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Posts Tagged ‘clopidogrel’

One of my otherwise  well behaving  patient ,  suddenly asked me this question ,  before leaving my  clinic  after a 15 minute consult .

Doctor  . . . I am taking the clopidgrel and aspirin  for 5 years like a vitamin tablet  . . . is that all right  doctor ?

I just got curious, I checked  the prescription again . Yeh ,  he was right !

I have  been mechanically writing  Tablet Clopitab  A  since 2008 !

Clopidogrel abuse long term

For what ?

Some sort of CAD !   Was it for ACS ?   No , it was for chronic stable angina . No PCI,  . . . no DES !

Why the hell  he is taking dual anti-platelet  therapy for 5 years ?

Some  body  , some  where  , has  prescribed it . This man  is taking it  for years together with absolute sanctity.

I was amused  . . . it is also  my mistake . Why it never struck me  to scrutinize the prescription ?

I thanked him . I  removed clopidogrel  from the list , and asked him to continue tablet Ecosprin 150mg  for some time .

( And  now I  had a genuine doubt  ! Does he have CAD at all ! I browsed his file , I couldn’t  find a true documentation for CAD  as I feared  !)

I asked him to get back with an  exercise test ,  . . .  if it comes negative i  can even stop the aspirin as well  I  explained  him  ! (Now he got amused !)

Final message

Who wants Knowledge ?

It is  dumped every  where , free of cost  . . .  both in real and cyber world .Applying it requires more sense  .  and my patient  taught me that  !

Patients  not only  help us  earn  our  bread  and butter , they  do  enrich  our brain  as well ! Never get humiliated when a patient teaches  you a lesson in medicine !

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Platelets  are the major culprits in initiating arterial thrombus.Platelet  inhibition is  the key  modality  to treat /prevent  acute and chronic coronary syndromes. It is  an approved indication for primary and secondary prevention of CAD.

Anti platelet  agents are the biggest drug  market among the cardiac drugs. It is  a billion dollar  medical game  played  with two  million  human  platelets !

Aspirin is the best anti-platelet agent known .It is not only most effective but also  available at a fraction of the cost other  drugs. Unfortunately  it is  a generic and not a patented one .Being cheap  ,   good safety profile  is the biggest  disadvantage of aspirin  !  So ,  consistent efforts were made to make this drug appear weaker. Hence came many new anti-platelet agents .

After analyzing  the available literature ,  I have compiled the following conclusions ( Mostly biased observation ! but I strongly believe the  bias is more  towards truth . . . )

All of the following statements can be termed either  true ,were true , believed to be true may  be  true ,  at some point of time  (Between the  last decade and today !)

  1. Aspirin alone is good enough in both  ACS and chronic CAD
  2. Clopidogrel is   equally effective like aspirin in ACS.
  3. Aspirin alone is dangerous in ACS.
  4. Clopidogrel alone is more  dangerous than aspirin alone in ACS,
  5. Aspirin + Clopidogrel  provides the best anti-platelet  action.
  6. Aspirin + Clopidogrel combination is still dangerous .
  7. Prasugrel is more effective than clopidogrel
  8. Prasugrel can never be as effective as aspirin *
  9. Never use clopidogrel alone in DES patient.
  10. Aspirin can be safe in most stented patients
  11. Mono platelet inhibition is a crime !
  12. Risk of  sudden death continues to be significant in spite of dual antiplatelet agents in many with DES.
  13. For prasugrel to be  really useful  it should always be prescribed with aspirin.
  14. Prasugrel alone can be dangerous in stented patients.
  15. If the patient is  getting heparin  simultaneously none of the above seems to be  really  important (Of course all patients with ACS will be getting this )

Above are my inferences in all those trials on platelets in the last three decades

What do you infer  ?

To  a discerned reader all of the above statements  may appear wrong   !

*Finally , it looks to me  both clopidogrel and prasugrel ride  a fake  ride on the shoulders of trusted war horse called Aspirin . There is  a strong basis for this  suspicion  as none of the researchers are ready to do a one to one direct comparison between aspirin and prasugrel  or clopidogrel !

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The funny thing in medicine is  ,   simpler the  question ,   greater the  difficulty to answer ! f  Clopidogrel  is   an  irreversible blocker of platelet aggregation . It  probably ,  is one  of the top  cardiovascular  drugs  used currently .It came into human domain as an aspirin killer and failed miserably , and currently piggy packing on the ageless aspirin for it ‘s action. The concept of dual antiplatelet agent is a classical example . The fact  that , Clopidogrel can rarely be used as a successful  mono anti platelet agent while aspirin can do this job with flying colors will unmask the secrets of  antiplatelet drug industry .

Do you know ,  this drug which  is considered  as a   great  antiplatelet drug , does  not even, pass the  basic test of   prolonging  the bleeding time  in a consistent fashion  ?

Still , we are not clear why it  does  or does not increase the bleeding time in vitro or vivo in linear  fashion.We have  confirmed this  in simple bedside experiments. (More dogmatic conclusions   can be drawn  in bed side , than those  double-blind studies) . In many patients 300 mg of clopidogrel failed to prolong the bleeding time even by  few seconds ! Surgeons who operate on clopdogelised patients differ  widely in their  experience  when they do emergency surgeries on them .

The issue is very vital  ,  Questions raised  are  critical  !

  • If clopidgorel  has a  notoriously unpredictable impact on prolonging  bleeding  time , Then ,  is it not  dangerous ? ,  for those millions of patients with DES(Drug eluting stents )  who live at at the  mercy of clopidogrel’s   erratic behavior.
  • Cardiology community  never got shocked  ,  even as  in this era of evidence based cardiology , a drug  which is being used for over 10 years without even a basic monitoring strategy for it’s efficacy.
  • Such is the scenario ,  it is not at all a surprise ,   to find a huge population  of DES patients   who  dial 911 or 108  with   sub-acute sent thrombosis  due to  clopidogrel failure and resistance.

Read this article published in one of the prestigious cardio thoracic  journal and comprehend  yourself   about clopidogrel’s controversy .

Final message

End of life , is  looming large on Clopidogrel , but it has done it’ s intended mission : Increasing the basic cost of cardiovascular   care in general population  .

A costly and a   dubious equivalent to  Aspirin   wrote a  phenomenal    success story in the narrow lanes of  medical wall street !

No doubt , it   will face the same fate as Ticlopidine ,   Prasugrel has just landed to repeat the same old story !

The easiest   job  to do  in   this wold is to fooling around   the public

and  it is an  irony medical professionals  and their patients  are  often

the   victims

Read also the herd mentality in  medical science

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              Intra coronary thrombosis is the sine qua non of acute coronary syndrome ( Both STEMI and NSTEMI.) But thrombolysis is the specific therapy in STEMI and is contraindicated in NSTEMI/UA.

Why is this apparent paradox ? What is basic differnce between UA and AMI ?

In STEMI there is a sudden & total occlusion of a coronary artery usually by a thrombus with or without a plaque .The immediate aim is to open up the blood vessel . Every minute is important as myocardium undergoes  a continuous process ischemic necrosis. So thrombolysis (or more specifically fibrinolysis should be attempted immediately) .The other option is primary angioplasty,  which will not be discussed here.

The thrombus in STEMI  is RBC &  fibrin rich and often called a red clot. Number of fibrinolytic agents like streptokinase, Tissue palsminogen activator,(TPA) Reteplace, Tenekteplace etc have been tested and  form the cornerstone of STEMI management.The untoward effect of stroke  during  thrombolysis  is well recognised , but usully the risk benefit ratio favors thrombolyis in most situations except in very elderly and previous history of stroke or bleeding disorder.

Unstable angina is a  close companion of STEMI . Many times it precedes STEMI often called preinfarction angina. During this phase blood flow in the coronary artery  becomes sluggish gradually,and patients develop  angina at rest .But unlike STEMI there is never a total occlusion and myocardium  is viable but ischemic,  and emergency salvaging of myocardium is not a therapeutic aim but prevention of MI becomes an aim. It is a paradox of sorts ,  even though thrombus is present in  UA ,  It has been learnt by experience thrombolytic agents are not useful in preventing an MI .

 

Why  thrombolysis is not useful in UA ?

1.In unstable angina  mechanical obstruction in the form of plaque fissure/rupture is more common than completely occluding thrombus. So lysis becomes less important.

2. Even if the thrombus is present , it is often intra plaque  or intra lesional and the  luminal  projection of thrombus is reduced  and hence thromolytic agents have limited area to act.

3.Further in UA/NSTEMI since it is a slow and gradual occlusion (Unlike sudden & total occlusion in STEMI) the platelets  get marginalised and trapped within the plaque .Hence in UA  thrombus is predominantly  white  . Often, a central platelet core  is  seen over which fibrin clot may also be  formed.

4.All available  thrombolytic agents act basically as a fibrinolytic agents,  and   so it finds   difficult to lyse the platelet rich clot.There is also a small risk of these agents lysing the fibrin cap and exposing underlying platelet  core and trigger a fresh thrombus.This has been documented in many trials( TIMI 3b to be specific) So if we thrombolyse in UA , there could be a risk of recurrent ACS episodes in the post thrombolytic phase.

5. UA is a semi emergency where  there is no race against time to salvage myocardium .Administering a  stroke prone thrombolytic agent tilts the risk benefit ratio against it.

6. Among UA, there is a significant group of secondary /perioperative UA   due to increased demand situations. Here there is absolutely no role for any thromolytic agents,  the  simple reason is , there is  no thrombus to get lysed. 

7.Many of the UA patient have multivessel CAD and might require surgical revascualarisation directly .

 

So fibrinolytic  agents are contraindicated in UA so what is the next step ?

The emergence of  intensive and aggressive platelet-lytic agents.

A combination of aspirin, clopidogrel, heparin, glycoprotien 2b 3a antagonist formed the major therapeutic protocol in these patients.Even though these are called antiplalet agents some of them  like 2b/3a antagonist eptifibatide, tirofiban, and many times even heparin has a potential to dissolve a thrombus. So technically one can call these agents  as thrombolytic agents.

What are the unresolved issues

                                       Even though clinical trials have convincingly shown thrombolytic agents  have no use in UA .There is a nagging belief  THAT  there could  be group of patients  with UA , still might benefit from thrombolysis as total occlusions have been documented  in some cases with UA.This is  especially true in peri-infarction unstable angina (Pre & post) as there is a fluctuation  between total and subtotal occlusions ) .But bed side recognition of this population is very difficult.

Many would consider this issue as redundant now,  since  most of  these patients  are taken up for emergency revascularisations

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Aspirin confusion spreads to clopidogrel !

It all started with 75 mg clopidogrel in CURE study  and others.

It went up to 150, 300, 600, and in some centres 900 mg.

No body knows how much clopidogrel optimally inhibits the platelet.

Aspirin had the same story three decades ago. It started from 40mg went up to 1200mg

and finally settled at 162mgs.

Why this confusion?

 It is because there is no simple platletlet function tests available in bedside.

and also the wide safety margin of this drug.At what level  clopidogrel  is unsafe

is also not clear !

Answers are expected soon .

 

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