LETTERS COMMENTS AND RESPONSES Changes in Mortality After Massachusetts Health Care Reform TO THE EDITOR: Sommers and colleagues (1) evaluated whether the 2006 Massachusetts health care reform, which reduced the proportion of persons without health insurance, affected mortality. They concluded that it did, in fact, decrease mortality. If true, this finding is important, because relatively little evidence shows a causal link between health insurance coverage and mortality. Moreover, the Massachusetts reform was the forerunner of the reform contained in the Patient Protection and Affordable Care Act. The widespread media attention that Sommers and colleagues' article received reflects the significance of their finding (2). One potential problem with the analysis is that inferences were based on an approach that was unlikely to be valid. The natural experiment that was the basis of the analysis was characterized by only 1 treatment state among 47 states and sample sizes with an uneven number of observations per state. In these settings, common approaches to inference have been shown to markedly overreject the null hypothesis (3, 4). I assessed the extent of the potential inference problem by calculating P values for estimates in the article by using randomization inference methods (5). The P values derived from these methods were large and ranged from 0.277 to 0.783. These values indicate that none of the estimates reported in the article is statistically significant at commonly accepted levels of significance. Moreover, given the relatively large magnitudes of the estimates that were reported, the large P values associated with these estimates suggest that the analysis lacked adequate statistical power to detect plausible effect sizes. In sum, my analysis indicates that the question of whether Massachusetts health care reform affected mortality remains unanswered.
Robert Kaestner, PhD Institute of Government and Public Affairs, University of Illinois Chicago, Illinois Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterest Forms.do?msNum=L15-0129.
References 1. Sommers BD, Long SK, Baicker K. Changes in mortality after Massachusetts health care reform: a quasi-experimental study. Ann Intern Med. 2014;160: 585-93. [PMID: 24798521] doi:10.7326/M13-2275 2. Tavernise S. Mortality drop seen to follow ‘06 health law. The New York Times. 5 May 2014. Accessed at www.nytimes.com/2014/05/06/health/death -rate-fell-in-massachusetts-after-health-care-overhaul.html?_r=0 on 30 January 2015. 3. Cameron AC, Gelbach JB, Miller DL. Bootstrap-based improvements for inference with clustered errors. Rev Econ Stat. 2008;90:414-27. 4. Conley TG, Taber CR. Inferences with “difference in differences” with a small number of policy changes. Rev Econ Stat. 2011;93:113-25. 5. Rosenbaum PR. Covariance adjustment in randomized experiments and observational studies. Stat Sci. 2002;17:286-327. doi:10.1214/ss/1042727942
Annals of Internal Medicine IN RESPONSE: We appreciate Dr. Kaestner's concerns. Testing the robustness of our findings by using alternative appropriate estimation techniques is a critical way to assess the reliability of our quasi-experimental approach. Because we lack sufficient detail on Dr. Kaestner's analysis, we cannot evaluate the soundness of his approach or the validity of his results. However, we believe that his concern about uneven cluster size driving spurious results is addressed by the state-level analysis presented in Appendix Table 4 of the Supplement, which the Supplemental Appendix describes in detail. We analyzed the study's 47 states by using annual state race-, age-, and sex-specific mortality rates. The analysis used a sample with an identical number of observations per state cluster—288 race-, age-, and sex-specific yearly mortality rates—in 43 of the 47 states. The other 4 states had some empty race-, age-, and sex-specific cells, leading to state sample sizes ranging from 241 to 285. In that analysis, which avoids Dr. Kaestner's primary methodological concern, we found large and statistically significant reductions in unadjusted all-cause mortality and adjusted and unadjusted health care–amenable mortality. Thus, the key results of our article do not seem to be driven by uneven cluster sizes. More generally, our article builds on many studies of Massachusetts health care reform that have taken similar approaches with state-level clustering, a well-established method for these sorts of analyses (1, 2). Our results remained statistically significant (Appendix Table 4 of the Supplement) when using county-level clustering, which other researchers have used in county-based analyses of Massachusetts health reform such as ours (3, 4). Of course, all statistical estimation techniques have strengths and weaknesses, and the SEs in quasi-experimental approaches are often sensitive to assumptions. This concern motivated the multiple approaches taken in the Supplement. We were reassured by the robustness of the results across approaches. We agree that great care must be taken with statistical inference in designs such as ours, but our analysis indicates that our use of comprehensive mortality statistics capturing every death in the study population of nearly 50 million persons over 9 years generated more than sufficient power to detect clinically meaningful mortality changes.
Benjamin D. Sommers, MD, PhD Harvard School of Public Health Boston, Massachusetts Sharon K. Long, PhD The Urban Institute Washington, DC Katherine Baicker, PhD Harvard School of Public Health Boston, Massachusetts Disclosures: Disclosures can be viewed at www.acponline.org /authors/icmje/ConflictOfInterestForms.do?msNum=M13-2275. References 1. Courtemanche CJ, Zapata D. Does universal coverage improve health? The Massachusetts experience. J Policy Anal Manage. 2014;33:36-69. [PMID: 24358528]
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LETTERS 2. Van Der Wees PJ, Zaslavsky AM, Ayanian JZ. Improvements in health status after Massachusetts health care reform. Milbank Q. 2013;91:663-89. [PMID: 24320165] doi:10.1111/1468-0009.12029 3. Miller S. The effect of insurance on emergency room visits: an analysis of the 2006 Massachusetts health reform. J Pub Econ. 2012;96:893-908. 4. Hanchate AD, Lasser KE, Kapoor A, Rosen J, McCormick D, D’Amore MM, et al. Massachusetts reform and disparities in inpatient care utilization. Med Care. 2012;50:569-77. [PMID: 22683590] doi:10.1097/MLR.0b013e31824e319f
Effects of Nurse-Managed Protocols TO THE EDITOR: Shaw and colleagues (1) do a nice job of
quantifying clinical outcomes for patients who receive care by nurses using protocols. Jauhar and Battinelli's editorial asks whether nurses are the answer to the national problem of primary care physician shortages at a time when demand for services continues to rise. We suggest that nurses are not the sole answer to the challenges in primary care; the solution is the implementation of high-performing, team-based care. However, nursing is a vital and untapped component of this high-performing team. It literally takes a village to manage health care needs, including chronic conditions, care coordination, and promotion of self-care and self-management, in a manner consistent with patients' desires and values. This village includes nurses (registered and licensed practical nurses), providers (doctors of medicine, doctors of osteopathic medicine, advanced practice registered nurses, and physician assistants), pharmacists, nutritionists, physical therapists, social workers, and others— the list is too long to complete here. But, in addition to having a full team, it is also essential that everyone functions to his or her full potential. As the Institute of Medicine report on teambased care explains, turf issues and verbalizing concerns about “independent practices” and who leads a team are barriers that emerge at a political level or at the top of organizations in which the players are removed from the reality of care (2). At the point of care, the most effective teams share leadership, recognize that professional practice can overlap, mentor each other, and develop deep mutual respect and appreciation. In our roles working directly in and with primary and specialty care teams, we regularly interact with the “front lines.” We frequently and clearly hear the desire for nurses to deliver patient care by using protocols that include the initiation and titration of medications as part of team-based care. In sites where we have seen these protocols piloted, teams reported an improved bond among pharmacists, nurses, and providers, often with bidirectional mentoring occurring at all levels. In addition, the nurses reported that the pilot training that they received for the responsibility of medication titration according to the protocol enhanced their ability to coach and mentor patients and ultimately improved their job satisfaction. In the United Kingdom, all primary care teams may engage in the use of protocols. The practice of nurse prescribing in the United Kingdom emerged in 1989 with an advisory group, followed by pilots, developing and funding training programs, and legislation sanctioning the role of nurse prescribers. The United Kingdom has 2 levels of nurse prescribers: an independent level requiring substantial academic www.annals.org
training and a supplementary level. The supplementary role requires the use of defined protocols for prescribing. Advanced practice registered nurses in the United States play the role of independent nurses who provide diagnostic and health care treatment in a full practice authority model. The United States has a great opportunity to define a supplementary protocol-based model of implementing treatment plans that include medications. We strongly support and endorse funding for piloting new programs, analysis of new and existing programs, and legislation to support a U.S. model for supplemental registered nurse practice. When will the United States catch up? Michelle A. Lucatorto, APRN, DNP, FNP-BC Storm Morgan, MSN, RN, MBA Veterans Health Administration Washington, DC Disclaimer: The contents of this letter do not represent the views of the U.S. Department of Veterans Affairs or the U.S. government. Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterest Forms.do?msNum=L14-0495. References 1. Shaw RJ, McDuffie JR, Hendrix CC, Edie A, Lindsey-Davis L, Nagi A, et al. Effects of nurse-managed protocols in the outpatient management of adults with chronic conditions: a systematic review and meta-analysis. Ann Intern Med. 2014;161:113-21. [PMID: 25023250] doi:10.7326/M13-2567 2. Mitchell P, Wynia M, Golden R, McNellis B, Okun S, Webb CE, et al; Institute of Medicine. Discussion Paper: Core Principles & Values of Effective TeamBased Health Care. Washington, DC: National Academies Pr; 2012.
The Role of Socioeconomic Status in Hospital Outcomes Measures TO THE EDITOR: Krumholz and Bernheim propose several arguments against adjustment of quality measures for socioeconomic status (SES) factors that might affect outcomes (1). First, SES effects are not large compared with overall quality differences among hospitals or the potential for improvement. Although this may be true in many cases, it is the wrong standard: Adjustment, or the failure to adjust, could still have significant implications, especially for hospitals with large proportions of disadvantaged patients. Second, Krumholz and Bernheim argue that acquisition and analysis of data required for SES adjustment may be difficult. Although collecting such data certainly has challenges, its importance is increasingly recognized and progress is being made (2). Furthermore, research reported in the same issue of Annals shows that readily available area measures of concentrated disadvantage linked to patient residential addresses can be highly predictive of outcomes (3); these are likely to indicate the SES composition of patients entering a hospital from the surrounding area. Krumholz and Bernheim's main argument on principle is that SES adjustment obscures differences in quality between hospitals used by advantaged and disadvantaged patients. We would find this argument more compelling if such differences in quality were in fact evident in unadjusted perforAnnals of Internal Medicine • Vol. 162 No. 9 • 5 May 2015 669
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LETTERS mance reports. In fact, the same unadjusted performance could represent inferior quality at hospitals serving disadvantaged patients or equally inferior outcomes for disadvantaged patients relative to others at all hospitals, with some hospitals simply having a higher proportion of disadvantaged populations (4). The nature of the underlying disparities can be revealed only by further systematic analysis; indeed the disaggregated data and analytic methods required to adjust reported measures are closely tied to those required to describe disparities and properly attribute responsibility for them. Furthermore, the same incentives to improvement operate with unadjusted and adjusted reporting. Unadjusted measures have their uses, especially in providing a straightforward description of shortcomings for internal use to target quality improvement. However, for distribution of performance incentives and informing patient choice, a well-considered adjustment can enhance the value of data for patients and providers. Alan M. Zaslavsky, PhD Harvard Medical School Boston, Massachusetts Ashish K. Jha, MD, MPH Harvard School of Public Health Boston, Massachusetts Disclosures: Disclosures can be viewed at www.acponline.org /authors/icmje/ConflictOfInterestForms.do?msNum=L15-0096. References 1. Krumholz HM, Bernheim SM. Considering the role of socioeconomic status in hospital outcomes measures [Editorial]. Ann Intern Med. 2014;161:833-4. [PMID: 25437411] doi:10.7326/M14-2308 2. Perrin E, Ver Ploeg M. Eliminating Health Disparities: Measurement and Data Needs: Washington, DC: National Academies Pr; 2004. 3. Kind AJ, Jencks S, Brock J, Yu M, Bartels C, Ehlenbach W, et al. Neighborhood socioeconomic disadvantage and 30-day rehospitalization: a retrospective cohort study. Ann Intern Med. 2014;161:765-74. [PMID: 25437404] doi: 10.7326/M13-2946 4. Jha AK, Zaslavsky AM. Quality reporting that addresses disparities in health care. JAMA. 2014;312:225-6. [PMID: 25027134] doi:10.1001/jama.2014.7204
IN RESPONSE: There is much in common between the letter
writers and us. We all agree that this a complex area in which causal pathways influence decisions about adjustment and there is important work remaining to understand the interaction of SES and outcomes. Our main point is that we can either assume that differences based on SES are unrelated to hospital quality and adjust them away, or allow that they might have a relationship to hospital quality and that hospitals are likely to be able to mitigate any disparities and not adjust the differences away. Given our nation's history and a large volume of studies showing a relationship between sociodemographic factors and quality, as well as the challenges and limitations we discussed, we believe that it is not appropriate to assume that black patients and poor patients intrinsically have higher risks for posthospital outcomes in ways that cannot be modified by the hospital itself or by the hospital collaborating with its community in constructive ways. Also, we agree with the Medicare Payment Advisory Commission that
payment policy must seek not to impose penalties on hospitals that treat vulnerable populations, have precarious finances, and would be better served by other strategies to incentivize and help promote improvement. In the end, we favor showing disparities in outcomes where they exist and challenging policymakers to devise wise approaches to promote performance improvements where we need them most, regardless of the cause. Harlan M. Krumholz, MD, SM Susannah M. Bernheim, MD, MHS Yale University School of Medicine New Haven, Connecticut Disclosures: Disclosures can be viewed at www.acponline.org /authors/icmje/ConflictOfInterestForms.do?msNum=M14-2308.
D-Dimer Testing in Patients With a First Unprovoked Venous
Thromboembolism TO THE EDITOR: In their study on D-dimer testing to assess the
risk for recurrence of venous thromboembolism (VTE) in patients with a first unprovoked VTE, Kearon and colleagues (1) concluded that the risk for recurrence in patients with negative results was not low enough to justify stopping anticoagulation. I was impressed by the low rate of positive D-dimer results reported in the study (71 of 410 patients; 17.3%) and, as a result, by the high proportion of patients who remained without anticoagulation and therefore at higher risk for recurrence. D-Dimer testing was performed using a whole-blood qualitative assay (Clearview Simplify [Alere]) designed to be calibrated for VTE diagnosis work-up. Some years ago, we used the same assay (marketed by Inverness Medical Professional Diagnostics) in 2 studies, obtaining positive rates of 36.7% (2) and 29.3% (3)—rates that were in line with studies that used quantitative assays (4). However, because Kearon and colleagues' study excluded patients older than 75 years, thus potentially contributing to the low rate of positive results, we analyzed patients younger than 76 years who were included in DULCIS (D-dimer and Ultrasonography in Combination Italian Study) (5). We found positive results at 1 month, using quantitative assays and cutoff values for VTE diagnosis, in 219 of 723 patients (30.1%). The unexpectedly low rate of positive results reported in Kearon and colleagues' study cannot therefore just be explained by the exclusion of very elderly patients, and other causes, such as poor sensitivity of the adopted qualitative assay, may be involved. To predict the risk for recurrence, D-dimer assays should be sensitive enough to detect a condition of “hypercoagulability,” which has been shown to be associated with the risk for recurrence. In DULCIS (D-dimer and Ultrasonography in Combination Italian Study) (5), using quantitative assays, specific cutoff levels (even lower in young men than those for VTE diagnosis [6]), and repeated D-dimer assessments, we detected positive results in 273 of 723 patients younger than 76 years (37.7%—twice the rate reported in Kearon and colleagues' study). Fourteen recurrences (2.1% per patient-year [95% CI, 1.2% to 3.5%]) were reported over 655 years of follow-up without anticoagulation in patients with persistently
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LETTERS negative D-dimer results (9 in men [2.6% per patient-year {CI, 1.2% to 4.9%}]). In my opinion, and in contrast with Kearon and colleagues' conclusions, these results confirm that in patients younger than 76 years, including men, with a first unprovoked VTE, measurement of D-dimer using sensitive assays after anticoagulation is stopped is an effective tool for identifying many patients who can definitively stop anticoagulation. Gualtiero Palareti, MD Fondazione Arianna Anticoagulazione Bologna, Italy Disclosures: Disclosures can be viewed at www.acponline.org /authors/icmje/ConflictOfInterestForms.do?msNum=L15-0076. References 1. Kearon C, Spencer FA, O’Keeffe D, Parpia S, Schulman S, Baglin T, et al; D-dimer Optimal Duration Study Investigators. D-dimer testing to select patients with a first unprovoked venous thromboembolism who can stop anticoagulant therapy: a cohort study. Ann Intern Med. 2015;162:27-34. [PMID: 25560712] doi:10.7326/M14-1275 2. Palareti G, Cosmi B, Legnani C, Tosetto A, Brusi C, Iorio A, et al; PROLONG Investigators. D-dimer testing to determine the duration of anticoagulation therapy. N Engl J Med. 2006;355:1780-9. [PMID: 17065639] 3. Cosmi B, Legnani C, Tosetto A, Pengo V, Ghirarduzzi A, Testa S, et al; PROLONG Investigators (on behalf of Italian Federation of Anticoagulation Clinics). Usefulness of repeated D-dimer testing after stopping anticoagulation for a first episode of unprovoked venous thromboembolism: the PROLONG II prospective study. Blood. 2010;115:481-8. [PMID: 19965693] doi:10.1182 /blood-2009-08-237354 4. Palareti G, Legnani C, Cosmi B, Valdre´ L, Lunghi B, Bernardi F, et al. Predictive value of D-dimer test for recurrent venous thromboembolism after anticoagulation withdrawal in subjects with a previous idiopathic event and in carriers of congenital thrombophilia. Circulation. 2003;108:313-8. [PMID: 12847064] 5. Palareti G, Cosmi B, Legnani C, Antonucci E, De Micheli V, Ghirarduzzi A, et al; DULCIS (D-dimer and ULtrasonography in Combination Italian Study) Investigators. D-dimer to guide the duration of anticoagulation in patients with venous thromboembolism: a management study. Blood. 2014;124:196-203. [PMID: 24879813] doi:10.1182/blood-2014-01-548065 6. Legnani C, Cini M, Cosmi B, Carraro P, Tripodi A, Erba N, et al. Age and gender specific cut-off values to improve the performance of D-dimer assays to predict the risk of venous thromboembolism recurrence. Intern Emerg Med. 2013;8:229-36. [PMID: 21584847] doi:10.1007/s11739-011-0608-5
twice as many patients having a positive D-dimer result and still receiving anticoagulant therapy as in our study. Dr. Palareti attributes the lower risk for recurrence in DULCIS patients who had negative D-dimer results to how testing was performed and interpreted. We suspect that this is not the most important reason for the lower reported risk for recurrence in DULCIS. We reported the risk for recurrent VTE separately for men and women with unprovoked VTE and for women with VTE associated with estrogen therapy. We did not enroll patients with VTE provoked by other reversible risk factors. DULCIS enrolled patients with unprovoked VTE, women with VTE associated with estrogen therapy, and patients with VTE provoked by other weak reversible risk factors. The risk for recurrence in the main DULCIS report (3) and in Dr. Palareti's letter is for all of these patients, rather than for those with unprovoked VTE. Consistent with other studies (4), DULCIS found that risk for recurrence in all patients with VTE provoked by a weak reversible risk factor was much lower than in DULCIS patients with unprovoked VTE (1.3% vs. 6.1% per patient-year; P = 0.036) (3). In fact, the risk for recurrence in the patients with unprovoked VTE in DULCIS (6.1% per patient-year for men and women combined) was similar to that in our patients with unprovoked VTE (9.7% and 5.4% per patient-year for men and women, respectively). Therefore, we suggest that that difference in the patient populations and reporting, as much as differences in how D-dimer testing was performed and interpreted, accounts for the apparently lower risk for recurrence in DULCIS. Clive Kearon, MB, PhD Hamilton Health Sciences Hamilton, Ontario, Canada Scott M. Stevens, MD Intermountain Medical Center Murray, Utah Jim A. Julian, MMath Ontario Clinical Oncology Group Hamilton, Ontario, Canada Disclosures: Disclosures can be viewed at www.acponline.org /authors/icmje/ConflictOfInterestForms.do?msNum=M14-1275. References
IN RESPONSE: We agree with Dr. Palareti's suggestion that
exclusion of patients older than 75 years explains the fewer positive D-dimer results in our study than in the 2 earlier studies he mentions (1, 2). Dr. Palareti, however, does not report the proportion of patients younger than 76 years who had positive D-dimer results in their early studies, so this remains uncertain. The recent DULCIS study also had a higher proportion of patients with positive D-dimer results than our study (3). As Dr. Palareti notes, a higher proportion of positive D-dimer results was also present in DULCIS patients younger than 76 years. In patients younger than 70 years, DULCIS used lower D-dimer cutoffs to define a positive result than the level that corresponds to a positive Clearview Simplify D-dimer result in our study. Also in DULCIS, D-dimer levels were measured on 4 occasions after anticoagulation was stopped, compared with once in our study. These differences in testing resulted in www.annals.org
1. Cosmi B, Legnani C, Tosetto A, Pengo V, Ghirarduzzi A, Testa S, et al; PROLONG Investigators (on behalf of Italian Federation of Anticoagulation Clinics). Usefulness of repeated D-dimer testing after stopping anticoagulation for a first episode of unprovoked venous thromboembolism: the PROLONG II prospective study. Blood. 2010;115:481-8. [PMID: 19965693] doi:10.1182 /blood-2009-08-237354 2. Palareti G, Cosmi B, Legnani C, Tosetto A, Brusi C, Iorio A, et al; PROLONG Investigators. D-dimer testing to determine the duration of anticoagulation therapy. N Engl J Med. 2006;355:1780-9. [PMID: 17065639] 3. Palareti G, Cosmi B, Legnani C, Antonucci E, De Micheli V, Ghirarduzzi A, et al; DULCIS (D-dimer and ULtrasonography in Combination Italian Study) Investigators. D-dimer to guide the duration of anticoagulation in patients with venous thromboembolism: a management study. Blood. 2014;124:196-203. [PMID: 24879813] doi:10.1182/blood-2014-01-548065 4. Iorio A, Kearon C, Filippucci E, Marcucci M, Macura A, Pengo V, et al. Risk of recurrence after a first episode of symptomatic venous thromboembolism provoked by a transient risk factor: a systematic review. Arch Intern Med. 2010; 170:1710-6. [PMID: 20975016] doi:10.1001/archinternmed.2010.367 Annals of Internal Medicine • Vol. 162 No. 9 • 5 May 2015 671
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LETTERS Pharmacologic Interventions for Knee Osteoarthritis TO THE EDITOR: In their complex review of pharmacologic interventions for treatment of knee osteoarthritis, Bannuru and colleagues (1) reported that intra-articular (IA) hyaluronic acid had the highest effect size for relief of pain compared with oral placebo. That comparison is misleading, because the appropriate control for IA hyaluronic acid is IA placebo injection. Although the authors and the accompanying editorial (2) note that the apparent efficacy of hyaluronic acid may result from the stronger placebo effect of an injection, the comparison with oral placebo gives unwarranted credibility to the efficacy of hyaluronic acid and is subject to misinterpretation. For example, a commentary by a physician in an online medical newsletter (3) ignored the issue of placebo effects and questioned recommendations against the use of hyaluronic acid. Another online newsletter (4) cited the biggest benefit from hyaluronic acid and failed to consider data from other reviews and guidelines. The best evidence is that IA hyaluronic acid has no clinically meaningful benefit for knee osteoarthritis compared with IA placebo injection (5). Bannuru and colleagues' review provides no basis for reconsidering current guidelines. Despite the lack of evidence supporting its use, injections of hyaluronic acid for knee osteoarthritis are used widely. It is unfortunate that this review may be misquoted in other popular health media and advertisements as providing evidence for the benefits of this treatment.
Donald M. Marcus, MD Baylor College of Medicine Houston, Texas Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterest Forms.do?msNum=L15-0098. References 1. Bannuru RR, Schmid CH, Kent DM, Vaysbrot EE, Wong JB, McAlindon TE. Comparative effectiveness of pharmacologic interventions for knee osteoarthritis: a systematic review and network meta-analysis. Ann Intern Med. 2015; 162:46-54. [PMID: 25560713] doi:10.7326/M14-1231 2. Mandl LA, Losina E. Relative efficacy of knee osteoarthritis treatments: are all placebos created equal? [Editorial]. Ann Intern Med. 2015;162:71-2. [PMID: 25560716] doi:10.7326/M14-2636 3. Altman R. Next round on hyaluronic acid: better even than acetaminophen? MedPageToday. 22 January 2015. Accessed at www.medpagetoday.com /Rheumatology/Arthritis/49672 on 26 March 2015. 4. Norton A. Knee arthritis drugs beat placebos, but study finds no clear winner. HealthDay. 6 January 2015. Accessed at http://consumer.healthday.com /bone-and-joint-information-4/arthritis-drug-news-39/knee-arthritis-drugs-are -better-than-nothing-study-695188.html on 26 March 2015. 5. Rutjes AW, Ju¨ni P, da Costa BR, Trelle S, Nu¨esch E, Reichenbach S. Viscosupplementation for osteoarthritis of the knee: a systematic review and metaanalysis. Ann Intern Med. 2012;157:180-91. [PMID: 22868835] doi:10.7326 /0003-4819-157-3-201208070-00473
IN RESPONSE: We wholeheartedly agree that all articles
should be faithfully reported and not spun to meet marketing agendas. We concur that comparison of IA hyaluronic acid with IA placebo is scientifically valuable but also maintain that
comparison with oral placebo is valuable as well. Both comparisons give valid estimates of treatment effect— but with different meanings. The former measures an explanatory treatment effect that might better indicate the incremental effect due to the biological activity of hyaluronic acid over and above a (potentially) pharmacodynamically inactive saline injection. However, the latter gives a more pragmatic measure that is likely to better indicate the degree of relief that a patient will feel because it incorporates all modes of IA hyaluronic acid activity. For the purposes of comparative effectiveness research, we feel that comparison with oral placebo provides a better evidentiary basis for clinical decision making. Our network meta-analysis enabled us to estimate the comparative effectiveness of IA agents relative to oral agents and rank these effects in a clinically useful way (1). That the derived comparative effect may incorporate a component of a placebo response should prompt thought and discussion on how to reformulate the way we perceive its role in therapy and the practice of medicine. Therefore, we should give careful consideration to strongly recommending against therapeutic products that have good comparative effectiveness, especially for conditions for which alternatives are limited and often precluded by comorbid contraindications. These complexities may explain why consensus recommendations from various groups differ on such products as hyaluronic acid (2– 4). Raveendhara R. Bannuru, MD Center for Treatment Comparison and Integrative Analysis, Tufts Medical Center Boston, Massachusetts David M. Kent, MD Institute for Clinical Research and Health Policy Studies, Tufts Medical Center Boston, Massachusetts Timothy E. McAlindon, MD Center for Treatment Comparison and Integrative Analysis, Tufts Medical Center Boston, Massachusetts Disclosures: Disclosures can be viewed at www.acponline.org /authors/icmje/ConflictOfInterestForms.do?msNum=M14-1231. References 1. Bannuru RR, Schmid CH, Kent DM, Vaysbrot EE, Wong JB, McAlindon TE. Comparative effectiveness of pharmacologic interventions for knee osteoarthritis: a systematic review and network meta-analysis. Ann Intern Med. 2015; 162:46-54. [PMID: 25560713] doi:10.7326/M14-1231 2. Brown GA. AAOS clinical practice guideline: treatment of osteoarthritis of the knee: evidence-based guideline, 2nd edition. J Am Acad Orthop Surg. 2013;21:577-9. [PMID: 23996989] doi:10.5435/JAAOS-21-09-577 3. Hochberg MC, Altman RD, April KT, Benkhalti M, Guyatt G, McGowan J, et al; American College of Rheumatology. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res (Hoboken). 2012;64:465-74. [PMID: 22563589] 4. McAlindon TE, Bannuru RR, Sullivan MC, Arden NK, Berenbaum F, BiermaZeinstra SM, et al. OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthritis Cartilage. 2014;22:363-88. [PMID: 24462672] doi: 10.1016/j.joca.2014.01.003
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Robert Kaestner, PhD Institute of Government and Public Affairs, University of Illinois Chicago, Illinois Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterest Forms.do?msNum=L15-0129.
References 1. Sommers BD, Long SK, Baicker K. Changes in mortality after Massachusetts health care reform: a quasi-experimental study. Ann Intern Med. 2014;160: 585-93. [PMID: 24798521] doi:10.7326/M13-2275 2. Tavernise S. Mortality drop seen to follow ‘06 health law. The New York Times. 5 May 2014. Accessed at www.nytimes.com/2014/05/06/health/death -rate-fell-in-massachusetts-after-health-care-overhaul.html?_r=0 on 30 January 2015. 3. Cameron AC, Gelbach JB, Miller DL. Bootstrap-based improvements for inference with clustered errors. Rev Econ Stat. 2008;90:414-27. 4. Conley TG, Taber CR. Inferences with “difference in differences” with a small number of policy changes. Rev Econ Stat. 2011;93:113-25. 5. Rosenbaum PR. Covariance adjustment in randomized experiments and observational studies. Stat Sci. 2002;17:286-327. doi:10.1214/ss/1042727942
Annals of Internal Medicine IN RESPONSE: We appreciate Dr. Kaestner's concerns. Testing the robustness of our findings by using alternative appropriate estimation techniques is a critical way to assess the reliability of our quasi-experimental approach. Because we lack sufficient detail on Dr. Kaestner's analysis, we cannot evaluate the soundness of his approach or the validity of his results. However, we believe that his concern about uneven cluster size driving spurious results is addressed by the state-level analysis presented in Appendix Table 4 of the Supplement, which the Supplemental Appendix describes in detail. We analyzed the study's 47 states by using annual state race-, age-, and sex-specific mortality rates. The analysis used a sample with an identical number of observations per state cluster—288 race-, age-, and sex-specific yearly mortality rates—in 43 of the 47 states. The other 4 states had some empty race-, age-, and sex-specific cells, leading to state sample sizes ranging from 241 to 285. In that analysis, which avoids Dr. Kaestner's primary methodological concern, we found large and statistically significant reductions in unadjusted all-cause mortality and adjusted and unadjusted health care–amenable mortality. Thus, the key results of our article do not seem to be driven by uneven cluster sizes. More generally, our article builds on many studies of Massachusetts health care reform that have taken similar approaches with state-level clustering, a well-established method for these sorts of analyses (1, 2). Our results remained statistically significant (Appendix Table 4 of the Supplement) when using county-level clustering, which other researchers have used in county-based analyses of Massachusetts health reform such as ours (3, 4). Of course, all statistical estimation techniques have strengths and weaknesses, and the SEs in quasi-experimental approaches are often sensitive to assumptions. This concern motivated the multiple approaches taken in the Supplement. We were reassured by the robustness of the results across approaches. We agree that great care must be taken with statistical inference in designs such as ours, but our analysis indicates that our use of comprehensive mortality statistics capturing every death in the study population of nearly 50 million persons over 9 years generated more than sufficient power to detect clinically meaningful mortality changes.
Benjamin D. Sommers, MD, PhD Harvard School of Public Health Boston, Massachusetts Sharon K. Long, PhD The Urban Institute Washington, DC Katherine Baicker, PhD Harvard School of Public Health Boston, Massachusetts Disclosures: Disclosures can be viewed at www.acponline.org /authors/icmje/ConflictOfInterestForms.do?msNum=M13-2275. References 1. Courtemanche CJ, Zapata D. Does universal coverage improve health? The Massachusetts experience. J Policy Anal Manage. 2014;33:36-69. [PMID: 24358528]
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LETTERS 2. Van Der Wees PJ, Zaslavsky AM, Ayanian JZ. Improvements in health status after Massachusetts health care reform. Milbank Q. 2013;91:663-89. [PMID: 24320165] doi:10.1111/1468-0009.12029 3. Miller S. The effect of insurance on emergency room visits: an analysis of the 2006 Massachusetts health reform. J Pub Econ. 2012;96:893-908. 4. Hanchate AD, Lasser KE, Kapoor A, Rosen J, McCormick D, D’Amore MM, et al. Massachusetts reform and disparities in inpatient care utilization. Med Care. 2012;50:569-77. [PMID: 22683590] doi:10.1097/MLR.0b013e31824e319f
Effects of Nurse-Managed Protocols TO THE EDITOR: Shaw and colleagues (1) do a nice job of
quantifying clinical outcomes for patients who receive care by nurses using protocols. Jauhar and Battinelli's editorial asks whether nurses are the answer to the national problem of primary care physician shortages at a time when demand for services continues to rise. We suggest that nurses are not the sole answer to the challenges in primary care; the solution is the implementation of high-performing, team-based care. However, nursing is a vital and untapped component of this high-performing team. It literally takes a village to manage health care needs, including chronic conditions, care coordination, and promotion of self-care and self-management, in a manner consistent with patients' desires and values. This village includes nurses (registered and licensed practical nurses), providers (doctors of medicine, doctors of osteopathic medicine, advanced practice registered nurses, and physician assistants), pharmacists, nutritionists, physical therapists, social workers, and others— the list is too long to complete here. But, in addition to having a full team, it is also essential that everyone functions to his or her full potential. As the Institute of Medicine report on teambased care explains, turf issues and verbalizing concerns about “independent practices” and who leads a team are barriers that emerge at a political level or at the top of organizations in which the players are removed from the reality of care (2). At the point of care, the most effective teams share leadership, recognize that professional practice can overlap, mentor each other, and develop deep mutual respect and appreciation. In our roles working directly in and with primary and specialty care teams, we regularly interact with the “front lines.” We frequently and clearly hear the desire for nurses to deliver patient care by using protocols that include the initiation and titration of medications as part of team-based care. In sites where we have seen these protocols piloted, teams reported an improved bond among pharmacists, nurses, and providers, often with bidirectional mentoring occurring at all levels. In addition, the nurses reported that the pilot training that they received for the responsibility of medication titration according to the protocol enhanced their ability to coach and mentor patients and ultimately improved their job satisfaction. In the United Kingdom, all primary care teams may engage in the use of protocols. The practice of nurse prescribing in the United Kingdom emerged in 1989 with an advisory group, followed by pilots, developing and funding training programs, and legislation sanctioning the role of nurse prescribers. The United Kingdom has 2 levels of nurse prescribers: an independent level requiring substantial academic www.annals.org
training and a supplementary level. The supplementary role requires the use of defined protocols for prescribing. Advanced practice registered nurses in the United States play the role of independent nurses who provide diagnostic and health care treatment in a full practice authority model. The United States has a great opportunity to define a supplementary protocol-based model of implementing treatment plans that include medications. We strongly support and endorse funding for piloting new programs, analysis of new and existing programs, and legislation to support a U.S. model for supplemental registered nurse practice. When will the United States catch up? Michelle A. Lucatorto, APRN, DNP, FNP-BC Storm Morgan, MSN, RN, MBA Veterans Health Administration Washington, DC Disclaimer: The contents of this letter do not represent the views of the U.S. Department of Veterans Affairs or the U.S. government. Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterest Forms.do?msNum=L14-0495. References 1. Shaw RJ, McDuffie JR, Hendrix CC, Edie A, Lindsey-Davis L, Nagi A, et al. Effects of nurse-managed protocols in the outpatient management of adults with chronic conditions: a systematic review and meta-analysis. Ann Intern Med. 2014;161:113-21. [PMID: 25023250] doi:10.7326/M13-2567 2. Mitchell P, Wynia M, Golden R, McNellis B, Okun S, Webb CE, et al; Institute of Medicine. Discussion Paper: Core Principles & Values of Effective TeamBased Health Care. Washington, DC: National Academies Pr; 2012.
The Role of Socioeconomic Status in Hospital Outcomes Measures TO THE EDITOR: Krumholz and Bernheim propose several arguments against adjustment of quality measures for socioeconomic status (SES) factors that might affect outcomes (1). First, SES effects are not large compared with overall quality differences among hospitals or the potential for improvement. Although this may be true in many cases, it is the wrong standard: Adjustment, or the failure to adjust, could still have significant implications, especially for hospitals with large proportions of disadvantaged patients. Second, Krumholz and Bernheim argue that acquisition and analysis of data required for SES adjustment may be difficult. Although collecting such data certainly has challenges, its importance is increasingly recognized and progress is being made (2). Furthermore, research reported in the same issue of Annals shows that readily available area measures of concentrated disadvantage linked to patient residential addresses can be highly predictive of outcomes (3); these are likely to indicate the SES composition of patients entering a hospital from the surrounding area. Krumholz and Bernheim's main argument on principle is that SES adjustment obscures differences in quality between hospitals used by advantaged and disadvantaged patients. We would find this argument more compelling if such differences in quality were in fact evident in unadjusted perforAnnals of Internal Medicine • Vol. 162 No. 9 • 5 May 2015 669
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LETTERS mance reports. In fact, the same unadjusted performance could represent inferior quality at hospitals serving disadvantaged patients or equally inferior outcomes for disadvantaged patients relative to others at all hospitals, with some hospitals simply having a higher proportion of disadvantaged populations (4). The nature of the underlying disparities can be revealed only by further systematic analysis; indeed the disaggregated data and analytic methods required to adjust reported measures are closely tied to those required to describe disparities and properly attribute responsibility for them. Furthermore, the same incentives to improvement operate with unadjusted and adjusted reporting. Unadjusted measures have their uses, especially in providing a straightforward description of shortcomings for internal use to target quality improvement. However, for distribution of performance incentives and informing patient choice, a well-considered adjustment can enhance the value of data for patients and providers. Alan M. Zaslavsky, PhD Harvard Medical School Boston, Massachusetts Ashish K. Jha, MD, MPH Harvard School of Public Health Boston, Massachusetts Disclosures: Disclosures can be viewed at www.acponline.org /authors/icmje/ConflictOfInterestForms.do?msNum=L15-0096. References 1. Krumholz HM, Bernheim SM. Considering the role of socioeconomic status in hospital outcomes measures [Editorial]. Ann Intern Med. 2014;161:833-4. [PMID: 25437411] doi:10.7326/M14-2308 2. Perrin E, Ver Ploeg M. Eliminating Health Disparities: Measurement and Data Needs: Washington, DC: National Academies Pr; 2004. 3. Kind AJ, Jencks S, Brock J, Yu M, Bartels C, Ehlenbach W, et al. Neighborhood socioeconomic disadvantage and 30-day rehospitalization: a retrospective cohort study. Ann Intern Med. 2014;161:765-74. [PMID: 25437404] doi: 10.7326/M13-2946 4. Jha AK, Zaslavsky AM. Quality reporting that addresses disparities in health care. JAMA. 2014;312:225-6. [PMID: 25027134] doi:10.1001/jama.2014.7204
IN RESPONSE: There is much in common between the letter
writers and us. We all agree that this a complex area in which causal pathways influence decisions about adjustment and there is important work remaining to understand the interaction of SES and outcomes. Our main point is that we can either assume that differences based on SES are unrelated to hospital quality and adjust them away, or allow that they might have a relationship to hospital quality and that hospitals are likely to be able to mitigate any disparities and not adjust the differences away. Given our nation's history and a large volume of studies showing a relationship between sociodemographic factors and quality, as well as the challenges and limitations we discussed, we believe that it is not appropriate to assume that black patients and poor patients intrinsically have higher risks for posthospital outcomes in ways that cannot be modified by the hospital itself or by the hospital collaborating with its community in constructive ways. Also, we agree with the Medicare Payment Advisory Commission that
payment policy must seek not to impose penalties on hospitals that treat vulnerable populations, have precarious finances, and would be better served by other strategies to incentivize and help promote improvement. In the end, we favor showing disparities in outcomes where they exist and challenging policymakers to devise wise approaches to promote performance improvements where we need them most, regardless of the cause. Harlan M. Krumholz, MD, SM Susannah M. Bernheim, MD, MHS Yale University School of Medicine New Haven, Connecticut Disclosures: Disclosures can be viewed at www.acponline.org /authors/icmje/ConflictOfInterestForms.do?msNum=M14-2308.
D-Dimer Testing in Patients With a First Unprovoked Venous
Thromboembolism TO THE EDITOR: In their study on D-dimer testing to assess the
risk for recurrence of venous thromboembolism (VTE) in patients with a first unprovoked VTE, Kearon and colleagues (1) concluded that the risk for recurrence in patients with negative results was not low enough to justify stopping anticoagulation. I was impressed by the low rate of positive D-dimer results reported in the study (71 of 410 patients; 17.3%) and, as a result, by the high proportion of patients who remained without anticoagulation and therefore at higher risk for recurrence. D-Dimer testing was performed using a whole-blood qualitative assay (Clearview Simplify [Alere]) designed to be calibrated for VTE diagnosis work-up. Some years ago, we used the same assay (marketed by Inverness Medical Professional Diagnostics) in 2 studies, obtaining positive rates of 36.7% (2) and 29.3% (3)—rates that were in line with studies that used quantitative assays (4). However, because Kearon and colleagues' study excluded patients older than 75 years, thus potentially contributing to the low rate of positive results, we analyzed patients younger than 76 years who were included in DULCIS (D-dimer and Ultrasonography in Combination Italian Study) (5). We found positive results at 1 month, using quantitative assays and cutoff values for VTE diagnosis, in 219 of 723 patients (30.1%). The unexpectedly low rate of positive results reported in Kearon and colleagues' study cannot therefore just be explained by the exclusion of very elderly patients, and other causes, such as poor sensitivity of the adopted qualitative assay, may be involved. To predict the risk for recurrence, D-dimer assays should be sensitive enough to detect a condition of “hypercoagulability,” which has been shown to be associated with the risk for recurrence. In DULCIS (D-dimer and Ultrasonography in Combination Italian Study) (5), using quantitative assays, specific cutoff levels (even lower in young men than those for VTE diagnosis [6]), and repeated D-dimer assessments, we detected positive results in 273 of 723 patients younger than 76 years (37.7%—twice the rate reported in Kearon and colleagues' study). Fourteen recurrences (2.1% per patient-year [95% CI, 1.2% to 3.5%]) were reported over 655 years of follow-up without anticoagulation in patients with persistently
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LETTERS negative D-dimer results (9 in men [2.6% per patient-year {CI, 1.2% to 4.9%}]). In my opinion, and in contrast with Kearon and colleagues' conclusions, these results confirm that in patients younger than 76 years, including men, with a first unprovoked VTE, measurement of D-dimer using sensitive assays after anticoagulation is stopped is an effective tool for identifying many patients who can definitively stop anticoagulation. Gualtiero Palareti, MD Fondazione Arianna Anticoagulazione Bologna, Italy Disclosures: Disclosures can be viewed at www.acponline.org /authors/icmje/ConflictOfInterestForms.do?msNum=L15-0076. References 1. Kearon C, Spencer FA, O’Keeffe D, Parpia S, Schulman S, Baglin T, et al; D-dimer Optimal Duration Study Investigators. D-dimer testing to select patients with a first unprovoked venous thromboembolism who can stop anticoagulant therapy: a cohort study. Ann Intern Med. 2015;162:27-34. [PMID: 25560712] doi:10.7326/M14-1275 2. Palareti G, Cosmi B, Legnani C, Tosetto A, Brusi C, Iorio A, et al; PROLONG Investigators. D-dimer testing to determine the duration of anticoagulation therapy. N Engl J Med. 2006;355:1780-9. [PMID: 17065639] 3. Cosmi B, Legnani C, Tosetto A, Pengo V, Ghirarduzzi A, Testa S, et al; PROLONG Investigators (on behalf of Italian Federation of Anticoagulation Clinics). Usefulness of repeated D-dimer testing after stopping anticoagulation for a first episode of unprovoked venous thromboembolism: the PROLONG II prospective study. Blood. 2010;115:481-8. [PMID: 19965693] doi:10.1182 /blood-2009-08-237354 4. Palareti G, Legnani C, Cosmi B, Valdre´ L, Lunghi B, Bernardi F, et al. Predictive value of D-dimer test for recurrent venous thromboembolism after anticoagulation withdrawal in subjects with a previous idiopathic event and in carriers of congenital thrombophilia. Circulation. 2003;108:313-8. [PMID: 12847064] 5. Palareti G, Cosmi B, Legnani C, Antonucci E, De Micheli V, Ghirarduzzi A, et al; DULCIS (D-dimer and ULtrasonography in Combination Italian Study) Investigators. D-dimer to guide the duration of anticoagulation in patients with venous thromboembolism: a management study. Blood. 2014;124:196-203. [PMID: 24879813] doi:10.1182/blood-2014-01-548065 6. Legnani C, Cini M, Cosmi B, Carraro P, Tripodi A, Erba N, et al. Age and gender specific cut-off values to improve the performance of D-dimer assays to predict the risk of venous thromboembolism recurrence. Intern Emerg Med. 2013;8:229-36. [PMID: 21584847] doi:10.1007/s11739-011-0608-5
twice as many patients having a positive D-dimer result and still receiving anticoagulant therapy as in our study. Dr. Palareti attributes the lower risk for recurrence in DULCIS patients who had negative D-dimer results to how testing was performed and interpreted. We suspect that this is not the most important reason for the lower reported risk for recurrence in DULCIS. We reported the risk for recurrent VTE separately for men and women with unprovoked VTE and for women with VTE associated with estrogen therapy. We did not enroll patients with VTE provoked by other reversible risk factors. DULCIS enrolled patients with unprovoked VTE, women with VTE associated with estrogen therapy, and patients with VTE provoked by other weak reversible risk factors. The risk for recurrence in the main DULCIS report (3) and in Dr. Palareti's letter is for all of these patients, rather than for those with unprovoked VTE. Consistent with other studies (4), DULCIS found that risk for recurrence in all patients with VTE provoked by a weak reversible risk factor was much lower than in DULCIS patients with unprovoked VTE (1.3% vs. 6.1% per patient-year; P = 0.036) (3). In fact, the risk for recurrence in the patients with unprovoked VTE in DULCIS (6.1% per patient-year for men and women combined) was similar to that in our patients with unprovoked VTE (9.7% and 5.4% per patient-year for men and women, respectively). Therefore, we suggest that that difference in the patient populations and reporting, as much as differences in how D-dimer testing was performed and interpreted, accounts for the apparently lower risk for recurrence in DULCIS. Clive Kearon, MB, PhD Hamilton Health Sciences Hamilton, Ontario, Canada Scott M. Stevens, MD Intermountain Medical Center Murray, Utah Jim A. Julian, MMath Ontario Clinical Oncology Group Hamilton, Ontario, Canada Disclosures: Disclosures can be viewed at www.acponline.org /authors/icmje/ConflictOfInterestForms.do?msNum=M14-1275. References
IN RESPONSE: We agree with Dr. Palareti's suggestion that
exclusion of patients older than 75 years explains the fewer positive D-dimer results in our study than in the 2 earlier studies he mentions (1, 2). Dr. Palareti, however, does not report the proportion of patients younger than 76 years who had positive D-dimer results in their early studies, so this remains uncertain. The recent DULCIS study also had a higher proportion of patients with positive D-dimer results than our study (3). As Dr. Palareti notes, a higher proportion of positive D-dimer results was also present in DULCIS patients younger than 76 years. In patients younger than 70 years, DULCIS used lower D-dimer cutoffs to define a positive result than the level that corresponds to a positive Clearview Simplify D-dimer result in our study. Also in DULCIS, D-dimer levels were measured on 4 occasions after anticoagulation was stopped, compared with once in our study. These differences in testing resulted in www.annals.org
1. Cosmi B, Legnani C, Tosetto A, Pengo V, Ghirarduzzi A, Testa S, et al; PROLONG Investigators (on behalf of Italian Federation of Anticoagulation Clinics). Usefulness of repeated D-dimer testing after stopping anticoagulation for a first episode of unprovoked venous thromboembolism: the PROLONG II prospective study. Blood. 2010;115:481-8. [PMID: 19965693] doi:10.1182 /blood-2009-08-237354 2. Palareti G, Cosmi B, Legnani C, Tosetto A, Brusi C, Iorio A, et al; PROLONG Investigators. D-dimer testing to determine the duration of anticoagulation therapy. N Engl J Med. 2006;355:1780-9. [PMID: 17065639] 3. Palareti G, Cosmi B, Legnani C, Antonucci E, De Micheli V, Ghirarduzzi A, et al; DULCIS (D-dimer and ULtrasonography in Combination Italian Study) Investigators. D-dimer to guide the duration of anticoagulation in patients with venous thromboembolism: a management study. Blood. 2014;124:196-203. [PMID: 24879813] doi:10.1182/blood-2014-01-548065 4. Iorio A, Kearon C, Filippucci E, Marcucci M, Macura A, Pengo V, et al. Risk of recurrence after a first episode of symptomatic venous thromboembolism provoked by a transient risk factor: a systematic review. Arch Intern Med. 2010; 170:1710-6. [PMID: 20975016] doi:10.1001/archinternmed.2010.367 Annals of Internal Medicine • Vol. 162 No. 9 • 5 May 2015 671
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LETTERS Pharmacologic Interventions for Knee Osteoarthritis TO THE EDITOR: In their complex review of pharmacologic interventions for treatment of knee osteoarthritis, Bannuru and colleagues (1) reported that intra-articular (IA) hyaluronic acid had the highest effect size for relief of pain compared with oral placebo. That comparison is misleading, because the appropriate control for IA hyaluronic acid is IA placebo injection. Although the authors and the accompanying editorial (2) note that the apparent efficacy of hyaluronic acid may result from the stronger placebo effect of an injection, the comparison with oral placebo gives unwarranted credibility to the efficacy of hyaluronic acid and is subject to misinterpretation. For example, a commentary by a physician in an online medical newsletter (3) ignored the issue of placebo effects and questioned recommendations against the use of hyaluronic acid. Another online newsletter (4) cited the biggest benefit from hyaluronic acid and failed to consider data from other reviews and guidelines. The best evidence is that IA hyaluronic acid has no clinically meaningful benefit for knee osteoarthritis compared with IA placebo injection (5). Bannuru and colleagues' review provides no basis for reconsidering current guidelines. Despite the lack of evidence supporting its use, injections of hyaluronic acid for knee osteoarthritis are used widely. It is unfortunate that this review may be misquoted in other popular health media and advertisements as providing evidence for the benefits of this treatment.
Donald M. Marcus, MD Baylor College of Medicine Houston, Texas Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterest Forms.do?msNum=L15-0098. References 1. Bannuru RR, Schmid CH, Kent DM, Vaysbrot EE, Wong JB, McAlindon TE. Comparative effectiveness of pharmacologic interventions for knee osteoarthritis: a systematic review and network meta-analysis. Ann Intern Med. 2015; 162:46-54. [PMID: 25560713] doi:10.7326/M14-1231 2. Mandl LA, Losina E. Relative efficacy of knee osteoarthritis treatments: are all placebos created equal? [Editorial]. Ann Intern Med. 2015;162:71-2. [PMID: 25560716] doi:10.7326/M14-2636 3. Altman R. Next round on hyaluronic acid: better even than acetaminophen? MedPageToday. 22 January 2015. Accessed at www.medpagetoday.com /Rheumatology/Arthritis/49672 on 26 March 2015. 4. Norton A. Knee arthritis drugs beat placebos, but study finds no clear winner. HealthDay. 6 January 2015. Accessed at http://consumer.healthday.com /bone-and-joint-information-4/arthritis-drug-news-39/knee-arthritis-drugs-are -better-than-nothing-study-695188.html on 26 March 2015. 5. Rutjes AW, Ju¨ni P, da Costa BR, Trelle S, Nu¨esch E, Reichenbach S. Viscosupplementation for osteoarthritis of the knee: a systematic review and metaanalysis. Ann Intern Med. 2012;157:180-91. [PMID: 22868835] doi:10.7326 /0003-4819-157-3-201208070-00473
IN RESPONSE: We wholeheartedly agree that all articles
should be faithfully reported and not spun to meet marketing agendas. We concur that comparison of IA hyaluronic acid with IA placebo is scientifically valuable but also maintain that
comparison with oral placebo is valuable as well. Both comparisons give valid estimates of treatment effect— but with different meanings. The former measures an explanatory treatment effect that might better indicate the incremental effect due to the biological activity of hyaluronic acid over and above a (potentially) pharmacodynamically inactive saline injection. However, the latter gives a more pragmatic measure that is likely to better indicate the degree of relief that a patient will feel because it incorporates all modes of IA hyaluronic acid activity. For the purposes of comparative effectiveness research, we feel that comparison with oral placebo provides a better evidentiary basis for clinical decision making. Our network meta-analysis enabled us to estimate the comparative effectiveness of IA agents relative to oral agents and rank these effects in a clinically useful way (1). That the derived comparative effect may incorporate a component of a placebo response should prompt thought and discussion on how to reformulate the way we perceive its role in therapy and the practice of medicine. Therefore, we should give careful consideration to strongly recommending against therapeutic products that have good comparative effectiveness, especially for conditions for which alternatives are limited and often precluded by comorbid contraindications. These complexities may explain why consensus recommendations from various groups differ on such products as hyaluronic acid (2– 4). Raveendhara R. Bannuru, MD Center for Treatment Comparison and Integrative Analysis, Tufts Medical Center Boston, Massachusetts David M. Kent, MD Institute for Clinical Research and Health Policy Studies, Tufts Medical Center Boston, Massachusetts Timothy E. McAlindon, MD Center for Treatment Comparison and Integrative Analysis, Tufts Medical Center Boston, Massachusetts Disclosures: Disclosures can be viewed at www.acponline.org /authors/icmje/ConflictOfInterestForms.do?msNum=M14-1231. References 1. Bannuru RR, Schmid CH, Kent DM, Vaysbrot EE, Wong JB, McAlindon TE. Comparative effectiveness of pharmacologic interventions for knee osteoarthritis: a systematic review and network meta-analysis. Ann Intern Med. 2015; 162:46-54. [PMID: 25560713] doi:10.7326/M14-1231 2. Brown GA. AAOS clinical practice guideline: treatment of osteoarthritis of the knee: evidence-based guideline, 2nd edition. J Am Acad Orthop Surg. 2013;21:577-9. [PMID: 23996989] doi:10.5435/JAAOS-21-09-577 3. Hochberg MC, Altman RD, April KT, Benkhalti M, Guyatt G, McGowan J, et al; American College of Rheumatology. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res (Hoboken). 2012;64:465-74. [PMID: 22563589] 4. McAlindon TE, Bannuru RR, Sullivan MC, Arden NK, Berenbaum F, BiermaZeinstra SM, et al. OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthritis Cartilage. 2014;22:363-88. [PMID: 24462672] doi: 10.1016/j.joca.2014.01.003
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