Residual Cardiovascular Risks: Don’t Forget Kidney and Vascular Disease

This evidence-based journey-which travels a spectrum from normal vessels on to fatal cardiovascular disease-began with 2 background articles^1,2 that introduced a recent concept: residual risk.That is to say, as effective as statins have been in reducing cardiovascular risk, 70% of that risk persists after statin titration to a target LDL-cholesterol level.

Exactly what is responsible for residual risk and how can we mitigate it? 

Chronic kidney disease (CKD) is complicated by myriad cardiovascular complications and fits into our scheme of residual risk. Reviewing both the risks and their potential causes in CKD is a good place to begin assessing future prevention strategies.

Remember, CKD stage 3 or worse (CKD4 and 5 and dialysis dependence) are on the rise. Here I will discuss traditional risk factors that contribute to risk in CKD and will follow with a consideration of  non-traditional factors unique to CKD.

It is not surprising that hypertension (which is more common in CKD), smoking, and diabetes (a potent risk factor for CKD) are on the list for traditional cardiovascular risk factors in this population. Cholesterol is as well, but 2 studies (Study of Heart & Renal Protection [SHARP]³ and Treat to New Targets [TNT]⁴) address cholesterol in the specific context of CKD. (Note: The italics that follow [without and with] are used in lieu of the terms "primary" and "secondary prevention".) CKD is considered a secondary prevention group per se. That is, target LDL is below 100 mg/dL in anyone with CKD stages 1 to 5;⁵ however, SHARP addressed CKD in individuals without and TNT with a history of cardiovascular events.

In SHARP, simvastatin and ezetimibe (20 mg/d and 10 mg/d, respectively), were compared with placebo in 9,270 patients (3,023 on dialysis and 6247 with CKD, but not on dialysis) without a history of myocardial infarction or coronary revascularization. It may sound trivial, but cholesterol lowering in CKD had not been demonstrated previously to improve outcomes in a prospective, blinded, placebo controlled trial.³ There was a 17% proportional reduction in major atherosclerotic events in the drug limb of the study.³ The combination was well tolerated.

In TNT, in a sub-analysis that focused on CKD patients with coronary heart disease, 10,001 patients (blinded) received either 80 mg/d or 10 mg/d of atorvastatin. The 80 mg group experienced a 32% reduction in the risks of major cardiovascular events compared with the 10 mg group. Both doses again were well tolerated. It is important to observe that the average LDL cholesterol was similar in both groups (ie, 99 mg/dL and 79 mg/dL in the 10 mg and 80 mg cohorts, respectively). Although cholesterol values averaged below a target of 100 in both limbs, additional atorvastatin was superior in mitigating risk. 

Regarding traditional residual risk factors for cardiovascular disease (in CKD patients with and without prior events), how should practices change in CKD?

Typical interventions in persons without CKD-for example, smoking cessation, treatment of blood pressure elevations to target, and diabetic control are essential. SHARP and TNT have added to our knowledge. Aggressive cholesterol lowering (probably also affecting LDL particle number as well as traditional measures of LDL) seems to afford better outcomes by lessening residual risk in those with CKD.


Acknowledgement: Background for this material and the references were obtained from Martin KJ, Block GA, Budoff MJ. Healthy kidneys, healthy heart: reducing cardiovascular risks in patients with chronic kidney disease. Accessed February 10th, 2013 at Medscape Education. 

          
References
1. Rutecki GW. Novel risk factors improve prediction of cardiovascular disease in intermediate-risk persons. February 12, 2012. www.consultantlive.com.
2. Rutecki GW. LDL-C and PCSK-9: new horizons for treating residual CV risk. February 11, 2013. www.consultantlive.com.
3. Baigent C, Landray MJ, Reith C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and  Renal Protection/SHARP): a randomized placebo-controlled trial. Lancet. 2011;377:2181-2192.
4. Shepherd J, Kastelein JJ, Bittner V, et al. Intensive Lipid Lowering with Atorvastatin in Patients with Coronary Heart Disease and Chronic Kidney Disease. (The Treat to New Targets Study/TNT). J Am Coll Cardiol. 2008;51:1448-1454.
5. K/DOQI Clinical practice guidelines for managing dyslipidemias in chronic kidney disease. Am J KidDis. 2003;41(suppl 3):I-IV,S1-91