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.

SOLVD & SOLVD-Px - Enalapril in HFrEF & asymptomatic LV dysfunction

The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;325:293-302.

The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 1992;327:685-91.

Bottom line: In patients with HFrEF, enalapril reduced the risk of death and HF hospitalization (NNT 11) over 3-4 years. Patients with asymptomatic reduced EF did not experience a reduced risk of death with enalapril, but did have a reduced risk of progressing to HF (NNT 10) and HF hospitalization (NNT 24).

 

Patients (n=2569 in SOLVD, 4228 in SOLVD-Px)

• Inclusion
  • HF (SOLVD) or no "overt" HF (SOLVD-Px)
  • EF 0.35 or less (mesaured by nuclear testing, angiography or echo)
• Exclusion
  • Age >80 y
  • MI <1 month
  • Hemodynamically serious valvular disease requiring surgery
  • Unstable angina or angina severe enough to require revascularization
  • Severe pulmonary disease
  • SCr >177 umol/L
  • "Any other disease that might substantially shorten survival"
• "Average" patient
  • SOLVD (overt HF)
    • Age 61 y
    • Female 20%
    • BP 125/77 mm Hg
    • HF characteristics
      • NYHA functional class I (11%), II (57%), III (30%), IV (<2%)
      • LVEF 25%
    • PMHx
      • CAD 70%, previous MI 66%
      • Dilated cardiomyopathy 18%
      • AF 10%
      • HTN 42%
    • Meds
      • Diuretics 85%
      • Digoxin 66%
      • Nitrate 40%
      • Beta-blocker 8%
  • SOLVD-Px
    • Age 59 y
    • Female 11%
    • BP 125/78 mm Hg
    • NYHA functional class I (67%), II (33%)
    • LVEF 28%
    • PMHx
      • CAD 83%, MI 80%
      • Dilated cardiomyopathy 9%
      • AF 4%
      • HTN 37%
    • Meds
      • Diuretics 17%
      • Digoxin 12%
      • Nitrate 30%
      • Beta-blocker 24%

Interventions

• I: Enalapril uptitrated up to maximum of 10 mg PO BID
  • SOLVD: At end of study, ~33% had discontinued study drug & ~50% were taking 10 mg PO BID
  • SOLVD-Px: 24% had discontinued study drug at end of study
• C: Matching placebo

Results

• SOLVD (overt HF) @ mean follow-up 3.4 y
  • Death or HF hospitalization: 47.7% vs 57.3% (NNT 11)
    • Death (primary outcome): 35.2% vs 39.7% (NNT 23)
  • All hospitalizations: 69% vs 74% (NNT 20)
  • Safety
    • Any adverse event: 87% vs 82% (NNH 20)
      • Dizziness or fainting: 57% vs 50% (NNH 15)
      • Cough: 37% vs 31% (NNH 17)
      • SCr >177 umol/L: 10.7% vs 7.7% (NNH 34)
      • Serum K >5.5 mmol/L: 6.4% vs 2.5% (NNH 26)
• SOLVD-Px @ mean follow-up 3.1 y
  • Death or HF hospitalization: 2.7% vs 4.8% (NNT 48)
    • Death (primary outcome): 14.8% vs 15.8% (p=0.30)
    • HF hospitalization: 8.7% vs 12.9% (NNT 24)
  • All hospitalizations: 41.5% vs 45.7% (NNT 23)
  • Development of HF: 20.7% vs 30.2% (NNT 10)
  • Safety
    • Any adverse event: 76% vs 72% (NNH 25)
    • Dizziness or fainting: 45.8% vs 39.2%
    • Cough: 33.8% vs 27.3%

Issues with internal validity?

• No: Randomized, allocation-concealed, blinded trial with blinded outcome adjudication, low loss-to-follow-up (<0.5%) analyzed using the intention-to-treat population
• Run-in phases:
  • Patients received enalapril 2.5 mg PO BID x2-7 days to identify intolerant individuals (only 4% excluded during this phase)
  • Then switched to placebo x14-17 days to identify patients who'd acutely decline off an ACEI (4% excluded during this phase)

Additional considerations

• A subsequent systematic review and meta-analysis including CONSENSUS, SOLVD, as well as numerous smaller trials of ACE inhibitors in patients with HFrEF confirmed a consistent 23% relative risk reduction in death with ACE inhibitors in HFrEF
  • Subgroup analyses suggested greatest relative mortality benefit in subgroups of individuals with NYHA class IV symptoms (dominated by CONSENSUS trial) and those with LVEF <25%

CONSENSUS - Enalapril in severe HF

The Consensus Trial Study Goup. Effects of enalapril on mortality in severe congestive heart failure. N Engl J Med 1987;316:1429-35.

Bottom line: In patients with NYHA class IV HF (presumably with reduced EF), enalapril reduced the risk of death (NNT 6-7) & reduced symptom burden at 6 & 12 months.

Patients (n=253)

• Inclusion
  • Clinical diagosis of HF
    • Hx of heart disease
    • Symptoms of dyspnea and/or fatigue
    • Signs of fluid retention
  • Symptomatic at rest (NYHA functional class IV)
  • Cardiomegaly on CXR, defined as heart size
    • Men: >600 mL/m^2
    • Women: >550 mL/m^2
  • No assessment of myocaridal function performed (? LVEF)
• Exclusion
  • NYHA <IV after optimization with diuretics & digoxin
  • Hemodynamically important aortic/mitral stenosis
  • MI <2 months
  • Unstable angina
  • Planned cardiac surgery
  • 1o pulmonary disease or right HF due to pulmonary disease
  • SCr >300 umol/L
• "Average" patient
  • Age 70
  • Female 30%
  • HF duration: <18 months (25%), 18 months to 4 y (~25%), >4 y (50%)
  • PMHx
    • CAD 73%, previous MI 48%
    • Cardiomyopathy 15%
    • Valvular heart disease ~20%
    • AF ~50%
  • BP 120/75 mm Hg
  • SCr 130 umol/L
  • K 4.0 mmol/L
  • Meds
    • Furosemide 90% (mean dose 200 mg)
    • Spironolactone 55% (mean dose 80 mg)
    • Digoxin 93%
    • Nitrate 45%, hydralazine 2%
    • Anticoagulant 33%

Interventions & co-interventions

• I: Enalapril
  • Initial dose 5 mg PO BID (started in hospital)
  • Then increased to 10 mg PO BID after 1 week
  • Then the dose could be increased up to 20 mg PO BID
  • Mean dose @ end of study: 18.4 mg/day (~10 mg PO BID)
• C: Matching placebo
• Co-interventions
  • Optimized on diuretics +/- digoxin at start of trial
  • Other non-ACEI vasodilators permitted, including nitrates, alpha-1 blockers, hydralazine

Results @ 6 months

• Death, statistically significant reduction
  • @ 6 months (primary outcome): 26% vs 44% (NNT 6 - relative risk reduction (RRR) 40%)
  • @ 1 year: 36% vs 52% (NNT 7 - RRR 31%)
• Improvement in NYHA functional class: 42% vs 22% (NNT 5)
• Study drug discontinuation: 17% vs 14% (NSS)

Issues with internal validity?

• Possible exaggeration of benefit due to early termination for mortality in enalapril group in unplanned interim analysis
• Otherwise well-designed: Randomized, allocation-concealed, blinded trial with low loss-to-follow-up analyzed according to the intention-to-treat principle

EMPA-REG - Empagliflozin for CV risk reduction in T2DM with hx of CVD

Zinman B, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117-28.

Bottom line: In patients with T2DM and CVD, empagliflozin (at either dose of 10 mg or 25 mg daily) reduced the risk of death (NNT 39) & CV events (NNT 63) over 3 years.

Patients

• Inclusion
  • Adults with T2DM
    • No glucose-lowering agents in previous 12 weeks: 7-9%
    • Receiving glucose-lowering agents, stable x12 weeks: 7-10%
  • Established CVD, defined as any of the following:
    • MI >2 months ago
    • CAD (confirmed with angiography)
    • Stroke >2 months ago
    • PAD documented by
      • Limb revascularization or amputation
      • Peripheral artery stenosis >50% on angiography or non-invasive evaluation
      • ABI <0.9 on at least 1 side
• Key exclusion criteria
  • Cancer within last 5 y
  • Stroke/TIA within 2 months
  • Planned cardiac surgery or PCI in next 3 months
  • BMI >45
  • Blood dyscrasias or any disorder causing hemolysis or unstable RBCs
  • eGFR <30 mL/min/1.73 m^2
  • ALT, AST or ALP >3x ULN
• 11,531 individuals screened across 590 sites in 42 countries -> 7028 randomized -> 7020 analyzed
• "Average" patient
  • Age 63 y
  • Male 72%
  • White 72%, Asian 22%, Black 5%, other 1%
  • Geography: Europe 41%, North America 20%, Asian 19%, Latin America 15%, Africa 4%
  • CV risk factors
    • CAD 76% (multivessel 47%)
    • MI 46%
    • CABG 24%
    • Stroke 24%
    • PAD 20%
  • Time since T2DM dx: >10 y (57%), 5-10 y (25%), 1-5 y (16%)
  • Wt 87 kg, BMI 31
  • BP 136/77
  • Lipids: total 4.2, LDL 2.2, HDL 1.1 mmol/L
  • A1c 8%
  • Meds
    • Metformin 74%
    • Insulin 49%
    • Sulfonylurea 43%
    • DPP-4 inhibitor 11%
    • Antihypertensives 95%
      • ACEI 80%
      • Beta-blocker 64%
    • ASA 83%
    • Statin 76%

Interventions & co-interventions (median 2.6 y)

• I: Empagliflozin 10 mg or 25 mg
  • A1c lowered by 0.5-0.6% at 12 weeks vs placebo
• C: Matching placebo
• Co-interventions:
  • 1st 12 weeks after randomization: No change to glycemic management unles fasting glucose >13.3 mmol/L
  • After 12 weeks: Adjustment to glucose-lowering therapy according to local guidelines

Results @ median 3.1 y

• Results for both doses of empaglifozin were similar, and therefore pooled
• Statistically significant reduction in:
  • The primary outcome (CV death, MI, stroke): Hazard ratio (HR) 0.86, 95% confidence interval 0.74-0.99 (p=0.04)
    • 10.5% vs 12.1% (NNT 63)
  • Death: HR 0.68 (0.57-0.82)
    • 5.7% vs 8.3% (NNT 39)
  • HF hospitalization: HR 0.65 (0.50-0.85)
    • 2.7% vs 4.1% (NNT 72)
• No statistically significant difference:
  • MI: HR 0.87 (0.70-1.09) - 4.8% vs 5.4%
  • Stroke: HR 1.18 (0.89-1.56) - 3.5% vs 3.0%
  • Coronary revascularization: HR 0.86 (0.72-1.04) - 7.0% vs 8.0%
• Safety
  • Serious adverse events: 38.2% vs 42.3% (NNT 25, p<0.001)
  • Premature discontinuation: 23.4% vs 29.3%
  • Hypovolemia: 5.1% vs 4.9%
  • Acute kidney injury: 1.0% vs 1.6%
  • UTI: 18.0% vs 18.1% (complicated 1.7% vs 1.8%)
  • Genital infection: 6.4% vs 1.8% (NNH 22)
  • DKA: 0.1% vs <0.1%
  • Hypoglycemia (glucose <3.9 mmol/L or requiring assistance): 27.8% vs 27.9%
• Numerous subgroup analyses were performed, which demonstrated inconsistent subgroup interactions with the primary outcome and CV death

Issues with internal validity?

• No: Randomized, allocation-concealed, blinded trial with low loss-to-follow-up (<0.1%) analyzed using intention-to-treat principles 
• Run-in: 2-week open-label placebo run-in

Additional considerations

• The reduction of CV events became apparent after only 3 months. Previous trials of diabetes drugs or glycemic control goals have never demonstrated a benefit this early, suggesting that the apparent benefit of empagliflozin may have resulted from another mechanism. 
• The reduction int the primary CV event resulted mainly from a reduction in CV death, but not MI or stroke. This further argues against glycemic control as the beneficial mechanism of empagliflozin.