Suffolk PCT Drug & Therapeutics Committee New Medicine Report (Adopted by the CCG until review and further notice)

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1 Suffolk PCT Drug & Therapeutics Committee New Medicine Report (Adopted by the CCG until review and further notice) This drug has been reviewed because it is a product that may be prescribed in primary care. Medicine Ticagrelor (Brilique, Astra Zeneca ) Document status Reviewed at Jan 2011 NHS Suffolk D&TC meeting Date of last revision 20th January 2011 Traffic light decision Green- Hospital initiated GP prescribed Prescribers rating Nothing new- The product may be new substance but is superfluous because it does not add to the clinical possibilities offered by previous products available. In most cases these are "me-too" products Mechanism of action Brilique contains ticagrelor a member of the chemical class cyclopentyltriazolopyrimidines (CPTP), which is a selective adenosine diphosphate (ADP) receptor antagonist acting on the P2Y12 ADP-receptor that can prevent ADP-mediated platelet activation and aggregation. Ticagrelor is orally active, and reversibly interacts with the platelet P2Y12 ADP-receptor. Ticagrelor does not interact with the ADP binding site itself, but interacts with platelet P2Y12 ADP-receptor to prevent signal transduction. (1) Medicine class Platelet aggregation inhibitor (1) Indication Ticagrelor, co-administered with aspirin, is indicated for the prevention of atherothrombotic events in adult patients with Acute Coronary Syndromes (unstable angina, non ST elevation Myocardial Infarction [NSTEMI] or ST elevation Myocardial Infarction [STEMI]); including patients managed medically, and those who are managed with percutaneous coronary intervention (PCI) or coronary artery by-pass grafting (CABG). (1)

2 Dosage Treatment alternatives Place in therapy Future alternatives Evidence for use Ticagrelor treatment should be initiated with a single 180 mg loading dose (two tablets of 90 mg) and then continued at 90 mg twice daily. Patients taking ticagrelor should also take aspirin daily, unless specifically contraindicated. Following an initial dose of ASA, ticagrelor should be used with a maintenance dose of ASA of mg. Treatment is recommended for up to 12 months unless discontinuation of ticagrelor is clinically indicated. Experience beyond 12 months is limited. In patients with Acute Coronary Syndromes (ACS), premature discontinuation with any antiplatelet therapy, including ticagrelor, could result in an increased risk of cardiovascular death, or myocardial infarction due to the patient's underlying disease. Therefore, premature discontinuation of treatment should be avoided. Patients treated with clopidogrel can be directly switched to ticagrelor if needed. Switching from prasugrel to ticagrelor has not been investigated. (1) Aspirin, dipyridamole, clopidogrel, prasugrel To be determined direct alternatives are clopidogrel and prasugrel; however, ticagrelor requires twice daily dosing. None known The evidence for use of ticagrelor comes from the PLATO (PLATelet inhibition and clinical Outcomes) trial. The details of the study are set out in table 1. (2) There have also been a number of sub-studies published examining results of the PLATO trial in various groups patients undergoing an invasive procedure, patients with chronic kidney disease, patients with diabetes and a genetic substudy. These are all summarised in table 1. (3-6)

3 NNT NNT = 53 for ticagrelor to prevent 1 death from vascular causes, myocardial infarction [MI] or stroke over 12 months compared to clopidogrel. (2, 7) NNT = 72 for ticagrelor to prevent 1 death from any cause over 12 months compared to clopidogrel. (2, 7) In comparison the NNT for the CURE study (clopidogrel in combination with aspirin vs. aspirin alone) to prevent 1 additional CV death, non-fatal MI or stroke was 48. (7) Contraindications / cautions / drug interactions This is a brief overview of information from the summary of product characteristics (SPC), more detail is given in the SPC. (1) Contra-indications Hypersensitivity to the active substance or to any of the excipients. Active pathological bleeding History of intracranial haemorrhage Use in moderate to severe hepatic impairment is contraindicated as ticagrelor has not been studied in these patients. Co-administration of ticagrelor with strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin, nefazodone, ritonavir, and atazanavir) is contraindicated, as co-administration may lead to a substantial increase in exposure to ticagrelor. Cautions Use of ticagrelor in patients at known increased risk for bleeding should be balanced against the benefit in terms of prevention of atherothrombotic events. Due to the limited clinical experience, ticagrelor should be used with caution in patients with an increased risk of bradycardic events (e.g. patients without a pacemaker who have sick sinus syndrome, 2nd or 3rd degree AV block or bradycardic-related syncope). Ticagrelor should be used with caution in patients with history of asthma and/or COPD. Creatinine levels may increase during treatment with

4 ticagrelor. Use of ticagrelor in patients with uric acid nephropathy is discouraged. Drug interactions Ticagrelor is primarily a CYP3A4 substrate and a mild inhibitor of CYP3A4. Ticagrelor is also a P-gp substrate and a weak P-gp inhibitor and may increase the exposure of P-gp substrates. Co-administration of ticagrelor and high maintenance dose aspirin (>300 mg) is not recommended. Co-administration of ticagrelor with strong CYP3A4 inducers (e.g. rifampicin, dexamethasone, phenytoin, carbamazepine and phenobarbital) is discouraged, as co-administration may lead to a decrease in exposure and efficacy of ticagrelor. Co-administration of ticagrelor and CYP3A4 substrates with narrow therapeutic indices (i.e., cisapride and ergot alkaloids) is not recommended, as ticagrelor may increase the exposure to these medicinal products. The concomitant use of ticagrelor with doses of simvastatin or lovastatin greater than 40 mg is not recommended as maximum plasma concentration of simvastatin can be increased up to 2-3 fold and could cause adverse effects of simvastatin. Close clinical and laboratory monitoring is recommended when giving digoxin concomitantly with ticagrelor. No data are available on concomitant use of ticagrelor with potent P-glycoprotein (P-gp) inhibitors (e.g. verapamil, quinidine, cyclosporin) that may increase ticagrelor exposure. If the association cannot be avoided, their concomitant use should be made with caution. Side effects Commonly reported ( 1/100 to < 1/10) adverse reactions in the ticagrelor group in the PLATO study were (1) dyspnoea (exertional, at rest and nocturnal); epistaxis; gastrointestinal haemorrhage (including rectal bleeding,

5 intestinal bleding, melaema and occult blood); subcutaneous or dermal bleeding (including subcutaneous haematoma / haemorrhage, skin haemorrhage, petechiae); bruising (including contusion, haematoma, ecchymosis, increased tendency to bruise, traumatic haematoma) procedural site haemorrhage (including vessel puncture site haemorrhage/haematoma, injection site haemorrhage, puncture site haemorrhage, catheter site haemorrhage). Dyspnoea was reported by 13.8% of ticagrelor patients compared to 7.8% of clopidogrel patients (P<0.001). In most cases the dyspnoea lasted less than one week. Discontinuation because of dyspnoea occurred in 0.9% of patients in the ticagrelor group. (2, 7) A number of bleeding events were rated as uncommon ( 1/1000 to < 1/100) (1) Intracranial haemorrhage (including cerebral haemorrhage and haemorrhagic stroke) Eye haemorrhage (intraocular, conjunctival, retinal) Gastrointestinal ulcer haemorrhage (including gastric, duodenal and peptic ulcer haemorrhage) Haemorrhoidal haemorrhage Oral haemorrhage (including gingival bleeding) Urinary tract haemorrhage (including haematuria) Vaginal bleeding (including metrorrhagia) Post procedural haemorrhage No significant difference in major bleeding was found between groups. 23.4% and 21.5% of ticagrelor and clopidogrel patients, respectively, stopped treatment early (P=0.002). 7.4% and 6.0% stopped due to adverse events (P<0.001). NNH NNH = 143 for ticagrelor to cause 1 incidence of major bleeding not related to CABG compared to clopidogrel. (2, 7)

6 NNH = 72 for ticagrelor for result in a discontinuation of therapy due to adverse events compared to clopidogrel (2, 7) In comparison, the NNH for major bleeding in the CURE study was 100. (7) Cost within PbR tariff? Cost (price from Pharmaceutical Journal Dec 2010) Comparative costs of other medicines (MIMS Dec 2010 & Drug Tariff Jan 2011) Potential number of patients & usage in Suffolk PCT Yes for 56 x 90mg tablets Annual cost = Drug Dose Annual cost Aspirin 75mg once daily Clopidogrel 75mg once daily Prasugrel 5-10mg once daily About 300 people per 100,000 are hospitalised each year with ACS. Applying this figure to Suffolk PCT (population ~600,000) there could be 1,800 people hospitalised with ACS and therefore eligible for clopidogrel, prasugrel or ticagrelor. If all patients are treated with aspirin + clopidogrel, total costs are around 94,300. The prevalence of clopidogrel resistance varies from 8-30%. (8) If 10% of patients switch to ticagrelor, costs would increase by roughly 120,000. If 30% of patients switch to ticagrelor, costs would increase by approximately 360,000.

7 Points for consideration One phase 3 trial has demonstrated that ticagrelor plus aspirin is statistically significantly more effective than clopidogrel plus aspirin at preventing vascular events in patients with ACS. The NNT for ticagrelor is 53 over 12 months compared to 48 for clopidogrel. There was no significant difference in the rates of major bleeding between the two groups. More patients taking ticagrelor withdrew from the study, mainly due to adverse effects. Patients taking ticagrelor were significantly more likely to suffer from non-procedure related bleeding (NNH=143) and breathlessness than those taking clopidogrel. There is no direct comparison with prasugrel so it is not clear how the 2 drugs compare. The place of ticagrelor in therapy is currently unclear. Ticagrelor would need to be initiated in secondary care and could then be continued in primary care. There are cost pressures from use of ticagrelor (and prasugrel) compared to clopidogrel plus aspirin as clopidogrel is now a generic, category M product. Is the drug on the WSH or IHT formularies? Decisions from other bodies Comments sought from West Suffolk Hospital no Ipswich Hospital no Cambridgeshire JPG reviewed May 2010, double red not funded for prescribing in primary or secondary care as place in therapy not defined. Norfolk TAG not assessed SMC not assessed AWMSG not assessed A NICE Single Technology Appraisal on ticagrelor for the treatment of acute coronary syndromes is due in July 2011.

8 Decision review date Following publication of NICE guidance, July 2011 References 1. Summary of Product Characteristics. Brilique 90 mg film coated tablets. AstraZeneca UK Limited. Last revised 3rd December mg film coated tablets/ 2. Wallentin L, Becker RC et al for the PLATO investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. New England Journal of Medicine 2009; 361 (11): Cannon CP, Harrington RA et al for the PLATO investigators. Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): a randomised double blind study. Lancet 2010; 375: James S, Budaj A et al. Ticagrelor versus clopidogrel in acute coronary syndromes in relation to renal function: results from the platelet inhibition and patient outcomes (PLATO) trial. Circulation 2010; 122: James S, Angiolillo DJ et al for the PLATO study group. Ticagrelor vs. clopidogrel in patients with acute coronary syndromes and diabetes: a substudy from the PLATelet inhibition and patient Outcomes (PLATO) trial. European Heart Journal; advance access published 29 August Wallentin L, James S et al for the PLATO investigators. Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet 2010; 376: Ticagrelor another antiplatelet for ACS. NPCi blog, 2 December Gurbel PA & Tantry US. Combination antithrombotic therapies. Circulation 2010; 121: Appendix 1 Summary of clinical trials Ref No 2 Randomised, multicentre, doubleblind, double dummy phase III trial Trial Design Trial Population Treatment Primary Outcomes 18,624 patients hospitalised because of ACS with (38%) or without (43%) ST-segment elevation. 17% had unstable angina. Patients were eligible if onset of symptoms had been within the previous 24 hours. Patients had a median age of Ticagrelor patients (n=9,333) received 180mg loading dose followed by 90mg twice a day. Clopidogrel patients (n=9,291), who had not received an open-label loading dose and had not been taking clopidogrel for at The primary outcome was a composite of death from vascular causes, MI, or stroke. At 12 months the results were as follows - Ticagrelor = 9.8% vs. Clopidogrel = 11.7% (HR 0.84; 95% CI 0.77 to 0.92; P<0.001). The primary safety variable was major bleeding - Ticagrelor = 11.6% vs. Clopidogrel = 11.2% (HR 1.04; 95% CI 0.95 to 1.13, P=0.43).

9 62 years. Patients were recruited from 862 centres in 43 countries. least 5 days before randomisation received 300mg as a loading dose then 75mg thereafter. Otherwise patients in this group just received 75mg daily. All patients received aspirin mg daily, unless intolerant. Secondary endpoints Rate of death from any cause - Ticagrelor = 4.5% vs. Clopidogrel = 5.9% (HR 0.78; 95% CI 0.69 to 0.89, P<0.001). Death from MIs Ticagrelor = 5.8% vs. Clopidogrel = 6.9% (HR 0.84; 95% CI 0.75 to 0.95, P=0.005) Death from stroke - Ticagrelor = 1.5% vs. Clopidogrel = 1.3% (HR 1.17; 95% CI 0.91 to 1.52, P=0.22) Death from vascular causes Ticagrelor = 4.0% vs. Clopidogrel = 5.1% (HR 0.79; 95% CI 0.69 to 0.91, P=0.001) Definite stent thrombosis - Ticagrelor = 1.3% vs. Clopidogrel = 1.9% (HR 0.67; 95% CI 0.50 to 0.91, P=0.009). Increased risk of major bleeding not related to CABG Ticagrelor = 4.5% vs. Clopidogrel = 3.8% (HR 1.19; 95% CI 1.02 to 1.38, P=0.03). Fatal or life threatening bleeding Ticagrelor = 5.8% vs. Clopidogrel = 5.8% Intracranial bleeding Ticagrelor = 0.3% vs. Clopidogrel = 0.2% (HR 1.87; 95% CI 0.98 to 3.58, P=0.06). Fatal intracranial bleeding Ticagrelor = 0.1% vs. Clopidogrel = 0.01% (P=0.02).

10 3 As above At randomisation, 13,408 of the 18,624 patients had an early invasive strategy (e.g. coronary angiography, PCI, coronary bypass surgery) 4 As above At baseline, serum creatinine levels were available for 15,202 patients (81.9%). Creatinine clearance was estimated using the Cockcroft Gault equation. 5 As above At randomisation, 4,662 of the 18,624 patients had preexisting diabetes mellitus, including 1,036 taking insulin. 6 As above At baseline, DNA samples were obtained from 10,285 Ticagrelor patients (n=6,732) Clopidogrel patients (n=6,676) Dosing as above. As above The paper does not state how many patients were taking ticagrelor and clopidogrel. 3,237 patients had chronic kidney disease (CrCl <60ml/min) As above The paper does not state how many patients were taking ticagrelor and clopidogrel. Ticagrelor patients (n=5,137) Other fatal bleeding Ticagrelor = 0.1% vs. Clopidogrel = 0.3% (P=0.03). The primary outcome was a composite of death from vascular causes, MI, or stroke. At 12 months the results were as follows - Ticagrelor = 9.0% vs. Clopidogrel = 10.7% (HR 0.84; 95% CI 0.75 to 0.94; P<0.0025). The primary safety variable was major bleeding - Ticagrelor = 11.6% vs. Clopidogrel = 11.5% (HR 0.99; 95% CI 0.89 to 1.10, P=0.8803). The primary outcome was a composite of death from vascular causes, MI, or stroke. At 12 months the results were as follows - Ticagrelor = 17.3% vs. Clopidogrel = 22% (HR 0.77; 95% CI 0.65 to 0.90; P=0.13). The primary safety variable was major bleeding - Ticagrelor = 15.1% vs. Clopidogrel = 14.3% (HR 1.07; 95% CI 0.88 to 1.30, P=0.92). The primary outcome was a composite of death from vascular causes, MI, or stroke. At 12 months the results were as follows - Ticagrelor = 14.1% vs. Clopidogrel = 16.2% (HR 0.88; 95% CI 0.76 to 1.03; P=0.49). The primary safety variable was major bleeding - Ticagrelor = 14.1% vs. Clopidogrel = 14.8% (HR 0.95; 95% CI 0.81 to 1.12, P=0.21). The primary outcome was a composite of death from vascular causes, MI, or stroke. At 12 months

11 patients and genotyped for CYP2C19 loss of function alleles, gain of function alleles and ABCB1 single nucleotide polymorphism. The metabolism of clopidogrel is dependent on a number of isoenzymes including CYP2C19. CYP2C19 is the most important determinant of the pharmacokinetic and pharmacodynamic response to clopidogrel. Ticagrelor does not need metabolic activation although its absorption may be affected by ABCB1 polymorphisms. Clopidogrel patients (n=5,148) Dosing as above. the results were as follows - CYP2C19 loss of function Ticagrelor = 8.6% vs. Clopidogrel = 11.2% (HR 0.77; 95% CI 0.60 to 0.99; P=0.0380). CYP2C19 gain of function Ticagrelor = 8.8% vs. Clopidogrel = 10% (HR 0.86; 95% CI 0.74 to 1.01; P=0.0608). ABCB1 polymorphism Ticagrelor = 8.8% vs. Clopidogrel = 11.9% (HR 0.71; 95% CI 0.55 to 0.92; P=0.39). Grids used to assist the NHS Suffolk PCT Drug & Therapeutics Committee in reaching a decision about new medications For many years scientists have recognised two types of research: Primary: original studies, based on observation or experimentation on subjects. Secondary: reviews of published research, drawing together the findings of two or more primary studies. In biomedical science there is general agreement over a hierarchy: the higher up a methodology is ranked, the more robust and closer to objective truth it is assumed to be. The orthodox hierarchy looks something like this- Rank: Methodology Description

12 1 Systematic reviews and meta-analyses Systematic review: review of a body of data that uses explicit methods to locate primary studies, and explicit criteria to assess their quality. Meta-analysis: A statistical analysis that combines or integrates the results of several independent clinical trials considered by the analyst to be "combinable" usually to the level of re-analysing the original data, also sometimes called: pooling, quantitative synthesis. Both are sometimes called "overviews." 2 Randomised controlled trials (finer distinctions may be drawn within this group based on statistical parameters like the confidence intervals) Individuals are randomly allocated to a control group and a group who receive a specific intervention. Otherwise the two groups are identical for any significant variables. They are followed up for specific end points. 3 Cohort studies Groups of people are selected on the basis of their exposure to a particular agent and followed up for specific outcomes. 4 Case-control studies "Cases" with the condition are matched with "controls" without, and a retrospective analysis used to look for differences between the two groups. 5 Cross sectional surveys Survey or interview of a sample of the population of interest at one point in time 6 Case reports. A report based on a single patient or subject; sometimes collected together into a short series 7 Expert opinion A consensus of experience from the good and the great. 8 Anecdotal Something a bloke told you after a meeting or in the bar. Adapted from Systematic reviews, What are they and why are they useful? ScHARR 2008 To Decide if a Medication Is To Be Used In Suffolk Criterion to be measured Tends to poor 2 Medium 4 Tends to good Quality of evidence in the papers reviewed- concerns as only 1 trial, normally expect minimum of 2 for licence Magnitude of effect inferred from trials reviewed Low Medium High Are trial end-points surrogate markers or clinical outcomes? Clinical outcome Clinical usefulness of trial end-points x Known Side Effect Profile High x Medium Low

13 Known Interactions High Medium Low Concern re Possible Side Effects Not Yet Uncovered High Medium Low Balance of Benefit To Harm (side effects toxicity interactions etc) Poor Medium Good NNT High Medium Low Comparison Of Effectiveness With Other Medicines In Use For The Poor Medium Good Same Condition Severity of Condition to be Treated Trivial Medium Severe Novel drug or member of existing class Uptake (estimated proportion of people with this condition likely to be prescribed the medication under consideration maximum and minimum uptake) Is the drug to be used in Suffolk? Existing class 2% Prescriber s Rating Definitions Bravo! -The drug is a major therapeutic advance in an area where previously no treatment was available. A real advance - The product is an important therapeutic innovation but has certain limitations. Offers an advantage - The product has some value but does not fundamentally change present therapeutic practice. Possibly Helpful - The product has minimal additional value, and should not change prescribing habits except in rare circumstances. Judgement reserved - The Committee postpones its judgement until better data and a more thorough evaluation of the drug are available. Nothing New - The product may be a new substance but is superfluous because it does not add to the clinical possibilities offered by previous products available. In most cases these are me-too products. Not acceptable - Product without evident benefit over others but with potential or real disadvantages. (With acknowledgement to Prescrire) To Decide Where A Medication Is To Be Used In Suffolk Skills of the prescriber Criterion Red Amber Green Blue Experience Of The Condition Specific Specific Specific General Diagnosis Specific Specific Specific General Monitoring Progress Of Treatment Difficult Specific General General

14 Therapy Patient Selection Difficult Specific Specific Easy Initiation Of Treatment Difficult Difficult Easy Easy Dose Titration Difficult Specific Easy Easy Monitoring Of Side Effects Complex Easy Easy Easy Method Of Administration Complex Normal Normal Normal Discontinuation Of Treatment Complex Complex Easy Easy References Jonsen A. Bentham in a box: Technology assessment and health care allocation. Law Med. Health Care. 1986;14: Suffolk Drug & Therapeutics Committee Responsibility for prescribing, Hospital Trust or GP Attached as Appendix 1 & Appendix 2