Pre-specified analyses of FOURIER trial look at impact on aortic valve stenosis, MI

Higher lipoprotein(a) Lp(a) levels were tied to a higher risk of subsequent severe aortic valve stenosis (AS) events, including aortic valve replacement (AVR), although long-term evolocumab (Repatha) therapy seemed to reduce AS events, researchers reported.

In a secondary analysis of the FOURIER trial, the overall hazard ratio for AS events with the PCSK9 inhibitor was 0.66 (95% CI 0.40-1.09), according to Brian A. Bergmark, MD, of the TIMI Study Group, Brigham and Women’s Hospital/Harvard Medical School in Boston, and co-authors.

While there was no apparent association in the first year (HR 1.09, 95% CI 0.48-2.47) the HR was 0.48 (95% CI 0.25-0.93) after the first year of treatment, they wrote in JAMA Cardiology.

However, an LDL cholesterol concentration corrected for Lp(a) content, age, sex, diabetes, hypertension, current smoking, and estimated glomerular filtration rate was not significantly associated with AS events (adjusted HR 1.23, 95% CI 0.93-1.61 per standard deviation, P=0.14), the authors added.

“Long-term therapy with evolocumab may reduce AS events, and this raises the possibility that specific pharmacologic lipid-lowering therapy could offer a means to prevent or slow the progression of AS,” according to Bergmark and co-authors.

In a second study also in JAMA Cardiology, evolocumab treatment led to benefits across multiple myocardial infarction (MI) subtypes.

Evolocumab received FDA approval in 2017 for the prevention of heart attacks, strokes, and coronary revascularizations in patients with established cardiovascular (CV) disease based on the results of the FOURIER trial. It was the first PCSK9 approved for this indication. A second PCSK9 inhibitor, alirocumab (Praluent), gained an indication for CV secondary prevention in 2019.

Historically, AS has been viewed as “inevitable and inexorable, a destructive sequence that may (or may not) run to completion, but a sequence we cannot influence,” noted George Thanassoulis, MD, MSc, of McGill University Health Center in Montreal, in an editorial accompanying the brief report from Bergmark’s group.

But evidence mounts that “AS has several overlapping features with atherosclerosis, a highly preventable disease,” he stated. Atherosclerotic risk factors have been tied to early subclinical forms of valve calcification, and to later stages of clinically manifest stenosis, Thanassoulis explained. For instance, a 2010 study by Thanassoulis and colleagues found that a higher Framingham risk score in early adulthood (ages ≤40 years) was associated with increased prevalence and severity of aortic valve calcium measured 3 decades later.

And studies focused on high blood pressure and obesity have also spotlighted “the many parallels between AS and atherosclerosis,” he said, but also noted that “in trials of lipid lowering, statins failed to reduce [AS] disease progression.”

However, Lp[a] is a viable target in AS, and “PCSK9 inhibitors could represent a viable option to prevent AS and avoid the long-term consequences of this disease,” Thanassoulis wrote. Bergmark and co-authors “provide some preliminary evidence that such a strategy may have promise…Dedicated trials for AS with PCSK9 inhibitors…are urgently needed to test the hypothesis that AS can be either slowed or avoided with medical therapy.”

In the FOURIER trial, nearly 28,000 patients (LDL cholesterol concentration ≥70 mg/dL) with atherosclerotic CV disease at increased CV risk, and taking statins, were randomized to evolocumab or placebo and followed for a median of 2.2 years. There was no exclusion criterion for AS or prior AVR, the authors stated.

“For this post hoc analysis, the safety database was searched for events of new or worsening AS or aortic valve replacement (termed AS events),” they explained.

Bergmark’s group reported that AS events occurred in 63 patients (76% men; mean age 69 years) in the full trial cohort. Among these, 26 events were AVRs, while the remainder were site-reported AS events without AVR. In the year 1 of treatment, 23 events occurred and 40 event happened after ≥12 months.

Elevated Lp(a) concentration was linked with higher rates of AS events (adjusted HR 1.55, 95% CI 1.17-2.05 per SD, P=0.002), including AVR (adjusted HR 2.22, 95% CI 1.38-3.58 per SD, P=0.001), after multivariable adjustment.

Also, for the first year of treatment, there was a 20% reduction in myocardial infarction (MI) at 1.9% versus 2.4% for placebo (HR 0.80, 95% CI 0.68-0.94, P=0.006). The reduction was greater beyond the year 1 at 35% (2.7% versus 4.2%, HR 0.65, 95% CI 0.55-0.77, P<0.001).

Bergmark and co-authors noted that “We observed that MIs were most frequently spontaneous type 1 MIs, non-STEMI [ST-Elevation MI], and with cardiac troponin level values greater than 10 times the upper limit of normal.”

They pointed out that the “key observations from this analysis are related to the natural history of MI in this population and the effects of evolocumab…The benefit for evolocumab was consistent for MIs generally considered more severe, including STEMI and those with larger elevations of cardiac biomarkers. In addition, the benefit for reduction of MI appeared to have a time dependence with a lesser reduction over the first 6 months and larger reductions thereafter.”

Study limitations included the fact that FOURIER was not designed or powered to look at MI as an isolated outcome, and “smaller MIs or procedural MIs” may not have been reported. Finally, “This analysis does not allow for a clear examination of the mechanism of benefits seen,” the authors wrote.

In the second pre-specified FOURIER analysis by Stephen D. Wiviott, MD, of Brigham and Women’s Hospital in Boston, 1,107 patients (mean age 62.5; 75% men) of the full study population experienced a total of 1,288 MIs.

MI “was defined based on the third universal MI definition, and further classified according to MI type (universal MI subclass…STEMI vs non–STEMI and by MI size (determined by peak troponin level),” they explained.

The majority (68%) of the MIs were atherothrombotic (type 1), with 15% from myocardial oxygen supply-demand mismatch (type 2) and 15% percutaneous coronary intervention-related (type 4). Sudden death (type 3) and coronary artery bypass grafting–related (type 5) accounted for <2% of the MIs, the authors reported.

They also found that evolocumab significantly reduced the following versus placebo:

  • Risk of first MI by 27%: 4.4% versus 6.3% (HR 0.73, 95% CI 0.65-0.82, P<0.001).
  • Risk of type 1 by 32%: 2.9% versus 4.5% (HR 0.68, 95% CI 0.59-0.79, P<0.001).
  • Risk of type 4 by 35%: 0.8% versus 1.1% (HR 0.65, 95% CI 0.48-0.87, P=0.004).
  • No effect on risk of type 2: 0.9% versus 0.8% (HR 1.09, 95% CI 0.82-1.45, P=0.56).

Additionally, 59.8% had troponin levels ≥10 times the upper limit of normal (ULN). The authors reported that the benefit was “highly significant and consistent regardless of the size of MI,” with a 34% reduction in MIs with troponin level ≥10 times the ULN at 2.6% vs 3.7% for placebo (HR 0.66, 95% CI 0.56 and 0.77, P<0.001) and a 36% reduction in the risk of STEMI at 1.0% vs 1.5% (HR 0.64, 95% CI 0.49-0.84, P<0.001).

“The benefit for evolocumab was consistent for MIs generally considered more severe, including STEMI and those with larger elevations of cardiac biomarkers,” Wiviott and co-authors wrote. “In addition, the benefit for reduction of MI appeared to have a time dependence with a lesser reduction over the first 6 months and larger reductions thereafter.”

“These data are consistent with the known benefits of [LDL-cholesterol] lowering and underscore the reduction in clinically meaningful events,” they concluded.

The findings are valuable in a “broader, big-picture way,” stated Glenn N. Levine, MD, of Baylor College of Medicine and Michael E. DeBakey VA Medical Center, both in Houston, in an invited commentary. “For any new drug, device, or intervention, one must weigh the benefit against any detriment (eg, bleeding), and increasingly, the benefit against the cost of the tested intervention (cost value).”

In the FOURIER trial, the “diagnostic biomarker elevation [for MI] is defined as any elevation above the 99th percentile of the upper reference limit,” Levine explained. A decision that clinicians struggle with is whether patients “who have a measured troponin level above the 99th percentile of the upper limit of normal have experienced a clinically meaningful MI or merely a chemical MI.”

He pointed out that there is currently no “no dualistic cutoff point for what degree of troponin elevation leads to clinically meaningful myocardial damage…this analysis of the results of FOURIER used peak troponin level, rather than cumulative troponin elevation (area under the curve), which may less accurately represent the extent of LV [left ventricular] myocardial cell death (at least for troponin values measured within 24 hours after onset of ischemia).”

Still, “most would agree that prevention of larger MIs (as assessed by troponin elevation), as well as STEMI and transmural MI, is desirable,” Levine argued.

“While different clinicians, guideline formulators, and policy makers may define clinically meaningful in different terms and with different cutoff values, reports such as the current one by Wiviott and colleagues allow for just such a more precise assessment of benefit,” he said, and added, “While this more detailed report on MI events in FOURIER alone will not single-handedly lead to such a paradigm shift, it is a much welcome and needed step in the right direction.”

  1. Elevated lipoprotein(a) concentrations were associated with higher rates of aortic stenosis (AS) events, including aortic valve replacement; long-term therapy with evolocumab (Repatha) may reduce the risk of AS events.

  2. LDL cholesterol-lowering therapy with evolocumab resulted in benefit across multiple myocardial infarction subtypes.

Shalmali Pal, Contributing Writer, BreakingMED™

The FOURIER trial was supported by Amgen. The TIMI Study Group is supported by Abbott, Amgen, Aralez, AstraZeneca, Bayer HealthCare Pharmaceuticals, BRAHMS, Daiichi-Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen, MedImmune, Merck, Novartis, Pfizer, Poxel, Quark Pharmaceuticals, Roche, Takeda, The Medicines Company, and Zora Biosciences.

Bergmark reported support from MedImmune, Amgen, AstraZeneca, and Abbott Vascular, as well as relationships with Quark Pharmaceuticals, Abbott Vascular, Philips, Daiichi Sankyo, and Janssen Pharmaceuticals.

Thanassoulis reported relationships with Amgen, Sanofi/Regeneron, Ionis, HLS Therapeutics, and Servier Canada, as well as support from Ionis, Servier, the Canadian Institutes of Health Research, the Heart and Stroke Foundation of Canada, the National Heart, Lung, and Blood Institute, the Doggone Foundation, the Courtois Foundation, and the Satoko Shibata and Richard Ingram Foundation, and the Fonds de Recherche Santé-Québec.

Wiviott reported relationships with, and/or support from, Amgen, Arena, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Eisai, Eli Lilly, Janssen, Merck, sanofi aventis, Aegerion, Allergan, Angelmed, Boehringer Ingelheim, Boston Clinical Research Institute, Icon Clinical, Lexicon, Servier, St Jude Medical, and Xoma. A co-author reported being deputy editor of JAMA Cardiology.

Levine reported no relationships relevant to the contents of this paper to disclose.

Cat ID: 308

Topic ID: 74,308,730,308,192,925