Gregory Piazza

A Prospective, Single-Arm, Multicenter Trial of Ultrasound-Facilitated, Catheter-Directed, Low-Dose Fibrinolysis for Acute Massive and Submassive Pulmonary Embolism : The SEATTLE II Study

OBJECTIVES This study conducted a prospective, single-arm, multicenter trial to evaluate the safety and efficacy of ultrasound-facilitated, catheter-directed, low-dose fibrinolysis, using the EkoSonic Endovascular System (EKOS, Bothell, Washington). BACKGROUND Systemic fibrinolysis for acute pulmonary embolism (PE) reduces cardiovascular collapse but causes hemorrhagic stroke at a rate exceeding 2%. METHODS Eligible patients had a proximal PE and a right ventricular (RV)-to-left ventricular (LV) diameter ratio ≥0.9 on chest computed tomography (CT). We included 150 patients with acute massive (n = 31) or submassive (n = 119) PE. We used 24 mg of tissue-plasminogen activator (t-PA) administered either as 1 mg/h for 24 h with a unilateral catheter or 1 mg/h/catheter for 12 h with bilateral catheters. The primary safety outcome was major bleeding within 72 h of procedure initiation. The primary efficacy outcome was the change in the chest CT-measured RV/LV diameter ratio within 48 h of procedure initiation. RESULTS Mean RV/LV diameter ratio decreased from baseline to 48 h post-procedure (1.55 vs. 1.13; mean difference, -0.42; p < 0.0001). Mean pulmonary artery systolic pressure (51.4 mm Hg vs. 36.9 mm Hg; p < 0.0001) and modified Miller Index score (22.5 vs. 15.8; p < 0.0001) also decreased post-procedure. One GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries)-defined severe bleed (groin hematoma with transient hypotension) and 16 GUSTO-defined moderate bleeding events occurred in 15 patients (10%). No patient experienced intracranial hemorrhage. CONCLUSIONS Ultrasound-facilitated, catheter-directed, low-dose fibrinolysis decreased RV dilation, reduced pulmonary hypertension, decreased anatomic thrombus burden, and minimized intracranial hemorrhage in patients with acute massive and submassive PE. (A Prospective, Single-arm, Multi-center Trial of EkoSonic® Endovascular System and Activase for Treatment of Acute Pulmonary Embolism (PE) [SEATTLE II]; NCT01513759).

Chronic Thromboembolic Pulmonary Hypertension

Currently, no pharmacologic regimen helps prevent chronic thromboembolic pulmonary hypertension, except anticoagulation with or without fibrinolysis. When administered in hemodynamically stable patients with right ventricular dysfunc- tion due to acute pulmonary embolism (submassive pulmonary embolism), fibrino- lytic therapy has been shown to reduce the frequency of chronic thromboembolic pulmonary hypertension. 11 Such therapy, which is most effective if administered within 2 weeks after acute pulmonary embolism is detected, is considered a life- saving intervention in patients with massive pulmonary embolism but remains

Acute Pulmonary Embolism: Part I: Epidemiology and Diagnosis

Case 1 : A 54-year-old previously healthy woman presented to the emergency department with a history of several days of progressive dyspnea. She was taking combined estrogen-progestin therapy for symptoms of menopause. On the basis of elements of her history and physical examination, she was considered to have a moderate clinical likelihood of pulmonary embolism (PE). Her D-dimer level was elevated, and a chest computed tomography (CT) scan with contrast demonstrated a right main pulmonary artery embolus. What is the strongest clinical clue suggesting PE? Case 2 : A 71-year-old man receiving hormonal therapy for prostate cancer presented to the emergency department with acute-onset chest discomfort, dyspnea, and lower extremity edema. Laboratory studies revealed normal cardiac biomarkers. The only electrocardiographic abnormality was sinus tachycardia; the chest x-ray was normal. Chest CT with contrast revealed multiple bilateral pulmonary emboli. Lower extremity venous ultrasonography showed thrombus in the left femoral vein. Should a D-dimer blood test have been ordered before the chest CT? The incidence of venous thromboembolism (VTE), which includes PE and deep venous thrombosis (DVT), has remained relatively constant, with age- and sex-adjusted rates of 117 cases per 100 000 person-years.1 VTE incidence rises sharply after age 60 in both men and women, with PE accounting for the majority of the increase.2 The mortality rate associated with PE is underappreciated; it exceeds 15% in the first 3 months after diagnosis.3 In nearly 25% of patients with PE, the initial clinical manifestation is sudden death.1 Risk factors for VTE include various inherited disorders, as well as the acquired conditions of endothelial injury, stasis, and hypercoagulability (Table). The majority of patients present with a combination of risk factors. View this table: Major Risk Factors for Venous Thromboembolism ### Inherited Conditions Inherited thrombophilias are often suspected in patients with VTE at a young age, multiple …

Acute Pulmonary Embolism Part II: Treatment and Prophylaxis

Case presentation : A 66-year-old man with a history of deep venous thrombosis (DVT) presented with acute dyspnea. He was normotensive, with a resting tachycardia of 110 beats per minute and an oxygen saturation of 76% on room air. The only electrocardiographic abnormality was sinus tachycardia. His brain-type natriuretic peptide (BNP) and cardiac troponin levels were elevated. Chest computed tomography (CT) with contrast demonstrated a large saddle pulmonary embolus and increased diameter of the right ventricle (RV) compared with the left ventricle (LV). The patient received intravenous bolus followed by continuous infusion unfractionated heparin. Within several hours, the patient became progressively more hypotensive and hypoxemic. Bedside transthoracic echocardiography (TTE) showed RV dilatation and hypokinesis. He then received intravenous fibrinolysis, with rapid improvement in hemodynamics and oxygenation. What were the clues that he was likely to suffer from progressive hypotension and hypoxemia? Pulmonary embolism (PE) represents a spectrum of syndromes ranging from small peripheral emboli causing pleuritic pain to massive PE resulting in cardiogenic shock or cardiac arrest. Most patients with PE present with normal blood pressure. However, some may rapidly deteriorate and manifest systemic hypotension, cardiogenic shock, and sudden death despite therapeutic levels of anticoagulation. Risk stratification to identify such patients has emerged as a critical component of care. The history and physical examination provide the starting point for risk stratification. The International Cooperative Pulmonary Embolism Registry (ICOPER) identified age >70 years, cancer, congestive heart failure, chronic obstructive pulmonary disease, and systolic blood pressure less than 90 mm Hg as significant predictors of increased mortality.1 Elevated cardiac biomarkers correlate with the presence of RV dysfunction, a powerful independent predictor of early mortality.2 Whereas cardiac troponins are released as a result of microinfarction due to RV pressure overload, BNP is secreted from cardiac myocytes in response to RV shear …

Physician Alerts to Prevent Symptomatic Venous Thromboembolism in Hospitalized Patients

Background— Venous thromboembolism (VTE) prophylaxis remains underused among hospitalized patients. We designed and carried out a large, multicenter, randomized controlled trial to test the hypothesis that an alert from a hospital staff member to the attending physician will reduce the rate of symptomatic VTE among high-risk patients not receiving prophylaxis. Methods and Results— We enrolled patients using a validated point score system to detect hospitalized patients at high risk for symptomatic VTE who were not receiving prophylaxis. We randomized 2493 patients (82% on Medical Services) from 25 study sites to the intervention group (n=1238), in which the responsible physician was alerted by another hospital staff member, or the control group (n=1255), in which no alert was issued. The primary end point was symptomatic, objectively confirmed VTE within 90 days. Patients whose physicians were alerted were more than twice as likely to receive VTE prophylaxis as control subjects (46.0% versus 20.6%; P<0.0001). The symptomatic VTE rate was lower in the intervention group (2.7% versus 3.4%; hazard ratio, 0.79; 95% CI, 0.50 to 1.25), but the difference did not achieve statistical significance. The rate of major bleeding at 30 days in the alert group was similar to that in the control group (2.1% versus 2.3%; P=0.68). Conclusions— A strategy of direct notification of the physician by a staff member increases prophylaxis use and leads to a reduction in the rate of symptomatic VTE in hospitalized patients. However, VTE prophylaxis continues to be underused even after physician notification, especially among Medical Service patients.

Management of Submassive Pulmonary Embolism

Case presentation : A 58-year-old woman with a history of cigarette smoking, chronic obstructive pulmonary disease, and recent intensive care unit admission for pneumonia presented with sudden onset of right-sided chest discomfort and dyspnea. On physical examination, she was tachycardic (heart rate 110 beats per minute), normotensive (blood pressure of 128/72 mm Hg), tachypneic (24 breaths per minute), and hypoxemic (oxygen saturation 88% on room air). She had jugular venous distension to the angle of her mandible, a grade 2/6 holosystolic murmur that increased to grade 3/6 with inspiration at the left lower sternal border, lung fields clear to auscultation bilaterally, and mild symmetrical lower-extremity edema. The ECG was notable for sinus tachycardia and T-wave inversions across the anterior precordium. Laboratory evaluation was remarkable for a D-dimer level of 1104 ng/mL (normal <500 ng/mL) and a cardiac troponin I level of 1.4 ng/mL (normal <0.1 ng/mL). Contrast-enhanced chest computed tomography demonstrated thrombus that filled the right main pulmonary artery and moderate right ventricular (RV) enlargement (RV-to-left ventricular [LV] dimension ratio=1.2). Bedside transthoracic echocardiography documented moderately severe RV hypokinesis, moderate tricuspid regurgitation, and an estimated pulmonary artery systolic pressure of 55 mm Hg. These clinical, laboratory, and imaging findings established the diagnosis of submassive pulmonary embolism (PE). The principal management question was whether to treat with anticoagulation alone (a “watch and wait” strategy) or to administer fibrinolysis immediately. Venous thromboembolism is the third most common cardiovascular disorder after myocardial infarction and stroke.1 The mortality rate for acute PE exceeds 15% in the first 3 months after diagnosis and surpasses that of myocardial infarction.2 Death most commonly results from progressive RV failure that culminates in cardiovascular collapse.3 Survivors of acute PE remain at risk for chronic thromboembolic pulmonary hypertension.4 Acute PE represents a spectrum of clinical syndromes with …

Neutrophil extracellular traps form predominantly during the organizing stage of human venous thromboembolism development.

A growing health problem, venous thromboembolism (VTE), including pulmonary embolism (PE) and deep vein thrombosis (DVT), requires refined diagnostic and therapeutic approaches. Neutrophils contribute to thrombus initiation and development in experimental DVT. Recent animal studies recognized neutrophil extracellular traps (NETs) as an important scaffold supporting thrombus stability. However, the hypothesis that human venous thrombi involve NETs has not undergone rigorous testing.

Venous Thromboembolism and Atherothrombosis An Integrated Approach

Case presentation 1: A 45-year-old man with a history of obesity, hypertension, dyslipidemia, deep vein thrombosis (DVT) complicated by pulmonary embolism (PE) 12 years earlier, and non–ST-elevation myocardial infarction treated with angioplasty and stenting of the left anterior descending coronary artery 4 years earlier presented to the emergency department with sudden onset of substernal chest pain. His ECG showed anterolateral ST-segment elevation, and emergent coronary angiography demonstrated in-stent thrombosis of his left anterior descending coronary artery (Figure 1A). Figure 1. Coronary angiography of the left coronary system, anterior-posterior cranial view. Total occlusion of the left anterior descending artery (arrow) was observed at the origin of the previously stented midsegment and was consistent with in-stent thrombosis (A). The occlusion was treated successfully with angioplasty and stenting (B). Case Presentation 2 : A 39-year-old man with a history of cigarette smoking, hypertension, dyslipidemia, and non–ST-elevation myocardial infarction 3 years earlier presented with progressive dyspnea and several hours of chest pressure. His ECG was unchanged, but his cardiac troponin I was elevated at 1.33 ng/mL (normal <0.1 ng/mL). Contrast-enhanced chest computed tomography demonstrated a large saddle PE (Figure 2). Figure 2. Contrast-enhanced chest computed tomography demonstrating a large saddle PE straddling the bifurcation of the main pulmonary artery and extending into the right main pulmonary artery and lobar branches (A). Extensive thrombus (arrows) occluding the left main pulmonary artery and distal right pulmonary artery branches was observed (B). Venous thromboembolism (VTE), including DVT and PE, is the third most common cardiovascular disorder after coronary artery disease and stroke. Furthermore, patients with acute coronary syndromes or stroke have an increased risk of VTE as a complication of hospitalization.1 Many risk factors for VTE, such as obesity, hypertension, dyslipidemia, diabetes, and smoking, overlap with those for atherothrombosis. Data from registry analyses and clinical …

Fibrinolysis for acute pulmonary embolism.

Acute pulmonary embolism (PE) presents as a constellation of clinical syndromes with a variety of prognostic implications. Patients with acute PE who have normal systemic arterial blood pressure and no evidence of right ventricular (RV) dysfunction have an excellent prognosis with therapeutic anticoagulation alone. Normotensive acute PE patients with evidence of RV dysfunction are categorized as having submassive PE and comprise a population at intermediate risk for adverse events and early mortality. Patients with massive PE present with syncope, systemic arterial hypotension, cardiogenic shock, or cardiac arrest and have the highest risk for short-term mortality and adverse events. The majority of deaths from acute PE are due to RV pressure overload and subsequent RV failure. The goal of fibrinolysis in acute PE is to rapidly reduce RV afterload and avert impending hemodynamic collapse and death. Although generally considered to be a life-saving intervention in massive PE, fibrinolysis remains controversial for submassive PE. Successful administration of fibrinolytic therapy requires weighing benefit versus risk. Major bleeding, in particular intracranial hemorrhage, is the most feared complication of fibrinolysis. Alternatives to fibrinolysis for acute PE, including surgical embolectomy, catheter-assisted embolectomy, and inferior vena cava (IVC) filter insertion, should be considered when contraindications exist or when patients have failed to respond to an initial trial of fibrinolytic therapy. Patients with massive and submassive PE may be best served by rapid triage to specialized centers with experience in the administration of fibrinolytic therapy and the capacity to offer alternative advanced therapies such as surgical and catheter-assisted embolectomy.

Long-term complications of medical patients with hospitalacquired venous thromboembolism

Long-term complications from hospital-acquired acute venous thromboembolism (VTE) include recurrent VTE, postthrombotic syndrome (PTS), and chronic thromboembolic pulmonary hypertension (CTEPH). We used a probability model to estimate the number of these events among hospitalised medical patients in the 2003 United States Healthcare Cost and Utilization Project (HCUP) Nationwide Inpatient Sample database. Of 8,077,919 hospitalised medical patients at risk for VTE, we calculate that 122,235 were stricken with deep vein thrombosis (DVT) and 32,654 with pulmonary embolism (PE). These events generated 49,843 VTE-related deaths, 28,052 recurrent DVTs, 6,680 recurrent PEs, 140,156 cases of PTS, and 5,288 cases of CTEPH over the ensuing 5 years, for a total of 180,176 patients afflicted with long-term complications of VTE. In our model, rates of pharmacological thromboprophylaxis prescribing varied across populations, ranging from 15.3% to 49.2%. When we modeled universal utilisation of pharmacological prophylaxis, the number of VTE-related deaths decreased from 49,843 to 20,739, recurrent DVT was reduced from 28,052 to 13,384, and recurrent PE was reduced from 6,680 to 3,187 events. Incident cases of PTS decreased from 140,156 to 54,651, and CTEPH decreased from 5,288 to 1,115 cases. The number of hospitalised medical patients with long-term VTE complications was reduced by 60% to 72,337. In conclusion, hospitalised medical patients are particularly vulnerable to the development of recurrent VTE, PTS, and CTEPH. These VTE complications would be reduced by more than half with universal thromboprophylaxis. Further efforts should focus on improving VTE prophylaxis utilisation.