Cardiovascular Outcomes in CKD: Risks in Women versus Men

Cardiovascular disease is the leading cause of death among individuals with chronic kidney disease (CKD). Results of previous epidemiologic studies of non-CKD populations demonstrated that the incidence of cardiovascular events is lower in women than in men, and that women have longer survival compared with men. Those results have been attributed to a more favorable cardiovascular risk profile among women and to other biological differences including sex hormone levels, estrogen in particular. Thus, sex-specific guidelines for prevention of cardiovascular disease have been in place for the past 20 years.

However, according to Stephanie M. Toth-Manikowski, MD, MHS, and colleagues, among a population of patients in the United States receiving maintenance dialysis, women have only a slightly lower risk of death compared with men. The researchers conducted a prospective cohort study to assess sex-related differences (women vs men) in different types of cardiovascular events and death in the CRIC (Chronic Renal Insufficiency Cohort) study. Results were reported in the American Journal of Kidney Diseases [2021;78(2):200-209].

The outcomes of interest were an atherosclerotic composite (myocardial infarction, stroke, or peripheral artery disease), incident heart failure, cardiovascular death, and all-cause death. Cox proportional hazards regression models were used to examine the association between sex and each outcome, stratified by clinical site and adjusted for key sociodemographic and clinical variables.

The study cohort included 3939 eligible participants in the CRIC study. Of those, 45% (n=1778) were women and 55% (n=2161) were men, with a mean age of 58 years at study entry. Of the 3939 participants, 41.5% were non-Hispanic White, 41.8% were non-Hispanic Black, 12.6% were Hispanic, and 3.9% were Asian, Pacific Islander, of other heritage, or of mixed heritage. Mean estimated glomerular filtration rate (eGFR) was 43.9 mL/min/1.73 m2 in women and 45.87 mL/min/1.73 m2 in men. Median urine protein excretion was 113 mg/d in women and 268 mg/d in men.

The women were more likely than the men to be of a racial/ethnic minority subgroup and to have less than a high school education, and less likely to be married or living with a partner, to have seen a nephrologist in the past, to have a family history of coronary heart disease, or to report a prior history of cardiovascular disease. Women were also less likely to report regular physical activity and more likely to have never smoked. Women were more likely than the men to have higher levels of high-sensitivity C-reactive protein (hs-CRP) and N-terminal pro ß-natriuretic peptide (NT-proBNP) and lower levels of high-sensitivity troponin T (hs-TnT). Women were also less likely to report the use of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, ß-blocker, aspirin, and statin.

A total of 460 participants (252 men and 208 women) were excluded from multivariable regression analyses due to missing covariate data. Compared with those included in the final regression  model, excluded participants were less likely to be non-Hispanic White and have a high school education or greater. The two groups were similar in baseline eGFR, median proteinuria, and all other clinical characteristics.

Median follow-up was 8.9 years. During follow-up, there were 698 atherosclerotic events (264 in women and 434 in men). The majority of those events were myocardial infarction events (163 in women, 247 in men). The rates of the atherosclerotic composite outcome events were lower in women than in men (1.9/100 person-years vs 2.7/100 person-years, respectively). The rates of myocardial infarction, stroke, and peripheral artery disease were lower in women than in men.

Following adjustment for sociodemographic characteristics, baseline kidney function, and clinical and laboratory characteristics, results of regression models demonstrated that women experienced 29% lower risk of atherosclerotic events compared with men (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.57-0.88). The risk of atherosclerotic composite events remained lower among women following adjustment for hs-CRP (HR, 0.70; 95% CI, 0.56-0.86), NT-proBNP (HR, 0.70; 95% CI, 0.56-0.86), hs-TnT (HR, 0.76; 95% CI, 0.62-0.95), or time-updated eGFR (HR, 0.69; 95% CI, 0.55-0.86). The association of sex with myocardial infarction and stroke was in the same direction but not statistically significant.

In analyses stratified by baseline age, cardiovascular disease, and eGFR, the risk of the atherosclerotic composite outcome was lower in women than in men. There was no evidence of interaction between sex and race/ethnicity or diabetes status.

There were 762 heart failure events during a median follow-up of 8.8 years (331 women and 431 men). The rates of heart failure were lower in women than in men (2.4/100 person-years vs 2.7/100 person-years, respectively). In multivariable analysis, the risk of heart failure was 26% lower in women than in men (HR, 0.74; 95% CI, 0.60-0.92). Following adjustment for hs-CRP, NT-proBNP, or time-updated eGFR, the association remained statistically significant. When hs-TnT was added to the model, the association was in the same direction, but not statistically significant.

Results were similar in analyses stratified by age, cardiovascular disease, and baseline eGFR, with the exception of participants with baseline eGFR <30 mL/min/1.73 m2, where the risk of heart failure in men and women was similar. There was no evidence of interaction between sex and race/ethnicity or diabetes status.

During a median follow-up of 9.6 years, there were 435 cardiovascular deaths (163 women and 274 men) and 1158 all-cause deaths (449 women and 709 men). The multivariable-adjusted risk of cardiovascular death and death from any cause was lower in women than in men (HR, 0.55; 95% CI, 0.42-0.72 and HR, 0.58; 95% CI, 0.49-0.69, respectively). After adding hs-CRP, NT-proBNP, hs-TnT, or time-updated eGFR, the associations remained statistically significant. The association of sex with cardiovascular or all-cause death was similar across strata of age and baseline eGFR.

Limitations to the study findings cited by the authors were not including assessment of sex hormones that may play a role in cardiovascular risk and the inability to assess cardiovascular health-seeking behaviors in women versus men.

In conclusion, the researchers said, “Women with CKD had a lower risk of cardiovascular events and mortality compared with men, and this difference was not explained by cardiac biomarkers of myocardial distention, injury, or inflammation. From the clinician’s perspective, it is concerning that most baseline risk factor control and cardioprotective medication use were suboptimal in both women and men. Importantly, women with CKD should still be considered to be at very high cardiovascular risk. Future work is needed to evaluate the differential impact of risk factor management to improve outcomes in women and men with CKD.”

Takeaway Points

  1. Researchers conducted a prospective cohort study among participants with chronic kidney disease in the Chronic Renal Insufficiency Cohort study to examine sex-related differences in different types of cardiovascular events and death.
  2. Compared with men, women had lower risks of cardiovascular events, cardiovascular mortality, and death from any cause.
  3. The differences were not explained by measured cardiovascular risk factors.