Doctor Urges Caution in Interpreting New Findings on Cholesterol Drug
Inexpensive blood test identifies people with a normal cholesterol at risk for heart attack, stroke – and a statin medicine may save lives and change preventive medicine
November 10, 2008Is your grocery store among America’s healthiest grocery stores?
November 12, 2008On March 31, 2008, pharmaceutical giant AstraZeneca trumpeted the early closing of its so-called JUIPITER trial of a cholesterol-lowering drug (statin), Crestor. The results after only two years yielded “unequivocal evidence” of the drug’s effectiveness, the trial concluded, and the company argued that it could not be withheld from anyone who was well and had normal cholesterol levels but had an elevation in another normal blood constituent, the C-reactive protein (CRP). But, what’s the “other side” of this story?
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Here’s an interesting opinion, by Norin M. Hadler, M.D., that I thought you’d enjoy. It was posted at ABC News.
Dr. Nortin Hadler is professor of medicine and microbiology/immunology at the University of North Carolina at Chapel Hill, and an attending rheumatologist at University of North Carolina Hospitals. He is the author of Worried Sick: A Prescription for Health in an Overtreated America and The Last Well Person.
I am the skeptical physician who is unwilling to let anyone test my cholesterol until I see unequivocal data that taking a statin yields meaningful benefit for me. Now AstraZeneca wants me to get my CRP measured so that I can swallow Crestor if it’s elevated.
On Nov. 9, 2008, the results of JUPITER were published in the online edition of the New England Journal of Medicine.
I knew there was a devil in the details. Let me flush it out for you.
AstraZeneca invested a great deal in this Herculean drug trial. They contracted with physicians in over 1,300 centers in 26 countries to recruit subjects. Some 90,000 were screened and nearly 18,000 enrolled.
At each center, half the recruits were randomly assigned to swallow a placebo pill, the other half Crestor. The intent was to monitor this army of volunteers for five years to see if the groups differed in their incidence of any of the following: heart attack, stroke, hospitalization for unstable angina or for surgery on their coronary arteries and death from cardiovascular causes.
JUPITER, as is true for all modern trials, had an oversight committee charged with breaking the code periodically to see if the volunteers on Crestor were fairing better or worse than the volunteers on the placebo. The JUPITER oversight committee comprised luminaries in the world of cardiology who, like nearly all the principal JUPITER trial investigators, had declared financial involvements with the industry that serves the cardiovascular enterprise, many with AstraZeneca.
After 1.9 years, the oversight committee sounded the alarm when they noted a highly statistically significant 56 percent reduction in the incidence of these feared outcomes. The trial was terminated; AstraZeneca trumpeted the benefit of Crestor and stockholders took notice.
A reduction of 56 percent is hard to ignore — at first blush. It conjures up an image of marshalling 100 soldiers armed with Crestor and 100 not so armed to assault the cardiovascular monster for two years, at the end of which 56 of the Crestor soldiers are the only ones left standing.
If that were true, I’d have my CRP tested today. But that’s not even close to truth.
At the end of two years, about 2 percent of study participants suffered a cardiovascular event. On Crestor, 1.6 percent suffered one of the cardiovascular events, whereas it was 2.8 percent of those not afforded Crestor — a difference of 1.2 percent.
However, not all these people were in the trial all of the first two years; they entered at different times reflecting the vagaries of recruitment. A more accurate reflection that takes this into account is to calculate for every 100 how many would have suffered one of the cardiovascular outcomes in a year in the trial. This event rate for any of the events (the “composite outcome”) is 0.77 on Crestor and 1.36 without Crestor.
That’s the 56 percent reduction that is being trumpeted. That means I’d have to treat a hundred or more people with Crestor for a year to spare one of them a cardiovascular event that they would not have otherwise had. I’d have to treat several hundred for a year to spare one a heart attack, and perhaps hundreds more to spare one a stroke. I am unwilling to even suggest a life-saving benefit.
So the reduction of 56 percent may be hard to ignore, but it calls for reflection rather than prescribing zeal. It is a reduction in a very small outcome to an even smaller outcome. Consider these two questions:
Are you convinced this small effect is real, that it will reproduce if one were to repeat the JUPITER trial?
I am not. I am reflexively skeptical of effects of this magnitude. My main reason relates to the nature of the randomized controlled trials we rely on for evidence. There are many factors vying to seal a well person’s cardiovascular fate.
For example, there are the so-called cardiovascular risk factors such obesity and tobacco abuse. By assigning volunteers randomly to Crestor or placebo, one hopes that the number of smokers and obese folks are equal in the two groups.
When the JUPITER investigators checked, indeed such measurable risk factors were distributed 50-50. One has to have faith that the factors that cannot be safely measured (such as the degree to which the blood vessels are diseased) also distribute 50-50. And one has to have faith that the factors that JUPITER was designed to ignore distribute 50-50.
Socioeconomic status, job security, education level are even more important risk factors that are independent of those measured and likely to vary widely across the research sites in these 26 countries. Slight imbalances between the Crestor and placebo groups could result in effects of the magnitude touted by JUPITER.
I never leap to act on the basis of such small effects. It’s why this year if you feed your family margarine, you’re not a caring person and last year it was butter that was bad for you.
If you’re convinced these small effects are real, are they meaningful to you?
Are you willing to swallow Crestor every day for two years in the hopes you’re the one in hundreds who just might be spared a non-fatal heart attack? Does it bother you that more of the volunteers on Crestor were diagnosed with diabetes?
This possible association aside, there is nothing to suggest that the volunteers for JUPITER were harmed in the two years. But that does not mean the drug is risk-free. Does it bother you that the occasional person on Crestor develops a muscle disease, or that some have liver or kidney irritation?
I am not tormented by such uncertainties as I doubt the small effects are real and therefore have no interest in taking Crestor. You and your prescribing physician should take pause, at the very least.
Small Effect, Big Benefit? Debate Continues
However, the JUPITER investigators and AstraZeneca do not share my concerns. Rather they take refuge in several of the tenets of contemporary small-effect epidemiology. They believe that these small effects are real.
Furthermore, they believe that the small effects recognized in the first two years are likely to prove cumulative and therefore grow as the years pass. It’s this belief that triggered the halting of the trial.
And finally they believe that the small likelihood of a good effect for an individual translates into a major public health benefit; benefiting one in a hundred means benefiting 1,000 in every million.
Therein lays a heated academic debate and an important philosophical conundrum. As for me, I won’t let you check my CRP either.
Dr. Nortin Hadler is professor of medicine and microbiology/immunology at the University of North Carolina at Chapel Hill, and an attending rheumatologist at University of North Carolina Hospitals. He is the author of Worried Sick: A Prescription for Health in an Overtreated America and The Last Well Person.
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Facts Believed to be Associated With All Statin Medications:
Statins are a class of medications specifically prescribed to lower LDL- one of five lipid parameters of a person’s lipid profile. There are 6 available statins to choose- with three that are combination drugs that have a statin as a component of these medications. There are other classes of medications for lipid management, such as bile acid sequestrants and nicotinic acid, which is known as niacin. Yet the side effect profile is more unfavorable of these classes of medications compared with the statin class.
One’s cholesterol level is primarily due to how they produce cholesterol in their liver, which is overall genetically determined. This level is also determined by one’s lifestyle and diet as well. If a person has too much cholesterol in their blood, it can lead to hardening and narrowing of their arteries, which can lead to cardiovascular events.
To measure one’s cholesterol, a blood test called a lipid profile is obtained from a person after they have fasted for at least 12 hours. The test should also be performed only if the person is free of any acute illness, as this may affect true lipid measures. If the results prove to be abnormal, lipid lowering therapy may be initiated, according to the discretion of the person’s health care provider. This therapy usually involves a statin medication.
Adverse events associated with the statin class of pharmaceuticals are thought to occur more often than they are reported- with high doses of statins prescribed to patients in particular at times that may not be necessary to control their dyslipidemia based on their lipid profile. However, since this class of drugs has existed for use for over 20 years, statins are considered safe and effective for enhancing the clearance of LDL noted to be elevated in the lipid profiles of patients. Also, they have proven to reduce cardiovascular mortality with one who is treated with a statin that has dyslipidemia. In addition to lowering LDL by up to 60 percent- depending on the statin- this class of drugs also raises HDL and lowers triglycerides, which are two other lipid parameters. Both of these effects from taking a statin drug are beneficial for the patient on a statin drug for lipid management.
Statin therapy is also recommended for those patients who have a greater than twenty percent risk of developing cardiovascular disease, or those patients that have clinical evidence of this disease
Additionally, there appears to be no comparable reduction in cardiovascular morbidity or mortality, as well as a difference in the increase of one’s lifespan, if one is on any particular statin medication for their lipid management over another, others have concluded. So caution should perhaps be considered if one chooses to prescribe a statin for a patient if they are absent of, or have only mild dyslipidemia to a significant degree. Furthermore, research should be done by the health care provider if they are under the belief that one statin medication provides a greater cardiovascular benefit over another. In other words, the health care provider should be assured that any choice of statin therapy for their patients is considered reasonable and necessary if the LDL in their patients need to be reduced, and the statin selection should be determined by the results that have been shown with a particular statin.
Abstract etiologies for those who choose to prescribe statin drugs on occasion for reasons not indicated by these statin drugs- such as reducing CRP levels, or for Alzheimer’s treatment, or anything else not involved with LDL reduction with prevention if not delaying the progression of cardiovascular disease, should be thoroughly evaluated by the health care provider. As statin therapy for such patients may not be considered appropriate prophylaxis at this point for any patient who does not have the indications for which statins are approved for and treat with patients. All other benefits that appear to have favorable effects in such areas are speculative at this point due to minimal research in other areas aside from lipid management, and require further research for these disease states aside from dyslipidemia, according to many.
Statins as a particular class of drugs that seem to in fact decrease the risk of cardiovascular events significantly, it has been proven. Statins also decrease thrombus formation as well as modulate inflammatory responses (CRP) as additional benefits of the medication. For those patients with dyslipidemia who are placed on a statin, the effects of that statin on reducing a patient’s LDL level can be measured after about five weeks of therapy on a particular statin drug.
Liver Function blood tests are recommended for those patients on continued statin therapy, and most are chronically taking statins for the rest of their lives to manage their lipid profile in regards to maintaining the suitable LDL level for a particular patient presently. Patients should be made aware of potential additional side effects as well, such as muscular issues.
Yet some have said that about half of all strokes and heart attacks that do occur are not because of increased cholesterol levels of these patients. Others believe that it is oxidized cholesterol that causes vulnerable plaques to form on coronary arterial walls, which is the catalyst for a heart attack, and that there is no medicinal treatment for the formation or stabilization of these plaques to prevent heart attacks or strokes. Others who promote and support statin medicinal therapy claim that these drugs, do, in fact, stabilize these plaques, and therefore are beneficial.
As stated previously, in regards to other uses of statins besides just primarily LDL reduction, there is some evidence to suggest that statins have other benefits besides lowering LDL. These other disease states include aside from what has been stated already, those patients with dementia or Parkinson’s disease, as well as those patients who may have certain types of cancer or even cataracts. Yet again, these other roles for statin therapy have only been minimally explored, comparatively speaking. Because of the limited evidence regarding additional benefits of statin medications, the drug should again be prescribed for those with dyslipidemia only at this time involving elevated LDL levels as detected in the patient’s bloodstream.
Yet overall, the existing cholesterol lowering recommendations or guidelines should possibly be re-evaluated, as they may be over-exaggerated upon tacit suggestions from the makers of statins to those who create these current lipid lowering guidelines. This is notable if one chooses to compare these cholesterol guidelines with others in the past. The cholesterol guidelines that exist now are considered by many health care providers and experts to be rather unreasonable, unnecessary, and possibly detrimental to a patient’s health, according to others. Yet statins are beneficial medications for those many people that exist with elevated LDL levels that can cause cardiovascular events to occur because of this abnormality. What that ideal LDL level is may have yet to be empirically determined.
Finally, a focus on children and their lifestyles should be amplified so their arteries do not become those of one who is middle-aged, and this may prevent them from being candidates for statin therapy now and in the future, regarding the high cholesterol issue. Treating children with a statin drug for dyslipidemia is controversial presently.
Dietary management should be the first consideration in regards to correcting lipid dysfunctions that may exist in patients,
Dan Abshear
Interesting Article. Thanks!