Drug Injury Watch

Relatively Little Is Known About Long-Term Safety Of Bisphosphonates Such As Fosamax, Boniva, Actonel

Doctors Should Inform Their Patients About Potential Serious Side Effects Like Osteonecrosis Of The Jaw And Femur Fractures

(Posted by Tom Lamb at DrugInjuryWatch.com)

The rather alerting headline above comes from an article, "Osteoporosis treatments and adverse events", which was published in the April 30, 2009 edition of Current Opinion in Rheumatology.

From the Abstract for this medical journal article:

Osteoporosis treatments will be used with increasing frequency as the population ages; however, relatively little is known about their long-term safety. Recent case reports cite a range of potential adverse events. We review data regarding atrial fibrillation, bone pain, osteonecrosis of the jaw (ONJ), atypical fractures, and osteosarcoma....

Although case reports of adverse events with osteoporosis medications suggest potential links, epidemiological analyses have largely failed to illuminate a strong, clear link between osteoporosis therapies and many adverse events, with ONJ an exception. Until further data are available, providers should be aware of these potential side effects, and inform their patients accordingly.

Because there are growing number of patients who use bisphosphonates like Merck's very popular Fosamax pill, and due to the range of possible different side effects that have been associated with the use of those osteoporosis drugs, I thought it would be worthwhile to do a "round-up" of our recent posts on this subject.

More About A "New" Fosamax Bone Side Effect, Leg Fractures In Region Of Thigh Or Femur

• March 2009 Drug Safety Update Article And BMJ Case Reports Item Bring Attention To Fosamax-Related Atypical Stress Fractures Or Insufficiency Fractures Of Femur

Fosamax Update January 2009: More Osteonecrosis Of Jaw Cases Reported In Medical Journal

• Possible Link Between Fosamax And Esophagus Cancer Surfaces; Merck Disputes This New Side Effect

When Will FDA Report Its Findings About Any Link Between Fosamax And Atrial Fibrillation

• In October 2007 The Agency Estimated It Would Need Up To 12 Months To Complete Investigation Regarding This Possible Bisphosphonate Side Effect

As regards to the numerous Fosamax lawsuits involving ONJ that have been filed against Merck, the first Fosamax trial is scheduled to start in August 2009 -- with many more trials in federal and state courts expected to follow.

We will continue to keep you informed about the medical and legal developments concerning serious side effects associated with bisphosphonates such as Fosamax, Boniva, Actonel, Aredia, and Zometa.

Have Yasmin-Related Blood Clot Side Effect Cases Flown Below Radar In US?

In Europe Reports Of Pulmonary Embolism And Deep Vein Thrombosis Were Made Soon After Yasmin Birth Control Pill Was Approved In 2000

(Posted by Tom Lamb at DrugInjuryWatch.com)

An April 13, 2002 BMJ article, "Dutch GPs warned against new contraceptive pill" (FREE registration required), was published the week before the Yasmin birth control pill was going to become available to women in the United Kingdom.  From that article we learn, now, that Yasmin was the subject of safety concerns right from the start in Europe:

Dutch GPs are being advised by their own professional body not to prescribe a new low dose, monophasic oral contraceptive, marketed under the trade name Yasmin, until studies have established whether it is as safe as other contraceptive pills.

The new contraceptive, which is a combination of drospirenone (a progestogen) and ethinylestradiol, has been available in several European countries since 2000 and was approved by the US Food and Drug Administration last May. It is licensed for use in the United Kingdom, where it is being launched next week.

Last year a 17 year old Dutch girl who had been taking Yasmin died from a venous thrombosis. Although no direct link with Yasmin has ever been shown, 40 cases of venous thrombosis among women taking Yasmin, two of which were fatal, have now been reported in Europe.

The Dutch College of General Practitioners has now reiterated its position that GPs should continue to choose the second generation pill, because of the lack of epidemiological data on the risk of thrombosis from Yasmin.

About a year later, in the February 1, 2003 edition of BMJ, there appeared a brief Drug Points piece, "Thromboembolism associated with the new contraceptive Yasmin", which provided some details about several cases of serious blood clot side effects in women using the Yasmin birth control pill.

Our centre, the Dutch spontaneous reporting system for adverse drug reactions, recently received five reports of thromboembolism as a suspected adverse drug reaction to the new oral contraceptive Yasmin (ethinylestradiol and drospirenone).

A 17 year old woman suddenly collapsed and died after taking the contraceptive [pill Yasmin] for six months. Autopsy showed that she had had a massive pulmonary embolism [(PE)]. No obvious risk factors for thromboembolism, such as smoking, a period of long immobilisation, air flights, or concomitant medication, were evident....

A 28 year old woman changed her oral contraceptive from ethinylestradiol with desogestrel (Marvelon) to ethinylestradiol with drospirenone [(Yasmin)]. Four months later she had thrombosis in one leg and was treated with acenocoumarol. Risk factors or concomitant drugs were unknown.

Another patient, a 45 year old woman, had deep vein thrombosis [(DVT)] in one leg after taking ethinylestradiol with drospirenone [(Yasmin)] for two months, as did a 50 year old woman who took the contraceptive for three months.

A 35 year old woman had pulmonary thrombosis 17 days after she started taking the contraceptive [pill Yasmin]. She had given birth four months earlier.

Only recently in the U.S. have there been products liability lawsuits filed on behalf of women who have developed a pulmonary embolism (PE) or deep vein thrombosis (DVT) after they used Yasmin -- or YAZ, a newer but very similar birth control pill that also contains the so-called "fourth generation" progestin drospirenone (DRSP).

We expect, however, to see an increasing number of Yasmin lawsuits -- and YAZ lawsuits -- as more women learn about the blood clot side effect risks associated with these "fourth generation" oral contraceptives only after they suffered a pulmonary embolism (PE) or a deep vein thrombosis (DVT).

Lancet Article About Avandia Study Omits Key Fact Says Nissen And Other Critics

Whether Avandia Causes Heart Attacks Remains An Open Issue, Despite Recent RECORD Study Results

(Posted by Tom Lamb at DrugInjuryWatch.com)

On June 5, 2009, at the annual meeting of the American Diabetes Association (ADA) in New Orleans, GlaxoSmithKline announced the results of a much-anticipated study regarding its diabetes drug Avandia (rosiglitazone).

As background, from a June 5, 2009 news article "ADA: Rosiglitazone Increases Risk of Heart Failure, but Not Mortality", published online by MedPage Today:

The results of the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD) trial came from an assessment of 4,447 patients with type 2 diabetes at 338 centers in 23 countries in Europe, Australia, and New Zealand who had five to seven years of follow-up.

The study was warranted in 1999 after the thiazolidinedione class [e.g., Avandia and Actos] had been thought to cause fluid retention and possibly heart failure in diabetes patients.

According to that same article, Philip D. Home, M.D., Ph.D., of Newcastle University in England and chairman of the RECORD steering committee, told a press briefing at the June 2009 ADA meeting:

"The heart failure answer hasn't changed," Dr. Home said, referencing interim results from the trial that were released two years ago. "We confirmed that there is an increase in heart failure -- a double increase with rosiglitazone compared to the control [group]."

"But in terms of overall cardiovascular risk, the drug is safe," Dr. Home said, noting a risk ratio of one between the two study groups. "There's no increased risk, no decreased risk. And that includes the heart failure element."

Soon after the RECORD study results were presented at the ADA meeting -- and published online by The Lancet-- Steven E. Nissen, M.D., of the Cleveland Clinic, weighed in with his comments and observations. 

First, you may recall a June 2007 New England Journal of Medicine article, "Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes", in which Dr. Nissen and Kathi Wolski, M.P.H. reported a meta-analysis of 42 clinical trials involving 27,847 patients which essentially started the ongoing controversy about the safety of Avandia.  They concluded that treatment with Avandia was associated with an approximately 43% greater risk for myocardial infarction and an approximately 64% greater risk for cardiovascular death than placebo or other antidiabetic regimens.

Returning to the June 2009 MedPage Today article and what Nissen had to say about the RECORD study:

"At the time of publication of the interim analysis in 2007, approximately 30% of patients in the trial originally assigned to receive [rosiglitazone] were no longer taking the drug" [Nissen said]....

"In The Lancet manuscript, the authors don't reveal the number of patients who were still taking Avandia by the end of the study," he said. "Obviously, it is impossible to assess the safety of a drug when patients are not actually taking it."

Due to this missing key data, for Dr. Nissen and others the issue of whether Avandia is associated with an increased risk of heart attacks, or myocardial infarction, is still unresolved, today.

Matthew Herper, of Forbes, focuses on the point Dr. Nissen makes about this missing data in his June 5, 2009 report, "Glaxo Fails To Learn Lesson of Avandia":

Nissen argues that in a drug safety study it is also necessary to look at just the patients who were taking the drug the whole time. But the dropout rates were not included in the Lancet paper.

"That's a problem," says Bernard Zinman, a researcher at the Samuel Lunenfeld Research Institute of Mount Sinai Hospital in Toronto who wrote an editorial on the study in The Lancet. The study "doesn't tell us anything" about Avandia's propensity for causing heart attacks, Zinman says....

[W]hen Glaxo published an earlier analysis of RECORD in 2007, before the trial was completed, that interim paper in the New England Journal of Medicine took great care to mention how many patients had stopped taking Avandia and other drugs.

... 27% of the patients had stopped taking an assigned drug in the Avandia arm and 33% had stopped taking an assigned drug in the control group.

That's key information because it means side effects could be washed out by the number of patients who were included in the final tally but weren't on the drug.

But these numbers, which were present in the New England Journal, are missing from the final publication in The Lancet. The Lancet did not return an e-mailed request for comment.

GlaxoSmithKline provided the figures at Forbes' request. At the end of the study, 1,344 patients 61% of the Avandia group were still on the drug, while 1,131 patients, or 51% of the control group, remained on their medicines.

Those numbers are not surprising or unusual for a study where patients were being followed for more than five years, says Mary Anne Rhyne, a Glaxo spokeswoman.

Rhyne said she could not explain why those numbers were not in The Lancet paper because the paper was written by the outside researchers running the trial, not Glaxo.

The RECORD study was funded by GlaxoSmithKline.

I am sure we will be hearing more from Dr. Home, Dr. Nissen, and others about what the RECORD study shows about the safety of Avandia, and what it does not.

Birth Control Pill YAZ Is Subject Of Ongoing Safety Study Regarding Cardiovascular Side Effects

A Comparison Of This "Fourth Generation" DRSP / EE Pill To Other Established Oral Contraceptives For Incidence Of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), Heart Attack (MI), And Stroke (CVA)

(Posted by Tom Lamb at DrugInjuryWatch.com)

YAZ (3 mg drospirenone/20 mcg ethinyl estradiol) is an oral contraceptive (OC) which is the first pill to combine 20 mcg of ethinyl estradiol (EE) with the so-called "fourth generation" progestin drospirenone (DRSP).  YAZ was approved by the FDA in March 2006.

A company press release, "FDA Approves YAZ(R), The First Oral Contraceptive To Offer Drospirenone In A 24-Day, Active-Pill Regimen", issued at the time of FDA approval, can be read so as to suggest that the list of possible serious side effects of YAZ about which women should be most concerned does not include any cardiovascular side effects:

YAZ contains 3 mg of the progestin drospirenone that has antimineralocorticoid activity, including the potential for hyperkalemia in high-risk patients, comparable to a 25-mg dose of spironolactone. YAZ should not be used in patients with conditions that predispose to hyperkalemia (i.e., renal insufficiency, hepatic dysfunction, or adrenal insufficiency). Women receiving daily, long-term treatment for chronic conditions or diseases with medications that may increase serum potassium should have their serum potassium levels checked during the first treatment cycle. Medications that may increase serum potassium include ACE inhibitors, angiotensin-ll receptor antagonists, potassium-sparing diuretics, potassium supplementation medications, aldosterone antagonists and NSAIDs.

In fact, the current YAZ package insert, or label (accessed 5/18/09), includes this same text in bolded font, while the warning about cardiovascular side effects like deep vein thrombosis (DVT), pulmonary embolism (PE), heart attack, and stroke is not bolded for emphasis.

Seemingly, however, the FDA has had some concerns about an association between YAZ and DVT, PE, heart attack, and stroke, as seen below.

A study called the International Active Surveillance Study of Women Taking Oral Contraceptives (INAS-OC), which was started in August 2005 and continues to date, is intended to evaluate the risk of those cardiovascular side effects for women who use DRSP/EE birth control pills like YAZ.

According to a May 11, 2009 article, "ACOG 2009: Preliminary Findings Favor 24-Day Regimen of Drospirenone and Ethinyl Estradiol for Contraception", published online by Medscape:

[P]reliminary findings from the International Active Surveillance Study of Women Taking Oral Contraceptives (INAS-OC) study were presented here at the American College of Obstetricians and Gynecologists (ACOG) 57th Annual Clinical Meeting by Jürgen Dinger, MD, PhD, from the Berlin Center for Epidemiology and Health Research in Germany....

"The INAS study is a transatlantic prospective cohort study that was requested by the [US Food and Drug Administration] to investigate the safety of a 24-day regimen of 3 mg DRSP and 20 μg ethinyl estradiol (24/4 regimen)," Dr. Dinger told the audience. To date, the INAS study has enrolled 52,219 women....

The study's objectives are to compare the cardiovascular safety of the 24/4 regimen of DRSP/EE to established oral contraceptives (OCs) during standard clinical practice (eg, deep venous thrombosis, pulmonary embolism, acute myocardial infarction, stroke); to investigate the incidence of rare serious adverse events associated with the use of 24/4 and established OCs; and to investigate contraceptive failure rates associated with the use of the 24-day and 21-day regimens of DRSP/EE and all other OCs.

For women using YAZ, here is some important information about the symptoms of these serious cardiovascular side effects from the WebMD.com web site:

This medication may rarely cause serious (sometimes fatal) problems from blood clots (e.g., pulmonary embolism, stroke, heart attack). Seek immediate medical attention if you experience: sudden shortness of breath, chest/jaw/left arm pain, confusion, coughing up blood, sudden dizziness/fainting, pain/swelling/warmth in the groin/calf, tingling/weakness/numbness in the arms/legs, headaches that are different from those you may have experienced in the past (e.g., headaches with other symptoms such as vision changes/lack of coordination, existing migraines becoming worse, sudden/very severe headaches), slurred speech, weakness on one side of the body, vision problems/changes.

A quick Internet search for the word "YAZ" will show among the results that there are discussion forums with "threads" like "WARNING ABOUT YAZ BIRTH CONTROL PILLS", at the SteadyHealth.com web site, where numerous women have reported having a DVT or PE while using YAZ pills.

All of this leaves us wondering whether YAZ is a possible unsafe birth control method, like Ortho Evra and NuvaRing....

If you or someone you know has developed a deep vein thrombosis (DVT), pulmonary embolism (PE), heart attack, or stroke while using YAZ -- and you want to share your experience with others -- you can do so by submitting a Comment, below.

Hydroxycut Weight-Loss Products Are Recalled Due To Cases Of Serious Liver Injury

Reports Made To The FDA Have Involved Hepatitis, Liver Failure, Liver Transplant, And Death

(Posted by Tom Lamb at DrugInjuryWatch.com)

On May 1, 2009 the FDA warned people to stop using Hydroxycut products -- made by Iovate Health Sciences Inc., of Oakville, Ontario and distributed by Iovate Health Sciences USA Inc. of Blasdell, N.Y. -- due to the fact that some Hydroxycut products are associated with a number of serious liver injuries. Furthermore, the manufacturer, Iovate, has agreed to immediately recall Hydroxycut products from the U.S. market.

The list of Hydroxycut products being recalled by Iovate currently includes:

Hydroxycut Regular Rapid Release Caplets
Hydroxycut Caffeine-Free Rapid Release Caplets
Hydroxycut Hardcore Liquid Caplets
Hydroxycut Max Liquid Caplets
Hydroxycut Regular Drink Packets
Hydroxycut Caffeine-Free Drink Packets
Hydroxycut Hardcore Drink Packets (Ignition Stix)
Hydroxycut Max Drink Packets
Hydroxycut Liquid Shots
Hydroxycut Hardcore RTDs (Ready-to-Drink)
Hydroxycut Max Aqua Shed
Hydroxycut 24
Hydroxycut Carb Control
Hydroxycut Natural

The FDA's reasoning for this May 2009 recall of Hydroxycut products can be found in a Health Hazard Evaluation Board document entitled "The Problem: Liver toxicity following consumption of dietary supplement, Hydroxycut".  From the Conclusion section of this Health Hazard Evaluation document:

Three lines of evidence derived from multiple disparate sources suggest it is very likely that exposure to Hydroxycut can cause idiosyncratic hepatotoxicity. First, many of the subjects described in the adverse event reports to CAERS, in the peer-reviewed literature, and in the case series described by hepatologists reported no history of liver disease or risk factors for liver disease (e.g., alcohol consumption, previous viral infection, hereditary factors, etc.) prior to experiencing liver injury following the ingestion of Hydroxycut. Second, in many subjects, thorough diagnostic evaluations performed in multiple settings ruled out a number of known causes of liver disease, including viral hepatitis, autoimmune diseases, and metabolic/inherited disorders. Third, prompt resolution of liver disease occurred in a number of patients following cessation of Hydroxycut ingestion.

In a Consumer Advisory, "FDA Warns Consumers Not to Use Dietary Supplements Labeled Hydroxycut because of the Potential Risk of Severe Liver Injury", the FDA provides the following medical information:

Consumers who use a Hydroxycut dietary supplement and who experience signs of illness associated with liver disease should immediately consult their health care provider. Symptoms of serious liver disease include jaundice (yellowing of the skin or whites of the eyes) and brown urine. Non-specific symptoms of liver disease can include nausea, vomiting, light-colored stools, unusual tiredness, weakness, stomach or abdominal pain, itching, and loss of appetite.  FDA has also identified several other serious adverse events associated with Hydroxycut, including cases of seizures, rhabdomyolysis (a type of muscle damage that can lead to other dangerous problems, such as kidney failure), and cardiovascular problems, ranging in severity from irregular heart beat to a heart attack.  [bold in original]

The FDA -- as opposed to Iovate, the manufacturer of Hydroxycut products --has issued a "Dear Doctor" letter to healthcare providers in the U.S.

In addition, the FDA has put on its web site a Consumer Questions and Answers document regarding this Hydroxycut recall.

In closing, the FDA has stated that it will continue to investigate the relationship between the use of Hydroxycut dietary supplements and liver injury.

If you are aware of any case of liver damage caused by the use of Hydroxycut products, please consider sharing that information with us by submitting a Comment, below.

P.S.  North of FDA-land, Health Canada says it will continue to monitor adverse reaction reports associated with Hydroxycut products, and will provide Canadians with any new safety information. 

From "Health Canada Reviewing Hydroxycut Products in light of U.S. Advisory":

Health Canada has received 17 domestic adverse reaction (AR) reports associated with Hydroxycut products in Canada. These adverse reactions relate to the cardiovascular, respiratory, gastrointestinal, and neurological systems. None of the adverse reactions reported in Canada relate to liver injury.

It will be interesting to see if Health Canada follows the lead of our FDA and issue a Hydroxycut recall in Canada.  (5/4/09)

P.S.  On May 7, 2009 the FDA announced that Iovate Health Sciences USA, Inc. has provided Universal Product Codes (UPCs) for its products that were part of the May 1 Hydroxycut recall.  (5/8/09)

Caraco Digoxin Recall Issued March 31, 2009 Is Due To Pill-Size Problems

Digitek Brand Of Generic Digoxin Tablets Had Been Recalled In April 2008 For Same Reason

(Posted by Tom Lamb at DrugInjuryWatch.com)

On March 31, 2009 the FDA announced another generic digoxin pill recall by posting this company press release on the agency's web site: "Caraco Pharmaceutical Laboratories, Ltd. Announces a Nationwide Voluntary Recall of All Lots of Digoxin Tablets Due to Size Variability".

This March 31 press release from Caraco, a generic pharmaceutical company, states that:

[A]ll tablets of Caraco brand Digoxin, USP, 0.125 mg, and Digoxin, USP, 0.25 mg, distributed prior to March 31, 2009, which are not expired and are within the expiration date of September, 2011, are being voluntarily recalled to the consumer level. The tablets are being recalled because they may differ in size and therefore could have more or less of the active ingredient, digoxin."

Almost a year ago, in late April 2008, all digoxin pills manufactured by Actavis Totowa -- marketed under the Digitek brand name -- were recalled due to this so-called "double-dose" manufacturing problem.  Those Digitek pills were distributed by Mylan Pharmaceuticals under the Bertek and UDL labels.

The Digitek recall has resulted in personal injury and wrongful death lawsuits being filed on behalf of patients who used Digitek digoxin tablets.

It is too early to tell whether there will be any product liability litigation involving the possible "double-dose" digoxin pills that are now being by Caraco Pharmaceutical.

P.S.  Read about a "new" May 11, 2009 digoxin recall by a company that repackaged Caraco digoxin tablets -- which were originally recalled in late March 2009. 

Why did AS Medication Solutions delay their digoxin recall notice for six weeks?  (5/13/09)

Watson Pharmaceuticals Recalls One Lot Of Generic Propafenone Pills Due To Possible Manufacturing Problem

At Present, This March 2009 Recall Is Limited To Propafenone HCL 225 mg Tablets Shipped Between October 15, 2008 And November 26, 2008

(Posted by Tom Lamb at DrugInjuryWatch.com)

By means of a MedWatch Email Alert, on March 25, 2009 the FDA informed us about yet another quality control problem at a generic drug manufacturing facility.

From the March 25 MedWatch Alert:

FDA and Watson Pharmaceuticals notified healthcare professionals and patients of a recall of Propafenone HCL 225 mg tablets, a drug product used to treat cardiac arrhythmias. The drug is being recalled because some tablets may contain slightly higher levels of the active ingredient than specified. Because it has a narrow therapeutic index, some patients who are particularly sensitive to small variations in dose may experience potentially serious side effects, including arrhythmias (irregular heartbeat) or low blood pressure. The affected lot [lot number 112680A, expiration date July 31, 2010] of Propafenone HCL tablets was shipped to customers between October 15, 2008 and November 26, 2008.

The FDA also posted on its web site a press release about this Propafenone recall from the drug company, "Watson Announces a Nationwide Voluntary Recall of Propafenone HCL Tablets Due to Oversized Tablets", which added this additional information and guidance:

• [Recall involves just] one lot of Propafenone HCL 225 mg Tablets sold in 100 count bottles in the United States....
• No other strengths or lots were affected and the Company does not anticipate any product shortages as a result of this recall.
• Anyone who has 225 mg Propafenone HCL tablets should check the bottle for the lot number and expiration date to see if they have tablets being recalled.
• Patients using 225 mg Propafenone HCL tablets who have medical questions should contact their health-care provider.

This recall is apparently due to the fact that current Good Manufacturing Practices (cGMP) were not being followed at the facility where Watson makes its Propafenone HCL 225 mg Tablets.

As we have reported previously, here, during the past year there have been other cGMP violations leading to generic drug recalls by Actavis, ETHEX / KV Pharmaceutical, and Sandoz / Novartis. 

The Digitek recall by Actavis-- which was manufacturing these generic digoxin pill for the Bertek and UDL divisions of Mylan Pharmaceuticals -- has given rise to hundreds of lawsuits filed by patients who used Digitek.

Some of those earlier generic drug recalls were initially limited to selected lots of one drug only to later be expanded to other generic drugs that were manufactured at the same plant.  We will wait to see if additional lots of Propafenone HCL tablets, or any additional different drugs, are recalled by Watson in the coming weeks and months.

Avandia And Actos Are In Same Class, But One Of These Diabetes Drugs Has More Safety Risks

New Study Shows Older Diabetics Were More Likely To Develop Heart Failure Or Die When Using Avandia As Opposed To Actos

(Posted by Tom Lamb at DrugInjuryWatch.com)

In late November 2008 the medical journal Archives of Internal Medicine published an article about a study that found patients aged 65 and older who were taking Avandia (rosiglitazone) had a 15 percent higher rate of death and a 13 percent greater risk of heart failure when compared with similar patients taking (pioglitazone).  Both of these diabetes drugs are part of a class of drugs called thiazolidinediones.

As you may recall, the controversy over whether there are increased heart risks caused by Avandia began with a 2007 study by Steven E. Nissen, M.D., and Kathy Wolski, M.P.H., that was published in the New England Journal of Medicine and which reported a 43 percent increased risk of heart attack among patients taking Avandia.

The more recent Archives of Internal Medicine article, "Comparison of Cardiovascular Outcomes in Elderly Patients With Diabetes Who Initiated Rosiglitazone vs Pioglitazone Therapy", seemingly renewed this controversy and certainly produced a mix of reactions in the days following its publication.

We begin with some comments from Dr. Wolfgang C. Winkelmayer, one of the authors, who explains the impetus for his study in a November 24, 2009 Reuters article, "Safety risks higher with Avandia than Actos - study":

Recent analyses of clinical studies found Avandia raised the risk of heart attacks, which has sent sales of the drug plummeting. An analysis of studies on Actos, meanwhile, suggested it reduced the risk of heart attacks and strokes....

"Altogether, the picture people got was it looks like rosiglitazone might be associated with badness and pioglitazone is neutral and even beneficial," Winkelmayer said in a telephone interview.

"For me, that left an important question open. What if you happen to directly compare those two treatments together," Winkelmayer said in a telephone interview....

Winkelmayer said the study was not a randomized clinical trial, which is the most reliable type of study, but he said the characteristics in both study populations were surprisingly similar, making the comparison quite strong.

"I think it's one more piece of the puzzle," he said.

"It will contribute to a more compelling picture that will inform policymakers with regard to how to move forward."

From a November 25 New York Times article, "Diabetes Drug Linked to Higher Risk of Death", we get these two rather divergent viewpoints:

Dr. John Buse, chief of endocrinology at the University of North Carolina School of Medicine and president of the American Diabetes Association, said the new study is important but limited.

“This is about the tenth report suggesting that rosiglitazone is associated with excess cardiovascular problems,” he said. “We don’t have proof yet.”...

Dr. Sidney Wolfe, director of Public Citizen’s Health Research Group, said he hoped this study would be “the last nail in the coffin of this drug.”

“The big attraction of these drugs is that they are insulin-sensitizing drugs and forestall the time when someone would have to go on to insulin,” Dr. Wolfe added. “But with a 15 percent excess mortality over even pioglitazone, which itself is dangerous, that doesn’t seem like a very good tradeoff.”

A November 24 HealthDay article, "Avandia's Heart Risk Higher Than Others in Its Class", included parts of the statement issued by GlaxoSmithKline -- the drug company that makes of Avandia -- concerning the Avandia vs. Actos study article by Dr. Winkelmayer and his colleagues:

The company "strongly supports the safety and efficacy of Avandia based on extensive clinical trial experience and widespread post-marketing use. This new study is inconsistent with evidence from randomized clinical trials and has significant limitations," the statement said.

A randomized clinical trial -- in which participants are randomly grouped and then followed prospectively over time -- is typically considered more reliable than an observational study, which is not as well-controlled.

"The primary outcome in this observational analysis is all-cause mortality," the company statement added. "The Avandia prescribing information includes data from RECORD, an ongoing long-term randomized clinical trial that has shown no statistically significant differences between the Avandia group and the control group regarding death from cardiovascular causes or any cause."

In that same HealthDay article, Eric J. Topol, M.D., offers an observation that serves to concisely sum-up the situation:

"The study reinforces the heart failure risk of rosiglitazone versus pioglitazone," Topol said. "Interestingly, it doesn't show any difference in heart attack, which is the one issue that has been so controversial. So it doesn't really change things that much."

Of the two drugs, Actos appears to have a more favorable track record, Topol added. "But the possibility of cardiovascular side effects, including heart failure and heart attack, can't be forgotten."

We will continue to monitor the medical journals for new reports about the safety profiles of Avandia and Actos.

Internal Glaxo Emails Show Drug Company Was Concerned In 2007 About Avandia's Heart Attack Risks

Senator Grassley's Report On How Glaxo Defended Avandia In Wake Of 2007 NEJM Article By Nissen And Wolski Is Expected To Be Released Soon

(Posted by Tom Lamb at DrugInjuryWatch.com)

On May 21, 2007, in our post titled "Glaxo's Diabetes Drug Avandia May Cause Significant Heart Attack Risk", we reported about the Los Angeles Times publishing a May 21 article which broke the story about a new analysis of Avandia data that had been published online earlier this same day by the New England Journal of Medicine (NEJM).

This now relatively well-known NEJM Avandia article, "Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death", was written by Steven E. Nissen, M.D., and Kathy Wolski, M.P.H.; it was published in the June 14, 2007 print edition of the NEJM.

It turns out, however, that GlaxoSmithKline PLC -- the drug company that makes Avandia -- had some (improper) advanced notice of the Nissen and Wolski NEJM article and (surprise, surprise) the drug company tried to do something about it. 

For the telling of this still-developing story, we turn to a January 14, 2009 Wall Street Journal (WSJ) article, "Glaxo's Emails on Avandia Reveal Concern", by reporters Alicia Mundy and Jared Favole.  We start by setting the stage:

The study by Dr. Nissen for the New England Journal was supposed to be kept under wraps until its release on May 21, but Glaxo obtained a copy on May 3 from a doctor, Steven Haffner of the University of Texas, who was reviewing it for the medical journal. Dr. Haffner had been a Glaxo consultant on Avandia since 2000 and received $433,000 from Glaxo between 2000 and August 2007. He confirms giving Glaxo the study, though he says doing so was "a terrible mistake."...

As soon as Glaxo got Dr. Nissen's draft, its researchers began a detailed analysis, according to the email excerpts. On May 4, one wrote, "There is no statistical reason for disregarding the [Nissen] findings as presented."...

In a May 8, 2007, email, Moncef Slaoui, the director of Glaxo research, told several executives: "FDA, Nissen and GSK all come to comparable conclusions regarding increased risk for ischemic events, ranging from 30% to 43%!"

The January 14 WSJ article suggests that there is more to come, soon, regarding Glaxo's conduct back in 2007, this time from Washington:

A leading Republican senator, Sen. Chuck Grassley of Iowa, has been pushing the FDA to ask Glaxo to withdraw the drug. He is preparing a report that may be released soon containing excerpts from Glaxo documents about the company's efforts to defend its drug from the New England Journal study, according to people familiar with the situation.

We will be watching for the release of Senator Grassley's report about Avandia and Glaxo.

If you know anything more regarding this apparent attempt by Glaxo to head-off the 2007 NEJM article by Nissen and Wolski that first revealed the increased heart attack risk associated with Avandia -- or you want to express an opinion about Glaxo's conduct in this instance -- please submit a Comment below.

(Posted by Tom Lamb at DrugInjuryWatch.com)

On May 21, 2007, in our post titled "Glaxo's Diabetes Drug Avandia May Cause Significant Heart Attack Risk", we reported about the Los Angeles Times publishing a May 21 article which broke the story about a new analysis of Avandia data that had been published online earlier this same day by the New England Journal of Medicine (NEJM).

This now relatively well-known NEJM Avandia article, "Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death", was written by Steven E. Nissen, M.D., and Kathy Wolski, M.P.H.; it was published in the June 14, 2007 print edition of the NEJM.

It turns out, however, that GlaxoSmithKline PLC -- the drug company that makes Avandia -- had some (improper) advanced notice of the Nissen and Wolski NEJM article and (surprise, surprise) the drug company tried to do something about it. 

For the telling of this still-developing story, we turn to a January 14, 2009 Wall Street Journal (WSJ) article, "Glaxo's Emails on Avandia Reveal Concern", by reporters Alicia Mundy and Jared Favole.  We start by setting the stage:

The study by Dr. Nissen for the New England Journal was supposed to be kept under wraps until its release on May 21, but Glaxo obtained a copy on May 3 from a doctor, Steven Haffner of the University of Texas, who was reviewing it for the medical journal. Dr. Haffner had been a Glaxo consultant on Avandia since 2000 and received $433,000 from Glaxo between 2000 and August 2007. He confirms giving Glaxo the study, though he says doing so was "a terrible mistake."...

As soon as Glaxo got Dr. Nissen's draft, its researchers began a detailed analysis, according to the email excerpts. On May 4, one wrote, "There is no statistical reason for disregarding the [Nissen] findings as presented."...

In a May 8, 2007, email, Moncef Slaoui, the director of Glaxo research, told several executives: "FDA, Nissen and GSK all come to comparable conclusions regarding increased risk for ischemic events, ranging from 30% to 43%!"

The January 14 WSJ article suggests that there is more to come, soon, regarding Glaxo's conduct back in 2007, this time from Washington:

A leading Republican senator, Sen. Chuck Grassley of Iowa, has been pushing the FDA to ask Glaxo to withdraw the drug. He is preparing a report that may be released soon containing excerpts from Glaxo documents about the company's efforts to defend its drug from the New England Journal study, according to people familiar with the situation.

We will be watching for the release of Senator Grassley's report about Avandia and Glaxo.

If you know anything more regarding this apparent attempt by Glaxo to head-off the 2007 NEJM article by Nissen and Wolski that first revealed the increased heart attack risk associated with Avandia -- or you want to express an opinion about Glaxo's conduct in this instance -- please submit a Comment below.

Sprint Fidelis Lead Wire Failures May Be On The Rise According To February 2009 Journal Article By Hauser And Hayes

Physicians Must Consider The Pros And Cons Of Surgical Removal Before Heart Device Shocks Unnecessarily Or Fails To Work When Patient Needed Shock

(Posted by Tom Lamb at DrugInjuryWatch.com)

On February 23, 2009 the medical journal HeartRhythm made available online an article by Robert G. Hauser, MD, and David L. Hayes, MD, "The Increasing Hazard of Sprint Fidelis Implantable Cardioverter-Defibrillator Lead Failure", which pits these two prominent cardiologists against Medtronic, Inc., the company that made the Sprint Fidelis lead wires.

As you may recall, Medtronic was forced to recall its Sprint Fidelis lead wires in 2007 following hundreds of reports from patients with defibrillators who were being shocked unnecessarily or having their heart device fail to deliver any shock when one was needed. 

According to the "Class 1 Recall: Medtronic Inc. Sprint Fidelis® Defibrillator Leads" issued by the FDA on October 15, 2007, the particular units that may have defective lead wires are: 

Medtronic Inc. Sprint Fidelis® Defibrillator Leads, model numbers 6930, 6931, 6948 and 6949 manufactured from September 2004 through October 15, 2007.

The February 2009 Sprint Fidelis medical journal article by Drs. Hauser and Hayes was picked up quickly by The Wall Street Journal (WSJ) and The New York Times (NYT) as well as other media.

A February 23, 2009 WSJ article by Thomas M. Burton, "New Concern Is Raised About Medtronic Wires", explains the significance of the study underlying this Hauser and Hayes article published by HeartRhythm:

Drs. Hauser and Hayes evaluated patients at both of their hospitals, looking at a total of 3,037 defibrillator leads of varying models. A total of 94 leads failed. Seventy-two of the failures were Sprint Fidelis leads, out of 848 Sprint Fidelis leads implanted....

The doctors said they saw a Sprint Fidelis failure rate of 3.75% a year, compared with 0.58% among other models. At three years after implant, 87.9% of the Sprint Fidelis leads were working, compared with 98.5% for other models studied.

Medtronic says that its "all cause" failure rate for the Sprint Fidelis at three years is 4.6%, meaning that 95.4% of the devices would be working at that point.

In turn, a February 24, 2009 NYT article by Barry Meier, "Study Finds More Failure of Heart Device", provides some additional information from Medtronic and some commentary:

Medtronic released a statement on Monday saying it still believed its own figures were accurate. “It is important to note that data collected from center to center would be expected to vary,” Medtronic said. “We believe that our analyses are representative of overall Fidelis performance.”...

Two experts not involved in the Hauser-Hayes study said it was difficult to explain the discrepancies between the new report and Medtronic’s data.

Dr. Douglas P. Zipes, a cardiologist and the editor of Heart Rhythm, said one possibility for the discrepancy in malfunction rates might reflect the failure of many physicians to report component problems to Medtronic....

Another cardiologist, Dr. Charles Swerdlow of Los Angeles, said that the discrepancy between Medtronic’s data and the new study might be a result of physicians reading patient symptoms as caused by lead fractures when actual fractures had not occurred.

As many of you know, all Sprint Fidelis lawsuits filed against dismissed Medtronic that were pending in the federal court Sprint Fidelis MDL were dismissed on federal preemption grounds in January 2009.  The U.S. District Court judge in Minnesota who made the ruling stated that he was simply following U.S. Supreme Court's Riegel vs. Medtronic ruling as precedent.

Just last week, however, we learned that some Congressmen and Senators are seeking to reverse by new legislation the effect of this Riegel preemption ruling by the Supreme Court.  In his February 19, 2009 article, "Lawmakers Seek to Return Right to Sue Device Makers", NYT reporter Barry Meier informed us that:

Two House Democrats, Henry A. Waxman of California, the chairman of the House Energy and Commerce Committee, and Frank Pallone Jr. of New Jersey, the head of its health subcommittee, plan to reintroduce soon legislation that would effectively nullify the Supreme Court decision.

A similar Senate bill, sponsored last year by Edward M. Kennedy, Democrat of Massachusetts, and Patrick J. Leahy, Democrat of Vermont, is expected to be reintroduced in coming months.

The lawmakers, as well as patient advocates and others, say the Supreme Court’s medical device decision has left patients legally powerless against what they criticize as spotty oversight of products by the F.D.A.

We will continue to monitor the debate about actual failure rates for Sprint Fidelis lead wires as well as watch for developments in Washington as concerns the preemption of medical device injury lawsuits.  We hope you stay tuned for our future reports on both issues.