- Email: [email protected]
The Efficacy and Safety of Megestrol Acetate in Protein-Energy Wasting due to Chronic Kidney Disease: A Systematic Review
ORIGINAL RESEARCH
The Efficacy and Safety of Megestrol Acetate in Protein-Energy Wasting due to Chronic Kidney Disease: A Systematic Review Lori D. Wazny, BSc (Pharm), PharmD,*,†,‡ Stewart Nadurak,‡ Cali Orsulak, BSc (Pharm), CDE,†,‡ Lori Giles-Smith, BA (Hons), MLIS,§ and Navdeep Tangri, MD, PhD, FRCPC{,‡ Objective: To assess the efficacy and safety of oral megestrol acetate (MA) in the management of protein-energy wasting in patients with chronic kidney disease (CKD). Design: A systematic review of English published literature from 1970 until April 1, 2014. Subjects: All adult patients with CKD including both dialysis and non–dialysis-dependent. Intervention: Oral MA. Main Outcome Measure: Efficacy outcomes included changes in body weight, serum albumin, and appetite. Safety outcomes examined included adverse events (AEs) and deaths. Results: A total of 9 studies met the inclusion criteria. No data on MA in non-dialysis CKD patients were available. Statistically significant increases in body weight (range 1.5-5 kg) were reported in 6 trials. Statistically significant increases in albumin (range of 0.22 g/dL-0.52 g/dL) were observed in 5 trials. Improved appetite was observed in 7 trials. All trials were limited by small sample sizes (range 9-32 subjects), short duration (range 8-24 weeks), a high degree of bias, and absence of clinical outcomes such as quality of life or hospitalizations. Forty-seven AEs were reported and included overhydration/excessive fluid gain, diarrhea, hyperglycemia, excessive weight gain, suppressed cortisol levels, thrombophlebitis, nausea/vomiting, confusion/hallucinations, vaginal bleeding, headache/dizziness, and elevated lactate dehydrogenase. There were 26 discontinuations due to death. Conclusion: The current evidence for treatment with MA in patients receiving dialysis is sparse with few high-quality trials. The safety of using MA beyond 24 weeks is unknown, and use of MA is associated with significant AEs. At this time, oral MA should be used with significant caution, and only when other treatment options are unavailable. Ó 2016 by the National Kidney Foundation, Inc. All rights reserved.
Introduction
P
ROTEIN-ENERGY WASTING IS common in patients with chronic kidney disease (CKD) and those on dialysis. This syndrome is defined as a loss of appetite, weight loss, and tissue wasting accompanied by a decrease in muscle mass and adipose tissue1 and is associated with a decreased quality of life, higher risks of hospitalization, and increased risk of death.2,3
*
College of Pharmacy, University of Manitoba, Winnipeg, MB, Canada. Pharmacy Program, Winnipeg Regional Health Authority, Winnipeg, MB, Canada. ‡ Manitoba Renal Program, Manitoba, Canada. § University of Manitoba, Health Sciences Libraries, Winnipeg, MB, Canada. { Departments of Medicine and Community Health Sciences, University of Manitoba, Winnipeg, MB, Canada. Financial Disclosure: The authors declare that they have no relevant financial interests. Address correspondence to Lori D. Wazny, BSc (Pharm), PharmD, Department of Pharmaceutical Services, Health Sciences Centre, 820 Sherbrook St., Winnipeg, Manitoba, Canada R3A 1R9. E-mail: [email protected] Ó 2016 by the National Kidney Foundation, Inc. All rights reserved. 1051-2276/$36.00 http://dx.doi.org/10.1053/j.jrn.2015.11.002 †
Journal of Renal Nutrition, Vol -, No - (-), 2015: pp 1-9
Complex signaling pathways and mechanisms are involved in the pathogenesis of protein-energy wasting in patients with CKD. These include the ubiquitinproteasome system, caspase-3, insulin resistance, endogenous glucocorticoids, metabolic acidosis, inflammation, and alterations in sex hormones.4 Appetite stimulants, nutritional supplements, and aerobic and strength training exercise have been used to stimulate appetite and reduce muscle wasting in patients with CKD, with conflicting reports of success.4 Megestrol acetate (MA), a synthetic progesterone, has been used as an appetite stimulant in patients with cancer, acquired immunodeficiency syndrome (AIDS), chronic obstructive pulmonary disease, cystic fibrosis, and in the elderly with CKD.1,2 The exact mechanism by which MA increases appetite is unknown.1 A recent meta-analysis of 35 trials in patients with cancer and AIDS showed that treatment with MA improves appetite and was associated with a slight weight gain (approximately 2 kg) compared with placebo. However, edema, thromboembolic events, and deaths were more frequent in patients treated with MA.1 This particular meta-analysis did not include any studies of MA in patients with CKD. As such, the efficacy and safety of MA in this 1
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patient population are not well described. To address this evidence gap, we performed a systematic review to assess the efficacy and safety of MA in the management of protein-energy wasting in patients with CKD.
Methods Search Strategy and Sources Our aim was to identify randomized controlled trials and observational studies assessing the efficacy and safety of MA therapy for anorexia or cachexia in adult patients with CKD. The search strategy (Appendix S1) was developed in collaboration with a medical librarian. We searched EMBASE, IPA, CINAHL, Cochrane, PubMed, and Scopus using this strategy for the years 1970 until April 1, 2014. Inclusion and Exclusion Criteria Articles were screened as abstracts and then the full texts were independently by 2 review authors (L.D.W. and C.O.). Disagreements were resolved by a third review author (N.T.). All English language prospective and observational studies of MA in humans with CKD or receiving dialysis that examined either change in serum albumin, body weight, or appetite as an outcome were included. Data Abstraction From the eligible studies, we collected information on study characteristics (MA dose, duration, dialysis type, inclusion and exclusion criteria, sample sizes), efficacy measures (changes in body weight, serum albumin or appetite), and safety (occurrence of any adverse event (AE), discontinuation due to AE, and discontinuation due to death). Risk of Bias Assessment and Grading the Quality of the Evidence We used the Cochrane Collaboration’s tool for assessing risk of bias for the randomized controlled trials.5 The Cochrane tool classifies the overall risk of bias into 3 grades: low risk if bias is unlikely to alter the results seriously, high risk if bias may alter the results seriously, and the remaining cases judged as unclear. For the observational studies, we used the NewcastleOttawa Quality Assessment Scale to evaluate risk of bias. The Newcastle-Ottawa Quality Assessment Scale evaluates studies for potential biases in selection, comparability, and outcome.6 Statistical Analysis Due to the clinical heterogeneity in the study design, population, and outcomes, a meta-analysis was not performed.
Results Search Results We screened 286 abstracts from the medical databases and evaluated 15 articles for full-text review. Of these, 3 randomized controlled trials and 6 observational studies were included in the final systematic review (Fig. 1).7
Study Characteristics Table 1 summarizes the randomized controlled trials. The trials tested a wide range of MA dosages varying from 80 mg to 800 mg per day with universally small number of subjects across all trials (range 9-22 subjects). Inclusion criteria also varied with 1 trial defining anorexia using an appetite questionnaire,8 whereas the others used serum albumin levels and other laboratory testing to determine which cachexic patients were eligible.9,10 The study durations were all short and ranged from 8 to 24 weeks. In the observational studies (Table 2), a wider range of MA dosages varying from 40 mg to 800 mg per day were observed with a small number of study subjects (range 9-32 subjects). Inclusion criteria included serum albumin less than 3.5 to 3.8 g/dL in all but 1 study, which used an appetite questionnaire.11 The study durations ranged from 12 to 24 weeks length. Only patients receiving peritoneal dialysis or hemodialysis were included. Baseline Patient Characteristics Participants’ baseline characteristics of age, serum albumin, and body weight were balanced in the randomized controlled trials. However, the trial by Yeh et al.9 had a mean difference of 8 years between the control and the study arms with the control group being significantly older at 75 years of age. The observational studies had a mean age range between 56 and 70 years. Baseline serum albumin in all observational studies ranged from 2.7 6 1 g/dL to 3.8 6 5.5 g/dL and baseline body weight ranged from 51.3 6 3.4 kg to 66.5 6 11.4 kg. Efficacy Tables 3 and 4 summarize the primary efficacy outcomes of change in serum albumin, body weight, and appetite for the randomized controlled trials and observational studies, respectively. Two of the three randomized controlled trials demonstrated a statistically significant increase in body weight for the MA group.8,9 The increase in average body weight varied from 1.7 kg to 5 kg in these 2 studies. However, only one of these trials also observed a statistically significant increase in serum albumin and appetite.8 The third study demonstrated no statistically significant change in body weight but did observe a statistically significant increase in serum albumin along with ‘‘almost all’’ patients reporting improved appetite.10 However, it is unclear whether a validated appetite questionnaire was used to assess this efficacy marker. It should be noted that the MA dose used in this particular trial was significantly lower at 40 mg twice daily, and this trial also had the shortest duration of 8 weeks.10 Four of 6 (67%) of the observational studies reported a statistically significant increase in body weight, and 3 of the 6 studies (50%) noted a statistically significant increase in serum albumin. Body weight increased by 1.5 kg to
SYSTEMATIC REVIEW OF MEGESTROL IN CKD
Records identified through database searching (n = 390 )
3
Additional records identified through other sources (n = 3)
Records after duplicates removed (n = 286)
Records screened (n = 286)
Records excluded (n = 271)
Full-text articles excluded, with reasons (n = 6)
Full-text articles assessed for eligibility
Studies included in qualitative synthesis (n = 9 )
Figure 1. Flow diagram.
4.6 kg in these studies, and serum albumin increased by 0.22 g/dL to 0.52 g/dL. Appetite was assessed in all but 1 study, and all patients reported increased appetite.
Safety Information about any AE, discontinuation due to clinical AEs, or death from any cause was available in 2 of the randomized controlled trials (Table 5).9,10 The only AE attributable to MA was an abnormal adrenocorticotropic hormone stimulation test; the other AEs were not believed to be drug-related (metatarsal bone fracture, dialysis-line sepsis, acute diverticulitis). One discontinuation due to death was reported in the MA arm of these trials. The cause of death was not specified.10 In contrast, 43 AEs were reported in the observational studies with 21 discontinuations from the study due to an AE (Table 6). AEs included overhydration/excessive fluid gain (11 subjects),12,13 diarrhea (8 subjects),12,14 hyperglycemia (6 subjects),12,13 excessive weight gain (greater than 5% increase in 4 weeks; 6 subjects),12 decreased baseline cortisol levels (3 subjects),11 thrombo-
phlebitis (3 subjects),11,12 nausea/vomiting (3 subjects),12 confusion/hallucinations (2 subjects),14 vaginal bleeding (1 subject),15 headache/dizziness (1 subject),14 and elevated lactate dehydrogenase (1 subject).14 All AEs were reported to disappear soon after discontinuation of MA. None of the 25 deaths in the observational trials was believed to be due to MA treatment.
Risk of Bias in the Included Studies and the Quality of the Evidence A risk of bias summary table of the included studies can be found in Appendix S2. We observed a high degree of potential bias in the reported randomized trials. The trials by Yeh et al. 9 and Monfared et al.10 had deficiencies in blinding, treatment allocation, and various other biases such as a wide mean age range between arms, and a very low MA dosage all of which could have significantly altered the results. The Fernandez-Lucas 2014 study was a letter to the editor instead of a complete report, and as such, the risk of bias was unclear as not enough study methodology was reported.8
4
Table 1. Study Descriptors, Randomized Controlled Trials (n 5 3) 8-10 MA Dose
Duration (wk)
Population
Inclusion Criteria
Exclusion Criteria
Number of Subjects
Fernandez-Lucas et al. 2014
160 mg once daily
12
HD
NR
19 (10 MA, 9 control)
MA 73 6 9 Control 69 6 18
Yeh et al. 2010
800 mg daily
20 1 4
HD
NR
9 (4 MA, 5 control)
MA 67.5* Control 75.4*
Monfared et al. 2009
40 mg twice daily
8
HD
Anorexia as defined by the appetite questionnaire from the HEMO and DOPPS studies .40 y old, diagnosed with cachexia, with 2 or more of the following: albumin level , 4.0 g/dL, total cholesterol , 150 mg/ dL, protein catabolic rate , 0.8 g/kg/d, and predialysis serum urea nitrogen , 60 mg/dL. Serum albumin , 3.5 g/dL for 2 mo, length of HD . 3 mo, CRP , 0.80 mg/dL
22 (11 MA, 11 control)
MA 54.09 6 4.09 Control 5 59.91 6 3.67
Study
CHF, congestive heart failure; CRP, C-reactive protein; DM, diabetes mellitus; DOPPS, Dialysis Outcomes and Practice Patterns Study; HD, hemodialysis; HEMO, Hemodialysis Study; MA, megestrol acetate; NR, not reported; SD, standard deviation. *Standard deviation not reported.
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Malignancy or active autoimmune disease, DM with debilitating endorgan damage, deep anemia, decompensated CHF, abnormal liver function, corticosteroid therapy, symptoms of inflammation, or infectious disease during study
Age, Mean 6 SD (y)
Table 2. Study Descriptors, Observational Studies (n 5 6) 11-18 Study
Duration (wk)
Golebiewska et al. 2012, 2011, 2009
160 mg once daily
24
Fernandez-Lucas et al., 2010
160 mg once daily
Rammohan et al., 2005
Population
Number of Subjects
Age, Mean 6 SD (y)
12
69.97 6 10.8
16
64.1*
10
60.2*
NR Any obstruction to oral intake; any digestive or absorptive impairment
32 9†
64.19 6 13.8 68.5 (range 44-87)*
NR
16
56 6 4
Inclusion Criteria
Exclusion Criteria
HD, PD
Dialysis for at least 3 mo, serum albumin # 3.8 g/dL
12
HD
Anorexia as defined by appetite questionnaire
400 mg once daily
16
HD, PD
Costero et al., 2004 Boccanfuso et al., 2000
160 mg daily 400 mg twice daily
12 12
PD HD
Lien and Ruffenach, 1996
20 mg twice daily
17.2 6 2.4
Albumin , 3.7 g/dL, dialysis for at least 4 mo, ABW , 85% IBW or BMI , 20 with 1 of the following: (1) recent unplanned weight loss .5% to 10% of target weight within a 6mo period not caused by intercurrent illness (2) serum albumin , 3.7 g/ dL for 3 consecutive mo NR HD for at least 2 mo; serum albumin , 3.5 g/dL for 2 mo; high nutritional risk based on dietitian assessment Serum albumin , 3.5 g/dL for 2 consecutive mo, adequate dialysis
Current use of glucocorticoids, inadequate dialysis (Kt/ V , 1.2 HD or ,2 PD) No calorie or protein supplements oral or intravenous Severe CHF, untreated DVT, uncontrolled DM, chronic liver disease, concurrent use appetite stimulants, use of total or IDPN in past 6 mo, concurrent use glucocorticoids, inadequate dialysis (defined as Kt/V , 1.2 HD and ,2 PD)
HD, PD
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MA Dose
ABW, actual body weight; BMI, body mass index; CHF, congestive heart failure; DM, diabetes mellitus; DOPPS, Dialysis Outcomes and Practice Patterns Study; DVT, deep vein thrombosis; HEMO, Hemodialysis Study; HD, hemodialysis; IBW, ideal body weight; IDPN, intradialytic parenteral nutrition; MA, megestrol acetate; NR, not reported; PD, peritoneal dialysis; SD, standard deviation. *SD not reported. †Only patients who completed 12 weeks were included.
5
6
Table 3. Efficacy Measures, Randomized Controlled Trials (n 5 3) 8-10 Efficacy Measures Study
Interventions MA 160 mg daily control group
Yeh et al. 2010
MA 800 mg once daily plus weights 23/wk for 40 min before HD control group
Monfared et al. 2009
MA 40 mg twice daily control group
MA 58.1 6 10.7 to 59.8 6 9.9 P 5 .003 (baseline-mo 3) Control 61.9 6 7.2 to 61.1 6 7 P 5 .100 (baseline-mo 3)
Serum Albumin 6 SD (g/ dL)
MA 11.7 Control 20.8
MA 3.25 6 0.62 to 3.49 6 0.68 (P 5 009) control 3.33 6 0.57 to 3.31 6 0.46 (P 5 .608)
NR
MA 15 6 1.3 Control 20.68 6 1.2 (P 5 .018)
No statistically significant changes from initial to 24-wk measurement both within and between the groups
MA 5 59.45 6 3.07 baseline Control 5 55.64 6 2.7 baseline ‘‘No significant change in MA group weight from baseline to 2 mo’’ (P . .5) End weights not reported.
NR
MA 3.31 6 0.31 to 4.41 6 0.31 (P 5 .008) Control 3.35 6 0.21 to 3.02 6 0.48 (P 5 .201) (Difference between group is P 5 .002)
Change in Serum Albumin (g/dL) MA 10.24 Control 20.02
NR
MA 11.1 Control 20.33
Appetite Nine of the 10 patients treated with MA and 4 of the 9 patients treated with placebo reported an improvement in appetite (P 5 .046) Appetite was measured on a 5-point Likert scale (1, very poor, 5, excellent). MA score 1.30 6 0.8 versus 0.5 6 0.3 placebo (P 5 NS) Almost all patients who received MA reported improved appetite.
DOPPS, Dialysis Outcomes and Practice Patterns Study; HEMO, Hemodialysis Study; HD, hemodialysis; MA, megestrol acetate; NR, not reported; NS, not statistically significant; SD, standard deviation.
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Fernandez-Lucas et al. 2014
Body Weight 6 SD (kg)
Change in Body Weight (kg)
7
MA 20 mg twice daily Lien and Ruffenach, 1996
DOPPS, Dialysis Outcomes and Practice Patterns Study; HEMO, Hemodialysis Study; MA, megestrol acetate; NR, not reported; NS, not statistically significant; SD, standard deviation. *Efficacy results for the 9 patients who completed at least 12 weeks.
2.7 6 1 to 3.1 6 2 (P , .05) 12
MA 400 mg once daily MA 160 mg once daily MA 400 mg twice daily
63 6 2 to 65 6 3 (baseline-end of follow-up, NS)
20.6
10.4
2/3 who completed 6 mo reported [ appetite (5-point Likert scale) NR 10.52
10.1
3.44 6 2.7 to 3.54 6 2.7 (NS) 3.14 to 3.66 (stats not done) 11.5
10.3 3.0 6 2 to 3.3 6 2 (P 5 .27) 14.6
11.9
Rammohan et al., 2005 Costero et al., 2004 Boccanfuso et al., 2000*
51.3 6 3.4 to 55.9 6 3.7 (baseline-wk 16, P , .0005) 66.5 6 11.4 to 68 6 10.4 (baseline-mo 3, P , .05) 64.1 to 63.5 (baseline-mo 3, NS)
10.22
All patients reported improved appetite 81% (13/16) reported improved appetite (appetite questionnaire from HEMO & DOPPS studies) All patients reported improvement 69% (22/32) reported [ appetite 10.38
3.65 6 1.82 to 4.03 6 2.71 (P , .001) 3.8 6 5.5 to 4.02 6 4.1 (P , .05) 12.32
MA 160 mg once daily MA 160 mg once daily Golebiewska et al. 2012, 2011, 2009 Fernandez-Lucas et al., 2010
63.26 6 13.04 to 65.58 6 12.53 (baseline-mo 6, P , .01) 58.9 6 10.8 to 60.8 6 10.8 (baseline-mo 3, P , .01)
Serum Albumin 6 SD (g/dL) Body Weight 6 SD (kg) Interventions Study
Table 4. Efficacy Measures, Observational Studies (n 5 6) 11-18
Change in Body Weight (kg)
Efficacy Measures
Change in Serum Albumin (g/dL)
Appetite
SYSTEMATIC REVIEW OF MEGESTROL IN CKD
Most of the observational study populations were highly selected, and none of the studies used a non-exposed cohort group. Over half of the studies demonstrated an interest for a particular outcome, present at the start of the study. We found that most of the studies had significant biases in cohort comparability leaving room for confounding variables to affect results. Only 1 of 6 observational studies followed up with their patients after treatment. Cumulatively, the studies, both observational and interventional, had a high risk of bias (Appendix S2).
Discussion In our systematic review of randomized trials and observational studies of oral MA in adult patients with CKD, we found evidence of modest efficacy as measured by weight gain and improved appetite. Six of the 9 trials demonstrated statistically significant increases in serum albumin (Tables 3 and 4). AEs did not appear to be associated with MA in the randomized controlled trials; however, the observational studies noted a higher incidence of AEs highlighting potential safety concerns. These findings are tempered by small sample sizes, short duration, and absence of hard clinical outcomes such as hospitalizations or mortality. The results of our review are consistent with a previous meta-analysis in patients with cancer and AIDS suggesting that MA results in a modest weight gain, in the range of 2 kg, improved appetite and potentially improved quality of life.1 This previous meta-analysis also compared MA to other drugs including an appetite stimulant (dronabinol), cytokine inhibitors (cyproheptadine, eicosapentaenoic ), anabolic drugs (nandrolone decanoate, fluoxymesterone, oxandrolone), and corticosteroids (prednisolone and dexamethasone). When compared to other drugs, MA showed statistically significant weight improvement but no improvement in appetite or quality of life.1 In our review, the doses of MA varied widely among studies, from 40 mg per day to 800 mg per day. There was no consistency in the change in body weight or serum albumin, or appetite improvement based on the MA dose in our review (Tables 3 and 4). The AEs described in our review are similar to those reported in the literature for MA use in non-CKD patients. In particular, the aforementioned meta-analysis noted an increase in dyspnea, edema, nausea and vomiting, and thrombophlebitis in patients receiving MA.1 Impotence was another significant AE reported in the Cochrane meta-analysis but was not observed in the CKD population.1 The most concerning finding from the meta-analysis was significantly more deaths in patients receiving MA and higher doses of MA producing more deaths.1 However, none of the trials included in our meta-analysis was designed to investigate mortality as a primary end point. Furthermore, the duration of follow-up was short in most trials, so, this unexpected result requires additional research using trials with longer follow-up and using mortality as a primary end point.
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Table 5. Safety, Randomized Controlled Trials (n 5 3) 8-10 Any AE (1 or more)* Study
Discontinuation due to AE*
Discontinuation due to Death
Megestrol Arm (AEs/n)
Placebo Arm (AEs/n)
Megestrol Arm (AEs/n)
Placebo Arm (AEs/n)
Megestrol Arm (AEs/n)
Placebo Arm (AEs/n)
NR 4/4 NR
NR 3/5 NR
NR 1/4 NR
NR 2/5 NR
NR 0/4 1/11
NR 0/5 2/11
Fernandez-Lucas et al. 2014 Yeh et al. 2010 Monfared et al. 2009
AEs, adverse events; NR, not reported. *Not including death.
The limited data on deaths in the randomized trials did not allow us to examine this issue further. Together, these findings suggest that oral MA should be used with significant caution, and only when other treatment options are unavailable. There are important clinical, research and health policy implications to our review. We believe that there is no evidence to suggest any meaningful health benefits with MA beyond weight gain and potential increase in appetite, while there is potential for harm. As such, clinicians prescribing MA should provide this information to their patents before discussing treatment. From a research perspective, we believe that protein-energy wasting is a major health problem in patients with CKD, and further research studies including larger trials with longer duration and clinical outcomes using MA or other agents in this population are urgently needed. Finally, from a policy perspective, payers should restrict the funding for oral MA for the treatment of protein-energy wasting in this population to exceptional cases with no other treatment options, as the drug is likely not efficacious and may be harmful. To our knowledge, this is the first systematic review on the effectiveness and safety of MA for the treatment of protein-energy wasting in patients with CKD. Our search strategy included multiple electronic databases to try to ensure that all the published literature on this topic was identified. We considered the quality of the included studies using validated criteria to assess for bias. In addition, the studies selected for review included different countries and are representative of various health-care systems.
There are several limitations to our review. First, we only included published literature, and thus, the results may be influenced by publication bias. As the included studies evaluated a wide range of MA doses and were of different durations, a meta-analysis was not feasible. All studies evaluated adult patients receiving dialysis, and thus, the results of this review may not be applicable to non–dialysisdependent CKD patients or children with CKD. Patientoriented clinical outcomes such as quality of life, hospitalization rates, and length of stay were not assessed in any of the published CKD studies. Finally, the included trials did not have a long duration of follow-up, and hence, we may not be aware of all serious AEs, including mortality due to this drug. In conclusion, our systematic review found the current evidence for treatment with MA in patients with CKD receiving dialysis is sparse with few high-quality trials. No data on MA in non-dialysis CKD patients were available. The safety of using MA beyond 24 weeks is unknown, and mortality data are lacking. Larger randomized controlled trials are needed to determine the role of MA in treating protein-energy wasting in patients with CKD.
Practical Application MA in adult patients receiving hemodialysis or peritoneal dialysis has a small effect on weight gain and improves appetite. Very limited data are available regarding the safety of long-term use of MA. MA has been associated with an increased risk of fluid retention, diarrhea, hyperglycemia, suppression of cortisol levels, and blood clots in patients receiving dialysis, and patients should be informed of these AEs. No data are available for the use of MA in
Table 6. Safety, Observational Studies (n 5 6) 11-18 Study Golebiewska et al. 2012, 2011, 2009 Fernandez-Lucas et al., 2010 Rammohan et al., 2005 Costero, 2004 Boccanfuso et al., 2000 Lien and Ruffenach, 1996 AE, adverse event. *Not including death.
Any AE (1 or more)*
Discontinuation due to AE*
Discontinuation due to Death
22/32 7/16 3/10 0/32 10/17 1/16
13/32 0/16 0/10 0/32 7/17 1/16
7/32 3/16 0/10 7/32 5/17 3/16
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non–dialysis-dependent CKD patients. Oral MA should be used with significant caution, and only when other treatment options are unavailable. Supplementary Data
Supplementary data related to this article can be found at http://dx.doi.org/10.1053/j.jrn.2015.11.002.
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trol acetate: treatment versus placebo controlled study. Nefrologia. 2014;34:416-417. 9. Yeh SS, Marandi M, Thode HC Jr, et al. Report of a pilot, double-blind, placebo-controlled study of megestrol acetate in elderly dialysis patients with cachexia. J Ren Nutr. 2010;20:52-62. 10. Monfared A, Heidarzadeh A, Ghaffari M, Akbarpour M. Effect of megestrol acetate on serum albumin level in malnourished dialysis patients. J Ren Nutr. 2009;19:167-171. 11. Fernandez Lucas M, Teruel JL, Burguera V, et al. Treatment of uraemic anorexia with megestrol acetate. Nefrologia. 2010;30:646-652. 12. Golebiewska JE, Lichodziejewska-Niemierko M, AleksandrowiczWrona E, Majkowicz M, Lysiak-Szydlowska W, Rutkowski B. Influence of megestrol acetate on nutrition, inflammation and quality of life in dialysis patients. Int Urol Nephrol. 2012;44:1211-1222. 13. Rammohan M, Kalantar-Zadeh K, Liang A, Ghossein C. Megestrol acetate in a moderate dose for the treatment of malnutritioninflammation complex in maintenance dialysis patients. J Ren Nutr. 2005;15:345-355. 14. Boccanfuso JA, Hutton M, McAllister B. The effects of megestrol acetate on nutritional parameters in a dialysis population. J Ren Nutr. 2000;10:36-43. 15. Lien YH, Ruffenach SJ. Low dose megestrol increases serum albumin in malnourished dialysis patients. Int J Artif Organs. 1996;19:147-150. 16. Golebiewska JE, Lichodziejewska-Niemierko M, AleksandrowiczWrona E, Majkowicz M, Lysiak-Szydlowska W, Rutkowski B. Megestrol acetate use in hypoalbuminemic dialysis patients. J Ren Nutr. 2011;21:200-202. 17. Golebiewska J, Lichodziejewska-Niemierko M, Aleksandrowicz E, Majkowicz M, Lysiak-Szydlowska W, Rutkowski B. Influence of megestrol acetate on nutrition and inflammation in dialysis patients—preliminary results. Acta Biochim Pol. 2009;56:733-737. 18. Costero O, Bajo MA, del Peso G, et al. Treatment of anorexia and malnutrition in peritoneal dialysis patients with megestrol acetate. Adv Perit Dial. 2004;20:209-212.
The Efficacy and Safety of Megestrol Acetate in Protein-Energy Wasting due to Chronic Kidney Disease: A Systematic Review Lori D. Wazny, BSc (Pharm), PharmD,*,†,‡ Stewart Nadurak,‡ Cali Orsulak, BSc (Pharm), CDE,†,‡ Lori Giles-Smith, BA (Hons), MLIS,§ and Navdeep Tangri, MD, PhD, FRCPC{,‡ Objective: To assess the efficacy and safety of oral megestrol acetate (MA) in the management of protein-energy wasting in patients with chronic kidney disease (CKD). Design: A systematic review of English published literature from 1970 until April 1, 2014. Subjects: All adult patients with CKD including both dialysis and non–dialysis-dependent. Intervention: Oral MA. Main Outcome Measure: Efficacy outcomes included changes in body weight, serum albumin, and appetite. Safety outcomes examined included adverse events (AEs) and deaths. Results: A total of 9 studies met the inclusion criteria. No data on MA in non-dialysis CKD patients were available. Statistically significant increases in body weight (range 1.5-5 kg) were reported in 6 trials. Statistically significant increases in albumin (range of 0.22 g/dL-0.52 g/dL) were observed in 5 trials. Improved appetite was observed in 7 trials. All trials were limited by small sample sizes (range 9-32 subjects), short duration (range 8-24 weeks), a high degree of bias, and absence of clinical outcomes such as quality of life or hospitalizations. Forty-seven AEs were reported and included overhydration/excessive fluid gain, diarrhea, hyperglycemia, excessive weight gain, suppressed cortisol levels, thrombophlebitis, nausea/vomiting, confusion/hallucinations, vaginal bleeding, headache/dizziness, and elevated lactate dehydrogenase. There were 26 discontinuations due to death. Conclusion: The current evidence for treatment with MA in patients receiving dialysis is sparse with few high-quality trials. The safety of using MA beyond 24 weeks is unknown, and use of MA is associated with significant AEs. At this time, oral MA should be used with significant caution, and only when other treatment options are unavailable. Ó 2016 by the National Kidney Foundation, Inc. All rights reserved.
Introduction
P
ROTEIN-ENERGY WASTING IS common in patients with chronic kidney disease (CKD) and those on dialysis. This syndrome is defined as a loss of appetite, weight loss, and tissue wasting accompanied by a decrease in muscle mass and adipose tissue1 and is associated with a decreased quality of life, higher risks of hospitalization, and increased risk of death.2,3
*
College of Pharmacy, University of Manitoba, Winnipeg, MB, Canada. Pharmacy Program, Winnipeg Regional Health Authority, Winnipeg, MB, Canada. ‡ Manitoba Renal Program, Manitoba, Canada. § University of Manitoba, Health Sciences Libraries, Winnipeg, MB, Canada. { Departments of Medicine and Community Health Sciences, University of Manitoba, Winnipeg, MB, Canada. Financial Disclosure: The authors declare that they have no relevant financial interests. Address correspondence to Lori D. Wazny, BSc (Pharm), PharmD, Department of Pharmaceutical Services, Health Sciences Centre, 820 Sherbrook St., Winnipeg, Manitoba, Canada R3A 1R9. E-mail: [email protected] Ó 2016 by the National Kidney Foundation, Inc. All rights reserved. 1051-2276/$36.00 http://dx.doi.org/10.1053/j.jrn.2015.11.002 †
Journal of Renal Nutrition, Vol -, No - (-), 2015: pp 1-9
Complex signaling pathways and mechanisms are involved in the pathogenesis of protein-energy wasting in patients with CKD. These include the ubiquitinproteasome system, caspase-3, insulin resistance, endogenous glucocorticoids, metabolic acidosis, inflammation, and alterations in sex hormones.4 Appetite stimulants, nutritional supplements, and aerobic and strength training exercise have been used to stimulate appetite and reduce muscle wasting in patients with CKD, with conflicting reports of success.4 Megestrol acetate (MA), a synthetic progesterone, has been used as an appetite stimulant in patients with cancer, acquired immunodeficiency syndrome (AIDS), chronic obstructive pulmonary disease, cystic fibrosis, and in the elderly with CKD.1,2 The exact mechanism by which MA increases appetite is unknown.1 A recent meta-analysis of 35 trials in patients with cancer and AIDS showed that treatment with MA improves appetite and was associated with a slight weight gain (approximately 2 kg) compared with placebo. However, edema, thromboembolic events, and deaths were more frequent in patients treated with MA.1 This particular meta-analysis did not include any studies of MA in patients with CKD. As such, the efficacy and safety of MA in this 1
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patient population are not well described. To address this evidence gap, we performed a systematic review to assess the efficacy and safety of MA in the management of protein-energy wasting in patients with CKD.
Methods Search Strategy and Sources Our aim was to identify randomized controlled trials and observational studies assessing the efficacy and safety of MA therapy for anorexia or cachexia in adult patients with CKD. The search strategy (Appendix S1) was developed in collaboration with a medical librarian. We searched EMBASE, IPA, CINAHL, Cochrane, PubMed, and Scopus using this strategy for the years 1970 until April 1, 2014. Inclusion and Exclusion Criteria Articles were screened as abstracts and then the full texts were independently by 2 review authors (L.D.W. and C.O.). Disagreements were resolved by a third review author (N.T.). All English language prospective and observational studies of MA in humans with CKD or receiving dialysis that examined either change in serum albumin, body weight, or appetite as an outcome were included. Data Abstraction From the eligible studies, we collected information on study characteristics (MA dose, duration, dialysis type, inclusion and exclusion criteria, sample sizes), efficacy measures (changes in body weight, serum albumin or appetite), and safety (occurrence of any adverse event (AE), discontinuation due to AE, and discontinuation due to death). Risk of Bias Assessment and Grading the Quality of the Evidence We used the Cochrane Collaboration’s tool for assessing risk of bias for the randomized controlled trials.5 The Cochrane tool classifies the overall risk of bias into 3 grades: low risk if bias is unlikely to alter the results seriously, high risk if bias may alter the results seriously, and the remaining cases judged as unclear. For the observational studies, we used the NewcastleOttawa Quality Assessment Scale to evaluate risk of bias. The Newcastle-Ottawa Quality Assessment Scale evaluates studies for potential biases in selection, comparability, and outcome.6 Statistical Analysis Due to the clinical heterogeneity in the study design, population, and outcomes, a meta-analysis was not performed.
Results Search Results We screened 286 abstracts from the medical databases and evaluated 15 articles for full-text review. Of these, 3 randomized controlled trials and 6 observational studies were included in the final systematic review (Fig. 1).7
Study Characteristics Table 1 summarizes the randomized controlled trials. The trials tested a wide range of MA dosages varying from 80 mg to 800 mg per day with universally small number of subjects across all trials (range 9-22 subjects). Inclusion criteria also varied with 1 trial defining anorexia using an appetite questionnaire,8 whereas the others used serum albumin levels and other laboratory testing to determine which cachexic patients were eligible.9,10 The study durations were all short and ranged from 8 to 24 weeks. In the observational studies (Table 2), a wider range of MA dosages varying from 40 mg to 800 mg per day were observed with a small number of study subjects (range 9-32 subjects). Inclusion criteria included serum albumin less than 3.5 to 3.8 g/dL in all but 1 study, which used an appetite questionnaire.11 The study durations ranged from 12 to 24 weeks length. Only patients receiving peritoneal dialysis or hemodialysis were included. Baseline Patient Characteristics Participants’ baseline characteristics of age, serum albumin, and body weight were balanced in the randomized controlled trials. However, the trial by Yeh et al.9 had a mean difference of 8 years between the control and the study arms with the control group being significantly older at 75 years of age. The observational studies had a mean age range between 56 and 70 years. Baseline serum albumin in all observational studies ranged from 2.7 6 1 g/dL to 3.8 6 5.5 g/dL and baseline body weight ranged from 51.3 6 3.4 kg to 66.5 6 11.4 kg. Efficacy Tables 3 and 4 summarize the primary efficacy outcomes of change in serum albumin, body weight, and appetite for the randomized controlled trials and observational studies, respectively. Two of the three randomized controlled trials demonstrated a statistically significant increase in body weight for the MA group.8,9 The increase in average body weight varied from 1.7 kg to 5 kg in these 2 studies. However, only one of these trials also observed a statistically significant increase in serum albumin and appetite.8 The third study demonstrated no statistically significant change in body weight but did observe a statistically significant increase in serum albumin along with ‘‘almost all’’ patients reporting improved appetite.10 However, it is unclear whether a validated appetite questionnaire was used to assess this efficacy marker. It should be noted that the MA dose used in this particular trial was significantly lower at 40 mg twice daily, and this trial also had the shortest duration of 8 weeks.10 Four of 6 (67%) of the observational studies reported a statistically significant increase in body weight, and 3 of the 6 studies (50%) noted a statistically significant increase in serum albumin. Body weight increased by 1.5 kg to
SYSTEMATIC REVIEW OF MEGESTROL IN CKD
Records identified through database searching (n = 390 )
3
Additional records identified through other sources (n = 3)
Records after duplicates removed (n = 286)
Records screened (n = 286)
Records excluded (n = 271)
Full-text articles excluded, with reasons (n = 6)
Full-text articles assessed for eligibility
Studies included in qualitative synthesis (n = 9 )
Figure 1. Flow diagram.
4.6 kg in these studies, and serum albumin increased by 0.22 g/dL to 0.52 g/dL. Appetite was assessed in all but 1 study, and all patients reported increased appetite.
Safety Information about any AE, discontinuation due to clinical AEs, or death from any cause was available in 2 of the randomized controlled trials (Table 5).9,10 The only AE attributable to MA was an abnormal adrenocorticotropic hormone stimulation test; the other AEs were not believed to be drug-related (metatarsal bone fracture, dialysis-line sepsis, acute diverticulitis). One discontinuation due to death was reported in the MA arm of these trials. The cause of death was not specified.10 In contrast, 43 AEs were reported in the observational studies with 21 discontinuations from the study due to an AE (Table 6). AEs included overhydration/excessive fluid gain (11 subjects),12,13 diarrhea (8 subjects),12,14 hyperglycemia (6 subjects),12,13 excessive weight gain (greater than 5% increase in 4 weeks; 6 subjects),12 decreased baseline cortisol levels (3 subjects),11 thrombo-
phlebitis (3 subjects),11,12 nausea/vomiting (3 subjects),12 confusion/hallucinations (2 subjects),14 vaginal bleeding (1 subject),15 headache/dizziness (1 subject),14 and elevated lactate dehydrogenase (1 subject).14 All AEs were reported to disappear soon after discontinuation of MA. None of the 25 deaths in the observational trials was believed to be due to MA treatment.
Risk of Bias in the Included Studies and the Quality of the Evidence A risk of bias summary table of the included studies can be found in Appendix S2. We observed a high degree of potential bias in the reported randomized trials. The trials by Yeh et al. 9 and Monfared et al.10 had deficiencies in blinding, treatment allocation, and various other biases such as a wide mean age range between arms, and a very low MA dosage all of which could have significantly altered the results. The Fernandez-Lucas 2014 study was a letter to the editor instead of a complete report, and as such, the risk of bias was unclear as not enough study methodology was reported.8
4
Table 1. Study Descriptors, Randomized Controlled Trials (n 5 3) 8-10 MA Dose
Duration (wk)
Population
Inclusion Criteria
Exclusion Criteria
Number of Subjects
Fernandez-Lucas et al. 2014
160 mg once daily
12
HD
NR
19 (10 MA, 9 control)
MA 73 6 9 Control 69 6 18
Yeh et al. 2010
800 mg daily
20 1 4
HD
NR
9 (4 MA, 5 control)
MA 67.5* Control 75.4*
Monfared et al. 2009
40 mg twice daily
8
HD
Anorexia as defined by the appetite questionnaire from the HEMO and DOPPS studies .40 y old, diagnosed with cachexia, with 2 or more of the following: albumin level , 4.0 g/dL, total cholesterol , 150 mg/ dL, protein catabolic rate , 0.8 g/kg/d, and predialysis serum urea nitrogen , 60 mg/dL. Serum albumin , 3.5 g/dL for 2 mo, length of HD . 3 mo, CRP , 0.80 mg/dL
22 (11 MA, 11 control)
MA 54.09 6 4.09 Control 5 59.91 6 3.67
Study
CHF, congestive heart failure; CRP, C-reactive protein; DM, diabetes mellitus; DOPPS, Dialysis Outcomes and Practice Patterns Study; HD, hemodialysis; HEMO, Hemodialysis Study; MA, megestrol acetate; NR, not reported; SD, standard deviation. *Standard deviation not reported.
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Malignancy or active autoimmune disease, DM with debilitating endorgan damage, deep anemia, decompensated CHF, abnormal liver function, corticosteroid therapy, symptoms of inflammation, or infectious disease during study
Age, Mean 6 SD (y)
Table 2. Study Descriptors, Observational Studies (n 5 6) 11-18 Study
Duration (wk)
Golebiewska et al. 2012, 2011, 2009
160 mg once daily
24
Fernandez-Lucas et al., 2010
160 mg once daily
Rammohan et al., 2005
Population
Number of Subjects
Age, Mean 6 SD (y)
12
69.97 6 10.8
16
64.1*
10
60.2*
NR Any obstruction to oral intake; any digestive or absorptive impairment
32 9†
64.19 6 13.8 68.5 (range 44-87)*
NR
16
56 6 4
Inclusion Criteria
Exclusion Criteria
HD, PD
Dialysis for at least 3 mo, serum albumin # 3.8 g/dL
12
HD
Anorexia as defined by appetite questionnaire
400 mg once daily
16
HD, PD
Costero et al., 2004 Boccanfuso et al., 2000
160 mg daily 400 mg twice daily
12 12
PD HD
Lien and Ruffenach, 1996
20 mg twice daily
17.2 6 2.4
Albumin , 3.7 g/dL, dialysis for at least 4 mo, ABW , 85% IBW or BMI , 20 with 1 of the following: (1) recent unplanned weight loss .5% to 10% of target weight within a 6mo period not caused by intercurrent illness (2) serum albumin , 3.7 g/ dL for 3 consecutive mo NR HD for at least 2 mo; serum albumin , 3.5 g/dL for 2 mo; high nutritional risk based on dietitian assessment Serum albumin , 3.5 g/dL for 2 consecutive mo, adequate dialysis
Current use of glucocorticoids, inadequate dialysis (Kt/ V , 1.2 HD or ,2 PD) No calorie or protein supplements oral or intravenous Severe CHF, untreated DVT, uncontrolled DM, chronic liver disease, concurrent use appetite stimulants, use of total or IDPN in past 6 mo, concurrent use glucocorticoids, inadequate dialysis (defined as Kt/V , 1.2 HD and ,2 PD)
HD, PD
SYSTEMATIC REVIEW OF MEGESTROL IN CKD
MA Dose
ABW, actual body weight; BMI, body mass index; CHF, congestive heart failure; DM, diabetes mellitus; DOPPS, Dialysis Outcomes and Practice Patterns Study; DVT, deep vein thrombosis; HEMO, Hemodialysis Study; HD, hemodialysis; IBW, ideal body weight; IDPN, intradialytic parenteral nutrition; MA, megestrol acetate; NR, not reported; PD, peritoneal dialysis; SD, standard deviation. *SD not reported. †Only patients who completed 12 weeks were included.
5
6
Table 3. Efficacy Measures, Randomized Controlled Trials (n 5 3) 8-10 Efficacy Measures Study
Interventions MA 160 mg daily control group
Yeh et al. 2010
MA 800 mg once daily plus weights 23/wk for 40 min before HD control group
Monfared et al. 2009
MA 40 mg twice daily control group
MA 58.1 6 10.7 to 59.8 6 9.9 P 5 .003 (baseline-mo 3) Control 61.9 6 7.2 to 61.1 6 7 P 5 .100 (baseline-mo 3)
Serum Albumin 6 SD (g/ dL)
MA 11.7 Control 20.8
MA 3.25 6 0.62 to 3.49 6 0.68 (P 5 009) control 3.33 6 0.57 to 3.31 6 0.46 (P 5 .608)
NR
MA 15 6 1.3 Control 20.68 6 1.2 (P 5 .018)
No statistically significant changes from initial to 24-wk measurement both within and between the groups
MA 5 59.45 6 3.07 baseline Control 5 55.64 6 2.7 baseline ‘‘No significant change in MA group weight from baseline to 2 mo’’ (P . .5) End weights not reported.
NR
MA 3.31 6 0.31 to 4.41 6 0.31 (P 5 .008) Control 3.35 6 0.21 to 3.02 6 0.48 (P 5 .201) (Difference between group is P 5 .002)
Change in Serum Albumin (g/dL) MA 10.24 Control 20.02
NR
MA 11.1 Control 20.33
Appetite Nine of the 10 patients treated with MA and 4 of the 9 patients treated with placebo reported an improvement in appetite (P 5 .046) Appetite was measured on a 5-point Likert scale (1, very poor, 5, excellent). MA score 1.30 6 0.8 versus 0.5 6 0.3 placebo (P 5 NS) Almost all patients who received MA reported improved appetite.
DOPPS, Dialysis Outcomes and Practice Patterns Study; HEMO, Hemodialysis Study; HD, hemodialysis; MA, megestrol acetate; NR, not reported; NS, not statistically significant; SD, standard deviation.
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Fernandez-Lucas et al. 2014
Body Weight 6 SD (kg)
Change in Body Weight (kg)
7
MA 20 mg twice daily Lien and Ruffenach, 1996
DOPPS, Dialysis Outcomes and Practice Patterns Study; HEMO, Hemodialysis Study; MA, megestrol acetate; NR, not reported; NS, not statistically significant; SD, standard deviation. *Efficacy results for the 9 patients who completed at least 12 weeks.
2.7 6 1 to 3.1 6 2 (P , .05) 12
MA 400 mg once daily MA 160 mg once daily MA 400 mg twice daily
63 6 2 to 65 6 3 (baseline-end of follow-up, NS)
20.6
10.4
2/3 who completed 6 mo reported [ appetite (5-point Likert scale) NR 10.52
10.1
3.44 6 2.7 to 3.54 6 2.7 (NS) 3.14 to 3.66 (stats not done) 11.5
10.3 3.0 6 2 to 3.3 6 2 (P 5 .27) 14.6
11.9
Rammohan et al., 2005 Costero et al., 2004 Boccanfuso et al., 2000*
51.3 6 3.4 to 55.9 6 3.7 (baseline-wk 16, P , .0005) 66.5 6 11.4 to 68 6 10.4 (baseline-mo 3, P , .05) 64.1 to 63.5 (baseline-mo 3, NS)
10.22
All patients reported improved appetite 81% (13/16) reported improved appetite (appetite questionnaire from HEMO & DOPPS studies) All patients reported improvement 69% (22/32) reported [ appetite 10.38
3.65 6 1.82 to 4.03 6 2.71 (P , .001) 3.8 6 5.5 to 4.02 6 4.1 (P , .05) 12.32
MA 160 mg once daily MA 160 mg once daily Golebiewska et al. 2012, 2011, 2009 Fernandez-Lucas et al., 2010
63.26 6 13.04 to 65.58 6 12.53 (baseline-mo 6, P , .01) 58.9 6 10.8 to 60.8 6 10.8 (baseline-mo 3, P , .01)
Serum Albumin 6 SD (g/dL) Body Weight 6 SD (kg) Interventions Study
Table 4. Efficacy Measures, Observational Studies (n 5 6) 11-18
Change in Body Weight (kg)
Efficacy Measures
Change in Serum Albumin (g/dL)
Appetite
SYSTEMATIC REVIEW OF MEGESTROL IN CKD
Most of the observational study populations were highly selected, and none of the studies used a non-exposed cohort group. Over half of the studies demonstrated an interest for a particular outcome, present at the start of the study. We found that most of the studies had significant biases in cohort comparability leaving room for confounding variables to affect results. Only 1 of 6 observational studies followed up with their patients after treatment. Cumulatively, the studies, both observational and interventional, had a high risk of bias (Appendix S2).
Discussion In our systematic review of randomized trials and observational studies of oral MA in adult patients with CKD, we found evidence of modest efficacy as measured by weight gain and improved appetite. Six of the 9 trials demonstrated statistically significant increases in serum albumin (Tables 3 and 4). AEs did not appear to be associated with MA in the randomized controlled trials; however, the observational studies noted a higher incidence of AEs highlighting potential safety concerns. These findings are tempered by small sample sizes, short duration, and absence of hard clinical outcomes such as hospitalizations or mortality. The results of our review are consistent with a previous meta-analysis in patients with cancer and AIDS suggesting that MA results in a modest weight gain, in the range of 2 kg, improved appetite and potentially improved quality of life.1 This previous meta-analysis also compared MA to other drugs including an appetite stimulant (dronabinol), cytokine inhibitors (cyproheptadine, eicosapentaenoic ), anabolic drugs (nandrolone decanoate, fluoxymesterone, oxandrolone), and corticosteroids (prednisolone and dexamethasone). When compared to other drugs, MA showed statistically significant weight improvement but no improvement in appetite or quality of life.1 In our review, the doses of MA varied widely among studies, from 40 mg per day to 800 mg per day. There was no consistency in the change in body weight or serum albumin, or appetite improvement based on the MA dose in our review (Tables 3 and 4). The AEs described in our review are similar to those reported in the literature for MA use in non-CKD patients. In particular, the aforementioned meta-analysis noted an increase in dyspnea, edema, nausea and vomiting, and thrombophlebitis in patients receiving MA.1 Impotence was another significant AE reported in the Cochrane meta-analysis but was not observed in the CKD population.1 The most concerning finding from the meta-analysis was significantly more deaths in patients receiving MA and higher doses of MA producing more deaths.1 However, none of the trials included in our meta-analysis was designed to investigate mortality as a primary end point. Furthermore, the duration of follow-up was short in most trials, so, this unexpected result requires additional research using trials with longer follow-up and using mortality as a primary end point.
8
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Table 5. Safety, Randomized Controlled Trials (n 5 3) 8-10 Any AE (1 or more)* Study
Discontinuation due to AE*
Discontinuation due to Death
Megestrol Arm (AEs/n)
Placebo Arm (AEs/n)
Megestrol Arm (AEs/n)
Placebo Arm (AEs/n)
Megestrol Arm (AEs/n)
Placebo Arm (AEs/n)
NR 4/4 NR
NR 3/5 NR
NR 1/4 NR
NR 2/5 NR
NR 0/4 1/11
NR 0/5 2/11
Fernandez-Lucas et al. 2014 Yeh et al. 2010 Monfared et al. 2009
AEs, adverse events; NR, not reported. *Not including death.
The limited data on deaths in the randomized trials did not allow us to examine this issue further. Together, these findings suggest that oral MA should be used with significant caution, and only when other treatment options are unavailable. There are important clinical, research and health policy implications to our review. We believe that there is no evidence to suggest any meaningful health benefits with MA beyond weight gain and potential increase in appetite, while there is potential for harm. As such, clinicians prescribing MA should provide this information to their patents before discussing treatment. From a research perspective, we believe that protein-energy wasting is a major health problem in patients with CKD, and further research studies including larger trials with longer duration and clinical outcomes using MA or other agents in this population are urgently needed. Finally, from a policy perspective, payers should restrict the funding for oral MA for the treatment of protein-energy wasting in this population to exceptional cases with no other treatment options, as the drug is likely not efficacious and may be harmful. To our knowledge, this is the first systematic review on the effectiveness and safety of MA for the treatment of protein-energy wasting in patients with CKD. Our search strategy included multiple electronic databases to try to ensure that all the published literature on this topic was identified. We considered the quality of the included studies using validated criteria to assess for bias. In addition, the studies selected for review included different countries and are representative of various health-care systems.
There are several limitations to our review. First, we only included published literature, and thus, the results may be influenced by publication bias. As the included studies evaluated a wide range of MA doses and were of different durations, a meta-analysis was not feasible. All studies evaluated adult patients receiving dialysis, and thus, the results of this review may not be applicable to non–dialysisdependent CKD patients or children with CKD. Patientoriented clinical outcomes such as quality of life, hospitalization rates, and length of stay were not assessed in any of the published CKD studies. Finally, the included trials did not have a long duration of follow-up, and hence, we may not be aware of all serious AEs, including mortality due to this drug. In conclusion, our systematic review found the current evidence for treatment with MA in patients with CKD receiving dialysis is sparse with few high-quality trials. No data on MA in non-dialysis CKD patients were available. The safety of using MA beyond 24 weeks is unknown, and mortality data are lacking. Larger randomized controlled trials are needed to determine the role of MA in treating protein-energy wasting in patients with CKD.
Practical Application MA in adult patients receiving hemodialysis or peritoneal dialysis has a small effect on weight gain and improves appetite. Very limited data are available regarding the safety of long-term use of MA. MA has been associated with an increased risk of fluid retention, diarrhea, hyperglycemia, suppression of cortisol levels, and blood clots in patients receiving dialysis, and patients should be informed of these AEs. No data are available for the use of MA in
Table 6. Safety, Observational Studies (n 5 6) 11-18 Study Golebiewska et al. 2012, 2011, 2009 Fernandez-Lucas et al., 2010 Rammohan et al., 2005 Costero, 2004 Boccanfuso et al., 2000 Lien and Ruffenach, 1996 AE, adverse event. *Not including death.
Any AE (1 or more)*
Discontinuation due to AE*
Discontinuation due to Death
22/32 7/16 3/10 0/32 10/17 1/16
13/32 0/16 0/10 0/32 7/17 1/16
7/32 3/16 0/10 7/32 5/17 3/16
SYSTEMATIC REVIEW OF MEGESTROL IN CKD
non–dialysis-dependent CKD patients. Oral MA should be used with significant caution, and only when other treatment options are unavailable. Supplementary Data
Supplementary data related to this article can be found at http://dx.doi.org/10.1053/j.jrn.2015.11.002.
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