Vytorin And Cancer: The Questions Continue
10 CommentsBy Ed Silverman // September 2nd, 2008 // 6:46 am
The much-anticipated release of the SEAS trial at the European cardiology meeting this morning is only enflaming the debate over the extent to which the controversial cholesterol pill is a safe choice. At issue is the same dilemma raised when the preliminary data was disclosed last month - how to interpret an unexpected finding of cancer and cancer-related deaths?
The findings showed a total of 105 cancer cases among Vytorin patients compared with 70 taking a placebo. That was an upward revision from the rates of 93 and 65 reported in July. And by the way, Vytorin had no impact on the progression of aortic stenosis or on cardiovascular clinical events in general, with the exception of coronary-artery bypass surgery.
A blunt editorial in The New England Journal of Medicine - which also published the SEAS study and an accompanying essay by Oxford University researchers who analyzed other, onging Vytorin trials and claim the cancer findings are a fluke - underscores the uncertainty and confusion.
“Although the Oxford group may ultimately prove to be correct, it is appropriate to raise a note of caution. Whether the increased mortality risk is due solely to the play of chance is uncertain,” write the editors of the journal. “Physicians and patients are unfortunately left for now with uncertainty about the efficacy and safety of the drug.”
Today’s release is only reigniting an intense debate about Vytorin, especially since the drug was approved by the FDA with no evidence that it had reduced heart attacks or cardiovascular disease. The FDA, however, is now investigating the cancer findings.
Meanwhile, Merck and Schering-Plough, which have a joint venture to market the drug, spent millions on consumer ads, and have since caused a furor over their disclosure of data from yet another failed trial, an episode being investigated by Congress.
Paul G
If the scaremongering results in people at CV risk stop taking their vytorin or zetia, then it could lead to a public health disaster.Their high risk should be managed aggressively.
Dan A.
First of all, this post illustrates what unfortunately is minimally required to approve a drug. Statins, half of vytorin, have the proof of reducing CV events/issues. Zetia, however, does not. Doctors appear to be more concerned with zetia lack of cv outcomes than any safety issue at this point, overall.
As with other new medications, doctors want the evidence before they will conclude anything about a drug.
Paul G
Dan, interesting point, except that when it came to Lipitor and Crestor, doctors jumped on those bandwagons blindly and in huge ways - even if they have zip data on outcomes and very limited on safety.
Condor
First — great coverage, here, Ed — I had to get some “short people” off to first day of school!
Paul G. — I think there ought to be a disctinction between a novel drug — one which meets an entirely unfilled need — and a “me too!” after the fact offering.
Vytorin is in the latter category; Lipitor: the former.
When statins were first being approved, there was nothing like them. More on this, soon, here:
http://shearlingsplowed.blogspot.com/2008/09/new-england-journal-of-medicine-weighs.html
Adding some other medicine to a statin strikes me as a “me too!” move. To properly frame the debate, we ought to accept that most responsible commentators seek outcomes, or “improvement” data primarily for “me too!” drugs — before granting FDA approval.
Thus, IMO, your concerns seem a little overblown.
Dan A.
Paul,
You are right about statins and doctors grasping them for thier patients since mevacor. Yet at that time (mid 1980s), cholesterol lowering drugs were cumbersome for patients as far as intake and side effects go, and LDL lowering was not in the spotlight then like it is now regarding the correlation between lowering LDL and reducing CV events.
Now, some are suggesting statins have the same status as aspirin as far as taking one for preventitive reasons, regardless of how well your cholesterol level is.
Doc
There are multiple alternatives to Zetia, why take any additional risk for cancer, unless every other therapy fails to control the lipids?
Salmon
Scare mongering and public health diaster for alerting to a risk of cancer?
The facts are we have a possible public health risk (Cancer) without out a clear demonstrable benefit on a clinical outcome. In fact the labeling for Vytorin (it’s available via googling Drugs@fda) clearly states that although Vytorin effects plasma clolesterols, triglycerides, and lipids there is no evidence that this will result in a clinical benefit. In other words these there may not be a cause and effect with clinical outcomes, e.g. heart attacks.
As for ‘accepting that most responsible commentators seek outcomes, or “improvement” data primarily for “me too!” drugs — before granting FDA approval.’
This is not the legal standard that FDA must use. Only that a drug is safe and effective and for a combination product that each drug together provides more oomph than either drug used alone (and is not more dangerous).
Determining whether a drug is safe is a judgment call and safety is perceived relative to the condition and to other drugs for the condition and whether there is evidence that some individuals may benefit from a new drug(s) who clearly don’t benefit from available treatments and that the benefits outweigh the risks.
Presumably when the judgement is close there should be an advisory committee and full discussions are made in public. In truth the advisory committees members are often not given all the information and in some cases the AC meetings are even rigged (personal knowledge).
Although FDA is calling for quantitative risk assessment in guidances, when you look at the references the FDA uses this quantitative assessment refers to the economic impact on the company. It is not what clinicians would think is important which is the marginal improvement relative to the risk, e.g. if 50% of people get a true clinical improvement on drug vs. 30% on placebo (thus only 20% of people taking drug get a benefit, yet 10% of everybody get a lifethreatening side effect within before you even have a chance to determine if the drug is working, thus for every 100 people started on drug 20 will get a benefit but of these 20, 2 (10%) will have a lifethreatening side effect. In addition 80 will have have no benefit and of these 80 8 will have a life threatening side effect. Consequently you get 10 people with lifethreatening side effects for every 2 people getting a benefit.
In addition the way the safety evalutions have been set up by Pharma and the International Conference on Harmonization (which FDA must follow) if side effects are due to long term exposure, e.g. Vioxx and possibly even Vytorin and CA it would only be picked up if the rate is greater than 3.3%, this includes death.
Plus new FDA labeling rules exclude inclusion unless the rate is greater than 5% and is double the placebo rate. Yet with noninferiority trials and the claimed unethical nature of using placebo in long term safety studies it’s impossible to detect or label this with initial approvals under FDA rules. Thus we’re left with epidemiological studies that may or may not be done and will be argued over for years.
Remember all of these rules were implemented with input from pharmaceutical companies and if there was any input from consumers they likely lacked the acumen to realize what was really going on.
Salmon
Salmon
FYI when I refer to personal knowledge of FDA advisory committees being rigged. It’s because I personally happened to overhear discussions of the plans to do this.
Salmon
Lipid Doc
Paul G. - It sounds like you’re giving the MSP line! You should get your facts straight! There was evidence that statins had clear benefits for the prevention of cardiovascular events in patients at high risk as far back as the early 1990s. Pravachol and Zocor were the first to demonstrated these effects. While it is true that Lipitor and Crestor came later, there was clearly a benefit of these drugs. Only Baycol caused a safety problem and was pulled, but it was quite different than the others. Ezetimibe is part of a new class of drugs and unfortunately has not yet shown any clinical benefit when added to a statin. Not only that, but we have the potential fro a detrimental effect on cancer incidence and death. Much more information is needed. I, for one, am only going to use it when all else fails. I care about my patients and don’t want to expose them to undue risk. I have plenty of other therapeutic choices that I can use and not lose any sleep at night.
CV Man
Rightly so. Patients should stay away from this drug if at all possible and be given the tried and true, proven to be truly effective, treatments for high cholesterol.