Analog SFF, September 2010 (6 page)

"Double-blinded” means that neither the patients in the study nor the physicians caring for them know what kind of medication (e.g. study drug or placebo) an individual patient is getting. This reduces the influence of any purely subjective feelings of well-being or harm that patients or physicians might feel if they knew what type of medication was being taken. This information is, however, kept in a central database for analysis by third-party monitors.

In the United States, drugs that meet appropriate safety and efficacy criteria following Phase III trials can be submitted to the Food and Drug Administration (FDA). This federal agency decides whether the drug can be approved for marketing and sale. If the drug is approved, it may be evaluated further via Phase IV trials. These are typically surveillance studies that monitor the safety of the drug in a much larger number of patients than were evaluated in Phase I, II, and III trials. Data are also obtained to assess the drug's interactions with other commonly used medications as well as its safety and efficacy in particular types of patients, including those usually excluded from pre-approval trials, such as pregnant women or the very elderly.

Medical devices and biologics (agents that include vaccines and biological substances produced using recombinant DNA) undergo similar stages of testing.

Overall, it may take twelve to fifteen years from the time a new drug is discovered to when it is approved for use. The average cost of developing an entirely new medicine has been estimated at around eight hundred million to two billion dollars.[1]

And yet, despite all the time and effort that go into developing new medications, things can go wrong. Only about one out of five drugs that reach the stage of human trials is ultimately approved. And even a few that are approved can turn out to be more hazardous than helpful.

The Terrible Swift SWORD

Over my career as a cardiologist, I've been an investigator for over two dozen clinical research trials involving new medications. It's sometimes been challenging for me to find patients who were suitable and willing to participate in these studies. But in one case, I'm grateful I didn't enroll a patient before the study was stopped.

The Survival With ORal D-sotalol (SWORD) study was a large Phase III multicenter trial conducted in the mid 1990s. Its goal was to see if d-sotalol, a medication used to treat arrhythmias (abnormal heart rhythms), could reduce the risk of death in certain patients following a myocardial infarction (a “heart attack,” usually caused by a blood clot completely or nearly completely blocking off one of the heart's arteries). The study included patients with at least moderately decreased systolic function of the left ventricle (the main pumping chamber of the heart, which contracts during “systole") and who'd either had a myocardial infarction within six to 42 days or who had symptoms of heart failure (such as shortness of breath) more than 42 days after a myocardial infarction.

People who survive a myocardial infarction and have at least moderately decreased left ventricular systolic function have an increased long-term risk of death. This greater mortality can be due to the occurrence of life-threatening arrhythmias such as ventricular tachycardia or ventricular fibrillation. With both arrhythmias, either the right ventricle or left ventricle produces electrical impulses at an abnormally fast rate. With ventricular tachycardia, this may be as fast as 300 times per minute. Ventricular fibrillation is even faster, generating impulses at 400 to 600 times per minute. These heart rates are too rapid for the heart to effectively pump blood and can cause irreversible brain injury and death within minutes.

The scientific rationale behind SWORD was to see if d-sotalol could reduce the risk of death by preventing these life-threatening arrhythmias. The sotalol molecule has two “isomers” with antiarrhythmic properties, d-sotalol and l-sotalol. (Isomers are molecules with the same numbers and types of atoms but in different arrangements.) D-sotalol differs from l-sotalol in that it essentially lacks “beta-blocking” properties. The heart contains a type of “beta receptor” (SS1) that, when stimulated by epinephrine (adrenaline) or similar chemicals, increases heart rate and how forcefully the left and right ventricles contract. Conversely, a beta-blocker reduces heart rate and contractility.

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.

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.

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.

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.