DIS News. Literature Highlight: The Efficacy and Safety of Ginkgo in Neuropsychiatric Dementia. Inside this issue: July 2012

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1 College of Health Professions and Biomedical Sciences Drug Informa tion Service Literature Highlight: The Efficacy and Safety of Ginkgo in Neuropsychiatric Dementia Previous dose-finding studies have shown that gingko improves cognitive and neuropsychiatric symptoms (e.g., hallucinations, delusions, agitation, depression) in patients with dementia. The current study was a multi-center, double-blind, randomized, placebo-controlled, 24- week trial to reaffirm previous findings of ginkgo s effects on cognition and neuropsychiatric symptoms in patients with dementia. All patients were at least 50 years old, had mild to moderate dementia confirmed by a score of 9 to 23 on the Syndrom Kurztes (SKT) scale, and were selected from 17 neurologic or psychiatric clinics in three Russianspeaking countries. Patients were randomized to receive either ginkgo extract 240 mg (EGb 761 ; n=198) or placebo (n=200) by mouth once daily. The two primary endpoints were the changes in cognition and neuropsychiatric symptoms measured by the SKT and the Neuropsychiatric Inventory (NPI) tests, respectively. A three-point decrease in the SKT score or a four-point decrease in the NPI score were both considered clinically significant. The SKT was used instead of the more common Alzheimer's Disease Assessment Scale- Cognitive Scale (ADAS-Cog) to circumvent the difficulties of translating it to Russian. There was a statistically significant difference between the two groups in the mean changes in both the SKT score (p<0.001) and the NPI score (p<0.001) at the end of the 24 weeks. Greater improvement in the mean SKT score was observed in the ginkgo group (-2.2±3.5, 95% CI -2.7 to -1.8) compared to the placebo group (0.3±3.7, 95% CI -0.9 to 0.2). The mean NPI score improved more in the ginkgo group (-4.6, 95% CI -5.6 to -3.6) than in the placebo group (-2.1, 95% CI 3.0 to 1.2). The ginkgo group experienced less dizziness than the placebo group (between group difference - 5.4%, 95% CI -9.9% to -1.3%). The authors confirmed previous findings that gingko caused significant improvement in cognition and neuropsychiatric symptoms compared to placebo. Generalizability from this trial was limited due to sampling bias. Another limitation in this trial was the questionable diagnostic equivalence between the SKT and the ADAS- Cog. At baseline, the groups had unbalanced proportions of patients with probable Alzheimer s dementia with or without cerebrovascular disease and vascular dementia. SUMMARY: The use of 240 mg standardized ginkgo extract once daily improved cognition and neuropsychiatric symptoms in patients with Alzheimer s or vascular dementia. Improvements in neuropsychiatric symptoms were clinically significant, but the cognition improvement was not. Herrschaft H, Nacu A, Likhachev S, Sholomov I, Hoerr R, Schlaefke S. Ginkgo biloba extract EGb 761 in dementia with neuropsychiatric features: a randomised, placebo-controlled trial to confirm the efficacy and safety of a daily dose of 240 mg. J Psi Res 2012;46: By Hann Choi, Pharm.D. Candidate July 2012 Volume 16, Issue 7 Inside this issue: Calcium Supplements Thyroid- Stimulating Hormone Omontys (peginesatide) Literature Highlight We welcome any comments and suggestions for future newsletter topics. Editors in Chief Sherrill Brown, DVM, Pharm.D., BCPS Tanner Higginbotham, Pharm.D

2 Are Calcium Supplements Associated With Myocardial Infarction Risk? Calcium supplements are recommended to promote bone health but have recently been associated with a modest increased risk of myocardial infarction (MI). Randomized, placebo-controlled studies have found conflicting associations between calcium and cardiovascular (CV) risk. Although the risk of MI is increased, there are inverse associations with hypertension and stroke. 1,2 This is of special concern because of the widespread use of higher doses of calcium in elderly patients with osteoporosis. Recent meta-analyses and cohort studies have further evaluated these associations. 3,4 A report re-analyzed data from the Women s Health Initiative Calcium\ Vitamin D Supplementation (WHI) Study to evaluate interactions between calcium with or without vitamin D and CV events. 3 The WHI was a seven-year, randomized, placebo-controlled trial of 1 g calcium with 400 IU vitamin D daily (CaD) in 36,282 community-dwelling, postmenopausal women. The WHI found no effect of CaD on CV events, but continuation of baseline personal calcium supplements was allowed in addition to the treatment supplements. Free patient access to the intervention posed an unusual, major confounder when determining associations between calcium supplement use and the incidence of CV events. To provide a more accurate estimate of these interactions, the WHI data was analyzed for women not using calcium supplements at randomization (n=16,718). The incidences of MI, coronary revascularization, death from coronary heart disease (CHD), and stroke were the four pre-specified endpoints in the WHI. Total deaths from MI or CHD, clinical MI or coronary revascularization, clinical MI or stroke, and total MI infarction + coronary revascularization + death due to CHD were the four composite endpoints. Women who were not taking personal calcium supplements at randomization but who then started CaD had an increased incidence of clinical MI or revascularization compared to women who received placebo (HR=1.16, 95% CI 1.01 to 1.34; p=0.04). The same group also had increases in MI (HR=1.22, 95% CI 1.00 to Page ; p=0.05) and MI or stroke (HR=1.16, 95% CI 1.00 to 1.35; p=0.05). The authors concluded that CaD supplementation for participants without baseline calcium supplementation increased the risk of MI or revascularization. 3 The same authors also performed a meta-analysis, incorporating the reanalyzed data from the WHI and two other studies with similar endpoints. 3 Compared to placebo, calcium with vitamin D significantly increased the risk of MI (RR=1.21, 95% CI 1.01 to 1.44; p=0.04) and MI or stroke (RR=1.16, 95% CI 1.02 to 1.32; p=0.02) in three placebocontrolled trials. In eight placebocontrolled trials (n=28,072), supplementation with calcium and vitamin D significantly increased the risk of MI (RR 1.24, 95% CI 1.07 to 1.45; p=0.004) and MI or stroke (RR=1.15, 95% CI 1.03 to 1.27; p=0.009). However, causal relationships cannot be determined from this data. Additionally, it was unclear if the authors adjusted for multiple testing; multiple testing adjustments decrease the chance of error. 3 A recent study prospectively evaluated associations between dietary and supplementary calcium and MI, stroke, and CV mortality in two German cohorts without baseline MI, stroke, or TIA. 4 Data was analyzed for 23,980 patients, years old, who were categorized as either supplement non-users, users of any supplements, users of calcium with other supplements, or users of only calcium. Groups were categorized into quartiles based on total daily calcium intake. Average daily dietary calcium intake was 513 mg (n=5986), 675 mg (n=5993), 820 mg (n=5998), and 1130 mg (n=6003) for the first, second, third, and fourth quartiles, respectively. Totals of 354 MI cases, 260 stroke cases, and 267 CVD deaths were documented after an average follow up of 11 years. There was a significant reduction in MI risk for the third quartile compared to the first quartile (HR=0.69, 95% CI 0.50 to 0.94); this was the only significant association found for inter-quartile comparisons. There was an increased MI risk for users of calcium with other supplements (HR=1.86, 95% CI 1.17 to 2.96) and users of calcium only (HR=2.39, 95% CI 1.12 to 5.12) compared to non-users of any supplements. The authors concluded that a dose-related association existed between calcium supplements and MI risk in both men and women. Reporting and subject biases may have influenced the results of this trial. Although cohort studies can find significant associations, they cannot prove causality. Also, this study did not examine non-dairy calcium-containing foods, so the influences of these other calcium sources are unknown. 4 It appears that the use of calcium supplements is associated with an increased risk of MI, but CV risk may be lower with dietary sources of calcium. Meta-analyses and cohort studies are limited in that only associations can be inferred. Given the limitations of the current evidence, a long-term, randomized, controlled study is needed to fully evaluate the effect of calcium supplementation on CV disease. By Hann Choi, Pharm.D. Candidate 1. Bolland MJ, Barber PA, Doughty RN, et al. Vascular events in healthy older women receiving calcium supplementation: randomised controlled trial. BMJ 2008;336: Bolland MJ, Avenell A, Baron JA, et al. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ 2010;341:c Bolland MJ, Grey A, Avenell A, Gamble GD, Reid IR. Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women s Health Initiative limited access dataset and meta-analysis. BMJ 2011;342: Kuanrong L, Kaaks R, Linseisen J, Rohrmann S. Associations of dietary calcium intake and calcium supplementation with myocardial (references continued on page 4)

3 Higher Thyroid-Stimulating Hormone Levels in Elderly Patients More than 20% of the elderly population receives thyroid hormone replacement. 1 As patients age, a decrease in the amount of thyroid replacement medication may be required. A normal dose in younger adults is 1.7 mcg/kg/day, whereas optimal doses for people over 65 years old may be as low as 0.5 mcg/kg/day. 1 Overtreatment can lead to arrhythmias and an increased risk of fractures. 1,2 Two recent studies indicate that targeting a higher thyroid-stimulating hormone (TSH) level in elderly patients may be associated with better outcomes. 1,3 The current TSH target range, regardless of age, is between 0.45 miu/l and 4.12 miu/l. 4 A recent retrospective study attempted to account for the effects of age, racial/ ethnic groups (REGs), gender, body weight, and urinary iodine concentration on TSH levels and establish TSH reference ranges for patients based on these characteristics. 3 A reference population of 13,296 patients composed of all races and age groups was used for analysis. Patients did not have thyroid disease or goiter, were not receiving thyroid medication, were not pregnant, did not have a TSH level <0.1 miu/l or >10 miu/l, and were not positive for anti-thyroid antibody. The estimated TSH reference ranges for certain age groups are listed in Table 1. The study listed several equations that clinicians could use to classify their patients according to their TSH reference limits. The authors concluded that their research provided a new way to develop TSH reference limits based on age, gender, and REGs and that the limits may vary throughout subpopulations. The reference limits for populations outside of the United States were not determined by this trial. Additionally, the models used by these investigators need to be validated. 3 A population-based, retrospective, cohort study with a nested case-control design was performed with the goal of quantifying the association between levothyroxine use and fracture risk in the elderly population. 1 A total of 213,511 patients between the ages of 65 and 105 years were selected based on the presence of at least one levothyroxine prescription between April 2002 and April Patients were excluded if they had been previously diagnosed with thyroid cancer or hyperthyroidism. Palliative care and dialysis within six months of entering the cohort were also criteria for exclusion. Cohort members who suffered a fracture were considered cases and were matched with up to five control patients of the same sex, similar age, and equal time in the cohort. The primary outcome of the study was any trip to the emergency room or hospital admission for the treatment of a fracture of the wrist, forearm, shoulder, upper arm, thoracic spine, lumbar spine, pelvis, hip, femur, lower leg, or ankle. Cohort members were divided into current, past, and remote levothyroxine users. Current members were still taking the medication at the time of data collection. Past users had discontinued the medication days before data collection, and remote users discontinued levothyroxine use more than 180 days before data collection. Current levothyroxine users were further categorized into low dose (<25% of the average dose among the cohort), medium dose (25%-75% of the average cohort dose), and high dose (>75% of the average cohort dose). A total of 22,236 patients (10.4%) suffered one or more fractures. Among the patients with fractures, most (20,514; 92.3%) were current levothyroxine users. Of the current users sustaining fractures, 15% were low-dose patients, 53.2% were patients receiving medium Table 1. TSH reference ranges as observed in the reference population (n=13,296) 3 Age 2.5 th Percentile Median 97.5 th Percentile All ages doses, and 31.8% were high-dose patients. Current (OR 1.88, 95% CI ) and previous users (OR 1.33, 95% CI ) were found to have an increased risk of fractures compared to remote levothyroxine users. Highand medium-dose patients also had a statistically significant increased risk of fracture compared to low-dose users. The authors concluded that current levothyroxine use was associated with a greater risk of fracture in the elderly population. The increased risk with levothyroxine use was significant for both sexes and was prevalent even if the prescription had been discontinued up to six months previously. Limitations of this study are the lack of TSH data and radiological data for the study patients. Additionally, the investigators could not control for factors such as body mass index, family history, smoking, and caffeine and alcohol use. 1 In conclusion, observational data show that elderly patients may have a higher TSH target level than younger adults. Targeting a higher TSH level would likely result in lower daily thyroid replacement doses, which may be associated with a decreased fracture risk in the older patient population. Prospective studies measuring TSH and radiologic data associated with levothyroxine use in the elderly are needed in order to make a direct connection between levothyroxine use and fracture risk. By Ryan Peterson, Pharm.D. Candidate 1. Turner MR, Camacho X, Fischer HD, et al. Levothyroxine dose and risk of fractures in older adults: nested case-control study. BMJ 2011;342:d Hester SA. Levothyroxine: are the elderly overtreated? Pharmacist s Letter 2011 July. Detail No.: [Electronic verstion]. Available at: pharmacistsletter.com. Accessed June 12, (references continued on page 5) Volume 16, Issue 7 Page 3

4 Omontys (peginesatide): Once Monthly Dosing for Patients on Dialysis Omontys (peginesatide) is a pegylated, peptide-based erythropoiesis-stimulating agent (ESA) approved in March 2012 for the treatment of anemia due to chronic kidney disease (CKD) in adult patients on dialysis. 1 The occurrence of anemia in CKD is frequently followed by an increased number of red blood cell (RBC) transfusions and a decreased quality of life. Traditionally, erythropoietin-replacement therapy is achieved with ESA, which improves quality of life and decreases RBC transfusions, but other available ESA therapies are dosed up to three times a week. 2 Peginesatide provides an advantage of once-monthly dosing. 2 Two multicenter, randomized, openlabel studies assessed the safety and efficacy of peginesatide in patients previously treated with epoetin for anemia associated with CKD due to hemodialysis. 2 The first study (EMERALD 1) enrolled 803 patients, and the second study (EMERALD 2) had 823 patients. Patients were on hemodialysis for more than three months, had an average hemoglobin concentration between 10 and 12 g/dl, were receiving epoetin therapy >8 weeks, and were on a stable dose >4 weeks. Patients in EMERALD 1 were randomized to receive either IV peginesatide every four weeks or continue IV epoetin therapy 1 to 3 times a week. Participants originally on IV epoetin in the EMERALD 2 trial were randomized to receive either IV peginesatide every four weeks or continue IV epoetin alfa therapy 1 to 3 times a week. In the same Page 4 trial, patients previously on subcutaneous epoetin were randomized to receive either subcutaneous peginesatide every four weeks or continue subcutaneous epoetin therapy. Initial doses were dependent on the patients epoetin dose prior to the trial, and they were then titrated to maintain hemoglobin levels between 10 to 12 g/dl. Hemoglobin levels were evaluated weekly to every two weeks unless dosing was delayed. Iron levels were monitored by measuring TSAT and serum ferritin levels. The primary efficacy endpoint in both EM- ERALD 1 and 2 was the average change in hemoglobin concentration from baseline to the evaluation period (29-36 weeks). Secondary efficacy endpoints included the number of patients who needed red blood cell transfusions. Baseline characteristics were similar between treatment groups. In both EM- ERALD 1 and EMERALD 2 patients on peginesatide maintained average hemoglobin levels from baseline to the evaluation period, similar to patients on epoetin. Hemoglobin levels were between 10 to 12 g/dl for 63% of the time with peginesatide compared to 71.7% with epoetin in EMERALD 1. In EM- ERALD 2, hemoglobin levels were maintained in 63.5% of participants on peginesatide and 65.9% of participants on epoetin. The number of patients needing RBC transfusion was similar between the groups (EMERALD 1: 10% on peginesatide and 9% on epoetin; EM- ERALD 2: 8% vs. 10%). Adverse events were similar between the two groups. The most common adverse events in both groups were dyspnea, headache, muscle spasm, nausea, and diarrhea. Cardiovascular (CV) event data was pooled from both EMERALD 1 and EMERALD 2 trials. A CV event occurred in 23% of participants on peginesatide compared to 24% on epoetin (HR 0.95, 95% CI ). The authors concluded that peginesatide therapy once monthly was similar to epoetin therapy 1 to 3 times a week in maintaining average hemoglobin levels between g/dl, without an increase in RBC transfusions. The authors further concluded once monthly peginesatide was similar in safety, both with similar amounts of CV events. 2 Common adverse events that occur with peginesatide are diarrhea (18.4%), shortness of breath (18.4%), nausea (17.4%), problem with access of dialysis site (16.1%), cough (15.9%), headache (15.4%), vomiting (15.3%), and muscle spasms (15.3%). 1 Furthermore, peginesatide may increase the risk of serious CV events, including heart attack, strokes, blood clots, and congestive heart failure. The recommended starting dose of peginesatide is 0.04 mg/kg of body weight every four weeks, with adjustments based on hemoglobin level. 1 Currently, anemia in CKD is treated with an ESA up to three times a week. Treating anemia in CKD patients provides a higher quality of life and a decreased amount of RBC transfusions. Peginesatide offers CKD anemia patients the option for a once monthly treatment. In conclusion, peginesatide is an ESA alternative for CKD patients needing anemia therapy, and is comparable in efficacy and safety to epoetin a traditional ESA treatment method. By Amber Walks Over Ice, Pharm.D. Candidate 1. Omontys [package insert]. Palo Alto, CA: Affymax, Inc; CL. Brandon, Takeda Pharmaceuticals International Inc., written communication, June 11, Calcium Supplements (from page 3) infarction and stroke risk and overall cardiovascular mortality in the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition study (EPIC-Heidelberg). Heart 2012;98:

5 Literature Highlight: Olaparib Maintenance Therapy in Platinum-Sensitive Relapsed Ovarian Cancer Of all forms of gynecologic cancer, ovarian cancer results in death most often. Patients with ovarian cancer can experience up to an 80% initial response rate to platinum-based chemotherapy. Following a response to initial therapy, relapse rates are high, and new treatments are needed for refractory cases. Studies indicate that poly-(adp ribose) polymerase (PARP) inhibitors (e.g., olaparib) are efficacious in patients with a previous response to platinum-based chemotherapy. A randomized, double-blind, phase 2 study enrolled 265 patients with a previous objective response to platinum-based chemotherapy according to the RECIST (Response Evaluation Criteria in Solid Tumors) guidelines. All patients had high-grade (grade 2 or 3) ovarian, fallopian, or peritoneal cancer with serous features. Patients were randomized to receive either 400 mg of the oral PARP inhibitor olaparib or placebo twice daily as maintenance therapy. Treatment continued until the cancer progressed or an adverse event requiring discontinuation occurred. Patients were stratified according to the elapsed time from platinum chemotherapy (>12 months or <12 months) and Jewish decent. The Jewish population is associated with a higher rate of mutation in the BRCA1/2 tumor suppressor gene line. Mutations in these genes have been associated with increased response to PARP inhibitors. The primary endpoint of progressionfree survival was measured every 12 weeks by CT scan and by monitoring cancer antigen 125 levels. Overall survival was a secondary endpoint. Median progression-free survival was 8.4 months in the treatment group compared to 4.8 months with placebo (HR for progression or death 0.35; CI ; p<0.001). Despite the increased time to cancer progression seen with olaparib, there were no differences in overall survival between the two groups (HR for death 0.94; 95% CI ). Adverse events occurred in 130 of the 136 patients receiving olaparib. Nausea, fatigue, and vomiting were the most commonly experienced adverse events, at rates of 93%, 66%, and 43%, respectively. Interruption or discontinuation of olaparib therapy occurred in nine patients due to fatigue and seven patients due to anemia. Thyroid-Stimulating Hormone (from page 4) The authors concluded that olaparib was superior to placebo in delaying the time to disease progression, but that there was no difference in overall survival between the groups. Confounding factors included the lack of screening for BRCA1/2 genes prior to the study and presence of varying degrees of cancer severity between patients. SUMMARY: Maintenance therapy with olaparib led to an increase in median time to cancer progression in patients who had relapsed following platinum chemotherapy. The increase in time to progression did not correlate with increased survivability. Additional studies comparing olaparib to other maintenance chemotherapies would be beneficial. Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med 2012;366: By Ryan Peterson, Pharm.D. Candidate 3. Boucai L, Hollowell JG, Surks MI. An approach for development of age-,gender-, and ethnicity-specific thyrotropin reference limits. Thyroid 2011;21(1): Staehling NW, Flanders WD, et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 2002;87: College of Health Professions and Biomedical Sciences Drug Information Service The University of Montana Skaggs School of Pharmacy 32 Campus Drive Missoula, MT Phone: Fax: druginfo@umontana.edu