HI-PEITHO will be one of the more important PE trials released this decade. Accurate interpretation requires placing this trial within the context of several other RCTs, especially the original PEITHO trial. So let's start there.

The original PEITHO trial (PEITHO-1)

PEITHO-1 was an RCT involving 1,006 patients with intermediate-high risk PE (defined as RV dysfunction plus elevated troponin). Patients were randomized to heparin infusion with or without full-dose tenecteplase. Tenecteplase reduced the rate of hemodynamic decompensation from 5% to 1.6% (p=0.002). However, this came at the cost of an increased risk of intracranial hemorrhage (2% with telecteplase plus heparin, as compared to 0.2% with heparin alone). There was no difference in all-cause mortality.

So, tenecteplase prevented hemodynamic deterioration, but it caused a lot of bleeding. Indeed, it seems that, for whatever reason, tenecteplase may cause more bleeding among PE patients than alteplase (table below). Honestly, I'd probably advocate for never combining full-dose tenecteplase with full-dose heparin for any PE patient.

Major changes between PEITHO-1 and HI-PEITHO

Based on these results, the investigators made several alterations when designing HI-PEITHO:

First, the patient selection was more stringent in order to isolate patients at higher risk of deterioration. Inclusion in the trial required ALL of the following:

• [1] RV:LV ratio >1 on CT scan and troponin elevation.
• [2] PE in at least one main or proximal lobar pulmonary artery on CT scan (this helps eliminate patients with chronic pulmonary hypertension plus a small acute PE).
• [3] At least two of the following:
  • SBP < 110 mm for over 15 minutes.
  • HR >100 b/m not due to hypovolemia, arrhythmia, or sepsis.
  • Tachypnea with a respiratory rate of >20 breaths/minute or hypoxemia.

Second, low-dose alteplase was used instead of full-dose tenecteplase. Most patients received 18 mg alteplase as a 4-mg bolus followed by 14 mg infused over seven hours. Patients could be treated with either unfractionated heparin or low-molecular-weight heparin at the discretion of the clinicians. About half of the patients received concurrent therapeutic low-molecular-weight heparin twice daily (e.g., enoxaparin 1 mg/kg q12hr). The other half of the patients received a concurrent heparin infusion (which was transiently reduced to 300-600 U/hr during the alteplase infusion).

Third, the alteplase was infused locally into the bilateral pulmonary arteries using catheters that exuded vibrational ultrasonic energy. Here is where things start getting messy. In the years since HI-PEITHO was designed, an emerging body of evidence has shown that ultrasonic energy is worthless. Similarly, there doesn't seem to be any advantage to infusing alteplase into the bilateral pulmonary arteries compared to a peripheral infusion of the same dose (every molecule of alteplase infused peripherally will reach the pulmonary arteries in a second). The recent STRATIFY RCT demonstrated equivalent efficacy of peripheral versus catheter-directed thrombolysis (discussed here). This will become a persistent point of contention when applying this trial to clinical practice.

Top-line results of HI-PEITHO

The study achieved its primary composite outcome. The rate of cardiorespiratory deterioration (defined using a NEWS score that integrates various vital sign abnormalities) was reduced from 10.3% in the control group to 4% in the treatment group (table above). There was no difference in PE-related deaths, but the rate of such deaths was so low as to be impossible to quantify accurately.

If we drill down into the data more granularly, patients in the treatment group had numerically lower rates of shock and of requiring ECMO. These differences weren't statistically significant (table below). As would be expected, patients in the control group required rescue therapy more frequently (9.2% vs. 2.9%).

The intervention was safe. There were no intracranial hemorrhages. Bleeding rates were statistically similar between the two groups.

Subgroup analysis is shown above. Although not statistically significant, there are some signals here that make sense:

• Patients >75 years old didn't seem to benefit from alteplase. This is consistent with the subgroup analysis of PEITHO-1, which also suggested reduced benefit among patients >75 years old (in that case, due to increased bleeding rates).
• Patients with RV/LV ratio between 1-1.5 didn't seem to benefit. This supports data from other recent RCTs (e.g., the STRATIFY trial) suggesting that patients with moderate RV dilation (e.g., RV/LV of ~1-1.2) are likely to do well without aggressive intervention.

Do we need to use an expensive vibrating catheter? 

No, we don't. As mentioned above and discussed further in this blog, emerging data show that peripheral thrombolysis is equally effective as compared to catheter-directed thrombolysis.

In fact, peripheral thrombolysis has numerous advantages over catheter-directed thrombolysis:

• Peripheral thrombolysis can be deployed in any hospital unit (without requiring transport to interventional radiology).
• Peripheral thrombolysis can be started immediately, without any time delay while awaiting appropriate personnel.
• Peripheral thrombolysis is less invasive, allowing us to avoid procedural complications. There were three patients in the HI-PEITHO trial who developed local hemorrhage at the insertion site of the catheter. One patient in the intervention group died from an inguinal hemorrhage. This could have been avoided.
• Peripheral thrombolysis is less expensive. An ultrasonic catheter used for local thrombolytic administration costs ~$5,000. When you add procedure costs, this is an insane cost for an intervention that has never been shown to be beneficial.
• Leaving a catheter lying across the tricuspid valve may worsen tricuspid valve function, potentially aggravating hemodynamic instability.

In short, peripheral administration of an equal dose of thrombolytic should be faster, easier, safer, and cheaper. I do worry that HI-PEITHO will lead to a resurgence of enthusiasm for catheter-directed thrombolysis. Although the study itself supports the use of catheter-directed thrombolysis, a broader understanding of the PE literature over the past decade indicates that the active ingredient is simply the thrombolytic itself (not the catheter). For example, other studies have shown that peripheral administration of ~20 mg alteplase is sufficient to hemodynamically stabilize patients with PE. (37188358, 39732696) 

I was surprised to see that the editorial accompanying HI-PEITHO didn't even mention emerging data showing that ultrasonic energy is ineffective and that delivering alteplase directly into the pulmonary artery is unnecessary. The senior author of that editorial is the primary investigator of a PE-TRACT trial evaluating the use of catheter-directed thrombolysis for pulmonary embolism, which is an obvious conflict of interest. Historically, the NEJM used to have stricter policies regarding conflicts of interest among authors of editorials and review articles.

Does alteplase improve dyspnea and functional outcomes?

Around ~2012-2017, a common concept was that thrombolysis might improve long-term functional outcomes (including a reduction in chronic thromboembolic pulmonary hypertension). However, the long-term follow-up data from PEITHO-1 demonstrated no difference in chronic functional outcomes. This created a cognitive model in which the primary benefit of thrombolysis is avoiding short-term decompensation, rather than improving functional status (discussed in a prior blog here). I believe that this general model remains valid today.

The question that remains is whether thrombolysis could improve short-term functional outcomes (e.g., within <1 month). Accelerating clot resolution should hasten recovery. There is some data that thrombolysis reduces hospital length of stay, possibly by helping patients mobilize more rapidly and feel better about going home. Occasionally, patients have severe dyspnea that limits physical therapy and return to their activities of daily life – accelerating clot lysis might accelerate their recovery.

The supplemental data for HI-PEITHO include some tantalizing information about this (see table below). After 1 month, patients in the treatment group were much less likely to have poor functional status (defined as WHO Class III-IV, indicating marked or severe symptoms with ordinary activity). Specifically, after one month, the risk of a poor functional status was 18/273 (6.5%) in patients treated with thrombolysis, compared with 14.7% (40/271) in the control group. This difference has a p-value of 0.002 with a fragility index of eight. However, there was no difference in median six-minute walk distance, suggesting that these differences in functional class may be due to a placebo effect from the procedure. A longer-term follow-up study of HI-PEITHO is currently underway and may eventually shed further light on this.

• Administration of ~18 mg alteplase over ~6 hours is reasonably safe. It reduces the risk of hemodynamic deterioration and might accelerate recovery (with regard to short-term functional status). The safety and efficacy of ~20 mg alteplase have already been demonstrated in other trials, so there is an expanding body of evidence that this is a safe and reasonable treatment option. (37188358, 39732696) 
• The subset of patients who may benefit from this treatment is small. This group (patients in the orange “intermediate-actionable” box in the figure below) might be described by the following criteria:
  • Troponin elevation.
  • RV/LV ratio well above 1 (patients with an RV/LV ratio close to 1 probably don't benefit much).
  • At least two of the three signs of cardiorespiratory instability: SBP <110; HR >100; hypoxemia or respiratory rate >20.
  • Absence of risk factors for bleeding (possibly including an age <75 years old).
  • Patients who aren't better served by Inari FlowTriever embolectomy.
  • PE in at least one main or proximal lobar pulmonary artery on CT scan (this helps eliminate patients with chronic pulmonary hypertension plus a small acute PE).
• Overall, I doubt that peripheral infusions of 20 mg alteplase will become broadly utilized. My prediction is that PEERLESS-II will be a positive trial, demonstrating the benefit of embolectomy with the Inari FlowTriever. So, my guess is that most patients in the “intermediate actionable” box will undergo interventional radiology embolectomy. However, 18 mg alteplase may be a useful option for selected patients who aren't good candidates for catheter-directed embolectomy, or at hospitals that don't offer catheter-directed embolectomy.
• There is no evidence that catheter-directed alteplase is superior to peripheral administration of the same alteplase dose. Consequently, all available data indicate that peripheral alteplase administration should be faster, easier, cheaper, and safer. The myth that catheter-directed thrombolysis for PE is superior to peripheral administration of the same thrombolytic dose will remain doggedly persistent in the years to come, driven by industry-funded trials promoting this intervention.

Going further

• HI-PEITHO trial full publication at NEJM.
• More on intermediate & high-risk PE in the IBCC here.

Image credit: by Mike Lewinski on Unsplash

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Josh Farkas

Josh is the creator of PulmCrit.org. He is an associate professor of Pulmonary and Critical Care Medicine at the University of Vermont.

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