Clopidogrel – the linchpin of antiplatelet therapy – do we know this medicine?

Clopidogrel – introduced in 1997, not so long ago was the second best-selling drug all over the World, next to the acetylic acid it positioned itself firmly in the field of cardiology as a dual antiplatelet therapy introduced in patients suffering from angina pectoris, NSTEMI, STEMI treated with anticoagulants or PCI as well as in prevention of thrombosis in symptomatic arterosclerosis.

Its position seemed to be stable and secure. The clopidogrel therapy is so common, that the drug has become an object of interest for many scientists and the conducted research has brought into light numerous blind spots – resistance to the drug, toxicity, adverse effects, difficulties to settle an optimal therapy scheme. These findings inclined to search for the alternative. Out of multiple drugs proposed two have been chosen as a substitute for the generally approved therapy. Many trials, especially PLATO and TRITON-TIMI 38, have confirmed the superiority of ticagrelor and prasugrel over clopidogrel. As a result, the latest update of AHA/ACC and ESC guidelines have introduced these medicines to therpeutic schemes.

Clopidogrel is a thienopyridine derivative. As a prodrug it requires bioactivation to a thiol metabolite, which is a two-step reaction catalised mainly by CYP3A4*1B, CYP3A5*3 and CYP2C19*2. Active substance binds irreversibly platelet receptor P2Y12 for ADP inhibiting this molecule as well as further activation of GP IIb/IIIa complex. As a result platelet aggregation and forming of the aggrgate induced by other agonists are inhibited. Repeated once daily standard dose of 75 mg lead to a steady state between 3. and 7. day. In the steady stated platelet inhibition level reaches 40-60%. The drug’s effects gradually fades away within 5 days. Absorbtion reaches 50%, main methabolite is a carboxylate derivative (~85%) which is pharmacologically inactive.

Ticlopidine – a thienopyridine structurally very similar to clopidogrel, introduced in 1991 as an alternative to warfarine in patients who had a stent placed in coronary artery has been shortly withdrawn due to major bleeding adverse reactions.It turned out that it causes also thrombotic thrombocytopenic purpura, aplastic anemia, neutropenia (~2,4%), severe neutropenia (~0,8%) including some cases of irreversible neutropenia as well as hepatotoxicity. As for clopidogrel (which has replaced ticlopidine) even large multicenter trials focus on hemorrhagical side effects of DAPT underestimating other adverse effects. However, many case reports suggest clopidogrel to be responsible for hematological and non-hematological side effects.



Investigations into thienopyridines’ toxicity demonstrate it to be dose-dependent. It turned out that the major damage is caused by clopidogrel carboxylate which oxydated by granulocytes’ myeloperoxidase (MPO) becomes toxic for bone marrow, and processed by CYP3A4 impairs hepatocytes. Meanwhile, immunological mechanisms cannot be ruled out.

Despite commonness and couple-year experience in clinical practice, it is still not clear how to use the drug to bring the greates benefit. Doubts appear already at the stage of timing of administration. As for the loading dose of 600 mg and maintenance dose of 75 mg numerous trials are unanimous, the timing is still being questioned. Research carried out by austrian group in 2011 proved that clopidogrel should be administered in case of suspected or diagnosed STEMI before reaching the catheterisation laboratory, in ambulance or at emergency department, as soon as possible. Such procedure diminishes the risk of death, re-infarction, congestive heart failure and stent thrombosis within 30 days, meanwhile it does not increase bleeding risk. Some of the investigations suggest doubling the dose of 600 mg of clopidogrel, since after one dose, sufficient platelet inhibition is achieved only after 2 hours. Up-to-date AHA guiedlines do not recommend waiting 2 hours before conducting PCI, the intervention should be immediate. The loading dose should be also applied in patients with acute coronary syndrome treated with fibrinolysis and patients on a long-term clopidogrel therapy. However, such recommendations create a new problem. What should be done with patients who had recieved clopidogrel pre-treatment and during PCI a decision to perform CABG (coronary artery bypass grafting) was made? The meta-analysis from 2010 prove that such pateints are exposed to a higher risk of peri-operative mortality, blood product transfusion and reoperation due to bleeding. On the other hand, it has been shown that number of bleeding complications is strongly associated with performing surgeon’s experience and method chosen. Finally, it is suggested to stop clopidogrel 5 days before planned operation, in the case of patients with DES (drug eluting stent) less than one year old to consider operating on clopidogrel or switch to tirofiban and heparin as a bridge to surgery. After the surgery clopidogrel should be reinstituted as soon as chest drain output enables it to improve graft survival and protect from thrombotic events.

Another question is how long the therapy should last. Present guidelines dictate 12-month treatment after NSTEMI or DES implantation and 30-day to 3-month treatment of STEMI. Still, study carried out in 2011 by scientists from Copenhagen states that after 12-month thearpy, during first 90 days of discontinuation risk of death or re-infarction in patients treated with PCI increases. The explanation of this phenomenon has not been found. Theory of „rebound effect”, which means increased platelet activity after clopidogrel discontinuation, seams to be unlikely. Possibly it is related to DES thrombosis. Premature discontinuation within the time suggested in guidelines results in higher mortality or infarction risk, which can increase even two-fold in case of DES applied. Unfortunatelly it happens quite often, especially for elderly patients or those who suffered from haemorrhage due to DAPT.

Many studies report existance of clopidogrel resistance which results from unsufficient platelet inhibition during standard DAPT. The issue turned out to be complex. There are evidence that some factors are responsible for increased platelet activity despite clopidogrel administration:
1) mutation of allel CYP2C19*2 (responsible for unsufficient bioactivation of clopidogrel),
2) fibrynogen serum concentration ≥375 mg/dl,
3) high body mass index (BMI),
4) diabetes (glycemia >8,5 mmol/l on admission, which presumably is due to altered platelet membrane permeability in conditions of increased osmolality).
Factors which are still not enough examined are: variability of absorbtion, drug-drug interactions, polymorphisms of P2Y12 and GP IIb/IIIa receptors, cellular factors such as accelerated platelet production, increased ADP concentration, up-regulation of P2Y12, reduced CYP3A activity. Clinical factors are also of great importance, according to some scientists they are the main reason for clopidogrel resistance – noncompliance and underdosing. Recent study proves higher activity of clopidogrel in smokers with diabetes mellitus. It revealed to be a dose-response effect resulting from induction of CYP1A2 – predominant isoenzyme catalising the first step on the way to active clopidogrel derivative. In order to overcome resistance it is suggested to either administer higher doses of clopidogrel in some patients, or switch to one of new antiplatelet agents.

Two substances have pierced through numerous new medicine – prasugrel and ticagrelor. The first to be included in AHA guidelines was prasugrel. It is also a thienopyridine derivative and as a prodrug requires bioactivation, but still is more rapid and efficient than in clopidogrel and the potency in inhibition is greater and more consistent. It also inhibits P2Y12 irreversibly, but acts faster and stronger than clopidogrel. It results in better prevention of death, infarction, stent thrombosis and stroke, but on the other hand there are major bleeding (2,4% vs. 1,8%), including fatal bleeding (0,4%), which in case of CABG performed reaches up to 15% more than after clopidogrel pretreatment. It is contraindicated incase of prior stroke or TIA (transient ischemic attack). Cost-effectivenes analysis conducted in 2009 in USA proves prasugrel to be dominant to clopidogrel in a 15-month therapy and to generic clopidogrel in a 30-day therapy. According to AHA guidelines it is an alternative to clopidogrel administered in a daily dose of 60 mg for one year after planned PCI with DES implantation.

Ticagrelor launched in december 2010 in Europe and in july 2011 in USA. It is a nonthienopyridine drug that does not require activation. After oral administration it absorbs and directly reversibly binds P2Y12 receptors. Efficiently inhibits platelet activity providing the protective level of antiaggregation both in clopidogrel responders and nonresponders. Short onset and offset of action make it easy to manipulate the therapy. PLATO study was concentrated on head-to-head examination of clopidogrel and ticagrelor. The new agent came out to prevent ishaemic events more succesfully with no significant increase in bleeding complications, moreover some decrease in risk of intracranial hemorrhages and mortality has been observed. For this reason it is not contraindicated in high risk patients with prior TIA or stroke, who until now constituted a great challenge for clinicians. In case of CABG following administration, results were similar for both agents. Unlike prasugrel, ticagrelor can be used both in medically managed and PCI patients. Additionally it is recommended to lower acetylic acid’s dose to 81 mg per day. Such „baby dose” ensures sufficient antiplatelet protection while risk of gastrointestinal bleeding is reduced. European Society of Cardiology guidelines give ticagrelor precedence over clopidogrel, saving the latter rather for those patients who cannot afford new drug. American Heart Association remains more distanced. Newly introduced in July this year guidelines’ actualisation places ticagrelor therapy on an equeal footing as clopidogrel. Before there will be greater recognition for the new medicine there must be a cost-efficiency analysis conducted and real-world benefits proved since the twice-daily therapy threatens compliance.

New therapies, powerful drugs, less side effects – rapid evolution of cardiology is undoubltful and fills with optimism both clinitians and patients. Despite prasugrel and ticagrelor manifestation it seams that clopidogrel’s position remains stable and unthreatened due to launch of clopidogrel generics which are much cheaper and available to patients. For this reason there are still many trials concerning clopidogrel use. It is certain to boost awareness and broaden knowledge on this substance, which will accompany great number of patients which grows with each year.

Written by: Agata Durdzińska

Source:
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