POPular Genetics: Using pharmacogenomics to guide antiplatelet management

Claassens DMF, et al. A genotype-guided strategy for oral P2Y12 inhibitors in primary PCI. NEJM 2019;381:1621-31.

Bottom line: Among STEMI patients undergoing primary PCI, CYP2C19 genotype-guided P2Y12 inhibitor selection (leading to targeted de-escalation to clopidogrel in 2/3 of patients) reduced the risk of minor bleeding by ~3% without increase thrombotic events over 1 year.

Patients (n=2751 randomized, n=2488 analyzed)

• Included:

  • STEMI treated with primary PCI with stent

• Excluded

  • Severe HTN (>180/110 mm Hg)

  • Cardiogenic shock (SBP ≤80 mm Hg for >30 min)

  • Active malignancy causing increased bleed risk (investigator’s opinion)

  • Dialysis-dependent CKD

• Baseline

  • Age 61, female 25%

  • Prior coronary stent 8%, prior MI 7-8%

  • Prior bleed 2%

  • Current smoker 46%, HTN 42%, diabetes 11%, CrCl <60 9%

  • Treated vessel: LAD 43%, RCA 42%, bifurcation lesion ~20%

  • Drug-eluting stent in 94%

  • Total stent length 28 mm

Intervention: CYP2C19 genotype-guided P2Y12 inhibitor de-escalation x12 months

• Assay: TaqMan StepOnePlus assay (central lab) or Spartan RX (point-of-care test) ASAP after randomization

• Tested for CYP2C19*2 and CYP2C19*3 loss-of-function alleles

• Genotype:

  • Extensive metabolizer (good clopidogrel response; *1/*1): 67%

  • Intermediate metabolizer (*1/*2 or *1/*3): 29%

  • Poor metabolizer (*2/*2, *2/*3 or *3/*3): 2-3%

  • Not done: 1.4%

• Strategy:

  • If any *2 or *3: Ticagrelor or prasugrel

  • Neither (extensive metabolizer): Clopidogrel

• Selected: Clopidogrel (61%), ticagrelor (38%), prasugrel (1%)

Comparator: Standard P2Y12 inhibitor selection x12 months

• Selected: ticagrelor (91%), clopidogrel (7%), prasugrel (2%)

Internal Validity: Low risk of allocation & attrition bias; unclear risk of performance & detection bias

• Computer-generated block randomization

• Internet-based allocation

• Open-label (patients, clinicians aware of allocation after randomization)

• Blinded adjudication committee

• Intention-to-treat (ITT) & per-protocol analyses (ITT for superiority, ITT+PP for non-inferiority)

• 3 patients lost to follow-up

Outcomes @ 12 months

• Composite

  • Definition: Death/MI/definite stent thrombosis/stroke/major bleeding (PLATO definition)

  • Genotype-guided: 5.1% vs control 5.9%

  • Hazard ratio (HR) 0.87 (95% confidence interval 0.62-1.21)

  • Absolute difference: -0.7% (-2.0% to 0.7%), meeting study’s non-inferiority criteria

• Death: 1.5% in both groups (HR 1.00, 0.53-1.89)

• MI: 1.5% vs 2.1% (HR 0.73, 0.41-1.32)

• Definite stent thrombosis: 0.2% in both groups (HR 0.67, 0.11-4.01)

• Stroke: 0.6% vs 0.9% (HR 0.73, 0.29-1.82)

• Major or minor bleed: 9.8% vs 12.5% (HR 0.78, 0.61-0.98)

  • Major bleed: 2.3% in both groups (HR 0.97, 0.58-1.63)

  • Minor bleed: 7.6% vs 10.5% (HR 0.72, 0.55-0.94)

• Dyspnea: Not compared between groups

Other Considerations

• Comparator changed from clopidogrel to ticagrelor/prasugrel part-way through the trial; patients enrolled before this amendment excluded from analyses

• Non-inferiority trial

  • Non-inferiority margin set as a 2% absolute risk increase for both primary outcomes (not well justified, large)

• Unlike PHARMCLO, POPular Genetics did not test for CYP2C19*17 (ultra-fast metabolizer; increased clopidogrel efficacy), or ABCB 13435

Other Studies

• Other studied de-escalation strategies include empiric de-escalation to clopidogrel after 1 month of potent P2Y12 inhibition, as well as platelet function testing-guided de-escalation

• PHARMCLO

  • Patients: 888 ACS patients in Europe

    • Baseline:

      • Age 71, female 32%

      • STEMI 27%, NSTEMI 68%, UA 2%, no ACS 3%

      • Prior PCI 19%, prior MI 21%

      • Current smoker 22%, HTN 74%, diabetes 26%, CKD 9%

      • 96% underwent coronary angiography: 62% got PCI, 11% CABG

      • Treated vessel: LAD 54%, RCA 47%

      • Genotype (intervention group)

        • ABCB1 3435 mutation: 47%

        • CYP2C19*2 29%, *2/*2 4%

        • CYP2C19*17 31%, *17/*17 8%

  • Intervention: Genotype-guided P2Y12 inhibitor selection (immediately on ACS diagnosis) x12 months

    • Assay: ST Q3 (point-of-care test that takes ~70 min for result)

    • Tested for ABCB13435, CYP2C19*2, and CYP2C19*17 (increased clopidogrel efficacy)

    • Selected: Clopidogrel 43%, ticagrelor 43%, prasugrel 8%

  • Control: Standard P2Y12 inhibitor selection x12 months

    • Selected: Clopidogrel 51%, ticagrelor 33%, prasugrel 8%

  • Outcomes:

    • Composite (CV death, MI, stroke, major bleed (BARC 3-5): 15.9% vs 25.9% (HR 0.58, 0.43-0.78)

    • CV death/MI/stroke: 12.9% vs 21.4% (HR 0.57, 0.41-0.80)

    • Major bleed: 4.2% vs 6.8% (HR 0.62, 0.35-1.11)

  • Caveats:

    • Stopped prematurely 1/4 of the way through by ethics committee as genotyping assay not previously certified; therefore, the observed benefit of genotype-guided intervention is likely a large overestimate

CONCERN: Naproxen vs celecoxib in patients with recent upper GI bleed with an indication for low-dose ASA

Chan FKL, et al. Gastrointestinal safety of celecoxib versus naproxen in patients with cardiothrombotic diseases and arthritis after upper gastrointestinal bleeding (CONCERN): an industry-independent, double-blind, double-dummy, randomised trial. Lancet [epub ahead of print]

Bottom line:

• Issues in reporting of this trial preclude a fully-informed interpretation of its results

• In patients receiving a PPI & ASA, recurrent upper GI bleed occurred in ~6% of patients also receiving daily celecoxib at a dose of 100 mg BID compared to ~12% of those receiving naproxen 500 mg BID over 18 months.

Patients (n=514)

• Included
  • Presenting with upper GI bleed while on NSAID + low-dose ASA
  • Follow-up endoscopy confirming ulcer healing 8 weeks after GI bleed
  • Negative for H pylori or successful H pylori eradication
  • Ongoing indication for low-dose ASA ("cardiothrombotic diseases" or "multiple CV risk factors")
  • Chronic arthritis pain anticipated to require regular NSAID use
• Key exclusion criteria
  • Erosive esophagitis
  • Gastric outlet obstruction
  • Renal failure (SCr >200 umol/L)
  • Use of anticoagulants
• Typical study patient
  • Age 72 y (>80 y in 24%)
  • Female 46%
  • Indication for NSAID: OA 70%, RA 3%, other 27%
  • Baseline upper GI bleed
    • Gastric origin 55%
    • Required endoscopic therapy ~30%
    • Required blood transfusions 55%
  • ASA indication: Secondary prevention (67%), primary prevention with 10-year CV risk >10% (33%)

Interventions x18 months

• I: Celecoxib 100 mg PO BID
• C: Naproxen 500 mg PO BID
• ~90% in both groups took at least 70% of their doses; ~18% in each group discontinued the study drug before 18 months
• Co-interventions:
  • Esomeprazole 20 mg PO once daily in all patients
  • ASA 80 mg/d (discontinued in ~30% of patients during trial in both groups)

Results @ median 18 months

• Efficacy (not designed or powered to evaluate this)
  • Patient's global assessment of disease activity scale (range 1-5, lower=better):
    • Baseline: 3.0 in both groups
    • Month 18: Celecoxib 2.1 versus naproxen 2.3, p=0.386 for difference between groups
  • Quality of life, pain, use of other analgesics: ?
• Safety
  • Primary outcome - recurrent upper GI bleed (hematemesis/melena or hemoglobin drop >20 g/L+ endoscopically-confirmed ulcers or bleeding erosions): Celecoxib 5.6%, naproxen 12.3% (NNT 15), hazard ratio (HR) 0.44 (0.23-0.82)
    • Fatal recurrent GI bleed: 0 in both groups
  • Major CV event (vascular death, MI or stroke): Celecoxib 4.4% vs naproxen 5.5%, HR 0.78 (0.36-1.73)
• Discontinued treatment before 18 months: Celecoxib 18% vs naproxen 19%

Subgroup analysis (reported in supplement of authors' reply to letter to the editor)

• Primary outcome
  • Continued ASA: Celecoxib 7.2%, naproxen 13.8% (p=.042)
  • Discontinued ASA: 1.4% vs 8.4% (p=.054)
• CV events: 
  • Continued ASA: Celecoxib 5.5% vs naproxen 6.0% (p=.825)
  • Discontinued ASA: 1.5% vs 4.3% (p=.312)

Internal validity

• Unclear/high risk of allocation bias
  • Computer-generated randomization list
  • Attempted to conceal allocation by sealed opaque envelopes, which are easy to subvert through tampering
• Unclear risk of performance/detection bias
  • Proper blinding dependent upon allocation concealment. If sealed opaque envelope method was subverted, then blinding would also be compromised
  • Blinding by "double-dummy" pills not prepared by manufacturer
  • GI & CV outcomes adjudicated by committee blinded to allocated treatment group
• Attrition bias
  • Premature discontinuation occurred in ~18% of patients in each group
  • Modified intention-to-treat analysis for GI safety outcome only counted outcomes that occurred "during treatment," therefore excluding any outcomes occurring after premature discontinuation

Generalizability

• Study conducted in single centre in Hong Kong, with enrolment taking ~10 years (2005-2015)
  • Many changes to GI bleed management (e.g. reduced transfusion threshold) & CV disease management (including ASA prescribing patterns in primary prevention). No reporting or comments on such trends in this publication, which complicates application of these trial results.
• Many aspects of this trial remain unreported, which further complicates application of these results
  • CV risk & indication for ASA?
    • This is the key reporting issue in this trial. The authors do not clearly describe the indication for ASA beyond "cardiothrombotic diseases or multiple coronary risk factors", and do not describe these in their 'baseline characteristics' table. Notably, the authors report that ~30% of patients discontinued ASA during the trial, suggesting that some of these patients had no clear indication for ASA
    • Addendum: The authors reported in a response to letter to the editor that 67% received ASA for secondary prevention, with the remaining 33% receiving ASA for primary prevention in the context of a calculated 10-year risk of a CV event >10%. The benefit of ASA for primary prevention is minimal, & the harms of continuing ASA (especially in these patients who already developed a GI bleed on ASA) likely outweighed any benefit. Furthermore, reported subgroup analyses showed that those who discontinued ASA had a lower risk of CV events, suggesting that mostly the lower-risk primary CV prevention patients discontinued ASA during the trial. 
    • Use of dual antiplatelet therapy (DAPT) was not specifically prohibited during this trial, though its use was not reported
  • Time from initial upper GI bleed to initiating of study NSAID?
    • Addendum: The authors later reported that endoscopy was routinely performed to confirm ulcer healing 8 weeks after the GI bleed, at which point patients were enrolled into this trial.
  • Previous history of NSAID use and efficacy (i.e. previous treatment failures with either study NSAID)?
• Effect of giving no NSAID or NSAID PRN?
  • The majority of patients with OA who use oral NSAIDs in practice do so on a PRN basis. The GI risk related to this kind of usage pattern is likely lower, and may be a reasonable alternative
  • In a previous trial by the same authors of patients with ASA-related upper GI bleed, recurrence using the same definition was <1% over 1 year in patients receiving ASA+PPI
• Clinical importance of primary outcome?
  • The primary outcome of this trial was recurrent endoscopically-confirmed upper GI bleed that presented as either hematemesis/melena or a >20 g/L hemoglobin drop. None of the recurrent GI bleeds in this trial resulted in patient death, and most would be classified as "minor bleeds" under most commonly-used bleeding definitions. As such, impact of these recurrent events on quality of life would be a key domain to measure (but it wasn't).
  • If we accept that this is a clinically-important outcome, the risk remains far too high even with celecoxib, particularly given that only 90% took at least 70% of their doses and that 30% discontinued ASA during the trial.