PRAGUE-18: Ticagrelor vs prasugrel in ACS

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References:

Bottom line: PRAGUE-18 was underpowered to identify clinically-important differences & was at high risk of bias. As a result, it could not rule out differences between prasugrel & ticagrelor.

Patients (n=1230)

  • Multicentre (14 tertiary-care cardiology centres in the Czech Republic)
  • Included MI (STEMI or NSTE-ACS with ST depression) requiring emergent (<120 min of admission to cardiac centre) angiography +/- PCI 
  • Key exclusion criteria:
    • Administration of clopidogrel loading dose or non-ASA antiplatelet before randomization (but could be on long-term clopidogrel-based DAPT before enrolment)
    • Indication for oral anticoagulant
    • Serious bleeding in past 6 months
    • Stroke, age >75 years, body weight <60 kg
  • Baseline characteristics
    • Age 62 y
    • Female 23-26%
    • At admission
      • EKG: STEMI 89%, LBBB 5%, NSTEMI 6%
      • Killip class: 1 (89%), 2 (6-7%), 3-4 (5-6%)
    • PMHx: Prior MI (7-9%), prior PCI (~7%), prior CABG (<2%), HF (1%), CKD (1%)
    • Procedural characteristics: PCI >99%, stent 96%, drug-eluting stent 68%
    • Meds @ discharge: ASA (97%), ACEI/ARB (83%), beta-blocker (82%), statin (94%), PPI 61%

Interventions

  • I: Ticagrelor (180 mg PO load, then 90 mg BID)
  • C: Prasugrel (60 mg PO load, then 10 mg daily [or 5 mg daily if age >75 y or wt <60 kg])
  • Common for both groups
    • Load generally administered immediately on hospital arrival before angiography
    • Duration recommended for 12 months
    • ASA administration required, with dose 100 mg/d recommended
    • Switch to clopidogrel if cost of prasugrel/ticagrelor was prohibitive for the patient

Results (prasugrel vs ticagrelor)

@ day 7 (or at discharge if discharged early)

  • Primary outcome (all-cause death, re-MI, stroke, serious bleed requiring transfusion or prolonging hospitalization, or urgent target vessel revascularization): 4.0% vs 4.1% (odds ratio [OR] 0.98, 0.55-1.73)
    • All-cause death: 1.3% vs 2.0% (p=0.30)
    • Re-MI: 1.0% vs 0.7% (p=0.59)
    • Urgent revascularization: 1.4% vs 1.2% (p=0.71)
    • Stroke: 0.2% vs 0.2% (p=0.96)
    • Serious bleed: 1.3% vs 1.2% (p=0.90)

@ day 30

  • CV composite (CV death, MI, stroke): 2.7% vs 2.5% (p=0.86)
  • All-cause death: 2.2% vs 2.7% (p=0.59)
  • Definite stent thrombosis: 0.5% vs 0.9% (p=0.43)
  • TIMI major bleed: 0.6% vs 0.7% (OR 0.86, 0.17-4.27)
  • No difference in bleeds based on BARC definition

@ 1 year

  • CV composite (CV death, MI, stroke): 6.6% vs 5.7% (hazard ratio [HR] 1.17, 0.74-1.84)
    • CV death: 3.3% vs 3.0% (p=0.77)
    • Non-fatal MI: 3.0% vs 2.5% (p=0.61)
    • Stroke: 1.1% vs 0.7% (p=0.42)
  • All-cause death: 4.7% vs 4.2% (p=0.65)
  • Definite stent thrombosis: 1.1% vs 1.5% (p=0.53)
  • TIMI major bleed: 0.9% vs 0.7% (p=0.75)
  • BARC major bleed: 2.4% vs 1.5% (p=0.31)
  • Dyspnea: Not reported

Considerations

  • Generalizability: Widely applicable to patients with STEMI requiring primary PCI.
  • High risk of several biases
    • High risk for allocation bias
      • Simple randomization, no use of permuted blocks or stratification by site;
      • Allocation concealment by sealed envelopes (prone to tampering).
    • High risk for performance & detection bias
      • No blinding of patients & clinicians to study drug;
      • Differential study drug discontinuation
        • Patients who could not afford the study drug could switch to clopidogrel
        • Study drug not free for participants, & there was differential funding for prasugrel & ticagrelor, as ticagrelor was not funded by the public insurance plan, whereas prasugrel was covered for patients with STEMI plus either left main disease, pLAD or multivessel disease
        • Switch to clopidogrel for financial reasons higher in ticagrelor group (44.4%) vs prasugrel (34.1%, p=0.003).
      • Blinded endpoint adjudication, however issues upstream as described above limit the value of blinded adjudication of potentially biased reports.
    • Low risk of attrition bias: Loss to follow-up: <1% at 30 days, 0% at 1 year.
  • Other issue: Study completely underpowered to detect a clinically-significant difference.
    • Initial power calculation with target sample size 2500 was based on unrealistic expectations
      • Done to detect a 2.5% absolute risk difference (or 39% relative risk difference) between ticagrelor & prasugrel (larger than difference between either drug compared to clopidogrel)
    • Confidence around point estimate of trial stopped early with sample size of 1230 cannot rule out a ~3% absolute risk difference in CV events between these drugs.

TACT: Heavy metal chelation for cardiovascular risk reduction

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Lamas, et al. Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. JAMA 2013;309:1241-50.

Bottom line:

  • The role of chelation in cardiovascular disease is unproven & unclear;

  • The TACT trial, which has unclear risk of bias due to possible unblinding, demonstrated a reduction in cardiovascular events in patients with prior MI (mainly driven by coronary revascularization) with a complex regimen that includes a chelator, as well as pharmacologically-active agents such as heparin & procaine;

  • If a patient chooses to undergo chelation, clinicians should encourage ongoing adherence to evidence-based pharmacological therapies, & implement harm-minimization strategy (i.e. avoid use in those with contraindication to chelation or frequent IV infusions; monitor for fluid overload & hypocalcemia).

Context

  • Chelation therapy (the act of administering a drug to bind metal ions) has been used in a non-evidence-based fashion to treat coronary artery disease (CAD) since the 1950s. The original rationale was to bind calcium and "decalcify the heart" following observations that autopsied hearts had heavily calcified coronary arteries.
    • Notably, we now know that calcification of arteries is a late consequence of atherosclerosis & not the direct cause of coronary events.
  • The rationale for chelation therapy in atherosclerotic CVD now centers around observations that increased exposure to heavy metals, particularly cadmium & lead, is associated with cardiovascular disease, possibly by causing endothelial dysfunction (cadmium), increased BP (lead), & inducing macrophage dysfunction & apoptosis (cadmium).
  • The only supporting evidence for chelation therapy in CAD prior to this trial came from uncontrolled case reports & case series.

Setting

  • 134 sites in US & Canada
  • 60% of sites already practiced chelation therapy (generally naturopathic & alternative medicine clinics)

Patients (n=1708)

  • Inclusion
    • Age >50 years
    • Prior MI (>6 weeks before enrollment)
  • Exclusion
    • Past intolerance to chelation or vitamin components
    • Inability to tolerate 500-mL infusions weekly
    • Chelation therapy within 5 years
    • Coronary/carotid revascularization planned or in prior 6 months
    • "Active" HF or HF hospitalization within 6 months
    • Current smoker or smoking in last 3 months
    • BP >160/100 mm Hg
    • SCr >170 umol/L
    • Plt <100
    • Abnormal LFTs
  • Baseline characteristics
    • 65 years
    • Female 18%
    • White 94%
    • CAD characteristics: Last MI 4.6 years ago, anterior MI 40%, angina 55%, prior CABG/PCI 83%
    • PMHx: Former smoker 56%, CHF 18%, diabetes 40%
    • BP 130/76
    • Meds: Antithrombotic 91% (ASA in 83%), ACEI/ARB 63%, beta-blocker 72%, statin 73%, multivitamin 44%, herbal products 34%
    • Labs: LDL 2.3 mmol/L, HDL 1.1 mmol/L, SCr 97 umol/L

Interventions

  • Intervention: Chelation+ infusion
    • Each infusion consists of 10 components commonly combined by US chelation practitioners: Disodium EDTA (ethylene-diamine-tetracetic acid) 3 g (decreased based on eGFR), procaine hydrochloride 100 mg, heparin 2500 units, ascorbic acid (vitamin C) 7 g, magnesium chloride 2 g, potassium chloride 2 mEq, sodium bicarbonate 840 mg, pantothenic acid 250 mg, thiamine 100 mg, pyridoxine (vitamin B6) 100 mg, & sterile water to total 500 mL
    • Each infusion administered over minimum 3h (slower if HF or albumin-corrected serum Ca 2.0-2.12 mol/L)
    • 30 weekly infusions, followed by 10 infusions q2-8 weeks
  • Control: Placebo infusion (500 mL of NS & 1.2% dextrose)
  • Co-intervention: Daily vitamin containing vitamin B6 25 mg, chromium 50 ug, copper 2 mg, manganese 15 mg, zinc 25 mg

Results @ median 4.6 years

Efficacy

  • Chelation reduced the primary outcome (all-cause death, re-MI, stroke, coronary revascularization, angina hospitalization): Chelation 26% vs placebo 30% (hazard ratio [HR] 0.82, 0.69-0.99)
    • Driven by fewer coronary revascularizations: 15% vs 18% (HR 0.81, 0.64-1.02)
  • No significant difference in secondary outcome (CV death, re-MI, stroke): 11% vs 13% (HR 0.84, 0.64-1.02)
  • No significant difference in death (10% vs 11%), MI (6% vs 8%), stroke (1% vs 1%), or angina hospitalization (2% vs 2%)
  • No difference in quality of life scores at 2 years (in either cardiac functional status measured using Duke Activity Status Index, or SF-36 Mental Health Inventory-5) in subset of 911 patients

Safety

  • Serious adverse events: Chelation 12% vs placebo 15% (p=0.10)
  • Non-serious adverse events: 68% vs 67% (p=0.60)
  • Hypocalcemia (serum Ca <2.0 mmol/L): 6.2% vs 3.5% (p=0.008)

Subgroups: 9 subgroups evaluated, 2 had significant interaction p-value (diabetes, anterior MI) for primary outcome

  • iabetes status (p=0.02 for interaction)
    • Diabetes: HR 0.61, 0.45-0.83
    • No diabetes: HR 0.96, 0.77-1.20
  • MI distribution (p=0.03 for interaction)
    • Anterior MI: HR 0.63, 0.47-0.86
    • Non-anterior MI: HR 0.96 (0.77-1.20)
  • No difference between complementary/alternative sites vs others (p=0.28)

Generalizability & other considerations

  • Key characteristics of included patients
    • Several groups of patients with CAD were excluded, notably current smokers (rationale unclear), and those with "active" heart failure or recent hospitalization for HF, uncontrolled HTN or renal dysfunction (who may not tolerate the weekly fluid infusions)
    • Patients with chelation in the past 5 years were also excluded, likely to remove bias from including any patients with a potential preference for this therapy
    • Use of evidence-based therapies for CAD at baseline was low (particularly for statins; only used at any dose in 73%), & rates later in the trial are not reported. It is unclear if use of chelation, or practitioners of chelation themselves, may have influenced the use of proven, evidence-based therapies.
  • The chelation regimen includes a number of other pharmacologically-active components, including heparin (anticoagulant) and procaine (pro/antiarrhythmic, vasodilator). TACT used this combination as it is the most commonly used by chelationists in the US, but the actual therapeutic rationale is unclear. The apparent benefit in the primary outcome of TACT may be in part explained by these other components rather than chelation. Moreover, these extra components could be harmful.
  • The difference in the primary outcome is marginally statistically significant (p=0.035, just below the modified 0.036 threshold), & completely driven by coronary revascularization, the softest endpoint in the composite.
  • The findings from the subgroup analysis should be interpreted cautiously in context of the limitations: large # of subgroup analyses performed (9); the beneficial effect found in diabetes & anterior MI was not expected; no biologic rationale to explain the benefit in diabetics & those with anterior MI but not in others; no other RCT with which to compare.

Internal validity: Unclear risk of bias

  • Allocation: Web-based randomization with permuted blocks, allocation concealed.
  • Performance: Patients, clinicians blinded, matching placebo
    • Concern has been raised about possible unblinding of participants due to the higher withdrawal of consent in the placebo group, suggesting that patients were somehow told that they were receiving placebo and decided to leave the trial. This is not proven, but is one possible explanation for this finding, and would therefore introduce bias in the softer outcome of revascularization, which drove the difference in the primary outcome.
  • Detection: Blinded adjudication committee.
  • Attrition: Intention-to-treat analysis, but high loss-to-follow-up with differences between groups
    • 18% lost-to-follow-up, mainly due to withdrawal of consent, which was higher with placebo (20%) than chelation (13%). Usually, differences in loss-to-follow-up between groups are because of tolerability issues with 1 of the interventions, however, in this case those receiving placebo left the trial more often. As discussed above, this suggests unblinding. Other explanations would include chance (unlikely with such a large difference), people receiving chelation feeling better than placebo, thus being motivated to continue treatment (but this is not corroborated by the quality of life results).
  • Selective outcome reporting: Reporting of all clinical outcomes of interest for both efficacy & safety.
  • Others:
    • Trial initially planned to enroll ~2400 patients, but decreased to 1700 midway due to slow patient recruitment.
    • Data safety monitoring board performed 11 interim analyses prior to the final analysis.

REVEAL: Anacetrapib in ASCVD

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The HPS3/TIMI55-REVEAL Collaborative Group. Effects of anacetrapib in patients with atherosclerotic vascular disease. N Engl J Med 2017;377:1217-27.

Bottom line: In patients with ASCVD & a risk of coronary events ~3%/year, anacetrapib reduced the risk of major coronary events (NNT 100 over 4.1 years, or NNT 410/year).

Anacetrapib's CV benefit is proportional to its LDL-C reduction, & may be unrelated to its effect on HDL-C.

Context

  • Lower HDL-C concentrations are associated with greater risk of CV disease; however, no trial has yet to show benefit of increasing HDL-C with pharmacological therapy;
  • Mechanism: Cholesteryl ester transfer protein (CETP) transfer triglycerides & cholesteryl esters between LDL or VLDL to HDL. Inhibiting CETP results in greater HDL-C serum concentrations & lower LDL-C & non-HDL-C serum concentrations;
  • Previous trials of CETP inhibitors have all failed to demonstrate clinical benefit, & some even caused harm:
    • ILLUMINATE: RCT of 15,067 patients at high risk of ASCVD. Torcetrapib increased the risk of CV events versus placebo over 550 days (6.2% vs 5.0% [NNH 84); hazard ratio [HR] 1.25, 1.09-1.44), as well as death (1.2% vs 0.8% [NNH 250], HR 1.58, 1.14-2.19);
    • dal-OUTCOMES: RCT of 15,871 patients with recent ACS. Dalcetrapib did not reduce the risk of CV events versus placebo over 31 months (8.3% vs 8.0%; HR 1.04, 0.93-1.16);
    • ACCELERATE: RCT of 12,092 patients with ASCVD stopped early for futility. Evacetrapib did not reduce CV events versus placebo over 26 months (12.9% vs 12.8%; HR 1.01, 0.91-1.11).
  • In October 2017, the maker of anacetrapib announced that it would not seek market approval, essentially ensuring that no CETP inhibitor would reach clinical use.

Patients (n=30,449)

  • Inclusion
    • Age >50 years
    • Hx of ASCVD (MI, cerebrovascular aatherosclerotic disease, PAD, or diabetes with symptomatic CAD)
  • Exclusion
    • ACS or stroke <3 months ago
    • Planned CABG/PCI
    • "Clinically significant liver, kidney, inflammatory muscle, or other disease"
    • Current tx with a fibrate, niacin, "or any drug contraindicated with anacetrapib or atorvastatin"
    • Previous statin-related adverse reaction
    • Known poor adherence to clinic visits or medications
  • Baseline characteristics
    • Age 67 y
    • Male 88%
    • PMHx
      • ASCVD: CAD 88%, cerebrovascular disease 22%, PAD 8%
      • Diabetes 37%
      • HF 6%
    • BP 131/78 mm Hg
    • HDL-C 1.0 mmol/L
    • LDL-C 1.6 mmol/L
    • Non-HDL-C 2.4 mmol/L

Interventions

  • Intervention: Anacetrapib 100 mg once daily
  • Control: Matching placebo
  • Co-intervention for all: Atorvastatin to reduce LDL-C <2.0 mmol/L

Results @ median 4.1 years

  • Effect on lipids (difference vs placebo) @ year 2:
    • HDL-C: +104% (+1.1 mmol/L)
    • LDL-C, non-HDL-C, ApoB: -18% (LDL-C -0.3 mmol/L)
    • Lp(a) -25%
  • Effect on BP: +0.7/0.3 mm Hg with anacetrapib vs placebo
  • Note 1: The reduction in major coronary events only became apparent after day 3; additionally, the relative risk reduction (RRR) increased over time (e.g. from 2% at year 1 up to 17% after year 4)
  • Note 2: Annualized NNT for major coronary events: ~410/year

Safety

  • Serious adverse events: Anacetrapib 58.4%, placebo 58.5%
  • Non-serious adverse events: Anacetrapib 5.4%, placebo 5.4%
  • eGFR <60 mL/min: Anacetrapib 11.5%, placebo 10.6%, p=0.04 (NNH 112)

Generalizability & other considerations

  • Key characteristics of included patients
    • Moderate risk for a population with existing ASCVD (risk of major vascular event ~3.5%/year & major coronary event ~3%/year) in control group)
    • Excellent LDL-C control (mean ~1.6 mmol/L), & low baseline HDL-C (mean ~1.0 mmol/L)
  • It's unclear if the coronary event reduction with anacetrapib resulted from the HDL-C increase or LDL-C reduction. However, the benefits in REVEAL are consistent with what would be expected based on the LDL-C reduction:

Internal validity: Low risk of bias

  • Allocation: Randomization by minimization, allocation concealed
  • Performance & detection: Patients, clinicians blinded, matching placebo
  • Attrition: Loss-to-follow-up 0.1%, intention-to-treat analysis
  • Selective outcome reporting: Reporting of all clinical outcomes of interest for both efficacy & safety

ASCEND-HF - Nesiritide for acute decompensated heart failure

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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

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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

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