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ACCA Comments the PEGASUS trial

When patients are admitted with ACS, cardiologists are keen to specify the exact duration of dual anti-platelet therapy (DAPT) after PCI to avoid any confusion in general practice.

The current standard is 12 months therapy but we have all been faced with the difficult problem of readmission due to bleeding whilst on DAPT, and so device companies have been improving stent design in an attempt to shorten this period. However trial data including the PEGASUS trial TIMI54 recently presented at the American College of Cardiology and published in NEJM have been challenging the concept of shorter DAPT.

So what do we now tell our patients?

In our viewpoint article interventional cardiologist Bob Gerber discusses the new data and considers three typical case studies.

Prof David Walker, ACCA Communcation committee Chairperson



The winged horse Pegasus helped the hero Bellerophon defeat the Chimera which was a sight to behold.

Pegasus was always accreted with magical powers and legend has it that everywhere the winged horse struck his hoof a spring burst forth. So we now are faced with the final data from the Pegasus TIMI 54 trial published recently in the NEJM [1] and simultaneously presented at the American College of Cardiology (ACC) 2015 San Diego, USA.

The question is did Pegasus aid our hero against the villains of recurrent myocardial infarction and cardiovascular events only to deliver him into the perils of the bleeding demon Chimera.

Dual Antiplatelet Therapy (DAPT)

The role of dual antiplatelet therapy (DAPT) post acute coronary syndromes (ACS) was recognized in the CURE series of trials [2] and currently the level of recommendation from the ESC is 12 months DAPT post ACS whether this is managed by conservative medical treatment, percutaneous coronary intervention (PCI) or surgical revascularization.[3]

The optimal duration of DAPT post PCI however, still remains controversial as the atherosclerotic process is ongoing and CV events occur predominantly in vascular beds and territories remote to the culprit vessel that caused the index ACS.

This was first recognised in the REACH Registry whereby 17% CV events out to 5 years post index ACS [4], and more recently reported in the follow-up of cardiovascular events in patients enrolled in the  Global Registry of Acute Coronary Events (GRACE) Registry post ACS.[5] GRACE patients (n=70.395) had a 8.7% re-PCI rate with a 2% CABG rate at 2 years follow-up and an additional 24% re-hospitalisation rate over the same time period.[5]

This has more recently been confirmed in the largest trial looking at duration of DAPT post PCI namely the DAPT study.[6]  DAPT investigated the prolonged treatment with DAPT for 30 vs. 12 months post PCI in 9000 patients.

The ischaemic events were significantly less in the prolonged DAPT treatment groups with a combined primary endpoint of death, myocardial infarction, or stroke significantly decreased with 30 months vs. 12 months DAPT (4.3 vs. 5.9%, p<0.001).

However, there was an excess in bleeds and also the trial predominately used clopidogrel. Moreover, there is a concern about responsiveness to this agent and that non-responsiveness may be related to CV events.[7]  Additionally, non-responsiveness may well be related to genetic  loss of CYP2C19 [8] and so newer antiplatelet agents Prasugrel or Ticagrelor have attracted interest in the context of ACS.

Therefore, the concept of prolonged DAPT is attractive but bleeding concerns is apparent with the newer stronger agents. Not to dwell too much on PLATO and TRYTON as they have been extensively discussed apart from to say that they both reduced the ischemic events and met their primary endpoints with approximately a 2% reduction in the composite endpoint of CV death, MI and Stroke as well as reduced stent thrombosis.(REFS).

However both agents were related to more significant bleeds and in some groups such as the elderly and low BMI Prasugrel dose adjustments are recommended. The bleeding events did translate into mortality and more worryingly fatal intracranial haemorrhage.  

PEGASUS TIMI 54

This brings us nicely to the PEGASUS TIMI 54 trial which evaluated Ticagrelor (90mg and 60mg BD dosing) in 21,162 patients all with prior ACS (mean 1.7 yrs prior) and additional risk factors (>65 yrs old, Diabetes, chronic kidney disease, further ACS, multi-vessel CAD) who had their index ACS more than 12 months prior.

The trial sought to reduce CV events as the primary end-point in the Ticagrelor treated patients and follow-up was for a median of 33 months.

It is worthwhile mentioning that the randomization was against Aspirin monotherapy and not clopidogrel, a question often asked. As a local primary investigator for the trial it was pleasing to see that the use of Ticagrelor in both doses did meet the primary composite efficacy endpoint (CV death, MI and stroke) with reduction in events by 7.85% vs 9.04 % (90mg dose) and 7.77% vs 9.04% (60mg dose) respectively (p=0.004).[1]

However the downside was the twofold increase in bleeds (TIMI Major bleed: 90mg (2.6%), 60mg (2.30%) vs. placebo (1.06%).

Furthermore, the tolerability of the agent was reduced with approx. threefold increase in dyspnoea and more study drug discontinuations in the Ticagrelor arm.

The Case Scenarios:

The current ESC 204 guidelines recommend the use of DAPT with Prasugrel or Ticagrelor after ACS rather than clopidogrel[3].

A personalised tailored approach to DAPT is however also recommended and I describe three cases below with differing indications for DAPT duration are indicated and like ‘cooking Pasta’ the duration of immersion in boiling water depends on how fresh the pasta and the co ingredients etc.

The cases highlight common scenarios and discussion related to post ACS DAPT and then subsequently we assess the relevance of PEGASUS-TIMI 54 to these patients.

Case 1:

57 year old male smoker presents with STEMI (Type 1a MI). He has no previous history of IHD and undergoes timely PPCI. He has a HS troponin 12 hr post procedure of 1120 but preserved LV systolic function. The operator opens an occluded LAD which was very thrombotic and needs to implant two drug eluting stents (DES). There is bystander lesion of 95% in the RCA and 50% lesion in the LCx and OM with an athermanous diagonal of reasonable size. He returns prior to discharge at day 4 post PPCI for PCI to the RCA with two further DES one in the proximal RCA and the other in a diseased PDA.

We now have several considerations as he is an ACS he ought to have DES for 12 months but the DES are second generation and so he could stop DAPT between 3-6 months. However the bleeding risk in this particular patient is far less than the thrombotic risk and more importantly the risk of ST as he now has 4 DES and may continue to smoke. Therefore the use of DAPT with Prasugrel or Ticagrelor for 12 months is mandated here. Of interest a real world use analysis of newer antiplatelet agents in a Swiss Registry with propensity matching found no significant adverse event profile with the use of Prasugrel compared to clopidogrel with a similar bleeding events defined by BARC, TIMI or GUSTO.[9]

Case 2:

69 year old lady with T2DM who has a long history of GORD. She had 10 years previously an episode of hematemesis. OGD at that time demonstrated ulceration with gastritis and she responded to medical treatment with PPI.

She presents with what she felt was indigestion but ECG changes were consistent with cardiac ischaemia and her HS troponin at 12 hr was 177.

She was diagnosed with NSTEMI (Type 1b MI). Angiography demonstrated a Type A lesion in the LAD which was stented with a large short DES. The risk of recurrent ischaemic events in this lady is <5% but concerns about GIB are real and so a reasonable approach would be to curtail DAPT at 6 months.

The ITALIC trial showed non-inferiority of DAPT at 6 months vs. prolonged (24 months) treatment. [10]

Case 3:

84 year old elderly man, suffers from hypertension, benign prostatic hypertrophy, hyperlipidaemia and sick sinus syndrome with intermittent paroxysmal atrial fibrillation (PAF). He had a collapse related to dyspnoea and diaphoresis and a positive troponin. Angiography demonstrated complex multivessel calcific and ectatic coronary diseases.

The multi-disciplinary team, in conjunction with the patient’s wishes, suggested medical management for his ACS. His CHADSDS2 VASC score is Y and triple therapy with Warfarin, Aspirin and Clopidogrel started.

The plan was to discontinue the clopidogrel at 6 months as per Woest trial data.[11] There is some concern that clopidogrel responsiveness and platelet reactivity are different in the Elderly patient and so this individual will be after 6 months on clopidogrel only antiplatelet therapy and if he is a non-responder will this translate into further thrombotic events given that he has MVD and is on medical management.

The role for platelet function testing in this group is currently being investigated and the results are eagerly anticipated.[12]

How does PEGASUS apply to our case scenarios?

The first question we must ask ourselves is do we stop statins, ACEI or beta blockers in patients post ACS? The answer is NO and we not only continue these treatments we maintain them for life.

There is however little randomised data to support indefinite use of these agents.

So why do we pursue this and the answer is the use of clinical acumen and practical understanding of the disease process.

We don’t extend this to DAPT because the concern of prolonged therapy and bleeding tendency and so the case scenarios above highlight my thoughts on how Pegasus fits in to daily practice.

Case 1 is a gentleman who had a high thrombotic risk with low bleeding tendency with multiple stents in complex anatomy. There is concern of stent thrombosis as well as stroke and re-MI.

Therefore this patient would be somebody who a 60mg BD dose of Ticagrelor could be continued.

The second case is a lady with a discrete lesion in a large vessel with a predisposition for large GIB. In this case we would be aiming to curtail DAPT and stop at 6 months. Lastly, the patient requiring triple therapy would not benefit from Ticagrelor as this is not tested and is currently under investigation.

The matter of sick sinus syndrome also needs to be considered as there were some associated bradyarrhythmias noted with Ticagrelor use.

Dr RT Gerber FRCP PhD

Consultant Cardiologist, East Sussex Healthcare NHS Trust

References

  1. Bonaca, M.P., et al., Long-Term Use of Ticagrelor in Patients with Prior Myocardial Infarction. New England Journal of Medicine, 2015. 372(19): p. 1791-1800.
  2. Effects of Clopidogrel in Addition to Aspirin in Patients with Acute Coronary Syndromes without ST-Segment Elevation. New England Journal of Medicine, 2001. 345(7): p. 494-502.
  3. Windecker, S., et al., 2014 ESC/EACTS Guidelines on myocardial revascularization. The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS)Developed with the special contribution of the European Association of Percutaneous Cardiovascular …. Vol. 35. 2014. 2541-2619.
  4. Bhatt, D.L., et al., Comparative determinants of 4-year cardiovascular event rates in stable outpatients at risk of or with atherothrombosis. JAMA, 2010. 304(12): p. 1350-7.
  5. Alnasser, S.M.A., et al., Late Consequences of Acute Coronary Syndromes: Global Registry of Acute Coronary Events (GRACE) Follow-up. The American Journal of Medicine, 2015. 128(7): p. 766-775.
  6. Mauri, L., et al., Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med, 2014. 371(23): p. 2155-66.
  7. Price, M.J., et al., Platelet reactivity and cardiovascular outcomes after percutaneous coronary intervention: a time-dependent analysis of the Gauging Responsiveness with a VerifyNow P2Y12 assay: Impact on Thrombosis and Safety (GRAVITAS) trial. Circulation, 2011. 124(10): p. 1132-7.
  8. Dahabreh, I.J., et al., Testing of CYP2C19 Variants and Platelet Reactivity for Guiding Antiplatelet Treatment. 2013, Rockville MD.
  9. Klingenberg, R., et al., Safety profile of prasugrel and clopidogrel in patients with acute coronary syndromes in Switzerland. Heart, 2015.
  10. Gilard, M., et al., 6- versus 24-month dual antiplatelet therapy after implantation of drug-eluting stents in patients nonresistant to aspirin: the randomized, multicenter ITALIC trial. J Am Coll Cardiol, 2015. 65(8): p. 777-86.
  11. Dewilde, W.J., et al., Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet, 2013. 381(9872): p. 1107-15.
  12. Cayla, G., et al., Platelet function monitoring in elderly patients on prasugrel after stenting for an acute coronary syndrome: design of the randomized antarctic study. Am Heart J, 2014. 168(5): p. 674-81.