmacy, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Denver (Delate, Clark). Corresponding Author: Nathan P. Clark, PharmD, Department of Clinical Pharmacy, Kaiser Permanente, 16601 E Centretech Pkwy, Aurora, CO 80011 ([email protected]) Conflict of Interest Disclosures: None reported. 1. Clark NP, Delate T, Riggs CS, et al; Warfarin-Associated Research Projects and Other Endeavors Consortium. Warfarin interactions with antibiotics in the ambulatory care setting. JAMA Intern Med. 2014;174(3):409-416.
Gabapentin Treatment for Alcohol Dependence To the Editor New treatments—both pharmacologic and nonpharmacologic—for one of the most devastating substance abuse disorders, alcoholism, are direly needed. We were therefore delighted to read an article reporting on a trial of gabapentin as a treatment option for alcohol dependence.1 Unfortunately, this article does not clarify whether gabapentin increases the proportion of abstinent patients or those without heavy drinking. While the research protocol had stipulated a sample size of 150 patients randomized to 1 treatment and 1 placebo control group, the same number of patients was split among 3 groups: 2 active treatment and 1 placebo control group (clinicaltrials.gov identifier: NCT00391716). The authors calculated their sample size based on an acamprosate trial from a different setting.2 Consequently, it seems that the odds ratio for one of the co-primary end points, abstinence, compares the higher dosage group, gabapentin 1800 mg/d, with placebo and was not statistically different (odds ratio, 4.8; 95% CI, 0.9-35.0). This fact is obscured by the article’s focus on a linear dose effect, with a P value below .05 from an extended Mantel-Haenszel χ2 test for linear association. In contrast, no P values were reported for the prespecified analysis. We believe that outcomes should not be selectively reported, and clinical trials should either adhere to their preregistered protocol or explain why they differed from it. Therefore, this present trial should be regarded as a dose-ranging study but not as a pivotal trial, which provides proof with traditional frequentist inference. Benjamin P. Geisler, MD, MPH Arnab Ghosh, MD, MA Author Affiliations: Department of Medicine, NYU School of Medicine, New York, New York. Corresponding Author: Benjamin P. Geisler, MD, MPH, NYU School of Medicine, 564 First Ave, 17E, New York, NY 10016 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Mason BJ, Quello S, Goodell V, Shadan F, Kyle M, Begovic A. Gabapentin treatment for alcohol dependence: a randomized clinical trial. JAMA Intern Med. 2014;174(1):70-77.
jamainternalmedicine.com
2. Pelc I, Verbanck P, Le Bon O, Gavrilovic M, Lion K, Lehert P. Efficacy and safety of acamprosate in the treatment of detoxified alcohol-dependent patients: a 90-day placebo-controlled dose-finding study. Br J Psychiatry. 1997; 171:73-77.
In Reply We are delighted to learn of Geisler and Ghosh’s interest in treating alcohol dependence and welcome the opportunity to address some of their misunderstandings about our report of a randomized clinical trial of gabapentin for the treatment of alcohol dependence.1 Contrary to their concern that ours was initially a 2-arm trial, our original protocol in fact specified a 3-arm dose-ranging design (gabapentin, 1800, 900, and 0 mg/d) and was reviewed as such by the National Institute on Alcohol Abuse and Alcoholism (NIAAA), the Scripps institutional review board, and the JAMA Internal Medicine (JAMA-IM) statistical reviewer (per JAMA-IM’s requirement that the original protocol be included with a clinical trial submission), and the clinicaltrials.gov link referenced by the authors specifies “dose ranging.” The authors also questioned the basis of our power analysis; no relevant gabapentin data were available in 2003, when the study was designed, so we used data from a dose-ranging trial of acamprosate, the most pharmacologically similar alcoholism treatment to gabapentin.2 Again, this was found acceptable across all the aforementioned levels of review. Given our dose-ranging design, testing for a linear dose-effect was the primary goal of the study and was significant, as reported in the article for all outcomes: abstinence, no heavy drinking, drinking quantity and frequency, γ-glutamyltransferase, craving, sleep, and mood. As noted by Schwenk,3 “The positive effects of gabapentin were dose-responsive, which suggest a biological basis for the benefits, and the improvement certainly justifies larger studies in more-typical patients.” With the linear dose response confirmed, we reported comparisons for gabapentin, 1800 mg, vs placebo: the rate of abstinence was 4 times greater (χ2 = 4.3, P = .04) and the rate of no heavy drinking doubled (χ2 = 5.3, P = .02). The numbers needed to treat (8 for abstinence and 5 for no heavy drinking) associated with gabapentin for these outcomes are equivalent or superior to those reported in a recent meta-analysis of clinical trials involving US Food and Drug Administration–approved treatments.4 Moreover, gabapentin was uniquely associated with significant improvements in mood and sleep. Geisler and Ghosh chose to disregard the a priori dose-ranging analytic plan and focus on a less robust odds ratio measure from a (statistically significant) comparison between 1 dosage group and the placebo group on a single outcome to support their negative conclusion. This highly selective use of data to craft a negative argument is misleading and can lead to an erroneous conclusion not supported by the full data set. Finally, we did not claim that ours was a pivotal trial, which refers to a trial intended to provide evidence for drugmarketing approval, but rather stated that “[l]arger studies in more diverse populations of patients with alcohol dependence are needed to replicate and extend these findings.”1(p76) The array of findings we present are solid evidence that gabapentin has clinically and statistically significant effects on drinking behavior and symptoms of early abstinence in alcoJAMA Internal Medicine July 2014 Volume 174, Number 7
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a Ndsu Library Periodicals User on 05/27/2015
1201
Letters
hol dependence, which bode well for developing a potential medication to relieve a significant amount of human suffering and cost to our health care system.
Author Affiliation: Department of Family and Social Medicine, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York.
Barbara J. Mason, PhD Vivian Goodell, MPH Farhad Shadan, MD, PhD
Conflict of Interest Disclosures: None reported. 1. Schiff GD, Puopolo AL, Huben-Kearney A, et al. Primary care closed claims experience of Massachusetts malpractice insurers. JAMA Intern Med. 2013;173 (22):2063-2068.
Author Affiliations: The Scripps Research Institute, Pearson Center for Alcoholism and Addiction, Research, La Jolla, California (Mason, Goodell, Shadan); Scripps Clinic and Scripps Green Hospital, La Jolla, California (Shadan). Corresponding Author: Barbara J. Mason, PhD, Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, 10550 N Torrey Pines Rd, TPC-5, La Jolla, CA 92037 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Mason BJ, Quello S, Goodell V, Shadan F, Kyle M, Begovic A. Gabapentin treatment for alcohol dependence: a randomized clinical trial. JAMA Intern Med. 2014;174(1):70-77. 2. Pelc I, Verbanck P, Le Bon O, Gavrilovic M, Lion K, Lehert P. Efficacy and safety of acamprosate in the treatment of detoxified alcohol-dependent patients: a 90-day placebo-controlled dose-finding study. Br J Psychiatry. 1997; 171:73-77. 3. Schwenk TL. Gabapentin improves rates of abstinence in alcohol-dependent patients. NEJM Journal Watch. November 21, 2013. http://www.jwatch.org /na32870/2013/11/21/gabapentin-improves-rates-abstinence-alcohol -dependent. Accessed March 7, 2014. 4. Maisel NC, Blodgett JC, Wilbourne PL, Humphreys K, Finney JW. Meta-analysis of naltrexone and acamprosate for treating alcohol use disorders: when are these medications most helpful? Addiction. 2013;108(2):275-293.
We Have Strict Statutes and Most Biting Laws To the Editor In their recent article, Schiff and colleagues1 computed the rate of malpractice claims filed against adult primary care physicians (PCPs) in Massachusetts. They found an annual rate of 3.3% (roughly 110 cases per year for 3305 physicians), noting that the rate was remarkably stable over the 5-year study period. A lawsuit rate of 3.3% per year may not seem like much. (Hyman and Sage2 proclaimed it a relatively “modest rate” in their Invited Commentary on the article by Schiff et al.1) But annual rates convey a false sense of well-being. A more meaningful indicator of risk is the career likelihood of a malpractice claim. Using the following binomial probability formula: 1 – (1 – λ)t, where λ is the annual risk of suit (eg, Schiff and coauthors’ rate of 0.033) and t is the duration of a medical career (eg, 40 years), I calculate that the probability of a Massachusetts PCP being sued at least once during his or her career as 74%. The binomial rests on a few assumptions: the annual risk of suit is the same each year, all PCPs face the same risk, and the risk to physicians each year is independent to what happened to them in any earlier year. While it is anticipated that reality will depart to some extent from the probability model, a 74% chance of suit, even as a first approximation, suggests that many PCPs will feel pressure to practice medicine defensively. A noteworthy contribution, then, is the authors’ identification of the breakdowns points in the process of care that most often result in legal liability. Rebecca Arden Harris, MD 1202
Corresponding Author: Rebecca Arden Harris, MD, 654 Lindley Rd, Glenside, PA 19038 ([email protected]).
2. Hyman DA, Sage WM. Medical malpractice in the outpatient setting: through a glass, darkly. JAMA Intern Med. 2013;173(22):2069-2070.
In Reply We thank Dr Harris for acknowledging the importance of malpractice risk that primary care physicians (and, we would add, their patients) painfully face, particularly the significant burden that the 3.3% annual rate translates to as it cumulatively accrues over a physician’s career. Dr Harris’ calculations, as well our findings, are consistent with other reported data.1,2 Aside from emphasis on the high statistical lifetime likelihood that a primary care physician might be sued, the author points out the value of the “identification of the breakdowns in care,” as well as raising the potential for resulting “defensive” medical practices. The Agency for Healthcare Research and Quality–funded PROMISES (Proactive Reduction of Outpatient Malpractice: Improving Safety, Efficiency, and Satisfaction) project, under whose auspices the Massachusetts insurers pooled the data we analyzed, specifically aimed to lower such risk by preventing failures and dropped balls in targeted areas of test result, referral, and medication management, as well as overarching communication breakdowns. However, we would point out that based on the literature and our work with participating Massachusetts primary care offices, practicing “defensive medicine” by ordering more tests and referrals can also add risks if health care practitioners do not reliably follow up and act on those results and referral recommendations. We hope that whatever added anxieties and stresses of malpractice "biting laws" Dr Harris invokes can also positively motivate and guide efforts to significantly improve primary care office systems. Toward that end, the PROMISES project has developed and made freely available a series of videos and guides on how to ensure safer and more reliable systems.3 Finally, regarding the need to practice more defensively, we also note the importance of being less defensive. Practitioners, particularly primary care physicians, need to build and maintain the trust of their patients, even when things go wrong. Thus candor, honest disclosure, willingness to modestly recognize that patients’ criticisms and concerns can both help us become better physicians and help in reducing malpractice suits and risks. Among the resources we have developed are a guide and video interview with Lucian Leape, MD, which give practical advice about how to share errors with patients and families.4,5 Gordon D. Schiff, MD Madeleine Biondolillo, MD Author Affiliations: Division of General Internal Medicine and Primary Care, Brigham and Women’s Hospital, Boston, Massachusetts (Schiff); Department of Medicine, Harvard Medical School, Boston, Massachusetts (Schiff); Bureau of
JAMA Internal Medicine July 2014 Volume 174, Number 7
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a Ndsu Library Periodicals User on 05/27/2015
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