Appendix 19b : ADS CLOPIDOGREL Session Content Draft

CLOPIDOGREL SESSION CONTENT DRAFT

Thank you very much for requesting this AD visit for ACS: ASA plus clopidogrel. We have focused on the patients who are managed medically, not those who have undergone revascularization.

The purpose of this academic detailing visit is to review the evidence from the CURE trial and its implications for management of patients with UA and NSTEMI (formerly non-Q-wave MI).

Issues to be discussed include:

• Patients to be considered for therapy with the combination of clopidogrel plus ASA
• Suggested dose of ASA to be used in combination, and
• Uncertainty about duration of combination therapy with clopidogrel plus ASA

The natural history of UA and NSTEMI places the time of greatest risk for a recurrent event within the first 30 days.

• This is confirmed by pooled data from 2 NSTEMI trials as can be seen in figure 1 (page 12) and by data from the CURE trial.

Therapy can be thought of in two phases:

1) Acute – first 30 days

2) Long term - > 30 days

The Atlantic Canada Consensus provides a protocol for both emergency room and in hospital management and also management after discharge. You are probably familiar with this and you will find it in tables 9 & 10 of the handout. It was revised in June of 2005.

Now let’s review the evidence from the CURE trial.

The Clopidogrel in Unstable angina to prevent Recurrent Events Trial (CURE)

• The CURE trial was a one-year trial designed to determine if clopidogrel plus ASA was superior to ASA alone in decreasing morbidity and mortality in ACS patients with UA and NSTEMI.
• We give a full description about the treatment groups here in the handout. However, unless you have a specific question let’s move on to the results.

Results

Here in table 2, you can see that there was a statistically significant benefit for both primary outcomes. (Show outcomes in table).

Within the composite, the only outcome that contributed significantly to the benefit was reduction in the rate of myocardial infarction.

• No other outcomes were statistically significant.

* ARR – absolute risk reduction

+ NNT – number needed to treat

# NS – not statistically significant

There were more adverse events from bleeding with clopidogrel plus ASA compared to ASA alone (See Table 3 below). For major bleeds, the absolute risk increase is 1.0% with numbers needed to harm of 100.

Table 3. Adverse events in CURE trial

*Major bleeding includes life-threatening bleeding

# Absolute risk increase

+ Number needed to harm

Do you have any questions so far?

Now let’s discuss the issues.

Who should be treated

• The original inclusion criteria for the CURE trial included patients who would fall into the low, intermediate and high risk categories of the Atlantic Canada Consensus. These patients did not experience enough events for adequate statistical analysis so the criteria were changed to include only intermediate and high risk patients.
• Therefore, the Atlantic Canada Consensus recommends that patients in the low risk category do not need to be treated with clopidogrel. However, the use of clopidogrel plus ASA is recommended for patients in the other risk categories as specified in their protocol.

Optimal dose of ASA

• When combining ASA with clopidogrel, it is suggested to prescribe ASA in a dose of ≤ 100 mg because there appear to be fewer adverse events with no reduction in efficacy.

Optimal duration of therapy

The question we want to consider is:

• Is the benefit of clopidogrel plus ASA compared to ASA alone
• sustained over the course of the CURE trial OR
• is it greater at the beginning of the trial and then decreases?

Here on the color side of the laminate is the breakdown of the treatment benefit over different time periods.

• Both are post-hoc analysis. This is an analysis of the data from a study after it is complete. Because of this and the fact that CURE was designed to detect a difference in the two treatments over a 1 year period, both results should be treated with caution.
• Over the full year of the trial, 22 CV deaths/ MIs/or strokes were prevented per 1000 patients treated.
• A published post-hoc analysis considers benefit over the time periods
• 0 to 30 days and
• 30 days to 12 months

(Mention only the events prevented line and talk about this being called a consistent benefit. Point out different in amount of time over which benefit was gained. Also point out that both results are statistically significant.)

• We think it is important to consider treatment benefit over
• 0 to 3 months and
• 3 months to 12 months

We contacted the author to obtain the event rates for the different time periods but he declined. Therefore, we had to calculate them.

We selected these time periods based on the comment from the author of CURE. He states that a substantial amount of the benefit with clopidogrel plus ASA over ASA alone is achieved by 3 months, with further small benefits over the remaining time period of the trial. Also, data from the trial indicate that most of the benefit is achieved by 3 months as can be seen here in Figure 3.

The curves showing differences in outcomes between the placebo arm (which is the ASA alone group) and the clopidogrel arm (clopidogrel plus ASA) separate early. However, by 2 to 3 months, the curves stop separating and remain roughly parallel indicating little difference in effects between the two groups.

(Go over events prevented and point out only the 0-3 months is statistically significant. You can see that including the events prevented in months 2 and 3 along with those prevented in the 3 to 12 month period leads to a statistically significant result.)

Other groups have looked at the benefits over different time periods:

• The UK National Health Service health technology assessment¹³ reports that results were not statistically significant at 6, 9, and 12 months (Table 6). The report states that “the results should be treated with caution since the CURE trial was not powered to detect temporal differences”.

Table 6. Relative risk reductions over time in CURE

Now let’s look at the risk of major bleeds

• The only available data on major bleeds over different time periods come from a post-hoc analysis¹⁰ of CURE. It reports results for
• 0 to 30 days and
• 30 days to 12 months

(Just point out absolute risk increases in the two time periods.

Table 7. Event rates of primary outcome and major bleeds at 0 to 30 days and 30 days to 1 year

*ARR – absolute risk reduction; ⁺ARI – absolute risk increase

Evidence from the MATCH trial¹⁷ and commentaries from other authors¹⁸ indicate that risk of bleeding with ASA plus clopidogrel is relatively constant after 30 days. Since the benefit of therapy appears to decrease after the first 3 months, it would be important to consider the benefits versus risks over the time frame after 3 months. Unfortunately, these data are not provided in the trial publications.

So:

In the CURE trial approximately 65% of the patients were managed medically and the rest underwent revascularization. Patients were recruited by 2000 and this treatment may not reflect treatment in 2006. Today, probably more patients are being managed by percutaneous coronary intervention.

Bottom line: The optimal duration of treatment with clopidogrel plus ASA in medically managed UA and NSTEMI patients is an area of uncertainty, especially considering that the benefit appears to decrease after 3 months.

The table here on our laminate, which is Appendix A in the handout, gives a summary of our findings along with current guideline recommendations.(Go over medically managed part).

In summary:

Patients with UA and NSTEMI who are considered to be in the low risk category do not need to be treated with clopidogrel.

When using ASA with clopidogrel, it is suggested to use a dose of ASA ≤ 100mg.

The duration of therapy with clopidogrel plus ASA is an area of uncertainty. However, a substantial part of the benefit is achieved by 3 months.

Do you have any questions?

You may soon be seeing this new form. Hopefully it will be faxed from the hospital to Pharmacare when the patient is being discharged and a copy will also be given to the patient. It will provide useful information about the procedure that your patient had while in the hospital and hopefully will facilitate Pharmacare coverage for patients who meet the criteria.

Thank you very much!