PRECISION - Comparison of different NSAIDs in patients with arthritis and an increased CV risk

in

Nissen SE, et al. Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis. N Engl J Med 2016;online

Bottom line: For patients with arthritis and a ~1%/year risk of CVD and low risk of GI bleeds, no NSAID (between celecoxib, ibuprofen or naproxen) is clearly safer. Consider a strategy of using the cheapest NSAID, PRN if possible, and optimizing other strategies to decrease the CV risk of NSAIDs (smoking cessation, statins, BP control, ASA for secondary prevention, etc). NSAIDs should be discontinued in patients who do not receive a noticeable improvement in pain & function from these agents.

 

Issues with internal validity?

  • Unclear risk of allocation, performance and detection bias  (likely low risk, but inadequate description in protocol and published report)
  • High risk of attrition and contamination bias
    • 68.8% stopped taking the study drug, though no differences in rates or timing between intervention groups
    • 27.4% discontinued follow-up, and 7.2% were outright lost-to-follow-up
    • The above decrease the study's power to find a difference between groups, especially in the ITT analysis, biasing the conclusions towards non-inferiority. With that said, estimates from ITT and on-treatment populations were almost identical

Special considerations: Non-inferiority trial

  • This study was designed as a non-inferiority safety study to determine that celecoxib was "not much more dangerous" from a CV perspective vs naproxen
  • Criteria to be met to achieve this study's non-inferiority conclusion:
    • Hazard ratio (HR) point estimate <1.12 for the primary outcome
    • Upper limit of HR 97.5% confidence interval <1.33
    • The above had to be met in both intention-to-treat (all patients randomized) and on-treatment populations (events occurring while patient taking study drug + extra 30 days after they discontinued it) to conclude non-inferiority
  • When developing these non-inferiority criteria, assumed would require 762 primary outcome events, and that these would occur at a rate of 2%/year (actual ~1%) & that 40% of patients would discontinue treatment (actual 68%)
    • Actual primary outcome event n=607

Patients (n=24,081)

  • Included
    • Age 18+ y
    • Need for daily NSAID for arthritis pain
    • Increased risk for/established atherosclerotic cardiovascular disease (ASCVD), defined as any of the following:
      • CAD
      • Cerebrovascular disease
      • Symptomatic peripheral vascular disease
      • Arterial surgery/angioplasty for any ASCVD >3 months prior to randomization
      • Diabetes (extra eligibility criterion for women: on insulin)
      • 3+ ASCVD risk factors from the following: Age >55 y, family history of CVD/stroke, current smoker >15 cigarettes/day, HTN, LVH on EKG, dyslipidemia, microalbuminuria or urine protein:creatinine ratio >2, ABI <0.9, waist:hip ratio 0.90 or greater)
  • Excluded
    • ACS, stroke/TIA or CABG within 3 months
    • HF with NYHA class III-IV symptoms or LVEF 35% or less
    • Planned revascularization procedure
    • Uncontrolled arrhythmia within 3 months
    • BP >140/90 mm Hg
    • Malignancy within 5 years
    • Any significant GI, hepatic, renal or coagulation disorders
    • Concomitant meds: Warfarin, prednisone equivalent >20 mg/d, lithium
  • Screened 31,857 -> randomized 24,222 -> analyzed 24,081
  • "Average" patient
    • Age 63 y
    • Female 64%
    • White 75%
    • Arthritis: OA (90%), RA (10%)
      • HAQ disability score 1.1 (0= no disability, 3= complete disability)
      • Pain visual analog score 54 mm (/100)
    • CV risk category: Primary prevention (77%), secondary prevention (23%)
    • PMHx
      • Current smoker 21%
      • HTN 78%
      • Diabetes 35%
      • Dyslipidemia 63%
    • BP 125/75 mm Hg
    • SCr 80 umol/L
    • Meds
      • ASA 46%
      • Statin 54%
      • DMARD 7%

Generalizability: Who does this apply to?

  • Middle-aged to elderly adults with arthritis (mainly OA) with a low-intermediate risk of CV events (~10% over 10 years), and minimal non-CV comorbidity
    • Despite enrolling patients with CV risk factors, actual CV event rates were closer to low-intermediate risk (~1%/year), likely resulting from concomitant treatments to lower CV disease & enrolment of a sample of patients generally healthier than the underlying population.

Interventions

  • Celecoxib
    • Initial dose 100 mg PO BID
    • (RA only) dose could be increased to 200 mg PO BID
    • Mean treatment duration: 20.8 months
  • Ibuprofen
    • Initial dose 600 mg PO TID
    • Dose could be increased to 800 mg PO TID
    • Note: In practice, most clinicians will recommend a lower dose than what was used in this trial (usually ~200-400 mg PO TID-QID)
    • Mean treatment duration: 19.6 months
  • Naproxen
    • Initial dose 375 mg PO BID
    • Dose could be increased to 500 mg PO BID
    • Mean treatment duration: 20.5 months
  • Co-intervention for all: Gastroprotection with daily PPI (esomeprazole 20-40 mg)

Results (reported in the following order: celecoxib, ibuprofen, naproxen)

ITT analyses (mean follow-up 2.8 years)

  • Death: 1.6% vs 1.8% vs 2.0%
    • Celecoxib vs naproxen: HR 0.80 (0.63-1.00)
  • CV
    • Primary outcome (CV death, non-fatal MI, non-fatal stroke): 2.3% vs 2.7% vs 2.5%
      • Celecoxib vs naproxen: HR 0.93 (0.75-1.13)
      • Ibuprofen vs naproxen: HR 1.08 (0.90-1.31)
    • Major adverse cardiovascular event (primary outcome, coronary revascularization, hospitalization for unstable angina, or TIA): 4.2% vs 4.8% vs 4.3%
      • Ibuprofen vs naproxen: HR 1.11 (0.96-1.29)
    • HF hospitalization: 0.6% in all groups
    • Hospitalization for HTN: 0.3% vs 0.5% vs 0.4%
  • GI - Clinically significant events (GI hemorrhage, obstruction, perforation, or symptomatic gastric/duodenal ulcer): 0.7% vs 0.9% vs 0.7%
    • Celecoxib vs naproxen: HR 0.97 (0.67-1.40)
  • Renal (creatinine increase to >177 umol/L, hospitalization for AKI, or initiation of dialysis): 0.7% vs 1.1% vs 0.9%
    • Celecoxib vs naproxen: HR 0.79 (0.56-1.12)
  • Change in pain visual analogue score from baseline (/100 mm): -9.3 vs -9.5 vs -10.2

On-treatment analyses (mean follow-up 1.8 y [mean treatment duration + 1 month])

  • Primary outcome: 1.7% vs 1.9% vs 1.8%
    • Celecoxib vs naproxen: HR 0.90 (0.71-1.15)
    • Ibuprofen vs naproxen: HR 1.12 (0.89-1.40)

Interpretation

  • Caveats to consider
    • The authors performed over 100 analyses including subgroup analyses in addition to the primary non-inferiority analysis, so chance is a plausible explanation for any differences (or lack of differences) in secondary & tertiary outcomes
    • The upper limit of the non-inferiority margin of 1.33 (a 33% relative risk increase) conceptually accepts that NSAIDs could offset the effect of 1-2 interventions to reduce CV events (i.e. CV risk reduction for smoking cessation, ASA, statins, BP & diabetes control are all in the ballpark of a 15-35% relative reduction)
    • Event rates were lower than predicted based on enrolment criteria, likely due to concomitant treatments to reduce CV events
    • Patients discontinued study treatment at a mean 1.7 years, limiting long-term follow-up and assessment of long-term risk
    • No comparison group that received placebo/no NSAID
  • In the context of the above caveats, this study provides some evidence that
    • Celecoxib, ibuprofen and naproxen have similar CV and renal safety profiles at the doses and duration used in this trial, but cannot absolutely refute other studies demonstrating a greater risk with celecoxib;
    • GI event rates between NSAIDs & celecoxib differed only when iron-deficiency anemia of presumed GI origin was added to the predefined outcome of clinically-significant GI events. The difference was not different when considering only serious events. This weakens the rationale for using celecoxib over a non-selective NSAID;
    • Ibuprofen used at doses higher than routinely prescribed may pose a greater risk of CV and non-serious GI events than celecoxib or naproxen. The implications of this for lower doses are unclear;
  • None of the drugs in this study achieved a minimally clinically important change in the pain score (13.7/100). It's likely that a subset achieved a demonstrable reduction in pain, but for the majority of the trial participants, the benefits were non-existent and therefore risks outweighed the benefits.

ACE inhibitors post-MI (CCS-1, CONSENSUS II, GISSI-3, ISIS-4, SMILE; AIRE, SAVE, TRACE)

in ,

Bottom line:

  • Short-term use of ACE inhibitors reduces the risk of death post-MI regardless of HF signs/symptoms or LVEF at time of initiation (NNT 125-200).

    • Note: The previously-reviewed HOPE trial then supports continuing ACE inhibitors in patients without HF or LV dysfunction. 

  • In patients with either clinical HF or reduced LVEF post-MI, long-term use of ACE inhibitors reduce the risk of death (NNT 14-20) and severe HF.

 

Short-term use of ACEI in MI all-comers:

  • Oral captopril versus placebo among 13,634 patients with suspected acute myocardial infarction: Interim report from the Chinese Cardiac Study (CCS-1). Lancet 1995;345:686-7.
  • ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group. ISIS-4: A randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction. Lancet 1995;345:669-85.
  • Swedberg K, et al. Effects of the early administration of enalapril on mortality in patients with acute myocardial infarction: Results of the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II). N Engl J Med 1992;327:678-84.
  • Gruppo Italiano per lo Study della Sopravvivenza nell'infarcto Miocardico. GISSI-3: Effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after myocardial infarction. Lancet 1994;343:1115-22.
  • The Survival of Myocardial Infarction Long-Term Evaluation (SMILE) Study Investigators. The effect of the angiotensin-converting-enzyme inhibitor zofenopril on mortality and morbidity after anterior myocardial infarction. N Engl J Med 1995;332:80-5.

Long-term use of ACEI started shortly post-MI with LV dysfunction or clinical HF:

  • Pfeffer MA, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: Results of the Survival and Ventricular Enlargement trial. N Engl J Med 1992;327:669-77.
  • The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet 1993;342:821-8.
  • Trandolapril Cardiac Evaluation (TRACE) Study Group. A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 1995;333:1670-6.

Issues with internal validity?

  • No: All but 1 trial double-blind (GISSI-3) with measurement of objective outcome (all-cause mortality) and consistency between all trials.

Patients

5 trials enrolled "all-comer" acute MI patients, regardless of the presence/absence of clinical HF or LVEF

About 20% of patients in the "all comer" trials had clinical HF. LVEF was not routinely measured & is not reported in the original trial reports

3 trials enrolled patients early after an MI if they had either clinical HF (AIRE) or reduced LVEF (SAVE, TRACE) for enrolment

The majority of patients in the 2 trials of patients with LV dysfunction (SAVE, TRACE) did not have any clinical signs of HF at baseline despite an average LVEF ~30%

Generalizability: Who do these results apply to?

  • Taken together, these 8 trials enrolled any patient within ~2 weeks of an MI with or without clinical HF or LV dysfunction in the fibrinolytic/pre-early invasive management era, as long as they did not have an absolute contraindication to ACEI such as SBP <90, AKI or hyperkalemia (exclusion criteria common to 2+ trials)
  • Baseline use of concomitant medications (ASA, beta-blockers, etc) was variable, & overall suboptimal (ASA use ranged 55-94%)

Interventions

  • Captopril studies
    • CCS-1: 6.25 mg PO test dose, followed by 12.5 mg PO TID x28 days
    • ISIS-4: 6.25 mg PO test dose, then 12.5 mg 2h later, then 25 mg 10h later, then 50 mg PO BID x28 days
      • 17% discontinued captopril before discharge
    • SAVE: Initial dose 6.25-12.5 mg PO TID, titrated up to 25 mg PO TID by hospital discharge, then increased to 50 mg PO TID & continued for trial duration (mean 3.3 y)
  • Enalaprilat/enalapril (CONSENSUS II)
    • Enalaprilat 1 mg IV over 2h, then enalapril 2.5 mg PO BID, doubled daily as tolerated up to 20 mg PO BID on day 5 onward & continued for trial duration (41-180 days)
  • Lisinopril (GISSI-3)
    • 5 mg PO daily x2 days, then 10 mg PO daily x6 weeks
    • 18% discontinued by week 6
  • Ramipril (AIRE)
    • 2.5 mg PO BID x2 days, then 5 mg PO BID for trial duration (mean 1.25 y)
      • 86% discharged on 10 mg/d
  • Trandolapril (TRACE)
    • 1 mg PO daily x2 days, then 2 mg PO daily x4 weeks, then 4 mg PO daily for trial duration (2-5.1 y)
  • Zofenopril (SMILE)
    • 7.5 mg PO BID x1 day, doubled daily to target 30 mg PO BID, continued for total 6 weeks

Results

The 5 all-comer trials all evaluated outcomes in the short term, & all but CONSENSUS II (which initiated ACEI therapy as IV) demonstrated a reduction in the incidence of death +/- HF with NNT ~125-200 for death at 4-6 weeks

The trials of patients with clinical HF/LV dysfunction post-MI all evaluated outcomes beyond 1 year, with all trials demonstrating a mortality benefit that ranged from NNT 14-20 at ~1-5 y. Superficially, the greatest absolute benefit was seen in the AIRE trial, which enrolled only patients with clinical HF

Beta-blockers in HFrEF (CIBIS-II, COPERNICUS, US Carvedilol HF study, MERIT-HF)

in

CIBIS-II: The cardiac insufficiency bisoprolol study II (CIBIS-II): A randomised trial. Lancet 1999;353:9-13.

US Carvedilol HF Study: Packer M, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure: U.S. Carvedilol Heart Failure Study Group. N Engl J Med 1996;334:1349-55.

COPERNICUS: Packer M, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001;344:1651-8.

MERIT-HF: Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL randomized intervention trial in congestive heart failure (MERIT-HF). Lancet 1999;353:2001-7.

Bottom line: Bisoprolol, carvedilol & extended-release metoprolol all reduced death in HFrEF (NNT ~10-20 @ 1 year). When evaluated, these beta-blockers also reduced hospitalizations to a similar degree.

 

Issues with internal validity?

  • No: All 4 were randomized, allocation-concealed, double-blind trials with <1% loss-to-follow-up analyzed using the intention-to-treat population
    • All 4 RCTs were stopped early during interim analyses due to overwhelming evidence of a mortality benefit from the beta-blocker
  • 2 trials had a run-in period:
    • US carvedilol study: 2-week open-label run-in phase where all patients received carvedilol 6.25 mg PO BID. Those who could tolerate this dose (94% of patients) were randomized.
  • MERIT-HF: 2-week run-in period with placebo, after which those who took >75% of doses were randomized.

Patients

Interventions & co-interventions

  • I: Beta-blocker
    • CIBIS 2: Bisoprolol started at 1.25 mg PO daily, increased weekly (-> 2.5 -> 5), then monthly (-> 7.5 -> 10) to a maximum tolerated dose of up to 10 mg PO daily
      • Achieved dose: 1.25-2.5 mg/d (33%), 5-7.5 mg/d (25%), 10 mg/d (42%)
    • US Carvedilol HF Study: After the run-in where patients initially received carvedilol 6.25 mg PO BID, the dose was increased to 12.5 mg PO BID, then incrementally up to 50 mg PO BID as tolerated
      • Mean dose achieved during study 45 mg/d (80% achieved target dose)
    • COPERNICUS: Carvedilol started at 3.125 mg PO BID x2 weeks, then doubled q2 weeks as tolerated to a target dose of 25 mg PO BID
      • As necessary, other drugs could be titrated or carvedilol titration frequency could be modified
      • Mean dose achieved @ 4 months: 37 mg/d 
    • MERIT-HF: Metoprolol extended-release 25 mg PO once daily (12.5 mg for NYHA III-IV at baseline), doubled q2 weeks as tolerated to a target dose of 200 mg PO daily
      • Mean dose achieved @ 6 months: 160 mg (64% achieved target dose)
  • C: Matching placebo

Results

  • Subroup analyses in the individual trials did not demonstrate any difference in relative benefit differences based on age, sex, HF etiology, NYHA functional class, or LVEF.
  • In all trials, the mortality benefit from beta-blockers stemmed from a reduction in both progression of HF & sudden cardiac death.

Other studies

  • The COMET trial is the largest RCT comparing different beta-blockers in HFrEF. It demonstrated a lower risk of death (NNT 17) over 4.8 years with carvedilol at a target dose of 25 mg PO BID versus metoprolol tartrate at a target dose of 50 mg PO BID
    • The benefit of carvedilol in this trial may be a result of an unfair comparison rather than a true benefit. The short-acting metoprolol tartrate was used in this trial instead of the once-dialy long-acting succinate salt proven to reduce mortality in MERIT-HF. Additionally, the target metoprolol was half the target dose in MERIT-HF. The carvedilol dose and formulation were the same as in the landmark trials demonstrating benefit over placebo.

PIONEER AF-PCI - Antithrombotics in patients with AF after PCI

in , ,

Bottom line: In patients with AF undergoing PCI, a novel antithrombotic regimen (reduced-dose rivaroxaban + P2Y12 inhibitor, or ATLAS trial-like triple therapy regimen) reduces the risk of hospitalization, bleeding requiring medical attention and study discontinuation (NNT ~10-15 each).

This trial does not answer whether these novel regimens retain stroke efficacy for AF (either regimen versus full anticoagulation) or MI/stent thrombosis efficacy for CAD (modified double therapy versus DAPT). While ongoing trials will provide further guidance on the ideal regimen and dose, the best available evidence suggests that dual therapy with clopidogrel plus full-dose anticoagulation provides the best balance of benefit and safety.

 

Patients (n=2124)

  • Inclusion
    • Age 18+ y
    • AFib (documented within 1 y before enrolment or taking OAC for at least 3 months before PCI)
    • Underwent PCI with stent placement (randomized within 3 days of PCI)
  • Exclusion
    • Prior stroke/TIA
    • Significant GI bleed within 1 year
    • Anemia of unknown cause with Hb <100 g/L
    • "Any other condition known to increase bleed risk"
    • CrCl <30 mL/min
  • Screened 2236 -> randomized 2124 -> analyzed 2099
  • "Average" patient
    • Age 71 y (36% 75+ y)
    • Female 26%
    • White 94%
    • Indication for PCI: Unstable angina (21%), NSTEMI (18%), STEMI (12%), non-ACS (49%)
    • Drug-eluting (2/3), bare-metal (1/3) stent
    • CHA2DS2-VASc score: 0 (<2%), 1 (9%), 2 (15%), 3 (18%), 4 (20%), 5 (20%), 6 (13%), 7 (3%)
    • CrCl 78 mL/min
    • P2Y12 inhibitor: Clopidogrel (93%), prasugrel (<2%), ticagrelor (~5%)
    • PPI used in ~40%

Generalizability

  • Represents the target population at the time when the decision on antithrombotics would be made.
  • Similar to WOEST and ISAR-TRIPLE, ACS was the indication for PCI in <50% of patients
    • Due to their higher risk of MI, stent thrombosis & CV death, thes benefit-risk profile of different antithrombotic regimens (& DAPT duration) likely differs in this subgroup. This trial is underpowered to evaluate this subgroup.
  • ~90% of patients had a CHA2DS2-VASc of 2 or more, corresponding to a risk of stroke or systemic thromboembolism of >1.5%/year & indication for anticoagulation by all major guidelines (AHA, CCS, ESC).
  • This trial included only patients without major bleeding risk factors (i.e. no recent GI bleed, intracranial hemorrhage, eGFR <30 mL/min, or chronic NSAID use)
    • The bleeding rates in this trial therefore represent a minimum risk that would be expected to increase substantially in the presence of any of these risk factors.

 

Interventions & co-interventions

  • I 1: Modified "double therapy" for trial duration
    • Rivaroxaban 15 mg daily + P2Y12 inhibitor at standard dose
      • If CrCl 30-50: Decrease rivaroxaban to 10 mg daily
    • Comments about this intervention:
      • Rivaroxaban dose 75% of the 20 mg/d dose determined to be non-inferior to warfarin in ROCKET-AF trial of non-valvular AF. It is unclear if the addition of 1 antiplatelet drug to this reduced dose provides similar ischemic stroke risk reduction compared to full-dose anticoagulation monotherapy
      • Full-dose apixaban may have been a better option, since it has demonstrated similar risk of major bleeding compared to ASA, with greater reduction in ischemic stroke in non-valvular AF (AVERROES)
  • I 2: Rivaroxaban 2.5 mg BID + DAPT (ATLAS trial regimen)
    • DAPT consisted of ASA 75-100 mg/d indefinitely + a standard dose of any of clopidogrel, prasugrel, ticagrelor x1 to 12 months (decided before randomization)
    • Comments about this intervention:
      • Rivaroxaban dose 25% of the 20 mg/d dose determined to be non-inferior to warfarin in ROCKET-AF trial. There is no prior evidence suggesting that this dose is adequate to reduce the risk of stroke in AF, nor is there evidence that adding DAPT to this reduced dose will reduce the risk of ischemic stroke.
  • C: Warfarin-based triple therapy
    • Warfarin to INR 2.0-3.0 (mean time in the therapeutic range 65%) + ASA 75-100 mg/d + P2Y12 inhibitor
      • Warfarin & ASA continued for trial duration
      • P2Y12 inhibitor continued x1 to 12 months (decided before randomization)

 

Outcomes @ 1 year

  • Efficacy
    • Death or hospitalization: Modified double therapy 35%, ATLAS regimen 32%, triple therapy 42%
      • Modified double therapy vs triple therapy: Hazard ratio (HR) 0.79 (95% confidence interval 0.66-0.94), NNT 10
      • ATLAS regimen vs triple therapy: HR 0.75 (0.62-0.90), NNT 15
      • Note: The lower risk of hospitalization in the 2 rivaroxaban-based regimens vs triple therapy were due to reductions in both CV- and bleeding-related hospitalizations
    • Death: 2.3-2.7% (no statistically significant differences)
    • Composite CV death, MI or stroke: 6.5% vs 5.6% vs 6.0%
      • Double vs triple therapy: HR 1.08 (0.69-1.68)
      • ATLAS regimen vs triple therapy: HR 0.93 (0.59-1.48)
    • Stent thrombosis: 0.8% vs 0.9% vs 0.7%
      • Double vs triple therapy: HR 1.20 (0.32-4.45)
      • ATLAS regimen vs triple therapy: HR 1.44 (0.40-5.09)
    • Stroke: 1.3% vs 1.5% vs 1.2%
      • Double vs triple therapy: HR 1.07 (0.39-2.96)
      • ATLAS regimen vs triple therapy: HR 1.36 (0.52-3.58)
  • Safety
    • Primary outcome (major + minor bleeding based on TIMI criteria or bleeding requiring medical attention): 16.8% vs 18.0% vs 26.7%
      • Double vs triple therapy: HR 0.59 (0.47-0.76), NNT 11
      • ATLAS regimen vs triple therapy: HR 0.63 (0.50-0.80), NNT 12
    • Major bleeding: 2.1% vs 1.9% vs 3.3%
      • Double vs triple therapy: HR 0.66 (0.33-1.31)
      • ATLAS regimen vs triple therapy: HR 0.57 (0.28-1.16)
  • Discontinuation before study termination: 21.0% vs 21.1% vs 29.4% (NNT ~12 for either double therapy or the ATLAS regimen versus triple therapy)

 

Context

 

Internal validity

  • Low risk of allocation bias (central randomization)
  • Unclear risk of certain biases
    • Performance bias
      • Open-label
      • Anticipated DAPT duration selected & recorded prior to randomization
      • PPI/H2RA use for gastroprotection encouraged but not mandated for all trial participants
    • Detection bias:
      • Open-label
      • Most outcomes included in the primary safety outcome were subjective "soft" outcomes ("bleeding requiring medical attention" accounted for >90% of bleeding outcomes reported) & prone to biased reporting from patients, and subsequently from the treating clinician
      • The more important & objective outcomes such as major hemorrhage or death occurred infrequently (~2-3%), with too few events to provide firm conclusions about differences or lack thereof
      • Blinded adjudication: All efficacy endpoints & a portion of bleeding events reported by patients & their clinicians were subsequently adjudicated by investigators blind to assigned intervention
    • Attrition bias:
      • Analyzed only patients who took at least 1 dose of the study drug (modified intention-to-treat [mITT] population)
      • None in the mITT population were lost-to-follow-up, but more patients in the triple therapy group discontinued the study regimen prematurely
  • Low risk of reporting bias (all clinically-important outcomes reported)

 

 

    Interpretation of study outcomes

    • Study underpowered to demonstrate superiority or non-inferiority of any intervention to each other for the outcomes of cardiovascular events or major hemorrhage
      • Could not rule out a 3-fold increased risk of stroke in the double therapy/ATLAS regimen versus triple therapy.
    • Contrary to WOEST, PIONEER did not demonstrate a lower risk of death with the modified double therapy regimen vs triple therapy. Due to the low number of events, either finding could be due to chance (false-negative in PIONEER or false-positive in WOEST).
    • The risk of major hemorrhage over 1 year with triple therapy (3.3%) was comparable to that in the ISAR-TRIPLE trial (2.4% at 9 months), & substantially lower than in the Danish registry (12.2%) and the WOEST trial (5.6%).

    DAPT Score - Risk stratifying for DAPT x12 vs >12 months after PCI

    in

    Yeh RW, et al. Development and validation of a prediction rule for benefit and harm of dual antiplatelet therapy beyond 1 year after percutaneous coronary intervention. JAMA 2016;315:1735-49.

    Bottom line: The DAPT Score is an easy-to-use tool to help select patients for extended DAPT duration after PCI, but it hasn't yet been sufficiently validated in a real-world population to use in practice.

    Particularly important issues that may crop up in future validation include poor discrimination in a real-world heterogeneous population (& already fairly low with c-statistic ~0.70 or less in RCT populations), poor calibration, & over-simplification from combining ischemic & bleeding risk into a single score.

     

    Context

    • Until publication of the DAPT trial in 2014, limited evidence to guide optimal dual antiplatelet therapy (DAPT) duration following acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI) with drug-eluting stent (DES) placement, so guidelines routinely recommended 12 months for all patients.

    • Numerous subgroup analyses looked at patient characteristics that could be used to identify patients that could obtain a net benefit from prolonged DAPT, but these only look at 1 characteristic at a time;

      • Decisions on DAPT duration are complex and require integration of multiple characteristics.

    • The newest AHA guidelines on DAPT recommend using a risk prediction tool such as the DAPT Score to aid in deciding on DAPT duration.

    DAPT score

    • Available here

    • Score-based risk calculator ranging from -2 to 10, with lower scores representing an unfavorable benefit/risk ratio from extended DAPT and higher scores representing a greater net benefit from extended DAPT.

    • The investigators divided the score into 2 categories:

      • With a DAPT Score <2 (-2 to 1), extending DAPT >1 yearr:

        • NNT 167 for MI/stent thrombosis

        • NNH 72 for GUSTO moderate-severe bleed

      • With a DAPT Score >2 (2-10), extending DAPT >1 year resulted in:

        • NNT 53 for MI/stent thrombosis

        • NNH 250 for GUSTO moderate/severe bleed

    Level of evidence

    • Derivation, internal validation & external validation: 2a (level of evidence ranges from 1 [highest] to 4 [lowest])
    • Hierarchy of evidence for clinical prediction rules: Level 3 (validated in only 1 narrow prospective sample)

    Study population

    • Data sources:
    • Study setting: Outpatient cardiology follow-up
    • Patient population: Individuals undergoing PCI with DES (elective or urgent)
    • Adequate proportion of patients with each predictor variables?
      • es, in DAPT ~300 patients (3%) with rarest included predictor variable (stent in vein graft); other characteristics present in >2000 (>20%) of patients

    Predictor variables

    • 37 predictor variables initially considered
      • Demographics: Age, sex, race
      • CV history: HF or LVEF <30%; prior CABG, PCI or MI; PAD; stroke/TIA; AF
      • Comorbidities: BMI; cancer at time of randomization; current smoking; diabetes; history of major bleed; hypertension; renal insufficiency (SCr >2 mg/dL)
      • Procedural characteristics: >2 lesions/vessel; bifurcation stenting; coronary lesion class C; number of stents; number of treated vessels; presentation with MI; pre-procedural stenosis; prior brachytherapy; prior in-stent thrombosis; severe coronary calcification; stenting of vein graft; stent diameter; stent type; thrombus-containing lesion; TIMI grade flow post-procedure; total stent length; unprotected left main stenting
      • Meds: Randomization arm (DAPT 12 vs >12 months); clopidogrel vs prasugrel; statin at time of randomization
    • Checklist for what makes good predictor variables (all were met):
      • Clear & reproducible predictor definition
      • Reliable 
      • Available at time of decision
    • Assessors were blind to the outcome at time of predictor variable determination (inherent in prospective design of these RCTs)
    • Predictor variable definition consistent between derivation, internal validation & external validation cohorts

    Outcome

    • Composites of:
      1. Death/MI/stroke
      2. MI/stent thrombosis
      3. Moderate/severe bleed (GUSTO definitions)
    • Checklist for what makes good outcomes (all were met):
      • Clinically important
      • Clear & reproducible definition
    • Caveat: Adjudicators not blind to predictor variables at time of outcome assessment (though blind to the existence of the DAPT Score derivation & related hypotheses)

    Accuracy

    • Analysis appropriate & well-described: Hazards ratios derived using Cox multivariable regression
    • Handling of missing data: Unclear
    • Overfitting? Low risk (far more than rule-of-thumb 10 outcome events/predictor variable included in statistical model)
    • Discrimination (tool's ability to distinguish between patients who do & those who don't experience the outcome, using the c-statistic, where a c-statistic of 0.50 = model is as good as chance, & a c-statistic of 1.00 = perfect discrimination): Good, not great
      • Internal validation (DAPT):
        • Ischemic outcome: 0.70 (moderate)
        • Bleeding outcome: 0.68 (moderate)
      • External validation (PROTECT): c-statistics = 0.64 for ischemic & bleeding outcomes
    • Calibration (tool's ability to correctly estimate the incidence of an outcome in a population)
      • Internal validation (DAPT): Good
      • External validation (PROTECT): Overestimated risks of outcomes (because PROTECT enrolled a lower-risk population than the DAPT trial). Good after re-calibration for this lower incidence in the overall study population.

    Generalizability (also known as transportability)

    • To RCT populations similar to the DAPT & PROTECT trials: Excellent
    • To different geographical areas, clinical settings, providers (e.g. GPs, internists, pharmacists, nurses. etc): Unknown
    • To different follow-up intervals (e.g. extended DAPT beyond 3 years): Unknown
    • To patients with different spectra of coronary artery disease or comorbidities: Unknown
    • To patients on different antiplatelet agents (e.g. ticagrelor) or on anticoagulant therapy (e.g. DOAC for AF): Unknown