CardioExchange Archive

The Avandia Saga Comes to an End — or Does It?

The FDA advisory panel wound up its two-day marathon meeting with a decisive mixed vote. Of the 33 voting members,

• 12 voted for rosiglitazone to be withdrawn from the marketplace,
• 10 voted to keep the drug on the marketplace but with severe new restrictions,
• 7 voted to keep the drug on the marketplace with a stronger warning, and
• 3 voted to keep the drug on the marketplace with no changes to the label.

There was one abstention. There were no votes for the option that would have lightened the warnings on the label.

The vote prompted a number of different interpretations. The New York Times headline, “FDA Panel Votes to Restrict Avandia,” contrasts sharply with the Wall Street Journal headline, “FDA Panel Backs Keeping Avandia on the Market.” On the one hand, it seems clear that the opponents of rosiglitazone didn’t achieve their goal of having the drug removed from the market. On the other hand, 22 out of 33 advisors voted to either withdraw the drug or impose severe restrictions on its use, which can hardly be taken as a strong endorsement. The FDA will have to find the right balance between these views. GlaxoSmithKline issued a press release in response to the panel vote.

Dick Cheney Receives an LVAD: Former Vice President Dick Cheney received a left ventricular assist device (LVAD) last week, according to reports in USA Today, the Wall Street Journal, and MSNBC. “A few weeks ago, it became clear that I was entering a new phase of the disease when I began to experience increasing congestive heart failure. After a series of recent tests and discussions with my doctors, I decided to take advantage of one of the new technologies available,” Cheney said in a statement to the media.

A few hours before the start of the FDA’s advisory panel meeting on Avandia, the New York Times published a story by Gardiner Harris that said GlaxoSmithKline (GSK) began a study comparing the safety of rosiglitazone (Avandia) to pioglitazone (Actos) back in 1999 and spent the next 11 years keeping the study a secret.

The Senate Finance Committee then released a letter sent to FDA leaders and accompanying documents detailing internal GSK discussions about the trial. GSK then issued its response to the Senate letter and documents.

You can read detailed coverage of the FDA advisory panel by Matt Herper at Forbes.com and by myself (Larry Husten) at CardioBrief.org.

European Medicines Agency Also Reviewing Avandia: In addition to all the rosiglitazone news surrounding the FDA advisory panel on July 13-14, the European Medicines Agency announced on Friday that it has initiated its own review of the cardiovascular safety of the drug.



AHA Publishes Scientific Statement on Diet and Exercise Interventions: The AHA has published a detailed scientific statement to assist physicians in changing the behavior of their patients. The most effective intervention is a combination of counseling, extended follow-up with a healthcare professional, and self-monitoring of diet and exercise, according to the statement. The authors also call for modification of healthcare policy to better allow healthcare professionals to encourage these changes.

“As healthcare providers, we’re pretty good at saying that you are at risk for a disease, you need to lose weight, be more physically active, and eat more fruits and vegetables. While that’s easy to say, it’s not easy for the person to actually translate it into their everyday life,” said the chair of the writing committee, Nancy T. Artinian, in an AHA press release.

Here are the issues:

1. The FDA has posted a black box warning that people with reduced CYP2C19 liver enzyme function (2% to 14% of the U.S. population) cannot effectively convert clopidogrel to its active form, which reduces its effectiveness in ACS patients. CYP2C19 function doesn’t influence prasugrel’s effectiveness.
2. The AHA and ACC do not support routine CYP2C19 genetic testing (and the test is not readily available).
3. Prasugrel (10 mg) is ≈2.5 times more potent than clopidogrel (75 mg); in TRITON-TIMI 38, ACS patients treated with prasugrel had a 50% higher rate of life-threatening hemorrhage and a 4-fold higher rate of fatal hemorrhage than those treated with clopidogrel.
4. Prasugrel was recently reported to be associated with an increase in cancer rates, prompting the authors of the report to recommend that  “physicians should consider the potential cancer risks before prescribing prasugrel, especially with prolonged use and in patients with known cancer.”

So, how do you decide which agent to prescribe for your ACS patients?

The FDA has posted the briefing documents for the July 13-14 Avandia advisory panel meeting. Here are links to the documents on the FDA website: Meeting Announcement Draft Agenda (PDF – 81KB) Draft Questions (PDF – 233KB) Pre-Meeting Posting of Slides Briefing Information Draft Meeting Roster (PDF – 105KB)

NEJM Editorial: DSMBs Need Protection and Independence: Data and safety monitoring boards (DSMBs) need more protection and independence, according to an editorial in the New England Journal of Medicine by the journal’s editor, Jeffrey M. Drazen, and Alastair J.J. Wood. Responding to recently uncovered events, in which company sponsors interfered with the independence and authority of the DSMBs in the RECORD, SHARP, and IMPROVE-IT trials, the editorialists “propose fundamental changes in the way DSMBs are constituted, are funded, and report,” and say that DSMBs “should be chosen and convened under the aegis of an independent public body.”

Promising Results for Self-Management of Hypertension: Some 527 hypertensive patients in the U.K. were randomized to either usual care or a self-managed strategy utilizing self-monitoring and telemonitoring of blood pressure and self-titration of antihypertensive drugs. Results of the TASMINH2 (Telemonitoring and Self-Management in the Control of Hypertension) study, which appear in the Lancet, show that patients in the self-management group achieved greater reductions in blood pressure than patients in the usual-care group. The authors conclude that “self-management represents an important new addition to the control of hypertension in primary care.”

In an accompanying comment, Gbenga Ogedegbe writes that “self-titration of antihypertensive drugs has come of age in terms of its feasibility, safety, and efficacy,” but cautions that “widespread dissemination into primary care practices might be premature until these findings are replicated by other investigators.”

Target systolic blood pressure in people with diabetes should be below 130 mm Hg, according to current guidelines, although there are no data for diabetics who also have coronary artery disease (CAD). Now, a large post-hoc analysis from INVEST (International Verapamil SR-Trandolapril Study) has found no evidence of benefit for tight blood pressure control below 130 mm Hg in patients with diabetes and CAD. The INVEST investigators performed a subgroup analysis of 6,400 subjects who were older than 50 years of age and had diabetes and CAD. After almost 17,000 patient-years of follow-up, the rate of death, nonfatal MI, or nonfatal stroke was nearly identical in the group that achieved tight BP control (systolic BP, <130 mm Hg) and the group that achieved usual control (systolic BP, 130 mm Hg to <140 mm Hg): 12.7% and 12.6%, respectively. By comparison, subjects with uncontrolled hypertension (systolic BP, 140 mm Hg or higher) had a significantly higher rate of events, 19.8%. Researchers observed a trend toward increased mortality in the tight control group versus usual control group (11.0% vs. 10.2%, 95% CI=0.99-1.45, P=0.06); upon extended follow-up, the difference between the groups achieved statistical significance (22.8% vs. 21.8%, CI=1.01-1.32, P=0.04).

In their report in JAMA, the authors conclude: “At this time, there is no compelling evidence to indicate that lowering systolic BP below 130 mm Hg is beneficial for patients with diabetes; thus, emphasis should be placed on maintaining systolic BP between 130 and 139 mm Hg while focusing on weight loss, healthful eating, and other manifestations of cardiovascular morbidity to further reduce long-term cardiovascular risk.”

Source is CardioExchange News, unless otherwise noted.

FDA Releases Briefing Documents for Avandia Panel, 09 Jul 2010

More Evidence Goes Against Avandia, 28 Jun 2010

FDA Panels to Review Rosiglitazone and Dabigatran, 10 Jun 2010

CANOE Paddles Into the Avandia Storm, 03 Jun 2010

European Heart Journal Editors Defend Nissen Editorial, 03 May 2010

Industry Affiliation and Position on the Rosiglitazone Controversy, 20 Apr 2010, Journal Watch, Paul S. Mueller, MD, MPH, FACP

Will the FDA Halt Avandia Safety Study?, 19 Apr 2010

Rosiglitazone: When Evidence Is Inconclusive Even After FDA Approval, 03 Mar 2010, BLOG: The Expert Is In , Sanjay Kaul, MD

More Data on Fracture Risk with Thiazolidinediones, 02 Mar 2010, Journal Watch, Allan S. Brett, MD

Krumholz on Avandia,  25 Feb 2010

Avandia Roundup: AHA & ACC Publish Science Advisory on TZDs; GlaxoSmithKline White Paper, 24 Feb 2010

Avandia Remains in the News, 23 Feb 2010

Senators and FDA Officials Attack Avandia, 20 Feb 2010

Thiazolidinediones in Clinical Practice, 26 Aug 2009, Journal Watch, Harlan M. Krumholz, MD, SM

Trial Raises Concerns Over CV Safety of Testosterone Gel: Shehzad Basaria and colleagues planned to randomize 252 men 65 years or older with limitations in mobility to testosterone gel or placebo for 6 months. The trial was terminated after enrolling 209 subjects after a higher rate of adverse events occurred in the testosterone group. The results are reported in the New England Journal of Medicine. There were 23 cardiovascular adverse events in the testosterone group versus 5 in the placebo group. Men receiving testosterone had significant improvements on several measures of strength.

In their conclusion, the authors state that “caution is warranted in interpreting this finding, because of the small numbers of events and because of limitations with respect to the ascertainment of adverse events. Caution is also warranted in extrapolating these findings to other doses and formulations of testosterone or to other populations, particularly young men who have hypogonadism without cardiovascular disease or limitations in mobility.”

Prasugrel and Cancer: Is There a Link? Two critics of prasugrel have again sought to link the drug to an increased risk of cancer. The paper, by  James Floyd and Victor Serebruany, appears in Archives of Internal Medicine. The cancer data are taken from the detailed FDA analysis of the TRITON-TIMI 38 trial. The authors acknowledge that with the current data it is impossible to demonstrate with certainty an increased risk of cancer, but say that “a safety concern has been raised” and that “physicians should consider the potential cancer risks before prescribing prasugrel, especially with prolonged use and in patients with known cancer.”

In an accompanying editorial, Sanjay Kaul and George Diamond write that although the prasugrel-cancer connection “has not been firmly established, sufficient credible evidence has emerged to raise concerns about a potential risk that arguably adversely alters the benefit-risk profile of its long-term use. Until this issue is resolved, we believe that to optimize the benefit-risk balance, prasugrel use should be limited to a duration of weeks rather than months.”

Responding to the News: It’s been an extraordinary week for cardiology news, with major papers and controversies about rosiglitazone, statins, JUPITER, and clopidogrel. Here are a few statements and news reports that you might want to know about: 

ACC/AHA release clinical alert in response to FDA boxed warning about anti-platelet agent, clopidogrel (ACC/AHA)

New analyses report different outcomes in use of thiazolidinedione (TZD) drugs for diabetes patients (AHA)
Daiichi Sankyo/Lilly respond to ACCF/AHA clinical alert on antiplatelet therapy (Daiichi Sankyo/Lilly)
A fix for the Avandia mess (Harlan Krumholz on Forbes.com)
Another leaked rosiglitazone manuscript? Controversy spikes as JAMA, Archives publish new papers (heartwire)
JUPITER gets a battering, but Ridker fights back (heartwire)
New meta-analysis of statins in primary prevention does not suggest significant reduction in all-cause mortality (heartwire)
Authors of JUPITER attack are members of obscure anti-cholesterol group (CardioBrief)
The cholesterol debate and journal disclosures (Pharmalot)

Retinopathy in ACCORD: In a paper presented at the American Diabetes Association and simultaneously published online in the New England Journal of Medicine, the ACCORD Study Group and the ACCORD Eye Study Group report findings of the ACCORD trials on the progression of diabetic retinopathy in a subset of 2856 ACCORD participants. At 4 years, the investigators found that intensive glycemic control and intensive combination treatment of dyslipidemia significantly slowed the progression of retinopathy, while intensive blood pressure control did not.

Intensive glycemia therapy vs. standard therapy: 7.3% vs 10.4% (P=0.003)
Fenofibrate vs. placebo: 6.5% vs 10.2% (P=0.006)
Intensive blood-pressure therapy vs. standard therapy: 10.4% vs 8.8% (P=0.29)