The NSAID and CVD Balancing Act

An Expert Interview With Daniel Solomon, MD

Linda Brookes; Daniel Solomon, MD

Disclosures

August 30, 2011

In This Article

PRECISION: A Randomized Trial Comparing the Safety of Celecoxib vs Ibuprofen or Naproxen

Medscape: The first randomized trial data about the cardiovascular adverse effects of NSAIDs will come from the Prospective Randomized Evaluation of Celecoxib Integrated Safety vs Ibuprofen or Naproxen (PRECISION) trial[24,25] and you are on the Executive Committee. PRECISION will compare the cardiovascular safety of celecoxib with the 2 most commonly prescribed nonselective NSAIDs, ibuprofen and naproxen, in patients with osteoarthritis or rheumatoid arthritis and established or be at high risk of developing cardiovascular disease. The high-risk patients you are enrolling have to meet 3 inclusion criteria: age > 55 years, hypertension, dyslipidemia, family history of premature cardiovascular disease, current smoker, left ventricular hypertrophy, documented ankle brachial index < 0.9, and history of microalbuminuria. So this will be a very mixed population.

Dr. Solomon: To some extent it is a real-world population of moderate to high cardiovascular risk patients because that is the group that we are most concerned about. We are on our way to enrolling 20,000 people; it is quite a task to keep such a large number in the trial and on a drug for several years.

Medscape: In the paper describing rationale and the design of the trial,[25] you say that the absence of a true placebo arm makes determination of the risk associated with each of these agents impossible.

Dr. Solomon: Yes, but you cannot have a placebo arm in any long-term trials of analgesics; it would be unethical. Furthermore, giving nothing is not an option for many patients in clinical practice.

Medscape: Drug dosages in the trial are celecoxib 100-200 mg twice a day, naproxen 375-500 mg twice a day, and ibuprofen 600-800 mg 3 times a day, with esomeprazole in all patients. Doses of naproxen and ibuprofen may be further increased in patients with osteoarthritis. How safe would the higher doses of ibuprofen be? Haven't doses above 1800 mg daily been associated with an increased risk for cardiovascular disease[4,26,27] and with increased risk for death in hospitalized cardiovascular patients on aspirin,[28] which is permitted in this trial?

Dr. Solomon: That ibuprofen dose is moderate to maximum; it is what you would give when you give prescription strength. We were trying to find an equally analgesic dose. It is not obvious what the right dose is. So, we tried to develop equally analgesic dosing and there was a lot of discussion and a lot of examination of the pharmacodynamic data. The choices we made were very reasonable but can be debated.

Medscape: According to the latest update, the estimated completion date for the PRECISION trial is 2014.[24] Do you think that by that time there will be any new NSAIDs available, ones that are known to be without cardiovascular side effects? There are a number of NSAIDs in various stages of clinical development, including new classes of molecules.

Dr. Solomon: There are always more on the horizon. I am not involved in drug development and am not aware of the details of such agents.

Medscape: Several drugs have reached phase 3, but these new first-in-class drugs have not yet reached regulatory approval.

Dr. Solomon: It is not for lack of trying. There has been a lot of work done on the COX-inhibiting nitric oxide donators (CINODs). The first in class was naproxcinod, but it failed to gain approval by the FDA.[29]

Medscape: Another class of drugs in development for chronic pain is the nerve growth factor (NGF) inhibitors, including the monoclonal antibodies tanezumab and fulranumab. At this time, clinical development of all anti-NGFs is on hold, following reports of a need for total joint replacements in some patients in the tanezumab trials.[30,31] The FDA's Arthritis Advisory Committee is due to decide in September whether development of these drugs should continue.[32] It does seem difficult to bring a new class of drugs for chronic pain in arthritis to the clinic.

Dr. Solomon: First, I should disclose that I am on the data and safety monitoring boards for several clinical trials of tanezumab. But yes, I think you are right -- it is tough. These drugs are tested in people who have many comorbidities, so it is not surprising that adverse outcomes develop. It is sometimes hard to determine whether these adverse outcomes are drug-related or related to an underlying condition. As well, in the NGF inhibitor trials, many subjects are very old and chronically disabled. These drugs are not being tested in healthy, young adults. One should not generalize from the CINODs to the NGF inhibitors; however, it is hard to do drug development in old sick people. Because this is a large population with an unmet need, I hope that companies continue to work in the area of chronic pain and osteoarthritis.

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