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Progress continues in the treatment of atherothrombosis
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BOSTON — Various approaches have been shown to be effective in the treatment of patients with atherothrombosis, according to a presentation at the Cardiometabolic Health Conference.
FOURIER, SPIRE 1 and 2
Marc S. Sabatine, MD, MPH, the Lewis Dexter, MD, Distinguished Chair in Cardiovascular Medicine at Brigham and Women’s Hospital, discussed the details of the FOURIER trial, which analyzed 27,564 patients who were at high risk and had established CVD. Patients were assigned to evolocumab (Repatha, Amgen) or placebo. The evolocumab group had a 59% mean LDL reduction (95% CI, 58-60) vs. placebo and an absolute reduction of 56 mg/dL (95% CI, 55-57). The reduction remained consistent for 4 years, according to the presentation.
The incidence of primary and secondary endpoints such as CV death, fatal and nonfatal MI, and a composite of CV death, stroke or MI was higher in patients assigned placebo vs. evolocumab, which started around 6 months after randomization.
“Even with the reduced exposure, even with attenuation of the lipid lowering, it’s still a significant reduction in cardiovascular outcomes. I think the data fit very nicely,” Sabatine said.
In studies that analyzed simvastatin or pravastatin, the benefit on mortality was not evident early in the trial, even when it was the primary endpoint, according to the presentation.
A landmark analysis showed that the evolocumab group had a 16% relative risk reduction at 12 months (HR = 0.84; 95% CI, 0.74-0.96) and 25% relative risk reduction at 36 months (HR = 0.75; 95% CI, 0.66-0.85) compared with placebo.
Overall safety and neurocognitive assessments were similar in both groups.
Patients in the evolocumab group who had a baseline LDL less than 70 mg/dL had a 66% mean LDL reduction and a median of 0.5 mmol/L vs. the placebo group.
The SPIRE 1 and SPIRE 2 trials compared 150 mg bococizumab (Pfizer) every 2 weeks with placebo in patients who had a CV event or were at high risk for an event. Patients assigned bococizumab had lower LDL levels in both studies compared with placebo. Those who were exposed to bococizumab for a shorter period still experienced risk reduction of CV events.
“There is a clear, proven benefit decreasing major cardiovascular events when adding PCSK9 inhibitor evolocumab and I would say even bococizumab to statin therapy,” Sabatine said.
Eugene Braunwald, MD, founding chairman of the TIMI Study Group and professor at Harvard Medical School, and colleagues from Oxford University and TIMI analyzed 30,000 patients with atherosclerotic vascular disease who were on a background statin and were treated with anacetrapib (Merck) for at least 4 years.
“Previous trials of other CETP inhibitors have been stopped after around 2 years of follow-up due to unexpected cardiovascular hazards (torcetrapib [Pfizer]) or apparent lack of efficacy (dalcetrapib [Roche], evacetrapib [Eli Lilly]),” said Braunwald, a member of the Cardiology Today Editorial Board.
The primary outcome was a major coronary event, including MI, coronary revascularization and coronary death.
Patients assigned anacetrapib had an absolute difference of 43 mg/dL for HDL and 42 mg/dL for apolipoprotein A-I. The absolute difference of non-HDL was –17 mg/dL.
The incidence of major coronary events was higher in the placebo group (11.8%) vs. anacetrapib (10.8%).
The rate ratio of coronary events at more than 1 year was 0.88 (95% CI, 0.81-0.95) and 0.91 throughout follow-up (95% CI, 0.85-0.97).
The relations between the reduction of MI or coronary death and of non-HDL in REVEAL were similar to those observed in previous LDL-lowering trials.
The anacetrapib group had a lower incidence of all components of the primary endpoint.
“There was no evidence of heterogeneity of effect on major coronary events among prespecified groups,” Braunwald said.
No effect was seen in vascular, nonvascular and all-cause mortality, in addition to other adverse events.
“There was a significant 9% proportional reduction in major coronary events, which appears to be greater in later years of treatment,” Braunwald said.
Braunwald stated that HDL appears to be a risk marker, but not a risk factor. Low HDL levels are linked to patients who smoke, are sedentary, insulin-resistant, obese, have hypertriglyceridemia and chronic inflammatory disorders.
CANTOS
Last year, Paul M Ridker, MD, director of the Center for Cardiovascular Disease Prevention and Eugene Braunwald Professor of Medicine at Brigham and Women’s Hospital, wrote an editorial in the European Heart Journal that detailed two concepts of risk: residual cholesterol risk and residual inflammatory risk. At that time, residual inflammatory risk, which regards patients who achieved an LDL of 70 mg/dL and a high-sensitivity C-reactive protein level of 3.8 mg/L with a high-intensity statin, did not have a prior proof of concept, but since results of the CANTOS trial were presented this year, it has given evidence toward this risk.
“Over the years, the ideas behind hs-CRP have evolved considerably,” Ridker said.
Ridker and colleagues published numerous studies involving the importance of measuring high-sensitivity CRP and the role statin therapy plays in the reduction of inflammation and high-sensitivity CRP.
The IMPROVE-IT trial in 2015 showed that aiming for two goals — lowering LDL and high-sensitivity CRP — conferred better outcomes compared with achieving only one of the goals. This combined effect was also seen in the results of the JUPITER trial, according to the presentation.
“Why was CANTOS a success? Part of the reason was our biological focus on interleukin-1 to interleukin-6 pathways,” Ridker said. “This was the first test of that pathway of inflammation.”
In CANTOS, Ridker and colleagues analyzed the effects of 50 mg, 150 mg and 300 mg canakinumab (Ilaris, Novartis) every 3 months for the treatment of interleukin-I beta-driven inflammatory diseases. Patients with stable CAD after an MI who were on statins and had persistent elevation of high-sensitivity CRP and had similar baseline characteristics to patients in the FOURIER and ODYSSEY trials were included in the study. High-sensitivity CRP was between 4.1 mg/L and 4.2 mg/L in this patient population.
Although there was no change in triglycerides, HDL and LDL, there was a dramatic decrease in interleukin-6 with patients assigned one of the three doses of canakinumab.
Those in the 150-mg and 300-mg groups had lower incidences of the primary and secondary endpoints compared with the placebo group. Patients assigned 50 mg had an insignificant reduction in both endpoints. When data from the 150-mg and 300-mg groups were combined, they achieved a 39% reduction in high-sensitivity CRP, a 15% reduction in major adverse CV events and a 30% reduction in the need for revascularization procedures, according to the presentation.
At 3 months, patients who had a reduction of high-sensitivity CRP greater than the median had an HR of 0.73 (95% CI, 0.63-0.83). Those who had a lesser reduction still had a benefit, but not to the extent of those with a greater reduction.
The reduction of inflammation can also affect cancers such as lung cancer, which can be predicted by the presence of high-sensitivity CRP. Various studies have shown how it is connected to interleukin-1.
Ridker and colleagues published results simultaneously with the main CANTOS results, which showed that 300 mg canakinumab reduced mortality from any cancer by 51% (P = .0009), a 67% reduction in incident lung cancer (P = .00008) and a 77% reduction in fatal lung cancer (P = .0002).
Residual inflammatory risk is more prevalent in patients with an LDL less than 70 mg/dL and a high-sensitivity CRP level of at least 2 mg/L compared with those with lower high-sensitivity CRP levels and higher LDL, as seen in the PROVE-IT and IMPROVE-IT trials.
“Lower is better appears to be true for both LDL-C and hs-CRP in both primary and secondary prevention,” Ridker said. – by Darlene Dobkowski
References:
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Ridker PM.
Sabatine MS. Attacking atherothrombosis: Which approach to take? All presented at: Cardiometabolic Health Conference; Oct. 4-7, 2017; Boston.
Cannon CP, et al. N Engl J. Med. 2015;doi:10.1056/NEJMoa1410489.
Bowman L, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1706444.
Ridker PM, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1614062.
Ridker PM, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1701488.
Ridker PM, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1707914.
Sabatine MS, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1615664.
Disclosures: Braunwald reports he receives grant/research support from Merck. Ridker reports he receives research support from AstraZeneca, Kawa, Novartis and Pfizer; nonfinancial support from Amgen; served as a research consultant for AstraZeneca, Quintiles, Sanofi and TEVA; and is listed as a co-inventor on patents held by Brigham and Women’s Hospital that are licensed to AstraZeneca and Siemens. Sabatine reports he consults for Amgen, CVS Caremark, Esperion, Ionis, MedImmune and Merck; and receives grant/research support from Amgen, AstraZeneca, Daiichi-Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen Research Development, MedImmune, Merck, Novartis, Pfizer, Poxel and Takeda.