| Discussion |
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:
- 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.
- 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.
- 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
- 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.
- 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.
- 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.
Recommendations
- 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.
- 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.
- 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.
- 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.
- 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.
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