Crestor sales also got a lift last year from the implosion of Vytorin in a PR debacle that was enormous even by pharma's standards.
The drug combined Merck and Schering-Plough's Zetia (ezetimibe), which blocks absorption of cholesterol from food, with simvastatin
to create a dual-action pill powerful enough to compete with Crestor. Approved in 2004, when Crestor safety fears were at
their peak, the Vytorin-Zetia franchise outsold Crestor in the US $5.2 billion to $2.8 billion in 2007.
But unlike statins, ezetimibe had yet to complete a single outcomes trial, so no one really knew if Zetia and Vytorin could
actually prevent heart attack or stroke. In the ENHANCE trial, Vytorin went head-to-head with simvastatin, aiming to beat
the statin and earn Vytorin an atherosclerosis indication. But from March 2006 on, as AstraZeneca released positive data from
ASTEROID and METEOR at one conference after another, ENHANCE results were MIA.
In January 2008, the drugmakers finally showed their hand. The data confirmed suspicions that Vytorin had flunked the test—in
fact, simvastatin slowed the progression of atherosclerosis twice as well as the simvastatin/ezetimibe combo. (Vytorin was,
however, strikingly effective at lowering cholesterol.)
At the American College of Cardiology (ACC) confab last March, an expert panel passed judgment, urging doctors to stop using
Zetia and Vytorin except as a last resort. "You've just seen a negative trial that should change practice, especially the
way we in this country have prescribed," Yale professor Harlan Krumholz told the throng of fellow cardiologists.
The day after the panel's recommendation, AstraZeneca announced a halt of a different kind. The company was stopping its JUPITER
trial six months ahead of schedule because an independent safety committee cited proof that the drug prevents heart attacks
and strokes. In the following months, scrips for Vytorin and Zetia fell 40 percent while Crestor rang up $768 million in US
sales for the first two quarters of 2008—a 10 percent jump over the same period in 2007. Still the industry awaited JUPITER's
A longtime mystery of cardiovascular medicine is why almost half of all heart attacks occur in people with normal LDL levels
and only one risk factor (high LDL, high blood pressure, smoking, etc.)—and fully 20 percent in people who have none. It seems
plain that something other than cholesterol is at work in heart disease, and for Paul Ridker, MD, (and an increasing number
of other researchers) that something else is inflammation associated with arterial plaque. Because C-reactive protein (CRP)
in the blood is a marker for inflammation in the artery, Ridker began advocating 10 years ago for testing CRP in people who
have already had a heart attack or who have multiple risk factors.
Ridker peddled his plans for a large trial to the government and Pfizer, but both passed. Then in 2005, AstraZeneca made the
leap. With Crestor sales still lagging, a new indication that could conceivably rope in 7 to 11 million additional consumers
sounded almost too good to be true. Thus the Justification for the Use of Statins in Primary Prevention: an Intervention Trial
Evaluating Rosuvastatin—JUPITER—was born.
The classic placebo-controlled study enrolled almost 18,000 people worldwide, men over 50 and women over 60. All had healthy
LDL levels (less than 130 mg/dl) but high CRP levels (more than 2 mg/l); half had a moderate to high risk of heart disease,
while the others were risk-free. Enrollees were randomly given 20 mg of Crestor or a sugar pill.
What data brought the trial to its speedy end? The Crestor crowd had 54 percent fewer heart attacks, 48 percent fewer strokes,
and 20 percent fewer deaths than the placebo group. Among people with no or low risk, the statin-takers had 37 percent fewer
cardiac events. In addition, JUPITER provided the first-ever proof that statins protect women against a first heart attack.