Horizon Scanning Centre November 2012

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1 Horizon Scanning Centre November 2012 Cangrelor to reduce platelet aggregation and thrombosis in patients undergoing percutaneous coronary intervention99 SUMMARY NIHR HSC ID: 2424 This briefing is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes or commissioning without additional information. Cangrelor is intended to be used in patients undergoing percutaneous coronary intervention for stable angina or acute coronary syndrome. If licensed, it would provide a rapidly reversible antiplatelet therapy option for this patient group. Acute coronary syndrome is usually caused by coronary atherosclerosis and encompasses a spectrum of disease including unstable angina, non-st segment elevation myocardial infarction and ST-segment elevation myocardial infarction. In , there were 71,583 hospital admissions for angina pectoris in England, of which 35,799 were specified as unstable angina. In the same time period, there were 49,070 hospital admissions for acute myocardial infarction, 13,767 admissions for subsequent myocardial infarction, 52,290 admissions for percutaneous transluminal balloon angioplasty with insertion of stent, and 2,872 admissions for transluminal angioplasty of coronary artery. In 2010, 25,960 deaths from acute myocardial infarction occurred in England and Wales. For patients undergoing percutaneous coronary intervention, current guidelines recommend antiplatelet therapy and antithrombin co-therapies. Cangrelor has been in phase III clinical trials comparing its effect on allcause mortality against treatment with clopidogrel. These trials have been published. This briefing presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health. NIHR Horizon Scanning Centre, University of Birmingham nihrhsc@contacts.bham.ac.uk Web:

2 TARGET GROUP Stable angina, acute coronary syndrome (ACS) or ST-segment-elevation myocardial infarction (STEMI) patients undergoing percutaneous coronary intervention (PCI). TECHNOLOGY DESCRIPTION Cangrelor (AR-C69931MX) is a direct-acting P2Y 12 platelet receptor antagonist that blocks adenosine diphosphate (ADP) induced platelet activation and aggregation. Its short plasma half-life yields a rapid loss of activity following discontinuation, which is a potentially significant safety advantage 1. Cangrelor is administered as a 30µg/kg bolus followed by intravenous (IV) infusion at 4µg/kg/min for 2-4 hours. Cangrelor is in phase III trials for the prevention of ischaemic heart disorders. INNOVATION and/or ADVANTAGES If licensed, cangrelor may provide an additional treatment option for this patient group that will be rapidly reversible. DEVELOPER The Medicines Company. AVAILABILITY, LAUNCH OR MARKETING In phase III clinical trials. PATIENT GROUP BACKGROUND ACS is usually caused by coronary atherosclerosis and encompasses a spectrum of disease including unstable angina (UA), non-st-segment elevation myocardial infarction (NSTEMI) and ST-segment elevation myocardial infarction (STEMI). In a large proportion of cases, the episode of coronary instability arises from thrombus formation on atheromatous plaques 2. Left untreated, prognosis is poor and mortality is high, particularly in people who have suffered myocardial damage 3. NHS or GOVERNMENT PRIORITY AREA This topic is relevant to the National Service Framework for Coronary Heart Disease (2005). CLINICAL NEED and BURDEN OF DISEASE In , there were 71,583 hospital admissions for angina pectoris (ICD10 I20) in England, of which 35,799 were specified as UA (ICD10 I20.0) 4. In the same time period, 2

3 there were 49,070 hospital admissions for acute myocardial infarction (MI) (ICD10 I21) and 13,767 admissions for subsequent MIs (ICD10 I22). For percutaneous transluminal balloon angioplasty with insertion of stent (OPCS-4 K75) and transluminal balloon angioplasty of coronary artery (OPCS4 K49), there were 52,290 and 2,872 hospital admissions respectively, accounting for a total of 156,764 bed days 4. In 2010, 25,960 deaths from acute MI (ICD10 I21) occurred in England and Wales 5. PATIENT PATHWAY RELEVANT GUIDANCE NICE Guidance NICE technology appraisal in development. Prasugrel with percutaneous coronary intervention for the treatment of acute coronary syndrome (review of TA182) (ID 648). Expected August NICE technology appraisal in development. Rivaroxaban for the prevention of adverse outcomes in patients after the acute management of acute coronary syndrome (ID532). Expected July NICE technology appraisal. Bivalirudin for the treatment of ST-segment-elevation myocardial infarction (TA230) NICE technology appraisal. Ticagrelor for the treatment of acute coronary syndromes (TA236) NICE technology appraisal. Clopidogrel and modified-release dipyridamole for the prevention of occlusive vascular events (TA210) NICE technology appraisal. Prasugrel for the treatment of acute coronary syndromes with percutaneous coronary intervention (TA182) NICE technology appraisal. Drug-eluting stents for the treatment of coronary artery disease (TA152) NICE technology appraisal. Clopidogrel in the treatment of non-st-segment-elevation acute coronary syndrome (TA80) NICE technology appraisal. Myocardial perfusion scintigraphy for the diagnosis and management of angina and myocardial infarction (TA73) NICE technology appraisal. Guidance on the use of coronary artery stents (TA71) NICE technology appraisal. Guidance on the use of glycoprotein IIb/IIIa inhibitors in the treatment of coronary syndromes (TA47) NICE clinical guideline. Management of stable angina (CG126) NICE clinical guideline. Unstable angina and NSTEMI: the early management of unstable angina and non-st-segment-elevation myocardial infarction (CG94) NICE quality standard. Quality standard for stable angina (QS21) Other Guidance European Society of Cardiology. ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation European Society of Cardiology. ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation SIGN. Acute Coronary Syndromes

4 Acute Coronary Syndrome Guidelines Working Group. Guidelines for the management of acute coronary syndrome EXISTING COMPARATORS and TREATMENTS For patients undergoing percutaneous coronary intervention (PCI), current guidelines recommend 2,19 : Antiplatelet therapy: aspirin, clopidogrel, prasugrel, ticagrelor, abciximab, eptifibatide, tirofiban. Antithrombin co-therapies: unfractionated or low molecular weight heparin, enoxaparin, bivalirudin, fondaparinux. EFFICACY and SAFETY EF Trial CHAMPION PCI, NCT , TMC- CAN-05-02; adults; cangrelor vs clopidogrel; phase III. CHAMPION-PLATFORM, NCT , TMC-CAN-05-03; adults; cangrelor vs clopidogrel; phase III. Sponsor The Medicines Company. The Medicines Company. Status Published. Published. Source of Publication 22, trial registry 23. Publication 24, trial registry 25. information Location USA. USA. Design Randomised, active-controlled. Randomised, active-controlled. Participants n=8,877; adults; stable angina, UA or NSTEMI due to undergo PCI. n=5,362; adults; ACS; atherosclerosis amenable to PCI with or without stent Schedule Randomised to cangrelor bolus 30µg/kg (within 30 mins of start of PCI) and IV infusion 4µg/kg/min (for 2-4hrs), or placebo bolus and infusion. Immediately prior to PCI procedure, patients received oral capsules containing placebo (cangrelor arm) or clopidogrel 600mg (clopidogrel arm); following cessation of IV infusion, patients received second set of oral capsules containing clopidogrel 600mg (cangrelor arm) or placebo (clopidogrel arm); for the following 30 days, all patients received clopidogrel 600mg at physician s discretion. implantation. Randomised to cangrelor bolus 30µg/kg and IV infusion 4µg/kg/min, or placebo bolus and infusion for duration of PCI procedure (for 2-4hrs). Immediately after PCI procedure patients received oral capsules containing placebo (cangrelor arm) or clopidogrel 600mg (clopidogrel arm); following cessation of IV infusion, patients received second set of oral capsules containing clopidogrel 600mg (cangrelor arm) or placebo (clopidogrel arm); for the following 30 days, all patients received clopidogrel 600mg at physician s discretion. Follow-up Primary outcomes Secondary outcomes Active treatment period 48 hours (primary), 30 days (secondary); 1 year follow-up. Composite incidence of all-cause mortality; MI; ischaemia-driven revascularisation. Stroke; abrupt vessel closure; threatened abrupt vessel closure; need for urgent coronary artery bypass graft or unsuccessful procedure during the index PCI; acute stent thrombosis and subacute stent thrombosis. Active treatment period 48 hours (primary), 30 days (secondary); 1 year follow-up. Composite incidence of all-cause mortality; MI; ischaemia-driven revascularisation. Q-wave MI; abrupt vessel closure; stroke. 4

5 Key results Adverse effects (AEs) For cangrelor and clopidogrel respectively, at 48 hrs, % (odds ratio, 95% CI): death, MI, or ischaemia driven revascularisation, 7.5, 7.1 (1.05, ); MI, 7.1, 6.6 (1.09, ); ischaemia-driven revascularisation, 0.3, 0.6 (0.56, ); death from any cause, 0.2, 0.3 (0.63, ); stent thrombosis, 0.2, 0.3 (0.63, ); stroke, 0.2, 0.2 (0.85, ); Q- wave MI, 0.1, 0.3 (0.40, ); death, Q-wave MI, or ischaemia-driven revascularisation, 0.6, 0.9 (0.67, ); death Q-wave MI, or stent thrombosis, 0.5, 0.6 (0.78, ). For cangrelor and clopidogrel respectively, % (odds ratio, 95% CI): access-site bleeding requiring radiologic or surgical intervention, 0.1, 0.2 (0.60, ); haematoma at puncture site 5cm, 1.9, 1.7 (1.12, ), <5cm, 5.7, 5.1 (1.14, ); bleeding requiring surgery, <0.1, <0.1 (1.00, ); retroperitoneal haemorrhage, 0.3, 0.2 (1.50, ); ecchymosis, 6.5, 5.4 (1.23, ); epistaxis, 0.2, 0.5 (0.41, ); oozing at puncture site, 9.1, 7.3 (1.28, ); thrombocytopenia, 0.1, 0.2 (0.86, ); haemodynamic compromise, 0.2, 0.3 (0.82, ); transfusion, blood, 1.1, 1.0 (1.09, ); platelet, 0.1, 0.1 (1.20, ); decrease in level of haemoglobin and/or haematrocrit, 2.1, 1.4 (1.45, ); ACUITY criteria, minor bleeding, 17.6, 15.2 (1.19, ), major bleeding, 3.6, 2.9 (1.26, ); GUSTO criteria, mild bleeding, 19.6, 16.9 (1.20, ), moderate bleeding, 0.9, 0.8 (1.21, ), severe or life-threatening bleeding, 0.2, 0.3 (0.91, ); TIMI criteria, minor bleeding, 0.8, 0.6 (1.39, ), major bleeding, 0.4, 0.3 (1.36, ); dyspnoea, 1.0, 0.4 (p=0.001). For cangrelor and placebo respectively at 48 hrs, % (odds ratio, 95% CI): death, MI, or ischaemia-driven revascularisation, 6.9, 8.0 (0.86, ); MI, 6.6, 7.2 (0.91, ); ischaemia-driven revascularisation, 0.7, 1.0 (0.72, ); death from any cause, 0.3, 0.7 (0.42, ); stroke, 0.3, 0.2 (1.16, ); stent thrombosis, 0.2, 0.6 (0.31, ); Q-wave MI, 0.1, 0.3 (0.44, ); death, Q-wave MI, or ischaemia-driven revascularisation, 0.9, 1.7 (0.56, ); death, Q-wave MI, or stent thrombosis, 0.6, 1.4 (0.41, ). For cangrelor and placebo respectively, at 35 days (%): death, MI, or ischaemiadriven revascularisation, 8.9, 9.6 (p=0.25); stent thrombosis, 0.38, 0.46 (p=0.65); death, 1.10, 1.10 (p=0.97). For cangrelor and placebo respectively, % (odds ratio, 95% CI): access-site bleeding requiring radiologic or surgical intervention, 0.3, 0.4 (0.80, ); haematoma at puncture site 5cm, 4.3, 2.7 (1.64, ), <5cm, 5.6, 4.5 (1.27, ); intracranial haemorrhage, 0.1, <0.1 (1.99, ); bleeding requiring surgery, <0.1, <0.1 (1.00, ); retroperitoneal haemorrhage, 0.1, <0.1 (1.99, ); eccymosis, 3.6, 2.2 (1.68, ); epistaxis, 0.2, 0.5 (0.50, ); oozing at puncture site, 4.7, 3.4 (1.39, ); thrombocytopenia, 0.1, 0.1 (0.66, ); haemodynamic compromise, 0.3, 0.2 (1.40, ); transfusion, any blood, 1.0, 0.6 (1.62, ), platelet, 0.2, 0.1 (1.99, ), red-cell, 0.9, 0.6 (1.67, ); drop in haemoglobin or haematocrit, 1.2, 1.3 (0.94, ); ACUITY criteria, minor bleeding, 12.0, 9.3 (1.34, ), major bleeding, 5.5, 3.5 (1.61, ); GUSTO criteria, minor bleeding, 16.0, 11.7 (1.44, ), moderate bleeding, 0.8, 0.5 (1.54, ), severe or life-threatening bleeding, 0.3, 0.2 (1.50, ); TIMI criteria, minor bleeding, 0.8, 0.6 (1.37, ), major bleeding, 0.2, 0.3 (0.44, ). Trial Sponsor Status CHAMPION-Phoenix, NCT , TMC-CAN-10-01; adults; cangrelor vs clopidogrel; phase III. The Medicines Company Ltd. Ongoing. 5

6 Source of information Location Design Participants Schedule Follow-up Primary outcomes Secondary outcome Expected reporting date FICACY a Trial registry 26. EU (inc UK), USA, and other countries. Randomised, active-controlled. n=10,900 (planned); adults; undergoing PCI. Randomised to cangrelor bolus 30µg/kg and IV infusion, 4µg/kg/min, plus clopidogrel, 600mg transition dose, or clopidogrel loading dose alone, administered as per institutional standard of care (i.e. 300mg or 600mg given pre or post PCI). Infusion to be initiated immediately prior to index procedure for 2-4hrs. Active treatment period 2-4 hours; follow-up 48 hours (primary) and 30 days (secondary) post-randomisation. Composite outcome of all-cause mortality, MI, ischaemia-driven revascularisation and stent thrombosis. Stent thrombosis. Q ESTIMATED COST and IMPACT COST The cost of cangrelor is not yet known. The annual costs of clopidogrel 75mg once daily and aspirin 75mg once daily are 30 and 6 respectively 27. IMPACT - SPECULATIVE Impact on Patients and Carers Reduced mortality/increased length of survival Reduced symptoms or disability Other: No impact identified Impact on Services Increased use of existing services: IV administration Decreased use of existing services Re-organisation of existing services Need for new services Other: None identified Impact on Costs Increased drug treatment costs Reduced drug treatment costs Other increase in costs: Other reduction in costs Other: uncertain unit cost compared to alternatives. None identified Other Issues Clinical uncertainty or other research question identified: None identified 6

7 REFERENCES 1 Fugate SE, Cudd LA. Cangrelor for treatment of coronary thrombosis. The Annals of Pharmacotherapy 2006;40(5): National Institute for Health and Clinical Excellence. Unstable angina and NSTEMI. The early management of unstable angina and non-st-segment-elevation myocardial infarction. Clinical guideline CG94. London: NICE; March Anderson JL, Adams CD and Antman EM. ACC/AHA 2007 Guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction: A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines. Journal of the American College of Cardiology 2007; 50: e1-e NHS. Hospital episode statistics. NHS England HES data Office for National Statistics. Mortality statistics. Deaths registered in 2010 (Series DR) Table National Institute for Health and Clinical Excellence. Prasugrel with percutaneous coronary intervention for the treatment of acute coronary syndrome (review of TA182). Expected August National Institute for Health and Clinical Excellence. Rivaroxaban for the prevention of adverse outcomes in patients after the acute management of acute coronary syndrome. Technology appraisal in development. Expected July National Institute for Health and Clinical Excellence. Bivalirudin for the treatment of ST-segmentelevation myocardial infarction. Technology appraisal TA230. London: NICE; July National Institute for Health and Clinical Excellence. Ticagrelor for the treatment of acute coronary syndromes (ACS). Technology appraisal TA236. London: NICE; October National Institute for Health and Clinical Excellence. Clopidogrel and modified-release dipyridamole for the prevention of occlusive vascular events. Technology appraisal TA210. London: NICE; December National Institute for Health and Clinical Excellence. Prasugrel for the treatment of acute coronary syndromes with percutaneous coronary intervention. Technology appraisal TA182. London: NICE; October National Institute of Health and Clinical Excellence. Drug-eluting stents for the treatment of coronary artery disease. Technology appraisal TA152. London: NICE; July National Institute for Health and Clinical Excellence. Clopidogrel in the treatment of non-stsegment-elevation acute coronary syndrome. Technology appraisal TA80. London: NICE; July National Institute for Health and Clinical Excellence. Myocardial perfusion scintigraphy for the diagnosis and management of angina and myocardial infarction. Technology appraisal TA73. London: NICE; November National Institute of Health and Clinical Excellence. Guidance on the use of coronary artery stents.technology appraisal TA71. London: NICE; October National Institute of Health and Clinical Excellence. Guidance on the use of glycoprotein Ilb/llla inhibitors in the treatment of acute coronary syndromes. Technology appraisal TA47. London: NICE; September Reviewed July National Institute for Health and Clinical Excellence. Management of stable angina. Clinical guideline CG126. London: NICE; July National Institute for Health and Clinical Excellence. Quality standard for stable angina. Quality standard QS21. London: NICE; August Steg G, James SK, Atar D et al. ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. European Heart Journal 2012:33; Hamm CW, Bassand JP, Agewall S et al. ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. European Heart Journal 2011;32; Scottish Intercollegiate Guidelines Network. Acute coronary syndromes. Clinical guideline 93. Edinburgh: SIGN; February Harrington RA, Stone GW, McNulty S, et al. Platelet inhibition with cangrelor in patients undergoing PCI. New England Journal of Medicine 2009:361(24):

8 23 ClinicalTrials.gov. A clinical trial to demonstrate the efficacy of cangrelor (PCI). Accessed 23 March Bhatt DL, Lincoff AM, Gibson CM, et al. Intravenous platelet blockade with cangrelor during PCI. New England Journal of Medicine 2009;361(24): ClinicalTrials.gov. Cangrelor versus standard therapy to achieve optimal management of platelet inhibition. (Platform). Accessed 23 March ClinicalTrials.gov. A clinical trial comparing cangrelor to clopidogrel standard therapy in subjects who require percutaneous coronary intervention (PCI) (CHAMPION PHOENIX). Accessed 16 March British Medical Association and Royal Pharmaceutical Society of Great Britain. British National Formulary. BNF 64. London: BMJ Group and RPS Publishing, September