Doctors wary after cholesterol drug flop

[Isolder74]

Link

Doctors wary after cholesterol drug flop

CHICAGO - Leading doctors urged a return to older, tried-and-true treatments for high cholesterol after hearing full results Sunday of a failed trial of Vytorin.

Millions of Americans already take the drug or one of its components, Zetia. But doctors were stunned to learn that Vytorin failed to improve heart disease even though it worked as intended to reduce three key risk factors.

"People need to turn back to statins," said Yale University cardiologist Dr. Harlan Krumholz, referring to Lipitor, Crestor and other widely used brands. "We know that statins are good drugs. We know that they reduce risks."

The study was closely watched because Zetia and Vytorin have racked up $5 billion in sales despite limited proof of benefit. Two Congressional panels launched probes into why it took drugmakers nearly two years after the study's completion to release results.

Results were presented at an American College of Cardiology conference in Chicago Sunday and published on the Internet by the New England Journal of Medicine.

Doctors have long focused on lowering LDL or bad cholesterol as a way to prevent heart disease. Statins like Merck & Co.'s Zocor, which recently came out in generic form, do this, as do niacin, fibrates and other medicines.

Vytorin, which came out in 2004, combines Zocor with Schering-Plough Corp.'s Zetia, which went on sale in 2002 and attacks cholesterol in a different way.

The study tested whether Vytorin was better than Zocor alone at limiting plaque buildup in the arteries of 720 people with super high cholesterol because of a gene disorder.

The results show the drug had "no result — zilch. In no subgroup, in no segment, was there any added benefit" for reducing plaque, said Dr. John Kastelein, the Dutch scientist who led the study.

That happened even though Vytorin dramatically lowered LDL, fats in the blood called triglycerides and a measure of artery inflammation — CRP.

Some doctors noted that hormone pills for menopausal women and torcetrapib, a promising cholesterol drug Pfizer Inc. recently abandoned, also lowered cholesterol but were found in big studies to raise heart risks, not lower them.

Another ominous sign was the decision Friday by other researchers to expand enrollment in a more pivotal study of Vytorin to 18,000 people because early results suggest it will be harder than anticipated to see if it is any better than Zocor alone.

"It will be 2012 — ten years after the drug was introduced — before we know the answer," said Dr. Steven Nissen, a Cleveland Clinic cardiologist who has no role in the studies and has criticized the drugmakers over the one reported Sunday.

Dr. Robert Spiegel, chief medical officer for Schering-Plough, said the study was done "with the highest integrity" and that doctors can believe the results "because of the time we took to make sure the data are right."

"We were disappointed that it was not a very balanced panel discussion" by the heart doctors who urged their peers to focus on more established treatments.

However, Kastelein said the data were far more consistent than anticipated and ample to show that the drug simply did not work.

"A lot of us thought that there would be some glimmer of benefit," said Dr. Roger Blumenthal, a Johns Hopkins University cardiologist and spokesman for the American Heart Association.

Many doctors have prescribed Vytorin without trying older, proven medications first, as guidelines advise. The key message from the study is "don't do that," Blumenthal said.

No one should ever stop any heart drug without talking with their doctors, heart specialists stressed.

However, doctors "should be thinking twice," said Duke University cardiologist Dr. Robert Califf. He takes the drug himself because he cannot tolerate the high dose of statins he otherwise would need.

Dr. James Stein, director of preventive cardiology at the University of Wisconsin-Madison, said many doctors prescribe Zetia and Vytorin because they seem to be safe ways to get cholesterol down quickly, without annoying side effects like flushing that some other medicines carry.

Stein, who has consulted for Schering-Plough, said that after six years on the market, it would have been good to see better results on a drug so many doctors believed would help, "but the reason we do research is so we don't have to rely on our 'beliefs' — we can rely on data."

The New England Journal also published a report showing that Vytorin and Zetia's use soared in the United States amid a $200 million advertising blitz. In Canada, where marketing drugs directly to consumers is not allowed, sales were four times lower.

Merck is based in Whitehouse Station, N.J.; Schering-Plough, in Kenilworth, N.J.

In addition to the two Congressional committee probes, New York State Attorney General Andrew Cuomo subpoenaed the companies in a similar probe in January.

"While these corporations profited, Americans were left in the dark," Cuomo said in a written statement Sunday. "The millions who take this drug, taxpayers who subsidize its use through the Medicaid and Medicare programs, and Merck and Schering-Plough's investors deserve to know why it took so long for the results to be made public. This new information underscores our concerns and advances our investigation, which we will pursue aggressively."

Seems it wasn't such a wonder drug afterall. What a shock!

[Gullible Jones]

This the one that claims to prevent absorption of cholesterol from foods?

[Tsyroc]

IIRC Vytorin has two different cholesterol lowering drugs in it. One is a "statin" for lowering cholesterol from food and the other drug I think is supposed to be for lowering cholesterol caused by the person's genetics.

[cosmicalstorm]

I've heard some people claim that too much emphasize is put on cholesterol just because thats so easy to measure compared to other things associated with heart conditions.

[mr friendly guy]

IIRC Vytorin has two different cholesterol lowering drugs in it. One is a "statin" for lowering cholesterol from food and the other drug I think is supposed to be for lowering cholesterol caused by the person's genetics.

Er no. The statin component reduces cholesterol synthesis by the liver. The other newer drug (Ezetimibe) works by reducing cholesterol absorption from food.

Generally over here statins are used first line. I don't know why some American doctors are prescribing the newer drugs first, since I generally take the attitude of trying older and cheaper and proven drugs first, then newer ones once they have been proven.

The only time I have seen it prescribed is if people can't tolerate statins (eg from some of the side effects), or if statins aren't lowering the cholesterol enough. That being said if you have one of these genetic diseases which cause you to have ridiculous high levels of cholesterol, you may need regular plasmapharesis as well as cholesterol drugs.

[Isolder74]

They knew and they still advertized for it anyway. One more reason why I feel that Precription drugs should not be advertized for on TV at all. Supposedly its to educate us peasents to the options available but from a doctor friend I know I can tell you what happens. People come to the doctor insisting that they have condition X and insist that they need drug Y that they saw on tv. If the doctor tells them that they don't have condition X with proof they go to another doctor until they find one that gives in and gives them drug Y.

[mr friendly guy]

Ah. I had forgotten about America's tendency to advertise prescription medicines to the general public.

[FireNexus]

Why doctors aren't advising patients to take whopping doses of phytosterols with meals along with statins I will never understand. Easy, tried and true and apparently safe method to reduce absorption.

[Melchior]

Why doctors aren't advising patients to take whopping doses of phytosterols with meals along with statins I will never understand. Easy, tried and true and apparently safe method to reduce absorption.

Advising patients to eat healthier meals seems a lot more responsible.

[Tsyroc]

Generally over here statins are used first line. I don't know why some American doctors are prescribing the newer drugs first, since I generally take the attitude of trying older and cheaper and proven drugs first, then newer ones once they have been proven.

The only time I have seen it prescribed is if people can't tolerate statins (eg from some of the side effects), or if statins aren't lowering the cholesterol enough. That being said if you have one of these genetic diseases which cause you to have ridiculous high levels of cholesterol, you may need regular plasmapharesis as well as cholesterol drugs.

Thanks for the clarification how the drugs in Vytorin work.

Statins are generally first line over here too. It's only been in the last couple years that I've seen a big increase in Vytorin use at our hospital. Not long ago we didn't even cary Vytorin on our formulary so we had to put patients who had been on Vytorin at home on our formulary statin and Ezetimibe as separate orders. It was a bit of a surprise when we started carrying Vytorin because we started carrying lots of different strengths of it all at once.

[Tsyroc]

Ah. I had forgotten about America's tendency to advertise prescription medicines to the general public.

It wasn't always that way.

Personally I think it sucks ass that the drug companies are allowed to do it now. Perfectly good and useful drugs that have been around for a long time, and are cheap, tend to get used less and less for more expensive drugs that may not be entirely appropriate.

It's bad enough when the physicians get convinced that something is the newest latest greatest thing by the drug reps for the pharmaceutical companies but it's much more annoying when the patients insist on specific drugs, and drug brands because they saw the commercials.

[Broomstick]

IIRC Vytorin has two different cholesterol lowering drugs in it. One is a "statin" for lowering cholesterol from food and the other drug I think is supposed to be for lowering cholesterol caused by the person's genetics.

Er no. The statin component reduces cholesterol synthesis by the liver. The other newer drug (Ezetimibe) works by reducing cholesterol absorption from food.

Generally over here statins are used first line. I don't know why some American doctors are prescribing the newer drugs first, since I generally take the attitude of trying older and cheaper and proven drugs first, then newer ones once they have been proven.

My Other Half wound up on Zetia because he had intolerable side effects to the older, cheaper statins. Zetia he tolerates, but it's his most expensive medication as there is (apparently) no generic for it yet.

My mom, however, I think is still on the old statins as she did tolerate them well.

Since my dad's total cholesterol is 110, he isn't on any of those (that also happens to be my cholesterol level - guess I got my liver from dad)

That being said if you have one of these genetic diseases which cause you to have ridiculous high levels of cholesterol, you may need regular plasmapharesis as well as cholesterol drugs.

Plasmepharesis is not used for lowering cholesterol in the US. No insurance company (that I am aware of) will pay for it, therefore, no one gets it except in connection with a clinical trial or if they can pay out of pocket for it.

[Justforfun000]

Funny enough....there is a brand new article at the top of the page of "Medical News Daily". You'll be interested to see this:

Astrazeneca Stops Cholesterol Drug Trial Because Of Promising Results


Pharmaceutical giant AstraZeneca announced yesterday, Monday 31st March, it was stopping the JUPITER clinical trial on its cholesterol-busting drug Crestor (rosuvastatin calcium) because early findings showed that the drug reduced deaths and risk of heart problems in patients compared to placebo.

A press statement on the company's website said that the trial's Steering Committee and also the Independent Data Monitoring Board recommended that JUPITER be stopped early because there was "unequivocal evidence of a reduction in cardiovascular morbidity and mortality amongst patients" who took Crestor compared to patients who took placebo.

JUPITER, which stands for Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin, is taking place at over 1,200 locations in 26 countries. It is part of a global set of Crestor trials called GALAXY, which involves over 64,000 patients in 55 countries.

The trial was designed to find out if Crestor (at a dose of 20 mg a day) would reduce major cardiovascular events in patients with no existing symptoms of cardiovascular disease and low to normal LDL cholesterol (the so-called "bad" cholesterol) but higher levels of C-reactive protein (CRP).

CRP is thought to be a marker of inflammation and increased risk of cardiovascular and other diseases.

The team in charge of the trial is already putting into place shut down procedures whereby over 15,000 patients will be scheduled for final assessments. They will then analyse and publish the results once this final set of data has been collected.

The drug giant hopes the early halt and success of the trial will allow it be offered to millions of new patients.

The success of the JUPITER trial follows last months' prediction by market research group GfK Market Measures that a competitor drug from Merck & Co, Vytorin, will be dropped by physicians as a first or second line drug.

This was after reports from the ENHANCE trial that showed the drug, which is a combination of the statin simvastatin (Zocor) and ezetimibe (Zetia), was no better than the older simvastatin alone in preventing plaque build up in arteries.

And more recently, a panel of doctors at a cardiology conference in Chicago recommended that Vytorin and Zetia should be tried only after patients have already tried the older drugs, according to reports from Reuters and the Independent. This news sent shares of Merck & Co and Schering-Plough plummetting. The two companies sell the drugs in a joint venture.

Crestor (rosuvastatin) was approved by the US Food and Drug Administration in August 2003 on the basis of several trials lasting at least 6 weeks where the drug was compared to both placebo and other statins. The trials showed that the drug reduced total cholesterol, LDL-cholesterol and triglycerides, and increased HDL-cholesterol (the "good" cholesterol). Patients responded within one to four weeks of starting the drug.

The most frequent side effects of the drug include muscle aches, stomach pain, nausea, constipation, and weakness.

In 2005 the FDA issued an alert stating that rhabdomyolysis (serious muscle damage) had been reported in patients taking Crestor in combination with other statins. The alert stated that (to date) it did not appear that the "risk is greater with Crestor than with other marketed statins".

However, the label was changed to highlight important information on safe use of Crestor to reduce the risk of myopathy/rhabdomyolysis (serious muscle toxicity), especially at the higher approved dose of 40 mg.

Also in 2005, the FDA refused a citizen petition from public interest group Public Citizen to withdraw Crestor from the market before "additional cases of rhabdomyolysis and kidney damage occur". The agency made the decision after reviewing a response from AstraZeneca and also repeated the intention to revise the product label.

The FDA's response was in a detailed letter that explained how in the view of the agency, Crestor was no riskier than other statins on the market and that the risks were detailed in the new labelling.

Crestor is AstraZeneca's third biggest drug, and is predicted to be the fastest growing.

[Shroom Man 777]

I also find it insidious that Big Pharma is courting doctors and physicians here in the Philippines as well. Prescribe our drugs and we'll invite you to these conferences in Japan, America and Europe! Don't forget your sunscreen!

But the free market will save us all from obesity, am i rite?

Thank god for the government (guvmint) subsidizing the production of generic medication.

[K. A. Pital]

Prescribe our drugs and we'll invite you to these conferences in Japan, America and Europe! Don't forget your sunscreen!

Same here. Huge "otkats" ("offers" which amount to little more than bribes, just legalized) to doctors who prescribe the most expensive, import medicines.

This shit has ruined our domestic pharmaceutic industry even in the most basic stuff like making antibiotics and stuff, and god knows we still have a good chemical industry. Funny how Eastern Europe supplies much of Russia's medication needs now, since they were a little more concerned about Western pharma bribing their docs to prescribe import medicines.

[Shroom Man 777]

Shame, since it was awesome Russian medicine that discovered the awesome of the bacteriophage.

Say what you will about Russia and Soviet Union, but they had some of the best scientific minds and made startling progress for such a "brute second-class expansionist imperialist" nation.

[mr friendly guy]

Plasmepharesis is not used for lowering cholesterol in the US. No insurance company (that I am aware of) will pay for it, therefore, no one gets it except in connection with a clinical trial or if they can pay out of pocket for it.

Thats a pity, but most probably not unexpected given that most people with cholesterol problems aren't necessarily due to known genetic disease and given the nature of American insurance companies. A simple google search revealed this abstract among others, so it has at least been trialled elsewhere.

However I just realise I may have inadvertantly given others the impression that plasmapharesis is used relatively common over here. To my knowledge its not. The doctors at the lipid clinic mention it being used by them only on those with genetic diseases which cause high cholesterol. Given our small population and the prevalence of these diseases, chances are its not going to be used commonly. It seems to be a tool for severe hypercholesteraemia rather than just the run of the mill obese person who eats too much McDonalds.

Funny enough....there is a brand new article at the top of the page of "Medical News Daily". You'll be interested to see this:

<snip>

Funny you should mention rosuvastatin. My knowledge of it is that it seems to show more promise vs existing statins, however data is only for the short term and no long term info is available (not surprising since its a new drug). That being said, its still more expensive, and I tend to go for atorvastatin, which IIRC has shown to be better vs other existing statins, although I don't recall the trial.

I also find it insidious that Big Pharma is courting doctors and physicians here in the Philippines as well. Prescribe our drugs and we'll invite you to these conferences in Japan, America and Europe! Don't forget your sunscreen!

But the free market will save us all from obesity, am i rite?

Thank god for the government (guvmint) subsidizing the production of generic medication.

Over here they court us as well. However they are not supposed to be able to do these expensive conferences any more. So I settle for the odd note pad, free pens etc and throw their advertising in the recycling bin (not that I necessarily think its bogus, but I just don't have time to peruse it).

[Keevan_Colton]

Prescribe our drugs and we'll invite you to these conferences in Japan, America and Europe! Don't forget your sunscreen!

Same here. Huge "otkats" ("offers" which amount to little more than bribes, just legalized) to doctors who prescribe the most expensive, import medicines.

This shit has ruined our domestic pharmaceutic industry even in the most basic stuff like making antibiotics and stuff, and god knows we still have a good chemical industry. Funny how Eastern Europe supplies much of Russia's medication needs now, since they were a little more concerned about Western pharma bribing their docs to prescribe import medicines.

The best term in english would be "junket". basically giving free stuff, trips, goodies etc. in hopes of a good review/promotion from someone that can help increase your profits.

Done a lot in the journalism field too.

[Broomstick]

Plasmepharesis is not used for lowering cholesterol in the US. No insurance company (that I am aware of) will pay for it, therefore, no one gets it except in connection with a clinical trial or if they can pay out of pocket for it.

Thats a pity, but most probably not unexpected given that most people with cholesterol problems aren't necessarily due to known genetic disease and given the nature of American insurance companies. A simple google search revealed this abstract among others, so it has at least been trialled elsewhere.

As it happens the high cholesterol cases in my family ARE due to a defective gene (which I, fortunately, did not inherit. Yay!) Not one of my affected relatives had had the option of plasmepharesis offered, although a couple of the more educated ones have asked. They were told nuh-uh, no way.