Coenzyme Q10 for statin-related myopathy (short)

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  • No attempts to uncover unpublished or gray literature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

• An RCT of 38 patients with confirmed statin-induced myalgia found no reduction in myalgia or CK, or improvement in muscle strength and endurance with CoQ10 600 mg/d versus placebo.
  • Of note, the investigators of this trial went to great lengths to confirm that myalgia was related to statins with a double-blind cross-over trial of simvastatin and placebo. Only ~33% of 120 patients initially enrolled for history of muscle complaints while on a statin had confirmed statin-related myalgia (& not with the placebo) during the cross-over phase. This is a good reminder that many cases "statin intolerance due to muscle pain" that we see in practice are in fact unrelated to statins. If they have an appropriate indication for a statin, these patients should be re-challenged on a statin, with consideration of an alternate statin at a lower dose that can later be titrated as tolerated.

IMPROVE-IT - Ezetimibe added to statin following ACS

Cannon CP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015;372:2387-97.

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

ODYSSEY ESCAPE - PCSK9 inhibitor alirocumab for heterozygous familial hypercholesterolemia requiring lipid apheresis (short)

Moriarty PM, et al. Alirocumab in patients with heterozygous familial hypercholesterolaemia undergoing lipoprotein apheresis: the ODYSSEY ESCAPE trial.

Bottom-line: 

In HeFH patients previously requiring lipoprotein apheresis for LDL-lowering, a PCSK9 inhibitor further lowered LDL by ~55%. LDL-lowering with a PCSK9 inhibitor allowed for a 75% reduction in the rate of apheresis sessions (e.g. from once-weekly to once-monthly), and allowed up to two-thirds of patients to completely stop apheresis during a 3-month period (NNT <2). Although apheresis is an intermediate outcome, the high cost and burden to quality of life associated with this procedure make it an important clinical outcome to reduce.

This 62-patient trial was too small to accurately assess safety and tolerability of alirocumab, so clinicians should monitor for neurocognitive decline, ophthalmologic events, myalgias and injection-site reactions as previously reported to occur more commonly with PCSK9 inhibitors.

 

Context (from our review of FH)

• Heterozygous familial hypercholesterolemia (HeFH) is genetic dyslipidemia that affects ~1/500 Canadians
• HeFH presents clinically with an LDL 5-13 mmol/L +/- physical stigmata of elevated cholesterol, and increased risk of atherosclerotic cardiovascular disease (ASCVD)
  • Patients with untreated HeFH experience a coronary event 20+ years earlier than the general population
  • The cumulative risk of coronary events by age 50 is 44% in men and 20% in women
• The treatment goal in patients with HeFH is to reduce LDL by >50% from baseline, generally with a max-tolerated statin dose and other lipid-lowering therapies
  • ipoprotein apheresis is an expensive last-line therapeutic procedure involving extracorporeal filtering of apoB-containing lipoproteins (i.e. LDL) from the blood
• PCSK9 inhibitors, including alirocumab and evolocumab, lower LDL by ~60% in addition to diet, exercise and other lipid-lowering therapies
  • Mega-trials evaluating clinically-important outcomes are underway

Patients

• Multicenter (14 centers in Germany & USA, enrollment March-September 2015)
• Inclusion criteria:
  • HeFH diagnosed by clinical criteria (Simon Broome or Dutch Lipid Network criteria) or genotyping
  • Consistently received lipoprotein apheresis q1week x4+ weeks or q2weeks x8+ weeks
  • Stable background lipid-lowering therapy, diet, exercise x8+ weeks
• Exclusion criteria: Homozygous FH
• Screened 76 patients -> randomized 62 (41 to alirocumab, 21 to placebo)
• "Average" patient @ baseline
  • 58 y
  • Male 58%
  • LDL: Alirocumab 4.5 mmol/L, placebo 5.0 mmol/L
  • Median apheresis duration before study: 4.9 y (range: 0.5-32.9 y)
  • Lipid-lowering therapies:
    • Statin ~55% (~half on max dose)
    • Others unknown (only reported "ever taken")
  • Apheresis regimen: q1w (43.5%), q2w (56.5%)

Interventions & Co-Interventions

• I: Alirocumab 150 mg (as 1 mL volume) subcutaneously q2weeks x18 weeks, administered at study site
  • # of injections: Mean 8.6 (SD 1.3)
• C: Placebo as per above regimen
  • # of injections: Mean 8.4 (SD 1.7)
• Co-i: Apheresis continued unless LDL measured as reduced by >30% from baseline

Results

• LDL
  • Baseline: 4.5 vs 5.0 mmol/L
  • @ week 6 (when pre-study apheresis regimen was maintained): 2.3 vs 4.8 mmol/L (55% greater reduction from baseline with alirocumab vs placebo)
  • @ week 18 (when apheresis sessions were omitted if LDL >30% lower than baseline): 2.9 vs 4.9 mmol/L
• Apheresis
  • Difference in apheresis rate in weeks 7-18: 75% fewer apheresis sessions with alirocumab vs placebo
    • % of apheresis sessions required, median (range): 0% (0-100) vs 83% (42-100)
  • % of patients requiring no apheresis in weeks 7-18: 63.4% vs 0% (NNT 2)
• Safety
  • Serious adverse events: 9.8% vs 9.5% 
  • Adverse event leading to study drug discontinuation: 4.9% vs 4.8%
  • Any adverse event: 75.6% vs 76.2%
    • Fatigue: 14.6% vs 9.5%
    • Myalgia: 9.8% vs 4.8%
    • CK >3x ULN: 7.3% vs 0%

Issues with internal validity?

• No: 2:1 randomization, allocation-concealed, double-blind (patients & apheresis site personnel blinded to LDL values) RCT with intention-to-treat analysis that accounted for drop-outs (8%)
• Design involved 2 intervals:
  • Weeks 0-6: Apheresis contined as per established pre-study regimen
  • Weeks 7-18: Apheresis frequency adjusted based on LDL response to treatment; not performed if LDL decreased 30% or more from baseline LDL

HPS2-THRIVE - Niacin for CV prevention

HPS2-THRIVE Collaborative Group. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med 2014;371:203-12.

Clinical Question

In patients with cardiovascular disease receiving moderate-intensity statin +/- ezetimibe, does niacin (+ laropiprant) safely reduce cardiovascular events?

Bottom Line

• In patients with cardiovascular disease already receiving moderate-intensity statin therapy (& half taking ezetimibe) who tolerated niacin for a month, niacin does not reduce cardiovascular events, definitely increases serious adverse events due to numerous causes (NNH 35), and may increase the risk of death (NNH 200) over 4 years.

• Niacin has no clear role in prevention of cardiovascular disease.

Design

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Allocation-concealed "superiority" RCT with all (patients, clinicians, investigators) blinded, low loss-to-follow-up (<1%), analyzed using the intention-to-treat population.

Note 1: All patients subjected to pre-randomization run-in phase where they discontinued previous statin therapy & switched to simvastatin 40 mg/day

• If total cholesterol >3.50 mmol/L or increased from previous therapy after 4 weeks, added ezetimibe 10 mg/d
• Once stable on LDL-lowering therapy, all patients given a single daily tablet of niacin extended-release 1 g + laropiprant 20 mg, if tolerated this was doubled x3-6 weeks
• Patients who tolerated the regimen without clinically-significant adverse effects were randomized to niacin/laropiprant or placebo

Note 2: Randomization performed using minimization algorithm.

Patients and Setting

• China, Scandinavia, UK, 245 centers
• April 2007 - July 2010
• Inclusion criteria:
  1. Men or women 50-80 y/o
  2. History of
     • Cerebrovascular atherosclerotic disease (previous ischemic stroke/TIA, carotid revascularization)
     • MI
     • PAD (intermittent claudication or previous revascularization)
     • Diabetes with above or symptomatic CAD
• Key exclusion criteria:
  • Receiving LDL-lowering therapy "more intensive" than simvastatin 40 mg + ezetimibe 10 mg
  • <3 months since ACS/MI or stroke
  • Planned revascularization procedure <3 months after randomization
  • SOB at rest for any reason
  • Contraindications to niacin/statin
    • Chronic liver disease, or current ALT >1.5x upper normal limit
    • Serum creatinine >200 mcmol/L
    • Evidence of active inflammatory muscle disease (e.g. dermatomyositis, polymyositis), or CK >3x upper normal limit
  • Concurrent treatment with ezetimibe, fibrate, or potent CYP3A4 inhibitor
• 51,698 screened -> 42,424 entered run-in phase -> 25,673 randomized (~50% screened)
• Average patient:
  • 64.9 y/o
  • 17% female
  • Region: Europe 57%, China 43%
  • PMHx
    • Cerebrovascular disease 32%
    • MI 68%
    • PAD 12%
    • Diabetes 32%
  • Lipids (after run-in phase on simvastatin 40 mg +/- ezetimibe 10 mg)
    • Total cholesterol 3.31 mmol/L 
    • HDL 1.14 mmol/L
    • LDL 1.64 mmol/L

Intervention and Control

• Intervention: Niacin extended-release 2 g + laropiprant 40 mg once daily
  • Average adherence during study: 78%
• Control: Placeb
  • Average adherence during study: 86%
• Co-interventions common to both groups: Simvastatin 40 mg +/- ezetimibe 10 mg to achieve total cholesterol <3.50 mmol/L
  • Simvastatin 40 mg: 100%
  • Ezetimibe 10 mg: 47%

Outcomes

• @ median 3.9 years
• Niacin improved lipids versus placebo
  • HDL +0.16 mmol/L
  • LDL -0.25 mmol/L
  • Triglycerides -0.37 mmol/L
• Efficacy: No benefit whatsoever of niacin.
• Safety: 
  • Significant INCREASE in serious adverse events with niacin (NNH 35), both due to predicted adverse effects of niacin (gastrointestinal issues, new/worsening diabetes), but also adverse effects not yet appreciated to be caused by niacin (serious bleeds & infections)
  • More patients in the niacin group discontinued study due to intolerable side-effects (1/4 patients in the group; NNH 12 versus placebo), despite every patient taking niacin x3-6 weeks in the run-in phase
• No benefit in any of the 30+ subgroup analyses conducted.

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HPS2-THRIVE outcomes

Key Considerations

Generalizability: 

• This was a secondary prevention trial of patients with existing atherosclerotic cardiovascular disease (cerebrovascular, coronary or peripheral) also taking simvastatin 40 mg/d (all patients) +/- ezetimibe (~1/2 of patients)
• Although there were no specific lipid criteria for enrollment, there was also lack of efficacy in the half of patients who had "low HDL [<1.0 mmol/L])
• Laropiprant is an antagonist of prostaglandin D2 (receptor responsible for niacin flush), designed to improve tolerability of niacin. Despite combining this drug with niacin, tolerability of niacin was abysmal.

Internal validity:

• This study was "enriched" to demonstrate a benefit with a rigorous run-in phase designed to enroll patients unlikely to discontinue niacin.
  • Despite this, more patients in the niacin group experience serious adverse events & discontinued drug therapy due to intolerability.

Context

• AIM-HIGH trial (2011) in patients with low HDL also taking moderate-intensity statin: Niacin provided no cardiovascular benefit.

• In a 2014 meta-analysis, fibrates, niacin & CETP inhibitors (drugs that lower HDL) did not reduce cardiovascular outcomes when added to statins.

• The Coronary Drug Project trial (1975), which enrolled its first patient in 1966, is the only trial that has demonstrated the cardiovascular benefit of niacin. In a population of men aged 30-64 years with prior MI, niacin reduced the risk of non-fatal MI over ~6 years (NNT 28), with no effect on mortality.

  • This trial is not generalizable to today's practice, being conducted >40 years ago in men with prior MI in an era where aspirin, ACE inhibitors, beta-blockers, statins, and PCI were not yet available/in use.

HOPE-3 (statin)

Yusuf S, et al. Cholesterol lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med 2016;online

Clinical Question

In patients without CVD with 1+ CV risk factors, does the indiscriminate use of a statin irrespective of LDL reduce the risk of CVD?

Bottom Line

In a population of patients without CVD with a ~1% annual risk of CVD/MI/stroke at baseline, a fixed "medium" dose of rosuvastatin lowered this risk by ~25% to 0.75%/year. These results are consistent with previous trials of statins in primary prevention.

Design

2x2 factorial, allocation-concealed RCT with "everybody" blinded, low loss-to-follow-up (<1%), analyzed using the intention-to-treat population.

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Special notes:

• Pre-enrollment run-in phase: Single-blind treatment with both HOPE-3 active treatments (BP-lowering & statin) x4 weeks. Advanced to randomization if:
  • Took at least 80% of doses
  • Tolerated regimen without unacceptable adverse events
• Change to pre-defined outcomes:
  • Single primary outcome changed to 2 co-primary outcomes (done before investigators saw unblinded data)

Patients and Setting

• 21 countries, 228 centers
• April 2007 - November 2010
• Included:
  1. Men 55+ y/o and women 65+ y/o + 1 additional CV risk factor:
     • FHx: Premature CHD in 1o-degree relative (age <55 in men or <65 in women)
     • SHx: Current/recent smoking (regular tobacco within 5 years)
     • O/E: Waist/hip ratio >89 in men and >84 in women
     • Labs:
       • Low HDL (<1.0 mmol/L in men, <1.3 mmol/L in women)
       • Renal dysfunction (microalbuminuria, eGFR <60 mL/min or SCr >124 micromol/L)
       • Dysglycemia (impaired fasting glucose or glucose tolerance test, but not diabetes requiring more than 1 oral antihypoglycemic)
  2. Women 60-64 y/o with 2 additional CV risk factors
  • NOTE: total cholesterol, non-HDL & LDL NOT included as CV risk factors for eligibility, & no minimum criteria for enrollment
• Excluded:
  • PMHx:
    • Manifest atherosclerotic CVD
    • Clear indication or contraindication for statin &/or ACEI/ARB/thiazide, as determined by subject's own local MD
    • • Chronic liver disease or abnormal liver enzymes (i.e. ALT or AST >3x ULN)
      • Inflammatory muscle disease or CK >3x ULN
  • Concurrent meds:
    • Statin or fibrate (patients taking other cholesterol-lowering drugs could be enrolled)
• 14,682 entered run-in phase -> 12,705 (86.5%) enrolled
• Average patient:
  • 65.7 y/o
  • 46% female
  • Race: 29% Chinese, 27% Hispanic, 20% White, 15% South Asian, <2% Black
  • Enrollment CV risk factors:
    • 26% with FHx premature CHD
    • 28% current/recent smoking
    • 87% with elevated waist/hip ratio (mean BMI 27)
    • 36% with low HDL
    • <3% with renal dysfunction
    • 13% with impaired glucose, 6% with diabetes
    • BP 138/82 mm Hg (38% with history of HTN)
    • SCr: 80 micromol/L
    • Lipids: Total cholesterol 5.2 mmol/L, HDL 1.2 mmol/L, LDL 3.3 mmol/L
    • Fasting plasma glucose: 5.3 mmol/L
    • Baseline meds
      • Any BP-lowering drug 22%
        • CCB 15%
        • Beta-blocker 8%
      • ASA 11%

Intervention and Control

• Intervention: Rosuvastatin 10 mg PO daily
  • Adherence: 88% @ 1 year, 84% @ 3 years, 75% @ 5 years
• Control: Matching placebo
  • Adherence: 88% @ 1 year, 83% @ 3 years, 73% @ 5 years
• Co-interventions common to both groups:
  • Randomized to candesartan 16 mg + hydrochlorothiazide 12.5 mg PO once daily or placebo
  • Individualized structured lifestyle advice
• Follow-up:
  • Visits q6 weeks x6 months, then q6 months
    • Monitoring parameters: Adherence, safety, trial outcomes

Outcomes

• @ median follow-up 5.6 years
• Mean LDL 1 mmol/L lower with rosuvastatin vs control @ 1 year
• Efficacy: Statistically significant reduction in both co-primary outcomes & a number of secondary outcomes. The effect on CV death/MI/stroke translates to a 1.1% absolute risk reduction at 5.6 years (i.e. a number needed to treat of 91 over 5.6 years, or ~500 per year)
• Safety:
  • No signal of clinically-relevant increased risk of cancer, dementia/neuropsychiatric abnormalities, changes in LFTs, or diabetes
  • 2 vs 1 cases of rhabdo; consistent with previous statin trials
  • Absolute risk increase of 1.1% in muscle pain/weakness with rosuvastatin 10 mg vs placebo that did not translate into a greater risk of drug discontinuation
• Subgroup analyses: None of 16+ significant. In other words, the relative effects (relative risk reduction) of statins on CVD events are consistent across the study population.

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Outcomes in HOPE-3 statin trial