Letters COMMENTS

AND

Annals of Internal Medicine RESPONSES

Personalized Estimates of Benefit From Preventive Care Guidelines TO THE EDITOR: We read Taksler and colleagues’ article (1) with

great interest. Prioritization of preventive interventions for patients with comorbid conditions via a mathematical model is interesting and practical (1, 2) and is more appropriate when taking the patient’s preferences and expectations into account. Prioritization might be an alternative to the total cardiovascular risk approach (for example, the Framingham Risk Score and the Systematic Coronary Risk Evaluation risk chart). In most people, atherosclerotic cardiovascular disease is the product of many risk factors (3) and interaction may play an important role. As such, we were surprised that the legend of Figure 2 states that “adherence to several recommendations may change life expectancy by less than the sum of individual recommendations.” In this context, we cannot agree with this statement because it is not scientifically proven and one could intuitively assume that the reverse seems even more possible, namely, that adherence to more recommendations may change life expectancy by more than the sum of individual recommendations. Furthermore, we must not forget that the most effective approaches have been shown to be multilevel—targeting more than 1 factor with more than 1 intervention (3, 4). A single-factor approach might be expected to have limited effectiveness if the factors determining adherence interact and potentiate each other’s influence, which they are likely to do (3). Aside from these comments, the shift of focus from the population burden of preventable morbidity and mortality to individual priorities makes this article very refreshing. Jan Matthys, MD University of Ghent, University Hospital Ghent, Belgium Potential Conflicts of Interest: None disclosed.

References 1. Taksler GB, Keshner M, Fagerlin A, Hajizadeh N, Braithwaite RS. Personalized estimates of benefit from preventive care guidelines: a proof of concept. Ann Intern Med. 2013;159:161-8. [PMID: 23922061] 2. Owens DK, Goldhaber-Fiebert JD. Prioritizing guideline-recommended interventions [Editorial]. Ann Intern Med. 2013;159:223-4. [PMID: 23922066] 3. Reiner Z, Catapano AL, De Backer G, Graham I, Taskinen MR, Wiklund O, et al; European Association for Cardiovascular Prevention & Rehabilitation. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J. 2011;32:1769-818. [PMID: 21712404] 4. Wood DA, Kotseva K, Connolly S, Jennings C, Mead A, Jones J, et al; EUROACTION Study Group. Nurse-coordinated multidisciplinary, family-based cardiovascular disease prevention programme (EUROACTION) for patients with coronary heart disease and asymptomatic individuals at high risk of cardiovascular disease: a paired, cluster-randomised controlled trial. Lancet. 2008;371:1999-2012. [PMID: 18555911] 140 © 2014 American College of Physicians

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IN RESPONSE: We agree with Dr. Matthys that combinations of interventions may have synergies (that is, greater-than-additive effects) when delivered together, which the editorial that accompanied our article also mentioned (1). We chose cautious language because combinations of interventions may confer not only greater-thanadditive effects but also less-than-additive effects.

Glen B. Taksler, PhD R. Scott Braithwaite, MD, MSc New York University School of Medicine New York, New York Potential Conflicts of Interest: Disclosures can be viewed at

www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum ⫽M12-2938. Reference 1. Owens DK, Goldhaber-Fiebert JD. Prioritizing guideline-recommended interventions [Editorial]. Ann Intern Med. 2013;159:223-4. [PMID: 23922066]

Absolute Systolic Ankle Blood Pressure Versus Ankle–Brachial Index TO THE EDITOR: I read McDermott’s editorial (1) with great inter-

est. It might be a global imperative to conduct “a definitive randomized, controlled trial” to determine whether absolute systolic ankle blood pressure screening independent of systolic brachial blood pressure improves health outcomes in persons at risk for peripheral artery disease and cardiovascular disease. Peripheral artery disease can be defined by an abnormally low or high ankle– brachial index (ABI), and both increase cardiovascular mortality. Most studies define peripheral artery disease by an ABI less than 0.9. An ABI does not discriminate between the independent predictive values of systolic ankle blood pressure and systolic brachial blood pressure, and these might differ in ethnically diverse populations. Although the benefits of screening for and treating high blood pressure in adults is established, the U.S. Preventive Services Task Force’s screening recommendations based on a threshold of the systolic brachial blood pressure miss more than one half of those who have undiagnosed diabetes (2). Increased systolic ankle blood pressure is associated with diabetes and higher hazard ratios for fatal and nonfatal cardiovascular events in Europeans (3, 4). South Asians (more than a billion persons globally) continue to have increasing rates of visceral obesity, diabetes, and cardiovascular mortality at a younger age, but the prevalence of hypertension and its association with cardiovascular disease in this population do not significantly differ from those of Europeans. The prevalence of an ABI less than 0.9 is decreased in South Asians with or without diabetes, but systolic ankle blood pressure increases with diabetes; this increase, along with the association with cardiovascular disease, is greater in South Asians than in Europeans (5). Therefore, in certain populations, the value of increased systolic ankle blood pressure (as one of the earliest signs of subclinical atherosclerosis) might be greater than that of increased systolic brachial blood pressure at a relatively younger age with short lifetime exposure to risk factors. If the predictive value for diabetes and cardiovascular disease in a South Asian population is confirmed, then increased absolute systolic ankle blood pressure can be used as a noninvasive, economical,

Letters and simple primary prevention screening tool for apparently healthy South Asians to reduce cardiovascular morbidity and mortality. Chronic diseases have increasing public health implications globally, and we should focus on prevention more during hard economic times. Moreover, developing countries have to deal with the expense of managing infectious diseases and the complications of chronic diseases. Kirti Kain, MD University of Leeds Leeds, United Kingdom Potential Conflicts of Interest: None disclosed. Forms can be viewed at

www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum ⫽L13-1071. References 1. McDermott MM. Ankle-brachial index screening to improve health outcomes: where is the evidence? [Editorial]. Ann Intern Med. 2013;159:362-3. [PMID: 24026321] 2. Casagrande SS, Cowie CC, Fradkin JE. Utility of the U.S. Preventive Services Task Force criteria for diabetes screening. Am J Prev Med. 2013;45:167-74. [PMID: 23867023] 3. Hietanen H, Pa¨a¨kko¨nen R, Salomaa V. Ankle and exercise blood pressures as predictors of coronary morbidity and mortality in a prospective follow-up study. J Hum Hypertens. 2010;24:577-84. [PMID: 20090773] 4. Sutton-Tyrrell K, Venkitachalam L, Kanaya AM, Boudreau R, Harris T, Thompson T, et al. Relationship of ankle blood pressures to cardiovascular events in older adults. Stroke. 2008;39:863-9. [PMID: 18258843] 5. Kain K, Brockway M, Ishfaq T, Merrick M, Mahmood H, Ingoe JC, et al. Ankle pressures in UK South Asians with diabetes mellitus: a case control study. Heart. 2013;99:614-9. [PMID: 23442538]

IN RESPONSE: First, Dr. Kain expresses concern that the ABI, a ratio of Doppler-recorded systolic pressures in the ankle and brachial arteries, does not distinguish between the independent predictive values of the systolic ankle and the systolic brachial blood pressures. However, because the ABI calculation requires measurement of the ankle and the brachial systolic pressures, previous prospective studies relating the ABI to subsequent cardiovascular events and mortality can separately analyze the independent predictive value of the systolic ankle and brachial blood pressures for cardiovascular events and mortality. For example, a meta-analysis relating the ABI to cardiovascular events and mortality included 16 prospective studies, 48 295 participants, and 480 325 person-years of follow-up (1). This metaanalysis alone provides a robust opportunity to evaluate the relative independent associations of the ABI, ankle systolic pressure, and brachial systolic pressure with cardiovascular events and mortality. Second, Dr. Kain states that systolic blood pressure screening fails to identify more than one half of persons with undiagnosed diabetes. She implies that measuring the ankle systolic pressure may identify more persons with this condition. Although Dr. Kain may be correct that an increased ankle systolic pressure is more sensitive for identifying diabetes than an increased brachial systolic pressure, neither test is likely to achieve optimal sensitivity as a diagnostic test for diabetes. For example, in MESA (Multi-Ethnic Study of Atherosclerosis), most of the men and women with diabetes mellitus did not have an ABI of 1.30 or higher, consistent with a high ankle pressure. Although further study is needed, these and other data www.annals.org

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suggest that most persons with diabetes mellitus do not have increased ankle pressure (2, 3). Third, given the high rate of diabetes and cardiovascular disease in South Asians (4), early diagnosis, treatment, and prevention of diabetes and cardiovascular disease in this population are public health imperatives. However, relatively little is currently known about the utility of screening systolic ankle blood pressure for identifying persons at high risk for cardiovascular events and preventing adverse outcomes. Dr. Kain and colleagues’ study supporting the hypothesis that increased ankle pressure may be useful for diagnosing diabetes and cardiovascular disease in South Asians (5) uses a case– control study design, which has limitations. Further research, including longitudinal prospective studies and randomized trials, is needed before large-scale screening of ankle systolic pressure in high-risk groups, such as South Asians, can be recommended. Mary McGrae McDermott, MD Northwestern University Chicago, Illinois Potential Conflicts of Interest: Disclosures can be viewed at www .acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum ⫽M13-1561.

References 1. Fowkes FG, Murray GD, Butcher I, Heald CL, Lee RJ, Chambless LE, et al; Ankle Brachial Index Collaboration. Ankle brachial index combined with Framingham Risk Score to predict cardiovascular events and mortality: a meta-analysis. JAMA. 2008;300: 197-208. [PMID: 18612117] 2. McDermott MM, Liu K, Criqui MH, Ruth K, Goff D, Saad MF, et al. Anklebrachial index and subclinical cardiac and carotid disease: the multi-ethnic study of atherosclerosis. Am J Epidemiol. 2005;162:33-41. [PMID: 15961584] 3. Sutton-Tyrrell K, Venkitachalam L, Kanaya AM, Boudreau R, Harris T, Thompson T, et al. Relationship of ankle blood pressures to cardiovascular events in older adults. Stroke. 2008;39:863-9. [PMID: 18258843] 4. Tillin T, Hughes AD, Mayet J, Whincup P, Sattar N, Forouhi NG, et al. The relationship between metabolic risk factors and incident cardiovascular disease in Europeans, South Asians, and African Caribbeans: SABRE (Southall and Brent Revisited)—a prospective population-based study. J Am Coll Cardiol. 2013;61:177786. [PMID: 23500273] 5. Kain K, Brockway M, Ishfaq T, Merrick M, Mahmood H, Ingoe JC, et al. Ankle pressures in UK South Asians with diabetes mellitus: a case control study. Heart. 2013;99:614-9. [PMID: 23442538]

Cost-Effectiveness of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease TO THE EDITOR: Erickson and colleagues (1) have published an elegant Markov-based cost-effectiveness analysis that extends the results of the TEMPO (Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes) trial (2) of tolvaptan for the treatment of adult autosomal dominant polycystic kidney disease (ADPKD). The authors indicate that a key input parameter was the change in estimated glomerular filtration rate (eGFR) in patients who would or would not receive chronic tolvaptan therapy. In fact, the parameter that was modeled was the change in the actual GFR. However, because the eGFR is a 21 January 2014 Annals of Internal Medicine Volume 160 • Number 2 141

Letters nonlinear function of the GFR, the change in eGFR does not numerically equal the change in GFR. For example, taking the average starting serum creatinine level and GFR that were observed in the TEMPO trial and assuming that net creatinine production would be constant over 1 year, one can calculate the expected change in serum creatinine level for a given change in GFR and use the Chronic Kidney Disease Epidemiology Collaboration equation (3) to compute the resulting expected change in eGFR. The observed difference in the change in eGFR between the tolvaptan and placebo groups in the TEMPO trial of 0.98 mL/ min per year corresponds to a difference in the change in GFR of 0.88 mL/min per year. The latter discrepancy is small over 1 year. However, when extrapolated over the decades that patients are likely to live with ADPKD, the authors’ model would substantially overestimate the beneficial effect of tolvaptan to retard progression to end-stage renal disease. In cost-effectiveness analyses, a key model outcome is the incremental cost-effectiveness ratio. For the tolvaptan model, where the numerator of the incremental cost-effectiveness ratio (incremental, discounted, lifetime costs) is large and the denominator (incremental, discounted quality-adjusted life-years) is small, a further reduction in the denominator would greatly increase the computed ratio. The result of this consideration is that the authors may have underestimated the incremental cost-effectiveness ratio for tolvaptan therapy for ADPKD. However, this would only bolster their conclusion that, given the current cost of the drug, it is not a cost-effective treatment strategy. In general, lack of numerical equivalence between the change in eGFR and the change in GFR is probably of little importance when the change in eGFR is used as a surrogate for end-stage renal disease because the change in eGFR and the change in GFR correlate highly. However, we believe that in clinical trials where the primary outcome of interest is the change in GFR, the use of change in eGFR may lead to an inaccurate estimate of benefit. James Lineen, MB BCh, MSc David M.J. Naimark, MD, MSc Sunnybrook Health Sciences Centre and Institute of Health Policy, Management, and Evaluation, University of Toronto Toronto, Ontario, Canada on behalf of the Sunnybrook Nephrology Journal Club

TO THE EDITOR: We acknowledge Erickson and colleagues’ (1) ef-

fort to study ADPKD, for which no approved treatment is available. Compared with placebo, tolvaptan was found to slow the increase in total kidney volume and decline in kidney function and led to more incidents of aquaresis (excretion of electrolyte-free water) and hepatic adverse events over 3 years in patients with this condition (2). Although a cost-effectiveness analysis of tolvaptan is necessary, it is premature to complete at this time because several key data points are unknown. Tolvaptan is available in the United States (3) but is not approved for the treatment of ADPKD; therefore, a price for this treatment cannot currently be determined. The price assumed in this study was based on the daily price for the current indication of tolvaptan in the United States. Any new indication that may be approved will require an independent pricing assessment, particularly in the context of such a chronic indication as the treatment of ADPKD. Further, the price of tolvaptan used in this analysis does not account for patent expiration and generic availability within the time horizon proposed. This constant price assumption substantially biases the results against the cost-effectiveness of tolvaptan. Some assumptions of Erickson and colleagues’ study have led to the underestimation of the true cost of managing this disease. For example, this study did not account for costly and burdensome renalrelated symptoms, such as hematuria, kidney stones, renal pain, and infections (4).The cost of recommended safety monitoring or treatment-related adverse events would also have to be fully included to provide a balanced assessment of cost-effectiveness. Although the placebo group of the TEMPO trial represents an adequate sample for comparison of the safety and efficacy of tolvaptan, established longitudinal cohorts (5, 6) may more accurately represent the natural course of disease. Moreover, Erickson and colleagues’ study did not evaluate cost-effectiveness in specific subgroups of patients with ADPKD, such as younger persons and persons with larger kidneys or in the early stage of disease. The current analysis is thought-provoking, but conclusions should be viewed with caution until these important data points are addressed. Christopher M. Blanchette, PhD, MBA Benjamin Gutierrez, PhD Keith Friend, MD Otsuka America Pharmaceutical Princeton, New Jersey

Potential Conflicts of Interest: None disclosed. Forms can be viewed at

www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum ⫽L13-1102.

Potential Conflicts of Interest: Disclosures can be viewed at www .acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum ⫽L13-1105.

References 1. Erickson KF, Chertow GM, Goldhaber-Fiebert JD. Cost-effectiveness of tolvaptan in autosomal dominant polycystic kidney disease. Ann Intern Med. 2013;159:382-9. [PMID: 24042366] 2. Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Grantham JJ, Higashihara E, et al; TEMPO 3:4 Trial Investigators. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2012;367:2407-18. [PMID: 23121377] 3. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, et al; CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration). A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150:604-12. [PMID: 19414839] 142 21 January 2014 Annals of Internal Medicine Volume 160 • Number 2

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References 1. Erickson KF, Chertow GM, Goldhaber-Fiebert JD. Cost-effectiveness of tolvaptan in autosomal dominant polycystic kidney disease. Ann Intern Med. 2013;159:382-9. [PMID: 24042366] 2. Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Grantham JJ, Higashihara E, et al; TEMPO 3:4 Trial Investigators. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2012;367:2407-18. [PMID: 23121377] 3. Otsuka Pharmaceutical. Full Prescribing Information for Tolvaptan. 2012. Accessed at www.accessdata.fda.gov/drugsatfda_docs/label/2012/022275s007lbl.pdf on 9 October 2013. www.annals.org

Letters 4. Grantham JJ, Chapman AB, Torres VE. Volume progression in autosomal dominant polycystic kidney disease: the major factor determining clinical outcomes. Clin J Am Soc Nephrol. 2006;1:148-57. [PMID: 17699202] 5. Schrier RW, McFann KK, Johnson AM. Epidemiological study of kidney survival in autosomal dominant polycystic kidney disease. Kidney Int. 2003;63:678-85. [PMID: 12631134] 6. Thong KM, Ong AC. The natural history of autosomal dominant polycystic kidney disease: 30-year experience from a single centre. QJM. 2013;106:639-46. [PMID: 23587574]

IN RESPONSE: We agree with Drs. Lineen and Naimark that the eGFR is an imperfect surrogate for the actual GFR and that decreases in the GFR are not identical to those in the eGFR. The treatment benefit that the TEMPO trial investigators describe may also seem greater when assessed using the eGFR instead of the true GFR, although measuring the latter would have been challenging given the relative large sample size and dispersed geography described in this trial. The eGFR necessarily introduces regression error. Ideally, we could relate our model inputs (for example, mortality rates, healthrelated quality of life, and health care costs) to a true rather than estimated GFR, although we note that our model using the eGFR matches the progression rates to end-stage renal disease observed in large cohorts of patients with ADPKD. However, measures of true GFR (for example, inulin or iothalamate clearance) are not without imprecision. Moreover, the true GFR does not encompass the totality of what the kidneys contribute to human health, because kidney function modulates volume and blood pressure, biochemical and hormonal balance, and pro- and anti-inflammatory and oxidant status, among other life-sustaining tasks beyond the filtration of solutes. Use of the eGFR is an imperfect but necessary simplification. Whether one uses the eGFR, true GFR, or a more comprehensive assessment of kidney function, our analysis and the input of our Canadian colleagues highlight the challenges of drawing firm conclusions about long-term risks and benefits of complex, sometimes costly interventions from clinical trials or related modeling exercises. We agree with Dr. Blanchette and associates that knowing the prices of brand-name and generic tolvaptan for treatment of ADPKD before conducting our cost-effectiveness analysis would have been ideal. Despite these price uncertainties, we believe that our analysis provides important information to inform decision makers about the use of tolvaptan for several reasons. The TEMPO trial relied on intermediate outcomes (that is, growth in kidney volume and change in eGFR) and did not assess the long-term benefits of treatment by using such end points as progression to end-stage renal disease and death. By combining trial information with longitudinal studies like those that Dr. Blanchette and associates cited, our analysis bridges intermediate and long-term end points. Our analysis determines price points at which tolvaptan would probably be deemed good value for money relative to other commonly used interventions. We find that a price reduction of more than 95% compared with the current price per milligram (for the hyponatremia indication) would probably be required to achieve reasonable cost-effectiveness.

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The potential availability of a generic does not guarantee the cost-effectiveness of tolvaptan. Although our price-point analysis did not consider generic availability explicitly, it provides information on a price at which a generic should be considered. Furthermore, the relevance of considering nongenerics remains even after a generic alternative becomes available. On the basis of experiences with other medications, such as statins, many patients continue to use brandname formulations even after generics are on the market. For example, a survey of physicians found that approximately 4 in 10 physicians reported sometimes or often providing brand-name drugs when a generic is available (1). We believe that many of the other concerns that Dr. Blanchette and associates raised are addressed in the sensitivity analyses that we reported. For example, we show that varying our assumptions about the cost of ADPKD did not materially change our conclusions. Because the TEMPO trial did not report quality of life from tolvaptan, we were limited in our ability to account for changes in quality of life resulting from use of this agent. In our base case, we assumed that the quality-of-life benefit from tolvaptan reducing symptoms of ADPKD equaled the loss of quality-adjusted life-years from the medication (in terms of increased thirst and polyuria). Again, our main findings showed no particular sensitivity to variations on this assumption. Kevin F. Erickson, MD, MS Glenn M. Chertow, MD, MPH Jeremy D. Goldhaber-Fiebert, PhD Stanford University Stanford, California Potential Conflicts of Interest: Disclosures can be viewed at www .acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum ⫽M13-0381. Reference 1. Campbell EG, Pham-Kanter G, Vogeli C, Iezzoni LI. Physician acquiescence to patient demands for brand-name drugs: results of a national survey of physicians [Letter]. JAMA Intern Med. 2013;173:237-9. [PMID: 23303297]

CORRECTIONS Correction: Stop Wasting Money on Vitamin and Mineral Supplements In a recent editorial (1), the last sentence of the first paragraph should read, “After reviewing 3 trials of multivitamin supplements and 24 trials of single or paired vitamins that randomly assigned more than 400 000 participants . . .” as opposed to 450 000. This has been corrected in the online version. Reference 1. Guallar E, Stranges S, Mulrow C, Appel LJ, Miller ER. Enough is enough. Stop wasting money on vitamin and mineral supplements. Ann Intern Med. 2013;159: 850-1

21 January 2014 Annals of Internal Medicine Volume 160 • Number 2 143

Letters Correction: Treatment of Anemia in Patients With Heart Disease The figure in a recent guideline (1) was incorrect. The correct version appears below.

ACP Summary of the American College of Physicians Guideline on Treatment of Anemia in Patients With Heart Disease Disease/Condition Target Audience Target Patient Population Interventions Outcomes

Benefits of Treatment

Harms of Treatment

Recommendations

High Value Care

Clinical Considerations

Anemia and heart disease Internists, family physicians, and other clinicians Adult patients with symptomatic CHF (with or without reduced systolic function) or CHD (acute coronary syndrome, postacute coronary syndrome, or a history of MI or angina) and anemia or iron deficiency Red blood cell transfusion, ESAs with or without iron (including erythropoietin and darbepoetin), and intravenous iron Mortality (all-cause and disease-specific); cardiovascular events (MI, CHF exacerbation, arrhythmia, or cardiac death); exercise tolerance (any metric, most commonly NYHA class, 6-min walk test); quality of life; hospitalization (all-cause and disease-specific); and harms, including hypertension, venous thromboembolic events, and ischemic cerebrovascular events Red blood cell transfusion: no benefits shown when comparing liberal to restrictive transfusion ESAs: no benefit Intravenous iron: increased exercise tolerance, improved quality of life Red blood cell transfusion: adverse events potentially associated with red blood cell transfusions, such as fever, transfusionrelated acute lung injury, and congestive heart failure ESAs: hypertension and venous thrombosis Intravenous iron: no harms identified but sparsely reported Recommendation 1: ACP recommends using a restrictive red blood cell transfusion strategy (trigger hemoglobin threshold of 7–8 g/dL compared with higher hemoglobin levels) in hospitalized patients with coronary heart disease. (Grade: weak recommendation; low-quality evidence) Recommendation 2: ACP recommends against the use of erythropoiesis-stimulating agents in patients with mild to moderate anemia and congestive heart failure or coronary heart disease. (Grade: strong recommendation; moderate-quality evidence) Current evidence does not support the benefit of liberal blood transfusions in patients with asymptomatic anemia and heart disease. Therefore, the ACP does not support the liberal use of blood transfusions in the management of mild to moderate anemia in patients with cardiovascular disease. The probability that transfusion may be beneficial is higher in patients with lower hemoglobin levels (10 g/dL) (67). The ACP does not support the use of ESAs for treating patients with mild to moderate anemia and heart disease because the harms outweigh the benefits for these patients. Patients with heart disease may have anemia because of iron deficiency, use of ACE inhibitors, renal insufficiency, and poor nutrition. Presence of anemia is associated with increased mortality and morbidity. However, it is uncertain if anemia is an independent risk factor for poor outcomes or if it is a marker of more severe illness. The impact of oral administration of iron and how it compares with IV iron for treating anemic patients with heart disease is unknown.

This has been corrected in the online version.

Reference 1. Qaseem A, Humphrey LL, Fitterman N, Starkey M, Shekelle P, for the Clinical Guidelines Committee of the American College of Physicians. Treatment of anemia in patients with heart disease: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2013;159:770-9

144 21 January 2014 Annals of Internal Medicine Volume 160 • Number 2

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Cost-effectiveness of tolvaptan in autosomal dominant polycystic kidney disease.

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