Clopidogrel

Is clopidogrel safe?

Clopidogrel is a well-understood medicine with a long record, and for most people the main risk is bleeding. It stops platelets from clumping, which prevents clots in narrowed arteries and in coronary stents. On its own its bleeding risk is close to aspirin's, and the two are often taken together for a time after a heart attack or stent.

Its boxed warningBoxed warningThe strongest safety warning the US FDA puts on a medicine's label, printed inside a black border at the top.More in the glossary is unusual because it is not about harm. In people who carry two inactive copies of the CYP2C19CYP450 enzymesA family of liver enzymes that break down many medicines. When another drug or supplement speeds them up or slows them down, drug levels change.More in the glossary gene, clopidogrel is converted poorly into its active form and may protect much less. We score clopidogrel 72, close to aspirin (70) and well above the anticoagulants apixaban (64) and warfarin (49). It is not a reason to stop: the label warns that stopping too soon after a stent or heart attack raises the risk of heart attack and death.

The gene warning

Clopidogrel is a prodrug. The liver, mainly through the CYP2C19CYP450 enzymesA family of liver enzymes that break down many medicines. When another drug or supplement speeds them up or slows them down, drug levels change.More in the glossary enzyme, turns it into the compound that blocks platelets. In March 2010 the FDA added a boxed warningBoxed warningThe strongest safety warning the US FDA puts on a medicine's label, printed inside a black border at the top.More in the glossary that "poor metabolizers", people with two non-working copies of the gene, form less active drug and get a weaker effect.

The US label says about 2% of White patients, 4% of Black patients and 14% of Chinese patients are poor metabolizers; the label notes poor metabolism is more common in Asian patients. People with one non-working copy, called intermediate metabolizers, sit in between. Genetic tests exist, and the label suggests considering another P2Y12 inhibitor, such as prasugrel or ticagrelor, for known poor metabolizers. Whether to test is a decision for the cardiologist.

How much bleeding does it cause?

The US label gives figures from the big trials:

Trial	Comparison	Bleeding result
CURE (12,562 patients after chest pain or minor heart attack)	Clopidogrel plus aspirin vs aspirin alone	Major bleeding 3.7% vs 2.7%; fatal 0.2% in both
COMMIT (about 45,800 heart attack patients)	Clopidogrel plus aspirin vs aspirin alone	Major bleeding 0.6% vs 0.5%
CAPRIE	Clopidogrel alone vs aspirin alone	Gut bleeding 2.0% vs 2.7%; brain bleeding 0.4% vs 0.5%

So clopidogrel alone causes about as much bleeding as aspirin, and adding it to aspirin adds roughly one major bleed per hundred patients in CURE. A rarer serious effect is thrombotic thrombocytopenic purpura (TTP), a blood disorder that the label says has sometimes been fatal and can appear within two weeks of starting. Fever, confusion, purple skin spots and yellowing of the skin need urgent care.

The omeprazole interaction

Many people on clopidogrel, especially with aspirin, are also prescribed a stomach protector. The choice matters. The label says to avoid omeprazole and esomeprazole, which block CYP2C19CYP450 enzymesA family of liver enzymes that break down many medicines. When another drug or supplement speeds them up or slows them down, drug levels change.More in the glossary and significantly reduce clopidogrel's effect on platelets even when taken 12 hours apart. Pantoprazole, lansoprazole and dexlansoprazole had less effect. Omeprazole is sold without prescription, so check with a pharmacist before buying it for heartburn.

Other interactions on the label:

• NSAIDs such as ibuprofen and naproxen raise the risk of gut bleeding.
• Warfarin, apixaban, rivaroxaban, SSRI and SNRI antidepressants add to bleeding risk.
• Rifampin increases its effect and should be avoided.
• Morphine and other opioids slow its absorption, which matters in an emergency heart attack.
• It raises levels of repaglinide, a diabetes medicine.

Doses, missed doses and overdose

The US label dose is 75 mg once a day, with a 300 mg loading dose after an acute coronary syndrome so the effect starts within hours. Without a loading dose it takes several days to work fully. A missed dose is taken when remembered unless the next one is close; never take two at once.

The effect on each platelet is permanent, so it fades only as new platelets are made over 7 to 10 days. There is no antidote, but the label notes that platelet transfusion may help in bleeding. Overdose mainly causes bleeding. Anyone who takes far too much, or a child who swallows tablets, should get medical help: Poison Control (1-800-222-1222) in the US or NHS 111 in the UK.

Who should be careful

• People with a stomach ulcer or bleeding in the brain: the label contraindicates it with active bleeding.
• Anyone booked for surgery: the label suggests stopping five days before high-bleeding-risk operations, decided with the cardiologist. After a recent stent this needs specialist input.
• People also taking anticoagulants, NSAIDs or omeprazole.
• People of East Asian ancestry, who are more often poor metabolizers.

Tell every doctor and dentist you take it, and talk to your doctor or pharmacist before stopping or adding anything.

How we scored it

Track record (95) and dependence (98) are strong, and overdose marginOverdose marginHow far a normal dose is from a harmful one. A wide margin means an accidental extra dose is unlikely to cause serious harm.More in the glossary (75) is reasonable. Serious side effects (65) reflect bleeding at about aspirin's level and rare TTP. The boxed warningBoxed warningThe strongest safety warning the US FDA puts on a medicine's label, printed inside a black border at the top.More in the glossary holds regulatory warnings at 45, and interactions (58) reflect the omeprazole problem and stacked bleeding risk with other blood thinners.