CLEVELAND, OH (Ivanhoe Newswire) - A landmark study has changed how some cardiologists view a popular drug used to lower bad cholesterol. Some are now prescribing it to patients with normal cholesterol, but some doctors think it might do more harm than good.
Portia Tibbs is taking steps to help control her cholesterol. She is also taking cholesterol lowering statins just like millions of other people.
"I don't really like taking medicine, but I have to," Portia Tibbs told Ivanhoe.
Now because of the so-called Jupiter study many doctors are urging some people with normal cholesterol to start taking them too. Jupiter tested more than 15,000 people who had normal LDL levels and high levels of an inflammation biomarker.
" For the group taking statins there was between a 40 and 50 % reduction in the risk of the things we really care about, like death, stroke, heart attack," Steven E. Nissen, MD, Fellow of the American College of Cardiology and Chairman of the Department of Cardiovascular Medicine at Cleveland Clinic, explained.
After less than two years the five year study was cut short because of those findings. Cleveland clinic cardiologist Steven Nissen said the study changed the way he practices medicine. He tells us before the results, he and a lot of other doctors occasionally did blood tests for inflammation.
"Well, we're making that measurement more often now," Dr. Nissen said.
Doctors may use the results to prescribe statins to prevent heart disease. But, University of California - San Diego, Dr. Beatrice Golomb said it is not known with longer term use and in real world users, whether the benefits outweigh the real risks.
"It's portrayed as being so fantastically safe it should be put in the water supply. The real world use this drug causes problems not infrequently," Beatrice Alexandra Golomb, M.D., Ph.D., an, associate professor of medicine at the University of California - San Diego School of Medicine, said.
Golomb said while some people benefit from statins others have reported symptoms similar to Alzheimer's. Muscle weakness, nerve damage, and cognitive problems have also been issues.
"There was evidence of a significant increase in incident diabetes," Dr.Golomb said about people in the Jupiter study.
She wants to see more studies on the drug's long term effects on patients with inflammation, but Dr. Nissen still believes in most of those cases statins work.
"It's taken more to convince others and I respect people who are cautious," Dr.Nissen said.
Dr.Golomb said she would like to see other, potentially safer, anti-inflammatory agents like low-dose aspirin tested to see if the effects are similar or even better than statins. As for people with normal cholesterol, other risk factors for heart disease inflammation blood tests are inexpensive and available at just about every hospital.
BACKGROUND: Cholesterol is a waxy substance that is found in the lipids of our blood. The body needs cholesterol to build healthy cells, however high amounts of bad cholesterol, low-density lipoprotein, LDL, can increase risk for heart disease. With high LDL cholesterol, fatty deposits may develop in the blood vessels. Eventually, these deposits can make it difficult for blood to flow through the arteries. This causes the heart to not get as much oxygen-rich blood as it needs, which increases the risk of a heart attack. Decreased blood flow to the brain can cause stroke. On the other hand, having high amounts of good cholesterol, high-density lipoprotein, HDL, is good because they act as cholesterol scavengers, picking up excess cholesterol in the blood and taking it to the liver where it is broken down. The higher the HDL, the lower the LDL. High cholesterol can be inherited, but is often preventable and treatable. (www.mayoclinic.com)
RISK FACTORS: There are certain risk factors that can increase a person's chance for heart disease if they already have high cholesterol. Smoking cigarettes damages the walls of blood vessels, making them more likely to accumulate fatty deposits. It can also lower levels of good cholesterol. Obesity, a BMI higher than 30, can put a person at a higher risk for high cholesterol. A poor diet, such as eating foods that are high in cholesterol, such as red meat and full-fat dairy products; eating saturated fats found in animal products; and trans fats found in some commercially baked cookies and crackers. High blood pressure, lack of exercise and a family history of heart disease are also risk factors. (www.mayoclinic.com)
TREATMENT: Statins are prescribed to patients with high cholesterol because it blocks a substance that the liver needs to produce cholesterol, causing the liver to remove cholesterol from the blood. Bile-acid-binding resins are used to prompt the liver to produce more bile acid with the cholesterol, an already naturally occurring process. (www.mayoclinic.com) The Jupiter Study tested a new treatment to give patients with normal cholesterol the drug Rosuvastatin, a medication typically given to patients with high cholesterol. The drug is meant to prevent patients with normal cholesterol levels from getting high cholesterol levels. (www.nejm.com ; www.ncbi.nlm.nih.gov)
APPLICATION: The study was randomized, double-blind, placebo-controlled and a multicenter trial. The study included 17,802 men and women. For the trial, men of 50 years of age or older and women 60 years of age or older, with no history of cardiovascular disease, and a low level of LDL cholesterol were eligible. Eligible subjects were randomly assigned to receive either 20 mg of rosuvastatin, or a matching placebo. At the 12-month visit, the rosuvastatin group, as compared with the placebo group had a 50 percent lower LDL cholesterol level. The results of the study showed that rosuvastatin reduced the risk of major cardiovascular events. However, it was reported that a small but significant increase in physician-reported diabetes with rosuvastatin did occur; this has also been reported in previous trials of pravastatin, simvastatin, and atorvastatin. (www.nejm)
Steven Nissen, M.D., Chairman of the Department of Cardiovascular Medicine at the Cleveland Clinic discusses the Jupiter Trial.
Why the Jupiter study?
Dr. Steven Nissen: We've known for many years how to treat patients with high cholesterol, especially those with high levels of the bad cholesterol or LDL. We could reduce the risk of death, stroke and heart attack by giving statin drugs. What the Jupiter investigators' asked is whether there's a group of people that don't have high cholesterol levels that actually benefit from the administration of the statin drugs -the very popular drugs like Zocor, Lipitor and Crestor that lower cholesterol. The question they asked is whether people who had normal levels of cholesterol, but evidence of inflammation in the body, whether they might benefit. We can measure inflammation with a blood test. It's a test known as high sensitivity C-reactive protein. It's a blood chemical that goes up when the body experiences inflammation. In the Jupiter Trial, they studied a very large group of people, more than 15,000 who had normal levels of cholesterol. Half of these people received a statin drug, in this case the drug Crestor. Half received a sugar pill called Placebo. They all had evidence of inflammation, a CRP level greater than two, which is the mid range for this marker.
The study was supposed to go for five years, and the medical community received a very big surprise because all studies are monitored by a safety board. The purpose of a safety board is that if the drug is either harmful or helpful, you don't want to keep people in a trial where they might be getting a sugar pill, if there's actually a benefit. Two years into a five year trial, the Data, Safety and Monitoring board said "stop." The evidence of benefit was so great that it was no longer ethical to give a sugar pill to these patients. That's obviously very surprising. What they found was that there was between a forty and fifty percent reduction in the risks of the things we really care about like death, stroke, heart attack, need for stenting or bypass surgery - the bad things that can happen to patients with coronary heart disease. The group that received the cholesterol lowering drug, who had evidence of inflammation, had as much or more benefit than we'd seen previously in people that had actually had elevated cholesterol levels. Does this say that the way we have thought about High Cholesterol has changed?
Dr. Steven Nissen: It does change thinking a lot, it says that the drugs that lower cholesterol probably work by multiple mechanisms. Certainly one of the things they do is to lower cholesterol levels. But, interestingly enough, in the Jupiter trial and in other studies, the statin drugs also lowered the levels of this marker of inflammation. They lowered the levels of C-reactive protein, so they're anti-inflammatory. Everybody kind of understands what inflammation is, if you burn your hand and it gets red, swollen, and inflamed that's inflammation. We now understand that the inflammation exists inside the coronary arteries in the heart. That inflammation is damaging, it causes plaques in the coronaries to fracture or rupture which is what causes a heart attack. If you settle down the inflammation with a statin drug you may reduce the risk that the plaque will rupture, cause a blood clot and thereby cause a heart attack. We are learning over time that statin drugs, taken over time by tens of millions of Americans, work in more complex ways than we ever thought. That complexity was really illuminated by the Jupiter trial. It seems like to not only lower the cholesterol level, it also stops inflammation in someone who does not have bad cholesterol levels anyway?
Dr. Steven Nissen: That's correct, one of the things that drive inflammation up is certainly cholesterol levels, but there are people that are biologically programmed to have more inflammation. We never know exactly why a drug works. While this is to some extent theorey, the test produced an answer that was so clearcut that the FDA subsequently awarded what's called a label claim. They told the makers of the drug you claim this benefit. We think the evidence is strong enough that this should be in the drug label, so it is. It was controversial, but I think for most mainstream cardiologists the principle is pretty clear. If you have elevated levels of inflammation, even if your cholesterol is normal, you may benefit from the administration of one of these cholesterol lowering drugs. What does this mean for these people, can they receive this medication even though they have good cholesterol levels, but there is inflammation?
Dr. Steven Nissen: In fact many of us have changed our practice to some extent on the basis of the Jupiter trial. Before the trial I was occasionally measuring CRP, the blood test that reflects inflammation. We are making that measurement more often now particularly in people that are a little bit older, maybe in their fifties, people who have other risk factors like high blood pressure. In fact in the study, the majority of the benefit occurred in people that had at least some risk factor for having a heart attack other than cholesterol. Maybe they were a smoker, or they had high blood pressure, or a family history. If you have a risk factor and you have high levels of CRP, those are the people where administration of a statin drug, in this case Rosuvastatin or Crestor, in a dose of 20 milligrams, dramatically reduced the risk of death, heart attack, stroke and the need for stenting or bypass surgery.
Could this also reduce the number of heart surgeries?
Dr. Steven Nissen: We know it's hard to extrapolate a clinical trial to the broader population. I'd be very cautious about whether patients could avoid heart surgery. Let me put it to you this way, the benefits were substantial, they were well-documented in the trial. They were convincing enough for the FDA and most of the mainstream medical community. How many heart attacks we can prevent, how many bypasses' we can prevent, is not so clear. Partly because we don't really know how many people out there have these elevated blood levels of CRP. Remember this is not a test done by everybody in every patient all the time. Over time as the test is used more frequently, we will learn more about how many people there are like this, normal cholesterol but high CRP who will benefit from the regiment that was used in the Jupiter trial. It seems amazing that something so simple that people who don't have high cholesterol could be dying because they're not on this medicine?
Dr. Steven Nissen: One of the wonderful things about science and medicine is that we always get these surprises. We find risks of drugs we didn't expect and we find benefits of drugs we didn't expect. The human body is incredibly complex. This was a very interesting piece of evidence and one single individual, one passionate physician Dr. Paul Ridker really pushed this concept forward, convinced the pharmaceutical industry to spend hundreds of millions of dollars to test this possibility. He hit an out-of-the-park homerun in finding that he could identify a group of people that could benefit. There are probably more surprises in store for us in medicine - this was a pleasant surprise. Are there more studies being done or has this set the standard?
Dr. Steven Nissen: I think right now the most interesting extension to this is the development of specific drugs that target inflammation. The same investigator who did the Jupiter trail is now trying or organize some studies not to use statins, not to use cholesterol lowering drugs, but to use drugs that are anti-inflammatory and have no effect at all on cholesterol to see if they can reduce the risk of heart attack, stroke and death. That will be very interesting because it will take this example to the next level. If we can develop entirely new drugs that might even work on top of the statin drugs to produce a further reduction in cholesterol. What would you advise patients to do if they don't have high cholesterol but have a family history of heart attacks or heart problems?
Dr. Steven Nissen: If you have risk factors, the big ones; diabetes, smoking, high blood pressure, family history and your cholesterol is fine, it might to reasonable to talk to your doctor about whether you should have your CRP level checked. If it comes back above two and the higher it is, the greater the risk. More than three you should discuss with your physician whether you would benefit from receiving a statin drug. We should use that test more frequently, but not everybody is. The best advocate for a patient is the patient themselves. Knowledge is power and I would advise people who have concerns to discuss with their doctor if a CRP test might make sense for them. Does the controversy involve the study itself or the test?
Dr. Steven Nissen: The controversy feeds into a couple of things. First of all a lot of people have difficulty with the concept of giving cholesterol lowering drugs to people with normal cholesterol and seem healthy. It's a lot easier when someone's had a heart attack, they come back in and you say look, we're going to give you this drug to prevent another heart attack. It's much harder to convince the medical community that people who look completely healthy are actually at an enough risk to warrant giving them a drug, a drug that they will probably take for the rest of their lives. Medicine never brings everybody along to the same conclusion simultaneously. The knowledge tends to trickle down slowly as this is and not everybody is ready to accept it. I think we're seeing more mainstream physicians who are thoughtful in adopting this strategy. Are there risk giving someone statins that do not have high cholesterol?
Dr. Steven Nissen: Sure. Every drug we give has risks. Fortunately statin drugs are very safe drugs. There is a very small risk of muscle injury. When used carefully and the patients and their physicians have a full understanding these risks are very, very rare. We give drugs whenever the benefits are much greater than the risks. It's easy with statin drugs, because the risks are quite small. The benefits can be substantial; the disease we're trying to prevent is catastrophic. If you have ever talked to anyone that's had a stroke or a heart attack, you know what I mean. So, what we're trying to prevent is a disorder which is very serious. The side effects and the adverse effects are rare and tend to be very limited. Benefit to risk ratio is very favorable. Did you find yourself buying in right away or were you skeptical?
Dr. Steven Nissen: I must tell you I was not skeptical in part because some of the previous work that had been done suggested that this strategy would work. It didn't take a lot to convince me, it's taken more to convince others. I respect people who are cautious. We don't want to be throwing drugs at every patient without good reason. We're not going to give statins to every patient or put statins in the water supply, but for selected patients carefully chosen the benefits are very substantial. Could it be so beneficial that is could be given to many people as a preventive medicine like a vaccine given to a three year old?
Dr. Steven Nissen: I wouldn't do that, there are people who have advocated wider spread usage. It has to be studied for me to buy into it. We would have to do a study in low risk patients. I think you'd find there wasn't good evidence that benefits would outway the risk. The people in Jupiter with high CRP levels had a lot of risk. It makes it worth it, but given the cost and the potential side effects treating everybody is not a good solution. Treating the right patients is what we try to do in medicine. That's what the Jupiter trial has helped us to figure out. Can CRP testing be done at all hospitals?
Dr. Steven Nissen: It's done in every hospital, every clinic in America. The test itself is very inexpensive, as little as $8.00, certainly no more than $25.00. Given the gravity of the disease, the seriousness of the disease we're trying to prevent, that's a small price to pay. The cholesterol test may not be all you need because if you don't have high cholesterol you may have other risk factors?
Dr. Steven Nissen: Sometimes it's easy, a patient has a high cholesterol level you don't need to worry about CRP, and you're going to treat them anyway. But, the person who is on the boarder of whether you want to treat them of not, but you are worried about them, this gives you added insight. Someone who goes in for a cholesterol test could only be getting half the information they need?
Dr. Steven Nissen: Yes. I think you can certainly make the case that having a cholesterol test is not the complete picture. I would worry about someone that had normal cholesterol and say a CRP level of four or five. That person is likely to be at a very substantial risk. I would rather know that than not.
FOR MORE INFORMATION, PLEASE CONTACT:
Steven E. Nissen MD FACC Department of Cardiovascular Medicine Cleveland Clinic firstname.lastname@example.org
Tuesday, December 10 2013 5:15 PM EST2013-12-10 22:15:07 GMT
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