Anti-platelet therapy with PCI – what do you need to know?

29th April 2023, Dr Chee L Khoo

anti-platelet therapy

We have a increasing number of patients who has undergone a percutaneous coronary intervention (PCI). This could be in the acute setting of an acute coronary syndrome (ACS) or electively during an exploratory angiogram. Stents used to be bare metal. Then came the first-generation drug eluting stents. The latest generation drug eluting stents are better at reducing subsequent thrombosis of the stented and unstented coronary segments. Current international guidelines recommend at least 12 months of dual anti-platelet therapy (DAPT) i.e. aspirin plus a high potency P2Y12 inhibitor (Ticagrelor or Prasugrel) except in patients with high bleeding risks. These patients are discharged to the care of their GPs but we are never formally informed of the grand plan or the rationale for therapy for these patients. Some of these patients are also on anti-coagulants and we must juggle between bleeding risks and ischaemic events. Without knowing all the issues surrounding anti-platelet therapy in these patients, it is often hard to answer questions from concerned patients when they are under our care.

In view of the major bleeding risks, there were earlier moves to reduce the duration of DAPT in the setting of ACS to three months (1). This resulted in increased ischaemic events. Searching through the literature can be confusing as in some of earlier trials the less potent P2Y12, clopidogrel and earlier generation stents were used. When the more potent P2Y12 agents were used in later trials, there was a small increase in bleeding events but there was net clinical benefit of reduced ischaemic events (2,3). The results were further improved with newer generation drug eluting stents. The focus for the last many years has been on reducing the bleeding complications.

There is a difference between PCI performed after ACS and PCI performed electively when coronary artery stenosis is diagnosed during angiography. Patients who had an ACS are at higher risk of further ischaemic events and demand more aggressive DAPT with more potent P2Y12.

To reduce the bleeding risks without increasing stent thrombotic events, experts had the following options:

  1. Early switching from a high potency P2Y12 inhibitor to clopidogrel;
  2. Early decrease in high potency P2Y12 inhibitor dosage;
  3. Early P2Y12 inhibitor discontinuation to aspirin monotherapy.
  4. Early cessation of aspirin with continuation of P2Y12 inhibitor monotherapy;

Other researchers looked into platelet function testing, genetic testing, and risk scores to guide de-escalation decisions compared with unguided de-escalation (4-7). As you can imagine, access to these testing is limited.

Some of landmark trials done to test the various strategies include:

  • The CREDO trial demonstrated a reduction in ischaemic events, including the risk of death, MI, or stroke, with a loading dose of clopidogrel and treatment up to 9 months after elective PCI (8)
  • In the CLARITY trial, clopidogrel pre treatment in conjunction with fibrinolytic therapy resulted in a 46% reduction in the rate of cardiovascular death or recurrent MI or stroke at 30 days among patients referred for PCI (9).
  • The TRITON-TIMI-38 (10) and the PLATO (11) trials demonstrated that treatment with prasugrel (TRITON-TIMI-38) and ticagrelor (PLATO), compared with clopidogrel, reduced the rate of the composite endpoint of death from vascular causes, MI, or stroke. These agents were also associated with a lower rate of stent thrombosis.

After PCI, the use of DAPT prevents stent thrombosis and reduces ischemic events at the cost of increased bleeding. Pooled data have demonstrated less bleeding with shorter-term DAPT (3–6 months) and fewer ischemic events (including stent thrombosis) with longer term DAPT (>12 months). The 2016 guideline focused update on duration of DAPT highlights the importance of balancing ischemic and bleeding risk when DAPT is considered and provides recommendations for short and prolonged DAPT followed by aspirin monotherapy after revascularization. Since the release of those guidelines, more recent trials have been published.

Shoji et al (2021) presented a network meta-analysis of RCTs looking at various de-escalation strategies model around the above de-escalation strategies (12). They found:

  1. de-escalation from a potent P2Y12 inhibitor to clopidogrel or low-dose prasugrel 1 month after PCI was the most effective strategy and was associated with a reduction in bleeding events without an increase in ischaemic events
  2. indirect comparisons revealed no significant differences in any ischaemic or bleeding outcomes between de-escalation to clopidogrel and de-escalation to low-dose prasugrel;
  3. ticagrelor was associated with a reduced risk of cardiovascular death and stent thrombosis compared with clopidogrel, but was associated with an increased risk of bleeding; and
  4. no significant differences were observed between standard-dose prasugrel and ticagrelor in any ischaemic or bleeding outcomes, except for stent thrombosis

As you can see, there are many safer options immediately after PCI to keep the stent open with acceptable bleeding risks. What about the chronic treatment after this period? Once we get over the period where stent thrombosis is a problem, we need to consider future cardiovascular events. Naturally, indefinite maintenance of single antiplatelet therapy is indicated for secondary prevention of atherosclerotic cardiovascular events. Typically, aspirin is the standard therapy in patients after PCI. We know from primary prevention studies when we weigh up the balance between the benefits of preventing cardiovascular events and bleeding risks, major bleeding risks wins.

HOST-EXAM (2021) is the first randomised trial to compare clopidogrel and aspirin monotherapy in patients who received percutaneous coronary intervention with a drug-eluting stent (13). In 5438 patients, clopidogrel monotherapy was associated with a reduced risk of adverse clinical events (a composite of all-cause death, non-fatal myocardial infarction, stroke, readmission due to acute coronary syndrome.

A recent post-hoc analysis of the study demonstrated clopidogrel was associated with lower rates of the 24-month composite end point of all-cause death, myocardial infarction, stroke, readmission due to acute coronary syndrome, and major bleeding in patients with and without diabetes (14).

Rather than automatically stopping the clopidogrel after 12 months and keeping the aspirin, we are now seeing the aspirin being ceased and the clopidogrel being continued.

In summary, various strategies have been devised to reduce stent thrombosis following PCI and yet minimise major bleeding. Antiplatelet therapy is required post PCI and current guidelines recommend 12 months of DAPT following PCI but in patients with higher bleeding risks, consideration of earlier de-escalation of DAPT should be considered. Obviously, the patient’s cardiologist needs to be consulted. Following 12 months of DAPT, perhaps, single anti-platelet therapy might be safer with clopidogrel rather than aspirin monotherapy.

References:

  1. Palmerini T., Benedetto U., Bacchi-Regiani L., et al. “Mortality in patients treated with extended duration dual antiplatelet therapy after drug-eluting stent implantation: a pairwise and Bayesian network meta-analysis of randomised trials”. Lancet 2015;385:9985: 2371-2382.
  2. Wallentin L., Becker R.C., Budaj A., et al. “Ticagrelor versus clopidogrel in patients with acute coronary syndromes”. N Engl J Med 2009;361:11: 1045-1057.
  3. Wiviott S.D., Braunwald E., McCabe C.H., et al. “TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes”. N Engl J Med 2007;357:
  4. Sibbing D., Aradi D., Jacobshagen C., et al. “TROPICAL-ACS Investigators. Guided de-escalation of antiplatelet treatment in patients with acute coronary syndrome undergoing percutaneous coronary intervention (TROPICAL-ACS): a randomised, open-label, multicentre trial”. Lancet 2017;390:10104: 1747-1757.
  5. Claassens D.M.F., Vos G.J.A., Bergmeijer T.O., et al. “A genotype-guided strategy for oral P2Y”. N Engl J Med 102019;381:17: 1621-1631.
  6. Cuisset T., Deharo P., Quilici J., et al. “Benefit of switching dual antiplatelet therapy after acute coronary syndrome: the TOPIC (timing of platelet inhibition after acute coronary syndrome) randomized study”. Eur Heart J 2017;38:41: 3070-3078.
  7. Sibbing D., Aradi D., Alexopoulos D., et al. “Updated expert consensus statement on platelet function and genetic testing for guiding P2Y12 receptor inhibitor treatment in percutaneous coronary intervention”. J Am Coll Cardiol Intv 2019;12:16: 1521-1537.
  8. Steinhubl SR, Berger PB, Mann JT 3rd, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002;288:2411–2420.
  9. Sabatine MS, Cannon CP, Gibson CM, et al. Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: the PCI-CLARITY study. JAMA. 2005;294:1224–1232.
  10. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357:2001–2015.
  11. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045–1057.
  12. Shoji et al. De-Escalation Therapy in Acute Coronary Syndrome JACC VOL. 78, NO. 8, 2021 Aug 24, 2021:763–777
  13. Bon-Kwon Koo et al. Aspirin versus clopidogrel for chronic maintenance monotherapy after percutaneous coronary intervention (HOST-EXAM): an investigator-initiated, prospective, randomised, open-label, multicentre trial, The Lancet, Volume 397, Issue 10293, 2021, Pages 2487-2496
  14. Rhee T, Bae J, Park KW, et al. Aspirin vs Clopidogrel for Long-term Maintenance After Coronary Stenting in Patients With Diabetes: A Post Hoc Analysis of the HOST-EXAM Trial. JAMA Cardiol. Published online April 12, 2023. doi:10.1001/jamacardio.2023.0592
  15. Lawton et al. 2021 ACC/AHA/SCAI Guideline for Coronary Artery Revascularization: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022;145:e18–e114. DOI: 10.1161/CIR.0000000000001038