- Email: [email protected]
An anticoagulant too good to be true for revascularisation
Comment
An anticoagulant too good to be true for revascularisation Revascularisation is recommended for most patients presenting with acute coronary syndromes,1,2 with percutaneous coronary intervention the most common procedure. Besides dual antiplatelet treatment with aspirin and a platelet P2Y12 blocker (eg, clopidogrel, prasugrel, or ticagrelor), parenteral anticoagulation is mandatory in patients undergoing this procedure. Heparin, low-molecular-weight heparin, and the specific thrombin (factor II) blocker bivalirudin are currently used for anticoagulation. Needless to say, bleeding occurs frequently during and after revascularisation. Since bleeding is associated with poor short-term and long-term outcomes,3 prevention of bleeding is of utmost importance. Factor IX contributes to activation of the coagulation cascade via the intrinsic route. REG1 is a two-component actively controllable anticoagulant system consisting of the factor IXa inhibitor pegnivacogin and a reversal agent, anivamersen, which has specific affinity for pegnivacogin.4,5 REG1 has been assessed with heparin in the randomised RADAR trial6 in 640 patients with nonST-elevation acute coronary syndromes undergoing percutaneous coronary intervention. At 30 days, fewer bleeding events had occurred with the 100% reversal strategy when compared with heparin (table). At least 50% pegnivacogin reversal was needed to prevent bleeding. Fewer ischaemic events occurred with REG1 (n=14 [3%]) than with heparin (n=9 [6%]). In three (1%) patients given pegnivacogin, allergic reactions occurred, two of which were serious.6 These findings warranted a phase 3 study with this new anticoagulant and an effective reversal agent in patients undergoing percutaneous coronary intervention. In The Lancet, Michael Lincoff and colleagues present the results of REGULATE-PCI,7 a randomised study intended to compare REG1 (pegnivacogin 1 mg/kg bolus, followed by 80% reversal with anivamersen) with bivalirudin in 13 200 patients at 225 hospitals in North America and Europe. The primary efficacy endpoint was a composite of all-cause death, myocardial infarction, stroke, and unplanned target lesion revascularisation by day 3 after randomisation. After 3232 patients had been enrolled, the safety committee advised halting of the trial because severe allergic reactions had occurred in ten (1%) of 1605 patients
receiving REG1, one of which was fatal, compared with one (<1%) of 1601 patients treated with bivalirudin. The decision was based on the absence of a clinical benefit of REG1, with no difference noted in the primary endpoint between groups (108 [7%] of 1616 patients assigned to REG1 vs 103 [6%] of 1616 on bivalirudin; odds ratio 1·05, 95% CI 0·80–1·39). Major bleeding occurred in seven (<1%) of 1605 patients assigned REG1 versus two (<1%) of 1601 in the bivalirudin group, but major or minor bleeding was increased in patients receiving REG1 (104 [7%] vs 65 [4%] patients, respectively). In view of the excess of bleeding events with REG1, despite availability of a reversal agent, and no reduction in hard ischaemic endpoints in more than 3000 patients, it is doubtful whether this approach to factor IXa blockade will go into further clinical development. A limitation of the REGULATE-PCI trial is that the comparator agent was bivalirudin, which has a better safety profile than heparin in acute coronary syndromes8 but not in elective percutaneous coronary intervention.9 Moreover, both acute and elective patients were enrolled. Additional anivamersen was administered in only 29 (2%) patients assigned to REG1,7 whereas reversal was done in up to 5% of patients in the phase 2b trial (table).6 Theoretically, correction of this shortcoming would have resulted in better bleeding outcomes. Yet it is too early to halt investigation of factor IXa blockade in percutaneous coronary intervention. The combination of a novel anticoagulant with a specific reversal molecule should be tested in more trials, but pegylated agents seem to be hazardous in patients with acute coronary syndromes. A new formulation of the factor IXa inhibitor without pegylation would be very welcome. But the agent—which in the REGULATEPCI trial was given as bolus (similar to the antidote)— would then be infused continuously in the same
Open reversal applied
See Online/Articles http://dx.doi.org/10.1016/ S0140-6736(15)00515-2
REG1 with 50% reversal (n=113)
REG1 with 75% reversal (n=119)
REG1 with 100% reversal (n=194)
8 (20%)
12 (11%)
10 (8%)
14 (7%)
12 (31%)*
6 (5%)
6 (5%)
5 (3%)
REG1 with 25% reversal (n=40) Major bleeding
Published Online November 4, 2015 http://dx.doi.org/10.1016/ S0140-6736(15)00727-8
Heparin (n=160) 16 (10%) NA
Data taken from reference 6. NA=not applicable. PCI=percutaneous coronary intervention. *One patient dropped out.
Table: Major bleeding in patients with non-ST-elevation acute coronary syndromes undergoing PCI and treated with REG1 versus heparin
www.thelancet.com Published online November 4, 2015 http://dx.doi.org/10.1016/S0140-6736(15)00727-8
1
Comment
way as bivalirudin or heparin, which is a practical disadvantage. Another limitation of the design and conduct of the REGULATE-PCI trial is that, because three (1%) of 479 patients assigned to REG1 in the phase 2b study6 had allergic reactions, the investigators would have anticipated that 40 patients (0·006 × 6600) would have a potentially fatal allergic reaction. Readers should realise that the investigators developed and applied a risk minimisation and action plan, which included prudent monitoring in the early hours after drug dosing. Yet the safety board had to halt the trial after 0·6% of patients had an allergic reaction, without clinical benefit.7 Nevertheless, the results of REGULATE-PCI are a wake-up call for the use of pegylated substances in acutely ill patients. In conclusion, parenteral anticoagulation with factor IXa blockade is feasible in the setting of coronary intervention for stable and unstable disease. However, relative to existing recommended anticoagulants, current efficacy and safety issues hamper further research and development of this new and theoretically promising approach. Freek W A Verheugt
I have received honoraria for speaking and consultancy from The Medicines Company, AstraZeneca, Daiichi-Sankyo, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, and Bayer Healthcare. 1
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Steg PG, James SK, Atar D, et al. ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2012; 33: 2569–619. Roffi M, Patrono C, Collet J-P, et al. 2015 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J 2015; published online Aug 29. DOI:10.1093/eurheartj/ehv320. Eikelboom JW, Mehta SR, Anand SS, Xie C, Fox KA, Yusuf S. Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation 2006; 114: 774–82. Dyke CK, Steinhubl SR, Kleiman NS, et al. First-in-human experience of an antidote-controlled anticoagulant using RNA aptamer technology: a phase 1a pharmacodynamic evaluation of a drug-antidote pair for the controlled regulation of factor IXa activity. Circulation 2006; 114: 2490–97. Chan MY, Cohen MG, Dyke CK, et al. Phase 1b randomized study of antidote-controlled modulation of factor IXa activity in patients with stable coronary artery disease. Circulation 2008; 117: 2865–74. Povsic TJ, Vavalle JP, Aberle LH, et al. A phase 2, randomized, partially blinded, active-controlled study assessing the efficacy and safety of variable anticoagulation reversal using the REG1 system in patients with acute coronary syndromes: results of the RADAR trial. Eur Heart J 2013; 34: 2481–89. Lincoff AM, Mehran R, Povsic TJ, et al, on behalf of the REGULATE-PCI Investigators. Effect of the REG1 anticoagulation system versus bivalirudin on outcomes after percutaneous coronary intervention (REGULATE-PCI): a randomised clinical trial. Lancet 2015; published online Nov 4. http://dx. doi.org/10.1016/S0140-6736(15)00515-2. Han Y, Guo J, Zheng Y, et al. Bivalirudin vs heparin with or without tirofiban during primary percutaneous coronary intervention in acute myocardial infarction: the BRIGHT randomized clinical trial. JAMA 2015; 313: 1336–46. Kastrati A, Neumann F-J, Nehilli J, et al, for the ISAR-REACT 3 Trial Investigators. Bivalirudin versus unfractionated heparin during percutaneous coronary intervention. N Engl J Med 2008; 359: 688–96.
Heartcenter, Onze Lieve Vrouwe Gasthuis (OLVG), 1091 AC Amsterdam, Netherlands [email protected]
2
www.thelancet.com Published online November 4, 2015 http://dx.doi.org/10.1016/S0140-6736(15)00727-8
An anticoagulant too good to be true for revascularisation Revascularisation is recommended for most patients presenting with acute coronary syndromes,1,2 with percutaneous coronary intervention the most common procedure. Besides dual antiplatelet treatment with aspirin and a platelet P2Y12 blocker (eg, clopidogrel, prasugrel, or ticagrelor), parenteral anticoagulation is mandatory in patients undergoing this procedure. Heparin, low-molecular-weight heparin, and the specific thrombin (factor II) blocker bivalirudin are currently used for anticoagulation. Needless to say, bleeding occurs frequently during and after revascularisation. Since bleeding is associated with poor short-term and long-term outcomes,3 prevention of bleeding is of utmost importance. Factor IX contributes to activation of the coagulation cascade via the intrinsic route. REG1 is a two-component actively controllable anticoagulant system consisting of the factor IXa inhibitor pegnivacogin and a reversal agent, anivamersen, which has specific affinity for pegnivacogin.4,5 REG1 has been assessed with heparin in the randomised RADAR trial6 in 640 patients with nonST-elevation acute coronary syndromes undergoing percutaneous coronary intervention. At 30 days, fewer bleeding events had occurred with the 100% reversal strategy when compared with heparin (table). At least 50% pegnivacogin reversal was needed to prevent bleeding. Fewer ischaemic events occurred with REG1 (n=14 [3%]) than with heparin (n=9 [6%]). In three (1%) patients given pegnivacogin, allergic reactions occurred, two of which were serious.6 These findings warranted a phase 3 study with this new anticoagulant and an effective reversal agent in patients undergoing percutaneous coronary intervention. In The Lancet, Michael Lincoff and colleagues present the results of REGULATE-PCI,7 a randomised study intended to compare REG1 (pegnivacogin 1 mg/kg bolus, followed by 80% reversal with anivamersen) with bivalirudin in 13 200 patients at 225 hospitals in North America and Europe. The primary efficacy endpoint was a composite of all-cause death, myocardial infarction, stroke, and unplanned target lesion revascularisation by day 3 after randomisation. After 3232 patients had been enrolled, the safety committee advised halting of the trial because severe allergic reactions had occurred in ten (1%) of 1605 patients
receiving REG1, one of which was fatal, compared with one (<1%) of 1601 patients treated with bivalirudin. The decision was based on the absence of a clinical benefit of REG1, with no difference noted in the primary endpoint between groups (108 [7%] of 1616 patients assigned to REG1 vs 103 [6%] of 1616 on bivalirudin; odds ratio 1·05, 95% CI 0·80–1·39). Major bleeding occurred in seven (<1%) of 1605 patients assigned REG1 versus two (<1%) of 1601 in the bivalirudin group, but major or minor bleeding was increased in patients receiving REG1 (104 [7%] vs 65 [4%] patients, respectively). In view of the excess of bleeding events with REG1, despite availability of a reversal agent, and no reduction in hard ischaemic endpoints in more than 3000 patients, it is doubtful whether this approach to factor IXa blockade will go into further clinical development. A limitation of the REGULATE-PCI trial is that the comparator agent was bivalirudin, which has a better safety profile than heparin in acute coronary syndromes8 but not in elective percutaneous coronary intervention.9 Moreover, both acute and elective patients were enrolled. Additional anivamersen was administered in only 29 (2%) patients assigned to REG1,7 whereas reversal was done in up to 5% of patients in the phase 2b trial (table).6 Theoretically, correction of this shortcoming would have resulted in better bleeding outcomes. Yet it is too early to halt investigation of factor IXa blockade in percutaneous coronary intervention. The combination of a novel anticoagulant with a specific reversal molecule should be tested in more trials, but pegylated agents seem to be hazardous in patients with acute coronary syndromes. A new formulation of the factor IXa inhibitor without pegylation would be very welcome. But the agent—which in the REGULATEPCI trial was given as bolus (similar to the antidote)— would then be infused continuously in the same
Open reversal applied
See Online/Articles http://dx.doi.org/10.1016/ S0140-6736(15)00515-2
REG1 with 50% reversal (n=113)
REG1 with 75% reversal (n=119)
REG1 with 100% reversal (n=194)
8 (20%)
12 (11%)
10 (8%)
14 (7%)
12 (31%)*
6 (5%)
6 (5%)
5 (3%)
REG1 with 25% reversal (n=40) Major bleeding
Published Online November 4, 2015 http://dx.doi.org/10.1016/ S0140-6736(15)00727-8
Heparin (n=160) 16 (10%) NA
Data taken from reference 6. NA=not applicable. PCI=percutaneous coronary intervention. *One patient dropped out.
Table: Major bleeding in patients with non-ST-elevation acute coronary syndromes undergoing PCI and treated with REG1 versus heparin
www.thelancet.com Published online November 4, 2015 http://dx.doi.org/10.1016/S0140-6736(15)00727-8
1
Comment
way as bivalirudin or heparin, which is a practical disadvantage. Another limitation of the design and conduct of the REGULATE-PCI trial is that, because three (1%) of 479 patients assigned to REG1 in the phase 2b study6 had allergic reactions, the investigators would have anticipated that 40 patients (0·006 × 6600) would have a potentially fatal allergic reaction. Readers should realise that the investigators developed and applied a risk minimisation and action plan, which included prudent monitoring in the early hours after drug dosing. Yet the safety board had to halt the trial after 0·6% of patients had an allergic reaction, without clinical benefit.7 Nevertheless, the results of REGULATE-PCI are a wake-up call for the use of pegylated substances in acutely ill patients. In conclusion, parenteral anticoagulation with factor IXa blockade is feasible in the setting of coronary intervention for stable and unstable disease. However, relative to existing recommended anticoagulants, current efficacy and safety issues hamper further research and development of this new and theoretically promising approach. Freek W A Verheugt
I have received honoraria for speaking and consultancy from The Medicines Company, AstraZeneca, Daiichi-Sankyo, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, and Bayer Healthcare. 1
2
3
4
5
6
7
8
9
Steg PG, James SK, Atar D, et al. ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2012; 33: 2569–619. Roffi M, Patrono C, Collet J-P, et al. 2015 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J 2015; published online Aug 29. DOI:10.1093/eurheartj/ehv320. Eikelboom JW, Mehta SR, Anand SS, Xie C, Fox KA, Yusuf S. Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation 2006; 114: 774–82. Dyke CK, Steinhubl SR, Kleiman NS, et al. First-in-human experience of an antidote-controlled anticoagulant using RNA aptamer technology: a phase 1a pharmacodynamic evaluation of a drug-antidote pair for the controlled regulation of factor IXa activity. Circulation 2006; 114: 2490–97. Chan MY, Cohen MG, Dyke CK, et al. Phase 1b randomized study of antidote-controlled modulation of factor IXa activity in patients with stable coronary artery disease. Circulation 2008; 117: 2865–74. Povsic TJ, Vavalle JP, Aberle LH, et al. A phase 2, randomized, partially blinded, active-controlled study assessing the efficacy and safety of variable anticoagulation reversal using the REG1 system in patients with acute coronary syndromes: results of the RADAR trial. Eur Heart J 2013; 34: 2481–89. Lincoff AM, Mehran R, Povsic TJ, et al, on behalf of the REGULATE-PCI Investigators. Effect of the REG1 anticoagulation system versus bivalirudin on outcomes after percutaneous coronary intervention (REGULATE-PCI): a randomised clinical trial. Lancet 2015; published online Nov 4. http://dx. doi.org/10.1016/S0140-6736(15)00515-2. Han Y, Guo J, Zheng Y, et al. Bivalirudin vs heparin with or without tirofiban during primary percutaneous coronary intervention in acute myocardial infarction: the BRIGHT randomized clinical trial. JAMA 2015; 313: 1336–46. Kastrati A, Neumann F-J, Nehilli J, et al, for the ISAR-REACT 3 Trial Investigators. Bivalirudin versus unfractionated heparin during percutaneous coronary intervention. N Engl J Med 2008; 359: 688–96.
Heartcenter, Onze Lieve Vrouwe Gasthuis (OLVG), 1091 AC Amsterdam, Netherlands [email protected]
2
www.thelancet.com Published online November 4, 2015 http://dx.doi.org/10.1016/S0140-6736(15)00727-8