Steve Nissen has a way of getting everybody’s attention. And he does that with tools that in anybody else’s hands would be deadly dull. This week he captured the attention of one of the country’s most prestigious medical journals, the Food and Drug Administration, U.S. senators and me...
Avandia Linked to Heart Attack and Death
5/23/07 12:51pm
What documentation is there on Actos not being the same problem?
5/23/07 1:34pm
Let's put it this way: There isn't much if any documentation that Actos causes heart attacks. Dr. Nissen in particular says that it's beneficial to the heart. The sternest critic of all three drugs in this class (Avandia, Actos, and Rezulin, which is no longer available) is Public Citizen, a group founded by Ralph Nader.
Public Citizen petitioned the FDA years ago for revised labels on these drugs. In particular, the petition says of Actos (pioglitazone) and the heart:
"Pioglitazone: The potential to cause cardiomegaly was anticipated from preclinical studies. For this reason, the sponsor performed a 26-week echocardiogram study in diabetics (those without valvular abnormalities, ischemic heart disease, or symptomatic heart failure). Four doses of pioglitazone were compared with placebo. The Medical Officer concluded that, “The results of this [echocardiogram] study provide little, if any reassurance that PIO [pioglitazone] does not damage the heart”.[49] In the other clinical trials, the Medical Officer noted that five patients on pioglitazone had cardiomegaly on chest x-ray; he did not mention this finding as occurring in the comparator groups.[50]"
That in the petition at http://www.citizen.org/publications/release.cfm?ID=6715
Public Citizen petitioned the FDA years ago for revised labels on these drugs. In particular, the petition says of Actos (pioglitazone) and the heart:
"Pioglitazone: The potential to cause cardiomegaly was anticipated from preclinical studies. For this reason, the sponsor performed a 26-week echocardiogram study in diabetics (those without valvular abnormalities, ischemic heart disease, or symptomatic heart failure). Four doses of pioglitazone were compared with placebo. The Medical Officer concluded that, “The results of this [echocardiogram] study provide little, if any reassurance that PIO [pioglitazone] does not damage the heart”.[49] In the other clinical trials, the Medical Officer noted that five patients on pioglitazone had cardiomegaly on chest x-ray; he did not mention this finding as occurring in the comparator groups.[50]"
That in the petition at http://www.citizen.org/publications/release.cfm?ID=6715
5/24/07 8:39pm
Hi David,
As someone who takes Avandia, I was extremely concerned when this news broke, but I did calm down somewhat after reading the NEJM paper on which the news was based. Actually I find this all a bit puzzling.
The study sombines 42 studies with 15,560 taking Avandia, and 12,283 in the combined control groups, with about 86 heart attacks int he Avandia groups and 72 in the control groups. In other words there are about 20% more heart attacks in the Avandia group, and that group is, coincidentally, about 20% largerthan the control group. Why the authors say this means a 43% greater risk of heart attack is therefore somewhat beyond me. Am I missing something here?
At the same time deaths from cardiovascular causes are clearly higher in the Avandia groups than the control groups; my calculator says about 39% higher.
Ultimately the short duration, less than a year, of 36 of the 42 studies considered, with the longest lasting only 4 years, the exclusion of 6 other studies that had no cardiac events in either the Avandia or control group, and the author's lack of access to much of the raw data of the studies combine to make me take it all with a grain of the proverbial salt. The conclusion that more study is needed makes sense, particularly since as the authors note , there has been no study specifically designed to examine the incidence of cardiac events amongst Avandia users, although one is in progress now.
We all know that the media can tend to get a story wrong and oversensationalize, but that point is often overlooked. When it comes to a drug that you or people you know may be taking, however, it gets more personal. We owe it to ourselves to carefuly examine what is being said, and, yes, to consult with our doctors before we panic.
As someone who takes Avandia, I was extremely concerned when this news broke, but I did calm down somewhat after reading the NEJM paper on which the news was based. Actually I find this all a bit puzzling.
The study sombines 42 studies with 15,560 taking Avandia, and 12,283 in the combined control groups, with about 86 heart attacks int he Avandia groups and 72 in the control groups. In other words there are about 20% more heart attacks in the Avandia group, and that group is, coincidentally, about 20% largerthan the control group. Why the authors say this means a 43% greater risk of heart attack is therefore somewhat beyond me. Am I missing something here?
At the same time deaths from cardiovascular causes are clearly higher in the Avandia groups than the control groups; my calculator says about 39% higher.
Ultimately the short duration, less than a year, of 36 of the 42 studies considered, with the longest lasting only 4 years, the exclusion of 6 other studies that had no cardiac events in either the Avandia or control group, and the author's lack of access to much of the raw data of the studies combine to make me take it all with a grain of the proverbial salt. The conclusion that more study is needed makes sense, particularly since as the authors note , there has been no study specifically designed to examine the incidence of cardiac events amongst Avandia users, although one is in progress now.
We all know that the media can tend to get a story wrong and oversensationalize, but that point is often overlooked. When it comes to a drug that you or people you know may be taking, however, it gets more personal. We owe it to ourselves to carefuly examine what is being said, and, yes, to consult with our doctors before we panic.
5/26/07 12:33pm
I was on metformin (1500mg) and avandia (4mg) and recently my gp decided that I should go onto insulin (my numbers were high and I couldn't get them down without not eating) but before I could do that I had to go to the diabetes clinic and see the diabetes nurse.
The nurse, in her infinite wisdom, decided that I was still producing insulin and I should double both the metformin and avandia.
I have done and my numbers are lower, which is good.
Now there's the avandia scare.
I wouldn't be so worried if the big killer in my family weren't heart problems.
Plus the fact that in England we don't have Januvia nor Byetta yet.
I did ask the nurse about Januvia but she looked at me blankly and said a definite no to the existence of Byetta here.
Even if they were here, NICE, the organisation that okays the availability of drugs used in England, mught not approve of them.
I'll make an appointment to see my gp next week to see what she says.
In July I do get to see the endo at the clinic for my yearly check-up. Hopefully I get a doctor that speaks English properly this time.
The nurse, in her infinite wisdom, decided that I was still producing insulin and I should double both the metformin and avandia.
I have done and my numbers are lower, which is good.
Now there's the avandia scare.
I wouldn't be so worried if the big killer in my family weren't heart problems.
Plus the fact that in England we don't have Januvia nor Byetta yet.
I did ask the nurse about Januvia but she looked at me blankly and said a definite no to the existence of Byetta here.
Even if they were here, NICE, the organisation that okays the availability of drugs used in England, mught not approve of them.
I'll make an appointment to see my gp next week to see what she says.
In July I do get to see the endo at the clinic for my yearly check-up. Hopefully I get a doctor that speaks English properly this time.
6/ 1/07 5:36pm
I went to see my gp today about Avandia and all she did was shrug her shoulders and said that since the diabetes nurse at the diabetes clinic was the one who upped my dosage then I should talk to her.
Trying to get an appointment there is almost impossible unless your gp gets in touch first.
Mine said that since I have an appointment next month (July 12th) I can talk to the endo then. That it probably wouldn't hurt to go until next month still on the Avandia.
Trying to get an appointment there is almost impossible unless your gp gets in touch first.
Mine said that since I have an appointment next month (July 12th) I can talk to the endo then. That it probably wouldn't hurt to go until next month still on the Avandia.
5/27/07 11:08pm
Rarely were the statistical flaws/ endemic biases in Nissen’s methodology mentioned in press accounts:<?xml:namespace prefix = o ns = "urn:schemas-microsoft-com:office:office" ?>
- Restriction of coverage issue: Nissen’s trial selections were not free of bias--trials of Avandia in which patients had no adverse cardiovascular events in either group were excluded from analyses;
- The pooled results were culled from a group of trials that were not originally powered to detect cardiovascular outcomes;
- It has been observed that the conclusions of a meta-view can be shown to be different from a subsequent, larger, randomized clinical trial. Nissen’s observed results were based on a relatively small number of events (86 myocardial infarctions in the rosiglitazone group and 72 in the control group); and,
- Fallibility of broad applicability for Nissen’s observed conclusions. Nissen said—and the press ran with his one comment—that rosiglitazone was associated with an increase in the risk(s) of cardiovascular morbidity and mortality.
….As the precise mechanisms underlying the actions of thiazolidinediones (TZDs) are largely unknown, it is a quantum leap to say that one drug in the class is safer than the other.
Re: PROACTIVE-ACTOS TRIAL. The primary end point, a broad composite that included coronary and peripheral vascular events, showed a trend toward benefit from pioglitazone (hazard ratio, 0.90; P=0.095). A secondary end point consisting of myocardial infarction, stroke, and death from any cause showed a significant effect favoring pioglitazone (hazard ratio, 0.84; P=0.027).”
In plain English, “a trend toward benefit” is not material. Specifically, the primary end point occurred in 21% of patients on pioglitazone, compared with 25.5% of the patients on placebo. Pioglitazone's total risk reduction of 10% was not considered statistically significant. The study was powered to show a 20% reduction in the composite of primary end-point events.
Albeit the secondary end point—death, nonfatal heart attack, and stroke—was statistically significant, Nissen failed to mention heart failure occurred more frequently in the pioglitazone group (10.8% of patients) than in the placebo group (7.5% of patients), with 5.7% versus 4.1% being hospitalized.
http://10qdetective.blogspot.com/2007/05/who-benefits-from-avandias-reported.html
Best-
David J. Phillips, Publisher
A KIPLINGER’S PERSONAL FINANCE & BUSINESSWEEK "MUST-READ" BLOG!
6/ 4/07 12:17pm
I have to wonder about Dr Nissen's true interest in this. He pulled the information for the article from selected studies. You can "create" any conclusion if you include only the studies that show what you want to find and ignore the ones that do not.
I understand Dr Nissen is interested in running the FDA. Could this be the real reason for all of this "noise" about Avandia?
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Looking at the numbers from another perspective, i.e. in relation to the total number of patients concerned, the difference is important, i.e. 86 - 72 = 14 and 39 - 22 = 17 in relation to 28,000 patients. Here these numbers may well lie within the statistical spread of the numbers concerned.
In other words, the numbers presented may be statistically insignificant to make such an alarming conclusion.
On the other hand where there is smoke, there might be fire, so the matter should be looked into more extensively.