Prasugrel and Ticagrelor What place in therapy

1. Prasugrel and TicagrelorWhat place in therapy? Andrew White Head of Medicines Management NHS Bolton

2. How does it feel sometimes?

3. Medicines Management QIPPQuality, Innovation, Productivity, Prevention Quality Best care for patients Cost effective, clinically effective, safe Patient orientated, affordable Innovation Getting good evidence into practice Productivity VFM medicines new and existing Prevention Using medicines to prevent exacerbations and admissions

4. Cost Growth Overall NHS growth 0% Primary care drug costs +3-5% Secondary care drug cost growth 12–15% p.a. Payment by results (PbR) exclusions driving this Far beyond NHS and general inflation Cannot be sustained. Patent expiries in CV 2011 - Valsartan, candesartan 2012 – Atorvastatin But savings already accounted for less than 0% drug budget uplift 2011-12 in most areas ANY new drug can only be used if in place of another or savings made elsewhere.

5. So what does this mean in real life?Maynard A. Lancet 1997; 349: 126-128 Medicine A cures 50% of people It costs £10 a month. So for the budget the NHS can treat 12,000 people and cure 6,000. Title of paper: EBM, an incomplete method for informing treatment choices!!!!Title of paper: EBM, an incomplete method for informing treatment choices!!!!

6. Where did it all begin? Cure!

7. What benefits does clopidogrel plus aspirin offer over aspirin alone in non-ST-segment-elevation ACS?The CURE Investigators. New Engl J Med 2001;345:494–502 RCT in non-ST-segment-elevation ACS (n=12,562) Clopidogrel (300mg loading dose, then 75mg daily) or placebo for 3–12 months (mean 9 months) Aspirin 75–325mg daily and usual care for all patients Primary outcome (CV death, MI or stroke) occurred in: 582 out of 6,259 people in the clopidogrel group (9.3%) 719 of 6,303 people in the placebo group (11.4%) RR 0.80 (95%CI 0.72 to 0.90), P<0.001 NNT 48 over 9 months. ACS part 2ACS part 2

8. ACSACS

9. ACSACS

10. What about adverse effects?The CURE Investigators. New Engl J Med 2001;345:494–502 Major bleeding occurred in: 231 of 6,259 people in the clopidogrel group (3.7%) 169 out of 6,303 in the placebo group (2.7%) RR 1.38 (95%CI 1.13 to 1.67), P=0.001 NNH 100 over 9 months So if 100 people with non-ST-segment-elevation ACS are treated with clopidogrel plus aspirin for a mean of 9 months, 2 fewer people will have CV death, MI or stroke and 1 will have a major bleed. ACSACS

11. Plavix® SPCwww.emc.medicines.org.uk. Accessed 16th December 2009 New cardiovascular events … prevented with relative risk reductions of: 22% (CI 8.6 to 33.4) during the 0–1 month study interval 32% (CI 12.8 to 46.4) during the 1–3 month study interval 4% (CI –26.9 to 26.7) during the 3–6 month study interval 6% (CI –33.5 to 34.3) during the 6–9 month study interval 14% (CI –31.6 to 44.2) during the 9–12 month study interval ‘Thus, beyond 3 months of treatment, the benefit observed in the clopidogrel plus [aspirin] group was not further increased, whereas the risk of haemorrhage persisted.’ ACSACS

12. What about ST-segment-elevation MI? COMMIT Collaborative Group. Lancet 2005;366:1607–21 n=45,852 RCT in Chinese patients Clopidogrel 75mg daily or placebo for mean 14.9 days All patients also received 162mg aspirin daily Primary outcomes: Death from any cause: 7.5% vs. 8.1%, RR 0.93 (95%CI 0.87 to 0.99), P=0.03, NNT 167 Death, MI or stroke: 9.2% vs. 10.1%, RR 0.91 (95%CI 0.86 to 0.97), P=0.002, NNT 111 Safety outcomes: Major bleeding: 0.58% vs. 0.55%, not significant Still not significant even in those thrombolysed, and >70 years Minor bleeding: 3.6% vs. 3.1%, P=0.005, NNH 200. In addition to aspirin and heparin Small RCT (n=78, Dogan) showed addition of clopidogrel increased angiographic and ECG outcomes - hypothesis generating really Majority in trial were STEMI, although perhaps around 10% were NSTEMI (85% had ST-elevation, 6% had LBBB) Excluded those for primary PCI, low chance of benefit or high risk of harm Randomised for 4 weeks or discharge from hospital, whichever came sooner MI outcome assessed by ECG changes, not silent MIIn addition to aspirin and heparin Small RCT (n=78, Dogan) showed addition of clopidogrel increased angiographic and ECG outcomes - hypothesis generating really Majority in trial were STEMI, although perhaps around 10% were NSTEMI (85% had ST-elevation, 6% had LBBB) Excluded those for primary PCI, low chance of benefit or high risk of harm Randomised for 4 weeks or discharge from hospital, whichever came sooner MI outcome assessed by ECG changes, not silent MI

13. What about ST-segment-elevation MI? Sabatine MS, et al. New Engl J Med 2005;352:1179–89 (CLARITY) RCT in patients with MI (n=3,491) Randomised to clopidogrel 300mg loading dose then 75mg daily, or placebo, for median 4 doses All patients also received standard treatment Primary outcome at angiography, day 8 or discharge (composite of angiographic findings in infarct-related artery, MI or death prior to angiography) 15.0% vs. 21.7%, RR 0.64 (95% CI 0.53 to 0.76), P<0.001, NNT 15 Due to improvement in flow-grade at angiography MI, death not significantly different 30-day outcomes: Composite primary endpoint:14.1% vs. 11.6%, P=0.03 MI: 4.1% vs. 5.9%, P=0.02, NNT 56 No significant reduction in death or stroke Major or minor bleeding by angiography, day 8, discharge or day 30 was not significantly different.

14. Acute coronary syndrome — prasugrel? NICE. Acute coronary syndrome – prasugrel. TA182. October 2009

15. What evidence supports use of prasugrel?? NICE. Acute coronary syndrome – prasugrel. TA182. October 2009 ERG = evidence review groupERG = evidence review group

16. Triton-TIMI 38WiviottSD, et al. New Engl J Med 2007;357:2001–15 13,608 patients with moderate to high-risk ACS with scheduled PCI Randomised to prasugrel? or clopidogrel for 6 to 15 months Primary efficacy endpoint (CV death, non-fatal MI or stroke) occurred in 12.1% of patients receiving clopidogrel and 9.9% of patients receiving prasugrel NNT 45 (CV death NS) HR 0.81 (95%CI 0.73 to 0.90), P<0.001 Stent thrombosis - HR 0.48 (95%CI 0.36 to 0.64), P<0.001 NNT 77 Major bleeding was observed in 2.4% of patients receiving prasugrel and in 1.8% of patients receiving clopidogrel NNH 167 HR 1.32 (95%CI1.03 to 1.68), P=0.03 Fatal bleeding: 0.4% vs. 0.1%, P=0.002 NNH 333 Overall mortality did not differ significantly between treatment groups.

17. Subgroup analyses www.npci.org.uk/blog/?p=319; www.npci.org.uk/blog/?p=216Montalescot G, et al. Lancet 2009;373:723–31 Wiviott SD, et al. Circulation 2008;118:1626–36 A pre-specified subgroup analysis of the TRITON-TIMI 38 trial suggests that prasugrel? may be more effective than clopidogrel in those with ST-segment-elevation MI ACS undergoing PCI NB 2oPCI drives outcome , NOT 1oPCI CV death only significant at 30 days, not 15 months! Major bleeding across the whole subgroup was around 2% for both treatments, but was significantly more common with prasugrel in those who had CABG surgery Another sub-group analysis suggests that prasugrel has a greater net treatment benefit in patients with diabetes mellitus compared to those without However, results from such analyses should be viewed with caution, and prasugrel’s overall increased risk of bleeding, as demonstrated in the full TRITON-TIMI 38 paper, remains a concern.

18. Prasugrel - What does NICE say? Extracts from TA 182 4.4.The Committee identified three main areas of uncertainty in the evidence for the clinical effectiveness of prasugrel compared with clopidogrel. Firstly, the Committee heard from clinical specialists that clopidogrel is administered to patients several hours before percutaneous coronary intervention (preloading) in most procedures carried out in England and Wales. Additionally, the preloaded dose of clopidogrel is often 600 mg. This dose and timing of clopidogrel differed from that used in TRITON-TIMI 38 in which 300 mg (as in the marketing authorisation) was given, without preloading. The Committee therefore considered that more cardiovascular events could have occurred in the clopidogrel group in the trial than might be experienced in a similar cohort of patients having percutaneous coronary intervention in routine clinical practice in England and Wales. As a result, the advantages of prasugrel over clopidogrel in preventing cardiovascular events may have been overstated in the manufacturer’s submission, especially for non-ST-segment-elevation MI patients for whom there would be adequate time to give a preloading dose of clopidogrel.

19. More from NICE – QALYS 3.16 For the licensed population, the manufacturer reported an ICER of £159,358 per quality-adjusted life year (QALY) gained for a time horizon of 1 year and an ICER of £3435 per QALY gained for prasugrel compared with clopidogrel for a time horizon of 40 years. […….]….£1441 per QALY gained for patients with diabetes and £2167 per QALY gained for patients with ST-segment-elevation MI …… [Simple ratio suggests that ICER for 1 year for ST-elevation population (recall final recommendation for ST-elevation MI requiring immediate PCI) = £114,450 and for patients with diabetes = £66,851 – all based on clopidogrel prices at time of TA]

20. More from NICE – QALYS 4.15 The Committee first considered the estimates of cost effectiveness presented in the manufacturer’s submission for the licensed population as a whole. It noted that the estimated QALY gains for prasugrel over the 40-year time horizon were small (in the region of 22 life-days, that is, 0.05 QALYs gained) and that the difference in cost between prasugrel treatment and clopidogrel treatment was also small over this timeframe. As a result, the cost effectiveness of prasugrel was highly susceptible to changes in key model assumptions. [But then went on to consider 40 year time horizons for subgroups with ST-elevation MI or diabetes (???) – with final recommendations based on the 40 year ICERs]

21. Use prasugrel? judiciouslywww.npci.org.uk/blog/?p=319 Action The Summary of Product Characteristics for prasugrel? emphasises that severe haemorrhagic events are more frequent in patients aged 75 years or older (including fatal events) or in those weighing less than 60kg Use in older patients is not usually recommended but, if deemed necessary, a reduced maintenance dose should be prescribed. Patients weighing less than 60kg should also receive a lower maintenance dose.

22. Ticagrelor — another antiplatelet for ACS www.npci.org.uk/blog/?p=668Wallentin L, et al. New Engl J Med 2009;361:1045–57 Action Ticagrelor’s place in therapy is unclear at present The PLATO study suggests that ticagrelor may reduce the risk of CV events compared with clopidogrel plus aspirin, and its rapid reversibility may give it advantages for acute treatment of patients who require surgery N.B. BD dosing – compliance issues? However the greater risk of non-procedural major bleeding and other treatment-related side effects (dyspnoea, bradyarrhythmia, increased serum levels of uric acid and creatinine) compared with clopidogrel, raise questions about its safety, particularly over the longer term As yet there is no direct clinical evidence for any advantage/disadvantage compared with prasugrel?.

23. Ticagrelor — the PLATO trial www.npci.org.uk/blog/?p=668Wallentin L, et al. New Engl J Med 2009;361:1045–57 Ticagrelor plus aspirin was significantly more effective than clopidogrel plus aspirin in preventing vascular events in patients with ACS in the PLATO trial (NNT=53) There was no significant difference in the rates of major bleeding between the two groups, although 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. Interactions with Simvastatin!!!

24. Summary — unstable disease Non-ST-segment-elevation ACS A combination of low-dose aspirin and clopidogrel 75mg daily is recommended Combination treatment is continued for 12 months after the most recent acute episode of non-ST-segment-elevation ACS ST-segment-elevation ACS In those treated within the first 24 hours, a combination of low-dose aspirin and clopidogrel 75mg daily is recommended for at least 1 month after the most recent acute episode of ST-segment-elevation ACS Patients undergoing coronary or carotid interventions e.g. stenting In general, low-dose aspirin is prescribed with clopidogrel (or prasugrel?) for up to 12 months after the procedure.

25. “Knowing is not enough; we must apply. Willing is not enough; we must do.” Johann Wolfgang von Goethe

26. What has changed over time 3 GMMMG recommendations March 2009 Drafts Nov 2010, Jan 2011 Massive drop in Clopidogrel cost – Plavix® £35.64

27. Prasugrel GMMMG – November 2010 draft

28. Prasugrel Draft GMMMG position – Jan 2011

29. Ticagrelor Draft GMMMG position – Jan 2011

30. A vision of something better “If you have an apple and I have an apple and if we exchange these apples then you and I will still each have one apple. But if you have an idea and I have an idea and we exchange these ideas, then each of us will have two ideas.” George Bernard Shaw

31. What could we have instead? 500 patients in DGH have ACS/MI per yearCost vs NNT comparison Ticagrelor Treat all with ticagrelor - £1,512,500 9.4 fewer deaths, MIs, strokes saved (NNT 53, NNH 143) , 3.5 life threatening bleeds £160,872 per event saved!!!!!, + transfusion costs 5.5 fewer deaths (NNT 90) To prevent one death from vascular cause, stroke or MI, the NNT for 12 months with ticagrelor is 53 people at a cost of £37,723. To treat the same population with generic clopidogrel would cost £2,051.

32. What could we have instead? 500 patients in DGH have ACS/MI per yearCost vs NNT comparison Prasugrel Treat all PPCIs in GM with Prasugrel (13% of all ACS/MI from trials) 713 procedures (10/11) - £448,099 vs £25,411 (+£422,888) 1200 projected (11/12) - £754,164 vs £42,768 (+£711,396) No additional lives saved over clopidogrel! Biggest benefit for Mortality 0-30 days GMMMG proposal 1200 x 1 month prasugel + 11 months clopidogrel = £161,748 £549,648 less than current projections for 2011/12

33. Or……. For £1,512,500 we could have TAVI - NNT 4 - £25K each 60 TAVIs - £100,000 per event saved! 30 Cardiac and pulmonary rehab nurses (50K each) 1522 AF patients treated with Dabigatran More bleeds but slightly better than warfarin Unlikely to shut Anti-coag clinics though! Help to mitigate growth in other areas notably Diabetes, Rheumatology, GI, neurological pain, dermatology

34. Food for thought Cardiologist: ‘If I told you that there was a drug available that would significantly improve the function of your heart but I was not going to prescribe this, you would be outraged, would you not. Patient : ’Naturally,-...’ Cardiologist:’ Well, there is such a drug-not drinking more than 20 units of alcohol each week, losing at least 5kg in weight, and taking some light exercise in the form of a 20 minute walk each day. At present you are depriving yourself of that prescription.’ There was a long silence. And the point was well made.

35. Options for the meeting to consider Prasugrel As NICE Use for all patients with PPCI, Diabetes, thrombosis on Clopidogrel As CURRENT Cardiac network guidance Use in PPCI patients only GMMMG Recommendations Prasugrel for 1 month then switch to clopidogrel Do not use at all Ticagrelor Does it have a role? If so what / where?