Treatment with Aspirin Alone Versus Aspirin in Combination with Fondaparinux Before Early Coronary Assessment in Patients with Non-ST-Elevation Myocardial Infarction

Background The current guidelines from European Society of Cardiology (2023) (ESC) and American Heart Association (2014) (AHA) provide a Class-I recommendation for the administration of aspirin together with an anticoagulant in the immediate treatment of Non-ST-Elevation Myocardial Infarction (NSTEMI). For patients scheduled for coronary angiography (CAG) within 24 hours, the recommendation is to initiate unfractionated heparin (UFH) bolus of 70-100 U/kg followed by an adjustable infusion until an activated partial thromboplastin time (APPT) of 60-80 seconds. Patients not planned for CAG within 24 hours are recommended to be treated with fondaparinux 2.5 mg subcutaneous (s.c.) once a day until potential revascularization with percutaneous coronary intervention (PCI) or discharge. According to the clinical guidelines from Danish Society of Cardiology (DSC), fondaparinux is recommended as the first choice for all patients with NSTEMI in Denmark, and heparin is rarely used on this indication.

A plaque rupture in NSTEMI results not only in the activation of platelets but also in the activation of the coagulation cascade through exposure of tissue factor in the extrinsic pathway. This cascade leads to activation of Factor VII and X, which cleave prothrombin to thrombin. Thrombin then converts fibrinogen to fibrin, leading to thrombus formation. Fondaparinux, a synthetic pentasaccharid, directly binds to and enhances the effect of antithrombin, specifically inhibiting activated factor X disrupting the coagulative cascade. Fondaparinux has a half-life of about 17 hours, compared to just 1.5 hours for UFH. This makes the administration and monitoring of UFH treatment substantially more difficult and time-consuming compared to treatment with fondaparinux.

The evidence behind the Class-I recommendation for anticoagulant treatment in patients with NSTEMI is based on two meta-analyses: Oler et al. (1996) and Eikelboom et al. (2000).

The meta-analysis from Oler et al. included six studies that investigated the effect of combination therapy with aspirin and heparin compared with aspirin alone in patients with Non-ST-elevation Acute Coronary Syndrome (NSTEACS), comprising unstable angina pectoris (UAP) and Non-ST-Elevation Myocardial Infarction (NSTEMI). The study showed no statistically significant reduction in the relative risk (RR) = 0.67 (95% CI 0.44-1.02) for new myocardial infarction (MI) or death. However, the results indicated a trend towards a potential positive effect of the combination treatment with both heparin and aspirin.

The indication of a possibly positive effect of combination treatment with both aspirin and anticoagulants was further strengthened with the publication of the FRISC I study (1996), which included 1506 patients with NSTEACS. This was twice as many patients as in all the studies included in the meta-analysis by Oler et al. The patients in the FRISC I study were randomized to treatment with either aspirin and placebo or aspirin and dalteparin (low molecular weight heparin [LMWH]). The primary endpoint was the occurrence of death or new MI within 6 days. The results showed a significant reduction in the primary endpoint, with a odds ratio (OR) of 0.37 (95% CI 0.20-0.68, p = 0.001).

Eikelboom et al. expanded the meta-analysis by Oler et al. to include the FRISC-I study (2000). The expanded meta-analysis demonstrated a statistically significant OR of 0.53 (95% CI 0.38-0.73, p<0.001) in favor of combination therapy compared to aspirin alone when considering death and new MI in patients with NSTEACS.

It's important to note that these studies were conducted at a time when invasive evaluation with CAG was not routinely performed in patients with NSTEACS. For instance, the FRISC-I study showed that the total number of revascularizations after 6 days amounted to 0.8 % and this was due to intractable angina despite relevant medication.

Early invasive evaluation in patients with NSTEMI was only introduced after 1999. A cornerstone of this change was the FRISC-II study (1999), which investigated the effect of an early invasive strategy versus medically treatment in patients with NSTEMI. Of the patients in the invasive arm 96% had a CAG performed within 7 days with an median of 4 days. All patients were treated with either LMWH or UFH prior to the CAG or at least five days in the non-invasive arm. Patients treated invasively compared to noninvasively showed a risk reduction in death or new MI after six months with a risk-ratio of 0.78 (95% CI 0.62-0.98, p=0.031). When considered alone, the occurrence of new MI the risk reduction was also significantly reduced. The difference on mortality alone was not reduced significantly, but there was a trend towards reduction in the invasive arm. Furthermore, the occurrence of symptoms and readmissions were halved. Today, early invasive treatment is recommended in all patients with NSTEMI.

In 2006, the OASIS 5 trial, a randomized controlled trial (RCT) of 20.078 patients, demonstrated that treatment with fondaparinux was non-inferior to treatment with enoxaparin (LMWH) in combinations therapy with aspirin in patients with NSTEACS. The primary endpoint was death, new MI or refractory ischemia within 9 days and the study showed a hazard ration of 1.01 (95% CI 0.90-1.13). Interestingly, treatment with enoxaparin was associated with a higher risk of bleeding, long-time mortality and morbidity. These results have been the foundation for the current guidelines by ESC, which recommend treatment with fondaparinux in patients with NSTEMI when CAG and possibly PCI are not available within 24 hours.

Risk of bleeding:

Intuitively, combination therapy with aspirin together with an anticoagulant will increase the bleeding risk compared with aspirin alone. In the meta-analysis from Eikelboom et al. (2000) they demonstrated an increased OR of 1.88 (CI 95% 0.60-5.87, p= 0.28) for severe bleeding when treated with UFH and aspirin compared to aspirin alone. This result was not significant, however, could imply an increased risk of bleeding with combination therapy.

The meta-analysis from Eikelboom et al. did not report results about minor bleedings. However, by reviewing the papers included in the meta-analysis from Eikelboom et al. one by one, a clear tendency towards an increased risk of minor bleedings can be observed. The occurrence of minor bleedings ranges from 6-14 % in the group with combination therapy compared to 0-3 % in the group with aspirin alone. Even though no statistical analysis was performed, the difference in minor bleeding is undoubtably significant.

Severe bleedings involved events such as intracranial bleeding, requirement of blood transfusion, and bleeding resulting in death. Minor bleedings referred to hematomas and bleeding from insertion site, although the accurate definitions of minor and severe bleedings varied from study to study.

A substantial part of the minor bleeding complications was associated with catheterization. This was also observed in the FRISC-II study, where an increased occurrence of bleeding was observed in the invasive arm compared to the non-invasive arm, despite the shorter treatment period with LMWH in the invasive arm.

Rationale:

All the above-mentioned studies were conducted in a period where early invasive treatment by no means were standard practice in the treatment of patients with NSTEMI. In the FRISC-I study, which must be seen as one of the main pillars in the introduction of anticoagulative treatment in the acute setting of NSTEMI, only 0.8% of all the patients were revascularized after 6 days. This stands in substantial contrast in todays practice, where the year rapport from the Danish Heart Registry from 2022 showed that 96% of patients with either NSTEMI or UAP were invasively assessed and potentially revascularized within 72 hours. This must in any case raise questions about the validity of the studies as a basis for the current guidelines in the treatment of NSTEMI.

A reconsideration of the current treatment strategy is further supported by the potential increased risk of bleeding associated with combination therapy compared to aspirin alone. It is therefore natural to question whether we are currently subjecting patients to unnecessary risk with the current treatment regime.

Additionally, reducing the extent of medical treatment for patients with NSTEMI would lead to decreased cost. Furthermore, you would expect a reduced workload at the cardiology departments, especially them using UFH as their first choice for anticoagulant treatment, as it requires close monitoring of the APPT.

Choice of comparators This study will only compare fondaparinux and aspirin versus aspirin alone as this is the standard practice in Denmark. According to AHA guidelines, options for anticoagulation include Enoxaparin, UFH, fondaparinux or bivalirudin. Similarly, ESC recommends using UFH if CAG is performed within 24 hours, and fondaparinux if the procedure is delayed beyond 24 hours. The evidence from prior studies (Eikelboom et al. and Yusuf et al.) showed that the efficacy of UFH is equivalent to LMWH and that fondaparinux is equivalent to LMWH. Based on this, the investigators believe that the results from this study can be applicable to the other options of anticoagulative options prior to CAG in NSTEMI patients and not exclusively to fondaparinux.

Objectives:

Primary objective:

To compare efficacy in patients treated with aspirin alone compared to combination therapy with fondaparinux and aspirin prior to early invasive strategy in patients with NSTEMI.

Secondary objective:

To evaluate and compare the relative bleeding risk associated with the use of aspirin alone and in combination with fondaparinux prior to an invasive strategy in patients with NSTEMI

Hypothesis's:

• Treatment with aspirin alone is non-inferior in prevention of death, new MI and refractory ischemia within 30 days compared to combination treatment with aspirin and fondaparinux in patients with NSTEMI prior to early invasive strategy

• Treatment with aspirin alone is superior to combination treatment with aspirin and fondaparinux regarding the risk of bleeding defined as BARC above 3 criteria (19)) in patients with NSTEMI prior to early invasive strategy

Sample Size:

According to the annual report from Danish Heart Registry (2022), patient with NSTEACS who underwent PCI had a 30-day mortality rate of 2.1 %. However, this data also includes patients with UAP and patients who was not treated with PCI. The investigators expect the 30-day mortality and 30-day new MI in a cohort with only NSTEMI patients to be slightly higher, around 3 %.

A local review of the data on patients with NSTEMI in Region Midtjylland showed that about 9% these patients were scheduled for an acute CAG after admission. Approximately half of these were assessed as possible subjects to this study.

Based on this, the investigators expect about 5 % of the subjects scheduled for a subacute CAG to convert to acute CAG. In total, this gives us an expected composite event rate of 8%.

The study will require a power of 80% and set a one-sided 97.5 % confidence interval (equivalently to a 95% two-sided confidence interval). Our absolute non-inferiority margin with an expected event rate of 8 % will be 2.2 %. This corresponds to a relative non-inferiority margin of 1.275.

Assuming that the composite event rate is the same in both groups and there truly is no difference between the two interventions, a total of 4776 (2388 in each group) patients are required. This sample size will ensure that the upper limit of a one-sided 97.5%-confidence interval with 80% certainty will exclude a difference of more than 2.2 % in favor of the aspirin group.

Adjustment sample size for loss and interim analysis:

By adjusting for an expected loss of 5 %, our new sample size is 5028. Additionally, to account for one interim analysis, a multiplication factor of 1.008 is applied, resulting in a total sample size of 5068 patients (2534 in each group).

Plans for assessment and collection primary outcome:

The data for assessment of primary endpoints and safety endpoints will mainly be obtained directly from the patient's electronic medical journal. The data will be obtained by study nurses or principal investigators and recorded in a predefined eCRF in REDCap/Corolog. This will include conversion to acute CAG, 30-day mortality, new MI within 30 days, CVA, Severe thrombotic event and severe bleedings as listed under outcomes. These endpoints will be obtained after 30 days. The primary endpoint of 30-day mortality will also be verified through the Danish Civil Registration System to cross-check for any delays or discrepancies in the reporting of deaths in the patients' electronic medical records.

Plans for assessment and collection of secondary outcome, baseline, and other trial data:

Secondary outcomes together with baselines characteristic will be obtained solely from Danish registries.

Location:

All cardiology departments or emergency departments in Denmark with admission of patients with NSTEMI are invited to participate.

Data Safety Monitoring Board (DSMB) - not assigned yet:

The DSMB will be composed of the following members:

• Two cardiologists not involved in the conduct of the trial

• Statistician

• Epidemiologist

The primary role of DSMB is to monitor the safety and efficacy of the trial. The members of DSMB will be independent and will not be involved in the otherwise conduction of the trial or have any financial interests in the outcome of the study. They will be responsible for conduction of the interim analysis.

The DSMB will report directly to the study sponsor, principal investigator and steering committee.

Research ethics and approval:

The trial will be approved through the Clinical Trial Information System (CTIS) by the Medical Ethics Committee (VMK) and the DKMA before initiation.

Publication:

The study expects to result in a publication in at least one recognized international peer-reviewed journal. The paper will be drafted irrespective of whether the results are neutral, positive, negative or inconclusive.