The Clopidogrel in Unstable angina to prevent Recurrent Events (PCI-CURE) trial1 showed that pretreatment with clopidogrel (300 mg loading dose, followed by 75 mg daily) in addition to aspirin for a median of 10 days before percutaneous coronary intervention (PCI), compared with aspirin alone, reduced the composite of cardiovascular death, myocardial infarction or urgent target vessel revascularisation by 30% (absolute risk reduction 1.9%,

\(p=0.03\)
) after 1 month. Long-term clopidogrel therapy, after 1 month of open-label ticlopidine or clopidogrel in stented patients in both groups, reduced the composite of death, myocardial infarction or any revascularisation by 16% (absolute risk reduction 3.4%,
\(p=0.03\)
) at the end of follow-up (mean 8 months). The authors concluded, “In patients with acute coronary syndrome receiving aspirin, a strategy of clopidogrel pretreatment (before PCI) followed by long-term therapy is beneficial in reducing major cardiovascular events, compared with placebo”.

The Clopidogrel for the Reduction of Events During Observation (CREDO) trial2 also suggested that pretreatment with clopidogrel in addition to aspirin is important. The CREDO trial showed a 38.6% relative reduction of the composite of death, myocardial infarction, and urgent target vessel revascularisation after 4 weeks, compared with aspirin alone, in the subgroup of patients receiving clopidogrel (300 mg loading-dose) at least 6 h before the procedure. This was equivalent to an absolute risk reduction of approximately 3%,

\(p=0.051\)
. However, the frequent use of glycoprotein IIb/IIIa antagonists (45%) in CREDO may have obscured the true value of pretreatment with clopidogrel. Long-term therapy, after 4 weeks of open-label clopidogrel in both groups, reduced the composite of death, myocardial infarction, or stroke by 26.9% (absolute risk reduction 3.0%,
\(p=0.02\)
) after 1 year. Fourteen percent of the patients in the 1-year analysis never underwent PCI, which is remarkable in a study of clopidogrel in PCI. The investigators stated, “Following PCI, long-term (1-year) clopidogrel therapy significantly reduced the risk of adverse ischaemic events.”

Clopidogrel given before a PCI clearly reduces major ischaemic events and is cost-effective.1,3 However, the extension of treatment beyond the first few months after the procedure is not supported by the data. The combination of pretreatment (including a loading dose) and 7 (PCI-CURE) or 11 (CREDO) months of additional clopidogrel therapy after the first 4 weeks of open-label thienopyridine administration explains the differences after 8 months/1 year. However, the value of long-term treatment with clopidogrel post-PCI isolated from pretreatment is impossible to determine. Only patients who received preprocedural clopidogrel continued to receive it long-term in both PCI-CURE and CREDO, while control patients were given a placebo after the first 4 weeks. The actual effect of long-term clopidogrel would have been possible to ascertain if the groups had been re-randomised after 1 month, or if both groups had been pretreated with clopidogrel. The CREDO-investigators argued that it is difficult to postulate an influence of pretreatment on late thrombotic events.2 However, platelet inhibition with a glycoprotein IIb/IIIa antagonist during PCI has been shown to improve long-term outcome after the procedure.4 Consequently, a sustained beneficial effect of preprocedural platelet inhibition with a thienopyridine cannot be excluded.

Differences in the number of events between the clopidogrel and placebo groups after the first 4 weeks post-PCI may be used to estimate the merits of long-term clopidogrel therapy. The best conceivable effects of isolated long-term clopidogrel treatment post-PCI are shown in Table 1.

Table 1

The maximum conceivable effects of isolated long-term clopidogrel therapy in PCI-CURE1 and CREDO2



 

Clopidogrel
\((n=1313)\)

 

Placebo
\((n=1345)\)

 
Events between 1 and 8 months (mean) after percutaneous coronary intervention in PCI-CURE   
Death 18 (1.4%) 18 (1.3%) 
Myocardial infarction 31 (2.4%) 34 (2.5%) 
Death or myocardial infarction 41 (3.1%) 49 (3.6%) 
Any revascularisation 161 (12.3%) 192 (14.3%) 
Major bleeding 15 (1.1%) 14 (1.0%) 
Death, myocardial infarction or any revascularisation 181 (13.8%) 206 (15.3%) 
   

 
Clopidogrel
\((n=1053)\)

 
Placebo
\((n=1063)\)

 
Events between day 29 and 1 year after percutaneous coronary intervention in CREDOa   
Death 18 (1.7%) 20 (1.9%) 
Myocardial infarction 18 (1.7%) 30 (2.8%) 
Death or myocardial infarction 32 (3.0%) 47 (4.4%) 
Stroke 9 (0.9%) 12 (1.1%) 
Any revascularisation 216 (20.5%) 211 (19.8%) 
Major bleeding 43 (4.1%) 33 (3.1%) 
Death, myocardial infarction or stroke
 
37 (3.5%)
 
58 (5.5%)
 


 

Clopidogrel
\((n=1313)\)

 

Placebo
\((n=1345)\)

 
Events between 1 and 8 months (mean) after percutaneous coronary intervention in PCI-CURE   
Death 18 (1.4%) 18 (1.3%) 
Myocardial infarction 31 (2.4%) 34 (2.5%) 
Death or myocardial infarction 41 (3.1%) 49 (3.6%) 
Any revascularisation 161 (12.3%) 192 (14.3%) 
Major bleeding 15 (1.1%) 14 (1.0%) 
Death, myocardial infarction or any revascularisation 181 (13.8%) 206 (15.3%) 
   

 
Clopidogrel
\((n=1053)\)

 
Placebo
\((n=1063)\)

 
Events between day 29 and 1 year after percutaneous coronary intervention in CREDOa   
Death 18 (1.7%) 20 (1.9%) 
Myocardial infarction 18 (1.7%) 30 (2.8%) 
Death or myocardial infarction 32 (3.0%) 47 (4.4%) 
Stroke 9 (0.9%) 12 (1.1%) 
Any revascularisation 216 (20.5%) 211 (19.8%) 
Major bleeding 43 (4.1%) 33 (3.1%) 
Death, myocardial infarction or stroke
 
37 (3.5%)
 
58 (5.5%)
 
a

Calculations from the CREDO-trial are approximate since per-protocol data were reported after 28 days and intent-to-treat data after 1 year.

After the first 4 weeks following PCI, there was no significant advantage of clopidogrel over placebo in terms of death or myocardial infarction in either PCI-CURE or CREDO. The number of myocardial infarctions tended to be slightly lower in the clopidogrel group in CREDO, but not in PCI-CURE. Fewer re-interventions were reported in PCI-CURE, but this was not the case in CREDO. In the CURE study,5 from which the patients in PCI-CURE were recruited, long-term clopidogrel did not reduce the need for a primary intervention (36.0% vs. 36.9%,

\(p=\mathrm{ns}\)
). Thus, there is no convincing evidence that clopidogrel reduces the need for revascularisation procedures. Moreover, outcomes like revascularisation for recurrent ischaemia are influenced not only by clinical needs but also by local traditions.6 Even when the composite endpoints in PCI-CURE and CREDO are considered, the absolute reductions in risk were small, and around 97% of the patients showed no apparent benefit of the combination of pretreatment and long-term clopidogrel therapy after the procedure.1,2

To prevent a myocardial infarction 4 weeks to 12 months after a PCI in CREDO, the number needed to treat was around 90. The number needed to treat to prevent a myocardial infarction in PCI-CURE 1–8 months post-PCI was more than 580. The daily cost of clopidogrel (75 mg) is around 1.8 EUR in Sweden. Consequently, the expenditure on clopidogrel to avoid a myocardial infarction after one month post-PCI ranged from 54,000 EUR in CREDO to more than 240,000 EUR in PCI-CURE.

Clopidogrel therapy aims firstly to reduce thrombotic complications by pacifying platelets after a plaque rupture or PCI, secondly at preventing complications of subsequent episodes of plaque rupture or erosion.7 Since most adverse ischaemic events occur within a few months of the initial presentation, it is probable that the absolute benefits of clopidogrel therapy are greater during the acute phase and decrease during the prevention phase. The excess risk of bleeding with clopidogrel is constant, however, which unfavourably changes the risk: benefit ratio of clopidogrel during the secondary prevention phase.7 The increased risk of bleeding with new antithrombotic regimens was taken into consideration in a novel combined efficacy and safety endpoint, the composite of cardiovascular death, myocardial infarction, urgent target vessel revascularisation, or major bleeding, used in the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 trial.8 This quadruple endpoint did not show any advantage of clopidogrel over placebo when applied to CREDO, clopidogrel 111/900 (12.3%) versus placebo 114/915 (12.5%) after 28 days; clopidogrel 202/1053 (19.2%) versus placebo 208/1063 (19.6%) after 1 year.

Why have the, at best, trivial effects of long-term clopidogrel therapy after PCI resulted in widespread application in routine clinical practice? The well-reputed authors of PCI-CURE and CREDO strongly advocated it, enthusiastically supported by distinguished clinicians and experts. Moreover, the marketing has been vigorous and extensive. Obviously, the medical profession has accepted the message without much serious consideration. However, clopidogrel therapy beyond a few months post-PCI does not influence mortality, has a questionable effect on the incidence of myocardial infarction, and drains substantial economical resources in a way that cannot be considered cost-effective in light of the evidence. An increase in major bleeding may further offset any advantages. Altogether, long-term therapy with clopidogrel after PCI does not seem justified on the basis of PCI-CURE or CREDO.

References

[1]
Mehta
SR
, Yusuf S, Peters RJG et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study.
Lancet
 .
2001
;
358
:
527
–533.
[2]
Steinhubl
SR
, Berger PB, Mann 3rd JT et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial.
JAMA
 .
2002
;
288
:
2411
–2420 (Erratum JAMA 2003;289:987).
[3]
Berglund
U
, Richter A. Clopidogrel treatment before percutaneous coronary intervention reduces adverse cardiac events.
J. Invas. Cardiol
 .
2002
;
14
:
243
–246.
[4]
Karvouni
E
, Katritsis DG, Ioannidis JPA. Intravenous glycoprotein IIb/IIIa receptor antagonists reduce mortality after percutaneous coronary interventions.
J. Am. Coll. Cardiol
 .
2003
;
41
:
26
–32.
[5]
The clopidogrel in unstable angina to present recurrent events trial investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494–502 (Erratum N Engl J Med 2001;345:1716).
[6]
Bogaty
P
, Brophy J. Increasing burden of treatment in the acute coronary syndromes: is it justified?
Lancet
 .
2003
;
361
:
1813
–1816.
[7]
Harding
SA
, Boon NA, Flapan AD. Antiplatelet treatment in unstable angina: aspirin, clopidogrel, glycoprotein IIb/IIIa antagonist, or all three?
Heart
 .
2002
;
88
:
11
–14.
[8]
Lincoff
AM
, Bittl JA, Harrington RA et al. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: Replace-2 randomized trial.
JAMA
 .
2003
;
289
:
853
–863 (Erratum JAMA 2003;289:1638).

Comments

0 Comments