Posts Tagged ‘heparin’

The economics of  parenteral  anti-coagulation  took a paradigm shift more than a decade ago.  That was the arrival of low molecular weight heparin in the early 1990s.  The conventional regular heparin ( so called  unpurified /unfractionated )  was ridiculed   over the years. Lobbying   for LMWH was so strong  no one could  dare – stop this pseudo academic onslaught  flying high  with series of powerful articles  in major journals .

The major plus point  claimed for LMWH was   the convenience of administration  without any monitoring .

This convenience masked  some of the vital  truths  about these drugs

  • First and foremost ,  LMWH never proved it’s cost  effectiveness  and worthiness in a convincing manner.
  • Acute administration  by IV route was rarely practiced globally  which was used in all major trials.
  • The onset of action with subcutaneous route  always lagged behind in real ACS.
  • It would  seem ,  the  greatest advantage claimed by LMWH ( of not requiring monitoring  ) is the biggest suspect ,  as we would not know , whether the drug really reaches the peak action or not.

If  raw economics  brought these futile drug to the fore front  ,  the  only  possible way to stop this  redundant  drug was again by the  same  economics ! This , exactly  is happening  now . Suddenly , many  research  papers  are coming out   claiming  the superiority of good old heparin  over LMWH .

Thanks to recession , new  global health polices and politics .

This week’s NEJM restores  at- least some of the   stolen credit  to the regular  heparin after 10

long years !


Assumptions and bias

The above observation by the author  can be labeled as an  extreme form of bias against a wonder drug called LMWH.

It may be  argued  not all LMWH can be considered equal .Will the  outcome from the above trial  results be extrapolated to  enoxaparine  as well  ?What  is your gut feeling ? Gut is many times right than  hyped up RCTS !

In a large tertiary  hospital  where we work  , we have  never switched to the LMWH   in the  bygone  decade (  Both in critical care unit and post op unit )  .We have to withstand   a big  hue and cry and  were   even  humiliated for using regular heparin in our ICU . Now  . . . we  stand fully vindicated !

There are many such falsehoods  that  need to be  corrected in the medical literature. Sooner it happens , better for the humans  of  this planet . We should be glad  . . .things are moving in that direction.

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  1. Do 64slice MDCT  in all patients who has  a coronary event and follow it up with catheter based CAG.
  2. Use liberally the new biochemical marker ,  serum  B-naturetic peptide (BNP) to diagnose cardiac failure in lieu of basal auscultation.
  3. Advice  cardiac resynchronisation therapy in all patients  who are in class 4 cardiac failure with a wide qrs complex .
  4. As it is may be considered a  crime to administer empirical  heparin, do ventilation perfusion scan in all cases with suspected pulmonary embolism.
  5. Do serial CPK MB and troponin levels in all patients with well  established  STEMI .
  6. Open up all occluded coronary arteries irrespective  of symptoms and muscle viability.
  7. Consider  ablation of pulmonary veins as an  initial strategy in  patients with recurrent idiopathic AF. If it is not feasible  atleast occlude their left atrial appendage with watch man  device.
  8. Never tell  your patients   the  truths  about the  diet , exercise &  lifestyle modification (That can  cure most of the early hypertension) . Instead encourage the  use of  newest ARBs  or even  try direct renin antoagonists   to treat all those patients in  stage 1 hypertension.
  9. Avoid regular heparin in acute coronary syndromes   as  it  is a disgrace to use it  in today’s world. Replace all prescription of heparin with  enoxaparine  or  still better ,  fondaparinux  whenever  possible.
  10. Finally never discharge  a  heftily  insured patient   until  he completes all the  cardiology investigations  that are available in your hospital  .

Coming soon :  10 more ways to  increase cost of cardiology care . . .beyond common man’s reach

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Heparin was invented accidentally by a 26 year old  , Jay McLean, a  pre clinical  medical student  in 1916 .It was one of the greatest discovery  in  medicine .It helped us prevent blood from clotting.Frozen blood inside human circulatory system constituted one of important mechanisms  of  human  death.This ranged from acute myocardial infarction to cerebral thrombosis  .


As we decoded the mechanism of action of heparin , it was clear it bound to the  naturally occurring molecule antithrombin 3 and effectively blocks the intrinsic coagulation mechanism and thus behaves as an important anticoagulation agent.

How heparin acts as a thrombolytic agent ?

We know , our hematological system has a powerful  natural  fibrinolytic mechanisms  to protect against unwarranted( pathological ) intravascular coagulation. This is mediated by  anti thrombin, protein C , protein S  ,  plasminogen  system etc  . Natural concentrations of tissue plasminogen activator (Tpa)  also  help in lysing intravascular clots.

There is a constant  , delicate balance between procoagulant , anticoagulant and antifibrinolytic molecules .Intra vascular  clots occur when a vascular  injury triggers  a clot formation and the clinical event occurs.

But,   once insulted ,   the  circulating blood   does not remain a silent spectator . It is  constantly  on the look out for a foe to attack the thrombus that is interfering  with its natural flow  . Antithrombin 3 is one such molecule. Success  of lysis depends on the power of natural forces. There are hundreds of episodes of microlysis that take place every day  (Which happen without our knowledge ) .In  patients with vascular  disease these episodes are likely to be further more.

What does  Intravenous heparin in high doses  do ?

Heparin immediately  blocks of powerful procaogualtion activity .One of the important heamatological principle  is “Thrombus begets thrombus “. It is  a vicious cycle. This is immediately  tackled by heparin .The powerful trigger of thrombus induced thrombus propogation is shut off .

This makes a  2 cm sized clot to remain  in  2cm . After  making sure of this , the blood in the immediate vicinity   start percolating the clot.  The heparinised blood   switches to  a pro- fibrinolytic mode as the balance of forces  is fully tilted in favor of fibrinolysis or thrombolysis.

Is there clinical evidence to call heparin as thrombolytic agent ?

Yes . Contrary to the popular scientific  principle we have only clinical evidence  . laboratory evidence is not convincing as heaprin lyses clot only in vivo . Since ,  evidnece based medicine requires  laboratory evidence  we hesitate to call this as  thrombolytic agent !

It has been a strong clinical observation ,   many  major intracardiac or  intravascular  clots  regress in size

(or totally dissolve )  with intensive heparin  regimen .The effect is seen in 48-72 hours.Some times in first 24 hours.

What are the clinical situations where heparin has successfully lysed the clots*?

  • Pulmonary embolism
  • LV clot
  • LA clot
  • Cortical venous thrombus
  • Deep vein thrombosis
  • Coronary thrombosis**
  • Portal vien thrombois
  • Renal vein thrombois

* Plenty of case reports available for each condition

** Sustained micro  thrombolysis  is the major mechanism of benefit in NSTEMI

If it is true ,  heparin dissolves thrombus , why  it is not called as thrombolytic agent ?

Why not ?  You decide yourself !

How does heparin compares with  the great thrombolytic agents*  like  Strepotiknase, Urokinase,Altepase, Retepalse , Teneckteplase (TNK TPA) ?

Many (Rather most . . .)  would consider it ,  as  foolish , to compare heparin with these agents .But the fact of the matter is except for streptokinase there is no comparison studies available. Attempting such a study  in humans will  be considered unethical. Without   a proper scientific  data  heparin  can not be ignored either.

But ,  some of the control groups in major  studies of thrombolysis  through some light !

In pulmonary embolism thrombolytic agents and heparin have similar effects on intrapulmonary thrombus

An important point to remember here is   , the powerful thrombolyic agents are administered  in as short duration (Bolus / 1  hour infusion ) .This is invariably  followed by heparin infusion . Why do we  do that ? because we know it is important . One may never know , how much of lysis is done  by the trhombolytic agent and how much by heparin .

if you analyse the  data  success rate of thrombolytic agents are infact attributable  to the follow up heparin

Thrombolytic agents  piggy packs on heparin and claims the  credit for thrombolysis *

In thrombolytic  therapy  , heparin  is considered  as an adjunct to streptokinsae but in reality  streptokinase  may an  adjunct to heparin

Importance of  heparin In Acute MI (HEAP Trial)

It should be realized  there is a time window for heparin too . . .  early administration  can have  great benefit

Early heparin prevents formation of  core  of the clot .The   importance of acute administration of  aspirin  in suspected STEMI  is well recognized  by paramedics  .  A bolus of heparin (10000 u)  immediately  could have great impact on the outcome as well  .Paradoxically we talk more  about emergency PCI,  on  transit TPA  etc . . . We have seen  number of patients  referred  with  STEMI   from   suburban areas traveling for hours with out any anticoagulants but promptly getting sorbitarate tablets ! Unfortunately prehospital heparin is rarely stressed in literature .

Watch the video : Heparin : The forgotten hero

Final message

  • Heparin is   an  under rated drug  as a thrombolytic agent.
  • Just because it has no direct action  on thrombus it is considered an inferior agent.( One other reason  for it to be  considered  inferior ,   it  is  very cheap  !)
  • Heparin too ,  has a time window effect in acute MI (Class 3 evidence ie   wide clinical experience)
  • It’s  usage should be early  and  liberal , especially  in out of hospital setting in vascular  emergency.
    Note of caution : This article is not meant  to  defame  the thrombolytic agents.It only stresses a point that , heparin has also a role , as a thrombolytic agent. *Whenever rapid thrombolysis is required in life threatening situations specific thrombolysis is indicated as per guidelines.

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 Selected on the basis of ,  impact  on survival , relief of  human suffering index and also innovation

10.Percuateneous interventions

9.  Electrocardiography

8 . Hemodynamics of cardiovascular system






2.Prosthetic valves

1.Coronary care units


Waiting list

Concept of vascular biology


RF ablation

Nitric oxide

Total Artifitial heart



Ten least important concepts and  inventions in cardiology

Selected based on duplication of research, futile scientific concepts and   of course impact on survival

10.Low molecular weight heparins

9.Cardiac resynchronisation


7.Multi  chamber pacing

6.Newer ARBs

5.C reactive protein

4.Three dimensional echocardiography


Comments welcome  and please contibute

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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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