All For One and FOURIER For All!


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Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017; 376: 1713-22.

Although statins have a proven benefit and are widely used, ASCVD continues to be the leading cause of death in the US.1-3  There is documented residual CV risk apparent even in patients treated with optimally-dosed statins.1,3 However, the 2013 ACC/AHA guidelines recommend against the routine use of statin add-on therapies.1 In 2015, two proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, alirocumab (Praluent®) and evolocumab (Repatha®), were approved to treat elevated cholesterol when added to maximally-tolerated statin therapy in patients with familial hypercholesterolemia or history of ASCVD.4-5  However, the lack of long-term CV outcomes data, high cost, and uncertainty regarding place in therapy have limited their wide-spread use.


In March 2017, results of the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial were published.6 This is the first true outcome trial published that examined the use of a PCSK9 inhibitor in a commonly encountered patient population. FOURIER was a randomized, double-blind, placebo-controlled trial with a composite of major CV events as the primary efficacy endpoint. Enrolled patients were between the ages of 40 to 85 with a history of clinically evident ASCVD in addition to the presence of at least one additional risk factor for CV disease. Participants had to have an LDL-C > 70 mg/dL and be taking a moderate or high-intensity statin.  They were also permitted to take ezetimibe in combination with a statin.  Patients were randomized to either evolocumab 140 mg every 2 weeks or 420 mg every month or matching placebo. Participants could choose their administration schedule. The median duration of follow up was 26 months and the major results of the trial are outlined in Table 1.6


TABLE 1: FOURIER Study – Major Results








Efficacy Outcome

No. of patients (%)

p value


Primary endpoint (composite of CV death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization)

1344 (9.8)

1563 (11.3)



Composite of CV death, myocardial infarction, or stroke

816 (5.9)

1013 (7.4)



Myocardial infarction

468 (3.4)

426 (3.1)




207 (1.5)

262 (1.9)



Coronary revascularization

759 (5.5)

965 (7.0)




While several trials have demonstrated the exceptional LDL-lowering capabilities of evolocumab, FOURIER is the first to demonstrate long-term CV benefit.7-10 Results of the OSLER 1 and 2 trials also showed positive CV benefits, with 29 (0.95%) events occurring in the evolocumab group and 31 (2.18%) occurring in the standard therapy group (HR 0.47; 95% CI 0.28-0.78; p = 0.003; NNT = 81). While intriguing, the results of OSLER 1 and 2 were rightfully met with some skepticism given the open-label study design and short duration of follow up (12 weeks).8


The positive CV outcomes observed in FOURIER, however, have significant implications for clinical practice. Not only did evolocumab significantly reduce the risk of major CV events including MI, stroke, hospitalization for unstable angina, and coronary revascularization, but the risk reduction was consistent regardless of age, sex, race, or statin intensity in subgroup analyses.11 While a reduction in the composite CV event rate is exciting and there was a mean 60% reduction in LDL concentrations, the addition of evolocumab to statin therapy did not reduce CV mortality or all-cause mortality when these outcomes were considered alone.6 In the IMPROVE-IT trial, ezetimibe, the only other statin add-on therapy with a proven CV benefit, had similar outcomes – with statistically significant improvements in the composite CV event rate, but not CV mortality or all-cause mortality (See Table 2).12


TABLE 2: Cardiovascular Outcomes – IMPROVE-IT and FOURIER



Ezetimibe in addition to statin therapy versus statin therapy alone


Evolocumab in addition to statin therapy (± ezetimibe) versus statin therapy alone

Composite CV events

2572 (32.7%) vs 2742 (34.7%);

HR 0.936; 95% CI 0.89-0.99;

p = 0.016; NNT = 50 over 7 years

1344 (9.8%) vs 1563 (11.3%);

HR 0.85; 95% CI 0.79-0.92

P <0.001; NNT = 67 over 2 years

Death from any cause

1215 (15.3%) vs 1231 (15.4%);

HR 0.99; 95% CI 0.91-1.13;


444 (3.2) vs 426 (3.1%);

HR 1.04; 95% CI 0.91-1.19

P = 0.54

Death from CV causes

537 (6.9%) vs 538 (6.8%);

HR 1.00; 95% CI 0.89-1.13;

p =1.00

251 (1.8%) vs 240 vs (1.7%)

HR 1.05; 95% CI 0.88-1.25

P = 0.62


The ACC released an expert consensus decision pathway on the role of non-statin therapies for LDL lowering in the management of ASCVD in July 2016. According to the pathway, when patients do not achieve LDL lowering of  at least 50% after taking a maximally-tolerated statin dose, or if LDL remains > 70 mg/dL (if history of clinical ASCVD) or  > 100 mg/dL (if baseline LDL >190), non-statin medications can be considered for further ASCVD risk reduction. The expert panel recommended that ezetimibe be used as the first-line add-on therapy and PCSK9 inhibitors second-line.2  Of note, this recommendation was published prior to the release of the FOURIER study results. Although both ezetimibe and evolocumab have a documented CV benefit when added to statin therapy, evolocumab has far greater LDL-lowering potential (60% versus 18%), proven benefit after only 2 years of use compared to 7 years with ezetimibe, and proven ability to substantially reduce CV risk when added to high-intensity statin therapy. In the IMPROVE-IT trial, ezetimibe 10 mg was added to simvastatin 40 mg daily, a moderate-intensity statin dose, leaving questions as to whether the CV benefit will materialize in patients who are already on high-intensity statins.12


It must be acknowledged that improvements in lipid parameters is not the primary goal of treatment.  Moreover, reductions in LDL cholesterol may not (fully) explain why statins, unlike other lipid-lowering medications, have consistently reduced morbidity and mortality. (See PCK9 Inhibitors: Blockbusters or Bust?But are clinicians doing enough to lower CV risk by prescribing statin monotherapy? Evolocumab combined with high-intensity statins significantly lowers residual CV risk. Sixty-three percent of patients included in the FOURIER trial had baseline LDL levels > 70 mg/dL despite treatment with high-intensity statin therapy. The addition of evolocumab lowered LDL levels from a baseline median of 92 mg/dL to 30 mg/dL – a level much lower than previous targets – at study conclusion.6 No concerns with adverse events were seen with these very low LDL concentrations.


Despite the favorable results in FOURIER, evolocumab is not a panacea. The lack of a mortality benefit is one issue. Cost is another. Currently, evolucumab costs over $13,000 per year and requires prior authorization by most payers.  Some insurers require a trial of ezetimibe, which costs only $440 per year, before a PCSK9 inhibitor can be used.13-14


Evolocumab is effective for the secondary prevention of ASCVD events and has a very respectable NNT. In our opinion, evolocumab should be used more often, but only for the secondary prevention of CV events in patients with multiple risk factors. The ODYSSEY OUTCOMES study, which is currently being analyzed, will provide long-term follow-up data for alirocumab.  If alirocumab reduces mortality, in addition to CV events, the cost of these agents becomes less relavent.  Is FOURIER the start of a PCSK9 inhibitor revolution in ASCVD management? Tell us what you think!



Dan Gillis's picture

While giving us assurance that we are not just treating the numbers with this class of drugs, this study will not greatly change the current paradigm due to the mentioned limitations of lack of mortality benefit and cost. Despite the "respectable" NNT, the cost to prevent one event (event, not death) is close to a million dollars. Mortality benefit labeling is the golden ticket, and FOURIER won't get it for evolocumab than IMPROVE-IT got it for ezetimibe. The cost relevance of a subsequently demonstrated mortality benefit from this class will depend on the magnitude of the benefit and resulting cost per QALY compared to societal willingness to pay, etc., etc., all that goes into cost-effectiveness analysis. cont'd
Dan Gillis's picture

The point that we could do more to further reduce risk in patients that we currently consider optimally treated is well taken. However, what that looks like remains to be defined. Guidelines discourage non-statins due to a lack of evidence of net benefit. They hedge toward ezetimibe but I think there is an apples to oranges element given the statin intensity used in IMPROVE-IT vs. current guidelines. I think the larger opportunity is in doing more to get everyone that we know, from a large robust body of evidence, would benefit from statin therapy on to optimal standard of care treatment. This means being sure everyone that should and can be on a statin is, and at the recommended intensity. We have to help prescribers raise the threshold for labeling patients "statin intolerant" by promoting strategies for establishing tolerable statin regimens and addressing knowledge gaps regarding statin intensities and even guidelines among prescribers.