Episode 12- “Clot Busters”: Part 1: Submassive and massive pulmonary embolism

In part 1 of 2 of our “clot-busters” Mini-Grand Rounds series, we start by looking at thrombolytic agents used in the setting of pulmonary embolism (PE). I will not be discussing catheter-direct thrombolysis or embolectomy. Next week, we will wrap it up by discussing the use of these agents in the setting of cardiac arrest.

To begin, we first have to define some terms. Per the American Heart Association, a “submassive PE” is defined as an acute PE without systemic hypotension, but with either right ventricular dysfunction or myocardial necrosis. “Massive PE” is defined as sustained hypotension (SBP < 90 mmHg for at least 15 minutes or requiring inotropic support), pulselessness, or persistent bradycardia (HR < 40 with signs and symptoms of shock).

Let’s also quickly review what “clot-busters” or thrombolytics are and how they work. Since one of the most commonly used agents is t-PA or alteplase, we will focus most of this episode on alteplase. Also to be clear, the terms “thrombolytic” and “fibrinolytic” can be used interchangeably. Alteplase works by binding to fibrin within a thrombus, then converting entrapped plasminogen to plasmin. Plasmin is the active form of plasminogen which works to dissolve the fibrin threads within the thrombus. The cool thing about alteplase is that it produces limited activation of plasminogen in the absence of fibrin—which is good because it won’t activate all of the plasminogen circulating in our bodies, which means we don’t bleed out. First generation thrombolytics such as streptokinase and urokinase are less specific for clot-bound plasminogen, which can cause significant thrombolysis, making them less favorable. As it happens, they are also not available in the US. Alteplase is a second-generation thrombolytic which is as I mentioned more specific to clot-targeted plasmin production, reducing the risk of major bleeding. 3rd- generation thrombolytics such as reteplase and tenecteplase also exist. These agents are only FDA approved in the setting of STEMI, but tenecteplase in particular has also been used in the setting of PE. These agents have the advantage of longer half-lives meaning they can be given as quick bolus injections.

Per the package insert, alteplase is FDA approved for MI (with a max dose of 100 mg), acute ischemic stroke (with a max dose of 90 mg given over 60 minutes) as well as acute massive PE (at a dose of 100 mg IV over 2 hours). Although several trials support the 100 mg over 2 hour regimen, the optimal regimen has not been well established, with other studies showing lower doses given as a bolus having similar efficacy and less bleeding rates. We’ll discuss this dosing controversy later in the episode.

In the setting of massive PE, we know that the benefits of thrombolytics generally outweigh the risks, and giving thrombolytics to these patients is recommended in multiple guidelines. In this setting, thrombolytics improve pulmonary artery pressure, oxygenation, pulmonary perfusion, prevent recurrent PE, and reduce mortality. But what about patients with submassive PE?

Let’s review a few studies that address this patient population. In the 2002 “MAPPET-3” trial in 118 patients with submassive PE, alteplase given at the FDA-approved dose of 100 mg over 2 hours (10 mg bolus then 90 mg over 2 hours) significantly reduced the composite primary endpoint of mortality or clinical deterioration when compared to patients given placebo. The rates were 11% vs 25%, with similar incidence of bleeding. However, there was no absolute difference in mortality alone.

Then in 2012, investigators of the “MOPETT” trial used “safe-dose” alteplase in 62 patients with submassive PE. This dose was a 10 mg bolus, then 40 mg over 2 hours for patients weighing >/= 50 kg, and a weight based dose of 0.5 mg/kg (as a 10 mg bolus and the remainder given over 2 hours) in patients weighing < 50 kg. Now this is very interesting. The authors reasoned that since all alteplase molecules will eventually converge in the lungs, you could give a lower dose. This is not the case in the setting of MI or stroke, where the arteries in those areas only receive up to 15% of total cardiac output and require a higher dose to achieve thrombolysis at their site of action. What they found was a reduction of the composite outcome of pulmonary hypertension and recurrent PE in the alteplase group compared to the placebo group (rates were 16% vs 63%), with no bleeding in either group. There once again was no absolute difference in mortality between the groups.

A third study, the “PEITHO” trial from 2014, actually used tenecteplase in 506 patients and found that death or hemodynamic decompensation was significantly reduced (2.6% vs 5.6%), but that came at a much higher rate of extracranial and intracranial bleeding. And echoing the two previous studies, there was no difference in mortality itself. I should note that in all three of the studies mentioned, the patients in both the thrombolytic group and placebo group received anticoagulation as a standard of care.

So, what do we make of this? Some studies show a benefit of thrombolytics vs anticoagulation alone with no risk of bleeding, others show benefit but at the risk of higher bleeding rates. It’s also interesting and confusing to note that these studies used different agents and different doses of alteplase.

What do the guidelines say? Per the 2016 CHEST guidelines, systemic thrombolytics are recommended in the setting of massive PE. This we know. However, in patients with PE not associated with hypotension, AKA submassive PE, they recommend against routinely giving thrombolytics. They do add a caveat that in patients with PE who deteriorate after starting anticoagulation but who have not yet developed hypotension and also have a low bleeding risk, they suggest that it is reasonable to give thrombolytics. These are reasonable recommendations as based on individual studies and systematic reviews, thrombolytics in the setting of submassive PE are associated with reductions in combined endpoints of mortality and hemodynamic decompensation, but no overall decrease in mortality. These agents can also increase the risk of bleeding. So overall, thrombolytics can be considered in the setting of submassive PE in a case-by-case basis assuming all of the risks and benefits are discussed, including the review of all contraindications to alteplase use.

But, if you decide to give alteplase, is less more? I won’t go into the details, but I will point out studies, both in the setting of submassive and massive PE, that have shown that lower doses of alteplase given as a bolus would work just as well with lower bleeding rates than the FDA approved 100 mg over 2 hour dose. The studies used either alteplase 0.6 mg/kg (max dose of 50 mg) given as a bolus or just gave 50 mg over 2 hours compared to the FDA approved dose with no difference in efficacy, bleeding, or death. One trial even showed lower bleeding rates, especially in lower-weight patients. When looking at these and other trials, we can conclude that in the setting of massive and submassive PE, lower doses of alteplase are safe and effective with potentially less bleeding rates.

At my site, for patients with a massive PE who weigh >/= 70 kg, we give 50 mg of alteplase as a bolus, which we can repeat in 15-30 minutes if needed. Patient’s weighing < 70 kg get the 0.6 mg/kg dose as an IV bolus. This makes administration of alteplase in this scenario easier, as alteplase comes in 50 and 100 mg vials, so we can quickly draw up the bolus dose and have the nurse administer it as an IV push. In the setting of submassive PE, we use the “MOPETT” trial dosing of a 10 mg bolus followed by 40 mg over 2 hours. We also have the option of giving a 100 mg dose (10 mg bolus followed by 90 mg over 2 hours) if the critical care team chooses. We use the 2 hour extended infusion in submassive PE as there is less evidence for the bolus-dosing regimen in this setting.

As always, thank you for your time and for tuning in. Next week, we discuss thrombolytics in the setting of cardiac arrest and wrap up with our final recommendations