INTRODUCTION: anticoagulation is generally considered adequate treatment.8 However, patients

INTRODUCTION: I would be discussing the role of Fibrinolysis for Patients with IntermediateRiskPulmonary Embolism in reference to this article.Acutepulmonary embolism occurs frequently and may cause death or serious disability.1Case fatality rates vary widely,2,3 but approximately 10% of allpatients with acute pulmonary embolism die within 3 months after the diagnosis.4,5Acute right ventricular pressure overload at diagnosis is an importantdeterminant of the severity and early clinical outcome of pulmonary embolism.6High-risk pulmonary embolism7 is characterized by overthemodynamic instability and warrants immediate advanced therapy, includingconsideration of fibrinolysis. In contrast, for patients presenting withoutsystemic hypotension or hemodynamic compromise, standard anticoagulation isgenerally considered adequate treatment.

8 However, patients who haveacute right ventricular dysfunction and myocardial injury without overthemodynamic compromise may be at intermediate risk for an adverse earlyoutcome.7,9 These patients (referred to henceforth as patients withintermediate-risk pulmonary embolism) may also be candidates for earlyreperfusion therapy.10 Randomized clinical trials that testfibrinolytic agents versus heparin alone in patients with acute pulmonaryembolism have enrolled, in total, fewer than 1000 patients over the past 40years.11 Although these drugs have been shown to rapidly improvehemodynamic variables,12 their effects on the clinical outcome,particularly in patients without hemodynamic instability at presentation, havenot been determined   LITERATUREREVIEW:  Acutepulmonary embolism occurs frequently and may cause death or serious disability.1Case fatality rates vary widely,2,3 but approximately 10% of allpatients with acute pulmonary embolism die within 3 months after the diagnosis.4,5Acute right ventricular pressure overload at diagnosis is an importantdeterminant of the severity and early clinical outcome of pulmonary embolism.6High-risk pulmonary embolism7 is characterized by overthemodynamic instability and warrants immediate advanced therapy, includingconsideration of fibrinolysis.

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In contrast, for patients presenting withoutsystemic hypotension or hemodynamic compromise, standard anticoagulation isgenerally considered adequate treatment.8 However, patients who haveacute right ventricular dysfunction and myocardial injury without overthemodynamic compromise may be at intermediate risk for an adverse earlyoutcome.7,9 These patients (referred to henceforth as patients withintermediate-risk pulmonary embolism) may also be candidates for earlyreperfusion therapy.10 Randomized clinical trials that testfibrinolytic agents versus heparin alone in patients with acute pulmonaryembolism have enrolled, in total, fewer than 1000 patients over the past 40years.11 Although these drugs have been shown to rapidly improvehemodynamic variables,12 their effects on the clinical outcome,particularly in patients without hemodynamic instability at presentation, havenot been determined.ThePulmonary Embolism Thrombolysis (PEITHO) trial was designed to investigate theclinical efficacy and safety of fibrinolytic therapy with a single-bolusinjection of tenecteplase, in addition to standard anticoagulation therapy withheparin, in normotensive patients with acute pulmonary embolism and anintermediate risk of an adverse outcome.    RESEARCHMETHODOLOGY: Theauthor has presented this article and its relevant references and study in a verysimple and narrative manner though with visual statistics like graphs tablesetc.

but he has managed to prove that ). In patients with intermediate-riskpulmonary embolism, fibrinolytic therapy prevented hemodynamic decompensationbut increased the risk of major hemorrhage and stroke.Besidesintroducing the role of this procedure he has proved with the help of differentstudies and clinical.  Hehas used sequences of tables to explain Table 1.

Characteristics of thePatients at Baseline of both the groups.. Demographic data. Medical historyTable 2. Diagnostic Evaluationand Initial ManagementIn which all forms of evaluationslike CTPA and also ECHO and trop T which was done for both the groups.

Alsothe treatment given as per the study protocol.Table3. Efficacy Outcomes.Exapliendabout the primary outcome, death from any cause, hemodynamic instability. Table4.

Safety Outcomes in the Intention-to-Treat PopulationLikethe outcome fo bleeding in the number of patients, be t major or minor.Alsoabout development of stroke if haemorragic or ischemic stroke.   ARTICLE SUMMARY: Thestudy was performed a multicenter, double-blind, placebocontrolled randomizedtrial.13 The trial was initiated by the investigators and sponsored byDirection de la Recherche Clinique at Assistance Publique–Hôpitaux de Paris, aconsortium of university hospitals in Paris.Theprincipal investigators had unrestricted access to the data after the databasewas locked.

The two cochairs of the steering committee and the trialstatistician wrote the first draft of the manuscript. The members of thesteering committee were involved in the analysis of the data; reviewed,amended, and approved the early version of the manuscript; and made thedecision to submit the manuscript for publication.Patientswere eligible for the study if they met all the following criteria: an age of18 years or older, objectively confirmed acute pulmonary embolism with an onsetof symptoms 15 days or less before randomization, right ventricular dysfunctionconfirmed by echocardiography or spiral computed tomography (CT) of the chest,and myocardial injury confirmed by a positive test for troponin I or troponinT. The full inclusion and exclusion criteria for the study, including thecriteria for right ventricular dysfunction.Eligiblepatients underwent central randomization with the use of a computerizedInternetbased system. Randomization was stratified by center and, withincenters, was performed in blocks to ensure balanced distribution of the treatmentgroups. We required that randomization be performed within 2 hours after theinvestigator became aware of the presence of both right ventricular dysfunction(by receiving the echocardiography or CT report) and myocardial injury (byreceiving a report of a positive cardiac troponin test). Patients who wereassigned to undergo fibrinolysis received a single weight-based intravenousbolus (given over a period of 5 to 10 seconds) of the fibrinolytic agenttenecteplase.

The dose ranged from 30 mg to 50 mg, depending on body weight(Table S1 in the Supplementary Appendix).13 Patients assigned to placebo weregiven a single intravenous bolus of the same volume and appearance as the bolusof tenecteplase.Themain efficacy and safety analyses were based on all events that occurred in theintention-totreat population, defined as all patients who underwentrandomization and who signed the informed consent form. In addition, analysisof safety outcomes was performed in the safety population, which was defined asall patients who received the study drug. The primary efficacy outcome wasanalyzed by means of a twosided chi-square test of proportions. A similaranalysis was performed for each of the secondary outcomes; all results were forthe intention-totreat population. All tests were performed with the use of SASsoftware, version 9.2 (SAS Institute).

Prespecified subgroup analyses includedage (?75 years vs. >75 years), sex, and country of recruitment.  The roleof fibrinolytic therapy in patients with intermediate-risk pulmonary embolismis controversial.In a randomized, double-blind trial, we compared tenecteplaseplus heparin with placebo plus heparin in normotensive patients withintermediate-risk pulmonary embolism. Eligible patients had right ventriculardysfunction on echocardiography or computed tomography, as well as myocardialinjury as indicated by a positive test for cardiac troponin I or troponin T.The primary outcome was death or hemodynamic decompensation (or collapse)within 7 days after randomization. The main safety outcomes were majorextracranial bleeding and ischemic or hemorrhagic stroke within 7 days afterrandomization.

Of 1006 patients who underwent randomization, 1005 were includedin the intentionto-treat analysis. Death or hemodynamic decompensation occurredin 13 of 506 patients (2.6%) in the tenecteplase group as compared with 28 of499 (5.6%) in the placebo group (odds ratio, 0.44; 95% confidence interval,0.23 to 0.87; P=0.02).

Between randomization and day 7, a total of 6 patients(1.2%) in the tenecteplase group and 9 (1.8%) in the placebo group died(P=0.

42). Extracranial bleeding occurred in 32 patients (6.3%) in thetenecteplase group and 6 patients (1.2%) in the placebo group (P =0.

42). Inpatients with intermediate-risk pulmonary embolism, fibrinolytic therapyprevented hemodynamic decompensation but increased the risk of major hemorrhageand stroke.    CONCLUSION: In thePEITHO trial, patients with intermediaterisk pulmonary embolism who weretreated with standard anticoagulation had a 5.6% incidence of death orhemodynamic decompensation (the primary efficacy outcome) within the first 7days after randomization. A single-bolus injection of the fibrinolytic agenttenecteplase, in a weightbased dose, resulted in a significantly lower risk ofthe primary outcome (2.6%). Fibrinolytic treatment was associated with a 2.

0%rate of hemorrhagic stroke and a 6.3% rate of major extracranial hemorrhage.In thepresent trial, the efficacy of thrombolysis was mainly driven by the preventionof hemodynamic decompensation; the study was not powered to detect differencesin rates of death, which occurred relatively infrequently in the two treatmentgroups. Moreover, our definition of hemodynamic decompensation or collapseincluded a persistent, isolated drop in systolic blood pressure, which could beof questionable clinical significance. Nevertheless, 14 patients withhemodynamic decompensation in the placebo group needed inotropic support and 5underwent cardiopulmonary resuscitation.

It is possible that the prognosis forsome of these patients would have been worse if they had not been closelymonitored and promptly treated when decompensation occurred; this notion issupported by the higher rates of death reported in noninterventional cohortstudies focused on this patient population.Areduced-dose strategy might also be beneficial in patients withintermediate-risk pulmonary embolism and warrants further investigation.Inconclusion, in normotensive patients with intermediate-risk pulmonary embolism,the composite primary outcome of early death or hemodynamic decompensation wasreduced after treatment with a single intravenous bolus of tenecteplase.However, tenecteplase was also associated with a significant increase in therisk of intracranial and other major bleeding.

Therefore, great caution iswarranted when considering fibrinolytic therapy for hemodynamically stablepatients with pulmonary embolism, right ventricular dysfunction, and a positivecardiac troponin test.   CRITICAL APPRAISAL: Thestudy was performed a multicenter, double-blind, placebocontrolled randomizedtrial.13 The trial was initiated by the investigators and sponsored byDirection de la Recherche Clinique at Assistance Publique–Hôpitaux de Paris, aconsortium of university hospitals in Paris.

Theprincipal investigators had unrestricted access to the data after the databasewas locked. The two cochairs of the steering committee and the trialstatistician wrote the first draft of the manuscript. The members of thesteering committee were involved in the analysis of the data; reviewed,amended, and approved the early version of the manuscript; and made thedecision to submit the manuscript for publication.Patientswere eligible for the study if they met all the following criteria: an age of18 years or older, objectively confirmed acute pulmonary embolism with an onsetof symptoms 15 days or less before randomization, right ventricular dysfunctionconfirmed by echocardiography or spiral computed tomography (CT) of the chest,and myocardial injury confirmed by a positive test for troponin I or troponinT.

The full inclusion and exclusion criteria for the study, including thecriteria for right ventricular dysfunction.Eligiblepatients underwent central randomization with the use of a computerizedInternetbased system. Randomization was stratified by center and, withincenters, was performed in blocks to ensure balanced distribution of thetreatment groups.

We required that randomization be performed within 2 hours afterthe investigator became aware of the presence of both right ventriculardysfunction (by receiving the echocardiography or CT report) and myocardialinjury (by receiving a report of a positive cardiac troponin test). Patientswho were assigned to undergo fibrinolysis received a single weight-basedintravenous bolus (given over a period of 5 to 10 seconds) of the fibrinolyticagent tenecteplase. The dose ranged from 30 mg to 50 mg, depending on bodyweight (Table S1 in the Supplementary Appendix).

13 Patients assigned to placebowere given a single intravenous bolus of the same volume and appearance as thebolus of tenecteplase.Themain efficacy and safety analyses were based on all events that occurred in theintention-totreat population, defined as all patients who underwentrandomization and who signed the informed consent form. In addition, analysisof safety outcomes was performed in the safety population, which was defined asall patients who received the study drug. The primary efficacy outcome was analyzedby means of a twosided chi-square test of proportions. A similar analysis wasperformed for each of the secondary outcomes; all results were for theintention-totreat population. All tests were performed with the use of SASsoftware, version 9.

2 (SAS Institute). Prespecified subgroup analyses includedage (?75 years vs. >75 years), sex, and country of recruitment.

 Analysis of graph/Image/Table He has usedsequences of tables to explain Table 1. Characteristics of thePatients at Baseline of both the groups..

Demographic data. Medical historyTable 2. Diagnostic Evaluationand Initial ManagementIn which all forms of evaluationslike CTPA and also ECHO and trop T which was done for both the groups. Alsothe treatment given as per the study protocol.

Table3. Efficacy Outcomes.Exapliendabout the primary outcome, death from any cause, hemodynamic instability. Table4. Safety Outcomes in the Intention-to-Treat PopulationLikethe outcome fo bleeding in the number of patients, be t major or minor.Alsoabout development of stroke if haemorragic or ischemic stroke.  Conclusion In thePEITHO trial, patients with intermediaterisk pulmonary embolism who weretreated with standard anticoagulation had a 5.6% incidence of death orhemodynamic decompensation (the primary efficacy outcome) within the first 7days after randomization.

A single-bolus injection of the fibrinolytic agenttenecteplase, in a weightbased dose, resulted in a significantly lower risk ofthe primary outcome (2.6%). Fibrinolytic treatment was associated with a 2.0%rate of hemorrhagic stroke and a 6.3% rate of major extracranial hemorrhage.In thepresent trial, the efficacy of thrombolysis was mainly driven by the preventionof hemodynamic decompensation; the study was not powered to detect differencesin rates of death, which occurred relatively infrequently in the two treatmentgroups. Moreover, our definition of hemodynamic decompensation or collapseincluded a persistent, isolated drop in systolic blood pressure, which could beof questionable clinical significance.

Nevertheless, 14 patients withhemodynamic decompensation in the placebo group needed inotropic support and 5underwent cardiopulmonary resuscitation. It is possible that the prognosis forsome of these patients would have been worse if they had not been closelymonitored and promptly treated when decompensation occurred; this notion issupported by the higher rates of death reported in noninterventional cohortstudies focused on this patient population.Areduced-dose strategy might also be beneficial in patients withintermediate-risk pulmonary embolism and warrants further investigation.Inconclusion, in normotensive patients with intermediate-risk pulmonary embolism,the composite primary outcome of early death or hemodynamic decompensation wasreduced after treatment with a single intravenous bolus of tenecteplase.

However, tenecteplase was also associated with a significant increase in therisk of intracranial and other major bleeding. Therefore, great caution iswarranted when considering fibrinolytic therapy for hemodynamically stablepatients with pulmonary embolism, right ventricular dysfunction, and a positivecardiac troponin test.