Ajcc feb 2013

In This Issue — Thrombolytic Agents: Past, Present, Future — ECG: A Simple Noninvasive Tool to Localize Culprit

Vessel Occlusion Site in Acute STEMI — Left Atrial Myxoma — Unmasking of Dual AV Node Physiology by Adenosine — Sudden Onset of Clicking Chest Pain — ADA Releases Updated Recommendations on Standards

of Medical Care in Diabetes — Liability of Hospital in Case of Treating Consultant’s

Negligence

Volume 15, Number 10, February 2013 Pages 353-392

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Asian

Journal of

IJCP Group of Publications

CLINICAL CARDIOLOGY

Dr Sanjiv Chopra Prof. of Medicine & Faculty Dean Harvard Medical School Group Consultant Editor

Volume 15, Number 10, February 2013

Dr Deepak Chopra Chief Editorial Advisor

Padma Shri and Dr BC Roy National Awardee Dr KK Aggarwal Group Editor-in-Chief Dr Veena Aggarwal MD, Group Executive Editor

from the desk of group editor-in-chief 357 Beware of Fatty Liver

KK Aggarwal

Dr Praveen Chandra Guest Editor, AJCC praveen.chandra@medanta.org Assistant Editor: Dr Nagendra Chouhan, Dr Dharmendar Jain

AJCC Speciality Panel International Dr Fayoz Shanl Dr Alain Cribier Dr Kohtian Hai Dr Tanhuay Cheem Dr Ayman Megde Dr Alan Young Dr Gaddy Grimes Dr Jung bo Geg Dr Rosli Mohd. Ali Dr S Saito National Dr Mansoor Hassan Dr RK Saran Dr SS Singhal Dr Mohd. Ahmed

Advisory Board Dr PK Jain Dr PK Gupta Dr Naresh Trehan Dr Sameer Shrivastava Dr Deepak Khurana Dr Ganesh K Mani Dr K S Rathor Dr Rajesh Kaushish Dr Sandeep Singh Dr Yugal Mishra Faculty Dr GK Aneja Dr Ramesh Thakur Dr Balram Bhargava Dr HK Bali Dr HM Mardikar

Dr Sanjay Mehrotra Dr Vivek Menon Dr Keyur Parikh Dr Ajit Mullasari Dr Kirti Punamiya Dr MS Hiramath Dr VS Narain Dr SK Dwivedi Dr Raja Baru Panwar Dr Vijay Trehan Dr Rakesh Verma Dr Suman Bhandari Dr Ravi Kasliwal Dr Atul Abhyankar Dr Tejas Patel Dr Samir Dani

Review Article 358 Thrombolytic Agents: Past, Present, Future

Harshal N Pise, Sudhir L Padwal, Vijay M Motghare, Vinod S Deshmukh, Swapnil C Jaykare, Chetanraj G Bhamare, Rakesh R Jadhav, Rushikesh P Deshpande

IJCP Editorial Board

Obstetrics and Gynaecology Dr Alka Kriplani Dr Thankam Verma, Dr Kamala Selvaraj

Cardiology Dr Praveen Chandra Dr SK Parashar Paediatrics Dr Swati Y Bhave Diabetology Dr CR Anand Moses, Dr Sidhartha Das Dr A Ramachandran, Dr Samith A Shetty ENT Dr Jasveer Singh Dentistry Dr KMK Masthan Dr Rajesh Chandna Gastroenterology Dr Ajay Kumar Dermatology Dr Hasmukh J Shroff Neurology Dr V Nagarajan Journal of Applied Medicine and Surgery Dr SM Rajendran, Dr Jayakar Thomas Anand Gopal Bhatnagar Editorial Anchor Advisory Bodies Heart Care Foundation of India Non-Resident Indians Chamber of Commerce & Industry World Fellowship of Religions

Original Article 368 ECG: A Simple Noninvasive Tool to Localize Culprit Vessel Occlusion Site in Acute STEMI

Biplab Ghosh, Manoj Indurkar, Mahendra Kumar Jain

Case report 376 Left Atrial Myxoma

A Agrawal, J Shah, R Hydrabadi, D Kothari, P Joshi, M Pandya

Case report Published, Printed and Edited by Dr KK Aggarwal, on behalf of IJCP Publications Ltd. and Published at E - 219, Greater Kailash, Part - 1 New Delhi - 110 048 E-mail: editorial@ijcp.com

379 Unmasking of Dual AV Node Physiology by Adenosine

Satish Ramteke, Saurabh Nagar, Mahendra Kumar Jain, Praveen Kumar Baghel, Dharmendra Jain

Printed at New Edge Communications Pvt. Ltd, New Delhi E-mail: edgecommunication@gmail.com © Copyright 2013 IJCP Publications Ltd. All rights reserved.

The copyright for all the editorial material contained in this journal, in the form of layout, content including images and design, is held by IJCP Publications Ltd. No part of this publication may be published in any form whatsoever without the prior written permission of the publisher.

Photo Quiz 382 Sudden Onset of Clicking Chest Pain

Editorial Policies The purpose of IJCP Academy of CME is to serve the medical profession and provide print continuing medical education as a part of their social commitment. The information and opinions presented in IJCP group publications reflect the views of the authors, not those of the journal, unless so stated. Advertising is accepted only if judged to be in harmony with the purpose of the journal; however, IJCP group reserves the right to reject any advertising at its sole discretion. Neither acceptance nor rejection constitutes an endorsement by IJCP group of a particular policy, product or procedure. We believe that readers need to be aware of any affiliation or financial relationship (employment, consultancies, stock ownership, honoraria, etc.) between an author and any organization or entity that has a direct financial interest in the subject matter or materials the author is writing about. We inform the reader of any pertinent relationships disclosed. A disclosure statement, where appropriate, is published at the end of the relevant article.

Note: Asian Journal of Clinical Cardiology does not guarantee, directly or indirectly, the quality or efficacy of any product or service described in the advertisements or other material which is commercial in nature in this issue.

Practice Guidelines 384 ADA Releases Updated Recommendations on Standards of Medical Care in Diabetes

Medi law 385 Liability of Hospital in Case of Treating Consultant’s Negligence MC Gupta

Lighter reading 386 Lighter Side of Medicine

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from the desk of group editor-in-chief Dr KK Aggarwal

Padma Shri and Dr BC Roy National Awardee Sr. Physician and Cardiologist, Moolchand Medcity, New Delhi President, Heart Care Foundation of India Group Editor-in-Chief, IJCP Group and eMedinewS National Vice President, Elect, IMA Chairman Ethical Committee, Delhi Medical Council Director, IMA AKN Sinha Institute (08-09) Hony. Finance Secretary, IMA (07-08) Chairman, IMA AMS (06-07) President, Delhi Medical Association (05-06) emedinews@gmail.com http://twitter.com/DrKKAggarwal Krishan Kumar Aggarwal (Facebook)

Beware of Fatty Liver Fatty liver is present in upto 30% of population, upto 60% in patients who are at risk for heart disease and in upto 90% of obese persons. ÂÂ

Nonalcoholic fatty liver disease (NAFLD) means presence of hepatic steatosis (fatty liver), when no other causes for secondary hepatic fat accumulation (heavy alcohol consumption) are present.

ÂÂ

NAFLD, if not treated, may progress to cirrhosis and is an important likely cause of cryptogenic cirrhosis.

ÂÂ

NAFLD is subdivided into

Nonalcoholic fatty liver (NAFL) or simple fatty liver with no liver inflammation.

Nonalcoholic steatohepatitis (NASH) or fatty liver with liver inflammation

ÂÂ

Patients with NAFLD may have mild or moderate elevations in serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) levels (liver enzymes).

ÂÂ

Normal SGOT and SGPT levels, however, do not exclude NAFLD.

ÂÂ

When elevated, the SGOT and SGPT levels are typically 2-5 times the upper limit of normal.

ÂÂ

In acute viral hepatitis, the SGOT/SGPT ratio is <1 (unlike alcoholic fatty liver disease, which typically has a ratio >2)

ÂÂ

The degree of SGOT and SGPT elevation does not predict the degree of liver inflammation or fibrosis, and a normal SGOT, SGPT levels does not exclude clinically important histologic injury.

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The alkaline phosphatase may be elevated to 2-3 times the upper limit of normal.

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Serum albumin and bilirubin levels are typically within the normal range, but may be abnormal in patients who have developed cirrhosis. When cirrhosis sets in, one may have prolonged prothrombin time and cytopenias.

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A serum ferritin >1.5 times the upper limit of normal in patients with NAFLD may mean presence of inflammation. mmmmm

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REview Article

Thrombolytic Agents: Past, Present, Future Harshal N Pise*, Sudhir L Padwal**, Vijay M Motghare†, Vinod S Deshmukh‡, Swapnil C Jaykare*, Chetanraj G Bhamare‡, Rakesh R Jadhav‡, Rushikesh P Deshpande#

Abstract In myocardial infarction, thrombolytic therapy is well-established and has become routine treatment. Thrombolytics, if administered early reduce extent of myocardial damage by restoration of patency of infarct related vessel. Though thrombolytic property of streptokinase was recognized in 1930’s, its use in myocardial infarction started only after 1980’s because initial trials with streptokinase use produced conflicting results. The need for a meticulously planned and systematically executed randomized multicentric trial was fulfilled by GISSI (Gruppo Italiano per la Sperimentazione della Streptochinasi nell’Infarto Miocardico) trial. Streptokinase, urokinase, anistreplase are nonfibrin specific drugs. Nonfibrin specific drugs activate both circulating as well as fibrin bound plasminogen and can induce systemic activation of fibrinolytic system while alteplase, reteplase, tenecteplase are fibrin specific and mainly activate fibrin bound plasminogen and have less chances of inducing systemic activation of fibrinolytic system. Many trials have been conducted to define dosing schedule, efficacy and safety of drugs. Of the available thrombolytic agents, tenecteplase has the highest fibrin specificity. Though, the clinical benefit with bolus fibrinolytics over the use of conventional thrombolytic has not been documented in many clinical trials, the bolus agents have many advantages, which favor their clinical utilization. Currently available thrombolytic agents have several important limitations. So, search for ideal thrombolytic continues. Lanoteplase, staphylokinase, saruplase, vampire bat salivary plasminogen activator are promising drugs. This review will describe the characteristics of the main thrombolytic drugs, various trials leading to wide spread utilization of these drugs.

Keywords: Thrombolytics, acute myocardial infarction, TIMI, streptokinase, alteplase

A

cute myocardial infarction (AMI) remains one of the most common cause of mortality in western world and significant cause of mortality and morbidity in India. Acute ST-segment elevation myocardial infarction (STEMI) is caused by coronary plug rupture and resultant thrombosis, which leads to the occlusion of coronary artery.1 In AMI, the two main strategies of treatment are thrombolysis and percutaneous coronary interventions (PCI). Although, the PCI are considered more effective intervention, the limited availability of these interventions makes thrombolysis more common mode of intervention.2 Thrombolysis remains the most utilized form of reperfusion treatment. Thrombolytics, if administered early, reduce the extent of myocardial damage by

*Junior Resident-II **Associate Professor †Professor and Head ‡Assistant Professor #Junior Resident-III Dept. of Pharmacology SRTR Govt. Medical College and Hospital, Ambajogai, Beed, Maharashtra Address for correspondence Dr Harshal N Pise Junior Resident-II, Dept. of Pharmacology SRTR Govt. Medical College and Hospital, Ambajogai, Beed, Maharashtra

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restoration of patency of infarct related vessel.

By restoration of patency in infarct related vessel thrombolytic therapy reduces the extent of myocardial damage.3 The use of streptokinase in treatment of myocardial infarction started in early 1980’s though its ability to lyse clot was recognized in 1930’s.4 Since then different studies have investigated the complex problems related to fibrinolytic treatment in AMI: Choice of drug, dose, survival, etc. The great effort directed to this area has stimulated the research of new drugs and more importantly increased our knowledge about old and new thrombolytics.

The aim of this review is to describe the characteristics of main thrombolytic drugs, to illustrate different trials that have led to their widespread utilization and to examine future development that is likely to affect the application of this therapy. This review will also summarize brief history of thrombolytic treatment and complications associated with thrombolytic therapy.

Pathophysiology of myocardial infarction Myocardial infarction results due to thrombus formation that prevents the coronary artery blood flow

review article and adequate oxygen supply distal to the thrombus leading to myocardial cell death.5 Unstable plaques of atheromatous coronary artery rupture unpredictably exposing the subendothelial thrombogenic core. The exposure of this core begins the sequence of event leading to thrombus formation.

The platelets play the major role in the thrombus formation. At the rupture site, the platelets adhere to the exposed collagen by vW factor, forming a blanket that covers the injured endothelium. Platelets then undergo degranulation releasing various thrombogenic substances which further causes platelet activation.5 Thromboxane A2 (TxA2) is formed from the membrane arachidonic acid within the platelets by the action of cyclooxygenase (COX). ADP and serotonin is formed in dense granules of the platelets. All these prothrombotic substances induce conformational change in glycoprotein (GP)IIb-IIIa. Also endothelin released from exposed endothelial cells, with above mentioned thrombogenic substances causes local vasoconstriction, which further potentiates the thrombogenic environment.

The fibrinogen is attached to GPIIb-IIIa receptors forming interplatelet bridges. These fibrinogen platelet crosslinks provide the framework for the thrombus formation and often called as white clot (platelet-rich).

The thrombus is completed with red clot (fibrin-rich).6 This platelet rich plug is unstable and it is further stabilized with contribution of fibrin. This fibrin is generated with the help of coagulation cascade. The coagulation cascade begins very early when platelet adheres to collegen. All the factors in this system are sequentially activated. This system consist of two pathways, intrinsic and extrinsic both converging at a common point i.e., activation of factor X. The fibrin generated in this cascade forms insoluble mesh, which surrounds the platelet plug stabilizing the clot and completing the coronary artery thrombus formation.6 At present two strategies are available for treatment of AMI, both having their merits and demerits.

History of Thrombolytics Until 1950, the available treatment for AMI was mostly palliative rather than curative. The ability of streptokinase to lyse the clot was first recognized in year 1933 by Dr William Smith Tillett through mere serendipity. Dr WS Tillett with his student Sol Sherry after many years of their work laid the foundation of use of streptokinase in myocardial infarction.4 The drug was initially used by virtue of its fibrinolytic activity to

Table 1. Comparison of the Advantages of Thrombolytics and PCI Thrombolytics

PCI

Quicker time to onset of therapy

Superior efficacy in clinical trials

Wider availability, given lack of hospitals performing primary PCI

Less time dependent (can be used in case of delayed patient presentation)

Not operator-dependent

Lower risk of bleeding

treat fibrinous, purulent pleural exudates, tuberculous meningitis. Soon concerns rose regarding possible adverse effects of streptokinase.4 Modern era of thrombolysis began with the demonstration by DeWood et al (1980) that myocardial infarction was associated with thrombotic coronary artery occlusion and demonstration by Rentrop et al (1979) that infusion of streptokinase within infarct related coronary artery early after symptom onset induced rapid recanalization.7 Though, the ability of streptokinase to decrease the mortality was recognized in 1950’s, no significant progress towards routine clinical use was made until 1980 mainly because initial trials that used streptokinase infusion produced conflicting results. So, there was a need for a meticulously planned and systematically executed randomized multicentric trial that could prove efficacy of streptokinase beyond any doubt.

In 1986, the landmark trial called GISSI (Gruppo Italiano per la Sperimentazione della Streptochinasi nell’Infarto Miocardico) trial, has fulfilled the need. This study demonstrated significant overall reduction in mortality with use of intravenous (IV) streptokinase.8 In late 1987, IV thrombolytic therapy had US Food and Drug Administration (US FDA) approval.

Genetic engineering has helped to produce new generation of fibrin specific thrombolytics. Nine years later, reteplase was approved and became commercially available, representing first of third generation thrombolytics.

Classification Thrombolytics can be classified on the basis of fibrin specificity9 into: Nonfibrin specific fibrinolytics ÂÂ

Streptokinase

ÂÂ

Urokinase

ÂÂ

Anistreplase

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review article Fibrin specific fibrinolytics ÂÂ

Recombinant tissue type plasminogen activator (rt-PA): Alteplase

ÂÂ

Reteplase (r-PA)

ÂÂ

Tenecteplase (TNK-tPA)

ÂÂ

Lanoteplase (n-PA)

ÂÂ

They can be also classified into6

ÂÂ

First generation: anistreplase

ÂÂ

Second generation: Tissue type plasminogen activator (alteplase), prourokinase

ÂÂ

Third generation: Reteplase (rt-PA), tenecteplase (TNK-tPA), lanoteplase

Streptokinase,

urokinase,

Characteristics of an Ideal Thrombolytic Agent3

The aim of thrombolytic therapy is to achieve TIMI Grade 3 flow. There is significant reduction in mortality when TIMI Grade 3 flow is achieved.

Although, the TIMI flow grade is a valuable and widely used qualitative measure in angiographic trials, it is limited by its subjective and categorical nature. So, other method of assessing artery patency is devised called TIMI frame count. In TIMI frame count the number of cineframes required for contrast material to first reach standard distal coronary landmarks (the TIMI frame count) is determined after thrombolysis.11 Thrombolytic Agents Used in Practice or Trials Thrombolytic agents which are most commonly used are streptokinase, anistreplase, alteplase, reteplase, tenecteplase. Thrombolytic agents differ in their efficacy of thrombolysis, fibrin selectivity and ability to activate thrombosis and platelet aggregation. Presently used thrombolytic agents have many limitations, which have prompted for a continued quest for better agents close to an ideal thrombolytic.

ÂÂ

Rapid reperfusion

ÂÂ

100% Thrombolysis In Myocardial Infarction (TIMI) Grade 3 flow reperfusion

ÂÂ

Administration as IV bolus

ÂÂ

Fibrin specific

ÂÂ

Low incidence of systemic bleeding

ÂÂ

Low incidence of intracranial hemorrhage

Streptokinase

ÂÂ

Resistant to plasminogen activator inhibitor

ÂÂ

Low re-occlusion rate

ÂÂ

No effect on blood pressure

ÂÂ

No antigenicity

This is the first thrombolytic agent clinically used.

It is relatively inexpensive. It is a nonfibrin specific agent, a protein obtained from Group C b-hemolytic streptococci.12

ÂÂ

Reasonable cost (cost-effective)

Evaluation of Efficacy of Thrombolysis To evaluate the coronary angiographic arterial patency after AMI, a grading system has been developed called TIMI.

Nonfibrin Specific Agents

It is interesting; to know that streptokinase is not an enzyme as other plasminogen activators are and does not directly convert plasminogen to plasmin. It is an indirect plasminogen activator. It works by binding with plasminogen to form an activator complex (1:1) complex that becomes active and converts the plasminogen to form plasmin. The plasmin thus generated is sufficient to overwhelm the levels of α2 antiplasmin. Also the streptokinase may increase the levels of circulating protein-C enhancing clot lysis.12

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TIMI Grade 0: It refers to absence of any antegrade flow beyond the point of occlusion.

ÂÂ

TIMI Grade 1: It refers to faint antegrade coronary flow beyond a coronary occlusion, although the filling of distal coronary bed is incomplete.

ÂÂ

TIMI Grade 2: In this grade, there is sluggish antegrade flow with complete filling of distal territory.

Streptokinase activates both circulating as well as fibrin bound plasminogen to plasmin. By virtue of this property it may produce systemic plasminemia with depletion of fibrinogen, plasminogen and other clotting factors viz. factor VII and factor V.

ÂÂ

TIMI Grade 3: Antegrade flow into the bed distal to the obstruction occurs as promptly as antegrade flow into the bed proximal to the obstruction i.e. flow is normal, fills distal territory bed completely.10

Streptokinase is used IV to reduce the mortality from AMI. The dose of streptokinase in myocardial infarction is 1.5 million units over 30-60 minutes. Plasma elimination half-life is about 18-23 minutes in man.9

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review article Majority of the patients have the circulating antibodies to streptokinase as a result of previous infection with b-hemolytic streptococci. So, sufficient dose must be given to neutralize these antibodies. But, the recommended dose schedule usually obviates the need for antibody titration. After streptokinase infusion, the titer of these antibodies in plasma increases dramatically and may rise to 50-100 times of preinfusion levels and may persists for many months even years. So, repeated administration is impractical.12 Streptokinase use is associated with adverse effects like allergic reactions, fever.

Anaphylaxis may occur with the use of streptokinase but fortunately it is rare.

Hypotension (not due to anaphylaxis or bleeding) may occur during streptokinase therapy. This adverse effect may be due to plasmin-induced Kallikrein activation and subsequent release of bradykinin or it may be due to various other mechanisms involving platelet activating factor.12 As with other thrombolytics, increased incidence of bleeding is seen with use of streptokinase (0.5%).

Though, the incidence of intracranial hemorrhage associated with use of streptokinase is 0.1%, the incidence of total stroke is not increased with the use of streptokinase (International Study of Infarct Survival-2 [ISIS-2]).13 Various studies have demonstrated the reduction in total mortality with use of streptokinase.

Given within three hours of onset of AMI, the mortality is reduced by 23% as shown in GISSI-1 trial.

The GISSI-1 trial has shown, the total 21 days mortality reduction is about 18%. The 21 days mortality with steptokinase is 10.7% as compared with control which is 13%. At one year, mortality with steptokinase is 17.2% as compared to 19% with control.8 The ISIS-2 study has shown reduction by about 25% in patients treated with streptokinase as compared to no treatment. This reduction in mortality can be increased with addition of aspirin. Their separate effects on vascular deaths appeared to be additive: 343/4292 (8.0%) among patients allocated both active agents versus 568/4,300 (13.2%) among those allocated neither (odds reduction: 42%).13 Although newer thrombolytics have become more popular in developed nations, streptokinase continues to be widely used in developing nations probably because of economic considerations.

Urokinase Urokinase was first isolated from human urine. Now it is generally synthesized from human fetal tissue cell culture. As like streptokinase, it is also a nonfibrin specific thrombolytic agent. As it is obtained from human sources the chances of allergic reactions are minimal.12 Urokinase is a two-chain serine protease containing 411 amino acid residues. Urokinase is a direct plasminogen activator. It does not form activator complex as streptokinase does. Urokinase converts plasminogen to plasmin directly by cleaving the Arg 560-Val 561 bond. Urokinase has a half-life of 15-20 minutes and molecular weight of 34,000.

The dose of urokinase in AMI is 2 million units as a bolus or 3 million units over 90 minutes.9 The chances of hypotension are minimal with urokinase.

Use of urokinase in AMI has been limited due to various factors. Like streptokinase it induces systemic lytic state and like t-pa it is expensive. Also because of production problems, the availability of urokinase is limited.14 Urokinase has never been systemically evaluated for coronary thrombolysis.

Anistreplase Anistreplase was the first bolus fibrinolytic agent developed. It is an equimolar complex of streptokinase and plasminogen. It is produced by combination of streptokinase with equimolar amounts of Lysplasminogen, a plasmin cleaved from plasminogen with Lys-residue at N-terminus. The active site of Lysplasminogen is then masked with anisoyl-group, which protects molecule from plasminogen inhibitors. After IV administration the agent become active following deacylation.15 It is given in a dose of 30 U. Anistreplase has a long half-life of about 100 minutes. So, it can be given as a single bolus infusion.

It is a nonfibrin specific thrombolytic as streptokinase.

It induces systemic activation of fibrinolysis. Other adverse effects like allergic reactions, hypotension are seen as frequent as with streptokinase.9 Formation of neutralizing antibodies is also seen with anistreplase.

In AIMS (APSAC interventional mortality study) trial, it has shown 47% decrease in 30-day mortality by virtue of its efficacy, resulting in premature termination of trial.16

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review article But when anistreplase was administered as a bolus over three minutes in ISIS-3 study, no mortality benefit was observed over streptokinase or rt-PA.17 There is slight increase in chances of stroke in patients receiving anistreplase as compared to streptokinase.

Anistreplase is not a widely used drug for AMI.

Fibrin Specific Thrombolytic Agents The agents in this class include alteplase (rt-PA), reteplase (r-PA), tenecteplase (TNK-PA) and newer thrombolytic agents like lanoteplase, staphylokinase, saruplase, vampire bat plasminogen activator.

These agents were developed to avoid the systemic thrombolytic state; however, they still can cause mild decrease in circulating fibrinogen and plasminogen.

The risk of intracranial hemorrhage is relatively higher in t-PAs as compared to streptokinase.14 These agents bind preferably with fibrin with high specificity in a thrombus and catalize the cleavage of plasminogen to plasmin. This causes initiation of local fibrinolysis with limited systemic proteolysis.

Alteplase (rt-PA) Alteplase (rt-PA) is a prototype of fibrin specific plasminogen activator and has high affinity for plasminogen in presence of fibrin. It is a serine protease containing single polypeptide chain of 527 amino acids.

It has a molecular weight of 68,000. It is produced by recombinant DNA technology.

The molecule of alteplase contains five domains: Finger, epidermal growth factor, kringle 1 and kringle 2, protease domain each having its own function.14 t-PA is a naturally occurring enzyme, which converts plasminogen to plasmin. It has greater affinity towards

Table 2. Showing Various Regions in t-PA Molecule and their Function18 Region of molecule

Function

Fibronectin finger

High affinity fibrin binding

Epidermal growth factor

Receptor binding (liver)

Kringle 1

Receptor binding

Kringle 2

Low affinity fibrin binding

Protease Domain

Plasminogen specific PAI-1 binding site

Carbohydrate

Mediators of plasma clearance

PAI-1 = Plasminogen activator inhibitor 1; t-PA = Tissue plasminogen activator.

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fibrin than streptokinase. In absence of fibrin it is a weak plasminogen activator. Fibrin provides scaffold on which t-PA and plasminogen are held in such a way that catalytic efficiency for plasminogen activation is increased many fold.14 The dose of alteplase in AMI is 100 mg administered intravenously. There are two dose regimens tested in trials. They are accelerated regime and standard 3-hour regime. The accelerated dose regime produces more rapid thrombolysis. In the accelerated regime, bolus infusion of 15 mg is given followed by 50 mg over next 30 minutes and remaining 35 mg in following hour.14 Alteplase has a short half-life of 3-5 minutes. It is rapidly cleared from plasma. The chances of allergic reactions, hypotension is rare.

Many studies have demonstrated the effectiveness of rt-PA in AMI. Results from GUSTO (Global Utilization of Streptokinase and TPA for Occluded arteries) trial indicate that a patient receiving alteplase has significant advantage in 30-day survival for alteplase in accelerated dose regime over streptokinase though cumulative 1-year cost was greater in patients who received alteplase.

The survival advantage was seen both below 75 years as well as above 75 years of age at least as great as seen with the use of streptokinase. Patients with anterior wall infarctions have shown greater improved outcome as compared to inferior wall infarction but reduction in mortality has been seen in both groups.19 The risk of stroke particularly hemorrhagic stroke is higher with alteplase as compared with streptokinase.

But the incidence of major stroke is comparable in both groups.

The greatest risk reduction is seen with patients in certain high-risk group such as those with anterior infarcts, selected elderly patients and those who present late after symptom onset.19 In ISIS-3 trial no difference in mortality was seen in endpoint at 35 days.17 In GISSI-2 trial, no specific differences between the two thrombolytic agents were detected as regards the combined endpoint i.e., death plus severe ventricular damage.

The incidence of major bleeds was significantly higher in streptokinase and heparin treated patients as compared to alteplase group. Streptokinase and rt-PA appear equally effective and safe for use in routine

review article conditions.20 Thus alteplase is at least as effective as streptokinase with lesser chances of adverse effects such as major bleed, allergy and hypotension.

Thus, due to fibrin selectivity and less adverse reactions, alteplase has become the first line of treatment in STEMI. Reteplase (r-PA) Reteplase (r-PA) is a single chain nonglycosylated deletion variant of alteplase. Because, it is produced in Escherichia coli, reteplase is nonglycosylated. It lacks the finger domain, epidermal growth factor, and kringle 1 domain as well as carbohydrate side chain. It contains amino acid 1 through 3 and 176 through 527 (deletion of amino acid 4-175).9 It has a molecular weight of about 39,000.

Because of deletion of finger domain and kringle 1 domain, fibrin specificity of the reteplase is very low as compared to alteplase (alteplase is more fibrin selective).

As a plasminogen activator, in absence of fibrin, the two molecules differ very little. Also as a result of deletion of finger domain, kringle 1 domain, as well as carbohydrate side chain, the plasma half-life of reteplase is 14-18 minutes more than that seen with alteplase (3-5 mins) due to reduced hepatic elimination.9 Due to increased half-life, reteplase can be administered as a bolus infusion, whereas alteplase has to be given as a bolus followed by infusion.

Optimal dose regime for reteplase has been evaluated in two open, randomized controlled trials, the Reteplase (r-PA) Angiographic Phase-II International Dose finding study (RAPID-1) and Reteplase (r-PA) versus Alteplase Patency Investigation During acute myocardial infarction (RAPID-2).

These very promising angiographic findings notwithstanding, r-PA fails to achieve superior mortality as compared to streptokinase in International Joint Efficacy Comparison of Thrombolytics (INJECT) study.

Mortality rate for reteplase at 35-day was found to be 9% for reteplase as compared to streptokinase, where it is about 9.5%. This study did not demonstrate superiority of reteplase. But, these two drugs can be considered equivalent as per trial definition.23 In the GUSTO-III trial, it was hypothesized that mortality would be lower in r-PA than with accelerated t-PA based on open-artery hypothesis and previous data showing an absolute difference of 15% in 90-minute TIMI Grade 3 flow between the agents. GUSTO-III study showed no significant difference in 30-day mortality for the agents (7.47% vs 7.24%, p = 0.61), respectively.24 These data shows multiplicity of factors other than coronary artery patency that ultimately translate into patient outcome.

Tenecteplase (TNK-tPA) Tenecteplase is a genetically engineered variant of t-PA. It is not a deletion mutant as in case of reteplase but it is a multiple point mutation of t-PA. It is a glycoprotein comprising of 527 amino acids.

In tenecteplase, arginine 103 is substituted for threonine, which creates a new glycosylation site, which results in prolongation of half-life. Further substitution of glutamine 117 for the amino acid asparagine 117, which results in reduction of its clearance contributing to extended half-life of this molecule.25 The sequence within the protease of Lys 296, His 297, Arg 298 and Arg 299 has been replaced by four alanine, which reduces the inhibition of tenecteplase by plasminogen activator inhibitor 1 (PAI- 1).25

The RAPID-1 trial has shown that when reteplase is given as a double bolus of 10 + 10 MU 30 minutes apart, it has resulted in achievement of more rapid, complete and sustained thrombolysis than standard dose alteplase (100 mg over 3 hours).

The net result of these changes produces a molecule, which is having greater half-life (18 minutes as compared to alteplase 3-4 minutes), resistant to inactivation by PAI-1 (80-fold), having high fibrin specificity (14-fold).3

In RAPID-1 trial, TIMI-3 grade rate at 90 minutes were 63% for reteplase as compared to 49% for alteplase. (p < 0.05).21

Of the available thrombolytic agents for use in AMI, tenecteplase has highest fibrin specificity.

In RAPID-2 trial, same r-PA dose regime yielded 90-minute reperfusion rate that were higher than those compared with accelerated dose regime of alteplase.

At 90-minute, TIMI-3 grade flow rate was 60% with reteplase as compared to 45% seen with alteplase. (p < 0.05).22

Tenecteplase binds with the fibrin rich clot with greater affinity and less extent to circulating plasminogen. It has fibrinolytic activity comparable to alteplase but less fibrinogenolysis has been observed with tenecteplase than with alteplase.

Tenecteplaseâ&#x20AC;&#x2122;s enhanced fibrin specificity causes increase in speed of patency and also permits compatibility with

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review article new adjunctive therapies. It does not cause significant depletion of Îą2-antiplasmin. It has less systemic fibrinolytic effect.3 Preclinical testing has revealed that it is associated with faster clot lysis, longer duration of artery patency and lower occurrence of bleeding as compared with rt-PA. Tenecteplase has been tested in various clinical trials for its pharmacokinetic properties and safety.

TIMI-10A trial evaluated the data from 113 patients suffering from AMI. The safety and efficacy of tenecteplase was very encouraging in this trial. TIMI Grade 3 flow at 90 minutes was achieved in 57-64% of patients at the 30- to 50-mg doses. Seven patients (6.2%) experienced a major hemorrhage, which occurred at a vascular access site in six patients. No stroke or intracranial hemorrhage was documented.26 In TIMI-10B trial, 886 patients, who were suffering from AMI, were enrolled to receive 30 mg, 50 mg of tenecteplase or accelerated t-PA 100 mg. The dose of 50 mg was soon stopped and replaced by dose of 40 mg due to increased bleeding and also dose of heparin reduced.27 The rate of 90-minute TIMI Grade 3 flow was identical in both groups i.e., with 40 mg single bolus dose of tenecteplase and accelerated t-PA activator (63%). But more Grade 3 TIMI flow was evident at 60 minutes with 40 mg dose of tenecteplase as compared to accelerated t-PA (55% vs 48%). Reperfusion was also evaluated on the basis of corrected TIMI frame count (CTFC).27 After reduction of heparin doses, rate of intracranial hemorrhages in all patients decreased significantly.

In ASSENT-2 (Assessment of the Safety and Efficacy of a New Thrombolytic) trial, single-bolus tenecteplase was compared with rapid infusion of alteplase in AMI to assess the efficacy and safety of tenecteplase.

Covariate-adjusted 30-day mortality rates were almost identical for the two groups - 6.18% for tenecteplase and 6.15% for alteplase. Also, the rate of intracranial hemorrhage was similar in both the groups. But, the use of tenecteplase was associated with fewer noncerebral bleeding complications and less need for blood transfusion.28 But due to single dose administration i.e., ease of administration with tenecteplase may facilitate prehospital initiation of treatment.

Reteplase and tenecteplase can be given as a bolus dose so they are also called as bolus thrombolytics.

Though, the clinical benefits with bolus fibrinolytics over the use of conventional thrombolytic have not been

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documented in many clinical trials, the bolus agents have many advantages, which favor their clinical utilization.

They are 1) Rapidity and ease of treatment: An increase in door-to-drug time has been associated with increase in mortality. Decrease in this time and also time for decision to start the drug can be reduced if simple bolus fibrinolytic agent is available. 2) Pre-hospital Treatment: A significant improvement in in-hospital mortality was evident by pre-hospital treatment approach due to significant early treatment of patients. Utilization of bolus fibrinolytic therapy enhances the feasibility of this promising strategy. 3) Decrease in medication errors: Due to ease of administration of bolus fibrinolytics medication errors such as wrong dose as seen with conventional thrombolytics can be reduced.29

Newer Antithrombolytics Currently available thrombolytic agents have several important limitations. At best, TIMI 3 flow within 90 minutes is obtained in somewhat over 50% of patients; acute coronary reocclusion occurs in roughly 10% of the patients, intracranial bleeding occurs in 0.3-0.7%, and the residual mortality of at least 50% of that without thrombolytic treatment.

To overcome these limitations new approaches to improve thrombolytic therapy have been tried.

Lanoteplase (n-PA) Lanoteplase is a novel plasminogen activator. It is a deletion and point mutant of wild type of t-PA. In lanoteplase finger domain as well as epidermal growth factor domain has been removed and glycosylation points in kringle 1 have been modified. The deletion of fibronectin finger-like epidermal growth factor results in slower clearance of this agent.3 The plasma half-life of lanoteplase is about 37 minutes so it can be given as a single bolus IV dose.

Developers have described this novel agent as a fibrin specific.

Lanoteplase has been evaluated in Intravenous n-PA for treatment of Infracting Myocardium Early (InTIME) trial.

The Phase II InTIME trial, total 602 patients presenting with AMI were randomized and treated with either a single-bolus injection of lanoteplase (15, 30, 60 or 120 kU/kg) or accelerated alteplase. In this study lanoteplase was found to have dose dependent increase in reperfusion rate. The highest lanoteplase dose of 120 kU was found to be significantly more effective than alteplase. At 90 minutes, coronary patency

review article (TIMI 2 or 3) increased across the dose range upto 83% of subjects at 120 kU/kg lanoteplase compared with 71.4% with alteplase. At dose of 120 kU lanoteplase was found to be more superior to alteplase in restoring coronary artery patency. In this study lanoteplase has safety comparable to alteplase.30 In Phase III mortality trial called InTIME-II, a single bolus dose of lanoteplase 120 kU was compared with Accelerated t-PA in 15,078 patients. Similar 30-day mortality rate was found: 6.61 for t-PA versus 6.75 for lanoteplase. However, hemorrhagic stroke rate was found to significantly more in lanoteplase treated group.

Hemorrhagic stroke rates were 0.64% for alteplase and 1.12% for lanoteplase (p = 0.004).31

Staphylokinase Staphylokinase is a protein produced by certain strains of Staphylococcus aureus. It has 136 amino acids.

Staphylokinase forms a 1:1 complex with plasminogen as seen with streptokinase. The staphylokinaseplasminogen complex is inactive and requires conversion to staphylokinase-plasmin complex to become active as a plasminogen activator. Fibrin is responsible for this activation.

The staphylokinase-plasmin complex thus formed is rapidly neutralized by Îą2-antiplasmin. The inhibition rate however is reduced by nearly 100 folds in presence of fibrin.3 In addition to this, when staphylokinase-plasmin complex is neutralized by Îą2 antiplasmin, staphylokinase is released and is recycled to other plasminogen molecule.

These interactions between staphylokinase, plasminogen and Îą2-antiplasmin gives it a unique mechanism of fibrin selectivity. In absence of fibrin no activation of plasminogen by staphylokinase occurs.

Staphylokinase has been evaluated in small scale studies.

In a recent randomized trial staphylokinase versus alteplase in 100 patients with AMI has been studied.

TIMI perfusion Grade 3 at 90 minutes was achieved in 62% of STAR patients versus 58% of rt-PA patients and staphylokinase was found to be at least as effective for early coronary recanalization and significantly more fibrin-specific than accelerated rt-PA in patients with evolving myocardial infarction.32 Vast majority of the patients developed neutralizing antibodies to staphylokinase after a period of 7-12 days.

These neutralizing antibodies remain elevated for well above pre-treatment levels for several months.

Some variants of staphylokinase (SakSTAR.M38& SakSTAR.M89) were found to be thrombolytically more active and less antigenic as compared to wild-type molecule. In the future it may be possible to develop nonimmunogenic staphylokinase.7 Available evidence suggests that recombinant staphylokinase is a potent; highly fibrin selective thrombolytic agent and larger clinical studies to determine its safety and efficacy are warranted.

Saruplase Saruplase is the nonglycosylated form of single chain urokinase t-PA; it is produced by recombinant technique in E. coli. Plasmin causes limited hydrolysis of saruplase molecule to become two chain urokinase.3 Saruplase has plasminogen activating properties.

Saruplase is not fibrin specific. Saruplase has a half-life of about nine minutes.

It is given as a 20 mg bolus followed by 60 mg infusion over one hour. It is nonimmunogenic.3 In early phase of development, a randomized controlled trial called PRIMI (Prourokinase In Myocardial Infarction) in 401 patients, the therapeutic value of saruplase was compared with that of streptokinase.

When given to patients with a first AMI within four hours of onset of symptoms, it was found to have significantly higher rate of TIMI Grade 3 flow rates at 60 minutes but comparable rates at 90 minutes. Fewer bleeding complications were seen with saruplase.33 In COMPASS trial, reduced 30-day mortality was seen with saruplase as compared with streptokinase (5.7 vs 6.7, respectively). But, the rate of intracranial hemorrhage was found significantly more in saruplase (0.9%) as compared to streptokinase (0.3%). The rate of bleeding was similar in the two treatment groups (10.4% vs 10.9%). Hypotension and cardiogenic shock occurred less frequently in the saruplase group.

Reinfarction rates were similar.34 The SUTAMI trial found that TIMI Grade 2/3 flow rates at 24-32 hours were comparable with saruplase and urokinase.35 In SESAM trial, saruplase was compared with three hours infusion of t-PA in 437 patients. It was shown that saruplase was associated with comparatively higher rates of TIMI Grade 3 flow at 60 and 90 minutes.36

Vampire Bat Plasminogen Activator The vampire bat (Desmodus rotundus) salivary plasminogen activator is homologos with human t-PA but lacks the second kringle domain. It is more

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review article fibrin specific than human t-PA in experimental animal models. In Phase 1 clinical study, the half-life was found to be 2.8 hours. This suggests that this agent would be appropriate for single dosing. In animal models of thrombosis, the mean time to reperfusion was fast with vampire bat salivary PA.3,7 This agent can prolong bleeding time to some extent.

In addition, animal studies have shown that this agent has some immunogenicity and antibody titer though variable; antibodies may persist for several weeks.7 Complications of Fibrinolytic Therapy Stroke: Excess stroke in fibrinolytic therapy is largely attributed to excess of intracranial hemorrhage. There is an excess of 3.9 strokes/1,000 patients treated with fibrinolysis vs placebo.

Major bleeding: The fibrinolytic therapy Trialists Group defined major bleeding as those that were considered life-threatening or required blood transfusion. They reported 1.1% incidence among patients receiving fibrinolytic therapy as compared with 0.4% among that receiving placebo an increase of seven major bleed/ 1,000 patients.

Anaphylaxis: This complication occurs with the use of streptokinase. It occurs in <2% of patients receiving streptokinase, but rarely in patients treated with t-PA. Hypotension can occur in patients receiving streptokinase.29 Summary Thrombolysis is still the most commonly used reperfusion strategy. Large multicentric trials have proved the efficacy of thrombolysis in mortality reduction. Though the fibrinolytic capacity of streptokinase was discovered in 1930’s, the use of streptokinase in practice was started only after 1980’s.

Fibrin nonspecific thrombolytic agents like streptokinase activate both circulating as well as fibrin bound plasminogen to plasmin. Despite development of more fibrin specific thrombolytic agents, streptokinase is still widely used.

Fibrin specific agents like alteplase, activate mainly the fibrin bound plasminogen. Alteplase has become first line of drug among thrombolytics in treatment of AMI. Reteplase and tenecteplase are bolus thrombolytics.

Though, they have not shown any clinical benefits over conventional thrombolytics, they have certain advantages, which favor their clinical utilization like

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rapidity and ease of treatment, pre-hospital initiation of therapy.

Despite of advancement in thrombolytic therapy, currently used thrombolytic agents have many limitations like increased chances of intracranial bleeding, reocclusion, etc. To overcome these limitations, new agents are being tested. Lanoteplase, saruplase, staphylokinase, vampire bat salivary plasminogen activator are most promising drugs.

References 1. Tsikouris JP, Tsikouris AP. A review of available fibrinspecific thrombolytic agents used in acute myocardial infarction. Pharmacotherapy 2001;21(2):207-17.

2. Mendoza CE, Bhatt MR, Virani S, Schob AH, Levine S, Ferreira AC, et al. Management of failed thrombolysis after acute myocardial infarction: an overview of current treatment options. Int J Cardiol 2007;114(3):291-9.

3. Van de Werf FJ. The ideal fibrinolytic: can drug design improve clinical results? Eur Heart J 1999;20(20):1452-8.

4. Sikri N, Bardia A. A history of streptokinase use in acute myocardial infarction. Tex Heart Inst J 2007;34(3):318-27.

5. Falk E, Shah PK, Fuster V. Coronary plaque disruption.

Circulation 1995;92(3):657-71.

6. Thacker H. Thrombolytic agents - old and new. Medicine Update 2010;20:322-8.

7. Collen D. Fibrin-selective thrombolytic therapy for acute myocardial infarction. Circulation 1996;93(5):857-65.

8. GISSI Investigators Group. Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction.

Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto Miocardico (GISSI). Lancet 1986;1(8478): 397-402.

9. Armstrong PW, Collen D. Fibrinolysis for acute myocardial infarction: current status and new horizons for pharmacological reperfusion, part 1. Circulation 2001;103(23):2862-6.

10. TIMI Study Group. The Thrombolysis in Myocardial Infarction (TIMI) trial. Phase I findings. N Engl J Med 1985;312(14):932-6.

11. Gibson CM, Cannon CP, Daley WL, Dodge JT Jr, Alexander B Jr, Marble SJ, et al. TIMI frame count: a quantitative method of assessing coronary artery flow. Circulation 1996;93(5):879-88.

12. Grignani G, Zucchella M, Brocchieri A, Saporiti A. Current concepts in coronary thrombolysis. Haematologica 1994;79(5):475-82.

13. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2.

Lancet 1988;2(8607):349-60.

review article 14. Khan IA, Gowda RM. Clinical perspectives and therapeutics of thrombolysis. Int J Cardiol 2003;91 (2-3):115-27.

15. Fauci, Braunwald et al. Harrison’s Principles of Internal Medicine. Vol. 1, 2008;17:745-7.

16. Julian DG. The APSAC interventional mortality study (AIMS) trial: mortality data. Clin Cardiol 1990;Suppl 5: V20-1; discussion V27-32.

17. ISIS-3 (Third International Study of Infarct Survival) Collaborative Group. ISIS-3: a randomised comparison of streptokinase vs tissue plasminogen activator vs anistreplase and of aspirin plus heparin vs aspirin alone among 41,299 cases of suspected acute myocardial infarction. Lancet 1992;339(8796):753-70.

18. Nordt TK, Bode C. Thrombolysis: newer thrombolytic agents and their role in clinical medicine. Heart 2003;89(11):1358-62.

19. GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993;329(10):673-82.

20. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico. GISSI-2: a factorial randomised trial of alteplase versus streptokinase and heparin versus no heparin among 12,490 patients with acute myocardial infarction. Lancet 1990;336(8707):65-71.

21. Smalling RW, Bode C, Kalbfleisch J, Sen S, Limbourg P, Forycki F, et al. More rapid, complete, and stable coronary thrombolysis with bolus administration of reteplase compared with alteplase infusion in acute myocardial infarction. RAPID Investigators. Circulation 1995;91(11):2725-32.

22. Bode C, Smalling RW, Berg G, Burnett C, Lorch G, Albfleisch JM, et al. Randomized comparison of coronary thrombolysis achieved with double-bolus reteplase (recombinant plasminogen activator) and front-loaded, accelerated alteplase (recombinant tissue plasminogen activator) in patients with acute myocardial infarction.

The RAPID II Investigators. Circulation 1996;94(5):891-8.

23. International Joint Efficacy Comparison of Thrombolytics.

Randomised, double-blind comparison of reteplase double-bolus administration with streptokinase in acute myocardial infarction (INJECT): trial to investigate equivalence. Lancet 1995;346(8971):329-36.

24. A comparison of continuous infusion of alteplase with double-bolus administration for acute myocardial infarction. The Continuous Infusion versus Double-Bolus Administration of Alteplase (COBALT) Investigators. N Engl J Med 1997;337(16):1124-30.

27. Cannon CP, Gibson CM, McCabe CH, Adgey AA, Schweiger MJ, Sequeira RF, et al. TNK-tissue plasminogen activator compared with front-loaded alteplase in acute myocardial infarction: results of the TIMI 10B trial.

Thrombolysis in Myocardial Infarction (TIMI) 10B Investigators. Circulation 1998;98(25):2805-14.

28. Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT-2) Investigators, Van De Werf F, Adgey J, Ardissino D, Armstrong PW, Aylward P, Barbash G, et al. Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the ASSENT-2 double-blind randomised trial. Lancet 1999;354(9180):716-22.

29. Menon V, Harrington RA, Hochman JS, Cannon CP, Goodman SD, Wilcox RG, et al. Thrombolysis and adjunctive therapy in acute myocardial infarction: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126(3 Suppl):549S575S. 30. den Heijer P, Vermeer F, Ambrosioni E, Sadowski Z, López-Sendón JL, von Essen R, et al. Evaluation of a weight-adjusted single-bolus plasminogen activator in patients with myocardial infarction: a double-blind, randomized angiographic trial of lanoteplase versus alteplase. Circulation 1998;98(20):2117-25.

31. InTIME-II Investigators. Intravenous NPA for the treatment of infarcting myocardium early; InTIME-II, a double-blind comparison of single-bolus lanoteplase vs accelerated alteplase for the treatment of patients with acute myocardial infarction. Eur Heart J 2000;21(24): 2005-13.

32. Vanderschueren S, Barrios L, Kerdsinchai P, Van den Heuvel P, Hermans L, Vrolix M, et al. A randomized trial of recombinant staphylokinase versus alteplase for coronary artery patency in acute myocardial infarction. The STAR Trial Group. Circulation 1995;92(8):2044-9.

33. PRIMI Trial Study Group. Randomised double-blind trial of recombinant pro-urokinase against streptokinase in acute myocardial infarction. Lancet 1989;1(8643):863-8.

34. Tebbe U, Michels R, Adgey J, Boland J, Caspi A, Charbonnier B, et al. Randomized, double-blind study comparing saruplase with streptokinase therapy in acute myocardial infarction: the COMPASS Equivalence Trial. Comparison Trial of Saruplase and Streptokinase (COMASS) Investigators. J Am Coll Cardiol 1998;31(3): 487-93.

25. Davydov L, Cheng JW. Tenecteplase: a review. Clin Ther 2001;23(7):982-97; discussion 981.

35. Michels R, Hoffmann H, Windeler J, Barth H, Hopkins G. A Double-Blind Multicenter Comparison of the Efficacy and Safety of Saruplase and Urokinase in the Treatment of Acute Myocardial Infarction: Report of the SUTAMI Study Group. J Thromb Thrombolysis 1995;2(2):117-24.

26. Cannon CP, McCabe CH, Gibson CM, Ghali M, Sequeira RF, McKendall GR, et al. TNK-tissue plasminogen activator in acute myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI) 10A doseranging trial. Circulation 1997;95(2):351-6.

36. Bär FW, Meyer J, Vermeer F, Michels R, Charbonnier B, Haerten K, et al. Comparison of saruplase and alteplase in acute myocardial infarction. SESAM Study Group.

The Study in Europe with Saruplase and Alteplase in Myocardial Infarction. Am J Cardiol 1997;79(6):727-32.

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Original Article

ECG: A Simple Noninvasive Tool to Localize Culprit Vessel Occlusion Site in Acute STEMI Biplab Ghosh*, Manoj Indurkar**, Mahendra Kumar Jainâ&#x20AC;

Abstract Introduction: Various electrocardiogram (ECG) patterns can determine the site of occlusion in culprit coronary artery in STelevation myocardial infarction (STEMI) and the size of the myocardium that is jeopardized. Objectives: The aim of this study was to assess diagnostic accuracy of the ECG localization of culprit vessel occlusion site as compared to coronary angiographic findings. Material and methods: ECG criteria for localization of culprit vessel occlusion site were specified and patients with STEMI (n = 21) were divided into three groups: Groups I, II and III, according to the localization of culprit vessel occlusion site in left anterior discending (LAD), right coronary artery (RCA) and left circumflex (LCx) coronary arteries, respectively. Group I was further divided into four subgroups: Ia, Ib, Ic and Ib+c according to whether occlusion in LAD was proximal to both first septal (S1) and first diagonal (D1) branches, distal to S1 but proximal to D1 branches, distal to both S1 and D1 branches or distal to S1 branch, respectively. Group II was further divided into two subgroups: IIa and IIb according to whether occlusion in RCA was proximal or distal to RV branch, respectively. The results of coronary angiograms were compared with those predicted by ECG. Results: The positive predictive accuracy (PPA) and negative predictive accuracy (NPA) of ECG criteria for LAD, RCA, and LCx coronary arteries were 90.91% and 100%, 90% and 100%, and undetermined and 90.48%, respectively. Among subgroups the sensitivity of ECG criteria was maximum for groups Ib+c and IIb (100%) followed by Group IIa (71.43%), Group Ic (50%), Group Ia (42.86%) and least for Group Ib (0%). The specificity was maximum for Groups Ia and IIa (92.86%) followed by Group Ib (90%), Group IIb (89.47%), Group Ic (78.95%) and Group Ib+c (77.78%) in that order. The PPA and NPA for Groups Ia, Ib, Ic, Ib+c, IIa and IIb were 75% and 76.47%, 0% and 94.74%, 20% and 93.75%, 42.86% and 100%, 83.33% and 86.67% and 50% and 100%, respectively. Conclusion: The present study demonstrates that ECG is an easily and widely available inexpensive tool to localize site of occlusion in culprit vessel in acute STEMI.

Keywords: Culprit vessels, STEMI, ECG, coronary angiography

T

he standard 12 lead electrocardiogram (ECG) has long been a reliable clinical tool for diagnosis of acute myocardial infarction (AMI). Specific ECG patterns for the site of occlusion in culprit coronary artery has been well-recognized.1 Larger the area at risk more aggressive should be the attempt to restore or improve perfusion of that area.

*Senior Resident Dept. of Nephrology, Institute of Medical Sciences Banaras Hindu University, Varanasi, Uttar Pradesh **Associate Professor â&#x20AC; Professor Dept. of Medicine, Shyam Shah Medical College Rewa, Madhya Pradesh Address for correspondence Dr Biplab Ghosh Senior resident Dept. of Nephrology, Institute of Medical Sciences Banaras Hindu University Varanasi - 221 005, Uttar Pradesh E-mail: dr.biplabghosh@gmail.com

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Objectives The aim of this study was to amalgamate various ECG criteria for localization of culprit vessel occlusion site and to assess its diagnostic accuracy as compared to follow-up coronary angiographic findings.

Material and Methods The present study was carried out on patients admitted with AMI after application of the following exclusion criteria: Patients with history of previous myocardial infarction and previous coronary artery bypass graft (CABG) surgery; ECG evidence of left bundle branch block (LBBB), pre-excitation and paced rhythm. Written informed consent was obtained from each patient. AMI was diagnosed as per standard criteria.1 A detailed history and physical examination was carried out.

ECG was recorded on admission and then 90 minutes and three hours after completion of thrombolysis,

Original Article and if thrombolysis was not done, at four hours and 24 hours after admission. Besides, ECG was recorded whenever symptoms and clinical situations demanded so. In inferior wall, AMI right sided leads and posterior leads were also recorded. Patients were referred to other hospitals for coronary angiography and the results were noted on subsequent follow-up. A lesion was considered to be the culprit when it occluded or severely narrowed the artery and was ulcerated and/or contained thrombus. The results of coronary angiograms were compared with that predicted by ECG. Patients were divided into three groups: Groups I, II and III according to the localization of occlusion site in left anterior discending (LAD), right coronary artery (RCA) and left circumflex (LCx) coronary arteries, respectively. Group I was further divided into four subgroups: Ia, Ib, Ic and Ib+c according to whether occlusion in LAD was proximal to both first septal (S1) and first diagonal (D1) branches, distal to S1 but proximal to D1 branch, distal to both S1 and D1 branches or distal to S1 branch (irrespective of D1 branch), respectively. Group II was further divided into two subgroups: IIa and IIb according to whether occlusion in RCA was proximal or distal to right ventricular (RV) branch, respectively.

ECG Criteria to Identify Site of Occlusion in LAD (in AWMI) Criteria

Occlusion site

1. Any one or more of the following

Proximal to S1

ECG Criteria to Identify whether Site of Occlusion is in RCA or LCx (in IWMI) Criteria

RCA

LCx

*1. ST ↑ III > ST ↑ II

Present

Absent

*2. ST ↓ aVL > ST ↓ I

Present

Absent

<1.2

>1.2

4. Lead V4R

*3. ST ↓ V3/ST ↑ III ratio

T-wave upright

Inverted T-wave

5. ST ↓ V1-V2

Absent (present in occlusion of dominant RCA causing posterior wall MI)

Present

Absent

Present

Absent (present if RCA dominant)

Present

6. Max ST ↓ V2-V3 7. ST ↑ V7-V9

*In case of discrepancy between criteria 1, 2 and 3, the localization was done as per criteria 1 and 2 rather than 3. Criteria 5 to 7 were used mainly for supportive evidence.

ECG Criteria for Site of Occlusion in RCA Criteria V4R

Proximal to RV branch

Distal to RV branch

ST ↑ ≥1 mm

No ST ↑

ST ↑ V1

Present

Absent

ST ↑ V4R > ST ↑ in V1-V3

Present

Absent

Ratio of ST ↓ V3/ST ↑ III

< 0.5

>0.5, but <1.2

AV nodal block

Present

Absent

Atrial infarction

Present

Absent

i. Complete RBBB ii. ST ↑ V1 > 2.5 mm iii. ST ↑ AVR

Results

iv. ST ↓ V5

Demographic and clinical parameters of all 21 patients are shown in Table 1. According to ECG criteria, Groups I, II, III, Ia, Ib, Ic, IIa and IIb had 11 (52.38%), 10 (47.62%), 0 (0.0%), 4 (19.05%), 2 (9.52%), 5 (23.81%), 6 (28.57%) and 4 (19.05%) patients, respectively. The mean left ventricular ejection fraction (LVEF) in Groups Ia, Ib, Ic, IIa and IIb were 35.25%, 34.0%, 42.2%, 42.6% and 55.2%, respectively. Lowest LVEF was noted in two diabetic patients (22% and 24%). ECG criteria correlated with coronary angiography fully in 11 patients (52.38%) and partially in eight patients (38.10%) but not at all in two patients (9.52%). Angiography revealed occlusion of LCx in two patients who were misclassified by ECG in Groups Ia and IIa. Out of the eight patients in whom ECG correlated partially, seven had involvement of the

v. New onset LAHB 2. Q in AVL

Proximal to D1

3. Any one or more of the following

Proximal to S1 and/or D1

i. ST ↓ II ≥ 1.0 mm ii. Maximum ST ↑ appeared in V2 4. Q in V5

Distal to S1

5. ST ↓ AVL

Distal to D1

6. No ST ↓ III

Distal to S1 and/or D1

Group Ia had criteria 1, 2 and 3; Group Ib had criteria 2 and 4 without 1 and 5; Group Ic had criteria 4, 5, and 6; Group Ib+c was the combination of Group Ib and Ic.

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Cardiology

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Cardiology

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Original Article each) followed by Group IIa (71.43%), Group Ic (50%), Group Ia (42.86%) and least for Group Ib (0%). The specificity was maximum for Groups Ia and IIa (92.86% each) followed by Group Ib (90%), Group IIb (89.47%), Group Ic (78.95%) and Group Ib+c (77.78%) in that order. The PPA and NPA for Group Ia, Ib, Ic, Ib+c, IIa and IIb were 75% and 76.47%, 0% and 94.74%, 20% and 93.75%, 42.86% and 100%, 83.33% and 86.67% and 50% and 100%, respectively.

Table 1. Demographic, Clinical and Laboratory Parameters (n = 21) Characteristic

Number (%)

Age, mean ± SD (years)

55.09 ± 10.08

Current smoker BMI ± SD

9 (42.86%)

(kg/m2)

22.56 ± 3.54

Diabetes mellitus (DM)

2 (9.52%)

Hypertension (HTN)

6 (28.57%)

Family history of DM, HTN and/or IHD

7 (33.33%)

No past and/or family history of DM, HTN

11 (52.38%)

Presented < 3 hours of chest pain onset

8 (38.10%)

Presented >12 hours of chest pain onset

7 (33.33%)

Thrombolytic therapy given

8 (38.10%)

Single vessel disease

13 (61.90%)

Double vessel disease

4 (19.05%)

Triple vessel disease

4 (19.05%)

Discussion With anterior wall myocardial infarction (AWMI), the occlusion is nearly always in the LAD coronary artery.

With inferior wall myocardial infarction (IWMI), however, either the RCA or the LCx coronary artery may contain the culprit lesion.1 Rarely, acute IWMI may result from occlusion of the recurrent LAD branch, which is the terminal portion of a ‘wraparound’ LAD.

same coronary artery but at a proximal location from that predicted by ECG and one had occlusion more distally. Correlation of ECG criteria with coronary angiography is shown in Table 2. The sensitivity of ECG to identify culprit vessel in AMI was 100% for both LAD coronary artery and RCA but 0% for LCx coronary artery. The specificity was maximum for LCx coronary artery (100%) followed by that for RCA (91.67%) and LAD coronary artery (90.91%). The positive predictive accuracy (PPA) and negative predictive accuracy (NPA) for LAD, RCA and LCx coronary arteries were 90.91% and 100%, 90% and 100%, and undetermined and 90.48%, respectively. The sensitivity of ECG criteria to further localize the site of occlusion in a culprit vessel in AMI was maximum for groups Ib+c and IIb (100%

In AWMI, ST-segment elevation in leads V1, V2, and V3 indicates occlusion of the LAD coronary artery.

ST-segment elevation in these three leads and in lead aVL in association with ST-segment depression of >1 mm in leads II, III and aVF indicates proximal occlusion of the LAD artery. In this case, the ST-segment vector is directed upward, toward leads V1, aVL and aVR, and away from the inferior leads. ST-segment elevation in leads V1, V2, and V3 without significant inferior STsegment depression suggests occlusion of the LAD artery after the origin of the first diagonal branch. STsegment elevation in leads V1, V2, and V3 with elevation in the inferior leads suggests occlusion of the LAD artery distal to the origin of the first diagonal branch, in a vessel that wraps around to supply the inferoapical region of the left ventricle. New right bundle-branch block (RBBB) with a Q-wave preceding the R-wave in

Table 2. Correlation of ECG Criteria with Coronary Angiography Groups by ECG

Sensitivity (%)

Specificity (%)

PPA (%)

NPA (%)

Ia

42.86

92.86

75.00

76.47

Ib

0.00

90.00

0.00

94.74

Ic

50.00

78.95

20.00

93.75

Ib+c

100.00

77.78

42.86

100.00

I

100.00

90.91

90.91

100.00

IIa

71.43

92.86

83.33

86.67

IIb

100.00

89.47

50.00

100.00

II

100.00

91.67

90.00

100.00

III

0.00

100.00

-

90.48

NPA: Negative predictive accuracy; PPA: Positive predictive accuracy.

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Original Article lead V1 is a specific but insensitive marker of proximal occlusion of the LAD artery in association with anteroseptal myocardial infarction.1 In IWMI several ECG criteria identify RCA or LCx as the artery containing the culprit lesion. Each of these criteria is based on one of two anatomic facts.2 First, the myocardial distribution of the RCA is slightly rightward in the frontal plane, and consequently the current of injury resulting from its occlusion will be reflected more in lead III than lead II and ST↓ will be more in lead aVL than in lead I. Conversely, the distribution of the LCx is slightly leftward in the frontal plane, and the current of injury from its closure will be seen more in lead II than lead III. Similarly, the current of injury with RCA occlusion is more or less perpendicular to the axis of lead aVR, whereas the current of injury resulting from occlusion of the LCx has a mean vector that forms an obtuse angle with the axis of aVR. Therefore, significant ST-segment depression in aVR is more likely to occur with LCx occlusion. An injury vector leftward enough to cause ST-segment elevation in lead I is common with LCx occlusion, but rare with RCA occlusion. Second, the RCA provides almost all of the blood supply to the right ventricle, which is rightward as well as anterior to left ventricle. When the RCA is occluded proximal to one or more of its major RV branches, ST-segment elevation is likely to be seen in lead V4R. Similarly, the ST-segment in lead V1 (V2R) may be elevated even when the more leftward precordial leads show STsegment depression due to the posterior injury that so frequently accompanies acute IWMI. Evidence of acute RV infarction is important, not only because it identifies the RCA as harboring the culprit lesion, but especially because it predicts a greatly increased morbidity and mortality. Consequently, right precordial leads or at least lead V4R should be recorded in all patients with acute IWMI. ST-segment depression in V1 and V2 indicates posterior injury and is typical of LCx occlusion.

Mortality and morbidity in part are determined by the location of the occlusion. For example, in patients with inferior MI who have RV infarction, the culprit artery virtually always is the RCA. Such patients, including those in whom ECG evidence of RV MI is masked, are at increased risk for death, shock and arrhythmias, including atrioventricular block.2 Thus, identifying the culprit artery in acute IWMI helps define those in whom aggressive reperfusion strategies are likely to yield most benefit. Coronary arteriography is the best means of determining the culprit artery in acute IWMI. When both the RCA and LCx are severely diseased, however, deciding which one the culprit is can be difficult and

having an independent predictor of the culprit artery, such as the ECG, can be very helpful.

Engelen et al in a study of patients with AWMI showed that for different ECG criteria we used in our study to localize LAD occlusion proximal to S1 and/or D1 (i.e., patients in group Ia and Ib in the present study), the sensitivity, specificity, PPA and NPA varied from 12% to 44%, 85 to 100%, 67 to 100% and 61 to 70%, respectively.3 Similar figures for ECG criteria to localize occlusion in LAD distal to S1 and/or D1 (i.e., patients in Group Ib and Ic in the present study) were 22-41%, 86-95%, 77-92% and 46-53%, respectively.

In a study by Herz et al in patients with inferior wall AMI, the sensitivity to localize RCA occlusion varied from 55% to 94%.4 The specificity, PPA and NPA varied from 71% to 100%, 88 to 100% and 29 to 75% respectively. The sensitivity, specificity, PPA and NPA for LCx coronary artery were 88%, 100%, 100% and 97%, respectively.4 Kosuge et al studied the criteria of ratio of ST ↓ V3/ST ↑ III in patients with acute IWMI and found the sensitivity, specificity, PPA and NPA for RCA occlusion proximal to RV branch to be 91%, 91%, 88% and 93%, respectively.5 The similar figure for RCA occlusion distal to RV branch were 84%, 93%, 91% and 88% and those for LCx coronary artery occlusion were 84%, 95%, 73% and 98%, respectively.5 Nair et al found that quantifying ST-segment depression in lead aVR distinguished a culprit LCx (≥1 mm) from a culprit RCA (<1 mm or no depression) as well or better than other criteria and the importance of lead V4R has been investigated by many a authors.6,7 Diagnostic accuracy of different ECG criteria in different studies are given in Tables 3 and 4.

The ECG criteria used in these previous studies were combined and used in the present study. The findings in the present study were in agreement with those of the study by Engelen et al except for the higher sensitivity and NPA and lower specificity and PPA in Group Ib+c.

The results were similar to that of the study by Herz et al except for the lower sensitivity for LCx and greater NPA for RCA in the present study. The present series also agreed with the findings by Kosuge et al except for the lower sensitivity and lower NPA in Group IIa, and higher sensitivity and NPA as well as lower PPA in Group IIb. The lower specificity and PPA in group Ib+c (distal to S1 branch occlusion of LAD) in the present study was because of the fact that ECG was false positive for five patients in that group with four of them having severe degree of occlusion proximally in LAD (three had single

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Original Article Table 3. Diagnostic Accuracy of Different ECG Criteria in AWMI (Engelen et al3) IRA LAD proximal to S1

LAD proximal to D1

LAD distal to S1

ECG criteria

Sensitivity

PPA

NPA

ST↑ aVR*

43

95

86

70

ST ↓ II ≥1.0 mm*

36

100

100

68

ST ↓ III ≥1.0 mm

60

71

60

71

ST ↓ III ≥2.5 mm

33

97

88

67

ST ↓ aVF ≥1.0 mm

52

84

71

71

ST ↓ aVF ≥2.0 mm

26

97

85

64

cRBBB*

14

100

100

62

ST ↓ V5 ≥1.0 mm*

17

98

88

62

ST ↑ V1 ≥2.5 mm*

12

100

100

61

ST ↓ II ≥1.0 mm*

34

98

93

68

ST ↓ III ≥1.0 mm

66

75

64

76

ST ↓ III ≥2.5 mm

32

95

81

67

ST ↓ aVF ≥1.0 mm

54

85

71

72

ST ↓ aVF ≥2.0 mm

27

97

85

66

Q aVL*

44

85

67

69

Absence of ST↓ II

67

74

78

62

Absence of ST↓ III*

34

86

77

49

Absence of ST↓ aVF

45

90

87

54

Q V6

17

100

100

47

24

93

82

47

Q V4

55

69

71

53

Q V 5* LAD distal to D1

Specificity

Absence of ST↓ II

66

73

78

60

Absence of ST↓ III*

41

95

92

53

Absence of ST↓ aVF

44

90

87

53

ST↓aVL*

22

95

87

46

* Criteria used in the present study; AWMI: Anterior wall myocardial infarction; IRA: Infarct related artery; NPA: Negative predictive accuracy, PPA: Positive predictive accuracy, ST↑: ST-segment elevation; ST↓: ST-segment depression.

Table 4. Diagnostic Accuracy of Different ECG Criteria in IWMI in Different Studies Studies

ECG criteria

Kosuge et al5

Ratio of ST ↓ V3/ST ↑ III

Herz et

al4

Various criteria

Verouden et al8 Verouden et al8 Zimetbaum et al9 Chia et al10 Bairey et al11

ST ↑ III >II, ST↓I or aVL >1 mm Above + ST deviation >18.5 mm ST ↑ in III>II and I and/or aVL <-1 mm ST ↑ in III>II and any ST↓ in I ST ↓ in I

Bairey et al11

ST ↓ in aVL

IRA

Sensitivity

Specificity

PPA

NPA

RCA proximal to RV branch (<0.5) RCA distal to RV branch (>0.5, <1.2) LCx (>1.2) RCA LCx RCA RCA RCA RCA RCA

91

91

88

93

84

93

91

88

84 55-94 88 70 90 70 76 79

95 71-100 100 72 72 66 61

73 88-100 100 90 89 89

98 29-75 97 39 42 44

RCA

95

24

82

56

IRA: Infarct related artery; IWMI: Inferior wall myocardial infarction; NPA: Negative predictive accuracy; PPA: Positive predictive accuracy, ST↑: STsegment elevation; ST↓: ST-segment depression.

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Asian Journal of Clinical Cardiology, Vol. 15, No. 10, February 2013

Original Article vessel disease) and one had LCx disease by coronary arteriogram (CART). As pre-existing severe stenosis in these patients could have made collateral circulation to develop adequately so as to minimize the amount of myocardium jeopardized even when the occlusion was in the proximal segment of LAD, ECG might have falsely mimicked that of distal LAD occlusion. The lower PPA in Group IIb in the present study might be because of the same reason as two of the 4 patients in that group had occlusion more proximally. The small sample size could be the possible explanation for lower sensitivity in Group III, which inherently also has a low sensitivity due to inability of ECG to localize LCx coronary artery occlusion as posterior and lateral wall supplied by the artery is poorly represented in the standard surface ECG. When patients were divided into six subgroups, ECG did not correlate fully with CART in 10 patients all of whom had severe degree of obstruction. Among them one each was in Group Ia and IIa, two each in Group Ib and IIb and four in Group Ic. One patient each from Group Ia and IIa had occlusion in LCx coronary artery which were not diagnosed by ECG, which is a known poor tool to diagnose such occlusion. One patient in Group Ib had more distal occlusion in LAD coronary artery (i.e., Group Ic by CART). Though, the occlusion was in distal LAD he had diseased posterior descending artery (PDA) and thus the amount of myocardium jeopardized might have been substantial by virtue of the severity of disease in other artery and hence less chance of good collateral circulation. Rest of the seven patients had more proximal lesion by CART but in the same artery as predicted by ECG. The more proximal lesions in these cases were of severe degree and all patients had single vessel disease. Thus the possible collateral circulation that might have developed long before the AMI in such cases could have led to better myocardial salvage in spite of a proximal lesion giving rise to false ECG diagnosis of distal lesion.

Conclusion The present study demonstrates that ECG is an easily and widely available inexpensive tool to localize site of occlusion in culprit vessel in acute STEMI.

Limitation The present study has two major limitations. Its sample size is small and coronary angiography was not done immediately on presentation but at a later date in other referral centers. Sometimes it becomes difficult to incriminate a lesion as the culprit one if angiography is

done later in the course especially if there is multivessel disease or thrombolytic therapy has been given.

References 1. Gorgels AP, Engelen DJ, Wellens HJ. The electrocardiogram in acute myocardial infarction. In: Hurst’s the Heart. 11th edition, Fuster V, Alexander RW, O’Rourke RA (Eds.), McGraw-Hill: New York 2004:p.1351-60.

2. Fiol M, Cygankiewicz I, Carrillo A, Bayés-Genis A, Santoyo O, Gómez A, et al. Value of electrocardiographic algorithm based on “ups and downs” of ST in assessment of a culprit artery in evolving inferior wall acute myocardial infarction. Am J Cardiol 2004;94(6):709-14.

3. Engelen DJ, Gorgels AP, Cheriex EC, De Muinck ED, Ophuis AJ, Dassen WR, et al. Value of the electrocardiogram in localizing the occlusion site in the left anterior descending coronary artery in acute anterior myocardial infarction.

J Am Coll Cardiol 1999;34(2):389-95.

4. Herz I, Assali AR, Adler Y, Solodky A, Sclarovsky S. New electrocardiographic criteria for predicting either the right or left circumflex artery as the culprit coronary artery in inferior wall acute myocardial infarction. Am J Cardiol 1997;80(10):1343-5.

5. Kosuge M, Kimura K, Ishikawa T, Hongo Y, Mochida Y, Sugiyama M, et al. New electrocardiographic criteria for predicting the site of coronary artery occlusion in inferior wall acute myocardial infarction. Am J Cardiol 1998;82(11):1318-22.

6. Nair R, Glancy DL. ECG discrimination between right and left circumflex coronary arterial occlusion in patients with acute inferior myocardial infarction: value of old criteria and use of lead aVR. Chest 2002;122(1):134-9.

7. Wellens HJ. The ECG in localizing the culprit lesion in acute inferior myocardial infarction: a plea for lead V4R? Europace 2009;11(11):1421-2.

8. Verouden NJ, Barwari K, Koch KT, Henriques JP, Baan J, van der Schaaf RJ, et al. Distinguishing the right coronary artery from the left circumflex coronary artery as the infarct-related artery in patients undergoing primary percutaneous coronary intervention for acute inferior myocardial infarction. Europace 2009;11(11):1517-21.

9. Zimetbaum PJ, Josephson ME. Use of the electrocardiogram in acute myocardial infarction. N Engl J Med 2003;348(10):933-40.

10. Chia BL, Yip JW, Tan HC, Lim YT. Usefulness of ST elevation II/III ratio and ST deviation in lead I for identifying the culprit artery in inferior wall acute myocardial infarction.

Am J Cardiol 2000;86(3):341-3.

11. Bairey CN, Shah PK, Lew AS, Hulse S. Electrocardiographic differentiation of occlusion of the left circumflex versus the right coronary artery as a cause of inferior acute myocardial infarction. Am J Cardiol 1987;60(7):456-9.

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Case Report

Left Atrial Myxoma A Agrawal, J Shah, R Hydrabadi, D Kothari, P Joshi, M Pandya

Abstract Primary cardiac tumors are rare myxomas, which are the most common benign tumors of the heart. Other primary cardiac tumors are papillary fibroelastoma, rhabdomyomas and sarcomas. Myxoma is derived from multipotential mesenchymal cells and involves interatrial septum.1 About 75% occur in the left atrium and rest in the right atrium. They are more common in females. In about 10% it is inherited. They tend to occur in more than one part of the heart at a time, and often cause symptoms at a younger age.

Keywords: Atrial myxoma, brain infarct, CT echo, surgery

S

ymptoms of cardiac myxomas may occur at anytime, but most often they accompany a change of body posture. They include shortness of breath at activity, platypnea-difficulty in breathing in the upright position with relief in the supine position, paroxysmal nocturnal dyspnea-breathing difficulty at sleep, dizziness, fainting, palpitation and sudden death (an autopsy finding) over and above common symptoms like cough, fever, malaise and loss of weight.

On examination, there might be clubbing, Raynaudâ&#x20AC;&#x2122;s phenomenon and occasionally a presystolic murmur.

Possible complications are arrhythmias, embolic phenomena leading to brain infarct, pulmonary edema blockage of mitral valve requiring an emergency surgery. Surgical removal is the only line of curative treatment.2

Past history - Nothing particular.

Menstrual history - Regular menstrual cycle - 4/28 days.

Obstetric history - 1 FTND - 8 years child. Antenatal and postnatal periods uneventful.

On examination: Pulse - 80/min regular

BP - 150/90 mmHg

JVP - Normal

SpO2 98% without O2

CVS S1, S2 - Normal, no murmur

P/A - Soft

CNS - Patient conscious, oriented

Power - Normal all for limbs.

Plantars normal

Investigations:

Hb - 13.2 g/dl

WBC - 8,200/mm3

Platelet - Normal

TSH - 1.92.

All other blood reports were normal.

Chest X-ray - Normal

USG abdomen - Small uterine fibroid

Otherwise - Normal

CASE REPORT A female patient aged 35 years was admitted to Dr Jivraj Mehta Hospital with history of transient weakness and tingling numbness in right upper limb for 1-2 hours, and giddiness since morning.

History of similar transient episodes of weakness in right and left upper limb off and on since last three months with spontaneous recovery.

Address for correspondence Dr D Kothori Jivraj Mehta Smarak Health Foundation Bakeri Medical Research Centre Ratubhai Adani Arogyadhama Dr Jivraj Mehta Marg, Ahmedabad - 380 007 E-mail: research@jivrajhealthcare.org

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Asian Journal of Clinical Cardiology, Vol. 15, No. 10, February 2013

RS - Clear

MRI OF BRAIN WITH CERVICAL SPINE SCREENING Technique: T1W, T2W and Flair brain images were obtained on a 1.5 Tesla scanner with high strength

case report gradients. Diffusion imaging was performed at different b values with ADC mapping.

Findings Evidence of multiple small hyperintensities were seen in cortical-subcortical areas of bilateral frontoparietal lobes more on left side. They showed restriction on DWI suggesting infarcts.

Rest of the unremarkable.

cerebral

parenchyma

appeared

Centrally located gray matter nuclei appeared normal in size, shape and intensity.

Image 1

Image 2

Image 3

Image 4

Image 5

Image 6

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377

case report Ventricular system appeared normal in size and shape.

No evidence of periventricular oozing.

Both optic nerves, optic chiasma and tracks appeared normal.

Midline structures like interhemispheric fissure, 3rd ventricle, mamillary bodies, pituitary gland, pineal region and brainstem appeared normal.

Posterior fossa structures appeared normal.

Both CP angle and 7th and 8th nerve complexes appeared normal.

Screening of cervical spine (sagittal T2WI) showed mild spondylotic changes.

Impression

Treatment Patient was referred to cardiovascular surgeon and emergency removal of myxoma was done. Intra- and postoperative periods were uneventful with gradual recovery in right upper limb.

CONCLUSION Tingling and numbness are common presentation in routine practice. There are many medical, surgical and even psychiatric cases of this complaint.

Whenever there are multiple infarcts in the brain, always look for cardiac conditions to rule out cardioembolic stroke. Myxoma is one of the rare causes of cardioembolic stroke and if left untreated may lead to mortality and long-lasting morbidity.3,4

The magnetic resonance imaging (MRI) findings showed: Multiple tiny areas of acute infarcts in bilateral frontoparietal lobe as described.

References

MRI brain with screening of cervical spine was suggestive of multiple tiny areas of acute infarct in bilateral frontoparital lobe. Considering these findings as suggestive of some cardioembolic phenomenon, 2/D echo was done which showed a large left atrial myxoma of 30 Ă&#x2014; 19 mm size arising from interatrial septum and prolapsing through mitral valve into left ventricle.

Normal systolic functions - LVEF - 60%.

2. Zuidema GD, Burke JF, Villegas AH, Scannell JG. Surgery of atrial myxoma. N Eng J Med 1961;264:1016-21.

3. May IA, Kimball KG, Golman PW, Dugan DJ. Left atrial myxoma. Diagnosis, treatment and pre - and postoperative physiological studies. J Thoroc Cardiovasc Surg 1967; 53(6):803-13.

4. Sterns LP, Eliot RS, Varco RL, Edwards JE. Intracavitary cardiac neoplasms. A review of 15 cases. Br Heart J 1966;28(1):75-83.

1. Prichard RW. Tumors of the heart: review of the subject and report of 150 cases. AMA Arch Pathol 1951; 51(1):98-128.

mmmmm

New Drugs, Awareness Needed for Growing Population with Arterial Stiffness and Hypertension An aging population grappling with rising rates of hypertension and other cardiometabolic risk factors should prompt an overhaul of how hypertension is diagnosed and monitored and should spur development of drugs with entirely new mechanisms of action, one expert says. Speaking here at the 2013 International Conference on Prehypertension and Cardiometabolic Syndrome, meeting cochair Dr Reuven Zimlichman (Tel Aviv University, Israel) argued that the definitions of hypertension, as well as the risk-factor tables used to guide treatment, are no longer appropriate for a growing number of patients.

(Source: Medscape)

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Asian Journal of Clinical Cardiology, Vol. 15, No. 10, February 2013

Case Report

Unmasking of Dual AV Node Physiology by Adenosine Satish Ramteke*, Saurabh Nagar**, Mahendra Kumar Jain†, Praveen Kumar Baghel‡, Dharmendra Jain#

Abstract During sinus rhythm antegrade atrioventricular (AV) conduction occurs over fast pathway. Rarely, antegrade AV conduction may involve slow pathway during sinus rhythm or following termination of paroxysmal supraventricular tachycardia by adenosine. We report a case, where following termination of long RP supraventricular tachycardia (atypical AVNRT) with adenosine, intermittent antegrade AV conduction over slow and fast pathway during sinus rhythm appeared.

Keywords: Dual AV node physiology

Case Report A 70-year-old lady presented in intensive coronary care unit (ICCU) with complaint of sudden onset of palpitation of 2-hour duration.

On examination, pulse rate was 186/min with blood pressure of 90/60 mmHg. Lungs were clear. Routine tests like complete blood count (CBC), blood urea, blood glucose, serum electrolytes were normal. Troponin-T was negative, echocardiogram was normal. ECG 1 recorded at the time of admission showed regular, narrow complex tachycardia at the rate of 191/min.

P waves (arrows) were present well after the QRS with RP interval of 120 ms, which was suggestive of long RP supraventricular tachycardia (SVT). Inverted P-wave in lead II, III and aVF was suggestive of retrograde atrial activation (Fig. 1).

Adenosine 6 mg I/V was given. Sinus rhythm was achieved (ECG 2 and 3). These strips show sinus

*Assistant Professor **Post Graduate Student †Professor and Head ‡Associate Professor Dept. of Medicine, Shyam Shah Medical College and Associated Sanjay Gandhi Memorial Hospital, Rewa, MP ‡Assistant Professor Dept. of Cardiology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, UP Address for correspondence Dr Satish Ramteke Assistant Professor, Dept. of Medicine E-4, Doctor’s Colony, Shyam Shah Medical College Rewa, Madhya Pradesh - 486 001 E-mail: satishh.ramteke@gmail.com

tachycardia at rate of 116/min with very long PR interval of 400 ms (Figs. 2 and 3).

ECG 4 recorded 1.5 hours after showed sinus tachycardia at the rate of 116/min with very short PR interval of 50 ms (Fig. 4).

DISCUSSION There are two pathways in atrioventricular (AV) node, one with fast conduction with relatively long refractory period and second with slower conduction with shorter refractory period. During sinus rhythm impulses are conducted over both pathways but reach the bundle of His through the fast pathway while antegrade conduction through slow pathway occurs in AV nodal re-entrant tachycardia (AVNRT).

During sinus tachycardia antegrade conduction over slow AV nodal pathway is unusual. In present case, ECG 1 is suggestive of long RP SVT. The differential diagnosis can be atypical AVNRT, atrial tachycardia, AV re-entrant tachycardia (AVRT) with slowly conducting pathway, sinus node re-entry and sinus tachycardia.

ECG 2, recorded following termination of SVT, reveals sinus tachycardia at the rate of 116/min with very long PR interval of 400 ms. ECG 3 recorded after 1.5 hours shows sinus tachycardia at same rate as it is in ECG 2, but with very short PR interval of 50 ms.

PR interval decreased by 350 ms. This also suggests that the mechanism of SVT in ECG 1 is actually AV nodal re-entry in form of atypical AVNRT, not the accessory pathway. PR interval was suddenly increased to 400 ms after termination of atypical AVNRT and

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379

case report

Figure 1. ECG 1.

Figure 2. ECG 2.

Figure 3. ECG 3 rhythm strip.

Figure 4. ECG 4.

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Asian Journal of Clinical Cardiology, Vol. 15, No. 10, February 2013

decreased by 350 ms, when there is change in antegrade conduction from slow to fast pathway. This is an evidence of dual AV node physiology.

Dual pathways can be manifest on ECG during sinus rhythm by sudden prolongation of the PR interval, PR alternans and two QRS complex in response to single P-wave.1 Reason for AV conduction through slow pathway in present case may be intermittent block in fast pathway.

The concept of dual AV nodal physiology was introduced by Moe et al in 1950s in an effort to explain AVNRT.2 AVNRT is most frequent regular, paroxysmal SVT. Typical form, observed in >95% of cases of AVNRT, is due a re-entry mechanism involving slow pathway in the antegrade direction and fast pathway in the retrograde direction. Adenosine is almost always effective in terminating AVNRT usually by blocking the antegrade slow pathway. Beside this wellknown therapeutic effect, ATP (adenosine-5â&#x20AC;&#x2122;-triphosphate) has been found useful in noninvasive diagnosis of dual AV node physiology (DAVNP).

Belhassen et al found that 75% of patients with inducible sustained typical AVNRT exhibited ECG signs suggesting of DAVNP during administration of adenosine in sinus rhythm while 36% exhibited DAVNP at the termination of AVNRT with adenosine.3 In control patients (inducible AVRT) none had DAVNP at adenosine test during sinus tachycardia but one patient showed signs of AVNP after termination of AVRT with adenosine. DAVNP was considered to be present

case report when at least one of the following events occurred following adenosine injection: 1) PR interval increased or decreased by >50 ms in two consecutive sinus beats; 2) an AV nodal echo beats was observed and 3) AVNRT developed. In our case, PR interval increased to 400 ms after termination of atypical AVNRT and decreased by 350 ms when there was change in antegrade AV conduction from slow to fast pathway.

In order for DAVNP to occur, antegrade conduction over the slow pathway should recover after the block that causes tachycardia termination and the disparity between the antegrade refractory periods of the fast and slow pathways should still be present when tachycardia terminates. In addition it should be pointed out that the electrophysiologic properties of the slow and fast pathways may also be influenced by neurally mediated changes resulting from sudden termination of the tachycardia. For example, upon tachycardia termination, overshoot of the blood pressure occurs that triggers a vagal reflex through extracardiac barorecepters.3,4 This in turn may markedly affect the refractory periods of both fast and slow pathways.

SUMMARY DAVNP is present in relatively high proportion (36.5%) of patients after termination of induced AVNRT with

adenosine. We may expect same phenomenon upon termination of spontaneously occurring AVNRT with adenosine. However, despite wide use of adenosine in management of AVNRT this phenomenon is under estimated. Such finding may be useful in noninvasive diagnosis of mechanism of paroxysmal SVT. REFERENCES 1. Jayam VKS, Calkins H. Supraventricular Tachycardia: AV nodal reentry and Wolfe-Parkinson-white syndrome. In: Hurst’s the Heart. Volume 1, 11th edition, McGrawHill Publication 2004:p.855-69.

2. Moe GK, Preston JB, Burlington H. Physiologic evidence for a dual A-V transmission system. Circ Res 1956;4(4): 357-75.

3. Belhassen B, Fish R, Viskin S, Glick A, Glikson M, Eldar M. Incidence of dual node physiology following termination of AV nodal reentrant tachycardia by adenosine-5’-triphosphate: a comparison with drug administration in sinus rhythm. Indian Pacing Eletrophysiol J 2003;3(1):3-9.

4. Waxman MB, Sharma AD, Cameron DA, Huerta F, Wald RW. Reflex mechanisms responsible for early spontaneous termination of paroxysmal supraventricular tachycardia. Am J Cardiol 1982;49(2): 259-72.

mmmmm

I appeared as a faculty at the time of MCI inspection of College A. In September, I want to leave College A and join college B in the absence of relieving certificate from the previous College. Will you advise me to do so? ÂÂ

If you are leaving College A as per the terms and conditions of the contract of service, it is illegal on the part of college A to deny you relieving certificate. I have had 3-4 cases where my clients (faculty members) were denied the relieving certificate but the same was issued when legal notice was sent.

ÂÂ

Employers deny relieving certificate pursuant to certain vague directions of the MCI, which have no legal force. In one case, a WP was filed in Delhi HC and MCI was also made a party. The WP was withdrawn because the HC felt it should be filed in the state where the college was situated. It could not be filed again because of miscellaneous reasons.

ÂÂ

I will not advise you to make the desired change on your own. You must do so in consultation with a lawyer.

Lawyers know how to proceed so that legal complications are avoided and the desired result achieved.

— Dr MC Gupta

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Photo Quiz

Sudden Onset of Clicking Chest Pain

A

42-year-old man presented with sudden-onset chest pain that began the previous day while he ran on a treadmill. The patient felt a sharp pain in the left side of his chest that radiated to his back and worsened with deep inspiration. He also felt a clicking sensation with inspiration. He stopped running when the pain occurred, but did not seek care until the following day. At the time of examination, he was pain-free except with deep inspiration. He denied having a cough, wheezing, fever, recent symptoms of upper respiratory tract infection, shortness of breath, or dyspnea on exertion.

The patient’s medical history included spondylosis and degenerative disk disease, and he was taking oxycodone and acetaminophen. He was athletic and used chewing tobacco. He had no family history of coronary artery disease.

On physical examination, he appeared to be well, had a temperature of 97.9° F (36.6° C), heart rate of 83 beats per minute, blood pressure of 155/74 mm Hg, respirations of 20 breaths per minute, and oxygen saturation of 99 percent. Cardiovascular auscultation was unremarkable. Auscultation of the lungs was also unremarkable, except for a subtle diminution of breath sounds at the left apex. Palpation of his left fourth and fifth ribs at the costosternal joints produced pain similar to his presenting complaint. He had strong and equal radial pulses. Results of electrocardiography were unremarkable. His posterior-anterior chest radiograph is shown in Figure 1.

Source: Adapted from Am Fam Physician. 2009;80(3):287-288.

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Figure 1.

Question Based on the patient’s history, physical examination, and radiographic findings, which one of the following is the most likely diagnosis?

A. Intercostal muscle strain.

B. Pneumothorax.

C. Pulmonary embolism.

D. Stress fracture of the rib.

E. Tietze syndrome.

See the following page for discussion.

photo quiz Summary Table Condition Characteristics Intercostal muscle strain Usually reproducible with palpation or exacerbated by trunk rotation Primary spontaneous Pleuritic chest pain with radiation to the back or scapula, pneumothorax dyspnea, diminished breath sounds; patient may have hypoxia, tachycardia, tachypnea, hypotension Pulmonary embolism Dyspnea, chest pain, hypoxia, tachycardia Stress fracture of the rib

Reproducible pain over the affected rib

Tietze syndrome

Reproducible pain over the costochondral or sternoclavicular joints, with associated swelling

Discussion The answer is B: pneumothorax.

The incidence of spontaneous pneumothorax is 20,000 per year in the United States.1 Spontaneous pneumothorax may be primary, occuring in patients with no preexisting pulmonary disease; or secondary, occuring with preexisting disease (usually chronic obstructive pulmonary disease). The patient’s radiograph confirms the diagnosis, showing displaced visceral pleura between the fourth and fifth ribs, above which there are no pulmonary markings (Figure 2).

Figure 2. Chest radiograph showing displaced visceral pleura (black box).

Risk factors Physical activity (e.g., in athletes) Smoking, increased height-to-weight ratio (ectomorphism), family history of spontaneous pneumothorax Recent trauma or surgery, malignancy, prolonged immobilization, clotting disorder History of severe cough, participation in sports that require strenuous use of the upper body (e.g., golfing, rowing) Unknown

need immediate needle decompression and chest tube placement. Stable patients with a small pneumothorax (less than 2 to 3 cm) may be treated conservatively; however, a chest tube may be needed if the pneumothorax is larger.1 Definitive treatment is recommended after the second episode of primary spontaneous pneumothorax.

Patients who are at a higher risk if the condition recurs (e.g., divers, airplane pilots) should receive definitive treatment after the first episode.1 Intercostal muscle strains are common and often reproducible with palpation or exacerbated by trunk rotation. Reproduction of chest pain by palpation may be misleading because some patients with pain of cardiac etiology report chest wall tenderness.

The clinical presentation of pulmonary embolism is similar to that of pneumothorax. Patients with pulmonary embolism may have identifiable risk factors (e.g., recent trauma, malignancy, prolonged immobilization, clotting disorder). Initial radiography usually is normal.

Stress fractures of the ribs are rare, but may occur in rowers and golfers,3 and in persons with a severe cough.4 Tietze syndrome is a form of costochondritis. The etiology is unknown.5

Risk factors for primary spontaneous pneumothorax include smoking, ectomorphism, and family history of the condition.1 Symptoms include dyspnea and pleuritic chest pain radiating to the back or scapula. Examination may reveal tachycardia, diminished breath sounds, and diminished chest movement. Some patients have no or few symptoms. Although the patient had no abnormal breath sounds, the clicking may have been from an air leak or movement of the pleura (Hamman sign).2

REFERENCES

Treatment is guided by the patient’s clinical status and size of the pneumothorax. Unstable patients

5. Landon J, et al. Tietze’s syndrome. Ann Rheum Dis. 1959;18:249-254.

1. Baumann MH. Management of spontaneous pneumothorax. Clin Chest Med. 2006;27(2):369-381.

2. Hamman L. Spontaneous interstitial emphysema of the lungs. Tr Assoc Am Physicians. 1937;52:311-319.

3. Jones GL. Upper extremity stress fractures. Clin Sports Med. 2006;25(1):159-174.

4. Tozzi AE, et al. Diagnosis and management of pertussis.

CMAJ. 2005;w172(4):509-515.

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Practice Guidelines

ADA Releases Updated Recommendations on Standards of Medical Care in Diabetes

T

he 2010 American Diabetes Associationâ&#x20AC;&#x2122;s (ADA) â&#x20AC;&#x153;Standards of Medical Care on Diabetesâ&#x20AC;? includes revisions based on new evidence. Several sections have undergone major changes; these changes are outlined below.

Diagnosis Current criteria for the diagnosis of diabetes mellitus include a fasting plasma glucose level of 126 mg per dL (6.99 mmol per L) or greater; two-hour plasma glucose level of 200 mg per dL (11.10 mmol per L) or greater during an oral glucose tolerance test; or a random plasma glucose level of 200 mg per dL in a patient with hyperglycemia or hyperglycemic crisis symptoms. A1C level is now included in the diagnosis of diabetes, with a cut point of 6.5 percent or greater.

Categories of Increased Risk An A1C level of 5.7 to 6.4 percent has been added as a category of increased risk of future diabetes. This is in addition to impaired fasting glucose (100 to 125 mg per dL [5.55 to 6.94 mmol per L]) and glucose tolerance (140 to 199 mg per dL [7.77 to 11.04 mmol per L]). Patients with any of these risk factors should be referred to a support program for weight loss and increased physical activity. Metformin may also be considered in persons at very high risk of diabetes who are obese and younger than 60 years.

Self-Management Education National standards suggest that persons with diabetes receive diabetes self-management education at diagnosis and on an as-needed basis, with the goals of improving effective self-management and quality of life. These outcomes should be monitored as part of standard care.

Because emotional well-being is associated with positive diabetes outcomes, self-management education should also focus on psychosocial issues. Third-party payors should provide reimbursement for self-management education.

Treatment with Antiplatelet Agents Aspirin (75 to 162 mg per day) should be considered as a primary prevention strategy in persons with type

Source: Adapted from Am Fam Physician. 2010;82(2):206-208.

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1 or 2 diabetes and an increased cardiovascular risk (10-year risk greater than 10 percent), including most men older than 50 years and most women older than 60 years with at least one additional major risk factor (i.e., family history of cardiovascular disease, hypertension, smoking, dyslipidemia, or albuminuria). There is insufficient evidence to recommend aspirin therapy as a primary prevention strategy in persons with lower risk, including men younger than 50 years or women younger than 60 years without major risk factors. Clinical judgment should be used when patients in these age groups have multiple other risk factors.

Aspirin therapy should be used as a secondary prevention strategy in persons with diabetes and a history of cardiovascular disease. Clopidogrel (75 mg per day) should be used in persons with cardiovascular disease who have an allergy to aspirin. Combination therapy with aspirin and clopidogrel is reasonable for up to one year after acute coronary syndrome.

Retinopathy Screening An initial dilated and comprehensive eye examination should be performed by an ophthalmologist or optometrist within five years of a type 1 diabetes diagnosis in persons at least 10 years of age; persons with type 2 diabetes should have the examination shortly after diagnosis. Subsequent examinations should be done annually; if retinopathy is progressing, examinations should be done more frequently. If the patient has one or more normal examinations, examinations may be considered every two to three years. Women with diabetes who are or may become pregnant should have a comprehensive eye examination and should be counseled about the risk of development or progression of retinopathy. The eye examination should be performed in the first trimester, with followup examinations throughout pregnancy and for one year postpartum.

The ADA now includes recommendations on the use of high-quality fundus photographs, which can detect most clinically significant diabetic retinopathy; however, even though photography can be used as a screening tool, it should not replace a comprehensive eye examination. A trained eye care professional should interpret the photographs.

Medi Law

Liability of Hospital in Case of Treating Consultant’s Negligencet MG Gupta

Q. I am Director (Medical Services) in a 350 bed hospital. I read an article in Times of India last year which stated that the hospital management does not have any responsibility if the treating consultant is negligent. Is this correct?

Ans. ÂÂ No. This is not correct. ÂÂ The reasons why it is not correct are as follows:

There is no contract between the patient and the consultant. The contract is between the patient and the hospital. Fees are paid to the hospital.

The ward where the patient is admitted is owned by the hospital. The OT where he is operated is owned by the hospital. The owner of a vehicle pays the damages, not the driver.

Let us look at it more analytically. There are three essential ingredients of a contract—offer; acceptance; and consideration. In the present case: zz Offer to treat is made by the hospital by way of advertisements, etc. and not by the consultant physician. (As a matter of fact, it is against the Code of Ethics Regulations, 2002, for a physician to advertise himself). zz The patient accepts an offer made by the hospital. He does not accept any offer made by the consultant whom he even does not know. zz Consideration by way of advance deposit and payment of bill, prepared by the hospital, is made to the hospital and not the physician.

Hence there is no way that there can be a legal contract between the physician and the patient.

The consultant has no independent entity.

He works as a part or agent of the hospital.

The principal is responsible for the acts of the agent. This is as per the principle of vicarious liability according to which, when negligence is committed by an employee such as a resident or nurse or a ward assistant, the responsibility

Advocate and Medicolegal Consultant, New Delhi

lies upon the hospital which is the principal under whom they work.

If negligence occurs and the court awards compensation, the patient/complainant has a right to recover it. He cannot exercise his right if the consultant is dead, untraceable or a pauper. The complainant cannot be left uncompensated. That is why a hospital has to be made liable. A hospital cannot be dead, untraceable or a pauper. Even if the hospital ceases to exist or becomes insolvent, its assets can be attached for payment of compensation. ÂÂ The above statements are supported by the decision in Sh. Naresh Mehra v. Dr. A.P. Choudhary, decided

by The Delhi State Consumer Commission on 31-10-2008, as follows: “18. We have taken a view that whenever any patient lands in any Hospital or Nursing Home, Medical Centre his direct relationship of consumer for hiring or availing the medical services is with the said Hospital or Nursing Home or Medical Center and not with the treating Doctors and other personnel, secondly, the entire consideration in the form of expenses including the component of charges or fees of the operating Doctor and other junior Doctors and staff engaged in pre- or postoperative care or any other kind of care are paid to the Nursing Home or Hospital or Medical Center directly and thirdly that there is totality or compendium of various services including medical and those of para staff and other conveniences and the privity of contract is not with the operating or treating or attending Doctors, nurses and other staff.

19. Thus if a patient suffers due to the medical negligence or carelessness of Doctors and staff of the Hospital or Nursing Home or Medical Center whose services he avails against consideration, said Hospital or Nursing Home or Medical Center alone is liable to compensate the patient as to loss or injury suffered by him and Nursing Home or Hospital or Medical Center has independent remedy to take any kind of action against such doctors or staff but no doctor or staff has a joint or several liability qua the patient.

20. Similarly Nursing Homes or Medical Centres or Hospitals alone are liable for the acts of omission or commission or medical negligence of visiting or consulting Doctors as the patient has no direct contract with such Doctors and services of such Doctors are availed by the Hospital or Nursing Home or Medical Center and not the patient”.

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lighter reading

A philosophy professor stood before his class with some items on the table in front of him.

When the class began, wordlessly he picked up a very large and empty mayonnaise jar and proceeded to fill it with rocks, about 2 inches in diameter.

He then asked the students if the jar was full.

They agreed that it was. So the professor then picked up a box of pebbles and poured them into the jar. He shook the jar lightly. The pebbles, of course, rolled into the open areas between the rocks.

He then asked the students again if the jar was full.

They agreed it was. The professor picked up a box of sand and poured it into the jar. Of course, the sand filled up everything else. He then asked once more if the jar was full. The students responded with a unanimous “Yes.” “Now,” said the professor, “I want you to recognize that this jar represents your life. The rocks are the important things – your family, your partner, your health and your children – things that if everything else was lost and only they remained, your life would still be full. The pebbles are the other things that matter – like your job, your house, your car.

The sand is everything else. The small stuff.” “If you put the sand into the jar first,” he continued “there is no room for the pebbles or the rocks. The same goes for your life.

If you spend all your time and energy on the small stuff, you will never have room for the things that are important to you. Pay attention to the things that are critical to your happiness. Play with your children. Take your partner out dancing. There will always be time to go to work, clean the house, give a dinner party and fix the disposal.

To be in news in Kalyuga Certain people learn the art of being in the news. There was a person who was nominated for a noble prize, so he remained in news for a month.

Next month he got the prize and again remained in news for a month. A month later, he said the he is going to return the noble prize, thus, again remained in news for another month.

Next month he said that he was going to retain his noble prize but he was going to donate the prize money in charity. It made him remain in news for another month. Next month, he donated the money to the charity and a month later people came to know that he donated the money to address where he was the lone surviving trustee.

This is an imaginary humor based fact. Remember publicity is earned and publicity like above in longer run will only harm.

Dr GM Singh

Dr. Good and Dr. Bad Situation: A patient with CKD wanted a cardiology

reference.

It’s not needed

You should get it done

©IJCP Academy

The Important Things in Life

laugh a while

An Inspirational Story

Lighter Side of Medicine

Take care of the rocks first – the things that really matter. Set your priorities. The rest is just sand.”

QUOTE

Lesson: Chronic

386

“Tis the set of the sail that decides the goal, and not the storm of life.”

Ella Wheeler Wilcox

Asian Journal of Clinical Cardiology, Vol. 15, No. 10, February 2013

renal dysfunction alone is an independent risk factor for the development of coronary artery disease, and for more severe coronary heart disease.

KK Aggarwal

Asian

Journal of

CLINICAL CARDIOLOGY

Information for Authors

Manuscripts should be prepared in accordance with the ‘Uniform requirements for manuscripts submitted to biomedical journals’ compiled by the International Committee of Medical Journal Editors (Ann. Intern. Med. 1992;96: 766-767).

Asian Journal of Clinical Cardiology strongly disapproves of the submission of the same articles simultaneously to different journals for consideration as well as duplicate publication and will decline to accept fresh manuscripts submitted by authors who have done so.

The boxed checklist will help authors in preparing their manuscript according to our requirements. Improperly prepared manuscripts may be returned to the author without review. The checklist should accompany each manuscript.

Authors may provide on the checklist, the names and addresses of experts from Asia and from other parts of the World who, in the authors’ opinion, are best qualified to review the paper.

Covering letter -

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The covering letter should explain if there is any deviation from the standard IMRAD format (Introduction, Methods, Results and Discussion) and should outline the importance of the paper.

Principal/Senior author must sign the covering letter indicating full responsibility for the paper submitted, preferably with signatures of all the authors.

Articles must be accompanied by a declaration by all authors stating that the article has not been published in any other Journal/Book. Authors should mentioned complete designation and departments, etc. on the manuscript.

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The manuscript should be arranged as follow: Covering letter, Checklist, Title page, Abstract, Keywords (for indexing, if required), Introduction, Methods, Results, Discussion, References, Tables, Legends to Figures and Figures.

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A subtitle can be added if necessary.

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Summary - The summary of not more than 200 words. It must convey the essential features of the paper.

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Introduction - The introduction should state why the study was carried out and what were its specific aims/objectives.

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Discussion -

This should consist of a review of the literature and relate the major findings of the article to other publications on the subject. The particular relevance of the results to healthcare in India should be stressed, e.g. practicality and cost.

References These should conform to the Vancouver style. References should be numbered in the order in which they appear in the texts and these numbers should be inserted above the lines on each occasion the author is cited (Sinha12 confirmed other reports13,14...). References cited only in tables or in legends to figures should be numbered in the text of the particular table or illustration. Include among the references papers accepted but not yet published; designate the journal and add ‘in press’ (in parentheses). Information from manuscripts submitted but not yet accepted should be cited in the text as ‘unpublished observations’ (in parentheses).

At the end of the article the full list of references should include the names of all authors if there are fewer than seven or if there are more, the first six followed by et al., the full title of the journal article or book chapters; the title of journals abbreviated according to the style of the Index Medicus and the first and final page numbers of the article or chapter. The authors should check that the references are accurate. If they are not this may result in the rejection of an otherwise adequate contribution.

Examples of common forms of references are: Articles

Figures - Two complete sets of glossy prints of high quality should be submitted. The labelling must be clear and neat.

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Illustrations must be drawn neatly by an artist and photographs must be sent on glossy paper. No captions should be written directly on the photographs or illustration. Legends to all photographs and illustrations should be typed on a separate sheet of paper. All illustrations and figures must be referred to in the text and abbreviated as ‘Fig.’.

Please complete the following checklist and attach to the manuscript: 1. Classification (e.g. original article, review, selected summary, etc.)_______________________________

Paintal AS. Impulses in vagal afferent fibres from specific pulmonary deflation receptors. The response of those receptors to phenylguanide, potato S-hydroxytryptamine and their role in respiratory and cardiovascular reflexes.

Q. J. Expt. Physiol. 1955;40:89-111.

2. Total number of pages ________________________

Books

6. Suggestions for reviewers (name and postal address)

Stansfield AG. Lymph Node Biopsy Interpretation Churchill Livingstone, New York 1985.

Indian 1.____________Foreign 1.________________

2.____________ 2.________________

Articles in Books

3.____________ 3.________________

Strong MS. Recurrent respiratory papillomatosis. In: Scott Brown’s Otolaryngology. Paediatric Otolaryngology Evans JNG (Ed.), Butterworths, London 1987;6:466-470.

4.____________ 4.________________

Tables -

These should be typed double spaced on separate sheets with the table number (in Roman Arabic numerals) and title above the table and explanatory notes below the table.

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The legend must include enough information to permit interpretation of the figure without reference to the text.

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3. Number of tables ____________________________ 4. Number of figures ___________________________ 5. Special requests _____________________________

7. All authors’ signatures________________________ 8.

Corresponding author’s name, current postal and e-mail address and telephone and fax numbers __________________________________________

Online Submission Also e-issue @ www.ijcpgroup.com For Editorial Correspondence

Dr KK Aggarwal

Group Editor-in-Chief Asian Journal of Clinical Cardiology E - 219, Greater Kailash, Part - 1, New Delhi - 110 048. Phone: 011-40587513 E-mail: editorial@ijcp.com, emedinew@gmail.com Website: www.ijcpgroup.com

R.N.I. No. 71217/98 Date of Publishing 25 of Same Month Date of Posting 25-26 Same Month

REGISTRATION NO. DL (S)-01/3288/2013-2015 POSTED IN NDPSO NEW DELHI

Dr KK Aggarwal Group Editor-in-Chief Dr Veena Aggarwal MD and Group Executive Editor Dr Alka Kriplani Dr Praveen Chandra Dr Swati Y Bhave Dr CR Anand Moses Dr Sidhartha Das Dr Wiqar Sheikh Dr Ajay Kumar Dr A Ramachandran Dr Samith A Shetty Dr SK Parashar Dr Kamala Selvaraj Dr Georgi Abraham Dr V Nagarajan Dr Thankam Verma Dr KMK Masthan Dr Hasmukh J Shroff Dr Rajesh Chandna Dr SM Rajendran

l

e 22,

er11

Peer Reviewed Journal

Drug Review

Review Article

Original Article

Case Report

Photo Quiz

Lighter Reading

April 2012, Pages 545-596