Prolonged dual antiplatelet therapy: Has PEGASUS landed in the real world?

Abstract

The winged horse Πήγασος (Pegasos, in Latin Pegasus) is traditionally seen as the source of wisdom and as the symbol of poetry. The authors of the PEGASUS study probably hoped for a wise answer to a significant problem in the treatment of patients with acute coronary syndrome (ACS) – namely if prolonged dual antiplatelet therapy (DAPT) beyond year one would reduce cardiac events – when they chose the acronym for their large-scale randomised trial.

In the PEGASUS–TIMI 54 trial¹ patients one to three years post-myocardial infarction (MI), who had at least one additional risk factor (age >65 years, diabetes, recurrent MI > 1 year, multivessel coronary artery disease (CAD), chronic kidney failure with glomerular filtration rate <60 ml/minute) were randomly assigned to either 90 mg or 60 mg ticagrelor bid or placebo in addition to aspirin 75–150 mg/day. Median follow-up was 33 months. Prolonged DAPT for up to four years following an acute MI resulted in significantly lower event rates in both ticagrelor arms (7.8% in both vs. 9.0% rate of cardiovascular death, MI or stroke, in clopidogrel treated patients P < 0.01).¹ The event reduction ranged between −21% and −10% per year and is sustained over time (year 1 hazard ratio (HR) 0.82; 95% confidence interval (CI) 0.67 to 0.99; year 2 HR 0.90; 95% CI 0.74 to 1.11; and year 3 HR 0.79; 95% CI 0.62 to 1.00).²

It is also important to keep in mind that ticagrelor and prasugrel are more potent P2Y12 inhibitors than clopidogrel, with greater effects on ischaemic cardiovascular events. In PLATO ticagrelor-treated patients had a relative 16% risk reduction for cardiovascular events (cardiovascular death, MI, stroke) over one year versus clopidogrel-treated patients (P = 0.0003).³ Real-world registries from Sweden show that the increased use of ticagrelor for post-ACS platelet inhibition led to a 21% lower stroke rate in ticagrelor-treated ACS survivors.⁴ Comprehensive exercise-based cardiac rehabilitation may further contribute to reducing post-ACS platelet hyperreactivity, as documented in a non-randomised controlled trial in which platelet reactivity and platelet-derived growth factor were measured at baseline and after three months.⁵

However, despite clear evidence of reduced rates of ischaemic events, the implementation of prolonged DAPT in the real world is slow. Several reasons for this situation need to be considered:

Because prolonged DAPT with ticagrelor did not significantly reduce all-cause mortality and cardiovascular death in PEGASUS this treatment approach was only recommended as IIb (B) intervention in ESC guidelines in ‘high ischaemic risk patients who have tolerated DAPT without a bleeding complication’. The lack of a mortality benefit was confirmed in a recent meta-analysis including 6962 randomly assigned patients outside PEGASUS.⁶

General practitioners (GPs) do not see the prevented events but mainly the bleeding complications. Although there were no more fatal bleeds in the prolonged DAPT group the perceived complication rate is higher with prolonged DAPT because of more thrombolysis in myocardial infarction (TIMI) major bleeds.

GPs may find it difficult to assess the individual ischaemic risk in post-MI patients because they may not have access to or an adequate understanding of the invasive findings regarding the extent of CAD or the complexity of interventional treatment. Decision instruments such as the DAPT score⁷ are not intuitive and need to be calculated electronically.

Finally, the perception of many clinicians and GPs is that randomised controlled trials (RCTs) do not reflect clinical reality. Therefore, real-world data are so important to confirm the evidence derived from RCTs.

Registry studies on prolonged DAPT

The number of registries which addressed the question, whether prolonged DAPT beyond year one after ACS reduces CV events, is quite limited.

The first data on the prognostic impact of prolonged DAPT post-ACS was derived from the SWEDEHEART registry. In a total of 56,440 ACS patients with either non ST-segment elevation myocardial infarction (NSTEMI) or ST-segment elevation myocardial infarction (STEMI) DAPT for less than three months was compared to DAPT for over three months. The authors found a significant reduction of death, stroke or non-fatal myocardial re-infarction in the patients on DAPT for more than three months.

However, the data from SWEDEHEART have relatively little to do with the DAPT regimen tested in the PEGASUS study:

In SWEDEHEART DAPT with aspirin plus clopidogrel was investigated. This regimen is no longer a class I recommendation for post-ACS platelet inhibition ever since the publication of the 2011 NSTEMI guideline of the European Society of Cardiology (ESC). Clopidogrel is a pro-drug with variable bioavailablity. In the PLATO study ticagrelor proved to be superior to clopidogrel as a second platelet inhibitor in addition to aspirin in post-ACS patients.

The standard duration of DAPT post-ACS is one year. The comparison in the SWEDEHEART registry tells nothing new in the sense that DAPT for a minimum of one year after ACS is superior to shorter periods of DAPT. It does not answer the question of whether prolonged DAPT beyond the first year after ACS reduces recurrent events.

The data derived from the French national claims registry examined the applicability of the selection criteria in the PEGASUS study to a real-world patient cohort. In this registry a total of 1585 patients after MI were followed for up to three years. When the published PEGASUS patient selection criteria are applied to a representative sample of the French population, the patients who are selected are older and probably have more non-cardiovascular diseases than the patients included in PEGASUS, resulting in higher all-cause death and severe haemorrhage rates in the real-life population compared to the clinical trial.⁸ However, in this registry the effects of prolonged ticagrelor treatment could not be assessed, because the drug was not on the market at the time of patient inclusion.

This is why the data derived from a subgroup of 4424 ACS patients taken from the Italian REgistry of New Antiplatelets in patients with Myocardial Infarction (RENAMI) are so important. In the analysis published by D’Ascenzo et al.⁹ in this issue of the European Journal of Preventive Cardiology the patient cohort was subdivided into three groups based on the duration of DAPT: patients shorter than 12 months (D1 group), 12 months (D2 group), and longer than 12 months (D3 group). All patients received a novel P2Y12 inhibitor on top of aspirin 100 mg/day (i.e. prasugrel 10 mg/day or ticagrelor 2 × 90 mg/day). Although the follow-up of a median of 20 months was significantly shorter than in PEGASUS, the authors confirmed a significant reduction in major adverse cardiac events (MACE) with the increasing duration of DAPT (10% in D1 vs. 6.2% in D2 vs. 2.4% in D3, P < 0.001). These differences were driven by a reduced risk of all-cause death (7.8% in D1 vs. 1.3% in D2 vs. 1.6% in D3, P < 0.001), cardiovascular death (5.1% in D1 vs. 1.0% in D2 vs. 1.2% in D3, P < 0.0001) and recurrent non-fatal MI (8.3% in D1 vs. 5.2% in D2 vs. 3.5% in D3, P = 0.002).

The RENAMI data support the findings derived from the prospective PEGASUS study and add some real-world data to the studies on the duration of DAPT in post-ACS patients. Of note, all-cause death and cardiovascular death were not different between D2 (12 months DAPT) and D3 (>12 months DAPT) – completely in line with the data in PEGASUS and other meta-analyses. The major driving force for event reduction beyond year one was the lower number of non-fatal re-infarctions, which were reduced from 5.2% to 3.5% – a reduction of 1/3.

Prolonged DAPT for everyone post-ACS?

Did all groups of patients benefit equally from prolonged DAPT? As expected, in some patient subgroups – elderly patients older than 75 years, women – the increased bleeding risk associated with DAPT led to a relative increase in net adverse clinical events at over 12 months versus 12 months of DAPT. Still, MACE continued to decrease with the prolonged duration of DAPT.

In contrast to the general class I guideline recommendations regarding DAPT in the first 12 months after ACS, prolonged DAPT requires an individual risk–benefit evaluation. Unfortunately, current guidelines only provide a list of criteria to take into consideration and do not assist in the evaluation by presenting clear algorithms for decision-making (compare Table 4, American College of Cardiology (ACC) guideline).¹⁰ One validated algorithm is the DAPT score,⁷ which is recommended in the ACC/American Heart Association (AHA) guidelines for decision-making. The DAPT score considers the following factors for evaluating the risk–benefit ratio of prolonged DAPT:

Age;

Smoking status;

Diabetes;

MI at presentation;

Prior percutaneous coronary intervention (PCI) or prior MI;

Small stent diameter (<3 mm);

Paclitaxel-eluting stents;

Chronic heart failure or left ventricular ejection fraction less than 30%;

Saphenous vein graft PCI.

As a simpler tool Costa and colleagues have proposed the PRECISE–DAPT score.¹¹ It is based on only five clinical characteristics (age, creatinine clearance, haemoglobin, white blood cell count and previous spontaneous bleeding) and may be more applicable for clinical use.

Whatever decision-making algorithm is used the key message from the RENAMI register – just as from the other clinical studies on the optimal duration of DAPT post-ACS – is that an individualised approach is needed to treat each patient according to his individual thrombotic and bleeding risk based on a personal risk–benefit evaluation. The ‘one size fits all’ 12 months DAPT post-ACS belongs to medical history.

Footnotes

Declaration of conflicting interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: the author received lecture and advisory board honoraria from AstraZeneca until 2017.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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