The Arthritis Drug Celebrex is as Safe as Ibuprofen and Naproxen
In December of 1998, the first of a new class of arthritis pain relievers was approved. Called Celebrex (generic name: celecoxib), this drug was a selective COX-2 inhibitor designed to maintain the pain-reducing properties of traditional non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and naproxen, but not be burdened with gastrointestinal side effects that plagued the older drugs. A month after Celebrex was jointly launched by Pharmacia and Pfizer, Merck launched its COX-2 inhibitor, Vioxx, and prescriptions for these two new drugs took off.
COX-2 inhibitors can do more than providing pain relief. Celebrex has been shown to reduce the formation of polyps in the colon of patients with familial adenomatous polyposis (FAP), a rare disease that if left untreated can lead to colon cancer. In fact, the FDA had approved an NDA supplement for the use of Celebrex in patients with FAP. Scientists believed that it was possible that COX-2 inhibitors could also be used to treat more patients with colon cancer. Thus, both Pfizer and Merck launched long-term studies in patients with colon cancer to test this hypothesis.
Then, on September 27, 2004, the Data Security Monitoring Board responsible for the Merck study, known as APPROVe (“Adenomatous Polyp Prevention on Vioxx”), dropped a bomb. They recommended stopping the study because the patients showed an increased risk of heart attacks and strokes, particularly those who had been on Vioxx for more than 18 months. Merck immediately withdrew Vioxx from the market. However, the FDA faced a dilemma. Celebrex was still on the market, and other COX-2 inhibitors entered the advanced stage of development.
Was the increase in cardiovascular risk (CV) considered to be unique for Vioxx, or were all COX-2 inhibitors produced adverse CV effects? To address this issue, the FDA called for a joint meeting of Osteoarthritis Advisory Committee and the Advisory Committee on Safety and Risk Control. The meeting lasted three days. It consisted of 30 advisers, an unusually high number. They covered the range of properties of COX-2 inhibitors to understand the risk-benefit profile of the drugs. At the end of the sessions, the joint committee voted to allow Celebrex to remain on the market because it was clear that long-term use of other NSAIDs also posed cardiovascular risks. The FDA agreed with the recommendation. In fact, one of the results of that meeting was the recognition that non-selective NSAIDs also posed a CV risk. As a result, the FDA made the following change to the label of Celebrex:
Celebrex can cause an increased risk of thrombotic cardiovascular events, myocardial infarction and stroke, which can be fatal. All NSAIDs may have similar risks. The risks may increase with the duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at increased risk.
While it seemed to address the issue, the FDA now had a bigger problem. Patients with arthritis tend to be older, heavier and not able to exercise because of joint pain. They are the same patients who are prone to heart disease. How should doctors be advised to treat arthritis pain in such patients? The FDA asked Pfizer to sponsor a study to answer that question. The study was led by esteemed cardiologist Dr. Steven Nissen of the Cleveland Clinic and involved 24,081 patients, of whom one third were randomized to Celebrex (“Celebrex Integrated Safety vs. Ibuprofen or Naproxen”). The primary goal of the study was to measure CV causes, including death, heart failure, heart failure, heart failure, and heart failure, hemorrhagic, nonfatal myocardial infarction, and nonfatal stroke.
PRECISION results are now available. They were presented yesterday by Dr. Nissen at the meeting of the American Heart Association with the simultaneous publication of the results in the New England Journal of Medicine. It is safe to say that what the PRECISION researchers found would have frightened attendees at FDA Advisory Committee meetings in 2004. There were 188 deaths (2.3%) from CV causes for Celebrex patients, 201 deaths (2.5% ) for Naproxen and 218 (2.7%) for Ibuprofen. In the NEJM article, the authors state that “the PRECISION trial provides statistical evidence that the cardiovascular risk associated with moderate doses of Celecoxib is not greater than that associated with non-selective NSAIDs.” They continue that “the trial results do not support the widely held belief that Naproxen treatment, compared to other NSAIDs, results in better cardiovascular outcomes.”
Also, the PRECISION results provided further insights. Although the primary objective of the trial was to evaluate CV causes, GI and renal outcomes were considered as secondary outcomes. It is not surprising that Celebrex had significantly fewer GI safety issues – after all, that is why it was first developed. Also, cases of renal adverse events and hospitalizations for high blood pressure were even significantly lower for Celebrex compared to Ibuprofen (although Celebrex and Naproxen were not different in this effect).
The researchers recognized that PRECISION had limitations:
Consistency and retention were lower than in most trials of cardiovascular outcomes. It reflects the challenges of long-term treatment of a painful condition in patients experiencing frustration with symptoms and then switching therapy or discontinuing the study. Low levels of consistency have also been found in the previous pain studies.
The withdrawal of Vioxx from the market led to a series of attacks on the pharmaceutical industry. The industry leaders, specifically Pfizer and Merck, were seen as speculators, interested more in profits than patients. It was alleged that COX-2 inhibitors were drugs that were not needed and harmed patients. PRECISION results show that this is not true. Celebrex is an important drug for physicians to use in treating patients with arthritis with significant pain. It is safer to use Celebrex from a GI perspective than non-selective NSAIDs in patients with impaired renal function.
PRECISION was a lengthy and expensive trial. I guess it cost Pfizer over $ 500 million. Now, Pfizer will not be able to benefit from these results. Celebrex is now available generically as Celecoxib. In any case, most manufacturers of generic drugs will benefit from these results, as it is likely that more Celecoxib will be prescribed based on the results of PRECISION. Finally, it should be noted that only a big pharmaceutical company such as Pfizer could have financed such a study. From a budget point of view, it would have been crippling for an agency like the NIH to fund it.