Revised: 20 May 2013


Minutes of a Meeting between the Medicines Adverse Reactions Committee and the Medsafe Pharmacovigilance Team Re: COX-2 Inhibitor Safety - 11 February 2005

At the Medsafe Large Meeting room, commencing at 8.30am


Associate Professor T Maling (Chair)
Dr S Jessamine (Principal Technical Specialist, Medsafe)
Ms S. Von Afehlt (Senior Pharmacy Advisor, Medsafe)
Dr S Sime (Medical Advisor, Medsafe)

Cardiovascular safety of the COX-2 inhibitors

  • Minutes of 238th ADEC (Australian Drug Evaluation Committee) meeting 3-4 February 2005. Item 3.1 COX-2 inhibitors - Cardiovascular Risk
  • TGA Media statement: 10 February 2005
  • TGA information to Doctors/Pharmacists: 10 February 2005
  • Incidence of cardiovascular events in patients taking celecoxib compared with those taking rofecoxib: interim results from the New Zealand Intensive Medicines Monitoring Programme (IMMP).
  • Notes from ADEC meeting February 2005
  • Request for ADEC advice re celecoxib. February 2005
  • Request for ADEC advice re meloxicam. February 2005
  • Request for ADEC advice re etoricoxib. February 2005
  • Request for ADEC advice re valdecoxib. February 2005
  • Request for ADEC advice re parecoxib. February 2005
  • Request for ADEC advice re lumiracoxib. February 2005
  • Report for ADEC (2005). Clinical evaluation of cardiovascular safety of celecoxib.
  • Report for ADEC (2005). Clinical evaluation of cardiovascular safety of meloxicam
  • Report for ADEC (2005). Clinical evaluation of cardiovascular safety of etoricoxib
  • Report for ADEC (2005). Clinical evaluation of cardiovascular safety of valdecoxib
  • Report for ADEC (2005). Clinical evaluation of cardiovascular safety of parecoxib
  • Report for ADEC (2005). Clinical evaluation of cardiovascular safety of lumiracoxib
  • Pre-ADEC response from Pfizer re celecoxib
  • Pre-ADEC response from Pfizer re parecoxib
  • Pre-ADEC response from Pfizer re valdecoxib
  • Pre-ADEC response from Boehringer Ingleheim re meloxicam
  • Pre-ADEC response from Novartis re lumiracoxib
  • Pre-ADEC response from Merck Sharp & Dohme re etoricoxib
  • Minutes of the 120th MARC meeting 16 December 2004
It was noted that the above background material was provided to the Medsafe pharmacovigilance team, the MARC Chair and to all MARC members, who were given the opportunity to provide written feedback for the meeting. In view of the limited resources available to Medsafe it had not been possible to complete an evaluation of the cardiovascular safety data provided by the product sponsors of the COX-2 inhibitors. As Medsafe and the TGA had been provided with the same data from the COX-2 inhibitor product sponsors, it was considered appropriate to use the data evaluations commissioned by the TGA. The recommendations made by both the TGA and ADEC were also reviewed.

It was noted that due to time constraints, it had not been possible to convene an extraordinary meeting of the MARC. However, MARC members have agreed that a meeting between the MARC Chair and Medsafe would be an appropriate initial course of action. It was agreed that MARC members would be contacted after the meeting to inform them of the result of the meetings discussions.

In New Zealand, six COX-2 inhibitors are approved for use: celecoxib (Celebrex), etoricoxib (Arcoxia), valdecoxib (Bextra), parecoxib (Dynastat), meloxicam (Mobic) and lumiracoxib (Prexige). Lumiracoxib is not yet marketed in New Zealand. As these medicines are not funded by PHARMAC it is not possible to ascertain accurate usage data. However, evaluation of IMMP data collected over the time period from 1 December 2000 to 30 November 2001 indicates that most patients in New Zealand are receiving treatment with COX-2 inhibitors for acute pain and osteoarthritis. Relatively few patients are receiving COX-2 inhibitors for the treatment of inflammatory arthritis. The Chair indicated that there are some anecdotal reports from rheumatologists that COX-2 inhibitors may be more efficacious for some patients than traditional NSAID therapy.

When considering the risks and benefits of COX-2 inhibitor use it was acknowledged by those present that the actual risk-benefit analysis for an individual patient would depend on a number of patient characteristics (such as an underlying genetic predisposition) that may not be readily predictable.

The recommendations made by the Australian Drug Evaluation Committee (ADEC) were reviewed in detail. In the opinion of those present there was some inconsistency in how the evidence was applied to manage the risks posed by each individual product. Thus it was not possible to support the ADEC recommendations in their entirety.

After review and discussion of the above information the following was concluded:

  1. There is a plausible biological mechanism to explain an increased risk of cardiovascular thrombo-embolic events associated with selective COX-2 inhibition. It is acknowledged that this degree of risk may be partly dependent on dose and degree of COX-2 specificity.
  2. There is evidence that in some patient groups there is an increase in cardiovascular risk associated with all COX-2 inhibitors and thus this can be considered to be a class effect. There is evidence of increased cardiovascular risk associated with:
    • Short-term use: Two trials were undertaken using parecoxib/valdecoxib for 10-17 days, in patients undergoing coronary bypass (CABG) surgery. In these studies COX-2 inhibitor use was associated with an excess cardiovascular risk compared to placebo. Preliminary IMMP data indicates that 5% of events associated with celecoxib occurred within 7 days of beginning treatment. Other short-term efficacy studies did not show an increased risk of cardiovascular events. However, these studies were generally underpowered to detect a difference in risk.
    • Chronic use: Studies involving rofecoxib (Vioxx) and celecoxib (Celebrex) have shown an increased risk of MI and stroke associated with chronic COX-2 inhibitor treatment. An analysis of etoricoxib chronic exposure studies demonstrated an increased cardiovascular risk when compared to naproxen. Long-term studies of sufficient quality have not been undertaken in the other COX-2 inhibitors, thus it is not possible to make an assessment of risk associated with chronic use of those agents.
    • Increasing dose: Clinical studies involving celecoxib, valdecoxib and rofecoxib provide some evidence of an increased cardiovascular risk with increasing dose of COX-2 inhibitor therapy.
    • Patients at high risk of cardiovascular disease: Studies involving parecoxib/valdecoxib use in CABG patients provide evidence for an increased cardiovascular risk associated with patients at high risk of cardiovascular disease. It is noted that most clinical trials involving the other COX-2 inhibitors excluded patients at high cardiovascular risk. Therefore these trials are not able to answer concerns regarding the level of cardiovascular risk associated with COX-2 inhibitor use in high-risk patients.
    • Patients at low risk of cardiovascular disease: The lumiracoxib "TARGET" study showed an increased cardiovascular risk, compared to naproxen, in patients who were not receiving aspirin. As this study excluded patients at risk of cardiovascular disease, and excluded patients who should be receiving aspirin for cardiovascular prophylaxis, this indicates a group of patients at low cardiovascular risk. The low rate of cardiovascular events in both the COX-2 inhibitor and placebo groups provides further evidence that the patients recruited were at low cardiovascular risk.
    • Degree of COX-2 specificity: Although there is evidence of an increased risk associated with the highly COX-2 specific rofecoxib compared to the less COX-2 specific celecoxib, evidence is less clear with the other COX-2 inhibitors.
  3. There is currently insufficient evidence to determine:
    • The size and degree of risk associated with each individual member of this class.
    • The size and degree of risk associated with increasing dose and increasing duration of use.
    • Predisposing factors that may result in an increase cardiovascular risk
  4. It was noted that the product sponsor for meloxicam contends that although meloxicam is COX-2 selective, it has a greater inhibitory effect on thromboxane than other COX-2 inhibitors, and thus is likely to have a reduced cardiovascular risk compared to other COX-2 inhibitors. It is acknowledged that members of this class differ with respect to chemical composition and degree of COX-2 specificity; thus it is likely that they will also differ with respect to cardiovascular risk. At present there are inadequate data available to clearly quantify a difference in risk. Therefore until data to the contrary can be assessed, all COX-2 inhibitors must be considered to be associated with a similar degree of cardiovascular risk, and any regulatory action must be applied to all members of the class.
  5. Risk/benefit analysis
    • Satisfactory clinical trial data is lacking to indicate COX-2 inhibitors are any more efficacious than traditional NSAIDs with respect to their registered indications.
    • COX-2 inhibitors are not disease-modifying agents. They are indicated for use in non life-threatening conditions and therefore only a very low level of risk can be tolerated for the general population.
    • Clinical trial data suggests that all COX-2 inhibitors are associated with a lower risk of GI bleeding and ulceration than traditional NSAIDs. However, it is noted that it may be difficult to predict which patients are likely to experience GI side effects from NSAID therapy and hence who might be predicted to benefit from the use of COX-2 inhibitor therapy.
    • In patients at low risk of gastric ulceration or bleeding, there is no benefit to be gained from COX-2 inhibitor therapy. In such patients, exposure to an increased risk of cardiovascular events cannot be clinically justified.
    • In patients at high risk of GI complications due to a past history of these events, COX-2 inhibitor use may reduce but not eliminate the risk of recurrence. Therefore, in this group of patients it would not be advisable to use a traditional NSAID or a COX-2 inhibitor.
    • The use of aspirin in combination with a COX-2 inhibitor has been shown in several studies to negate the gastro-protective effects. Therefore, patients at risk of cardiovascular disease who require aspirin should not be treated with a COX-2 inhibitor.
  6. Conclusions
    • Medsafe and the MARC Chair accept that although there is clear evidence that an increased cardiovascular risk is a class effect, the level of cardiovascular risk associated with each individual COX-2 inhibitor cannot be defined from the available evidence. However, the available evidence implicates one or more COX-2 inhibitors as having an increased cardiovascular risk associated with short-term and long-term use, and in patients at high and low risk of cardiovascular disease. Therefore, Medsafe and the MARC Chair consider that it is not possible to identify any particular patient group, or indication for use, as being free from an increased cardiovascular risk associated with the use of a COX-2 inhibitor.
    • Similarly it is difficult to clearly define which subgroup of patients is likely to benefit from the gastro-protection provided by COX-2 inhibitor therapy, and in whom the benefits of treatment may outweigh the risks.
    • After evaluation of the available evidence, it is concluded that the potential risks outweigh the potential benefits of COX-2 inhibitor therapy for most patients. In view of the inability of current evidence to quantify the risk associated with each individual product or to clearly establish "at risk populations', a cautious approach to use of these medicines is warranted.
  1. The MARC Chair will contact all MARC members to inform them of the preliminary conclusions reached by Medsafe and the MARC Chair. Members will be informed that the cardiovascular safety of the COX-2 inhibitors will be placed on the agenda for discussion at the next MARC meeting scheduled for Tuesday 15 March 2005.
  2. Whilst awaiting final review of the evidence by the full MARC, the following precautionary advice should be communicated to prescribers:
    • COX-2 inhibitor treatment should be stopped immediately in all patients with a previous history of MI or stroke or at high cardiovascular risk (eg positive family history, diabetes, smoking, hypercholesterolaemia or hypertension).
    • All other patients should discuss alternative treatment options with their GP at their next scheduled appointment.
    • Medsafe recommends that prescribers refer to the recently issued BPAC guidance for advice on the use of alternative analgesia (NSAIDs-strategies for minimising harm - BPAC 2004). This publication also provides advice on the management of patients at high risk of GI ulceration or bleeding.
  3. Medsafe should inform the COX-2 inhibitor product sponsors of the outcome of the review undertaken by the Medsafe and the MARC Chair. Medsafe should inform the product sponsors of the potential options available under the Medicines Act (1981) to manage the risk associated with the COX-2 inhibitors. Product sponsors should be given the opportunity to respond to the concerns identified by Medsafe and the MARC Chair and should be requested to provide any additional safety data to Medsafe by 1 March 2005 for consideration by the MARC on 15 March 2005.
  4. Medsafe should review the results of regulatory reviews currently being undertaken by the FDA and the EMEA and provide this information to the MARC for consideration on 15 March 2005.
  5. It is anticipated that the MARC will issue definitive advice on the cardiovascular safety of the COX-2 inhibitors following their March meeting. Medsafe should be prepared to communicate this advice to prescribers and consumers via a media statement and a "Dear Health Professional" letter.

The meeting ended at 10.30am

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