Horizon Scanning Centre November 2012

Cangrelor to reduce platelet aggregation and thrombosis in patients undergoing percutaneous coronary intervention99

SUMMARY NIHR HSC ID: 2424

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. This briefing is based on Acute coronary syndrome is usually caused by coronary atherosclerosis and information encompasses a spectrum of disease including unstable angina, non-ST available at the time segment elevation myocardial infarction and ST-segment elevation of research and a myocardial infarction. In 2010-11, there were 71,583 hospital admissions for limited literature angina pectoris in England, of which 35,799 were specified as unstable search. It is not angina. In the same time period, there were 49,070 hospital admissions for intended to be a acute myocardial infarction, 13,767 admissions for subsequent myocardial definitive statement infarction, 52,290 admissions for percutaneous transluminal balloon on the safety, angioplasty with insertion of stent, and 2,872 admissions for transluminal efficacy or angioplasty of coronary artery. In 2010, 25,960 deaths from acute myocardial effectiveness of the infarction occurred in England and Wales. health technology covered and should For patients undergoing percutaneous coronary intervention, current not be used for guidelines recommend antiplatelet therapy and antithrombin co-therapies. commercial Cangrelor has been in phase III clinical trials comparing its effect on all- purposes or cause mortality against treatment with clopidogrel. These trials have been commissioning published. without additional information.

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 Email: [email protected] Web: http://www.hsc.nihr.ac.uk NIHR Horizon Scanning Centre

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 P2Y12 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 advantage1. 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 plaques2. Left untreated, prognosis is poor and mortality is high, particularly in people who have suffered myocardial damage3.

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 2010-11, 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,

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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 days4. In 2010, 25,960 deaths from acute MI (ICD10 I21) occurred in England and Wales5.

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 20146.  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 20137.

 NICE technology appraisal. Bivalirudin for the treatment of ST-segment-elevation myocardial infarction (TA230). 20118.  NICE technology appraisal. Ticagrelor for the treatment of acute coronary syndromes (TA236). 20119.  NICE technology appraisal. Clopidogrel and modified-release dipyridamole for the prevention of occlusive vascular events (TA210). 201010.  NICE technology appraisal. Prasugrel for the treatment of acute coronary syndromes with percutaneous coronary intervention (TA182). 200911.  NICE technology appraisal. Drug-eluting stents for the treatment of coronary artery disease (TA152). 200812.  NICE technology appraisal. Clopidogrel in the treatment of non-ST-segment-elevation acute coronary syndrome (TA80). 200413.  NICE technology appraisal. Myocardial perfusion scintigraphy for the diagnosis and management of angina and myocardial infarction (TA73). 200314.  NICE technology appraisal. Guidance on the use of coronary artery stents (TA71). 200315.  NICE technology appraisal. Guidance on the use of glycoprotein IIb/IIIa inhibitors in the treatment of coronary syndromes (TA47). 200216.

 NICE clinical guideline. Management of stable angina (CG126). 201117.  NICE clinical guideline. Unstable angina and NSTEMI: the early management of unstable angina and non-ST-segment-elevation myocardial infarction (CG94). 20102.

 NICE quality standard. Quality standard for stable angina (QS21). 201218.

Other Guidance

 European Society of Cardiology. ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. 201219.  European Society of Cardiology. ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. 201120.  SIGN. Acute Coronary Syndromes. 200721.

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 Acute Coronary Syndrome Guidelines Working Group. Guidelines for the management of acute coronary syndrome. 20063.

EXISTING COMPARATORS and TREATMENTS

For patients undergoing percutaneous coronary intervention (PCI), current guidelines recommend2,19:  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, NCT00305162, TMC- CHAMPION-PLATFORM, CAN-05-02; adults; cangrelor vs NCT00385138, TMC-CAN-05-03; clopidogrel; phase III. adults; cangrelor vs clopidogrel; phase III. Sponsor The Medicines Company. The Medicines Company. Status Published. Published. Source of Publication22, trial registry23. Publication24, trial registry25. information Location USA. USA. Design Randomised, active-controlled. Randomised, active-controlled. Participants n=8,877; adults; stable angina, UA or n=5,362; adults; ACS; atherosclerosis NSTEMI due to undergo PCI. amenable to PCI with or without stent implantation. Schedule Randomised to cangrelor bolus 30µg/kg Randomised to cangrelor bolus 30µg/kg (within 30 mins of start of PCI) and IV and IV infusion 4µg/kg/min, or placebo infusion 4µg/kg/min (for 2-4hrs), or bolus and infusion for duration of PCI placebo bolus and infusion. Immediately procedure (for 2-4hrs). Immediately after prior to PCI procedure, patients received PCI procedure patients received oral oral capsules containing placebo capsules containing placebo (cangrelor (cangrelor arm) or clopidogrel 600mg arm) or clopidogrel 600mg (clopidogrel (clopidogrel arm); following cessation of arm); following cessation of IV infusion, IV infusion, patients received second set patients received second set of oral of oral capsules containing clopidogrel capsules containing clopidogrel 600mg 600mg (cangrelor arm) or placebo (cangrelor arm) or placebo (clopidogrel (clopidogrel arm); for the following 30 arm); for the following 30 days, all days, all patients received clopidogrel patients received clopidogrel 600mg at 600mg at physician’s discretion. physician’s discretion.

Follow-up Active treatment period 48 hours Active treatment period 48 hours (primary), 30 days (secondary); 1 year (primary), 30 days (secondary); 1 year follow-up. follow-up. Primary Composite incidence of all-cause Composite incidence of all-cause outcomes mortality; MI; ischaemia-driven mortality; MI; ischaemia-driven revascularisation. revascularisation. Secondary Stroke; abrupt vessel closure; Q-wave MI; abrupt vessel closure; outcomes threatened abrupt vessel closure; need stroke. for urgent coronary artery bypass graft or unsuccessful procedure during the index PCI; acute stent thrombosis and subacute stent thrombosis.

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Key results For cangrelor and clopidogrel For cangrelor and placebo respectively respectively, at 48 hrs, % (odds ratio, at 48 hrs, % (odds ratio, 95% CI): 95% CI): death, MI, or ischaemia-driven death, MI, or ischaemia driven revascularisation, 6.9, 8.0 (0.86, 0.70- revascularisation, 7.5, 7.1 (1.05, 0.88- 1.05); MI, 6.6, 7.2 (0.91, 0.73-1.12); 1.24); MI, 7.1, 6.6 (1.09, 0.91-1.29); ischaemia-driven revascularisation, 0.7, ischaemia-driven revascularisation, 0.3, 1.0 (0.72, 0.40-1.31); death from any 0.6 (0.56, 0.28-1.11); death from any cause, 0.3, 0.7 (0.42, 0.18-0.95); stroke, cause, 0.2, 0.3 (0.63, 0.25-1.63); stent 0.3, 0.2 (1.16, 0.39-3.44); stent thrombosis, 0.2, 0.3 (0.63, 0.25-1.63); thrombosis, 0.2, 0.6 (0.31, 0.11-0.84); stroke, 0.2, 0.2 (0.85, 0.29-2.54); Q- Q-wave MI, 0.1, 0.3 (0.44, 0.14-1.43); wave MI, 0.1, 0.3 (0.40, 0.12-1.27); death, Q-wave MI, or ischaemia-driven death, Q-wave MI, or ischaemia-driven revascularisation, 0.9, 1.7 (0.56, 0.34- revascularisation, 0.6, 0.9 (0.67, 0.39- 0.92); death, Q-wave MI, or stent 1.4); death Q-wave MI, or stent thrombosis, 0.6, 1.4 (0.41, 0.22-0.75). thrombosis, 0.5, 0.6 (0.78, 0.42-1.44). For cangrelor and placebo respectively, at 35 days (%): death, MI, or ischaemia- driven 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). Adverse For cangrelor and clopidogrel For cangrelor and placebo respectively, effects (AEs) respectively, % (odds ratio, 95% CI): % (odds ratio, 95% CI): access-site access-site bleeding requiring radiologic bleeding requiring radiologic or surgical or surgical intervention, 0.1, 0.2 (0.60, intervention, 0.3, 0.4 (0.80, 0.31-2.02); 0.22-1.65); haematoma at puncture site haematoma at puncture site ≥5cm, 4.3, ≥5cm, 1.9, 1.7 (1.12, 0.82-1.53), <5cm, 2.7 (1.64, 1.21-2.22), <5cm, 5.6, 4.5 5.7, 5.1 (1.14, 0.94-1.37); bleeding (1.27, 0.99-1.63); intracranial requiring surgery, <0.1, <0.1 (1.00, 0.06- haemorrhage, 0.1, <0.1 (1.99, 0.18- 15.96); retroperitoneal haemorrhage, 21.98); bleeding requiring surgery, <0.1, 0.3, 0.2 (1.50, 0.67-3.34); ecchymosis, <0.1 (1.00, 0.06-15.92); retroperitoneal 6.5, 5.4 (1.23, 1.03-1.47); epistaxis, 0.2, haemorrhage, 0.1, <0.1 (1.99, 0.18- 0.5 (0.41, 0.19-0.89); oozing at puncture 21.98); eccymosis, 3.6, 2.2 (1.68, 1.21- site, 9.1, 7.3 (1.28, 1.10-1.49); 2.35); epistaxis, 0.2, 0.5 (0.50, 0.19- thrombocytopenia, 0.1, 0.2 (0.86, 0.29- 1.33); oozing at puncture site, 4.7, 3.4 2.55); haemodynamic compromise, 0.2, (1.39, 1.05-1.83); thrombocytopenia, 0.3 (0.82, 0.34-1.97); transfusion, blood, 0.1, 0.1 (0.66, 0.22-3.97); 1.1, 1.0 (1.09, 0.72-1.67); platelet, 0.1, haemodynamic compromise, 0.3, 0.2 0.1 (1.20, 0.37-3.93); decrease in level (1.40, 0.44-4.40); transfusion, any blood, of haemoglobin and/or haematrocrit, 2.1, 1.0, 0.6 (1.62, 0.87-3.03), platelet, 0.2, 1.4 (1.45, 1.05-2.01); ACUITY criteria, 0.1 (1.99, 0.37-10.89), red-cell, 0.9, 0.6 minor bleeding, 17.6, 15.2 (1.19, 1.06- (1.67, 0.88-3.17); drop in haemoglobin 1.33), major bleeding, 3.6, 2.9 (1.26, or haematocrit, 1.2, 1.3 (0.94, 0.58- 0.99-1.60); GUSTO criteria, mild 1.51); ACUITY criteria, minor bleeding, bleeding, 19.6, 16.9 (1.20, 1.07-1.34), 12.0, 9.3 (1.34, 1.12-1.59), major moderate bleeding, 0.9, 0.8 (1.21, 0.76- bleeding, 5.5, 3.5 (1.61, 1.23-2.10); 1.90), severe or life-threatening GUSTO criteria, minor bleeding, 16.0, bleeding, 0.2, 0.3 (0.91, 0.39-2.14); TIMI 11.7 (1.44, 1.23-1.69), moderate criteria, minor bleeding, 0.8, 0.6 (1.39, bleeding, 0.8, 0.5 (1.54, 0.76-3.09), 0.84-2.30), major bleeding, 0.4, 0.3 severe or life-threatening bleeding, 0.3, (1.36, 0.68-2.71); dyspnoea, 1.0, 0.4 0.2 (1.50, 0.53-4.21); TIMI criteria, minor (p=0.001). bleeding, 0.8, 0.6 (1.37, 0.72-2.62), major bleeding, 0.2, 0.3 (0.44, 0.14- 1.44).

Trial CHAMPION-Phoenix, NCT01156571, TMC-CAN-10-01; adults; cangrelor vs clopidogrel; phase III. Sponsor The Medicines Company Ltd. Status Ongoing.

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Source of Trial registry26. information Location EU (inc UK), USA, and other countries. Design Randomised, active-controlled. Participants n=10,900 (planned); adults; undergoing PCI. Schedule 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. Follow-up Active treatment period 2-4 hours; follow-up 48 hours (primary) and 30 days (secondary) post-randomisation. Primary Composite outcome of all-cause mortality, MI, ischaemia-driven revascularisation outcomes and stent thrombosis. Secondary Stent thrombosis. outcome Expected Q1 2013. reporting date FICACY a 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 respectively27.

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  Decreased use of existing services administration

 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  None identified alternatives.

Other Issues

 Clinical uncertainty or other research question  None identified identified:

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REFERENCES

1 Fugate SE, Cudd LA. Cangrelor for treatment of coronary thrombosis. The Annals of Pharmacotherapy 2006;40(5):925-930. 2 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 2010. 3 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-e157. 4 NHS. Hospital episode statistics. NHS England 2010-11. HES data 2012. www.hesonline.nhs.uk 5 Office for National Statistics. Mortality statistics. Deaths registered in 2010 (Series DR) Table 5. www.ons.gov.uk 6 National Institute for Health and Clinical Excellence. Prasugrel with percutaneous coronary intervention for the treatment of acute coronary syndrome (review of TA182). Expected August 2014. 7 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 2013. 8 National Institute for Health and Clinical Excellence. Bivalirudin for the treatment of ST-segment- elevation myocardial infarction. Technology appraisal TA230. London: NICE; July 2011. 9 National Institute for Health and Clinical Excellence. Ticagrelor for the treatment of acute coronary syndromes (ACS). Technology appraisal TA236. London: NICE; October 2011. 10 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 2010. 11 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 2009. 12 National Institute of Health and Clinical Excellence. Drug-eluting stents for the treatment of coronary artery disease. Technology appraisal TA152. London: NICE; July 2008. 13 National Institute for Health and Clinical Excellence. Clopidogrel in the treatment of non-ST- segment-elevation acute coronary syndrome. Technology appraisal TA80. London: NICE; July 2004. 14 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 2003. 15 National Institute of Health and Clinical Excellence. Guidance on the use of coronary artery stents.Technology appraisal TA71. London: NICE; October 2003. 16 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 2002. Reviewed July 2010. 17 National Institute for Health and Clinical Excellence. Management of stable angina. Clinical guideline CG126. London: NICE; July 2011. 18 National Institute for Health and Clinical Excellence. Quality standard for stable angina. Quality standard QS21. London: NICE; August 2012. 19 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;2569-2619 20 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;2999-3054. 21 Scottish Intercollegiate Guidelines Network. Acute coronary syndromes. Clinical guideline 93. Edinburgh: SIGN; February 2007. 22 Harrington RA, Stone GW, McNulty S, et al. Platelet inhibition with cangrelor in patients undergoing PCI. New England Journal of Medicine 2009:361(24):2318-2329.

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23 ClinicalTrials.gov. A clinical trial to demonstrate the efficacy of cangrelor (PCI). http://clinicaltrials.gov/ct2/show/NCT00305162 Accessed 23 March 2012. 24 Bhatt DL, Lincoff AM, Gibson CM, et al. Intravenous platelet blockade with cangrelor during PCI. New England Journal of Medicine 2009;361(24):2330-2341. 25 ClinicalTrials.gov. Cangrelor versus standard therapy to achieve optimal management of platelet inhibition. (Platform). http://clinicaltrials.gov/ct2/show/NCT00385138?term=nct00385138&rank=1 Accessed 23 March 2012. 26 ClinicalTrials.gov. A clinical trial comparing cangrelor to clopidogrel standard therapy in subjects who require percutaneous coronary intervention (PCI) (CHAMPION PHOENIX). http://clinicaltrials.gov/ct2/show/NCT01156571?term=nct01156571&rank=1 Accessed 16 March 2012. 27 British Medical Association and Royal Pharmaceutical Society of Great Britain. British National Formulary. BNF 64. London: BMJ Group and RPS Publishing, September 2012.

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