NEWSLETTER 9: BAD VIOXX

NSAID Chronology

Aspirin, the New Anti-Inflammatory Anti-Pyretic Medication
In the beginning, there was Aspirin. Aspirin was first discovered by Charles Gerhardt in 1853. Acetylsalicylic acid, a natural by product of coal tar, was developed by Felix Hoffman from the Bayer Company in 1875. In 1899, Heinrich Dreser named the compound "Aspirin." It was originally marketed by Bayer Pharmaceuticals in the late 1890s. It was the first NSAID (Non Steroidal Anti Inflammatory Drug) and, for a long time, the only NSAID. Aspirin is a very effective pain reliever medication. Its short comings are most people can not tolerate high dose (2 Aspirins four times a day) Aspirin for very long without placing themselves at risk of getting serious side effects like: bleeding stomach ulcers; kidney failure; high blood pressure, etc... This wonder drug works by blocking an enzyme called Cyclooxygenase, or COX, for short. It turns out there are two forms or isoenzymes of COX: COX-1 and COX-2. They each have separate and distinct functions. Aspirin blocks COX-1 and COX-2 equally. That is, for every COX-1 that Aspirin blocks, it also blocks one COX-2.

Blocking COX-1 causes "side effects." That is, blocking COX-1 is associated with: thinning of the blood; bleeding stomach ulcers; kidney failure; and can interfere with the blood pressure lowering effect of some high blood pressure medications. COX-1 stimulation produces one class of prostaglandins that protect the lining of the stomach and duodenum against injury. This is how blocking COX-1 causes peptic ulcer formation. At the same time stimulation of COX-1 produces thromboxane A-2, a chemical which assists in blood clotting (hemostasis). It is through COX-1 inhibition that Aspirin and other NSAIDs exert their blood thinning effect. Thus, administration of NSAIDs has the undesirable side effect of causing erosions or ulcers in the upper gut, and interfering with blood clotting when they bleed.

Blocking COX-2 is associated with pain relief through reducing inflammation. That is, COX-2 is an "inducible" isoenzyme that increases as a result of inflammation, such as, inflammation from OA (Osteoarthritis). So, the OA induces production of COX-2 which leads to pain and swelling of the joints. Inhibition of COX-2 leads to diminished inflammation and can be very useful as a treatment for all kinds of illnesses that have inflammation associated with them. NSAIDs decrease the production of prostaglandins [a group of compounds that transmit messages between cells] from a component of cells called arachadonic acid by inhibiting the isoenzyme COX-2. Certain of these prostaglandins play a role in inflammation and the generation of pain in conditions such as RA (Rheumatoid Arthritis) and OA (Osteoarthritis). Therefore, by inhibiting COX-2, NSAIDs reduce inflammation and pain.

So, for each unit good Aspirin does by blocking one COX-2, it does one unit of bad through its blocking COX-1. Thus, we learned early that we have to take the good with the bad if we are going to use Aspirin or other NSAIDs as pain relievers.

NSAIDs Beyond Aspirin
NSAIDs or Non-Steroidal Anti-Inflammatory Drugs are a group of drugs commonly used to treat arthritis because of their analgesic (pain-killing), anti-inflammatory, and antipyretic (fever-reducing) properties. The mechanism of action of NSAIDs is the inhibition of the enzyme Cyclooxygenase (or COX, for short), which catalyzes arachidonic acid to prostaglandins and leukotrienes. Arachidonic acid is released from membrane phospholipids as a response to inflammatory stimuli. Prostaglandins establish the inflammatory response.

Indomethacin (Indocin) was discovered in 1963 and it was first approved for use in the US by the Food and Drug Administration in 1965. Its claim to fame was that it blocks two COX-2s for every COX-1. This should theoretically make it twice as safe as Aspirin as it preserves twice the amount of the good COX-1 as it inhibits the bad COX-2 that was induced from the inflammatory response. There are many NSAIDs available. High dose Aspirin (two 325 mgm pills 4x daily) acts like an NSAID by blocking one COX-1 for every COX-2. The first generation NSAIDs block two COX-2s for every COX-1 and include: Ibuprofen, Motrin, Advil, Aleve, Naprosyn, Anaprox, Voltaren, Arthrotec, Dolobid, Lodine, Ansaid, Indocin, Orudis, Toradol, Relafen, Daypro, Feldene, Clinoril, Tolectin, Mobic, and others. In an attempt to make NSAIDs safer, the idea of blocking more COX-2 than COX-1 came about. The second generation COX-2 inhibitors block many (about 100) COX-2s for every COX-1, and are theoretically safer for the stomach and include: Celebrex, Vioxx, and Bextra.

Vioxx Woes
In the 1990s, there was tremendous hope of reducing GI morbidity and mortality with drugs that more selectively blocked COX-2. FDA originally approved Vioxx in May 1999. Its approval was "fast tracked" as it was considered to be a quantum leap forward in safety compared with first generation NSAID competitors. The 1998 NDA included over 5000 subjects who were exposed up to 86 weeks with 12.5 or 25 mgm of Vioxx. They also had a group of 272 subjects that took Vioxx 50 mgm for at least six months. They failed to uncover any CV signals in clinical trials, but they were looking for them closely over concern of the pro-thrombotic effects in vitro. By not blocking COX-1 as much, the blood was thicker. Merck & Co Inc. voluntarily recalled the widely prescribed arthritis drug Vioxx® on September 30, 2004, amidst evidence that it drastically increased users' risk of heart attack and stroke. In light of the Vioxx® recall, the FDA has been accused of having a "far too cozy" relationship with drug companies and of being "incapable of protecting America," according to Reuters' news wire service. According to CNN.com, the U.S. Food and Drug Administration (FDA) allegedly quieted one of its scientists, Dr. David J. Graham, when he voiced safety concerns about the drug Vioxx® several weeks before pharmaceutical giant Merck & Co Inc. pulled it from the market. Newsday.com reported that while the recent three-year study of 1,300 Vioxx® users yielded enough frightening evidence to warrant a recall of the drug, Vioxx® was known for years to be dangerous, as it has been linked to numerous injuries. Side effects of Vioxx® include heartburn, nausea, diarrhea, upper respiratory tract infection, swelling of the lower extremities, high blood pressure, itching, stomach ulcers or bleeding, fatigue, vomiting, dark urine, and black stools. Vioxx® has also been more recently linked to an increased risk of heart attack, stroke, and blood clots. Merck may have been aware of the risks associated with Vioxx®. Some allege that the company altered its original study findings in the late '90s - omitting information about dangerous side effects - in order to gain faster FDA approval. In 2002, Merck acknowledged that Vioxx® can cause stomach bleeding and ulcers, yet it did not pull the drug or scale back its promotion campaigns. Instead, it included warnings on its labels as mandated by the FDA. Vioxx® -induced strokes are serious. They can cause permanent injury and, oftentimes, death. A stroke occurs when the blood flow to the brain somehow disrupted. Such disruption is typically caused by either a blocked blood vessel or hemorrhaging. Vioxx® can cause either type of stroke. Merck may have been aware of the risks associated with Vioxx®. The Sept. 2004 withdrawal of Vioxx® initiated a wave of lawsuits from patients who suffered health problems related to the drug. About 20 million Americans had taken the medication when it was recalled. A conservative estimate reported in a study by the Food and Drug Administration links as many as 28,000 deaths to Vioxx®. Another study completed by a physician at the Cleveland Clinic estimates 160,000 individuals have suffered heart attacks or strokes in connection with Vioxx® use. CBS 60 Minutes Story - CBS News correspondent Ed Bradley reveals that according to internal Merck documents that 60 Minutes has seen, and interviews with outside scientists, Merck had concerns that Vioxx could possibly cause cardiovascular risks long before it was pulled off the market.

In November 1999 Merck initiated the APPROVe study [Adenomatous Polyp Prevention on VIOXX] and it was designed to measure the effects of Vioxx 25 mgm vs. Placebo on colon polyps. The study came to an abrupt halt after eighteen months. At this time researchers discovered that patients taking Vioxx 25 mgm for at least eighteen months had double the risk of suffering life threatening side effects like a Vioxx stroke or heart attack. This was in 2001, however. Vioxx didn’t get off the market until 30 Sep. 2004! They should have pulled it in 2001 as soon as these results were available. Merck’s side of the story was that it only represented a 2% increase from 25 per thousand events (Heart Attack & Stroke) in the placebo group to 45 per thousand in the Vioxx 25 mgm group after 18 months. In addition, Merck contends that definitive confirmation of risk was not evident until the 36 month assessment was completed. That is still 2002 and Merck should have acted sooner to describe the thrombotic effects of Vioxx and to withdraw it sooner. FDA originally approved Vioxx in May 1999. The original safety database included approximately 5000 patients on Vioxx and did not show an increased risk of heart attack or stroke.

In June 2000, the APPROVe protocol was modified to allow concomitant use of low dose aspirin to prevent Vioxx induced thrombosis (blood clots that can cause heart attacks and strokes). In January 1999 Merck initiated VIGOR (VIOXX GI Outcomes Research). This study was primarily designed to look at the effects of Vioxx on side effects such as stomach ulcers and bleeding and was submitted to the FDA in June 2000. The study showed that patients taking Vioxx had fewer stomach ulcers and bleeding than patients taking naproxen, another NSAID, however, the study also showed a greater number of heart attacks in patients taking Vioxx. The VIGOR study was discussed at a February 2001 Arthritis Advisory Committee and the new safety information from this study was added to the labeling for Vioxx in April 2002. Merck then began to conduct longer-term trials to obtain more data on the risk for heart attack and stroke with chronic use of Vioxx. Results from the VIGOR trial also indicated a significant Vioxx stroke risk. The findings even found that the Vioxx stroke risk for individuals with a history of heart and stroke problems was five times the risk for the trial participants taking naproxen. Instead of looking seriously into the Vioxx stroke risks associated with their medication, Merck decided to spin the research results in a different direction. The pharmaceutical giant argued that naproxen was actually somehow (possibly by blocking more COX-1) preventing heart attack and stroke in patients. This, Merck posited, was the reason it seemed as if Vioxx stroke risks seemed significant. Somehow this excuse was accepted, despite the fact that naproxen has never been associated with stroke or heart attack prevention properties. A Vioxx stroke is a serious and potentially fatal side effect of this pain reliever. Many argue that the potential Vioxx stroke risks should have been promptly evaluated after the first study produced evidence of these serious risks. Had Merck taken the appropriate precautions at that point, many Vioxx stroke cases might have been prevented. A Vioxx stroke is an interruption in the brain's blood supply as a result of a hemorrhage or an obstruction. A Vioxx stroke can result in permanent and serious damages and even death. When the results of VIGOR were released in March 2000 including increased risk of heart attacks, letters to all investigators went out describing this and the ICFs (Informed Consent Forms) for subjects currently in Vioxx trials were modified to reflect the possibility that Vioxx may increase their risk of stroke. In June 2000, VIGOR was sent to FDA as NDA supplement to include increases in CV thrombotic events, mostly MI 0.5% vs. 0.1%. In November 2000, VIGOR was published in the NEJM.

Richard Horton, editor of a leading international medical journal, The Lancet, criticized the FDA's science and regulatory components from having a "clear breakdown in communications," which Horton said, "suggests the FDA is dysfunctional." Horton's comments come after turbulent months for the drug industry and the FDA. The Lancet published a paper online yesterday submitted by Dr. David Graham, an FDA scientist, which suggested Vioxx had caused up to 140,000 serious injuries or deaths since the FDA approved its use in 1999 up to its September 2004 recall.

The popular arthritis drug Vioxx is once again the subject of concern among heart specialists. A study conducted by Andrew Whelton, MD, of Universal Clinical Research Center in Maryland has shown that taking Vioxx in combination with high blood pressure medications will double the risk of heart attack. After eliminating other factors that increase heart attack risks, such as history of heart problems and age of the patient, Vioxx was the only drug that increased the heart attack risk, although the risk was only significant among patients also on medication to treat high blood pressure.

By 2002, Merck was in discussions with the FDA regarding label changes to reflect the mixed picture of CV (Cardiovascular) risk. In April 2002, the label includes the CV risk and goes further to state that the 50mgm dose should not be used for more than 5 days.

In 2003, Merck had continued focus on ongoing trials and data collection and assessment for CV safety. Clearly they were aware of the potential problem at this point. Instead of promoting it so strongly and to groups where the potential benefit was not worth the risk, they should have been placing a black box warning for thrombosis and advising anyone concerned about a heart attack or a stroke to avoid this product. Failure to act here in this manner is what caused Merck's Vioxx heart break.

In August 2004, the Kaiser Cohort analysis was nearing completion and an abstract was presented at ISPE (International Society for Pharmacoepidemiology) which confirmed VIGOR's results regarding risk of Vioxx 50mgm. In September 2004, the APPROVe 36 month study results were reviewed by the DSMB (Data Safety Monitoring Board) and finally on September 30, 2004, Merck voluntarily withdrew Vioxx from the market.

The exact mechanism of risk is uncertain. It may involve: platelet stimulation; BP elevation; or some other mechanism. In any case, in my mind all NSAIDs are suspect, and in light of this data, should be used less often, in lower doses, and for shorter periods of time until the dust settles regarding NSAID induced CV risk. Vioxx’s data was mixed from very early on. Merck should have focused on the CV risk form the beginning. They should have black box warned it from the start until definitive studies proved it unwarranted. They should have not promoted so strongly and pervasively. Most patients got the message that Vioxx was a stronger, safer NSAID compared with the first generation NSAIDs. This is not true and Merck knew this from the start!


Sincerely:

Joseph Saponaro, MD, DABIM, FACP, CPI, CCI, CCTI, CCRC, CCRP
Expert Medical Witness, ExpertMD
PI (Principal Investigator), DSI (Drug Study Institute)
Board Certified Internist, JPMC (Jupiter Preventive Medicine Center)
DABIM (Diplomat American Board of Internal Medicine)
FACP (Fellow American College of Physicians)
CPI (Certified Physician Investigator) by the AAPP (American Academy of Pharmaceutical Physicians)
CCTI (Certified Clinical Trial Investigator) by the ACRP (Association of Clinical Research Professionals)
CCI (Certified Clinical Investigator) by the DIA (Drug Information Association)
CCRC (Certified Clinical Research Coordinator) by the ACRP (Association of Clinical Research Professionals)
CCRP (Certified Clinical Research Professional) by SoCRA (Society of Clinical Research Associates)
Member, SIMPD (Society for Innovative Medical Practice Design)
Member, ACPM (American College Preventive Medicine)
Ethics Committee Member, Jupiter Medical Center
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