TWILIGHT: DAPT x3 months followed by ticagrelor monotherapy vs continued DAPT after PCI

Mehran R, et al. Ticagrelor with or without aspirin in high-risk patients with PCI. NEJM 2019;381:2032-42.

Bottom Line:

• Among patients at high risk of thrombosis who underwent PCI & tolerated ticagrelor + ASA for 3 months without thrombotic or major bleeding events, switching to ticagrelor monotherapy reduced the risk of bleeding (NNT=34) with similar risk of thrombotic events vs continued ticagrelor+ASA for up to 15 months.

• It remains unclear how this “TWILIGHT” regimen compares to a standard regimen of ASA + clopidogrel, or other novel antiplatelet de-escalation strategies), in the era of 2nd-generation drug-eluting stents with low risk of stent thrombosis.

Patients (n=7119)

• 9006 enrolled at time of PCI -> 7119 randomized 3 months post-PCI

  • 21% enrolled excluded before randomization, mostly due to non-adherence (13% of enrolled, 1/2 of related to dyspnea) or major thrombotic/bleeding event (3% of enrolled) in 1st 3 months post-PCI

• Inclusion:

  • Underwent successful PCI with drug-eluting stent, with “intent to discharge the patient with a regimen of ticagrelor + ASA”

  • At least 1 clinical feature + 1 angiographic feature associated with high thrombotic or bleeding risk:

    • Clinical: Age >65 y, female, troponin+ ACS, established vascular disease (previous MI, known PAD or CAD/PAD revascularization), diabetes treated with medications, CKD

    • Angiographic: Multivessel CAD, total stent length >30 mm, thrombotic target lesion, bifurcation lesion treated with 2 stents, obstructive LM or pLAD lesion, or calcified target lesion treated with atherectomy

  • Did not experience major bleed (BARC 3b, 4 or 5) or thrombotic event (stroke, MI, coronary revascularization) in 1st 3 months post-PCI

  • Adherent to ticagrelor + ASA based on manual pill count after 1st 3 months

• Excluded:

  • Presentation: STEMI, fibrinolytic therapy <24h of PCI, cardiogenic shock

  • PMHx: Prior stroke, dialysis-dependent CKD, cirrhosis, life expectancy <1 y contraindication to ASA/ticagrelor

  • Other: Ongoing OAC use, strong CYP3A inducer/inhibitor, active bleeding or “extreme” risk for major bleed, platelet count <100

• Baseline

  • Age 65, female 24%, non-white 31%, North America 42%

  • Indication for PCI: NSTEMI 30%, UA 35%, stable angina 29%, asymptomatic 6%

  • Multivessel CAD 63%, previous MI 29%, previous PCI 42%, previous CABG 10%, PAD 7%

  • Smoker 22%, diabetes 37%, CKD 17%

  • Anemia 20%, previous major bleed 1%

  • Angiographic/procedural:

    • LM treated in ~5%, LAD in 56%

    • Mean # of vessels treated 1.3, mean total stent length 40 mm, mean minimum stent diameter 2.8 mm

    • Bifurcation 12%, thrombus ~10%, chronic total occlusion 6%, SVG 2%

    • 2nd-generation drug-eluting stent used in >97%

Interventions & Controls

• For the 1st 3 months after PCI, all patients received open-label enteric-coated ASA 81-100 mg/d + ticagrelor 90 mg BID

• After the 1st 3 months, randomized to open-label ticagrelor plus 12 months of:

• Intervention (ticagrelor monotherapy after 3 months of ticagrelor-based DAPT): Placebo

• Control (continued ticagrelor-based DAPT): ASA

• Similar % of patients took >80% of ticagrelor (86-87%) & study drug (82-83%)

Outcomes @ month 3 to 15 (during study intervention after 1st 3 months of DAPT)

No difference in thrombotic events

• Death/MI/stroke (per-protocol analysis): 3.9% in both groups

  • Hazard ratio (HR) 0.99 (95% confidence interval [CI] 0.78-1.25)

  • Absolute difference -0.1 (-1% to +0.8), meeting non-inferiority criteria (see below)

  • Death: 1.0% vs 1.3%

  • MI: 2.7% in both groups

  • Stroke: 0.5% vs 0.2%

• Stent thrombosis (definite/probable): 0.4% vs 0.6% (HR 0.74, 0.37-1.47)

Fewer bleeding events with abbreviated DAPT

• BARC 2, 3 or 5 bleed (1o outcome) @ month 15 after PCI: 4.0% vs 7.1% (NNT 34)

  • HR 0.56 (0.45-0.68)

  • Identical results for TIMI minor/major definition

  • BARC 3 or 5: 1% vs 2% (HR 0.49, 0.33-0.74)

• ISTH major: 1.1% vs 2.1% (HR 0.54, 0.37-0.80)

• GUSTO moderate/severe: 0.7% vs 1.4% (HR 0.53, 0.33-0.85)

Subgroup analyses: No subgroup effect for bleeding or thrombotic outcomes.

Internal Validity

• Low risk of

  • Allocation bias: Random sequence using permuted blocks stratified by site generated by independent statistician; concealed allocation via secure web-based system

  • Performance bias: Use of matching placebo (patients, clinicians, etc) unaware of treatment assignment

  • Detection bias: Outcomes adjudicated by committee unaware of study drug assignment

• Unclear risk of attrition bias

  • Loss-to-follow-up 1.6% for the primary outcome & 0.3% for death

  • Bleeding outcome analyzed using intention-to-treat principle (low risk), but thrombotic outcome analyzed using per-protocol (unclear risk)

Other Considerations

• Non-inferiority design for the key thrombotic endpoint (death/MI/stroke)

  • Pre-specified non-inferiority margin: Absolute difference of 1.6% assuming 8.0% incidence in the continued DAPT group

    • However, event rates lower than anticipated (3.9% instead of 8.0%). Ideally, a more conservative relative risk non-inferiority margin equivalent to a 1.6% increase above 8.0% would have been used (RR=9.6%/8.0%=1.20)

    • Using this stricter relative risk-based non-inferiority margin of 1.20, the study does not technically meet the study’s pre-specified non-inferiority criteria for this outcome.

  • Non-inferiority should only be concluded if both ITT & PP analyses consistently demonstrate non-inferiority; however, only PP analysis of thrombotic outcome reported in this trial.

Other Studies

• PLATO: The landmark study demonstrating the superiority of ticagrelor + ASA vs clopidogrel + ASA among all-comer ACS patients (except STEMI patients treated with fibrinolytics) in the era of bare-metal & 1st-generation drug-eluting stents.

• GLOBAL LEADERS: In a trial of patients who underwent PCI, ticagrelor-based DAPT x1 month, followed by ticagrelor monotherapy x23 months vs standard DAPT for ACS/stable angina did not reduce the risk of death/Q-wave MI.

• In a contemporary population-based registry study of ACS patients who underwent PCI, ticagrelor + ASA was not associated with a lower risk of major adverse coronary events compared to clopidogrel + ASA. However, it was associated with significantly more major bleeding & dyspnea

  • Similar to TWILIGHT, this cohort study was done in the era of second-generation drug-eluting stents with low risk of stent thrombosis.

DAPA-HF & DEFINE-HF: Dapagliflozin in heart failure with reduced ejection fraction

McMurray JJV, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. NEJM 2019

Bottom line:

• Among patients with symptomatic heart failure with reduced ejection fraction (HFrEF), the SGTL2 inhibitor dapagliflozin reduced the risk of a composite of CV death, HF hospitalization or urgent visit for HF requiring IV diuretics vs placebo (NNT 21), death (NNT 44) & HF hospitalizations (NNT 28) at 1.5 years in patients with OR WITHOUT diabetes.

• Dapagliflozin also improves quality of life beyond the clinically important difference as early as 12 weeks (NNT 10-14), without any differences in adverse effects (e.g. hypovolemia, kidney injury, severe hypoglycemia).

Patients (n=4744)

• From Feb 2017-Aug 2018, 8134 screened -> 4744 randomized

• Included

  • HF with ejection fraction of 40% or less (HF with reduced ejection fraction [HFrEF])

  • NYHA functional class 2-4

  • NT-proBNP

    • >900 pg/mL if AF/atrial flutter

    • >400 pg/mL if HF hospitalization within 1 year

    • >600 pg/mL if neither of the above

  • +/- type 2 diabetes

  • Stable doses (at least 4 weeks) of standard HF medications (ACEI/ARB/ARNI + beta-blocker as tolerated, + MRA)

• Key exclusion criteria: Type 1 diabetes, symptomatic hypotension or SBP <95, eGFR <30

• Baseline (average/proportions)

  • 66 y/o

  • Female 23%

  • White 70%, Asian 24%, Black 5%

  • North America 14%

  • HF characteristics

    • Etiology: Ischemic (56%), non-ischemic (36%), unknown (8%)

    • Prior HF hospitalization 47%

    • NYHA 2 (68%), 3 (32%), 4 (<1%)

    • LVEF 31%

    • NT-proBNP ~1400

  • PMHx: Diabetes 42%, AF 38%

  • Clinical variables: SBP 122, eGFR 66

  • Therapies

    • Diuretic 93%, digitalis 19%

    • ACEI 56%, ARB 27%, ARNI 11%

    • Beta-blocker 96%

    • MRA 71%

    • ICD 26%, CRT 7%

    • Antihyperglycemics (% of those with T2DM): Metformin (51%), sulfonylurea (22%), DPP4i (16%), GLP1RA (1%), insulin (27%)

Intervention & Control

• Intervention: Dapagliflozin 10 mg daily

  • Dose reduced to 5 mg/d or temporary discontinuation if acute, unexpected decline in eGFR, volume depletion, or hypotension (or to avoid these)

• Control: Matching placebo

• Standardized monitoring: Follow-up at 14 days & 60 days (focus on HF/volume assessment, adverse events, & evaluation of renal function & potassium), then q4 months

Outcomes

CV outcomes @ median 18 months

• Primary outcome (CV death, HF hospitalization, or urgent visit for HF resulting in IV therapy): Dapagliflozin 16.3% vs placebo 21.2%

  • Hazard ratio (HR) 0.74 (95% confidence interval 0.65-0.85); Absolute difference 4.9%, NNT 21

  • CV death: 9.6% vs 11.5%; HR 0.82 (0.69-0.98)

  • HF hospitalization: 9.7% vs 13.4%; HR 0.70 (0.59-0.83)

  • Consistent across subgroups (HR 0.75 for type 2 diabetes, HR 0.73 for those without diabetes)

• All-cause mortality: Dapagliflozin 11.6% vs placebo 13.9%; HR 0.83 (0.71-0.97)

Quality of life (QoL) @ month 8

• Measured using Kansas City Cardiomyopathy Questionnaire [KCCQ] total symptom score, range from 0 [worst] to 100 [best], Minimal clinically-important difference is a 5-point improvement/worsening)

• Mean change: +6.1 vs +3.3 (/100); “win ratio” 1.18 (1.11-1.26)

• Improvement 5+ points: Dapagliflozin 58.3% vs placebo 50.9%, odds ratio (OR) 1.15 (1.08-1.23)

• Deterioration 5+ points: Dapagliflozin 25.3% vs placebo 32.9%, OR 0.84 (0.78-0.90)

Safety @ median 18 months (none statistically significant vs placebo)

• Discontinuation due to adverse events: 4.7% vs 4.9%

• Volume depletion: 7.5% vs 6.8% (p=0.4); serious in 1.2% vs 1.7%

• Worsening renal function (sustained eGFR reduction >50%, ESRD [eGFR <15 >28 days], or death from renal disease): 1.2% vs 1.6%

• Amputations: 0.5% in both groups

• Fournier’s gangrene: 0 vs <0.1%

• Bone fractures: 2.1% in both groups

• Major hypoglycemia: 0.2% in both groups

• DKA: 0.1% vs 0

Lab changes (difference vs placebo)

• Weight -0.9 kg, SBP -1.3 mm Hg

• NT-proBNP -303 pg/mL

• HbA1c -0.24%

• SCr +1.8 umol/L

Internal validity: Low risk of allocation, performance, detection & attrition bias

• Computer-generated randomization, stratified by presence of type 2 diabetes

• Allocation concealed by interactive voice/web-response system

• Participants, clinicians unaware of treatment assignment (blinded)

• Blinded adjudication of outcomes

• Loss-to-follow-up <0.8%

• Analysis of the intention-to-treat (ITT) population

Other trial of dapagliflozin in HFrEF: DEFINE-HF (PMID: 31524498)

• Participants (n=263)

  • Included: HF with LVEF 40% or less, NYHA 2-3, elevated natriuretic peptide (NT-proBNP 400+ pg/mL or BNP 100+ pg/mL), +/- T2DM

  • Excluded: Type 1 diabetes, HF hospitalization within last 30 days, eGFR <30

  • Baseline characteristics:

    • 61 y/o, male 73%, white 55%/black 40%

    • ischemic etiology 53%, prior HF hospitalization ~80%, HF duration 7 years

    • NYHA 2 (70%), 3 (30%), KCCQ overall summary score 67/100

    • LVEF 26%

    • T2DM 62%, AF 40%

    • SBP 123, HR 72, eGFR 65-70, HbA1c ~7%

    • Meds: ACEI/ARB 60%/ARNI 30%, BB 95-100%, MRA 60%, ICD 60%, CRT 20-30%

• Dapagliflozin 10 mg/d (intervention) vs placebo (control)

• Outcomes @ 12 weeks:

  • QoL measured using KCCQ overall summary score

    • Mean 3-point improvement with dapagliflozin vs placebo

    • Improvement of 5+ points: Dapagliflozin 43% vs placebo 33% (NNT 10)

    • Difference in KCCQ sub-domains of clinical summary score, total symptom score, physical limitation score & QoL score, but not social limitation score

  • No difference between dapagliflozin vs placebo in:

    • Change in NT-proBNP

    • Any adverse effects

• Internal validity: Low risk of bias.

ISAR-REACT 5: Ticagrelor vs prasugrel in ACS

Schupke S, et al. Ticagrelor or prasugrel in patients with acute coronary syndromes. NEJM 2019

Bottom line: In patients with ACS planned for invasive management (90% treated with new-gen drug-eluting stent), prasugrel reduced death/MI/stroke versus ticagrelor (NNT=42) at 1 year, which was driven by fewer MIs.

Patients (n=4018 randomized)

• Enrolled from 21 centres in Germany & 2 centres in Italy

• Included if:

  • Hospitalized for ACS (STEMI, NSTEMI or unstable angina)

  • Planned invasive strategy (i.e. scheduled for coronary angiogram)

• Key exclusion criteria:

  • Hx of any stroke, TIA or intracranial hemorrhage

  • Intracranial abnormality at risk of bleeding

  • Lysis <24h before randomization

  • Ticagrelor or prasugrel <5 days before randomization

• Average baseline characteristics

  • Age 65 y, female 24%

  • Diagnosis @ admission: STEMI 41%, NSTEMI 46%, UA 13%

  • Final diagnosis of ACS at discharge 91%

  • Index ACS managed with: PCI 84% (90% of which were drug-eluting stents), CABG 2%, medical management only 14%

  • Prior MI 16%, prior PCI 23%, prior CABG 6%

  • Cardiac risk factors: HTN 70%, diabetes 22%, dyslipidemia 58%

  • BMI 28, wt <60 kg 5%

Interventions: Ticagrelor ASAP vs Prasugrel x1 year

• Ticagrelor: Loading dose of 180 mg x1 ASAP after randomization (i.e. pre-loading before coronary angiogram), then 90 mg PO BID

• Prasugrel: Loading dose of 60 mg x1, then 10 mg once daily

  • If STEMI: Loading dose given ASAP after randomization

  • If NSTEMI/UA: Loading dose given after coronary angiogram

  • Lower maintenance dose of 5 mg daily given if age age 75+ or weight <60 kg

• ~20% in both groups were not discharged on their assigned study P2Y12i (most because they were not confirmed to have obstructive CAD on angiography, had indication for oral anticoagulant, or underwent CABG)

• Note: Patients did not get the medication for free as part of the trial; they had to obtain it as they otherwise would need to do in standard practice

Outcomes @ 1 year

• Primary outcome (composite of all-cause death, MI, stroke): Ticagrelor 9.3% vs prasugrel 6.9%

  • Hazard ratio (HR) 1.36, 95% confidence interval (CI) 1.09-1.70

  • NNT (using prasugrel instead of ticagrelor)=42 @ 1 year

• Secondary outcomes

  • Death: 4.5% vs 3.7% (HR 1.23, 95% CI 0.91-1.68)

  • CV death: 3.2% vs 3.0%

  • MI: 4.8% vs 3.0% (HR 1.63, 1.18-2.25), NNT=56 in favor of prasugrel

  • Definite/probable stent thrombosis: 1.3% vs 1.0%

  • Stroke: 1.1% vs 1.0%

  • Major bleed (BARC 3, 4 or 5): 5.4% vs 4.8% (HR 1.12, 0.83-1.51)

• Discontinued study intervention: Ticagrelor 15.2% vs prasugrel 12.5%

  • Median time to D/C: 84 vs 109 days

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Risk of bias: Overall some concern

• Some concerns re: bias arising from the randomization process (allocation bias)

  • Computer-generated random sequence

  • Allocation concealment only by sealed, opaque envelopes (no details on storage location, sequential numbering or assignment); prone to tampering & less robust than other methods

• Some concerns re: bias due to deviations from intended interventions

  • Open-label design

  • Higher & earlier discontinuation of study drug in ticagrelor group, though no other evidence of differences in management between groups

  • Predicted direction of bias in favor of prasugrel for the primary efficacy outcome

• Low risk of bias due to missing outcome data (attrition bias)

  • Low loss-to-follow-up: <1% in both groups

  • Analyzed the intention-to-treat population

• Low risk of bias in measurement of the outcome (detection bias)

  • Open-label design; however objective outcome definition (especially for MI, the driver of the difference between ticagrelor & prasugrel), & outcomes adjudicators not aware of assigned intervention

• Low risk of bias in selection of the reported result (outcome reporting bias)

Other considerations

• The findings of this trial conflict with results of prior trials of prasugrel & ticagrelor:

  • The results of the primary outcome of ISAR-REACT 5 expressed as prasugrel vs ticagrelor are 6.9% vs 9.3%, HR 0.74 (0.59-0.92)

  • In the PLATO trial comparing ticagrelor to clopidogrel in ACS patients managed medically or with PCI, ticagrelor reduced death/MI/stroke vs clopidogrel.

    • 10.2% vs 12.3%, HR 0.84 (0.77-0.92)

    • Notably, ticagrelor also reduced death vs clopidogrel (HR 0.78)

  • Similarly, in the TRITON-TIMI 38 trial comparing prasugrel to clopidogrel in ACS patients managed almost exclusively with PCI, prasugrel reduced death/MI/stroke vs clopidogrel @ 15 months

    • 10.7% vs 12.7%, HR 0.83 (0.75-0.92)

    • Prasugrel did not reduce death vs clopidogrel (HR 0.96)

  • Conversely, in TRILOGY, in which only medically-managed ACS patients were randomized, prasugrel did not reduce CV death/MI/stroke vs clopidogrel, HR 0.96 (0.86-1.07)

  • Note: The previous PRAGUE-18 trial (n=1230) that also compared prasugrel to ticagrelor was severely underpowered & inconclusive.

• In terms of pharmacodynamics, ticagrelor inhibits platelet function at least as well as prasugrel, irrespective of assay technique (e.g. Rollini et al., SWAP-2, SWAP-3).

• Adherence to the P2Y12 inhibitor was apparently assessed (as briefly described in the protocol), but not reported in sufficient detail in this article. Of patients who discontinued the study P2Y12 inhibitor, those in the ticagrelor discontinued approximately 1 month earlier than prasugrel, which may explain at least in part the early higher MI rate with ticagrelor vs prasugrel.

• Overall, it’s unclear how much the findings of this trial are attributable to:

  • A yet-unidentified pharmacodynamic benefit of prasugrel;

  • Lower adherence to ticagrelor due to BID dosing;

  • Greater & earlier discontinuation of ticagrelor due to dyspnea.

• Arguably, it’s also unclear how the efficacy of prasugrel compares to clopidogrel in the era of modern drug-eluting stents with incredibly low rates of stent thrombosis, and in this emerging era of complete revascularization.

IV iron in HFrEF with iron deficiency

Updated Jan 4, 2021

Bottom line: In patients with HFrEF who have iron deficiency, IV iron therapy:

• has no clear effect on all-cause or CV mortality;

• reduces the risk of HF hospitalizations (NNT 17 at 12 months);

• improves quality of life (~4-point improvement on 100-point scale), functional capacity, & walking distance.

• Current evidence does not suggest that oral iron supplementation offers any benefit.

Context

• In patients with heart failure with reduced ejection fraction (HFrEF), iron deficiency is defined as having a serum ferritin <100 ug/L OR ferritin 100-300 ug/L + transferrin saturation (tsat) <20%

• In HFrEF, iron deficiency is:

  • Present in 2/3 of patients with anemia & 1/2 of patients without anemia;

  • Associated with higher NYHA class (i.e. worse symptom burden), higher serum NT-proBNP, & higher risk of death (independent of hemoglobin concentration).

• In the IRONOUT HF trial, oral iron supplementation (using Feramax 150 mg BID x4 months) in patients with HFrEF + iron deficiency did not improve quality of life or exercise capacity;

  • Importantly, 4-months of oral supplementation only modestly improved tsat (+3%) & non-significantly increased ferritin (+11 ug/L, 95% confidence interval [CI] -0.3 to +23), suggesting that this does not efficiently replace iron stores;

  • It remains unknown if other PO iron formulations, such as sulfate or fumarate salts, may be effective in these patients;

  • Also unknown whether PO iron could adequately maintain iron stores in patients first treated with IV iron.

• 3 prior meta-analyses (Can J Cardiol 2016, Eur J Heart Fail 2016, Eur J Heart Fail 2018) demonstrated a reduction in HF hospitalizations with intravenous iron (number needed to treat [NNT] over 6-12 months of 10-12); however, these studies were limited by restrictive eligibility criteria that included only 4-5 of the ~10 randomized controlled trials (RCTs).

2019 Meta-Analysis - Zhou X, et al. Iron supplementation improves cardiovascular outcomes in patients with heart failure. Am J Med 2019;132:955-63.

Design

• Search timeframe: Database inception to March 2018

• Databases searched: PubMed, Embase, CENTRAL

• Additional measures: None

• Eligibility criteria:

  • Published in English

  • Design: Randomized controlled trial (RCT), at least single-blind

  • Population: “systolic” HF (i.e. HFrEF)

  • Intervention: Iron supplementation

• 10 trials identified (including the 2 largest trials, FAIR-HF & CONFIRM-HF)

• Risk of bias: Variable, 2 largest IV iron trials (FAIR-HF & CONFIRM-HF) rated as being at overall low risk of bias

Patients (n=1404)

• Inclusion criteria of FAIR-HF & CONFIRM-HF, the 2 largest trials:

  • HF with LVEF ≤45%

  • NYHA 2-3

  • Hb 95-135 g/L in FAIR-HF, <150 g/L in CONFIRM-HF

  • Iron deficiency (ferritin <100 ug/L or 100-300 ug/L plus tsat <20%)

• Baseline characteristics in FAIR-HF:

  • Age 67, female 55%

  • Ischemic cardiomyopathy ~80%, prior MI ~58%

  • NYHA 2 (19%) or 3 (81%); 6-minute walk test (6MWT) distance 270 m

  • LVEF ~33%

  • Hb 119 g/L, MCV 92 um^3, ferritin ~60 ug/L, tsat ~17%

  • eGFR 65 mL/min/1.73 m^2

  • Meds: ACEI/ARB >90%, beta-blocker ~85%, MRA ?, digoxin ~15%

• Baseline characteristics in CONFIRM-HF:

  • Age 69, female 45-50%

  • Ischemic cardiomyopathy 83%, prior MI 60%

  • NYHA 2 (~55%) or 3 (~45%); 6MWT distance ~290 metres

  • LVEF ~37%

  • Hb 124 g/L, ferritin 57 ug/L, tsat 18-20%

  • eGFR ~65 mL/min/1.73 m^2

  • Meds: ACEI 77%, ARB 23%, beta-blocker ~90%, MRA ?, digoxin 19-27%

Interventions

• Intervention: Iron

  • IV iron in 8 studies, with variable doses

    • e.g. mean 1850 mg given over 24 weeks in FAIR-HF, mean 1500 mg given over 1 year in CONFIRM-HF

  • PO iron in 3 studies, 200-600 mg/d

• Control: Matching placebo infusion

Results @ ~6-12 months (range 2 weeks to 1 year)

• Mortality (6 trials): Iron 3.3% vs control 4.6%; odds ratio (OR) 0.76, 95% CI 0.43-1.37

• HF hospitalizations: (5 trials, all IV iron): 5.3% vs 14.5%; OR 0.39, 95% CI 0.19-0.80

  • However, there was an important error in this analysis, with a far wider confidence interval after re-analysis

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• Quality of life (4 trials; measured with Kansas City Cardiomyopathy Questionnaire [KCCQ]): 4.1 points better with iron than control

  • KCCQ range 0-100; 5-point change considered minimally clinically important difference (MCID)

  • Note: Mean improvement over placebo of 4.4 (CONFIRM-HF), 6.6 (FAIR-HF), & 7.6 in 3 trials of IV iron vs placebo; mean improvement 0.1 in 1 trial of PO iron vs placebo (the aforementioned neutral IRONOUT HF trial)

  • Other QoL scales: EQ-5D (2 trials; 4 points better with IV iron), MLHFQ (2 trials; 19 points better with IV iron)

• NYHA functional class (5 trials): -0.7 (better) with IV iron vs control

• 6MWT (5 trials): Distance 33 m farther with IV iron vs control

• LVEF (3 trials): 3.8% higher with IV iron vs control

AFFIRM-AHF - Ponikowski P, et al. Ferric carboxymaltose for iron deficiency at discharge after acute heart failure: a multicentre, double-blind, randomised, controlled trial. Lancet 2020;396:1895-904.

Design

• RCT at low risk of bias (randomized; allocation concealed; blinding of patients; clinicians & outcome assessors; modified intention-to-treat; <0.5% loss to follow-up before 1st event)

Patients (n=1132)

• Included: Adults hospitalized for acute HF, receiving IV furosemide >=40 mg/d with LVEF <=50% & iron deficiency (per definition in context)

• Baseline:

  • Age 71, female 45%

  • Ischemic cardiomyopathy ~47%, prior MI ~40%

  • NYHA 1 (1-3%), 2 (45%), 3 (50%), 4 (~3-4%)

  • LVEF ~33%

  • Hb ~120 g/L, ferritin ~86 ug/L, TSat ~15%

  • eGFR <60 (52%)

  • Meds: ACEI/ARB/ARNI ~75%, beta-blocker 83%, MRA 65%, digoxin ~17%

Intervention: IV iron

• Ferric carboxymaltose, initial dose #1 & #2 dosed based on initial hemoglobin & patient weight, & doses #3 & #4 only if persistently iron deficient

• Initial IV bolus dose #1 - before discharge

  • Hb 140-150 g/L at any weight: 500 mg

  • Hb 80-140 g/L at any weight: 1000 mg

• Initial IV bolus dose #2 - at week 6

  • Hb >=140 g/L: No dose

  • Wt <70 kg

    • Hb 100-140 g/L: No dose

    • Hb 80-99 g/L: 500 mg

  • Wt >=70 kg

    • Hb 100-140 g/L: 500 mg

    • Hb 80-99 g/L: 1000 mg

• Mean total dose throughout trial: 1352 mg

Comparator: Matching placebo

Outcomes @ 12 months

• Primary outcome (total CV death + HF hospitalizations):

  • IV iron 57.2 vs placebo 72.5 per 100 patient-years

  • Rate ratio 0.79 (95% confidence interval [CI] 0.62-1.01)

  • Note: Rate includes recurrent HF hospitalizations

  • No difference in CV death: 14% in both groups, hazard ratio (HR) 0.96 (95% CI 0.70-1.32)

• First HF hospitalization or CV death:

  • IV iron 32% vs placebo 38% (number needed to treat 17)

  • HR 0.80 (95% CI 0.66-0.98)

  • Note: This is the more traditional & commonest way to report outcomes in HF trials

• Serious adverse events: 45% vs 51%

• Premature study drug discontinuation: 28% vs 29%

Ongoing areas of uncertainty:

• What is the long-term efficacy & safety of IV iron therapy for HFrEF? Does IV iron therapy reduce the risk of death in patients with HFrEF? (ongoing trials: FAIR-HF2, HEART-FID, IRONMAN)

• Would a different PO iron formulation be effective for iron replacement in patients with HFrEF? (ongoing trial: NCT03344523)

• What is the optimal duration, route & maintenance regimen for iron therapy following IV iron replacement?

• Is IV iron beneficial in patients with HF with LVEF >45%? (ongoing trials to assess this: FAIR-HFpEF)

AUGUSTUS - Antithrombotic regimens including apixaban vs warfarin, & aspirin vs placebo, in patients with AFib plus PCI &/or ACS

Reference: Lopes RD, et al. Antithrombotic therapy after acute coronary syndrome or PCI in atrial fibrillation. NEJM 2019.

Bottom line: In patients with atrial fibrillation who either undergo PCI and/or have ACS, in combination with a P2Y12 inhibitor (almost always clopidogrel):

• Apixaban reduces the risk of major or clinically-relevant non-major bleeding (NNT=24), hospitalizations (NNT=27), & stroke (NNT=84) compared to warfarin at 6 months;

• Aspirin (beyond the first week) increases the risk major or clinically-relevant non-major bleeding (NNH=15), without a clear effect on hospitalization/death or ischemic events compared to placebo at 6 months;

• Therefore, an antithrombotic regimen of apixaban + clopidogrel (without aspirin) should be routinely considered in these patients. Warfarin should be limited to patients for whom a DOAC is contraindicated, intolerable or unaffordable; & aspirin beyond the first week should be limited to patients with very high risk of stent thrombosis/recurrent coronary events.
  

Patients (n=4614 from 33 countries)

• Included if (all of the following):

  • Age 18+ years

  • Known AF (paroxysmal, persistent or permanent) with planned long-term oral anticoagulation

  • Recent (<14 days) ACS &/or PCI with plan for 6+ months of P2Y12 inhibitor

• Key exclusion criteria:

  • Other indication for anticoagulation (prosthetic valve, VTE, mitral stenosis, etc)

  • History of intracranial hemorrhage, ongoing bleeding or coagulopathy

  • Recent/planned CABG

  • “Severe” renal insufficiency

• Average baseline characteristics:

  • Age 71 years, male (71%), white (92%)

  • Qualifying event: ACS+PCI (37%), medically-managed ACS (24%), elective PCI (39%)

    • ~6.6 days from ACS/PCI to randomization

  • CHA2DS2-VASc ~4, HAS-BLED ~3

  • Prior stroke/TIA/thromboembolism (14%), HF (43%), HTN (88%), diabetes (36%)

  • SCr >133 (8%)

  • Previous oral anticoagulant (49%)

Interventions x6 months

• 2x2 factorial design: Patients were simultaneously randomized to apixaban vs warfarin & aspirin vs placebo within 14 days of ACS &/or PCI, so total of 4 different intervention groups.

• Management prior to randomization: At the discretion of treating physicians according to local standard of care (likely that all at least received DAPT +/- anticoagulation leading up to randomization, though not recorded/reported)

• Anticoagulation: Apixaban vs warfarin

  • Apixaban arm: 5 mg PO BID

    • Reduced to 2.5 mg PO BID if 2 of the following: Age >80 years, wt <60 kg, SCr >133 umol/L

    • Discontinued study regimen prematurely: 13%

  • Warfarin to target INR 2.0-3.0

    • Median time in therapeutic range (TTR)=59%; INR<2.0 23% of the time, INR>3.0 3% of the time

    • Discontinued study regimen prematurely: 14%

• Antiplatelet: Aspirin 81 mg PO daily vs matching placebo

  • Discontinued study drug prematurely: 15-17%

• All: P2Y12 inhibitor left at the discretion of the treating clinicians (clopidogrel 93%, prasugrel 1%, ticagrelor 6%)

• After 6 months, anticoagulation & antiplatelets were managed according to local standard of care (i.e. not standardized for the trial)

Results @ 6 months

• Primary outcome: Major or clinically-relevant non-major bleeding, ISTH definition

• Key secondary outcomes: Composite of death or hospitalization; composite of death or ischemic events (stroke, MI, definite/probable stent thrombosis, or urgent revascularization).

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Outcomes at 6 months of apixaban versus warfarin in combination with P2Y12 inhibitor +/- aspirin

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Outcomes at 6 months of aspirin versus placebo in combination with P2Y12 inhibitor + apixaban or warfarin

Risk of bias

• Low risk of: Allocation bias (allocation concealed via interactive voice-response system), attrition bias (low [0.3%] loss to follow-up & analyzed by intention-to-treat), outcome reporting bias (all outcomes of interest defined & reported).

• Variable risk of performance/detection bias:

  • Apixaban vs warfarin comparison was open-label (i.e. patients & clinicians aware of treatment assignment):

    • All outcomes were adjudicated by a blinded clinical endpoint committee, therefore providing some protection against (but not eliminating) detection bias.

  • Aspirin vs placebo comparison was blinded (patients, clinicians, outcome adjudicators unaware of treatment assignment): Low risk of performance & detection bias.