A Personal Experience in Developing A Risk Prediction Algorithm

Selection of Patients for Systemic Thrombolysis in Pulmonary Embolism (PE)

Selecting the correct patient for systemic thrombolysis necessitates a thorough assessment of the patient’s preexisting comorbidities, mode of presentation and focused clinical examination to assess the immediate risk of hemodynamic collapse, the risk of long term complications, and the risk of major bleeding associated with the thrombolytic agent. As described above, high-risk PE patients warrant strong consideration of aggressive treatment options, including systemic thrombolysis with a high incidence of adverse outcomes if not instituted expediently. In patients who present with acute high-risk PE, the risk of mortality is high which makes the decision for systemic thrombolysis relatively easier as compared to the people who are hemodynamically stable. The case fatality of these hemodynamically unstable patients ranges from 35% to 58%. Therefore, benefits clearly outweigh the risk of adverse outcomes in the grand majority of high-risk PE patients who are not experiencing severe active bleeding.

Clinical Assessment:

Ideally, a prognostic model should be able to precisely identify the risk of mortality and recurrent PE in patients so that escalation of treatment can be performed when necessary. Also useful would be a risk model that predicted risks of various therapies beyond anticoagulation. Various risk predicting tools have been described in the literature with the Pulmonary Embolism Severity Index (PESI) (Table 1) being the best validated to determine short term mortality (30-day) in patients with PE. This prognostic model classifies patients from risk Class I (very low risk) to Class V (very high risk) based on demographics (age and sex), comorbidities (history of cancer, heart failure, chronic lung disease), and clinical findings (mentation, oxygenation, blood pressure, pulse and respiratory rate). Mortality risk ranged from 1% in Class I patients to 24.5% in Class V patients. With most patients falling in Class II and Class III, the negative predictive value reaches above 90% in low risk patients (Class I-III). Modified PESI was also introduced which is a simpler version of above described PESI with similar predictive precision but simpler to use. It includes age, history of heart failure or cancer and blood pressure, pulse rate and oxygen saturation.Both prognostic models can be used to risk stratify patients who can be eligible for thrombolytic therapy, but these models failed to predict the risk of adverse outcomes in these patients. In fact, there is no well-validated prediction model to assess the risk of bleeding in patients receiving thrombolysis for PE. Therefore, absolute and relative contraindications for thrombolytic therapy along with clinical judgment are the only tools available to risk stratify for bleeding.


Pulmonary Embolism severity Index (PESI) Simplified Pulmonary Embolism Severity Index (sPESI)
Demographics Demographics
Age >80 years Age >80 years
Male Sex
Comorbidities Comorbidities
History of Heart Failure History of cancer
History of cancer History of chronic lung disease
History of chronic lung disease
Clinical findings Clinical findings
Tachycardia>110 beats/min Heart Rate> 110/min
Systolic blood pressure <100 mm Hg Systolic blood pressure <100 mm Hg
Respiratory Rate >30/min Arterial oxygenation saturation <90% (with or without supplemental oxygenation)
Temperature <36 C
Altered mental status (lethargy, stupor, Coma)
Arterial oxygen saturation <90% (with or without supplemental oxygenation)

Table 1: Original and simplified pulmonary embolism severity index (PESI) (prognostic model to predict 30-day outcomes in patients with acute pulmonary embolism)


Biomarkers and Imaging assessment:

Rise in cardiac biomarkers, including troponin and brain-type natriuretic peptide (BNP) may represent right heart dysfunction and have been associated with an increased risk of PE related deaths. Chest CT scan is the gold standard imaging modality for patients who come to the ED with suspicion of PE. Easy-to-measure dimensions can be prognostically important in selecting patients who are at elevated risk of early deterioration.

Bedside transthoracic echocardiography can be utilized to detect RV dysfunction in the setting of acute PE. It can detect a  wide range of imaging indicators form very nonspecific right ventricular dilatation and hypokinesis to the very specific McConnell’s sign, in which the right ventricle has a characteristic appearance of significant enlargement with free wall dysfunction and relative apical sparing. Echocardiography should be performed to further risk stratify patients with clinical evidence of RV failure, elevated cardiac enzymes or in clinical decompensation. All these modalities can be helpful in not only classifying these patients as intermediate or high risk patients but also to segregate patients with high likelihood of early deterioration so that systemic thrombolysis can be utilized.

Summarizing the patient selection criteria for systemic thrombolysis, it is clear that the clinical judgment to utilize a thrombolytic agent in addition to anticoagulation in a patient with acute PE necessitates an individualized assessment of the benefits  of improving morbidity and mortality versus risk of major bleeding.


Absolute Contraindications Relative contraindications
§  Prior intracranial hemorrhage §  History of chronic severe uncontrolled hypertension
§  Known structural cerebral lesion §  Severe uncontrolled hypertension (systolic >180 mmHg or diastolic >110mmHg
§  Known malignant intracranial neoplasm §  History of ischemic CVA >3 months
§  Ischemic stroke within 3 months §  Trauma or prolonged CPR >10mins
§  Suspected aortic dissection §  Major surgery within 3 weeks
§  Active bleeding (excluding menses) §  Recent internal bleed (2-4 weeks)
§  Significant closed-head or face trauma within 3 months §  Pregnancy, active peptic ulcer, pericarditis, age>75years, diabetic retinopathy, recent invasive procedure, current anticoagulant use

Up to two third of acute PE patients do not receive thrombolytic therapy due to contraindications.

Table 2: Contraindications to systemic thrombolysis in acute pulmonary embolism patients


Often patients with acute pulmonary embolism (PE) do not receive thrombolytic therapy even if they could potentially benefit from such, mainly due to concerns for bleeding, especially intracranial hemorrhage (ICH).There are no known risk predictor algorithm(s) for assessing ICH risk in PE patients. A simple, novel risk score was developed to predict ICH in patients with PE treated with thrombolytics – the risk predictors including peripheral vascular disease (P), age>65 (Elderly-E), prior stroke (CVA-C) and prior heart attack (H)-components of the PE-CH score. The strongest risk predictor was a history of prior stroke, including both ischemic and hemorrhagic.

This is the first risk assessment algorithm to look at ICH risk in PE patients-future research should be directed towards refining this initial risk score by incorporating laboratory and radiographic parameters for optimal risk prediction. For patients, and healthcare providers alike, the risk score provides an easy opportunity to evaluate the risk of ICH for patients with acute PE being considered for thrombolytics. The PE-CH score provides an initial risk prediction model for ICH risk in patients with PE receiving thrombolytics. In patients with more than one risk predictor, especially those with a prior history of stroke, great caution must be exercised prior to consideration of thrombolytic use.



Thromb Haemost 2017; 117(02): 246-251
DOI: 10.1160/TH16-07-0588



News from the International Stroke Conference: Minimally Invasive Surgery for ICH

Intracerebral hemorrhage (ICH) accounts for 10-15% of all strokes and is associated with a high early mortality and poor long term functional outcomes. It is the only subtype of stroke which still does not have a proven and effective treatment available. Clinical trials investigating craniotomy and surgical evacuation of the hematoma have not shown improvement in outcomes1,2. Current in-hospital treatment of ICH has mainly involved medical stabilization and management of complications. More recently, there has been an increased interest in minimally invasive surgical methods for hematoma removal as a treatment strategy for intracerebral hemorrhage3.

Results of the recently concluded MISTIE III trial were presented at the International Stroke Conference in Honolulu earlier this week. This was an open label phase 3 trial which evaluated if minimally invasive catheter evacuation followed by thrombolysis can improve functional outcomes in ICH. The trial enrolled 499 adult patients with spontaneous/non traumatic supratentorial intracerebral hemorrhage measuring at least 30 ml. The patients were randomized 1:1 into the MISTIE and standard medical care groups.  Patients with a vascular etiology, such as an AVM or with an infratentorial hemorrhage were excluded from the study. The MISTIE treatment involved image guided catheter evacuation of the hemorrhage utilizing local thrombolysis with 1 mg alteplase doses given every 8 hours, up to a total of 9 doses.

Primary outcome was defined as a good functional outcome measured by modified Rankin Scale score of 0-3 at 1 year. 45% patients in the MISTIE group achieved the target primary outcome as compared to 41% in the medical care group. The 30 day mortality rates were 9% in the MISTIE group and 15% in the standard medical group. These results were not statistically significant to indicate a benefit of the minimally invasive surgical treatment. There was no significant difference in the rates of symptomatic bleeding and brain bacterial infections between the two treatment arms. Removal of the hematoma volume was associated with a significant increase in the probability of good outcomes. Patients who achieved final hematoma volume of less than 15 ml were more likely to have a good functional outcome in the MISTIE group:  53.4% vs. 41.9%, with p =0.03.

Even though the results were neutral without a signal towards overall benefit, this study does show that the minimally invasive surgery can be safely performed without an increase in the rates of death or other serious adverse outcomes. This is a promising result and should encourage further studies evaluating minimally invasive surgical treatments for ICH. Three ongoing trials are evaluating minimally invasive surgical treatments for ICH: ENRICH, INVEST and MIND (www.clinicaltrials.gov). With improved procedural protocols in the future, lowered hematoma volumes could be obtained more consistently, which would lead to better functional outcomes for this devastating neurological condition.


  1. Mendelow AD Gregson BA Fernandes HM et al.Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the International Surgical Trial in Intracerebral Haemorrhage (STICH): a randomised trial. Lancet. 2005; 365: 387-397
  2. Mendelow AD Gregson BA Rowan EN Murray GD Gholkar A Mitchell PM. Early surgery versus initial conservative treatment in patients with spontaneous supratentorial lobar intracerebral haematomas (STICH II): a randomised trial. Lancet. 2013; 382: 397-408
  3. Hanley DF Lane K McBee N et al. Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial. Lancet. 2017; 389: 603-611