MAPPET 3

Alteplase with or without heparin for submassive PE

Included 256 patients with submassive pulmonary embolism and RV dysfunction or PA hypertension
Randomized patients to alteplase (10 mg IV bolus, then 90 mg over 2 hrs) or placebo. Both groups received full anticoagulation with unfractionated heprin
Open-label secondary (“rescue”) thrombolytics were allowed for the following indications:
- worsening dyspnea or respiratory failure
- hypotension/shock
- persistent or worsening RV dysfunction
Primary endpoint (hospital mortality or escalation of treatment) was higher in patients receiving placebo (11% vs. 24.6%, p=0.006, NNT 7), but was Primarily driven by the use of secondary (“rescue”) thrombolytics (7.6% vs. 23.2%, p=0.001, NNT 6)
There was no difference in mortality (3.4% vs. 2.2%, p=0.71)
Major bleeding events was not different between alteplase and placebo (0.8% vs. 35%, P=0-29)
Patients received the same dose (alteplase 100 mg) regardless of weight (mean weight 75-86 kg).
Because alteplase is typically considered a weight-based drug, these results may be different in significantly underweight patients

TBL

Alteplase, in conjunction with unfractionated heparin, in patients with submassive PE decreased the rate of escalation of treatment compared to heparin alone. Mortality and bleeding complication were not different than placebo.

See the paper here

MENDS

Dexmedetomidine vs lorazepam

Included 103 medical/surgical patients requiring mechanical ventilation for > 24 hrs at two centers
Randomized patients to dexmedetomidine (0.15 to 1.5 mcg/kg/hr) or |orazepam (1 to 10 mg/hr) until extubation or up to 5 days.
Bolus dosing was not allowed
Open-label fentanyl and propofol allowed, but benzodiazepines was not permitted (reduces external validity)
Primary endpoint was clays alive without delirium (based on CAM-ICU) or coma (RASS -4 or -5) over 12 days
Primary endpoint was better with dexmedetomidine (7 days vs. 3 days, P=0.01), which was primarily driven by coma-free days
There was no difference in delirium-free days (9 vs. 7 days, p=0.09), duration of mechanical ventilation, ICU length of stay, or 28-day mortality
Median study drug closes:
- dexmedetomidine 0.74 mcg/kg/hr
  and lorazepam 3 mg/hr
Dexmedetomidine patients received more open-label fentanyl (575 vs. 150 mcg/day).
Open-label propofol was uncommonly used
Dexmedetomidine patients were more likely to be within 1-point of RASS goal (67% vs. 55%, p=0.08, NNT 8)
Dexmedetomidine associated with more bradycardia (HR < 60, 17% vs. 4%, p=0.03, NNH 8), hypotension (Systolic BP < 80 mqu, 25% vs: 20%, p=NS), and more self- extubations (8% vs. 4%, p=NS)

TBL

In mechanically ventilated patients, dexmedetomidine improved coma-free days and time within goal level of sedation compared to lorazepam, but required more open-label fentanyl and had a higher incidence of bradycardia.

See the paper here

MOPPET

Alteplase for moderate PE

Included 121 patients with “moderate” pulmonary embolism (a newly defined term by the authors based on CTA or V/Q scan criteria)
Excluded patients with contraindications to thrombolytics and those with systolic BP < 95 mmHg (who would generally meet the criteria for massive PE and should
receive thrombolytics)
Randomized patients to standard care or alteplase 50 mg (10 mg bolus and 40 mg infusion over two hours). A reduced alteplase close was used for those weighing less than 50 kg
All patients received anticoagulation; however, alteplase patients received capped doses of either enoxaparin (max 80 mg) or heparin (max bolus 6000 units; max infusion 1000 unit/hr until 3 hours after alteplase)
Primary endpoint (pulmonary hypertension [PA systolic pressure > 40 mmHg] at a mean of 28 months) was lower with alteplase than control (16% vs. 57%, p<0.001, NNT 2)
Mean pulmonary artery pressures at six months were also lower with alteplase (31 mmHg vs. 49 mmHg, p<0.001) Alteplase was associated with a reduced hospital length of stay (2.2. vs. 4.9 days, p<0.001)
Recurrent PE or mortality were not different between the two groups surprisingly, there were no major or minor bleeding events reported in either study arm (suggesting underreporting of events, enrollment selection bias of “healthier” patients, and/or small sample size)
Of note, the alteplase dose used in MOPE’I’I’ was 50% of the recommended dose for massive PE (100 mg) — termed a “safe close” by the authors
The definition of pulmonary hypertension is a surrogate endpoint.
It is not clear whether alteplase patients had improved functional outcomes (eg, quality of life, able to walk farther, activities of daily living limitations, etc.)
While this trial has many limitations (single center, open label, use of non- standardized “moderate PE” term, close capping of anticoagulants in one arm), it is one of only a few studies that examine the use of thrombolytics in “moderate” (submassive) PE

TBL

The use of reduced-dose alteplase with dose-capped anticoagulants reduced the risk of long-term pulmonary hypertension compared to those who received standard doses of anticoagulants alone.

See the paper here

Mr Clean

Intraarterial intervention for acute ischemic stroke

Included 500 patients from the Netherlands with a proximal arterial occlusion in the anterior cerebral circulation within 6 hours of stroke symptom onset
Randomized patients to intraarterial intervention (catheter-directed thrombolytic agents, mechanical thrombectomy, or both) versus usual care.
About 90% of patients in both groups received systemic IV alteplase
Intraarterial intervention was initiated a median of 260 minutes (4.3 hours) from stroke onset and a retrievable stent for thrombectomy was utilized in about 80% of patients
Primary endpoint (modified Rankin score distribution at day 90) was more favorable for intraarterial therapy compared to usual care (OR 1.67, 95% CI 1.21 to 2.3)
The percent of patients who were functionally independent (modified Rankin 2 or lower) was better with intraarterial therapy (32.6% vs. 19.1%, 95% CI 1.39 to 3.38)
Intraarterial patients were significantly more likely to have no intracranial occlusion on follow-up CT angiography (75.4% vs. 32.9%) and also significantly more likely to have a smaller infarct volume on final CT (49 vs. 79 mL)
There was no difference in short or long-term mortality and no difference in intracranial hemorrhage between the two groups
At 90 days, patients randomized to intraarterial therapy were more likely to have a new ischemic stroke in a different vascular territory (5.6% vs.
0.40/0)
Intraarterial intervention was associated with a risk of embolization into a new downstream territory (8.6%), procedure-related vessel dissection (1.7%), and vessel perforation (0.9%)

TBL

Among patients with a proximal artery occlusion in the anterior cerebral circulation, the use of intraarterial intervention with IV alteplase was superior in neurologic functional outcomes compared to usual care with IV alteplase.

See the paper here

Mayer 2005

rFVIIa for acute ICH

Included 399 patients with spontaneous intracranial hemorrhage (ICH) within 3 hrs of onset
Excluded deep coma (Glasgow <= 5), aneurysm, AV malformation, trauma, known coagulopathy, and a history of thromboembolic or vaso-occlusive disease
Randomized to receive 40, 80, or 120 mcg/kg recombinant activated factor VII (rFVIIa) or placebo. Treatment was given within 4 hours of symptom onset
Primary endpoint (hematoma expansion from baseline at 24 hrs) was improved with 160 mcg/kg (11% vs. 29%, p=0.02, NNT 6), although 40 and 80 mcg/kg did not show a significant improvement;
The total increase in hematoma Size from baseline was improved with both 80 mcg/kg (4.2 mL) and 160 mcg/kg (2.9 mL) versus placebo (8.7 mL)
Subgroup analysis suggested that those treated beyond 3 hrs of onset may have not benefited from rFVIIa, although this subgroup may be underpowered (29% of entire study)
90-day mortality was improved with rFVIIa (18% vs. 29%, p=0.02, NNT 9).
Similarly, all neurological global outcome scales showed improvement with rFVIIa compared to placebo
Arterial thromboembolic serious events (primarily CVA and MI) were more common with rFVIIa (5% vs. 0%, p=0.01, NNH 20)

TBL

Recombinant activated factor VII reduced hematoma growth and improved mortality in patients with spontaneous intracranial hemorrhage but increased arterial thromboembolic events.

See the paper here

Meduri 1998

Meduri protocol for unresolving ARDS

Included 24 patients with ARDS who did not have improving lung injury scores after 7 days, randomized 2:1 to methylprednisolone or placebo “Meduri 1998” methylprednisolone protocol (unresolving ARDS):
Doses given as IV infusions and divided into Q6h.
Once able to take PO, doses given as single oral doses.
- Protocol: 2 mg/kg loading dose, then 2 mg/kg/day (days 0-14), then 1 mg/kg/day (days 15- 21), then 0.5 mg/kg/day (days 22- 28), then 0.25 mg/kg/day (days 29- 30), then 0.125 mg/kg/day (days 31- 32).
- If extubated prior to day 14, treatment was advanced to day 15 of therapy.
Primary endpoint (improvement in lung injury score (LIS) after 10 days) was improved with methylprednisolone (100% vs. 25%, p<0.001, NNT 1)
Methylprednisolone improved ICU mortality (0% vs. 63%, p=0.002, NNT 2) and hospital mortality (13% vs. 63%, p=0.03, NNT 2)
Half of placebo group (4 of 8 patients) crossed over to methylprednisolone therapy due to lack of improvement in LIS at 10 days
Instead of a traditional power analysis, the study used a sequential analysis of study results as data accumulated. This analysis led to an incredibly small trial size, which is one of the study’s biggest limitations

TBL

Prolonged, low-dose methylprednisolone in unresolving ARDS improved ICU survival and lung function; however, some experts believe that larger studies are necessary in order to characterize the efficacy and safety of this regimen in unresolving ARDS

See the paper here

Meduri 2007

Meduri protocol for early ARDS

Included 91 patients with ARDS onset within 72 hours, randomized to methylprednisolone or placebo
“Meduri 2007” methylprednisolone protocol (early ARDS). Doses given as IV infusions once daily. Once able to take PO, doses were given as single oral doses.
- Protocol: 1 mg/kg loading dose, then 1 mg/kg/day (days 0—14), then 0.5 mg/kg/day (days 15-21), then 0.25 mg/kg/day (days 22-25), then 0.125 mg/kg/day (days 26-28).
- If extubated prior to day 14, treatment was advanced to day 15 of therapy
If placebo patients failed to improve between days 7-9, unblinded methylprednisolone was provided using the treatment protocol
Baseline characteristics were unbalanced, with the placebo group having more catecholamine— dependent shock (46.4% vs. 23.8%, p=0.03)
Primary endpoints: improvement in lung injury score (LIS) after 7 days of treatment
Methylprednisolone was associated with a higher incidence of extubation or LIS improvement at day 7 (69.8% vs. 35.7%, p=0.002, NNT 3)
At day 7, the methylprednisolone group had more patients breathing without assistance (54% vs. 25%, p=0.01, NNT 3) and fewer patients receiving open-label methylprednisolone clue to unresolving ARDS (7.9% vs. 35.7%, p=0.002)
Methylprednisolone was associated with fewer days of mechanical ventilation (5 vs. 9.5 days, p=0.002) a reduction in ICU length of stay (7 vs. 14.5 days, p=0.007), and greater ICU survival (79.4% vs. 57.4%, p=0.03, NNT 5).
Hospital length of stay and hospital mortality were non- significantly improved with methylprednisolone.