PCI-CURE findings show benefit of pre- and post-PCI treatment with clopidogrel

Susan Jeffrey

August 15, 2001

Wed, 15 Aug 2001 20:20:00

London, UK - Results of the PCI-CURE study show pretreatment followed by long-term therapy with clopidogrel reduced the occurrence of major cardiovascular events among patients with non-ST-elevation acute coronary syndromes (ACS) undergoing PCI. The strategy was judged superior to one of no pretreatment followed by short-term (4 weeks) clopidogrel therapy.

PCI-CURE is a substudy of the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study. The results are published in the August 18, 2001 issue of the Lancet, to coincide with the publication of CURE results in the August 16, 2001 issue of the New England Journal of Medicine.

"These results imply that in patients with non-ST-elevation acute coronary syndromes in whom an invasive strategy with PCI is planned, clopidogrel started on admission before the procedure and continued long-term afterwards is beneficial in reducing both early and later major ischemic cardiovascular events," Dr Shamir R Mehta (McMaster University, Hamilton) and colleagues conclude.

Clopidogrel in conservative ACS strategy

The CURE study, first presented last March at the American College of Cardiology Annual Scientific Sessions, randomized 12562 patients within 24 hours of the onset of unstable angina symptoms to clopidogrel or placebo for 3 to 12 months. All patients received aspirin. Both primary endpoints of this trial, cardiovascular death, MI and stroke, and CV death, MI, stroke and refractory ischemia, were significantly reduced with clopidogrel, although the addition of the study drug was also associated with a significant increase in major, but not life-threatening bleeding.

By design, CURE was meant to examine clopidogrel in the setting of a conservative approach to ACS management, and institutions whose policy it is to treat these patients with early angiography and revascularization were excluded.

However, some patients did undergo PCI at the discretion of the investigator, generally in response to refractory symptoms or adverse events. PCI-CURE was a prospectively designed study of patients randomized to double-blind therapy with clopidogrel or placebo in the CURE trial, who underwent PCI.

PCI patients

Of the 2658 patients, 1313 received clopidogrel and 1345 placebo. PCI was performed during the initial hospital stay in 1730, and the remaining 928 after discharge.

Patients were pretreated with aspirin and the study drug for a median of 6 days before PCI during the initial hospital admission, and a median of 10 days overall. After PCI, most patients received open label thienopyridine (either clopidogrel or ticlopidine) for 4 weeks, after which they began the study drug again for a mean of 8 months. GP IIb/IIIa inhibitors were discouraged except during PCI, and when the patient developed refractory ischemia.

The primary endpoint was a composite of cardiovascular death, MI, or urgent target-vessel revascularization (TVR), although events at all time points were recorded.

 

This is really the first time that we've shown in a prospective, randomized fashion that pretreatment with clopidogrel is beneficial.

 

Patients treated with clopidogrel had significantly fewer primary endpoint events (between PCI and 30 days) than those on placebo. Most of this benefit was derived from pretreatment with clopidogrel and aspirin versus aspirin alone, Mehta told heart wire in an interview, given most (>80%) received open label clopidogrel after the procedure as standard practice after implantation of a stent.

"This is really the first time that we've shown in a prospective, randomized fashion that pretreatment with clopidogrel is beneficial in patients undergoing angioplasty." Mehta said. "This is something that interventional cardiologists have suspected is important to do many of us pretreat our patients but we really did not have good prospective, randomized evidence to demonstrate this."

Among patients receiving clopidogrel over the long-term, there were significantly lower rates of CV death, MI, or any revascularization, and of CV death or MI compared to placebo.

"Overall (including events before and after PCI) there was a 31% reduction [in] cardiovascular death or myocardial infarction," Mehta et al write.

PCI-CURE: Major endpoints


Events

Placebo

Clopidogrel

RR

(95% CI)

p value

206 (15.3%)
159 (12.1%)
0.76
(0.62-0.93)
0.008
86(6.4%)
59 (4.5%)
0.70
(0.50-0.97)
0.03
292 (21.7%)
240 (18.3%)
0.83
(0.70-0.99)
0.03
169 (12.6%)
116 (8.8%)
0.69
(0.54-0.87)
0.002
* MI or refractory ischemia **CV death, MI or urgent TVR ***CV death, MI, any revascularization ****CV death, MI

In CURE, majorbut not life-threateningbleeding was significantly increased with clopidogrel compared to placebo, but an excess of major bleeding in PCI-CURE did not reach significance. Life-threatening bleeding was also similar between the groups. However, minor bleeding was significantly more common in the clopidogrel group between PCI and follow-up.

PCI-CURE: Bleeding


Endpoint

Placebo

Clopidogrel

RR

(95% CI)

p value

19 (1.4%)
21 (1.6%)
1.13
(0.61-2.10)
0.69
33 (2.5%)
36 (2.7%)
1.12
(0.70-1.78)
0.64
10 (1.1%)
13 (1.0%)
1.33
(0.59-3.03)
0.49
28 (2.1%)
46 (3.5%)
1.68
(1.06-2.68)
0.03
To download tables as slides, click on slide logo below

Among patients who received GP IIb/IIIa inhibitors, no increase in major bleeding (p=0.97) or life-threatening bleeding (p=0.98) was seen between those randomized to receive the addition of clopidogrel versus placebo.

Limited information?

In a commentary accompanying the publication, Dr Rodney H Stables (Royal Liverpool University Hospital) points out that PCI-CURE is an observational study, with PCI or surgical revascularization undertaken by the investigators only in response to clinical need. A policy of early invasive management and use of GP IIb/IIIa inhibitors was discouraged.

"Hence, the external validity of the findings is less clear for the growing number of institutions and health-care systems that have introduced a policy of aggressive medical therapy as a prelude to early angiography and revascularization than it is for those pursuing conservative management," he writes.

Stables points out that findings from recent trials have suggested an advantage of early invasive management over the more conservative ("CURE-like") strategy in the setting of the universal early administration of GP IIb/IIIa inhibitors, such as in the TACTICS trial.

 

Unfortunately, this analysis provides only limited information that might refine current approaches to early invasive therapy.

 

Of the PCI-CURE data, he says, "Unfortunately, this analysis provides only limited information that might refine current approaches to early invasive therapy, not least because surgical revascularization has been ignored."

This assertion by Stables was met with some puzzlement on the part of PCI-CURE investigators Mehta and Dr Salim Yusuf (McMaster University).

"The PCI-CURE paper is actually specifically dealing with people who undergo the invasive procedure, so we found it rather inconsistent, because the whole paper is about management when you do interventions," Yusuf told heart wire . "That's where the benefit is shown."

He pointed to a subanalysis published with the main CURE data in the NEJM showing a similar benefit from clopidogrel treatment both among those who underwent revascularization after randomization and those who did not. "The effect is identical," he said.

The data from the CURE and PCI-CURE papers do suggest that clopidogrel should be started when the patient presents with ACS, and not be reserved for loading prior to PCI, Stables writes. The use of GP IIb/IIIa inhibitors may negate the need for clopidogrel altogether, although there is some evidence the two may be complementary, he adds. "The prescription of these two agents together is not a major variation on current patterns of use and is probably the preferred option."

However, Stables questions any conclusion from this paper on the value of long-term clopidogrel therapy. The findings were grouped from PCI to 30 days and from PCI to end of follow-up, which includes the events from the intervention to the 30-day mark when clopidogrel is routinely used.

 

The optimum duration of therapy with clopidogrel, irrespective of invasive or conservative management, is yet to be determined.

 

"Beyond 30 days post PCI there is no significant advantage of active therapy over placebo in terms of the rates of cardiovascular death or non-fatal myocardial infarction (3.1% versus 4.0%, RR 0.78, 95% CI 0.5-1.17)," he concludes. "For patients presenting with non-ST-elevation ACS the optimum duration of therapy with clopidogrel, irrespective of invasive or conservative management, is yet to be determined."

Again though, Yusuf and Mehta pointed to data published with the main CURE paper, and noted their information was that Stables had perhaps not seen the main results. The rate of the first primary outcome was lower in the clopidogrel group both within the first 30 days after randomization (RR 0.79 [0.67-0.92]) and between 30 days and the end of the study (RR 0.82 [0.70-0.95]) in that data, Yusuf noted.

"So in the main paper we explicitly show the data under 30 days, clear benefit, about 20%, and then... 30 days till the end of the study, again, 20%, in fact highly significant," he said. However, that same measure did not reach significance in the PCI-CURE paper because the calculation there was based on only 2500 of the 12500 patients forming the CURE data, Yusuf said. "By looking at 1/12th of the data, he comes to a misleading conclusion."

The editorialist replies

Stables, however, had a variety of issues with the comments made by Yusuf and Mehta in response to his commentary. "The CURE trial represents an important advance and will have a real impact for the many ACS patients that are managed conservatively," Stables told heart wire . PCI-CURE also provides important information that will be of value in guiding clinical practice, he added, principally reinforcement of the accepted practice of clopidogrel pre-treatment. However, Stables said, "My Lancet commentary aims to sound a note of caution, because PCI-CURE has some important limitations."

First, the study reports outcomes of PCI cases performed as part of an otherwise conservative strategy. "We cannot assume that the findings will translate to patients managed with a more aggressive approach based on up-front GP IIb/IIIa use and routine in-hospital angiography and revascularization," he said.

Secondly, the PCI-CURE study was not itself randomized, but was an observational study of those who underwent PCI after randomization, Stables adds: "The initial allocation to clopidogrel or placebo may have created a selection bias, particularly in cases when PCI was required soon after randomization. The main CURE paper tells us that active therapy with clopidogrel was associated with a reduced burden of refractory ischemia and need for early revascularization."

Finally, Stables notes, his commentary states that the optimum duration of therapy is yet to be determined. "This is a self-evident fact," he asserts. "I suspect that life-long therapy would be advantageous but cannot substantiate this on the basis of the CURE data."

The PCI-CURE data do not provide evidence to support prolonged therapy beyond the usual post-PCI course, and those from the main CURE paper, "are not strictly relevant to the PCI-CURE presentation," Stables says. Moreover, "readers must not allow themselves to become confused about follow-up timings," he adds. In the CURE data mentioned in the response by Yusuf (above), events were grouped as those occurring before and after 30 days from randomization. "Follow-up events in PCI-CURE are not timed from randomization but grouped with reference to the first PCI procedure," occurring anywhere from 3 to 106 days after randomization," he concluded. "This variation makes it difficult to draw firm conclusions."



Related links

1. [Heartwire > News; Mar 19, 2001]

2. [Heartwire > News; Aug 15, 2001]

3. [Heartwire > News; Jun 20, 2001]


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