In December 1998, the first of a new class of painkillers for arthritis was approved. Called Celebrex (generic name: celecoxib), this drug was a selective COX-2 inhibitor designed to maintain the pain-reducing properties of traditional nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and naproxen, but not loaded with Gastrointestinal side effects that plagued the older drugs. One month after Celebrex was jointly launched by Pharmacia and Pfizer, Merck launched its own COX-2 inhibitor, Vioxx, and the prescriptions for these two new drugs took off.
However, COX-2 inhibitors had potential use beyond 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 the broader population of 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 monitoring the Merck study, known as APPROVe (“Adenomatous Polyp Prevention on Vioxx”), dropped a bomb. They recommended that the study be stopped because patients on the drug 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 was in a dilemma. Celebrex was still on the market and other COX-2 inhibitors were in advanced stage of development. Was the increase in cardiovascular risk (CV) considered to be unique for Vioxx, or were all COX-2 inhibitors suffering from adverse CV effects? To help with this problem, the FDA convened a joint meeting of its Osteoarthritis Advisory Committee and the Advisory Committee on Safety and Risk Control. This meeting lasted three days and consisted of 30 advisers, an unusually high number. It covered the range of 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 remain on the market, as it was clear that long-term use of other NSAIDs also posed cardiovascular risks. The FDA agreed with this recommendation. In fact, one of the great results of this meeting was 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 serious thrombotic cardiovascular events, myocardial infarction and stroke, which can be fatal. All NSAIDs may have a similar risk. This risk may increase with the duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at increased risk.
While this solved the immediate problem, the FDA now had a bigger problem. Patients with arthritis tend to be older, heavier and not easily able to exercise because of joint pain, the same patients who are prone to heart disease. How should doctors be advised to better treat arthritis pain in this population? 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,” a The primary outcome measure was death from 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% ) By those of naproxen and 218 (2.7%) for patients with ibuprofen. In the NEJM article, the authors state that “the PRECISION trial provides statistically robust evidence that the cardiovascular risk associated with moderate doses of celecoxib is not greater than that associated with non-selective NSAIDs.” They continue to say that “the trial results do not support the widely held belief that naproxen treatment, compared to other NSAIDs, results in better cardiovascular outcomes.”
In addition, the PRECISION results provided further insights. Although the main objective of the trial was to evaluate CV results, GI and renal outcomes were considered as secondary endpoints. It is not surprising that Celebrex had significantly fewer GI safety issues – after all, that is why these drugs were first developed. But 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 not different in this effect).
The study investigators recognized that PRECISION had limitations:
Adherence and retention were lower than in most trials evaluating cardiovascular outcomes, reflecting the challenges of long-term treatment of a painful condition in patients experiencing frustration with undisturbed symptoms and switching therapy or discontinuing the study . Low levels of adherence have also been found in previous pain studies.
The events surrounding Vioxx’s withdrawal from the market led to a series of attacks on the pharmaceutical industry. The industry, specifically Pfizer and Merck, were seen as speculators, committed not to patients but to profits. It was alleged that COX-2 inhibitors were drugs that were not needed and actually harmed patients. PRECISION results show that this is not the case. Celebrex is an important drug for physicians to use in treating patients with arthritis in significant pain. It is safer to use from a GI perspective than non-selective NSAIDs and, in patients with impaired renal function, is safer than ibuprofen.
PRECISION was a long and expensive trial. I guess it cost Pfizer over $ 500 million. In addition, Pfizer will benefit little from these results. Celebrex is now available generically as celecoxib. In any case, manufacturers of generic drugs will benefit from these results, as it is likely that more celecoxib will be prescribed as a result of PRECISION. Finally, it should be noted that only a pharmaceutical company of size 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 have paid for this.