Thursday, January 8, 2009

Vytorin: To Switch or Not to Switch? That is the Question

The FDA has just released their review of the ENHANCE trial involving Vytorin. I have blogged about Vytorin, a combination of a statin medication (simvastatin) and another cholesterol lowering medication that blocks cholesterol absorption from the gut called ezetimibe (Zetia), and the ENHANCE trial many times (here, here, here, here, here, and here)

The FDA's analysis concluded that after 2 years of treatment with either Vytorin or simvastatin alone, carotid artery thickness (a marker of risk for cardiovascular disease) increased by 0.011 mm in the Vytorin group and by 0.006 mm in the simvastatin group, which was not statistically significantly different. However, the levels of LDL (bad) cholesterol decreased by 56% in the Vytorin group and by 39% in the simvastatin group, which was statistically significantly different.

Here's what the FDA concluded:

The results from ENHANCE do not change FDA’s position that an elevated LDL cholesterol is a risk factor for cardiovascular disease and that lowering LDL cholesterol reduces the risk for cardiovascular disease. Based on current available data, patients should not stop taking Vytorin or other cholesterol lowering medications and should talk to their doctor if they have any questions about Vytorin, Zetia, or the ENHANCE trial.

First, the FDA is stating that despite the fact that LDL lowering did not correlate with improvement in atherosclerosis, LDL is still a reliable surrogate marker for cardiovascular disease and thus a good target of therapy.

As I have mentioned previously, when you take a drug to prevent a heart attack or stroke, you want to know whether that drug actually decreases heart attacks or strokes (outcomes). The problem is that doing outcomes studies requires a large number of patients to be studied over a long period of time, which is difficult and costly. Therefore, many of the studies we use to make medical decisions rely on markers or proxies for disease called "surrogates." Cholesterol (specifically the bad cholesterol or LDL) is a known surrogate marker for heart attack and stroke, as is carotid artery thickness, the endpoint in ENHANCE. Though both surrogates correlate well with the outcome of heart attacks and stroke, in the ENHANCE study lowering the LDL did not cause a decrease in carotid artery thickness. Despite this, the FDA still believes that LDL is a good surrogate.

Second, the FDA states that because LDL is still a good surrogate and because Vytorin lowered LDL, depsite that fact that it failed to do any good in the ENHANCE study, the FDA recommends that patients NOT stop Vytorin. This one is more problematic.

I agree that LDL is a good surrogate, but we have been burned by surrogates before. High levels of homocysteine are linked to heart attacks, and folic acid lowers homocysteine, but when we looked at whether folic acid reduced heart attacks (outcomes), it actually caused MORE heart attacks, and is no longer recommended.

We know the lowering the LDL with a statin reduces heart attacks, and this relationship is in fact linear (the lower the LDL with a statin the lower the risk of heart attacks-see figure from 2004 NIH guideline update). The questions is whether lowering the LDL with something other than a statin, i.e. ezetimibe (Zetia) will reduce the risk of heart attacks and strokes. It may very well, but we have no evidence to date. Though ENHANCE may not have been the perfect trial to look at this, it is the only study we have using Vytorin/Zetia looking at something other than LDL, and this study was negative. Finally, it may be more about the statin than the LDL. The JUPITER study (which I have also blogged about) showed that lowering the CRP with a statin (Crestor)decreased heart attacks. LDL's were also lowered, but where CRP was elevated at the beginning of the study, LDL was relatively normal and would not have normally required a statin.
Thus, though the FDA suggests to not to stop taking Vytorin because it does lower LDL (and also does not appear to have a major safety issue), the question is whether or not you should be on Vytorin (statin plus zetia) or just a statin? Based on the figure above, by using a combination (Vytorin) instead of a statin alone to achieve LDL lowering, are you denying yourself the maximum amount of statin that you need to acheive outcomes? We don't have the studies to answer this question, but in my opinion it would be better to lower your LDL with a stronger statin like Lipitor and Crestor, then to use a weaker statin (like simvastatin) plus Zetia, i.e. Vytorin. The highest dose of Vytorin lowers cholesterol just a little bit more than the highest dose of Lipitor and Crestor, but not by much. In addition, adding Zetia to any statin will lower your LDL an additional 25%. Thus, based on the available data, it would be better to use the dose of a statin needed to lower your LDL. If the maxium dose of a statin failed to achieve the LDL to goal, or one could not tolerate the maxium dose of a statin, the adding Zetia seems a reasonable option.
Bottom Line:
1. LDL is still a good surrogate market and target for therapy.
2. The best way to lower LDL is with a statin, and lower appears to be better.
3. If you are on Vytorin, I wouldn't stop it, but would discuss with your doctor about of switching to something like Crestor or Lipitor.
4. If you are unable to reach your LDL goal on the highest tolerable dose of Crestor or Lipitor, than adding Zetia seems reasonable.


Mr. MedSaver said...

Dr. Mintz, what do you think about using either Vytorin or high potency statins (eg. Lipitor or Crestor) as first-line agents for patients? I've always thought that the appropriate thing to do would be to start off with cheaper, generics that run as little as $20-$60/year rather than immediately pulling out the $1,300-$1,600/year "big guns."

Jacob Milbradt, PharmD

Anonymous said...

Seems to me that we know that statins work well, at virtually all doses, but we know that statins at higher doses probably give some benefit (PROVE IT study, etc). So the most logical thing is to maximize the statin dose to the highest tolerated dose, and add zetia on top of that. That should have been pretty clear five years ago, and its clear now. Zetia/Vytorin is for when lipitor 80 doesnt work.

The ENHANCE study should have no effect upon any therapies - its not an oucomes trial, its a surrogate trial. At best - its a curiosity... the drug should have worked, but it didnt. If I was a betting man... I'd bet that zetia probably does lower atherosclarotic burden though.

Dr. Matthew Mintz said...

Anonymous is correct regarding maximizing the highest tolerated dose of a statin and then add Zetia if not at goal. ENHANCE was not an outcomes trial and Zetia may indeed lower atherosclerotic burden. The real question is whether at eqivalent LDL reduction (i.e Vytorin 10/20 vs. Lipitor 20) is there any difference in plaque burder, heart attack or death. We may never know the answer since this study has not been planning. I am not a betting man, but wouldn't bet alot on it.
Mr. MedSaver,
You ask a challenging question: should we start off with the cheaper generic medications and use the expensive big guns only when needed, or should we start off with Lipitor or Crestor right off the bat.
This is a tough on. All statins show positive outcomes. On the other hand, more recent data suggests, especially for patients at higher risk, more aggressive lipid lowering may be needed.
I think for those patients at low risk who only need a 20% or less lowering of LDL, generic statins are just fine. For high risk patients or patients who need dramatic reductions in LDL, only Crestor or Lipitor is going to work.
The problem is those moderate risk patients who need a 30-40% reduction in LDL, which is a lot of patients. In order to achieve this, you will need 40 to 80mg of simvastatin. The problem is that as you increase the dose, you increase side effects. Potency does not correlate to side effects (acutually, the more powerful the statin, the fewer the side effects), it % maximal dose. 40 mg and 80mg is 50% and 100% respectively the maximal dose of Simva, wheras 10mg and 20mg is 12.5% and 25% the maximal dose of Lipitor. Finally, the bulk of substantial outcomes studies (reductions in plaque burden, CRP reduction, decreased MI, stroke, deat, etc.) have been with the potent statins. The one study that did not show benefit (A to Z trial) was with simvastatin.
The real question is whether it is worth the extra money for fewer side effects and the possible difference in outcomes. Since Lipitor and Crestor are second tier on most my patient's insurances, that difference is about $10-$15 a month.
This difficult question will be non-existant in a few years when Lipitor goes generic.

Dan said...

Published on

A Failed Attempt to Improve Misperceived Greatness: The ENHANCE Trial

While it seems that pharmaceutical company sponsors of clinical trials usually end up with results that clearly favor their meds studied in their trial, there are rare exceptions, and Merck and Schering proved that with their disappointing ENHANCE Trial, which many have heard about through the media not long ago. The drugs studied were Vytorin, which was compared with Zocor
Vytorin is a combination med for high cholesterol and contains Merck’s Zocor, which is now generic, and Schering’s Zetia, which works differently than Zocor, which is one of many statin drugs. Both Vytorin and Zetia are co-promoted by Merck and Schering. So, several years ago, an outcomes study was initiated to prove superiority of Vytorin over Zocor. The trial was named the ENHANCE trial, and possibly this trial was initiated because Zocor is generic now, and not a priority from a profit paradigm of its creator.
After several years passed, a disappointment arrived for the sponsors of this trial, which was first brought to the attention of Schering in March of 2007, yet the results existed since the spring of 2006, I believe upon information and belief.
The disappointment is that Vytorin lacked anticipated benefit or superiority over Zocor. Since about 1 million scripts were written for both Vytorin and Zetia every week in 2007, combined with what I believe was about 5 billion in revenue for these two drugs that year, this was a problem for the drug makers, meaning a fear of shareholder reaction. Perhaps for Schering in particular, it was more of a calamity, since over half of their profits and earnings were from these two drugs with Schering, I understand.
Being the responsible corporations both companies are, of course, alterations occurred after such events were discovered that fractured numerous rules and regulations with clinical trials, possibly in illegal and unethical tactics.
The trial sponsors delayed the release of the trial results for secrecy reasons, it has been speculated. Results from the trial existed, yet were not disclosed at the time of their discovery. After several months of possessing these trial results that were only known to the manufacturers, they created or implemented some atrocious tactics to improve the trial’s unimpressive results following the original results of this ENHANCE study. At the end of 2007, the companies changed the primary endpoint of the trial, which is what the results were measured upon during the entire course of the trial. Sort of like sorting cards to make a good hand not dealt to you. Anyway, since their deliberate concealment of these trial results was clearly wrong, to respond to those who asked where the results were actually as they had been anticipated for quite some time, and while such trial manipulation was occurring and results were being kept secret, Schering stated that continued data analysis from the trial results was the etiology for the delay.
With clinical trials, case report forms are used to record data from the trials, and are created in a manner where further analysis is not normally necessary, as such forms are quite clear and often not subject to interpretation as implied by the trial sponsors, one could conclude. So at the end of 2007, both Merck and Schering got the attention of relevant government officials who contacted both companies regarding this ENHANCE trial due to such suspicions on the facts known and presented, and an investigation began into the activities of both companies regarding this trial at that point.
This became a catalyst for the ENHANCE trial results to be finally released at the beginning of 2008, which caught the attention of major media organizations, as expected. In the spring of 2008, a very large cardiology meeting was held, where the audience was told, I understand, to stick with statins due to this trial’s lack of outcomes for Vytorin, when the ENHANCE trial was discussed at this meeting. Furthermore, it has been said that a cardiologist at this meeting also suggested that a moratorium should occur with the utilization of Vytorin by prescribers, since statins are much less expensive, and are highly regarded, as they have been available for a couple of decades, starting with Mevacor in the 1980s. Of course and as expected, Merck and Schering were not pleased, nor were they surprised at the review of Vytorin at this particular meeting. The following month after this cardiology meeting, Schering’s earnings dropped by 48 percent, as I recall. Also during much of this year, Schering in particular blamed the media for amplifying the situation regarding the ENHANCE trial.
Now, these cholesterol drugs promoted by Merck and Schering, Zetia and Vytorin, were aggressively marketed in a number of ways, including investing I believe about 200million dollars in 2007 for DTC ads for these products. To add to this, and soon after both meds were launched, reps from both companies made inferences to doctors about outcomes regarding plaque accumulation and how Vytorin was superior in that area, which, of course, this ENHANCE trial proved it is in fact not the case whatsoever. It did not matter, apparently, to both Merck and Schering that such claims were is entirely void of proof, which is not unique to any pharma rep, in my opinion. No remorse or regret from the makers of these drug makers, either, which did not shock many. Yet what is known now is that these companies, as stated by other researchers, performed junk science with their deliberate manipulation of this ENHANCE trial using such tactics. Also, last year, Zetia and Vytorin had about 20 percent of the cholesterol lowering market. It does not seem that there will be an increase of this percentage because of this scandal. Possibly if they presented the truth, the future of these meds might be better than what is anticipated presently.
Worst of all regarding this ENHANCE trial scandal is the harm caused to both doctors and patients. The ENHANCE trial concerned and confused both of these participants in the health care system. Furthermore, it’s likely they were devastated by being so clearly misled by the marketing of both Merck and Schering regarding the false benefits of Vytorin they were led to believe by the companies that promoted them- the health care providers in particular.
This whole situation is another example of the progressively frequent discovery of corruption of the scientific method by placing profits over the well-being of patients, which harms the well being of patients. In addition, most were shocked by Merck behaving in such a way in particular because of what use to be their excellent reputation as an ethical pharmaceutical company. And this alone shows the progression and infiltration of such damaging ethical atrophy that desperately needs to be stopped and corrected for the sake of others- for everyone.
Don’t just say something. Have something to say- to the right people, with conviction and with others who share your views.
“Try not to become a man of success, but rather try to become a man of value.” --- Albert Einstein
Dan Abshear

Author’s note: What you have read is based upon information and belief. Thank you

Dan said...

Facts Believed to be Associated With All of the Statin Medications:

Statins are a class of medications specifically prescribed to lower LDL- one of five lipid parameters of a person’s lipid profile, which is a blood test to measure these parameters.

There are about 6 available statins to choose for lipid management as needed- with three that are combination drugs that have a statin along with another cholsterol enhancing drug in such combination medications.

There are other classes of medications for lipid management, such as bile acid sequestrants and nicotinic acid, which is known as niacin. Yet the side effect profile is more unfavorable of these classes of medications compared with the statin class of drugs.

One’s cholesterol level is primarily due to how they produce cholesterol in their liver, which is overall genetically determined. This level is also determined by one’s lifestyle and diet as well. If a person has too much cholesterol in their blood, it can lead to hardening and narrowing of their arteries as well as the formation of cornorary plaques in the cornorary arteries. If these plaques break off of the arterial wall, this leads to a myocardial infarction. Statins are believed to stabalize coronary plaques so this does not occur.

To measure one’s cholesterol, a blood test called a lipid profile is obtained from a person after they have fasted for at least 12 hours. The test should also be performed only if the person is free of any acute illness, as this may affect true lipid measures. If the results prove to be abnormal, lipid altering medicinal therapy may be initiated- according to the discretion of the person’s health care provider. This therapy usually involves a statin medication.

Adverse events associated with the statin class of pharmaceuticals are thought to occur more often than they are reported- with high doses of statins prescribed to patients in particular at times that may not be necessary to control their dyslipidemia based on their lipid profile.

However, since this class of drugs has existed for use for over 20 years, statins are considered safe and effective for enhancing the clearance of LDL noted to be elevated in the lipid profiles of patients. Also, they have proven to reduce cardiovascular mortality with one who is treated with a statin that has dyslipidemia. In addition to lowering LDL by up to abpit 60 percent- depending on the choice of the statin prescribed. This class of drugs also and to the patient's benefit raise their HDL lipid parameter as well as lower to their benefit their triglycerol parameter of their lipid profile. Both of these additional effects in addition to lowering the LDL parameter from taking a statin drug is ultimately beneficial for the patient on a statin drug for lipid management.

Statin therapy is also recommended for those patients who have a greater than twenty percent risk of developing cardiovascular disease, or those patients that have clinical evidence of this disease.

Additionally, there appears to be no comparable reduction in cardiovascular morbidity or mortality, as well as a difference in the increase of one’s lifespan, if one is on any particular statin medication for their lipid management over another, others have concluded. So caution should perhaps be considered if one chooses to prescribe a statin for a patient if they are absent of, or have only mild dyslipidemia to a significant degree.

Furthermore, research should be done by the health care provider if they are under the belief that one statin medication provides a greater cardiovascular benefit over another. In other words, the health care provider should be assured that any choice of statin therapy for their patients is considered reasonable and necessary if the LDL in their patients need to be reduced, and the statin selection should be determined by the results that have been shown with a particular statin.

There exists abstract etiologies for health care providers at times to choose to prescribe statin drugs on occasion for reasons not indicated with the medicinal treatment of these statin drugs. Examples include the speculated benefits associated with statins- such as reducing CRP levels, or for Alzheimer’s treatment, or other reasons not directly related to cholesterol management.

Statin therapy for such patients may not be considered appropriate, reasonable, or necessary prophylaxis at this point for any patient who does not have the indications for which statins are approved for to treat patients with dyslipidemia. All other benefits that appear to have favorable effects in such areas not involved with a patient's cholesterol are suggested at this point due to minimal research in these other variables aside from lipid management.

Other reasons for placing a patient on a statin drug at this time require further research for these disease states and dysfunctions that may exist with a patient aside from dyslipidemia.

Statins as a particular class of drugs seem to in fact decrease the risk of cardiovascular events significantly, it has been proven. Statins also decrease thrombus formation as well as modulate inflammatory responses (CRP) as additional benefits of the medication.

For those patients with dyslipidemia who are placed on a statin, the effects of that statin on reducing a patient’s LDL level can be measured after about five weeks of therapy on a particular statin drug.

Liver Function blood tests are recommended for those patients on continued statin therapy, and most are chronically taking statins for the rest of their lives to manage their lipid profile in regards to maintaining the suitable LDL level for a particular patient presently. Patients should be made aware of potential additional side effects as well, such as myopathy and muscular dysfunctions that occur on occasion when one is on statin therapy.

Yet some have said that about half of all strokes and heart attacks that do occur are not because of increased cholesterol levels of these patients. So high cholesterol may not be an absolute for cardiovascular events.

Others believe that it is oxidized cholesterol that causes vulnerable plaques to form on coronary arterial walls, which is the catalyst for a heart attack, and that there is no medicinal treatment for the formation or stabilization of these plaques to prevent heart attacks or strokes.

Some who support statin medicinal therapy for their clinically appropriate patients claim that these drugs, do, in fact, stabilize these plaques, and therefore are beneficial.
As stated previously, in regards to other uses of statins besides just primarily LDL reduction, there is some evidence to suggest that statins have other benefits besides lowering LDL.

These other disease states include aside from what has been stated already, such as those patients with neurological disease, as well as statins being beneficial for certain cancer patients. Some have suggested that statins interfere with cancer treatment with bladder cancer patients as well. Yet again, these other roles for statin therapy have only been minimally explored and researched, comparatively speaking.

Because of the limited evidence regarding additional benefits of statin medications, the drug should again be prescribed for those with dyslipidemia only at this time involving elevated LDL levels as detected in the patient’s bloodstream.

Yet overall, the existing cholesterol lowering recommendations or guidelines should possibly be re-evaluated. The cholesterol guidelines that presently exist may be over-exaggerated possibly due to tacit suggestions from the makers of statins to those who create these current lipid lowering guidelines.

This is notable if one chooses to compare these cholesterol guidelines with the other guidelines that have existed in the past. The cholesterol guidelines that exist now are considered by many health care providers and experts to be rather unreasonable and unnecessary, as well as possibly have the potential to be detrimental to a patient’s health.

Yet statins are beneficial medications for those many people that exist with elevated LDL levels that can cause cardiovascular events to occur because of this abnormality. What that ideal LDL level is may have yet to be empirically determined.

Finally, a focus on children and their lifestyles should be amplified so their arteries do not become those of one who is middle-aged, and this may prevent them from being candidates for statin therapy now and in the future, regarding the high cholesterol issue. Treating children with a statin drug for dyslipidemia is controversial presently.

Dietary management should be the first consideration in regards to correcting lipid dysfunctions that may exist in patients,

Dan Abshear

Unknown said...

I think the caption of the graph you have is wrong. Because the Y axis is the log of risk, a 30mg change is actually a 10^.3 % change, so for example going from 40-70mg only increases risk by 20%, whereas going from 160-190mg actually over sextuples your risk of heart disease

simvastatin side effects said...

Discussed first to your doctor if you have plans to swithch to another medication to ensure your health safetyness.