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Drug update: lipid modification for secondary prevention of coronary events.

Mitchel L. Zoler, editor Bruce Jancin, writer

Current consensus is that virtually everyone with known coronary disease ought to be on an HMG-CoA reductase inhibitor, regardless of LDL cholesterol level. These well-studied drugs, commonly known as statins, cut risk by lowering LDL cholesterol and through anti-inflammatory and plaque-stabilizing effects.

The Adult Treatment Panel III Report guidelines of the National Cholesterol Education Program (NCEP) also recommend statins for all patients who have diabetes, peripheral artery disease, and other conditions placing an individual at very high risk for coronary events. The LDL cholesterol treatment goal is in flux. The existing NCEP recommendation is that drug therapy be reserved for patients with an LDL level above 100 mg/dL. But some experts are now comfortable driving LDL levels to 70 mg/dL or less, especially in a patient who's had a coronary event despite a modest LDL level.

Experts frequently use combination drug therapy for secondary coronary event prevention, mainly in patients who have a mixed hyperlipidemia featuring a low HDL level and elevated triglycerides, those with a modest LDL response to statins, and patients with familial hypercholesterolemia and very high cholesterol levels. Combinations consisting of a statin and niacin are the most popular, but combinations of a statin and a fibrate or a statin and a bile acid sequestrant are also used. The lipidmodifying effects of combination therapy are additive, with evidence of markedly enhanced risk reduction. Triple-drug and occasionally quadruple-drug therapy is warranted in patients with familial hypercholesterolemia and very high LDL levels.

Marketing approval is anticipated soon for two new agents: rosuvastatin (Crestor), a drug that, like atorvastatin, lies at the high end of the LDL-lowering potency spectrum, and ezetimibe (Zeria). Ezetimibe is drawing considerable interest because of its unique mechanism of action--it affects cholesterol transport in the gut--and because in combination with a statin, it results in a further 18%-20% LDL level reduction, equivalent to a threefold boost in a patient's statin dose.

Ali lipid-modifying drugs are safe in the elderly without the need for dosage reductions. Because of insufficient safety data in pregnant and breast-feeding women, prudence dictates a 1- to 2-year drug holiday in what is otherwise lifelong therapy.

Most physicians believe that the roughly 30% risk reduction in coronary
events obtained with statin therapy is a class effect. They select a
statin based upon what the patient's insurance plan covers, provided the
drug's potency is sufficient to get close to the LDL goal. Experts like
to begin a regimen during hospitalization for an acute coronary event to
effects as soon as possible and because doing so promotes long-term
compliance. They pick a low- or midrange does; muscle soreness and other
tolerability issues generally become a problem only at the highest does
of each statin. A useful dosage rule of thumb is that, on average, a 27%
reduction in LDL level results from a daily dosage of 5 mg atorvastatin,
10 mg simvastatin, 20 mg lovastatin, 20 mg pravastatin, and 40 mg
fluvastatin. Every doubling of statin dosage thereafter results in about
a further 6% drop in LDL level. By increasing from 40 mg/day to 80
mg/day atorvastatin, for example, a patient's LDL level will drop by
only another 6%. All statins cause elevated liver enzymes in about 1% of
patients; these drugs shouldn't be used in patients with active liver
disease or unexplained transaminase elevations.

Drug Dosage Cost/Day *

atorvastatin 5-80 mg/day $1.16 (5 mg)

fluvastatin 20-80 mg/day $1.48
 (Lescol) (40 mg)

lovastatin 20-80 mg/day $2.39 (20 mg)

pravastatin 10-40 mg/day $2.78 (20 mg)

simvastatin 5-80 mg/day $2.53
 (Zocor) (10 mg)


niacin, extended- 1-2.5 g/day $1.41 (1 g)


cholestyramine 4-16 g/day $2.96 (8 g)

colesevelam 2.5-3.75 $4.74
 (WelChol) g/day (3.75 g)

colestipol 5-20 g/day $2.40 (5 g)


gemfibrozil 600 mg b.i.d $1.98

fenofibrate 200 mg/day $2.58

Drug Comment **

atorvastatin Most widely prescribed statin, most
 (Lipitor) potent LDL reducer, and the sole
 statin not backed by a larger
 clinical trial demonstrating
 reductions in acute Ml, mortality,
 and other key end points. Such
 studies are ongoing. Exports reach
 for atorvastatin preferentially
 only for patients with LDL levels
 in excess of 160 mg/dL. Smallest
 pill size is 10 mg; 5-mg dosage
 listed in cost column is achieved
 by cutting pill in half, which
 also lowers the cost.

fluvastatin Well-used option despite its lower
 (Lescol) potency, compared with others in
 class. Attractive price and
 presence on many formularies
 make it a reasonable choice for
 patients who need only a modest
 drop in LDL level.

lovastatin The first approved statin has
 generic. Also available
 combined with extended-release
 niacin (Advicor).

pravastatin Starred in 11-year, 4,200-patient
 (Pravachol) Cholesterol and Recurrent Events
 (CARE) trial that helped usher
 in the era of statins for
 secondary coronary prevention.

simvastatin Some partisans of the nearly
 (Zocor) 21,000-patient Heart Protection
 Study (HPS) now recommend
 giving everyone with known
 coronary disease 40 mg/day
 simvastatin and not bothering
 to measure LDL level. It's
 their blanket treatment of
 choice for secondary prevention
 based upon convincing clinical
 benefits across a broad spectrum
 of HPS patients, including
 diabetics, the elderly, women,
 those with a history of stroke,
 and patients with peripheral
 vascular disease.


niacin, extended- The unsung hero of cardiovascular
 release risk reduction. Other niacin
 (Niaspan) preparations are available, but
 experts say Niaspan is easiest to
 use and safer than OTC products. A
 user-friendly niacin, tolerated
 by up to 90% of patients. Start
 with 500 mg at bedtime following
 a small, nonfatty snack and
 increase by 500 mg/month until
 side effects become limiting.
 Taking an aspirin 30 minutes
 beforehand reduces flushing.


cholestyramine Resin powder. Shunned by some as
 messy and inconvenient; others
 say the lowest maintenance dose,
 8 g, is very well tolerated and
 provides a further 10%-15%
 reduction in LDL. That's about
 equivalent to quadrupling a
 patient's statin dose. A bile
 acid sequestrant should not be
 used by patients with high
 triglycerides; it will
 worsen the problem. Must be
 taken at least 1 hour after
 or 4 hours before any other

colesevelam More convenient than other bile
 (WelChol) acid sequestrants; can be taken
 with other medications. Fewer
 Gl side effects, too.

colestipol Micronized tablets avoid mess.
 (Colestid) But even using the lowest dosage
 to minimize Gl distress and
 constipation means swallowing
 five large tablets per day.
 Must be taken at least 1 hour
 after or 4 hours before any
 other medication.


gemfibrozil Impressive triglyceride-lowering
 and HDL cholesterol-boosting
 effects make fibric acid
 derivatives especially
 attractive in diabetic patients.
 In class, gemfibrozil is
 preferred by some for its
 longer track record. Some
 lingering concern over increase
 in Gl cancers seen with
 gemfibrozil at 9-year follow-up
 in Helsinki Heart Study. Class
 requires monitoring of liver
 function when used with a

fenofibrate Micronized formulation allows
 (Tricor) once-daily dosing for most

* Cost/day is based in the average wholesale price for a 100-unit
container or closest available size of the generic formumation, unless
otherwise indicated, in the 2002 Red Book.

** Comments reflect the viewpoints and expertise of the following
sources: Dr. Louis Kuritzky, a family physician at the University of
Florida, Gainesville.

Dr. C. Noel Bairey Merz, director of the preventive and rehabilitative
cardiac center at Cedars-Sinai Medical Center, Los Angeles, and a member
of the NCEP Coordinating Committee.

Dr. Richard Pasternak, director of preventive cardiology and cardiac
rehabilitation at Massachusetts General Hospital, Boston, and a member
of the NCEP Coordinating Committee.
COPYRIGHT 2002 International Medical News Group
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2002 Gale, Cengage Learning. All rights reserved.

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Author:Zoler, Mitchel L.
Publication:OB GYN News
Date:Nov 1, 2002
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