Remark: This rec- ommendation does not apply to non life-threatening bleeding. Summary of the evidence. We updated evidence from 2 systematic reviews that addressed this question,198,199 and 13 observational studies that measured relevant outcomes for patients receiving protamine for LMWH/UFH reversal when undergoing invasive procedures, not for major bleeding during VTE treatment.203-215 Most studies did not specify whether heparin included UFH or LMWH; therefore, we could not analyze according to heparin subgroup. Given that only 74 patients receiving protamine were included in the RCTs, the panel elected to consider only the evidence from the observa- tional studies. Six studies reported the effect of protamine administration on 10 studies reported development of 10 studies assessed the risk of and 6 studies reported the risk of myocardial infarction.205-207,212-214 No studies reported the risk of PE or DVT. The EtD framework is shown online at https://dbep. gradepro.org/profile/770de24b-7077-4e3d-a7b9-cd7f401d31b4. Benefits. For benefits, see the evidence profile in the EtD framework referenced at the end of the previous section, available online. Studies assessing mortality reported no difference between those receiving protamine and control groups (RR, 0.98 [95% CI, 0.66-1.45]; ARR, 0 fewer deaths per 1000 [95% CI, 6 fewer to 9 more per 1000]; very low certainty). Protamine administration reduced the risk of de- veloping major bleeding (RR, 0.61 [95% CI, 0.39-0.96]; ARR, fewer per 1000]; very low certainty). Harms and burden. The risk of stroke (RR, 0.87 [95% CI, more per 1000]; very low certainty) and myocardial infarction (RR, fewer to 4 more per 1000]; very low certainty) did not differ among those receiving protamine and controls. Other EtD criteria and considerations. 