View Article PDF

Pulmonary embolism (PE) is a frequent cause for hospital admission and a significant proportion of cases are first diagnosed at autopsy.1 The in-patient or 30-day mortality is variable with a stepwise increase in mortality observed subject to the degree of haemodynamic instability, with a mortality of up to 65% for patients who require cardiopulmonary resuscitation.2,3 Patients with right ventricular (RV) dysfunction have a higher mortality than those without in whom the mortality of acute PE is close to 0% with anticoagulation. 2-4 Subsequent mortality is also high, the overall mortality at 3 months was reported between 10.5-15.3%,2,5 with the majority of patients dying of recurrent PE or cancer.2 Multiple studies have demonstrated rapid resolution of vascular obstruction, reduced pulmonary hypertension and improved haemodynamics following treatment with a thrombolytic agent in acute PE.6-8 Thrombolysis has been incorporated into international guidelines for PE with haemodynamic instability with undisputable mortality benefits.1,9 However for normotensive patients with large clot burden, the role of thrombolysis remains controversial. Meta-analyses of published trials show no mortality benefit from thrombolysis in normotensive patients even in the presence of RV dysfunction.1,10-13 Despite the controversy, thrombolysis has been liberally used in patients at Christchurch Hospital in the setting of acute PE with hypotension or evidence of RV strain, as per the managing clinician. In this report we describe our experience with PE for the 6 years from January 2002 and December 2007. We aim to assess the safety, short and intermediate term outcomes with thrombolysis and to identify imaging and biochemical risk markers that can distinguish a higher risk subgroup who would benefit from thrombolysis. Method An audit of patients admitted with PE under Cardiology service between January 2002 and December 2007 was performed. Patients were identified using International Statistical Classification of Diseases and Related Health Problem, Tenth Revision, Australian Modification (ICD-10-AM) code, I26.0 or I26.9 for pulmonary embolism with or without acute cor pulmonale. This included all patients treated with thrombolysis except those in the Intensive Care Unit as per hospital protocol. A chart-based review was carried out with data collected comprising basic demographics, clinical status, investigations, treatment received and outcomes both as in-patient and at 6 months. For patients who had no further contact with the hospital system, a questionnaire was sent out to their General Practitioner. Hypotension was defined as the lowest systolic blood pressure 226490 mmHg. All computed tomography pulmonary angiograms (CTPA) were reviewed by both a radiology fellow and an experienced cardiothoracic radiologist for evidence of RV strain. RV strain was defined as RV/LV ratio on axial 4-chamber view 22651, straightening or bowing to the left of the interventricular septum (IVS) or reflux of contrast into the inferior vena cava or hepatic veins. Clot burden was quantified using the Qanadli score.14 The Qanadli score is the sum of the presence of clot to each segmental artery, 0 for no clot, 1 for partial occlusion and 2 for total occlusion. A clot proximal to the segmental artery is scored as the sum of affected segmental arteries arising distally. The maximum score is 40. A score of 226516 is regarded as severe as it indicates 226540% of pulmonary circulation is involved. Superior vena cava, azygous vein and main pulmonary artery sizes were also measured. Evidence of RV strain on echocardiogram was defined as dilated RV, RV hypokinesis, abnormal interventricular septal motion or estimated right ventricular systolic pressure 226530 mmHg using Doppler. Statistical analysis was performed with GraphPad Prism version 5. Continuous variables were expressed as mean 00b1 standard error. Two- tailed unpaired t-test for difference between two groups, Fishers exact test for contingency and Pearsons coefficient for correlation were used. A p-value of less than 0.05 was considered statistically significant. Results During the audit period 120 patients, age 22-87 years, mean 63 00b1 1.3 years, with PE were admitted under the Cardiology service at Christchurch Hospital. (Table 1) Patients had PE confirmed on CTPA or ventilation-perfusion scan (4), except one PE diagnosed at post mortem. Apart from this patient, all but one patient who had a concurrent diagnosis of type B aortic dissection, received heparin or low molecular weight heparin and 46 patients received thrombolysis. Bleeding problems occurred in 17 patients, seven (six in the thrombolysed group) of which required a blood transfusion. There were two deaths during admission, one from untreated PE diagnosed at post-mortem and one from an unrelated cause. Follow-up data to 6 months was available in 111 patients, 7 patients were lost to follow-up. There were three recurrences during the follow-up period, one resulting in death. Two more patients died during the follow-up period, one from cancer and the other from heart failure following bone marrow transplant. Table 1. Patient characteristics of all patients and thrombolysed patients Relationship of biomarkers and haemodynamicsPeak troponin levels were significantly higher in the hypotensive patients compared with the normotensive patients, (1.13 00b1 0.67 vs 0.13 00b1 0.02 03bcg/L (p=0.0035)). Eight of 22 hypotensive and 33 of 98 normotensive patients had brain natriuretic peptide (BNP) levels measured. There was no significant difference for BNP between normotensive and hypotensive groups with range between 22 to 899pmol/L and 6 to 1241pmol/L respectively. Imaging markers Right ventricular strainEchocardiogram was predominantly performed in those with or suspected of having large clot burden but was not routinely performed on all patients. Seventy nine patients had an echocardiogram during the admission. Forty out of 62 patients in the normotensive group and 14 out of 17 patients in the hypotensive group had evidence of RV strain (p= NS). Seventy-eight patients had both CTPA and echocardiography. Of 54 patients with evidence of RV strain on echocardiogram, 44 had an RV/LV ratio 22651 on CTPA (p= 0.027). The sensitivity of CTPA detecting RV strain using RV/LV ratio was 80% (95% CI 67-89.6%), specificity 57% (95% CI 35-77%), positive predictive value 82% (95% CI 69-91%) and negative predictive value 54% (95% CI 43-75%). Clot burdenClot burden in the pulmonary circulation, as assessed by Qanadli scores, was significantly higher for those in the hypotensive group, 21.3 00b12.2 vs 15.6 00b1 1.1 (p= 0.03). Qanadli score had a positive correlation with CTPA RV/LV ratio, r= 0.53 (p< 0.0001) and a weak positive correlation with pulmonary pressures, r= 0.42 (p< 0.001). It also had a weak negative correlation with the worst blood pressure during admission r= -0.19 (p=0.045) but no correlation with troponin levels. Qanadli score was associated with echocardiographic measures of RV strain; of 54 patients with evidence of RV strain on echocardiogram, 45 had a Qanadli score 226516. Patients with Qanadli score 226516 were 1.87 times more likely to have RV/LV ratio 22651, 1.95 times more likely to have straightening of the IVS, 1.73 times more likely to have reflux of contrast into IVC and/or hepatic veins and 2.76 times more likely to have evidence of RV strain on echocardiogram. (Table 2) When using CTPA RV/LV ratio 22651 as a marker of RV strain, there was a weak correlation of SVC size to RV strain but no significant correlation with azygous diameter or main pulmonary artery diameter on CT. The clinical event rate was too low to have any meaningful assessment of risk markers and their association with clinical outcomes. Table 2. RV, right ventricle. LV, left ventricle. IVS, interventricular septum. IVC, inferior vena cava. Imaging markers of RV strain Likelihood ratio if Qanadli score 226516 RV/LV ratio 2265 1 on CTPA Straightening of IVS on CTPA Reflux of contrast into IVC and/or hepatic veins on CTPA RV strain on echocardiogram 1.87 00d7 1.95 00d7 1.73 00d7 2.76 00d7 Thrombolysis group Forty-six patients, age 22-87 years, mean 60.2 00b1 2.2 years had thrombolysis with alteplase or tenecteplase using the standard protocols for thrombolysis for acute ST segment elevation myocardial infarction. Thirty four patients were normotensive, 12 hypotensive, whilst one patient had a cardiac arrest. Forty two patients had large clot burden reported on the original CTPA report (clot seen in pulmonary artery or more than three lobar arteries involved). For the rest, one patient received empiric thrombolysis after a community cardiac arrest coming off a long haul flight, with a subsequent CTPA confirming the diagnosis of PE. One patient had a V/Q scan but not a CTPA due to end-stage renal failure from polycystic kidney disease. In the remaining two patients thrombolysis was administered following clinical deterioration, though the initial CTPA did not show a large clot burden. Thirty-one patients in the thrombolysis group had an echocardiogram prior to thrombolysis, all had evidence of RV strain whilst 85% of all patients and 100% of hypotensive patients had evidence of RV strain on CTPA. There was a high concordance in the assessment of RV strain in the thrombolysed group, with 28 out of 31 patients showing RV strain on both CTPA and echocardiogram. Most thrombolysed patients had a relatively uneventful hospital stay. (Figure 1) One patient died during admission due to an unrelated cause, not from PE or thrombolysis. No intracranial haemorrhage occurred. Transfusion was required in 6 patients for bleeding following thrombolysis. Of these patients requiring transfusion, three had a history of orthopaedics surgery within the preceding 2 weeks, two of whom were thrombolysed within 72 hours of surgery, one had ongoing wound ooze. Six patients had minor bleeding not requiring transfusion. Of the surviving 45 patients followed at 6 months, three overseas patients were lost to follow-up. Two PE recurrences occurred during this period, one resulting in death, the other was due to sub-therapeutic anticoagulation. Persistent pulmonary hypertension was present in six patients, two of whom had symptomatic heart failure. (Figure 2). Figure 1. In-patient outcome for thrombolysed patients Figure 2. Six-month outcome for thrombolysed patients. HF, heart failure. PHT, pulmonary hypertension Large clot burden without thrombolysis group (Table 3) Vascular obstruction on CTPA of 226540% (Qanadli score 226516) was present in 28 patients who did not receive thrombolysis. In this group, 5 were hypotensive at some stage. None died of PE during their hospital stay, 2 patients had minor bleeds. Six-month follow-up data was available in 26 patients. No recurrences occurred during the follow-up period, whilst two patients had persistent pulmonary hypertension. Large clot burden group A total 68 patients were identified with large PEs (Qanadli score 226516), of which 40 were thrombolysed. There was no significant difference in mean troponin or BNP levels, but there was a significantly higher in-patient event rate (death one, bleed with or without transfusion 12, heart failure four) in the thrombolysed group, 17/40 thrombolysed vs 4/28 not thrombolysed (p=0.02), with the main difference being bleeding. No significant difference of events (death, recurrences, pulmonary hypertension) was observed at 6 months, 11/37 thrombolysed vs 2/26 not thrombolysed (p=NS). Table 3. Patient characteristics in the large clot burden (Qanadli score 226516) group Discussion We document our experience with thrombolysis for PE with evidence of right heart strain, irrespective of the blood pressure status. Overall clinical outcomes were good, but we could not demonstrate an advantage for thrombolysis, and bleeding rates were increased with thrombolysis. While our major bleeding complication rate was similar to published data from randomised trials at 13%, 1 half of the patients experiencing bleeding in our series had a history of recent surgery so the drop in haemoglobin was at least in part explainable by perioperative blood lost. The lack of an advantage in clinical outcome in the thrombolysed group in our study should be interpreted with caution. This study was a retrospective review, with treatment being determined by the managing clinician. The thrombolysed group had a greater clot burden, all had RV strain or circulatory compromise. Indeed, the thrombolysed group had similar clinical outcomes to the nonthrombolysed group despite having more severe PE suggested that thrombolysis may have favourably affected outcomes. Persistent pulmonary hypertension and right heart failure occur in approximately 4% of patients after PE. 15 Some older, small or non-randomised trials showed a reduction of chronic pulmonary hypertension development in thrombolysed patients. 16-18 While a recent small prospective cohort showed a higher likelihood of a subgroup of haemodynamically stable patients with large PE of developing chronic symptomatic pulmonary hypertension with heparin only compared to thrombolysed patients, 19 more recent randomised controlled trials have focused on short term analysis only and longer term outcomes are lacking. In our series we did not find any evidence that thrombolysis reduced the incidence of persisting pulmonary hypertension, however our numbers are small. RV dysfunction is a well recognised marker for worse outcome in PE regardless of blood pressure.20, 21 However, echocardiography, the gold standard for right heart dysfunction, is not always readily available. A previous study showed raised RV/LV ratio on CTPA to be associated with >four-fold increase in mortality 22, 23 thus a raised RV/LV ratio identifies a higher risk group and closer observation or more aggressive therapy should be considered.24, 25 Our study confirmed good predictive value of CTPA for RV strain using the RV/LV ratio or a high Qanadli score of 226516. Therefore CTPA is a good initial test in suspected PE, as it provides important information on clot burden and right heart strain in addition to its diagnostic utility and is readily available in most hospitals. The elevation of biomarkers for myocardial strain or injury in acute PE is a reflection of RV involvement, as a result of sudden development of pulmonary hypertension.26-29 It is associated with increased mortality even in normotensive patients. 30 More recent meta-analysis suggested combined raised troponin and BNP reflected higher risk. 31 Unfortunately, our study is heavily limited by its retrospective design with no standardised management plan of all patients and the overall low event rate, we are unable to draw any meaningful conclusions with biomarkers. The question would be better answered by a prospective cohort. Conclusion We document our experience with PE over the last 6 years. Our study confirmed clot burden and RV strain on CTPA were good predictors for RV strain on echocardiography. The role of thrombolysis in normotensive patients with large clot burden remains uncertain. However, our experience shows that thrombolysis can be used, albeit with a modest risk of bleeding complication but with otherwise good clinical outcome.

Summary

Abstract

Aim

Thrombolysis for normotensive patients with large clot burden pulmonary embolism remains debatable. We aim to document our current management of pulmonary embolism, examining determinants of therapy and outcomes.

Method

A retrospective chart-based review of all patients admitted with pulmonary embolism under Cardiology service in Christchurch Hospital between 2002-2007. All related CT pulmonary angiograms were also reviewed for quantification of clot burden and evidence of right ventricular strain.

Results

120 patients were admitted during the audit period. Hypotensive patients had a significantly higher troponin level and Qanadli scores. RV/LV ratio >1 in CTPA was 80% sensitive and 57% specific in predicting RV strain on echocardiogram. Forty-six patients were thrombolysed, most with large clot burden and right ventricular strain. No treatment related death or intracranial haemorrhages occurred; however six patients required blood transfusion and six patients had persistent pulmonary hypertension at 6 months. There was a higher in-patient event rate in thrombolysed group, due to increased bleeding, compared to non-thrombolysed patients.

Conclusion

Thrombolysis was successfully performed with relatively low in-patient and 6-month event rate. Long term advantage over routine anticoagulation was not demonstrated. The role of thrombolysis in normotensive patients with large clot burden remains uncertain. CTPA markers of RV strain correlated well with echocardiography.

Author Information

Wandy Chan, Senior Cardiology Registrar; Tiffany Campbell, Radiology Fellow; Sharyn MacDonald, Radiologist; Ian Crozier, Cardiologist, Christchurch Hospital, Christchurch

Acknowledgements

Correspondence

Wandy Chan, Cardiology Department, Christchurch Public Hospital, Private Bag 4710, Christchurch 8140, New Zealand. Fax: +64 (0)3 3641415

Correspondence Email

wandyc@cdhb.govt.nz

Competing Interests

None.

- Torbicki A, Perrier A, Konstantinides S, et al. Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). European heart journal. Sep 2008;29(18):2276-2315.-- Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet. Apr 24 1999;353(9162):1386-1389.-- Kasper W, Konstantinides S, Geibel A, et al. Management strategies and determinants of outcome in acute major pulmonary embolism: results of a multicenter registry. Journal of the American College of Cardiology. Nov 1 1997;30(5):1165-1171.-- Kreit JW. The impact of right ventricular dysfunction on the prognosis and therapy of normotensive patients with pulmonary embolism. Chest. Apr 2004;125(4):1539-1545.-- Conget F, Otero R, Jimenez D, et al. Short-term clinical outcome after acute symptomatic pulmonary embolism. Thrombosis and haemostasis. Nov 2008;100(5):937-942.-- Goldhaber SZ, Haire WD, Feldstein ML, et al. Alteplase versus heparin in acute pulmonary embolism: randomised trial assessing right-ventricular function and pulmonary perfusion. Lancet. Feb 27 1993;341(8844):507-511.-- Dalla-Volta S, Palla A, Santolicandro A, et al. PAIMS 2: alteplase combined with heparin versus heparin in the treatment of acute pulmonary embolism. Plasminogen activator Italian multicenter study 2. Journal of the American College of Cardiology. Sep 1992;20(3):520-526.-- Tibbutt DA, Davies JA, Anderson JA, et al. Comparison by controlled clinical trial of streptokinase and heparin in treatment of life-threatening pulmonary embolism. British medical journal. Mar 2 1974;1(5904):343-347.-- Kearon C, Kahn SR, Agnelli G, et al. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. Jun 2008;133(6 Suppl):454S-545S.-- Tardy B, Venet C, Zeni F, et al. Short term effect of recombinant tissue plasminogen activator in patients with hemodynamically stable acute pulmonary embolism: results of a meta-analysis involving 464 patients. Thrombosis research. Dec 2009;124(6):672-677.-- Wan S, Quinlan DJ, Agnelli G, Eikelboom JW. Thrombolysis compared with heparin for the initial treatment of pulmonary embolism: a meta-analysis of the randomized controlled trials. Circulation. Aug 10 2004;110(6):744-749.-- Thabut G, Thabut D, Myers RP, et al. Thrombolytic therapy of pulmonary embolism: a meta-analysis. Journal of the American College of Cardiology. Nov 6 2002;40(9):1660-1667.-- Konstantinides S, Geibel A, Heusel G, et al. Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. The New England journal of medicine. Oct 10 2002;347(15):1143-1150.-- Qanadli SD, El Hajjam M, Vieillard-Baron A, et al. New CT index to quantify arterial obstruction in pulmonary embolism: comparison with angiographic index and echocardiography. Ajr. Jun 2001;176(6):1415-1420.-- Pengo V, Lensing AW, Prins MH, et al. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. The New England Journal of Medicine. 2004 May 27;350(22):2257-2264.-- The urokinase pulmonary embolism trial. A national cooperative study. Circulation. Apr 1973;47(2 Suppl):II1-108.-- Urokinase-streptokinase embolism trial. Phase 2 results. A cooperative study. JAMA. Sep 16 1974;229(12):1606-1613.-- Sharma GV, Folland ED, McIntyre KM, Sasahara AA. Long-term benefit of thrombolytic therapy in patients with pulmonary embolism. Vascular medicine (London, England). 2000;5(2):91-95.-- Kline JA, Steuerwald MT, Marchick MR, et al. Prospective evaluation of right ventricular function and functional status 6 months after acute submassive pulmonary embolism: frequency of persistent or subsequent elevation in estimated pulmonary artery pressure. Chest. Nov 2009;136(5):1202-1210.-- Kucher N, Rossi E, De Rosa M, Goldhaber SZ. Prognostic role of echocardiography among patients with acute pulmonary embolism and a systolic arterial pressure of 90 mm Hg or higher. Archives of internal medicine. Aug 8-22 2005;165(15):1777-1781.-- Sanchez O, Trinquart L, Colombet I, et al. Prognostic value of right ventricular dysfunction in patients with haemodynamically stable pulmonary embolism: a systematic review. European heart journal. Jun 2008;29(12):1569-1577.-- van der Meer RW, Pattynama PM, van Strijen MJ, et al. Right ventricular dysfunction and pulmonary obstruction index at helical CT: prediction of clinical outcome during 3-month follow-up in patients with acute pulmonary embolism. Radiology. Jun 2005;235(3):798-803.-- Ghuysen A, Ghaye B, Willems V, et al. Computed tomographic pulmonary angiography and prognostic significance in patients with acute pulmonary embolism. Thorax. Nov 2005;60(11):956-961.-- Quiroz R, Kucher N, Schoepf UJ, et al. Right ventricular enlargement on chest computed tomography: prognostic role in acute pulmonary embolism. Circulation. May 25 2004;109(20):2401-2404.-- Schoepf UJ, Kucher N, Kipfmueller F, et al. Right ventricular enlargement on chest computed tomography: a predictor of early death in acute pulmonary embolism. Circulation. Nov 16 2004;110(20):3276-3280.-- Kruger S, Graf J, Merx MW, et al. Brain natriuretic peptide predicts right heart failure in patients with acute pulmonary embolism. American Heart Journal. Jan 2004;147(1):60-65.-- Binder L, Pieske B, Olschewski M, et al. N-terminal pro-brain natriuretic peptide or troponin testing followed by echocardiography for risk stratification of acute pulmonary embolism. Circulation. Sep 13 2005;112(11):1573-1579.-- Becattini C, Vedovati MC, Agnelli G. Prognostic value of troponins in acute pulmonary embolism: a meta-analysis. Circulation. Jul 24 2007;116(4):427-433.-- Scridon T, Scridon C, Skali H, et al. Prognostic significance of troponin elevation and right ventricular enlargement in acute pulmonary embolism. The American journal of cardiology. Jul 15 2005;96(2):303-305.-- Kostrubiec M, Pruszczyk P, Bochowicz A, et al. Biomarker-based risk assessment model in acute pulmonary embolism. European heart journal. Oct 2005;26(20):2166-2172.-- Lega JC, Lacasse Y, Lakhal L, Provencher S. Natriuretic peptides and troponins in pulmonary embolism: a meta-analysis. Thorax. Oct-

For the PDF of this article,
contact nzmj@nzma.org.nz

View Article PDF

Pulmonary embolism (PE) is a frequent cause for hospital admission and a significant proportion of cases are first diagnosed at autopsy.1 The in-patient or 30-day mortality is variable with a stepwise increase in mortality observed subject to the degree of haemodynamic instability, with a mortality of up to 65% for patients who require cardiopulmonary resuscitation.2,3 Patients with right ventricular (RV) dysfunction have a higher mortality than those without in whom the mortality of acute PE is close to 0% with anticoagulation. 2-4 Subsequent mortality is also high, the overall mortality at 3 months was reported between 10.5-15.3%,2,5 with the majority of patients dying of recurrent PE or cancer.2 Multiple studies have demonstrated rapid resolution of vascular obstruction, reduced pulmonary hypertension and improved haemodynamics following treatment with a thrombolytic agent in acute PE.6-8 Thrombolysis has been incorporated into international guidelines for PE with haemodynamic instability with undisputable mortality benefits.1,9 However for normotensive patients with large clot burden, the role of thrombolysis remains controversial. Meta-analyses of published trials show no mortality benefit from thrombolysis in normotensive patients even in the presence of RV dysfunction.1,10-13 Despite the controversy, thrombolysis has been liberally used in patients at Christchurch Hospital in the setting of acute PE with hypotension or evidence of RV strain, as per the managing clinician. In this report we describe our experience with PE for the 6 years from January 2002 and December 2007. We aim to assess the safety, short and intermediate term outcomes with thrombolysis and to identify imaging and biochemical risk markers that can distinguish a higher risk subgroup who would benefit from thrombolysis. Method An audit of patients admitted with PE under Cardiology service between January 2002 and December 2007 was performed. Patients were identified using International Statistical Classification of Diseases and Related Health Problem, Tenth Revision, Australian Modification (ICD-10-AM) code, I26.0 or I26.9 for pulmonary embolism with or without acute cor pulmonale. This included all patients treated with thrombolysis except those in the Intensive Care Unit as per hospital protocol. A chart-based review was carried out with data collected comprising basic demographics, clinical status, investigations, treatment received and outcomes both as in-patient and at 6 months. For patients who had no further contact with the hospital system, a questionnaire was sent out to their General Practitioner. Hypotension was defined as the lowest systolic blood pressure 226490 mmHg. All computed tomography pulmonary angiograms (CTPA) were reviewed by both a radiology fellow and an experienced cardiothoracic radiologist for evidence of RV strain. RV strain was defined as RV/LV ratio on axial 4-chamber view 22651, straightening or bowing to the left of the interventricular septum (IVS) or reflux of contrast into the inferior vena cava or hepatic veins. Clot burden was quantified using the Qanadli score.14 The Qanadli score is the sum of the presence of clot to each segmental artery, 0 for no clot, 1 for partial occlusion and 2 for total occlusion. A clot proximal to the segmental artery is scored as the sum of affected segmental arteries arising distally. The maximum score is 40. A score of 226516 is regarded as severe as it indicates 226540% of pulmonary circulation is involved. Superior vena cava, azygous vein and main pulmonary artery sizes were also measured. Evidence of RV strain on echocardiogram was defined as dilated RV, RV hypokinesis, abnormal interventricular septal motion or estimated right ventricular systolic pressure 226530 mmHg using Doppler. Statistical analysis was performed with GraphPad Prism version 5. Continuous variables were expressed as mean 00b1 standard error. Two- tailed unpaired t-test for difference between two groups, Fishers exact test for contingency and Pearsons coefficient for correlation were used. A p-value of less than 0.05 was considered statistically significant. Results During the audit period 120 patients, age 22-87 years, mean 63 00b1 1.3 years, with PE were admitted under the Cardiology service at Christchurch Hospital. (Table 1) Patients had PE confirmed on CTPA or ventilation-perfusion scan (4), except one PE diagnosed at post mortem. Apart from this patient, all but one patient who had a concurrent diagnosis of type B aortic dissection, received heparin or low molecular weight heparin and 46 patients received thrombolysis. Bleeding problems occurred in 17 patients, seven (six in the thrombolysed group) of which required a blood transfusion. There were two deaths during admission, one from untreated PE diagnosed at post-mortem and one from an unrelated cause. Follow-up data to 6 months was available in 111 patients, 7 patients were lost to follow-up. There were three recurrences during the follow-up period, one resulting in death. Two more patients died during the follow-up period, one from cancer and the other from heart failure following bone marrow transplant. Table 1. Patient characteristics of all patients and thrombolysed patients Relationship of biomarkers and haemodynamicsPeak troponin levels were significantly higher in the hypotensive patients compared with the normotensive patients, (1.13 00b1 0.67 vs 0.13 00b1 0.02 03bcg/L (p=0.0035)). Eight of 22 hypotensive and 33 of 98 normotensive patients had brain natriuretic peptide (BNP) levels measured. There was no significant difference for BNP between normotensive and hypotensive groups with range between 22 to 899pmol/L and 6 to 1241pmol/L respectively. Imaging markers Right ventricular strainEchocardiogram was predominantly performed in those with or suspected of having large clot burden but was not routinely performed on all patients. Seventy nine patients had an echocardiogram during the admission. Forty out of 62 patients in the normotensive group and 14 out of 17 patients in the hypotensive group had evidence of RV strain (p= NS). Seventy-eight patients had both CTPA and echocardiography. Of 54 patients with evidence of RV strain on echocardiogram, 44 had an RV/LV ratio 22651 on CTPA (p= 0.027). The sensitivity of CTPA detecting RV strain using RV/LV ratio was 80% (95% CI 67-89.6%), specificity 57% (95% CI 35-77%), positive predictive value 82% (95% CI 69-91%) and negative predictive value 54% (95% CI 43-75%). Clot burdenClot burden in the pulmonary circulation, as assessed by Qanadli scores, was significantly higher for those in the hypotensive group, 21.3 00b12.2 vs 15.6 00b1 1.1 (p= 0.03). Qanadli score had a positive correlation with CTPA RV/LV ratio, r= 0.53 (p< 0.0001) and a weak positive correlation with pulmonary pressures, r= 0.42 (p< 0.001). It also had a weak negative correlation with the worst blood pressure during admission r= -0.19 (p=0.045) but no correlation with troponin levels. Qanadli score was associated with echocardiographic measures of RV strain; of 54 patients with evidence of RV strain on echocardiogram, 45 had a Qanadli score 226516. Patients with Qanadli score 226516 were 1.87 times more likely to have RV/LV ratio 22651, 1.95 times more likely to have straightening of the IVS, 1.73 times more likely to have reflux of contrast into IVC and/or hepatic veins and 2.76 times more likely to have evidence of RV strain on echocardiogram. (Table 2) When using CTPA RV/LV ratio 22651 as a marker of RV strain, there was a weak correlation of SVC size to RV strain but no significant correlation with azygous diameter or main pulmonary artery diameter on CT. The clinical event rate was too low to have any meaningful assessment of risk markers and their association with clinical outcomes. Table 2. RV, right ventricle. LV, left ventricle. IVS, interventricular septum. IVC, inferior vena cava. Imaging markers of RV strain Likelihood ratio if Qanadli score 226516 RV/LV ratio 2265 1 on CTPA Straightening of IVS on CTPA Reflux of contrast into IVC and/or hepatic veins on CTPA RV strain on echocardiogram 1.87 00d7 1.95 00d7 1.73 00d7 2.76 00d7 Thrombolysis group Forty-six patients, age 22-87 years, mean 60.2 00b1 2.2 years had thrombolysis with alteplase or tenecteplase using the standard protocols for thrombolysis for acute ST segment elevation myocardial infarction. Thirty four patients were normotensive, 12 hypotensive, whilst one patient had a cardiac arrest. Forty two patients had large clot burden reported on the original CTPA report (clot seen in pulmonary artery or more than three lobar arteries involved). For the rest, one patient received empiric thrombolysis after a community cardiac arrest coming off a long haul flight, with a subsequent CTPA confirming the diagnosis of PE. One patient had a V/Q scan but not a CTPA due to end-stage renal failure from polycystic kidney disease. In the remaining two patients thrombolysis was administered following clinical deterioration, though the initial CTPA did not show a large clot burden. Thirty-one patients in the thrombolysis group had an echocardiogram prior to thrombolysis, all had evidence of RV strain whilst 85% of all patients and 100% of hypotensive patients had evidence of RV strain on CTPA. There was a high concordance in the assessment of RV strain in the thrombolysed group, with 28 out of 31 patients showing RV strain on both CTPA and echocardiogram. Most thrombolysed patients had a relatively uneventful hospital stay. (Figure 1) One patient died during admission due to an unrelated cause, not from PE or thrombolysis. No intracranial haemorrhage occurred. Transfusion was required in 6 patients for bleeding following thrombolysis. Of these patients requiring transfusion, three had a history of orthopaedics surgery within the preceding 2 weeks, two of whom were thrombolysed within 72 hours of surgery, one had ongoing wound ooze. Six patients had minor bleeding not requiring transfusion. Of the surviving 45 patients followed at 6 months, three overseas patients were lost to follow-up. Two PE recurrences occurred during this period, one resulting in death, the other was due to sub-therapeutic anticoagulation. Persistent pulmonary hypertension was present in six patients, two of whom had symptomatic heart failure. (Figure 2). Figure 1. In-patient outcome for thrombolysed patients Figure 2. Six-month outcome for thrombolysed patients. HF, heart failure. PHT, pulmonary hypertension Large clot burden without thrombolysis group (Table 3) Vascular obstruction on CTPA of 226540% (Qanadli score 226516) was present in 28 patients who did not receive thrombolysis. In this group, 5 were hypotensive at some stage. None died of PE during their hospital stay, 2 patients had minor bleeds. Six-month follow-up data was available in 26 patients. No recurrences occurred during the follow-up period, whilst two patients had persistent pulmonary hypertension. Large clot burden group A total 68 patients were identified with large PEs (Qanadli score 226516), of which 40 were thrombolysed. There was no significant difference in mean troponin or BNP levels, but there was a significantly higher in-patient event rate (death one, bleed with or without transfusion 12, heart failure four) in the thrombolysed group, 17/40 thrombolysed vs 4/28 not thrombolysed (p=0.02), with the main difference being bleeding. No significant difference of events (death, recurrences, pulmonary hypertension) was observed at 6 months, 11/37 thrombolysed vs 2/26 not thrombolysed (p=NS). Table 3. Patient characteristics in the large clot burden (Qanadli score 226516) group Discussion We document our experience with thrombolysis for PE with evidence of right heart strain, irrespective of the blood pressure status. Overall clinical outcomes were good, but we could not demonstrate an advantage for thrombolysis, and bleeding rates were increased with thrombolysis. While our major bleeding complication rate was similar to published data from randomised trials at 13%, 1 half of the patients experiencing bleeding in our series had a history of recent surgery so the drop in haemoglobin was at least in part explainable by perioperative blood lost. The lack of an advantage in clinical outcome in the thrombolysed group in our study should be interpreted with caution. This study was a retrospective review, with treatment being determined by the managing clinician. The thrombolysed group had a greater clot burden, all had RV strain or circulatory compromise. Indeed, the thrombolysed group had similar clinical outcomes to the nonthrombolysed group despite having more severe PE suggested that thrombolysis may have favourably affected outcomes. Persistent pulmonary hypertension and right heart failure occur in approximately 4% of patients after PE. 15 Some older, small or non-randomised trials showed a reduction of chronic pulmonary hypertension development in thrombolysed patients. 16-18 While a recent small prospective cohort showed a higher likelihood of a subgroup of haemodynamically stable patients with large PE of developing chronic symptomatic pulmonary hypertension with heparin only compared to thrombolysed patients, 19 more recent randomised controlled trials have focused on short term analysis only and longer term outcomes are lacking. In our series we did not find any evidence that thrombolysis reduced the incidence of persisting pulmonary hypertension, however our numbers are small. RV dysfunction is a well recognised marker for worse outcome in PE regardless of blood pressure.20, 21 However, echocardiography, the gold standard for right heart dysfunction, is not always readily available. A previous study showed raised RV/LV ratio on CTPA to be associated with >four-fold increase in mortality 22, 23 thus a raised RV/LV ratio identifies a higher risk group and closer observation or more aggressive therapy should be considered.24, 25 Our study confirmed good predictive value of CTPA for RV strain using the RV/LV ratio or a high Qanadli score of 226516. Therefore CTPA is a good initial test in suspected PE, as it provides important information on clot burden and right heart strain in addition to its diagnostic utility and is readily available in most hospitals. The elevation of biomarkers for myocardial strain or injury in acute PE is a reflection of RV involvement, as a result of sudden development of pulmonary hypertension.26-29 It is associated with increased mortality even in normotensive patients. 30 More recent meta-analysis suggested combined raised troponin and BNP reflected higher risk. 31 Unfortunately, our study is heavily limited by its retrospective design with no standardised management plan of all patients and the overall low event rate, we are unable to draw any meaningful conclusions with biomarkers. The question would be better answered by a prospective cohort. Conclusion We document our experience with PE over the last 6 years. Our study confirmed clot burden and RV strain on CTPA were good predictors for RV strain on echocardiography. The role of thrombolysis in normotensive patients with large clot burden remains uncertain. However, our experience shows that thrombolysis can be used, albeit with a modest risk of bleeding complication but with otherwise good clinical outcome.

Summary

Abstract

Aim

Thrombolysis for normotensive patients with large clot burden pulmonary embolism remains debatable. We aim to document our current management of pulmonary embolism, examining determinants of therapy and outcomes.

Method

A retrospective chart-based review of all patients admitted with pulmonary embolism under Cardiology service in Christchurch Hospital between 2002-2007. All related CT pulmonary angiograms were also reviewed for quantification of clot burden and evidence of right ventricular strain.

Results

120 patients were admitted during the audit period. Hypotensive patients had a significantly higher troponin level and Qanadli scores. RV/LV ratio >1 in CTPA was 80% sensitive and 57% specific in predicting RV strain on echocardiogram. Forty-six patients were thrombolysed, most with large clot burden and right ventricular strain. No treatment related death or intracranial haemorrhages occurred; however six patients required blood transfusion and six patients had persistent pulmonary hypertension at 6 months. There was a higher in-patient event rate in thrombolysed group, due to increased bleeding, compared to non-thrombolysed patients.

Conclusion

Thrombolysis was successfully performed with relatively low in-patient and 6-month event rate. Long term advantage over routine anticoagulation was not demonstrated. The role of thrombolysis in normotensive patients with large clot burden remains uncertain. CTPA markers of RV strain correlated well with echocardiography.

Author Information

Wandy Chan, Senior Cardiology Registrar; Tiffany Campbell, Radiology Fellow; Sharyn MacDonald, Radiologist; Ian Crozier, Cardiologist, Christchurch Hospital, Christchurch

Acknowledgements

Correspondence

Wandy Chan, Cardiology Department, Christchurch Public Hospital, Private Bag 4710, Christchurch 8140, New Zealand. Fax: +64 (0)3 3641415

Correspondence Email

wandyc@cdhb.govt.nz

Competing Interests

None.

- Torbicki A, Perrier A, Konstantinides S, et al. Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). European heart journal. Sep 2008;29(18):2276-2315.-- Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet. Apr 24 1999;353(9162):1386-1389.-- Kasper W, Konstantinides S, Geibel A, et al. Management strategies and determinants of outcome in acute major pulmonary embolism: results of a multicenter registry. Journal of the American College of Cardiology. Nov 1 1997;30(5):1165-1171.-- Kreit JW. The impact of right ventricular dysfunction on the prognosis and therapy of normotensive patients with pulmonary embolism. Chest. Apr 2004;125(4):1539-1545.-- Conget F, Otero R, Jimenez D, et al. Short-term clinical outcome after acute symptomatic pulmonary embolism. Thrombosis and haemostasis. Nov 2008;100(5):937-942.-- Goldhaber SZ, Haire WD, Feldstein ML, et al. Alteplase versus heparin in acute pulmonary embolism: randomised trial assessing right-ventricular function and pulmonary perfusion. Lancet. Feb 27 1993;341(8844):507-511.-- Dalla-Volta S, Palla A, Santolicandro A, et al. PAIMS 2: alteplase combined with heparin versus heparin in the treatment of acute pulmonary embolism. Plasminogen activator Italian multicenter study 2. Journal of the American College of Cardiology. Sep 1992;20(3):520-526.-- Tibbutt DA, Davies JA, Anderson JA, et al. Comparison by controlled clinical trial of streptokinase and heparin in treatment of life-threatening pulmonary embolism. British medical journal. Mar 2 1974;1(5904):343-347.-- Kearon C, Kahn SR, Agnelli G, et al. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. Jun 2008;133(6 Suppl):454S-545S.-- Tardy B, Venet C, Zeni F, et al. Short term effect of recombinant tissue plasminogen activator in patients with hemodynamically stable acute pulmonary embolism: results of a meta-analysis involving 464 patients. Thrombosis research. Dec 2009;124(6):672-677.-- Wan S, Quinlan DJ, Agnelli G, Eikelboom JW. Thrombolysis compared with heparin for the initial treatment of pulmonary embolism: a meta-analysis of the randomized controlled trials. Circulation. Aug 10 2004;110(6):744-749.-- Thabut G, Thabut D, Myers RP, et al. Thrombolytic therapy of pulmonary embolism: a meta-analysis. Journal of the American College of Cardiology. Nov 6 2002;40(9):1660-1667.-- Konstantinides S, Geibel A, Heusel G, et al. Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. The New England journal of medicine. Oct 10 2002;347(15):1143-1150.-- Qanadli SD, El Hajjam M, Vieillard-Baron A, et al. New CT index to quantify arterial obstruction in pulmonary embolism: comparison with angiographic index and echocardiography. Ajr. Jun 2001;176(6):1415-1420.-- Pengo V, Lensing AW, Prins MH, et al. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. The New England Journal of Medicine. 2004 May 27;350(22):2257-2264.-- The urokinase pulmonary embolism trial. A national cooperative study. Circulation. Apr 1973;47(2 Suppl):II1-108.-- Urokinase-streptokinase embolism trial. Phase 2 results. A cooperative study. JAMA. Sep 16 1974;229(12):1606-1613.-- Sharma GV, Folland ED, McIntyre KM, Sasahara AA. Long-term benefit of thrombolytic therapy in patients with pulmonary embolism. Vascular medicine (London, England). 2000;5(2):91-95.-- Kline JA, Steuerwald MT, Marchick MR, et al. Prospective evaluation of right ventricular function and functional status 6 months after acute submassive pulmonary embolism: frequency of persistent or subsequent elevation in estimated pulmonary artery pressure. Chest. Nov 2009;136(5):1202-1210.-- Kucher N, Rossi E, De Rosa M, Goldhaber SZ. Prognostic role of echocardiography among patients with acute pulmonary embolism and a systolic arterial pressure of 90 mm Hg or higher. Archives of internal medicine. Aug 8-22 2005;165(15):1777-1781.-- Sanchez O, Trinquart L, Colombet I, et al. Prognostic value of right ventricular dysfunction in patients with haemodynamically stable pulmonary embolism: a systematic review. European heart journal. Jun 2008;29(12):1569-1577.-- van der Meer RW, Pattynama PM, van Strijen MJ, et al. Right ventricular dysfunction and pulmonary obstruction index at helical CT: prediction of clinical outcome during 3-month follow-up in patients with acute pulmonary embolism. Radiology. Jun 2005;235(3):798-803.-- Ghuysen A, Ghaye B, Willems V, et al. Computed tomographic pulmonary angiography and prognostic significance in patients with acute pulmonary embolism. Thorax. Nov 2005;60(11):956-961.-- Quiroz R, Kucher N, Schoepf UJ, et al. Right ventricular enlargement on chest computed tomography: prognostic role in acute pulmonary embolism. Circulation. May 25 2004;109(20):2401-2404.-- Schoepf UJ, Kucher N, Kipfmueller F, et al. Right ventricular enlargement on chest computed tomography: a predictor of early death in acute pulmonary embolism. Circulation. Nov 16 2004;110(20):3276-3280.-- Kruger S, Graf J, Merx MW, et al. Brain natriuretic peptide predicts right heart failure in patients with acute pulmonary embolism. American Heart Journal. Jan 2004;147(1):60-65.-- Binder L, Pieske B, Olschewski M, et al. N-terminal pro-brain natriuretic peptide or troponin testing followed by echocardiography for risk stratification of acute pulmonary embolism. Circulation. Sep 13 2005;112(11):1573-1579.-- Becattini C, Vedovati MC, Agnelli G. Prognostic value of troponins in acute pulmonary embolism: a meta-analysis. Circulation. Jul 24 2007;116(4):427-433.-- Scridon T, Scridon C, Skali H, et al. Prognostic significance of troponin elevation and right ventricular enlargement in acute pulmonary embolism. The American journal of cardiology. Jul 15 2005;96(2):303-305.-- Kostrubiec M, Pruszczyk P, Bochowicz A, et al. Biomarker-based risk assessment model in acute pulmonary embolism. European heart journal. Oct 2005;26(20):2166-2172.-- Lega JC, Lacasse Y, Lakhal L, Provencher S. Natriuretic peptides and troponins in pulmonary embolism: a meta-analysis. Thorax. Oct-

For the PDF of this article,
contact nzmj@nzma.org.nz

View Article PDF

Pulmonary embolism (PE) is a frequent cause for hospital admission and a significant proportion of cases are first diagnosed at autopsy.1 The in-patient or 30-day mortality is variable with a stepwise increase in mortality observed subject to the degree of haemodynamic instability, with a mortality of up to 65% for patients who require cardiopulmonary resuscitation.2,3 Patients with right ventricular (RV) dysfunction have a higher mortality than those without in whom the mortality of acute PE is close to 0% with anticoagulation. 2-4 Subsequent mortality is also high, the overall mortality at 3 months was reported between 10.5-15.3%,2,5 with the majority of patients dying of recurrent PE or cancer.2 Multiple studies have demonstrated rapid resolution of vascular obstruction, reduced pulmonary hypertension and improved haemodynamics following treatment with a thrombolytic agent in acute PE.6-8 Thrombolysis has been incorporated into international guidelines for PE with haemodynamic instability with undisputable mortality benefits.1,9 However for normotensive patients with large clot burden, the role of thrombolysis remains controversial. Meta-analyses of published trials show no mortality benefit from thrombolysis in normotensive patients even in the presence of RV dysfunction.1,10-13 Despite the controversy, thrombolysis has been liberally used in patients at Christchurch Hospital in the setting of acute PE with hypotension or evidence of RV strain, as per the managing clinician. In this report we describe our experience with PE for the 6 years from January 2002 and December 2007. We aim to assess the safety, short and intermediate term outcomes with thrombolysis and to identify imaging and biochemical risk markers that can distinguish a higher risk subgroup who would benefit from thrombolysis. Method An audit of patients admitted with PE under Cardiology service between January 2002 and December 2007 was performed. Patients were identified using International Statistical Classification of Diseases and Related Health Problem, Tenth Revision, Australian Modification (ICD-10-AM) code, I26.0 or I26.9 for pulmonary embolism with or without acute cor pulmonale. This included all patients treated with thrombolysis except those in the Intensive Care Unit as per hospital protocol. A chart-based review was carried out with data collected comprising basic demographics, clinical status, investigations, treatment received and outcomes both as in-patient and at 6 months. For patients who had no further contact with the hospital system, a questionnaire was sent out to their General Practitioner. Hypotension was defined as the lowest systolic blood pressure 226490 mmHg. All computed tomography pulmonary angiograms (CTPA) were reviewed by both a radiology fellow and an experienced cardiothoracic radiologist for evidence of RV strain. RV strain was defined as RV/LV ratio on axial 4-chamber view 22651, straightening or bowing to the left of the interventricular septum (IVS) or reflux of contrast into the inferior vena cava or hepatic veins. Clot burden was quantified using the Qanadli score.14 The Qanadli score is the sum of the presence of clot to each segmental artery, 0 for no clot, 1 for partial occlusion and 2 for total occlusion. A clot proximal to the segmental artery is scored as the sum of affected segmental arteries arising distally. The maximum score is 40. A score of 226516 is regarded as severe as it indicates 226540% of pulmonary circulation is involved. Superior vena cava, azygous vein and main pulmonary artery sizes were also measured. Evidence of RV strain on echocardiogram was defined as dilated RV, RV hypokinesis, abnormal interventricular septal motion or estimated right ventricular systolic pressure 226530 mmHg using Doppler. Statistical analysis was performed with GraphPad Prism version 5. Continuous variables were expressed as mean 00b1 standard error. Two- tailed unpaired t-test for difference between two groups, Fishers exact test for contingency and Pearsons coefficient for correlation were used. A p-value of less than 0.05 was considered statistically significant. Results During the audit period 120 patients, age 22-87 years, mean 63 00b1 1.3 years, with PE were admitted under the Cardiology service at Christchurch Hospital. (Table 1) Patients had PE confirmed on CTPA or ventilation-perfusion scan (4), except one PE diagnosed at post mortem. Apart from this patient, all but one patient who had a concurrent diagnosis of type B aortic dissection, received heparin or low molecular weight heparin and 46 patients received thrombolysis. Bleeding problems occurred in 17 patients, seven (six in the thrombolysed group) of which required a blood transfusion. There were two deaths during admission, one from untreated PE diagnosed at post-mortem and one from an unrelated cause. Follow-up data to 6 months was available in 111 patients, 7 patients were lost to follow-up. There were three recurrences during the follow-up period, one resulting in death. Two more patients died during the follow-up period, one from cancer and the other from heart failure following bone marrow transplant. Table 1. Patient characteristics of all patients and thrombolysed patients Relationship of biomarkers and haemodynamicsPeak troponin levels were significantly higher in the hypotensive patients compared with the normotensive patients, (1.13 00b1 0.67 vs 0.13 00b1 0.02 03bcg/L (p=0.0035)). Eight of 22 hypotensive and 33 of 98 normotensive patients had brain natriuretic peptide (BNP) levels measured. There was no significant difference for BNP between normotensive and hypotensive groups with range between 22 to 899pmol/L and 6 to 1241pmol/L respectively. Imaging markers Right ventricular strainEchocardiogram was predominantly performed in those with or suspected of having large clot burden but was not routinely performed on all patients. Seventy nine patients had an echocardiogram during the admission. Forty out of 62 patients in the normotensive group and 14 out of 17 patients in the hypotensive group had evidence of RV strain (p= NS). Seventy-eight patients had both CTPA and echocardiography. Of 54 patients with evidence of RV strain on echocardiogram, 44 had an RV/LV ratio 22651 on CTPA (p= 0.027). The sensitivity of CTPA detecting RV strain using RV/LV ratio was 80% (95% CI 67-89.6%), specificity 57% (95% CI 35-77%), positive predictive value 82% (95% CI 69-91%) and negative predictive value 54% (95% CI 43-75%). Clot burdenClot burden in the pulmonary circulation, as assessed by Qanadli scores, was significantly higher for those in the hypotensive group, 21.3 00b12.2 vs 15.6 00b1 1.1 (p= 0.03). Qanadli score had a positive correlation with CTPA RV/LV ratio, r= 0.53 (p< 0.0001) and a weak positive correlation with pulmonary pressures, r= 0.42 (p< 0.001). It also had a weak negative correlation with the worst blood pressure during admission r= -0.19 (p=0.045) but no correlation with troponin levels. Qanadli score was associated with echocardiographic measures of RV strain; of 54 patients with evidence of RV strain on echocardiogram, 45 had a Qanadli score 226516. Patients with Qanadli score 226516 were 1.87 times more likely to have RV/LV ratio 22651, 1.95 times more likely to have straightening of the IVS, 1.73 times more likely to have reflux of contrast into IVC and/or hepatic veins and 2.76 times more likely to have evidence of RV strain on echocardiogram. (Table 2) When using CTPA RV/LV ratio 22651 as a marker of RV strain, there was a weak correlation of SVC size to RV strain but no significant correlation with azygous diameter or main pulmonary artery diameter on CT. The clinical event rate was too low to have any meaningful assessment of risk markers and their association with clinical outcomes. Table 2. RV, right ventricle. LV, left ventricle. IVS, interventricular septum. IVC, inferior vena cava. Imaging markers of RV strain Likelihood ratio if Qanadli score 226516 RV/LV ratio 2265 1 on CTPA Straightening of IVS on CTPA Reflux of contrast into IVC and/or hepatic veins on CTPA RV strain on echocardiogram 1.87 00d7 1.95 00d7 1.73 00d7 2.76 00d7 Thrombolysis group Forty-six patients, age 22-87 years, mean 60.2 00b1 2.2 years had thrombolysis with alteplase or tenecteplase using the standard protocols for thrombolysis for acute ST segment elevation myocardial infarction. Thirty four patients were normotensive, 12 hypotensive, whilst one patient had a cardiac arrest. Forty two patients had large clot burden reported on the original CTPA report (clot seen in pulmonary artery or more than three lobar arteries involved). For the rest, one patient received empiric thrombolysis after a community cardiac arrest coming off a long haul flight, with a subsequent CTPA confirming the diagnosis of PE. One patient had a V/Q scan but not a CTPA due to end-stage renal failure from polycystic kidney disease. In the remaining two patients thrombolysis was administered following clinical deterioration, though the initial CTPA did not show a large clot burden. Thirty-one patients in the thrombolysis group had an echocardiogram prior to thrombolysis, all had evidence of RV strain whilst 85% of all patients and 100% of hypotensive patients had evidence of RV strain on CTPA. There was a high concordance in the assessment of RV strain in the thrombolysed group, with 28 out of 31 patients showing RV strain on both CTPA and echocardiogram. Most thrombolysed patients had a relatively uneventful hospital stay. (Figure 1) One patient died during admission due to an unrelated cause, not from PE or thrombolysis. No intracranial haemorrhage occurred. Transfusion was required in 6 patients for bleeding following thrombolysis. Of these patients requiring transfusion, three had a history of orthopaedics surgery within the preceding 2 weeks, two of whom were thrombolysed within 72 hours of surgery, one had ongoing wound ooze. Six patients had minor bleeding not requiring transfusion. Of the surviving 45 patients followed at 6 months, three overseas patients were lost to follow-up. Two PE recurrences occurred during this period, one resulting in death, the other was due to sub-therapeutic anticoagulation. Persistent pulmonary hypertension was present in six patients, two of whom had symptomatic heart failure. (Figure 2). Figure 1. In-patient outcome for thrombolysed patients Figure 2. Six-month outcome for thrombolysed patients. HF, heart failure. PHT, pulmonary hypertension Large clot burden without thrombolysis group (Table 3) Vascular obstruction on CTPA of 226540% (Qanadli score 226516) was present in 28 patients who did not receive thrombolysis. In this group, 5 were hypotensive at some stage. None died of PE during their hospital stay, 2 patients had minor bleeds. Six-month follow-up data was available in 26 patients. No recurrences occurred during the follow-up period, whilst two patients had persistent pulmonary hypertension. Large clot burden group A total 68 patients were identified with large PEs (Qanadli score 226516), of which 40 were thrombolysed. There was no significant difference in mean troponin or BNP levels, but there was a significantly higher in-patient event rate (death one, bleed with or without transfusion 12, heart failure four) in the thrombolysed group, 17/40 thrombolysed vs 4/28 not thrombolysed (p=0.02), with the main difference being bleeding. No significant difference of events (death, recurrences, pulmonary hypertension) was observed at 6 months, 11/37 thrombolysed vs 2/26 not thrombolysed (p=NS). Table 3. Patient characteristics in the large clot burden (Qanadli score 226516) group Discussion We document our experience with thrombolysis for PE with evidence of right heart strain, irrespective of the blood pressure status. Overall clinical outcomes were good, but we could not demonstrate an advantage for thrombolysis, and bleeding rates were increased with thrombolysis. While our major bleeding complication rate was similar to published data from randomised trials at 13%, 1 half of the patients experiencing bleeding in our series had a history of recent surgery so the drop in haemoglobin was at least in part explainable by perioperative blood lost. The lack of an advantage in clinical outcome in the thrombolysed group in our study should be interpreted with caution. This study was a retrospective review, with treatment being determined by the managing clinician. The thrombolysed group had a greater clot burden, all had RV strain or circulatory compromise. Indeed, the thrombolysed group had similar clinical outcomes to the nonthrombolysed group despite having more severe PE suggested that thrombolysis may have favourably affected outcomes. Persistent pulmonary hypertension and right heart failure occur in approximately 4% of patients after PE. 15 Some older, small or non-randomised trials showed a reduction of chronic pulmonary hypertension development in thrombolysed patients. 16-18 While a recent small prospective cohort showed a higher likelihood of a subgroup of haemodynamically stable patients with large PE of developing chronic symptomatic pulmonary hypertension with heparin only compared to thrombolysed patients, 19 more recent randomised controlled trials have focused on short term analysis only and longer term outcomes are lacking. In our series we did not find any evidence that thrombolysis reduced the incidence of persisting pulmonary hypertension, however our numbers are small. RV dysfunction is a well recognised marker for worse outcome in PE regardless of blood pressure.20, 21 However, echocardiography, the gold standard for right heart dysfunction, is not always readily available. A previous study showed raised RV/LV ratio on CTPA to be associated with >four-fold increase in mortality 22, 23 thus a raised RV/LV ratio identifies a higher risk group and closer observation or more aggressive therapy should be considered.24, 25 Our study confirmed good predictive value of CTPA for RV strain using the RV/LV ratio or a high Qanadli score of 226516. Therefore CTPA is a good initial test in suspected PE, as it provides important information on clot burden and right heart strain in addition to its diagnostic utility and is readily available in most hospitals. The elevation of biomarkers for myocardial strain or injury in acute PE is a reflection of RV involvement, as a result of sudden development of pulmonary hypertension.26-29 It is associated with increased mortality even in normotensive patients. 30 More recent meta-analysis suggested combined raised troponin and BNP reflected higher risk. 31 Unfortunately, our study is heavily limited by its retrospective design with no standardised management plan of all patients and the overall low event rate, we are unable to draw any meaningful conclusions with biomarkers. The question would be better answered by a prospective cohort. Conclusion We document our experience with PE over the last 6 years. Our study confirmed clot burden and RV strain on CTPA were good predictors for RV strain on echocardiography. The role of thrombolysis in normotensive patients with large clot burden remains uncertain. However, our experience shows that thrombolysis can be used, albeit with a modest risk of bleeding complication but with otherwise good clinical outcome.

Summary

Abstract

Aim

Thrombolysis for normotensive patients with large clot burden pulmonary embolism remains debatable. We aim to document our current management of pulmonary embolism, examining determinants of therapy and outcomes.

Method

A retrospective chart-based review of all patients admitted with pulmonary embolism under Cardiology service in Christchurch Hospital between 2002-2007. All related CT pulmonary angiograms were also reviewed for quantification of clot burden and evidence of right ventricular strain.

Results

120 patients were admitted during the audit period. Hypotensive patients had a significantly higher troponin level and Qanadli scores. RV/LV ratio >1 in CTPA was 80% sensitive and 57% specific in predicting RV strain on echocardiogram. Forty-six patients were thrombolysed, most with large clot burden and right ventricular strain. No treatment related death or intracranial haemorrhages occurred; however six patients required blood transfusion and six patients had persistent pulmonary hypertension at 6 months. There was a higher in-patient event rate in thrombolysed group, due to increased bleeding, compared to non-thrombolysed patients.

Conclusion

Thrombolysis was successfully performed with relatively low in-patient and 6-month event rate. Long term advantage over routine anticoagulation was not demonstrated. The role of thrombolysis in normotensive patients with large clot burden remains uncertain. CTPA markers of RV strain correlated well with echocardiography.

Author Information

Wandy Chan, Senior Cardiology Registrar; Tiffany Campbell, Radiology Fellow; Sharyn MacDonald, Radiologist; Ian Crozier, Cardiologist, Christchurch Hospital, Christchurch

Acknowledgements

Correspondence

Wandy Chan, Cardiology Department, Christchurch Public Hospital, Private Bag 4710, Christchurch 8140, New Zealand. Fax: +64 (0)3 3641415

Correspondence Email

wandyc@cdhb.govt.nz

Competing Interests

None.

- Torbicki A, Perrier A, Konstantinides S, et al. Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). European heart journal. Sep 2008;29(18):2276-2315.-- Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet. Apr 24 1999;353(9162):1386-1389.-- Kasper W, Konstantinides S, Geibel A, et al. Management strategies and determinants of outcome in acute major pulmonary embolism: results of a multicenter registry. Journal of the American College of Cardiology. Nov 1 1997;30(5):1165-1171.-- Kreit JW. The impact of right ventricular dysfunction on the prognosis and therapy of normotensive patients with pulmonary embolism. Chest. Apr 2004;125(4):1539-1545.-- Conget F, Otero R, Jimenez D, et al. Short-term clinical outcome after acute symptomatic pulmonary embolism. Thrombosis and haemostasis. Nov 2008;100(5):937-942.-- Goldhaber SZ, Haire WD, Feldstein ML, et al. Alteplase versus heparin in acute pulmonary embolism: randomised trial assessing right-ventricular function and pulmonary perfusion. Lancet. Feb 27 1993;341(8844):507-511.-- Dalla-Volta S, Palla A, Santolicandro A, et al. PAIMS 2: alteplase combined with heparin versus heparin in the treatment of acute pulmonary embolism. Plasminogen activator Italian multicenter study 2. Journal of the American College of Cardiology. Sep 1992;20(3):520-526.-- Tibbutt DA, Davies JA, Anderson JA, et al. Comparison by controlled clinical trial of streptokinase and heparin in treatment of life-threatening pulmonary embolism. British medical journal. Mar 2 1974;1(5904):343-347.-- Kearon C, Kahn SR, Agnelli G, et al. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. Jun 2008;133(6 Suppl):454S-545S.-- Tardy B, Venet C, Zeni F, et al. Short term effect of recombinant tissue plasminogen activator in patients with hemodynamically stable acute pulmonary embolism: results of a meta-analysis involving 464 patients. Thrombosis research. Dec 2009;124(6):672-677.-- Wan S, Quinlan DJ, Agnelli G, Eikelboom JW. Thrombolysis compared with heparin for the initial treatment of pulmonary embolism: a meta-analysis of the randomized controlled trials. Circulation. Aug 10 2004;110(6):744-749.-- Thabut G, Thabut D, Myers RP, et al. Thrombolytic therapy of pulmonary embolism: a meta-analysis. Journal of the American College of Cardiology. Nov 6 2002;40(9):1660-1667.-- Konstantinides S, Geibel A, Heusel G, et al. Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. The New England journal of medicine. Oct 10 2002;347(15):1143-1150.-- Qanadli SD, El Hajjam M, Vieillard-Baron A, et al. New CT index to quantify arterial obstruction in pulmonary embolism: comparison with angiographic index and echocardiography. Ajr. Jun 2001;176(6):1415-1420.-- Pengo V, Lensing AW, Prins MH, et al. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. The New England Journal of Medicine. 2004 May 27;350(22):2257-2264.-- The urokinase pulmonary embolism trial. A national cooperative study. Circulation. Apr 1973;47(2 Suppl):II1-108.-- Urokinase-streptokinase embolism trial. Phase 2 results. A cooperative study. JAMA. Sep 16 1974;229(12):1606-1613.-- Sharma GV, Folland ED, McIntyre KM, Sasahara AA. Long-term benefit of thrombolytic therapy in patients with pulmonary embolism. Vascular medicine (London, England). 2000;5(2):91-95.-- Kline JA, Steuerwald MT, Marchick MR, et al. Prospective evaluation of right ventricular function and functional status 6 months after acute submassive pulmonary embolism: frequency of persistent or subsequent elevation in estimated pulmonary artery pressure. Chest. Nov 2009;136(5):1202-1210.-- Kucher N, Rossi E, De Rosa M, Goldhaber SZ. Prognostic role of echocardiography among patients with acute pulmonary embolism and a systolic arterial pressure of 90 mm Hg or higher. Archives of internal medicine. Aug 8-22 2005;165(15):1777-1781.-- Sanchez O, Trinquart L, Colombet I, et al. Prognostic value of right ventricular dysfunction in patients with haemodynamically stable pulmonary embolism: a systematic review. European heart journal. Jun 2008;29(12):1569-1577.-- van der Meer RW, Pattynama PM, van Strijen MJ, et al. Right ventricular dysfunction and pulmonary obstruction index at helical CT: prediction of clinical outcome during 3-month follow-up in patients with acute pulmonary embolism. Radiology. Jun 2005;235(3):798-803.-- Ghuysen A, Ghaye B, Willems V, et al. Computed tomographic pulmonary angiography and prognostic significance in patients with acute pulmonary embolism. Thorax. Nov 2005;60(11):956-961.-- Quiroz R, Kucher N, Schoepf UJ, et al. Right ventricular enlargement on chest computed tomography: prognostic role in acute pulmonary embolism. Circulation. May 25 2004;109(20):2401-2404.-- Schoepf UJ, Kucher N, Kipfmueller F, et al. Right ventricular enlargement on chest computed tomography: a predictor of early death in acute pulmonary embolism. Circulation. Nov 16 2004;110(20):3276-3280.-- Kruger S, Graf J, Merx MW, et al. Brain natriuretic peptide predicts right heart failure in patients with acute pulmonary embolism. American Heart Journal. Jan 2004;147(1):60-65.-- Binder L, Pieske B, Olschewski M, et al. N-terminal pro-brain natriuretic peptide or troponin testing followed by echocardiography for risk stratification of acute pulmonary embolism. Circulation. Sep 13 2005;112(11):1573-1579.-- Becattini C, Vedovati MC, Agnelli G. Prognostic value of troponins in acute pulmonary embolism: a meta-analysis. Circulation. Jul 24 2007;116(4):427-433.-- Scridon T, Scridon C, Skali H, et al. Prognostic significance of troponin elevation and right ventricular enlargement in acute pulmonary embolism. The American journal of cardiology. Jul 15 2005;96(2):303-305.-- Kostrubiec M, Pruszczyk P, Bochowicz A, et al. Biomarker-based risk assessment model in acute pulmonary embolism. European heart journal. Oct 2005;26(20):2166-2172.-- Lega JC, Lacasse Y, Lakhal L, Provencher S. Natriuretic peptides and troponins in pulmonary embolism: a meta-analysis. Thorax. Oct-

Contact diana@nzma.org.nz
for the PDF of this article

Subscriber Content

The full contents of this pages only available to subscribers.

LOGINSUBSCRIBE