Vytorin continues to get hit hard. Information they released today to calm critics seemed to only intensify the scrutiny, with the FDA announcing they plan to review the safety and efficacy of ezetimibe (Zetia) which is also in Vytorin.
I have previously blogged about not taking an alarmest view on Vytorin (Vytorin and Zetia: What to do now? ) since it may be appropriate for some patients (though not likely most). However, I received a "Dear Doctor" letter today regarding the ENHANCE study that I thought non-recipients might be interested in.
"Dear Doctor" letters are often required by the FDA when there is a label change to a drug or signifcant concern. This is usually, but not always bad news. I have received many of these letters over the years, which have always beed delivered by my US postal carrier, but today's letter was delivered by UPS. It appears today's letter was not prompted by the FDA, but a proactive approach by Merck/Schering to ensure I don't stop writing prescriptions for Vytorin. Unfortunately, the letter is not yet posted on their web site. However, below are direct "several key points to consider" that appear in bold, with my interpretation (in italics) of what they are really trying to tell me below (capital letters Merk's editing not mine):
Lowering LDL-C remains the primary target of lipid-modifying therapy.
Just because our study showed that lowering the LDL didn't make a difference, doesn't mean you shouldn't follow guidelines that recommend lowering the LDL! Of course, the latest update to these guidelines were written in 2004. It is likely that they will change based on this study. The Medical Letter (non-comerically biased source of drug information for clinicians) just came out with its guidelines yesterday and recommended limited use of Vytorin and Zetia.
ENHANCE was an imaging study; it was not designed to examine differences in clinical outcomes, such as reductions in heart attacks or strokes.
Just because our drugs didn't prevent artery clogging doesn't' mean that they won't prevent heart attacks and strokes! Of course if there study did show that it prevented artery clogging, I guarantee Merk reps would be in my office the next day telling me that this data suggested Vytorin would likely prevent heart attacks and strokes. You can't have it both ways. Also, Lipitor has show to both reduce plaque build up and prevent heart attacks and strokes.
A Clinical Outcomes Study Comparing VYTORIN and Simvastatin is Under Way.
Don't draw any conclusions until the real study comes out. Of course, it will take a few years until these results are public. That's millions of prescriptions they hope we doctors write until their study (which will likely show similar disappointing results) is done.
What should you tell your patients who are taking VYTORIN (ezetimibe/simvistatin)?
When counselling your patients on VYTORIN or ZETIA, we would encourage you to respond based on your independent clinical judgement about the importance of lowering LDL-C by eating right, staying active, and following recommended prescribed medications.
We hope you will blow off this study and tell your patients everything's OK.
Merck/Schering -Plough hopes to present addtional results of the ENHANCE trial at the American College of Cardiology in March.
Pay attention to this one folks! They have just told you there next step in how they will try to persuade doctors, patients and legistlators that these results should not be taken seriously. Basically, their premise is that the results don't make sense, since other studies have shown that simvistatin does indeed decrease artery clogging. They have already used this as their rationale for delaying the results. What they will likely do at the big cardiology meeting is show (with lots of graphs, tables and images) how bad their data was, how inaccurate the ultrasound readings were, and how none of the results can be trusted. They were hoping to have all of this evidence ready when the results were announced, but the media and public forced their hand in presenting the data early.
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6 comments:
The FDA allowed Zetia on the market using results that measured a surrogate endpoint (LDL-C reduction.) This isn't a bad thing in itself. The problem is that the FDA allowed them to use an inferior surrogate endpoint.
Why are cardiologists still treating to LDL-C outcomes when more specific outcomes are available? You're going to the effort and expense of running a randomized clinical trial. You've got the patient in the lab and are already drawing blood. Why not run a VAP or a Berkeley cholesterol test and look at the LDL and HDL subtypes? Why didn't the FDA make them look at (and report) hs-CRP and Lp(a)? While you're at it, howabout checking urine albumin, fasting blood glucose, fasting insulin and A1c?
A much smaller, shorter trial with a more comprehensive set of tests would have told us a lot more about Zetia at lot earlier — $3+ billion worth of prescriptions ago.
While I agree that FDA requiring additional surrogate endpoints prior to a drug's approval might have been a good idea, it is not entirely clear that CRP and Lp(a) are substantially better at predicting cardiovascular disease than LDL-C ( Arch Int Med 2006 , JAMA 2005 ). To me the bigger issue is that 1) the FDA ought to focus on hard outcomes rather than surrogate markers before a drug is approved and 2) this is especially true if there are already products on the market that do a good job with a proven track record.
Dr. Mitz, if outcomes studies must be completed prior to approval drugs will have little patent life left by the time they hit the market. Laws governing intellectual property right laws regarding drugs need to be changed if this is to become a reality.
Yes, it is true that if outcome studies were required for all products, then not only would patents expire soon after approval, but there would also likely be a several year delay in getting a good drug to market.
However, there should be some sort of balance when approving a drug so that industry gets a return on investment and novel products that are safe and effective get to market, but products without a proven benefit to health don't get heavily promoted and overused.
Zetia, which was a novel product without outcome data, according to the FDA is indicated "as adjunctive therapy to diet for the reduction of elevated" cholesterol. Perhaps the FDA could have added to the indication "for patients who can not tolerate or achieve goal cholesterol reduction with a statin alone." The label could have remained that way until outcome studies showed that it could be used as initial therapy. Same restrictions could have applied to Vytorin. This is important because it would have limited the way the industry could have promoted the drug to physicians and patients. Also, maybe drugs should not be allowed to be marketed directly to patients until their is clearer outcome data? Additionally, maybe when there is a new drug without a clear benefit in the same class of medication with an older drug ("me too") that does have outcome data, be similarly restricted until that outcome data is available? For example, Boniva which is a newer drug for osteoporosis was shown to reduce vertebral factures, but not non-vertebral fractures, such as hip fractures. Since similar drugs, like Actonel and Fosamax have been shown to reduce both types of fractures, there could be restrictions on Boniva until similar outcomes can be demonstrated.
Dr. Mintz, you are an Alarmist. You fail to mention the patient type (HF) with LDL cholesterol of 319, that the patients arteries were considered healthy to begin with, or that 80% of the patients had been on aggressive therapy for up to 10 years. You should stick with your internal medicine and leave the smart comments to physicans who know what they are talking about.
I am not sure what alarmist statement you are referring to, so I am not sure how to respond.
There mulitple problems with the ENHANCE study, including studying patients with familial hypercholesterolemia, of which most have been on statins. I did not design the study. (Are these the doctors you are referring to that know what they are talking about?). The point is not that the study is a negative study which proves Vytorin is worthless. The point is that there are no outcomes data showing that zetia with or withot a statin improves vascular markers (IVUS, CIMT) or cardiovascular outcomes. All the other statins have both . If Merk-Schering produces a well-designed, randomized control trial that shows that lowering the ldl with a statin + zetia is as good as a statin alone, and is either more effective or has fewer side effects, I will be the first to jump on the bandwagon. However, until this happens, it is prudent not to use zetia +/- a statin as a first line agent. In addition to that fact that the ENHANCE results were unimpressive, there is reason to believe the statins have benefit beyond LDL reduction, and by lowering the LDL with a lower dose of statin + zetia instead of a higher dose statin, you might be denying the statin dose required to achieve outcomes. I welcome a study by Merk-Schering to prove me wrong on this point. The study I would actually like to see is patients with cardiovsacular risk factors who are not able to achieve LDL goal on maximum dose tolerated statin randomized to zetia or placebo. In this situation, I would bet that you would see benefit of adding zetia (which is why I use it in this situation). However, I will leave that study to physicians who know what they are talking about.
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