September 2016 FAQs

Dexrazoxane and the risk secondary cancer in pediatric patients: Can this controversy be laid to rest?

Introduction

Mortality from childhood cancer has been steadily decreasing.  The mortality rate for childhood cancer in 2010 was less than half of what it was in 1975.1  Advances in cancer survival are largely due to the development of highly effective chemotherapy agents such as anthracyclines; however, the use of these agents can cause varied forms of toxicity in survivors.  Anthracyclines exert their effects by directly binding to DNA and blocking the synthesis of DNA, RNA, or both, inhibiting topoisomerase II, and generating free-radicals in malignant cells.2  Anthracyclines carry a known risk of cardiotoxicity, both acutely, and for decades following therapy.  It has been estimated that almost 1 in 8 childhood cancer survivors exposed to anthracycline therapy will experience severe heart disease within 30 years.3   The exact molecular mechanism of anthracycline-induced cardiotoxicity is not completely understood, and although anthracyclines are toxic to both cancer and cardiac cells, the mechanisms underlying cell injury may differ.2  One theory is that the quinone group on the anthracycline molecule causes the production of free radicals that react with oxygen and produce cardiotoxicity.  Other theories include apoptosis of cardiac cells, decreased adenosine triphosphate production, direct damage to mitochondria, and peroxidation of the cardiac myocyte lipid membrane.

Dexrazoxane is a free-radical scavenger derived from ethylenediaminetetraacetic acid (EDTA).4  Dexrazoxane also reversibly inhibits topoisomerase II with a mechanism distinct from anthracyclines.5  Dexrazoxane is only approved as a cardioprotectant in women with metastatic breast cancer who have received a cumulative doxorubicin dose of greater than 300 mg/m2 and will continue to receive doxorubicin to maintain tumor control.4  However, there is a significant amount of published evidence exploring its use in pediatric patients.  Early trials using dexrazoxane for prevention of cardiotoxicity in pediatric patients showed promising results.6  In 2004, Lipshultz and colleagues  published results of a randomized controlled trial in 206 pediatric patients with acute lymphocytic leukemia (ALL).7  Patients were randomized to receive doxorubicin alone or doxorubicin plus dexrazoxane.  Immediate cardiotoxicity as measured by elevated troponin T was seen in 50% of patients receiving doxorubicin alone as compared to 21% of patients who received dexrazoxane and doxorubicin (P<0.001), with similar rates of event-free survival.  Other similarly efficacious results were seen in early trials conducted by the Children’s Oncology Group which are summarized elsewhere.6

Secondary malignancies are cancers that occur as a result of the treatment of cancer.  The risk of developing secondary malignancy is 6% to 10% among all cancer patients, and that risk is 3.6 to 10 times higher in children than adults.8  Most secondary cancers appear approximately 2 years after the primary cancer, but the onset can be up to 10 years for solid tumors and as early as 0.8 years for leukemia development after exposure to epipodophyllotoxins.   Known risk factors for secondary cancer development include radiation, certain genetic abnormalities such as Li-Fraumeni syndrome, younger age, female sex, and exposure to alkylating agents and topoisomerase inhibitors.  Primary cancers that carry the largest risk for development of secondary malignancy include Hodgkin’s Lymphoma (HL), Non-HL, thyroid carcinoma, brain tumors, retinoblastoma, and soft tissue sarcomas. 

Literature Evaluation

The article that sparked the controversy regarding the possible increased risk of secondary malignancy in patients receiving dexrazoxane was published by Tebbi and colleagues in 2007, and was based on the Pediatric Oncology Group (POG) studies 9426 and 9425.9   POG studies 9426 and 9425 were designed for the treatment of newly diagnosed low- and advanced-stage HL, respectively, using doxorubicin, bleomycin, vincristine, and etoposide (ABVE) or dose-intensified ABVE with prednisone and cyclophosphamide (ABVE-PC), with and without dexrazoxane.  A total of 478 patients were enrolled and the median follow-up was 58 months.  Ten patients developed secondary malignancies; 8 patients developed acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) and 2 patients developed solid tumors.  Of the patients who developed AML or MDS, 6 patients received dexrazoxane (2.55% ± 1.0%) and 2 did not receive dexrazoxane (0.85% ± 0.6%, p=0.160). Both solid tumors occurred in patients who received dexrazoxane.  One was papillary thyroid carcinoma occurring within the radiation field and the other osteosarcoma developed outside the radiation field.  For any secondary malignancy, the incidence with dexrazoxane was 3.43% ± 1.2% versus 0.85% ± 0.6% without the cardioprotectant (P=0.060). Four-year event-free survival and overall survival were similar between the dexrazoxane (86%, 96%, respectively) and non-dexrazoxane groups (88%, 97%, respectively); however, p-values were not given by the authors despite these being the primary outcomes the studies were designed to evaluate.  Cumulative doses of cytotoxic agents varied significantly between patients depending on the protocol and the number of cycles of chemotherapy patients received.  Doses of doxorubicin used were between 100 and 300 mg/m2, etoposide doses ranged from 1250 to 1875 mg/m2, and doses of cyclophosphamide were between 0 and 4000 mg/m2. The authors did not provide details of the average cumulative doses in patients who did not develop secondary malignancies compared to those who did, however they stated that the risk of secondary malignancy did not depend on the number of chemotherapy cycles received.  The authors concluded based on this evidence that adding dexrazoxane to ABVE regimens may increase the incidence of secondary malignancy. A limitation discussed by the authors was that these studies were not designed to evaluate the risk of secondary malignancies and that their results did not reach statistical significance, and therefore could have been due to chance alone.

The publication of this article immediately sparked controversy.  In letters to the editor published in the same journal in the following months, critics detailed flaws in the claim of increased secondary malignancy associated with dexrazoxane in the study by Tebbi and colleagues.10,11   Firstly, the authors acknowledge that these studies were not designed for statistical comparison of risk of secondary malignancies.9  Lipshultz and colleagues criticized that the claim is based on only 10 secondary malignancy events that occurred in 478 patients, and these results did not reach statistical significance based on both the time-to-event analysis used by the authors nor Fisher’s exact tests.10   They also point out that the authors only found statistically significant differences after adjusting results for baseline characteristics, despite the fact that there was no imbalance between arms in terms of these characteristics. Furthermore, patients in this trial who developed secondary malignancies all had cumulative doses of doxorubicin and/or etoposide substantially above doses known to be leukemogenic and the cumulative doses of etoposide, doxorubicin, and cyclophosphamide varied considerably between patients, therefore it is unknown to what extent this could have affected the outcomes.11  The cumulative dose found to be associated with increased risk of secondary malignancy is 170 mg/m2 for doxorubicin and 1,200 mg/m2 for etoposide, both of which are within the range of doses received by patients in the trial.12

Since the publication of this article, results of multiple clinical trials addressing this issue have been published.13-18  In 2010, Silverman published the long-term results of studies conducted between 1985 and 2000 by the Dana-Farber Cancer Institute consortium in newly diagnosed pediatric acute lymphoblastic leukemia.13  Of these studies, protocol 95-01 included 491 high risk patients who were randomized to receive doxorubicin alone or with dexrazoxane. The cumulative doxorubicin dose was 300 mg/m2.  After 10 years, event-free survival (76.4% dexrazoxane vs. 73.5% without, p=0.813) and overall survival (83.1% dexrazoxane vs. 85.8% without, p=0.662) remained similar between the groups.  At the time of the review, no secondary malignancy had been observed in patients who received dexrazoxane.  In 2011, Vrooman and colleagues published updated results of this protocol (95-01) and two other Dana-Farber Cancer Institute protocols, 00-01 and 05-01, which also used doxorubicin and dexrazoxane.14 The authors specifically analyzed the data as it relates to rates of secondary malignancy.  Patients were followed for a median of 9.6 years, 5.2 years, and 2.1 years on protocols 95-01, 00-01, and 05-01 respectively.  Similar to protocol 95-01, the cumulative doxorubicin dose in the other protocols was 300 mg/m2.  A total of 553 patients with high risk or very high risk ALL received dexrazoxane, and of those patients only one developed a secondary malignancy.  The overall 5-year estimated incidence of secondary malignancy was 0.24% (95% CI 0.02 to 1.29%). The authors discussed their results in contrast with those of Tebbi and colleagues and argue that the high rates of secondary malignancy observed by Tebbi and colleagues may be due to the fact that patients with HL and those treated with etoposide have higher rates of secondary malignancy independent of exposure to dexrazoxane.

In March 2015, Seif and colleagues published results of a retrospective cohort study of patients at the Children’s Hospital of Philadelphia who received anthracyclines for newly diagnosed malignancies (excluding AML) between 1999 and 2011.15  Of 15,532 total patients, 1,406 received dexrazoxane.  Patients were followed for all subsequent admissions to identify occurrence of secondary AML, defined by International Classification of Diseases (ICD)-9 codes or AML induction chemotherapy.  Logistic regression was used to create a propensity model for the association of dexrazoxane and secondary AML risk.  This estimated the risk of developing secondary AML associated with dexrazoxane exposure, while controlling for covariates including age, gender, race, insurance, diagnosis group, hospital, and total etoposide exposure.  The authors did not find increased risk of developing secondary malignancies.  The overall rate of secondary AML was 0.52%.  The incidence of secondary AML in the dexrazoxane-exposed group was 0.21% (95% CI 0.04 to 0.62) and was 0.55% (95% CI 0.43 to 0.68) in the unexposed group (OR 0.39, 95% CI 0.12 to 1.24). Using the regression model the authors found an association between etoposide exposure and secondary AML (OR=2.36, 95% CI 1.48 to 3.79, p=0.0003) but no association between dexrazoxane exposure and secondary AML (OR=0.38, 95% CI 0.12 to 1.27, p=0.1166). 

The results of the Children’s Oncology Group (COG) trials P9404, P9425, and P9426 in pediatric ALL and HL were published by Chow et al in August 2015.16  Of note, this report included all children reported by Tebbi and colleagues, but with longer follow-up.  Protocol P9404 included children with T-cell acute lymphoblastic leukemia/lymphoma and the other 2 protocols evaluated patients with HL.  All patients were randomized to receive doxorubicin with dexrazoxane (n=507) or without (n=501) prior to each dose.  The cumulative doxorubicin dose ranged from 100 to 360 mg/m2.  In 1,008 patients followed for a median of 12.6 years, the investigators did not find an increased risk of secondary malignancies or significant differences in overall survival between the groups.  Overall mortality at 10 years was 12.8% with dexrazoxane and 12.2% without; (HR 1.07; 95% CI, 0.75 to 1.52).  The incidence of secondary malignancy was low.  In 1,008 patients there were 18 deaths attributed to secondary cancers (13 AML/MDS, 1 non-HL and 4 solid tumors), and 10 occurred in patients who received dexrazoxane (7 AML/MDS, 1 non-HL and 2 solid tumors). The 10-year AML/MDS mortality rate was 1.4% for those treated with dexrazoxane and 0.8% for those without (HR 1.39, 95% CI=0.44 to 4.37).

In a meta-analysis combining the results of the above mentioned trials with some observational data, the authors concluded that dexrazoxane was associated with a reduction in both clinical and subclinical cardiotoxicity, without decreasing event-free survival.17  The meta-analysis included 5 randomized controlled trials with a total of 1,254 patients, including the 478 patients from the article published by Tebbi and colleagues.  The cumulative doxorubicin dose ranged from 100 to 410 mg/m2.  Among patients treated with dexrazoxane, 17 of 635 (2.7%) developed a secondary malignancy, compared with 7 of 619 (1.1%) patients who did not receive dexrazoxane (RR = 2.37, p=0.06).  Dexrazoxane was associated with a statistically borderline increase in the risk of secondary malignancies, however, the type varied. There was an increase in secondary AML in 2 trials that used etoposide with doxorubicin and dexrazoxane in patients with HL and an increase in brain tumors in a trial that used cranial radiation for all patients with T-cell malignancies. All excess cases of secondary malignancy were accounted for by these additional cases of AML and brain tumors.  The authors concluded based on this observation that dexrazoxane likely accentuates the risk of secondary malignancy if used concurrently with cancer therapies that contribute independently to secondary cancer development.

Most recently in March 2016, Asselin and colleagues published the results of the  Pediatric Oncology Group Protocol POG 9406, which was designed to determine the oncologic efficacy, cardioprotective effectiveness, and safety of dexrazoxane added to chemotherapy that included a cumulative doxorubicin dose of 360 mg/m2 in newly diagnosed pediatric T-cell acute lymphoblastic leukemia or lymphoblastic non-HL patients.18 The study enrolled 537 patients, of which 273 received dexrazoxane and 264 received doxorubicin alone.  For all patients, event-free survival at 5 and 10 years was 76.4% and 75.2%, respectively and overall survival at 5 and 10 years was 82.1% and 80.6%, respectively.  Neither outcome differed between the 2 groups (p = 0.9).  Secondary malignancy occurred in 11 patients of which 8 received dexrazoxane. The incidence of secondary malignancy was similar between groups, 0.7% with dexrazoxane and 0.8% without dexrazoxane after 5 years (p=0.17) and 1.8% and 1.2%, respectively after 10 years.  The mean ventricular fractional shortening, wall thickness, and thickness to dimension ratios 3 years after treatment were significantly better in the dexrazoxane arm, demonstrating a cardioprotective effect for dexrazoxane without compromising efficacy.

Conclusion:

The American Society of Clinical Oncology 2008 practice guideline on use of chemotherapy protectants do not recommend the use of dexrazoxane in pediatric patients, however this same statement did recommend its use in adult patients receiving more than 300 mg/m2 doxorubicin based on a randomized controlled trial in breast cancer patients that showed a beneficial effect.19  This pediatric recommendation was based on a lack of definitive evidence of benefit in pediatric patients, and specifically cited the study by Tebbi and colleagues as evidence of possible risk.  In an editorial published by Kremer and van Dalen in July 2015, the authors briefly reviewed the evidence for dexrazoxane use in pediatric patients and published recommendations.20  The authors concluded with high confidence that there are beneficial effects of dexrazoxane as a cardioprotectant in adults and with low to moderate confidence that there are beneficial effects of dexrazoxane as a cardioprotectant in children.  With respect to harmful effects, they concluded with moderate confidence that there is no difference in mortality in children treated with or without dexrazoxane, and with low confidence that there is no difference in secondary malignancy. 

The majority of evidence in pediatric patients demonstrates no significant difference in rates of secondary malignancies in patients receiving dexrazoxane as a cardioprotective agent with anthracyclines; however, some evidence suggests the risk may be increased in certain patients.  The evidence from the study by Tebbi and colleagues that sparked this debate has been called into question.  However, a meta-analysis combining this data with other randomized controlled trials also shows a trend toward higher rates of secondary malignancies in some dexrazoxane- treated patients.9,17  It is important to consider the limitations of the trials that suggest this trend toward increased likelihood of secondary malignancy as well as the characteristics of the patients who developed secondary malignancy.  Although these trials were not specifically designed to evaluate efficacy or toxicity of dexrazoxane when used as a cardioprotectant, they do suggest that dexrazoxane may accentuate the risk of secondary malignancy when used with cancer therapies that contribute independently to secondary cancer development, such as treatment with etoposide or treatment of patients with HL. In randomized controlled trials that were designed to evaluate efficacy and toxicity of dexrazoxane when used as a cardioprotectant,  no significant difference in secondary malignancy has been found; however, these trials contained more patients with ALL than HL.16,18  The body of evidence to support the use of dexrazoxane as a cardioprotectant in pediatric patients is growing and until more data are available that conclusively addresses the inconsistencies in the literature, clinicians should cautiously weigh the possible risks and expected benefits of dexrazoxane use for each patient. 

References:

1.        Howlader N, Noone A, Krapcho M, et al. SEER Cancer Statistics Review, 1975–2010, National Cancer Institute. Bethesda, MD; 2016. http://seer.cancer.gov/csr/1975_2013/. Accessed August 29, 2016.

2.        Raj S, Franco VI, Lipshultz SE. Anthracycline-induced cardiotoxicity: A review of pathophysiology, diagnosis, and treatment. Curr Treat Options Cardiovasc Med. 2014;16(6):315.

3.        Van Der Pal HJ, Van Dalen EC, Van Delden E, et al. High risk of symptomatic cardiac events in childhood cancer survivors. J Clin Oncol. 2012;30(13):1429-1437.

4.        Zinecard [package insert].  New York, NY: Pfizer, Inc.; 2014.

5.        Totec [package insert].  San Diego, CA: Apricus Pharmaceuticals USA, Inc.; 2013.

6.        Anderson B. Dexrazoxane for the prevention of cardiomyopathy in anthracycline treated pediatric cancer patients. Pediatr Blood Cancer. 2005;44(7):584-588.

7.        Lipshultz SE, Rifai N, Dalton VM, et al. The effect of dexrazoxane on myocardial injury in doxorubicin-treated children with acute lymphoblastic leukemia. N Engl J Med. 2004;351(2):145-153.

8.        Varan A, Kebudi R. Secondary malignant neoplasms after childhood cancer. Pediatr Hematol Oncol. 2011;28(5):345-353.

9.        Tebbi CK, London WB, Friedman D, et al. Dexrazoxane-associated risk for acute myeloid leukemia/myelodysplastic syndrome and other secondary malignancies in pediatric Hodgkin’s disease. J Clin Oncol. 2007;25(5):493-500.

10.      Lipshultz SE, Lipsitz SR, Orav EJ. Dexrazoxane-associated risk for secondary malignancies in pediatric Hodgkin’s disease: a claim without compelling evidence. J Clin Oncol. 2007;25(21):3179-3179.

11.      Hellmann K. Dexrazoxane-associated risk for secondary malignancies in pediatric Hodgkin’s disease: A claim without evidence [1]. J Clin Oncol. 2007;25(29):4689-4690.

12.      Le Deley MC, Leblanc T, Shamsaldin A, et al. Risk of secondary leukemia after a solid tumor in childhood according to the dose of epipodophyllotoxins and anthracyclines: a case-control study by the Société Française d’Oncologie Pédiatrique. J Clin Oncol. 2003;21(6):1074-1081.

13.      Silverman LB, Stevenson KE, O’Brien JE, et al. Long-term results of Dana-Farber Cancer Institute ALL Consortium protocols for children with newly diagnosed acute lymphoblastic leukemia (1985-2000). Leukemia. 2010;24(2):320-334.

14.      Vrooman LM, Neuberg DS, Stevenson KE, et al. The low incidence of secondary acute myelogenous leukaemia in children and adolescents treated with dexrazoxane for acute lymphoblastic leukaemia: A report from the Dana-Farber Cancer Institute ALL Consortium. Eur J Cancer. 2011;47(9):1373-1379.

15.      Seif A, Walker D, Li Y, et al. Dexrazoxane exposure and risk of secondary acute myeloid leukemia in pediatric oncology patients. Pediatr Blood Cancer. 2015;62:704-709.

16.      Chow EJ, Asselin BL, Schwartz CL, et al. Late mortality after dexrazoxane treatment: A report from the Children’s Oncology Group. J Clin Oncol. 2015;33(24):2639-2645.

17.      Shaikh F, Dupuis LL, Alexander S, Gupta A, Mertens L, Nathan PC. Cardioprotection and second malignant neoplasms associated with dexrazoxane in children receiving anthracycline chemotherapy: a systematic review and meta-analysis. J Natl Cancer Inst. 2016;108(4):djv357.

18.      Asselin BL, Devidas M, Chen L, et al. Cardioprotection and safety of dexrazoxane in patients treated for newly diagnosed T-cell acute lymphoblastic leukemia or advanced-stage lymphoblastic mon-Hodgkin lymphoma: a report of the Children’s Oncology Group Randomized Trial Pediatric Oncology Group. J Clin Oncol. 2016;34(8):854-862.

19.      Hensley ML, Hagerty KL, Kewalramani T, et al. American society of clinical oncology 2008 clinical practice guideline update: Use of chemotherapy and radiation therapy protectants. J Clin Oncol. 2009;27(1):127-145.

20.      Kremer LCM, Van Dalen EC. Dexrazoxane in children with cancer: From evidence to practice. J Clin Oncol. 2015;33(24):2594-2596.

Prepared by:
Sara Brown, PharmD
PGY2 Pediatric Resident
College of Pharmacy
University of Illinois at Chicago

September 2016

The information presented is current as August 1, 2016. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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What are alternatives to sublingually administered ophthalmic atropine for treatment of noisy breathing in terminally ill patients?

Introduction
As of July 2016, there is a shortage of atropine sulfate ophthalmic solution.1 This anticholinergic medication is commonly used to induce mydriasis during ophthalmic examinations and to reduce secretions of the respiratory tract.2,3 Also, atropine is often utilized in terminally ill patients who experience distressing noisy breathing (ie, “death rattle”), a common symptom in the terminal days of life that occurs because of respiratory secretions.4  The ophthalmic solution formulation of atropine is often administered as sublingual drops in these patients to avoid subcutaneous infusions and to prevent somnolence.5 Throughout the shortage of atropine ophthalmic solution, questions have arisen regarding appropriate alternatives for patients experiencing end-of-life secretions and noisy breathing.

Guideline recommendations for anticholinergic medications
Anticholinergic medications are the standard of care in treatment of noisy breathing due to respiratory secretions in terminally ill patients.3 The antimuscarinic effect of these agents can help dry secretions, but it also may cause anticholinergic adverse events, including blurred vision, sedation, confusion, palpitations, and urinary retention. These adverse events increase proportionally with the drugs’ ability to cross the blood-brain barrier. Tertiary amines (scopolamine and atropine) cross the blood-brain barrier, while quaternary amines (hyoscyamine and glycopyrrolate) do not.3 For this reason, recommendations generally favor quaternary amines, specifically glycopyrrolate.

Few recommendations exist regarding the use of medications to reduce noisy breathing in terminally ill patients.3 Practices vary, but the most commonly recommended medications are scopolamine, atropine, and glycopyrrolate. Some guidance is available from the 2016 National Comprehensive Cancer Network (NCCN) guidelines for palliative care. In these patients with a life expectancy of weeks to days, NCCN provides dosing recommendations for scopolamine, atropine, and glycopyrrolate administered via various routes (Table). Other review sources generally mirror recommendations from NCCN, although some dosages differ.3,6 They also give preference to glycopyrrolate because it has fewer central adverse events because of its quaternary amine structure. Notably, transdermal administration of scopolamine patches is associated with a time to onset of approximately 12 hours.7 Therefore, scopolamine patches are not an optimal selection in imminently dying patients. A subcutaneous injection of scopolamine can be administered at the time of patch placement or in patients with inadequate control of secretions.

 

Table. Recommended medication regimens for treatment of noisy breathing.3,7

Drug

Route of administration: dosage

Atropine

SL: 1% ophthalmic solution, 1 to 2 drops7 or 1 to 3 drops3 every 4 to 6 hours as needed

SC/IM: 0.2 to 0.5 mg3

Glycopyrrolate

IV: 0.2 to 0.4 mg every 4 hours as needed 7 or 0.4 to 1.2 mg/day by continuous infusion3

PO: 1 mg 1 to 4 times daily (maximum 8 mg/24 hours)3

SC: 0.2 to 0.4 mg every 4 hours as needed7, 0.1 to 0.2 mg every 4 to 6 hours3, or 0.4 to 1.2 mg/day by continuous infusion3

Hyoscyamine sulfate

PO/SL: 0.125 to 0.375 mg every 4 to 6 hours3

Scopolamine

IV: 0.1 to 0.2 mg/hour by continuous infusion3

PO: 0.2 to 0.4 mg every 4 to 6 hours 3

SC: 0.4 mg every 4 hours as needed7, 0.2 to 0.5 mg 4 to 6 times daily3, or 0.1 to 0.2 mg/hour by continuous infusion3

TD: 1.5 mg patches, 1 to 3 patches every 3 days 3,7

Abbreviations: IM=intramuscular; IV=intravenous; PO=oral; SL=sublingual; SQ=subcutaneous; TD=transdermal.

Published evidence for treatment of noisy end-of-life breathing
There is very little systematic study of atropine or other anticholinergics when used to reduce noisy breathing and respiratory secretions in the care of terminally ill patients.5 Although systematic reviews are available, they are derived from very few high-quality individual studies. A 2008 Cochrane meta-analysis of interventions for noisy breathing at the end of life concluded there was no significant difference among treatments in reduction of noise intensity based on 4 randomized controlled trials (RCTs) evaluating atropine, glycopyrrolate, scopolamine, hyoscine butylbromide (not available in US),  octreotide, and scopolamine.8 However, because of the emotional distress that patients and families may experience because of noisy breathing and the desire for clinicians to alleviate this distress, the authors do not explicitly recommend against the use of these medications. Instead, they suggest that monitoring for adverse events be performed when they are used. A subsequent systematic review including a total of 11 RCTs and retrospective studies also found no significant benefit with any anticholinergic medication in reducing the intensity of noisy breathing.4 Among all included studies, only 2 prospective studies identified significant differences, which were contradictory – each favored either scopolamine or glycopyrrolate in direct comparisons.9,10 Other publications have described the use of octreotide and hyoscine butylbromide, which similarly found no difference between these agents and comparators in reduction of noisy breathing intensity.4

Conclusion
Overall, literature does not conclusively support a benefit with any anticholinergic medication, including sublingually administered atropine solution, to reduce end-of-life noisy breathing. This is recognized by various publications; however, the emotional distress caused by this condition and the desire of patients and families to pursue comfort measures may nonetheless lead to the use of anticholinergic medications in this indication. In the absence of atropine availability, other medications recommended for treatment of noisy breathing include hyoscyamine, scopolamine, and glycopyrrolate.

References

1.         ASHP Drug Shortages. American Society of Health-System Pharmacists website. http://www.ashp.org/menu/DrugShortages. Accessed August 4, 2016.

2.         Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. http://clinicalpharmacology.com/. Accessed August 4, 2016.

3.         Muller-Busch HC, Jehser T. Death rattle. In: Walsh D, Caraceni AT, Fainsinger R, et al., eds. Palliative Medicine. Philadelphia, PA: Saunders-Elsevier; 2009: 956-960.

4.         Lokker ME, van Zuylen L, van der Rijt CC, van der Heide A. Prevalence, impact, and treatment of death rattle: a systematic review. J Pain Symptom Manage. 2014;47(1):105-122.

5.         Shinjo T, Okada M. Atropine eyedrops for death rattle in a terminal cancer patient. J Palliat Med. 2013;16(2):212-213.

6.         Bruera E, Dev R. Overview of managing common non-pain symptoms in palliative care. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate; 2016. http://www.uptodate.com.

7.         Palliative care. National Comprehensive Cancer Network website. https://www.nccn.org/professionals/physician_gls/PDF/palliative.pdf. Published November 17, 2015. Updated July 29, 2016.

8.         Wee B, Hillier R. Interventions for noisy breathing in patients near to death. Cochrane Database Syst Rev. 2008(1):CD005177.

9.         Hugel H, Ellershaw J, Gambles M. Respiratory tract secretions in the dying patient: a comparison between glycopyrronium and hyoscine hydrobromide. J Palliat Med. 2006;9(2):279-284.

10.       Back IN, Jenkins K, Blower A, Beckhelling J. A study comparing hyoscine hydrobromide and glycopyrrolate in the treatment of death rattle. Palliat Med. 2001;15(4):329-336.

September 2016

The information presented is current as of August 8, 2016.  This information is intended as an educational piece and should not be used as the sole source for clinical decision making.

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How should medications be appropriately managed following bariatric surgery?

Introduction

According to the Centers for Disease Control and Prevention (CDC), over one-third (34.9%) of adult Americans are obese.1  Obesity is a chronic condition for many individuals and is associated with a variety of comorbidities including heart disease, stroke, type 2 diabetes, cancer, depression, and degenerative joint disease.1,2  For obese individuals, successfully attaining and maintaining an appropriate weight through diet and exercise alone can be quite difficult.  Concurrent use of weight loss medications, such as orlistat or lorcaserin, does not usually produce significant weight reduction and these products may be associated with significant adverse effects.2  Therefore, more and more patients are turning toward bariatric surgery as a viable option to reduce significant weight gain and potentially reverse concurrent health conditions.  An estimated 179,000 bariatric surgeries were performed in 2013 with the primary procedure being sleeve gastrectomy (42.1%) followed by the Roux-en-Y gastric bypass (RYGB; 34.2%), and gastric banding (14%).3 

Bariatric surgery and medications

The growth in bariatric surgical procedures has increased concerns with regard to the effects these surgeries may have on medications due to pharmacokinetic changes and rapid, extensive weight loss.3  For most medications, specific clinical data on the effects of bariatric procedures are unavailable.  Additionally, the surgical procedure performed may play a role in the occurrence and magnitude of an effect.  For example, gastric banding, which simply reduces stomach size, may result in fewer pharmacokinetic effects than RYGB, which bypasses portions of the small intestine in addition to decreasing stomach size.

In a recently published 2016 clinical review, Bland and colleagues evaluated long-term pharmacotherapy considerations in the bariatric surgery patient population with an emphasis on recommendations for chronic disease management.3  A summary of their recommendations for various disease states is presented in Table 1.

Table 1.  Chronic disease management in bariatric surgery.3

Disease State

Comments

Hypertension
  • Diuretics should be the first antihypertensive agents discontinued in the majority of patients in order to limit volume depletion, hypotension, and acute kidney injury; however, these agents should be reinstated as soon as possible after patients are maintained on a long-term diet due to their morbidity and mortality benefits
  • Beta-blockers should be continued in the postoperative period and chronically in patients with CAD, HF, or MI
  • ACEIs or ARBs should be continued indefinitely for their renal protective effects in patients with CKD; however, a dose reduction or discontinuation in the immediate postoperative period may be needed in order to avoid hypotension or acute kidney injury
  • CCBs are excellent options in the perioperative period (and as chronic therapy) due to their lack of effect on renal function and volume status

Hyperlipidemia
  • Bariatric procedures may have a positive effect on various lipid parameters; however, more studies are needed in order to definitively determine these effects and whether or not lipid-lowering therapy needs to be adjusted or discontinued

Anticoagulation
  • Unfractionated heparin may potentially be more useful for VTE treatment in this obese/overweight patient population due to the lack of clinical data with LMWHs
  • Appropriate management of warfarin therapy may be quite challenging after bariatric surgery as patients generally ingest significantly less vitamin K initially (due to a clear liquid or full liquid diet) and warfarin absorption may be altered; INR values should be monitored closely
  • May be prudent to withhold warfarin or reduce the dose in the early postoperative period until the patient is advanced to solid foods
  • Minimal clinical data are available for the novel oral anticoagulants; however, apixaban is largely absorbed in the colon and is not likely to be affected by bariatric procedures

Diabetes
  • Immediately after surgery, sulfonylureas should be discontinued to minimize the risk of hypoglycemia
  • Due to hypoglycemic risk, insulin dosages may need to be reduced by 50% to 75% immediately after surgery 
  • Avoid thiazolidinediones after bariatric procedures; these agents potentiate weight gain
  • Metformin does not produce weight gain or hypoglycemia and therefore may be an ideal agent in the postoperative setting; however, the drug does cause diarrhea which may be worse in the post-bariatric surgery population

Contraception
  • Rapid weight loss after bariatric surgery can result in improved fertility and the potential for an unplanned pregnancy
  • Women should avoid pregnancy for 12 to 18 months post-surgery
  • Use of a copper or levonorgesterol IUD remains the most recommended contraceptive method; IUD placement avoids the potential for reduced absorption of oral contraceptives or weight gain associated with hormonal implants

Urinary symptoms
  • Urinary symptoms (increased frequency and urgency; incontinence) are common in obese individuals and many patients receive pharmacologic therapy for these symptoms
  • Patients who receive anticholinergics for urinary symptoms should be monitored closely for hypotension and anticholinergic effects following bariatric surgery; a discontinuation of therapy may be needed after significant weight loss is achieved

Psychiatric diseases
  • Little clinical data are available regarding the management of psychiatric medications following bariatric surgery
  • Patients should be monitored closely for symptom exacerbation especially during the initial 6 months after the procedure

ACEI(s)=angiotensin converting enzyme inhibitor(s); ARB(s)=angiotensin receptor blocker(s); CAD=coronary artery disease; CCB(s)=calcium channel blocker(s); CKD=chronic kidney disease; HF=heart failure; INR=international normalized ratio; IUD=intrauterine device; LMWH(s)=low molecular weight heparin(s); MI=myocardial infarction; VTE =venous thromboembolism

Beyond conventional medications, vitamin and mineral supplementation may be required in bariatric surgical patients in order to prevent or treat deficiencies.3  In the immediate postoperative setting (ie., 3 to 6 months after the procedure), patients should receive 2 chewable adult multivitamins plus mineral supplements on a daily basis.  In order to optimize absorption, chewable or liquid formulations are generally recommended.  Recommended intake for vitamins and minerals after gastric banding and gastric bypass are summarized in Table 2.

Table 2.  Vitamin and mineral supplementation recommendations for patients after gastric banding and gastric bypass.3

Supplement

Recommended Amount (as % of Recommended Daily Allowance)

Comments

Ascorbic acid

200

May be given with iron supplements in order to aid absorption

Calcium*

100

Administer 1200 to 1500 mg of elemental calcium orally daily; use a calcium citrate salt as it does not rely on gastric pH for absorption

Copper

50

Routine supplementation may be achieved with recommended multivitamin use

Cyanocobalamin

300

Administer 1000 mg orally daily if adequate absorption is confirmed; if oral absorption is inadequate, weekly intranasal therapy or monthly SC or IM therapy (1000 mg) may be needed

Folate

150

Administer 400 mg orally daily usually provided through multivitamin and mineral intake

Iron

50

At least 45 to 60 mg of oral elemental iron daily, provided either in multivitamins or supplements; data on the ideal iron form for supplementation are lacking

Thiamine

150

For routine supplementation, thiamine within a multivitamin should be adequate; however, for patients with signs and symptoms of deficiency, thiamine 500 mg IV for 3 to 5 days followed by a 250 mg IV dose daily for an additional 3 to 5 days or until resolution of symptoms is recommended

For those patients who have had Wernicke’s encephalopathy, additional supplementation should occur indefinitely (minimum of 100 mg orally daily)

Vitamin D*

100

At least 3000 IU orally per day; if vitamin D deficiency is documented, oral doses of vitamin D2 or D3 50,000 IU once daily or once weekly may be required

Zinc

33

Routine supplementation may be achieved with recommended multivitamin use

*The use of powdered vs tablet formulations is recommended in order to increase absorption.

IM=intravenous; IU=international units; IV=intravenous; SC=subcutaneous.

Conclusion

The number of bariatric surgical procedures in the United States has increased dramatically over the last decade.  However, limited evidence-based recommendations are available regarding medication management in the immediate and prolonged postoperative setting.  Bland and colleagues recently reviewed the data regarding chronic disease management in this patient population.  Their recommendations may be a starting point for clinicians when determining appropriate medication therapy; however, a consistent reassessment of each medication may be required as patients advance through the post-surgical period.

References
 

1.  Adult obesity facts.  Centers for Disease Control and Prevention website.  https://www.cdc.gov/obesity/data/adult.html.  Updated September 21, 2015.  Accessed August 16, 2016.

2.  Miller AD, Smith KM.  Medication and nutrient administration considerations after bariatric surgery.  Am J Health-Syst Pharm. 2006;63(19):1852-1857.

3.  Bland CM, Quidley AM, Love BL, Yeager C, McMichael B, Bookstaver PB.  Long-term pharmacotherapy considerations in the bariatric surgery patient.  Am J Health-Syst Pharm. 2016;73(16):1230-1242.

September 2016

The information presented is current as of August 16, 2016.  This information is intended as an educational piece and should not be used as the sole source for clinical decision making.