Consequences of inadequate direct oral anticoagulant (DOAC) dosing

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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).

AF-CHF - Rhythm vs rate control in AF with HFrEF

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Roy D, et al. Rhythm control versus rate control for atrial fibrillation and heart failure. N Engl J Med 2008;358:2667-77.

Bottom-line: In individuals with both AF & HFrEF, a rhythm-control strategy is not superior to an aggressive rate-control strategy targeting resting HR <80 bpm. More patients starting with the rhythm-control strategy will require a strategy change (NNH 9), but neither strategy works for everybody.

 

Patients (n=1376)

  • Inclusion
    • AF
      • Episode with EKG documentation lasting at least 6h or requiring cardioversion in previous 6 months, or
      • Episode lasting 10+ minutes in previous 6 months & previous cardioversion for AF
    • HF
      • NYHA II-IV in previous 6 months, or
      • Hospitalized for HF in previous 6 months, or
      • LVEF 25% or less
    • LVEF 35% or less measured in last 6 months
  • Exclusion
    • Persistent AF >12 months
    • Reversible cause of AF or HF
    • Decompensated HF in previous 48h
    • Use of antiarrhythmics for other arrhythmias
    • 2o-3o AVB with bradycardia <50 bpm
    • Hx long QT syndrome
    • Dialysis-dependent renal failure
  • "Typical" patient
    • Age 66 y
    • Male 78-85%
    • NYHA class III-IV 32%
    • HF etiology: Ischemic (48%), hypertensive (10%), valvular (5%)
    • Prior hospitalization for AF (50%), HF (55%)
    • AF paroxysmal (1/3), persistent (2/3)
    • PMHx
      • Previous stroke/TIA 10%
      • HTN 49%
      • Diabetes 22%
    • AF on EKG (55-60%)
    • LVEF 27%
    • Concomitant meds
      • ACEI 86%, ARB 11%
      • Mineralocorticoid antagonist 45%
      • OAC 85-90%
      • ASA 40%
      • Lipid-lowering 43%
    • ICD 7%

Interventions

  • I: Rhythm control: Aggressive pharmacotherapy + electrical cardioversion to prevent and cardiovert AF
    • Drug of choice: Amiodarone, then sotalol or dofetilide as required
    • Drugs @ 1 year: Amiodarone (82%), sotalol (2%), dofetilide (<1%)
      • Beta-blocker (80%), digoxin (~50%), anticoagulant (88%)
    • Electrical cardioversion
      • 1st recommended <6 weeks after enrollment not converting to NSR with pharmacological rhythm control alone
    • 2nd recommended <3 months after enrollment if still not in NSR
    • Subsequent cardioversions PRN
  • C: Rate control: Adjusted doses of beta-blocker & digoxin to achieve resting HR <80 bpm & <110 bpm during 6-min walk test (tested @ month 4 & 12, then yearly)
    • Drugs @ 1 year: Beta-blocker (88%), digoxin (75%), verapamil/diltiazem (3%)
      • Amiodarone (7%), sotalol or dofetilide (<1%), anticoagulant (92%)
  • Interventions common to both groups:
    • Max-tolerated doses of beta-blockers (for HFrEF management)
    • Anticoagulation

Results @ mean 3 y f/u

  • Death: 32% vs 33% (p=0.68)
    • CV death (primary outcome): 27% vs 25% (p=0.53)
  • Hospitalization: 64% vs 59% (p=0.06)
    • AF hospitalization: 14% vs 9% (p=0.001)
  • Worsening HF: 28% vs 31% (p=0.17)
  • Switched to other intervention: 21% vs 10%
  • AF on EKG at study visit:
    • Month 4, years 1-3: ~20% vs ~60% (during f/u, >55% in rhythm-control group had at least 1 AF recurrence)
    • Year 4: ~25% vs ~70%

Generalizability

  • Representative of individuals with HFrEF and moderately good use of HFrEF medical therapies & low ICD use
  • Rhythm-control intervention consistent with real world use; rate-control intervention similar to "intensive" intervention from AFFIRM trial

Internal validity

  • Unclear risk of allocation bias
    • Allocation concealment not described + some moderately-large baseline differences in certain characteristics (e.g. male 78% vs 85%, AF on baseline EKG 54% vs 61%)
  • Unclear risk of performance & detection bias
    • Predefined treatment protocols accounted for most potential differences in interventions
    • Rhythm-control group required more AF-related hospitalizations, likely cardioversion-related
    • Higher rate of cross-over in rhythm-control group
    • Once outcomes reported, adjudicated by committee unaware of treatment allocation
  • Unclear risk of attrition bias
    • 5-6% loss-to-follow-up, which could be enough to hide differences between groups in main outcomes

PIONEER AF-PCI - Antithrombotics in patients with AF after PCI

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Bottom line: In patients with AF undergoing PCI, a novel antithrombotic regimen (reduced-dose rivaroxaban + P2Y12 inhibitor, or ATLAS trial-like triple therapy regimen) reduces the risk of hospitalization, bleeding requiring medical attention and study discontinuation (NNT ~10-15 each).

This trial does not answer whether these novel regimens retain stroke efficacy for AF (either regimen versus full anticoagulation) or MI/stent thrombosis efficacy for CAD (modified double therapy versus DAPT). While ongoing trials will provide further guidance on the ideal regimen and dose, the best available evidence suggests that dual therapy with clopidogrel plus full-dose anticoagulation provides the best balance of benefit and safety.

 

Patients (n=2124)

  • Inclusion
    • Age 18+ y
    • AFib (documented within 1 y before enrolment or taking OAC for at least 3 months before PCI)
    • Underwent PCI with stent placement (randomized within 3 days of PCI)
  • Exclusion
    • Prior stroke/TIA
    • Significant GI bleed within 1 year
    • Anemia of unknown cause with Hb <100 g/L
    • "Any other condition known to increase bleed risk"
    • CrCl <30 mL/min
  • Screened 2236 -> randomized 2124 -> analyzed 2099
  • "Average" patient
    • Age 71 y (36% 75+ y)
    • Female 26%
    • White 94%
    • Indication for PCI: Unstable angina (21%), NSTEMI (18%), STEMI (12%), non-ACS (49%)
    • Drug-eluting (2/3), bare-metal (1/3) stent
    • CHA2DS2-VASc score: 0 (<2%), 1 (9%), 2 (15%), 3 (18%), 4 (20%), 5 (20%), 6 (13%), 7 (3%)
    • CrCl 78 mL/min
    • P2Y12 inhibitor: Clopidogrel (93%), prasugrel (<2%), ticagrelor (~5%)
    • PPI used in ~40%

Generalizability

  • Represents the target population at the time when the decision on antithrombotics would be made.
  • Similar to WOEST and ISAR-TRIPLE, ACS was the indication for PCI in <50% of patients
    • Due to their higher risk of MI, stent thrombosis & CV death, thes benefit-risk profile of different antithrombotic regimens (& DAPT duration) likely differs in this subgroup. This trial is underpowered to evaluate this subgroup.
  • ~90% of patients had a CHA2DS2-VASc of 2 or more, corresponding to a risk of stroke or systemic thromboembolism of >1.5%/year & indication for anticoagulation by all major guidelines (AHA, CCS, ESC).
  • This trial included only patients without major bleeding risk factors (i.e. no recent GI bleed, intracranial hemorrhage, eGFR <30 mL/min, or chronic NSAID use)
    • The bleeding rates in this trial therefore represent a minimum risk that would be expected to increase substantially in the presence of any of these risk factors.

 

Interventions & co-interventions

  • I 1: Modified "double therapy" for trial duration
    • Rivaroxaban 15 mg daily + P2Y12 inhibitor at standard dose
      • If CrCl 30-50: Decrease rivaroxaban to 10 mg daily
    • Comments about this intervention:
      • Rivaroxaban dose 75% of the 20 mg/d dose determined to be non-inferior to warfarin in ROCKET-AF trial of non-valvular AF. It is unclear if the addition of 1 antiplatelet drug to this reduced dose provides similar ischemic stroke risk reduction compared to full-dose anticoagulation monotherapy
      • Full-dose apixaban may have been a better option, since it has demonstrated similar risk of major bleeding compared to ASA, with greater reduction in ischemic stroke in non-valvular AF (AVERROES)
  • I 2: Rivaroxaban 2.5 mg BID + DAPT (ATLAS trial regimen)
    • DAPT consisted of ASA 75-100 mg/d indefinitely + a standard dose of any of clopidogrel, prasugrel, ticagrelor x1 to 12 months (decided before randomization)
    • Comments about this intervention:
      • Rivaroxaban dose 25% of the 20 mg/d dose determined to be non-inferior to warfarin in ROCKET-AF trial. There is no prior evidence suggesting that this dose is adequate to reduce the risk of stroke in AF, nor is there evidence that adding DAPT to this reduced dose will reduce the risk of ischemic stroke.
  • C: Warfarin-based triple therapy
    • Warfarin to INR 2.0-3.0 (mean time in the therapeutic range 65%) + ASA 75-100 mg/d + P2Y12 inhibitor
      • Warfarin & ASA continued for trial duration
      • P2Y12 inhibitor continued x1 to 12 months (decided before randomization)

 

Outcomes @ 1 year

  • Efficacy
    • Death or hospitalization: Modified double therapy 35%, ATLAS regimen 32%, triple therapy 42%
      • Modified double therapy vs triple therapy: Hazard ratio (HR) 0.79 (95% confidence interval 0.66-0.94), NNT 10
      • ATLAS regimen vs triple therapy: HR 0.75 (0.62-0.90), NNT 15
      • Note: The lower risk of hospitalization in the 2 rivaroxaban-based regimens vs triple therapy were due to reductions in both CV- and bleeding-related hospitalizations
    • Death: 2.3-2.7% (no statistically significant differences)
    • Composite CV death, MI or stroke: 6.5% vs 5.6% vs 6.0%
      • Double vs triple therapy: HR 1.08 (0.69-1.68)
      • ATLAS regimen vs triple therapy: HR 0.93 (0.59-1.48)
    • Stent thrombosis: 0.8% vs 0.9% vs 0.7%
      • Double vs triple therapy: HR 1.20 (0.32-4.45)
      • ATLAS regimen vs triple therapy: HR 1.44 (0.40-5.09)
    • Stroke: 1.3% vs 1.5% vs 1.2%
      • Double vs triple therapy: HR 1.07 (0.39-2.96)
      • ATLAS regimen vs triple therapy: HR 1.36 (0.52-3.58)
  • Safety
    • Primary outcome (major + minor bleeding based on TIMI criteria or bleeding requiring medical attention): 16.8% vs 18.0% vs 26.7%
      • Double vs triple therapy: HR 0.59 (0.47-0.76), NNT 11
      • ATLAS regimen vs triple therapy: HR 0.63 (0.50-0.80), NNT 12
    • Major bleeding: 2.1% vs 1.9% vs 3.3%
      • Double vs triple therapy: HR 0.66 (0.33-1.31)
      • ATLAS regimen vs triple therapy: HR 0.57 (0.28-1.16)
  • Discontinuation before study termination: 21.0% vs 21.1% vs 29.4% (NNT ~12 for either double therapy or the ATLAS regimen versus triple therapy)

 

Context

 

Internal validity

  • Low risk of allocation bias (central randomization)
  • Unclear risk of certain biases
    • Performance bias
      • Open-label
      • Anticipated DAPT duration selected & recorded prior to randomization
      • PPI/H2RA use for gastroprotection encouraged but not mandated for all trial participants
    • Detection bias:
      • Open-label
      • Most outcomes included in the primary safety outcome were subjective "soft" outcomes ("bleeding requiring medical attention" accounted for >90% of bleeding outcomes reported) & prone to biased reporting from patients, and subsequently from the treating clinician
      • The more important & objective outcomes such as major hemorrhage or death occurred infrequently (~2-3%), with too few events to provide firm conclusions about differences or lack thereof
      • Blinded adjudication: All efficacy endpoints & a portion of bleeding events reported by patients & their clinicians were subsequently adjudicated by investigators blind to assigned intervention
    • Attrition bias:
      • Analyzed only patients who took at least 1 dose of the study drug (modified intention-to-treat [mITT] population)
      • None in the mITT population were lost-to-follow-up, but more patients in the triple therapy group discontinued the study regimen prematurely
  • Low risk of reporting bias (all clinically-important outcomes reported)

 

 

    Interpretation of study outcomes

    • Study underpowered to demonstrate superiority or non-inferiority of any intervention to each other for the outcomes of cardiovascular events or major hemorrhage
      • Could not rule out a 3-fold increased risk of stroke in the double therapy/ATLAS regimen versus triple therapy.
    • Contrary to WOEST, PIONEER did not demonstrate a lower risk of death with the modified double therapy regimen vs triple therapy. Due to the low number of events, either finding could be due to chance (false-negative in PIONEER or false-positive in WOEST).
    • The risk of major hemorrhage over 1 year with triple therapy (3.3%) was comparable to that in the ISAR-TRIPLE trial (2.4% at 9 months), & substantially lower than in the Danish registry (12.2%) and the WOEST trial (5.6%).