SWORD - d-sotalol in patients with previous MI & LV dysfunction

Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. Lancet 1996;348:7-12.

Bottom line: In patients with MI & LV dysfunction (the majority with moderately symptomatic HFrEF), d-sotalol (a pure potassium channel-blocking antiarrhythmic) increased the risk of death within 5 months of treatment. 

Although there was no difference in arrhythmias captured on EKG, the majority of the deaths attributable to d-sotalol are presumed to be from induced polymorphic arrhythmias (TdP).

Patients

• Inclusion
  • Adults with either:
    • Recent MI (6-42 days), or
    • Remote MI (>42 days) + heart failure with NYHA functional class II or III
  • LVEF <40%
• Exclusion
  • Unstable angina
  • Heart failure NYHA IV
  • PMHx
    • Life-threatening arrhythmia (sustained VT, VF, or cardiac arrest) unrelated to anMI
    • Sick sinus syndrome, 3rd degree AV block, 2nd degree AV block type 2 not treated with pacemaker
    • PCI or CABG within 14 days
    • QTc >460 msec
    • CrCl <50 mL/min
    • Serum K <4.0 mmol/L
    • Serum Mg <0.75 mmol/L
    • Use of concomitant class I or III antiarrhythmic
• ? screened -> 3121 randomized & analyzed
• "Average" patient
  • Age 60 y
  • Female 14%
  • White 93%
  • Recent MI 29%
  • Mean time from index MI - "recent" (3 weeks), "remote" (4 years)
  • Heart failure NYHA class I (7%), II (72%), III (22%)
  • LVEF 31%
  • Baseline QTc 420 msec
  • 24h Holter:
    • Mean 54 PVCs/hour
    • Patients with VT runs 36%

Interventions

• I: d-sotalol
  • Initial dose: 100 mg PO BID x1 week,
  • If initial dose tolerated & QTc <520 msec: Dose increased to 200 mg PO BID x1 week
  • If 200 mg PO BID tolerated & QTc <560 msec: Continued for rest of trial
  • Throughout trial, dose reduced if >560 msec (d-sotalol discontinued if QTc >560 msec with 100 mg PO BID)
  • Note: d-sotalol is the dextro enantiomer of sotalol, which has potassium-blocking activity, but minimal beta-blockade. Sotalol used in practice includes both the l & d enantiomers of sotalol.
• C: Matching placebo

Results @ mean 5 months

• Death (primary outcome): Relative risk 1.65 (95% confidence interval 1.15-2.36)
  • d-sotalol 5.0% vs placebo 3.1% (number needed to harm = 53)
  • Harmful effect consistent among all subgroup analyses
• Arrhythmic events
  • Deaths presumed to be due to arrhythmia: RR 1.77 (1.15-2.74)
    • 3.6% vs 2.0% (NNH 63)
  • VF: 0.4% vs 0.2%
  • Sustained VT: 0.2% vs 0.3%
  • Torsade de pointes (TdP): 0.1% vs 0.1%
• Discontinuation due to adverse events: 6.5% vs 5.2%

Issues with internal validity?

• Unclear: Described as "randomized, double-blind trial", but no details provided on sequence generation, allocation concealment, blinding method, loss-to-follow-up, or use of intention-to-treat population;
  • Despite the above, low risk of allocation, performance or detection bias as patients were quite similar at baseline, and the primary was as objective and unfalsifiable as it gets (all-cause mortality)
• Trial stopped early (due to unexpected increased mortality in d-sotalol group)

OPTIC - Beta-blockers +/- amiodarone vs sotalol to prevent ICD shocks

Connoly SJ, et al. Comparison of beta-blockers, amiodarone plus beta-blockers, or sotalol for prevention of shocks from implantable cardioverter defibrillators: The OPTIC study: A randomized trial. JAMA 2006;295:165-71.

Bottom-line: In patients with new ICD placement for secondary prevention of VT/VF already receiving a beta-blocker, addition of amiodarone to beta-blocker therapy reduced the risk of ICD shocks from 4 to 0.5 over 1 year (NNT 4), including shocks for ventricular and non-ventricular tachyarrhythmias. This increased efficacy came with a greater risk of discontinuing therapy (NNH 8) and greater risk of known amiodarone-related side-effects, including symptomatic bradycardia (NNH 18), pulmonary adverse events (NNH 20), and hypothyroidism (NNH 24).

Replacing beta-blocker therapy with sotalol may also reduce ICD shocks in this population, though it is less efficacious than adding amiodarone, and also carries a greater risk of discontinuation (NNH 6), and possibly pulmonary adverse events (NNH 34).

Patients (n=412)

• Inclusion
  • New ICD placement <21 days, + 1 of the following:
    • Sustained VT/VF or cardiac arrest (not <72h of MI) + LVEF <40%, or
    • Inducible VT/VF + LVEF <40%, or
    • Unexplained syncope with inducible VT/VF
• Exclusion
  • HF with NYHA functional class IV
  • Long QT syndrome
  • Absence of structural heart disease
  • Symptomatic AF likely to require class I or III agents
  • QTc >450 msec (or >480 msec if LBBB/RBBB present)
  • CrCl <30 mL/min
  • Receiving class I or III antiarrhythmic
  • Received amio or sotalol >20 consecutive days at any time (patients who previously received amio x10-20 days required 10-day washout before randomization)
• "Average" patient
  • Age 63 y
  • Female ~20%
  • Arrhythmia hx: Unmonitored syncope (30%), any spontaneous VT/VF 70%, inducible VT/VF only (30%)
  • HF NYHA functional class II-III ~50% (rest were class I)
  • LVEF 34%
  • Past medical hx
    • MI 80%
    • Non-ischemic cardiomyopathy 10%
    • AF 16%
  • Meds at baseline
    • Beta-blocker 80%
    • Amio 3-7%
    • Sotalol <2%

Interventions

• I 1: Amiodarone + beta-blocker
  • Amiodarone
    • Loading dose: 400 mg PO BID x2 weeks, then 400 mg PO daily x 4 weeks
    • Then maintenance dose of 200 mg PO daily for rest of study
  • Beta-blocker per dose recommendations below
• I 2: Sotalol
  • CrCl >60 mL/min: Recommended dose 240 mg/d (divided BID or TID)
  • CrCl 30-60 mL/min: Recommdended dose 160 mg/d
• C: Beta-blocker
  • Bisoprolol @ recommended dose 10 mg daily
  • Carvedilol @ recommended dose 25 mg PO BID
  • Metoprolol @ recommended dose 50 mg PO BID

Results @ median 1 year

• ICD shocks
  • Any shock (primary outcome): Amio+beta-blocker 10.3%, sotalol 24.3%, beta-blocker 38.5%
    • Amio+beta-blocker vs beta-blocker alone: Hazard ratio (HR) 0.27, 95% confidence interval 0.14-0.52 (NNT 4)
    • Sotalol vs beta-blocker: HR 0.61 (0.37-1.01) (NNT 8, though not statistically significant)
  • Inappropriate shock (ICD shocked for non-ventricular tachyarrhythmia): Amio+bet-blocker 3.3%, sotalol 9.4%, beta-blocker 15.4%
    • Amio+beta-blocker: HR 0.22 (0.07-0.64) (NNT 9)
    • Sotalol vs beta-blocker: HR 0.61 (0.29-1.30)
  • Mean number of shocks/year: Amio 0.5, Sotalol ~1, beta-blocker ~4
• No measure of quality of life evaluated
• Safety
  • Death: Amio+beta-blocker 4.3%, sotalol 3.0%, beta-blocker 1.4% (p=0.36)
  • Discontinued study drug: Amio+beta-blocker 17.9%, sotalol 23.1%, beta-blocker 5.1%
    • NNH 8 for amio+beta-blocker vs beta-blocker alone; NNH 6 for sotalol vs beta-blocker
  • Torsades de pointes: 0 in all groups
  • Symptomatic bradycardia: Amio+beta-blocker 6.4%, sotalol 1.5%, beta-blocker 0.7%
    • NNH 18 for amio+beta-blocker vs beta-blocker alone
  • Pulmonary adverse event: Amio+beta-blocker 5%, sotalol 3%, beta-blocker 0%
    • NNH 20 for amio+beta-blocker vs beta-blocker alone; NNH 34 for sotalol vs beta-blocker
  • Hypothyroidism: Amio+beta-blocker 4.3%, sotalol 0.8%, beta-blocker 0%
    • NNH 24 for amio+beta-blocker vs sotalol
  • Skin adverse event: Amio+beta-blocker: 2.9%, sotalol 2.2%, beta-blocker 1.5%

Issues with internal validity?

• No: Randomized, allocation-concealed, open-label trial with moderate loss-to-follow-up (3.6%) analyzed using intention-to-treat principles
  • Open-label: Risk for performance bias, however, low risk of detection. Shock was based on ICD interrogation and adjudicated by blinded investigators
  • Loss-to-follow-up: Differential loss-to-follow-up that was greater in beta-blocker group was unlikely to impact results
• Stopped early due to slow recruitment (412/700 planned patients) with change in primary analysis (amio+beta-blocker & sotalol combined in 1 group vs beta-blocker)

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%