Combination therapy could prevent thousands of cardiovascular deaths

The largest analysis to examine the best way to lower levels of 'bad' cholesterol in patients with blocked arteries shows that they should immediately be given a combination of a statin and another drug called ezetimibe, rather than statins alone. This could prevent thousands of deaths a year from heart attacks, strokes and other cardiovascular diseases.

The meta-analysis of 108,353 patients in 14 studies who were at very high risk of suffering heart attack or stroke, or who had already suffered one of these cardiovascular events is published in the journal Mayo Clinic Proceedings. It shows that when ezetimibe was combined with a high dose statin to reduce levels of low density lipoprotein cholesterol (LDL-C), there was a significant 19% reduction in the risk of death from any cause, a 16% reduction in deaths from cardiovascular causes, and a significant reduction in the incidence of major adverse cardiovascular events or stroke by 18% and 17% respectively, compared to high doses of statins alone.

The combination therapy also significantly reduced LDL-C levels by an extra 13mg per decilitre (dL) of blood compared to statins alone, measured from the baseline – the time at which the patient first started the treatment. This increased the chances of reaching the ideal goal of less than 70mg/dL of LDL-C by 85%.

"These results were even more pronounced in the network meta-analysis, which enables a direct comparison of different therapy regimens used in the study. This showed a 49% reduction in all-cause mortality and a 39% reduction in major adverse cardiovascular events, when compared to high dose statin therapy alone," said the first author of the study, Maciej Banach, Professor of Cardiology at the John Paul II Catholic University of Lublin, Poland, and Adjunct Professor at the Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, who also leads the International Lipid Expert Panel and the Blood Pressure Meta-analysis Collaboration group that carried out the study.

"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."

Until now, there have been inconsistent findings about whether or not combined cholesterol lowering therapy should be given to high risk patients immediately, even before they suffer a heart attack or stroke, or whether doctors should start these patients on a high dose statin first and monitor the effects on cholesterol levels after at least two months before deciding if the patients need ezetimibe as well.

Co-author of the study, Peter Toth, Professor of Clinical Family and Community Medicine, University of Illinois, and Adjunct Associate Professor of Medicine at Johns Hopkins University, USA, said: "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.

"This approach does not require additional funding or reimbursement of new expensive drugs. 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."

According to the data from the Global Burden of Disease and the American Heart Association, deaths occurring as a result of high LDL-C alone are highest in Eastern Europe and Central Asia, and 4.5 million deaths worldwide were attributed to it in 2020.

Cardiovascular disease kills around 20 million people a year worldwide. Based on our previous analysis, we estimate that if combination therapy to reduce LDL-C was included in all treatment guidelines and implemented by doctors everywhere for patients with high cholesterol levels, it would prevent over 330,000 deaths a year among patients who have already suffered a heart attack, and almost 50,000 deaths alone in the USA. We recommend combination therapy should be considered the gold standard of treatment for these patients and included in all future treatment guidelines."

Maciej Banach, Professor of Cardiology, John Paul II Catholic University of Lublin, Poland

Statins have been used safely for years. They help to lower LDL-C by reducing the production of it by the liver. Ezetimibe reduces the amount of cholesterol that the body takes from food by inhibiting the absorption of it in the intestines. Some patients do not respond adequately to statins and are prescribed ezetimibe in combination with a statin. High doses of statins are known as 'high intensity' statins and moderately high doses are known as 'moderate intensity' or 'medium intensity' statins.

Prof. Toth said: "Our findings underline the importance of the adages 'the lower for better for longer' but also the equally important 'the earlier the better' for treating patients at high risk of cardiovascular conditions and to avoid further medical complications and deaths."

A strength of the study is its large size, as it includes the greatest number of patients studied so far. The patients were included in 14 studies, 11 of which were randomised controlled trials and three were cohort studies. Limitations relate mainly to the type of studies that were included in the meta-analysis, including their size and the observational nature of some of them.