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Enhanced vascular protection for high-risk patients: What’s your best option?

Patient case: When the risk of a cardiovascular event outweighs that of bleeding, what treatment should you use?

Think about the following clinical situation:

  • Valerie has coronary artery disease (CAD) and comes into the clinic for a routine
  • She is a bright and lively 72-year-old woman who, in her own words, has been a smoker since “before it was bad for you”
  • Imaging has revealed that Valerie has stenosis of the cardiac artery, although she has no symptoms associated with this. She has a creatinine clearance rate of 48 ml/min and has recently been diagnosed with type II diabetes. She has no history of haemorrhagic stroke or other bleeding events, and her glucose levels, blood pressure and cholesterol are all well managed
  • Despite her optimistic demeanour, Valerie confesses that she is increasingly worried about the chance that she could suffer a heart attack
Valerie has coronary artery stenosis

Valerie has coronary artery stenosis

Although she has never had a major cardiovascular event, Valerie has a number of co-morbidities and lifestyle-related risk factors that mean she is at high risk of such events. Conversely, her medical history indicates that she is at low risk of the occurrence of a bleeding event.


How would you decide on the best treatment for Valerie?


The impact of risk factors on cardiovascular and bleeding events

CAD is associated with an increased risk of cardiovascular events, including stroke and myocardial infarction.1 Antithrombotic therapy may offer protection from these events, but it comes with associated safety considerations in the form of an increased risk of bleeding events.2 The physician’s role is to balance these two opposing risks against each other and to make evidence-based decisions on a choice of treatment. However, the concerns of the patient also need to be considered. Is Valerie likely to fear a bleed more than the debilitating effects of a stroke? Which of these is likely to be associated with the greatest irreversible harm and would have the greatest impact upon the lives of both Valerie and her loved ones?


Physicians also need to consider the additional factors that increase the likelihood of a cardiovascular event occurring in patients with CAD. An analysis of patients from the Reduction of Atherothrombosis for Continued Health (REACH) Registry was performed to evaluate the increase in cardiovascular risk associated with increasing numbers of enrichment criteria.3 The enrichment criteria for this analysis were based on selection criteria from the COMPASS study (i.e. age >65 years, asymptomatic cardiac stenosis, diabetes, moderate renal failure and smoking, as well as heart failure, ischaemic stroke and peripheral artery disease).4 The results showed that patients with just one enrichment criterion faced a 7% increased risk of major adverse cardiovascular events (MACE) over 4 years compared with patients without any enrichment criteria.3 This risk of MACE also increased in line with the number of enrichment criteria, rising to 23% in patients with at least four enrichment criteria. Although there was also a corresponding increase in the 4-year risk of serious bleeding events in patients with more enrichment criteria, the rate of this increase was not as marked as with MACE.3

An analysis of COMPASS data looking at the effect of risk factors on study outcomes found that, consistent with the analysis of the REACH Registry, factors such as renal insufficiency, diabetes or history of heart failure increased the risk of MACE more than that of bleeding events.5 Treatment with rivaroxaban vascular dose 2.5 mg twice daily (bid) plus aspirin resulted in a proportionally greater reduction in the risk of cardiovascular events in these high-risk patients compared with patients without high-risk features, and there was no concurrent proportional increase in the risk of severe bleeding events.5


Therefore, there are substantial benefits associated with the use of rivaroxaban in patients identified as high risk.5


How can I balance the benefits and risks of treating this patient?

Results from the COMPASS trial showed that treatment with rivaroxaban vascular dose 2.5 mg bid plus aspirin 100 mg once daily (od) reduced the incidence of cardiovascular events, but increased the number of International Society on Thrombosis and Haemostasis (ISTH) major bleeding events compared with treatment with aspirin alone in a broad population of patients.6 Importantly, there was no significant increase in the most serious types of bleeding events; these remained comparable to aspirin alone.6


An analysis of the timings of bleeding and cardiovascular events in the trial concluded that the benefits of treatment with rivaroxaban vascular dose 2.5 mg bid plus aspirin increased over time compared with aspirin alone, while the risk of bleeding stayed stable.7

Absolute risk difference for severe bleeding and MACE with rivaroxaban vascular dose 2.5 mg bid plus aspirin versus aspirin alone

Absolute risk difference for severe bleeding and MACE with rivaroxaban vascular dose 2.5 mg bid plus aspirin versus aspirin alone7

The rates of major bleeding events in patients treated with rivaroxaban vascular dose 2.5 mg bid plus aspirin were also highest in the first year, and decreased substantially thereafter (hazard ratio [HR]=2.32; 95% confidence interval [CI] 1.78–3.02 in year 1, compared with HR=1.21; 95% CI 0.87–1.70 and HR=1.08; 95% CI 0.66–1.77 in years 2 and 3, respectively).7



There is a potential benefit in intensifying Valerie’s antithrombotic therapy to reduce her risk of suffering a life-threatening cardiovascular event. However, the benefits of doing so must always be weighed up against the increased risk of bleeding events.


Because she has a number of risk factors, Valerie is more likely to have a cardiovascular event without additional treatment than she is to suffer a bleeding event with it.5 Therefore, rivaroxaban vascular dose 2.5 mg bid plus aspirin may be a valid treatment option for a patient like Valerie, and could be beneficial even if she is already receiving all standard-of-care medications for cardiovascular risk management.


This is reflected in the most recent version of the European Society of Cardiology (ESC) guidelines on chronic coronary syndromes, which indicate that a second antithrombotic drug, such as rivaroxaban, should be considered in patients at high risk of ischaemic events without high bleeding risk.8

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What is new in the ESC guidelines?
Martin Cowie on the new CCS Guidelines

  • Steg PG, Bhatt DL, Wilson PW et al. One-year cardiovascular event rates in outpatients with atherothrombosis. JAMA 2007;297:1197–1206. Return to content
  • Chan NC, Weitz JI. Antithrombotic agents. Circ Res 2019;124:426–436. Return to content
  • Darmon A, Sorbets E, Ducrocq G et al. Association of multiple enrichment criteria with ischemic and bleeding risks among COMPASS-eligible patients. J Am Coll Cardiol 2019;73:3281–3291. Return to content
  • Bosch J, Eikelboom JW, Connolly SJ et al. Rationale, design and baseline characteristics of participants in the Cardiovascular OutcoMes for People using Anticoagulation StrategieS (COMPASS) trial. Can J Cardiol 2017;33:1027–1035. Return to content
  • Anand SS, Eikelboom JW, Dyal L et al. Rivaroxaban plus aspirin versus aspirin in relation to vascular risk in the COMPASS trial. J Am Coll Cardiol 2019;73:3271–3280. Return to content
  • Eikelboom JW, Connolly SJ, Bosch J et al. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med 2017;377:1319–1330. Return to content
  • Eikelboom JW, Bosch JJ, Connolly SJ et al. Major bleeding in patients with coronary or peripheral artery disease treated with rivaroxaban plus aspirin. J Am Coll Cardiol 2019;74:1519–1528. Return to content
  • Knuuti J, Wijns W, Saraste A et al. 2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J 2020;41:407–477. Return to content

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