NEJM: The Market-Cap Executioner ... You're Next, ARBs

I received a call on Monday from a close friend of The RPM Report who started the conversation with: "So, has the New England Journal of Medicine ever destroyed as much market cap in two days as they did in the past 48 hours?"

Well, the issue in late May 2007, which contained cardiologist Steve Nissen's Avandia meta-analysis was not good for GlaxoSmithKline's market cap. Remember when GSK lost $13 billion in cap in a few days? If you forgot, click here or here.

NEJM may be on its way to eclipsing the old record the magazine already owns. Of course, on Sunday, everyone was privy to the actual ENHANCE study results on Merck and Schering-Plough's Zocor/Zetia combo Vytorin. I couldn't help but think of this when I contemplated how badly burned the companies must feel by the study results. As my blolleague (blog colleague) Chris Morrison pointed out earlier, Merck lost about $12 billion in market cap and Schering-Plough lost about $8 billion in market cap during early trading. Yuck. To see the results from ENHANCE, click here.

But one study that's getting drowned out in the ENHANCE frenzy is the ONTARGET study comparing angiotensin-receptor blockers (ARBs) against angiotensin-converting–enzyme (ACE) inhibitors. ONTARGET compared the ACE inhibitor ramipril (Altace) with the ARB telmisartan (Boehringer Ingelheim's Micadis, Bayer Schering Pharma's Pritor/Kinzal) and a combination of the two.

Here's what the investigators found:

"Telmisartan was equivalent to ramipril in patients with
vascular disease or high-risk diabetes and was associated with less angioedema. The combination of the two drugs was associated with more adverse events without an increase in benefit."

You can read the whole study, published in the May 31 NEJM, by clicking here. Wasn't the whole point of taking an ARB to reduce side effects?

An editorial in the same issue of NEJM written by John McMurray titled "ACE Inhibitors in Cardiovascular Disease--Unbeatable? " was pretty explicit in advising prescribers. Here's an excerpt:

As the fourth and largest comparative trial, the ONTARGET study confirms, beyond doubt, that angiotensin-receptor blockers (ARBs) are not better than angiotensin-converting–enzyme (ACE) inhibitors at reducing fatal and nonfatal cardiovascular events. Of course, physicians and patients might still choose to use an ARB if it is as effective as an ACE inhibitor but better tolerated or less costly.

Wow. Here are some of the ARBs on the market: AstraZeneca's candesartan (Alatacand), Sanofi-Aventis' irbesartan (Avapro), Sankyo/Forest Labs' olmesartan (Benicar), Merck's losartan (Cozaar), and Novartis' valsartan (Diovan). These are not nothing products: Novartis generated over $4 billion in sales from Diovan in 2007; Benicar accounted for more than $750 million in revenue in 2007 and is growing quickly in the US.

McMurray concluded by saying that ONTARGET together with an earlier study

"show that telmisartan and valsartan provide a benefit similar to that of a proven ACE inhibitor. ... However, because ARBs are more costly than ACE inhibitors and have more side effects, their primary value is as an alternative for patients who cannot tolerate ACE inhibitors because of cough."

McMurray ends with nixing an ARB/ACE combo:

"The addition of an ARB to an ACE inhibitor has no benefit and causes an increased number of adverse events in patients with arterial disease but seems to be beneficial in patients with heart failure, although the trials in heart failure did not test the addition of an ARB to a full dose of a proven ACE inhibitor."

To read the full editorial, click here.

There's been a lot of buzz around comparative effectiveness, a comparative center, the impact of comparative effectiveness on personalized medicine, so on and so forth. The ONTARGET study and NEJM editorial should prove to be an interesting marker of how comparative effectiveness will impact the commercial market.

We already saw what ENHANCE did to Vytorin. And it wasn't pretty.