Dual antithrombotic therapy with a factor Xa inhibitor plus aspirin in elderly and middle-aged patients

Dr. Wai-Hong Chen
Specialist in Cardiology
Private practice, Hong Kong
06 May 2021

Case 1: An elderly patient with NSTEMI

History and presentation

The patient is an 85-year-old female who presented in September 2014 with cholangitis due to common bile duct stones. It was complicated by non-ST-segment elevation myocardial infarction (NSTEMI). She was diagnosed with hypertension and hyperlipidaemia and had an ischaemic stroke 7 years prior to presentation. Subsequently, she was found to have severe triple-vessel coronary artery disease (CAD).

Treatment and response

The patient underwent percutaneous coronary intervention (PCI). Angiography revealed heavily calcified coronary arteries with left main (LM) ostial to mid 70-80 percent stenosis, mid left anterior descending artery (LAD) chronic total occlusion, left circumflex artery (LCx) proximal 70 percent stenosis, right coronary artery (RCA) proximal 80 percent stenosis and diffuse distal disease. Rotational atherectomy followed by drug-eluting stent (DES) implantation was performed from LM to proximal LCx. Multiple guidewires could not be advanced to the distal RCA because of heavy calcification and severe tortuosity. Hence, attempt for percutaneous revascularization of the RCA was abandoned. (Figure 1)

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The patient had an unremarkable post-PCI in-hospital course. She received maintenance dual antiplatelet therapy (DAPT) with ticagrelor and aspirin for approximately 3 years and remained asymptomatic. In October 2017, she was switched to dual antithrombotic therapy (DAT) with low-dose oral rivaroxaban at 2.5 mg BID and aspirin at  100 mg QD, based on a remarkable re-duction in risk of the composite primary endpoint of cardiovascular (CV) death, stroke or MI with the DAT regimen vs aspirin alone demonstrated in the phase III randomized COMPASS trial.1 Dual pathway inhibition (DPI) with rivaroxaban 2.5 mg BID and aspirin 100 mg QD was also shown to be effective in high-risk patients with multivessel disease following PCI in the trial.2

Due to the patient’s high CV risk, she was ineligible for general anaesthesia and open bile duct surgery for choledocholithiasis. She instead underwent endoscopic retrograde cholangiopancreatographies and biliary stent placement on a regular basis to ensure and maintain patency of the common bile duct. Throughout these interventions, the patient’s atherosclerotic disease remained stable, with no CV or bleeding events. The patient’s journey and management are illustrated in Figure 2.

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Case 2: A middle-aged patient with diabetes

History and presentation

The patient is a 49-year-old male who presented to a public hospital in July 2016 with progressive shortness of breath following an episode of chest pain a week ago. He was a smoker with type 2 diabetes mellitus and hyperlipidaemia. ECG and biomarkers showed recent anterior STEMI. Echocardiogram revealed severely impaired left ventricular (LV) function and an ejection fraction (EF) of 30 percent.

Treatment and response

The patient underwent coronary angiography, which showed proximal LAD occlusion and proximal RCA 70 percent stenosis. PCI to the proximal LAD was successfully performed using a DES. He presented again to the public hospital 3 weeks after PCI with chest discomfort. Echocardiogram revealed deteriorated LVEF to 15 percent. Myocardial perfusion study showed infarct and ischaemia in the LAD territory. Coronary angiography showed LAD distal diffuse disease and PCI was not attempted. A repeat coronary angiography was performed 6 weeks following the PCI and showed in-stent re-occlusion at the mid LAD, which was revascularized with implantation of multiple DES. The proximal RCA stenosis was also treated with DES. He was initially prescribed DAPT with ticagrelor and aspirin. Due to his high CV risk, DAPT was subsequently switched to DAT with low-dose rivaroxaban and aspirin in May 2019.1 The patient’s journey and management are illustrated in Figure 3.

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Discussion

The 2020 ESC guidelines recommend antithrombotic therapy for all patients with NSTE acute coronary syndrome (NSTE-ACS). In these patients, the standard treatment is DAPT with aspirin and a potent P2Y12 receptor inhibitor. DAPT for 12 months is recommended for patients who undergo coronary stent implantation unless there is excessive risk of bleeding (Class I, Level A).3

For long-term extended antithrombotic treatment in the secondary prevention setting, the ESC guidelines stated that clinicians should consider adding a second antithrombotic agent to aspirin (eg, a DAT regimen with rivaroxaban [2.5 mg BID]) in patients with high ischaemic risk without increased risk of major or life-threatening bleeding (Class IIa, Level A).3

The elderly patient in case 1 initially received ticagrelor plus aspirin after PCI for NSTEMI. She was maintained on this regimen for approximately 3 years, but was subsequently switched to rivaroxaban plus aspirin based on results of the COMPASS trial published in 2017.1

The COMPASS trial included 27,395 patients with stable atherosclerotic disease (ie, CAD, peripheral artery disease, or both) who were randomized to receive rivaroxaban (2.5 mg BID) plus aspirin (100 mg), rivaroxaban alone (5 mg BID), or aspirin alone (100 mg OD). Results showed that the primary outcome (ie, a composite of CV death, stroke or MI) occurred in significantly fewer patients in the rivaroxaban plus aspirin group vs the aspirin alone group (4.1 percent vs 5.4 percent; hazard ratio [HR], 0.76; 95 percent confidence interval [CI], 0.66 to 0.86; p<0.001).1

Although major bleeding events were significantly increased in the rivaroxaban plus aspirin group vs the aspirin adding a second antithrombotic agent to aspirin (eg, a DAT regimen with rivarox alone group (3.1 percent vs 1.9 percent; HR, 1.70; 95 percent CI, 1.40 to 2.05; p<0.001), this was mainly driven by gastrointestinal (GI) tract bleeding (1.5 percent vs 0.7 percent; HR, 2.15; 95 percent CI, 1.60 to 2.89; p<0.001), with no significant between-group differences in rates of fatal bleeding, intracranial bleeding, or symptomatic bleeding into a critical organ.1,4 Importantly, the COMPASS trial showed that the risk of the composite net-clinical-benefit outcome (ie, a composite of CV death, stroke, MI, fatal bleeding, or symptomatic bleeding into a critical organ) was significantly lower with rivaroxaban plus aspirin vs aspirin alone (4.7 percent vs 5.9 percent; HR, 0.80; 95 percent CI, 0.70 to 0.91; p<0.001).1

In patients at risk of GI bleeding, the usual practice is to use rivaroxaban concomitantly with proton pump inhibitor (PPI) therapy, as this was shown to significantly reduce the risk of upper GI tract bleeding hospitalizations (incidence rate ratio, 0.75; 95 percent CI, 0.68 to 0.84).5

A subgroup analysis of COMPASS was conducted in patients with stable CAD (ie, MI within 20 years, multivessel CAD, history of stable or unstable angina, previous multivessel PCI, or previous multivessel coronary artery bypass graft surgery). Results remained consistent with those of the main trial (HR for primary outcome, 0.74; 95 percent CI, 0.65 to 0.86; p<0.0001) (HR for major bleeding, 1.66; 95 percent CI, 1.37 to 2.03, p<0.0001), reaffirming the benefits of rivaroxaban plus aspirin in patients with stable CAD with a history of multivessel disease, such as our patient in case 1.2

For patients with CAD younger than 65 years of age, eligibility for COMPASS required evidence of at least two other risk factors (eg, current smoking, DM, an estimated glomerular filtration rate of <60 mL/minute, heart failure, or nonlacunar ischaemic stroke ≥1 month earlier).1 The profile of our 49-year-old patient in case 2 was consistent with these inclusion criteria (ie, diabetes and heart failure), making the switch from DAPT with ticagrelor plus aspirin to DAT with rivaroxaban plus aspirin a valid treatment strategy. Similar benefits of rivaroxaban in patients with vs without diabetes were shown in the prespecified analysis of COMPASS, in terms of the primary endpoint (2.3 percent vs 1.4 percent; pinteraction<0.0001), all-cause mortality (1.9 percent vs 0.6 per-cent; pinteraction=0.02), and major vascu-lar events (2.7 percent vs 1.7 percent;  pinteraction<0.0001) at 3 years.6

These two cases illustrate that long-term DAT with low-dose rivaroxaban and aspirin is an appropriate and effective strategy in the secondary prevention setting for high-risk elderly patients with  stable CAD, such as our patient in case 1, and for younger patients with diabetes, such as our patient in case 2. While COMPASS reported increased major bleeding with rivaroxaban plus aspirin, the increase was driven mainly by GI bleeding. No bleeding complications or ischaemic events occurred in either of our patients who received DAP with rivaroxaban plus aspirin, further supporting the use of this regimen in this patient population.

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