Very few drugs have been received in the world of medicine with so much enthusiasm as Clopidogrel. It is one of the few drugs which received wide spread acceptance in its ‘infancy’. It was introduced in the world as Plavix but is available in the country under more than a dozen names like Cloxidil, Noclot, Lowplat, Ogrel, Dogrel, Clogrel, Deplat, Deplug, Platagg, Cumplat etc. Antiplatelet drugs are useful means of preventing acute blockages of vessels causing occlusions in cardiovascular diseases. Clopidogrel is a thienopyridine compound and produces irreversible platelet inhibition.
Clpidogrel inhibits platelet aggregation and that can be seen 2 hours after single oral dose of clopidogrel. Early and more pronounced inhibition can be achieved by using a loading dose using 4-8 tablets providing 300 – 600 mg. Such doeses are used when early inhibition of platelets is required in emergency situations like angioplasty and stenting in unprepared patients and patients presenting with unstable angina and heart attack. Repeated doses of 75 mg clopidogrel per day inhibit platelet aggregation on the first day, and inhibition reaches a steady state between Day 3 and Day 7. Plateleet aggregation and bleeding time gradually return to baseline values after treatment is discontinued, generally in about 5 days. Absorption is rapid and is not affected by food or antacids. It is extensively metabolized through liver and the elimination half-life is 8 hours.
Many major trials have been conducted to test the efficacy and safety of the drug in various expanding list of indications.
1. Clopidogrel in Angina:
In a large trial employing patients from 16 countries was carried for three years. The aim was to assess the relative efficacy of Clopidogrel and aspirin in reducing the risk of storke, heart attack, or vascular death. There was a relative-risk reduction in favor of Clopidogrel. There were no major differences in terms of safety for both Clopidogrel and Aspirin. So it proved that Clopidogrel was as effective as Aspirin in patients with stable angina and Clopidogrel can be used in patients who cannot tolerate Aspirin.
2. Clopidogrel in Unstable Angina:
Clopidogrel has become the drug of choice in patients presenting with unstable angina. The drug was studied in patients presenting with unstable angina in a study called CURE – Clopidogrel in unstable angina to prevent recurrent events. The aim was to assess the safety and efficacy of combination of clopidogrel and aspirin in tweleve thousand patients presenting within 24 hours of unstable angina. There were significant reduction in primary and secondary outcomes. Significantly fewer patients had recurrent chest pain and underwent angioplasty or surgery. Overall, there was no significant excess of major bleeding episodes after coronary grafting.
3. Clopidogrel in Heart Attack:
The effects of Clopidogrel were studied in a large study employing patients from many centres in China. The trial proved that adding Clopidogrel to Aspirin in acute heart attack prevents around ten major vascular event per thousand treated. There was no excess bleeding in breain-fatal or major. The result confirmed that each million heart attack patients treated for more than two weeks would avoid 5000 deaths and 5000 non-fatal events. Nowe it has become manadatory to administer loading dose 4-8 tablets to patients after a heart attack as soon as possible.
4. Clopidogrel in Angioplasty and Stenting:
One of the major advantages of Clopidogrel lies in prevention of clot formation in patients undergoing stenting with different types of stents. In a large study, patients planned for percutaneous coronary intervention (PCI) were randomized to either Clopidogrel and Aspirin as a loading dose or placebo and aspirin prior to PCI. Patients receiving Clopidogrel with Aspirin showed fewer cases of acute blockage due to clots in the stent. Recent guidelines dictate to start Clopidogrel a few days before the procedure or administer loading dosage of Clopidogrel immediately before the procedure.
The long term effects of antiplatelet therapy in patients following PCI have been evaluated in many trials. The drug has to be continued for long term (3-12 months) in patients receiving bare metal stents and one year to indefinite in those receiving drug eluting stent. The rationale behind this recommendation being the delayed healing of inside layer – endothelium of the vessel after drug eluting stent.
Clpidogrel inhibits platelet aggregation and that can be seen 2 hours after single oral dose of clopidogrel. Early and more pronounced inhibition can be achieved by using a loading dose using 4-8 tablets providing 300 – 600 mg. Such doeses are used when early inhibition of platelets is required in emergency situations like angioplasty and stenting in unprepared patients and patients presenting with unstable angina and heart attack. Repeated doses of 75 mg clopidogrel per day inhibit platelet aggregation on the first day, and inhibition reaches a steady state between Day 3 and Day 7. Plateleet aggregation and bleeding time gradually return to baseline values after treatment is discontinued, generally in about 5 days. Absorption is rapid and is not affected by food or antacids. It is extensively metabolized through liver and the elimination half-life is 8 hours.
Many major trials have been conducted to test the efficacy and safety of the drug in various expanding list of indications.
1. Clopidogrel in Angina:
In a large trial employing patients from 16 countries was carried for three years. The aim was to assess the relative efficacy of Clopidogrel and aspirin in reducing the risk of storke, heart attack, or vascular death. There was a relative-risk reduction in favor of Clopidogrel. There were no major differences in terms of safety for both Clopidogrel and Aspirin. So it proved that Clopidogrel was as effective as Aspirin in patients with stable angina and Clopidogrel can be used in patients who cannot tolerate Aspirin.
2. Clopidogrel in Unstable Angina:
Clopidogrel has become the drug of choice in patients presenting with unstable angina. The drug was studied in patients presenting with unstable angina in a study called CURE – Clopidogrel in unstable angina to prevent recurrent events. The aim was to assess the safety and efficacy of combination of clopidogrel and aspirin in tweleve thousand patients presenting within 24 hours of unstable angina. There were significant reduction in primary and secondary outcomes. Significantly fewer patients had recurrent chest pain and underwent angioplasty or surgery. Overall, there was no significant excess of major bleeding episodes after coronary grafting.
3. Clopidogrel in Heart Attack:
The effects of Clopidogrel were studied in a large study employing patients from many centres in China. The trial proved that adding Clopidogrel to Aspirin in acute heart attack prevents around ten major vascular event per thousand treated. There was no excess bleeding in breain-fatal or major. The result confirmed that each million heart attack patients treated for more than two weeks would avoid 5000 deaths and 5000 non-fatal events. Nowe it has become manadatory to administer loading dose 4-8 tablets to patients after a heart attack as soon as possible.
4. Clopidogrel in Angioplasty and Stenting:
One of the major advantages of Clopidogrel lies in prevention of clot formation in patients undergoing stenting with different types of stents. In a large study, patients planned for percutaneous coronary intervention (PCI) were randomized to either Clopidogrel and Aspirin as a loading dose or placebo and aspirin prior to PCI. Patients receiving Clopidogrel with Aspirin showed fewer cases of acute blockage due to clots in the stent. Recent guidelines dictate to start Clopidogrel a few days before the procedure or administer loading dosage of Clopidogrel immediately before the procedure.
The long term effects of antiplatelet therapy in patients following PCI have been evaluated in many trials. The drug has to be continued for long term (3-12 months) in patients receiving bare metal stents and one year to indefinite in those receiving drug eluting stent. The rationale behind this recommendation being the delayed healing of inside layer – endothelium of the vessel after drug eluting stent.
5. Stroke and Transient Ischaemic Attacks:
Clopidogrel is the focus of research in many fields in Cardiology, vascular medicine and neurology. It has been shown to produce salutary effects in prevention of stroke in patients with minor strokes called transient ischemic attack (TIA). Further strokes can be prevented by using Clopidogrel in ischemic stroke patients.
6. Peripheral Vascular Disease:
Clopidogrel has been evaluated in patients with blockages in vessels supplying arms and legs and internal organs. It has been used after surgery, angioplasty and stenting in such vessels and also when intervention is required, with gratifying results. A large trial is being conducted, focusing peripheral arterial disease patients.
7. Irregular Beating of Heart:
Patients with irregular beating of hear called atrial fibrillation develop pooling of blood in left sided storage chamber called left atrium. This stasis of blood can lead to formation of clot, which can dislodge and hit any vessel/part of the body. This results in blockage of that vessel hence cessation fo blood supply to that organ or part. Stroke and heart attack can be result of embolism of clot to brain or heart. Blood can be thinned down and such clots can be prevented by using Dispirin and Clopidogrel on their own or in combination.
Clopidogrel Compared To Other Antiplatelet:
It has some major advantages over ticlopidine – another potent antiplatelet drug. Clopidogrel is six times more potent thatn ticlopidine. It has reduced metabolic burden on liver – the main site of clearance. It has an improved benefit/risk ratio. Clopidogrel related reduction in white blood cells called neutropenia has not been reported whereas all of the earlier trials on ticlopidine reported severe neutropenia.
Side Effects Associated with Clopidogrel:
Clopidogrell may cause side effects, most frequent side effects are rash, bleeding, gastrointestinal upset, and gastro –intestinal bleeding. The personal physician should be informed if a patient experiences excessive tiredness, headache, dizziness, upset stomach, stomach pain, diarrhea, or nose blood. Some side effects can be serious. The following symptoms are uncommon, but if experienced one should report to doctor immediately; black and tarry stools, blood in stools, bloody vomit, vomiting material that looks like coffee ground, unusual bleeding or bruising, fever, sore throat, chills, and other sings of infection, slow or difficult speech, weakness or numbness of an arm or a leg or vision loss.
Clopidogrel is a novel antiplatelet, has definite advantages over aspirin like less severe gastro intestinal bleeding and superiority in reducing major ischemic events. In most of clinical indications clopidogrel is combined with aspirin but it can safely substitute aspirin if the drug cannot be tolerated due to stomach upet. With every passing day, newer indications are being discovered. There has been an exponential increase in the usage of the drug on both sides of Atlantic. All this has been possible because of well conducted mega trials proving the efficacy and safety in large groups of patients.
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Ref: Heal Thy Heart written by Prof: Dr. Muhammad Hafizullah
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