A Danish study has provided new information about the cardiovascular safety of using pain-killing medicinal products of the NSAID type. The study is a well-designed pharmacoepidemiological study based on, among other things, information from the Danish Register of Medicinal Product Statistics, and it was published on 5 November 2008 at the website of the journal Clinical Pharmacology & Therapeutics. You can see the article via the factbox to the right.
In 2004, the COX-2 inhibitor Vioxx® (rofecoxib) was withdrawn. There were a number of reasons for the withdrawal, one of which was the increased risk of serious cardiovascular adverse reactions, including death. Since then, there has been much focus on the cardiovascular safety of medicinal products with the same or closely related mechanisms of action (NSAID). In 2006, the Committee for Medicinal Products for Human Use (CHMP) at the European Medicines Agency (EMEA) reviewed the cardiovascular safety of a wide range of medicinal products of the NSAID type.
The CHMP recommended caution in the use of these products, and it also recommended that the products should only be used after a thorough assessment of each individual patient’s risk (see the factbox to the right). At the same time, the product information for a number of NSAID products was updated with warnings about this increased risk of adverse reactions.
What are the main findings of this new study?
The study comprises over 1 million Danes, who did not use a number of specific medicinal products for the treatment of heart disease. On average, the NSAID users were 40 years old and used the medicinal products for an average of 2-3 weeks.
It came as no surprise that the study found a statistically significant increased risk of heart attack or death from the use of the two COX-2 inhibitors (rofecoxib and celecoxib). What was more surprising, was that the study also found an increased risk of death or heart attack from the use of especially diclofenac and to a lesser extent ibuprofen. The study did not find any increased cardiovascular risk from the use of naproxen. For all of the medicinal products studied, there was an increased risk from the use of large doses compared to small doses, but the statistically significant risk of death/heart attack was also present from the use of small doses of rofecoxib, celecoxib and diclofenac.
The Danish Medicines Agency’s assessment
The Danish Medicines Agency finds this new data disturbing. It is particularly of concern that the risk of serious cardiovascular adverse reactions is seen for the traditional NSAID products diclofenac and to a lesser extent ibuprofen, even in low doses. The low doses of both diclofenac and ibuprofen can be purchased over the counter in Denmark and many other European countries.
During this week, the Danish Medicines Agency has presented the matter and the findings of the study to the CHMP’s Pharmacovigilance Working Party (PhVWP) with the aim of initiating a common European review of the safety of NSAID products relative to cardiovascular adverse reactions. Likewise, the Danish Medicines Agency has requested the Danish Licensing Committee to assess the matter – especially whether medicinal products containing ibuprofen and diclofenac should maintain their status as over-the-counter products in Denmark.
Until the results of these assessments are available, the Danish Medicines Agency continues to recommend that NSAID products are used with caution, i.e. in the smallest dose possible and for the shortest period of time possible. NSAID products should only be prescribed after careful consideration of alternative treatments, and only after a weighing of benefits and risks in the individual patient – including the individual patient's risk of cardiovascular disease. Patients treated with an NSAID product should therefore discuss alternative treatments with their general practitioner.
The Danish Medicines Agency recommends pharmacies to advise consumers to use NSAID products with due consideration, and preferably in the smallest dose possible and for the shortest period of time possible. If any medicine users with a prescription for an NSAID product feel insecure about their medicine, they should consult their general practitioner.
For further information, please contact Chief Medical Officer Steffen Thirstrup, tel. +45 2246 7811.
Danish Medicines Agency, 19 November 2008