EAGLES - Efficacy & neuropsychiatric safety of smoking cessation products (varenicline, bupropion, nicotine patch)

Anthenelli RM, et al. Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomised, placebo-controlled clinical trial. Lancet 2016;387:2507-20.

Clinical Question

In people, with or without a psychiatric disorder, who smoke, is there a difference in neuropsychiatric events or smoking abstinence rates between varenicline, bupropion, nicotine patch or placebo?

 

Bottom Line

In people who smoke who either have no psychiatric disorder or clinically stable psychiatric disorder, bupropion, nicotine patch and varenicline do not increase the risk of serious or overall neuropsychiatric events. All 3 of these drugs effectively increase the likelihood of smoking abstinence at 6 months compared to placebo, with patients receiving varenicline having the greatest likelihood of abstaining.

 

Design

Allocation-concealed RCT with all (patients, clinicians, investigators) blinded, loss-to-follow-up of ~6%, analyzed using the intention-to-treat population.

Notes:

  • Randomization stratified based presence/absence of psychiatric disorder & disorder type (mood, anxiety, psychotic, personality), as well as geography
  • 21% and 26% of non-psychiatric and psychiatric groups, respectively, dropped out
    • Overall similar dropout rates between treatment groups

 

Patients and Setting

  • 16 countries, 140 centers
  • November 30 2011 to January 13 2015
  • Inclusion criteria:
    1. Men or women
    2. 18-75 y
    3. Smoking average 10+ cigarettes/day during previous year
    4. Exhaled carbon monoxide concentration >10 ppm at screening
    5. Motivated to stop smoking
    6. +/- current or past psychiatric disorder, according to DSM-IV-TR definition
      • Stable, defined as
        • No exacerbation in previous 6 months, on stable treatment (drug & dose) x3+ months, no treatment changes anticipated during study, plus
        • Considered not to be at high risk of self-injury or suicidal behavior, based on responses on the Suicide Behaviors Questionnaire-Revised or Columbia-Suicide Severity Rating Scale
      • Mood disorder (including major depressive disorder, bipolar disoder)
      • Anxiety disorder (panic disorder +/- agoraphobia, PTSD, OCD, social phobia, GAD)
      • Psychotic disorder (schizophrenia, schizoaffective disorders)
      • Borderline personality disorder
  • Key exclusion criteria:
    • Suicidal behavior or suicidal ideation associated with intent/plan in the past year
    • Seizure disorder or risk of seizure (bupropion contraindication)
    • Substance abuse within previous 12 months (including ETOH & other substances)
    • Delirium, demention & other cognitive disorders
    • Substance-induced, factitious, dissociative & impulse control disorders
  • 11,186 screened -> 8,144 randomized (73%)
  • Average patient:
    • 46.5 y/o
    • 56% female
    • Race: White ~80%, Black ~15%
    • Region: USA 52%, Western Europe & others (including Canada) 30%, Eastern Europe 10%, South/Middle America 8%
    • Wt 80 kg
    • Smoking hx
      • Duration of smoking ~28 y
      • ~21 cigs/d (1 ppd)
      • 3-4 previous quit attempts
    • Psychiatric hx: Yes (50%)
      • Mood 70%, anxiety 20%. psychotic 10%, personality <1%
      • Those with psychiatric disorder: Hx suicidal ideation 34%, suicidal behavior 13%
    • Psychotropic medications in subgroup with psychiatric disorder: Any 50%
      • Antidepressant ~1/3, anxiolytic ~15%, antipsychotic ~15%, mood stabilizer 2%

 

Interventions and Control

  • Intervention 1: Bupropion x12 weeks
    • 1 week before quit date: Start 150 mg PO daily
    • 4 days before quit date: Increase to 150 mg PO BID (target dose) x11.5 weeks
  • Intervention 2: Nicotine patch x11 weeks
    • On quit date: Start 21 mg patch x7 weeks, then decrease to 14 mg patch x 2 weeks, then 7 mg patch x2 weeks, then stop
    • Note: Not stated whether patch removed at bedtime, but likely that it was kept on 24h/day given reported higher risk of abnormal dreams versus placebo (see outcomes below)
  • Intervention 3: Varenicline x12 weeks
    • 1 week before quit date: Start 0.5 mg PO daily
    • 3 days before quit date: Increase to 0.5 mg PO BID
    • Quit date: Increase to 1 mg PO BID (target dose) x11 weeks
  • Control: Placebo
  • Co-interventions common to all groups:
    • 12-week treatment phase, then 12-week follow-up phase
      • Up to 15 in-person visits + 11 telephone visits
        • Patch + pill counts at each visit to measure adherence (overall 80%)
        • Tobacco/nicotine product use evaluated at each in-person/telephone visit via questionnaire
        • Expired air carbon monoxide measurement performed at every in-person visit
    • Received identical placebo for other interventions (e.g. varenicline group received inert pill that looked like bupropion & inert patch that looked like a nicotine patch)

 

Outcomes

EAGLES trial outcomes in patients WITH psychiatric disorder

EAGLES trial outcomes in patients withOUT psychiatric disorder

NNT for abstinence from smoking in EAGLES trial

  • Efficacy:
    • All 3 drugs were more effective than placebo at achieving continuous abstinence from weeks 9 to 24 in both patients with and without psychiatric disorder
      • Varenicline was more effective than bupropion or nicotine patch in both patients with and without psychiatric disorder
    • Abstinence rates were slightly higher in patients without psychiatric disorder, but drugs had similar efficacy regardless of presence of psychiatric disorder
  • Safety: 
    • No statistically significant increase in overall or serious neuropsychiatric events with any smoking cessation agent versus placebo in both patients with and without previous psychiatric disorder
      • The 1 completed suicide occurred in the non-psychiatric placebo group
    • Low rates (<1%) of serious adverse events in all groups
    • Predictable drug-specific adverse events consistent with previous studies
      • Bupropion: Insomnia, dry mouth
      • Nicotine patch: Abnormal dreams and insomnia (likely from keeping patch on at night), patch-site irritation and itching
      • Varenicline: Abnormal dreams and insomnia, nausea (the latter occurs in 1/4 patients who take varenicline)

 

Generalizability

Patients: Represent those without psychiatric disorder and those with current very stable mood, anxiety or psychotic disorder

  • The results do not apply to those patients with recent suicide attempt, at otherwise high risk of suicide or patients whose psychotropic medications are undergoing tinkering
  • Neuropsychiatric safety of various smoking cessation products has not been demonstrated, and perhaps smoking cessation attempts should be deferred for these patients until clinical stability has been achieved, and patient conviction to quit is high.

Interventions: All 1st-line agents for smoking cessation with regimens generally reflecting clinical practice, with exception of the nicotine replacement therapy (NRT)

  • Though it's unclear if this was done in the study, the nicotine patch should be removed at bedtime to avoid abnormal dreams and insomnia
    • Unless the patient has a significant history of nocturnal nicotine cravings 
  • Patients were instructed to universally wean their nicotine patch dose after only 7 weeks, which may led to breakthrough withdrawal and nicotine cravings, negatively impacting these patients' quit attempt
  • Ideally, patients would combine the nicotine patch with short-acting nicotine products (e.g. gum, lozenges), as this has previously demonstrated greater abstinence rates
  • Previous RCTs have demonstrated greater abstinence rates with longer user of smoking cessation products. Patients should thus be encouraged to continue their smoking cessation product beyond 12 weeks if there is risk of relapse with discontinuing these at the 12-week mark.

Outcomes: Abstinence only measured until 6 months after start of smoking cessation. Some patients will restart smoking after 6 months & will need further quit attempts to successfully quit.

Summary author: Ricky Turgeon BSc(Pharm), ACPR, PharmD
Summary date: 22 June 2016

COGENT - PPI added to DAPT in patients after ACS/PCI

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Bhatt DL, et al. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med 2010;363:1909-17

Bottom Line: In patients on clopidogrel + ASA following ACS or stent placement, the addition of omeprazole reduced the risk of clinical GI events (NNT 56 over 6 months), including overt upper GI bleed (NNT 100 over 6 months) with no increase in CV events. Because this trial was stopped early, the benefits (& reported NNTs) may be overestimated.

 

Integrating This Study Into Practice

Despite this uncertainty caused from stopping the trial early, it's reasonable to consider a PPI for the duration of dual antiplatelet therapy in patients without prior GI bleed, especially if they have other risk factors or medications that further increase their risk. PPIs should be mandatory in those with prior GI bleed while taking dual antiplatelet therapy unless contraindicated.

 

Design

Allocation-concealed "superiority" RCT with all (patients, clinicians, outcome adjudicators) blinded, low loss-to-follow-up (3%), analyzed using the intention-to-treat population. 

Study stopped early due to abrupt loss of funding (sponsor went bankrupt), leading to accumulation of only ~1/3 of planned GI primary outcome events.

 

Patients and Setting

  • 15 countries, 393 centers
  • Enrolled between January-December 2008
  • Inclusion criteria:
    1. Age 21+ y/o
      • (designed to have >60% of patients 65+ y/o)
    2. Required DAPT (ASA + clopidogrel) x 12+ months, specifically
      • NSTE-ACS
      • STEMI
      • Coronary stent implantation
  • Key exclusion criteria:
    • Erosive esophagitis, esophageal or gastric varices, non-endoscopic gastric surgery
    • Hx of hemorrhagic stroke, intracranial neoplasm, AVM, aneurysm
    • Active pathological bleeding or hx of hereditary/acquired hemostatic disorder
    • Other indication for gastroprotection (PPI, H2RA, sucralfate, misoprostol)
    • CABG <30 days prior to randomization
    • Cardiogenic shock, refractory ventricular arrhythmias or HF with NYHA class IV at time of randomization
    • Meds
      • >21 days of clopidogrel or another thienopyridine prior to randomization
      • Needs oral anticoagulation
      • Recent fibrinolytic therapy
      • Steroids equivalent to >5 mg/d of prednisone
    • Labs
      • Hemoglobin <100 g/L
      • Platelets <100
  • 4444 screened for eligibility -> 3873 randomized -> 3761 analyzed
  • Average patient:
    • 66 y/o
    • Female 32%
    • Race: White 94%
    • BMI 28
    • CV hx
      • PCI 72%
      • ACS 42%
      • MI 30%
      • PAD 12%
      • Stroke 8%
      • Other vascular disease 50%
    • Hx of GI bleed/ulcer 4%
    • PMHx
      • Current smoker 13%
        • HTN 80%
        • Diabetes 30%
        • Dyslipidemia 78%

 

Intervention and Control

  • Intervention: Omeprazole 20 mg/d
    • Note: Part of proprietary product CGT-2168, which is a fixed-dose combination of clopidogrel 75 mg + omeprazole 20 mg
  • Control: Placebo
  • Co-interventions common to both groups:
    • ASA 75-325 mg/d + clopidogrel 75 mg/d (planned duration of at least 12 months)

 

Outcomes

  • Median follow-up 106 days (max 341 days)
    • Note: Outcomes standardized to 180 days
  • Primary efficacy outcome: Composite upper GI events (ulcer complications [perforation, obstruction, bleed], occult bleeds presumed to be from GI, symptomatic non-bleeding ulcer or erosions
  • Primary safety outcome: Composite CV events (CV death/ischemic stroke/non-fatal MI/coronary revascularization)
  • Subgroup analysis: Outcomes did not differ based on baseline H pylori status or use/non-use of non-ASA NSAIDs (randomization stratified based on these 2 factors)

Outcomes in COGENT trial

 

Key Considerations & Interpretation

Trial stopped early: This trial with otherwise low risk of bias was truncated (stopped early) due to loss of funding. Truncated trials tend to exaggerate effect sizes (overestimate benefits/harms), especially when few events have occurred. It's therefore possible that the observed 1.8% absolute risk reduction (NNT 56) in clinical GI events over 6 months seen with omeprazole versus clopidogrel in COGENT based on only 55 GI events may be an overestimate of the real benefit.

Who does this apply to? 

  • COGENT enrolled patients with new indication for 12 months of DAPT (3/4 PCI, 1/4 ACS), without high-risk features for GI bleed. This is therefore a trial to determine whether routine use of PPIs with DAPT is beneficial in patients at otherwise low risk of GI bleed. Given the issue with stopping early described above, the GI benefits of routinely adding a PPI to DAPT in patients without previous GI bleed/ulcer remain uncertain.
  • This doesn't apply to patients with prior upper GI bleed, where previous trials have demonstrated a large reduction in GI events when adding a PPI to antiplatelet therapy in patients who've previously bled (1, 2). 

Does this trial prove that PPIs don't increase CV risk? 

  • COGENT wasn't designed to demonstrate the absolute CV safety of omeprazole (or to dispel the possible interaction with clopidogrel), and in isolation can't be used to demonstrate safety. Despite this, omeprazole did not numerically increase the risk of CV events in this population at high risk of CV events (4.9% versus 5.7% with placebo).
  • Interpreted in the context of all of the observational and pharmacokinetic evidence, it appears that the association between PPIs & increased CV events may be due to confounding factors (i.e. weight, smoking, and other lifestyle factors that predispose a patient to be prescribed a PPI) rather than a true cause-and-effect.

PROACT - Reduced INR goal (1.5-2) with On-X mechanical aortic valve

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Puskas J, et al. Reduced anticoagulation after mechanical aortic valve replacement: interim results from the prospective randomized on-x valve anticoagulation clinical trial randomized Food and Drug Administration investigational device exemption trial. J Thorac Cardiovasc Surg. 2014;147:1202-10. 

Puskas J, et al. Anticoagulation and antiplatelet strategies after On-X mechanical aortic valve replacement. JACC 2018;71:2717-26.

Clinical Question

In patients with isolated aortic valvular replacement (AVR) with On-X mechanical valve treated with standard target warfarin (INR 2-3) + ASA x3 months, does lowering the chronic INR target to 1.5-2.0 increase the risk of thromboembolic events?

Bottom Line

In a population of patients with isolated AVR with On-X mechanical valve at generally low thromboembolic risk, warfarin with a lower INR target of 1.5-2.0 was not as good as INR target 2-3 at preventing thromboembolism when added to ASA. Although this trial demonstrated a 2.3%/year reduction in major bleeding with the lower INR target, it was also unable to rule-out a 2%/year greater risk of thromboembolic events.

Notably, despite the substantial limitations noted below, the FDA approved an expanded label for use of the On-X valve for isolated AVR with a target INR 1.5-2.0 (+ ASA 81 mg/d).

Design

Unblinded non-inferiority RCT with high loss-to-follow-up/analysis with differences between groups (24% vs 13%) that was stopped early & analyzed using modified intention-to-treat population.

Non-inferiority trial details:

  • Non-inferiority margin: 1.0% PER YEAR absolute risk increase in 1o outcome (composite of thromboembolism/bleed) with intervention vs control
    • No minimum clinically important difference provided
  • Final sample size calculation of 1000 patient-years of follow-up/group would have provided 80% power for non-inferiority with 1-sided alpha of 0.05 (actual follow-up ~755 and ~675 pt-y/group)

Patients (n=374)

  • 33 centres in Canada + US
  • Enrolled from June 2006 to October 2009, followed to March 1, 2013
  • Inclusion criteria:
    1. Adult (18+ y/o)
    2. Isolated mechanical AVR
    3. 1+ risk factor for thromboembolism, including:
      • Hx of neurologic events
      • Chronic AF
      • LV ejection fraction <30%
      • Left or right ventricular aneurysm
      • Enlarged left atrium (diameter >50 mm)
      • Spontaneous echo contrast in left atrium
      • Hypercoagulability (as determined by testing for factor V Leiden, prothrombin mutation, antithrombin III, protein C, S & factor VIII activity, LDL)
      • Vascular pathologic features
      • Lack of platelet response to ASA or clopidogrel
      • Women receiving estrogen replacement therapy
    4. Received warfarin with target INR 2-3 + ASA 81 mg/d for the first 3 months post-op
    5. No thromboembolism during first 3 months post-AVR
  • Key exclusion criteria:
    • Note: Did not exclude if concomitant cardiac surgery such as CABG or mitral/tricuspid repair, ascending aortic replacement, maze procedure
    • Double left-sided valve replacement (i.e. also had MVR)
    • Right-sided valve replacement
    • Active endocarditis at implantation
  • 425 screened -> 375 randomized -> 374 analyzed as part of intention-to-treat analysis
  • Average patient:
    • 55 y/o
    • 20% female
    • Concomitant procedures during AVR
      • CABG 27%
      • Aortic aneurysm repair 14%
      • Other 25%
    • Valve characteristics
      • Etiology: Calcified ~2/3, bicuspid ~1/3
      • Lesion: Stenosis (~50%), regurgitation (~25%), both (~25%)
    • Risk factors
      • Hx neurologic event 3-5%
      • AF <5%
      • LVEF <30% 5%
      • Enlarged left atrium ~10%
      • Estrogen replacement therapy 1-2%
      • Abnormal labs
        • Antithrombin III activity 15%
        • Other hypercoagulable states (<5% each)
        • P2Y12 inhibition ~25%
        • Urine thromboxane ~35-45%

Intervention and Control

  • Co-interventions common to both groups:
    • 1st 3 months post-AVR: Both groups treated with warfarin to target INR 2.0-3.0 + ASA 81 mg/d
    • Patients in both groups received a home "point-of-care" INR monitor & instructed to check INR q1week
      • >80% of patients checked their INR at least 3x/month
    • Warfarin dose adjustment made by study sites (rather than by family doctor or other local anticoagulation service)
  • Intervention: Lower INR target
    • Starting 3 months post-AVR: Warfarin to target INR 1.5-2.0 + ASA 81 mg/d
      • Time in therapeutic range (INR 1.5-2.0): 66%
      • Mean INR: 1.9 +/- 0.5
      • Patients who experienced a thromboembolic event had their INR target increased to 2.0-3.0
  • Control: Standard INR target
    • 3 months post-AVR: Continue warfarin to target INR 2.0 to 3.0 + ASA 81 mg/d
      • Mean INR 2.5 +/- 0.6
      • Time in therapeutic range (INR 2.0-3.0): 55%

Outcomes

  • Median follow-up: Low-target 5.1 years, standard target 5.7 years
  • Major bleeding: Low target 1.6%/year, standard target 3.9%/year (NNT 44/year)
  • Thromboembolism: Non-inferiority NOT demonstrated
    • Study did not report any formal non-inferiority statistical testing; reported as "similar/no different" rates of thromboembolic events between groups
    • Stroke/TIA: Low target 2%, standard target 1.65% (rate ratio 1.22, 95% CI 0.64-2.32)
      • 95% CI crosses the 1.0%/y non-inferiority margin, & cannot rule out 2% absolute increase PER YEAR
    • Peripheral thromboembolism: Low target 0.4%, standard target <0.1% (rate ratio 4.61, 95% CI 0.52-41.28)
    • 12% of patients in the low-target group crossed over to the standard target due to thromboembolism or valve thrombosis

Key Considerations

The study did not demonstrate non-inferiority of the lower INR target

  • Based on the 95% CI, the absolute risk of stroke/TIA could be as much as 2.2% higher per year, which is far greater than the 1.0%/y non-inferiority margin.
    • Notably, theis non-inferiority margin was not based on any statistically appropriate criteria or an agreed-upon minimum clinically important difference (MCID)
  • Additional problems with this non-inferiority analysis:
    • Primary outcome included competing events (thrombosis & bleed). Inclusion of bleeding events in this composite outcome attenuates any difference between groups in favor of the lower target INR group, biasing the results towards non-inferiority
    • The initial 2014 publication was based on an unplanned interim analysis
    • The non-inferiority margin changed between publications (1.5%/year in the 2014 publication and 1.0%/year in the 2018 publication), and was based on absolute instead of relative risk differences
    • Done on ITT population only (non-inferiority trials should report both ITT & per-protocol analyses)
  • In summary, the results of this trial suggest that loosening the INR target from 2.0-3.0 to 1.5-2.0 may increase the risk of the primary outcome by up to 8% over ~4 years.

Generalizability: Most patients in this trial did not have typical high-risk features for thromboembolism, These risk factors (including AF, enlarged LA, reduced LVEF, hypercoagulability, vascular disease or history of embolism) were each present in <10% of the study population. Therefore, these results only truly apply to patients with On-X AVR at relatively low risk of thromboembolism.

Internal validity: Unclear/high risk of bias in multiple domains likely underestimate differences between groups in terms of thromboembolic events, & overestimate differences in favor of the lower-target group for bleeding events.

Summary updated: July 30, 2018

 

SOCRATES - Ticagrelor vs aspirin in minor ischemic stroke or TIA

Johnston SC, et al. Ticagrelor versus aspirin in acute stroke or transient ischemic attack. N Engl J Med 2016;online

Clinical Question

In patients with non-cardioembolic transient ischemic attack (TIA) or minor acute ischemic stroke, does ticagrelor reduce the risk of CV events without increasing bleeding events compared to ASA?

Bottom Line

In patients with non-cardioembolic TIA or minor ischemic stroke, ticagrelor did not statistically significantly reduce the risk of stroke or other cardiovascular events at 90 days, though this trial was underpowered to identify a clinically significant reduction in favor of ticagrelor.

Given this statistical uncertainty, some clinicians may elect to use ticagrelor instead of ASA in certain patients. Key considerations in favor of sticking to ASA include a lower risk of drug discontinuation (3% absolute lower risk), minor bleed and dyspnea (5% absolute lower risk), and a much lower cost (~$260 cheaper/3 months).

Design

Allocation-concealed "superiority" RCT with all (patients, clinicians, investigators) blinded, low loss-to-follow-up (1.5%), analyzed using the intention-to-treat population.

Patients and Setting

  • 33 countries, 674 centers
  • January 2014 - October 2015
  • Inclusion criteria:
    1. Men or women 40+ y/o
    2. Stroke or TIA
      • Acute ischemic stroke with NIHSS score 5 or less (/42), or
      • High-risk TIA
        • ABCS^2 score 4+ (/7), or
        • Documented symptomatic intracranial arterial occlusion, or
        • Documented internal carotid artery occlusive disease
    3. <24h of symptom onset
    4. Head CT/MRI to rule out hemorrhage or other pathology (e.g. AVM, tumor, abscess) that could explain symptoms
  • Key exclusion criteria:
    • Suspicion of cardioembolic origin of stroke/TIA
    • Planned revascularization (cerebrovascular, carotid, or coronary) requiring stopping study medications <7 days of randomization 
    • PMHx:
      • Any hx of AF, ventricular aneurysm
      • Hx of symptomatic non-traumatic ICH at any time, GI bleed within 6 months, major surgery within 30 days, bleeding diathesis or coagulation disorder
      • Severe liver disease or renal failure requiring dialysis
    • Concurrent meds:
      • Receipt of any IV or intra-arterial thrombolytic or mechanical thrombectomy <24h prior to randomization
      • Planned use of other antiplatelets or anticoagulants for other indication
      • Patients receiving dual antiplatelet therapy (DAPT)
      • Anticipated use of strong CYP3A4 inhibitor/substrate
      • Anticipated need for NSAIDs >7 days
  • ? screened -> 13,199 randomized
  • Average patient:
    • 65.8 y/o
    • 42% female
    • Race: ~2/3 White, ~1/3 Asian, <5% other
    • Region: Europe 57%, Asia/Australia 30%, North America 7%, Central/South America 5%
    • BMI 26
    • Event: Ischemic stroke ~3/4, TIA ~1/4
    • PMHx
      • Previous ischemic stroke 12%
      • Previous TIA 6%
      • CAD (MI) 9% (4%)
      • HTN 73%
      • Dyslipidemia 38%
      • Diabetes 25%
    • Taking ASA before randomization ~1/3

Intervention and Control

  • Intervention: Ticagrelor
    • Loading dose: 180 mg PO x1
    • Maintenance dose: 90 mg PO BID x90 days
  • Control: ASA
    • Loading dose: 300 mg PO x1
    • Maintenance dose: 100 mg PO once daily x90 days
  • Co-interventions common to both groups:
    • NO thrombolytic or endovascular therapy to treat the event
    • After 1st 90 days, treated at discretion of investigator x30 days & followed at 120 days (this extended follow-up is not reported in this paper)

Outcomes

  • @ 90 days
  • Efficacy: No statistically significant difference in primary outcome, though the lower end of the confidence interval suggests a possible risk reduction with ticagrelor as high as 1.65% (absolute). Additionally, although this trial wasn't designed as a non-inferiority trial, the upper end of the confidence interval (HR 1.01) provides definite evidence that ticagrelor is at least as good as ASA for this outcome in this patient population.
  • Safety: 
    • Bleeding: No significant difference in major or intracranial hemorrhages
    • Dyspnea: As in other studies of ticagrelor (see PLATO and PEGASUS), ticagrelor increased the risk of dyspnea
    • Discontinuation: Patients on ticagrelor were more likely to permanently discontinue the study drug, which was due to a greater risk of dyspnea & any bleeding
  • Subgroup analyses: None of 15 subgroup analyses were significant, including evaluating the impact of aspirin use prior to admission (p for test for interaction = 0.10)

Outcomes in SOCRATES

Key Considerations

Generalizability: This trial enrolled a very specific population of patients with TIA or stroke with low symptom burden, but high risk of recurrence. It's unclear from the study flow diagram how many patients were assessed for eligibility to identify the 13,000+ randomized patients. It's also unclear how the net effect (on both recurrent ischemic CVA and hemorrhagic strokes) in a population of ischemic stroke patients with higher NIHSS score.

Overall balance of considerations for ticagrelor versus ASA

  • Efficacy: Though not statistically significantly different, there is high likelihood that ticagrelor is marginally better than ASA in reducing stroke recurrence in this patient population
  • Safety: No difference in major bleeding, but significantly more dyspnea in the ticagrelor group, which led to study drug discontinuation and may have had unmeasured consequences on patient quality of life
    • Anecdotally, in some cases ticagrelor-related dyspnea leads to excessive and unnecessary testing (e.g. chest CT, pulmonary function tests, sputum cultures) that may result in additional unnecessary treatment
  • Cost of 90-days of treatment (approximate): Ticagrelor $280, aspirin $12
  • Convenience: Ticagrelor needs to be taken twice daily versus once daily for ASA
  • Drug interactions: Ticagrelor has a number of pharmacokinetic drug interactions with CYP3A4 inhibitors that ASA is free from

Unanswered questions

  • How does ticagrelor monotherapy compare to other interventions, including clopidogrel monotherapy, dual antiplatelet therapy with ASA + clopidogrel (CHANCE trial regimen) or ASA + dipyridamole?
  • If patients are event-free in these first 90 days, what regimen should they continue in the long term? If ticagrelor was initially used, would continuing it indefinitely provide additional benefit compared to switching back to ASA?
  • Do patients who have a stroke/TIA on ASA (those who "fail ASA") benefit from switching to a different antiplatelet regimen?

 

Summary author: Ricky Turgeon BSc(Pharm), ACPR, PharmD
Summary date: updated 26 May 2016

 

Trimethoprim-sulfamethoxazole for uncomplicated skin abscess

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Talan DA, et al. Trimethoprim-sulfamethoxazole versus placebo for uncomplicated skin abscess. N Engl J Med 2016;374:823-32.

 

Clinical Question

In patients with an uncomplicated abscess treated with incision & drainage (I&D), does a 1-week course of trimethoprim-sulfamethoxazole (TMP-SMX) increase the likelihood of abscess cure?

 

Bottom Line

In a population of patients with first uncomplicated abscess and a ~50% prevalence of MRSA, addition of TMP-SMX for 1 week to I&D increased the chance of clinical cure from ~73% to ~80% without any clinically-important adverse effects. 

 

Integrating This Study Into Practice

For patients who would meet this study's eligibility criteria, consider having a shared decision-making discussion with the following options:

  1. I&D alone (no antibiotics): ~75% chance of cure @ 1-2 weeks
  2. I&D + antibiotic x7 days*:
    • Increases chance of cure @ 1-2 weeks to 80%
    • Generally well-tolerated, but could cause headache, GI discomfort, rash in 10-20% of people who take it (estimates based on overall studies)
    • <1/10,000 risk of serious reaction or allergy (e.g. anaphylaxis, Stevens-Johnson Syndrome, DRESS)
    • Costs $0-10 depending on patient's drug plan

*In my opinion, clindamycin, doxycycline & TMP-SMX are all reasonable PO options here despite this study only evaluating TMP-SMX. The choice between these agents should be based on previous allergies/intolerances & interactions with concomitant medications.

 

Design

Allocation-concealed RCT with "everybody" blinded, low loss-to-follow-up (4%), analyzed using a modified intention-to-treat population (mITT).

 

Patients and Setting

  • USA, 5 emergency departments
  • Enrollment timeline: April 2009 - April 2013
  • Inclusion criteria:
    1. >12 y/o
    2. Suspected cutaneous abscess
      • Based on physical exam or ultrasound
      • Found to have purulent material on surgical exploration
    3. Lesion characteristics
      • Present for <1 week
      • Diameter 2+ cm
    4. Expected outpatient management
  • Exclusion criteria:
    • "Complicated" abscess:
      • Indwelling device
      • Suspected osteomyelitis or septic arthritis
      • Diabetic foot, decubitus, or ischemic ulcer
      • Mammalian bite
      • Wound with organic foreign body
      • Infection of another organ system/site
      • Perirectal, perineal or paronychial location
    • PMHx:
      • IVDU within previous month + fever
      • Immunodeficiency (absolute neutrophil count <500/mm^3, on immunosuppressive drugs, active chemotherapy, known AIDS assessed by history)
      • Cardiac condition with risk of endocarditis (e.g. prosthetic valve)
      • CrCl <50 mL/min
      • Allergy/intolerance to trimethoprim-sulfamethoxazole
      • Known G6PD or folate deficiency
      • Underlying skin condition
    • SHx
      • Long-term care residence
      • Incarceration
    • Concurrent meds:
      • Trimethoprim-sulfamethoxazole within 24h
      • Other topical or systemic antibiotic
      • Methotrexate
      • Phenytoin
      • Warfarin
  • 1308 screened -> 1265 randomized -> 1247 analyzed in primary analysis (modified intention-to-treat population 1)
  • Average patient:
    • 35 y/o
    • 42% female
    • PMHx
      • Diabetes 11%
      • Previous MRSA infection 7-8%
    • Clinical presentation
      • 4 days with symptoms before I&D
      • Fever within 1 week of enrollment 18%
      • Abscess location: Head/neck 14%, trunk/abdo/back 21%, groin/buttocks 20%, arms/hands 24%, lower extremities 22%
      • Abscess dimensions: Median 2.5 cm x 2 cm x 1.5 cm (depth)
      • Erythema dimensions: median 7 cm x 5 cm
      • Vital signs
        • Temp >38 degrees Celsius - 0.8%
        • HR >90 - 25%
        • RR >20 - <3%
    • Wound culture result
      1. MRSA ~45% (96% of which were Panton-Valentine leukocidin [PVL]-positive)
      2. MSSA ~15%
      3. Coagulase-negative Staph ~10-15%
      4. Streptococcus ~5%
      5. Other 10-15%

 

Intervention and Control

  • Intervention: TMP-SMX 2 double-strength (DS) tabkets (total 320/1600 mg) PO BID x7 days
    • Adherence: 2/3 took all tablets
  • Control: Matching placebo
  • Co-interventions common to both groups:
    • Incision & drainage of the abscess (standardized training on technique)
    • Culture & susceptibility of drainage sample

 

Outcomes

  • Death: 1 in each group (unrelated to study intervention)
  • Efficacy: 
    • Clinical cure (not meeting clinical failure criteria 1-3) @ day 7-14 (primary outcome): TMP-SMX 80.5%, placebo 73.6% (p=0.005)
      • Statistically significant 6.9% higher probability of clinical cure with TMP-SMX versus placebo (number needed to treat = 15)
      • Clinical failure defined as any of the criteria below:
        1. Study withdrawal, lost-to-follow-up, or missing outcomes
        2. Worsening @ day 3-4: Fever attributable to the infection, increase in erythema >25% from baseline, worsening of wound swelling/tenderness
        3. No improvement @ day 8-10: Fever, no decrease in erythema from baseline, or no decrease in swelling or tenderness
        4. No resolution @ day 14-21: fever or more than minimal erythema, swelling or tenderness
      • Results consistent in analyses of more selective subpopulations (per-protocol and a second miTT)
    • Clinical response (so-called FDA guidance early endpoint) @ day 2-3
      • TMP-SMX 36.3%, placebo 33.7% (p=0.38)
      • Definition: Temp 37.7 degrees Celsius + decrease/no increase in erythema from baseline + no worsening in swelling/induration
    • No statistically significant differences in: Hospitalization, recurrent skin infection, presence of swelling or induration, change in mean area of erythema from baseline, days missed from normal activities or work/school, or days of use of analgesics
  • Safety
    • Discontinuation due to adverse events: TMP-SMX 1.9% versus placebo 0.6%, not statistically significant different
    • Overall adverse events: TMP-SMX 65.4%, placebo 65.2%, not statistically significant different
      • GI-related: TMP-SMX 42.7% versus 36.1%
    • C. difficile infection: 0 in both groups

 

Generalizability & Application

  • Patients/Intervention: 
    • Had no systemic signs of infection (SIRS) or shock
    • High prevalence of community-acquired MRSA (almost half of all positive cultures), for which other PO alternatives include clindamycin or doxycycline.
  • Outcomes
    • Must balance discordance between
      • Statistically & clinically significant improvement in clinical cure at 1-2 weeks (primary outcome)
      • No difference in response @ day 2-3, in speed of resolution of erythema, or in days to return to normal activities
    • Secondary outcomes reported only for per-protocol population, which introduces attrition bias, & therefore any differences between groups are unreliable.

Summary author: Ricky Turgeon BSc(Pharm), ACPR, PharmD
Summary date: 10 May 2016