NYT Letter to the Editor from Dr. Richard Pasternak

November 13, 2009

Letter to the Editor
The New York Times
620 Eighth Avenue
New York, NY 10018

To the Editor:

The New York Times story today about a clinical study called ARBITER-6 misses two key points that we believe your readers should know.

First, the results of ARBITER-6 have been described by others as largely predictable, as an analyst quoted in your story notes. But that is not because one drug is necessarily better than the other. Patients in ARBITER-6 were extensively pre-treated with statins, and had well controlled LDL but relatively low HDL, which is a study design that strongly favors a drug with niacin's effects on HDL over an LDL-focused medicine such as ezetimibe.

Second, because ARBITER-6 did not include a true control group, absolute benefit for either medicine in this study cannot be determined. The lack of a control arm, as well as the statin pre-treated patient population, should lead one to be extremely cautious in the interpretation of the results of this small study.

Robust cardiovascular outcomes studies, by definition, need to include a larger number of patients than ARBITER-6 did, and need to follow patients over a longer period of time than in ARBITER-6, and they also must have a true control group, all of which are essential to assess actual clinical impact. An example is Merck's IMPROVE-IT study, which will track up to 18,000 patients for a minimum of 2.5 years to determine whether ezetimibe provides an additional benefit beyond statin therapy alone in reducing cardiovascular risk. At this point, more than 15,000 patients are already enrolled.

We believe that interpretation of the ARBITER-6 results beyond what the study is designed to assess would be scientifically inappropriate, and could actually be harmful to some patients in the long run. Current treatment guidelines reflect a clear consensus among experts that lowering LDL should be the primary target of lipid-lowering therapy. Even with statin therapy, more than 50 percent of patients do not reach recommended LDL target goals. That is why physicians often determine that their patients need an add-on therapy to a statin along with a healthy diet. Your story failed to note that Zetia (ezetimibe) and Vytorin (ezetimibe/simvastatin) remain effective, FDA-approved treatment choices for physicians to consider using for their patients with high cholesterol when diet and exercise alone are not enough.

Dr. Richard Pasternak
Vice President – Clinical Research
Merck & Co.
One Merck Drive
Whitehouse Station, NJ 08889-0100

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Important Information about VYTORIN
VYTORIN contains simvastatin and ezetimibe. VYTORIN is indicated as adjunctive therapy to diet for the reduction of elevated total cholesterol, LDL cholesterol, Apo B¹, triglycerides and non-HDL cholesterol and to increase HDL cholesterol in patients with primary (heterozygous familial and non-familial) hypercholesterolemia or mixed hyperlipidemia.

VYTORIN is a prescription medicine and should not be taken by people who are hypersensitive to any of its components. VYTORIN should not be taken by anyone with active liver disease or unexplained persistent elevations of serum transaminases. Women who are of childbearing age (unless highly unlikely to conceive), are nursing or who are pregnant should not take VYTORIN. VYTORIN has not been shown to reduce heart attacks or strokes more than simvastatin alone.

Muscle pain, tenderness or weakness in people taking VYTORIN should be reported to a doctor promptly because these could be signs of a serious side effect. VYTORIN should be discontinued if myopathy is diagnosed or suspected. To help avoid serious side effects, patients should talk to their doctor about medicine or food they should avoid while taking VYTORIN. In three placebo-controlled, 12-week trials, the incidence of consecutive elevations (≥3 X ULN) in serum transaminases were 1.7 percent overall for patients treated with VYTORIN and 2.6 percent for patients treated with VYTORIN 10/80 mg. In controlled long-term (48-week) extensions, which included both newly-treated and previously-treated patients, the incidence of consecutive elevations (≥3 X ULN) in serum transaminases was 1.8 percent overall and 3.6 percent for patients treated with VYTORIN 10/80 mg. These elevations in transaminases were generally asymptomatic, not associated with cholestasis and returned to baseline after discontinuation of therapy or with continued treatment. Doctors should perform blood tests before, and periodically during treatment with VYTORIN when clinically indicated to check for liver problems. People taking VYTORIN 10/80 mg should receive an additional liver function test prior to and three months after titration and periodically during the first year.

Due to the unknown effects of increased exposure to ezetimibe (an ingredient in VYTORIN) in patients with moderate or severe hepatic insufficiency, VYTORIN is not recommended in these patients. The safety and effectiveness of VYTORIN with fibrates have not been established; therefore, co-administration with fibrates is not recommended. Caution should be exercised when initiating VYTORIN in patients treated with cyclosporine and in patients with severe renal insufficiency.

VYTORIN has been evaluated for safety in more than 10,100 patients in clinical trials and was generally well tolerated at all doses (10/10 mg, 10/20 mg, 10/40 mg, 10/80 mg). In clinical trials, the most commonly reported side effects, regardless of cause, included headache (5.8 percent), increased ALT (3.7 percent), myalgia (3.6 percent), upper respiratory tract infection (3.6 percent), and diarrhea (2.8 percent).

VYTORIN is available as tablets containing 10 mg of ezetimibe combined with 10, 20, 40 or 80 mg of simvastatin (VYTORIN 10/10, 10/20, 10/40 or 10/80 mg, respectively).

Important Information about ZETIA
ZETIA, along with diet, is indicated for use either by itself or together with statins or fenofibrate in patients with high cholesterol to reduce LDL cholesterol and total cholesterol when the response to diet and exercise has been inadequate.

ZETIA is a prescription medication and should not be taken by people who are allergic to any of its ingredients. When ZETIA is prescribed with a statin, it should not be taken by women who are nursing or pregnant or who may become pregnant, or by anyone with active liver disease. Statins should not be taken by anyone with these conditions. If you have ever had liver problems or are pregnant or nursing, your doctor will decide if ZETIA is right for you. Your doctor may do blood tests to check your liver before you start taking ZETIA with a statin and during treatment. ZETIA has not been shown to prevent heart disease or heart attacks.

Due to the unknown effects of increased exposure to ZETIA in patients with moderate or severe hepatic insufficiency, ZETIA is not recommended in these patients. In clinical trials, there was no increased incidence of myopathy (muscle pain) or rhabdomyolysis (muscle breakdown) associated with ZETIA; however myopathy and rhabdomyolysis are known adverse reactions to statins and other lipid-lowering drugs. There are no adequate and well-controlled studies of ZETIA in pregnant women. ZETIA should not be used in pregnant or nursing women unless the benefit outweighs the potential risks.

When ZETIA was co-administered with a statin, consecutive elevations in liver enzymes, more than three times the upper limit of normal, were slightly higher than those with the statin alone (1.3 percent vs. 0.4 percent). These elevations were generally asymptomatic and returned to baseline after discontinuation of therapy or with continued treatment. When ZETIA was co-administered with fenofibrate, consecutive elevations in liver enzymes more than three times the upper limit of normal, were 2.7 percent, and 4.5 percent in patients treated with fenofibrate alone. Caution should be exercised when initiating ZETIA in patients treated with cyclosporine, particularly in patients with severe renal insufficiency, due to increased blood levels of ZETIA.

In clinical trials, regardless of causality assessment, the most frequent side effects for ZETIA co-administered with a statin vs. statin alone included nasopharyngitis (3.7 percent vs. 3.3 percent), myalgia (3.2 percent vs. 2.7 percent), upper respiratory tract infection (2.9 percent vs. 2.8 percent), arthralgia (2.6 percent vs. 2.4 percent), and diarrhea (2.5 percent vs. 2.2 percent); for ZETIA administered alone vs. placebo: upper respiratory tract infection (4.3 percent vs. 2.5 percent), diarrhea (4.1 percent vs. 3.7 percent), arthralgia (3.0 percent vs. 2.2 percent), sinusitis (2.8 percent vs. 2.2 percent), and pain in extremity (2.7 percent vs. 2.5 percent).

¹ Apo B is the protein compound of lipoproteins, LDL and VLDL, which carry cholesterol in the blood.

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