Management Strategies and Prognosis of Pulmonary Embolism-3 Trial - MAPPET-3

Description:

MAPPET-3 was a randomized, placebo-controlled trial to compare the effects of treatment with heparin plus alteplase vs. heparin alone on the outcome of hemodynamically stable patients with acute submassive pulmonary embolism (PE) and pulmonary hypertension and/or right ventricular dysfunction.

Hypothesis:

Compared to treatment with heparin alone, treatment with alteplase plus heparin in patients with sumbassive PE would be associated with a reduced incidence of the combined endpoint of in-hospital death or clinical deterioration requiring an escalation of treatment.

Study Design

Study Design:

Patients Enrolled: 256
Mean Follow Up: in-hospital
Mean Patient Age: mean 61 years
Female: 52%

Patient Populations:

Acute PE with: echocardiographically detected right ventricular dysfunction; echocardiographically detected pulmonary-artery hypertension followed by confirmation of pulmonary embolism; a diagnosis of precapillary pulmonary hypertension based on right heart catheterization followed by confirmation of pulmonary embolism; or new electrocardiographic signs of right ventricular strain followed by confirmation of pulmonary embolism.

Exclusions:

Age ≥ 80; hemodynamic instability with or without signs of cardiogenic shock; onset of symptoms more than 96 hours before diagnosis; thrombolytic treatment, major surgery, or biopsy within the preceding 7 days; major trauma within the preceding 10 days; stroke, transient ischemic attack, craniocerebral trauma, or neurologic surgery within the preceding 6 months; gastrointestinal bleeding within the preceding 3 months; uncontrolled hypertension; known bleeding disorder; known inability to tolerate alteplase; known diabetic retinopathy; current therapy with an oral anticoagulant; current pregnancy or lactation; a life expectancy of less than 6 months because of underlying disease; planned use of thrombolytic agents for extensive deep-vein thrombosis.

Primary Endpoints:

In-hospital death or clinical deterioration that required an escalation of treatment. Escalation of treatment was defined as the use of at least one of the following: infusion of a catecholamine because of persistent arterial hypotension or shock (except for dopamine infused at a rate no more than 5 µg per kilogram of body weight per minute); secondary, or "rescue," thrombolysis (for one of the following indications: worsening clinical symptoms, particularly dyspnea, or worsening respiratory failure due to pulmonary embolism; arterial hypotension or shock; and persistent or worsening pulmonary hypertension or right ventricular dysfunction detected by echocardiography or right heart catheterization); endotracheal intubation; cardiopulmonary resuscitation; and emergency surgical embolectomy or thrombus fragmentation by catheter.

Secondary Endpoints:

Recurrent pulmonary embolism, major bleeding, and ischemic stroke.

Drug/Procedures Used:

All patients received an intravenous bolus of 5000 U of unfractionated heparin. Patients then either received 100 mg of alteplase (10-mg bolus, followed by a 90-mg intravenous infusion over a period of two hours) or matching placebo.

Concomitant Medications:

Intravenous infusion of unfractionated heparin, started at a rate of 1000 U per hour, and subsequently adjusted to maintain the aPTT at 2.0-2.5 times the upper limit of normal. Overlapping oral anticoagulant therapy was started on day 3 after randomization, with a goal INR of 2.5 to 3.5.

Principal Findings:

256 patients were randomized, and the two study arms were well-matched. The frequency of right ventricular dysfunction was 31% in both arms, and the pulmonary arterial pressures were similar.

Overall, the incidence of the primary end point (death or escalation of treatment) was significantly greater in the heparin alone group than in the alteplase/heparin group (24.6% vs. 11.0%, p=0.006). Although the rate of in-hospital death was similar in both study arms, the rate of escalation of treatment because of clinical deterioration was greater in the heparin alone group than in the alteplase/heparin group (24.6% vs. 10.2%, p=0.004). This was primarily due to an increased frequency of secondary (rescue) thrombolysis performed in the heparin alone group compared to the alteplase/heparin group (23.2% vs. 7.6%, p=0.001). Secondary thrombolysis was performed more frequently in the heparin alone group due to a greater incidence of cardiogenic shock, arterial hypotension requiring catecholamine infusion, and worsening symptoms/respiratory failure.

Bleeding complications were generally infrequent, and occurred with a similar frequency in both groups (3.6% in heparin alone group vs. 0.8% in alteplase/heparin group, p=NS).

Interpretation:

Among hemodynamically stable patients with acute submassive PE and pulmonary hypertension and/or right ventricular dysfunction, treatment with alteplase/heparin was associated with a reduction in the combined primary endpoint of death or escalation of therapy when compared to heparin alone. The results of the trial were almost entirely driven by a reduction in escalation of treatment (primarily a reduction in secondary or rescue thrombolysis), with no difference in mortality or other endpoints.

Although the strengths of the study are its size and the randomization of treatment assignments, the lack of differences in “harder” clinical endpoints makes it difficult to apply these results into daily clinical practice. Prior studies have demonstrated the efficacy of thrombolysis in treating massive PE or in treating patients with PE and right ventricular dysfunction. Whether these findings can be extended to all patients with sumbassive PE or to those without right ventricular dysfunction remains to be determined.

References:

Konstantinides S, Geibel A, Heusel G, et al. Heparin plus Alteplase Compared with Heparin Alone in Patients with Submassive Pulmonary Embolism. N Engl J Med 2002;347:1143-1150.

Clinical Topics: Anticoagulation Management, Dyslipidemia, Heart Failure and Cardiomyopathies, Pulmonary Hypertension and Venous Thromboembolism, Vascular Medicine, Lipid Metabolism, Acute Heart Failure, Pulmonary Hypertension

Keywords: Thrombolytic Therapy, Arterial Pressure, Pulmonary Embolism, Cardiac Catheterization, Catecholamines, Heparin, Hypotension, Respiratory Insufficiency, Fibrinolytic Agents, Ventricular Dysfunction, Right, Shock, Cardiogenic, Hypertension, Pulmonary, Infusions, Intravenous, Tissue Plasminogen Activator


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