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EFFICACY OF TISSUE PLASMINOGEN ACTIVATOR, HEPARIN AND STREPTOKINASE IN PATIENTS WITH SUB MASSIVE PULMONARY EMBOLISM IN A TERTIARY CARE CARDIAC HOSPITAL: A CASE SERIES.

Byline: Abdul Hameed Siddiqui, Hasnain Yousaf, Sarfaraz Ali Zahid, Javeria Kamran, Saleha Abbas, Jasia Abbas, Farhan Tuyyab and Anum Fatima

Keywords: Pulmonary embolism, NYHA class, CT Pulmonary Angiogram, Deep venous thrombosis.

INTRODUCTION

Pulmonary embolism (PE) is a relatively common cardiovascular emergency occurring in 60 to 112 of every 100,000 individuals1. About 430,000 people each year in Europe are affected by pulmonary emboli. In the United States between 300,000 and 600,000 cases occur each year, which results in between 50,000 and 200,000 deaths2. Rates are similar in males and females. They become more common as people get older. It is the third most common cause of cardiovascular mortality and is responsible for 100,000 to 180,000 deaths annually1. The prevalence of Pulmonary embolism among hospitalized patients in the United States, according to data collected between 1979 and 1999, was 0.4% though only 40-53 per 100 000 persons were diagnosed with Pulmonary embolism per year3. By occluding the pulmonary arterial bed it may lead to acute life-threatening but potentially reversible right ventricular failure6.

Pulmonary embolism is a difficult diagnosis that may be missed because of non-specific clinical presentation. However, early diagnosis is fundamental, since immediate treatment is highly effective. PE should be part of differential diagnosis in patients who present with new or worsening dysnoea, chest pain or hypotension. Based on physician's level of suspicion, the diagnostic workup may include a clinical decision rule, biomarkers (e.g. d-dimers) and/or imaging modalities such as computed tomographic pulmonary angiography (CTPA) or a ventilation perfusion scan. Additional evaluations may be performed with Troponins, B-type natriuretic peptide (BNP) and/or echocardiography. PE is commonly classified as massive (high-risk), submassive (intermediate-risk) and low risk to help determine the required treatment. Massive PE is defined as suspected or confirmed PE in the presence of shock, sustained hypotension, pulselessness or persistent profound bradycardia.

Sub-massive PE is defined as suspected or confirmed PE with right ventricular dysfunction in the absence of shock9. Depending on the clinical presentation, initial therapy is primarily aimed either at life-saving restoration of flow through occluded pulmonary arteries (PA) or at the prevention of potentially fatal early recurrences. Both initial treatment and the long-term anticoagulation that is required for secondary prevention must be justified in each patient by the results of an appropriately validated diagnostic strategy6,7,11. Epidemiology, predisposing factors, natural history, and the pathophysiology of pulmonary embolism have been described more extensively worldwide4,5,7. Pulmonary embolism and deep venous thrombosis are two clinical presentations of venous thromboembolism (VTE) and share the same predisposing factors. In most cases pulmonary embolism is a consequence of DVT.

Among patients with proximal DVT, about 50% have an associated, usually clinically asymptomatic pulmonary embolism at lung scan5,7,8. In about 70% of patients with Pulmonary embolism, DVT can be found in the lower limbs if sensitive diagnostic methods are used6. The risk of death related to the initial acute episode or to recurrent PE is greater in patients who present with Pulmonary embolism than in those who present with DVT. According to prospective cohort studies, the acute case fatality rate for Pulmonary embolism ranges from 7 to 11%11,24. Although Pulmonary embolism can occur in patients without any identifiable predisposing factors, one or more of these factors are usually identified (secondary Pulmonary embolism)14. The proportion of patients with idiopathic or unprovoked Pulmonary embolism was about 20% in the International Cooperative Pulmonary Embolism Registry (ICOPER)24.

Patient-related predisposing factors include age, history of previous VTE, active cancer, neurological disease with extremity paresis, medical disorders causing prolonged bed rest, such as heart or acute respiratory failure, and congenital or acquired thrombophilia, hormone replacement therapy and oral contraceptive therapy20-22. An association between idiopathic Pulmonary embolism and cardiovascular events, including myocardial infarction and stroke, has recently been reported12,17. Reports of a high risk of Pulmonary embolism among obese people, smokers and patients affected by systemic hypertension or metabolic syndrome have renewed interest in the link between arterial thrombo-embolism and VTE9,10.

MATERIAL AND METHODS

A descriptive cross-sectional study was carried out at Armed forces Institute of Cardiology (AFIC and NIHD) Rawalpindi from 1st October 2017 till 31st December, 2017. A total of 25 patients of pulmonary embolism were included in the study, using consecutive sampling technique. Data collection tool was used to collect the different variables. Data was entered analyzed using SPSS-23 Version.

Table-I: NYHA class findings was statistically significant with mortality

S No###Demographic###Mean(+- SD)

###Characteristics

1.###Age###43.64(+- 17.88)

S No###Variables###Frequency(%)

###(N =57)

1.###Outcome

###Dead###7(12.3%)

###Alive###50(87.7%)

2.###Gender

###Male###47(82.5%)

###Female###10(17.5%)

3.###NYHA

###I###6(10%)

###II###9(50%)

###III###27(20%)

###IV###15(26.3%)

4.###dDimers

###2004001200###11(19.3%)

5.###Treatment

###SK###22(38.6%)

###Heparin###25(43.9%)

###tPA###10(16%)

6.###Echo

###Dilated RA/RV###27(80)

###Normal###30(20%)

7.###DVT

###Yes###9(15.6%)

###No###48(84.4%)

8.###CTPA

###Bil segmental###30(52.6%)

###embolism

###Saddle Embolus###2(3.5%)

###Bil massive###17(28.8%)

###Lobar embolism###8(14.1%)

Table-II: Chi-square test between mortality and gender, NYHA Class, Thrombolytic therapy, DVT and CT pulmonary angiogram findings.

Variables###Outcome###x2 results

###Alive###Dead

###(n=50)(%)###(n=7)(%)

Gender

Male###42(84%)###5(71.4%)###p=0.56

Female###8(16)###2(28.60%)

dDimer

200400<800###8(40%)###0

1200###1(5%)###0

NYHA

I###6(12%)###0

II###10(50%)###0###p=0.001

III###4(20%)###4(80%)

IV###13(26%)###2(28.6%)

DVT

###p=0.01

Yes###8(16%)###1(14.3%)

No###42(84%)###46(85.7%)

Echo

Dilated RA/RV###24(75%)###3(100%)###p=.33

Normal###26(25%)###4(57.1)0

Treatment

Heparin+SK###16(32%)###6(85.7%)###p=0.001

Heparin###25(50%)###0

tPA###9(18%)###1(14.3%)

RESULTS

Fifty seven cases of acute pulmonary embolism were included in thestudywho were admitted in the coronary care unit (CCU) during study period. Mean age of patients was 43.64 +- 17.88 years with minimum age 20 years and maximum 83 years. There were 47 (82.50%) male patients while 10 (17.50%) female patients. Most common NYHA class with which patients presented was, class III 27 (47.5%) followed by class IV 15 (26.3%). The most common CT Pulmonary Angiogram finding of the patients was bilateral segmental embolism in 30 (52.6%) followed by bilateral massive in 17 patients (29.8%). Out of 57 patients, 22 (38.6%) patients received streptokinase. Nine patients were found to have deep venous thrombosis. Mortality was 12.3% (n=7). Chi-square test was applied to find out the association between mortality and different variables. Results showed that only NYHA class findings was statistically significant (p50% obstruction of pulmonary vasculature or occlusion of 2 or more lobar arteries. It is now more commonly defined by hemodynamic instability, which is a function of both PE size and underlying cardiopulmonary status. Massive acute pulmonary embolism is now defined as sustained hypotension (systolic blood pressure <90 mmHg for at least 15 min or requiring inotropic support not due to a cause other than PE such as arrhythmia, hypovolemia, sepsis or LV dysfunction), pulselessness, or persistent profound bradycardia (heart rate 90 mmHg but with RV dysfunction or myocardial necrosis)26. In PEITHO trial intermediate risk PE was defined as presence of RV dysfunction or a positive Troponin18. In MOPPET trial moderate PE was defined as the presence of signs and symptoms of PE plus computed tomographic pulmonary angiographic involvement of >70% involvement of thrombus in >2 lobar or left or right main pulmonary arteries or by a high probability ventilation/perfusion scan showing ventilation/perfusion mismatch in >2 lobes19,10. Sub-massive PE accounts for 20% of all PEs with in-hospital mortality of 2-5%. There is evidence from registries. Data that the. Short term mortality rate directly attributable to sub-massive PE treated with Heparin anticoagulation is probably <3%.

It accounts for most deaths from PE, leads to long term morbidity especially chronic pulmonary hypertension and worst functional outcome. Cho et al22 found that haemodynamically stable patients with PE, 37% have RV dysfunction on echo and also found higher short term mortality in this group. (Odds ratio 2.29; 13.7 vs 6.5 without RV dysfunction). RV dysfunction and elevated Troponins are also predictors of poor outcome in sub-massive PE. As such a smaller PE in a patient with poor cardiopulmonary reserve could produce similar outcomes to a larger PE in a patient without prior cardiopulmonary disease21.

The use of thrombolytic agents for the treatment of sub-massive PE is somewhat debateable - the limited documented benefit (e.g. improved hemodynamics, potential for less chronic pulmonary hypertension) must be weighed against the increased risk of life threatening hemorrhage and the availability of other therapies (e.g. catheter-directed thrombolysis or clot retrieval)23. The present study was conducted to document efficacy of thrombolytic and anti coagulant agents in sub-massive PE. We used Streptokinase and tissue plasminogen activator and Heparin and studied their usein terms of efficacy, resolution of symptoms, improvement in haemodynamic profile and echocardiographic parameters. This is an ongoing study and presently data of initial twenty five patients is being analyzed and presented. Streptokinase was used in 22 patients in a dose of 250,000 initial bolus followed by 100,000 units/hour for next 24 hour.

Out of these twenty two patients, 16 survived and six succumbed to their illness. Tissue plasminogen activator (tPA) was used in ten patients in a dose of 100 mg over 2 hours preceded by 10 mg bolus. Out of these ten patients, nine made an uneventful recovery and one patient died. In the remaining twenty five patients only Heparin was use in a dose of 18 units/Kg/hour preceded by intravenous bolus of 5000 units. Tissue plasminogen activator was used preferentially in young soldiers who developed venous thromboembolism (VTE) at high altitude and later confirmed on CT pulmonary angiogram. The patient who died after tPA administration was because of massive haemoptysis which is in line with higher bleeding risk after thrombolysis12,24. Patients who were given Heparin only did reasonably well as no patient died in this group.

This was well demonstrated in earlier studies like MAPPET-3 trial which compared Heparin with alteplase in sub-massive pulmonary embolism and showed no difference for in-hospital mortality (3.4% versus 2.2%; p=0.71)25. However, in PEITHO trial which compared Heparin with Tenecteplase, substantial reduction in combined end point of early mortality or haemodynamic collapse was seen butat the cost of significant increase in major haemorrhage (including intracranial haemorrhage)18.

CONCLUSION

Cardiologists may be asked to manage patients with massive and submassive PE because cardiovascular medical specialists are trained to treat hemodynamic derangements with a variety of interventional and pharmacological approaches. A rapid and accurate assessment of risk and a decisive treatment plan should be established. Fortunately, fibrinolysis, catheter intervention, and possible col-laboration with cardiac surgeons for desperately sick patients are tools that will assist cardiovascular specialists in maximizing the likelihood of prompt and complete recovery in these seriously ill patients.

CONFLICT OF INTEREST

This study has no conflict of interest to be declared by any author.

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Publication:Pakistan Armed Forces Medical Journal
Date:Feb 28, 2019
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