The year in vascular surgery: papers you should be aware of

Transcription

1 The year in vascular surgery: papers you should be aware of { Christopher D. Owens, MD UCSF Vascular Symposium 2015 Disclosure: None relevant to this talk 15,153,100 different scientist publishing papers in major scientific journals in ,805, 462 different papers in the same period Each paper can include anywhere from a few to many thousands of results A Bird s eye view of science 1

2 A. Always, I have read most of the PAD guidelines and have a PDF or hard copy B. Occasionally, I have seen them but it has been a while C. Rarely, I know they exist and I heard Mike Conte talk about them once, I think D. Never, I can not identify the journal who published them 41% 33% A. Journal of Vascular Surgery B. Journal of Endovascular Therapy C. Endovascular Today D. Catheterization and Cardiovascular Intervention 74% E. none of the above F. All of the above 21% How often do you use guidelines to inform your practice? A l w a y s, I h a v e r e a d m o s t.. O c c a s i o n a l l y, I h a v e s e e... R a r e l y, I k n o w t h e y e x i s t... 15% 11% N e v e r, I c a n n o t i d e n t i f y... 0% Which journal do you look at least once per month to get most of the data that drives your practice? J o u r n a l o f V a s c u l a r S u r g e r y J o u r n a l o f E n d o v a s c u l a r... E n d o v a s c u l a r T o d a y 5% 0% 0% C a t h e t e r i z a t i o n a n d C a r d... n o n e o f t h e a b o v e A l l o f t h e a b o v e The evidenced based quality mark has been misappropriated by vested interested The volume of evidence, especially expert guidelines, has become unmanageable Statistically significant benefits may be marginal in clinical practice Inflexible rules and technology driven prompts may produce care that is management driven rather than patient centered Evidence based guidelines often map poorly to complex multimorbidity Crisis in Evidence based medicine BMJ 2014; 348:3725 The evidenced based quality mark has been misappropriated by vested interested Creation of new disease states Low T syndrome testosterone Female sexual arousal disorder sildenafil Male baldness finasteride Venous hypertension for multiple sclerosis stent Venous stenting for iliac outflow stenosis Industry does not publish negative results or delays publication, decides which treatments to test, overstating surrogate endpoints, mis-coding data, Crisis in Evidence based medicine BMJ 2014; 348:3725 2

3 Venous reflux trends. Is this trend due to a compelling scientific question? Pubmed search: venous reflux Industry drives biomedical science agenda and societies and investigators spend energy and resources activity and resources filling in the gaps, add on studies AAA Bypass surgery Today 1952 Is This a bad thing? Academic promotion and publication vs. market forces, investors, and profit FDA-regulated studies only 31% were reported Studies viewed as negative by the FDA were either, Not published, N=22 Published in a way that conveyed a positive outcome, N=11 Or published in a way consistent with the FDA, N=3 The net effect to the consumer is that 94% of trials appeared positive in the public literature N Engl J Med 2008; 358:

4 Stated purpose of the trial. to evaluate the safety and effectiveness of directional atherectomy and distal embolic protection treat moderate to severely calcified lesions. Silverhawk and Turbohawk + Definitive Ca++ SpiderFX Prospective, multicenter, single-arm trial Rutherford clinical category 2-4 Angiographic Core Laboratory Clinical Events Committee N=133 patients, 168 lesions Statistically designed to compare performance goals to the TALON* registry. Ramaiah V. J Endov Ther. 2006;13:592 Effectiveness 90% - successful revascularization of the target lesion defined as 50% stenosis of the target lesion Safety Major Adverse Event free rate of 85% at 30 days Definitive Ca++ *data from TALON registry was site reported and without independent evaluation. PIs were equity owners in the company. 4

5 Definitive Ca++ Mean Lesion length 3.9 cm, 12% restenosis, 18% occlusions Definitive Ca++ Effectiveness achieved in 92 ± 5% of patients therefore they did not meet their PG of 90% But the mean residual stenosis was 33% And adjunctive therapy 53.8% Conclusions Visible debris found in the filter in 88.4% of cases or (122/138) Definitive Ca++: Safety Turbohawk is relatively safe when used in combination with EPD. Modest effectiveness (technical success) in calcified lesions Maybe of benefit in preparing vessel to receive drug in DCB technology Phase IV post-marketing study BUT REALLY it is a safety/feasibility proof-of-principle study Definitive Ca++: Effectiveness 5

6 CONGRATULATIONS Study design and endpoints Randomized trial comparing PTX-coated Amphirion balloon to uncoated Amphirion balloon in the treatment of 358 CLI patients with BTK lesions. Efficacy Endpoint #1. Primary statistical hypothesis: Superiority of LLL at 12 months assessed by a t-test. Efficacy Endpoint#2. Superiority of TLR at 12 months assessed by Fisher s Exact test What is wrong with these endpoints? No time-to-stenosis data. Log- Rank test Study design and endpoints Primary safety endpoint: composite all-cause death, major amputation, TLR at 6 months tested in non-inferiority with a 10% and 4.8% one-sided α. Non-inferior to what? The non-coated Amphirion balloon. The DCB is allowed 10% more SAEs and still meet the noninferiority pre-specified benchmark. α = the probability of false positive and is one sided because you can only have false positives with more SAEs, not less. Study Results: Efficacy DCB vs. PTA Efficacy Endpoint #1. Superiority of LLL at 12 months ± vs ± 0.781; P=0.950 Efficacy Endpoint#2. Superiority of TLR at 12 months. 27/226 (11.9%) vs. 15/111 (13.5%); P=.682 Small N, outliers, inaccurate measurements, non-normal For LLL the standard deviation > mean? distribution, may be fine. 6

7 Study Results: Safety DCB vs. PTA Efficacy Safety composite endpoint #1. 41/232(17.7%) vs. 18/114 (15.8%), p=.021, P-value is the probability that we would falsely reject the null hypothesis when it is true. DCB is not inferior to PTA P=0.080 a)liistro. Single center This RCT is why Medtronic b)amphirion PTX-coated pulled balloon the product! c)n=132 diabetic patients with CLI d)self-adjuticated e)restenosis rate: 27% vs. 74%, P<.001 f) CD-TLR: 18% vs. 43%, P=.002 What g)amputation: went wrong? 0 vs. 1! influenced h)schedule by bias of assessments: BIWk x 2 mo, QWk x 1mo, every 2 wks thereafter! 1. Previous studies were positively 2. The trialist did not know what they were doing a. No standardized wound care b. Status of the pedal circulation, wound infection/location. c. Wrong endpoints and wrong statistical tests The volume of evidence, especially expert guidelines, has become unmanageable Quiet ER shift saw 18 patients 44 conditions. 3,679 pages of guidelines only from the last 3 years. Read, remembered and applied correctly. 122 hours spent reading guidelines for the one shift. Surveyed diabetic specialists in Denmark about new guidelines patients with PAD in Denmark No 44% aspirin reported 41.9% guidelines would not be read No 35% statin insufficient 27.6% evidence base 56% reported the guideline were too rigid % said AHA/ACCP that they did PAD not like guidelines imposed published activities Crisis in Evidence based medicine No difference in clinical practice BMJ 2014; 348:3725 Statistically significant benefits may be marginal in clinical practice Ms. D. is a 74 year old who is put on high dose statin because the clinician applies a fragment of the guideline uncritically and who as a result develops muscle pains that interfere with her hobbies. Care shifts away from the patient (Ms. D) to subgroups (women aged 70-75) Crisis in Evidence based medicine BMJ 2014; 348:3725 7

8 No difference in Function outcomes following treatment with the Admiral DCB Mean Difference [95% CI] Favors Control PTA Favors IN.PACT Admiral DCB Walking Distance at 12 Mo Walking Speed at 12 Mo -20% -10% 0% 10% 20% Quality of life by EQ-ED index at 12 mo Follow up 30d- 12 mos Treatment assignment Lesion length (mm)* B. Restenosis (%) LEVANT 2 Blinded In.Pact SFA Non - Blinded DCB control DCB control CD-TLR(%) R/T Why is this an outlier? Is there bias involved? Evidence based guidelines often map poorly to complex multi-morbidity A state that defies efforts to produce or apply objective scores, metrics, interventions or guidelines. Management of one disease state may worsen another Vascular surgeons are best at this Crisis in Evidence based medicine BMJ 2014; 348:3725 8

9 Statin β-blocker Aspirin ACE/ARB Metforman Makes the ethical care of the patient its top priority Demands individualized evidence in the format of that clinicians and patents can understand Shares decisions with patients through meaningful conversations Builds on a strong clinician patient relationship and the human aspects of care Applies these principles at the community levels for evidenced based public health Polypharmacy: a necessary evil? We should not be nihilists. Real evidenced based medicine The Bullfrog Micro-Infusion Device (Mercator MedSystems) JVS 2014 INJURY Lumen loss Stretching Recoil Denudation Injury response programs Inflammation Inflammation Leukocyte adherence Recruitment Progenitor cell differentiation Negative remodeling Phenotypic switch: quiescent prolifera ve and synthetic Proliferation Myofibroblast proliferation Neointima Fibrosis Fibrosis Media Lumen Adventitia Microvascular networks Paracrine factors Restenosis Summary Perivascular tissue 9

10 Pre-Revascularization Post-Revascularization Without Angio Post-Infusion With Angio PAD Trials of Adventitial Dexamethasone Baseline angiogram and biomarker blood draw (1/3 of pts) 150 PTA DANCE N= atherectomy SFA and Popliteal Long lesions ISR Rutherford 5 N 1,000 DANCE-R Revascularization N=240 Below the Knee LIMBO (2 Trials) Beginning Q Baseline angiogram and biomarker blood draw 120 PTA and 120 ATX revascularization (2 trials) Adventitial DEX treatment Adventitial DEX treatment 60 controls (each) 60 DEX treatment (each) 20% contrast, 80% drug Bullfrog Infusion (DANCE Trial of Adventitial Dexamethasone) 24-hour blood draw for biomarkers (1/3 of pts) 1-month blood draw for biomarkers (1/3 of pts) Clinical, hemodynamic and duplex 38 U/S follow-up at 6, 12, 18, 24 months Clinical, hemodynamic and duplex U/S follow-up at 12 months 24-hour blood draw for biomarkers 1-month blood draw for biomarkers Clinical, hemodynamic and angiographic follow-up at 6 months 10