TREAT - Ticagrelor vs clopidogrel after fibrinolytic therapy for STEMI

Berwanger O, et al. Ticagrelor vs clopidogrel after fibrinolytic therapy in patients with ST-elevation myocardial infarction: a randomized clinical trial. JAMA Cardiol 2018;3:391-9

Berwanger O, et al. Ticagrelor versus clopidogrel in patients with STEMI treated with fibrinolysis: TREAT trial. J Am Coll Cardiol 2019;73:2819-28.

Bottom line: In patients <75 y/o who received fibrinolytic therapy plus a loading dose of clopidogrel for STEMI, switching to ticagrelor with a loading dose 8-24h after administration of the fibrinolytic agent

• does not appear to increase the risk of major, fatal or intracranial bleeding at 30 days versus continuing with clopidogrel.

• does not clearly reduce the risk of cardiovascular events up to 1 year, but does increase the risk of any bleeding (NNH 25) & dyspnea (NNH 10).

There is not currently a role for routine use of ticagrelor in STEMI patients treated with fibrinolysis.

Patients (n=3799)

• Setting: 10 countries including Canada, enrolled from Nov 2015 to Nov 2017

• Included:

  • 18-75 y/o

  • STEMI presenting <24h after symptom onset

  • Received fibrinolytic therapy

• Excluded:

  • Contraindication to clopidogrel, ticagrelor or fibrinolysis; use of oral anticoagulant therapy; dialysis-dependent; clinically-important anemia or thrombocytopenia, or active bleeding (therefore excluding those who bled early with the initial fibrinolytic+antiplatelet regimen)

  • Increased risk of bradycardia (not further defined); concomitant use of a strong CYP3A4 inhibitor/inducer

• Baseline characteristics:

  • Age 59 y; female 23%; white 57%, Asian 33%

  • STEMI type: Anterior involvement (~37%), inferior only (~30%), LBBB only (1%)

  • Killip class 2-4: 9%

  • PMHx: MI (8-9%), stroke (~5%), PCI (5-6%), CABG (<1%)

  • Meds (baseline + in-hospital):

    • ASA 99%

    • Anticoagulant during admission: Heparin (40%), LMWH (69%), fondaparinux (4%), bivalirudin (~1%), warfarin (<1%)

    • ACEI ~60%, ARB ~10%

    • Beta-blocker 74%

    • Statin 93%

    • PPI ~55%

  • PCI during initial ACS hospitalization: ~56% (DES ~34%)

Intervention & control

• Intervention: Ticagrelor 180 mg PO x1, then 90 mg BID (plan to continue 12+ months per standard ACS management)

• Control: Clopidogrel 300-600 mg PO x1, then 75 mg daily (plan to continue 12+ months per standard ACS management)

• Co-interventions:

  • Mean adherence of 90% to P2Y12 inhibitor at 30 days & 12 months

  • Clopidogrel dose administered before randomization: >300 mg (3%), 300 mg (87%), none or <300 mg (10%)

  • All received ASA 75-100 mg daily unless intolerant

  • Fibrinolytic selection: TNK ~40%, alteplase ~20%, reteplase, 17%, other 23%

  • Median 2.6 h from symptom onset to fibrinolytic administration

  • Median 11.4 h from fibrinolytic administration to randomization

  • PCI during hospitalization in 56%, drug-eluting stent in 34%

Results

@ 30 days

• Bleeding

  • 1o outcome (major bleed, TIMI definition): Ticagrelor 0.7%, clopidogrel 0.7%

    • (95% confidence interval for absolute risk difference -0.5% to +0.6%, p<0.001 for non-inferiority based on a non-inferiority margin of 1.0%)

  • Other bleeding outcomes:

    • Intracranial hemorrhage: 0.4% in both groups (95% CI -0.35% to +0.45%)

    • Fatal bleeding: 0.2% vs 0.1% (95% CI -0.2% to +0.3%)

    • PLATO major bleed / BARC type 3-5: 1.2% vs 1.4%

    • TIMI major bleed based on time from fibrinolytic administration to administration of study antiplatelet

      • <4h: 1.5% vs 1.2%

      • 4-8h: 0.8% vs 1.2%

      • 8-16h: 0.5% vs 0.3%

      • 16+h: 0.5% vs 0.2%

• Efficacy

  • Death from any cause: 2.6% in both groups; Hazard ratio (HR) 0.99 (95% confidence interval 0.66-1.47)

  • Vascular death, MI, stroke: 4.0% vs 4.3%; HR 0.91 (0.67-1.25)

    • MI: 1.0% vs 1.3%; HR 0.79 (0.44-1.42)

• Dyspnea: 13.9% vs 7.6%

@ 1 year

• Efficacy

  • Vascular death/MI/stroke: Ticagrelor 6.7%, clopidogrel 7.3%; HR 0.93 (0.73-1.18)

  • Death from any cause: 4.2% vs 4.6%; HR 0.92 (0.68-1.24)

• Bleeding

  • TIMI major: 1.0% vs 1.2%; HR 0.86 (0.47-1.56)

  • TIMI clinically significant: 5.3% vs 3.8%; HR 1.41 (1.04-1.91)

  • Any bleeding: 10.2% vs 6.2%; HR 1.69 (1.34-2.13)

  • Intracranial hemorrhage: 0.5% in both groups; HR 1.10 (0.44-2.69)

• Dyspnea: 23.9% vs 13.7% (NNH 10)

Generalizability

• TREAT enrolled a representative population of STEMI patients who received fibrinolytic therapy.

• Logistics of this trial are key to interpretation & application. Fibrinolytic therapy is generally reserved as 2nd-line to primary PCI for patients who cannot get to a PCI-capable hospital in a reasonable timeframe, & is therefore often administered in the pre-hospital or community hospital setting. This trial was undertaken at academic sites, and therefore generally enrolled patients & administered the study therapy hours after administering a fibrinolytic, with 90% having already received a clopidogrel load.

  • This is therefore NOT a trial comparing SIMULTANEOUS fibrinolysis + ticagrelor vs fibrinolysis + clopidogrel, but rather a trial comparing an early switch from clopidogrel to ticagrelor within 24h of administering a fibrinolytic. With a median time from fibrinolytic administration to study P2Y12 administration of 11.4h, the fibrinolytic was long-gone by the time they entered the study (e.g. half-life <30 min for 3 most-commonly-used fibrinolytics)

  • Therefore the most direct application of these results would be to administer a loading dose of clopidogrel 300 mg PO with the fibrinolytic, & then switch to ticagrelor by starting with a loading dose 8-24h later (ensuring that the fibrinolytic is eliminated, & therefore pharmacodynamic interaction & bleed risk is minimized)

Internal validity

• Low risk of allocation bias due to use of an automated web-based system in permuted blocks of 4 stratified according to site

• Unclear risk of performance and detection bias due to open-label design with blinded adjudication of outcomes (though low risk for important "hard" endpoints of death, major, fatal and intracranial bleeds)

• Low risk of attrition bias due to very low loss-to-follow-up (0.1-0.2%) & use of ITT analysis

• Non-inferiority design (for 30-day safety outcomes) was appropriate, design decisions were well-justified & conclusion of non-inferiority is reasonable based on threshold set & consistency in analyses

  • Justified based on potential long-term benefits of ticagrelor as observed in the PLATO trial (i.e. to 12 months after ACS)

  • Non-inferiority margin for major bleed set at an absolute risk increase of 1.0%, which the authors justify empirically based on thresholds used in other non-inferiority RCTs

  • Analyzed 3 separate definitions of "major bleed" using both ITT & per-protocol analyses, which were all nearly identical & consistent

AVERROES - Apixaban versus ASA in patients with AF not suitable for warfarin

Connolly SJ, et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011;364:806-17.

Bottom line:

• In patients with non-valvular AF, apixaban is more effective at reducing stroke risk than ASA (relative risk reduction 55%; NNT ~46/year), with a small increase in minor bleeding (NNH 84/year) but no significant increase in major bleeding;

• This favorable benefit/risk profile of apixaban over ASA was present even in patients with a CHADS2 score of 0-1.

Patients

• Included:
  • 50+ y/o
  • AF (documented within 6 months before enrolment or by 12-lead EKG)
  • At least 1 stroke risk factor (any CHADS2 criteria or PAD):
    • HF (NYHA class 2-4 symptoms or LVEF 35% or less), HTN, Age 75+, diabetes (on treatment), prior stroke/TIA, or documented PAD
  • Not receiving a warfarin because previously demonstrated to be "unsuitable" or expected to be unsuitable
• Excluded:
  • Additional indication for anticoagulation other than AF
  • Serious bleeding within 6 months
  • High risk of bleeding (eg active peptic ulcer, plt <100, Hb <100 g/L, stroke within 10 days, blood dyscrasias)
  • Serum creatinine >221 umol/L or CrCl <25 mL/min
• Baseline characteristics:
  • Age 70, male 59%
  • AF type: Paroxysmal (27%), persistent (21%), permanent (52%)
  • CHADS2 mean 2 (0 or 1 in 36%)
  • Stroke risk factors: Clinical HF (40%), LVEF <35% (5%), HTN (86%), diabetes (20%), prior stroke/TIA (14%)
  • Most common reason warfarin was "unsuitable" (multiple reasons in 51%):
    • Unable to measure INR frequently enough 43%
    • Patient refused to take warfarin 38% (the only reason in 15%)
    • CHADS2=1 so warfarin not recommended by physician 21%
    • Unable to keep INR therapeutic 17%
    • Unsure if patient can adhere to instructions to take warfarin 16%

Intervention & control

• Intervention: Apixaban 5 mg PO BID
  • Decreased to 2.5 mg BID if 2/3 of: Age 80+ y, wt <60 kg, SCr >132 umol/L (occurred in 6%)
• Control: ASA 81-324 mg/d (64% on 81 mg/d)

Results @ mean 1.1 years

• Efficacy
  • Primary outcome (any stroke or systemic embolism): Apixaban 1.8% versus ASA 4.0%, hazard ratio (HR) 0.45 (0.32-0.62), NNT=46
  • Death from any cause: 4.0% vs 5.0%, HR 0.79 (0.62-1.02)
  • CV hospitalization: 13.1% vs 16.3%, HR 0.79 (0.69-0.91), NNT=32
• Safety
  • Major bleed (overt bleed with Hb decrease 20+ g/L over 24h, transfusion 2+ units of RBCs, or bleeding at a critical site [e.g. brain, eyes, pericardium, retroperitoneum): 1.6% vs 1.4%, HR 1.13 (0.74-1.75)
    • Intracranial: 0.4% vs 0.5%, HR 0.85 (0.38-1.90)
    • Extracranial: 1.2% vs 1.0%, HR 1.23 (0.74-2.05)
  • Minor bleed: 6.7% vs 5.5%, HR 1.24 (1.00-1.53), NNH=84
  • Serious adverse events: 22% vs 27%, NNT=20
• Subgroup analysis by baseline CHADS2 score demonstrated consistent relative risk reductions with apixaban over ASA regardless of score, with higher-risk patients deriving greater ABSOLUTE reductions in stroke (NNT=143/year for CHADS2=0 to 1, NNT=23/year for CHADS2=3+)

Generalizability

• Representative sample of elderly patients with AF & a wide spectrum of stroke risk who had a difficult time maintaining INRs in the therapeutic range, going to the lab for INR monitoring, or who were expected not to do well with warfarin based on clinical judgement. Results were similar regardless of the reason for being unsuitable for warfarin.

Internal validity

• Low risk of allocation, performance, detection, attrition, selective reporting bias
  • Central, computerized, automated randomization
  • Double-dummy blinding
  • Blinded outcome adjudication
  • No patients lost to follow-up
  • All relevant & important outcomes reported
• Trial stopped early after 1st interim analysis for efficacy based on 104 events between groups

PRAGUE-18: Ticagrelor vs prasugrel in ACS

References:

• Motovska Z, et al. Prasugrel versus ticagrelor in patients with acute myocardial infarction treated with primary percutaneous coronary intervention: Multicenter randomized PRAGUE-18 study. Circulation 2016;134:1603-12.
• Motovska Z, et al. One-year outcomes of prasugrel versus ticagrelor in acute myocardial infarction treated with primary angioplasty: The PRAGUE-18 study. J Am Coll Cardiol 2017 Nov 9 [Epub ahead of print].

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

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.
  • TACT2 trial now underway to replicate these findings in 1200 patients with diabetes & prior MI.

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

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

View fullsize

• 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:
  • Relative risk reduction 7% in major vascular events
  • Average LDL-C reduction: 0.3 mmol/L
  • 23% RRR in major coronary events per 1-mmol/L LDL-C reduction (similar to ~20-25% RRR in major vascular events seen with statins in Cholesterol Treatment Trialist meta-analysis).

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