Risk differences were 15.8 (95% CI, 12.2-18.1) for heart failure, 16.1 (95% CI, 13.2-19.0) for coronary heart disease, and 8.6 (95% CI, 6.4-10.7) for stroke.
Adjusted for age, sex, race/ethnicity, cohort, hypertension, diabetes, tobacco use, hyperlipidemia, prevalent heart failure, prevalent coronary heart disease, and prevalent stroke.
eTable 1. Baseline Characteristics of Study Participants From Each Cohort in the Pooled Analysis
eTable 2. Adjusted Risk Differences (per 1000 Person-years) for Adjudicated Incident Cardiovascular Events By Estimated Glomerular Filtration Rate and Urine Albumin-to-Creatinine Ratio
eTable 3. Incidence Rates (IR) and Risk Differences (per 1000 person-years) of Adjudicated Incident Cardiovascular Events in Participants by eGFR Category
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Bansal N, Katz R, Robinson-Cohen C, et al. Absolute Rates of Heart Failure, Coronary Heart Disease, and Stroke in Chronic Kidney Disease: An Analysis of 3 Community-Based Cohort Studies. JAMA Cardiol. 2017;2(3):314–318. doi:10.1001/jamacardio.2016.4652
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How do the absolute rates and risk differences of incident heart failure, coronary heart disease, and stroke differ in participants with and without chronic kidney disease?
This analysis of 3 community-based cohort studies fount that the adjusted risk differences comparing participants with vs without chronic kidney disease (per 1000 person-years) were highest for heart failure and coronary heart disease (and lower for stroke).
Chronic kidney disease is associated with an excess risk of heart failure that was similar in magnitude to coronary heart disease and greater than stroke.
Cardiovascular disease is the leading cause of morbidity and mortality in patients with chronic kidney disease (CKD). Understanding the relative contributions of cardiovascular disease event types to the excess burden of cardiovascular disease is important for developing effective strategies to improve outcomes.
To determine absolute rates and risk differences of incident heart failure (HF), coronary heart disease (CHD), and stroke in participants with vs without CKD.
Design, Setting and Participants
We pooled participants without prevalent cardiovascular disease from 3 community-based cohort studies: the Jackson Heart Study, Cardiovascular Health Study, and Multi-Ethnic Study of Atherosclerosis. The Jackson Heart Study was conducted between 2000 and 2010, the Cardiovascular Health Study was conducted between 1989 and 2003, and the Multi-Ethnic Study of Atherosclerosis was conducted between 2000 and 2012.
Chronic kidney disease was defined as estimated glomerular filtration rate less than 60 mL/min/1.73 m2, calculated using the combined creatinine–cystatin C CKD–Epidemiology Collaboration Equation.
Main Outcomes and Measures
Poisson regression was used to calculate incidence rates (IRs) and risk differences of adjudicated incident HF, CHD, and stroke, comparing participants with vs without CKD.
Among 14 462 participants, the mean (SD) age was 63 (12) years, 59% (n = 8533) were women, and 44% (n = 6363) were African American. Overall, 1461 (10%) had CKD (mean [SD] estimated glomerular filtration rate, 49  mL/min/1.73 m2). Unadjusted IRs for participants with and without CKD, respectively, were 22.0 (95% CI, 19.3-24.8) and 6.2 (95% CI, 5.8-6.7) per 1000 person-years for HF; 24.5 (95% CI, 21.6-27.5) and 8.4 (95% CI, 7.9-9.0) per 1000 person-years for CHD; and 13.4 (95% CI, 11.3-15.5) and 4.8 (95% CI, 4.4-5.3) for stroke. Adjusting for demographics, cohort, hypertension, diabetes, hyperlipidemia, and tobacco use, risk differences comparing participants with vs without CKD (per 1000 person-years) were 2.3 (95% CI, 1.2-3.3) for HF, 2.3 (95% CI, 1.2-3.4) for CHD, and 0.8 (95% CI, 0.09-1.5) for stroke. Among African American and Hispanic participants, adjusted risk differences comparing participants with vs without CKD for HF were 3.5 (95% CI, 1.5-5.5) and 7.8 (95% CI, 2.2-13.3) per 1000 person-years, respectively.
Conclusions and Relevance
Among 3 diverse community-based cohorts, CKD was associated with an increased risk of HF that was similar in magnitude to CHD and greater than stroke. The excess risk of HF associated with CKD was particularly large among African American and Hispanic individuals. Efforts to improve health outcomes for patients with CKD should prioritize HF in addition to CHD prevention.
Chronic kidney disease (CKD) is associated with significantly increased risk of cardiovascular disease and cardiovascular death.1,2 Specifically, studies of patients with CKD have noted an increased relative risk of coronary heart disease (CHD), heart failure (HF), and stroke compared with those without CKD.3-6 However, direct comparisons in differences in risk for these subtypes of cardiovascular disease in patients with and without CKD have not been well characterized, which may guide prioritization of targeted therapies to improve the poor prognosis in this high-risk population.
To address these gaps in knowledge, we pooled data from 3 diverse community-based cohorts with considerable representation of African American individuals and older adults and subgroups with a higher burden of CKD as well as cardiovascular disease. We focused on absolute risk differences in CHD, HF, and stroke among patients with CKD vs those without CKD for the purpose of estimating the potential public health benefits that could be achieved through effective prevention and treatment.
A total of 14 462 participants free of HF, CHD, and stroke from 3 community-based cohorts were pooled in this analysis: the Jackson Heart Study, the Cardiovascular Health Study, and the Multi-Ethnic Study of Atherosclerosis. Each cohort was a multicenter study, and institutional board review approval was obtained at each participating site for each cohort. See the eAppendix in the Supplement for additional details. Chronic kidney disease was defined as estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m2 calculated from baseline serum creatinine and cystatin C.7 The outcomes of our study were incident fatal and nonfatal HF, fatal and nonfatal CHD, and fatal and nonfatal stroke. Covariates included demographics, cohorts, hypertension, diabetes, tobacco use, and dyslipidemia. We calculated the unadjusted incidence rates of each primary outcome (incident HF, CHD, and stroke) by CKD status using Poisson regression. We then estimated risk differences, comparing participants with vs without CKD. We evaluated interactions of CKD across strata of age, sex, race/ethnicity, and study cohort. In a sensitivity analysis, we considered urine albumin to creatinine ratio in the definition of CKD. In a second sensitivity analysis, we evaluated incidence rates (IRs) and risk differences across 3 categories of eGFR: greater than 60 mL/min/1.73 m2, 45 to 59 mL/min/1.73 m2 and less than 45 mL/min/1.73 m2.
Among 14 462 participants, the mean (SD) age was 63 (12) years, 59% (n = 8533) were women, 44% (n = 6363) were African American, and 10% (n = 1461) had CKD (eTable 1 in the Supplement). The mean (SD) time to first HF event was 8.2 (2.5) years, 7.5 (3.1) years to first CHD event, and 7.6 (3.1) years to first stroke event. The unadjusted rates of incident HF, incident CHD, and incident stroke were highest for those with CKD vs without CKD, with HF and CHD having the largest unadjusted risk differences (Figure 1). Unadjusted IRs for participants with and without CKD, respectively, were 22.0 (95% CI, 19.3-24.8) and 6.2 (95% CI, 5.8-6.7) per 1000 person-years for HF; 24.5 (95% CI, 21.6-27.5) and 8.4 (95% CI, 7.9-9.0) per 1000 person-years for CHD; and 13.4 (95% CI, 11.3-15.5) and 4.8 (95% CI, 4.4-5.3) for stroke. The risk differences for HF, CHD, and stroke were attenuated with adjustment; however, all remained statistically significant, with patients with CKD having the greatest absolute risk differences of HF and CHD compared with those without CKD (Table). Adjusting for demographics, cohort, hypertension, diabetes, hyperlipidemia, and tobacco use, risk differences comparing participants with vs without CKD (per 1000 person-years) were 2.3 (95% CI, 1.2-3.3) for HF, 2.3 (95% CI, 1.2-3.4) for CHD, and 0.8 (95% CI, 0.09-1.5) for stroke.
Among subgroups by age, sex, race/ethnicity, and cohort, risks of CHD and stroke events were consistently higher in those with CKD compared with those without CKD (Figure 2). Across age and/or sex strata, adjusted risk differences in those with CKD vs without CKD were greatest for HF and CHD. Among African American participants, the risk difference between participants with and without CKD was only statistically significant for HF. Among white participants, risk differences in those with vs without CKD were comparable for HF and CHD. The risk difference for HF and CHD in participants with CKD vs participants without CKD was particularly large in Hispanic participants, although there were fewer participants in this subgroup. Among African American and Hispanic participants, adjusted risk differences comparing participants with vs without CKD for HF were 3.5 (95% CI, 1.5-5.5) and 7.8 (95% CI, 2.2-13.3) per 1000 person-years, respectively.
In a sensitivity analysis, the adjusted risk difference for HF and CHD was highest for those with both low eGFR and high urine albumin to creatinine ratio (eTable 2 in the Supplement). In a second sensitivity analyses, compared with eGFR greater than 60 mL/min/1.73 m2, the adjusted risk differences for incident HF, CHD, and stroke were greatest for participants with eGFR less than 45 mL/min/1.73 m2 (eTable 3 in the Supplement).
In a pooled analysis of 3 diverse community-based cohorts, we compared participants with vs without CKD and found that the absolute risk difference for incident HF was large, comparable with that of incident CHD, and greater than that for stroke. The excess risk of HF associated with CKD was particularly large among African American and Hispanic participants. These results suggest that a focus on prevention and treatment of HF in addition to CHD may improve the overall poor prognosis in patients with CKD.
Our findings are consistent with prior reports that have shown that CKD is associated with excess risk of cardiovascular disease.1,2 Our study augments this body of work by comparing rates of specific cardiovascular disease subtypes in patients with vs without CKD. We evaluated risk in absolute terms, which may translate most directly to the public health benefit that could be derived from effectively preventing or treating a specific subtype of cardiovascular disease.
It has long been recognized that CKD is associated with accelerated coronary atherosclerosis.8 Cardiovascular prevention and treatment in CKD has largely focused on therapies to decrease risk of CHD,9 and recent data suggest that development and application of effective medical therapies has reduced the burden of CHD in patients with CKD and patients without CKD.10,11
We found that the excess risk of HF among patients with CKD was large and comparable with that of CHD. One possible explanation is that primary prevention therapies for HF remain limited, particularly for preserved ejection fraction HF, which is the most common type of HF in CKD.12 Second, several novel mechanisms specific to CKD may contribute to the excess risk of HF in patients with CKD including retention of uremic toxins, endothelial dysfunction, inflammation, impaired sodium handling, and deranged mineral metabolism. Thus, identification and modification of novel CKD-specific risk factors for HF may be critical to improving cardiovascular outcomes in this high-risk patient population.
African American and Hispanic participants had the highest incidence rates of HF, CHD, and stroke. Findings from other studies support our data that suggests that African American individuals with CKD are a particularly high-risk subgroup.13,14 We also noted that Hispanic patients with CKD had large excess risks of HF and CHD. A 2011 study also found that left ventricular hypertherapy and elevated coronary artery calcification score was more common among Hispanic participants with CKD compared with non-Hispanic participants with CKD.15 Combined with these earlier studies, our data provide evidence that the excess burden of HF and CHD associated with CKD is particularly great among African American and Hispanic populations.
Our study had several strengths. We pooled 3 large, community-based patient populations that were diverse in age, race/ethnicity, and geographical location. Glomerular filtration rate was estimated using the combined creatinine and cystatin C equation, which may perform better for classifying CKD across a range of kidney function.7 We recognize limitations as well. Each study was conducted during different times, so secular trends may exist (eg, in cardiovascular disease medication use) for which we were not able to account. Most participants across all 3 cohorts had moderate CKD, and results may not apply to more advanced stages of CKD.
The excess risk of HF in patients with CKD is large and comparable with the excess risk of CHD. African American and Hispanic participants with CKD had particularly high risks of HF. Our study highlights the need for future investigations to understand and prevent cardiovascular disease among patients with CKD to improve long-term outcomes in this vulnerable population.
Corresponding Author: Nisha Bansal, MD, MAS, Kidney Research Institute, University of Washington, 908 Jefferson St, 3rd Floor, Seattle, WA 98104 (firstname.lastname@example.org).
Accepted for Publication: October 13, 2016.
Published Online: December 21, 2016. doi:10.1001/jamacardio.2016.4652
Author Contributions: Dr Katz had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Young and de Boer share senior authorship.
Concept and design: Bansal, Siscovick, Psaty, Kestenbaum, Young, de Boer.
Acquisition, analysis, or interpretation of data: Bansal, Katz, Robinson-Cohen, Odden, Dalrymple, Shlipak, Sarnak, Siscovick, Zelnick, Psaty, Correa, Afkarian, Young.
Drafting of the manuscript: Bansal, Young.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Bansal, Katz, Robinson-Cohen, Zelnick.
Administrative, technical, or material support: Bansal, Robinson-Cohen, Correa, Afkarian, Young.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
Funding/Support: This study was supported by University of Washington grants R01HL096875 (Drs de Boer and Kestenbaum), UH2HL125122 (Dr de Boer), R01DK102134 (Dr Young), and K23DK088865 (Dr Bansal). Dr Young is also supported in part by funding from the Veterans Affairs Puget Sound Health Care System. The Jackson Heart Study is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, and HHSN268201300050C from the National Heart, Lung, and Blood Institute and the National Institute on Minority Health and Health Disparities. The Cardiovascular Health Study was supported by contracts HHSN268201200036C, HHSN268200800007C, N01 HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, and N01HC85086 and grant HL080295 from the National Heart, Lung, and Blood Institute, with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided by AG023629 from the National Institute on Aging. The Multi-Ethnic Study of Atherosclerosis was supported by contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168 and N01-HC-95169 from the National Heart, Lung, and Blood Institute and by grants UL1-TR-000040 and UL1-RR-025005 from the National Center for Research Resources.
Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: We thank the other investigators, staff, and participants of the Multi-Ethnic Study of Atherosclerosis for their valuable contributions.
Additional Information: A full list of participating Multi-Ethnic Study of Atherosclerosis investigators and institutions can be found at http://www.mesa-nhlbi.org.
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