ASCEND-HF - Nesiritide for acute decompensated heart failure

O'Connor CM, et al. Effect of nesiritide in patients with acute decompensated heart failure. N Engl J Med 2011;365:32-43.

Bottom line: In patients hospitalized with acute decompensated HF, nesiritide does not provide any clinically meaningful benefit when added to standard care, & increases the risk of symptomatic hypotension (NNH 32).

Context

• Nesiritide, a recombinant form of B-type natriuretic peptide (BNP) & the first therapeutic natriuretic peptide, was approved for use in 2001 based on surrogate benefit (reduction in pulmonary capillary wedge pressure [PCWP]) & reduction in dyspnea at 3 hours compared to placebo or nitroglycerin.
• Meta-analyses of small nesiritide trials found a possible increased risk of AKI & death vs placebo.

Patients (n=7007 analyzed)

• Included:
  • Hospitalized for HF (regardless of EF)
  • Within 24h of initiation of in-hospital IV treatment of HF <24h of enrolment
  • Dyspnea at rest or with minimal activity (ie leading to NYHA functional class 3-4)
  • Plus at least 1 of: RR 20+, pulmonary congestion/edema with rales 1/3 of the way up or more of the lung fields
  • Plus at least 1 objective measure of HF (congestion/edema on CXR, BNP >400 pg/mL or NTproBNP >1000 npg/mL, PCWP >20 mm hg, LVEF <40% in the previous 12 months)
• Excluded:
  • SBP <100 mm Hg, or <110 mm Hg if using IV nitroglycerin
  • Dobutamine (at rate of 5+ ug/kg of body wt/min)
  • Milrinone, levosimendan within 30 days
  • Persistent uncontrolled HTN; ACS; severe pulmonary disease; ESRD with renal replacement therapy; clinically-significant anemia
  • "Other contraindications for vasodilators"
• Baseline characteristics
  • Age 67 y
  • Female 34%
  • PMHx: Ischemic heart disease 60%, HTN 73%, AF 37%
  • Median ~16h from hospitalization to study drug initiation
  • SBP 124, HR 82
  • EF <40% (80%), 40% or more (20%)
  • BNP ~990 pg/mL, NTproBNP ~4500 ph/mL
  • Na 139, SCr ~106 umol/L 
  • Meds: Loop diuretic 95%, ACEI/ARB 60%, BB 58%, MRA 28%, digoxin 27%
• Generalizability: Good; trial population is representative of patients hospitalized for ADHF, excluding those at high risk of hypotension & those on inotropes

Interventions

• I: Nesiritide
  • Optional loading dose: 2 ug/kg IV bolus
  • Maintenance dose: 0.010 ug/kg/min continuous infusion for >24h, max 7 days
  • Median infusion duration 41h (IQR 24-48h)
• C: Matching placebo infusion
• Co-interventions for all: Diuretics, morphine, other vasoactive medications guided by use of a standard-of-care manual

Results

• Co-primary outcome 1: Self-reported dyspnea on 7-point Likert scale (range markedly better to markedly worse)
  • Moderately/markedly better @ 6h: Nesiritide 44.5%, placebo 42.1% (p=0.03)
  • Moderately/markedly better @ 24h: Nesiritide 68.2%, placebo 66.1% (p=0.007)
  • Although these differences were statistically significant, they are not clinically important
• Co-primary outcome 2: All-cause mortality or re-hospitalization for HF @ 30 days:
  • Nesiritide 9.4%, placebo 10.1% (hazard ratio [HR] 0.93, 95% confidence interval 0.9-1.08)
  • Death: 3.6% vs 4.0% (p>0.05)
• Secondary outcomes
  • Persistent/worsening HF or death prior to discharge: Nesiritide 4.2%, placebo 4.8% (p=0.30)
• Adverse effects
  • Symptomatic hypotension: Nesiritide 7.2%, placebo 4.0%, number needed to harm (NNH) 32 (p<0.001)
  • Asymptomatic hypotension: Nesiritide 21.4%, placebo 12.4%, NNH 12
  • eGFR decreased by >25% from baseline: Nesiritide 31.4%, placebo 26.2% (p=0.11)

Internal validity

• Unclear risk of allocation bias (randomization & allocation concealment procedures not adequately reported)
• Low risk of performance & detection bias (double-blind with matching placebo)
• Low risk of attrition bias
  • Modified ITT analysis of all patients who received study drug (98% of randomized)
  • <3% loss-to-follow-up for evaluation of symptoms at 6-24h 

Other studies of nesiritide

• 2000 NEJM study:
  • In the first part of the trial, 127 ADHF patients were randomized to double-blind treatment with nesiritide 0.015 ug/kg/min, nesiritide 0.03/ug/kg/min or placebo. At 6h, nesiritide reduced dyspnea, improved global clinical status & reduced PCWP more than placebo.
  • In the second part of this trial, 305 ADHF patients were randomized to open-label nesiritide 0.015 ug/kg/min, nesiritide 0.03/ug/kg/min or another vasoactive agent (inotrope, nitroglycerin or nitroprusside at attending physician's discretion). There was no difference in any efficacy measure between groups.
• VMAC: This was a double-blind RCT of 489 ADHF patients comparing nesiritide to nitroglycerin IV & placebo x3h, followed by a comparison of nesiritide vs nitroglycerin x24h.
  • By 3h, nesiritide decreased PCWP (-5 mm Hg) & right atrial pressure (-3 mm Hg) more than nitroglycerin (-3 & -2) & placebo (-2 & 0). Nesiritide also reduced dyspnea @ 3h more than placebo, but not nitroglycerin.
  • There were no differences in dyspnea or global clinical status @ 24h. The rate of adverse effects was higher in the nitroglycerin group, largely due to more headaches vs nesiritide. Rates of hypotension were similar between these 2 groups.
• ROSE: In this double-blind trial of 360 ADHF patients with renal dysfunction, there was no difference between nesiritide, dopamine or placebo in cumulative urine output or renal function after 72h of study treatment.

ATLAS - Rivaroxaban in patients with a recent ACS

ATLAS ACS 2-TIMI 51: Mega JL, et al. Rivaroxaban in patients with a recent acute coronary syndrome. NEJM 2012;366:9-19.

Bottom line:

• Over ~13 months of follow-up, the addition of rivaroxaban 2.5 mg BID to ASA+clopidogrel/ticlopidine reduced the risk of CV events, mainly driven by fatal events, which led to lower all-cause mortality (NNT 63) in patients post-ACS. Adding rivaroxaban also reduced stent thrombosis (NNT 143). This came at the cost of a greater risk of major bleeds (NNH 84), including intracranial hemorrhages (NNH 500).

• Adding rivaroxaban 5 mg BID did not reduce mortality, & further increased the risk of major bleeds.

• It remains unclear which of the following regimens would have the best balance between efficacy & safety: Ticagrelor-based DAPT, clopidogrel-based DAPT + low-dose rivaroxaban, or ticagrelor-based DAPT + low-dose rivaroxaban.

Patients (n=15,526)

• Included
  • ACS (within 7 days of admission, after revascularization if planned)
  • Plus either
    • Age >55 y
    • Previous MI
    • Diabetes
  • Excluded
    • Previous intracranial hemorrhage
    • Clinically-significant GI bleed within 12 months
    • CrCl <30 mL/min
    • Hb <100 g/L
    • Platelet count <90
• Baseline characteristics
  • Age 61.5 y (9.6% 75 y or greater)
  • Female 25%
  • STEMI (~50%), NSTEMI (~25%), UA (~25%)
  • Previous MI 27%
  • CV risk factors: HTN ~67%, diabetes ~32%, dyslipidemia ~50% 
  • CrCl 86 mL/min
  • Meds
    • ASA 99%, P2Y12 inhibitor ~93%
    • ACEI/ARB ~40%
    • Beta-blocker ~66%
    • Statin ~15%

Interventions

• Intervention1: Rivaroxaban 2.5 mg BID
• Intervention2: Rivaroxaban 5 mg BID
• Control: Placebo
• All groups: ASA + clopidogrel or ticlopidine

Results @ 13.1 months

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Considerations

• Low risk of bias (allocation, performance, detection & attrition)
  • Allocation concealed by central computer/phone allocation
  • Participants, clinicians & investigators blinded to study drug
  • Modified ITT & full ITT analysis
  • 0.3% lost to follow-up, though ~28% in all groups discontinued study drug before end of study
• Generalizability
  • Patients represented a group of post-ACS patients at very high risk of recurrent ASCVD with very low use of proven secondary prevention therapies
  • Additionally, this trial was performed before approval of more potent P2Y12 inhibitors (prasugrel & ticagrelor), so background DAPT included ASA + clopidogrel/ticlopidine (how many specifically received clopidogrel not reported)
  • Based on the preliminary results from ATLAS ACS-TIMI 46 (see below), the investigators selected 2.5 and 5 mg BID doses of rivaroxaban for this trial; this is pharmacokinetically rational given the 5-13h half-life of rivaroxaban (apixaban & dabigatran have similar half-lives and are generally dosed BID), however, it is a very different regimen than that used for AF/VTE. As a result, it's unclear if this regimen preserves the efficacy of rivaroxaban for these other conditions.

Summary of ATLAS ACS-TIMI 46

• Dose-ranging study with identical enrolment criteria as ATLAS ACS 2-TIMI 51

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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)