Letters
Conflict of Interest Disclosures: None reported. 1. Ross MA, Aurora T, Graff L, et al. State of the art: emergency department observation units. Crit Pathw Cardiol. 2012;11(3):128-138.
Murray M. Finkelstein, PhD, MD
2. Sheehy AM, Graf B, Gangireddy S, et al. Hospitalized but not admitted: characteristics of patients with “observation status” at an academic medical center [published online July 8, 2013]. JAMA Intern Med. doi:10.1001 /jamainternmed.2013.8185.
Author Affiliation: Department of Family and Community Medicine, University of Toronto, Toronto, Ontario, Canada.
3. Ross MA, Compton S, Medado P, Fitzgerald M, Kilanowski P, O’Neil BJ. An emergency department diagnostic protocol for patients with transient ischemic attack: a randomized controlled trial. Ann Emerg Med. 2007;50(2):109-119.
Corresponding Author: Murray Finkelstein, PhD, MD, Granovsky-Gluskin Family Medicine Centre, Mt Sinai Hospital, Department of Family and Community Medicine, University of Toronto, 60 Murray St, Fourth Floor, Toronto, ON M5T 3L9, Canada ([email protected]).
4. Decker WW, Smars PA, Vaidyanathan L, et al. A prospective, randomized trial of an emergency department observation unit for acute onset atrial fibrillation. Ann Emerg Med. 2008;52(4):322-328.
Conflict of Interest Disclosures: None reported.
5. Department of Health and Human Services Office of Inspector General. Hospitals’ use of observation stays and short inpatient stays for medicare beneficiaries (report OEI-02-12-00040). July 29, 2013. http://oig.hhs.gov/oei /reports/oei-02-12-00040.asp. Accessed November 9, 2013.
1. Mansi I, Frei CR, Pugh MJ, Makris U, Mortensen EM. Statins and musculoskeletal conditions, arthropathies, and injuries. JAMA Intern Med. 2013;173(14):1318-1326. 2. Knol MJ, Le Cessie S, Algra A, Vandenbroucke JP, Groenwold RH. Overestimation of risk ratios by odds ratios in trials and cohort studies: alternatives to logistic regression. CMAJ. 2012;184(8):895-899. 3. Zhang J, Yu KF. What’s the relative risk? a method of correcting the odds ratio in cohort studies of common outcomes. JAMA. 1998;280(19):1690-1691.
Statins and Musculoskeletal Adverse Events To the Editor Mansi and colleagues1 have published an analysis of musculoskeletal conditions, arthropathies, and injuries among users and nonusers of statins. They reported higher adjusted odds ratios (ORs) for statin users in all outcome groups. Are their findings clinically significant? The OR is (Ps/1 − Ps)/(Pn/1 − Pn), where Ps is the probability of adverse outcomes in statin users and Pn is the probability in nonusers. The OR is not easy to interpret. More desirable for interpretative purposes is the relative risk (RR), Ps/ Pn. It may not be widely known to nonepidemiologists that the OR is a good approximation to the RR when the outcome is “rare” (80%), with a small but significant difference toward statin users. These unusual rates could be related to the type of the population (mainly active-duty soldiers and veterans) and/or the use of International Classification of Diseases, Ninth Revision, Clinical Modification codes that lack specificity and do not inform on the severity of the symptoms nor the need to stop therapy. The authors state that these findings are concerning owing to the use of statins in primary prevention in young and/or physically active patients. However, additional data analyses are needed to support such a general statement. For example, the reported adverse effects were obtained by simply grouping subjects into statin users or nonusers. This classification, correct from a mechanism of action perspective, is insensitive to differences of the safety profile of the 6 statins analyzed. This information would be needed to determine what effect statin type, dose, or other pharmacological properties has on the incidence of adverse effects, as we learned with cerivastatin. Increasing evidence has shown that musculoskeletal adverse effects depend on the dose, potency, and lipophilicity of the statin.2,3 Recently, the Food and Drug Administration recommended, after analyzing the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) trial and others, avoiding high-dose simvastatin treatment and required an addition to its label new contraindications (gemfibrozil) and interactions (amlodipine).4 Since 70% used simvastatin and 34% used maximal dose in this cohort, it would be important to test if the difference rates of adverse events are driven by patients on high-dose simvastatin, which is probably overrepresented according to current clinical practice.
JAMA Internal Medicine February 2014 Volume 174, Number 2
Copyright 2014 American Medical Association. All rights reserved.
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Letters
In addition, some studies have reported that lipophilicity, which modulates statin uptake in different tissues, hepatic metabolism, and drug interaction may explain differences in pleiotropic and adverse effects.2 Hydrophilic type of statins, especially with low potency such as pravastatin, may have a better risk profile and less muscle cytotoxicity and could eventually be safer in physically active patients.2,3,5 Thus, comparing muscle complaints by type of statin could also be informative. This suggested analysis may explain why statin use, when adjusted by cumulative equivalent dose, was not a significant predictor of the outcomes analyzed.
of statins and increases discussion between physicians and their patients about the known and potential benefits and risks of these drugs. Mitchell H. Katz, MD Rita F. Redberg, MD, MSc Author Affiliations: Department of Health Services, Los Angeles County, Los Angeles, California (Katz); Department of Medicine, University of California, San Francisco (Redberg). Corresponding Author: Mitchell H. Katz, MD, Department of Health Services, Los Angeles County, 313 N Figueroa St, Room 912, Los Angeles, CA 90012 ([email protected]). Conflict of Interest Disclosures: None reported.
Rene Baudrand, MD Gordon H. Williams, MD
1. Mansi I, Frei CR, Pugh MJ, Makris U, Mortensen EM. Statins and musculoskeletal conditions, arthropathies, and injuries. JAMA Intern Med. 2013;173(14):1318-1326.
Author Affiliations: Department of Endocrinology, Diabetes, and Hypertension, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts.
2. Taylor F, Ward K, Moore THM, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2011;(1):CD004816.
Corresponding Author: Rene Baudrand, MD, Department of Endocrinology, Diabetes, and Hypertension, Brigham and Women’s Hospital, Harvard Medical School, 221 Longwood Ave, Boston, MA 02115 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Mansi I, Frei CR, Pugh MJ, Makris U, Mortensen EM. Statins and musculoskeletal conditions, arthropathies, and injuries. JAMA Intern Med. 2013;173(14):1318-1326. 2. McClure DL, Valuck RJ, Glanz M, Hokanson JE. Systematic review and meta-analysis of clinically relevant adverse events from HMG CoA reductase inhibitor trials worldwide from 1982 to present. Pharmacoepidemiol Drug Saf. 2007;16(2):132-143. 3. Hoffman KB, Kraus C, Dimbil M, Golomb BA. A survey of the FDA’s AERS database regarding muscle and tendon adverse events linked to the statin drug class. PLoS One. 2012;7(8):e42866. 4. FDA Drug Safety Communication. New restrictions, contraindications, and dose limitations for Zocor (simvastatin) to reduce the risk of muscle injury. 2011. http://www.fda.gov/drugs/drugsafety/ucm256581.htm. Accessed June 25,2013. 5. Kobayashi M, Chisaki I, Narumi K, et al. Association between risk of myopathy and cholesterol-lowering effect: a comparison of all statins. Life Sci. 2008;82(17-18):969-975.
In Reply Dr Finkelstein asks that the Editor “advance the appropriate cautions” about the findings of Mansi et al, 1 showing higher rates of musculoskeletal conditions and pain in statin users. His concern is that an unintended consequence of the publication and its associated media coverage is that patients will stop using their medication and jeopardize their health. With publication of any article suggesting an adverse effect of a medication, there is a risk that patients will make an ill-considered decision to stop using a needed medication. However, we believe that patients and their physicians are best served by publication and discussion of adverse effects of medications. We agree that the results of any observational study, including this one, are subject to confounding. However, the study has the advantage of a large number subjects seen in a real-world setting. The recent Cochrane review of statins for primary prevention of cardiovascular disease concluded that “there was evidence of selective reporting of outcomes, and failure to report adverse events.”2 We hope that publication of this study serves to increase research on the adverse effects jamainternalmedicine.com
In Reply Dr Finkelstein argues that the increase in odds ratios (ORs) of musculoskeletal diseases in statin users may be attributable to imperfect propensity score matching. In addition to the propensity score–matched cohort, we examined the risk of outcomes in different cohorts (Table 2 of our article)1 including a whole population cohort, a no-comorbidity index cohort, a musculoskeletal incident cohort, and a 2-year statin cohort. Each of these cohorts included different populations who varied in baseline characteristics. We also used different definitions for musculoskeletal outcomes. Our results remained consistent throughout. Dr Finkelstein also questions the clinical significance of our findings. Our findings are clinically significant. First, we reported for the first time that statin use was associated with increased risk of dislocation/strain/sprain and maybe osteoarthritis. With the increasing call for patients to increase their physical activity, it would be ironic if we are prescribing at the same time medications that increase the risk of sport injury. Second, the number needed to harm for various outcomes ranged from 37 to 58, indicating its clinical significance, particularly in light of the call to extend statin use to young healthy patients in their 30s.2,3 Third, the increased risk of dislocation/ strain/sprain may carry specific relevance to some categories of patients. For example, such injuries may be life threatening for active duty soldiers in the battle field (active duty soldiers constituted 17% of our data source) or career ending for athletes. While we do not advocate for public policy change in all populations, we definitely caution the use of statins for primary prevention in young, healthy populations, where statins were not adequately tested for prolonged periods. Lastly, Dr Finkelstein worried that media-wide coverage of our article might encourage statins noncompliance. We believe that patients’ compliance should not be maintained through secrecy of medical research but through patientphysician dialogue and informed decisions. Drs Baudrand and Williams are concerned that associating statins with musculoskeletal adverse events lack specification. The factors that may be associated with musculoskeletal adverse events of statins are not fully elucidated.4 Our JAMA Internal Medicine February 2014 Volume 174, Number 2
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: by a University of Birmingham User on 12/25/2017
303
Letters
study cohort received different statins at different doses throughout the study period (2003-2010). Therefore, deciding which statin caused which adverse effect is problematic. In addition, the associations of statin use with increased risk of dislocation/strain/sprain and maybe osteoarthritis were not reported previously; we have no knowledge if these findings are related to a particular statin or to all statins as a group. Most statin observational studies have used time-to-event analysis. However, this approach is not suitable for our research questions; therefore, we looked at the cumulative incidence of outcomes at the follow-up period. Time-to-event analysis was not suitable for our research because the timeline of occurrence of statin-associated musculoskeletal adverse events outcomes is not known.4 In addition, the risk of some musculoskeletal outcomes may not be related to the timing of drug intake but rather to the timing of the event that lead to the diagnosis of this outcome. For example, an individual may be taking a statin for long time but joint dislocation occurred when he or she fell in a skiing event or during a hiking trip. Therefore, time-to-event analysis may be misleading. More research is needed to better elucidate the longterm relationship between statin use and musculoskeletal diseases. Ishak Mansi, MD Eric M. Mortensen, MD, MSc Christopher R. Frei, PharmD, MSc
To the Editor In their Research Letter, Kakkar and Jacobson1 report low patient viewership of an online instructional video describing colonoscopy preparation. Their analysis is significantly confounded by technical challenges with viewing the video. The authors mention that “[t]here were no technical problems reported by those instructed to watch the video, although we did not inquire as to why they did not view the video.”1(p1375) At the time of writing, the training video (at http: //www.bmc.org/digestivedisorders.htm) is provided as a “.wsx” file, which is not a valid file extension for any current video format. This video will not open in Windows Media Player (as the authors suggest) on any operating system, without being manually renamed to “.asf.” Only users accessing this site in Internet Explorer on Windows will have the filename automatically corrected to the “.asf” extension. It seems unlikely that other patients in the authors’ study had the technical wherewithal to determine the correct file format and rename the video accordingly. Nicholas P. Semenkovich, SB Author Affiliation: Center for Genome Sciences, Washington University School of Medicine in St Louis, St Louis, Missouri. Corresponding Author: Nicholas P. Semenkovich, SB, Center for Genome Sciences, Washington University School of Medicine in St Louis, 4444 Forest Park Ave, Room 5401, Campus Box 8510, St Louis, MO 63108 ([email protected]).
Author Affiliations: VA North Texas Health Care System, University of Texas Southwestern Medical Center, Dallas (Mansi, Mortensen); Department of Internal Medicine and Clinical Sciences, University of Texas Southwestern Medical Center, Dallas (Mansi, Mortensen); College of Pharmacy, The University of Texas at Austin, Austin (Frei); Pharmacotherapy Education and Research Center, School of Medicine, University of Texas Health Science Center, San Antonio (Frei).
Conflict of Interest Disclosures: None reported.
Corresponding Author: Ishak Mansi, MD, Department General Internal Medicine, Dallas VA Medical Center, 4500 S Lancaster, Ste 111E, Dallas, TX 75216 ([email protected]).
To the Editor The recent Research Letter by Kakkar and Jacobson1 shows yet another e-health intervention that failed to live up to the initial expectations. e-Health interventions are often portrayed as a method to revolutionize health care, leading to higher quality, lower costs, and better patient outcomes. However, actual results of e-health are somewhat disappointing, sometimes increasing costs.2 e-Health has weak evidence of effectiveness on patient outcomes and has consistently low uptake despite considerable implementation efforts.3,4 Does this mean that we should refrain from further investment in e-health? On the contrary, we believe that if we want to give e-health a fair chance, we should rethink the development process and increase investments in e-health. If we compare the development cycle of e-health to the development cycle of pharmaceuticals, we see that pharmaceuticals are often developed for decades,5 going through various stages of trial and error from preclinical stages to phase 0 to 3 trials, whereas e-health interventions are often developed and implemented in 1 stage within a few years. Currently, e-health interventions do not go through such a development process. e-Health interventions are not tested and retested, and investigators often rush to pragmatic trials including large and heterogeneous populations, which in turn makes finding an effect unlikely. e-Health interventions are thus evaluated for their effectiveness without sufficient knowledge of the efficacy.
Conflict of Interest Disclosures: Dr Frei was supported by the US National Institutes of Health (NIH) in the form of a NIH/KL2 career development award (RR025766) during this work. In addition, Dr Frei has received research grants and/or served as a scientific consultant/advisor for AstraZeneca, Bristol Myers Squibb, Elan, Forest, Ortho-McNeil Janssen, and Pfizer. No other disclosures were reported. Funding/Support: This material is the result of work supported with resources and the use of facilities at the Department of Veterans Affairs (VA) North Texas Health Care System. Role of the Sponsor: The VA healthcare system had no role in the preparation, review, or approval of the manuscript or the decision to submit the manuscript for publication. Disclaimer: The views expressed herein are those of the authors and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the Department of Veterans Affairs. Two of the authors are employees of the US government. 1. Mansi I, Frei CR, Pugh MJ, Makris U, Mortensen EM. Statins and musculoskeletal conditions, arthropathies, and injuries. JAMA Intern Med. 2013;173(14):1318-1326. 2. Steinberg D. Earlier intervention in the management of hypercholesterolemia: what are we waiting for? J Am Coll Cardiol. 2010;56(8):627-629. 3. Forrester JS. Redefining normal low-density lipoprotein cholesterol: a strategy to unseat coronary disease as the nation’s leading killer. J Am Coll Cardiol. 2010;56(8):630-636. 4. Mansi I, Mortensen E. The controversy of a wider statin utilization: why? Expert Opin Drug Saf. 2013;12(3):327-337. 304
Technical Difficulties and Evaluating e-Health Interventions
1. Kakkar A, Jacobson BC. Failure of an Internet-based health care intervention for colonoscopy preparation: a caveat for investigators. JAMA Intern Med. 2013;173(14):1374-1376.
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Conflict of Interest Disclosures: None reported. 1. Ross MA, Aurora T, Graff L, et al. State of the art: emergency department observation units. Crit Pathw Cardiol. 2012;11(3):128-138.
Murray M. Finkelstein, PhD, MD
2. Sheehy AM, Graf B, Gangireddy S, et al. Hospitalized but not admitted: characteristics of patients with “observation status” at an academic medical center [published online July 8, 2013]. JAMA Intern Med. doi:10.1001 /jamainternmed.2013.8185.
Author Affiliation: Department of Family and Community Medicine, University of Toronto, Toronto, Ontario, Canada.
3. Ross MA, Compton S, Medado P, Fitzgerald M, Kilanowski P, O’Neil BJ. An emergency department diagnostic protocol for patients with transient ischemic attack: a randomized controlled trial. Ann Emerg Med. 2007;50(2):109-119.
Corresponding Author: Murray Finkelstein, PhD, MD, Granovsky-Gluskin Family Medicine Centre, Mt Sinai Hospital, Department of Family and Community Medicine, University of Toronto, 60 Murray St, Fourth Floor, Toronto, ON M5T 3L9, Canada ([email protected]).
4. Decker WW, Smars PA, Vaidyanathan L, et al. A prospective, randomized trial of an emergency department observation unit for acute onset atrial fibrillation. Ann Emerg Med. 2008;52(4):322-328.
Conflict of Interest Disclosures: None reported.
5. Department of Health and Human Services Office of Inspector General. Hospitals’ use of observation stays and short inpatient stays for medicare beneficiaries (report OEI-02-12-00040). July 29, 2013. http://oig.hhs.gov/oei /reports/oei-02-12-00040.asp. Accessed November 9, 2013.
1. Mansi I, Frei CR, Pugh MJ, Makris U, Mortensen EM. Statins and musculoskeletal conditions, arthropathies, and injuries. JAMA Intern Med. 2013;173(14):1318-1326. 2. Knol MJ, Le Cessie S, Algra A, Vandenbroucke JP, Groenwold RH. Overestimation of risk ratios by odds ratios in trials and cohort studies: alternatives to logistic regression. CMAJ. 2012;184(8):895-899. 3. Zhang J, Yu KF. What’s the relative risk? a method of correcting the odds ratio in cohort studies of common outcomes. JAMA. 1998;280(19):1690-1691.
Statins and Musculoskeletal Adverse Events To the Editor Mansi and colleagues1 have published an analysis of musculoskeletal conditions, arthropathies, and injuries among users and nonusers of statins. They reported higher adjusted odds ratios (ORs) for statin users in all outcome groups. Are their findings clinically significant? The OR is (Ps/1 − Ps)/(Pn/1 − Pn), where Ps is the probability of adverse outcomes in statin users and Pn is the probability in nonusers. The OR is not easy to interpret. More desirable for interpretative purposes is the relative risk (RR), Ps/ Pn. It may not be widely known to nonepidemiologists that the OR is a good approximation to the RR when the outcome is “rare” (80%), with a small but significant difference toward statin users. These unusual rates could be related to the type of the population (mainly active-duty soldiers and veterans) and/or the use of International Classification of Diseases, Ninth Revision, Clinical Modification codes that lack specificity and do not inform on the severity of the symptoms nor the need to stop therapy. The authors state that these findings are concerning owing to the use of statins in primary prevention in young and/or physically active patients. However, additional data analyses are needed to support such a general statement. For example, the reported adverse effects were obtained by simply grouping subjects into statin users or nonusers. This classification, correct from a mechanism of action perspective, is insensitive to differences of the safety profile of the 6 statins analyzed. This information would be needed to determine what effect statin type, dose, or other pharmacological properties has on the incidence of adverse effects, as we learned with cerivastatin. Increasing evidence has shown that musculoskeletal adverse effects depend on the dose, potency, and lipophilicity of the statin.2,3 Recently, the Food and Drug Administration recommended, after analyzing the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) trial and others, avoiding high-dose simvastatin treatment and required an addition to its label new contraindications (gemfibrozil) and interactions (amlodipine).4 Since 70% used simvastatin and 34% used maximal dose in this cohort, it would be important to test if the difference rates of adverse events are driven by patients on high-dose simvastatin, which is probably overrepresented according to current clinical practice.
JAMA Internal Medicine February 2014 Volume 174, Number 2
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: by a University of Birmingham User on 12/25/2017
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Letters
In addition, some studies have reported that lipophilicity, which modulates statin uptake in different tissues, hepatic metabolism, and drug interaction may explain differences in pleiotropic and adverse effects.2 Hydrophilic type of statins, especially with low potency such as pravastatin, may have a better risk profile and less muscle cytotoxicity and could eventually be safer in physically active patients.2,3,5 Thus, comparing muscle complaints by type of statin could also be informative. This suggested analysis may explain why statin use, when adjusted by cumulative equivalent dose, was not a significant predictor of the outcomes analyzed.
of statins and increases discussion between physicians and their patients about the known and potential benefits and risks of these drugs. Mitchell H. Katz, MD Rita F. Redberg, MD, MSc Author Affiliations: Department of Health Services, Los Angeles County, Los Angeles, California (Katz); Department of Medicine, University of California, San Francisco (Redberg). Corresponding Author: Mitchell H. Katz, MD, Department of Health Services, Los Angeles County, 313 N Figueroa St, Room 912, Los Angeles, CA 90012 ([email protected]). Conflict of Interest Disclosures: None reported.
Rene Baudrand, MD Gordon H. Williams, MD
1. Mansi I, Frei CR, Pugh MJ, Makris U, Mortensen EM. Statins and musculoskeletal conditions, arthropathies, and injuries. JAMA Intern Med. 2013;173(14):1318-1326.
Author Affiliations: Department of Endocrinology, Diabetes, and Hypertension, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts.
2. Taylor F, Ward K, Moore THM, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2011;(1):CD004816.
Corresponding Author: Rene Baudrand, MD, Department of Endocrinology, Diabetes, and Hypertension, Brigham and Women’s Hospital, Harvard Medical School, 221 Longwood Ave, Boston, MA 02115 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Mansi I, Frei CR, Pugh MJ, Makris U, Mortensen EM. Statins and musculoskeletal conditions, arthropathies, and injuries. JAMA Intern Med. 2013;173(14):1318-1326. 2. McClure DL, Valuck RJ, Glanz M, Hokanson JE. Systematic review and meta-analysis of clinically relevant adverse events from HMG CoA reductase inhibitor trials worldwide from 1982 to present. Pharmacoepidemiol Drug Saf. 2007;16(2):132-143. 3. Hoffman KB, Kraus C, Dimbil M, Golomb BA. A survey of the FDA’s AERS database regarding muscle and tendon adverse events linked to the statin drug class. PLoS One. 2012;7(8):e42866. 4. FDA Drug Safety Communication. New restrictions, contraindications, and dose limitations for Zocor (simvastatin) to reduce the risk of muscle injury. 2011. http://www.fda.gov/drugs/drugsafety/ucm256581.htm. Accessed June 25,2013. 5. Kobayashi M, Chisaki I, Narumi K, et al. Association between risk of myopathy and cholesterol-lowering effect: a comparison of all statins. Life Sci. 2008;82(17-18):969-975.
In Reply Dr Finkelstein asks that the Editor “advance the appropriate cautions” about the findings of Mansi et al, 1 showing higher rates of musculoskeletal conditions and pain in statin users. His concern is that an unintended consequence of the publication and its associated media coverage is that patients will stop using their medication and jeopardize their health. With publication of any article suggesting an adverse effect of a medication, there is a risk that patients will make an ill-considered decision to stop using a needed medication. However, we believe that patients and their physicians are best served by publication and discussion of adverse effects of medications. We agree that the results of any observational study, including this one, are subject to confounding. However, the study has the advantage of a large number subjects seen in a real-world setting. The recent Cochrane review of statins for primary prevention of cardiovascular disease concluded that “there was evidence of selective reporting of outcomes, and failure to report adverse events.”2 We hope that publication of this study serves to increase research on the adverse effects jamainternalmedicine.com
In Reply Dr Finkelstein argues that the increase in odds ratios (ORs) of musculoskeletal diseases in statin users may be attributable to imperfect propensity score matching. In addition to the propensity score–matched cohort, we examined the risk of outcomes in different cohorts (Table 2 of our article)1 including a whole population cohort, a no-comorbidity index cohort, a musculoskeletal incident cohort, and a 2-year statin cohort. Each of these cohorts included different populations who varied in baseline characteristics. We also used different definitions for musculoskeletal outcomes. Our results remained consistent throughout. Dr Finkelstein also questions the clinical significance of our findings. Our findings are clinically significant. First, we reported for the first time that statin use was associated with increased risk of dislocation/strain/sprain and maybe osteoarthritis. With the increasing call for patients to increase their physical activity, it would be ironic if we are prescribing at the same time medications that increase the risk of sport injury. Second, the number needed to harm for various outcomes ranged from 37 to 58, indicating its clinical significance, particularly in light of the call to extend statin use to young healthy patients in their 30s.2,3 Third, the increased risk of dislocation/ strain/sprain may carry specific relevance to some categories of patients. For example, such injuries may be life threatening for active duty soldiers in the battle field (active duty soldiers constituted 17% of our data source) or career ending for athletes. While we do not advocate for public policy change in all populations, we definitely caution the use of statins for primary prevention in young, healthy populations, where statins were not adequately tested for prolonged periods. Lastly, Dr Finkelstein worried that media-wide coverage of our article might encourage statins noncompliance. We believe that patients’ compliance should not be maintained through secrecy of medical research but through patientphysician dialogue and informed decisions. Drs Baudrand and Williams are concerned that associating statins with musculoskeletal adverse events lack specification. The factors that may be associated with musculoskeletal adverse events of statins are not fully elucidated.4 Our JAMA Internal Medicine February 2014 Volume 174, Number 2
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: by a University of Birmingham User on 12/25/2017
303
Letters
study cohort received different statins at different doses throughout the study period (2003-2010). Therefore, deciding which statin caused which adverse effect is problematic. In addition, the associations of statin use with increased risk of dislocation/strain/sprain and maybe osteoarthritis were not reported previously; we have no knowledge if these findings are related to a particular statin or to all statins as a group. Most statin observational studies have used time-to-event analysis. However, this approach is not suitable for our research questions; therefore, we looked at the cumulative incidence of outcomes at the follow-up period. Time-to-event analysis was not suitable for our research because the timeline of occurrence of statin-associated musculoskeletal adverse events outcomes is not known.4 In addition, the risk of some musculoskeletal outcomes may not be related to the timing of drug intake but rather to the timing of the event that lead to the diagnosis of this outcome. For example, an individual may be taking a statin for long time but joint dislocation occurred when he or she fell in a skiing event or during a hiking trip. Therefore, time-to-event analysis may be misleading. More research is needed to better elucidate the longterm relationship between statin use and musculoskeletal diseases. Ishak Mansi, MD Eric M. Mortensen, MD, MSc Christopher R. Frei, PharmD, MSc
To the Editor In their Research Letter, Kakkar and Jacobson1 report low patient viewership of an online instructional video describing colonoscopy preparation. Their analysis is significantly confounded by technical challenges with viewing the video. The authors mention that “[t]here were no technical problems reported by those instructed to watch the video, although we did not inquire as to why they did not view the video.”1(p1375) At the time of writing, the training video (at http: //www.bmc.org/digestivedisorders.htm) is provided as a “.wsx” file, which is not a valid file extension for any current video format. This video will not open in Windows Media Player (as the authors suggest) on any operating system, without being manually renamed to “.asf.” Only users accessing this site in Internet Explorer on Windows will have the filename automatically corrected to the “.asf” extension. It seems unlikely that other patients in the authors’ study had the technical wherewithal to determine the correct file format and rename the video accordingly. Nicholas P. Semenkovich, SB Author Affiliation: Center for Genome Sciences, Washington University School of Medicine in St Louis, St Louis, Missouri. Corresponding Author: Nicholas P. Semenkovich, SB, Center for Genome Sciences, Washington University School of Medicine in St Louis, 4444 Forest Park Ave, Room 5401, Campus Box 8510, St Louis, MO 63108 ([email protected]).
Author Affiliations: VA North Texas Health Care System, University of Texas Southwestern Medical Center, Dallas (Mansi, Mortensen); Department of Internal Medicine and Clinical Sciences, University of Texas Southwestern Medical Center, Dallas (Mansi, Mortensen); College of Pharmacy, The University of Texas at Austin, Austin (Frei); Pharmacotherapy Education and Research Center, School of Medicine, University of Texas Health Science Center, San Antonio (Frei).
Conflict of Interest Disclosures: None reported.
Corresponding Author: Ishak Mansi, MD, Department General Internal Medicine, Dallas VA Medical Center, 4500 S Lancaster, Ste 111E, Dallas, TX 75216 ([email protected]).
To the Editor The recent Research Letter by Kakkar and Jacobson1 shows yet another e-health intervention that failed to live up to the initial expectations. e-Health interventions are often portrayed as a method to revolutionize health care, leading to higher quality, lower costs, and better patient outcomes. However, actual results of e-health are somewhat disappointing, sometimes increasing costs.2 e-Health has weak evidence of effectiveness on patient outcomes and has consistently low uptake despite considerable implementation efforts.3,4 Does this mean that we should refrain from further investment in e-health? On the contrary, we believe that if we want to give e-health a fair chance, we should rethink the development process and increase investments in e-health. If we compare the development cycle of e-health to the development cycle of pharmaceuticals, we see that pharmaceuticals are often developed for decades,5 going through various stages of trial and error from preclinical stages to phase 0 to 3 trials, whereas e-health interventions are often developed and implemented in 1 stage within a few years. Currently, e-health interventions do not go through such a development process. e-Health interventions are not tested and retested, and investigators often rush to pragmatic trials including large and heterogeneous populations, which in turn makes finding an effect unlikely. e-Health interventions are thus evaluated for their effectiveness without sufficient knowledge of the efficacy.
Conflict of Interest Disclosures: Dr Frei was supported by the US National Institutes of Health (NIH) in the form of a NIH/KL2 career development award (RR025766) during this work. In addition, Dr Frei has received research grants and/or served as a scientific consultant/advisor for AstraZeneca, Bristol Myers Squibb, Elan, Forest, Ortho-McNeil Janssen, and Pfizer. No other disclosures were reported. Funding/Support: This material is the result of work supported with resources and the use of facilities at the Department of Veterans Affairs (VA) North Texas Health Care System. Role of the Sponsor: The VA healthcare system had no role in the preparation, review, or approval of the manuscript or the decision to submit the manuscript for publication. Disclaimer: The views expressed herein are those of the authors and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the Department of Veterans Affairs. Two of the authors are employees of the US government. 1. Mansi I, Frei CR, Pugh MJ, Makris U, Mortensen EM. Statins and musculoskeletal conditions, arthropathies, and injuries. JAMA Intern Med. 2013;173(14):1318-1326. 2. Steinberg D. Earlier intervention in the management of hypercholesterolemia: what are we waiting for? J Am Coll Cardiol. 2010;56(8):627-629. 3. Forrester JS. Redefining normal low-density lipoprotein cholesterol: a strategy to unseat coronary disease as the nation’s leading killer. J Am Coll Cardiol. 2010;56(8):630-636. 4. Mansi I, Mortensen E. The controversy of a wider statin utilization: why? Expert Opin Drug Saf. 2013;12(3):327-337. 304
Technical Difficulties and Evaluating e-Health Interventions
1. Kakkar A, Jacobson BC. Failure of an Internet-based health care intervention for colonoscopy preparation: a caveat for investigators. JAMA Intern Med. 2013;173(14):1374-1376.
JAMA Internal Medicine February 2014 Volume 174, Number 2
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