Lipoprotein(a), cardiovascular events, and benefit of P2Y12 inhibition: insights from the PEGASUS-TIMI 54 trial
Given its structural homology with plasminogen but lack of protease activity, lipoprotein(a) [Lp(a)] has been theorised to exert prothrombotic effects by inhibiting fibrinolysis1; as such, it is suggested that antithrombotic therapy may be more beneficial in patients with an above average concentration of Lp(a). Dr Siddharth Patel and colleagues investigated whether patients with elevated Lp(a) levels benefit more from P2Y12 inhibition with ticagrelor versus placebo when aspirin is prescribed2.

As part of PEGASUS-TIMI 54, a randomised trial in which ticagrelor is compared with placebo in patients who had a myocardial infarction (MI) in the previous 3 years3, the Lp(a) concentration was measured in a nested cohort of 8,967 patients and the risk threshold was established at 200 nmol/L. The pre-specified major adverse cardiovascular event (MACE) endpoint was a composite of cardiovascular death, MI or stroke, with Kaplan Meier rates reported at 3 years. Dr Patel's team used Cox proportional hazards to assess the relationship between Lp(a), MACE and the benefits of treatment, and the models were adjusted to consider relevant baseline characteristics, such as the level of apolipoprotein B.
An Lp(a) value exceeding 200 nmol/L is associated with an increased risk of MACE in patients with prior myocardial infarction.
The data presented show that the median Lp(a) concentration was 29 nmol/L among the study group. Lp(a) levels were elevated (≥ 200 nmol/L) in 1,053 patients (11.7%). There was a 29% increase in MACE risk associated with high Lp(a) concentrations in the pooled trial population (9.1% vs 7.6%; adjusted hazard ratio [adj HR] 1.29, 95% confidence intervals [CI]: 1.02–1.62; P=0.03), with a 37% increase in MI risk (6.9% vs 5.3%; adj HR 1.37, CI: 05–1.79; P=0.02). HRs for MACE with ticagrelor, compared with placebo, were 0.73 (CI: 0.48–1.11) in patients with elevated Lp(a) levels and 0.88 (CI: 0.74-1.05) in those with lower Lp(a) levels (P-interaction = 0.41). The data showed an absolute risk reduction of 2.4% and 1.2% for both groups.
Dr Patel concluded his presentation by highlighting that an Lp(a) value exceeding 200 nmol/L is associated with an increased risk of MACE in patients with prior MI. These patients may see benefits from treatment with ticagrelor in terms of absolute risk reduction. As a result of these experimental observations, insights can be gained for therapeutics evaluating the clinical potential of reducing Lp(a).
Should dual antiplatelet therapy be maintained beyond one year after a myocardial infarction?
Dual antiplatelet therapy (DAPT) consisting of aspirin and a P2Y12 inhibitor (clopidogrel, prasugrel or ticagrelor) is recommended for patients with acute coronary syndrome (ACS), for secondary prevention of cardiovascular disease (CVD). Optimal duration of DAPT requires consideration of ischaemic and bleeding risks; standard DAPT duration is 1 year, unless there are contraindications4. Myocardial infarction (MI) confers a high risk of thrombotic events; however, it is controversial to maintain DAPT beyond 1 year following MI5.
Dr Patrick Blin and his colleagues compared DAPT with single antiplatelet therapy (SAPT) with aspirin beyond 1 year after MI, in terms of the risk of MI, ischaemic stroke (IS), major bleeding (MB) and death6.
The French nationwide claims database (SNDS) was used to identify all adults hospitalised for acute MI (trigger event) with intensive care unit stay in 2013 and 2014. The study cohort consisted of patients who survived at least a year without MI or MB and had a DAPT medication possession ratio (MPR) >80%. After the index date of the study (defined as 365 days after the MI trigger event), all patients were followed for 3 years, except those who died after the index date or ceased taking aspirin after sixty days after the index date. Outcomes evaluated included: a primary composite of all-cause death, MI, IS and MB; a secondary composite of all-cause death, MI and IS; and individual outcomes. Data analysis included 3-year cumulative incidence of outcomes using Kaplan-Meier estimates or cumulative incidence function to account for death as a competing risk. The Cox proportional hazards model was used to determine associations between fatal outcomes and exposure to DAPT and SAPT. Fine and Gray models were used to assess non-fatal outcomes, which were adjusted for age, sex and exposure to specific treatments, including secondary prevention CVD medications, oral glucose-lowering medications, insulin, anticoagulants, non-steroidal anti-inflammatory drugs, corticosteroids and proton pump inhibitors.
In the absence of contraindications, standard DAPT duration of 1 year following a myocardial infarction is recommended for secondary prevention of cardiovascular disease
In total, 53,399 adults were included in the study cohort out of 105,080 admitted to intensive care units for acute MI in 2013 or 2014. Non-inclusion was most commonly attributed to death (n=12,012) and a DAPT MPR of 80% (n=25,000). At the index date, mean age was 65 years, 74.6% of those attending were men, 21.8% had diabetes, 9.4% had heart failure, 5.6% had peripheral artery disease, 72.2% had DAPT scores of 2, 61.9% had a Charlson index of 1, 79.2% had an ST-segment elevation myocardial infarction (STEMI) trigger event, and 82.6% had cardiac revascularisation (PCI 98.6%). Clopidogrel (41.5%), ticagrelor (41.1%) and prasugrel (26.2%) were among the P2Y12 inhibitors that were used at least once between the trigger event and the index date. The 3-year HR for DAPT compared with SAPT was 1.21 (CI: 1.13–1.30) for the primary composite of all-cause death, MI, IS and MB. HRs for individual outcomes were 1.16 (CI: 1.06–1.27) for death, 1.22 (CI: 1.07–1.38) for MI, 0.98 (CI: 0.80–1.20) for IS and 1.89 (CI: 1.55–2.30) for MB.
Compared with SAPT, DAPT was associated with increased risks of the primary composite outcome (21% higher, CI: 13–30), MI (22% higher, CI: 7–38), MB (89% higher, CI: 55–130) and death (16% higher, CI: 6–27). The risk of IS was similar for SAPT and DAPT. The study concluded that DAPT beyond 1 year after MI was associated with a significant risk of harm when compared with SAPT.

Takostubo syndrome during the COVID-19 pandemic
Takostubo syndrome (TTS), or stress cardiomyopathy, is a reversible cardiac condition characterised by acute ventricular dysfunction triggered by physical or emotional stress7. Activation of the sympathetic nervous system by acute stress has been suggested as a possible pathophysiological mechanism for TTS7. An increase in TTS cases was reported during the SARS-COV-19 pandemic and a recent study suggested that individuals may be more susceptible to TTS because of the psychological, mental and physical consequences of anti-pandemic measures8.
Professor Loukianos Rallidis and colleagues investigated whether TTS incidence had increased in a major tertiary hospital in Athens during the SARS-CoV-19 pandemic9. As part of the study, 316 consecutive patients with acute coronary syndrome (ACS) were admitted to the coronary care unit (CCU) of the hospital over 16 months, from March 2020 to June 2021. In order to provide a comparison with the incidence before the pandemic, 342 patients with ACS admitted to the CCU between November 2018 and February 2020 were also included in the study. Within 48 hours of admission, all patients with ACS underwent coronary angiography.
Takostubo syndrome has been reported as a cardiovascular complication of COVID-197
Patients with TTS were predominantly female (95%), with an average age of 71.1±15.4 years. The frequency of TTS was significantly higher during the pandemic (20 TTS cases among 316 ACS patients, 6.3%) than during the 16 months prior to the pandemic (9 TTS cases among 342 ACS patients, 2.6%). A comparison of the TTS cases occurring during the COVID-19 pandemic period with those occurring during the pre-pandemic period revealed an incidence rate ratio of 2.22 (95% CI: 0.97–5.54, P=0.021).
Further studies are needed to confirm whether psychological stresses associated with the SARS-COV-19 pandemic contributed to the increased incidence of TTS during the pandemic.
Patients with TTS were predominantly female (95%), with an average age of 71.1±15.4 years. The frequency of TTS was significantly higher during the pandemic (20 TTS cases among 316 ACS patients, 6.3%) than during the 16 months prior to the pandemic (9 TTS cases among 342 ACS patients, 2.6%). A comparison of the TTS cases occurring during the COVID-19 pandemic period with those occurring during the pre-pandemic period revealed an incidence rate ratio of 2.22 (95% CI: 0.97–5.54, P=0.021).
Read more on Antiplatelet therapy in ACS
References
- Boffa M, Marar T, Yeang C, Viney N, Xia S, Witztum J. et al. (2019). J Lipid Res, 60(12): 2082-2089. doi: 10.1194/jlr.p094763
- Patel S. Lipoprotein(a), cardiovascular events, and benefit of P2Y12 inhibition: insights from the PEGASUS-TIMI 54 trial. Presented at the European Society of Cardiology Congress 2022, 29 August. Barcelona. Coronary artery disease – Pharmacotherapy 3.Moderated ePosters
- Bonaca, M., Bhatt, D., Braunwald, E., Cohen, M., Steg, P., & Storey, R. et al. (2014). Am Heart J, 167(4), 437-444.e5. doi: 10.1016/j.ahj.2013.12.020
- Valgimigli M, Bueno H, Byrne RA, et al. 2017 Focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS. Eur Heart J.2018;39:213–254.
- Lev E, Ben-Assa E, et al. Dual antiplatelet therapy in patients with prior myocardial infarction. J Am Coll Cardiol Intv. 2022;15(3):294–296.
- Blin P. Should dual antiplatelet therapy be maintained beyond one year after a myocardial infarction? A cohort study within the French SNDS nationwide claims database. Presented at the European Society of Cardiology Congress 2022, 29 August. Barcelona. Acute coronary syndromes – Imaging and beyond. Moderated ePosters.
- Sharma K, Desai H, Patoliya J, Jadeja D, Gadhiya D. Takostubo syndrome a rare entity in COVID-19: a systematic review – focus on biomarkers, imaging, treatment and outcomes. SN Compr Clin Med. 2021;3(1):62-72. doi: 10.1007/s42399-021-00743-4.
- Jabri A, Kalra A, Kumar A. JAMA Netw Open. 2020; 3(7):e2014780. doi:10.1001/jamanetworkopen.2020.14780.
- Rallidis L. Takostubo syndrome during the COVID-19 pandemic: a single center experience. Presented at the European Society of Cardiology Congress 2022, 27 August. Barcelona. COVID-19 and acute coronary syndromes. Moderated ePosters.