A number of landmark clinical studies on lipid lowering and cardiovascular health have been published, shaping how patients are treated.
More than 73 million American adults have high levels of low-density lipoprotein (LDL), also known as “bad cholesterol," according to the CDC.
Of these, the CDC estimates that fewer than half are receiving treatment to lower their levels. Alarmingly, statistics show that people with high total cholesterol have about twice the risk of heart disease as people with ideal levels, while 1 of every 3 deaths in the United States are caused by heart disease, stroke, and other cardiovascular diseases.
Over the years, a number of landmark clinical studies on lipid lowering and cardiovascular health have been published, shaping patients are treated. In Part 1, we covered 5 studies that every pharmacist should know about. In this article we will cover 5 additional studies.
6. 4S (1994)1
Hyperlipidemia was first identified as a risk factor for coronary artery disease (CAD) in the early 1960s; however, drug therapy for hypocholesteremia had remained controversial for decades due to insufficient evidence for improved survival. Following the introduction of statins in the 1980s several studies, including 4S, began evaluating the effect of cholesterol lowering with statins on mortality and morbidity in patients with coronary heart disease (CHD).
A total of 4,444 patients with CAD and hyperlipidemia were randomized to receive simvastatin or placebo. After a median follow-up of 5.4 years the trial was stopped early due to a significant 30% relative risk reduction in all-cause mortality with the simvastatin group versus placebo (11.5% vs 8.2%; p=0.0003).
7. MIRACL (2001)2
By the early 2000s statins had been widely regarded as a long-term strategy to reduce the risk of death and ischemic cardiovascular events in patients with stable CHD. Previous trials however, had excluded patients with recent unstable angina or acute myocardial infarction (MI) despite the fact that the early period after an acute coronary syndrome (ACS) is associated with the highest rate of death and recurrent ischemic events. MIRACL was conducted to determine whether initiation of a statin after an ACS can reduce the occurrence of early events.
The study was a randomized, double-blind trial conducted at 122 clinical centers across the world. A total of 3086 adults aged 18 years or older with a recent hospitalization for unstable angina/NSTEMI were randomized to receive either atorvastatin 80mg or placebo daily. At 16 weeks, there was found to be a statistically significant 16% reduction in the occurrence of the primary endpoint with atorvastatin compared to placebo (14.8% vs 17.4%; RR=0.84; p=0.048). High-dose atorvastatin would later be studied against moderate-dose pravastatin in the PROVE-IT study.
8. SEARCH (2010)3
Lowering of LDL cholesterol has been shown to reduce major vascular events, but whether more intensive therapy safely produces additional benefit was uncertain. Therefore, the SEARCH trial was conducted to further delve into the efficacy and safety of more intensive LDL-cholesterol-lowering therapy.
The study was designed as a double-blind, randomized trial in over 12,000 individuals aged 18-80 with a history of MI. Participants were randomized to simvastatin 80mg or 20mg daily and followed up for a mean 6.7 years. Analysis of the data revealed a 6% reduction in major vascular events in those allocated to the higher strength of simvastatin although it did not reach statistical significance (24.5% vs 25.7%; HR=0.94; p=0.10). Despite a higher rate of myopathy in the simvastatin 80mg group, there were no major differences in the rate of serious side effects. In June 2011, the FDA issued a safety alert to limit use of simvastatin 80mg due to increased risk of myopathy.
9. AIM-HIGH (2011)4
High-density lipoprotein (HDL) cholesterol has been shown to be an independent predictor of the risk of CHD, with a strong inverse association between HDL cholesterol levels and the rates of CHD events. Several preliminary studies had suggested addition of niacin could improve cardiovascular outcomes in high risk patients; however, well-designed studies were lacking. AIM-HIGH was conducted to further assess whether niacin added to intensive statin therapy, as compared with statin therapy alone, would reduce the risk of cardiovascular events in patients with established ASCVD and dyslipidemia.
A total of 3414 patients were randomly assigned in a 1:1 ratio to receive extended-release niacin or placebo. All patients received simvastatin plus ezetimibe, if needed, to maintain an adequate LDL level. At 2 years, niacin therapy had significantly increased the median HDL cholesterol level from 35 mg/dL to 42 mg/dL, and lowered triglyceride and LDL levels. Despite this, there was no difference in occurrence of the primary endpoint, a composite of cardiovascular events (16.4% in niacin group vs 16.2% with placebo; HR=1.02; p=0.79). A higher percentage of patients discontinued treatment in the niacin group (20.1% vs 25.4%) which was driven due to higher rates of flushing or itching.
10. FOURIER (2017)5 and ODYSSEY OUTCOMES (2018)6
In 2015, the FDA approved alirocumab (Praluent) and evolocumab (Repatha), cholesterol-lowering treatment in a new class of drugs known as PCSK9 inhibitors. Initial studies demonstrated significant reductions in LDL levels ranging from 39 to 59%; however long-term clinical outcomes were not initially known.
In the FOURIER trial of more than 27,000 individuals receiving statin therapy, evolocumab significantly reduced the risk of the primary end point, a composite of cardiovascular outcomes, as compared to placebo (9.8% vs 11.3%; HR=0.80; p<0.001). ODYSSEY OUTCOMES enrolled nearly 19,000 individuals and found that after a median follow-up of 2.8 years, there was a reduction in the primary endpoint in those treated with alirocumab as compared to placebo (9.5% vs 11.1%; HR=0.85; p<0.001). In both trials, therapy was relatively well-tolerated and no new major safety concerns were noted.