Alteplase is the only second generation tPA approved for thrombolysis in cardiac arrest by AHA. Although tenecteplase and reteplase are studied but they are not approved. The recommended dose of alteplase is 100mg; 10mg as bolus over 1 minute and rest over 2 hours. There also few studies claiming low dose alteplase is safer and has similar efficacy compared to full dose. There multiple studies on Tenecteplase as well. Lets look at the evidences of these agents.
Studies on Alteplase
Konstantinides et al (N Engl J Med.2002) done a multicentric, randomised double study on submassive PE to assess the effficacy of alteplase (100mg) with heparin compared to placebo with heparin. of 256 patients 118 were assigned to altepalse group and 138 to placebo group. Incidence of the primary endpoint (mortality or clinical deterioration requiring an escalation of treatment) was significantly higher in placebo group compared to alteplase group(p=0.006).
Studies on Low dose Alteplase
Wang et al (Chest. 2010) done a prospective randomised, multicentric trial to compare the efficacy and safety of rt-PA 50mg over 2 hours (n=65) with 100mg over 2 hours (n=53) in patients with acute PE. Study found that low dose rtpa exhibits similar efficacy and lesser bleeding tendency (14.8% vs 41.2%, p =0.49). A subgroup ana lysis of the study among hemodynamic unstable patients thrombolysed with low dose rtpa produced similiar results.
Sharifi et al (Am J Cardiol. 2013) MOPETT Trial is a single centre study done to asses the role of low dose thrombolysis. Study was done on 121 patients with moderate PE, they were randomised to receive a "safe dose" (50mg for > 50kg & 0.5mg/kg <50kg; 10mg bolus rest over 2 hours)of tissue plasminogen plus anticoagulation (n=61) or anticoagulation alone . Pulmonary hypertension and the composite end point developed in 9 of 58 patients(16%) in the TG and 32 of 56 patients (57%) in the CG (p <0.001) and 9 of 58 patients (16%) in the TG and 35 of 56 patients (63%) in the CG (p <0.001), respectively. The duration of hospitalization was 2.2 – 0.5 days in the TG and 4.9 – 0.8 days in the CG (p <0.001). The combination of death plus recurrent PE was 1 (1.6%) in TG and 6 (10%) in the CG (p [ 0.0489). No bleeding occurred in any group, and despite a positive trend in favor of a “safe dose” thrombolysis,no significant difference was noted in the rate of individual outcomes of death and recurrent PE when assessed independent.
Studies on tenecteplase
TIPES Trial by Becattini et al (Thromb Res. 2010) is a multicentric, randomised, double blind, placebo controlled study where they assesed the clinical benefit of thrombolytic treatment over heparin in patients with PE (n=51)without hemodynamic compromise based Right Ventricular dysfunction assesed by echcocardiography. 23 patients were randomised to tenecteplase and 28 to placebo. reduction of right to left ventricular end diastolic dimension ratio at 24 hours was 0.310.31+/-0.08 in patients randomized to tenecteplase as compared to 0.10+/-0.07 in patients randomized to placebo (p=0.04). Two major bleedings occured with tenecteplase (1 intracranial) and one with placebo.
TOPCOAT Trial done by kline (J Thromb Haemost. 2014)at al is a multicenter, double-blinded, intention to treat, placebo-controlled done to test if tenecteplase increases the probability of favourable outcome in submassive PE. Eighty-three patients were randomized; 40 to tenecteplase and 43 to placebo. The trial was terminated prematurely. 1 patients died in both placebo and treatment group within 5 days. 16 (37%) placebo-treated and six (15%) tenecteplase-treated patients had at least one adverse outcome (exact two-sided P = 0.017) at 90 days. Adverse outcomes are defined as recurrent VTE, poor functional capacity alone or combined.
PEITHO Trial by Meyer et al (N Engl J Med.2014) done a randomised, double-blind trial study on fibrinolysis on patients (n=1006) with intermediate risk PE by comparing tenecteplase (506)plus heparin v/s placebo with heparin (499). Death or hemodynamic decompensation occured in tenecteplase group 13 (2.6%) compared with placebo group 28 (5.6% ) p=0.02. Extracranial bleeding occured in 6.3% in tenecteplase group compared to placebo 1.2%. Mortality was 12(2.4%) in tenecteplase group and 16 (3.2%) in placebo group (p=0.42).
Studies on thrombolysis for PE in cardiac arrest
AHA advices thrombolysis as a reasonable option in confirmed cases of PE leading to cardiac arrest and advices to consider in suspected cases. AHA says there is no consensus on the ideal dose of thrombolytic therapy in PE associated cardiac arrest. They suggest use of altepelase 50mg IV bolus with an option for repeat bolus in 15 minutes or a single weight based tenecteplase.
TROICA Trial (NEJM,2008) done by bottiger et al was a double blinded, multicentric trial. Study was done on randomly assigned adult patients with witnessed out-of-hospital cardiac arrest presumed to be cardiac in origin (ACS/PE) to receive tenecteplase or placebo during cardiopulmonary resuscitation. The trial was terminated prematurely for futility after enrolling a total of 1050 patient. The study did not detect any significant differences between tenecteplase and placebo in the primary end point of 30-day survival (14.7% vs. 17.0%; P=0.36; relative risk, 0.87; 95% confidence interval, 0.65 to 1.15) or in the secondary end points of hospital admission (53.5% vs. 55.0%, P=0.67), return of spontaneous circulation (55.0% vs. 54.6%, P=0.96), 24-hour survival (30.6% vs. 33.3%, P=0.39), survival to hospital discharge (15.1% vs. 17.5%, P=0.33), or neurologic outcome (P=0.69). There were more intracranial hemorrhages in the tenecteplase group
PEAPETT Study (j.ajem.2016) was done to evaluate the outcome of low dose tPA on patients presenting with PEA due to PE . Study was done on 23 patients with 50mg tPA (Alteplase) as push in one minute while CPR was ongoing. Study achieved ROSC in 22 patients. Mortality at discharge was only 2. There was no significant bleeding risk.
Reference
- Konstantinides S, Geibel A, Heusel G, Heinrich F, Kasper W; Management Strategies and Prognosis of Pulmonary Embolism-3 Trial Investigators. Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med. 2002 Oct 10;347(15):1143-50. doi: 10.1056/NEJMoa021274. PMID: 12374874.
- Yousuf T, Brinton T, Ahmed K, Iskander J, Woznicka D, Kramer J, Kopiec A, Chadaga AR, Ortiz K. Tissue Plasminogen Activator Use in Cardiac Arrest Secondary to Fulminant Pulmonary Embolism. J Clin Med Res. 2016 Mar;8(3):190-5. doi: 10.14740/jocmr2452w. Epub 2016 Jan 26. PMID: 26858790; PMCID: PMC4737028.
- Wang C, Zhai Z, Yang Y, Wu Q, Cheng Z, Liang L, Dai H, Huang K, Lu W, Zhang Z, Cheng X, Shen YH; China Venous Thromboembolism (VTE) Study Group. Efficacy and safety of low dose recombinant tissue-type plasminogen activator for the treatment of acute pulmonary thromboembolism: a randomized, multicenter, controlled trial. Chest. 2010 Feb;137(2):254-62. doi: 10.1378/chest.09-0765. Epub 2009 Sep 9. PMID: 19741062; PMCID: PMC7126994.
- Sharifi M, Bay C, Skrocki L, Rahimi F, Mehdipour M; “MOPETT” Investigators. Moderate pulmonary embolism treated with thrombolysis (from the "MOPETT" Trial). Am J Cardiol. 2013 Jan 15;111(2):273-7. doi: 10.1016/j.amjcard.2012.09.027. Epub 2012 Oct 24. PMID: 23102885.
- Becattini C, Agnelli G, Salvi A, Grifoni S, Pancaldi LG, Enea I, Balsemin F, Campanini M, Ghirarduzzi A, Casazza F; TIPES Study Group. Bolus tenecteplase for right ventricle dysfunction in hemodynamically stable patients with pulmonary embolism. Thromb Res. 2010 Mar;125(3):e82-6. doi: 10.1016/j.thromres.2009.09.017. Epub 2009 Oct 14. PMID: 19833379.
- Sharifi M, Berger J, Beeston P, Bay C, Vajo Z, Javadpoor S; “PEAPETT” investigators. Pulseless electrical activity in pulmonary embolism treated with thrombolysis (from the "PEAPETT" study). Am J Emerg Med. 2016 Oct;34(10):1963-1967. doi: 10.1016/j.ajem.2016.06.094. Epub 2016 Jun 30. PMID: 27422214.
- Kline JA, Nordenholz KE, Courtney DM, Kabrhel C, Jones AE, Rondina MT, Diercks DB, Klinger JR, Hernandez J. Treatment of submassive pulmonary embolism with tenecteplase or placebo: cardiopulmonary outcomes at 3 months: multicenter double-blind, placebo-controlled randomized trial. J Thromb Haemost. 2014 Apr;12(4):459-68. doi: 10.1111/jth.12521. PMID: 24484241.
