American Journal of Kidney Diseases
Volume 49, Issue 1 , Pages 8-11, January 2007

Should CKD Be a Coronary Heart Disease Risk Equivalent?

  • Marcello Tonelli, MD, SM, FRCPC

      Affiliations

    • Corresponding Author InformationNo reprints will be available. All correspondence to Marcello Tonelli, MD, 7-129 Clinical Sciences Bldg, 8440-112 St, Edmonton, Alberta T6G 2G3, Canada.

Departments of Medicine, Critical Care, and Public Health Sciences, Institute of Health Economics, University of Alberta, Edmonton, Canada

Article Outline

 

A fundamental principle of the National Cholesterol Education Adult Treatment Panel III (ATP III) guidelines is that therapeutic targets for low-density lipoprotein (LDL) cholesterol should be lower in patients with increased risk of coronary heart disease (CHD) events.1 For patients in the highest risk category (CHD or CHD equivalent, termed “high risk” in a recent update to ATP III), LDL level reduction to less than 100 mg/dL (<2.59 mmol/L) is recommended.2 The term “CHD equivalent” refers to people with a 10-year risk of coronary death or nonfatal myocardial infarction at least as high as those who have known CHD (including those with stable angina or prior myocardial infarction), which generally exceeds 20%.1 Examples of CHD risk equivalents specifically mentioned in ATP III include type 2 diabetes mellitus and noncoronary atherosclerosis, such as peripheral vascular disease.

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Expert groups associated with the National Kidney Foundation and American Heart Association recently suggested that patients with chronic kidney disease (CKD) be included in the highest risk category for future CHD events3 based on a large body of evidence linking CKD to adverse cardiovascular outcomes.4 A timely article by Hyre et al5 in this month’s issue of American Journal of Kidney Diseases addresses the potential impact of this change on the number of Americans with stage 3 CKD (estimated glomerular filtration rate [GFR], 30 to 59 mL/min/1.73 m2 [0.50 to 0.98 mL/s/1.73 m2]) for whom statin therapy would be recommended. Although persons with evidence of kidney damage (such as albuminuria for ≥3 months) also are considered to have CKD even when GFR is 60 mL/min/1.73 m2 or greater (≥1.00 mL/s/1.73 m2), such individuals were not specifically considered in the report by Hyre et al.5

Why does the ATP III use the concept of CHD risk equivalency? As mentioned by the National Cholesterol Education Adult Treatment Panel guidelines and Hyre et al,5 basing lipid-level targets on such common and readily ascertained characteristics as the presence or absence of diabetes is easier for clinicians to apply than such more complex risk stratification schemes as the Framingham equation.6 Patients considered to have a CHD risk equivalent will have a lower recommended LDL level target and thus be more likely to receive lipid-lowering treatment (usually a statin). This more aggressive treatment will tend to result in lower LDL levels, leading to a greater relative decrease in CHD event rates. The greater baseline risk in these people also should yield a greater absolute risk reduction for any given relative reduction in risk of CHD events, improving the cost-effectiveness of treatment. However, do available data justify extending CHD equivalent status to people with CKD? To answer this question, it may be helpful to consider whether the rationale for defining diabetes as a CHD risk equivalent7 also applies to those with CKD.

Like diabetes, CKD often coexists with other risk factors for atherosclerosis and increases in prevalence with older age. CKD also is similar to diabetes because both are associated with increased risk of CHD events8 and a greater likelihood of death after myocardial infarction.9, 10 These greater risks experienced by patients with diabetes were part of the rationale for defining diabetes as a CHD risk equivalent. Is the risk for CHD in patients with CKD as high as in those with diabetes? A recent analysis from the Atherosclerosis Risk in Communities Study showed that the risk of fatal CHD or first nonfatal myocardial infarction in patients without diabetes with CKD aged 45 to 64 years was 8.0/1,000 patient-years,11 considerably less than the expected rate of 20 to 25/1,000 patient-years in similarly aged people with diabetes1 and less than the observed rate of 18.8 in 45- to 64-year-old people with prior myocardial infarction and no CKD or diabetes.11 These data suggest that the risk observed in middle-aged people with stage 3 CKD but no diabetes (although substantially greater than average) is not as high as that in those with established CHD or people with type 2 diabetes. These data argue against adding CKD to the existing list of CHD risk equivalents because persons affected by this change would all be without diabetes.

Data are limited about the risk of CHD events in patients with CKD who are younger than 45 years. Unpublished data from the Alberta Kidney Disease Network indicate that the absolute risk of hospitalization for myocardial infarction among community-dwelling Canadian adults aged 20 to 39 years with a GFR of 30 to 59 mL/min/1.73 m2 (0.50 to 0.98 mL/s/1.73 m2) is only 0.5 events/1,000 patient-years (95% confidence interval, 0.1 to 3.6). Unpublished data from the First National Health and Nutrition Examination Survey are similar (1 cardiovascular death in 1,307 person-years of follow-up for 18- to 45-year-old adults with a GFR <60 mL/min/1.73 m2 [<1.00 mL/s/1.73 m2] at baseline; 95% confidence interval, 0.1 to 5.4 deaths/1,000 person-years). Despite the preliminary nature of these observations, it seems unlikely that intensive lipid-lowering therapy would be indicated in individuals with these low absolute rates of CHD.

However, a limitation of these analyses is that CKD and diabetes commonly occur together, and the risk in people with both conditions is greater than in those with either alone.12, 13 Because several studies used to justify diabetes as a CHD risk equivalent did not exclude people with impaired kidney function or albuminuria, some of the excess risk attributed to diabetes in these analyses was caused by concomitant CKD. Future studies should assess the increase in CVD risk caused by diabetes, CKD, and both across the spectrum of age to determine whether to modify the list of National Cholesterol Education Adult Treatment Panel CHD risk equivalents.

Because CKD, CHD, and CHD risk factors often occur together, one might suspect that adding CKD to the current list of CHD risk equivalents would have little impact on medication use. The report by Hyre et al5 refutes this suggestion by using data from the Third National Health and Nutrition Examination Survey to estimate the number of Americans for whom lipid-lowering therapy would be recommended, first using current ATP III guidelines and then after reclassifying GFR of 30 to 60 mL/min/1.73 m2 (0.50 to 1.00 mL/s/1.73 m2) as a CHD risk equivalent. As expected, known CHD and CHD risk equivalents were more common in people with CKD (53.0% versus 13.8%), and a greater proportion of those with CKD had 2 or more CHD risk factors (70.7% versus 31.7%). However, the overall proportion of people with CKD for whom drug therapy would be recommended increased from 61.4% under the status quo to 87.7% with the proposed change, representing 2 million additional medication recipients.

Who are the people that the proposed change would affect? Data from Hyre et al5 suggest that those younger than 65 years or women were more likely to be affected. Of note, statin therapy would be recommended for 66.9% of people with CKD and 1 or 0 CHD risk factors if such a change were adopted. Although only representing 22.2% of those with a GFR of 30 to 60 mL/min/1.73 m2 (0.50 to 1.00 mL/s/1.73 m2), the number of Americans in this category is relatively large and their absolute risk of future CHD events is not well described. In addition, considering CKD as a risk equivalent would imply that even young adults with a decreased GFR and little or no comorbidity would be advised to use lipid-lowering treatment. Including all patients with CKD in the highest risk category would result in the prescription of lipid-lowering medicines to many lower-risk individuals for whom the cost-effectiveness and clinical benefit of treatment is unknown.

Against these caveats must be set the facts that CHD is an enormous clinical problem in people with stages 3 and 4 CKD3, 14; statins appear to be effective in preventing vascular events in patients with stage 3 CKD, but perhaps not in dialysis patients13, 15, 16; and the designation of high-risk status seems to have improved health by increasing statin uptake in North Americans with diabetes or known CVD. Therefore, although CHD risk equivalency for all people with stage 3 or higher CKD may not be the answer, public health strategies that target those with CKD before kidney failure ensues clearly are needed.

Restricting CHD-equivalent status to people with a GFR less than 45 mL/min/1.73 m2 (<0.75 mL/s/1.73 m2) or even less than 30 mL/min/1.73 m2 (<0.50 mL/s/1.73 m2; or those with albuminuria) might be a consideration because the risk of cardiovascular events and death appears to increase sharply at lower levels of kidney function17 or when proteinuria is present,18 and such individuals are much less prevalent in the general population.19 Another might be to include CKD in the risk prediction models used to calculate 10-year CHD risk.6 The latter should increase the proportion of higher risk patients with CKD for whom statins were recommended while tending to limit lipid-lowering therapy in those with decreased GFR, but at lower overall risk. However, this would compromise the appealing simplicity that characterizes the concept of CHD risk equivalency.

Perhaps the most appealing strategy is to focus on delivering multifactorial vascular risk reduction to patients with CKD for whom such therapies are of proven benefit based on existing evidence. Multiple studies indicate that people with stage 3 or 4 CKD are significantly less likely than those with normal kidney function to receive potentially beneficial therapies, even in the presence of established vascular disease, including, but not limited to, lipid-lowering medication.20, 21, 22 Designing and implementing ways to close this “quality gap” may represent a more prudent use of resources than revising the ATP III guidelines to include all patients with CKD as a CHD risk equivalent, at least based on currently available evidence.

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Acknowledgment 

The author thanks Drs Brenda Hemmelgarn and Amit Garg for providing unpublished data.

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References 

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 Support: Dr Tonelli was supported by salary awards from the Canadian Institutes of Health Research and the Alberta Heritage Foundation for Medical Research. Potential conflicts of interest: Dr Tonelli received a research grant (>$10,000) from Bristol-Myers-Squibb in 2003, served on a Pfizer advisory board in 2004, received honoraria (<$10,000) from Pfizer for continuing medical education lectures in 2004-2005, and received a research grant from AstraZeneca (<$10,000) in 2005. Honoraria (<$10,000) provided by Merck and Astra-Zeneca for academic grand rounds given in 2006 were donated directly to charity.

PII: S0272-6386(06)01689-1

doi:10.1053/j.ajkd.2006.11.020

Refers to article:

  • The Impact of Reclassifying Moderate CKD as a Coronary Heart Disease Risk Equivalent on the Number of US Adults Recommended Lipid-Lowering Treatment , 12 December 2006

    Amanda D. Hyre, Caroline S. Fox, Brad C. Astor, Andrew J. Cohen, Paul Muntner
    American Journal of Kidney Diseases January 2007 (Vol. 49, Issue 1, Pages 37-45)

American Journal of Kidney Diseases
Volume 49, Issue 1 , Pages 8-11, January 2007

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