Zetia and proprotein convertase subtilisin/kexin type 9 inhibitors may reduce nonfatal myocardial infarction and stroke in adults with high or very high cardiovascular risk, according to findings published in The BMJ.

These adults must also be receiving maximally tolerated statin therapy or are statin-intolerant, according to Safi U. Khan, MD, MS, a cardiovascular outcome researcher and cardiology fellow at Houston Methodist Hospital, and colleagues.

“The absolute cardiovascular benefits of the therapies depend on individuals’ baseline cardiovascular risk,” Khan and colleagues wrote.

As part of a multiprofessional BMJ Rapid Recommendations panel, the researchers conducted a network meta-analysis of 14 randomized controlled trials that assessed Zetia (ezetimibe, Merck) and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. The trials included 83,660 adults on statins. Khan and colleagues evaluated the patients’ level of risk, values and preferences by performing frequentist fixed-effects analyses and grading of recommendations, assessment, development and evaluation (GRADE). This information was used to ascertain the certainty of evidence in the 14 trials. The panel included cardiologists, general practitioners, general internists, endocrinologists, a geriatrician, methodologists and three patient partners. The four effective critical outcomes the panel selected were nonfatal myocardial infarction (MI), nonfatal stroke, all-cause mortality and cardiovascular mortality.

Risk reductions

Overall, evidence from the 14 trials indicated that ezetimibe and PCSK9 inhibitors may benefit high-risk patients. However, the treatments yielded little or no benefit among patients with moderate or low cardiovascular risk, according to Khan and colleagues.

Specifically, adding ezetimibe to statins reduced MI (RR = 0.87; 95% CI, 0.8-0.94) and stroke (RR = 0.82; 95% CI, 0.71-0.96) but not all-cause mortality (RR = 0.99; 95% CI, 0.92-1.06) or cardiovascular mortality (RR = 0.97; 95% CI, 0.87-1.09).

The researchers also reported that adding a PCSK9 inhibitor to statins reduced MI (RR = 0.81; 95% CI, 0.76-0.87) and stroke (RR = 0.74; 95% CI, 0.64-0.85) but not all-cause mortality (RR = 0.95; 95% CI, 0.87-1.03) or cardiovascular mortality (RR = 0.95; 95% CI, 0.87-1.03).

Likely reductions in MI and stroke

Among adults with very high cardiovascular risk, the researchers reported with moderate to high certainty that adding a PCSK9 inhibitor to statins was likely to reduce MI by 16 incidences per 1,000 and stroke by 21 incidences per 1,000. Meanwhile, adding ezetimibe was likely to reduce stroke by 14 incidences per 1,000, and adding ezetimibe to a PCSK9 inhibitor and statins may reduce stroke by 11 incidences per 1,000, according to Khan and colleagues.

The researchers reported with lower certainty that adding a PCSK9 inhibitor to statins and ezetimibe may reduce MI by 14 incidences per 1,000 and stroke by 17 incidences per 1,000 among adults with very high cardiovascular risk.

Among those with high cardiovascular risk, adding a PCSK9 inhibitor probably reduced MI by 12 incidences per 1,000 and stroke by 16 incidences per 1,000 (moderate certainty), the researchers reported. Also, adding a PCSK9 inhibitor to ezetimibe and statins may reduce stroke by 13 incidences per 1,000 (low certainty). These findings were consistent in statin-intolerant patients.

“Prescribing these lipid-lowering agents should be considered among appropriate candidates with very high or high cardiovascular risk patients to achieve desired cardiovascular benefits,” the researchers wrote.