In the Journals

FOURIER: Very low LDL concentrations reduce risk for CV events

Robert Giugliano
Robert P. Giugliano

Patients who achieved LDL levels of less than 0.2 mmol/L with PCSK9 inhibitors had decreased risk for recurrent CV events, according to a secondary analysis of the FOURIER trial published in The Lancet.

Robert P. Giugliano, MD, associate professor at Harvard Medical School, and colleagues analyzed data from 25,982 patients from the FOURIER trial aged 40 to 85 years with stable atherosclerotic CVD who were considered high risk due to additional risk factors. Patients in this analysis had LDL measurements at 4 weeks and did not have any of the endpoints at that time. The group had LDL concentrations of at least 1.8 mmol/L and non-HDL concentrations of at least 2.6 mmol/L with lipid-lowering treatment.

Randomization in FOURIER

Patients were assigned either 140 mg every 2 weeks or 420 mg once per month of subcutaneous evolocumab (Repatha, Amgen) or matching placebo injections. Follow-up visits were conducted for a median of 2.2 years, which included blood specimens, lipid concentrations and LDL measurements.

The primary endpoint was the composite of MI, CV death, coronary revascularization, stroke or hospital admission for unstable angina. The key secondary endpoint was defined as a composite of MI, stroke or CV death. Ten prespecified safety endpoints were also reviewed, including adverse events leading to drug discontinuation and non-CV death.

At 4 weeks, 10% of patients had an LDL less than 0.5 mmol/L, 31% had an LDL between 0.5 mmol/L and 1.3 mmol/L, 13% had an LDL between 1.3 mmol/L and 1.8 mmol/L, 29% of patients achieved an LDL between 1.8 mmol/L and 2.6 mmol/L and 17% of patients had an LDL at or above 2.6 mmol/L.

 

Researchers observed a significant monotonic relationship between low LDL concentrations and the reduced risk for primary (P = .0012) and secondary (P = .0001) composite endpoints that extended to patients who achieved LDL concentrations less than 0.2 mmol/L.

Achieved LDL concentrations were not associated with all serious adverse events or the prespecified safety events.

Effects of LDL lowering

“These data support the use of intensive lipid-lowering therapies to prevent recurrent [CV] events in high-risk patients and suggest that a lower target LDL cholesterol than recommended in current guidelines (eg, < 0.5 mmol/L) can safely be considered for the highest-risk patients,” Giugliano and colleagues wrote.

“Collectively, this body of evidence heralds the transition from a concept of the ‘lower the better’ towards LDL-cholesterol eradication,” G. Kees Hovingh, of the department of vascular medicine at University of Amsterdam Academic Medical Center, and colleagues wrote in a related editorial. “For clinicians who prescribe PCSK9 inhibitors, however, the findings from the FOURIER trial, with regards to the potential adverse events, are of even greater importance. Having been trained to first, do no harm, many physicians might wonder whether they would infringe this idea by prescribing PCSK9 inhibitors.”

The results were also presented at the European Society of Cardiology Congress. – by Darlene Dobkowski

Disclosure: The study was funded by Amgen. Giugliano reports he receives grants from Amgen, Daiichi Sankyo and Merck and personal fees from Amarin, American College of Cardiology, Amgen, Angel Med, Beckman-Coulter, Boehringer Ingelheim, Bristol-Myers Squibb, CVS Caremark, Daiichi-Sankyo GlaxoSmithKline, Janssen, Lexicon, Merck, Portola, Pfizer, Regeneron, Sanofi-Aventis, St. Jude and Stealth Peptides. Hovingh reports he serves in advisory boards for Amgen, Regeneron and Sanofi Aventis and receives lecture fees from Amgen, Pfizer, Regeneron and Sanofi Aventis. Please see the full study for a list of the other authors’ relevant financial disclosures.

Robert Giugliano
Robert P. Giugliano

Patients who achieved LDL levels of less than 0.2 mmol/L with PCSK9 inhibitors had decreased risk for recurrent CV events, according to a secondary analysis of the FOURIER trial published in The Lancet.

Robert P. Giugliano, MD, associate professor at Harvard Medical School, and colleagues analyzed data from 25,982 patients from the FOURIER trial aged 40 to 85 years with stable atherosclerotic CVD who were considered high risk due to additional risk factors. Patients in this analysis had LDL measurements at 4 weeks and did not have any of the endpoints at that time. The group had LDL concentrations of at least 1.8 mmol/L and non-HDL concentrations of at least 2.6 mmol/L with lipid-lowering treatment.

Randomization in FOURIER

Patients were assigned either 140 mg every 2 weeks or 420 mg once per month of subcutaneous evolocumab (Repatha, Amgen) or matching placebo injections. Follow-up visits were conducted for a median of 2.2 years, which included blood specimens, lipid concentrations and LDL measurements.

The primary endpoint was the composite of MI, CV death, coronary revascularization, stroke or hospital admission for unstable angina. The key secondary endpoint was defined as a composite of MI, stroke or CV death. Ten prespecified safety endpoints were also reviewed, including adverse events leading to drug discontinuation and non-CV death.

At 4 weeks, 10% of patients had an LDL less than 0.5 mmol/L, 31% had an LDL between 0.5 mmol/L and 1.3 mmol/L, 13% had an LDL between 1.3 mmol/L and 1.8 mmol/L, 29% of patients achieved an LDL between 1.8 mmol/L and 2.6 mmol/L and 17% of patients had an LDL at or above 2.6 mmol/L.

 

Researchers observed a significant monotonic relationship between low LDL concentrations and the reduced risk for primary (P = .0012) and secondary (P = .0001) composite endpoints that extended to patients who achieved LDL concentrations less than 0.2 mmol/L.

Achieved LDL concentrations were not associated with all serious adverse events or the prespecified safety events.

Effects of LDL lowering

“These data support the use of intensive lipid-lowering therapies to prevent recurrent [CV] events in high-risk patients and suggest that a lower target LDL cholesterol than recommended in current guidelines (eg, < 0.5 mmol/L) can safely be considered for the highest-risk patients,” Giugliano and colleagues wrote.

“Collectively, this body of evidence heralds the transition from a concept of the ‘lower the better’ towards LDL-cholesterol eradication,” G. Kees Hovingh, of the department of vascular medicine at University of Amsterdam Academic Medical Center, and colleagues wrote in a related editorial. “For clinicians who prescribe PCSK9 inhibitors, however, the findings from the FOURIER trial, with regards to the potential adverse events, are of even greater importance. Having been trained to first, do no harm, many physicians might wonder whether they would infringe this idea by prescribing PCSK9 inhibitors.”

The results were also presented at the European Society of Cardiology Congress. – by Darlene Dobkowski

Disclosure: The study was funded by Amgen. Giugliano reports he receives grants from Amgen, Daiichi Sankyo and Merck and personal fees from Amarin, American College of Cardiology, Amgen, Angel Med, Beckman-Coulter, Boehringer Ingelheim, Bristol-Myers Squibb, CVS Caremark, Daiichi-Sankyo GlaxoSmithKline, Janssen, Lexicon, Merck, Portola, Pfizer, Regeneron, Sanofi-Aventis, St. Jude and Stealth Peptides. Hovingh reports he serves in advisory boards for Amgen, Regeneron and Sanofi Aventis and receives lecture fees from Amgen, Pfizer, Regeneron and Sanofi Aventis. Please see the full study for a list of the other authors’ relevant financial disclosures.