Key points from the evidence

Summary

Cangrelor statistically significantly reduced the risk of periprocedural ischaemic events compared with clopidogrel in a large RCT of people receiving periprocedural aspirin who underwent percutaneous coronary intervention (PCI) for mixed indications without P2Y12 inhibitor pre‑treatment, with a number needed to treat of 84 at 48 hours. However, it did not statistically significantly reduce mortality and clinical benefits were described by the European Medicines Agency as modest. Bleeding and dyspnoea events were more frequent in the cangrelor group (numbers needed to harm of 26 and 142 at 48 hours for mild bleeding and dyspnoea respectively).

There are no published studies comparing cangrelor with other oral antiplatelet agents for people undergoing PCI. In the pivotal study, the treatment pathway differed from usual UK practice regarding choice of oral antiplatelet drug and this limits the applicability of the evidence to UK practice where prasugrel and ticagrelor have superseded clopidogrel as the standard of care for people with unstable angina, non‑ST‑segment‑elevation myocardial infarction and myocardial infarction with ST‑segment‑elevation. Cangrelor, co‑administered with aspirin, is therefore a second‑line treatment option for use in people with coronary artery disease undergoing PCI for whom oral therapy with P2Y12 inhibitors is not feasible or desirable.

Cangrelor was considered appropriate for a NICE technology appraisal but NICE is unable to make a recommendation about the use in the NHS of cangrelor for the licensed indication because no evidence submission was received from the manufacturer of the technology.

Regulatory status: Cangrelor received a European marketing authorisation in March 2015 and was launched in the UK in July 2015.

Effectiveness

  • In 1 double‑blind, double‑dummy RCT in people with non‑ST‑segment‑elevation myocardial infarction (NSTEMI), ST‑segment‑elevation myocardial infarction (STEMI) or stable angina undergoing PCI (n=11,145) and receiving aspirin, cangrelor bolus plus infusion followed by transition to a loading dose of clopidogrel statistically significantly reduced the risk of a composite outcome of death from any cause, myocardial infarction (MI), ischaemia‑driven revascularisation or stent thrombosis at 48 hours compared with a single loading dose of clopidogrel (number needed to treat [NNT] 84, p=0.005).

  • The European public assessment report for cangrelor states that the results of the pivotal study were driven by the statistically significantly lower incidence of MI and stent thrombosis; there was no statistically significant reduction in mortality.

Safety

  • In a pooled analysis of 3 RCTs of similar design to the efficacy study (n=25,107), the incidence of GUSTO‑defined severe bleeding at 48 hours was not statistically significantly increased in the cangrelor group compared with the clopidogrel group. There was a statistically significant increase in the risk of ACUITY‑defined major bleeding at 48 hours (number needed to harm [NNH] 71). The NNH for GUSTO‑defined mild bleeding at 48 hours was 26.The NNH for dyspnoea was 142.

  • Cangrelor is contraindicated in people with active bleeding or at increased risk of bleeding, and in people with a history of stroke or transient ischaemic attack. It should be used with caution in people with severe renal impairment (creatinine clearance 15–30 mL/minute) because of a risk of worsening of renal function and increased risk of bleeding.

Patient factors

  • Cangrelor is administered intravenously over 2 to 4 hours during PCI procedures.

  • There are no comparative data with either prasugrel or ticagrelor during PCI procedures.

  • The summary of product characteristics for cangrelor states that when clopidogrel is administered during infusion of cangrelor, the expected inhibitory effect of clopidogrel on platelets is not achieved. For transition, a loading dose of oral P2Y12 therapy (clopidogrel, ticagrelor or prasugrel) should be administered immediately following discontinuation of cangrelor infusion.

Resource implications

  • The cost of cangrelor 50 mg powder for injection is £250 per vial (excluding VAT; prices taken from MIMS October 2015). This equates to £250 to £500 per PCI procedure (for an average 70 kg person)

  • PCI periprocedural costs for other oral antiplatelet agents range from 26p to £10.19 (excluding VAT; prices taken from Drug Tariff October 2015).

Abbreviations:

GUSTO: Global Utilisation of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries

ACUITY: Acute Catheterization and Urgent Intervention Triage strategy

Introduction and current guidance

Coronary revascularisation (widening of blocked or narrowed coronary arteries) is undertaken using a procedure called coronary angioplasty where a balloon catheter is used to dilate the artery from within. Most modern angioplasty procedures also involve inserting a permanent stent into the artery during the procedure to improve blood flow. This procedure is called percutaneous coronary intervention (PCI).

NICE guidance on stable angina recommends that coronary revascularisation is an option for people whose symptoms are not satisfactorily controlled with optimal medical treatment. In such circumstances, PCI is usually a pre‑planned (elective) process. NICE guidance on the acute management of myocardial infarction with ST-segment-elevation (STEMI) and NICE guidance on unstable angina and non-ST-segment-elevation myocardial infarction (NSTEMI) recommend that people with unstable angina, NSTEMI or STEMI usually require PCI more urgently. For all people undergoing PCI, there is an increased risk of periprocedural ischaemic events. The full NICE guideline on unstable angina and NSTEMI explains that antithrombotic therapy reduces this and subsequent risk. NICE guidance recommends oral antiplatelet agents in addition to aspirin for people undergoing PCI.

The NICE pathways stable angina and acute coronary syndromes bring together all related NICE guidance and associated products on these conditions in a set of interactive topic-based diagrams.

Full text of introduction and current guidance.

Product overview

Cangrelor (Kengrexal) is licensed for reducing the risk of thrombotic cardiovascular events in adults with coronary artery disease undergoing PCI who have not received an oral P2Y12 inhibitor prior to the PCI procedure and in whom oral therapy with P2Y12 inhibitors is not feasible or desirable. It is licensed only for co‑administration with aspirin. Oral P2Y12 inhibitors include clopidogrel, prasugrel and ticagrelor.

Cangrelor is administered intravenously and provides reversible, rapid‑onset but short‑acting P2Y12 platelet receptor inhibition. The recommended dose of cangrelor is a 30 micrograms/kg intravenous bolus followed immediately by 4 micrograms/kg per minute intravenous infusion. The bolus and infusion should be initiated prior to the PCI procedure and continued for at least 2 hours or for the duration of the procedure, whichever is longer. At the discretion of the physician, the infusion may be continued for a total duration of 4 hours. For continuation of long‑term treatment, people should be changed onto oral antiplatelet therapy, such as clopidogrel, prasugrel or ticagrelor, post‑procedure.

Cangrelor was considered appropriate for a NICE technology appraisal. NICE is unable to make a recommendation about the use in the NHS of cangrelor for reducing atherothrombotic events in people with coronary artery disease undergoing PCI (or in people awaiting surgery requiring interruption of antiplatelet therapy) because no evidence submission was received from the manufacturer of the technology (terminated appraisal 351).

Full text of product overview.

Evidence review

  • The efficacy and safety of cangrelor in its licensed indication have been studied in 3 large double‑blind, phase III, randomised controlled trials (RCTs) conducted as part of the CHAMPION programme. These have all been published in full.

  • CHAMPION PHOENIX (Bhatt et al. 2013) provides the best available evidence for the efficacy of cangrelor in its licensed indication. Two earlier RCTs of a very similar design, CHAMPION PLATFORM (Bhatt et al. 2009, n= 5362) and CHAMPION PCI (Harrington et al. 2009, n= 8877) were stopped early as interim analysis showed that the primary outcome would not be achieved. The definition of myocardial infarction (MI) used in CHAMPION PHOENIX was amended from that used in the earlier CHAMPION studies, to avoid confounding periprocedural MIs with evolving preprocedural MIs. CHAMPION PLATFORM and CHAMPION PCI are not discussed in detail but combined pooled data from all 3 RCTs (Steg et al. 2013) provide the main body of safety data for cangrelor and are discussed in the safety section.

  • CHAMPION PHOENIX (Bhatt et al. 2013) had a double‑blind, double‑dummy design and recruited people with stable angina, NSTEMI or STEMI who were undergoing either urgent or elective PCI. Participants in the cangrelor group received oral placebo plus cangrelor as a bolus (30 microgram/kg) followed immediately by infusion at 4 microgram/kg per minute for at least 2 hours or until the end of the procedure, whichever was the longer. At the discretion of the treating physician, the infusion could be continued for a total duration of 4 hours. At the end of the infusion, participants in this group received a 600 mg dose of clopidogrel orally. Participants in the clopidogrel group received placebo bolus and infusion and a single oral dose of either 300 mg or 600 mg clopidogrel immediately before or immediately after PCI (dose and time at the discretion of the treating physician), with oral placebo at the end of the placebo infusion.

  • In CHAMPION PHOENIX the rate of the primary composite outcome of periprocedural ischaemic events (all‑cause death, MI, ischaemia‑driven revascularisation, or stent thrombosis at 48 hours) was statistically significantly lower in the cangrelor group compared with the clopidogrel group (4.7% compared with 5.9%, odds ratio [OR] 0.78, 95% confidence interval [CI] 0.66 to 0.93, p=0.005). A statistically significant reduction in the rate of periprocedural MI accounted for most of the benefit (3.8% compared with 4.7%, OR 0.80, 95% CI 0.67 to 0.97, p=0.02). The incidence of stent thrombosis at 48 hours also was statistically significantly lower in the cangrelor group. The European public assessment report for cangrelor (EPAR) describes these benefits as modest.

  • In the pooled analysis of the 3 CHAMPION studies (Steg et al. 2013) there was no statistically significant difference in the rate of GUSTO‑defined severe non‑CABG‑related bleeding at 48 hours (p=0.49). However, there was a statistically significant increase in ACUITY‑defined major bleeding in the cangrelor group (4.2% compared with 2.8%, OR 1.53, 95% CI 1.34 to1.76, p<0.0001). This was due in part to the increased number of large haematomas in the cangrelor group but persisted after excluding these. Cangrelor was also associated with an increased rate of less severe bleeding events compared with clopidogrel such as GUSTO mild bleeding (absolute risk reduction [ARR] 3.8%, OR 1.35, 95% CI 1.26 to 1.45, p<0.0001). Transient dyspnoea was reported more frequently with cangrelor than with clopidogrel (1.1% compared with 0.4%, p<0.0001). Serious adverse events were reported at the same frequency in both the cangrelor and comparator groups (2.2%).

  • The Kengrexal summary of product characteristics (SPC) states that in pivotal studies conducted in patients undergoing PCI, there were more intracranial bleeds, including fatal bleeds, at 30 days with cangrelor (0.07%) than with clopidogrel (0.02%), and a higher rate of cardiac tamponades at 30 days with cangrelor (0.12%) than with clopidogrel (0.02%). In patients with severe renal impairment (creatinine clearance 15–30 mL/min) a higher rate of worsening in renal function (3.2%) was reported with cangrelor compared to clopidogrel (1.4%) and a higher rate of GUSTO moderate bleeding was reported with cangrelor (6.7%) compared to clopidogrel (1.4%).

  • The EPAR states that the study design of CHAMPION PHOENIX was not optimal and may have favoured cangrelor, although it was accepted as reliable and representative of the diversity of current EU clinical practice. The EPAR notes inclusion in the study population of 3 subsets of people with different diagnoses but states that the size of the effect of cangrelor appeared consistent irrespective of the initial presentation and that the results can be generalised to all 3 patient groups. Nevertheless, the EPAR also states that the exclusion of people with a history of prior stroke limits the validity of the study to clinical practice. Furthermore, in the control arm the loading dose of clopidogrel was either 300 mg or 600 mg and could be given at the beginning or end of PCI, although the EPAR states that the effect of cangrelor seemed consistent irrespective of the timing of clopidogrel administration.

  • In addition to these issues with the study design, the treatment pathway in CHAMPION PHOENIX (Bhatt et al. 2013) differs from usual UK practice regarding choice of antiplatelet drug. Specialists involved the production of this evidence summary advise that in UK practice prasugrel and ticagrelor have superseded clopidogrel as the standard of care for people with unstable angina, NSTEMI and STEMI. This limits the applicability to UK practice of evidence from CHAMPION PHOENIX and the wider CHAMPION programme. The EPAR states that prasugrel and ticagrelor may have been more valid comparators.

Full text of evidence review.

Context

The P2Y12 inhibitors clopidogrel, prasugrel and ticagrelor are licensed for use, in combination with aspirin, for the prevention of thrombotic events in people with acute coronary syndrome or STEMI, including those people undergoing PCI (see summaries of product characteristics for specific licensed indications). NICE guidance and European guidelines recommend the use of these oral antiplatelet agents as treatment options for people with coronary artery disease undergoing PCI (in specified circumstances). Cangrelor is licensed for use only if it is co‑administered with aspirin and only in people undergoing PCI who have not received an oral P2Y12 inhibitor prior to the PCI procedure and in whom oral therapy with P2Y12 inhibitors is not feasible or desirable.

Full text of context.

Estimated impact for the NHS

Based on the evidence and licensed indication, cangrelor is a second‑line treatment option. It should be considered only when treatment with oral antiplatelet agents is not feasible or desirable. During assessment of the marketing authorisation application for cangrelor, the Committee for medicinal products for human use (CHMP) stated that the benefit of cangrelor was modest but noted that intravenous administration of an antiplatelet agent with a fast offset of action can be useful in selected people undergoing PCI (CHMP meeting minutes, January 2015).

Two further caveats apply to the use of cangrelor. Firstly, in CHAMPION PHOENIX (Bhatt et al. 2013) almost all participants received periprocedural aspirin and this is reflected in the licenced indication. Only oral forms of aspirin are available as licensed products in the UK, thus the person would usually be conscious and able to take aspirin orally (or have taken it that day) and have no contraindications to its use. Administering cangrelor without periprocedural aspirin would be an off‑label use of the drug (note that prasugrel and ticagrelor are also both licensed for use only when co‑administered with aspirin).

Secondly, the SPC states that when clopidogrel is administered during infusion of cangrelor, the expected inhibitory effect of clopidogrel on platelets is not achieved. Consequently, it is important that the loading dose of clopidogrel is delayed until the infusion finishes. The SPC states that no clinically relevant interruption of P2Y12 inhibition was observed in phase III studies when 600 mg clopidogrel was administered immediately after discontinuation of the cangrelor infusion, but this is an unlicensed dose of clopidogrel.

Any potential clinical benefits must be considered in the context of potential harms and RCT data show an increased risk of bleeding events and transient breathlessness with cangrelor compared with clopidogrel.

As well as efficacy, safety and individual user factors, local decision makers will need to take cost into account when considering the likely place in therapy of cangrelor. Costs for oral antiplatelet agents used periprocedurally range from 26p to £10.19 per procedure, whereas the estimated average cost of cangrelor per procedure is £250 to £500.

Full text of estimated impact for the NHS.

About this evidence summary

'Evidence summaries: new medicines' provide summaries of key evidence for selected new medicines, or for existing medicines with new indications or formulations, that are considered to be of significance to the NHS. The strengths and weaknesses of the relevant evidence are critically reviewed within this summary to provide useful information for those working on the managed entry of new medicines for the NHS, but this summary is not NICE guidance.