rospective studies, which have been inconclusive regarding the effect of preoperative psychological factors. These findings may be useful in developing strategies for preventing persistent pain following breast cancer treatment. To identify patients who would benefit from preventive interventions, a risk assessment tool is needed. We used the first half of the patients of the current cohort to develop a 6-factor model for pain at 6 months.6 However, the 6-factor model did not include any treatment-related factors. A limitation of the study is that we did not perform a detailed clinical investigation at 1 year to diagnose the type of persistent pain.

3. Spielberger CD, Gorsuch RL, Lushene PR, et al. Manual for the State-Trait Anxiety Inventory (Form Y). Palo Alto, CA: Consulting Psychologists Press; 1983. 4. Dworkin RH, Turk DC, Farrar JT, et al. Core outcome measures for chronic pain clinical trials: IMMPACT recommendations. Pain. 2005;113(1-2):9-19. 5. Goldhirsch A, Wood WC, Gelber RD, et al. Progress and promise: highlights of the international expert consensus on the primary therapy of early breast cancer 2007. Ann Oncol. 2007;18(7):1133-1144. 6. Sipilä R, Estlander AM, Tasmuth T, et al. Development of a screening instrument for risk factors of persistent pain after breast cancer surgery. Br J Cancer. 2012;107(9):1459-1466.


Combination Pill for Cardiovascular Disease Tuomo J. Meretoja, MD, PhD Marjut H. K. Leidenius, MD, PhD Tiina Tasmuth, MD, PhD Reetta Sipilä, MPsych Eija Kalso, MD, PhD Author Affiliations: Breast Surgery Unit, Helsinki University Central Hospital, Helsinki, Finland (Meretoja, Leidenius); Department of Oncology, Helsinki University Central Hospital (Tasmuth); Department of Anaesthesia, Intensive Care Medicine, Emergency Medicine and Pain Medicine, Helsinki University Central Hospital (Sipilä, Kalso). Corresponding Author: Tuomo J. Meretoja, Helsinki University Central Hospital, PO Box 140, FI-00029 HUS, Finland ([email protected]). Author Contributions: Dr Meretoja had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Leidenius, Tasmuth, Kalso. Acquisition of data: Leidenius, Tasmuth, Kalso. Analysis and interpretation of data: Meretoja, Leidenius, Tasmuth, Sipilä, Kalso. Drafting of the manuscript: Meretoja, Leidenius, Kalso. Critical revision of the manuscript for important intellectual content: Meretoja, Leidenius, Tasmuth, Sipilä, Kalso. Statistical analysis: Meretoja. Obtained funding: Meretoja, Kalso. Administrative, technical, or material support: Tasmuth, Kalso. Study supervision: Kalso. Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Kalso reported serving as a consultant to Pharmaleads and Orion Pharma; receiving payment for lectures from Pfizer, Mundipharma, Jansen-Cilag, Merck Sharp Dohme, Gruenental, and Orion Pharma; holding patents with Orion Pharma and Licentia (formerly the University of Helsinki patent office); receiving payment for the development of educational presentations from Jansen-Cilag and Gruenenthal; and owning stock in Orion Pharma. Funding/Support: This work was supported by grants from the Academy of Finland and Helsinki and Uusimaa Hospital District and by funding from the Orion-Pharmos Research Foundation and the Emil Aaltonen Foundation. Role of the Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Additional Contributions: We also thank Eija R. Ruoppa, RN, and Minna Kaiponen, RN (Department of Anaesthesia, Intensive care Medicine, Emergency Medicine and Pain Medicine, Helsinki University Central Hospital), and the nurses, physicians, and physiotherapists who participated in the treatment and recruitment of the patients. We are grateful to the patients who participated in this study and diligently returned several questionnaires. The persons named were not compensated for study assistance beyond their salaries. 1. Gärtner R, Jensen MB, Nielsen J, et al. Prevalence of and factors associated with persistent pain following breast cancer surgery. JAMA. 2009;302(18): 1985-1992. 2. Beck AT, Ward CH, Mendelson M, et al. An inventory for measuring depression. Arch Gen Psychiatry. 1961;4:561-571.


To the Editor The Use of a Multi-drug Pill in Reducing Cardiovascular Events (UMPIRE) trial1 assessed the effects of longterm use of a fixed-dose combination (FDC) containing antiplatelet, statin, and antihypertensive drugs compared with usual care in patients with or at high risk of cardiovascular disease. Although this study yielded many important findings on FDC use, the results should be interpreted carefully. The FDC group had better adherence than the usual care group; this is important because many studies have proven the efficacy of aspirin use for the secondary prevention of cardiovascular events.2,3 However, we believe that the assessments of systolic blood pressure (SBP), diastolic blood pressure (DBP), and low-density lipoprotein cholesterol (LDL-C) were misleading. Achievement of the target value for these parameters is more important than changes in the values. Although a significant decrease in SBP and DBP in the FDC group compared with the usual care group was observed at the end of the study (−2.6 mm Hg and −2.5 mm Hg, respectively), SBP and DBP at the end of the study in the latter group were 131.7 mm Hg and 75.2 mm Hg, respectively. Therefore, blood pressure control in the usual care group might be sufficiently good, and further reductions might not be required.4 In addition, although a significant difference in LDL-C level between the FDC and usual care groups was observed (84.2 and 88.4 mg/dL, respectively), the achievement of the target LDL-C level might not be significantly different between these groups.5 Therefore, the reductions with FDC use may have no clinical benefits. Moreover, the 15-month follow-up was not sufficiently long. The creatinine levels at the end of the study were significantly higher in the FDC group than in the usual care group, which may be one of the disadvantages of FDC use. Because renal function could worsen with time, additional problems such as electrolyte abnormalities may limit FDC use in the longterm. Further research is required to reveal the effectiveness of FDC use. Tetsuro Tsujimoto, MD Ritsuko Yamamoto-Honda, MD, PhD Author Affiliations: Department of Diabetes and Metabolic Medicine, National Center for Global Health and Medicine, Tokyo, Japan. Corresponding Author: Tetsuro Tsujimoto, MD, National Center for Global Health and Medicine, Toyama 1-21-1, Shinjuku-ku, Tokyo 162-8655, Japan ([email protected]).

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Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

2. Feldman SR, Camacho FT, Krejci-Manwaring J, Carroll CL, Balkrishnan R. Adherence to topical therapy increases around the time of office visits. J Am Acad Dermatol. 2007;57(1):81-83.

1. Thom S, Poulter N, Field J, et al; UMPIRE Collaborative Group. Effects of a fixed-dose combination strategy on adherence and risk factors in patients with or at high risk of CVD: the UMPIRE randomized clinical trial [published correction appears in JAMA. 2013;310(14):1507]. JAMA. 2013;310(9):918-929.

3. Soliman EZ, Mendis S, Dissanayake WP, et al. A polypill for primary prevention of cardiovascular disease: a feasibility study of the World Health Organization. Trials. 2011;12:3.

2. Berger JS, Brown DL, Becker RC. Low-dose aspirin in patients with stable cardiovascular disease: a meta-analysis. Am J Med. 2008;121(1):43-49. 3. Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;324(7329):71-86. 4. Cushman WC, Evans GW, Byington RP, et al; ACCORD Study Group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362(17):1575-1585. 5. Wilt TJ, Bloomfield HE, MacDonald R, et al. Effectiveness of statin therapy in adults with coronary heart disease. Arch Intern Med. 2004;164(13):1427-1436.

To the Editor Dr Thom and colleagues1 addressed medication adherence by analyzing the effects of an FDC pill for patients with or at high risk of cardiovascular disease. Thom et al1 assessed participants at 6-month intervals for a minimum of 12 months up to a maximum of 24 months from the initial intervention. Adherence was addressed by self-report in the week prior to each of these visits. Thus, for participants assessed at all end points, adherence was evaluated for a maximum of 5 weeks out of a total 104 weeks of enrollment. Although the authors stated that the modest improvement in SBP and LDL-C level justified this method, failure to include data on medication adherence throughout the entire study period may have biased the results toward a more favorable outcome. White coat compliance, which is the tendency of patients to take medications closer to their physician office visits, is a well-documented phenomenon and could have affected the results of this study. Feldman et al2 assessed adherence to topical medications in relation to office visits, with results supporting better adherence during periods closer to physician appointments. Thom et al1 could have used pill counts instead to assess adherence. Soliman et al3 used both pill counts and selfreported adherence to determine use of a polypill. Antihypertensive medication adherence was also assessed using pill counts in research by Adeyemo et al.4 Pill counts offer a more objective measurement of adherence than the subjective assessment of patient reports. Thom et al1 could have used pill counts to assess not only the whole treatment period but also to eliminate variability in patient reporting. Michelle Carey, PharmD Author Affiliation: Family Medicine Pharmacy Residency Program, ProMedica Toledo Hospital, Toledo, Ohio. Corresponding Author: Michelle Carey, PharmD, ProMedica Toledo Hospital, 2051 W Central Ave, Toledo, OH 43606 ([email protected]).

4. Adeyemo A, Tayo BO, Luke A, Ogedegbe O, Durazo-Arvizu R, Cooper RS. The Nigerian antihypertensive adherence trial: a community-based randomized trial. J Hypertens. 2013;31(1):201-207.

In Reply Drs Tsujimoto and Yamamoto-Honda note that improvements in adherence are of benefit in terms of increasing uptake of proven antiplatelet therapy, but question the importance of the improvements in mean LDL-C level and SBP. In contrast to their suggestion, in high-risk cardiovascular patients there is clear evidence of benefits of blood pressure lowering in patients without hypertension and of more vs less blood pressure lowering1-3; similarly, there are benefits of LDL-C level lowering in patients without hyperlipidemia and of more vs less LDL-C level lowering.4,5 In our trial setting, focusing on hypertension and dyslipidemia thresholds as a treatment outcome was not ideal. Nonetheless, there were significant increases in the rate of hypertension control (defined as SBP

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