DECLARATION OF CONFLICT OF INTEREST None
Statistical Interpretation of Clinical Trial Reports: Limitations and Pitfalls Stuart Pocock London School of Hygiene and Tropical Medicine 2
Topics Covered PLATO SPIRIT IV PARTNER HORIZONS-AMI PALLAS Strength of evidence: P values Subgroup analysis Non-inferiority trials Exploratory data analysis Stopping trials early 3
PLATO [NEJM 2009; 361 p 1045] Ticagrelor vs Clopidogrel in ACS 18624 patients, followed for 1 year primary endpoint: CV death, MI, stroke ticagrelor clopidogrel hazard ratio (95%CI) primary 9.8% 11.7% 0.84 (0.77-0.92) P<.001 death 4.5% 5.9% 0.78 (0.69-0.89) P<.001 very strong evidence, proof beyond reasonable doubt ticagrelor is superior re 4
Results by Geographic Region: tricky to Interpret PLATO trial: ticagrelor vs clopidogrel in ACS Primary Endpoint by Region N hazard ratio (95% CI) Asia/Australia 1714 0.80 (0.61, 1.04) Central/South America 1237 0.86 (0.65, 1.13) Europe/Middle East/Africa 13859 0.80 (0.72, 0.90) North America 1814 1.25 (0.93, 1.67) interaction P=0.0453 ticagrelor is superior, unless you re American!? One of 32 subgroup analyses, beware of data dredging 5
Primary Endpoint for US and non-us [post hoc interaction P=.009] 6
median aspirin dose US vs non-us 300mg dose in 54% US and 1.7% non-us 7
Ticagrelor vs Clopidogrel by Aspirin Dose [interaction P=.0006] 8
Questions? Is the US anomaly a reality, or just a chance finding? Is maintenance aspirin dose an explanation, or a consequence of data dredging? Is the FDA boxed warning use of ticagrelor with aspirin doses exceeding 100 mg/day decreases its effectiveness a wise decision? 9
SPIRIT IV [NEJM 2010; 362 p 1663-] XIENCE V vs TAXUS drug-eluting stent N=2416 N=1195 Primary Endpoint: Target Lesion Failure (TLF) at 1 year Overall: 4.2% vs 6.8% P=.001 In diabetics: 6.4% vs 6.9% P=.8 Interaction test P=.02, one of 12 subgroup analyses Conclusion: reduced rates of TLF consistent in all patients except those with diabetes, in whom the results were nonsignificantly different An over-reaction to a subgroup finding? 10
SPIRIT IV: Xience V not superior in diabetics?! Diabetics interaction P=.02 11
PARTNER Trial [NEJM 2011; 364 p 2187-] Transcatheter versus Surgical Aortic-Valve Replacement TAVI Surgery N 348 352 Deaths at 1 year* 84 (24.2%) 89 (26.8%) P=0.44 non-significance not sufficient to claim non-inferiority difference 2.6% upper 95% confidence limit +3.0% pre-defined margin +7.0%, hence non-inferiority claimed *all percentages adjusted for loss to follow-up 12
Strokes in the PARTNER Trial TAVI Surgery Major strokes at 1 year 17 (5.1%) 8 (2.4%) P=0.07 TAVI might increase the risk of stroke Death or major stroke 92 (26.5%) 93 (28.0%) P=0.68 composite primary endpoint for future trials? 13
Problem in PARTNER trial 4 TAVI and 38 surgery patients did not get intended treatment Supplementary as treated analysis at 1 year TAVI Surgery N 344 313 Deaths 81 (23.7%) 78 (25.2%) P=.64 Major stroke 17 (5.2%) 8 (2.7%) P=.11 consistent with analysis by intention to treat 14
Subgroup analyses interpret with caution, data dredging they lack power use interaction tests, not subgroup P-values PARTNER trial: deaths for TA and TF separately TAVI Surgery Hazard Ratio Transapical 30 104 Transfemoral 54 244 interaction P=0.43 27 103 62 248 1.10 0.89 no evidence that transapical fares worse 15
HORIZONS-AMI 3 year results [Lancet 2009; 374 p 1149-] Bivalirudin vs heparin + GPI in 3602 STEMI patients findings on all-cause mortality 5.9% vs 7.7% at 3 years P=.03 3.5% vs 4.8% at 1 year P=.037 2.1% vs 3.1% at 30 days P=.047 transfer one early death and all P-values exceed.05 P<.05 is a very fickle beast! 16
Meta-analysis of 3 Trials One Year Mortality Bivalirudin Heparin + GPI Hazard Ratio REPLACE 2 56/2994 72/3008 0.78 (0.55, 1.10) ACUITY 170/4612 178/4603 0.96 (0.77, 1.18) HORIZONS 61/1800 86/1802 0.71 (0.51, 0.98) Overall 287/9406 336/9413 0.84 (0.72, 0.99) P=.035 Is it real? What s the reason? 17
Deaths by Bleeding and Thrombocytopenia Bivalirudin Heparin + GPI Hazard Ratio Attributable Deaths TIMI Major Bleed 20/95 42/170 5.81 18.2 Other Major Bleed 26/317 48/597 2.03 12.3 New Thrombocytopenia (no major bleed) 26/742 46/857 1.64 7.8 Others 215/8252 200/7789 1 - Total Attributable Deaths 38.3 78% of mortality difference statistically explained by reduced bleeding and thrombocytopenia observational association: caution re causality 18
PALLAS trial stopped early Dronedarone vs Placebo in permanent atrial fibrillation Results as of June 30, 2011 CV death, MI, stroke and systemic embolism Placebo N=1577 Dronedarone N=1572 Hazard Ratio 14 32 2.31 (1.23, 4.32).009 Death, unplanned CV hosp n. 81 118 1.49 (1.12, 1.97).006 Death 7 16 2.31 (0.95, 5.61).065 Heart Failure hosp n. 15 34 2.29 (1.8, 4.20).008 P when to stop? risk of over-reaction? eg. Heart. Org: Deaths doubled with dronedarone! await final data 19
Topics Covered PLATO SPIRIT IV PARTNER HORIZONS-AMI PALLAS Strength of evidence: P values Subgroup analysis Non-inferiority trials Exploratory data analysis Stopping trials early 20