CASE REVIEW

Prolonged use of DAPT with ticagrelor in a high-risk post-myocardial infarction patient: A local case report

01 Sep 2020
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Dr, Yip, Wai-Kwok, Gabriel

Specialist in Cardiology

After myocardial infarction (MI) and/or percutaneous coronary intervention (PCI), dual anti-platelet therapy (DAPT) with aspirin and platelet adenosine diphosphate P2Y12 receptor inhibitors, such as clopidogrel, prasugrel or ticagrelor, is the mainstay of antithrombotic therapy.1 Long term use of DAPT with ticagrelor and aspirin have shown clinically meaningful outcomes in patients with previous MI.2 Dr. Yip, Wai-Kwok Gabriel, Specialist in Cardiology, shared a case of a patient with multiple cardiovascular (CV) risk factors and a history of MI, stabilized by prolonged use of DAPT with ticagrelor.

Introduction

DAPT with aspirin and P2Y12 receptor inhibitor is recommended for patients with acute coronary syndrome (ACS) for a duration of 12 months to achieve optimum balance of efficacy and safety.1  Premature discontinuation of P2Y12 inhibitors is discouraged as it is associated with an increased risk of stent thrombosis.1

Prolonged use of DAPT has long been a subject of debate. It has been shown that long-term DAPT is beneficial in reducing death/MI and stroke in patients with prior MI despite increase in moderate-severe bleeding.3 In order to prevent bleeding associated with DAPT, Dr. Yip stated, “We need to give the DAPT therapy in accordance to the CV risks of the patients. The treatment should be tailored to patients’ risk indicators to reduce both ischemic events and bleeding.”

However, latest guidelines from ESC recommend adding a second antithrombotic drug to aspirin for long-term secondary prevention in patients with a high risk of ischemic events and without high bleeding risk.1 The guidelines also suggested a ticagrelor dose of 60mg twice daily in combination with an aspirin dose of 75-100mg daily, for post-MI patients who have tolerated an initial 12-month course of DAPT with a higher/moderate risk of ischemic events, and do not have a high bleeding risk.1

Compared to clopidogrel, ticagrelor has the most predictable and consistently higher level of P2Y12 inhibition with more rapid onset, as well as a more swift and predictable offset of action.1 In patients with a previous history of MI of more than 1 year, treatment with ticagrelor significantly reduced the risk of CV death, myocardial infarction or stroke.2

In this case review, Dr. Yip presented a post-MI patient who had multiple CV risk factors stabilized without secondary events by long-term use of DAPT with ticagrelor. “DAPT is definitely effective after PCI with stenting and these patients benefit for at least a year. The long-term use of DAPT and the regimen of DAPT should be decided through individualized assessment of prevalent risk factors for ischemia and bleeding,” stated Dr. Yip.

Case report

The patient is a female of 41 years old, who is a chronic smoker, with existing hypertension and hyperlipidemia. She was hospitalized in May 2018 due to a discomfort in the chest. The blood tests on admission during the indexed event showed elevated troponin I level of 120.5pg/mL. Her hemoglobin levels (14.2g/dL), platelet count (231x109/L), hemoglobin A1c (5.5%), and serum creatinine (69umol/L) were under the normal range.

The lipid profile indicated hyperlipidemia with low density lipoprotein (LDL)-cholesterol of 7.2mmol/L, high density lipoprotein (HDL)-cholesterol of 0.88mmol/L, and triglycerides of 2.85mmol/L. On the electrocardiogram (ECG), sinus tachycardia was detected with a heart rate of 101bpm. Poor R wave progression and strain pattern in the ECG depicted left ventricular hypertrophy.

Echocardiography did not show any significant valvular lesions. The left ventricle was dilated with global left ventricular (LV) hypokinesia. Her LV ejection fraction (LVEF) was estimated approximately 21%. Pulmonary venous hypertension with restrictive LV filling pattern was also evident without pericardial effusion.

Coronary computer tomography angiography had shown a dominant right coronary system with a coronary calcium score of 305.4 (Agatston). Also, there was a subtotal occlusion in the proximal left anterior descending (LAD) artery involving the ostial first diagonal branch. In addition, severe stenosis was present in the ostial first diagonal branch, proximal left circumflex (LCX) artery and proximal right coronary artery (RCA). Urgent invasive coronary angiography had been carried out and revealed mild left main disease with a subtotal proximal LAD occlusion, severe proximal-distal LCX stenosis (70-80%) and proximal RCA stenosis (80%). The diagnosis was a non-ST elevation MI.

Ad-hoc percutaneous coronary intervention (PCI) with drug-eluting stents to the ostial-mid LAD, ostial-distal LCX and proximal RCA, and plain old balloon angioplasty (POBA) to the ostial first diagonal branch was carried out at the same time. The procedure was uneventful, and the patient was to continue with a standard DAPT using ticagrelor 90mg twice daily and aspirin 100mg once daily for the next 12 months.

Being a chronic smoker, hypertension and hyperlipidemia placed the patient at high risk of secondary events. In addition, her prognosis was poor due to lower LVEF and the stenosis of major heart vessels. In order to optimize the benefit of DAPT, the patient was first assessed of her ischemic burden and risk of bleeding for initial short or long DAPT (i.e. 6 months versus standard 12 months). This should be reassessed again before extending the DAPT beyond 12 months. The PRECISE-DAPT score introduced in the European Society of Cardiology’s 2017 focused update on DAPT and the DAPT Risk Score from the American College of Cardiology were used to assess her suitability for initial short versus long, and extended DAPT after stenting in post-MI patients respectively. Dr. Yip mentioned, “These scores pointed out that she is at high risk of ischemia rather than bleeding”. After completion of an initial 12-month standard DAPT without bleeding complication or ischemic event, the patient is currently on an extended DAPT regimen of reduced dose of ticagrelor 60mg twice daily and aspirin 100mg once daily for two years without any secondary CV events and subsequently the LVEF has improved to 31%.

Discussion

PEGASUS-TIMI 54 is a randomized, double-blind and placebo-controlled trial which investigated the long-term therapy with ticagrelor added to a low-dose aspirin on major adverse cardiovascular events (MACE) among patients with a history of MI (1-3 years prior) who were randomized to ticagrelor 90mg twice daily (n=7,050) or ticagrelor 60mg twice daily (n=7,045) versus placebo (n=7,067).2

Ticagrelor significantly reduced the rate of the primary composite end point of cardiovascular death, myocardial infarction or stroke compared with placebo.2 At 3 years, only 7.85% in the group that received 90mg of ticagrelor (HR=0.85; 95% CI :0.75-0.98; p=0.008) twice daily and 7.77% in the group that received 60mg of ticagrelor (HR=0.84; 95%CI:0.74-0.95; p=0.004) twice daily encountered MACE, as compared to 9.04% in the placebo group (Figure 1).2 This translates into 83 individuals who need to be treated to prevent one adverse event. The association of ticagrelor on the primary outcome was the same in all tested subgroups.

Both high and low dose ticagrelor had a similar degree of efficacy (MACE) and safety (bleeding). Ticagrelor 60mg twice daily was associated with a reduction in all stroke compared with placebo. Cost-effectiveness for ticagrelor could be enhanced if certain high-risk characteristics (e.g. >1 prior MI, multivessel disease, diabetes, renal dysfunction, age <75 years, and peripheral artery disease) were present.4

Furthermore, long term use of ticagrelor has shown evidence of secondary prevention of MACEs in patients with prior MI and multivessel disease.5 Thus, for these patients, ticagrelor is an effective option for long-term DAPT.5

“DAPT with ticagrelor can be continued for up to 3 years. The addition of a proton pump inhibitor could also minimize bleeding. We offer patients with ACS the treatment option of long-term DAPT therapy. However, it is important to discuss with the patient on the bleeding risk to allow them to have an informed decision.”

According to the sub analysis of the PEGASUS-TIMI 54 trial, treatment with ticagrelor 60mg twice daily for 36 months in patients with recent MI reduced the risk of stroke by 20%, CV death by 29%, and all-cause mortality by 20%.6 Although major bleeding was increased, fatal or intracranial bleeding were not significantly different from placebo.6 Overall, a favorable benefit-risk balance for long-term ticagrelor 60mg twice daily was apparent in this population.6

Dr. Yip commented on the ESC guidelines for the long-term use of DAPT, “They are absolutely necessary and are indicated with strong evidence. The question is not whether to prolong DAPT, but the bleeding risk.” He pointed out that there are no specific guidelines for the prediction and management of antiplatelet-related bleeding complications in Chinese populations. However, it has been shown that the body mass index is an independent risk predictor for antiplatelet-related bleeding complications in Chinese elderly population with ACS.7

Dr. Yip added, “Due to the characteristic body stature of Hong Kong people, the muscle mass is less, thus the bleeding risk could be higher. Therefore, it is important to pay attention to these factors to obtain a better effectiveness of DAPT.”

Additionally, in a sub analysis of PEGASUS-TIMI 54, the effect of antiplatelet therapy with ticagrelor on recurrent ischemic events in patients with DM and prior MI was assessed.8 In this population of patients, adding ticagrelor to aspirin significantly reduced the risk of recurrent ischemic events, including death due to CV and coronary heart disease.8 Moreover, patients with renal dysfunction and prior MI also exhibited a robust absolute risk reduction with long-term treatment with ticagrelor.9

Dr. Yip explained, “Patients with DM or renal dysfunction are at a prothrombotic status and the anti-platelet therapy could prevent clot formation. Patients with hypertension and hyperlipidemia, as shown in the case presented, are prone to plaque rupture and thromboembolism. DAPT can prevent clot formation and eventually avoid myocardial injury or MI.”

As shown in the presented case, it is important to assess the ischemic and bleeding risk before prescribing long-term DAPT. Bonaca et al. identified clinical characteristics which predicted bleeding and ischemic risks to identify subgroups who derive greater benefit with DAPT with lower bleeding risk.10 They have proposed a patient selection strategy (Figure 2) which firstly identifies those at low bleeding risk and then stratifies the population according to the number of ischemic high-risk features in order to identify a subgroup which derives significant ischemic benefit with reductions in all-cause mortality and net outcomes.10

“DAPT continuing beyond 12 months is recommended for ACS patients with risk factors. Risk score assessments could be utilized together with clinical judgement. The main learning point is the individualization of therapy based on risk stratification,” concluded Dr. Yip.

Conclusion

The choice of optimal DAPT duration in patients with post-MI requires a tailored approach based on the clinical presentation of the patient, baseline risk profile and management strategy. According to the clinical trial data, continuing DAPT for more than 1 year has resulted in clinically meaningful outcomes in post-MI patients. The patient described in the case report also benefitted from DAPT with ticagrelor, without any secondary CV events. It is evident that with careful risk assessments for ischemia and bleeding risks, an extended DAPT beyond the standard 12-month duration could be successfully utilized to prevent MACE in high-risk post-MI patients.

This is an independent editorial article, published and distributed through unrestricted educational support from AstraZeneca Hong Kong Limited, for the purpose of continuing medical education only. The views expressed in this publication reflect the experience and/or opinion of the author(s) and are not necessarily those of editors, publisher and sponsor(s). Because of rapid advances in medicine, independent verification of clinical diagnoses, medical suitability and dosage should be made before treatment prescription. The appearance of advertisement, if any, has no influence on editorial content or presentation and does not imply the endorsement of products by the publication, or its authors and editors.


References
  1. Knuuti J et al. 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J. 2020;41(3):407-477.
  2. Bonaca MP et al. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med. 2015;372(19):1791-1800.
  3. Fanari Z et al. Long-term use of dual antiplatelet therapy for the secondary prevention of atherothrombotic events: Meta-analysis of randomized controlled trials. Cardiovasc Revasc Med. 2017;18(1):10-15.
  4. Magnuson EA et al. Cost-Effectiveness of Long-Term Ticagrelor in Patients With Prior Myocardial Infarction: Results From the PEGASUS-TIMI 54 Trial. J Am Coll Cardiol. 2017;70(5):527-538.
  5. Bansilal S et al. Ticagrelor for Secondary Prevention of Atherothrombotic Events in Patients With Multivessel Coronary Disease. J Am Coll Cardiol. 2018;71(5):489-496.
  6. Dellborg M et al. Efficacy and safety with ticagrelor in patients with prior myocardial infarction in the approved European label: insights from PEGASUS-TIMI 54. Eur Heart J Cardiovasc Pharmacother. 2019;5(4):200-206.
  7. Wan J et al. Predictors and Management of Antiplatelet-Related Bleeding Complications for Acute Coronary Syndrome in Chinese Elderly Patients. CPB. 2018;50(3):1164-1177.
  8. Bhatt DL et al. Reduction in Ischemic Events With Ticagrelor in Diabetic Patients With Prior Myocardial Infarction in PEGASUS-TIMI 54. J Am Coll Cardiol. 2016;67(23):2732-2740.
  9. Magnani G et al. Efficacy and safety of ticagrelor for long-term secondary prevention of atherothrombotic events in relation to renal function: insights from the PEGASUS-TIMI 54 trial. Eur Heart J. 2016;37(4):400-408.
  10. Bonaca Marc P et al. Abstract 16658: Patient Selection for Long-Term Secondary Prevention With Ticagrelor: Insights From PEGASUS-TIMI 54. Circulation. 2018;138(Suppl_1):A16658-A16658
DAPT
TICAGRELOR
POST-MYOCARDIAL INFARCTION
ESC
POST-MI
DUAL ANTI-PLATELET THERAPY