ORLANDO--An era is grinding to a halt, as the best-selling drugs in the world begin their slow extinction as a financial force.

Cholesterol-lowering medicines, known as statins, lost their position as the top-selling drugs in the U.S. last year, thanks to the fact that two top brands have lost patent protection and are being replaced by cheaper generics, according to industry consultants IMS Health (nyse: RX - news - people ). That is a huge shift. According to IMS, statins and other cholesterol drugs first became America's top-selling drugs in 1999. Between 1999 and 2008, the death rate from heart attacks fell 30%, and statins and other heart drugs get a lot of the credit.

With patents running out on old blockbusters and new medicines underperforming, drug companies are losing the appetite to do the big studies of thousands of patients that have been a major scientific driver of the blockbuster age. In 2008, cholesterol drug sales fell 12% to $14.5 billion.

"Is this area of pharmacology for cardiology dead?" says James Stein, a professor of medicine at the University of Wisconsin, Madison. "Have we maxed out with very powerful statins and excellent blood-pressure drugs? Is there going to be another cardiology blockbuster ever again?"

The buzz here at the annual meeting of the American College of Cardiology has been for a collection of old generics: a single capsule dubbed a "polypill" that some say could benefit the public health. Data are due out today.

The other big story is from a study that already made news twice. Last March, it was announced that Crestor from AstraZeneca (nyse: AZN - news - people ) cut the rate of heart attacks, strokes and deaths in patients with inflamed arteries, as measured by the c-reactive protein (CRP) blood test. Full results were presented last November.

Sales of Crestor jumped 30% to $3.6 billion last year, even as Lipitor from Pfizer (nyse: PFE - news - people ) and the Vytorin combo pill from Merck (nyse: MRK - news - people ) and Schering-Plough (nyse: SGP - news - people ) saw their sales drop, largely thanks to those results.

In that same study, Crestor also prevented clots in the veins that can lead to blocked circulation in the legs or, if dislodged, can wind up in the lungs, potentially killing the patient. There were only 90 of these events, called venuous thromboembolisms (VTE), in the study, but patients who got Crestor were only half as likely to get them.

Crestor and the other statins are thought of as cholesterol-lowering drugs. But though burst cholesterol plaque in the arteries causes the blood clots that lead to heart attacks and strokes, cholesterol plays no role in VTEs. Paul Ridker of Brigham & Women's Hospital, the lead scientist on the Crestor study and pioneer of using c-reactive protein to measure heart risk (he has a patent on it), argues that this provides even more proof of the key role of inflammation in statins' effectiveness. Other drugs that prevent VTE are blood-thinners, which inevitably cause risky increased bleeding.

Roger Blumenthal, director of cardiology at Johns Hopkins University, says that the VTE results are "very impressive." But although he screens for CRP, he says that he won't yet be using the test as cholesterol used, upping a patients' statin dose until the CRP goes down. "I don't think we're there yet," Blumenthal says.

So what about new drugs? There was one with some impressive data, but it only seems to highlight the changes in the drug industry further, because it came from a tiny, privately held firm called Corthera, not from a big pharma or even a publicly traded biotech.

The drug is called relaxin, and it is a hormone released in pregnancy that was discovered at the beginning of the Great Depression. Now the idea is to use it to combat acute heart failure. Pregnant women, the idea goes, are dramatically increasing their blood supply, and the same kinds of biological changes might help people whose hearts are not pumping hard enough.

Preliminary results were encouraging, and even showed a benefit on reducing deaths in one dose--although experts warn to view that as preliminary until a larger study is done. John Teerlink of the University of California, San Francisco, who headed the study, says he's optimistic relaxin will help patients' hearts without causing other, pregnancy-like effects such as weakened tendons. "I was intrigued but not convinced," says Clyde Yancy, director of the Baylor Heart and Vascular Institute in Dallas.

In the past, heart failure drugs that have helped patients feel better have sometimes not helped them--and have even hurt them--in the long run. The last attempt at a treatment for hospitalized heart failure patients, Natrecor, wound up having its use severely restricted by its maker, Johnson & Johnson (nyse: JNJ - news - people ). The drug is currently the subject of two whistle-blower suits in which former employees accuse J&J of improperly marketing Natrecor before it became controversial.

As a result of controversies like Natrecor, industry is on the defensive. For the first time in years, the bags handed out to doctors here at the ACC meeting are not branded with any drug or company name. Neither are the lanyards from which badges hang.

Worse yet, this same story is repeating itself across medicine. Cholesterol drugs were replaced at the top of the U.S. pharmaceutical sales charts by schizophrenia drugs like Zyprexa from Eli Lilly (nyse: LLY - news - people ) and Seroquel from AstraZeneca. Antipsychotics are nearing patent expiry too, and they are controversy magnets. A Harvard doctor who argued for their use in kids is under attack, and Astra is being accused of burying bad data on Seroquel.

Last week, the American Psychiatric Association decided to phase out drug-company sponsored lectures and meals at its annual meeting. And today, Eli Lilly's top hope for a new anti-psychotic failed in a clinical trial, a result that JPMorgan labeled "a major setback."

You can find the full report on the Platinum 400, the Best Big Companies in America, at www.forbes.com/platinum/. Online you will find tear sheets on all 400 companies; industry median charts; reports on stock market winners and losers, Platinum newcomers, drop-offs and long-term members; a slide show of the Best Managed Company in each of 26 industries and much more. Below: a look at 14 of the standouts from the list.

McDonald's

Hotels, Restaurants & Leisure | Big Mac, Quarter Pounder, and Chicken McNuggets-- McDonald's has served some of the world's favorite fast foods for more than half a century. The yellow letter M is the largest global food service retailer with more than 30,000 restaurants serving 52 million people in more than 100 countries each day. More than 75% of McDonald's restaurants worldwide are owned and operated by franchisees and affiliates.

Westinghouse Air Brake

Capital Goods | George Westinghouse founded an air brake company in 1869, shortly after he demonstrated that air pressure was a clever way to operate the brakes on a string of railcars. This 19th-century business lives on. After a series of owners, Westinghouse Air Brake Co. became Wabtec Corp. (nyse: WAB - news - people ) in a November 1999 merger with MotivePower Industries. Wabtec, with $1.5 billion in sales, manufactures a broad range of products for locomotives, freight cars and passenger transit vehicles. The company also builds new locomotives up to 4,000 horsepower in size.

Gilead Sciences

Drugs & Biotechnology | In a little over two decades after its start in 1987, Gilead Sciences has become one of the largest biopharmaceutical companies in the world, with a rapidly expanding product portfolio, growing pipeline of investigational drugs and operations on three continents. Primary areas of focus of the Foster City, Calif. company include antivirals (such as for HIV/AIDs and chronic hepatitis), cardiovascular conditions and respiratory diseases. Truvada, a drug used in the treatment of HIV infection in adults, is its sales leader with $1.54 billion in revenue for the first nine months of 2008.