Adrenal insufficiency in a woman secondaryto standard-dose inhaled fluticasonepropionate therapy1Department of Obstetrics and Gynecology 2Division of Reproductive Endocrinology and Infertility,Maine Medical Center, 22 Bramhall Street, Portland, Maine 04102, USAA 55-year-old woman with asthma presented with adrenal insufficiency of unknown origin. She was referred to our Divisionof Reproduc
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March 06 jmcpEditorial Subjects—In This Issue and in Previous Issues
affirms our intuition that (a) patients can discern among specific meals or rosiglitazone (Avandia) 4 mg twice daily.17 The mean sensory attributes of intranasal steroid products, (b) some A1c values at baseline were 9.5% in the INH group versus 9.4% attributes have higher economic value in their avoidance for the rosiglitazone group. After 12 weeks of the therapy, the(e.g., no aftertaste versus strong aftertaste), and (c) the absolute INH group (71 of 76 randomized patients completed the trial) WTP amount is higher for some attributes (i.e., a lot of throat achieved a mean A1c of 7.2% versus 8.0% for the 63 of 69 rundown and nose runout) for persons with higher household patients who completed the rosiglitazone treatment arm, yielding income. It may also be reasonable to extrapolate these findings 64% greater reduction in A1c (-2.3 absolute points vs. -1.4 to the conclusion that physicians and patients should be absolute points) for INH compared with rosiglitazone, with andiscussing product attributes, particularly for patients who will adjusted treatment group difference of -0.89, 95% confidence be using intranasal steroids on a regular basis due to persistent interval [CI], -1.23 to -0.55.18 At 12 weeks of treatment, 82.7% of the INH group achieved A1c of 8% or less versus 58.2% for The implications of the research on WTP for sensory attributes rosiglitazone, adjusted odds ratio (OR), 7.14; 95% CI, 2.48- beyond these conclusions are less clear. The graphs (Figure 1) 20.58; P <0.001. By the American Diabetes Association in the article by Mahadevia et al. are remarkably similar in slope standard of <7.0% A1c, the proportion achieving the primary and clustering except for aftertaste (Figure 1C). Second, at $50 end point was more than twice the proportion for rosiglitazone, per prescription, the sensory attributes have little differentiation.
44.0% for INH vs. 17.9% for rosiglitazone, (adjusted OR, 4.43; (Readers are encouraged to examine the Choice Set in Table 3 95% CI, 1.94-10.12). According to the guidelines of the of the article to make their own inferences.) Based upon the American Association of Clinical Endocrinologists (A1c ≤6.5%), actual costs of the 7 therapeutic alternatives in 2005 (Table 1 the success rate was even higher for INH versus rosiglitazone, page 168), there is only an absolute difference of $5 per month 28.0% vs. 7.5% (OR, 5.34; 95% CI, 1.83-15.57).
between budesonide, mometasone, triamcinolone, and fluticasone.
Pharmacy and therapeutics (P&T) committees have an inter- Members of pharmacy and therapeutics (P&T) committees esting question to debate in 2006: the relative value and need are challenged in decision making by the absence of information for the thiazolidinediones (TZDs) rosiglitazone (Avandia and about sensory attributes in the labeling for intranasal steroids.
Avandamet) and pioglitazone (Actos) now that clinicians and But, Kaliner found, in a telephone survey of 503 patients with patients have access to INH, which has been found to be supe- seasonal and perennial allergic rhinitis, that 86% of the patients rior to rosiglitazone in the intermediate outcome of A1c. TZDs reported that they had not complained to their physician about have a larger hole to crawl out of when relative safety is a sensory attribute of their nasal steroid treatment.13 Since the considered by P&T committees and clinicians. More than work by Kaliner was performed 6 years ago, this research, if 2 years ago, at the end of 2003, the American Heart Association conducted today, may find that patients are more outspoken.
and the American Diabetes Association released a joint consensus On the other hand, perhaps sensory attributes of intranasal statement warning that patients with moderate-to-severe congestive steroids are important to only a small proportion of the popula- heart failure (CHF) should not be prescribed either rosiglitazone tion that suffers from allergic rhinitis. One wonders how impor- or pioglitazone.19 Analysis of administrative claims data reported tant the sensory attributes of intranasal steroids should be in in November 2003 by Delea found a 55% higher incidence of clinical and P&T committee decision making. The one apparent heart failure for 5,441 TZD patients compared with 28,103 opportunity for quality improvement is in increasing, to more control patients with diabetes (hazard ratio = 1.7, P <0.001); the than 7%, the proportion of physicians that base their choice of adjusted incidence of heart failure at 40 months was 8.2% for a nasal steroid on patient preference14 for sensory attributes.
TZD patients and 5.3% for control subjects (absolute difference2.9%, relative difference 55%).20 The TZDs have a tendency to ■■ What Is the Future of Thiazolidinediones (TZDs)
cause fluid retention and edema, particularly of the feet, a hall- After Market Introduction of Inhaled Insulin?
mark of CHF. The incidence of fluid retention and edema The U.S. Food and Drug Administration (FDA) approved appear to be exacerbated by concomitant use of insulin and inhaled insulin (INH) under the trade name Exubera on dose-related for both rosiglitazone21 and pioglitazone.22,23 January 27, 2006, for use in adult patients with type 1 and type The black cloud over TZDs does not end with fluid retention, 2 diabetes.15 Exubera is an inhalable, powdered form of insulin edema, and heart failure. The first TZD, troglitzone (Rezulin), delivered by a device developed by Nektar Therapeutics. Earlier approved by the FDA for marketing in the Unites States in in January 2006, Pfizer agreed to acquire the world-wide rights January 27, 1997,24 was withdrawn in March 2000 after its asso- to Exubera from sanofi-aventis for $1.3 billion.16 ciation with hepatotoxicity was no longer in doubt. By year-end One of the clinical trials that favored FDA approval of INH 1998, the FDA had record of a total of 32 reported deaths and was a multicenter clinical trial that randomized 145 persons 4 liver transplants associated with the use of troglitzone.25 Prior with uncontrolled type 2 diabetes (with glycosylated hemo- to the market withdrawal of troglitazone, the manufacturer had globin [A1c] in the range of 8%-11%) to either INH before distributed 2 warning letters to physicians, including a notice to www.amcp.org Vol. 12, No. 2 March 2006 JMCP
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monitor liver enzymes monthly, and the United Kingdom had the absence of a pharmacy claim for TZD or insulin plus another withdrawn troglitazone from the market more than 2 years 12% of patients who did not have continuous eligibility duringearlier, in November 1999.26 For pioglitazone, introduced to the study period. LaFleur, in a previous issue of JMCP, provided the U.S. market in July 1999,27 the first death from liver failure a comprehensive and useful review of the limitations of admin- associated with its use was reported in 2004.28 A “Dear istrative claims data specific to the measurement of costs of care Prescriber” letter dated April 26, 2002, highlighted changes in the precautions section of labeling of rosiglitazone regarding the Third, the time period for the administrative claims used in potential for hepatic effects, even a rare case of hepatic failure, the analyses by Kalsekar et al. is confounded by the TZD market and, in other parts of product labeling, a possibility of weight disruption caused by the withdrawal of troglitazone in March 2000, in the middle of their 1999-2001 study period. While Add to peripheral edema, weight gain, and possible hepato- troglitazone patients were excluded from the 12-month follow- toxicity an apparent increased risk of macular edema. In up period, 12.8% of the TZD patients and 13.0% of the insulin January 2006, the FDA notified health care professionals of patients in the final analysis received troglitazone in the preperiod reports of both new-onset and worsening cases of diabetic (Table 3 in Kalsekar et al.). One wonders why the outpatientmacular edema associated with the use of rosiglitazone, albeit costs, which included office visits and laboratory tests for liver reversible and apparently dose related.29 enzymes, were not higher in the preperiod for both groups and With an apparent black eye for safety and inferior to INH in why the outpatient costs were similar ($177 mean difference, efficacy for lowering A1c, the cost outcomes for the TZDs may $1,070 for the insulin group compared with $893 for the TZD offer a refuge in the storm. Kalsekar et al., in this issue of JMCP, group, P = 0.458 for the comparison) in the postperiod, partic- found, from administrative claims data in a Medicaid fee-for- ularly since there was considerable media attention to the market service population, that patients who started TZD therapy withdrawal of troglitazone at the time. Consumer groups, incurred 35% lower costs in a 12-month follow-up period in represented by Public Citizen, petitioned the FDA in early 2000 2000-2001 for emergency room (ER) visits and hospitalization to revise the product labeling for all 3 TZDs to describe the compared with patients who initiated therapy with insulin, an adverse effects that include liver toxicity and heart failure.33 average of $3,727 versus $5,793, respectively (P <0.01).30 For Fourth, a threat to validity seems inherent in the premise diabetes-related costs only, the 53% higher pharmacy costs in that higher drug costs for TZDs are offset by lower costs for ER the TZD patients ($1,678) versus insulin patients ($1,096, visits and hospitalizations, in only 12 months of administrativeP <0.01) was offset by lower costs for emergency room (ER) claims data. For diabetes-related costs, the insulin group had avisits and hospitalization ($2,855 vs. $5,090, P <0.01), resulting higher average number of physician office visits, but the average in 25% lower total diabetes-related costs for the TZD group outpatient costs (including physician office visits) were not compared with the insulin group ($5,425 vs. $7,255, P <0.05).
different between the 2 groups over 12 months of follow-up.
Limitations in the study by Kalsekar et al. are significant.
However, the contribution of the $177 mean difference ($1,070 Important among these limitations was the inability to measure for the insulin group vs. $893 for the TZD group, P = 0.458 for disease severity. Lacking clinical values for A1c and blood the comparison) may have contributed to the $1,830 differenceglucose, the researchers attempted to assure the comparability ($153 per month) in total diabetes-related costs ($7,255 for the of the 2 groups through the use of propensity matching.
insulin group vs. $5,425, P = 0.022 for the comparison).
However, the propensity matching technique would tend to Stephens et al. provide a useful context for interpreting these exclude patients with more-severe diabetes who were, therefore, absolute and relative values in their summary of the literature using insulin and could not be matched to TZD patients. The on economic studies in this issue of JMCP, including their Table 1, magnitude of this limitation can be gleaned from the authors’ showing the breakdown of total direct costs for managed care Table 1, which shows that 65% (n = 1,271) of otherwise study- organization (MCO) enrollees with diabetes.34 eligible patients were excluded in the process of propensity The place in therapy for TZDs in type 2 diabetes is summa- matching, leaving only 690 patients in the final analyses: 345 rized clearly and succinctly in the NICE (National Institute for patients with type 2 diabetes in the TZD group and 345 patients Clinical Excellence) appraisal released in November 2002.
TZDs are third-line therapy in type 2 diabetes after sulfonyl- Second, Medicaid patients, particularly those not enrolled in ureas and metformin have proved unsuccessful when used as managed Medicaid, are most likely not representative of the monotherapy and in combination to achieve glycemic goals.35 general population of patients with type 2 diabetes, and discon- NICE concluded that “the use of glitazone combination therapy tinuous eligibility contributes to discontinuous care in this with either metformin or sulphonylurea is not likely to be costpopulation.31 A hint of the problem of discontinuous care might effective when compared with the combination of metformin be found in the 75% of patients identified with a diagnosis and sulphonylurea.”of type 2 diabetes who were excluded from the study because of So, much of the market future of TZDs may have to do with 170 Journal of Managed Care Pharmacy JMCP
Editorial Subjects—In This Issue and in Previous Issues
relative cost. In previous research reported in JMCP, Shetty et al.
12. Drug Facts and Comparisons (Clinisphere version, ISBN 1-57439-036-8).
found that patients with type 2 diabetes maintained at target St. Louis, MO: Wolters, Kluwer Health, Inc.; December 2005. Respiratoryinhalant products, intranasal steroids. Accessed January 31, 2006.
A1c (≤7%) had 24% lower total diabetes-related medical costs 13. Kaliner MA. Patient preferences and satisfaction with prescribed nasal compared with patients who were above target A1c (>7%).36 steroids for allergic rhinitis. Allergy Asthma Proc. 2001;22(6 suppl 1):S11-S15.
The actual daily direct drug costs for INH are not yet known.
14. Kaliner MA. Physician prescribing practices: the role of patient preference What is known is that the TZDs are not inexpensive. Based in the selection of nasal steroids. Allergy Asthma Proc. 2001;22(6 suppl upon MCO pharmacy claims for the fourth quarter of 2005, the average direct drug cost, including pharmacy dispensing fees, 15. U.S. Food and Drug Administration. FDA approves first-ever inhaled was $4.34 per day ($130 per month) for Avandia, $4.55 insulin combination product for treatment of diabetes. January 27, 2006.
Available at: http://www.fda.gov/bbs/ topics/news/2006/NEW01304.html.
per day ($136 per month) for Avandamet, and $5.13 ($154 per month) for Actos. The evidence presents a classic conundrum 16. Loftus P. Pfizer receives FDA approval for inhaled-insulin treatment. for P&T members: a product—INH—with superior efficacy Wall Street Journal. January 28-29, 2006:A6.
and safety but (probable) higher direct drug cost compared 17. U.S. Food and Drug Administration. Statistical review and evaluation.
with TZDs. Still, the market introduction of INH in February Clinical study no. 110 in NDA/Serial No. 21-868. Available at: 2006 seems likely to knock pioglitazone and rosiglitazone from http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4169B1_02_05-FDA-Clin-Stats-Efficacy.pdf. Accessed February 15, 2006.
their status in the top 12 drugs by expenditure at year-end 2005.
18. DeFronzo RA, Bergenstal, RM, Cefalu WT, et al. Efficacy of inhaledinsulin in patients with type 2 diabetes not controlled with diet and exercise.
Frederic R. Curtiss, PhD, RPh, CEBS
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19. Nesto RW, Bell D, Bonow RO, et al. Thiazolidinedione use: fluid reten- tion, and congestive heart failure. A consensus statement from the AmericanHeart Association and American Diabetes Association. Circulation. 2003;108:2941-48; Diabetes Care. 2004;27:256-63. REFERENCES
20. Delea TE. Use of thiazolidinediones and risk of heart failure in people with 1. Buntin MB, Damberg C, Haviland A, et al. Consumer-driven health plans: type 2 diabetes: a retrospective cohort study. Diabetes Care. 2003;26(11):2983-89.
implications for health care quality and cost. June 2005. RAND Corp. for the 21. Raskin P, Rendell M, Riddle MC, et al. A randomized trial of rosigltazone California HealthCare Foundation. Available at: http://www.chcf.org/docu- therapy in patients with inadequately controlled insulin-treated type 2 dia- ments/insurance/ ConsumerDirHealthPlansQualityCost.pdf. Accessed January betes. Diabetes Care. 2001;24:1226-32.
22. Rubin C, Egan J, Schneider Ra, et al. Combination therapy with pioglita- 2. Wasserfallen JB, Currat-Zweifel C, Cheseaux JJ, Hofer M, Fanconi S. Parents’ zone and insulin in patients with type 2 diabetes. Diabetes [abstract].
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23. Rosenstock J, Einhorn D, Hershon K, et al. Efficacy and safety of pioglita- 3. Whynes DK, Frew EJ, Wolstenholme JL. Willingness-to-pay and demand zone in type 2 diabetes: a randomized, placebo-controlled study in patients curves: a comparison of results obtained using different elicitation formats. receiving stable insulin therapy. Intern J Clin Pract. 2002;56:251-57.
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24. U.S. Food and Drug Administration. Approvals for January 1997. Available 4. Covey J, Smith RD. How common is the ‘prominence effect’? Additional at: http://www.fda.gov/cder/da/da0197.htm. Accessed February 5, 2006.
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25. Langreth R, Sharpe R. Warner-Lambert diabetes drug set to be reviewed 5. King JT, Tsevat J, Lave JR, Roberts MS. Willingness to pay for a quality- by FDA panel. Wall Street Journal. January 18, 1999:B7.
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costs for compliant patients initiating therapy with pioglitazone or rosiglitazoneversus insulin in a Medicaid fee-for-service population. J Manag Care Pharm. 10. Mahadevia PJ, Shah S, Leibman C, et al. Patient preferences for sensory attributes of intranasal corticosteroids and willingness to adhere to prescribedtherapy for allergic rhinitis: a conjoint analysis. Ann Allergy Asthma Immunol. 31. Gold M, Felt S. Reconciling practice and theory: challenges in monitoring Medicaid managed-care quality. Health Care Finance Rev. 1995;16(4):85-105.
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33. Adams C. Three diabetes drugs need revisions in labels, consumer grouptells FDA. Wall Street Journal. March 8, 2000:B10.
Letters to the Editor
34. Stephens JM, Botteman MF, Hay JW. Economic impact of antidiabetic JMCP welcomes letters that serve to clarify subjects published in medications and glycemic control on managed care organizations: a review previous issues of the Journal or regarding subject matter of interest to of the literature. J Manag Care Pharm. 2006;12(2):130-42.
managed care pharmacists. Letters in JMCP are not peer reviewed but are 35. National Institute for Clinical Excellence. Appraisal consultation docu- subjected to editorial review. Letters should be prepared in a word ment: review: the clinical effectiveness and cost effectiveness of glitazones for the treatment of type 2 diabetes. November 25, 2002. Available at: processing program, preferably Microsoft Word, and submitted electron- http://www.nice.org.uk/ page.aspx?o=39365. Accessed February 6, 2006.
ically at jmcp.msubmit.net. See www.amcp.org for details.
36. Shetty S, Secnik K, Oglesby AK. Relationship of glycemic control to total diabetes-related costs for managed care health plan members with type 2 diabetes. J Manag Care Pharm. 2005;11(7):559-64.
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CGTMSE – Form for First Instalment of Claim Credit Guarantee Fund Trust for Micro & Small Enterprises Application for Invocation of Guarant ee Cover and Preferment of Claim under CGS In terms of Clause 10 of Credit Guarantee Fund Scheme for Micro and Small Enterprises (CGFSMSE), we prefer the claim 1. Online Claim Application Ref. No 2. Details of Operating Office & Len