CANTOS - Canakinumab for patients with previous MI

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Ridker PM, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. NEJM 2017

Bottom line:

  • In patients with prior MI & hsCRP >2 mg/L, canakinumab reduced the risk of non-fatal coronary events (NNT ~160/year), but increased the risk of fatal infections (NNH ~1000/year).

  • Due to unresolved issues of cost & feasibility of use of this therapy, CANTOS has limited direct applicability to real-world practice, but serves as a proof of concept for anti-inflammatory therapy to reduce the risk of ASCVD.

 

Patients (n=10,061 after 17,482 were screened)

  • Included
    • Hx of MI
    • High-sensitivity CRP 2 mg/L or higher
  • Exclusion
    • Hx of chronic/recurrent infection
    • Previous CA
    • Known/suspected immunocompromised
    • Hx/high risk of TB or HIV-related disease
    • Ongoing use of other systemic anti-inflammatory tx
  • Baseline characteristics
    • 61 y
    • Female 26%
    • STEMI 54%, NSTEMI 34%, unknown 12%
    • Previous PCI 66%, CABG 14%
    • HF 22%
    • CV risk factors: Smoker 23%, HTN ~80%, diabetes ~40%
    • Labs
      • Median hsCRP 4.2 mg/L
      • LDL-C 2.1 mmol/L
    • Meds
      • ACEI/ARB ~80%
      • Anti-ischemic therapy 92%
      • Statin ~90%

Interventions

  • Interventions: Canakinumab 50 mg, 150 mg or 300 mg subcutaneously q3 months
    • 300 mg dose group: 300 mg q2 weeks x2 doses, then q3 months
  • Control: Matching placebo
     

Results @ median 3.7 years

Labs

  • hsCRP reduction: 50 mg (26%), 150 mg (37%), 300 mg (41%)
  • LDL, HDL: No effect

Efficacy

  • Primary outcome (CV death, MI or stroke):
    • Canakinumab 150 mg: 14.0% over follow-up (incidence rate: 3.86 per 100 patient-years)
    • Placebo: 16.0% over follow-up (incidence rate: 4.50 per 100 patient-years)
    • HR 0.85 (0.74-0.98), NNT 50 (NNT ~160/y)
  • Secondary efficacy outcome (primary + unstable angina hospitalization leading to unplanned revascularization):
    • Canakinumab 150 mg: 4.29 per 100 patient-years
    • Placebo: 5.13 per 100 patient-years
    • HR 0.83 (0.73-0.95)
  • Death: Canakinumab 150 mg 2.73/100 pt-y, placebo 2.97/100 pt-y, HR 0.92 (0.78-1.09)
  • MI: Canakinumab 150 mg 1.90/100 pt-y, placebo 2.43/100 pt-y, HR 0.76 (0.62-0.92)
  • Stroke: HR 0.98 (0.71-1.35)
  • Revascularization: Canakinumab 150 2.49/100 pt-y, placebo 3.61/100 pt-y, HR 0.68 (0.58-0.81)
  • Note: For brevity, I only include the efficacy data for the 150-mg dose here (50 mg generally ineffective/less effective, & 300 mg similar to 150 mg)

Safety/tolerance

  • Discontinued study drug: Canakinumab 18.7%, placebo 18.1%
  • Serious adverse events: Canakinumab 11.8/100 pt-y, placebo 12/100 pt-y, p=0.79
  • Serious adverse event from infection: Canakinumab 3.1/100 pt-y, placebo 2.9/100 pt-y, p=0.14
  • Fatal infection or sepsis: Canakinumab 0.3/1000 pt-y, placebo 0.2/100 pt-y, p=0.02

Considerations

  • Low risk of bias
    • Central, computerized randomization (allocation concealed)
    • Participants, clinicians & investigators blinded
    • 0.3% lost to follow-up
  • Generalizability
    • Eligibility criteria for this trial are broad (any prior MI + hsCRP >2 mg/L) & primarily excluded patients at high risk of adverse effects of immunosuppressive therapy, though enrolled patients had a relatively high risk of ASCVD (~4%/year in the placebo group)
  • Currently, canakinumab is approved under the organ drug status for rare diseases, & is priced at $200,000/year (US price in USD)

COMPASS - ASA + rivaroxaban (or riva alone) vs ASA alone in stable CVD

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Eikelboom JW, et al. Rivaroxaban with or without aspirin in stable cardiovascular disease. NEJM 2017

Note: This was a factorial trial; the other intervention under study - pantoprazole vs placebo - will be reported later in a separate report.

Bottom line:

  • In patients with stable CAD/PAD, addition of rivaroxaban 2.5 mg PO BID to low-dose ASA resulted in a reduction in cardiovascular events, primarily driven by all-cause mortality & stroke (NNT ~144 each), and an increase in major & minor bleed (NNH 84 & 28, respectively) over an average duration of 1.9 years;

    • In patients with PAD, rivaroxaban + ASA also reduces the risk of major adverse limb events (NNT 100).

  • Monotherapy with rivaroxaban 5 mg PO BID did not reduce events compared to ASA monotherapy, but increased major & minor bleeds (NNH 112 & 39).

Patients (n=27,402)

  • Included either CAD or PAD:
    • CAD (MI within 20 years, multivessel CAD with symptoms or history of angina, multivessel PCI, multivessel CABG), plus
      • Age >65 y
      • Atherosclerosis in at least 2 vascular beds
      • At least 2 more risk factors (current smoking, diabetes, eGFR <60, non-lacunar stroke >1 month earlier)
    • PAD (with either claudication, previous revasc [including carotid], or amputation)
  • Exclusion
    • High bleeding risk
    • Recent stroke, or previous hemorrhagic or lacunar stroke
    • Severe HF
    • eGFR <15
    • Use of DAPT, anticoagulation, or other antithrombotic therapy
  • Baseline characteristics
    • Age 68 y
    • Female 22%
    • CV history
      • Previous MI 62% (mean 7.1 years ago)
      • CAD 90% (multivessel 62%; enrolled within 2 weeks of CABG ~5%)
      • PAD 27%
    • Risk factors: Tobacco use 21%, HTN 75%, diabetes 38%
    • eGFR: <30 (<1%), 30-59 (22%), 60+ (77%)
    • Meds: ACEI/ARB ~70%, BB 70%, lipid-lowering ~90%

Interventions

  • Intervention1: Enteric-coated ASA 100 mg/d + rivaroxaban 2.5 mg PO BID
  • Intervention2: Rivaroxaban 5 mg PO BID
  • Control: Enteric-coated ASA 100 mg/d

Results @ mean 1.9 years (max 3.92 years)

Subgroup analyses published in separate papers:

  • CAD (91% of study population, n=24,824)
    • Of the 69% with prior MI, timing: <1 y (5%), 1-5 y (29%), >5 y (34%)
    • 4-5% received DAPT during trial follow-up, & most in rivaroxaban groups D/Ced rivaroxaban
    • Efficacy & safety results virtually identical to full trial
    • Additional analyses:
      • Post-hoc defined coronary event composite (MI, coronary death, sudden death, resuscitated cardiac arrest, or unstable angina): ASA+riva vs ASA HR 0.83 (0.81-0.98)
      • Stent thrombosis: ASA+riva vs ASA HR 1.08 (0.72-1.61)
      • Coronary revascularization: ASA+riva vs ASA HR 0.95 (0.84-1.07)
      • Post-hoc landmark analysis suggests that efficacy HR consistent between years 1, 2 & >2, whereas bleeding risk is front-loaded & decreases after year 1
      • Further subgroups suggest that relative risk reduction similar across most subgroups, including those with vs without prior PCI, optimal use of 2o CV prevention vs not, & different risk categories. Notably, however, significant p-value for interaction suggesting no/less benefit in patients with history of CABG.
  • PAD or carotid disease (27% of study population, n=7470)
    • Efficacy & safety results virtually identical to full trial
    • Additional analyses:
      • Prespecified limb outcomes - Major adverse limb event or major amputation: ASA+riva 1% vs ASA 2%: HR 0.54 (0.35-0.82)
      • Composite of 1o outcome + limb outcome: ASA+riva 6% vs ASA 9% (NNT 34), HR 0.69 (0.56-0.85)
  • Modified ISTH definition of major bleed included standard ISTH major bleed components (fatal bleed, symptomatic bleed into a critical organ, bleeding into a surgical site requiring re-operation) plus bleeding that led to hospitalization (including ED visits without overnight stay)

Considerations

  • Risk of bias
    • Low for allocation, performance, detection, attrition bias
      • Computer-generated randomization (reported in Lancet substudies)
      • Allocation concealed by using central web-based randomization (reported in Lancet substudies)
      • Blinding of all participants, clinicians & investigators
      • 0.2% lost to follow-up, ~16% discontinued study drug before last follow-up (but continued follow-up)
      • ITT analysis
    • Trial stopped early after 1st interim analysis for efficacy of ASA + rivaroxaban
    • Run-in phase (active ASA & placebo rivaroxaban BID) to ensure patient able to adhere to trial regimen (~8% excluded after run-in)
  • Generalizability
    • This trial applies to patients with previous MI or clear history of angina/ischemia/coronary revascularization + angiographically-proven CAD, or with PAD
      • Unclear how these results may translate to use of higher doses of rivaroxaban once daily (i.e. rivaroxaban 15-20 mg once daily as used in AF +/- PCI)

DOSE - Diuretic strategies (low vs high dose & IV bolus vs continuous infusion) for acutely decompensated HF

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Bottom line: In patients with acutely decompensated HF patients not in cardiogenic shock,

  • Higher versus lower doses of loop diuretics did not significantly affect primary efficacy & safety outcomes
    • However, secondary outcomes consistently demonstrated a lower risk of serious adverse events (NNT 9), more rapid resolution of dyspnea & congestion, & greater weight loss (extra -1.2 kg in first 72h), at the cost of an increased risk of AKIN stage 1 AKI (NNH 12)
  • Continuous IV administration of loop diuretics does not appear to have any advantage over q12h IV boluses.

Patients (n=300)

  • Included
    • Presented for acutely decompensated HF (ADHF) within 24h
      • Diagnosed based on 1+ symptoms (SOB, orthopnea, edema) & 1+ sign (crackles, peripheral edema, ascites, pulmonary vascular congestion on CXR) of HF
    • Hx of chronic HF (any LV ejection fraction [LVEF])
    • Receiving an oral loop diuretic equivalent to furosemide 80-240 mg/d +/- chronic thiazide diuretic
  • Excluded
    • SBP <90 mm Hg
    • SCr >265 umol/L
    • Requiring IV vasodilators or inotropes
  • Average baseline characteristics
    • Age 66 y
    • Male ~74%
    • Median time from presentation to randomization ~15h
    • Ischemic CM 57%
    • Hospitalized for HF within 1 y ~75%
    • Home dose of furosemide PO ~130 mg/d
    • Clinical characteristics
      • Orthopnea ~90%
      • SBP 120 mm Hg
      • SpO2 96%
      • JVP 8+ cm 91%
      • LVEF 35% (27% with EF 50%+)
      • NT-proBNP ~680-8200 pg/mL
      • Sodium 138
      • SCr 133 umol/L
    • Meds
      • ACEI/ARB ~65%
      • BB ~85%
      • MRA ~27%

Interventions

  • Dose comparison
    • High dose: Daily IV dose = 2.5x total home PO dose
    • Low dose: Daily IV dose = total home PO dose
  • Administration method comparison
    • Continuous IV infusion
    • IV bolus dose divided as q12h administration
  • Assigned treatment continued for up to 72h, after which treatment was open-label at discretion of treating physician
    • At 48h, could either
      • Increase dose by 50%
      • Maintain same strategy
      • D/C IV & switch to open-label PO
  • At 48h:
    • Change to PO diuretics: High 31%, low 17% (p<0.001)
    • Need for dose increase
      • High 9%, low 24% (p=0.003)
      • Continuous 11%, bolus 21% (p=0.01)
  • Median dose over first 72h
    • High 773 mg, low 358 mg
    • Continuous 480 mg (160 mg/d), bolus 592 mg (~200 mg/d)

Results

At 72h

  • Primary efficacy outcome: Global assessment of symptoms (serial 0-100 visual analogue scale measurements tallied using area under the curve [AUC] from baseline to 72h, HIGHER=better)
    • High 4430, low 4171 (p=0.06)
    • Continuous 4373, bolus 4236 (p=0.47)
  • Dyspnea AUC (higher=better)
    • High 4668, low 4478 (p=0.04)
    • Continuous 4699, bolus 4456 (p=0.36)
  • Free from congestion (JVP <8 cm [<3 cm ASA], no orthopnea & trace/np peripheral edema)
    • High 18, low 11 (p=0.09)
    • Continuous 15%, bolus 14% (p=0.78)
  • Wt change (kg)
    • High -3.9, low -2.7 (p=0.01)
    • Continuous -3.6, bolus -3.0 (p=0.20)
  • Primary safety outcome: Change in SCr (umol/L) from baseline to 72h
    • High +7.1, low +3.5 (p=0.21)
    • Continuous +6.2, bolus +4.4 (p=0.45)
  • SCr increase >26 umol/L
    • High 23%, low 14% (p=0.04)
    • Continuous 19%, bolus 17% (p=0.64)

At 60 days

  • Serious adverse event
    • High 38%, low 50% (p=0.03)
    • Continuous 44%, bolus 44% (p=0.92)
  • Composite of death, hospitalization or ED visit: 42% overall, no difference between groups

No difference between groups in median length of stay (5 days for all)

Generalizability

  • Included a mix of HFrEF & HFpEF patients at high risk of HF hospitalization with moderate to high home doses of loop diuretics, a reasonable proportion of whom were receiving good HF medical therapy
  • Outcomes were clinically important and easily measurable and translatable to practice

Internal validity

  • Low risk of bias
    • 2x2 factorial randomization using permuted blocks
    • Allocation concealed
    • Double-blind, dummy-dummy design (saline placebos with identical appearance)
    • ITT analysis
    • Threshold for significance p<0.025 for coprimary outcomes (global assessment of wellbeing & change in SCr from baseline to 72h) 

 

Consequences of inadequate direct oral anticoagulant (DOAC) dosing

in

Yao X, et al. Non-vitamin K antagonist oral anticoagulant dosing in patients with atrial fibrillation and renal dysfunction. J Am Coll Cardiol 2017;69:2779-90.

Bottom line:

  • Many patients with non-valvular AF receiving a DOAC receive inappropriate doses.

  • In patients with an indication to reduced the DOAC dose, "overdosing" (using regular doses) is associated with a 2-fold higher risk of major bleeding vs using appropriate reduced doses.

  • In patients taking apixaban without an indication to reduce the dose, "underdosing" (using reduced doses) apixaban is associated with a ~5-fold increased risk of stroke/systemic embolism.

 

Design summary

  • Cohort study using administrative claims database & linked lab data
  • Included: US patients enrolled with Medicare Advantage with non-valvular AF treated with apixaban, dabigatran or rivaroxaban between Oct 2010-Sept 2015 who had serum creatinine results available within 1 year
  • Excluded: Valvular heart disease, other indication for DOAC, eGFR <15 (calculated using CKD-EPI)
  • Account for bias & confounding: Propensity score matching to balance baseline characteristics, statistical adjustment with Cox proportional hazards regression, numerous sensitivity analyses (such as changing criteria for apixaban dose reduction to age >80 + SCr >132 umol/L, dabigatran dose reduction criteria to eGFR <50), different matching criteria, subgroup analyses based on baseline criteria & individual DOACs, analysis of ICH as individual outcome, & analysis of 'falsification outcomes')
    • Note on the point of evaluating falsification outcomes: Falsification outcomes are outcomes that should not be associated with the presence/absence of an exposure. This is used to identify residual confounding after matching & statistical adjustment (i.e. if there's an association with an outcome that the exposure shouldn't affect, it implies residual confounding).

Results for PICO 1: Normal renal function (no need for DOAC dose reduction), n=13,392

  • Overall, 16.5% of patients underdosed
  • Increased risk of stroke/systemic embolism with reduced dose ("underdosed") vs normal dose of apixaban
    •  2.6% vs 0.5% per year, hazard ratio (HR) 4.87 (1.30-18.26)
  • No statistically significant difference in stroke/systemic embolism with reduced vs normal doses of dabigatran or rivaroxaban, though confidence intervals are very wide
  • No statistically significant difference in major bleeding with reduced vs normal doses of any DOAC

PICO 2: Renal impairment (indication for DOAC dose reduction), n=1,473

  • Overall, 48.5% of patients were overdosed
  • Definition of indication for dose reduction: Apixaban (SCr >132 umol/L), dabigatran (eGFR <30), rivaroxaban (eGFR <50)
  • Increased risk of major bleeding with normal ("overdosing") vs reduced dose of any DOAC
    • 11.3% vs 5.1% per year, HR 2.19 (1.07-4.46)
  • No difference of stroke/systemic embolism with normal vs reduced dose of any DOAC
    • 2.32% vs 1.85%, HR 1.66 (0.40-6.88)

Caveats

  • Due to a limited sample size & low outcome event rates, many analyses were underpowered, particularly when evaluating DOACs individually.
  • Due to limitations with available data, study definitions for criteria to reduce DOAC dose were not entirely consistent with drug label (e.g. weight for apixaban)
  • The analyses only partially accounted for known drug interactions (e.g. amiodarone, digoxin), & could not account for unknown or novel drug interactions (e.g. P-glycoprotein interaction between dabigatran & simvastatin).