Initial Treatment with Dual Statin + Ezetimibe Cuts All-Cause Mortality by 50%: New Meta-Analysis
The reductions observed in all-cause mortality (49%) and MACE (39%) in high-risk patients compared with statin monotherapy could be practice changing, researchers said.
The largest analysis of its kind to date, involving more than 108 000 adults at high-risk for myocardial infarction or stroke, found that initiating treatment with a combination of a statin and the cholesterol absorption inhibitor ezetimibe to reduce LDL cholesterol significantly reduced the risk of death and major adverse cardiovascular events (MACE) compared with initial treatment with high-dose statins alone.1
Published in Mayo Clinic Proceedings, the meta-analysis included 14 studies (11 randomized controlled trials, 3 cohort studies) with 108,373 high- or very-high risk adults with a mean age of 67.5 years, according to the study.1 The pooled analysis demonstrated a significant 19% reduction in all-cause mortality (OR, 0.81; 95% CI, 0.67 to 0.97; P =.02), an 18% reduction in MACE (OR, 0.82; 95% CI, 0.69 to 0.97; P =.02), and 17% reduction in stroke (OR, 0.83; 95% CI, 0.75 to 0.91; P <.001) when combination therapy vs monotherapy was used. The effect of the dual therapy on CV mortality, however, did not reach statistical significance (OR, 0.86; 95% CI, 0.65 to 1.12; P =.26) when compared with statin monotherapy, authors reported.1
First author Maciej Banach, MD, PhD, Professor of Cardiology at the John Paul II Catholic University of Lublin, Poland, who also leads the International Lipid Expert Panel and the Blood Pressure Meta-analysis Collaboration group that carried out the study, and his colleagues also reported that the addition of ezetimibe to a high-dose statin reduced LDL-C levels from baseline by an additional ~13 mg/dL compared to statins alone (mean difference, −12.96 mg/dL; 95% CI, −17.27 to −8.65; P <.001) and increased the likelihood of achieving the the guideline-recommended LDL-C target (less than 70 mg/dL) by 85%.1
Banach and the international team also conducted a network meta-analysis, enabling direct comparison of the different therapy regimens represented. The results further strengthened their overall findings, showing a 49% reduction in all-cause mortality and a 39% decrease in MACE with combination therapy compared to high-dose statins alone, according to a statement.2
“The combination therapy is safe and efficacious; the risk of adverse events and the therapy discontinuation rate was comparable between groups. In the network meta-analysis, we showed a significant 44% reduction in the risk of discontinuation in those treated with moderately high dose statin therapy plus ezetimibe versus a high dose statin alone,” Banach said in the statement.2
Clinical Implications
Evidence for the value of immediate combination cholesterol-lowering therapy as primary prevention for adults at high CV risk has been inconsistent, according to the statement. Traditionally initial therapy for these patients has been with a high-dose statin, with ezetimibe added only if LDL-C levels remain high after 2 months. However, findings from the meta-analysis challenge the protocol and suggest a reconsideration. One study co-author supports a strong reconsideration.
“This study confirms that combined cholesterol lowering therapy should be considered immediately and should be the gold standard for treatment of very high-risk patients after an acute cardiovascular event,” Peter Toth, MD, PhD, professor of clinical family and community medicine, University of Illinois, and adjunct associate professor of medicine at Johns Hopkins University, said in the statement.
“This study confirms that combined cholesterol lowering therapy should be considered immediately and should be the gold standard for treatment of very high-risk patients after an acute cardiovascular event.”
“Simply adding ezetimibe to statin therapy, without waiting for at least two months to see the effects of statin monotherapy, which is suboptimal in many patients, is associated with more effective LDL-C goal achievement and is responsible for significant incremental reductions in cardiovascular health problems and deaths.”
Toth also stressed the economic feasibility of the approach, noting there is no additional funding or reimbursement of new therapies required. “In fact, it may translate into lower rates of first and subsequent heart attacks and stroke, and their complications like heart failure, which are extremely costly for all healthcare systems.”
Opportunity for Population Health
According to data from the Global Burden of Disease and the American Heart Association, global deaths occurring as a result of high LDL-C alone reached 4.5 million in 2020. Given that CVD overall claims 20 million lives annually worldwide, implementing this strategy in clinical practice could prevent over 330,000 deaths per year, including nearly 50,000 in the US alone.3,4
“Forthcoming guidelines should consider the lipid-lowering combination therapy as early as possible, preferably up-front, for more effective LDL-C goal achievement and significant reduction of cardiovascular disease outcomes and mortality in high- and very high-risk patients,” Banach and team concluded.1 "The sooner we lower LDL-C effectively, the better the outcomes. Early and aggressive lipid-lowering therapy should be the norm, not the exception."2
