Avandia^® and Cardiovascular Risk – Implications for Patients and Providers

On July 30, 2007, the Food and Drug Administration’s (FDA) Endocrinologic and Metabolic Drugs and Drug Safety and Risk Management Advisory Committees voted 22 to 1 to keep Avandia on the market, finding that the potential benefits of the drug outweigh the risks.  However, the committees also voted that the Avandia data submitted by manufacturer GlaxoSmithKline suggests some ischemic risk associated with the drug and that Avandia should carry additional warnings about cardiac risks.  The committees declined to comment on Avandia’s comparative risk to other oral antidiabetic medications.  The FDA will review the panel's recommendation before rendering a final decision on warnings regarding ischemic risks.¹

On August 14, 2007, the FDA announced that a black box warning regarding heart failure risks for these medications would be added emphasizing that the drugs may cause or worsen heart failure in certain patients.¹  A decision on any warnings regarding ischemic risks is still pending.

RegenceRx recently performed a review of the latest available clinical data on Avandia and concluded:

• The risk of MI or cardiovascular death with Avandia is still uncertain.
• The existing data does constitute a signal and additional research on this issue is needed.
• It is still unclear whether this risk is specific to Avandia or generalizable to the thiazolidinediones (TZDs) as a class.

Avandia – Pharmacology and Place in Therapy
Avandia (rosiglitazone) is a member of the class of antidiabetic drugs known as TZDs, which also includes pioglitazone (Actos^®).^{2, 3}  These medications are indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus as monotherapy, or combined with sulfonylureas or metformin. 

Known safety issues with all TZDs include:

• Fluid retention, which may lead to or exacerbate heart failure.
• Dose related weight gain.
• Increased rate of upper arm, hand and foot fractures in female patients with type 2 diabetes.
• Common side effects with TZDs include headache, upper respiratory tract infection, sinusitis, edema, hypoglycemia (especially when combined with other agents) and diarrhea.^{2, 3}

The American Diabetes Association (ADA) guidelines recommend metformin for initial treatment in newly diagnosed type 2 diabetes.4  If additional pharmacotherapy is needed, the guidelines recommend that insulin, a sulfonylurea, or a TZD, such as Avandia or Actos, be added to metformin to control blood glucose.

History of the Current Avandia Controversy
The Nissen Meta-Analysis⁵
On May 21, 2007, the New England Journal of Medicine (NEJM) published a meta-analysis by Dr. Steven Nissen and Kathy Wolski that reported an association between the use of Avandia and an increased incidence of MI.⁵  The authors reported that in the patients receiving Avandia, relative to the control group, there was a statistically significant increase in risk for MI. (Odds ratio equal to 1.43 [95% CI, 1.03 to 1.98; P=0.03]).  This means that the odds of experiencing an MI for patients taking Avandia was found to be 43% higher than those patients not taking Avandia and that this relationship was statistically significant.  However, the difference in absolute risks were very low, ranging from 0.07% to 0.41%.⁵ 

Several weaknesses of this meta-analysis were identified by the authors and others.^{5, 6} For instance, trials were pooled that were not originally designed to evaluate cardiovascular harms.  In addition, definitions of cardiovascular events were not available.  The authors did not have access to original source data for any of these trials and this lack of source data prevented the use of more statistically powerful analyses.  Finally, six trials were explicitly excluded for statistical reasons that reported no CV or MI events.  This potentially eliminated studies favorable to Avandia.  The justification was based on statistical necessity, but it raises the issue of whether or not the association between Avandia and the risk of MI would have remained statistically significant had those studies been included.

FDA Response
On the same day the Nissen analysis was published, the FDA issued a safety alert on the potential cardiovascular risk with Avandia.⁷  It acknowledged the Nissen meta-analysis, but indicated that other published and unpublished data provided contradictory evidence about Avandia’s risk of ischemic cardiovascular events.  The FDA stated that its review of all available data was ongoing.  In addition, the FDA also announced that it would request the manufacturers of both Avandia and Actos to add a black-box warning regarding the risk of CHF and other cardiovascular risks.  At this time, the strengthened warning advises health care professionals to observe patients starting these medications carefully for the signs and symptoms of heart failure, including excessive, rapid weight gain, shortness of breath, and edema.  The warning also states that these drugs should not be used by people with serious or severe heart failure who have marked limits on their activity and who are comfortable only at rest or who are confined to bed or a chair.¹

Additional Published Data
In response to the Nissen meta-analysis, the RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes) study group published an unplanned, interim analysis to assess the risk of MI in patients receiving Avandia.⁸  The interim analysis found no statistically significant difference in the risk of MI or death from cardiovascular causes between the Avandia group and the control group.  However, a statistically significant risk of heart failure for rosiglitazone was found. 

In addition to RECORD, the manufacturer commissioned a balanced-cohort study of 33,363 patients who initiated antidiabetic therapy in a major national health plan.⁹  The primary endpoint was a composite of hospital admissions for MI, coronary revascularization or both.  Comparators were Avandia, metformin, or sulfonylureas as monotherapy, dual-therapy combinations and insulin combinations.  Overall, the risks of MI for Avandia-containing regimens was not statistically different from non-Avandia-containing regimens. 

Of note, neither the ADOPT nor DREAM trials comparing Avandia to other therapies showed a statistically significant increased risk of MI or death from cardiovascular causes, but neither were designed specifically to evaluate these endpoints.^{10, 11}

The FDA Advisory Committees’ Briefing Document¹²
Prior to the advisory committees’ meeting on July 30, 2007, briefing materials were released.  For this document, the FDA reviewed 42 short term studies of Avandia as monotherapy and in combination with a sulfonylurea, metformin and insulin, and 3 long-term studies; ADOPT, DREAM and RECORD.  The results of the analysis were mixed.¹²  The reviewer observed that:

• A statistically significant risk associated with Avandia over comparators was only seen for the endpoint of total myocardial ischemic events which included both non-serious and serious events.
• The results for serious myocardial events were borderline significant (p=0.06) when considering all 42 short-term trials but not significant when excluding the 5 insulin trials (p=0.15). 
• The results for the insulin trials consistently suggest increased risk of serious ischemic events associated with Avandia compared to placebo.
• The data did not convincingly rule out a myocardial ischemic risk due to Avandia.  However, comparisons against metformin or sulfonylurea generally yielded risk ratios close to 1.

The FDA Advisory Committees’ Vote¹
On July 30, 2007, after review of this analysis and discussion, the committees voted 22 to 1 to keep Avandia on the market, finding that the potential benefits of the drug outweigh the risks.  However, the committees also voted that the Avandia data submitted by manufacturer GlaxoSmithKline suggests some ischemic risk associated with the drug.  The committees declined to comment on Avandia’s comparative risk to other oral antidiabetic medications.

Actos - Cardiovascular Risks
It’s still unknown if the increased risk of heart attacks suggested with Avandia is a class effect and would apply to Actos.  Switching a patient who is well-controlled on Avandia to Actos has an unknown safety benefit.  Both Avandia and Actos have proven benefit of improving glycemic control in type 2 diabetes, but at the expense of known side effects of edema and/or heart failure.

The PROactive study, published in 2005, compared all-cause mortality of Actos versus placebo in patients with type 2 diabetes and evidence of microvascular disease.¹³  Although the PROactive study included cardiovascular events, such as myocardial infarction, as clinical endpoints, it failed to reach statistical significance for its primary endpoint.  It is unclear based on the PROactive data whether the same association between Actos and MI or other cardiovascular events is present as that shown in the Nissen and FDA analyses.  More research needs to be done to determine whether the reported risk is specific to Avandia or exists for the TZD class as a whole.

RegenceRx Response
While many limitations and shortcomings of the current data are present, the current controversy raises awareness about the need to consider the risks and benefits in selecting diabetes medications for patients.

RegenceRx will be notifying providers via a safety mailing to prescribers to increase awareness of this issue.  At this time, no changes to the formulary/preferred medication list will be made.  RegenceRx will also continue to monitor the emerging clinical data and will work to keep our providers informed of new developments as they arise.

For a copy of the letter sent to providers, please see:
www.regencerx.com/meet/physicianNews

For a copy of the RegenceRx medication policy for Avandia, please see:
www.regencerx.com/learn/policy

Avandia – Patient Information
Your patients on Avandia may have contacted you with questions about this medication.  In response to patient questions, the FDA has placed several patient resources on its website. 

For a patient information sheet on Avandia, please see:
www.fda.gov/cder/drug/InfoSheets/patient/rosiglitazonePIS.htm

For the latest  patient information on Avandia and cardiovascular risks, go to:
www.fda.gov/consumer/updates/avandia052507.html

Evidence Based Medicine

Quick Review: ITT – Intent to Treat Analysis

The randomized controlled trial is considered to be the most convincing way to demonstrate the value of a therapy.  Proper randomization helps to ensure that the trial is not biased in favor of any particular treatment arm.  However, in all clinical trials, noncompliance, protocol deviations and withdrawals are likely to occur.  Such events chip away at the original randomization and may lead to bias in favor of a particular treatment.^{14, 15} 

One method of dealing with such potential bias is the Intent to Treat (ITT) analysis.  An ITT analysis includes “all randomized patients in the groups to which they were randomly assigned, regardless of their adherence with the entry criteria, regardless of the treatment they actually received, and regardless of subsequent withdrawal from treatment or deviation from the protocol.”¹⁴  In most circumstances, use of the ITT analysis helps to avoid overestimating clinical effectiveness of a particular treatment by maintaining the original randomization and minimizing the effect of non-compliance.  This approach, “as randomized, so analyzed” is considered to mimic clinical practice more closely than an analysis that includes only those patients who completed the study.^{15, 16}

When evaluating a clinical trial for application to your practice, always ask yourself if the results have been reported in clinically significant format.  In randomized trials look to see if an Intent to Treat (ITT) analysis was performed.  Where an ITT analysis has not been performed, carefully review the reported results to see if noncompliance, protocol deviations and dropout rates may have led to an erosion of the original randomization and bias in favor of the treatment.

Next issue: Study Design Overview and Risks versus Odds Ratios

For more information on RegenceRx’s commitment to Evidence Based Medicine, please see:
www.delfini.org/page_Project_Regence.htm

RegenceRx P&T Decisions

The following medications were added to the Preferred Medication List:

Baraclude^® indicated for the treatment of active type B chronic viral hepatitis.
Ciprodex^® indicated for acute otitis externa and otitis media in patients with tympanostomy tubes.
Vagifem^® indicated for the treatment of atrophic vaginitis.

The following medications will remain Non-Preferred/Non-Formulary at this time:

Tekturna^® indicated for the treatment of hypertension.
Tykerb^® indicated for breast cancer, advanced or metastatic, HER2 overexpression, in combination of with Xeloda^® after prior therapies.

For Preferred Medication List/Formulary alternatives for non-preferred products, please see:
www.regencerx.com/learn/covered/therapeutic

For our most recently released Therapeutic Class Summaries^SM, please see:
www.regencerx.com/learn/physicianRx

Medication Policy Updates

The following medications have new or updated Medication Policies:

Blood Modifiers – Aranesp^®, Epogen^®, Procrit^®.  The medication policies for these erythropoietic-stimulating agents (ESAs) have been updated to reflect recent FDA labeling changes and safety data.

When used in dialysis and end stage renal disease patients, ESAs increase the risk for death and for serious cardiovascular events when administered to target a hemoglobin of greater than 12 g/dL.^{17, 18}  In cancer, doses larger than the recommended product labeling have been studied, but there is no direct useful evidence that these doses improve patient outcomes.^{19, 20}  These products have not been shown to improve or relieve the symptoms of anemia nor to improve quality of life in patients with cancer.

The medication policies for these blood modifiers have been updated to reflect:

• Clarification of the definitions of anemia related to kidney failure and cancer.
• Recent Medicare proposals suggesting that anemias related to chemotherapy would be covered; however, anemias related to cancer that are not associated with chemotherapy would not be covered.
• A summary of FDA safety data.

For more information, please see our medication policies and coverage criteria at: 
www.regencerx.com/learn/policy

A full list of the most recent prior authorization changes can be found at:
www.regencerx.com/docs/summaryOfRecentPriorAuthChanges.pdf

Generic Medications

New Generic Medications at the Pharmacy or Coming Soon! ²¹
Consumers stand to save billions of dollars in prescription drug costs in the next few years as a wave of brand name medications come off of patent.  The chart below includes a list of generic medications already at the pharmacy or coming soon to a pharmacy near you!

Attention Deficit Agents dexmethylphenidate (Focalin®) – on shelves methylphenidate ER (Concerta®)  - Fall/Winter 2007	GI balsalazide (Colazal®)  - Fall/Winter 2007 mesalamine (Rowasa®) – on shelves
Infectious Disease cefdinir (Omnicef®) – on shelves ciprofloxacin XL (Cipro XL® ) - on shelves ofloxacin (Floxin Otic®) - Fall/Winter 2007 terbinafine (Lamisil®) -  on shelves valacyclovir (Valtrex®)  - Fall/Winter 2007	Other acarbose (Precose®)  - Fall/Winter 2007 alendronate (Fosamax®)  - Spring 2008 latanoprost (Xalatan®)  - Fall/Winter 2007 testosterone gel (AndroGel®)  - Fall/Winter 2007

 

Special Member Program Spotlight

RegenceRx – Diabetic Meter Programs   

RegenceRx has a unique program for members with diabetes. We offer all members with diabetes the opportunity to receive a new Bayer blood glucose meter at no cost.  To order their new Bayer meter, RegenceRx members should call 1 (888) 787-0233.  The new meter can be shipped directly to the member’s home or office. Members can also ask for a training video about using their new meter when they call the toll-free number.

For information on the available meters, please see:
/www.regencerx.com/docs/bloodGlucoseMeterComparison.pdf

For more information on the Diabetic Meter Program, please go to:
www.regencerx.com/programs/physicianPrograms/bloodGlucose

For more information on all RegenceRx special member programs, please see:
www.regencerx.com/programs/physicianPrograms

Provider Feedback

We Want to Hear From You!
Please take a few minutes to tell us what you think of our new electronic newsletter for providers.  Send your feedback to MDeNews@regence.com

Thank you for helping to keep prescription benefits affordable for our members!

References

1. Food and Drug Administration News Release.  Manufacturers of Some Diabetes Drugs to Strengthen Warning on Heart Failure Risk - Companies Will Include Boxed Warning on Drug Label.  2007 August (Last accessed August 15, 2007).  Available from: www.fda.gov/bbs/topics/NEWS/2007/NEW01683.html
2. Avandia® [package insert]. Research Triangle Park, NC: GlaxoSmithKline; September 2006
3. Actos® [package insert]. Lincolnshire, IL: Takeda Pharmaceuticals America, Inc.; August 2006
4. Nathan, DM et al.  Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2006; 29:1963.
5. Nissen SE, Wolski K.  Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007 Jun 14;356(24):2457-71. Epub 2007 May 21.  (It was also reported that the odds ratio for death from all cardiovascular causes was reported as 1.64 (95% CI, 0.98 to 2.74; P=0.06) but was not statistically significant.)
6. Psaty BM, Furberg CD. Rosiglitazone and cardiovascular risk. N Engl J Med. 2007 Jun 14;356(24):2522-4. Epub 2007 May 21.
7. Food and Drug Administration News Release.  Rosiglitazone maleate (marketed as Avandia, Avandamet, and Avandaryl) Information.  2007 August (Last accessed August 15, 2007).  Available from: www.fda.gov/cder/drug/infopage/rosiglitazone/default.htm
8. Home PD, Pocock SJ, Beck-Nielsen H, Gomis R, Hanefeld M, et. al. Rosiglitazone Evaluated for Cardiovascular Outcomes Regulation of Glycemia in Diabetes- An Interim Analysis. N Engl J Med. 2007 Jun 5; [Epub ahead of print]
9. McAfee AT, Koro C, Landon J, Ziyadeh N, Walker AM.  Coronary heart disease outcomes in patients receiving antidiabetic agents. Pharmacoepidemiol Drug Saf. 2007 Jun 6; [Epub ahead of print]
10. Kahn S st al.  Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. NEJM 2006;355;2427-43.
11. The DREAM (Diabetes Reduction Assessment with ramipril and rosiglitazone Medication) Investigators. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet 2006;368:1096-1105. [Erratum, Lancet 2006;368:1770.] 
12. Food and Drug Administration Briefing Information.  Cardiovascular ischemic/thrombotic risks of the thiazolidinediones, with focus on rosiglitazone, as presented by FDA and GlaxoSmithKline.  2007 July (Last accessed August 15, 2007).  Available from: www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4308b1-00-index.htm
13. Dormandy JA et al., Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial.  Lancet 2005;366:1279-1289.
14. Fisher LD et al. Intention-to-Treat in clinical trials, in KE Peace (Ed.), Statistical Issues in Drug Research and Development. Marcel Dekker, 1990
15. Hollis S, Campbell F.  What is meant by intention to treat analysis? Survey of published randomised controlled trials. BMJ 1999;319;670-674.  Available online at:  www.bmj.com/cgi/reprint/319/7211/670.pdf
16. Allen J.  Applying study results to patient care: Glossary of study designs and statistical terms.  Pharmacist’s Letter Detail Document #210610.  2005 June;21: 210610.
17. Aranesp® (darbepoetin alpha) Product Information. Amgen Inc. Thousand Oaks, CA, March 2007.
18. Epogen® (epoetin alpha) Product Information. Amgen Inc. Thousand Oaks, CA, March 2007.
19. Justice G et. al. A randomized, multicenter study of subcutaneous and intravenous darbepoetin alfa for the treatment of chemotherapy-induced anemia. Ann Oncol. 2005 Jul;16(7):1192-8. Epub 2005 Apr 28.
20. NCCN: Cancer and Treatment Related Anemia. Clinical Practice Guidelines in Oncology. V.2.2006.  (Last accessed July 31, 2007).  Available at:   www.nccn.org/professionals/physician_gls/PDF/anemia.pdf
21. Predicted market availability is based on either current expiration date of patent, resolution date of patent challenges, or end of 30-month stay blocking FDA from approving generics.  When a generic may become available largely depends upon the action by the courts, the FDA, and the manufacturer; therefore, actual availability date may be subject to change.