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Posts Tagged ‘fibrinolysis’

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  .

heparin3

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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.The  forgotten “Gem of a study” from lancet 2002 .

The fight between Primary angioplasty and thrombolysis was actually over in 2002 itself. But the cardiology community failed to ,( rather reluctant ) to accept the truth. The issue is being dragged without any useful purpose (for the patient !)  still trying to keep up the non existing superiority of pPCI.

A bolus thrombolytic agent (TPA/RPA) or even streptokinase  can do almost the same if not better than a highly complex procedure called  Primary PCI with lots of logistics issues and most important an unacceptable early procedure related  hazard.

Timely lysis can kick pPCI out of the ring . . . in three aspects with 100% certainty !

1.If symptom to TIMI 2/3 flow in IRA is the true parameter of success .pPCI can never ever come closer to pre hospital lysis.

2.The poor lytics do not differentiate in the efficacy . It simply acts whoever administer it. While results of pPCI are never reproducible and lots of expertise involved.

3.Thrombolytic agents never need to bother  about the complexity of lesions , (or  where is the IRA dilemma ? Is it a CTO or ATO confusion etc ) for the simple reason it doesn’t need to think before acting. It does its job fast.

What did CAPTIM prove ?

  • It proved pPCI has no mortality advantage over pre hospital lysis.
  • Perhaps the most Important conclusion from CAPTIM is pre hospital lysis significantly reduced  number of new onset cardiogenic shock . This alone nullifies the self inflicted pseudoscientific delay wasting the golden hour in the process ! (By the way who fixed the arbitrary acceptable delay conferred to pPCI of I hour .The whole evidence base for this delay to be scrutinised in view of CAPTIM !)

Final message

It is an irony,  a simple intravenous push of a drug (Thrombolytic agent)  very early after an STEMI can save many patients and reduce complication rate .But because it is simple ,it is considered  inferior .

Probably the only role for pPCI is high risk complicated STEMI at presentation or after an attempt of lysis has not stabilised the patient.(Where its referred to as Pharamco Invasive strategy )

2018 update

This post was originally posted in 2008. Now as I see this in 2018 . It is shocking  to know we haven’t  learnt any lesson from this study for 16 years since its published.

In this era of medical  commerce and  simple ,cheap ,and effective treatment can never compete with  sophisticated , glamorous , less effective  treatment modalities !

Read the full version of CAPTIM and comments

Comparison of Angioplasty and Prehospital Thrombolysis in Acute Myocardial Infarction (CAPTIM) study group, are published in the September 14, 2002 issue of theLancet.

Primary angioplasty “no better” than prehospital fibrinolysis: CAPTIM

London, UK – In a finding that would appear to go against the swelling tide of support for primary angioplasty as the treatment of choice for acute MI, investigators comparing primary angioplasty with prehospital administration of alteplase with rescue angioplasty have concluded that the 2 strategies are comparable. The results, from the Comparison of Angioplasty and Prehospital Thrombolysis in Acute Myocardial Infarction(CAPTIM) study group, are published in the September 14, 2002 issue of theLancet.1

“Our findings indicate that primary angioplasty is no better than prehospital fibrinolysis followed by transfer for possible emergency coronary angioplasty in patients presenting within 6 hours of an acute myocardial infarction,” the researchers, led by Dr Eric Bonnefoy and Dr Paul Touboul(Hopital Louis Pradel, Hospices Civils de Lyon, Lyon, France), write.

However, they point out that cessation of funding during the trial resulted in a lower-than-expected enrollment, 840 of 1200 planned patients, reducing their statistical power. “The CI (confidence interval) for the primary end point shows that there could be a real difference in the treatment effects,” they write.

Still, the researchers feel their conclusion is valid. “This was and is for us a very pragmatic question for our care system in France,” Bonnefoy told heartwire. “Is our current management, with prehospital thrombolysis with transfer, in a time when primary angioplasty is promoted as the best-of-the-best treatment, still sufficient? Even if the power of the study is lower than expected, we think that we have our answer, and we can go on with that practice.”

The strategy also means less strain on their cath labs, Bonnefoy added, since only 1 in 4 patients underwent rescue angioplasty. A cost analysis comparing the 2 strategies is currently being carried out.

Earlier thrombolysisPrevious studies comparing primary angioplasty with in-hospital thrombolysis have shown a “definite, albeit modest” benefit of angioplasty over thrombolysis, with lower rates of recurrent infarction and higher patency rates, Bonnefoy et al write. However, it does impose additional treatment delays, and “delay to treatment is an essential consideration for any revascularization strategy.”
In France, where this multicenter trial was carried out, ambulance crews include a physician, and so thrombolysis with intravenous tPA is possible in the prehospital setting. In this trial, they randomized MI patients to either prehospital administration of accelerated alteplase or primary angioplasty and transferred all of the patients to a center where emergency angioplasty could be carried out if it were determined that thrombolysis had not been successful.
The primary end point was a composite of death, nonfatal reinfarction, and nonfatal disabling stroke at 30 days, with analysis by intention to treat.
Of the 840 patients, 419 were randomized to prehospital fibrinolysis and 421 to primary angioplasty. Rescue angioplasty was used “liberally,” they write, in 26% of patients assigned to fibrinolysis.

Time to treatment, as expected, was longer in the primary angioplasty group: the median delay between onset of symptoms and treatment was 130 minutes in the prehospital fibrinolysis group, and time to first balloon inflation was 190 minutes in the angioplasty group.

At 30 days, there was no significant difference in the primary end point between groups. Overall mortality was lower than expected, they note. Deaths were fewer in the prehospital thrombolysis group, but mortality was not significantly different between groups. There was a trend toward less reinfarction and less disabling stroke favoring the primary angioplasty strategy.

CAPTIM: Primary end point

Outcome    

 

Prehospital fibrinolysis    

 

Primary angioplasty    

 

Risk difference (95% CI)    

 

p    

 

Composite end point 8.2% 6.2% 1.96
(-1.53-5.46)
0.29
Mortality 3.8% 4.8% -0.93
(-3.67-1.81)
0.61
Reinfarction 3.7% 1.7% 1.99
(-0.27-4.24)
0.13
Disabling stroke 1.0% 0 1.00
(0.02-1.97
0.12

To download table as a slide, click on slide logo below

Among secondary end points, the researchers noted a nonsignificant trend toward a higher frequency of cardiogenic shockthe most common cause of death in this studyin the primary angioplasty group, noting that cardiogenic shock between randomization and hospital admission occurred only in that group.

The CAPTIM results were first presented at the European Society of Cardiology Congress in September 2001 and reported by heartwire.

 

Strong wordsIn an accompanying commentary, Dr Gregg W Stone (Lenox Hill Heart and Vascular Institute, New York, NY) calls the CAPTIM results “the latest salvo in the ‘primary PTCA vs thrombolytic therapy wars’,” a “well-designed and carried out” trial.2
“Unfortunately,” because of funding issues and slow enrollment, the trial ended before the planned recruitment of 1200 patients that would have been required to show a 40% reduction in the primary end point with primary PTCA, he writes. “Nonetheless, the results demonstrate a trend toward a 24% relative reduction in the occurrence of adverse events favoring the interventional strategy, driven by strong reductions in reinfarction and stroke (which would be expected, after all, to be largely independent of reperfusion time),” Stone notes.
He attributes the lack of mortality benefit from primary angioplasty to the lower-than-expected mortality risk in this population, since the survival benefit of primary angioplasty is seen primarily in the highest-risk patients, the elderly and those with anterior MIs or shock. The lack of mortality benefit, though, “does not diminish the clinical relevance of fewer strokes, reinfarctions, a reduction in urgent revascularization procedures, and the shorter hospital stay” seen with the interventional strategy in this and other studies, he writes.
Perhaps the most novel finding is the reduction in early-onset cardiogenic shock with prehospital thrombolysis, a result that “adds fuel to the fire calling for facilitated primary PTCA trials.” However, several trials of the combined approach to date have shown it to be either inferior to or no better than primary PTCA, he notes. Even in CAPTIM, prehospital thrombolysis was supported by rescue angioplasty in 26% of patients, and Stone speculates these patients may have been “better off” if they had simply been transferred for routine immediate primary PTCA.

“Thus, until the large trials of facilitated PTCA are completed (none of which have even begun enrolling), the best therapy for most patients with evolving AMI should no longer be debated; administer antiplatelet therapy (aspirin, a thienopyridine, and possibly abciximab), withhold thrombolytic therapy, and transfer the patient for primary PTCA, regardless of whether the nearest catheterization suite is 3 floors or 3 hours away,” Stone concludes.

“To do less should no longer be considered standard care. Strong words, yes, but it is time for a wake-up call.”

 

CAPTIM researchers respondAsked to respond, Bonnefoy pointed out that “Dr Stone is surely a primary angioplastician and very convinced, but it’s quite ideological. CAPTIM is quite pragmatic. His arguments are acceptable, but they are not convincing; that is his opinion rather than scientific data.”
Bonnefoy asserts that no study has clearly demonstrated the superiority in terms of mortality of primary angioplasty over prehospital thrombolysis. “And in CAPTIM, we have the surprise and intriguing observation to have lower mortality in the prehospital thrombolysis groupit may be hazard, but it is present.”
Moreover, while high-risk patients may benefit from primary angioplasty, high-risk patients do not represent the majority of the MI population. In patients such as those in the CAPTIM study, he said, “our conclusions are quite valid.”
 

 

 

Sources
  1. Primary angioplasty versus prehospital fibrinolysis in acute myocardial infarction: a randomized study2002; 360:825-829
  2. Primary angioplasty versus “earlier” thrombolysis–time for a wake-up call2002; 360:814-815

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