January 2013 FAQs

Does parenteral iron administration increase the risk of infection?

Introduction

Iron deficiency anemia (IDA) is a common complication in critically ill and renally impaired patients, particularly those with chronic kidney disease (CKD) receiving hemodialysis (HD).1 IDA can be treated with intravenous iron, which is often preferred over oral formulations due to its greater bioavailability and favorable tolerance, and when oral administration is unfeasible in critically ill patients. However, there is concern that when iron is administered via the parenteral route, the increased bioavailability may promote bacterial growth and increase the risk of infection.

Physiology of Iron in Bacterial Infection

Bacteria require iron for growth and use iron as an enzyme cofactor.2 Human defense barriers are well accommodated to this requirement; the iron concentration in human plasma is practically zero because of the high affinity of the iron-binding protein transferrin for free iron.3 Indeed, some theorize that the decreased iron concentrations seen in critically ill patients may be advantageous by further reducing the availability of iron for bacterial growth.1 Natural barriers such as tissue fluid and phagocytes require these low-iron environments in order to function effectively, andthe antibacterial effectiveness of human serum can be attenuated by increased free iron concentrations.3,4

To deal with the low-iron environment, many pathogenic bacteria have evolved mechanisms to compete with the host for iron.5 For example, Escherichia coli and Salmonella sp. produce siderophores that compete with unsaturated transferrin by chelating iron and promoting bacterial uptake. Additionally, Haemophilus influenzae and Neisseria meningitides produce receptors that can directly remove iron from transferrin.

Laboratory Evidence

Many laboratory studies have associated increased iron levels with infection risk, contributing to the concern over iron administration in patients at risk for or with established infection. Bacterial growth in human serum has been shown to increase when transferrin saturations exceed normal levels by 30 to 50%.5 Furthermore, 2 studies documented that transferrin saturations exceeding 60% or 80% caused a loss of bacterial inhibition and subsequent growth of K. pneumonia and S. epidermidis, respectively, in human serum.6,7

Indeed, administration of intravenous iron has been shown to oversaturate transferrin.8 Dose- and infusion time-dependent effects were noted with ferric gluconate. Infusion protocols that utilized higher doses and shorter infusion times produced significantly higher serum iron levels and transferrin saturations than protocols that used lower doses and longer infusion times.

Risk of Infection with Intravenous Iron

While laboratory studies have shown a deleterious effect of increased free iron concentration on host immune function, human clinical data are limited. To date, studies are small and confined to CKD patients because of their frequent receipt of intravenous iron therapy and baseline risk for infection. 5 Not surprisingly, results are conflicting and lack generalizability.

Brewster and colleagues prospectively compared the rate of new catheter colonization during and after iron treatment.9 Fifteen HD patients received 125 mg iron gluconate intravenously for 5 HD sessions and were compared with 6 control HD patients that received no iron.After treatment, there was no difference in the rate of new colonization between the iron-treated and control groups (50% versus 0%, respectively; p=0.13). Of the 15 iron-treated patients, 5 were colonized at baseline compared with 10 after iron treatment (33% versus 66%; p=0.07). Throughout a 30-day follow-up period, only 1 patient (an iron-treated patient who developed candidemia) experienced infection (7%; p>0.99). These results indicate no significantly increased risk for acute catheter colonization or rate of infection with intravenous iron gluconate.

Conflicting findings were reported by Canziani and colleagues, who found a dose-dependent risk of infection with iron treatment.10 One hundred eleven HD patients were prospectively assigned to 3 iron treatment groups. Group 1 received a total cumulative dose of 1 g of iron saccharate over 28 days, group 2 received 2 g cumulative dose over 70 days, and group 3 received 1 g cumulative dose over 70 days. After 150 days, the incidence of infectious episodes per patient per month was not significantly different between groups 1 and 3 (0.08 versus 0.06, respectively; p=0.24), suggesting different treatment durations for an equivalent dose did not affect infection rate. In contrast, incidence was significantly higher in group 2 versus group 3 (0.13 versus 0.06, respectively; p=0.04), suggesting that a higher dose in an equivalent time period may contribute to increased infection risk.

Additional dose-dependent risk was reported by Hoen and colleagues, who reviewed prospective data of 985 HD patients who received oral or intravenous iron. 11 Intravenous administration of iron was not a significant risk factor for development of bacteremia. However, among patients treated with IV iron, administration was more frequent and at higher doses in patients that developed bacteremia than in patients who did not.

Lastly, a phase IV safety study compared 665 HD patients receiving iron sucrose for both treatment and prevention of IDA to historical control patients from the United States Renal Data System.12 In secondary analyses, the authors found no significant difference between intervention and historical control patients in infection-related mortality rates (21 versus 34.2 deaths per 1000 patient-years, respectively; p=0.08). However, the infection-related hospitalization rate was significantly lower in intervention versus historical controls (226.5 versus 422 hospitalizations per 1000 patient-years, respectively, p<0.001).

Compared with data describing the effect of intravenous iron on risk of new infection, no human data are available in established infection. Nonetheless, many clinicians are averse to using intravenous iron in patients with concomitant infection based on animal data in experimental models of sepsis that suggest exacerbation of infection after intravenous iron administration.13,14

Application

While data remain conflicting, the practical application of information on infection risk with intravenous iron is potentially great. The national prevalence of CKD is approximately 15%, with new cases of later disease stages increasing in frequency.15 Patients with CKD, particularly those receiving HD, frequently receive intravenous iron treatment and are at increased baseline risk for infection. This risk should be considered in conjunction with the necessity of iron therapy, as illustrated by findings at a university hospital. Of 100 patients receiving intravenous iron sucrose, 22% also had concomitant active infection and 20% were either not iron deficient or were actually iron overloaded.16 Furthermore, the Kidney Disease Outcomes Quality Initiative guidelines for treatment of anemia in CKD recommend targeting serum ferritin and transferrin saturation levels; however, the correlation between infection risk and levels of these indices of iron status has not been explored.17

Conclusion

No conclusive data are available to predict the risk of new infection or exacerbation of existing infection as a result of intravenous iron treatment. Cause for this concern is mostly due to animal and laboratory data, which indicate increased bacterial growth with higher free iron concentrations and an exacerbation of existing infection with iron administration. Human data are limited, confined to patients with CKD, and conflicting, but suggest any risk may be dose-dependent. Patients with clear indications should not be deprived of iron therapy based on the limited evidence that is currently available. Clinicians must assess the benefits and risks of intravenous iron therapy for individual patients when deciding if this treatment is appropriate. 13

References

1. Cook K, Ineck B, Lyons W. Anemias. In: Talbert RL, DiPiro JT, Matzke GR, Posey LM, Wells BG, Yee GC, eds. Pharmacotherapy: A Pathophysiologic Approach. 8th ed. New York: McGraw-Hill; 2011. http://www.accesspharmacy.com/content.aspx?aID=799956. Accessed December 17, 2012.

2. Donnenberg MS. Enterobacteriaceae. In: Mandell GL. Mandell, Douglas, And Bennett's Principles and Practice of Infectious Disease. 7th ed. Philadelphia, PA: Elsevier Inc; 2010:2815-2833.

3. Bullen J, Griffiths E, Rogers H, Ward G. Sepsis: the critical role of iron. Microbes Infect. 2000;2(4):409-415.

4. Bullen JJ, Spalding PB, Ward CG, Rogers HJ. The role of Eh, pH and iron in the bactericidal power of human plasma. FEMS Microbiol Lett. 1992;73(1-2):47-52.

5. Maynor L, Brophy DF. Risk of infection with intravenous iron therapy. Ann Pharmacother. 2007;41(9):1476-1480.

6. Cieri E. Does iron cause bacterial infections in patients with end stage renal disease? ANNA J. 1999;26(6):591-596.

7. Brewster UC, Perazella MA. Intravenous iron and the risk of infection in end-stage renal disease patients. Semin Dial. 17(1):57-60.

8. Zanen AL, Adriaansen HJ, Van bommel EF, Posthuma R, Th de jong GM. 'Oversaturation' of transferrin after intravenous ferric gluconate (Ferrlecit®) in haemodialysis patients. Nephrol Dial Transplant. 1996;11(5):820-824.

9. Brewster UC, Coca SG, Reilly RF, Perazella MA. Effect of intravenous iron on haemodialysis catheter microbial colonization and blood-borne infection. Nephrology. 2005;10(2):124-128.

10. Canziani ME, Yumiya ST, Rangel EB, Manfredi SR, Neto MC, Draibe SA. Risk of bacterial infection in patients under intravenous iron therapy: dose versus length of treatment. Artif Organs. 2001;25(11):866-869.

11. Hoen B, Paul-Dauphin A, Kessler M. Intravenous iron administration does not significantly increase the risk of bacteremia in chronic hemodialysis patients. Clin Nephrol. 2002;57(6):457-461.

12. Aronoff GR, Bennett WM, Blumenthal S, et al. Iron sucrose in hemodialysis patients: safety of replacement and maintenance regimens. Kidney Int . 2004;66(3):1193-1198.

13. Daoud E, Nakhla E, Sharma R. Q: Is iron therapy for anemia harmful in the setting of infection? Cleve Clin J Med. 2011;78(3):168-170.

14. Zager RA, Johnson AC, Hanson SY. Parenteral iron therapy exacerbates experimental sepsis. Kidney Int. 2004;65(6):2108-2112.

15. Derebail VK, Kshirsagar AV, Joy MS. Chronic kidney disease: progression-modifying therapies. In: Talbert RL, DiPiro JT, Matzke GR, Posey LM, Wells BG, Yee GC, eds. Pharmacotherapy: A Pathophysiologic Approach. 8th ed. New York: McGraw-Hill; 2011. http://www.accesspharmacy.com/content.aspx?aID=7981349. Accessed December 17, 2012.

16. Hein B. Iron sucrose medication use evaluation. Poster presented at: 2011 American Society of Health-Systems Pharmacists Midyear Clinical Meeting; December 5, 2011; New Orleans, LA.

17. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease. Am J Kidney Dis. 2006;47(5 Suppl 3):S11-S145.

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Drug-induced QT prolongation (Part 1): presentation, risks, and management

Introduction

Healthcare professionals have become increasingly frustrated with electronic drug alerts concerning QT prolongation. The alerts associated with commonly prescribed drugs such as fluoroquinolones, ondansetron, and azithromycin are particularly troublesome. Many drugs are known to cause or have the potential to cause QT prolongation and, more importantly, torsade de pointes (TdP). In addition, there have been several medications removed from the market due to adverse cardiac events such as TdP.1 The actual incidence of TdP is unknown. However, one small study estimated an annual incidence rate of approximately 12,000 cases of drug-induced TdP in the United States.2 Although TdP is a rare drug-induced disease, it is a serious, life-threatening, ventricular arrhythmia which can lead to sudden cardiac death. Thus, there is a need for a better understanding of QT prolongation and the risk of TdP induced by these drugs. This is part 1 of a 2-part paper on drugs associated with QT prolongation.

Pathophysiology

The QT interval is the time of cardiac depolarization and ventricular repolarization, which are represented by the QRS complex and ST segment with T wave, respectively.3 During cardiac depolarization, positive ions such as sodium and calcium flow into the cardiac cells. This is followed by an efflux of potassium which exceeds the influx of sodium and calcium resulting in ventricular repolarization. Disruption of this process may lead to an excess of positive ions intracellularly causing further ventricular repolarization and prolongation of the QT interval.4 Typically, the QT interval is measured at the onset of the QRS complex and terminates at the T wave.2-4 The QT interval varies with changes in heart rate; therefore, it is usually corrected for heart rate (QTc). A normal QTc interval ranges from 370 milliseconds (msec) to 440 msec for men, and up to 460 msec in women. A QTc greater than or equal to 500 msec or an increase in the QTc interval by 60 msec from baseline, increases the risk of drug-induced TdP. 2

Although the majority of QT prolongation is due to lengthening repolarization, it may also be caused by depolarization abnormalities.3 Furthermore, lengthening the duration of the ventricular repolarization may increase the susceptibility to early afterdepolarizations (EADs), which are oscillations in the membrane potential that may trigger another action potential. These EADs can propagate into a rapid polymorphic ventricular tachycardia known as TdP or “twisting of the points”.2,5-6 Thus, QT prolongation may subsequently lead to TdP; however, prolonged QT may occur without TdP. One may consider QT interval prolongation a surrogate marker for adverse events such as TdP.

Presentation

Symptoms related to TdP are similar to other arrhythmias and include tachycardia, hypotension, dizziness, chest pain, shortness of breath, syncope, and seizure. Accordingly, the diagnosis of TdP is dependent on the electrocardiogram (ECG). The ECG in patients with TdP is characterized by twisting around the central axis with a long-short initiating sequence resulting from a premature beat followed by a pause. 2,7 Moreover, it is associated with a rapid heart rate ranging from 150 beats to 300 beats per minute. Torsade de pointes can be self-limiting but may also rapidly degenerate into ventricular fibrillation causing sudden cardiac death due to lack of circulation.5,7 QT prolongation and TdP can be congenital or acquired, with the latter being more common. In addition, the majority of acquired TdP with QT prolongation is drug-induced via inhibition of voltage-gated potassium channels, especially the rapid component of the delayed rectifier potassium current (IKr), expressed by human ether-a-go-go-related gene (HERG). 1,2,6 Although characteristic of TdP, inhibition of IKr and QT prolongation do not alone cause this arrhythmia. Many patients taking drugs that block IKr may have QT prolongation but do not have TdP. In addition, some drugs, such as verapamil, block IKr but do not cause QT prolongation or TdP. Therefore, drugs that block IKr are not the only medications screened for TdP with QT prolongation. Drugs such as tricyclic antidepressants, phenothiazines, and antihistamines may block sodium channels that slow ventricular conduction thus causing re-entry and risk of ventricular arrhythmia.

Risk factors

Specific risk factors for TdP have been identified (see Table 1). Most patients with drug-induced TdP have concomitant risk factors. One study found that 96% of patients who had TdP associated with a non-cardiac drug had at least 1 concomitant risk factor and 71% of patients had at least 2 risk factors. 8 Therefore, one method of TdP prevention is identification of patients with risk factors.

Table 1. Risk factors for drug-induced TdP. 2-4,9,10

Abbreviations: ACC/AHA/AACN/ISCE = American College of Cardiology/American Heart Association/American Association of Critical Care Nurses/International Society for Computerized Electrocardiology, EADs = early afterdepolarizations, LQTS = long QT syndrome, TdP = torsade de pointes.

Drugs commonly associated with TdP

The following tables (Table 2 through 4) are lists of drugs commonly associated with TdP. An updated list of drugs is maintained by CredibleMeds and can be found at www.azcert.org. This non-profit research education center reviews scientific literature and provides recommendations regarding the QT-prolonging potential of drugs.11 For drugs in the “risk” category, there is significant evidence that these drugs cause QT prolongation and have an increased risk of TdP. For the drugs in the “possible risk” category, there is significant evidence that these drugs prolong the QT interval; however, there is insufficient evidence as to whether these drugs have an increased risk of causing TdP. Finally, the drugs with “conditional risk” have significant evidence of prolonging QT and causing TdP but only under certain conditions, such as excessive dose or drug interaction. Of note, all 3 lists below include drugs which should be avoided in patients with congenital long QT syndrome. The most common drug classes associated with QT prolongation and/or TdP are antiarrhythmics, antibiotics, antipsychotics, and antidepressants.

Table 2. Drugs with risk of TdP. 1,2,4,11-20

Abbreviations: ECG = electrocardiogram, IV = intravenous, TdP = torsade de pointes.
* Incidence rates of anti-arrhythmics2: amiodarone (0.7%), dofetilide (0-10%), ibutilide (1.4%-11.5%), procainamide (0-3.6%), quinidine (2%-12%), sotalol (0.4%-5%); the incidence with dofetilide, procainamide, and sotalol depends on the presence of left ventricular dysfunction and whether the drug was dose adjusted appropriately for renal function
† Incidence rates of anti-infectives2: erythromycin (0.4%), pentamidine (< 21%)
‡ Incidence rates of anti-psychotics2: haloperidol (3.6%; reported with intravenous use in critically ill patients)
§ Chlorpromazine is also an antinausea medication

Table 3. Drugs with possible risk of TdP. 2,11,14-17,21,22

Abbreviations: ECG = electrocardiogram, IV = intravenous, TdP = torsade de pointes.

Table 4. Drugs with conditional risk of TdP. 2,11,12,14,15,17

Abbreviations: TdP = torsade de pointes

Prevention and management

There are many factors to consider when initiating a drug with QT prolonging potential. The benefit must outweigh the risk of TdP. There are several questions to address including:

• Are the benefits clinically important, and are the risks minimized?
• Will this medication affect mortality or morbidity compared to other medications?
• Is this medication superior to other medications or do other medications carry the same risk?

To reduce or prevent TdP, consider the medication’s route of elimination, drug interactions, and other risk factors mentioned above.4 Ideally when starting a new medication with a risk for TdP, obtain a baseline ECG prior to initiation and at steady state, and monitor/correct electrolyte abnormalities throughout the course of therapy.4,16 Some clinicians believe the measurement of the QT interval at baseline may not be cost-effective for medications that have low potential for TdP.4 However, it is practical to consider the cost versus benefit with each individual drug and patient. Well-known risk factors should be considered and minimized if possible. Furthermore, IV administration may have greater association with TdP than oral administration due to exposure to higher serum drug concentrations. Therefore, it is appropriate to measure the QT interval at the time of higher plasma concentrations to assess the risk for TdP. Minimally, an ECG should be obtained when a patient has symptoms (e.g., tachycardia, hypotension, chest pain, syncope), when 2 or more QT-prolonging medications are prescribed concomitantly, or when electrolyte abnormalities or cardiovascular disease is evident.16

Treatment of drug-induced TdP

When TdP occurs offending agents must be discontinued. Hemodynamically stable patients should be treated with 2 g of IV magnesium over 5 minutes followed by 1 to 2 g over 60 minutes .10,23 In patients who are hemodynamically unstable, defibrillation with asynchronous shocks may be necessary. 2 It may be difficult to cardiovert a patient with TdP. It is almost impossible to synchronize multiple QRS complexes with varying heart rates. Moreover, cardiac overdrive pacing may be used to shorten the QT interval and thus terminate TdP.2,9 Similarly, intravenous isoproterenol, dopamine, and atropine may be used to increase the heart rate and shorten the QT interval.2,3 However, this must be done cautiously in patients with heart block as this may worsen TdP. Other therapeutic options include agents that block sodium channels, such as phenytoin and lidocaine, and calcium channel blockers, such as verapamil. Patients with congenital long QT syndrome are at increased risk and may require long-term prophylactic therapy with beta-blockers or permanent cardiac pacing to prevent TdP.

Summary

Prolongation of the QT-interval may occur with a variety of medications. The most common classes of medications implicated in QT prolongation are antiarrhythmics, antibiotics, antipsychotics, and antidepressants. As a result, these medications are associated with an increased risk of TdP, which is a serious life-threatening arrhythmia. However, TdP is a rare complication, especially in patients without contributing risk factors. The majority of patients with drug-induced TdP present with 2 or more risk factors. Risk factors for TdP include: female gender, age greater than or equal to 65 years, cardiovascular disease, electrolyte abnormalities, 2 or more QT prolonging medications, and drug-drug interactions. An ECG may not always be warranted prior to initiation of a medication associated with QT prolongation. However, if a patient presents with symptoms of TdP, has evidence of cardiovascular disease (i.e., left ventricular systolic dysfunction or a history of myocardial infarction), or is prescribed 2 or more drugs with potential for QT prolongation, then ECG monitoring should be performed. Risk factors should be identified and minimized, including electrolyte supplementation for hypokalemia and hypomagnesemia. As a rule of thumb, a QTc interval greater than 500 msec deserves discontinuation of the offending agent and reevaluation of therapy. Understanding QT prolongation and the risks associated with TdP may help healthcare professionals better manage therapy with QT prolonging medications.

References:

1. Van Noord C, Eijgelsheim M, Stricker BH. Drug- and non-drug-associated QT interval prolongation. Br J Clin Pharmacol. 2010;70(1):16-23.

2. Tisdale JE. Ventricular arrhythmias. In: Tisdale JE, Miller DA, eds. Drug Induced Diseases: Prevention, Detection, and Management. 2nd Ed. Bethesda, MD: American Society of Health-System Pharmacists; 2010:405-515.

3. Kramer DB, Zimetbaum PJ. Long-QT syndrome. Cardiol Rev. 2011;19(5):217-225.

4. Al-Khatib SM, LaPointe NM, Kramer JM, Califf RM. What clinicians should know about the QT interval. JAMA. 2003;289(16):2120-2127.

5. Mohrman DE, Heller LJ. Cardiac abnormalities. In: Mohrman DE, Heller LJ, eds. Cardiovascular Physiology. 7th ed. New York: McGraw-Hill; 2010. http://www.accessmedicine.com/content.aspx?aID=6553504. Accessed November 7, 2012.

6. Kannankeril P, Roden DM, Darbar D. drug-induced long QT syndrome. Pharmacol Rev. 2010;62(4):760-781.

7. Rho RW, Page Rl. Ventricular arrhythmias. In: Fuster V, Walsh RA, Harrington RA, eds. Hurst’s The Heart. 13th ed. New York: McGraw-Hill; 2011. http://www.accessmedicine.com/content.aspx?aID-7814365. Accessed November 7, 2012.

8. Zeltser D, Justo D, Halkin A, Prokhorov V, Heller K, Viskin S. Torsade de pointes due to noncardiac drugs: most patients have easily identifiable risk factors. Medicine. 2003;82(4):282-290.

9. Gillis AM. Cardiac arrhythmias, pacing, cardioversion, and defibrillation in the critical care setting. In: Hall JB, Schmidt GA, Wood LD, eds. Principles of Critical Care. 3rd ed. New York: McGraw-Hill; 2005. http://www.accessmedicine.com/content.aspx?aID=2284882. Accessed November 7, 2012.

10. Drew BJ, Ackerman MJ, Funk M, et al; on behalf of the American Heart Association and the American College of Cardiology Foundation. Prevention of Torsade de pointes in Hospital Settings. J Am Coll Cardiol. 2010;55(9):934-947.

11. CredibleMeds Website. www.azcert.org. Accessed November 7, 2012.

12. Nelson S, Leung J. QTc prolongation in the intensive care unit: a review of offending agents. AACN Adv Crit Care. 2011;22(4):289-295.

13. Vieweg WV, Hasnain M, Howland RH, Hettema JM, Kogut C, Wood MA, et al. Citalopram, QTc interval prolongation, and torsade de pointes. How should we apply the recent FDA ruling? Am J Med. 2012;125(9):859-868.

14. Briasoulis A, Agarwal V, Pierce WJ. QT prolongation and torsade de pointes induced by fluoroquinolones: infrequent side effects from commonly used medications. Cardiology. 2011;120(2):103-110.

15. Wenzel-Seifert K, Wittmann M, Haen E. QTc prolongation by psychotropic drugs and the risk of Torsade de Pointes. Dtsch Arztebl Int. 2011;108(41):687-693.

16. Nielsen J, Graff C, Kanters JK, Toft E, Taylor D, Meyer JM. Assessing QT interval prolongation and its associated risks with antipsychotics. CNS Drugs. 2011;25(6):473-490.

17. Alvarez PA, Pahissa J. QT alterations in psychopharmacology: proven candidates and suspects. Curr Drug Saf. 2010;5(1):97-104.

18. Patanwala AE, Amini R, Hays DP, Rosen P. Antiemetic therapy for nausea and vomiting in the emergency department. J Emerg Med. 2010;39(3):330-336.

19. Charbit B, Albaladejo P, Funck-Brentano C, Legrand M, Samain E, Marty J. Prolongation of QTc interval after postoperative nausea and vomiting treatment by droperidol or ondansetron. Anesthesiology. 2005;102(6):1094-1100.

20. Krantz MJ, Martin J, Stimmel B, Mehta D, Haigney MC. QTc interval screening in methadone treatment. Ann Intern Med. 2009;150(6):387-395.

21. Hafermann MJ, Namdar R, Seibold GE, Page RL 2nd. Effect of intravenous ondansetron on QT interval prolongation in patients with cardiovascular disease and additional risk factors for torsades: a prospective, observational study. Drug Healthc Patient Saf. 2011;3:53-58.

22. U.S. Food and Drug Administration. 2012. FDA Drug Safety Communication: New information regarding QT prolongation with ondansetron (Zofran). U.S. Food and Drug Administration Web site. http://www.fda.gov/Drugs/DrugSafety/ucm310190.htm. Accessed November 7, 2012.

23. Heidenreich J. Cardiac arrhythmias. In: Humphries RL, Stone C, eds. CURRENT Diagnosis & Treatment Emergency Medicine. 7th ed. New York: McGraw-Hill; 2011. http://www.accessmedicine.com/content.aspx?aID=55753892. Accessed November 7, 2012.

Prepared by:
Roseanne Patel, PharmD, PGY1

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Should tamoxifen therapy be extended up to 10 years in women with early breast cancer?

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