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Medical therapies are created with the goal of improving health. However, the use of medical therapies involves risk. We focus on uncovering such risks because people need an accurate picture of both the benefits and risks of the medical therapies they use. The CERTs work to improve our ability to detect both the beneficial and harmful effects of medical therapies so that the benefits can be maximized and the risks minimized.

UNDERSTANDING MEDICINES THAT CAN CAUSE SERIOUS HEART RHYTHM DISTURBANCES AND DEATH 1,2,3

Many different types of drugs, including some antihistamines, antibiotics, and antipsychotics, have been shown to cause serious heart rhythm disturbances. The CERTs help to identify individual drugs, drug interactions, and genetic mutations that are associated with torsades de pointes, a potentially fatal irregular heart rhythm. Torsades de pointes can develop because of an inherited gene or as the result of taking certain drugs. Women are more susceptible than men, and we have identified the basis for this increased sensitivity to these drugs.

As a result of reports received by CERTs investigators, we suspect that methadone, which is used for pain and to treat heroin addiction, might cause torsades de pointes. Normal electrical impulses that coordinate heartbeat require potassium. Drugs known to cause torsades de pointes actually block the channels that allow potassium to move out of heart cells. Therefore, we examined the effects of methadone on these channels in single heart cells. This past year we reported that methadone does block these potassium channels. Chlorobutanol, a preservative found in intravenous methadone, also blocks potassium channels. With further clinical studies, we found that intravenous methadone causes heart rhythm disturbances that often precede torsades de pointes. Because of this work, there is a much better appreciation of the risk factors for this condition.

Unfortunately, not all drugs have been characterized as to their ability to cause heart rhythm disturbances. To gather more information on the risks associated with various drugs, we developed the Web site www.qtdrugs.org. This is an Internet-based registry that physicians can use to report cases of torsades de pointes caused by drugs.

We know that using two or more drugs that interfere with potassium channels can further increase the risk of torsades de pointes, but it was not known how often people are prescribed two or more such drugs at once. Using data from an insurance claims database, we reviewed the prescriptions of nearly 5 million people. We identified overlapping prescriptions among drugs that can either interfere with potassium channels or slow the breakdown of such drugs. We found that 9.4% of people filled overlapping prescriptions for two or more of these drugs. More studies are needed to determine the exact risks for these patients and how the risks weigh against the benefits of taking the drugs. With that information, we hope it will be possible to prevent these irregular heart rhythms before they harm patients.

Transmyocardial revascularization (TMR) is a procedure developed to relieve severe chest pain in patients who cannot undergo angioplasty or traditional bypass surgery known as coronary artery bypass grafting (CABG). In the procedure, a surgeon uses a laser to make a series of small holes in the heart to deliver more blood to the heart muscle. TMR is also used with CABG, but this combination has not been widely studied and is not approved by the FDA.

To learn more about the use of TMR and its associated risks, we collaborated with the Society of Thoracic Surgeons and the FDA. We reviewed the use of the procedure between 1998 and 2002 in more than 400 hospitals that contribute to the Society of Thoracic Surgeons National Cardiac Database.

We found that nationwide the use of TMR is on the rise. However, in two-thirds of cases, it was used in combination with CABG. Thus, there is a crucial need to determine whether the combined procedure is safe and effective. We also found that patients who underwent TMR after having a recent heart attack or having a diagnosis of unstable angina had higher risks of dying during the procedure or having major complications. These findings are consistent with FDA guidance to avoid using TMR in patients with unstable angina or recent heart attack.

This study underscores the value of collaboration between professional societies, universities, and the FDA to study how therapies are used once they are approved by the FDA.

Tumor necrosis factor (TNF) is a molecule that helps the body fight diseases caused by invading bacteria and viruses. However, excess TNF may have adverse consequences in autoimmune disorders. In the case of rheumatoid arthritis, which is one type of autoimmune disorder, the molecule participates in the inflammation response and can contribute to joint swelling and pain.

Three FDA-approved drugs-infliximab, etanercept, and adalimumab-block the activity of TNF. This may help relieve some of the pain and swelling in people with rheumatoid arthritis. Despite the potential benefit, there is concern that certain people who take these agents may be more vulnerable to infections such as tuberculosis, to some types of cancer, and to worsening heart failure.

Our studies evaluate whether infliximab and etanercept increase the risk of serious infections. We are examining enrollment, physician, and pharmacy claims data in the UnitedHealthcare Research Database, which includes more than 2,000 people taking these prescription medications. We are comparing the frequency of serious infections in rheumatoid arthritis patients who have received these medications with those who have not. We are also evaluating the frequency of heart failure in these two groups from the UnitedHealthcare Research Database.

We also study the effectiveness of efforts by the Federal government and the pharmaceutical industry to communicate the risk of infections. Patients who have latent tuberculosis and then take infliximab are at an increased risk for becoming sick with tuberculosis. Therefore, the manufacturers of these products and the FDA now recommend that patients undergo a skin test for tuberculosis before taking infliximab. In a study of 1,396 infliximab users, we found that rates of tuberculosis skin testing increased following efforts to convey information about the need for such tests. In fact, the number of people who received the test doubled during a two-year time frame. We are currently trying to learn which methods of communication worked best.

Controlling blood glucose levels closely can prevent or delay the serious complications of type 1 diabetes (low insulin production) in children, adolescents, and adults. Yet controlling glucose too closely can lead to episodes of hypoglycemia (low blood glucose) severe enough to cause unconsciousness. It is harder in developing children than in adults to maintain close glucose control without causing hypoglycemia. Also, compared with adults, young children are less able to recognize and respond to early symptoms of hypoglycemia.

Continuous glucose monitors may help doctors control glucose ranges in children. The systems have a small sensor that is inserted under a patient's skin and connects to a pager-sized monitor. The device measures glucose every few minutes and stores the records for up to three days. Then the records are transferred to a computer in a manner similar to downloading pictures from a digital camera.

Continuous glucose monitors have been used in adults for nearly two decades. However, experience in children is very limited. We are conducting a study among children and adolescents with type 1 diabetes to determine whether continuous glucose monitoring devices are better than current techniques in helping doctors control glucose and reduce hypoglycemia. This study should assist doctors in deciding whether continuous glucose monitoring is feasible, well tolerated, and beneficial in children and adolescents with type 1 diabetes.

Fractures caused by osteoporosis can harm a person's health and well-being. Therefore, medicines that lower the risk of fractures are of great benefit. Recent reports suggest that people who take statins, the most commonly used cholesterol-lowering drugs, have fewer osteoporotic fractures than people who do not. But factors other than the use of statins may explain the difference. For example, patients who take cholesterol-lowering drugs are likely to weigh more than people who do not, and extra weight protects against hip and other fractures.

We compared rates of hip fracture between people taking statins and people taking other cholesterol-lowering drugs. There was no difference between the two groups. This study shows that currently there is no reason to use statins for preventing fractures caused by osteoporosis. This study highlights the importance of studying therapies used in ways not approved by the FDA.

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Annual Report Year 4

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Advancing Knowledge