ACE-PROTAVI Data Solidify Protamine’s Role in Aortic Interventions

The routine use of protamine for heparin reversal during TAVI improves and hastens hemostasis, data from the randomized ACE-PROTAVI trial confirm.

The results, published online this week in JAMA Cardiology, also show the strategy offers other advantages, with reductions in minor vascular complications, procedural time, and length of hospital stay.

Protamine is often used in cardiac surgery, but fewer studies have documented its impact in transfemoral TAVI, Pieter A. Vriesendorp, MD, PhD (Maastricht University Medical Center, the Netherlands), and colleagues point out in their paper. Potential risks of protamine include allergic reactions, hypotension, bronchospasm, and skin reactions, though in ACE-PROTAVI there were no adverse events.

Vriesendorp told TCTMD the choice to use protamine—or not—during TAVI “is super operator-dependent, even within the same hospital.” Those variations in practice, which also existed within the ACE-PROTAVI investigators’ own groups, are what led them to pursue their trial, he said.

Around the world, “I still think we have some people who believe in it or are a bit more skeptical of it, or afraid of the adverse events, but now at least we’ve shown that for [increasing] the chance of a quick and successful hemostasis, protamine works,” said Vriesendorp, who noted that the trial wasn’t intended to show safety, as that’s already been established.

Protamine use “is just a little trick that helps people to get slightly better outcomes. We’re in that stage now with TAVI [where] we’re getting it better, quicker, and safer, and this is a small step.”

Gilbert Tang, MD (Mount Sinai Health, New York, NY), said that protamine is already widespread in TAVI—and for good reason. “The more minor vascular issues are not benign,” he commented to TCTMD. “These patients have [better] mobilization and especially if they’re at low surgical risk, they want to be recovering faster.”

Improved Hemostasis, Fewer Complications

For the investigator-initiated, double-blind trial, researchers enrolled 410 transfemoral TAVI patients across three Australian hospitals between December 2021 and June 2023. Study participants were randomized to up-front protamine administration (median age 82 years; 34.2% female) or placebo (median age 80 years; 42.2% female). Patients who’d undergone PCI within the past 3 months were excluded due to the potential for increased risk of stent thrombosis.

Median TAVI procedural times were shorter with protamine than with placebo (58 minutes; interquartile range [IQR] 49-70 vs 60 minutes; IQR 52-73; P= 0.007), as were the median lengths of postprocedural hospital stay (3 days; IQR 2-3 vs 3 days; IQR 2-4; P = 0.02).

ACE-PROTAVI’s co-primary endpoints of hemostasis success and time to hemostasis (TTH) each were improved when patients received protamine versus placebo.

ACE-PROTAVI: Co-Primary Endpoints

Additionally, routine protamine use produced a lower risk of the trial’s composite outcome: all-cause death, major/minor bleeding complications, and major/minor vascular complications (5.2% vs 12.8%; OR 0.37; 95% CI 0.1-0.8), with the difference primarily driven by a reduction in minor vascular complications (2.1% vs 8.4%; OR 0.23; 95% CI 0.08-0.70).

Protamine did not lead to any changes in major or life-threatening bleeding, the investigators note. “Heparin reversal might improve closure and hemostasis and reduce minor vascular complications, but it is unlikely to affect catastrophic vascular complications, such as the rupture or perforation of arteries,” they write. “However, a reduction in minor bleeding and vascular complications will lead to earlier mobilization and less nursing requirement on the ward and is associated with reduced length of stay, as demonstrated in this trial.”

Vriesendorp, to TCTMD, noted the potential for better patient comfort and satisfaction as well. “It will help,” he said, adding that the trial showed a positive impact on clinical events despite not being powered for those endpoints.

The POPular ACE TAVI trial, slated to enroll 1,000 patients, is now testing whether protamine lowers the risk of cardiovascular mortality or bleeding within 30 days after TAVI, Vriesendorp noted. “Once that study is done, I think we can put the issue to rest if it also shows a beneficial effect, and then everyone should use protamine.” Patients with a known protamine allergy are of course an exception, he specified.