Pooled RCTs: Lowering LDL-C levels using statins reduces major vascular events in all age groups

Abstract

Question What is the effectiveness of statin therapy for reducing major vascular events (MVEs) in different patient age groups? Scope Included studies evaluated statin therapy, had 1 intervention intended to lower low-density lipoprotein cholesterol (LDL-C) levels but not specifically affect other risk factors, enrolled 1000 patients, and had scheduled treatment duration 2 years. Outcomes included MVEs (major coronary event [nonfatal myocardial infarction or coronary death], coronary revascularization, or stroke). Methods 28 randomized controlled trials (RCTs) (n =186854, mean age 63 y, 72% men, mean LDL-C level 3.3 mmol/L, 56% with a history of vascular disease) met inclusion criteria: 27 provided individual patient data, and 1 had detailed summary data. 4 additional eligible trials (n =9264, all with vascular disease) were excluded because data were not available. 23 RCTs compared statin-based therapy with placebo or usual care (n =147242), and 5 compared more- with less-intensive statin therapy (n =39612). Main results The main results are in the Table. Conclusion Lowering low-density lipoprotein cholesterol levels with statin therapy reduces risk for major vascular events, regardless of age at baseline. Meta-analysis of statin therapy vs control (placebo or usual care) or more- vs less-intensive statin therapy* Outcomes Age groups (% of patients) Annual event rates At a median 4.9 y RRR (95% CI) per 1.0 mmol/L (39 mg/dL) reduction in LDL-C P value for trend by age Major vascular event All 3.0% vs 3.7% 21% (19 to 23) 0.06 Major coronary event All 1.4% vs 1.7% 24% (21 to 27) 0.009 Coronary revascularization All 1.4% vs 1.8% 25% (22 to 27) 0.6 Stroke All 0.6% vs 0.7% 16% (11 to 20) 0.7 RRR (99% CI) per 1.0 mmol/L (39 mg/dL) reduction in LDL-C Major vascular event 55 y (21%) 2.7% vs 3.4% 25% (19 to 30) 56 to 60 y (17%) 2.6% vs 3.2% 20% (13 to 26) 61 to 65 y (20%) 2.8% vs 3.5% 20% (14 to 26) 66 to 70 y (20%) 3.0% vs 3.9% 24% (18 to 29) 71 to 75 y (15%) 3.8% vs 4.5% 19% (12 to 26) >75 y (7.8%) 4.5% vs 5.0% 13% (1 to 23) *LDL-C = low-density lipoprotein cholesterol; other abbreviations defined in Glossary. Data were analyzed using an intention-to-treat approach. RRR and CI calculated from data in article based on individual patient data for 27 trials and detailed summary data for 1 trial. Major coronary events, coronary revascularization, or stroke. RRR decreased with age. Commentary Although there is compelling evidence supporting the use of statins for secondary prevention (1), their role in primary prevention for the oldest patients is debatable. This is reflected in inconsistencies in lipid management guidelines internationally (2) and in opinions on statins as a target for deprescribing in later life (3). The Cholesterol Treatment Trialists Collaboration analyzed mainly individual patient data from 186854 patients in statin trials, including >14000 patients who were >75 years of age. This is probably the largest (albeit subgroup) sample of randomized data on statins for this age group. In the secondary prevention analyses, the best estimate of absolute risk reduction for MVEs with statins in patients >75 years of age suggests a number needed to treat of 125 over 1 year. However, in the primary prevention analyses, there was a trend toward smaller (and eventually nonsignificant) relative risk reductions in MVEs with statins as age increased. In addition, statin use in persons >75 years of age did not show benefits for any measures of mortality. It is unclear whether there is a true interaction with age or simply a lack of statistical power in the oldest subgroups. Although chronological age is an important consideration, biological age and individual patient context are essential for personalized decision making. The probability and magnitude of benefit differ for an active 76-year-old person who had a myocardial infarction compared with a frail institutionalized 80-year-old person without known vascular disease. Decisions about statin use for the oldest patients need to consider net benefit. This requires 1) meta-analyses of drug-related harm and other patient-important outcomes (e.g., quality of life, function); 2) direct evidence from primary prevention trials (pending completion of the STAREE trial, NCT02099123); 3) consideration of whether there is time to benefit from statins based on estimated life expectancy; and 4) judgments on whether the absolute benefits (0.5%/y for MVEs) are meaningful to patients and consistent with their values and preferences.