RE-DUAL PCI - Dabigatran-based dual antithrombotic regimen in patients with AF after PCI

Cannon CP, et al. Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation. NEJM 2017

Bottom line:

• RE-DUAL PCI provides further evidence supporting dual therapy with an oral anticoagulant + P2Y12 inhibitor in patients with AF post-PCI instead of triple therapy.

• Dual therapy with dabigatran 150 mg BID reduced clinically relevant bleeds (NNT 19) as well as major bleeds (NNT 36-56 depending on definition), & was non-inferior in terms of thromboembolic events over approximately 1 year.

• Dual therapy with dabigatran 110 mg BID showed a possible increase in death, MI & definite stent thrombosis, & was potentially inferior for the composite efficacy outcome. Despite reducing major & clinically-relevant bleeds, this regimen can't be recommended due to inadequate evidence of efficacy in this setting.

  • Notably, the PIONEER trial did not assess for non-inferiority of rivaroxaban-based dual therapy regimens to triple therapy, but if it had, it would not have met the non-inferiority criteria from RE-DUAL PCI. However, the PIONEER results did not show the concerning numerical trends seen here with dabigatran 110 mg BID.

Patients (n=2725)

• Included

  • Non-valvular AFib (paroxysmal, persistent or permanent)

  • PCI (bare-metal or drug-eluting stent) within 120h for stable CAD or ACS

• Exclusion

  • Bioprosthetic or mechanical heart valve

  • CrCl <30 mL/min

  • "Other major coexisting conditions"

• Baseline characteristics

  • ~72 y

  • Female ~24%

  • AF characteristics

    • Paroxysmal (~50%), persistent (~17%), permanent (33%)

    • CHA2DS2-VASc score ~4, HAS-BLED score ~3

    • Previous stroke 10%

  • PCI characteristics

    • Previous: MI ~25%, PCI ~33%, CABG ~10%

    • Indication for PCI: ACS (~50%), stable angina/+ stress test (44%), other (~6%)

    • Drug eluting stent 85%

Interventions

• Intervention1: Dabigatran 150 mg BID + clopidogrel/ticagrelor

  • Note: Elderly outside the US not eligible for this group due to dabigatran labeling

• Intervention2: Dabigatran 110 mg BID + clopidogrel/ticagrelor

• Control ("triple therapy"): Warfarin (INR 2-3) + clopidogrel/ticagrelor + low-dose ASA

  • ASA D/Ced after 1 month with bare-metal stent or 3 months with drug-eluting stent

  • Time in therapeutic INR: 64%

• In all groups

  • P2Y12 inhibitor was continued for at least 12 months

  • P2Y12 inhibitor chosen: Clopidogrel 88%, ticagrelor 12%

  • Mean duration of trial anticoagulant: 12.3 months

Results @ mean 14 months

Dabigatran 150 mg BID vs triple therapy (control group excludes elderly outside US not eligible for higher dabigatran dose)

• Primary outcome (major or clinically relevant non-major bleed, ISTH definition):

  • Dabi150 20.2%, control 25.7%, NNT 19

  • HR 0.72 (0.58-0.88), p<0.001 for non-inferiority

• Major bleed:

  • ISTH definition: Dabi150 5.6%, control 8.4%, HR 0.64 (0.43-0.94), NNT 36

  • TIMI definition: Dabi150 2.1%, control 3.9%, HR 0.51 (0.28-0.93), NNT 56

  • Intracranial hemorrhage: Dabi150 0.1%, control 1.0%, p=0.047

• Composite efficacy outcome (death, MI, stroke, or systemic embolism, or unplanned PCI/CABG): Dabi150 11.8%, control 12.8%, HR 0.89 (0.67-1.19)

Dabigatran 110 mg BID vs triple therapy

• Primary outcome:

  • Dabi110 15.4%, control 26.9%, NNT 9

  • HR 0.52 (0.42-0.63), p<0.001 for non-inferiority

• Major bleed:

  • ISTH definition: Dabi110 5.0%, control 9.2%, HR 0.52 (0.37-0.74), NNT 24

  • TIMI definition: Dabi110 1.4%, control 3.8%, HR 0.37 (0.20-0.68), NNT 42

  • Intracranial hemorrhage: Dabi110 0.3%, control 1.0%, p=0.06

• Composite efficacy outcome: Dabi110 15.2%, control 13.4%, HR 1.13 (0.90-1.43) - did not meet non-inferiority criteria

  • Thromboembolic events or death: Dabi110 11.0%, control 8.5%, HR 1.30 (0.98-1.73)

    • Death Dabi110 5.6%, control 4.9%

    • MI: Dabi110 4.5%, control 3.0%

    • Definite stent thrombosis: Dabi110 1.5%, control 0.8%

Considerations

• Low to unclear risk of bias

  • Unclear randomization & allocation concealment (not adequately reported)

  • Open-label design - low risk of performance bias, but high risk of detection bias for softer outcomes (ie clinically significant non-major bleeds)

  • Low risk of attrition bias (ITT analysis that included all randomized patients regardless of receipt of study intervention; 0.2% lost to follow-up, <4% withdrew consent with no vital status available at end of study)

• Non-inferiority trial

  • Non-inferiority margin 1.38 for HR upper end of 95% confidence interval for both efficacy & safety outcomes

  • Primary analysis using ITT population with sensitivity on-treatment analysis

  • Dual therapy with dabi150 met non-inferiority for both bleeding & thromboembolic outcomes, but dabi110 only met non-inferiority criteria for bleeding

• Excellent generalizability due to broad eligibility criteria & enrolment of a representative, relatively elderly population

• Unadjusted bleed rates from a subgroup analysis by choice of P2Y12 inhibitor (clopidogrel vs ticagrelor) suggest that risk of bleeding increases gradually with number of antithrombotic agents as well as potency of the inhibitor, e.g. ISTH major bleed over mean 14 months from Figure 2:

  • Clopidogrel + dabigatran: ~5%

  • Clopidogrel + ASA + warfarin OR ticagrelor + dabigatran: ~8%

  • Ticagrelor + ASA + warfarin: ~16.5%

CANTOS - Canakinumab for patients with previous MI

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

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)

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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)

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• 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

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

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).