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

INTRODUCTION:

 

I would be discussing the role of Fibrinolysis for Patients with IntermediateRisk
Pulmonary Embolism in reference to this article.

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Acute
pulmonary embolism occurs frequently and may cause death or serious disability.1
Case fatality rates vary widely,2,3 but approximately 10% of all
patients with acute pulmonary embolism die within 3 months after the diagnosis.4,5
Acute right ventricular pressure overload at diagnosis is an important
determinant of the severity and early clinical outcome of pulmonary embolism.6
High-risk pulmonary embolism7 is characterized by overt
hemodynamic instability and warrants immediate advanced therapy, including
consideration of fibrinolysis. In contrast, for patients presenting without
systemic hypotension or hemodynamic compromise, standard anticoagulation is
generally considered adequate treatment.8 However, patients who have
acute right ventricular dysfunction and myocardial injury without overt
hemodynamic compromise may be at intermediate risk for an adverse early
outcome.7,9 These patients (referred to henceforth as patients with
intermediate-risk pulmonary embolism) may also be candidates for early
reperfusion therapy.10 Randomized clinical trials that test
fibrinolytic agents versus heparin alone in patients with acute pulmonary
embolism have enrolled, in total, fewer than 1000 patients over the past 40
years.11 Although these drugs have been shown to rapidly improve
hemodynamic variables,12 their effects on the clinical outcome,
particularly in patients without hemodynamic instability at presentation, have
not been determined

 

 

 

LITERATURE
REVIEW:

 

Acute
pulmonary embolism occurs frequently and may cause death or serious disability.1
Case fatality rates vary widely,2,3 but approximately 10% of all
patients with acute pulmonary embolism die within 3 months after the diagnosis.4,5
Acute right ventricular pressure overload at diagnosis is an important
determinant of the severity and early clinical outcome of pulmonary embolism.6
High-risk pulmonary embolism7 is characterized by overt
hemodynamic instability and warrants immediate advanced therapy, including
consideration of fibrinolysis. In contrast, for patients presenting without
systemic hypotension or hemodynamic compromise, standard anticoagulation is
generally considered adequate treatment.8 However, patients who have
acute right ventricular dysfunction and myocardial injury without overt
hemodynamic compromise may be at intermediate risk for an adverse early
outcome.7,9 These patients (referred to henceforth as patients with
intermediate-risk pulmonary embolism) may also be candidates for early
reperfusion therapy.10 Randomized clinical trials that test
fibrinolytic agents versus heparin alone in patients with acute pulmonary
embolism have enrolled, in total, fewer than 1000 patients over the past 40
years.11 Although these drugs have been shown to rapidly improve
hemodynamic variables,12 their effects on the clinical outcome,
particularly in patients without hemodynamic instability at presentation, have
not been determined.

The
Pulmonary Embolism Thrombolysis (PEITHO) trial was designed to investigate the
clinical efficacy and safety of fibrinolytic therapy with a single-bolus
injection of tenecteplase, in addition to standard anticoagulation therapy with
heparin, in normotensive patients with acute pulmonary embolism and an
intermediate risk of an adverse outcome.

 

 

 

 

RESEARCH
METHODOLOGY:

 

The
author has presented this article and its relevant references and study in a very
simple and narrative manner though with visual statistics like graphs tables
etc. but he has managed to prove that ). In patients with intermediate-risk
pulmonary embolism, fibrinolytic therapy prevented hemodynamic decompensation
but increased the risk of major hemorrhage and stroke.

Besides
introducing the role of this procedure he has proved with the help of different
studies and clinical.

 

He
has used sequences of tables to explain

Table 1. Characteristics of the
Patients at Baseline of both the groups.

. Demographic data

. Medical history

Table 2. Diagnostic Evaluation
and Initial Management

In which all forms of evaluations
like CTPA and also ECHO and trop T which was done for both the groups.

Also
the treatment given as per the study protocol.

Table
3. Efficacy Outcomes.

Exapliend
about the primary outcome, death from any cause, hemodynamic instability.

 

Table
4. Safety Outcomes in the Intention-to-Treat Population

Like
the outcome fo bleeding in the number of patients, be t major or minor.

Also
about development of stroke if haemorragic or ischemic stroke.

 

 

 

ARTICLE SUMMARY:

 

The
study was performed a multicenter, double-blind, placebocontrolled randomized
trial.13 The trial was initiated by the investigators and sponsored by
Direction de la Recherche Clinique at Assistance Publique–Hôpitaux de Paris, a
consortium of university hospitals in Paris.

The
principal investigators had unrestricted access to the data after the database
was locked. The two cochairs of the steering committee and the trial
statistician wrote the first draft of the manuscript. The members of the
steering committee were involved in the analysis of the data; reviewed,
amended, and approved the early version of the manuscript; and made the
decision to submit the manuscript for publication.

Patients
were eligible for the study if they met all the following criteria: an age of
18 years or older, objectively confirmed acute pulmonary embolism with an onset
of symptoms 15 days or less before randomization, right ventricular dysfunction
confirmed by echocardiography or spiral computed tomography (CT) of the chest,
and myocardial injury confirmed by a positive test for troponin I or troponin
T. The full inclusion and exclusion criteria for the study, including the
criteria for right ventricular dysfunction.

Eligible
patients underwent central randomization with the use of a computerized
Internetbased system. Randomization was stratified by center and, within
centers, was performed in blocks to ensure balanced distribution of the treatment
groups. We required that randomization be performed within 2 hours after the
investigator became aware of the presence of both right ventricular dysfunction
(by receiving the echocardiography or CT report) and myocardial injury (by
receiving a report of a positive cardiac troponin test). Patients who were
assigned to undergo fibrinolysis received a single weight-based intravenous
bolus (given over a period of 5 to 10 seconds) of the fibrinolytic agent
tenecteplase. The dose ranged from 30 mg to 50 mg, depending on body weight
(Table S1 in the Supplementary Appendix).13 Patients assigned to placebo were
given a single intravenous bolus of the same volume and appearance as the bolus
of tenecteplase.

The
main efficacy and safety analyses were based on all events that occurred in the
intention-totreat population, defined as all patients who underwent
randomization and who signed the informed consent form. In addition, analysis
of safety outcomes was performed in the safety population, which was defined as
all patients who received the study drug. The primary efficacy outcome was
analyzed by means of a twosided chi-square test of proportions. A similar
analysis was performed for each of the secondary outcomes; all results were for
the intention-totreat population. All tests were performed with the use of SAS
software, version 9.2 (SAS Institute). Prespecified subgroup analyses included
age (?75 years vs. >75 years), sex, and country of recruitment.

 

 

The role
of fibrinolytic therapy in patients with intermediate-risk pulmonary embolism
is controversial.In a randomized, double-blind trial, we compared tenecteplase
plus heparin with placebo plus heparin in normotensive patients with
intermediate-risk pulmonary embolism. Eligible patients had right ventricular
dysfunction on echocardiography or computed tomography, as well as myocardial
injury 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 major
extracranial bleeding and ischemic or hemorrhagic stroke within 7 days after
randomization.Of 1006 patients who underwent randomization, 1005 were included
in the intentionto-treat analysis. Death or hemodynamic decompensation occurred
in 13 of 506 patients (2.6%) in the tenecteplase group as compared with 28 of
499 (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 the
tenecteplase group and 6 patients (1.2%) in the placebo group (P =0.42). In
patients with intermediate-risk pulmonary embolism, fibrinolytic therapy
prevented hemodynamic decompensation but increased the risk of major hemorrhage
and stroke.

 

 

 

 

CONCLUSION:

 

In the
PEITHO trial, patients with intermediaterisk pulmonary embolism who were
treated with standard anticoagulation had a 5.6% incidence of death or
hemodynamic decompensation (the primary efficacy outcome) within the first 7
days after randomization. A single-bolus injection of the fibrinolytic agent
tenecteplase, in a weightbased dose, resulted in a significantly lower risk of
the 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 the
present trial, the efficacy of thrombolysis was mainly driven by the prevention
of hemodynamic decompensation; the study was not powered to detect differences
in rates of death, which occurred relatively infrequently in the two treatment
groups. Moreover, our definition of hemodynamic decompensation or collapse
included a persistent, isolated drop in systolic blood pressure, which could be
of questionable clinical significance. Nevertheless, 14 patients with
hemodynamic decompensation in the placebo group needed inotropic support and 5
underwent cardiopulmonary resuscitation. It is possible that the prognosis for
some of these patients would have been worse if they had not been closely
monitored and promptly treated when decompensation occurred; this notion is
supported by the higher rates of death reported in noninterventional cohort
studies focused on this patient population.

A
reduced-dose strategy might also be beneficial in patients with
intermediate-risk pulmonary embolism and warrants further investigation.

In
conclusion, in normotensive patients with intermediate-risk pulmonary embolism,
the composite primary outcome of early death or hemodynamic decompensation was
reduced after treatment with a single intravenous bolus of tenecteplase.
However, tenecteplase was also associated with a significant increase in the
risk of intracranial and other major bleeding. Therefore, great caution is
warranted when considering fibrinolytic therapy for hemodynamically stable
patients with pulmonary embolism, right ventricular dysfunction, and a positive
cardiac troponin test.

 

 

 

CRITICAL APPRAISAL:

 

The
study was performed a multicenter, double-blind, placebocontrolled randomized
trial.13 The trial was initiated by the investigators and sponsored by
Direction de la Recherche Clinique at Assistance Publique–Hôpitaux de Paris, a
consortium of university hospitals in Paris.

The
principal investigators had unrestricted access to the data after the database
was locked. The two cochairs of the steering committee and the trial
statistician wrote the first draft of the manuscript. The members of the
steering committee were involved in the analysis of the data; reviewed,
amended, and approved the early version of the manuscript; and made the
decision to submit the manuscript for publication.

Patients
were eligible for the study if they met all the following criteria: an age of
18 years or older, objectively confirmed acute pulmonary embolism with an onset
of symptoms 15 days or less before randomization, right ventricular dysfunction
confirmed by echocardiography or spiral computed tomography (CT) of the chest,
and myocardial injury confirmed by a positive test for troponin I or troponin
T. The full inclusion and exclusion criteria for the study, including the
criteria for right ventricular dysfunction.

Eligible
patients underwent central randomization with the use of a computerized
Internetbased system. Randomization was stratified by center and, within
centers, was performed in blocks to ensure balanced distribution of the
treatment groups. We required that randomization be performed within 2 hours after
the investigator became aware of the presence of both right ventricular
dysfunction (by receiving the echocardiography or CT report) and myocardial
injury (by receiving a report of a positive cardiac troponin test). Patients
who were assigned to undergo fibrinolysis received a single weight-based
intravenous bolus (given over a period of 5 to 10 seconds) of the fibrinolytic
agent tenecteplase. The dose ranged from 30 mg to 50 mg, depending on body
weight (Table S1 in the Supplementary Appendix).13 Patients assigned to placebo
were given a single intravenous bolus of the same volume and appearance as the
bolus of tenecteplase.

The
main efficacy and safety analyses were based on all events that occurred in the
intention-totreat population, defined as all patients who underwent
randomization and who signed the informed consent form. In addition, analysis
of safety outcomes was performed in the safety population, which was defined as
all patients who received the study drug. The primary efficacy outcome was analyzed
by means of a twosided chi-square test of proportions. A similar analysis was
performed for each of the secondary outcomes; all results were for the
intention-totreat population. All tests were performed with the use of SAS
software, version 9.2 (SAS Institute). Prespecified subgroup analyses included
age (?75 years vs. >75 years), sex, and country of recruitment.

 

Analysis of graph/Image/Table

He has used
sequences of tables to explain

Table 1. Characteristics of the
Patients at Baseline of both the groups.

. Demographic data

. Medical history

Table 2. Diagnostic Evaluation
and Initial Management

In which all forms of evaluations
like CTPA and also ECHO and trop T which was done for both the groups.

Also
the treatment given as per the study protocol.

Table
3. Efficacy Outcomes.

Exapliend
about the primary outcome, death from any cause, hemodynamic instability.

 

Table
4. Safety Outcomes in the Intention-to-Treat Population

Like
the outcome fo bleeding in the number of patients, be t major or minor.

Also
about development of stroke if haemorragic or ischemic stroke.

 

 

Conclusion

In the
PEITHO trial, patients with intermediaterisk pulmonary embolism who were
treated with standard anticoagulation had a 5.6% incidence of death or
hemodynamic decompensation (the primary efficacy outcome) within the first 7
days after randomization. A single-bolus injection of the fibrinolytic agent
tenecteplase, in a weightbased dose, resulted in a significantly lower risk of
the 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 the
present trial, the efficacy of thrombolysis was mainly driven by the prevention
of hemodynamic decompensation; the study was not powered to detect differences
in rates of death, which occurred relatively infrequently in the two treatment
groups. Moreover, our definition of hemodynamic decompensation or collapse
included a persistent, isolated drop in systolic blood pressure, which could be
of questionable clinical significance. Nevertheless, 14 patients with
hemodynamic decompensation in the placebo group needed inotropic support and 5
underwent cardiopulmonary resuscitation. It is possible that the prognosis for
some of these patients would have been worse if they had not been closely
monitored and promptly treated when decompensation occurred; this notion is
supported by the higher rates of death reported in noninterventional cohort
studies focused on this patient population.

A
reduced-dose strategy might also be beneficial in patients with
intermediate-risk pulmonary embolism and warrants further investigation.

In
conclusion, in normotensive patients with intermediate-risk pulmonary embolism,
the composite primary outcome of early death or hemodynamic decompensation was
reduced after treatment with a single intravenous bolus of tenecteplase.
However, tenecteplase was also associated with a significant increase in the
risk of intracranial and other major bleeding. Therefore, great caution is
warranted when considering fibrinolytic therapy for hemodynamically stable
patients with pulmonary embolism, right ventricular dysfunction, and a positive
cardiac troponin test.