All-cause death was also reduced (3.5 percent for alirocumab vs. 4.1 percent for placebo; hazard ratio [HR], 0.84; p=0.026 based on hierarchical testing). The benefit for all-cause death was even greater for patients with a baseline LDL-C ≥100 mg/dL, with a reduction from 5.7 percent with placebo to 4.1 percent with alirocumab (HR, 0.71), according to a post hoc analysis of prespecified LDL-C subgroups.

The trial’s principal investigator, Philippe Gabriel Steg, MD, FACC, stressed that the all-cause mortality findings must be interpreted cautiously as it was a secondary outcome.

Commenting on the study, Valentin Fuster, MD, PhD, was concise: “The hypothesis has been fulfilled,” he said, adding that “this study is going to change practice.” He reiterated a call that the prices for PCSK9 inhibitors be lowered to open the drugs to greater use. Indeed, what physicians really have been waiting for are lower prices and a less obstructed path for prescribing PCSK9 inhibitors. Several analyses based on pre-ACC.18 data have shown a striking lack of cost effectiveness at the current prices of about $14,000 per year for both alirocumab and evolocumab. As well, many clinicians report finding it extremely difficult, complex and time-consuming to get their patients approved for PCSK9 inhibitors.

In an unusual move, on the same day the new findings were released, Sanofi and Regeneron, the manufacturer of alirocumab, announced a plan to reduce the price for alirocumab contingent on insurers and pharmacy benefit managers showing a greater willingness to reduce barriers to access. No specific price has been set, but the company said it would be in line with an updated analysis from the Institute for Clinical and Economic Review (ICER) that was released to coincide with the trial’s presentation.¹

The preliminary assessment from the independent, U.S.-based ICER, which received the data early “in confidence,” set an updated value-based price benchmark net of rebates and discounts for alirocumab between $2300 and $3400 per year if used to treat all recent acute coronary syndrome (ACS) patients who meet the trial’s eligibility criteria. Or between $4500 and $8000 per year if reserved for higher-risk patients with LDL-C ≥100 mg/dL despite intensive statin therapy.

ICER plans to publish a final cost-effectiveness update for alirocumab by May 3, 2018, but noted that this newest estimate does not alter their September 2017 assessment of evolocumab. That value-based assessment set a lower price range, from approximately $1,700 to $2,200, based primarily on FOURIER’s failure to demonstrate a statistically significant reduction in cardiovascular or all-cause mortality, nor a trend toward improved clinical benefit in patients with higher LDL-C levels.

Reference

1. Institute for Clinical and Economic Review. Alirocumab for Treatment of High Cholesterol: Effectiveness and Value. Preliminary New Evidence Update. Available here. Accessed March 27, 2018.

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However, according to one panel discussant, David J. Wilber, MD, FACC, these reasons “didn’t seem very plausible.” Only two deaths in each arm (representing 0.1 percent and 0.3 percent of the total deaths in each arm, respectively) were classified as indeterminate. Wilber is also editor-in-chief of JACC: Clinical Electrophysiology.

In the WCD arm, the secondary endpoint of stroke deaths was significantly lower than in the placebo arm (0.0 percent vs. 0.5 percent). There was also less shortness of breath with the WCD (38.7 percent vs. 45.4 percent of controls).

VEST, conducted at 108 sites in the U.S., Germany, Poland and Hungary, enrolled 2,302 patients within seven days of an acute MI and with left ventricular ejection fractions ≤35 percent and randomly assigned them 2:1 to either standard medical therapy alone or standard medical therapy plus the WCD. On average, the vest was worn for 14.1 hours per day. Twenty individuals in the control arm (2.6 percent) crossed over to LifeVest use and 19 percent of the study arm did not wear the vest.

Despite missing the primary endpoint, Olgin suggested that “based on the associated lower total mortality, it’s reasonable to prescribe the wearable cardioverter-defibrillator in patients who are post-MI and have a reduced ejection fraction until further evaluation for an ICD at 40 to 90 days.” The investigators plan to conduct subgroup analyses to determine if there are populations more likely to benefit from the device, along with a cost effectiveness analysis of the LifeVest, which costs about $10,000 for three months of wear.

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Canakinumab treatment did lower HbA1c during the first six to nine months of therapy (significantly so in those with prediabetes and nonsignificantly in those with established diabetes), but this effect was attenuated over time, which Everett called “a bit of a mystery...”

Despite this disappointment for those who had hoped that IL-6 inhibition might also reduce diabetes risk, late-breaking session panelist Kim A. Eagle, MD, MACC, suggested there is still reason for enthusiasm: “You’ve opened a whole new window to the world with this class of therapies. I know you’re disappointed that you were not able to prevent diabetes, but you’ve got cardiovascular disease and lung cancer already under your belt,” he said with a smile.

In another session, Paul M. Ridker, MD, FACC, presented data on the efficacy of canakinumab in individuals with moderate (estimated glomerular filtration rate [eGFR] 30-60 ml/min/1.73m²) chronic kidney disease (CKD).

Not surprisingly, significantly increased rates of MACE, cardiovascular death and all-cause mortality were noted in patients with moderate CKD as compared with those with normal renal function (p<0.0001 for all three endpoints).

Canakinumab reduced adverse events by 18 percent compared with placebo in those with reduced renal function (p=0.05), and by 14 percent in those with normal renal function, with no evidence of heterogeneity. As with the main trial findings, greater benefit was noted in those deemed “responders,” with on-treatment hsCRP protein levels <2 mg/L (HR, 0.69 for the MACE+ outcome; p=0.0039).

Canakinumab treatment offered no meaningful benefits nor substantive harms with response to adverse clinical renal events, including eGFR, creatinine levels or the need for dialysis.

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In the intention-to-treat analysis, MACE (defined as a composite of all-cause mortality, MI, stroke and unplanned coronary revascularization) was seen in 6.2 percent of patients given two loading doses of atorvastatin 80 mg and in 7.1 percent of those given placebo (HR, 0.88; p=0.27).

However, when considering only the 65 percent of patients who ultimately underwent PCI, the MACE rates favored statin loading (HR, 0.71; p=0.02). This difference was driven by a significant reduction in MI, but no difference in death, revascularization, stroke or stent thrombosis.

Periprocedural atorvastatin therapy raised no safety concerns and there were no cases of hepatic failure or rhabdomyolysis reported in the study arm. In the (matching) placebo arm, three cases of rhabdomyolysis were recorded.

In his presentation of the findings, Otavio Berwanger, MD, PhD, suggested periprocedural atorvastatin might be an “attractive treatment strategy for patients with acute coronary syndromes.” The general consensus of the panelists commenting on the study was, roughly, why not, it won’t hurt.

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For the composite endpoint of death from vascular causes, MI or stroke, no difference was seen at 30 days (4.0 percent and 4.3 percent, respectively; p=0.57), but Berwanger noted that this finding was only exploratory and the 12-month follow-up will be more telling on efficacy.

Of note, the upper age limit for inclusion was 75 years (mean, 58 years), making the findings not applicable to older adults, an age group at inherently greater bleeding risk.

TREAT enrolled 3,799 STEMI patients (within 24 hours of symptom onset) treated with fibrinolytic therapy at 152 sites in 10 countries. They were randomly assigned to open-label ticagrelor (180 mg loading dose, 90 mg twice daily for 12 months) or clopidogrel (300 mg to 600 mg loading dose, 75 mg daily for 12 months). The majority of patients (90 percent) were pretreated with clopidogrel.

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“As black men have many CVD risk factors, marked blood pressure reductions – if sustained and initiated widely – may reduce high hypertension-related disability and death among black men in the United States,” said Victor. A cost effectiveness analysis and an additional six months of follow-up will be presented in the near future.

The study included 319 black male patrons with systolic blood pressures of at least 140 mm Hg who frequented 52 black-owned barbershops. The shops were assigned to the intervention or active control intervention using a cluster design. “Taking the treatment to where people live, work and play is going to be essential to chronic disease management,” said late breaking session panelist Karol E. Watson, MD, FACC.

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According to genotyping, 28 percent of participants in the study arm were LOF carriers. Overall, prasugrel or ticagrelor were used more often in patients who underwent genotyping than in the standard care arm (30 percent vs. 21 percent; p=0.03).

More specifically, of those genotyped, 53 percent of LOF carriers were prescribed prasugrel or ticagrelor, compared with 22 percent of no-LOF participants (p<0.001), which calculated to an agreement rate (with genotyping) of 71 percent. In the control arm, 21 percent were given prasugrel or ticagrelor.

Compared with those without LOF alleles, LOF carriers treated with clopidogrel were at increased risk of a composite endpoint of MACE, major bleeding and death in a post hoc analysis (HR, 1.84; p=0.03).

While it is well known that the presence of LOF alleles impacts clopidogrel response, current ACC/AHA guidelines do not recommend routine CYP2C19 genetic testing. Tuteja suggested genotyping needs to be paired with “a lot of education” to help clinicians understand how to best use the results.

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