Protamine With DAPT in Percutaneous Coronary Intervention

In patients receiving percutaneous coronary intervention, protamine therapy can be used to reverse the effect of heparin.

Protamine may be a useful therapy for reversing the effects of heparin in patients who are receiving transfemoral percutaneous coronary intervention (PCI) pretreated with dual antiplatelet therapy (DAPT), according to findings published in the International Journal of Cardiology.

Investigators sought to assess the efficacy and safety of protamine for heparin reversal in PCI. Stent thrombosis was the primary endpoint. Mortality, major bleeding complications, and hospitalization length of stay were secondary endpoints.

The investigators conducted a systematic review and meta-analysis searching the Cochrane, Embase, and PubMed databases from inception through most of April 2023. The search included randomized controlled trials (RCTs) or cohort studies published in English that examined protamine as the intervention in any PCI.

There were11 studies included in the analysis, of which 2 were RCTs (n=316) and the others were not randomized, with 1 dissertation. It is unclear if the data in the dissertation manuscript was the same data as in the associated abstract. This study was included in the analysis nonetheless, however it was excluded in the sensitivity analysis.

Among the 9 nonrandomized studies, 3 were rated poor quality based on the Newcastle Ottawa Quality Assessment for cohort studies and subsequently excluded during sensitivity analysis. Among the 2 RCTs, 1 was rated fair using the Cochrane risk of bias assessment tool and the other had an unclear risk of selection bias and reporting bias, however current review authors believed these biases did not affect the outcome and subsequently rated the quality of this RCT as fair.

…protamine may be a safe and efficacious option to facilitate earlier sheath removal, reduce major bleeding complications, and reduce length of hospitalization without increased risk of stent thrombosis.

The pooled analysis included almost 14,991 patients, of which 9541 had procedures with protamine and 5450 had procedures without protamine. Among 9 of the included studies, stent thrombosis was defined 3 different ways, and the remaining 2 studies failed to define stent thrombosis. Between studies, the time frame for stent thrombosis was inconsistent, ranging from within 24 hours after PCI to more than 1 year after PCI, and some of the studies failed to mention time frame.

Investigators found no association between protamine and stent thrombosis (odds ratio [OR], 0.58; 95% CI, 0.33-1.01; P =.05) and no association between protamine and mortality (OR, 0.94; 95% CI, 0.42-2.13; P =.89).

Protamine was associated with decreased incidence of major bleeding complications (OR, 0.48; 95% CI, 0.25-0.95; P =.03), and protamine was associated with decreased length of hospitalization, however this outcome was associated with significant heterogeneity.

Limitations of the study include the RCTs being older studies predating newer generation drug-eluting stents thus limiting generalizability of findings.

“In patients pretreated with dual antiplatelet therapy (DAPT), protamine may be a safe and efficacious option to facilitate earlier sheath removal, reduce major bleeding complications, and reduce length of hospitalization without increased risk of stent thrombosis,” the investigators wrote. “Protamine should not be withheld when major bleeding events occur in PCI as the risk of stent thrombosis appears to be minimal and no more than that of patients not receiving protamine.”


Lee PY, Bello J, Ye C, et al. Safety of routine protamine in the reversal of heparin in percutaneous coronary intervention: a systematic review and meta-analysis. Int J Cardiol. Published online July 8, 2023. doi:10.1016/j.ijcard.2023.131168