Novel screening method for familial hypercholesterolemia: Child-parent screening in primary care

Wald DS, et al. Child-parent familial hypercholesterolemia screening in primary care. N Engl J Med 2016;375:1628-37.

Bottom-line: In the UK, a child-parent FH screening strategy done at the time of routine immunizations by a GP identified FH in 1 child and 1 parent for every 360 children screened.

Lipid or FH mutation testing alone are each inadequate to diagnose FH in this population due to high false-positive rates.

Context

• Familial hypercholesterolemia (FH) is a genetic dyslipidemia that affects ~1 in 500 Canadians
• Untreated FH leads to accelerated atherosclerosis;
  • By age 50, almost half of men and 20% of women with untreated FH have experienced a coronary event.
• Only 5% of individuals with FH are properly diagnosed, often only after experiencing a cardiovascular event
• Multiple countries have implemented various screening strategies, including screening of all adults +/- children ("universal screening"), to more selective screening of first-degree relatives of individuals identified to have FH ("cascade screening")
• The goal of screening programs is to identify and treat FH before patients manifest clinical atherosclerosis

Who was involved in this study?

• Timeframe: 2012-2015
• Country: UK
• Setting: 92 GP offices
• Participants: 11,010 children (10,095 with valid screening test) presenting for their routine immunizations at ~1 year of age
• Baseline characteristics
  • Median age 12.7 months
  • Family hx of premature MI 11%
  • Lipid panel, median
    • Total cholesterol 3.93 mmol/L
    • LDL 2.20 mmol/L
    • HDL 0.93 mmol/L
    • Triglycerides 0.67 mmol/L
  • Median age of parents: Mother 31 y, father 34 y

What was the screening intervention?

1. Heel-stick capillary blood sample from the child to measure:
   • Lipid panel (total cholesterol, HDL, triglycerides)
   • Possible FH mutations (48 tested, including mutations of the LDL receptor, ApoB, & PCSK9)
2. Both parents of a child with a positive screening test for either of the above: Venipuncture for same screening test

What counted as a "positive" screening test?

• Children
  1. Total cholesterol >5.95 mmol/L (>99th percentile) + at least 1 FH mutation, or
  2.  Total cholesterol >5.95 mmol/L x2 (test repeated 3 months later)
• Parents of children with a positive screening test
  1. If child had a FH mutation: Same FH mutation, or
  2. Higher cholesterol level of the 2 parents

How many children & parents had a positive screen for FH?

• Children: Positive screening test = ~0.28% (prevalence & number needed to screen = ~360)
  • False positives:
    • 0.6% (64/10,095) had a single elevated cholesterol level (negative on repeat + no known FH mutation)
    • 0.17% (17/10,095) had a FH mutation without hyperlipidemia
• Parents: Prevalence 0.28% (based on definition above)

What was the impact of screening?

• Identified 1 in 360 children with FH. Notably, this likely captured every case of FH in this population based on a previous estimated prevalence of ~1 in 500;
• Identified parents with FH at an age (31-34 y/o) where they may have already had years of atherosclerotic buildup, but were not likely to have developed a coronary event. These parents could therefore receive therapy early enough to modify their cardiovascular risk and at least delay their first coronary event.

What gaps in our knowledge remain?

1. How do we treat these children with FH once we've identified them? At what age do we start lipid-lowering therapies?
2. How do we treat and/or monitor individuals with a FH mutation but normal cholesterol levels?
3. What is the financial impact of child-parent screening? Considerations include costs to society (cost of lipid + FH mutation screening, lipid-lowering therapies including PCSK9 inhibitors) and to individuals (lipid-lowering therapy and insurance premiums).
4. Which is most effective and cost-effective between the 3 available screening methods: Cascade, child-parent, or universal screening? Would a hybrid cascade+child-parent screening strategy be best?

Reducing LDL & improving CV outcomes - systematic review

Silverman MG, et al. Association between lowering LDL-C and cardiovascular risk reduction among different therapeutic interventions: A systematic review and meta-analysis. JAMA 2016;316:1289-97.

Clinical question: Does reduction of CV outcomes with lipid-lowering therapy correlate with degree of LDL-lowering?

Bottom line:

• The value of this study is mechanistic; it does not provide clinical guidance. 

• The analysis demonstrates that CV outcome reduction of proven lipid-lowering drugs is closely associated with degree of LDL-lowering. This supports the lipid hypothesis, i.e. that lipid-lowering drugs which lower CV risk outcomes (statins, bile acid sequestrants, & ezetimibe) do so primarily by lowering LDL.

• This study does not validate a particular lipid target, nor does it support using interventions with neutral, harmful or conflicting evidence (fibrates, niacin, or CETP inhibitors) to achieve a lipid target.

Search

• Databases: MEDLINE, Embase
• Timeframe: 1966 to July 2016
• Inclusion criteria:
  • Randomized controlled trials (RCTs)
  • Compared (1) LDL-lowering intervention to control/placebo or (2) more vs less intensive statin therapy
  • Reported cardiovascular outcomes including MI
  • Duration of at least 6 months
  • At least 50 events
• Exclusion criteria: Trial with populations with "significant competing risks", including heart failure & chronic kidney disease
• Additional measures for comprehensiveness:
  • References lists of identified studies, review and meta-analyses
  • Reviewed abstracts of major cardiovascular meetings held in past 2 years (no mention of which)
  • Contacted content experts

Results of systematic review

• Included 49 RCTs (n=312,175)
  • Statin (25 trials)
  • Fibrate (9 trials)
  • Diet (4 trials)
  • CETP inhibitor (3 trials)
  • Niacin (3 trials)
  • Bile acid sequestrants (2 trials)
  • PCSK9 inhibitor (2 trials)
  • Ezetimibe (1 trial)
  • Ileal bypass surgery (1 trial)

Results of the meta-analysis

• Mean follow-up 4.3 years
• Mean ~absolute reduction in LDL vs placebo in trials
  • PCSK9 inhibitor -1.85 mmol/L
  • Ileal bypass -1.6 mmol/L
  • Bile acid sequestrant -0.90 mmol/L
  • Statin -0.85 mmol/L (all drugs & doses pooled)
  • Diet -0.75 mmol/L
  • Niacin -0.35 mmol/L
  • Ezetimibe -0.3 mmol/L
  • Fibrate -0.25 mmol/L
• ~23% relative risk reduction (RRR) in major vascular events per 1 mmol/L reduction in LDL with any interventions except CETP inhibitors

Considerations & limitations

• Generalizability & internal validity
  • Investigators excluded studies that included patients with "significant competing risk", which includes some of the landmark "negative" statin trials (CORONA, GISSI-HF, 4D, etc)
    • Results of this analysis don't apply to the subpopulations of these studies (primarily heart failure & chronic kidney disease)
    • The analysis may overestimate the true relative risk reduction since this exclusion criterion primarily excluded "negative" studies.
  • Numerous differences in populations between trials, including
    • Era (e.g. 1st fibrate/niacin trial conducted in 60s, most statin trials conducted in 1990s-2000s)
    • Primary vs secondary prevention
    • LDL before initiation of study treatment & background CV therapies
• Results
  • Although interventions produced comparable RRRs in CV outcomes per 1-mmol/L reduction in LDL, actual achievable LDL reduction & therefore realistic CV reductions with each agent are quite different
  • This study evaluated a composite CV outcome, which bundles together outcomes of different severity & importance to patients. Different interventions may have the same effect on a composite CV outcome, but not specific components. For example, statins reduce every type of CV event (death, MI, stroke, revascularization), whereas fibrates only reduce non-fatal MI, but not death or stroke.

CORONA & GISSI-HF - Statins in heart failure

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

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

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.