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Insider Interview: Reducing the risk of adverse cardiovascular events

Published on 03/02/20 at 12:35pm

Rodrigo Gribble, Vice President Cardiovascular at AstraZeneca, breaks down recently published data from the PEGASUS trial of ticagrelor, a potential new treatment for patients with coronary artery disease, and how this may benefit patients who have suffered from previous heart attacks.

Recent published data in the European Heart Journal – Cardiovascular Pharmacotherapy show efficacy and safety in a large study with antithrombotic therapy ticagrelor, with a significant reduction in the risk of major adverse cardiovascular events.

These study results are timely, given that the European Society of Cardiology’s (ESC) recently updated 2019 guidelines for diagnosing and managing chronic coronary syndromes now indicate that clinicians should consider using long-term antithrombotic therapies, like ticagrelor, to treat their patients.

Can you first explain how high-risk patients with coronary artery disease are currently treated, as this is a serious chronic and often progressive disease? What are the risks of current treatment?

Coronary artery disease (CAD) is characterised by plaque build-up in the arteries. Lifestyle adjustments, pharmacological therapies, and invasive interventions aim to clear the blockage, help relieve symptoms, and reduce the risk of future cardiovascular events. CAD can have periods of stability; however, it can also become unstable at any time due to plaque rupture or erosion, causing blood clots to form that can completely block the artery on the spot or break off and travel through the bloodstream to another organ. The importance of care and treatment in the acute setting is well recognised, but the longer-term, chronic setting does not always receive the focus it should, and the significant ischaemic risk in these patients is often overlooked.

Currently, the mainstay of antithrombotic therapy (therapy that reduces the formation of blood clots) for patients after a heart attack, otherwise known as a myocardial infarction (MI), is dual antiplatelet therapy (DAPT) containing an oral P2Y12 inhibitor and aspirin, administered for up to 12 months. Research has shown that there is up to a nine-fold increase in incidence of subsequent cardiovascular events in patients who’ve previously had an MI if five cardiovascular risk factors are present, compared to patients with only one risk factor. In patients who have had a heart attack, who have two or more risk factors that have tolerated DAPT for 12 months, the guidelines recommend that these patients may benefit from ongoing DAPT beyond 12 months.

What is the takeaway from the published data from the PEGASUS trial, and how might patients benefit from ticagrelor?

The rationale for the PEGASUS-TIMI 54 trial was to identify the potential benefit of ticagrelor in patients who had a heart attack more than one year ago. This is important as 20% of people who are discharged after a heart attack and remain event-free at one year experience a second cardiovascular event within a 3-year period, and remain at a heightened risk.

PEGASUS-TIMI 54 enrolled 21,162 patients and was conducted to investigate if the addition of ticagrelor 60mg to standard therapy (low-dose aspirin) would reduce the incidence of major adverse cardiovascular events (MACE), including cardiovascular death, MI, or stroke, in high-risk patients who had experienced an MI 1-3 years previously. The primary efficacy endpoint was the composite of cardiovascular death, MI, or stroke (MACE) and demonstrated a relative risk reduction of 16%. The challenge is that ticagrelor is a more potent antiplatelet agent, so , as expected, there is more bleeding. As always in cardiology, it’s about dealing with the balance between the ischaemic benefit and the bleeding risk, and the situation is no different in these patients. 

The recently published PEGASUS EU Label includes a post-hoc analysis of PEGASUS-TIMI 54 focused on data from the nearly 11,000 patients in the trial who were treated according to the approved EU label. The data demonstrate that patients who were less than two years from the index heart attack or had stopped their adenosine diphosphate (ADP) receptor inhibitors less than one year before entering the study had a 29% relative risk reduction in cardiovascular mortality and a 20% reduction in all-cause mortality. Though there was increased bleeding in the patients who were receiving ticagrelor, there was a significant favourable benefit-risk ratio in this population. 

Long-term care, even just 6 months after a heart attack, can be variable, and I hope that with the evidence from such clinical trials demonstrating the benefit in patients, chronic care will receive the education and focus it requires to ensure good patient outcomes.

Can you highlight what clinicians on the front lines should know about these recent study results and the implications of the updated ESC guidelines?

For patients who have experienced a heart attack, there is a significant risk for a subsequent cardiovascular event, making long-term management critical. Firstly, the recently updated ESC guidelines recognise the chronicity of the disease with the name change from “stable coronary disease” to “chronic coronary syndromes”. The long-term risk for patients who have experienced a heart attack needs to be further highlighted – the risk of experiencing another cardiovascular event remains high for up to 5 years, and for patients with two or more risk factors, the risk is even greater. The 2019 ESC guidelines now indicate that clinicians should consider using long-term antithrombotic therapies, like ticagrelor, in their patients.

When you consider the results from PEGASUS-TIMI 54, physicians can feel confident with ticagrelor-based DAPT in patients that have experienced a heart attack more than a year previous.

Dr Marc Bonaca, the principal investigator for the PEGASUS-TIMI 54 trial, presented an abstract at the European Congress of Cardiology last year that helped identify which patient subgroups benefit the most from prolonged DAPT with ticagrelor. In patients with two or more risk factors, without anaemia or a previous hospitalisation for bleeding, cardiovascular mortality was relatively reduced by 34%. This included nearly 60% of the trial population, and risk factors included but were not limited to: patients being diagnosed with type 2 diabetes, multivessel disease, or kidney disease, as well as those who experienced a previous heart attack and/or are at most two years from a qualifying heart attack or no more than one year from prior treatment with an ADP receptor inhibitor. Both this study and the recently published EU Label subgroup analysis demonstrates the ongoing cardiovascular protection offered by ticagrelor and aspirin in patients who have been on therapy for 12 months without bleeding and are at high risk.

Do the ESC guidelines suggest a different long-term treatment plan for patients with coronary artery disease? What will this different treatment plan look like for patients?

The 2019 ESC guidelines suggest that, for post MI patients with CAD with a moderate or high risk of ischaemic events but without a high bleeding risk, practitioners should consider adding a second antithrombotic drug to aspirin for long-term secondary prevention. It’s an ongoing paradigm shift from our current management, but it’s important when considering the long-term treatment of patients with CAD.

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