The Latest Information on New Drugs and New Indications
Atorvastatin (lipitor), basking in the glow of its reputation as the most potent of statins (and picking up various nicknames such as "Turbostatin" and "Gorillastatin"), has rapidly gained a dominant market share, more than 34%, in the competitive cholesterol-lowering drug market. Now, Merck is seeking to gain some of the market back with its newly approved 80 mg dose for simavastatin (Zocor). Studies show the new dose is roughly equivalent to 40 mg of atorvastatin in its ability to lower LDL and triglycerides. Several other companies are also seeking FDA approval for higher dose regimens for their statins.
Celecoxib (Celebra), Searle's new pain reliever, is receiving a priority review from the FDA, meaning the drug may be available for marketing as soon as early 1999. Celecoxib is significant because it is the first of an important new class of drugs known as COX-2 inhibitors. These drugs are specific for cycloxygenase receptors that cause pain and inflammation, while having minimal effect on COX-1 receptors, the cycloxygenase receptors in the gastric mucosa and platelets. These drugs relieve pain and inflammation without the side effects common to NSAIDS such as gastric irritation, bleeding, and renal toxicity. Celebra will be co-marketed with Pfizer and is expected to be a huge new product. Other drug companies are also working on COX-2 inhibitors, including Merck, Glaxo, J&J, and Roche. Merck's product is reported to be about six months behind Searle's celecoxib in the FDA pipeline.
Two recent studies from Yale and the University of Maryland have again demonstrated the value of beta blockers after myocardial infarction. The Yale study (JAMA 1998;280:623-629) looked at more than 45,000 cases of acute MI in patients older than 65 years. In this retrospective cohort study, half of the patients were given a beta blocker at discharge. Beta blocker use was associated with a 14% lower risk of mortality at one year post discharge. The Maryland study (N Engl J Med 1998;339:489-497) was also a retrospective study of more than 200,000 patients with myocardial infarction. Thirty-four percent of these patients were given beta blockers. Various subgroups of patients were reviewed, including those with CHF, COPD, renal insufficiency, and diabetes. Mortality was lower in every subgroup of patients treated with beta blockers compared with untreated patients. In otherwise healthy patients with no complications or comorbid conditions, mortality was reduced by 40% in the beta blocker group. Other subgroups, including the elderly, blacks, and those conditions noted above, had less benefit but still had a significantly lower mortality rate. Both studies concluded that beta blockers are underused post MI, especially in the elderly and in subgroups of patients who might not be considered to be candidates for beta blockade because of preexisting conditions.
Estrogen and a progestin are commonly given to women with coronary heart disease (CHD) to prevent another heart attack (secondary prevention). A recent study questions the appropriateness of this therapy (JAMA 1998;280:605-613). A total of 2763 women with a mean age of 66.7 years who had not undergone hysterectomy and who had documented CHD were entered into this randomized, blinded, placebo-controlled study. After an average of four years of follow-up, there was a slight improvement in LDL and HDL cholesterol levels in the treatment group, but there was no difference in the rate of MI or CHD death. Additionally, more women in the treatment group experienced venous thromboembolic events and gallbladder disease. There was no difference in overall mortality seen between the treatment and placebo groups. The authors state they cannot recommend ERT for secondary prevention based on their findings.
New antiplatelet drugs are showing promise just as a "Dear Doctor" letter is being issued for ticlopidine (Ticlid). The warning concerns the risk of thrombotic thrombocytopenic purpura (TTP) associated with the use of the drug. About 100 cases have been reported in this country in the last five years. This is in addition to the risk of neutropenia and agranulocytosis associated with the drug. New antiplatelet agents include clopidogrel (Plavix), which is similar to ticlopidine but does not carry the hematologic risks, and the new glycoprotein (GP) IIb-IIIa inhibitors tirofiban (Aggrastat) and eptifibatide (Integrilin). These last two drugs are only available in a parenteral form and are often given with aspirin and heparin in high-risk patients such as those with unstable angina, non-Q wave MI, or post PTCA. A recent study (N Engl J Med 1998;339:436-443) used eptifibatide or placebo in addition to standard therapy of aspirin or heparin for patients with unstable angina or acute coronary syndromes without persistent ST-segment elevation. In the nearly 11,000 patients studied, a 1.5% absolute reduction in death and MI was seen in the eptifibatide group (15.7 vs 14.2). These drugs are expensive, and their role in the prevention of atherosclerotic events is still to be determined. The use of another GP IIb-IIIa inhibitor, abciximab (ReoPro), in the prevention of stent thrombosis is reviewed later in this issue.
The popularity of Viagra seems to waning a bit as sales have fallen off from more than 300,000 prescriptions during the week ending May 8, to 184,000 for the week ending July 10. Don't sell your Pfizer stock quite yet, however; the drug is still on track to reach $1 billion in sales in its first year. The FDA has now received 123 reports of deaths in patients who have been prescribed Viagra, but only 69 were confirmed to have used the drug before death. Most deaths were cardiac events. The FDA has not changed its stance on the safety or labeling of the drug, but the American College of Cardiology and the American Heart Association have issued a joint statement regarding the risk of Viagra taken in combination with nitrates.