Editors' note: Low-density lipoprotein cholesterol and risk of intracerebral hemorrhage: A prospective study

Abstract

In their community-based cohort study including more than 96,000 patients over a 9-year period, Drs. Ma and colleagues sought to validate the relationship between very-low-density lipoprotein (LDL) levels and intracerebral hemorrhage (ICH). Compared with patients with a cumulative average LDL of ≥70 mg/dL, those with an average LDL of 50–69 mg/dL were at significantly greater risk of experiencing a primary ICH (odds ratio [OR] 1.65, 95% confidence interval [CI] 1.32–2.05); in addition, patients with an average LDL <50 mg/dL were at even greater risk (OR 2.69, 95% CI 2.03–3.57). Although these relative estimates may appear concerning, the low overall event rate may attenuate the absolute clinical risk, as summarized by Drs. Lima and Fraiman in their response. With only 768 events over 9 years, the absolute increase in ICH risk is approximately 0.0015 events/person/year, which may pale in comparison to the robust benefits of a lower LDL target for cardiovascular protection. That said, the investigators comment that the lower LDL observed in their cohort was not likely due to treatment with cholesterol-lowering therapies—as only 2% of included patients were on therapy—and the effect persisted after exclusion of these patients, although these results are not shown. As Dr. Schiele also indicates, the investigators did not report on whether lipid-lowering therapy in the small number of treated patients influenced the effect on ICH. Unfortunately, as this was a large community-based cohort, statin use was not specifically collected. Therefore, any analysis estimating the effect of statin use on ICH could not be performed. Wenqin Guo also comments on the controversial nature of these findings, referencing a 2012 meta-analysis of 31 randomized clinical trials evaluating outcomes of patients randomized to statins, which concluded that there was no relationship between statin use and ICH. Drs. Sampietro et al. also caution the interpretation of the findings in this report and encourage clinicians to consider alternative lipid-lowering therapies—such as PCSK-9 inhibitors—which have not been shown to increase the risk of ICH. Although the results of this observational study add to our understanding of the relationship between lower serum LDL levels and the risk of an index ICH event, and are applauded by Noda and Iso in their comment, there is universal agreement that the clinical relevance of this small risk should be weighed against the large benefit of lipid-lowering therapies in at-risk populations. In their community-based cohort study including more than 96,000 patients over a 9-year period, Drs. Ma and colleagues sought to validate the relationship between very-low-density lipoprotein (LDL) levels and intracerebral hemorrhage (ICH). Compared with patients with a cumulative average LDL of ≥70 mg/dL, those with an average LDL of 50–69 mg/dL were at significantly greater risk of experiencing a primary ICH (odds ratio [OR] 1.65, 95% confidence interval [CI] 1.32–2.05); in addition, patients with an average LDL <50 mg/dL were at even greater risk (OR 2.69, 95% CI 2.03–3.57). Although these relative estimates may appear concerning, the low overall event rate may attenuate the absolute clinical risk, as summarized by Drs. Lima and Fraiman in their response. With only 768 events over 9 years, the absolute increase in ICH risk is approximately 0.0015 events/person/year, which may pale in comparison to the robust benefits of a lower LDL target for cardiovascular protection. That said, the investigators comment that the lower LDL observed in their cohort was not likely due to treatment with cholesterol-lowering therapies—as only 2% of included patients were on therapy—and the effect persisted after exclusion of these patients, although these results are not shown. As Dr. Schiele also indicates, the investigators did not report on whether lipid-lowering therapy in the small number of treated patients influenced the effect on ICH. Unfortunately, as this was a large community-based cohort, statin use was not specifically collected. Therefore, any analysis estimating the effect of statin use on ICH could not be performed. Wenqin Guo also comments on the controversial nature of these findings, referencing a 2012 meta-analysis of 31 randomized clinical trials evaluating outcomes of patients randomized to statins, which concluded that there was no relationship between statin use and ICH. Drs. Sampietro et al. also caution the interpretation of the findings in this report and encourage clinicians to consider alternative lipid-lowering therapies—such as PCSK-9 inhibitors—which have not been shown to increase the risk of ICH. Although the results of this observational study add to our understanding of the relationship between lower serum LDL levels and the risk of an index ICH event, and are applauded by Noda and Iso in their comment, there is universal agreement that the clinical relevance of this small risk should be weighed against the large benefit of lipid-lowering therapies in at-risk populations.