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Cangrelor infusion is associated with an increased risk for bleeding: Meta-analysis of randomized trials
IJCA-16973; No of Pages 4 International Journal of Cardiology xxx (2013) xxx–xxx
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Cangrelor infusion is associated with an increased risk for bleeding: Meta-analysis of randomized trials Victor L. Serebruany a,⁎, Daniel Aradi b, Moo Hyun Kim a, Dirk Sibbing c a b c
HeartDrug™ Research Laboratories, Johns Hopkins University, Osler Medical Building, 7600 Osler Drive, Suite 307, Towson, MD 21204, United States Interventional Cardiologist, Department of Cardiology, Heart Center Balatonfüred, Hungary Medizinische Klinik and Poliklinik I, Department of Cardiology, Ludwig-Maximilians-University, Munich, Germany
a r t i c l e
i n f o
Article history: Received 24 July 2013 Accepted 30 August 2013 Available online xxxx Keywords: Cangrelor Bleeding Safety Clinical trials
a b s t r a c t Context: Aggressive antiplatelet strategies unquestionably cause extra hemorrhagic risks. Bleeding episodes are associated with poor outcomes including increased mortality. However, lack of uniform reporting and adjudication of bleeding events might prevent objective evaluation of the efficacy/safety profile of antithrombotic agents. Objective: We analyzed the bleeding rates by several previously used bleeding scales (TIMI, GUSTO, ACUITY, and BARC) after cangrelor in recent head-to-head randomized, controlled clinical trials (RCTs). Results: Data for meta-analyses were pooled from 3 RCTs (CHAMPION-PLATFORM, CHAMPION-PCI and CHAMPION-PHOENIX) including 25,106 patients. In addition, the bleeding risks were also assessed from the small (n = 210) BRIDGE RCT. Cangrelor caused a significantly increased risk for major bleeding at 48 h according to the ACUITY scale (RR: 1.51, 95% CI: 1.32–1.72, p b 0.00001); however, this impact was less prominent according to less sensitive bleeding scales (GUSTO severe: RR: 1.21, 95% CI: 0.70–2.11, p = 0.49; TIMI major: RR: 1.00, 95% CI: 0.59–1.68, p = 0.99). There was also an obvious trend towards an increased risk for any transfusions (RR: 1.31, 95% CI: 0.97–1.77, p = 0.08) and TIMI major + minor bleeding events (RR: 1.30, 95% CI: 0.96–1.76, p = 0.09). Conclusions: Cangrelor on top of aspirin or/and clopidogrel increases the risk for early bleeding events after PCI; however, it largely depends on the bleeding definition used, and how this excess risk of bleeding was captured. The bleeding hazard needs to be verified in the ongoing FDA secondary cangrelor review. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction One of the largest controversies of modern antiplatelet strategies is the uncertain relation among their potency, associated degree of platelet inhibition, bleeding risks, and adverse vascular outcomes. There are consistent ongoing, yet controversial attempts to improve vascular outcomes by applying more aggressive or/and potent antiplatelet regimens. However, this strategy cause increased risks of bleeding, which are already borderline acceptable to the patients treated with conventional clopidogrel and low-dose aspirin. In fact, bleeding may be equally or even more dangerous than classical myocardial infarction with regard to associated mortality. Personal communications with the FDA officials in charge of clinical reviews in cardio-renal division reveal that overall mortality in the ACS trials is ≈3–4%, after myocardial infarction is ≈7.0–7.5%, but if a patient experience a single bleeding event, the death rate is close to 10%. It is impossible to reference such data since it belongs to different agents, and trial designs, however, this statement cannot be ignored. Such a disproportional mortality patterns are ⁎ Corresponding author. Tel.: +1 410 847 9490; fax: +1 443 583 0205. E-mail addresses: [email protected] (V.L. Serebruany), [email protected] (D. Aradi).
indirectly supported by extra deaths associated with astronomical bleeding rates after oral GP IIb/IIIa inhibitors [1,2], and questionable death benefit after intravenous GP IIb/IIIa antiplatelet agents, when single trials show no significant mortality reduction, but many metaanalyses suggest some mortality benefit (e.g. [3,4]). Also supportive that bleeding per se may be more dangerous than coronary thrombotic occlusions, was the cornerstone paper from the OASIS group suggesting strong, consistent, temporal, and dose-related association between bleeding and death [5]. However, it is still unclear how to adequately measure the bleeding risks. One of the reasons why this question remains unanswered is a difficulty to apply the appropriate type of classifications used to adequately categorize bleeding. Both conventional TIMI [6] and GUSTO [7] bleeding scales emerged a quarter century ago, during the era of intensive development of thrombolytic agents, when intracranial hemorrhages were the most common life-threatening complications of drug-induced fibrinolysis. Therefore, both classifications are not well suitable to assess less severe bleeding events. Later, in the era of antiplatelet agents, these scales survived due to the dominant role of TIMI and GUSTO groups in clinical trials, and mostly, due to the fact that most non-catastrophic bleeding complications can be easily “hidden” or unreported in the trial. ACUTY trial offered more liberal than TIMI and GUSTO classification allowing more realistic assessment of
0167-5273/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.08.133
Please cite this article as: Serebruany VL, et al, Cangrelor infusion is associated with an increased risk for bleeding: Meta-analysis of randomized trials, Int J Cardiol (2013), http://dx.doi.org/10.1016/j.ijcard.2013.08.133
2
V.L. Serebruany et al. / International Journal of Cardiology xxx (2013) xxx–xxx
bleeding risks [8]. Finally, standardized bleeding definitions for cardiovascular clinical trials from the Bleeding Academic Research Consortium issued a consensus report [9], although the “real-life” survival of this scale remains to be seen. Cangrelor, a nonthienopyridine adenosine triphosphate analog, is an intravenous antagonist of the P2Y12-receptor characterized by potent, and reversible platelet inhibition with presumably rapid offset of action [10]. There is a solid clinical evidence yielded from 4 randomized trials, namely BRIFGE [11], CHAMPION-PCI [12], CHAMPION-PLATFORM [13], and finally the largest CHAMPION-PHOENIX [14]. The cangrelor development program offers a major advantage since bleeding events were uniformly assessed in all 4 trials applying the same TIMI, GUSTO and ACUITY bleeding scales. In addition, CHAMPION-PHOENIX report bleeding rates by BARC definition in its supplemental materials. Each trial consistently assessed the bleeding risks after cangrelor when compared to placebo, or clopidogrel. 2. Analysis and results In the current analysis, we compared bleeding rates after cangrelor infusion by applying TIMI, GUSTO and ACUITY bleeding scales and using other bleeding-related metrics (rate of transfusions). Absolute event rates were tabulated from the three RCTs and analyzed in fixedeffect Mantel–Heanszel models. Risk ratios (RR) were calculated with 95% confidence intervals (CI). A p value less than 0.05 was considered statistically significant in all analyses. Main results of the included studies according to each bleeding criterion are summarized in Table 1. The evidence from the table suggests an excess risk for bleeding after cangrelor when compared to placebo.
Table 1 Bleeding events in cangrelor trials. Trial/event
Cangrelor
Placebo
Relative risk (95% CI)
BRIDGE (n = 210) Protocol defined ACUITY major ACUITY minor GUSTO severe GUSTO moderate GUSTO mild TIMI major TIMI minor
11.8% 2.8% 17.9% 0 1.9% 17.9% 0.9% 0.9%
10.4% 1.0% 9.9% 0 1.0% 9.9% 0 0
1.1 (0.5–2.5) 2.9 (0.3–27.0) 1.8 (0.9–3.7) N/A 1.9 (0.2–20.7) 1.8 (0.9–3.7) N/A N/A
PLATFORM (n = 5362) Transfusion required ACUITY major ACUITY minor GUSTO severe GUSTO moderate GUSTO mild TIMI major TIMI minor
1.0% 5.5% 12.0% 0.3% 0.8% 16.0% 0.2% 0.8%
0.6% 3.5% 9.3% 0.2% 0.5% 11.7% 0.3% 0.6%
1.62 (0.87–3.03) 1.61 (1.23–2.10) 1.34 (1.12–1.59) 1.50 (0.53–4.21) 1.54 (0.76–3.09) 1.44 (1.23–1.69) 0.44 (0.14–1.44) 1.37 (0.72–2.62)
PCI (n = 7754) ACUITY major ACUITY minor GUSTO severe GUSTO moderate GUSTO mild TIMI major TIMI minor
3.6% 17.6% 0.2% 0.9% 19.6% 0.4% 0.8%
2.9% 15.2% 0.3% 0.8% 16.9% 0.3% 0.6%
1.26 (0.99–1.60) 1.19 (1.06–1.33) 0.91 (0.39–2.14) 1.21 (0.76–1.90) 1.20 (1.07–1.34) 1.36 (0.68–2.71) 1.39 (0.84–2.30)
PHOENIX (n = 11,145) Transfusion required ACUITY major ACUITY minor GUSTO severe GUSTO severe or moderate GUSTO moderate TIMI major TIMI minor BARC type 3
0.5% 4.3% 11.8% 0.2% 0.6% 0.4% 0.1% 0.2% 0.4%
0.3% 2.5% 8.6% 0.1% 0.3% 0.2% 0.1% 0.1% 0.2%
1.56 (0.83–2.93) 1.72 (1.39–2.13) 1.42 (1.26–1.61) 1.50 (0.53–4.22) 1.63 (0.92–2.90) 1.69 (0.85–3.37) 1.00 (0.29–3.45) 3.00 (0.81–11.10) 1.69 (0.85–3.37)
When results were pooled into a meta-analysis, there was a significantly elevated risk for bleeding according to the most sensitive ACUITY criteria (RR: 1.51, 95% CI: 1.32–1.72, p b 0.0001), whereas this effect was less prominent with the more conservative and less inclusive GUSTO (RR: 1.21, 95% CI: 0.70–2.11, p = 0.49) and TIMI criteria (RR: 1.00, 95% CI: 0.59–1.68, p = 0.99). We also observed a clear trend (about 30%) towards an excess risk of transfusions (RR: 1.31, 95% CI: 0.97–1.77, p = 0.08) and combination of major and minor bleedings (RR: 1.30, 95% CI: 0.96–1.76, p = 0.09) (Fig. 1). Importantly, all discussed scales will miss double-digit nuisance bleedings, while the clinical significance of such gap is unclear, and was never tested in a large randomized trial. 3. Discussions Few issues merit brief discussion. First, applying the same 3 bleeding scales for all 4 published trials with cangrelor is a definite recent achievement offering uniformed fair assessment of affiliated bleeding risks. This approach is better than modification of a single scale, as what happened in INOVATE-PCI trial with elinogrel, when TIMI classification has been changed to major, minor, or newly introduced “bleeding required medical attention” [15]. Also confusing is introducing a new bleeding scale in the frame of a single trial, as have happened in PLATO, and matching the bleeding data with the conservative TIMI scale [6,16]. These efforts cannot be supported and represent an attempt to create a “safety net” for more potent aggressive antiplatelet regimens. Second, most of the patients undergoing dual antiplatelet therapy develop minor superficial bleeding events, which are usually disregarded, and never reported, especially in the frame of large outcome driven studies. It is entirely unclear whether or not these minor bleeding episodes impact vascular outcomes. Not surprisingly, TIMI bleeding classification initially characterized such bleeding events as “insignificant” [6]. Third, the index analyses rely on the bleeding rates outlined in the official trial publications [11–14]. Since, cangrelor manufacturer submitted a new drug application, applying for the FDA approval, the bleeding data will be under scrutiny by the Agency Secondary Clinical Review. Historically, the FDA reports usually challenge the overoptimistic calculation of benefit/safety ratios as have happened with prasugrel [17] and ticagrelor [18], so the verified bleeding risks after cangrelor may be even higher than initially reported [11–14]. Fourth, cangrelor utilization (if any) will be tailored to seek “bridging” indication specifically to the patients undergoing heart surgery. Indeed, BRIDGE trial was done in thienopyridine-free patients undergoing CABG [11]. The actual surgery bleeding risks look better for cangrelor, but the study was very small (n = 210), with no fatal bleeding, or intracranial hemorrhages [11], so the reported numbers may represent a play of chance. How transparent the general PCI data with the low rate of STEMI and CABG, and moderate ischemic burden will be relevant to the future heart surgery population is entirely unknown. Moreover, whether the promising but woefully small BRIDGE post-CABG data transform into the bleeding advantage of cangrelor (if approved) in “real-life” heart surgery patients is also unclear. It will be logical to run the outcome driven exclusive CABG trial, but this was not done. Finally, the lack of “mild” GUSTO bleeding reporting in the CHAMPION-PHOENIX trial, and placing it to the supplement materials the doubled BARC-defined bleeding risks suggest that it may be some unpleasant safety “surprises” in the FDA cangrelor review. This is especially confusing since the “severe and life-threatening” GUSTO bleeding represents the primary safety end point in CHAMPIONPHOENIX, and there is no reason not to report all GUSTO types of bleeds, which were definitely counted, and should be mandatorily presented. 4. Conclusion We conclude that administration of cangrelor on top of aspirin or/ and clopidogrel increases the risk for early bleeding events after PCI. However, it largely depends on the bleeding definition used, and how this excess risk of bleeding was captured.
Please cite this article as: Serebruany VL, et al, Cangrelor infusion is associated with an increased risk for bleeding: Meta-analysis of randomized trials, Int J Cardiol (2013), http://dx.doi.org/10.1016/j.ijcard.2013.08.133
V.L. Serebruany et al. / International Journal of Cardiology xxx (2013) xxx–xxx
3
Fig. 1. Relative risks (RR) for bleeding events according to various definitions in randomized trials with cangrelor.
Disclosures VLS received research grants and consulting fees from SanofiAventis, Bayer and McNeil Consumer Products (the manufacturers of clopidogrel and aspirin). He is listed as an inventor for the U.S. Patent Application “Treating Cardiac Arrhythmias, heart failure, peripheral artery disease and stroke with cyclopentyl-triazolo-pyrimidine or derivative thereof” (USN 61/253,829) assigned to HeartDrug™ Research. He received funding for research studies with clopidogrel, and consultant fees from the clopidogrel, ticagrelor, and elinogrel manufacturers. DS reports research grants/consulting: Daiichi Sankyo, Verum Diagnostica, and lecture fees: Roche, CSL Behring, Eli Lilly. DA received speaker's honoraria, congress participations and consultancy fees from SanofiAventis. None of these funds were linked to the present research and
publication. Special thanks to Dr. D. Angiolillo (BRIDGE) for the trial data clarification. The paper represents the content of a report issued for the FDA on July 18, 2013 but solely reflects the viewpoint of the authors, and has been subjected to peer review. The article does not necessarily reflect the views of the editors or publishers. The cangrelor new drug application has been submitted for the FDA secondary review in July, 2013. References [1] Chew DP, Bhatt DL, Sapp S, Topol EJ. Increased mortality with oral platelet glycoprotein IIb/IIIa antagonists: a meta-analysis of phase III multicenter randomized trials. Circulation 2001;103:201–6. [2] Cannon CP. Learning from the recently completed oral glycoprotein IIb/IIIa receptor antagonist trials. Clin Cardiol 2000;23(Suppl. 6:VI):14–7.
Please cite this article as: Serebruany VL, et al, Cangrelor infusion is associated with an increased risk for bleeding: Meta-analysis of randomized trials, Int J Cardiol (2013), http://dx.doi.org/10.1016/j.ijcard.2013.08.133
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[3] De Luca G, Gibson CM, Bellandi F, et al. Early glycoprotein IIb–IIIa inhibitors in primary angioplasty (EGYPT) cooperation: an individual patient data meta-analysis. Heart 2008;94:1548–58. [4] DE Luca G, Bellandi F, Huber K, et al. Early glycoprotein IIb–IIIa inhibitors in primary angioplasty-abciximab long-term results (EGYPT-ALT) cooperation: individual patient's data meta-analysis. J Thromb Haemost 2011;9:2361–70. [5] 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. [6] Rao AK, Pratt C, Berke A, et al. Thrombolysis in myocardial infarction (TIMI) Trial— phase I: hemorrhagic manifestations and changes in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase. J Am Coll Cardiol 1988;11(1):1–11. [7] The GUSTO investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993;329(10):673–82. [8] Stone GW, McLaurin BT, Cox DA, et al. ACUITY investigators. Bivalirudin for patients with acute coronary syndromes. N Engl J Med 2006;355:2203–16. [9] Mehran R, Rao SV, Bhatt DL, et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation 2011;123:2736–47. [10] Ferreiro JL, Ueno M, Angiolillo DJ. Cangrelor: a review on its mechanism of action and clinical development. Expert Rev Cardiovasc Ther 2009;7:1195–201.
[11] Angiolillo DJ, Firstenberg MS, Price MJ, et al. Bridging antiplatelet therapy with cangrelor in patients undergoing cardiac surgery: a randomized controlled trial. JAMA 2012;307:265–74. [12] Harrington RA, Stone GW, McNulty S, et al. Platelet inhibition with cangrelor in patients undergoing PCI. N Engl J Med 2009;361:2318–29. [13] Bhatt DL, Lincoff AM, Gibson CM, et al. Intravenous platelet blockade with cangrelor during PCI. N Engl J Med 2009;361:2330–41. [14] Bhatt DL, Stone GW, Mahaffey KW, et al. Effect of platelet inhibition with cangrelor during PCI on ischemic events. N Engl J Med 2013;368(14):1303–13. [15] Welsh RC, Rao SV, Zeymer U, et al. A randomized, double-blind, active-controlled phase 2 trial to evaluate a novel selective and reversible intravenous and oral P2Y12 inhibitor elinogrel versus clopidogrel in patients undergoing nonurgent percutaneous coronary intervention: the INNOVATE-PCI trial. Circ Cardiovasc Interv 2012;5:336–46. [16] Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045–57. [17] The FDA prasugrel secondary review. Available for download at http://www.fda.gov/ ohrms/dockets/ac/09/briefing/2009–4412b1–00-FDA.htm. (Assessed March 24, 2013). [18] FDA ticagrelor review of complete response — drug approval package. http://www. accessdata.fda.gov/drugsatfda_docs/nda/2011/022433Orig1s000TOC.cfm. (Assessed March 24, 2013).
Please cite this article as: Serebruany VL, et al, Cangrelor infusion is associated with an increased risk for bleeding: Meta-analysis of randomized trials, Int J Cardiol (2013), http://dx.doi.org/10.1016/j.ijcard.2013.08.133
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Cangrelor infusion is associated with an increased risk for bleeding: Meta-analysis of randomized trials Victor L. Serebruany a,⁎, Daniel Aradi b, Moo Hyun Kim a, Dirk Sibbing c a b c
HeartDrug™ Research Laboratories, Johns Hopkins University, Osler Medical Building, 7600 Osler Drive, Suite 307, Towson, MD 21204, United States Interventional Cardiologist, Department of Cardiology, Heart Center Balatonfüred, Hungary Medizinische Klinik and Poliklinik I, Department of Cardiology, Ludwig-Maximilians-University, Munich, Germany
a r t i c l e
i n f o
Article history: Received 24 July 2013 Accepted 30 August 2013 Available online xxxx Keywords: Cangrelor Bleeding Safety Clinical trials
a b s t r a c t Context: Aggressive antiplatelet strategies unquestionably cause extra hemorrhagic risks. Bleeding episodes are associated with poor outcomes including increased mortality. However, lack of uniform reporting and adjudication of bleeding events might prevent objective evaluation of the efficacy/safety profile of antithrombotic agents. Objective: We analyzed the bleeding rates by several previously used bleeding scales (TIMI, GUSTO, ACUITY, and BARC) after cangrelor in recent head-to-head randomized, controlled clinical trials (RCTs). Results: Data for meta-analyses were pooled from 3 RCTs (CHAMPION-PLATFORM, CHAMPION-PCI and CHAMPION-PHOENIX) including 25,106 patients. In addition, the bleeding risks were also assessed from the small (n = 210) BRIDGE RCT. Cangrelor caused a significantly increased risk for major bleeding at 48 h according to the ACUITY scale (RR: 1.51, 95% CI: 1.32–1.72, p b 0.00001); however, this impact was less prominent according to less sensitive bleeding scales (GUSTO severe: RR: 1.21, 95% CI: 0.70–2.11, p = 0.49; TIMI major: RR: 1.00, 95% CI: 0.59–1.68, p = 0.99). There was also an obvious trend towards an increased risk for any transfusions (RR: 1.31, 95% CI: 0.97–1.77, p = 0.08) and TIMI major + minor bleeding events (RR: 1.30, 95% CI: 0.96–1.76, p = 0.09). Conclusions: Cangrelor on top of aspirin or/and clopidogrel increases the risk for early bleeding events after PCI; however, it largely depends on the bleeding definition used, and how this excess risk of bleeding was captured. The bleeding hazard needs to be verified in the ongoing FDA secondary cangrelor review. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction One of the largest controversies of modern antiplatelet strategies is the uncertain relation among their potency, associated degree of platelet inhibition, bleeding risks, and adverse vascular outcomes. There are consistent ongoing, yet controversial attempts to improve vascular outcomes by applying more aggressive or/and potent antiplatelet regimens. However, this strategy cause increased risks of bleeding, which are already borderline acceptable to the patients treated with conventional clopidogrel and low-dose aspirin. In fact, bleeding may be equally or even more dangerous than classical myocardial infarction with regard to associated mortality. Personal communications with the FDA officials in charge of clinical reviews in cardio-renal division reveal that overall mortality in the ACS trials is ≈3–4%, after myocardial infarction is ≈7.0–7.5%, but if a patient experience a single bleeding event, the death rate is close to 10%. It is impossible to reference such data since it belongs to different agents, and trial designs, however, this statement cannot be ignored. Such a disproportional mortality patterns are ⁎ Corresponding author. Tel.: +1 410 847 9490; fax: +1 443 583 0205. E-mail addresses: [email protected] (V.L. Serebruany), [email protected] (D. Aradi).
indirectly supported by extra deaths associated with astronomical bleeding rates after oral GP IIb/IIIa inhibitors [1,2], and questionable death benefit after intravenous GP IIb/IIIa antiplatelet agents, when single trials show no significant mortality reduction, but many metaanalyses suggest some mortality benefit (e.g. [3,4]). Also supportive that bleeding per se may be more dangerous than coronary thrombotic occlusions, was the cornerstone paper from the OASIS group suggesting strong, consistent, temporal, and dose-related association between bleeding and death [5]. However, it is still unclear how to adequately measure the bleeding risks. One of the reasons why this question remains unanswered is a difficulty to apply the appropriate type of classifications used to adequately categorize bleeding. Both conventional TIMI [6] and GUSTO [7] bleeding scales emerged a quarter century ago, during the era of intensive development of thrombolytic agents, when intracranial hemorrhages were the most common life-threatening complications of drug-induced fibrinolysis. Therefore, both classifications are not well suitable to assess less severe bleeding events. Later, in the era of antiplatelet agents, these scales survived due to the dominant role of TIMI and GUSTO groups in clinical trials, and mostly, due to the fact that most non-catastrophic bleeding complications can be easily “hidden” or unreported in the trial. ACUTY trial offered more liberal than TIMI and GUSTO classification allowing more realistic assessment of
0167-5273/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.08.133
Please cite this article as: Serebruany VL, et al, Cangrelor infusion is associated with an increased risk for bleeding: Meta-analysis of randomized trials, Int J Cardiol (2013), http://dx.doi.org/10.1016/j.ijcard.2013.08.133
2
V.L. Serebruany et al. / International Journal of Cardiology xxx (2013) xxx–xxx
bleeding risks [8]. Finally, standardized bleeding definitions for cardiovascular clinical trials from the Bleeding Academic Research Consortium issued a consensus report [9], although the “real-life” survival of this scale remains to be seen. Cangrelor, a nonthienopyridine adenosine triphosphate analog, is an intravenous antagonist of the P2Y12-receptor characterized by potent, and reversible platelet inhibition with presumably rapid offset of action [10]. There is a solid clinical evidence yielded from 4 randomized trials, namely BRIFGE [11], CHAMPION-PCI [12], CHAMPION-PLATFORM [13], and finally the largest CHAMPION-PHOENIX [14]. The cangrelor development program offers a major advantage since bleeding events were uniformly assessed in all 4 trials applying the same TIMI, GUSTO and ACUITY bleeding scales. In addition, CHAMPION-PHOENIX report bleeding rates by BARC definition in its supplemental materials. Each trial consistently assessed the bleeding risks after cangrelor when compared to placebo, or clopidogrel. 2. Analysis and results In the current analysis, we compared bleeding rates after cangrelor infusion by applying TIMI, GUSTO and ACUITY bleeding scales and using other bleeding-related metrics (rate of transfusions). Absolute event rates were tabulated from the three RCTs and analyzed in fixedeffect Mantel–Heanszel models. Risk ratios (RR) were calculated with 95% confidence intervals (CI). A p value less than 0.05 was considered statistically significant in all analyses. Main results of the included studies according to each bleeding criterion are summarized in Table 1. The evidence from the table suggests an excess risk for bleeding after cangrelor when compared to placebo.
Table 1 Bleeding events in cangrelor trials. Trial/event
Cangrelor
Placebo
Relative risk (95% CI)
BRIDGE (n = 210) Protocol defined ACUITY major ACUITY minor GUSTO severe GUSTO moderate GUSTO mild TIMI major TIMI minor
11.8% 2.8% 17.9% 0 1.9% 17.9% 0.9% 0.9%
10.4% 1.0% 9.9% 0 1.0% 9.9% 0 0
1.1 (0.5–2.5) 2.9 (0.3–27.0) 1.8 (0.9–3.7) N/A 1.9 (0.2–20.7) 1.8 (0.9–3.7) N/A N/A
PLATFORM (n = 5362) Transfusion required ACUITY major ACUITY minor GUSTO severe GUSTO moderate GUSTO mild TIMI major TIMI minor
1.0% 5.5% 12.0% 0.3% 0.8% 16.0% 0.2% 0.8%
0.6% 3.5% 9.3% 0.2% 0.5% 11.7% 0.3% 0.6%
1.62 (0.87–3.03) 1.61 (1.23–2.10) 1.34 (1.12–1.59) 1.50 (0.53–4.21) 1.54 (0.76–3.09) 1.44 (1.23–1.69) 0.44 (0.14–1.44) 1.37 (0.72–2.62)
PCI (n = 7754) ACUITY major ACUITY minor GUSTO severe GUSTO moderate GUSTO mild TIMI major TIMI minor
3.6% 17.6% 0.2% 0.9% 19.6% 0.4% 0.8%
2.9% 15.2% 0.3% 0.8% 16.9% 0.3% 0.6%
1.26 (0.99–1.60) 1.19 (1.06–1.33) 0.91 (0.39–2.14) 1.21 (0.76–1.90) 1.20 (1.07–1.34) 1.36 (0.68–2.71) 1.39 (0.84–2.30)
PHOENIX (n = 11,145) Transfusion required ACUITY major ACUITY minor GUSTO severe GUSTO severe or moderate GUSTO moderate TIMI major TIMI minor BARC type 3
0.5% 4.3% 11.8% 0.2% 0.6% 0.4% 0.1% 0.2% 0.4%
0.3% 2.5% 8.6% 0.1% 0.3% 0.2% 0.1% 0.1% 0.2%
1.56 (0.83–2.93) 1.72 (1.39–2.13) 1.42 (1.26–1.61) 1.50 (0.53–4.22) 1.63 (0.92–2.90) 1.69 (0.85–3.37) 1.00 (0.29–3.45) 3.00 (0.81–11.10) 1.69 (0.85–3.37)
When results were pooled into a meta-analysis, there was a significantly elevated risk for bleeding according to the most sensitive ACUITY criteria (RR: 1.51, 95% CI: 1.32–1.72, p b 0.0001), whereas this effect was less prominent with the more conservative and less inclusive GUSTO (RR: 1.21, 95% CI: 0.70–2.11, p = 0.49) and TIMI criteria (RR: 1.00, 95% CI: 0.59–1.68, p = 0.99). We also observed a clear trend (about 30%) towards an excess risk of transfusions (RR: 1.31, 95% CI: 0.97–1.77, p = 0.08) and combination of major and minor bleedings (RR: 1.30, 95% CI: 0.96–1.76, p = 0.09) (Fig. 1). Importantly, all discussed scales will miss double-digit nuisance bleedings, while the clinical significance of such gap is unclear, and was never tested in a large randomized trial. 3. Discussions Few issues merit brief discussion. First, applying the same 3 bleeding scales for all 4 published trials with cangrelor is a definite recent achievement offering uniformed fair assessment of affiliated bleeding risks. This approach is better than modification of a single scale, as what happened in INOVATE-PCI trial with elinogrel, when TIMI classification has been changed to major, minor, or newly introduced “bleeding required medical attention” [15]. Also confusing is introducing a new bleeding scale in the frame of a single trial, as have happened in PLATO, and matching the bleeding data with the conservative TIMI scale [6,16]. These efforts cannot be supported and represent an attempt to create a “safety net” for more potent aggressive antiplatelet regimens. Second, most of the patients undergoing dual antiplatelet therapy develop minor superficial bleeding events, which are usually disregarded, and never reported, especially in the frame of large outcome driven studies. It is entirely unclear whether or not these minor bleeding episodes impact vascular outcomes. Not surprisingly, TIMI bleeding classification initially characterized such bleeding events as “insignificant” [6]. Third, the index analyses rely on the bleeding rates outlined in the official trial publications [11–14]. Since, cangrelor manufacturer submitted a new drug application, applying for the FDA approval, the bleeding data will be under scrutiny by the Agency Secondary Clinical Review. Historically, the FDA reports usually challenge the overoptimistic calculation of benefit/safety ratios as have happened with prasugrel [17] and ticagrelor [18], so the verified bleeding risks after cangrelor may be even higher than initially reported [11–14]. Fourth, cangrelor utilization (if any) will be tailored to seek “bridging” indication specifically to the patients undergoing heart surgery. Indeed, BRIDGE trial was done in thienopyridine-free patients undergoing CABG [11]. The actual surgery bleeding risks look better for cangrelor, but the study was very small (n = 210), with no fatal bleeding, or intracranial hemorrhages [11], so the reported numbers may represent a play of chance. How transparent the general PCI data with the low rate of STEMI and CABG, and moderate ischemic burden will be relevant to the future heart surgery population is entirely unknown. Moreover, whether the promising but woefully small BRIDGE post-CABG data transform into the bleeding advantage of cangrelor (if approved) in “real-life” heart surgery patients is also unclear. It will be logical to run the outcome driven exclusive CABG trial, but this was not done. Finally, the lack of “mild” GUSTO bleeding reporting in the CHAMPION-PHOENIX trial, and placing it to the supplement materials the doubled BARC-defined bleeding risks suggest that it may be some unpleasant safety “surprises” in the FDA cangrelor review. This is especially confusing since the “severe and life-threatening” GUSTO bleeding represents the primary safety end point in CHAMPIONPHOENIX, and there is no reason not to report all GUSTO types of bleeds, which were definitely counted, and should be mandatorily presented. 4. Conclusion We conclude that administration of cangrelor on top of aspirin or/ and clopidogrel increases the risk for early bleeding events after PCI. However, it largely depends on the bleeding definition used, and how this excess risk of bleeding was captured.
Please cite this article as: Serebruany VL, et al, Cangrelor infusion is associated with an increased risk for bleeding: Meta-analysis of randomized trials, Int J Cardiol (2013), http://dx.doi.org/10.1016/j.ijcard.2013.08.133
V.L. Serebruany et al. / International Journal of Cardiology xxx (2013) xxx–xxx
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Fig. 1. Relative risks (RR) for bleeding events according to various definitions in randomized trials with cangrelor.
Disclosures VLS received research grants and consulting fees from SanofiAventis, Bayer and McNeil Consumer Products (the manufacturers of clopidogrel and aspirin). He is listed as an inventor for the U.S. Patent Application “Treating Cardiac Arrhythmias, heart failure, peripheral artery disease and stroke with cyclopentyl-triazolo-pyrimidine or derivative thereof” (USN 61/253,829) assigned to HeartDrug™ Research. He received funding for research studies with clopidogrel, and consultant fees from the clopidogrel, ticagrelor, and elinogrel manufacturers. DS reports research grants/consulting: Daiichi Sankyo, Verum Diagnostica, and lecture fees: Roche, CSL Behring, Eli Lilly. DA received speaker's honoraria, congress participations and consultancy fees from SanofiAventis. None of these funds were linked to the present research and
publication. Special thanks to Dr. D. Angiolillo (BRIDGE) for the trial data clarification. The paper represents the content of a report issued for the FDA on July 18, 2013 but solely reflects the viewpoint of the authors, and has been subjected to peer review. The article does not necessarily reflect the views of the editors or publishers. The cangrelor new drug application has been submitted for the FDA secondary review in July, 2013. References [1] Chew DP, Bhatt DL, Sapp S, Topol EJ. Increased mortality with oral platelet glycoprotein IIb/IIIa antagonists: a meta-analysis of phase III multicenter randomized trials. Circulation 2001;103:201–6. [2] Cannon CP. Learning from the recently completed oral glycoprotein IIb/IIIa receptor antagonist trials. Clin Cardiol 2000;23(Suppl. 6:VI):14–7.
Please cite this article as: Serebruany VL, et al, Cangrelor infusion is associated with an increased risk for bleeding: Meta-analysis of randomized trials, Int J Cardiol (2013), http://dx.doi.org/10.1016/j.ijcard.2013.08.133
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Please cite this article as: Serebruany VL, et al, Cangrelor infusion is associated with an increased risk for bleeding: Meta-analysis of randomized trials, Int J Cardiol (2013), http://dx.doi.org/10.1016/j.ijcard.2013.08.133