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 own COX-2 inhibitor, Vioxx, and prescriptions for these two new drugs took off.
However, the COX-2 inhibitors had a potential use beyond pain relief. Celebrex was shown to reduce the formation of polyps in the colon of patients with familial adenomatous polyposis (FAP), a rare disease which if untreated can lead to colon cancer. In fact, the FDA had approved a supplemental NDA for the use of Celebrex in FAP patients. Scientists believed that it was possible that the COX-2 inhibitors could be used as to treat the broader colon cancer population as well. Thus, both Pfizer and Merck launched long-term studies in colon cancer patients to test this hypothesis.
Then, on September 27, 2004, the data safety monitoring board responsible for oversight of Merck’s study, known as APPROVe (“Adenomatous Polyp Prevention on Vioxx”), dropped a bombshell. They recommended that the study be stopped because patients on the drug showed an increased risk of heart attacks and strokes, particularly in those who had been on Vioxx for more than 18 months. Merck immediately withdrew Vioxx from the market. However, the FDA was in a dilemma. Celebrex was still on the market and other COX-2 inhibitors were in late-stage development. Was the increased cardiovascular (CV) risk seen unique to Vioxx, or did all COX-2 inhibitors suffer from adverse CV effects? To help with this problem, the FDA called a joint meeting of their Arthritis Advisory Committee and the Drug Safety & Risk Management Advisory Committee. This meeting lasted three days and consisted of 30 advisors–an unusually high number. It covered the gamut of the properties of COX-2 inhibitors in order to understand the risk-benefit balance that these drugs posed to patients. At the end of these sessions, the joint committee voted to allow Celebrex to stay on the market as it became clear that long-term use of other NSAIDs also posed CV hazards. The FDA agreed with this recommendation. In fact, one of the big outcomes of this meeting was that the non-selective NSAIDs also posed a CV risk. As a result, the FDA made the following change to the Celebrex label:
Celebrex may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction and stroke, which can be fatal. All NSAIDs may have a similar risk. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk.
While this solved the immediate problem, the FDA now had a bigger issue. Patients with arthritis tend to be older, heavier and not easily able to exercise due to joint pain–the very patients that are prone to heart disease. How should physicians be advised as to best treat arthritis pain in this population? The FDA asked Pfizer to sponsor a study to answer that question. Known as PRECISION (“Prospective Randomized Evaluation of Celebrex Integrated Safety vs. Ibuprofen or Naproxen”), the study was led by the esteemed cardiologist Dr. Steven Nissen of the Cleveland Clinic and involved 24,081 patients, a third of whom were randomly assigned to Celebrex, a third each to prescription doses of ibuprofen and naproxen. The key inclusion criteria for the trial were that patients had established CV disease or increased risk for the development of CV disease. The primary outcome measured was death from CV causes, including hemorrhagic death, nonfatal myocardial infarction and non-fatal stroke.
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The PRECISION results are now available. They were presented yesterday by Dr. Nissen at the ongoing American Heart Association meeting with simultaneous publication of the results in the New England Journal of Medicine. It is safe to say that what the PRECISION investigators found would have startled those attendees at the FDA Advisory Committee meetings held back in 2004. There were 188 deaths (2.3%) from CV causes for the Celebrex patients, 201 deaths (2.5%) for those on naproxen and 218 (2.7%) for the ibuprofen patients. In the NEJM article, the authors state that “the PRECISION trial provides statistically strong evidence that the cardiovascular risk associated with moderate doses of celecoxib is not greater than that associated with non-selective NSAIDs.” They go on to say that “the trial results do not support the widely advocated belief that naproxen treatment, as compared to other NSAIDs, results in better cardiovascular outcomes.”
Furthermore, the PRECISION results provided other revelations. While the primary purpose of the trial was to assess CV outcomes, GI and renal outcomes were looked at as secondary endpoints. It is no surprise that the Celebrex had significantly fewer GI safety issues–after all, that’s why these drugs were first developed. But the rates of renal adverse events and hospitalizations for high blood pressure were also significantly lower for Celebrex compared to ibuprofen (although Celebrex and naproxen were no different on this effect.)
The study investigators acknowledged that PRECISION had limitations:
- Adherence and retention were lower than in most trials that assess cardiovascular outcomes, which reflects the challenges of long-term treatment of a painful condition in patients who frequently experience frustration with unrelieved symptoms and switch therapies or leave the trial. Low levels of adherence have also been found in previous pain studies.
- The events that surrounded the withdrawal of Vioxx from the market led to a slew of attacks on the pharmaceutical industry. The industry, specifically Pfizer and Merck, were looked at as profiteers, committed not to patients but to profits. It was alleged that the COX-2 inhibitors were drugs that weren’t necessary and which actually harmed patients. The PRECISION results show that this isn’t the case. Celebrex is an important drug for physicians to use in treating arthritis patients in significant pain. It is safer to use from a GI perspective than non-selective NSAIDs and, in patients with kidney function issues, it is safer than ibuprofen.
- PRECISION was a long and expensive trial. I would guess that it cost Pfizer more than $500 million. Furthermore, Pfizer will benefit little from these results. Celebrex is now generically available as celecoxib. If anything, generic drug makers will benefit from these results, as it is likely that more celecoxib will be prescribed as a result of PRECISION. Finally, it must be noted that only a pharmaceutical company of Pfizer’s size could have funded such a study. From a budgeting standpoint, it would have been crippling for an agency like the NIH to have paid for this.
- PRECISION has helped physicians and patients better understand the risks and benefits of the drugs used to treat arthritis pain. They have Pfizer to thank for that.