CURE results show significant benefits of clopidogrel in acute coronary syndromes

March 19, 2001

Orlando, FL - The results of the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial have shown a highly significant and clinically important benefit of the oral antiplatelet agent, clopidogrel, when given in addition to aspirin for the chronic treatment of acute coronary syndromes (unstable angina or non-Q-wave MI).

Results released on March 19, 2001 at the American College of Cardiology 50th Annual Scientific Session in Orlando, FL showed a 20% relative reduction in the primary composite endpoint of cardiovascular death, MI or stroke. There was an increase in bleeding, but this was said to be acceptable and a ?small price to pay for the benefits seen."

The CURE trial, which is being referred to by experts as a "blockbuster," will have a considerable impact on the treatment of ACS, extending it into the primary care market. It could also turn clopidogrel into one of the best-selling drugs in the world.

 
The widespread use of clopidogrel in addition to aspirin in ACS could prevent about 50 000-100 000 heart attacks, strokes, or deaths every year in North America.
 

Although there are now many treatments for the acute phase of ACS, so far only aspirin is used long-term. Clopidogrel therefore becomes only the second agent ever to be used chronically in this population, which represents a truly massive market. ACS is the most common cause of admission to coronary care units, and accounts for 2 million hospitalizations each year in the US alone.

Lead investigator Dr Salim Yusuf (McMaster University, Hamilton, ON), said the finding of an added benefit with clopidogrel "is one of the most significant advances for patients with acute coronary syndromes since aspirin." He added, "The widespread use of clopidogrel in addition to aspirin in ACS could prevent about 50000-100000 heart attacks, strokes, or deaths every year in North America." He said the global impact could be several times greater, with 250000 -500000 major events prevented every year even if only 20% of eligible patients receive treatment.

"The super-aspirin that has actually lived up to its name"

Most doctors questioned after the presentation of the results said they would now start all their ACS patients on clopidogrel, with the intention of continuing treatment long-term. These included Dr Chris Cannon (Brigham & Women's Hospital, Boston, MA) and Dr Robert Califf (Duke University, Durham, NC).

Cannon described clopidogrel as "the super-aspirin that has actually lived up to its name." He said the drug would now become standard of care. "This is an oral pill, it's safe and it has a dramatic benefit. It is exactly what we've been hoping for, and has succeeded where the oral Gp IIb/IIIa blockers failed. There should be a rush on pharmacies next week. We will start giving it to our patients tomorrow." Califf was just as enthusiastic. "I will treat all my ACS patients now. It's hard to see who you wouldn't give it to."

Clopidogrel is currently approved for the reduction of events in patients with atherosclerosis documented by recent stroke, MI, or established peripheral artery disease. This is based on the CAPRIE trial, which came out in 1996. This trial directly compared clopidogrel with aspirin and showed a modest benefit of clopidogrel (8% relative reduction in events).

 
Clopidogrel has succeeded where the oral Gp IIb/IIIa blockers failed. There should be a rush on pharmacies next week. We will start giving it to our patients tomorrow.
 

Although this has led to the drug being used instead of aspirin in some patients (particularly those intolerant of aspirin) many felt this modest benefit did not justify exchanging it for aspirin in all patients given its additional cost. The CURE trial, which has shown a much larger benefit when clopidogrel is given on top of aspirin, should therefore also now encourage increased use of clopidogrel (in addition to aspirin) in the CAPRIE indication. This population encompasses around 6 million patients in the US alone. The drug is also routinely used to prevent in-stent thrombosis, and has now replaced ticlopidine in this setting.

Califf actually went one step further and said he would also consider starting clopidogrel in stable CAD patients, of whom there are 12 million in the US alone. Although he admitted this was extrapolating the results somewhat, he said it seemed likely that it would also benefit this population, and a trial is now called for in this setting.

Calculating the cost of clopidogrel

The only barrier to treatment is cost. Clopidogrel costs around $3 per day in the US (and somewhat less elsewhere). Although this will be no problem for in-hospital costs, it may be a barrier to long-term treatment, especially in the US, where elderly patients (the majority of ACS patients) do not receive Medicare reimbursement for drug treatment outside the hospital.

Yusuf said that preliminary calculations suggest that clopidogrel treatment would be cost-saving if used for 6 months, and cost-neutral if used for 1 year. He is planning full-scale economic analysis of the study, to be presented later in the year.

Many clinicians said that, if costs allowed, they would leave their patients on clopidogrel indefinitely. Others said they would advise stopping treatment after a year.

Either way, sales of clopidogrel should now rocket. Current sales of the drug, which is marketed by Sanofi-Synthelabo and Bristol-Myers Squibb, are around $1.1 billion. Analysts are forecasting that, with these positive results from CURE, sales could rise to $5 billion in a few years time. This would make clopidogrel one of the best-selling drugs in any field.

Trial design

The CURE trial randomized 12562 ACS patients to aspirin alone (75-325 mg per day) or aspirin plus clopidogrel. Clopidogrel was given as a 300-mg loading dose followed by a regular chronic dose of 75 mg per day. Patients were followed for 3-12 months (average 9 months).

The trial was conducted in 28 countries, with most patients recruited in Canada (2000) and Europe (5000). Around 500 patients came from the US; 61% of patients were male, 75% had unstable angina, 93% had abnormal ECGs, and 25% had elevated enzymes/troponins. Forty-six percent of patients were on heparin, 50% on LMW heparin, 78% on beta blockers, 36% on calcium blockers, 50% on ACE inhibitors and 47% on lipid lowering drugs.

Main efficacy results

End point

Aspirin (n=6303)

Aspirin plus clopidogrel (n=6259)

Risk ratio

p value

CV death, MI, stroke (primary end point) 11.47% 9.28% 0.80 0.00005
CV death 5.4% 5.06% 0.92 N/A
MI 6.68% 5.19% 0.77 <0.001
Stroke 1.4% 1.2% 0.85 N/A
Non-CV death 0.70% 0.67% 0.96 N/A

  Other efficacy results

End point

Aspirin (n=6303)

Aspirin plus clopidogrel (n=6259)

Risk ratio

p value

CV death, MI, stroke, refractory ischemia (2nd primary end point) 19.02% 16.68% 0.86 0.0004
Refractory ischemia 9.4% 8.8% 0.93 N/A
Refractory ischemia in hospital 2.08% 1.42% 0.69 Significant
Refractory ischemia after discharge 7.66% 7.67% 1.00 N/A
Severe ischemia 5.03% 3.83% 0.76 0.001

Safety

No major safety problems with clopidogrel were seen. There was a 1% absolute increase in major bleeding in the clopidogrel group, but Yusuf described this as "modest," and "identical to that seen with aspirin versus placebo." "This 1% increase in major bleeds, which are not life-threatening, is a small price to pay for the benefits seen," he said.

Bleeding results

End point

Aspirin (n=6303)

Aspirin plus clopidogrel (n=6259)

Risk ratio

p value

Major bleeding 2.7% 3.6% 1.34 0.003
Life-threatening bleeding 1.8% 2.1% 1.15 N/A
Transfusions 2.2% 2.8% 1.28 0.03

Yusuf pointed out that there was no increase in fatal bleeding, and all the additional life-threatening bleeds could be attributed to transfusions of more than 4 units of blood. "These bleeds defined as life-threatening can therefore be dealt with by blood transfusions," he said.

"The results show that treating 1000 patients for 9 months prevents 28 major events in 23 patients at a cost of 3 life-threatening bleeds, which are wholly reversible, and 3 other transfusions."

Benefit starts early and continues long-term

Yusuf noted that the primary endpoint curves diverged (within 2 hours of starting treatment) and continued to diverge until the end of the study. This shows that the benefit of clopidogrel takes effect immediately and continues long-term.

In an interview with heartwire , Yusuf said that there was a 20% relative reduction in the primary endpoint in the first 30 days and a 20% relative reduction after 30 days, showing that it is worth continuing the drug long-term. "What's more, there was no excess in major bleeding in the clopidogrel group after 30 days, so if anything the risk-benefit ratio is enhanced in the long-term," he added.

Subgroups all benefit

Subgroup analysis showed that there was consistent benefit of clopidogrel across all groups, including both high-risk and low-risk patients as shown in the table below:

High-risk/low-risk subgroup analysis: primary end point

Subgroup

Aspirin (n=6303)

Aspirin plus clopidogrel (n=6259)

Risk ratio

ST changes 14.3% 11.5% 0.79
No ST changes 8.7% 7.0% 0.80
Enzyme elevations 13.1% 10.7% 0.81
No enzyme elevations 10.9% 8.8% 0.79
Previous revascularizations 14.6% 8.4% 0.55
No previous revascularizations 10.8% 9.5% 0.87
Postrandomization revascularizations 13.9% 11.4% 0.81
No postrandomization revascularizations 10.1% 8.1% 0.79

Yusuf noted that there were 30 other subgroups analyzed, and all showed consistent benefit with clopidogrel.

PCI substudy

Around 3000 patients had a percutaneous intervention (PCI), an average of 6 days after starting study medication. These patients are the subjects of a separate PCI substudy, the results of which will be presented at the ESC meeting in Stockholm in September 2001.

CABG

In addition, 1500 patients underwent coronary bypass surgery. As expected, bleeding rates were increased in both groups in CABG patients, but the relative excess with clopidogrel was not increased, Yusuf noted.

What about patients given early PCI/Gp IIb/IIIa blockers?

One thing CURE does not address is the role of clopidogrel in patients who are started on a IIb/IIIa blocker and/or given an intervention as soon as admitted, which is standard practice for high-risk ACS patients in some US centers.

The trial was mainly conducted outside the US, and specifically excluded patients who had received a IIb/IIIa blocker within the previous 3 days or who had received a revascularization within the previous 3 months.

Yusuf said the results could probably be extrapolated to this setting, as there had been no problem giving clopidogrel with Gp IIb/IIIa blockers or PCI later on. "This trial should not challenge any practice patterns. Clopidogrel works whether you believe in aggressive or conservative management. These results should not upset anyone." Califf said most patients at Duke were already given clopidogrel in this setting, as they were routinely taken to the cath lab early on and clopidogrel was given beforehand to prevent in-stent thrombosis. He said they routinely started clopidogrel at the same time as Gp IIb/IIIa blockers soon after hospital admission.

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