At the time the SWORD study was initiated, it was controversial whether beta-blockers were primarily detrimental or beneficial for people with reduced left ventricular systolic function. One concern was that beta-blockers could reduce heart function to the point that a person would develop problems with heart failure—the inability of the heart to pump blood well enough to meet the body's needs. Based on this rationale, d-sotalol, with its lack of beta-blocking properties, was deemed potentially safer than l-sotalol, which has significant beta-blocker effects.
SWORD was stopped after 3,121 of the planned 6,400 patients were recruited. This was due to a significantly increased percentage of people receiving d-sotalol dying (78 of 1549, 5%) compared to those receiving placebo (48 of 1572, 3.1%).[2] A potential reason for this increased mortality included d-sotalol actually increasing rather than decreasing the risk of life-threatening arrhythmias.[3] Also, subsequent studies have established that medications with beta-blocking properties can reduce the risk of death in patients like those enrolled in SWORD, as well as certain others with at least moderately decreased left ventricular systolic function.
In retrospect, SWORD went wrong because two key hypotheses considered reasonable at the time turned out to be incorrect. Using d-sotalol to reduce mortality by suppressing life-threatening arrhythmias instead increased that risk. Beta-blockade was, on balance, found to be beneficial rather than detrimental.
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CASTing Stones
SWORD was only one nail in the coffin of using antiarrhythmic medications to reduce the risk of death in patients after myocardial infarction. The C ardiac A rrhythmia S uppression T rial (CAST) in the late 1980s used three antiarrhythmic agents with a different mechanism of action than sotalol. Encainide, flecainide, and moricizine were compared to placebo in a randomized trial involving groups of patients who'd experienced a prior myocardial infarction. At the time CAST was done, encainide and flecainide were already approved by the FDA for treating ventricular arrhythmias.
The CAST study was stopped after patients were followed for only an average of ten months due to those receiving encainide or flecainide having a significantly greater mortality than those taking placebo. Sixty-three of 755 (8.3%) patients taking either of those two antiarrhythmic agents died, compared to 26 of 743 (3.5%) receiving placebo.[4]
Moricizine was not found to be associated with excess mortality in the CAST study. It was further evaluated in a follow-up trial, CAST II. However, this study met the same fate of early termination, for reasons similar to CAST. Patients who'd had a myocardial infarction were randomized to receive moricizine or placebo during an initial 14-day period. Significantly more people taking moricizine died or had a cardiac arrest (17 of 665, 2.6%) than those taking placebo (3 of 660, 0.5%).[5], [6]
Largely due to CAST's findings, encainide was removed from the U.S. market in 1991. Flecainide remains available, but for only restricted indications in patients who do not have characteristics similar to those treated in the CAST study. Moricizine was available for restricted use until its manufacturer stopped making it in 2007.
As with d-sotalol in the SWORD study, the antiarrhythmic agents used in CAST increased the risk of death in patients following a myocardial infarction. But although those particular agents were (literally) a dead end for treating those patients, the good news is that other methods to suppress life-threatening arrhythmias have been successful. Another antiarrhythmic agent, amiodarone, may be modestly useful for reducing risk of death after myocardial infarction.[7] Other medications, including beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers have been shown to reduce mortality in patients following a myocardial infarction who have at least moderately reduced left ventricular systolic function.
Currently, one of the most effective ways to reduce the risk of death in certain patients with moderately to severely reduced left ventricular systolic function due to a myocardial infarction or other cause doesn't involve a medication at all. In such patients, an implantable cardioverter-defibrillator (ICD) can be used.[8] An ICD is slightly larger than a conventional pacemaker and is usually implanted under the skin just below the clavicle (collarbone). A plastic-coated wire attached to the ICD is inserted into the subclavian vein and advanced into the right ventricle.
The ICD is programmed to monitor the heart for development of life-threatening ventricular arrhythmias (e.g. ventricular fibrillation and rapid ventricular tachycardia) and to treat them. It delivers a mild electric shock to the heart or, for some types of ventricular tachycardia, gives a short burst of rapid electrical impulses that interrupts the arrhythmia.
Overall, the basic scientific idea that suppressing life-threatening arrhythmias in certain high-risk patients could improve survival turned out to be correct. However, discovering an effective way to do this required studying multiple approaches, with the CAST and SWORD studies showing that some initially promising ones were harmful instead. And that's a key reason why clinical trials are performed—to see how well theory matches reality.
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Good News and Bad News
Another reason why medical research goes wrong falls under the category of “What's good for one part of the body may be bad for another."
The rise and fall of cyclooxygenase-2 (COX-2) inhibitors, a class of medications introduced in the late 1990s, illustrates this principle. COX-2 inhibitors are one type of a larger class of medications called NSAIDs ("nonsteroidal anti-inflammatory drugs"). NSAIDs are used to treat arthritis and inflammation, and include such commonly used medicines as aspirin, ibuprofen (Motrin), and naproxen (Naprosyn). These and some other NSAIDs inhibit both the COX-1 and COX-2 receptors present to varying degrees in most tissues in the body.
Inhibiting COX-2 receptors reduces inflammation—a beneficial effect. However, inhibiting COX-1 receptors can lead to irritation, inflammation, and ulceration of the lining of the stomach and other parts of the gastrointestinal tract. These adverse effects can cause bleeding and other complications. NSAIDs designed to selectively inhibit COX-2 receptors were developed with the idea that this would maximize their good effects (e.g. reducing inflammation and joint pain) and minimize bad ones, such as damaging the stomach.
Two selective COX-2 inhibitors, rofecoxib (Vioxx) and celecoxib (Celebrex), were approved by the FDA in the late 1990s and a third, valdecoxib (Bextra), in 2001. For several years they were widely prescribed for treatment of arthritis. Some studies, including the C elecoxib L ong-term A rthritis S afety S tudy (CLASS) and the VI oxx G astrointestinal O utcomes R esearch (VIGOR) study, reported that selective COX-2 inhibitors were indeed associated with a lower incidence of gastrointestinal side effects than other types of medications used to treat arthritis.[9], [10]
However, VIGOR and later studies found that COX-2 inhibitors were also associated with an increased risk of myocardial infarction, stroke, heart failure, and high blood pressure.[11] Although the exact mechanisms for some of these increased risks are still debated, they may include increased chance of a blood clot (thrombus) forming, as well as excessive retention of sodium and water. Based on these reported adverse cardiovascular effects, rofecoxib was withdrawn from the U.S. market in 2004 and valdecoxib in 2005.
Celecoxib remains available by prescription. However, current guidelines state that it should be used for treatment of arthritis only if less risky medications have failed; duration of treatment should be as short as possible and at the lowest effective dose; and it should be used with special caution or not at all in patients at highest risk of cardiovascular events. That includes those with prior myocardial infarction or otherwise known to have or to be at high risk of having coronary artery disease (one or more blockages in the arteries of the heart).
Interestingly, this research also indicated that older NSAIDs that produce a milder degree of selective COX-2 inhibition, such as ibuprofen, might also be associated with increased risk of cardiovascular events, but not as much as rofecoxib and
similar medications. These older NSAIDs should also be used with caution in patients with known or suspected cardiovascular disease.
The COX-2 inhibitors aren't alone in initially appearing to be reasonably effective and benign, only to be found when used in larger numbers of patients to have unexpected bad effects on other parts of the body besides those being treated. In the 1990s, a medication that combined fenfluramine and phentermine (Fen-Phen) was marketed as an aid to weight loss. As use of this medication became more widespread, however, its use was found to be associated with serious and even fatal cardiovascular problems—development of increased pressure in the arteries of the lungs (pulmonary hypertension), and abnormalities of heart valves such as increased thickening and leaking.[12], [13]
In 1997, the FDA recommended that medications containing fenfluramine, the component of Fen-Phen thought to be the primary cause for these problems, be removed from the U.S. market. Phentermine remains approved for use. Injuries attributed to Fen-Phen have been part of thousands of product liability lawsuits.
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The WHIs and Wherefores of Estrogen Therapy
Certain diseases are caused by a person's body producing inadequate amounts of a hormone or other chemical needed for good health. “Hypothyroidism” occurs when the thyroid gland doesn't produce enough of two hormones—thyroxine and triiodothyronine— to meet a person's metabolic needs. Diabetes mellitus is associated with either an absolute deficiency of insulin (Type 1), or an at least relative deficiency of insulin and resistance to its effects (Type 2). Having too little of other hormones—growth hormone, parathyroid hormone, aldosterone, etc.—also causes well-described symptoms and diseases. Replacement of a hormone when its blood level is too low may improve or cure the disease caused by its lack.
However, levels of some hormones fall not because of a clearly pathological process, but as a “normal” part of aging. These include dehydroepiandrosterone (DHEA), a hormone produced by the adrenal glands, and growth hormone. Although further studies might change this assessment, so far research has not definitively shown that replacement of these hormones to “youthful” levels produces a clinically significant improvement in health.
In women, levels of the female sex hormone estrogen fall dramatically at menopause. The higher level of estrogen present in premenopausal women compared to men is associated with a significantly lower risk of these women developing coronary artery disease (CAD). Roughly speaking, the risk of a woman developing CAD prior to menopause is about the same as a man ten years younger with similar risk factors (e.g. high blood pressure, an abnormal blood cholesterol level, diabetes, or tobacco use). The drop in estrogen level that occurs with menopause is associated with a significant increase in the risk of a woman developing CAD.
The “logical” conclusion was that, if a woman's estrogen level were restored to what it was before menopause, her risk of developing CAD would fall. The possibility that giving estrogen replacement might have effects that reduce the risk of developing CAD seemed to support this idea. These potentially beneficial effects include lowering low-density lipoprotein (LDL) cholesterol, increasing high-density lipoprotein (HDL) cholesterol, and reducing blood sugar. Some known effects of giving estrogen, such as raising the blood level of triglycerides (another component of cholesterol) and increasing the risk of developing blood clots, were recognized as being potentially harmful. However, these bad effects were not thought to be as significant as estrogen's good effects.
Some small studies done in the early and mid-1990s did in fact suggest that estrogen replacement was, overall, beneficial for preventing CAD in postmenopausal women. These studies contributed to the expanded use of estrogen for this indication and an unsuccessful attempt to have the FDA give official approval for it. In general, post-menopausal women were prescribed “hormone replacement therapy” (HRT) as a combination of estrogen and either another female sex hormone, progesterone, or a chemical with progesteronelike effects called a “progestin,” such as medroxyprogesterone. Giving estrogen by itself increases a woman's risk of developing cancer involving the lining of her uterus (endometrial cancer). Using estrogen with a progestin reduces this risk significantly. If a woman had a hysterectomy (removal of the uterus), she could receive estrogen alone.
However, large studies conducted in the late 1990s and in this century reached different conclusions about the effects of HRT on cardiovascular disease. They showed that using estrogen and a progestin together didn't reduce the risk of myocardial infarction or death from CAD in postmenopausal women either with or without known heart disease. HRT also didn't reduce how rapidly blockages in the arteries of the heart associated with CAD got worse.
In fact, some studies found HRT might increase risk to the heart, especially in the first year after this therapy was started. The W omen's H ealth I nitiative (WHI) study randomized 16,608 postmenopausal women between 50 and 79 years of age without known CAD to receive either an estrogen- medroxyprogesterone combination as HRT, or placebo. The women who received HRT had a 24% higher risk of having a myocardial infarction or dying from CAD than those receiving placebo.[14]
Another group of 10,739 women in WHI who'd previously had a hysterectomy were randomized to either estrogen therapy alone or placebo. In these women, treatment with estrogen showed no significant benefit or harm regarding CAD compared to placebo, but it was associated with an increased risk of stroke.[15]
Current guidelines recommend that HRT should not be used in postmenopausal women to prevent heart disease.[16] Here again, an idea that was once conventional wisdom and supported by preliminary research was not confirmed by further studies.
But the final word on this subject might not have been written yet. It's been suggested that giving HRT to younger postmenopausal women, such as those ages 50 to 59, or using a lower dose of estrogen in women age 60 or older may not be associated with increased cardiovascular risk and might still turn out to have a protective effect regarding CAD. HRT can also have good and bad effects on other parts of the body. Potential benefits include preventing osteoporosis (thinning of bones) and treating symptoms associated with menopause, such as “hot flashes.” Possible risks of HRT with an estrogen-progestin combination include increasing the chance of getting breast cancer. The overall decision whether or not to use HRT in individual postmenopausal women remains complex and hopefully will be clarified by further research.
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Pills and Pregnancy
A dramatic example of how inadequate research can result in tragedy involves a woman's use of medications during preg- nancy. Both the mother and the developing baby (called an embryo from about the first four days through the eighth week after conception, and afterward a fetus until birth) share a single blood supply. During most of pregnancy, blood and nutrients are supplied to the baby through the placenta (specialized tissue attached to the inner wall of the uterus) and the umbilical cord. If the mother takes a medication, the baby can, to some degree, receive it too.
Thalidomide is a medication marketed from the late 1950s through 1961 as a treatment for morning sickness and a sleeping aid for pregnant women.[17] However, by 1961 it was belatedly recognized that use of thalidomide was associated with a high risk of serious birth defects in children born to women who'd taken it. These included severe shortening of the arms and legs—"phocomelia,” in which the hands or feet are connected to the trunk by only abnormally short or even absent long bones.
Over 10,000 children affected by thalidomide-induced malformations were born worldwide. An application to market thalidomide in the United States was submitted to the FDA in 1960. However, the physician who reviewed the application, Frances Kelsey, delayed approval pending further evaluation of the drug's safety and effectiveness. Because of her concerns, thalidomide didn't become available for general use in the United States before its “teratogenic” (birth defect-producing) effects were recognized.
As a result of these events, the FDA received increased authority and re
sponsibility to ensure that drugs were both safe and effective. The thalidomide tragedy also showed that an idea commonly held before then, that medications given to the mother did not cross the placenta to her embryo or fetus, was wrong. It's now recognized that medications can adversely affect the developing baby in different ways throughout pregnancy.
For example, medications can cause death of the embryo soon after conception. The brain, internal organs, and limbs are most vulnerable to injury from about the first two weeks to two months following conception, when they are beginning to form and develop. Later in pregnancy, the major body parts of a fetus are better developed and mainly just growing larger. However, medicines taken at that time can cause harm by having too strong an effect on the fetus, due to its much smaller size compared to the mother, as well as interfering with normal growth and function of its organs.
The FDA has five categories for medications regarding risk to the embryo or fetus. Some medications fall into more than one category, with increased risk early in pregnancy but not later, or vice versa.
Category A medications have the lowest level of risk. Scientific studies in human mothers have not shown that these medicines cause harm when taken during pregnancy. They include ferrous sulfate (iron) tablets for treating anemia and standard doses of vitamins B and C.
Category B medications have either not been shown to harm the embryo or fetus in animal studies, or if they have been shown to cause harm in animals, studies have not shown them to be harmful in humans. Category C medicines are those known to cause harm in animal studies, but there are no studies to assess their safety in humans.
Analog SFF, September 2010 Page 5