Lipid-lowering powerhouses wage war on cholesterol
A pale white, blood-tinged gel to the eye, this seemingly innocuous glob is almost effortlessly transported through the body to its arterial residence. Once there, it amplifies with each double bacon cheeseburger, ultimately leading to an ischemic nightmare by cluttering up vulnerable vessels and denying vital organs oxygenated blood.
One may not think to classify elevated cholesterol (see Table 1) in the
same disastrous category as cancer
or AIDS--but why not? Hyperlipidemia--a known risk factor for coronary heart disease (CHD), a leading cause of morbidity and mortality in the United States--truly is the root of all evil. Hundreds of thousands of victims succumb annually to myocardial infarctions, strokes, and other catastrophic sequelae of arteries suffocated by fatty plaques.
Front-line lipid busters
The pharmaceutical army against the insidious gunk appears to be headed by HMG-CoA reductase inhibitors (see Table 2), a class that acts by inhibiting an enzyme crucial to the early stage of cholesterol biosynthesis. And the statins' current high rank, as indicated by their placement on fast-moving pharmacy shelves, certainly seems logical. These agents have been shown in an abundance trials to provide a multitude of risk reductions.
Barry Bleidt, Ph.D., Pharm.D., R.Ph., clinical coordinator-director of experiential programs, Hampton University, School of Pharmacy, equated the use of statins in hyperlipidemia to the use of beta-blockers in hypertension: "These classes are preferred to the others because they have been proven to reduce cardiovascular morbidity and mortality and can therefore be used as preventive medicine." And the statins' currently known mechanism of action may not be totally responsible for their acquired fame.
An article published recently in the Journal of the American Medical Association suggested that the statins' ability to lower LDL cholesterol is only weakly associated with their beneficial effects on cardiovascular events. According to the authors, there may be involvement of nonlipid mechanisms that modify endothelial function, inflammatory responses, plaque stability, and thrombus formation. These potential properties of the statins may help to explain their significant risk reductions, demonstrated in several clinical studies.
The landmark Scandinavian Simvastatin Survival Study (4S) is one of the earliest and most memorable statin prevention trials, confirming 50 years of suspicion by many researchers that cholesterol is the culprit behind deaths from heart disease.
The trial, which evaluated more than 4,000 patients for more than five years, found that Zocor (simvastatin, Merck) substantially improved survival and outcome in patients with CHD and high cholesterol. The drug, which lowered LDL levels by 35%, was shown to reduce death from heart disease by 42%, and it also reduced the risk of myocardial infarction and surgical procedures. In addition, simvastatin reduced the overall risk of mortality and coronary death by 30% and 42%, respectively, in patients with a history of cardiac complications and elevated cholesterol levels (213 mg/dl to 309 mg/dl). Based on these results, simvastatin was officially cleared by the Food & Drug Administration for reduction in the risk of MIs and heart-related surgical procedures.
Pravachol (pravastatin, Bristol-Myers Squibb) has demonstrated similar benefits in diverse patient populations and expanded its indications to include cardiovascular risk reductions as well. The statin was shown in a large, well-controlled study to provide a 23% and 29% reduction in the risk of death and MI, respectively, in patients with mildly elevated cholesterol (155 mg/dl to 270 mg/dl) and a history of CHD. In addition, Pravastatin was shown in the Cholesterol and Recurrent Events (CARE) study to reduce the risk of recurrent coronary events in patients with average cholesterol levels (less then 240 mg/dl) and a history of CHD. Newcomers, such as Lipitor (atorvastatin, Parke-Davis) and Baycol (cerivistatin, Bayer), are expected to follow in the older statins' footsteps by demonstrating their risk-reducing powers in studies as well.
Besides capturing cardiologists' undivided attention, these studies raised the eyebrows of researchers studying the effects of statins on various conditions, such as stroke and vascular complications of diabetes. In a post hoc analysis of 4S, simvastatin was shown to reduce major coronary events, including MIs, by 55% in a subgroup of 202 patients afflicted with diabetes. These patients were able to reduce their total cholesterol, LDL levels, and triglycerides by 27%, 36%, and 11%, respectively. HDL levels rose by 7%.
These results have prompted the medical community to make cholesterol control a high priority in diabetic patients. "We often focus on glucose levels and forget that a high lipid level is the greatest factor for development of coronary artery disease," cautioned Ralph A. DeFronzo, M.D., professor of medicine and chief of the Diabetes Division at the University of Texas Health Science Center.
Maria Deutsch, R.Ph., M.S., C.D.E., former ambulatory care pharmacist, VA Medical Center, East Orange, N.J., noted that hyperlipidemic diabetic patients at her outpatient cholesterol clinic were prescribed statins, as opposed to any other cholesterol-lowering agent, specifically because of their risk-reducing benefits. Deutsch is a now a drug information specialist at Medical Economics Co.
Another analysis of the 4S study, published in the American Journal of Cardiology, indicates that simvastatin provides a 28% reduction in the risk of stroke, transient ischemic attack (TIA), and other vascular events by slowing down or even reversing the clogging of arteries that leads to the ischemic events. Based on these results, simvastatin received clearance for use in reducing the risk of first stroke or TIA in patients with high cholesterol and CHD.
Pravastatin has also expanded its indication to include the aforementioned vascular risk reductions based on similar results from the CARE trial. In the study, the drug was shown to provide a 26% reduction in stroke or TIA in patients with normal cholesterol levels (total cholesterol less than 240 mg/dl; LDL cholesterol 101 mg/dl to 180 mg/dl) who have suffered an MI in the two years prior to enrollment and were already receiving aspirin.
Since the National Stroke Association believes that these findings show a direct correlation between lowering cholesterol and the prevention of stroke, the agency has recommended that certain measures, which include diet, exercise, and medication, be used to lower high cholesterol levels in order to reduce the risk of stroke.
Without a past
Thus far, data have documented the benefits of statins in patients with a cardiovascular history. But what about preventing the damage in patients without a past history. The idea was actually taken to heart in one recent trial. The results of the Air Force/Texas Coronary Atherosclerosis Prevention study (AFCAPS/TEX/CAPS), published in the May 27 issue of the Journal of the American Medical Association (JAMA), found that treatment with lovastatin led to a 37% reduction in the risk of first acute major coronary events--defined as fatal or nonfatal MI, unstable angina, or sudden cardiac death--in patients with no prior history, signs, or symptoms of heart disease. All participants had average levels of total cholesterol and LDL cholesterol but below average HDL levels.
The study, which is distinct in the fact that it involved healthy patients who were not considered candidates for treatment before, has led researcher Antonio M. Gotto Jr., M.D., of Cornell University Medical College, to caution: "Even if your LDL levels are considered average, you still may be at risk for a heart attack if your HDL levels are too low." Bleidt noted that patients with very low HDL levels face similar cardiovascular risks as those with high cholesterol levels.
The study's researchers believe that treating a broader patient population--individuals who are not sick but rather are at an increased risk due to factors such as low HDL levels--with statins is likely to bring about the greatest cumulative long-term benefit in the prevention of coronary heart disease. In essence, "don't just treat the numbers," treat the patient and his or her risk factors, "that's the art of medicine," declared Roger S. Blumenthal, M.D., director of the Ciccarone Center for the Prevention of Heart Disease, Johns Hopkins University.
So if patients have multiple risk factors, such as a history of diabetes, heart disease, and smoking, their target lipid levels should be lower than those of patients without risk factors, Blumenthal continued. His view is supported by current guidelines on the detection, evaluation, and treatment of high blood cholesterol, published by the National Institutes of Health (see Table 3). But are health professionals ready to pharmacologically treat patients who don't actually present with typically high lipid levels? The answer appears to be a cautious maybe. "I don't like using drugs if I don't have to, and these statins are not benign," said Bleidt. He takes a "wait and see more data" attitude with respect to this question.
Taking a similarly conservative view, Janice Bopp, R.Ph., of Mar-Main Pharmacy, feels that it would be premature to place a patient who is not hyperlipidemic on a statin--even if that individual has a cardiovascular history. She believes that patients should be monitored first.
Deutsch stated that "the aforementioned study is encouraging and might sway physicians to consider instituting a statin in patients who present with no cardiovascular history, average cholesterol levels, but below average HDL levels." But this decision also depends on the number of drugs these patients are taking and the potential interactions, she added.
But no matter who is given a statin or when, good old-fashioned diet (see Table 4) and exercise are always dispensed first. Bleidt feels that "patients have really moved away from lifestyle modifications, since that requires a lot more effort than popping a pill every night." That may be why Frederick Mayer, Pharm.D., M.P.H., president of Pharmacists Planning Service Inc., San Rafael, Calif., has been urging pharmacists for some time to counsel hyperlipidemic patients on nonpharmacologic ways to lower lipids. Deutsch stressed that patients at her clinic were always given a chance to improve lipid profiles through diet and exercise before receiving statin scripts. In Bopp's practice, "patients who do not present with a cardiovascular history are given six months to improve lipid profiles with lifestyle modifications before pharmacologic intervention is attempted."
After all, drugs should be a last resort. And "as glorified as the statins are, not everyone needs to be on one," said Mayer. Bleidt believes that the statins are fairly well tolerated, but again, "they are not benign." The class has been associated with rare biochemical abnormalities of the liver and skeletal muscle effects, including rhabdomyolysis and myalgia.
Liver function tests (LFTs) are essential with all statins. As a rule of thumb, patients with persistent serum transaminase values greater than three times the upper limit of normal are
discontinued from therapy. Deutsch acknowledged that some patients did experience significant increases in LFTs while on statins. "But because some of these patients were on multiple drugs, it was difficult to determine whether the statins or the other agents were causing the rise," she said. At Deutsch's clinic, statins were usually discontinued in patients with substantially increased LFTs, and doctors were hesitant about reinstituting therapy after values returned to baseline.
Blumenthal stated that the statins carry an "extremely low risk" of rhabdomyolysis, which occurs mainly in patients receiving multiple medications or an immunosuppressant, such as cyclosporine. Although he believes there are sufficient long-term safety data on statin therapy, he emphasized that patients must be regularly evaluated for possible dose reductions.
Dollars and sense
The issue of cost associated with statin therapy has been stirring up some turmoil among uninsured patients who must reach deep into their pockets each month for their refills. Managed care guardians will also be financially pressured by a growing number of statin scripts used in patients who don't exactly fit the profile of a typical hyperlipidemic individual on the verge of a second heart attack. "It's easy to see the cost-effectiveness of instituting a statin in a clearly hyperlipidemic patient who is at an absolute risk for a cardiovascular event," said Blumenthal. But he believes physicians will definitely be reluctant about handing statin scripts to everyone with mildly elevated cholesterol levels--especially if they don't have a cardiovascular history.
According to a commentary in JAMA, authored by Thomas A. Pearson, M.D., Ph.D., University of Rochester, School of Medicine, patients in the aforementioned AFCAPS/ TEX/CAPS study were treated at a cost of $1,075 to $1,766 per year--for a total cost of drugs of $1,420,500. Authors of the study concluded that five years of lovastatin therapy in 1,000 individuals would prevent 12 myocardial infarctions, seven presentations of unstable angina, and 17 revascularization procedures. An economic analysis of these data is expected to be performed by the authors. But, in the meantime, Pearson has indicated that statin intervention "in AFCAPS/TEX/ CAPS may be statistically significant but not cost-effective in such a low-risk group of patients."
So which patients should be treated--from a cost perspective? "A subgroup analysis of the recent lovastatin study may identify specific patient groups in whom statin therapy is highly cost effective on the basis of their risk factors," said Pearson. His other approach, used by the European Society of Cardiology, "advocates statin therapy in patients with elevated LDL levels and risk of a coronary event of 2% per year or greater, as based on a coronary risk score." Whatever the approach may be, "preventive medicine saves lives, and, in the end, it's surely worth the costs," declared Deutsch.
A compliance issue
Are patients adhering to their antihyperlipidemic regimens? A recent study, published in JAMA, found that patients treated for hyperlipidemia did not have their prescriptions filled for at least a third of the studied year. Researchers evaluated more than 7,000 patients older than 65 years of age who were enrolled in New Jersey's Medicaid and PAAD drug assistance programs. They found that an alarming 40% of Rxs were not filled annually, and, when rates were measured for five years following the study, only 52% of surviving patients who were initially prescribed antihyperlipidemics were still filling prescriptions. Interestingly, patients were more likely to fill statin scripts and considerably less likely to continue filling scripts for bile acid sequestrants.
These products and other nonstatin antihyperlipidemics (see Table 5), although still frequently prescribed, seem to be declin-
ing in popularity--apparently because of tolerability issues. Linda Garrelts, R.Ph., Jones Pharmacy, has seen a lot of problems with compliance in patients receiving nonstatin drugs, due to bothersome side effects.
Deutsch acknowledged that bile acid sequestrants--commonly used as initial therapy in hyperlipidemic patients with no cardiovascular history--caused patients to complain of gastro-intestinal side effects, such as gas and bloating. In addition, many patients didn't comply with the required multiple daily dosing and the inconvenient granule or powder forms that need to be mixed with water before use, she continued. As a result, physicians often switched patients to statins, which incidentally did not always produce the expected lipid-lowering results. "Patients felt they no longer needed to comply with dietary restrictions and exercise since they had this powerful drug on board, and, as a result, many gained weight and didn't notice very significant changes in cholesterol," said Deutsch.
Mayer advocates the use of niacins, which are significantly less expensive than other antihyperlipidemics, as a next step up if lifestyle modifications don't lower lipids. The B vitamin is known to raise HDL levels and lower total cholesterol, LDL levels, and lipoprotein a--a lipid particle associated with an increased risk of CHD. But niacin is no simple vitamin. In high doses, it's considered a drug--and very much acts like one. Besides producing the embarrassing side effect of flushing, the drug can also cause skin reactions, GI distress, glucose intolerance, hepatitis, and flare-ups of gout symptoms. In addition, the water-soluble vitamin is contraindicated in those with hepatic dysfunction, active peptic ulcers, severe hypotension, hemorrhaging, and arterial bleeding. Most niacin products are unfortunately sold over the counter and are classified as nutritional supplements with no antihyperlipidemic dose recommendations.
Last year, Niaspan (niacin extended-release, Kos Pharmaceuticals) was the first sustained-release (SR) formulation of the drug to be approved for prescription sale. The manufacturer claims the product's delivery system minimizes patient flushing--associated with immediate-release niacins--and liver enzyme elevations--associated with SR niacins. Although fewer than 1% of patients in clinical trials were discontinued from therapy due to a transient rise in transaminases, Niaspan's labeling calls for monitoring of liver function tests.
In an effort to minimize the potentially harmful adverse effects experienced by patients taking niacin, ASHP recently released a statement recommending that patients check with pharmacists before beginning nonprescription niacin therapy. ASHP believes that R.Ph.s are in a unique position to monitor patients' selection of OTC niacin and discourage self-treatment. The society also encourages R.Ph.s to work with other health-care providers to ensure that patients are achieving the desired cholesterol-reducing effects. And, from the looks of things, pharmacists are rolling up their sleeves and going to work.
More than 700 willing and able R.Ph.s are currently participating in a two-year, ambulatory, pharmacy-based cholesterol management program called Project imPACT (improve persistence and compliance with therapy). Under the direction of the American Pharmaceutical Association, the project is designed to demonstrate that R.Ph.s--who had to meet certain criteria that indicated their readiness to provide pharmaceutical care--can play a key role in helping patients manage their cholesterol. Data on whether R.Ph.s' efforts improved patient compliance, brought lipid levels to target goals, and reduced other risk factors for heart disease will be available sometime this year.
But how are they doing so far? ImPACT participant Bopp evaluates her hyperlipidemic patients' lipid profiles and drug regimen regularly during their scheduled appointments. "Working closely with physicians, we look to improve patients' quality of life,
decrease chances of adverse effects, assist with drug compliance, and counsel on diet and exercise," she said. And since the program is service oriented and not linked to any particular product, patients are not seen just when they need a refill. So far, Bopp's pharmacy has had "outstanding results" in lowering lipid levels and producing grateful patients.
Garrelts' pharmacy, also a participant in imPACT, has enrolled 35 patients into the cholesterol management program which she runs with another staff R.Ph., whose sole job is to work on pharmacy care projects. Patients are regularly sent letters reminding them of upcoming appointments, and doctors are kept abreast of their progress, she said. All patient clinical information that is gathered at each appointment is directly faxed to the patients' physicians, who then make therapeutic adjustments based on the information. "Not every imPACT patient is a success story, but we've had enough [happy endings] to make us feel pretty good," declared Garrelts.
Apparently, R.Ph.s in the hospital setting have also become involved in the lipid arena. Deutsch participated in an outpatient cholesterol clinic at the VA where she met weekly with patients to evaluate their lipid profiles and compare the values with those from their previous visit. "Usually, I would make recommendations to physicians about adjusting dosage or switching to another drug if I noticed that patients' lipid levels had not significantly decreased." Through cooperation with other health-care professionals, she kept the evil glob at bay in many patients with hard-to-control hyperlipidemia.