Physicians' Academy for Cardiovascular Education

Antithrombotic therapy in patients with CKD

Literature - Capodanno D, Angiolillo DJ. Circulation. 2012;125:2649-61.

Antithrombotic therapy in patients with chronic kidney disease.

Capodanno D, Angiolillo DJ.
Circulation. 2012;125:2649-61.


Background

Chronic kidney disease (CKD) is a global health problem. Over 500 million people worldwide are estimated to have some form of kidney injury [1]. Patients with all stages of CKD experience higher rates of atherothrombotic disease manifestations and thrombo-embolic processes, such as atrial fibrillation [2-5]. Antithrombotic treatment strategies are thus very important in these patients, but risk/benefit ratio can be different in CKD patients.
This review gives an overview of currently available evidence on antithrombotic treatment in patients with CKD.


Pharmacological considerations in patients with CKD

Dosing for patients with varying renal function is based on guidelines and summaries of product characteristics [6-9]. CKD may affect the pharmacokinetic parameters of antithrombotic drugs in several ways, for example by increasing bioavailability or distribution, prolonging the time to reach maximum drug concentration or half life, or by reducing the excretion of a drug.
Depending on the mechanism of action of antithrombotic agents, they can be affected by reduced renal function, requiring dosing considerations.

Recommendations

Patients receiving antithrombotic medications should be screened for CKD. General measures to prevent progression of CKD should be considered. This includes control of contributing risk factors, such as hypertension and diabetes mellitus, and avoidance of potential nephrotoxic medications, such as nonsteroidal anti-inflammatory drugs. The choice and dose of antithrombotic drugs need to be carefully evaluated in patients with CKD.
  • Aspirin: low-dose regimens (< 100 mg), if possible.
  • P2Y12 receptor antagonists: neither clopidogrel (ACS and non-ACS), ticagrelor (ACS), of prasugrel (ACS undergoing PCI) require renal dosing adjustments. Prasugrel and ticagrelor are contraindicated in patients at high risk of bleeding. Other contra-indications should also be taken into account.
  • GPIIb/IIIa inhibitors: dose adjustments are necessary
  • Warfarin: long-term anticoagulation requires careful dosing and more frequent INR monitoring

Novel anticoagulants

The pharmacokinetics of novel selective oral anticoagulants are depicted in figure 1.

Figure 1

Pharmacokinetics of novel selective oral anticoagulants, with overview of target, hours to Cmax, half-life, and metabolism.

Click on image to enlarge
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  • dabigatran: (AF) renal function should be assessed before starting therapy, tested annually in patients > 75 years and patients with creatinine clearance < 50 mL/min. FDA recommends the 75 mg bid dose in patients with stage 4 CKD; EMA recommend to use the 110 mg bid dose on an individual basis and to be careful in patients with low thromboembolic and high bleeding risks
  • rivaroxaban: in patients with AF, a dose modification from 20 to 15 mg once daily is required in patients with creatinine clearance < 50 mL/min.
  • Other oral direct factor Xa inhibitors such as apixaban and edoxaban are at advanced stages of clinical development and have predominantly nonrenal clearance, thereby being potentially interesting alternatives to warfarin and other selective coagulation factor antagonists in CKD patients.

Conclusion

The choice and combination of antithrombotic drugs used should be balanced against the individual risk of thrombotic and bleeding complications. For the newer agents, more data from large-scale clinical trials or dedicated studies in patients with CKD are warranted.


References

1. Ritz E, Bakris G. World Kidney Day: hypertension and chronic kidney disease. Lancet. 2009;373:1157–1158.
2. Tveit DP, Hypolite IO, Hshieh P, et al. Chronic dialysis patients have high risk for pulmonary embolism. Am J Kidney Dis. 2002;39:1011–1117.
3. Abbott KC, Cruess DF, Agodoa LY, et al. Early renal insufficiency and late venous thromboembolism after renal transplantation in the United States. Am J Kidney Dis. 2004;43:120 –130.
4. Wattanakit K, Cushman M, Stehman-Breen C, et al. Chronic kidney disease increases risk for venous thromboembolism. J Am Soc Nephrol. 2008;19:135–1340.
5. Mahmoodi BK, Gansevoort RT, Veeger NJ, et al. Prevention of Renal and Vascular End-stage Disease (PREVEND) Study Group. Microalbuminuria and risk of venous thromboembolism. JAMA. 2009;301:1790 –1797.
6. Fraker TD Jr, Fihn SD, Gibbons RJ, et al; American College of Cardiology; American Heart Association; American College of Cardiology/American Heart Association Task Force on Practice Guidelines Writing Group. 2007 Chronic angina focused update of the ACC/AHA 2002 guidelines for the management of patients with chronic stable angina: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines Writing Group to develop the focused update of the 2002 guidelines for the management 2762–2772.
7. Kushner FG, Hand M, Smith SC, et al; American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. 2009 Focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2009;120:2271–2306.
8. Wright RS, Anderson JL, Adams CD, et al. 2011 ACCF/AHA focused update of the guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2011;123:2022–2060.
9. Writing Committee Members, Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation. 2011;124:e574–e651.

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