Few of Those Most at Risk Receive Powerful Cholesterol Drugs, and Most Can’t Meet Targets, Study Finds

A new study finds that less than a fifth of very high-risk cardiovascular patients across 18 European countries are meeting their cholesterol goals based on current guidelines, and there’s a simple reason—only a fraction of them take the right medication to meet the targets.

The study, called DA VINCI, reviewed how lipid-lowering therapies were used in both primary and specialty care, and whether patients were able to achieve cholesterol-reduction goals based on European guidelines: those of the European Atherosclerosis Society (EAS) and the European Society of Cardiology (ESC).

Results from DA VINCI were presented early Friday at the opening of the ESC Congress 2020, being presented in a virtual format. Findings were simultaneously published in the European Journal of Preventive Cardiology.

Study authors from the United Kingdom’s Imperial School of Public Health say their findings show that physicians in Europe are not following clinical guidelines in everyday practice, and that even when patients receive optimal doses of statins, those who are most at risk still need other non-statin lipid-lowering therapy to meet cholesterol targets.

“In order to tackle the burden of cardiovascular disease, a global approach is needed,” Kausik Ray, MD, MPhil, of the Imperial School and the study’s lead author, said in a statement. “After diet and lifestyle, cholesterol lowering with medications is a key approach to lowering risk of heart disease and strokes. Based on trial data, we have compelling evidence that lower cholesterol levels benefit those at highest risk particularly.”

EAS/ESC guidelines classify as “very high risk” those persons with one of the following:

• Documented atherosclerotic cardiovascular disease (ASCVD), a condition caused by plaque buildup on the arterial walls, which is a leading risk factor for heart attacks or strokes;
• Those with diabetes with target organ damage;
• Patients with familial hypercholesterolemia with ASCVD or another risk factor; or
• Patients with severe chronic kidney disease.

In 2016, the EAS/ESC goal for low-density lipoprotein (LDL) cholesterol among very high-risk patients was <1.8 mmol/L (<70 mg/dL). In 2019, the standard was changed, calling for very high risk patients to reduce their LDL cholesterol by at least 50% and to achieve a more rigorous goal of <1.4 mmol/L, or <55 mg/dL; patients at high risk were given the target of <1.8 mmol/L (<70 mg/dL).

The new guideline, set at last year’s ESC meeting in Paris, came with the advice, “There is no lower limit of LDL cholesterol that is known to be unsafe.”

To achieve this new target, the guidelines called for making statins and other drugs more widely available. This would include combinations with ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, the latter having come to market with great fanfare but lukewarm uptake, after health systems and payers in Europe and the United States balked at their cost.

According to a 2019 statement from ESC, “The addition of a PCSK9 inhibitor is recommended in patients at very high risk who are not achieving treatment goals on a maximum tolerated dose of a statin and ezetimibe.”

Two PCSK9 inhibitors, evolocumab (Repatha, Amgen) and alirocumab (Praluent, Sanofi and Regeneron) were approved by FDA and European regulators in 2015, after clinical trials showed an ability to reduce LDL cholesterol up to 60% by targeting the PCSK9 enzyme—preventing its ability to stymie the liver from filtering cholesterol out of the blood.

But in both the United States and in Europe, only a sliver of the patients that cardiologists thought would use PCSK9 inhibitors could gain access, due to prices that started at $14,500 in the United States and ranged from $6700 to $12,000 in Europe. In Europe, evolocumab gained an expanded indication in 2018, and alirocumab countered with an indication based on the ODYSSEY Outcomes trial in 2019, but sales never reached initial expectations.

Over time, manufacturers have redesigned pricing programs worldwide, and in the United States the price is around $5850. Nonetheless, DA VINCI found that less than 10% of very-high risk patients in Europe receive some form of combination therapy; with only 9% receiving ezetimibe and just 1% receiving PCSK9 inhibitors.

For the study, investigators examined data from 5888 patients, including 2794 who met the criteria for ASCVD. Of those with ASCVD, 1036 (37%) also had peripheral artery disease (PAD), a circulatory problem that causes poor blood flow to the limbs and puts patients at risk for lower limb amputation. The mean age of the patients was 69.

Patients had a variety of comorbidities and health risks, including diabetes (46%), hypertension (78%), smoking (77%), coronary vascular disease (26%), and cerebrovascular disease (12%).

Investigators found:

• About half the patients with PAD were taking a moderate intensity statin (497 of 1036, or 48%), and 421 were taking a high-intensity statin (41%).
• Among the PAD patients, 818 (73%) had a treatment-stabilized low-density lipoprotein (LDL) cholesterol measurement, with a median of 2.20 mmol/L.
• Only 40% met the 2016 LDL cholesterol target of 1.8 mmol/L (326 of 818)
• Just 19% (159/818) meeting the 2019 target of 1.4 mmol/L

Ray said that bringing the very high risk group from an average of 2.20 mmol/L to below 1.4 mmol/L could create relative risk reductions of 11% in cardiovascular events and 5% in mortality. But this will not happen without combination therapy, he said.

“We need to think about cholesterol the same way we look at blood pressure, where often combinations of treatments are needed to optimize targets,” Ray said.

Amgen, the maker of evolocumab, funded the study.

Reference

Ray KK, Tepie MF, Catapano AL, et al. EU-wide cross-sectional observational study of lipid-modifying therapy use in secondary and primary care: the DA VINCI study. Eur J Preven Cardiol. Published online August 28, 2020.