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Evaluating the Association Between Low-Density Lipoprotein Cholesterol Reduction and Relative and Absolute Effects of Statin Treatment A Systematic Review and Meta-analysis

Author/s: 
Byrne, P., Demasi, M., Jones, M., Smith, S. M., O'Brien, K. K., DuBroff, R.

Importance: The association between statin-induced reduction in low-density lipoprotein cholesterol (LDL-C) levels and the absolute risk reduction of individual, rather than composite, outcomes, such as all-cause mortality, myocardial infarction, or stroke, is unclear.

Objective: To assess the association between absolute reductions in LDL-C levels with treatment with statin therapy and all-cause mortality, myocardial infarction, and stroke to facilitate shared decision-making between clinicians and patients and inform clinical guidelines and policy.

Data sources: PubMed and Embase were searched to identify eligible trials from January 1987 to June 2021.

Study selection: Large randomized clinical trials that examined the effectiveness of statins in reducing total mortality and cardiovascular outcomes with a planned duration of 2 or more years and that reported absolute changes in LDL-C levels. Interventions were treatment with statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) vs placebo or usual care. Participants were men and women older than 18 years.

Data extraction and synthesis: Three independent reviewers extracted data and/or assessed the methodological quality and certainty of the evidence using the risk of bias 2 tool and Grading of Recommendations, Assessment, Development and Evaluation. Any differences in opinion were resolved by consensus. Meta-analyses and a meta-regression were undertaken.

Main outcomes and measures: Primary outcome: all-cause mortality. Secondary outcomes: myocardial infarction, stroke.

Findings: Twenty-one trials were included in the analysis. Meta-analyses showed reductions in the absolute risk of 0.8% (95% CI, 0.4%-1.2%) for all-cause mortality, 1.3% (95% CI, 0.9%-1.7%) for myocardial infarction, and 0.4% (95% CI, 0.2%-0.6%) for stroke in those randomized to treatment with statins, with associated relative risk reductions of 9% (95% CI, 5%-14%), 29% (95% CI, 22%-34%), and 14% (95% CI, 5%-22%) respectively. A meta-regression exploring the potential mediating association of the magnitude of statin-induced LDL-C reduction with outcomes was inconclusive.

Conclusions and relevance: The results of this meta-analysis suggest that the absolute risk reductions of treatment with statins in terms of all-cause mortality, myocardial infarction, and stroke are modest compared with the relative risk reductions, and the presence of significant heterogeneity reduces the certainty of the evidence. A conclusive association between absolute reductions in LDL-C levels and individual clinical outcomes was not established, and these findings underscore the importance of discussing absolute risk reductions when making informed clinical decisions with individual patients.

Keywords 
cholesterol Statin Treatment meta-analysis LDL

Omega-3 Fatty Acids and Cardiovascular Disease: Current State of the Evidence

Author/s: 
Balk, Ethan M., Adam, Gaelen P., Langberg, Valerie, Halladay, Christopher, Chung, Mei, Lin, Lin, Robertson, Sarah, Yip, Agustin, Steele, Dale, Smith, Bryant T., Lau, Joseph, Lichtenstein, Alice H., Trikalinos, Thomas A.

Focus of This Summary

This is a summary of a systematic review that evaluated the recent evidence regarding the effects of omega-3 fatty acids (FAs), primarily from marine oil supplements, on clinical and selected intermediate cardiovascular (CV) outcomes (i.e., blood pressure, lipid concentrations) and the association of omega-3 FA dietary intake and biomarkers with CV outcomes. The systematic review included 147 articles published between 2000 and June 2015. Studies that analyzed levels of fish (or other food) consumption without exact quantification of omega-3 FA intake were excluded from this review. This summary is provided to assist in informed clinical decisionmaking. However, reviews of evidence should not be construed to represent clinical recommendations or guidelines.

Background

The first observation of a link between fish consumption and cardiovascular (CV) health was made in the late 1970s in a Greenland Eskimo population. This population exhibited a comparatively low rate of CV mortality and consumed a greater than average amount of fish. Since this original observation, there have been hundreds of studies conducted to evaluate the effect of omega-3 fatty acids (FAs) on cardiovascular disease (CVD), its risk factors, and its biomarkers.

The omega-3 FAs include eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), docosapentaenoic acid (DPA), and alpha-linolenic acid (ALA). These are essential long-chain and very-long-chain polyunsaturated fatty acids that have many physiological effects, including inflammation regulation. EPA, DHA, and DPA are found in fish and other seafood (called dietary marine oils), as well as in supplements prepared from these foods (referred to here as marine oil supplements). ALA is found in walnuts, leafy green vegetables, and oils such as canola, soy, and flaxseed.

An original systematic review of omega-3 FAs was prepared by the Agency for Healthcare and Research Quality in 2004.1,2 Based on the observational studies available at that time, several expert panels suggested that regular consumption of fish and seafood is associated with lower risk of coronary heart disease (CHD) and cardiac death. The recommendations were based on assumptions of benefits from EPA and DHA and their content in fish and seafood.

The current systematic review aimed to update the evidence in light of the more recent literature published on the topic and included both randomized controlled trials (RCTs) and observational studies. Studies that analyzed levels of fish (or other food) consumption without exact quantification of omega-3 FA intake were excluded.

Conclusions

Observational studies suggest possible benefits of dietary intake of marine oils (such as through consumption of fish) for CV death and total stroke (mainly ischemic stroke).

In contrast, there is high strength of evidence (SOE) from RCTs that marine oil supplements do not affect the risk of major adverse cardiac events (MACE), all-cause death, sudden cardiac death, revascularization, or high blood pressure (BP). Marine oil supplements also have no effect on the risk of atrial fibrillation (moderate SOE). Importantly, RCTs focused primarily on marine oil supplements, not on food sources.

Marine oil supplements affect several intermediate outcomes. First, they significantly lower triglycerides (TGs)—possibly having greater effects in higher doses and in people with higher baseline TGs. Second, they cause small increases in both high-density lipoprotein cholesterol (HDL-c) and low-density lipoprotein cholesterol (LDL-c). Finally, marine oil supplements produce small changes in the ratio of total cholesterol to HDL-c (high SOE).

Keywords 
omega-3 fatty acids cholesterol blood pressure
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