The Arbiter Study Is Another Setback For Merck
14 CommentsBy Ed Silverman // November 16th, 2009 // 8:08 am
Abbott Labs’ Niaspan appeared safer and more effective that Merck’s Zetia as a secondary cholesterol treatment, according to a study released Sunday night. Funded by Abbott and called Arbiter-6, the study measured thickness of the carotid artery leading to the brain in 208 patients, who were given simvastatin along with either Niaspan or Zetia over 14 months.
The study only looked at patients who had already lowered their LDL cholesterol to the recommended level by taking a statin. The upshot: Niaspan patients had reductions in artery wall thickness, while those on Zetia had no change. Docs view artery thickness as a way of predicting heart attack and stroke risks (here is the abstract). There were nine heart attacks among Zetia patients but just two in the Niaspan group.
Researchers enrolled 363 people with heart disease or a high risk for it who had been taking statins for six years on average, but it was stopped in June because one group was faring much better than the other. “Niacin is the clear winner and led to very clear reductions in the amount of atherosclerosis that patients had,” Allen Taylor, the lead investigator told Reuters wihle at the American Heart Association scientific meeting in Orlando, Florida. [Please keep reading for UPDATES from analysts...]
The findings could further lower revenue of Merck’s Zetia and Vytorin (which includes simvastatin and Zetia) by 20 percent, or $800 million, according to Seamus Fernandez, an analyst with Leerink Swann, Bloomberg News writes. Sales of the drugs have declined ever since the controversial Enhance study results, which Merck and Schering-Plough delayed releasing, raised questions about their effectiveness. Vytorin and Zetia sell for about $3 to $4 each per day while generic niacin is cheap.
One editorial accompanying the study, which was co-authored by John Kastelein, who has consulted for Merck and was the primary investigator on the Enhance study, noted some limitations. In particular, one issue was the small patient population of just 208 participants.
But Steve Nissen, chief of cardiology at the Cleveland Clinic tells Bloomberg that, “yes it is a small study, yes it isn’t a substitute for a large definitive outcomes trial, but I do think it will get attention and I do think it will inform us about the choices we have about what therapies we should administer. There are issues with niacin, some people get flushing, but we are talking about a lethal disease, and I do think there will be an uptick in the use of niacin because of this. It was quite a compelling result.”
But in yet another editorial, Roger Blumenthal, a cardiology professor at Johns Hopkins University, wrote that doctors shouldn’t draw definitive conclusions because of the small number of patients and because the study used a secondary measurement, artery thickness, rather than gauging the total number of heart attacks and strokes. However, he also tells the Associated Press that Zetia “has been on the market for about seven years and we still haven’t proven that it improves clinical outcomes.”
Ken Frazier, Merck’s president of global human health, tells the AP that “the question is, how important is the study?” Shrinking plaque is no guarantee that heart attacks will be prevented, and not all studies have found a correlation, he argues, adding that Merck is doing an 18,000-patient clinical trial to try to measure the heart effects of Zetia and Vytorin, although the results won’t be known for at least a few years (here is the Merck statement and here is the Abbott statement).
But the difference in plaque that Niaspan made in this study “is precisely the same as the difference” that earlier studies found from statins, James Stein, a University of Wisconsin-Madison cardiologist, tells the AP. He previously consulted for Schering-Plough, which was bought by Merck.
This morning, Sanford Bernstein analyst Tim Anderson writes: “All of these trials have their flaws and limitations, such that impugning Zetia like many have done seems excessive and inappropriate. Critics keep pointing to the fact that Zetia was approved on the basis of trials that measured only a surrogate marker for true, clinical efficacy. What is seldom mentioned is that this is how most drugs, in most disease categories, are currently approved in the US.”
And DeutscheBank analyst Barbara Ryan wrote this: “Positive for Niacin, but study limitations suggest little potential downside for Zetia…We continue to expect that the Zetia and Vytorin products will lose additional market share over time from currently low levels, but the incremental negative impact of ARBITER-6 will be limited. In our opinion, pressures will increase more significantly with the availability of generic Lipitor in late ‘2012..”
Condor
This bit — courtesy Larry Husten at CardioBrief, from two former Merck/Schering-Plough joint venture PIs — may be the most troubling admission I’ve seen so far, tonight:
. . . .Kastelein and Bots raise the question whether we will ever find out the truth about ezetimibe: In their editorial they write that “the large number of hard clinical end points (>5000) required to achieve sufficient statistical power in IMPROVE-IT makes it uncertain whether the trial will ever reach completion“. . . .
[Dr. Kastelein, my sharper readers will recall, was the PI on ENHANCE; Dr. Bots was brought in later, to evaluate the readability of the CIMT data in ENHANCE, and declared it "fine" -- "no better, or worse, than other similar studies' data", despite Merck/Schering-Plough's insistence that much of the ENHANCE CIMT data was poor.]
So — IMPROVE-IT (see my left margin count-down clock, still at least 1,506 days to go!) — May. Never. Reach. Completion.
Well — if that is remotely close to accurate, “game over”, for Vytorin/Zetia. IMPROVE-IT was to be the pair’s last best hope.
Namaste
Condor
Shorter NEJM (editorials plainly included here): It is hard to imagine a worse set of outcomes from such a smallish study — for the “New” Merck’s cholesterol franchise drugs.
Namaste
Condor
$20 billion.
From 2003 through 9.30.09, that is how much, worldwide, was spent on Vytorin/Zetia.
That is breathtaking. Consider also that from 2006 through 2008 alone, MRK/S-P spent more than $472 million on DTC, and other adverts, to stoke demand for Vytorin/Zetia. . . .
All for something that — it seems — may provide no clinical outcome benefit, at all.
These two drugs will be the poster children for reform, I predict — they are not lethal; they are just of marginal benefit. And they carry an astonishingly-high per pill price-tag.
Namaste
Paul
I am not sure this is a fair and practical comparison in the real world. Isn’t Zetia just an add-on product that by itself has never really been much but when added to Zocor lowers cholesterol even more?
Very smart of Abbott to have done this study and confuse things, but doesn’t really sound that clinically relevant:
- So what is Niaspan is better than Zetia, no one is really using Zetia
- Zocor is better than Niaspan in terms of outcomes, no?
- The outcomes that matter are hospitalization and death, not carotid intima thickening
- Carotid intima thickness has not been shown to be correlated to hospitalization and outcomes
- Vytorin is Zocor plus some Zetia
- So how can anyone conclude that Niaspan is better than Vytorin…it just doesn’t make sense.
This study by Abbott seems to have been a purely marketing study with no redeeming scientific or clinical value.
Response to Paul
Dear Paul,
Thanks for the perspective from the new Merck! However, it is a bit delusional. The results from this study again indicate no additional value of ezetimibe when added to a statin, making Zetia worthless x3. In addition, because Vytorin simply combines ezetimibe with simvastatin, there is no reason to prescribe Vytorin. Statins still rule the roost and now niacin, alongside resins and fibrates, remain the additive choices for those patients who do not completely respond to a statin. No doubt Zetia and Vytorin will start dropping like flies off of formularies nationwide. Their market share will be lost. It is no wonder that the top execs at Schering-Plough got out while they could. Now merck is holding and empty bag. So sad!
A friend
Another Ressponse to Paul
carotid Intima Media Thickness has been shown to corralate to CHD events. Over and Over again.
Zetia is used- quite a bit as the 1st add on to a statin. Good advertizing, and the ease of use make it an easy drug to add on. it lowers LDL too- patients come back and see the LDL lower and think “great this copay was worth it” However, I think it’s pretty clear that this is not the best add on to a statin- and should be reserved for later use. LDL isn’t everything- and other drugs like Niaspan provide LDL lowering + HDL raising and TG lowering that Zetia can’t provide. These other measures make the difference.
The study compaired 2 treatments in patients who were already on Zocor- they recieved either Zetia or Niaspan. so you can infer that Zocor+ Niaspan did better then Zocor + Zetia. Vytorin was not used in the study- but its components were.
It’s well accepted that statins are the best 1st line agent- what isn’t clear is what do do next when a statin isn’t enough- which is often being you only get a 30-40% reduction in events on a statin. A direct compairison of Niaspan to a statin has never been done. But Niaspan has been shown to provide benifit beyond on top of what the statin can do.
There is plenty of other data on Niaspan out there to back the results of this trial up. Niacin’s been around 50 years.
Condor
TO all of the above I would add that though a small study, it is true that patients taking Niaspan had five times fewer cardiac events than patients taking Zetia. (1% on Niaspan; 5% on Zetia). This finding was statistically significant.
How can a doctor responsibly ignore this data — even though it is from a small study?
Answer: doctors won’t ignore it. Equally ominiously, Sen. Grassley wrote on Friday to HHS Secretary Sebelius — to discuss reimbeursement levels (by Medicare Part D, among other government programs), for these drugs.
As goes reimbursement, so goes the prospect for these two drugs — Zetia and Vytorin.
[Not to be politically-incorrect, here but] I think the fat lady is clearing her throat.
Namaste
Condor
Really. I know how to spell reimbursement. Sheesh. Sorry.
Condor
New MRK is up, this morning, in early-NYSE trading.
At the moment it appears the market is betting that HHS Secretary Sebelius won’t acquiesce to Senator Grassley’s strong suggestion that Vytorin/Zetia be moved to Tier III, or dropped altogether, from the formularies of approved meds — just as Illinois, New York and California did in 2008 (dropping it from top tier status, to one notch down), in response to ENHANCE.
I think that is a foolish bet.
Co-Pays are going to rise for the Vytorin/Zetia combination, and insurance coverage is going to decrease (or evaporate, altogther) — so MRK’s only possible remaining option will be to cut price to keep share. It will take time, but you will see it.
That “price drop” strategy can’t work long term, for the level of expense MRK carries to sell and support the cholesterol franchises.
Let’s see what the next four to six weeks bring.
Namaste
Paul
Dearest friends and bloc colleagues,
You have all reinforced exactly what I said, perhaps unknowingly so.
This study had little relevance and everyone went three degrees of separation to making a statement about Vytorin. No one commented on the study exactly for what it was, a marketing gimmick.
Zetia did exactly what it was supposed to do. It was never meant to raise HDL or lower trigs. All it does is lower LDL by a bit. But patients on both arms before going into the study already had their cholesterols aggressively lowered. So NO SURPRISE, zetia didn’t do any new tricks it has never done before.
It’s like comparing a Hummer with a Mini on climbing a rocky hill. Duh! That doesn’t make the mini a bad choice, just a bad choice to climb a rocky hill.
oh, by the way, Niacin in any of its forms has never been shown to reduce mortality or hospitalizations. What’s the excitement all about?
Condor
Hello Paul —
Sincerly, I do not mean to be pendantic, but what do you make of the statistically-significant Elevated Major Cardiac Event Risk seen in the Arbiter 6 study for the patients taking statins along with Zetia, as compared to those taking statins along with Niaspan?
Seriously, please explain — as your-supposed “marketing gimic” — the notion that Zetia patients had a 5% risk of major cardiac event, over 14 months, v. a 1% risk of major cardiac events, for the Niaspan patients.
I am all ears (erh. . . eyes) here.
Namaste
Paul
Nice try Condor. In a small study, with small numbers, that is not a statistically-significant difference…as noted by the authors. If you read the analysis and editorials released yesterday you’ll see that your conclusions are a big stretch.
Condor
Well, Paul — it shows a p value of 0.047 — that puts the five fold difference OUTSIDE the margin for error — but only just.
Yes it is a small study, but this refutes the notion that it is all a “gimic” study;
“. . . .Major adverse cardiovascular events occurred at a significantly higher incidence in the ezetimibe group (9 of 165 patients [5%]) than in the niacin group (2 of 160 patients [1%]) (P=0.04 by the chi-square test) (Figure 3, and Table 3 in the Supplementary Appendix). The effects of niacin on the mean carotid intima–media thickness were consistent across the prespecified subgroups: those stratified according to sex, presence or absence of diabetes, quartile of baseline HDL cholesterol level, and median cutoff points for baseline carotid intima–media thickness and C-reactive protein level. . . .
Just the same, namaste. . .
Response to Paul
ARBITER-6 was an atherosclerosis study, comparing the effect of two drugs on the progression of the disease. For the primary endpoint, niacin clearly beat ezetimibe when both were added to a statin. This is a valid and important result to people who have followed this field for the past 25-30 years. In addition, ezetimibe did not do as well as niacin for the prevention of events when added to a statin. Small numbers, but big differences. You would do well to read up on previous trials. Niacin was shown more than 25 years ago to reduce events and has been shown many times since. It’s a great drug that is a little difficult to tolerate. Sadly, ezetimibe is not a great drug, but a multi-billion dollar con!