TOPIC - Continuing ticagrelor/prasugrel vs switching to clopidogrel 1 month after ACS

Benefit of switching dual antiplatelet therapy after acute coronary syndrome: The TOPIC (timing of platelet inhibition after acute coronary syndrome) randomized study. Eur Heart J 2017 [online]

Bottom line: In patients with ACS who underwent PCI & tolerated prasugrel/ticagrelor x1 month, discontinuing prasugrel/ticagrelor & switching to a pill that combines ASA+clopidogrel reduced the risk of mainly minor bleeding over the subsequent 11 months.

TOPIC was underpowered to evaluate ischemic events, & is inadequate to inform practice or change routine care. Based on results from PLATO, employing this strategy would result in an increased risk of death/MI/stroke, particularly during the crossover period between stopping ticagrelor & waiting for clopidogrel to achieve its full antiplatelet effect (up to 7 days).

Patients (n=645)

• Included: 
  • Adults with ACS, & PCI within 3 days of ACS admission initially treated with prasugrel/ticagrelor
  • No major adverse event in 1st month (including ischemia or bleed)
• Key exclusion: Major bleed (BARC criteria) in last year, long-term use of anticoagulation
• Baseline characteristics
  • Age ~60 y
  • Male ~83%
  • ACS type: STEMI ~40%, NSTE-ACS 60%
  • Previous CAD 30%
  • CV risk factors: Smoker ~45%, HTN ~50%, T2DM ~25%
  • Meds
    • P2Y12 inhibitor: Prasugrel ~55%, ticagrelor ~45%
    • ACE inhibitor or ARB ~75%
    • Beta-blocker ~70%
    • Statin ~95%
    • PPI 100%

Interventions

ASA 75 mg/d + ticagrelor/prasugrel (clinician selection) x1 month, then randomized to:

• I ("switch"): Switch to clopidogrel 75 mg/d + ASA 75 mg/d (combined in 1 pill) x11 months (total 1 year on DAPT)
  • The published report does not specify what strategy was used to perform the switch to clopidogrel. This is critical as clopidogrel 75 mg/d takes 5-7 days to achieve its full antiplatelet effect
  • 86% still receiving at 1 year (~6% switched back to ticagrelor/prasugrel, ~6% on ASA only, <1% on no antiplatelet)
• C ("continue"): Continue ticagrelor/prasugrel + ASA 75 mg/d (not combined into 1 pill) x11 months (total 1 year on same P2Y12 inhibitor)
  • 75% still receiving at 1 year (~17% switched to clopidogrel, ~7% on ASA only, <1% on no antiplatelet)

Results @ 1 year

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• BARC bleeding definitions

 

Generalizability

• P: This trial applies to ACS patients who tolerated ticagrelor/prasugrel for 1 month without issue, including recurrent coronary event or clinically-important bleeding
• I/C:
  • The "switch" intervention was actually 2 distinct interventions:
    1. Consolidation of multiple pill administrations into a single tablet
       • For initial ticagrelor users, simplified from 3 tabs/day to 1
       • For initial prasugrel users, simplified from 2 tabs/day to 1
    2. Switch to lower-potency antiplatelet agent (clopidogrel)
    • Reduced bleeding rates in this trial are a combined result of decreased antiplatelet potency, as well as more consistent adherence due to decreased pill burden and simplification of administration regimen. This also reduces any apparent benefit on ischemic outcomes with the prasugrel/ticagrelor continuation, since non-adherence dulls their efficacy
  • Use of either prasugrel or ticagrelor in the control group complicates this further, as these agents have different efficacy/safety profiles (ticagrelor generally considered more efficacious + safer), & administration methods (ticagrelor is dosed BID)

Internal validity

• Use of inappropriate composite primary outcome
  • Includes biologically disparate events (both ischemic/efficacy & bleeding/safety events)
  • Largely driven by the least "clinically important" outcome (bleeding requiring medical evaluation)
  • Inadequate power to evaluate more important components (CV/overall death, stroke, revascularization), & cannot rule in/out a difference nor determine consistency between different components
• Enrolment occurred in a single center in France 2014-2016
  • Single-center trials systematically overestimate benefits compared to multi-center trials, likely related issues in minimizing typical bias domains (allocation, performance & detection)
• Unclear risk of allocation bias
  • Allocation concealed by sequentially-numbered sealed envelopes: Application of this strategy varies, and is prone to manipulation
• High risk of performance and detection bias
  • Patients, caretakers and clinicians not blinded to study intervention
  • "Switch" intervention simpler, easier to adhere to
  • Adjudicated by physician unaware of allocated intervention, though reporting of events to adjudicators may have been biased (particularly the subjective BARC 2 bleeds)
• Low risk of attrition bias (intention-to-treat analysis with 2% loss-to-follow-up at 1 year)
• Potential selective outcome reporting
  • Reporting of coronary events limited to those "requiring unplanned hospitalization for urgent coronary revascularization," but investigators did not report ACS events not requiring revascularization

GEMINI-ACS-1: Rivaroxaban vs ASA added to P2Y12 inhibitor following ACS

Ohman EM, et al. Clinically significant bleeding with low-dose rivaroxaban versus aspirin, in addition to P2Y12 inhibition, in acute coronary syndromes (GEMINI-ACS-1): A double-blind, multicentre, randomised trial. Lancet 2017 (epub ahead of print)

Bottom-line:

• In patients with ACS, low-dose rivaroxaban produces a similar or greater risk of clinically-significant or major bleed compared to ASA (potential NNH 100), with unclear effect on efficacy outcomes.

• Although this trial is insufficient to change practice, it provides preliminary evidence that will guide further trials refining antithrombotic regimens in various ACS subpopulations.

 

Context

• The ATLAS trial demonstrated that adding low-dose rivaroxaban to clopidogrel-based DAPT reduces CV events and death following PCI, offset by an increase in major bleeds
• The PIONEER trial and other studies have investigated various anticoagulation-based regimens in patients with AF who undergo PCI

Patients (n=3037)

• Included:
  • Age > 18 years
  • ACS (unstable angina, NSTEMI or STEMI)
  • If age <55 years, at least 1 of the following:
    • Diabetes
    • Previous MI
  • If unstable angina, at least 1 of the following:
    • TIMI score 4+
    • Ischemic changes on EKG
    • Revascularization for this event
• Key exclusion criteria:
  • Hx of bleeding, ICH or GI bleed within past year
  • CrCl <20 mL/min
  • Need for full-dose anticoagulation
• Typical study patient
  • Age 62 years
  • Male 75%
  • ACS type: unstable angina 11%, NSTEMI 40%, STEMI 49%
  • Procedure for ACS: Cath 94%, PCI 87% (DES 67%, BMS 33%), CABG <1%
  • Randomized median 5.5 days after ACS
  • Previous MI 22%
  • Previous PCI/CABG 20%/4%
  • PAD 5%
  • CV risk factors
    • Smoker 33%
    • HTN 73%
    • Dyslipidemia 56%
    • Diabetes 30%
  • Meds
    • ACEI/ARB 63%
    • Beta-blocker 64%
    • Statins 69%

Interventions

• I: Rivaroxaban 2.5 mg PO BID for a minimum 180 days
• C: ASA 100 mg PO daily for a minimum 180 days
• Median duration of study drug 9.6 months
• Co-interventions:
  • Clopidogrel 75 mg daily (44%) or ticagrelor 90 mg BID (56%) based on investigator preference (i.e. choice of P2Y12 inhibitor not randomized)
    • Prematurely discontinued in 4%

Results @ median 10.7 months

• Primary outcome (TIMI non-CABG clinically significant bleeding): 5% in both groups, hazard ratio (HR) 1.09 (0.80-1.50)
• Results vary based on bleeding definition
  • ISTH major bleeding: Rivaroxaban 2% versus ASA 1% (NNH 100), HR 1.83 (1.01-3.31)
  • BARC 3a or higher: 1% in both groups, HR 1.70 (0.85-3.37)
  • GUSTO life-threatening or severe: <1% in both groups, HR 1.50 (0.25-8.95)
  • TIMI major bleeding: 1% in both groups, HR 1.25 (0.49-3.17)
• Efficacy outcomes
  • Death: Rivaroxaban 1%, ASA 1.5%, HR 0.95 (0.53-1.71)
  • CV death, MI, stroke or definite stent thrombosis: 5% in both groups, HR 1.06 (0.77-1.46)
  • Any stent thrombosis: 1% in both groups, HR 1.06 (0.54-2.11)

Internal validity

• Low risk of bias (including allocation, performance, detection, attrition and reporting biases)
  • Computer-generated randomization
  • Centralized, electronic allocation (allocation concealment)
  • Blinding using identical placebos
  • <0.5% (1 patient) lost to follow-up

Generalizability & applicability

• Excluded patients with an indication for full-dose anticoagulation (e.g. AF, LV thrombus, VTE)
• Rivaroxaban dose is dose found to be efficacious in ACS in ATLAS trial, but only 25% of dose demonstrated to have efficacy in AF & VTE
• Majority used ticagrelor as P2Y12 inhibitor
• Phase 2 trial:
  • Not powered to compare low-dose rivaroxaban to ASA for: Death, major bleed, and efficacy (including MI, stroke or stent thrombosis)
  • Not formally designed as a non-inferiority trial, but primary analysis met wide pre-defined non-inferiority margin (HR <2.0)

Beta-blocker side-effects

Ko DT, et al. Beta-blocker therapy and symptoms of depression, fatigue, and sexual dysfunction. JAMA 2002;288:351-7.

Bottom line: In patients with HF, MI or HTN, beta-blockers increased the risk of fatigue (NNH 34) & sexual dysfunction (NNH 24), particularly erectile dysfunction in men.

Design

• Systematic review and meta-analysis of 15 trials (n= ~35,000) published up to 2001
• Included RCTs HF, MI or HTN with >100 patients & >6 months of follow-up

Results @ 0.5-6 years

• Fatigue: Beta-blockers 33.4% vs placebo 30.4% (NNH 34), relative risk (RR) 1.15 (1.05-1.26)
  • Absolute risk increase 1.8%/year
  • Risk greater for older beta-blockers (e.g. propranolol; RR 1.78) than new beta-blockers (e.g. atenolol, metoprolol; RR 1.06)
• Sexual dysfunction: Beta-blockers 21.6% vs placebo 17.4%, RR 1.10 (0.96-1.25)
  • Impotence in men: RR 1.22 (1.05-1.41)
• Depression: Beta-blockers 20.1% vs placebo 20.5%, relative risk RR 1.12 (0.89-1.41)
• None of the risks differed based on lipid solubility

ARBs vs ACEIs patients post-MI or at high risk of CVD

Dickstein K, et al. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Lancet 2002;360:752-60.

The ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008;358:1547-59.

VALIANT: Pfeffer MA, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003;349:1893-906.

Bottom line:

• In patients post-MI or at high risk of CVD, telmisartan & valsartan generally prevent CV events as well as ACE inhibitors with similar safety;

• The combination of ACEI+ARB is no better than monotherapy & increases the risk of adverse events (e.g. hypotension, hyperkalemia & renal impairment);

• Losartan is inferior to captopril for prevention of CV events.

 

Patients

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Interventions

• OPTIMAAL: ARB vs ACEI
  • ARB: Losartan started at 12.5 mg PO daily; increased to target 50 mg PO daily
    • 83% achieved target dose
  • ACEI: Captopril started at 12.5 mg PO TID; increased to target 50 mg PO TID
    • 81% achieved target dose
• ONTARGET: ARB, ACEI or combination of both
  • ARB: Telmisartan started at 20 mg PO daily; increased to target 80 mg PO daily
    • 87% achieved target dose
  • ACEI: Ramipril started at 2.5 mg PO daily; increased to target 10 mg PO daily (HOPE dose)
    • 82% achieved target dose
• VALIANT: ARB, ACEI or combination of both
  • ARB: Valsartan started at 20 mg PO BID; increased to target 160 mg PO BID
  • ACEI: Captopril started at 6.25 mg PO TID; increased to target 50 mg PO TID
  • 56% in each monotherapy group achieved target dose, 47% in combination group achieved target doses

Results @ 2-4.7 years

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Generalizability & internal validity

• Design of these trials essentially identical to the original 'ACEI vs placebo' trials that they mimic
  • I.e. high-quality allocation-concealed double-blind RCTs
• All 3 trials are non-inferiority trials with fair non-inferiority margins and analyses
  • Note: OPTIMAAL is the only of the 3 that does not demonstrate of the ARB (losartan) & in fact points towards significant inferiority to an ACEI
• As with the 'ACEI vs placebo' RCTs, results of these trials apply to patients that are post-MI, especially those with clinical HF & LV dysfunction, and those at high risk of CVD

CAPRICORN - Carvedilol in LV dysfunction post-MI

The CAPRICORN Investigators. Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial. Lancet 2001;357:1385-90.

Bottom-line: In patients with LV dysfunction post-MI, carvedilol reduces the risk of death, MI & ventricular arrhythmias (NNT 34 for each) at ~1 year.

Patients (n=1959)

• Included
  • Age 18+ y
  • 3-21 days post-MI
  • LVEF 40% or less
  • Receiving ACEI >48h with stable dose >24h (or intolerance to ACEI)
• Excluded
  • Uncontrolled HF or HF requiring IV diuretics or inotropes
  • Unstable angina
  • SBP <90 mm Hg or uncontrolled HTN
  • HR <60 bpm
• Typical study patient
  • Age 63 y
  • Female 27%
  • Site: Anterior (57%), inferior (21%)
  • PMHx
    • Prior MI 31%, angina 57%
    • Smoker 33%
    • HTN 55%
    • Diabetes 21%
  • BP 121/74 mm Hg
  • HR 77 bpm
  • LVEF 33%
  • Meds
    • ASA 86%
    • ACEI 98%

Interventions

• I: Carvedilol
  • Initial dose of 6.25 mg PO BID, doubled or halved to max target dose of 25 mg PO BID
  • Conditions for uptitration, done q3-10 days:
    • Absence of clinical HF or adverse events
    • SBP >80 mm Hg & HR >50 bpm
  • 74% achieved target dose
• C: Matching placebo

Results @ mean 1.3 years

• Death: Carvedilol 12%, placebo 15% (hazard ratio 0.77, 0.60-0.98), NNT 34
• Death or CV hospitalization: 35% vs 37% (HR 0.92, 0.80-1.07)
  • HF hospitalization: 12% vs 14% (HT 0.86, 0.67-1.09)
• Non-fatal MI: 3% vs 6% (HR 0.59, 0.39-0.90), NNT 34%
• Ventricular arrhythmia (tach/flutter/fib): 0.9% vs 3.9% (HR 0.24, 0.11-0.49), NNT 34