About three-quarters of people with CVD have one or more comorbid conditions that can impact medical management and make optimal care more difficult. A number of studies have lent insights into managing antithrombotic therapy in patients with common comorbidities that could influence the choice of therapy.

Chronic Kidney Disease
In the United States, an estimated 20 million people have chronic kidney disease (CKD) and, as the population ages, this huge number is likely to increase exponentially in the coming years. Studies consistently suggest that persons with CKD are at risk of developing CVD and, once they experience an acute coronary event, patients with CKD fare worse than those without CKD. Moreover, individuals with CKD oftentimes die of CVD-related events long before there is significant progression in their CKD.

Conversely, CKD is usually a factor triggering more conservative approaches to CVD with less revascularization, less drugs, and utilization of lower doses. Lipid-lowering and BP-lowering strategies are both effective in reducing the risk of CV events in people with early CKD; however, CKD is associated with abnormal platelet function, leaving patients at potentially increased hemorrhagic risk when treated with anticoagulants, including antiplatelet agents. Substantial uncertainty persists regarding the balance between the risks and benefits associated with antiplatelet agents for patients with CKD. Consistent with this uncertainty, patients with CKD and end-stage kidney disease are less likely to be prescribed aspirin after an acute MI. So, what is the role of aspirin in patients with CKD?

Jardine et al. analyzed data from the Hypertension Optimal Treatment (HOT) study, which randomized nearly 20,000 participants with diastolic hypertension to aspirin (75 mg) or placebo.¹ Aspirin reduced the rate of major CV events by 9%, 15%, and 66% for individuals with baseline estimated glomerular filtration rate (eGFR) of ≥60, 45–59, and <45 ml/min/1.73 m², respectively. Total mortality was reduced by 0%, 11%, and 49%, respectively, with a nonsignificant trend toward increased major bleeding events with lower eGFR.

What about more powerful antiplatelet therapy? The inherent risk of bleeding in patients with CKD leads physicians to use lower doses of clopidogrel in patients with CKD than they would in individuals with normal renal function. Investigators used data from the Platelet Inhibition and Patient Outcomes (PLATO) trial to specifically evaluate ACS patients with CKD.² The most striking finding: independently of renal function, ticagrelor compared with clopidogrel reduced ischemic endpoints and mortality with no significant increase in major or fatal bleedings. In this particularly high-risk group, ticagrelor reduced incidence of the primary composite endpoint by 4.7% per year, compared to a 1% yearly reduction with clopidogrel, in those with normal renal function. The incidence of major bleeding did not differ significantly between the ticagrelor and clopidogrel groups in patients with normal renal function or in patients with CKD.

The TRITON-TIMI 38 trial demonstrated that prasugrel was associated with significantly reduced rates of ischemic events, including stent thrombosis, but with an increased risk of major bleeding (including fatal bleeding in an ACS population).³ While overall mortality did not differ significantly between treatment groups, in subgroup analysis, individuals with a creatinine clearance <60 ml/min tended to do better with prasugrel based on the combined primary endpoint of death from CV, nonfatal MI, or nonfatal stroke.

Previous Stroke
Recurrent stroke is a frequent, disabling event after ischemic stroke. How should antiplatelet therapy be managed in the setting of prior stroke? In the Management of Atherothrombosis with Clopidogrel in High-Risk Patients with Recent Transient Ischemic Attacks or Ischemic Stroke (MATCH) trial, patients with a recent stroke or TIA were randomized to aspirin plus clopidogrel or to clopidogrel alone.⁴ The investigators reported that dual therapy significantly doubled the risk of intracranial bleeding. The same was observed in the much larger Prevention Regimen For Effectively avoiding Second Strokes (PROFESS) study with similar patients.⁵ The combination of aspirin and dipyridamole increased significantly the risk of intracranial bleeding, compared with clopidogrel alone.

In a recent editorial, Freek W.A. Verheugt, MD, stated "there is no safe ground to treat ACS patients with a previous stroke or TIA routinely with the novel platelet P2Y12 receptor antagonists prasugrel or ticagrelor rather than with clopidogrel."⁶

In June 2012, in a substudy of the ARISTOTLE trial, researchers compared the effectiveness of apixaban and warfarin in patients with AF and a history of stroke.⁷ There were more than 18,000 patients enrolled in the ARISTOTLE trial; 19% of these patients had a history of stroke and were included in the substudy. The analysis confirmed the original ARISTOTLE results that patients who received apixaban, regardless of stroke history, had fewer strokes, bleeding complications, and better mortality rates than patients who received warfarin. Owing to the higher risk of these outcomes in patients with previous stroke or TIA, the authors suggested that the absolute benefits of apixaban might be greater in this population.

Atrial Fibrillation
In a review article by Gregory YH Lip, MD, and colleagues, they noted that several clinical trials have studied the effects of aspirin in AF, with doses ranging from 25 mg twice daily to 1,200 mg a day.⁸ Overall, aspirin reduced the relative risk of stroke by about 20% (a figure which just reaches statistical significance) with no apparent benefit of increasing aspirin dose. Aspirin seems to carry greater benefit in reducing smaller nondisabling strokes than disabling strokes.

On the other hand, adjusted-dose warfarin reduced stroke by about 60% in patients with AF (versus nil), with absolute risk reductions of 3% a year for primary prevention and 8% a year for secondary prevention. There does not seem to be a role for mini-dose warfarin (1mg/day regardless of INR), alone or in combination with antiplatelet agents or aspirin, as thromboprophylaxis in AF. A meta-analysis of trials directly comparing full-dose warfarin with aspirin confirmed significant reductions in stroke risk about three times greater with warfarin.

According to ACCF/AHA guidelines, adjusted-dose oral anticoagulant (OAC) therapy is more efficacious than aspirin for prevention of stroke in patients with AF.⁹ Oral anticoagulation may be most beneficial for AF patients at higher intrinsic thromboembolic risk, offering only modest reductions over aspirin in both the relative risk and absolute rates of stroke for patients at low risk. Individual risk varies over time, so the need for anticoagulation must be reevaluated periodically in all patients with AF.

The ESC guidelines specifically suggest OAC therapy when a patient with AF has a CHA2DS2-VASc score of ≥2.¹⁰ When there is only one clinically relevant non-major risk factor (a CHA2DS2-VASc score of 1), either OAC therapy or aspirin 75-325 mg daily is appropriate, but the document states that OAC is preferred to aspirin. As for AF patients with no risk factors for stroke, the ESC guidelines state a preference for no OAC and no aspirin.

A recent analysis from ARISTOTLE evaluated patients with AF and outcomes analyzed by renal function. Apixaban was more effective than warfarin in preventing stroke or systemic embolism and reducing mortality irrespective of renal function in patients with AF.¹¹ These results were consistent, regardless of methods used to derive eGFR. Adverse CV events and bleeding were more likely in patients with impaired renal function (those with an eGFR <80 ml/minute), but apixaban was more effective than warfarin at reducing bleeding in all patients, regardless of renal function, although the greatest reduction was found in patients with diminished renal function.

References
1. Jardine MJ, Ninomiya T, Perkovic V, et al. J Am Coll Cardiol. 2010;56:956-65. http://content.onlinejacc.org/article.aspx?articleid=1143145
2. James S, Budaj A, Aylward P, et al. Circulation. 2010;122:1056-67.
3. Wiviott SD, Braunwald E, McCabe CH, et al. N Engl J Med. 2007;357:2001-15.
4. Diener HC, Bogousslavsky J, Brass LM, et al. Lancet. 2004;364:331-7.
5. Sacco RL, Diener HC, Yusuf S, et al. N Engl J Med. 2008;359:1238-51.
6. Verheugt FW. Circulation. 2012;125:2821-3.
7. Easton JD, Lopes RD, Bahit MC, et al. Lancet Neurol. 2012;11:503-11.
8. Lip GY, Hart RG, Conway DS. BMJ. 2002;325:1022-5.
9. Fuster V, Rydén LE, Cannom DS, et al. J Am Coll Cardiol. 2011;57:e101-e198. http://content.onlinejacc.org/article.aspx?articleid=1144258
10. Camm AJ, Kirchhof P, Lip GY, et al. Eur Heart J. 2010;31:2369-429.
11. Hohnloser SH, Hijazi Z, Thomas L, et al. Eur Heart J. 2012;33:2821-30.

Keywords: Ischemic Attack, Transient, Platelet Aggregation Inhibitors, Comorbidity, Ticlopidine, Blood Platelets, Risk Factors, Creatinine, Primary Prevention, Thrombosis, Pyridones, Risk Assessment, Hypertension, United States, Uncertainty, Stroke, Kidney Failure, Chronic, Piperazines, Pyrazoles, Stents, Incidence, Secondary Prevention, Glomerular Filtration Rate, Embolism, Dipyridamole

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