Clopidogrel

What it is

Clopidogrel is an oral antiplatelet tablet. It is a prodrug: it does nothing until the liver, mainly the enzyme CYP2C19, converts it into an active metabolite. That metabolite binds irreversibly to the P2Y12 ADP receptor on platelets, so a platelet it has hit stays blunted for its whole life. It is usually taken as 75 mg once daily, sometimes after a loading dose.

What the research says

Clopidogrel reduces heart attacks, strokes and cardiovascular deaths in people who already have arterial disease, and it increases bleeding. In the CURE trial in acute coronary syndrome, adding clopidogrel to aspirin cut the primary composite outcome from 11.4% to 9.3% over 3 to 12 months - an absolute reduction of about 2.1 percentage points - while major bleeding rose from 2.7% to 3.7%. Against aspirin alone in stable atherosclerosis (CAPRIE), the absolute difference was 9.8% versus 10.6%. Adding it to aspirin in largely stable, lower-risk patients (CHARISMA) produced no benefit on the primary endpoint. How well it works also depends on a person's CYP2C19 genotype, which is the subject of its boxed warning.

Evidence grade: Well established.

How it works

Drug class: Thienopyridine P2Y12 ADP-receptor antagonist (antiplatelet)

Clopidogrel itself is inactive. The liver converts it, chiefly through CYP2C19, into an active metabolite that permanently blocks the P2Y12 ADP receptor on platelets, so platelets clump together less and clots are less likely to form on damaged arteries or stents. Because the binding is irreversible, the effect wears off only as new platelets are made. (Source 1)

Boxed warning

WARNING: DIMINISHED EFFECTIVENESS IN POOR METABOLIZERS

(Source 1)

What it is used for

• In 12,562 patients randomised within 24 hours of symptoms, clopidogrel added to aspirin reduced cardiovascular death, heart attack or stroke from 11.4% to 9.3% over 3 to 12 months (RR 0.80, 95% CI 0.72 to 0.90), at the cost of more major bleeding. Evidence: established. (Source 2)
• The CAPRIE trial compared clopidogrel with aspirin and found a lower rate of the composite outcome, 9.8% versus 10.6%, a relative risk reduction of 8.7% (p=0.045). The absolute difference is under one percentage point. Evidence: established. (Source 1)
• The CHARISMA trial of 15,603 such patients found no difference in the primary composite of cardiovascular death, heart attack or stroke (6.8% versus 7.3%, p = 0.22), while moderate bleeding increased. A broader secondary endpoint that also counted hospitalisation for an ischaemic event was lower with clopidogrel (16.7% versus 17.9%, p = 0.04), but a secondary endpoint in a trial with a null primary endpoint does not establish benefit. Evidence: not-supported. (Source 3)

Interactions

• Omeprazole and other CYP2C19-inhibiting proton pump inhibitors (pharmacokinetic study): Omeprazole blocks the enzyme that turns clopidogrel into its active form, so less active drug is made and platelets are less inhibited. Spacing the doses apart does not fix it. (Source 4)
• St John's wort (Hypericum perforatum) (clinical trial): St John's wort induces the liver enzymes that activate clopidogrel, so it increases rather than decreases clopidogrel's antiplatelet effect. A small open-label randomised trial in people who were not responding to clopidogrel found platelet reactivity fell more on St John's wort, though the difference was gone by four weeks. This means it can push antiplatelet effect up unpredictably, and bleeding risk with it. (Source 5)
• Grapefruit juice (clinical trial): Grapefruit juice inhibits enzymes involved in activating clopidogrel, so it has been proposed to reduce its antiplatelet effect. A randomised crossover study in healthy volunteers given a 300 mg loading dose and 75 mg/day maintenance clopidogrel with grapefruit juice or water concluded that its own data were not sufficient to establish whether the interaction is real. (Source 6)

Stopping it

• Stopping clopidogrel early is itself a risk. The prescribing information states that gaps in therapy should be avoided and that stopping prematurely can raise the chance of a cardiovascular event; this is recorded as a regulator's position on a label updated in 2023, not as a trial result. (Source 1)
• Because the active metabolite binds platelets irreversibly, the antiplatelet effect does not stop when the last tablet is taken; it fades only as the body makes new platelets. The trials ran clopidogrel for defined periods - CURE for 3 to 12 months - rather than testing a taper. (Source 2)

What goes wrong

Clopidogrel added to aspirin increased major bleeding in acute coronary syndrome. (Source 2)

• Randomized trial, High certainty.
• Size: 12,562 participants.
• Who: adults with acute coronary syndrome without ST-segment elevation.
• How long: 3 to 12 months.
• Result: major bleeding 3.7% versus 2.7%, relative risk 1.38, P=0.001 (about 1 extra major bleed per 100 people treated); life-threatening bleeding 2.1% versus 1.8%, P=0.13, not significant.
• Funding: industry-funded - Sanofi-Synthelabo and Bristol-Myers Squibb.

There were significantly more patients with major bleeding in the clopidogrel group than in the placebo group (3.7 percent vs. 2.7 percent; relative risk, 1.38; P=0.001), but there were not significantly more patients with episodes of life-threatening bleeding (2.1 percent vs. 1.8 percent, P=0.13) or hemorrhagic strokes.

The trial investigators themselves framed the result as a trade-off, not an unqualified benefit. (Source 2)

• Randomized trial, High certainty.
• Size: 12,562 participants.
• Who: adults with acute coronary syndrome without ST-segment elevation.
• How long: 3 to 12 months.
• Result: benefit on ischaemic events alongside an increase in major bleeding.
• Funding: industry-funded - Sanofi-Synthelabo and Bristol-Myers Squibb.

However, the risk of major bleeding is increased among patients treated with clopidogrel.

People who are CYP2C19 poor metabolizers get less antiplatelet effect and have higher cardiovascular event rates on standard doses. (Source 1)

• Official position, Certainty not rated.
• Size: not stated; the label cites published genotype frequencies.
• Who: people with acute coronary syndrome or undergoing percutaneous coronary intervention.
• How long: not stated.
• Result: poor metabolizer genotype frequencies given as approximately 2% for whites, 4% for blacks and 14% for Chinese.
• Funding: not applicable - regulatory document.

Published frequencies for poor CYP2C19 metabolizer genotypes are approximately 2% for whites, 4% for blacks and 14% for Chinese.

CHARISMA showed the harm side of adding clopidogrel to aspirin without the benefit, with more moderate bleeding and no primary-endpoint gain. (Source 3)

• Randomized trial, Moderate certainty.
• Size: 15,603 participants.
• Who: stable cardiovascular disease or multiple risk factors.
• How long: median 28 months.
• Result: Severe bleeding 1.7% versus 1.3% (RR 1.25; p = 0.09); moderate bleeding 2.1% versus 1.3% (p < 0.001), against no difference in the primary composite endpoint.
• Funding: not stated on the page read.

Severe bleeding trended higher in the clopidogrel group (1.7% vs. 1.3%; RR, 1.25; p = 0.09), while moderate bleeding was significantly higher in the clopidogrel group (2.1% vs. 1.3%, p < 0.001).

What the evidence supports

Adding clopidogrel to aspirin in acute coronary syndrome reduced cardiovascular death, heart attack or stroke by about 2 absolute percentage points. (Source 2)

• Randomized trial, High certainty.
• Size: 12,562 participants (6259 clopidogrel, 6303 placebo)
• Who: adults presenting within 24 hours of an acute coronary syndrome without ST-segment elevation, all on aspirin.
• How long: 3 to 12 months.
• Result: 9.3% versus 11.4%; relative risk 0.80 (95% CI 0.72 to 0.90), P<0.001; absolute risk reduction about 2.1 percentage points, number needed to treat about 48.
• Funding: industry-funded - Sanofi-Synthelabo and Bristol-Myers Squibb.

occurred in 9.3 percent of the patients in the clopidogrel group and 11.4 percent of the patients in the placebo group (relative risk with clopidogrel as compared with placebo, 0.80; 95 percent confidence interval, 0.72 to 0.90; P<0.001)

Against aspirin alone in stable atherosclerotic disease, clopidogrel's advantage was under one absolute percentage point. (Source 1)

• Randomized trial, Moderate certainty.
• Size: CAPRIE, as summarised in the FDA label.
• Who: patients with recent myocardial infarction, recent stroke or established peripheral arterial disease.
• How long: 1 to 3 years.
• Result: 9.8% versus 10.6% primary outcome events; relative risk reduction 8.7%, p=0.045.
• Funding: not stated in the label; the original trial was industry-funded.

The overall relative risk reduction (9.8% vs. 10.6%) was 8.7%, p=0.045.

What the evidence does not support

In largely stable patients already on aspirin, adding clopidogrel did not reduce cardiovascular death, heart attack or stroke. (Source 3)

• Randomized trial, Moderate certainty.
• Size: 15,603 participants.
• Who: patients with stable cardiovascular disease or multiple risk factors, median age 64.9, all on aspirin.
• How long: median 28 months.
• Result: Primary composite of CV death, MI or stroke: 6.8% with clopidogrel plus aspirin versus 7.3% with placebo plus aspirin; relative risk 0.93, p = 0.22. A broader secondary endpoint (death, MI, stroke or hospitalisation for an ischaemic event) was lower with clopidogrel, 16.7% versus 17.9%, p = 0.04.
• Funding: not stated on the page read; the original trial was industry-funded.

Limit of this finding: The trial's own primary endpoint showed no benefit. A wider secondary endpoint did come out lower with clopidogrel (16.7% versus 17.9%, p = 0.04, about one extra person in a hundred avoiding an event), but a secondary endpoint in a trial whose primary endpoint was null is a signal to be tested, not proof of benefit, and it has to be weighed against the increase in moderate bleeding seen in the same trial. Read this as 'no benefit shown on the outcome the trial set out to change', not as 'clopidogrel helped'.

There was no difference in the primary endpoint of CV death, myocardial infarction (MI), or stroke between the clopidogrel plus aspirin group (6.8%) and the placebo plus aspirin group (7.3%; relative risk [RR], 0.93; p = 0.22).

Where the evidence is mixed

In the same CHARISMA trial, a broader secondary endpoint that also counted hospitalisation for an ischaemic event was lower with clopidogrel added to aspirin. (Source 3)

• Randomized trial, Low certainty.
• Size: 15,603 participants.
• Who: patients with stable cardiovascular disease or multiple risk factors, median age 64.9, all on aspirin.
• How long: median 28 months.
• Result: Secondary composite of death, MI, stroke or hospitalisation for an ischaemic event: 16.7% with clopidogrel plus aspirin versus 17.9% with placebo plus aspirin; relative risk 0.92, p = 0.04 - an absolute difference of about 1.2 percentage points.
• Funding: not stated on the page read; the original trial was industry-funded.

Limit of this finding: This is a secondary endpoint from a trial whose primary endpoint showed no difference. When the main question a trial was designed to answer comes out null, a secondary result that reaches p = 0.04 is a lead worth following rather than an established benefit, and it does not undo the null primary result or the extra moderate bleeding recorded in the same trial.

The secondary endpoint of death, MI, stroke, or hospitalization for ischemic event was lower in the clopidogrel plus aspirin group (16.7% vs. 17.9%; RR, 0.92; p = 0.04).

Where the research disagrees

Whether clopidogrel should be added to aspirin in people with stable disease rather than an acute event

• CURE investigators, 2001, in acute coronary syndrome, randomised controlled trial, 12,562 participants: The antiplatelet agent clopidogrel has beneficial effects in patients with acute coronary syndromes without ST-segment elevation. (Source 2)
• CHARISMA investigators, 2006, in stable disease and high-risk primary prevention, randomised controlled trial, 15,603 participants: Among high-risk patients with stable CV disease, dual antiplatelet therapy with aspirin plus clopidogrel was not associated with a difference in the primary composite endpoint of CV death, MI, or stroke compared to aspirin monotherapy. (Source 3)

How much

• Reference intake: There is no reference intake for a prescription medicine; the prescriber sets the dose. The FDA label (updated 2023) is recorded as a position and states the usual daily dose. (Source 1)
• Upper limit: No upper limit exists in the nutrition sense. The label's stated maintenance dose is 75 mg once daily, with a 300 mg loading dose in non-ST-elevation acute coronary syndrome; recorded as a label position. (Source 4)
• Studied: CURE gave 300 mg immediately followed by 75 mg once daily, on top of aspirin, for 3 to 12 months. (Source 2)
• Studied: The label's summary of CAPRIE describes clopidogrel compared with aspirin in patients with recent myocardial infarction, recent stroke or established peripheral arterial disease. (Source 1)

A common belief, and what the research shows

The belief: Clopidogrel is a blood thinner that roughly halves your risk of a heart attack or stroke.

What the research shows: The relative reduction in CURE was 20%, but in absolute terms the composite outcome fell from 11.4% to 9.3% - about two people in a hundred avoided an event. Against aspirin in stable disease the absolute difference was smaller still, "9.8% vs. 10.6%". And the benefit comes with a real cost: "There were significantly more patients with major bleeding in the clopidogrel group than in the placebo group (3.7 percent vs. 2.7 percent; relative risk, 1.38; P=0.001)".

Questions and answers

What is it?

Clopidogrel is a prescription antiplatelet tablet, one of the thienopyridine class. It is inactive as swallowed and must be converted by the liver into its working form before it does anything. (Source 1)

What does it do in the body?

Its active metabolite locks onto the P2Y12 ADP receptor on platelets and does not let go, so platelets are less able to stick together. That makes clots on diseased arteries and stents less likely, and bleeding more likely. (Source 1)

Is it good or bad for you?

Both, and the balance depends on who is taking it. After an acute coronary syndrome it prevented about two events per hundred people over up to a year. In stable, lower-risk people added to aspirin it prevented nothing measurable. It caused about one extra major bleed per hundred people in the acute coronary syndrome trial. (Source 2)

How do you get more of it?

Does not apply. Clopidogrel is a prescription-only synthetic medicine with no food or supplement source. The usual dose set by prescribers is 75 mg once daily, sometimes after a loading dose. (Source 1)

If it is harmful, what reduces it?

The effect cannot be reversed quickly, because the active metabolite binds platelets permanently; it fades as new platelets are made over several days. Stopping is not risk-free either, since the label warns that stopping early can increase cardiovascular events. (Source 1)

Why might someone be low in it or missing it?

Does not apply as a deficiency, but a person can effectively get less of its action than intended. If they carry two low-function CYP2C19 variants, or take a drug like omeprazole that blocks the same enzyme, less active metabolite is formed and the drug works less well. (Source 1)

Which whole foods contain it or feed it?

No food contains clopidogrel. Grapefruit juice is the food most studied alongside it, because it inhibits enzymes involved in activating the drug; a randomised crossover study in healthy volunteers (Campbell et al., Cardiology Research, 2014) tested loading and maintenance doses with grapefruit juice and concluded its own results could not settle the question. (Source 6)

What happens if you do not have it?

In the acute coronary syndrome trial, the people who did not get clopidogrel had more cardiovascular deaths, heart attacks and strokes: 11.4% versus 9.3%. In stable disease already treated with aspirin, adding it made no measurable difference. (Source 2)

How can you test for it?

A CYP2C19 genotype test identifies people who convert clopidogrel poorly, and the label says such tests can help decide treatment. Platelet function tests such as VerifyNow P2Y12 reaction units are used in research to measure how much the drug is working, as in the grapefruit and St John's wort studies. (Source 1)

References

1. DailyMed, U.S. National Library of Medicine. CLOPIDOGREL tablet, film coated (FDA prescribing information). 2023. Read the source
2. New England Journal of Medicine. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. 2001. PMID 11519503, DOI 10.1056/NEJMoa010746. Read the source
3. American College of Cardiology, Latest in Cardiology / Clinical Trials. CHARISMA - Clopidogrel for High Atherothrombotic Risk, Ischemic Stabilization, Management, and Avoidance: American College of Cardiology trial summary page (page dated 2012) of Bhatt DL, Fox KA, Hacke W, et al., N Engl J Med 2006;354:1706-17. 2012. PMID 16531616, DOI 10.1056/NEJMoa060989. Read the source
4. DailyMed, U.S. National Library of Medicine. Plavix- clopidogrel bisulfate tablet, film coated (FDA prescribing information). 2010. Read the source
5. Journal of Cardiovascular Translational Research. St. John's Wort in Patients Non-responders to Clopidogrel Undergoing Percutaneous Coronary Intervention: a Single-Center Randomized Open-Label Trial (St. John's Trial). 2013. PMID 23463297, DOI 10.1007/s12265-013-9455-2. Read the source
6. Cardiology Research (Cardiol Res 2014;5(1):1-7); authors Campbell JA, Teply R, Mooss AN, Hilleman DE. Impact of Grapefruit Juice on the Antiplatelet Activity of Loading and Maintenance Doses of Clopidogrel in Healthy Volunteers. 2014. PMID 28392868, DOI 10.14740/cr307w. Read the source