Cyclo-oxygenase-2 (COX 2) inhibitors should be used only as the last choice after other types of non-steroidal anti-inflammatory drugs (NSAIDs) to relieve chronic pain in people with heart disease or at high risk of it, the American Heart Association has recommended. Its statement, which will be published this month in Circulation (http://circ.ahajournals.org), was designed to end any remaining confusion about the cardiovascular risk of these agents.
The association has recommended a stepped approach to treatment. The first step should be non-pharmacological approaches, such as physical therapy and weight loss, for patients with known cardiovascular disease or with risk factors for ischaemic heart disease. Drug treatment should start with agents with the lowest reported risk of cardiovascular events, before other agents are prescribed, and at each step account should be taken of the risk-benefit balance.
First line drug choices include paracetamol (acetaminophen), aspirin, tramadol, and short term use of other narcotic analgesics. If these fail to achieve adequate pain control, the next option is non-acetylated salicylates, such as naproxen.
The expert committee recommended NSAIDs that aren't COX 2 inhibitors if pain is still inadequately controlled, then NSAIDs with some COX 2 activity as the next step, and then COX 2 selective NSAIDs as the last choice. The committee considered the risk of all three of these classes to be sufficiently high to require that patients taking them should be monitored regularly for sustained hypertension (or worsening of prior blood pressure control), oedema, worsening renal function, or gastrointestinal bleeding.
Elliott Antman, professor of medicine at Harvard Medical School and Brigham and Women's Hospital and the lead author of the statement, said, “Some physicians have been prescribing the COX 2 selective inhibitors as the first line of treatment, thinking that they reduce the risk of cardiovascular and gastrointestinal side effects. We are turning that around and saying that, for chronic pain in patients with known heart disease or who are at risk for heart disease, these drugs should be the last line of treatment. They are not safer from a cardiovascular perspective, and the gastrointestinal benefits are marginal at best.”
An expert group developed the statement after reviewing all relevant research, including a total of 121 trials with a total of more than 30 000 patients.
They found several studies showing an increased risk of cardiovascular complications with COX 2 selective NSAIDs, particularly in patients with prior cardiovascular disease or risk factors for that disease. The complications included myocardial infarction, stroke, heart failure, and hypertension. One meta-analysis showed a relative risk of myocardial infarction of 1.9 (95% confidence interval 1.3 to 2.6) in patients treated with COX 2 inhibitors, compared with placebo (BMJ 2006;332:1302-8).
“We can now say there is convincing, incontrovertible evidence that COX 2 inhibitors are associated with increased cardiovascular risk,” said Professor Antman.
He said that recent studies had shown that cells lining the blood vessels contain more COX 2 enzyme than initially thought. Inhibiting the COX 2 pathway may increase the tendency of blood to clot, raising the risk of thrombosis. Studies have also indicated an increase in sodium and water retention with COX 2 inhibitors, which could worsen heart failure and increase blood pressure.
At the same time, the group found recent studies showing that non-COX 2 selective NSAIDs also increased cardiovascular risk, which is why they have recommended their use only after drugs such as paracetamol and aspirin.