QUOTE FROM STUDY WHICH CONFIRMS THE APRIL 1979, SCIENTIFIC AMERICAN ARTICLE THAT INFLAMATION (INJURY REPSONSE) IS THE PRIMARY CAUSAL FACTOR IN CARANARY ARTERY DISEASE.   {The secondary one would be a high fat diet and the associated high cholesterol level}.  This explains why both cigarette smokers and diabetics have double the rate of heart attacks. 

He thinks that inflammation in the walls of the coronary arteries is behind many heart events and that Lipitor has a stronger anti-inflammatory effect than Pravachol does. For evidence, he notes that in the PROVE-IT patients, Lipitor was much more effective than Pravachol at lowering the level of C-reactive protein, which seems to be an indicator of inflammation. "This is not just about cholesterol lowering," he insists.

The Lipid Wars

U.S. NEWS & WORLD REPORT, 3/15/4

BY Avery Caomarow

How low can you go? How low should you go? Suddenly heart research has become a limbo contest, and the question is how low people with heart risk should push the level of LDL, the blood lipid commonly known as "bad" cholesterol. Two powerful studies presented last week at the annual science meeting of the American College of Cardiology shredded the prevailing wisdom, that for people with heart disease it's enough to push their LDL blood level below 100 milligrams per deciliter. The impact in doctors' offices everywhere will be stunning.

People with heart disease or at high risk for it, diabetics, and the obese are among those taking cholesterol-lowering statin drugs who can expect their doctors to bump up their dose or move them to a more muscular statin. Some physicians already have made the move. "I think there will be substantial changes in just a few months," says Lee Green, a family practitioner in Ann Arbor, Mich., whose high-risk patients have found their Lipitor (news - web sites) dose suddenly doubled. But no one yet can answer the question: Is there a threshold that might be risky to cross?

The two headline-grabbing studies, tagged PROVE-IT and ALLIANCE, squared off Lipitor, a potent statin and also the world's best-selling prescription drug, against Pravachol--a weaker statin but a long-established standard choice for safely reducing LDL, or low-density lipoprotein-- or the physician's choice of statin. The PROVE-IT study--principally funded by Bristol-Myers Squibb, which markets Pravachol--looked at more than 4,000 patients hospitalized because of heart attack or the severe and uncontrolled chest pain called unstable angina. Upon discharge, half were treated aggressively with 80 milligrams a day of Lipitor, while the other half got 40 milligrams of the weaker Pravachol.

The PROVE-IT acronym was deliberate. It was what researchers call a "noninferiority trial." In essence, that means Bristol-Myers hoped and expected the trial would demonstrate that Lipitor, although it is more potent and was being used at the highest dose, would not beat out Pravachol in effectiveness over a two-year period. Given Lipitor's potency and the high dose, that may seem unlikely. Not so, says cardiologist Christopher Cannon of Brigham and Women's Hospital in Boston, PROVE-IT's lead researcher: "It's actually very hard to be better than a standard effective therapy." But some cardiology researchers felt the study was stacked by limiting the follow-up to two years, because it usually takes at least that long for patients on different drugs to start showing meaningful differences.

Short but sweet. To the surprise of many, including scientists at Bristol-Myers Squibb, PROVE-IT proved that sometimes two years is long enough. The risk of a second heart attack or comparable event in the Lipitor group was 16 percent lower than in the Pravachol group, and differences between the two groups began to appear as early as 30 days. The study, which will be published in an upcoming issue of the New England Journal of Medicine (news - web sites), was released early for the heart meeting.

The results meshed nicely with the results of a trial called REVERSAL. Using ultrasound, Steven Nissen of the Cleveland Clinic showed that the fatty plaque that builds up inside the walls of the coronary arteries of people at risk for heart disease stopped accumulating in patients given Lipitor. In many of them, the fatty deposits actually shrank. In the patients who got Pravachol, the rate of accumulation slowed, but the effects of Lipitor were clearly superior. In short, all the evidence seemed to be pointing toward an aggressive statin attack. What this means for the average person with elevated cholesterol is less clear.

Meanwhile the five-year ALLIANCE study, funded by Pfizer, was conducted on heart patients being treated by primary-care doctors rather than in a more rarefied academic setting. "What made this study different was that it was a real-world trial," says Donald Hunninghake, the principal investigator and a professor of medicine and pharmacology at the University of Minnesota. That made the results especially impressive to physicians. The intent was to get LDL levels to 80 or below. There was an overall reduction in heart problems of 17 percent in aggressively treated Lipitor patients compared with a second group of patients whose physicians were free to use the statin of their choice. The risk for nonfatal heart attacks was reduced by 47 percent.

No one knows why dialing up the dosage and using Lipitor had the protective effect shown in these studies. Nissen has long argued, however, that the answer goes beyond the idea of lowering LDL levels. "The PROVE-IT people have been pitching the idea that it's the LDL, stupid. Well, it's not," he says. He thinks that inflammation in the walls of the coronary arteries is behind many heart events and that Lipitor has a stronger anti-inflammatory effect than Pravachol does. For evidence, he notes that in the PROVE-IT patients Lipitor was much more effective than Pravachol at lowering the level of C-reactive protein, which seems to be an indicator of inflammation. "This is not just about cholesterol lowering," he insists.

Most cardiologists asked to comment on these studies agreed: The important message is that most people at risk for heart disease aren't being treated aggressively enough. Cannon estimates that patients are getting about half the dose they require, partly because many doctors have traditionally been cautious with statins. They tend to start at a low dose and gradually move to a higher dose one step at a time. "It doesn't work," says Cannon, who now advocates starting high, using doses shown in trials to be effective.

New cholesterol guidelines will inevitably be issued within two or three years. Hunninghake thinks the LDL target could be as low as 70, rather than today's standard of 100. For people with a history or serious risk of heart disease, he says, "there's no doubt that the lower you get the LDL, the better you're going to be."

Magic number? What is that magic LDL level, and is it possible that it might be risky to dip below it? "Part of the reason for doing big trials is to find out whether pushing LDL way down, say below 50, might be dangerous," says John LaRosa, who is involved in the design and execution of another Lipitor trial as well as serving as president of SUNY Downstate Medical Center in Brooklyn, N.Y. "A decade ago, there was a lot of fussing about lowering cholesterol too far--that it caused stroke and traumatic death." The evidence was limited, he says, but the issue will surely resurface. He observes that the LDL level in umbilical cord blood is about 35, "so maybe that's the natural level." In many trials, investigators are alerted when a patient's LDL falls below a certain point, often 25. It's more a heads-up than an alarm, however. "I don't think we've established any basis for believing there's an LDL too low to treat to," says Nissen. "I've had patients with LDLs of 20, and they had no problem."

It may be that ultra low LDL is safe--but how about the safety of the high-dose statins themselves? No one wants another Baycol. That statin was removed from the market in 2001 following 31 deaths in this country from what's called rhabdomyolysis, a condition in which the muscles dissolve and the kidneys may shut down. Guidelines issued by the American College of Cardiology (ACC) and the American Heart Association (news - web sites) (AHA) in the wake of the withdrawal specified that statin doses should be no higher than needed in order to meet the target LDL goals, and none of those goals are below 100 mg/dL.

There isn't much question that all statins can cause joint soreness and muscle pain, sometimes worse, in some people. But as is true of such side effects in general, establishing cause and effect can be difficult. Patients in clinical trials report muscle aches and joint pain at about the same rate whether they are in a statin-taking group or a placebo group. Some problems seem to occur more often at higher doses; others are absent in study patients taking high doses but reported for low doses. The general advice for patients is to listen to your body and tell your physician if something feels strange or wrong. You may need a lower dose or a different statin. And while there has never been a reported case of liver failure caused by statin use, liver enzymes need to be checked regularly.

The newest statin, Crestor, is extremely effective at lowering LDL. But it was approved last year only after AstraZeneca, its marketer, took an 80-mg dose off the table because of the Food and Drug Administration (news - web sites)'s concerns about possible kidney damage. Last September, Group Health Cooperative, a large health maintenance organization based in Seattle, decided not to include Crestor in its coverage. "We lacked evidence that it reduced cardiovascular disease, we lacked evidence of long-term safety, and we had three other statins that were cost effective and we knew quite a bit about," says Jim Carlson, director of clinical pharmacy services.

Unique? Earlier this month, Public Citizen Health Research Group, a consumer organization in Washington, D.C., petitioned the FDA to withdraw Crestor from the market. The petition cited the death of one American woman and more than 20 reports in the United States, Canada, and the United Kingdom of patients who experienced severe muscle breakdown, kidney damage or failure, or abnormal bleeding. "Crestor is uniquely dangerous," says Sidney Wolfe, director of the group. "It never should have been approved at all." AstraZeneca calls the claims "misleading, irresponsible, and needlessly alarming to patients." The FDA has not responded to the petition.

In the real world, a drug, no matter how good, can't work if patients don't get it--or if they get it but don't take it. Both happen frequently. Studies show, for example, that when patients hospitalized because of a heart attack or uncontrolled angina are put quickly on a statin and kept on it when they are discharged, the possibility that they will return because of another episode is reduced significantly. Accordingly, ACC/AHA guidelines published in October 2002 call for hospitals to start such patients, if their LDL level is high, on a statin within 24 to 96 hours.

More than 1 in 4 hospitals don't comply, says Eric Peterson, a cardiologist at Duke Clinical Research Institute in Raleigh, N.C. Peterson surveyed 430 hospitals for compliance with the guidelines on statins and other medications, such as aspirin and beta blockers. His findings, released at last week's heart meeting, show that 26 percent of the hospitals overall did not comply with the statin guidelines. The rate ranged from an average of 19 percent at the most compliant hospitals to 35 percent at the worst performers.

 Peterson and his fellow analysts then calculated the consequences. "If all hospitals followed the aspirin guidelines," says Peterson, "we figured about 1,000 lives a year would be saved. If 100 percent of hospitals followed the statin guidelines, the number of lives saved would be around 10,000 a year."

Even when statins are handed out and prescriptions written, many patients simply stop taking them. Conventional wisdom among doctors is that for drugs in general, the dropout rate by the end of the first year is 40 to 50 percent. A small survey released at the heart meeting supports that guesstimate.

University of Michigan researchers contacted 154 patients six months after they were discharged from the university's medical center following a heart attack or episode of unstable chest pain. They asked them whether they were still taking the four heart medications--an anticlotting drug, ACE inhibitor, beta-blocker, and statin--prescribed for them. About half said they were having trouble with the dosage or timing of at least one drug--nearly half were struggling with the statin--and about 10 percent of the patients had completely stopped taking at least one of the drugs. Cost wasn't the reason. The main factors, the patients reported, were that they forgot or were careless.

Some researchers believe that the results of PROVE-IT and ALLIANCE, besides demonstrating that aggressive statin treatment reduces risk, might offer a serendipitous solution. "Starting at a higher dose is likely to make people more compliant," says LaRosa. Patients on a higher dose will get reinforcement by seeing their LDL number shrink faster and further. And by starting at and staying on a high dose, they won't be inconvenienced by trekking to the pharmacy every time they get bumped up another dose.

HEALTHY PAYOFF

In the PROVE-IT study, patients on a daily dose of 80 milligrams of Lipitor had a much lower rate of heart events after two years than patients who took 40 milligrams of Pravachol.  28% lower for deaths from all causes; 29% lower for unstable angina needing hospital stay; 30% lower for deaths from coronary heart disease; 13% lower for sudden heart attacks

Source: New England Journal of Medicine

Second article

Meet the cholesterol busters

BY BERNADINE HEALY, M.D., March 15, 2004

The killer beast of heart disease is something now called acute coronary syndrome. It still eludes us, robbing more than 200,000 Americans of their lives each year. News out of Boston last week suggests that intensive treatment with one of the cholesterol-busting drugs called statins offers the best defense against this culprit.

This syndrome is not a pretty sight. Over many years, the smooth pearly linings of coronary arteries are transformed by expanding mounds of fatty plaques filled with gruel of scar, fat, calcium, and white blood cells. The coronary crisis occurs when suddenly--and still inexplicably--this plaque (technically known as atheroma) bursts like a hot pustule. With that volcanic eruption, the atheroma's inner debris oozes out into the vessel, triggering a cascade of blood clotting in the wounded vessel. This clotting in turn starts to choke off the vessel's blood flow, and the part of the heart that has been nourished by the artery struggles for oxygen. At that point, the patient is stricken with intense and persistent chest pain, which often becomes a full-blown heart attack.

OK, enough of Cardiology 101. But these critical coronary events explain the flurry of excitement over heavy-duty statin treatment for coronary-prone patients. In these patients, treatment with the more potent statin Lipitor (news - web sites) (80 mg of atorvastatin a day), compared with a standard 40 mg pill of another highly effective statin, Pravachol (pravastatin), brought more dramatic reduction in the level of LDL, or "bad" cholesterol, with an associated lifesaving heart benefit evident within a month. These findings came on the heels of an equally stunning report from Cleveland that the same dose of Lipitor halts the progression of atheromas and in some cases appears to shrink them, also in a matter of weeks. It does not usually work out that more of a good thing is better, but that's just what seems to be happening here.

What is especially intriguing is that intense statin therapy may be doing more than cutting bad cholesterol levels in half. It may in fact be changing the very structure of the plaque--converting it to a more stable form that is less likely to rupture. We know statins lower cholesterol, but it now appears they also can restore healthy function to cells lining the artery wall. There are many theoretical explanations for how statins might stabilize plaque, including reduction of inflammation. Statins consistently reduce the levels of a key marker of the body's inflammatory response. Whatever the mechanism, the bottom line is a previously unrecognized benefit for heart patients.

Side effects? Does all this good news mean that everyone at risk for coronary artery disease should be started on intensive statin therapy? In my mind, the answer is no. These results apply to the highest of all coronary risk groups--those who have experienced an acute coronary artery syndrome such as a heart attack. For most of these patients, the benefits of intensive treatment seem to outweigh increased side effects. But side effects are inevitable. As a general caveat, drug toxicity is almost always dose related, and side effects usually increase in direct proportion to increases in the dose of the drug. This was the case for liver toxicity for those on the higher dose of Lipitor. The rate is low at 3.3 percent, but that's three times as high as expected.

For most of the 11 million Americans who take cholesterol-reducing statins, the goal is to prevent both the development and the progression of coronary artery disease. We try this with dietary changes first, but when that doesn't work, statins can help many people get their LDL below 100 mg per deciliter, the commonly accepted guideline. In that context the statins most commonly used in the United States--Lipitor, Pravachol, Zocor (simvastatin), and Lescol (fluvastatin)--have all proved to be wonder drugs of a sort, reducing coronary risk by as much as 30 percent and mortality by 20 percent.

The rule of thumb for statin choice for most patients is still the lowest possible dose to get your cholesterol into the desired range. With a doctor's supervision and a heart-healthy diet, as little as 5 mg can sometimes do the trick. For others, who are at particularly high risk for heart attack and who need drastic cholesterol reduction, as much as 80 mg may well be needed. These drugs should be periodically reviewed and adjusted to you and your lifestyle. That medicine bottle has your name on it for a good reason.