CORONA & GISSI-HF - Statins in heart failure

in ,

Bottom line: Issues with generalizability strongly limit the applicability of CORONA and GISSI-HF to the real world.

CORONA selected an ischemic HFrEF population at lower risk of coronary events (>6 months from most recent MI), and was unable to rule out the 25-30% relative risk reduction in coronary events consistently demonstrated in statin RCTs.

GISSI-HF, on the other hand, may have washed out any effect in ischemic HFrEF by also enrolling patients with no CAD and at low risk for an atherosclerotic CV event. However, it is reasonable to conclude from GISSI-HF that patients with HF of non-ischemic origin likely will not benefit from statin therapy unless at high risk due to other coronary risk factors (i.e. traditional threshold of Framingham 10-year risk >20%).

 

(1) CORONA

Kjekshus J, et al. Rosuvastatin in older patients with systolic heart failure. N Engl J Med 2007;357:2248-61.

    Patients

    • Inclusion
      • 60+ y/o
      • Chronic HFrEF with NYHA II-IV symptoms & LVEF <40% (<35% if NYHA II symptoms)
      • HF of ischemic etiology, as reported by investigators
      • Not already on statin & not thought to have absolute indication/contraindication by patient's physician
      • Stable on optimal therapy x 2+ weeks
    • Exclusion
      • Decompensated HF
      • Need for inotropes
      • MI in past 6 months
      • PCI, CABG, ICD or biventricular pacemaker in past 3 months (or planned)
      • Multifactorial HF
        • Clinically significant uncorrected primary valvular heart disease or malfunctioning prosthetic valve
        • HoCM
        • Acute endomyocarditis/myocarditis
        • Pericardia disease
        • Systemic disease (e.g. amyloidosis)
      • Significant competing causes of morbidity & mortality
        • Liver disease or ALT >2x ULN
        • SCr >221 micromol/L
        • TSH >2x ULN
        • Chronic muscle disease or unexplained CK >2.5x ULN
        • "Any other condition that would substantially reduce life expectancy or limit compliance"
    • ? screened -> 5459 entered placebo run-in -> 5011 randomized
    • "Average" patient
      • 73 y
      • Male 59%
      • HF characteristics
        • NYHA class II (37%), III (62%)
        • EF 31%
      • PMHx
        • MI 60%
        • Past/current angina 72%
        • CABG/PCI 26%
        • AFib 24%
        • ICD <3%
      • Lipids: Total cholesterol 5.35, LDL 3.54, HDL 1.23 mmol/L
      • Meds
        • Loop diuretic 75%
        • Digoxin 33%
        • ACEI or ARB 92%
        • Beta-blocker 75%

    Issues with external validity (generalizability)?

    • Yes, multiple:
      • Subjective inclusion criteria with unclear rationale (i.e. why the patients' physicians felt that they did not have an indication for a statin despite ischemic HFrEF)
      • Extensive exclusion criteria ensured enrollment of patients without any significant comorbidities (& therefore fewer competing risks for death or hospitalization)

    Interventions

    • I: Rosuvastatin 10 mg PO once daily
    • C: Matching placebo

    Results @ median 2.75 y

    • LDL reduced by 44% from baseline with rosuvastatin
      • @ baseline: 3.54 mmol/L
      • @ 3 months: 1.96
    • No statistically significant difference in primary outcome (composite of CV death, MI or stroke): Hazard ratio 0.92 (95% CI 0.83-1.02)
      • 11.4% vs 12.3% (p=0.12)
    • No statistically significant difference in secondary outcomes
      • All-cause death: 11.6% vs 12.2% (p=0.31)
      • Hospitalizations: 35.6% vs 38% (p=0.09)
        • Note: Statistically significant only when considering overall # of hospitalizations in each group
        • For worsening HF: 11.3% vs 12.3% (p=0.11)
      • Any coronary event: 9.3% vs 10% (p=0.18)
        • MI: 1.9% vs 2.4% (HR 0.84, 0.70-1.00)
    • Safety: 
      • All-cause discontinuation & discontinuation due to adverse events statistically significantly LOWER with rosuvastatin vs placebo
      • No statistically significant difference in myalgias, regardless of definition used (~9% in both groups)

    Issues with internal validity?

    • No; Randomized (using minimization), allocation concealed, blinded (patients, clinicians, investigators) with unknown loss-to-follow-up, analyzed using intention-to-treat population.
    • Run-in phase of single-blind placebo x2-4 weeks to ensure adherence (excluded if took <80% of doses)

     

    (2) GISSI-HF

    Tavazzi L, et al. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a raondomised, double-blind, placebo-controlled trial. Lancet 2008;372:1231-9.

      Patients

      • Inclusion
        • Adults with HF NYHA class II-IV
        • Patients with HFpEF (LVEF >40%) had 1+ hospital admissions for HF in the last year
      • Exclusion
        • Any non-cardiac comorbidity "unlikely to be compatible with a sufficiently long follow-up", including
          • Liver disease
          • SCr >221 micromol/L
          • ALT/AST >1.5x ULN
          • CK >1x ULN
        • ACS within 1 month
        • Planned cardiac surgery in next 3 months
      • 7046 assessed for eligibility -> 4631 randomized -> 4574 analyzed
      • "Average" patient
        • 68 y
        • Male 76%
        • HF characteristics
          • Ischemic 40%, dilated CM 34%, hypertensive 18%
          • NYHA class II (61%), III (36%)
          • On exam: S3 25%, MR murmur 64%, crackles 28%
          • EF 33%, >40% in 10%
        • PMHx
          • MI 33%
          • CABG 13%, PCI 8%
          • AFib 20%
          • ICD 6.5%
        • Lipids: LDL ~3.15, HDL 1.2 mmol/L
        • Med
          • Diuretic 90%
          • Digoxin 40%
          • Nitrate 32%
          • ACEI or ARB 94%
          • Beta-blocker 62%

      Issues with external validity?

      • Yes: Enrolled a broad range of patients with heart failure, with variable risk of atherosclerotic/statin-modifiable events
        • Negative results here may not necessarily reflect lack of benefit in population of interest

      Interventions

      • I: Rosuvastatin 10 mg PO once daily
      • C: Matching placebo

      Results @ median 3.9 y

      • LDL reduced by ~30% in rosuvastatin group
        • @ baseline: 3.16 mmol/L
        • @ 1 y: 2.15 mmol/L
      • No statistically significant difference in either co-primary outcomes
        • All-cause death: 28.8% vs 28.1%, HR 1.03 (95.5% CI 0.92-1.15) 
        • All-cause death or CV hospitalization: 57% vs 56%, HR 1.02 (99% CI 0.92-1.13)
      • Low rate of MI, with no statistically significant difference between groups: 2.7% vs 3.1%, R 0.88 (95% CI 0.63-1.24)
        • Similar results for stroke: 3.6% vs 2.9% (HR 1.25, 0.91-1.73)

      Issues with internal validity?

      • No: Randomized, allocation concealed, blinded (patients, clinicians & investigators) with low (<0.1%) loss-to-follow-up, analyzed using intention-to-treat population
      • No run-in phase

      OSLER - Evolocumab (PCSK9 inhibitor) for LDL lowering

      in ,

      Sabatine MS, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1500-9.

      Bottom line: In patients previously enrolled in a phase 2/3 trial of evolocumab due to elevated LDL in the context of HeFH, statin intolerance, or maximum-tolerated statin therapy, addition of evolocumab lowered LDL by ~60% versus standard therapy alone. This LDL reduction resulted in a reduction in CV events (NNT 82 at 11 months), which may be an inaccurate estimate due to high risk of performance and detection bias.

       

        Patients (n=4465)

        • Inclusion
          • Patients who completed one of the 12 phase 2 & 3 RCTs of evolocumab without discontinuation due to an adverse event
          • No unstable medical condition
          • Basic patient populations enrolled in phase 2 & 3 trials:
            • MENDEL-1 & 2: LDL 2.6-4.9 mmol/L without background lipid lowering
            • GAUSE-1: LDL >2.6 mmol/L, statin intolerant
            • GAUSE-2: LDL 2.6-4.9 mmol/L, statin intolerant
            • DESCARTES, THOMAS1&2: LDL >1.9 mmol/L with statin (DESCARTES: +/- ezetimibe)
            • LAPLACE-TIMI 57: LDL >2.1 mmol/L with statin +/- ezetimibe
            • LAPLACE-2: LDL >2.0 mmol/L with "intensive" statin, >2.6 mmol/L on "non-intensive" statin, or >3.9 mmol/L without statin at baseline, added to statin +/- ezetimibe
            • RUTHERFORD-1 & 2: HeFH with LDL >2.6 mmol/L with statin +/- ezetimibe
            • YUKAWA-1: "High-risk" Japanese patients with LDL 3.0 mmol/L or greater while receiving statin
        • 4465 randomized (74.1% of eligible from phase 2 & 3 trials)
        • "Average" patients (baseline of phase 2 & 3 trials)
          • 58 y
          • Male 51%
          • White 85%
          • North American 47%
          • CV risk factors
            • Smoker 15%
            • Known CAD 20%, MI 9%, PCI 11%, CABG 7%
            • Cerebrovascular or peripheral-artery disease 9%
            • Family hx of premature CAD 24%
            • HTN 52%
            • Diabetes 13%
            • Known FH 10%
          • Lipids: Total cholesterol 5.1, LDL 3.1, HDL 1.3, trig 1.35 mmol/L
          • Meds
            • Statin 70%, high-intensity 27%
            • Ezetimibe 14%

        Issues with generalizability (external validity)?

        • Yes: The patients in OSLER 1 & 2 represent a highly-selected patient population enrolled into early phase 2/3 mechanistic efficacy trials who were adherent and tolerant to their allocated therapy in the phase 2/3 trial
          • In care of real-world patients with greater likelihood of comorbid conditions and frailty, we'd expect lower eficacy, adherence, tolerability and safety than estimated from these trials.

        Interventions

        • I: Evolocumab x56 weeks + standard of care lipid-lowering therapy per local guidelines
          • OSLER-1: 420 mg q1 month
          • OSLER-2: Patient's choice of 140 mg q2weeks or 420 mg q1month
          • In-person clinic visit q3 months
        • C: No evolocumab x48 weeks + standard of care lipid-lowering therapy per local guidelines
          • Telephone contact only
        • After trial: Open-label evolocumab for all patients completing OSLER-1&2

        Results @ median ~11 months

        • LDL reduction
          • Change from baseline to week 12 of OSLER for evolocumab+standard therapy vs standard therapy alone = 61%
            • @ baseline: Median 3.1 mmol/L in both groups
            • @ week 12 of OSLER trial (variable time from baseline): Median 1.2 vs 3.1 mmol/L
          • <1.8 mmol/L target: 73.6% vs 3.8%
        • Statistically significant reduction in composite CV outcome (death, MI, unstable angina requiring hospitalization, coronary revascularization, stroke/TIA, or HF requiring hospitalization): Hazard ratio 0.47 (0.28-0.78)
          • 0.95% vs 2.18% (NNT 82)
          • Not clearly driven by any single component of the composite outcome (e.g. MI or stroke)
        • No patients developed neutralizing antibodies against evolocumab

        Issues with internal validity?

        • Yes: Randomized, allocation-concealed, open-label (participants, clinicians and investigators aware of allocated treatment) non-placebo controlled trial with ? lost-to-follow-up analyzed using intention-to-treat population
          • High risk of performance and detection bias, particularly relating to "soft" CV outcomes such as hospitalizations and decision to revascularize
        • Notably, this is actually a pooled report of 2 RCTs: OSLER-1 is an extension of 5 phase-2 trials, and OSLER-2 is an extension of 7 phase-3 trials

        ODYSSEY LONG TERM - Alirocumab (PCSK9 inhibitor) in heterozygous FH or with established ASCVD

        in ,

        Robinson JG, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1489-99.

        Bottom line: In patients at high risk of ASCVD, alirocumab lowered LDL by 62% more than placebo when added to maximum-tolerated statin therapy. This trial provides weak and mixed statistical evidence that additional LDL reduction with alirocumab may reduce CV events, primarily from reduction in non-fatal MI (NNT 72 over 78 weeks). This underpowered trial also suggests that alirocumab increases the risk of myalgia (NNH 40), and cannot rule out an increased risk of neurocognitive and ophthalmic events.

        The ongoing ODYSSEY OUTCOMES trial should provide definitive CV and safety outcome data.

         

          Patients

          • Multicenter (320 sites in 27 countries in Africa, Europe, & North/South America)
          • Inclusion
            • Adults at high risk of ASCVD, defined as
              • HeFH (diagnosed based on clinical criteria or genotyping)
              • Established coronary artery disease (CAD), defined as history of
                • MI, silent MI or unstable angina
                • PCI or CABG
                • CAD diagnosed by invasive (coronary angiography) or non-invasive testing (treadmill stress test, stress echo, nuclear imaging)
              • "Coronary heart disease equivalent"
                • Peripheral artery disease (PAD; current intermittent claudication with ABI <0.9 in either leg, history of intermitent claudication treated with endovascular or surgical procedure, or history of critical limb ischemia treated with thrombolysis or procedure)
                • Ischemic stroke
                • eGFR <60 for at least 3 months
                • Type 2 diabetes + 1 more risk factor (HTN, ABI <0.90, albuminuria, retinopathy, family hx of premature CAD)
            • LDL 1.8 mmol/L or more at screening (on maximum-tolerated statin dose)
          • Exclusion
            • Recent cardiovascular event leading to hospitalization or intervention
            • Planned revascularization (carotid, coronary or peripheral) during study
            • HF NYHA III-IV in past year
            • SBP/DBP >180/110 mm Hg at screening/randomization visit
            • PMHx
              • Hemorrhagic stroke
              • Optic nerve disease
              • Hep B or C, or ALT/AST >3x ULN
              • CKD with eGFR <30 mL/min
              • Homozygous FH
              • Trigs >4.5 mmol/L on 2 tests
              • HbA1c >10%
              • Known loss-of-function of PCSK9
              • CK >3x ULN
              • HIV
              • Other major systemic disease that may preclude ability to complete study
              • Meds
                • Taking statin other than atorvastatin, rosuvastatin or simvastatin
                • Not taking statin daily
                  • Use of systemic steroids (unless for pituitary/adrenal replacement stable for at least 6 weeks)
                  • Use of HRT (unless stable x6 weeks & no plan to change regimen during study)
            • Involved in any previous PCSK9 inhibitor trial
          • 5142 screened -> 2341 randomized
          • "Average" patient
            • 60.5 y
            • Male 62%
            • White 93%
            • CV risk factors
              • HeFH 18%
              • CAD ~70%
              • CAD-risk equivalent 41%
              • Smoker 20%
              • T2 diabetes 34%
            • Meds
              • Statin ~100%, high-dose 47%
              • Other lipid-lowering therapy 28%
                • Ezetimibe 15%
            • Lipid panel: LDL 3.2, HDL 1.29, fasting trig 1.52 mmol/L

          Interventions

          • I: Alirocumab 150 mg subcutaneously (1 mL) q2 weeks administered at home
            • Mean exposure 70 weeks (max 78)
            • Mean adherence 98% of doses
          • C: Matching placebo
          • Co-intervention: Maximum-tolerated statin, diet per NCEP ATP III guidelines

          Issues with generalizability (external validity)?

          • High-risk CV population: Doesn't apply to "primary prevention" population without HeFH
            • Excluded patients with any significant comorbidity who would be expected to have competing risks for death and hospitalization, as well as a greater absolute risk of adverse effects and intolerability with these drugs
              • We'd expect overestimation of benefit and underestimation of harm in frail patients and in those with significant comorbid conditions (including those with heart failure)

          Results

          • LDL reduction
            • Change from baseline to 24 weeks for alirocumab vs placebo = 62% difference
              • @ baseline: 3.2 mmol/L in both groups
              • @ 24 weeks: 1.2 vs 3.1 mmol/L
            • Achieved goal <1.8 mmol/L @ week 24: 79.3% vs 8% 
            • Highlights:
              • Differences in LDL remained consistent between groups through to week 78 among patients continuing study treatment
              • Similar % reduction in LDL in patients with & without HeFH
          • Uncertain effect on CV outcomes
            • No statistically significant difference in composite CV outcome (death due to CAD or from unknown cause, non-fatal MI, ischemic stroke, unstable angina requiring hospitalization, HF hospitalization, ischemia-driven coronary revascularization)
              • 4.6% vs 5.1% (p=0.68)
            • Statistically significant reduction in post-hoc analysis of components of above non-significant outcome
              • "Major adverse CV event" (coronary death, non-fatal MI, ischemic stroke, unstable angina requiring hospitalization): 1.7% vs 3.3% (NNT 63, p=0.02)
                • Driven by difference in non-fatal MI: 0.9% vs 2.3% (NNT 72, p=0.01)
          • Safety
            • Serious adverse event: 18.7% vs 19.5% (p=0.40)
            • Discontinued study drug: 28.2% vs 24.5% (NNH 27)
              • Discontinued due to adverse event: 7.2% vs 5.8% (p=0.26)
            • Select adverse events
              • Neurocognitive disorder: 1.2% vs 0.5% (p=0.17)
              • Ophthalmic event: 2.9% vs 1.9% (p=0.65)
              • Myalgia: 5.4% vs 2.9% (NNH 40, p=0.006)
              • No statistically significant difference in new diabetes (1.8% vs 2.0%) or worsening of existing diabetes (12.9% vs 13.6%)
              • No statistically significant difference in AST/ALT or CK elevations

          Issues with internal validity?

          • Randomized, allocation-concealed, triple-blind (patients, clinicians & investigators) trial with ~27% drop-out rate analyzed using the intention-to-treat population
            • The high drop-out rate does not necessarily introduce between-group bias, but may have led to underestimation of CV and safety outcome events
          • Stratified based on (1) HeFH status, (2) hx of MI or stroke, (3) background statin of atorva 40-80/rosuva 20-40 vs simvastatin at any dose or atorva <40/rosuva <20, (4) geography.

          Coenzyme Q10 for statin-related myopathy (short)

          in

          Banach M, et al. Effects of coenzyme Q10 on statin-induced myopathy: A meta-analysis of randomized controlled trials. Mayo Clinic Proc 2015;90:24-34.

          Bottom line: Coenzyme Q10 has no effect on statin-related myopathy. Clinicians should investigate and manage other causes and risk factors for myalgias. In those with likely statin-related myalgias, strategies include alternate-day statin dosing, decreasing the dose, or switching to a different statin.

           

          Context

          • ~5-10% of patients report myalgias while taking statins
            • Described as a heaviness/stiffness/cramping or weakness/loss of strength, more often in the lower limbs, that's worse with exertion, with a median onset 4 weeks after starting the statin
            • Risk factors for statin-related myalgia:
              • Higher statin dose
              • Demographics: Older age, female sex, asian
              • Other conditions: CKD, electrolyte disorders, hypothyroidism, existing myalgias
          • One of the hypothesized mechanisms of statin-related myopathy is the interference of Coenzyme Q10 (CoQ10) production

          Methods

          • Systematic review of MEDLINE, Embase, the Cochrane Library, and Scopus up to May 2014
            • No attempts to uncover unpublished or gray literature
          • Included 6 RCTs of CoQ10 versus placebo in 302 patients with statin-induced myopathy that reported on outcomes of changes in creatine kinase (CK) or myalgia
          • Evaluated study quality using the flawed Jadad score
            • Although reviewers rated all trials as "high quality", trials often had questionable allocation concealment and blinding, biasing results in favor of the CoQ10 group
          • Meta-analyzed using a random-effects model to account for heterogeneity in study design

          Interventions

          • I: CoQ10 100-400 mg/day x30 days (1 trial) to 12 weeks (5 trials)
          • C: Placebo (in at least 1 trial, "placebo" not inert (vitamin E) and looked different from CoQ10 capsule)

          Results

          • No statistically significant difference in muscle pain in 5 trials with high heterogeneity (I^2 = 89%)
            • 2/5 trials reported statistically significant differences (at least 1 of which wasn't truly placebo-controlled or properly blinded), whereas 3/5 reported no difference or trend towards increased myalgia
            • Standard mean difference -0.53 (95% confidence interval -1.33 to 0.28,)
              • No single validated statin myalgia scale, so various scales used in different studies
          • No statistically or clinically significant difference in CK in 5 trials
            • Mean difference +11.69 units (95% confidence interval -14.25 to +37.63, p=0.38)
          • Sensitivity analysis suggested no greater chance of benefit with higher doses
          • Did not report other important outcomes, such as % of patients able to tolerate statins, or able to increase dose

          Additional evidence

          IMPROVE-IT - Ezetimibe added to statin following ACS

          in
          Visual abstract - Ezetimibe.png

          Bottom line: In patients within 10 days of ACS, ezetimibe lowered LDL by 0.4 mmol/L and reduced the relative risk of CV events by 6% more than placebo when added to simvastatin. At a median 6 years, the addition of ezetimibe had no effect on mortality and reduced the absolute risk of any MI by 1.7% (NNT 59) and stroke by 0.6% (NNT 167).

           

          Context

          • Ezetimibe reduces LDL by ~25%
          • Prior to IMPROVE-IT, none of the available ezetimibe trials enrolled enough patients to adequately evaluate cardiovascular outcomes

            Patients

            • Multicenter (1147 sites in 39 countries)
            • Inclusion:
              • Men & women 50+ y
              • Hospitalized for ACS within 10 days
              • LDL 1.3-3.2 mmol/L measured <24 hours of ACS onset (1.3-2.6 mmol/L if receiving lipid-lowering therapy at baseline)
            • Exclusion:
              • Clinically unstable (cardiogenic shock, severe decompensated HF, acute MR, acute VSD)
              • Recurrent symptoms of cardiac ischemia
              • Arrhythmias (vfib, sustained VT, 3o AVB, 2o AVB type 2) 
              • Planned CABG
              • CrCl <30 mL/min
              • Active liver disease
              • Statin dose equal to simvastatin >40 mg/d
            • ? screened -> 18,144 randomized
            • "Average" patient @ baseline
              • 64 y
              • Female 24%
              • White 84%, North American 38%
              • Index event: STEMI 29%, NSTEMI 47%, unstable angina 24%
              • PCI 70%
              • Time from event to randomization: 5 days
              • PMHx
                • Current smoker 33%
                • Previous MI 21%, PCI 20%, CABG 9%
                • HTN 61%
                • HF 4%
                • PAD 5%
                • Diabetes 27%
              • LDL: 2.4 mmol/L
              • Meds
                • ASA 97%
                • P2Y12 inhibitor 87%
                • ACEI 75%
                • Beta-blocker 87%

            Interventions & co-interventions

            • I: Ezetimibe 10 mg PO once daily (60% still taking at end of study)
            • C: Placebo
              • Co-interventions:
                • Simvastatin 40 mg PO once daily
                  • Before 2011 amendment: If LDL >2.0 mmol/L x2 consecutive measurements: Simvastatin increased to 80 mg daily
                • If LDL >2.6 mmol/L x2 consecutive measurements: Study drug discontinued, started on open-label lipid-lowering therapy (outcomes followed & included in intention-to-treat analysis)

            Results @ median 6 years

            • LDL lowered by ~0.4 mmol/L (24%) more with ezetimibe than placebo
              • @ baseline: 2.4 mmol/L in both groups
              • @ 1 y: 1.4 vs 1.8 mmol/L
            • Statistically significant reduction in primary outcome (CV death, non-fatal MI, unstable angina requiring hospitalization, coronary revascularization occurring >30 days after randomization, or non-fatal stroke) with ezetimibe+simvastatin versus placebo+simvastatin: Hazard ratio (HR) 0.94 (95% confidence interval 0.89-0.99, p=0.016)
              • 32.7% vs 34.7% (NNT 50)
            • Key secondary outcomes
              • Death: 15.4% vs 15.3% (p=0.78)
              • Serious adverse events: Not reported
              • Any MI: 13.1% vs 14.8% (NNT 59, p=0.002)
              • Any stroke: 4.2% vs 4.8% (NNT 167, p=0.05)
            • No statistically significant differences in any adverse events
              • Cancer: 10.2% in both groups (p=0.57)
              • ALT/AST elevated 3x or more above ULN: 2.5% vs 2.3% (p=0.43)
              • Rhabdomyolysis, myopathy, or myalgias with CK elevation 5x or more above ULN: 0.6% in both groups (p=0.90)
            • Subgroups
              • Statistically significant (p<0.10) tests for interaction suggested greater relative risk reduction in primary outcome with OLDER patients (both >65 or >75), and in those with diabetes.

            Issues with internal validity?

            • Randomized, allocation-concealed, all-blind (investigators, clinicians, patients) trial analyzed using intent-to-treat analysis
            • Missing data for ~10% for primary outcome (sensitivity analyses did not show that this made any meaningful difference)
            • Notes:
              • Randomization stratified according to: Prior use of lipid-lowering therapy (yes/no), type of ACS, enrolment in EARLY ACS trial (yes/no)
              • Study continued until each patient followed >2.5 y + occurrence of 5250 events

            Additional publications of IMPROVE-IT

            • The TIMI Risk Score in Secondary Prevention may be useful to identify patients more likely to benefit from adding ezetimibe
              • 9-point risk score, 1 point for each:
                • Prior CVD: HF, prior CABG, prior stroke, PAD
                • CV risk factors: Age 75+ y, smoking, HTN, diabetes, eGFR <60
              • Significant interaction (p=0.01) between TIMI Risk Score for Secondary Prevention & benefit of adding ezetimibe in IMPROVE-IT:
                • Low risk (score 0-1): Simva+ezetimibe 14.0%, simva+placebo 13.1% (no benefit, non-significant 5% relative risk increase)
                • Intermediate risk (score 2): Simva+ezetimibe 19.3%, simva+placebo 21.5% (NNT 46, 11% relative risk reduction [RRR]; similar to overall IMPROVE-IT population)
                • High (score 3+): SImva+ezetimibe 33.9%, simva+placebo 40.2% (NNT 16, RRR 19%)
              • Importantly, baseline LDL not included in this risk score, & absolute LDL reduction was similar in all risk groups (i.e. ~0.4 mmol/L greater than placebo)
                • RRR differed between risk groups & was not proportional to LDL reduction within the range of baseline LDL (1.3-3.2 mmol/L) in IMPROVE-IT. This may represent a fundamental difference from statins (which reduce CV events proportional to LDL reduction), or reflect the low variation in baseline LDL within the study population
            • Achieving an LDL <0.8 mmol/L did not reduce in greater risk of adverse events & was associated with a lower risk of the primary outcome compared to an achieved LDL >1.8 mmol/L