Is there a shift from cardiovascular to cancer death in lipid-lowering trials? A systematic review and meta-analysis.

BACKGROUND: Lipid-lowering therapy (LLT) reduces cardiovascular (CV) events, but data are conflicting on all-cause mortality, especially among older adults. Though LLT does not induce cancer, some randomized clinical trials (RCTs) found a pattern of increased cancer death under LLT. Our objective was to assess a possible shift from CV to cancer death in LLT trials (i.e. an increase in cancer and decrease in CV death) and to investigate potential subgroups at risk. METHODS: We performed a systematic review and meta-analysis. We retrieved RCTs from MEDLINE, Embase, and Cochrane Central until 08/2023. We extracted the number of CV and cancer deaths in the treatment vs. in the control arm, calculated the relative risk (RR) by dividing the risk of death in the treatment over the risk of death in the control group and then pooled them using random-effect meta-analysis. We performed subgroup analyses on primary and secondary prevention, and according to different age cut-offs. RESULTS: We included 27 trials with 188'259 participants (23 statin; 4 ezetimibe trials). The trials reported 4056 cancer deaths, 2061 under LLT and 1995 in control groups. Overall, there was no increased risk of cancer mortality (RR 1.03, 95% confidence interval 0.97-1.10), with no difference between primary and secondary prevention. In the subgroup analyses for RCTs with ≥15% of participants aged ≥75 years, the RR of cancer death was 1.11 (1.00-1.23), while the RR for CV death was 0.96 (0.91-1.01). For RCTs with a mean age ≥ 70 years, the RR for cancer death was 1.21 (0.99-1.47). CONCLUSION: LLT does not lead to a shift from CV to cancer death. However, there might be a possible shift with a pattern of increased cancer deaths in trials with more older adults, particularly ≥75 years. Individual participant data from LLT trials should be made public to allow further investigations. PROSPERO REGISTRATION: CRD42021271658.

Lipid-Lowering Therapy and Risk of Hemorrhagic Stroke: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: There is debate over whether statins increase risk of hemorrhagic stroke, so we assessed current evidence, including data from new statin trials and trials of nonstatin low-density lipoprotein-cholesterol (LDL-C)- and triglyceride-lowering therapies. METHODS AND RESULTS: We performed a systematic review of large randomized clinical trials (≥1000 patients with ≥2 years follow-up) of LDL-C-lowering therapy (statin, ezetimibe, and PCSK-9 [proprotein convertase subtilisin/kexin type 9] inhibitor) and triglyceride-lowering therapy (omega-3 supplements and fibrate) that reported hemorrhagic stroke as an outcome. We searched MEDLINE, Embase, and Cochrane Library up to July 2, 2021 and updated a meta-analysis of cardiovascular statin trials published in 2012. Among our several subgroup analyses, we looked at difference depending on stroke status and also depending on age. We identified 37 trials for LDL-C lowering (284 301 participants) and 11 for triglyceride lowering (120 984 participants). Overall, we found a higher risk of hemorrhagic stroke for LDL-C lowering, risk ratio (RR) 1.16 (95% CI, 1.01-1.32, P=0.03). For statins (33 trials, 216 258 participants), RR=1.17 (95% CI, 1.01-1.36); for PCSK-9 inhibitors (2 trials, 46 488 participants), RR=0.86 (95% CI, 0.43-1.74); and for ezetimibe (2 trials, 21 555 participants), RR=1.14 (95% CI, 0.64-2.03). In statin trials of patients with previous stroke/transient ischemic attack, RR was 1.46 (95% CI, 1.05-2.04), and in trials with mean age ≥65 years old, RR=1.34 (95% CI, 1.04-1.73) (Pint=0.14 and Pint=0.23 respectively); for triglyceride lowering (11 trials, 120 984 participants), RR=1.05 (95% CI, 0.86-1.30). CONCLUSIONS: We found evidence for a small increased risk of hemorrhagic stroke events with LDL-C-lowering therapies but no clear evidence for triglyceride-lowering therapies. REGISTRATION: URL: https://www.crd.york.ac.uk/prospero; Unique identifier: CRD42021275363.

Omega-3 Fatty Acids and Markers of Thrombosis in Patients with Atrial Fibrillation.

Omega-3 fatty acids (n-3 FAs) are associated with a lower risk of ischemic stroke in patients with atrial fibrillation (AF). Antithrombotic mechanisms may in part explain this observation. Therefore, we examined the association of n-3 FAs with D-dimer and beta-thromboglobulin (BTG), markers for activated coagulation and platelets, respectively. The n-3 FAs eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), docosapentaenoic acid (DPA) and alpha-linolenic acid (ALA) were determined via gas chromatography in the whole blood of 2373 patients with AF from the Swiss Atrial Fibrillation cohort study (ClinicalTrials.gov Identifier: NCT02105844). In a cross-sectional analysis, we examined the association of total n-3 FAs (EPA + DHA + DPA + ALA) and the association of individual fatty acids with D-dimer in patients with detectable D-dimer values (n = 1096) as well as with BTG (n = 2371) using multiple linear regression models adjusted for confounders. Median D-dimer and BTG levels were 0.340 ug/mL and 448 ng/mL, respectively. Higher total n-3 FAs correlated with lower D-dimer levels (coefficient 0.94, 95% confidence interval (Cl) 0.90-0.98, p = 0.004) and lower BTG levels (coefficient 0.97, Cl 0.95-0.99, p = 0.003). Likewise, the individual n-3 FAs EPA, DHA, DPA and ALA showed an inverse association with D-dimer. Higher levels of DHA, DPA and ALA correlated with lower BTG levels, whereas EPA showed a positive association with BTG. In patients with AF, higher levels of n-3 FAs were associated with lower levels of D-dimer and BTG, markers for activated coagulation and platelets, respectively. These findings suggest that n-3 FAs may exert antithrombotic properties in patients with AF.