最新国际心血管临床研究 汇报 acc2014 霍勇 北京大学第一医院. ●...
TRANSCRIPT
最新国际心血管临床研究 汇报 ACC2014
霍勇
北京大学第一医院
●美国心脏病学院年会:
2014 年 3 月 28 日 --31 日,美国华盛顿
主要临床研究:
失望 , 希望并存
共识 , 争议交织
Renal Denervation in Patients with Uncontrolled Hypertension: Results
of the SYMPLICITY HTN 3 Trial
Deepak L. Bhatt, M.D., M.P.H., David E. Kandzari, M.D., William W. O’Neill, M.D., Ralph D'Agostino, Ph.D., John M. Flack, M.D., M.P.H., Barry T. Katzen, M.D., Martin B.
Leon, M.D., Minglei Liu, Ph.D., Laura Mauri, M.D., M.Sc., Manuela Negoita, M.D., Sidney A. Cohen, M.D., Ph.D.,
Suzanne Oparil, M.D., Krishna Rocha-Singh, M.D., Raymond R. Townsend, M.D., George L. Bakris, M.D.,
for the SYMPLICITY HTN-3 Investigators
失望
Trial Objectives
• SYMPLICITY HTN-3 is the first prospective, multi-center, randomized, blinded, sham controlled study to evaluate both the safety and efficacy of percutaneous renal artery denervation in patients with severe treatment-resistant hypertension.
• The trial included 535 patients enrolled by 88 participating US centers.
Bhatt DL, Kandzari DE, O’Neill WW, et al...Bakris GL. N Engl J Med 2014
SYMPLICITY HTN-3 Trial Design
• Office SBP ≥160 mm Hg
• Full doses ≥3 meds
• No med changes in past 2 weeks
• No planned med changes for 6 M
Home BP &HTN med
confirmation
• Office SBP ≥160 mm Hg
• 24-h ABPM SBP ≥135 mm Hg
• Documented med adherence
Screening Visit 1 Screening Visit 2
Renal angiogram;
Eligible subjects
randomized
Home BP &HTN med
confirmation
Home BP &HTN med
confirmation
Primary endpoint
2 weeks
2 weeks
Sham Procedure
Renal Denervation
1 M
1 M 3 M
3 M 6 M
6 M 12-60 M
• Patients, BP assessors, and study personnel all blinded to treatment status
• No changes in medications for 6 M
2 weeks
Bhatt DL, Kandzari DE, O’Neill WW, et al...Bakris GL. N Engl J Med 2014
Patient Disposition
1441 subjects assessed for eligibility
Excluded:•880 not eligible for randomization•26 eligible but not randomized because randomization cap was reached
535 subjects randomized
364 subjects randomly allocated to renal
denervation
171 subjects randomly allocated to sham
control
350 (96.2%) subjects with6 month follow-up
169 (98.8%) subjects with 6 month follow-up
• 1 subject died• 1 missed 6-month visit
• 2 subjects died• 1 subject withdrew • 11 missed 6-month
visit
Bhatt DL, Kandzari DE, O’Neill WW, et al...Bakris GL. N Engl J Med 2014
Results: Population Demographics
Characteristicmean ± SD or %
Renal Denervation(N=364)
Sham Procedure(N=171 ) P
Age (years) 57.9 ± 10.4 56.2 ± 11.2 0.09
Male sex (%) 59.1 64.3 0.26
Office systolic blood pressure (mm Hg) 180±16 180±17 0.77
24 hour mean systolic ABPM (mm Hg) 159±13 160±15 0.83
BMI (kg/m2) 34.2 ± 6.5 33.9 ±6.4 0.56Race* (%) 0.57
African American 24.8 29.2 White 73.0 69.6 Medical history (%)
Renal insufficiency (eGFR<60 ml/min/1.73m2) 9.3 9.9 0.88
Renal artery stenosis 1.4 2.3 0.48Obstructive sleep apnea 25.8 31.6 0.18
Stroke 8.0 11.1 0.26
Type 2 diabetes 47.0 40.9 0.19
Hospitalization for hypertensive crisis 22.8 22.2 0.91
Hyperlipidemia 69.2 64.9 0.32
Current smoking 9.9 12.3 0.45*Race also includes Asian, Native American, or other Bhatt DL, Kandzari DE, O’Neill WW, et al...Bakris GL. N Engl J Med 2014
Baseline Hypertensive Therapy
Characteristicmean ± SD or %
Renal Denervation(N=364)
Sham Procedure(N=171 )
No. of antihypertensive medications 5.1 ± 1.4 5.2 ± 1.4 Angiotensin-converting enzyme inhibitors % at max tolerated dose
49.245.9
41.537.4
Angiotensin receptor blockers % at max tolerated dose
50.049.5
53.251.5
Aldosterone antagonists 22.5 28.7 Alpha-adrenergic blockers 11.0 13.5 Beta blockers 85.2 86.0 Calcium channel blockers % at max tolerated dose
69.857.1
73.163.7
Centrally-acting sympatholytics 49.2 43.9 Diuretics % at max tolerated dose
99.796.4
10097.7
Direct renin inhibitors 7.1 7.0 Direct-acting vasodilators 36.8 45.0
Bhatt DL, Kandzari DE, O’Neill WW, et al...Bakris GL. N Engl J Med 2014
Primary Efficacy Endpoint
Δ = -14.1±23.9
P<0.001
Δ = -11.7±25.9
P<0.001
Δ = -2.39 (95% CI, -6.89 to 2.12)
P=0.26*
(N=364) (N=171)
Offi
ce S
BP
(m
m H
g)
(N=353) (N=171)
180 mm Hg
166 mm Hg
180 mm Hg
168 mm Hg
*P value for superiority with a 5 mm Hg margin; bars denote standard deviations Bhatt DL, Kandzari DE, O’Neill WW, et al...Bakris GL. N Engl J Med 2014
Safety Event Rate
Safety Measures (%) Renal Denervation
(N=364)
Sham Procedure
(N=171)
Difference(95% CI)
P
Major Adverse Events 1.4 0.6 0.8 (-0.9, 2.5) 0.67To 6 Months 6-Month Composite Safety 4.0 5.8 -1.9 (-6.0, 2.2) 0.37
Death 0.6 0.6 0.0 (-1.4, 1.4) 1.00 Myocardial infarction 1.7 1.8 0.0 (-2.4, 2.3) 1.00 New onset ESRD 0 0 - -Serum creatinine elevation >50% 1.4 0.6 0.8 (-0.8, 2.5) 0.67 Embolic event resulting in end-organ
damage 0.3 0 0.3 (-0.3, 0.8) 1.00
Renal artery intervention 0 0 - -Vascular complication requiring treatment 0.3 0 0.3 (-0.3, 0.8) 1.00 Hypertensive crisis/emergency 2.6 5.3 -2.7 (-6.4, 1.0) 0.13 Stroke 1.1 1.2 0.0 (-2.0, 1.9) 1.00 Hospitalization for new onset heart failure 2.6 1.8 0.8 (-1.8, 3.4) 0.76 Hospitalization for atrial fibrillation 1.4 0.6 0.8 (-0.8, 2.5) 0.67 New renal artery stenosis >70% 0.3 0 0.3 (-0.3, 0.9) 1.00
Bhatt DL, Kandzari DE, O’Neill WW, et al...Bakris GL. N Engl J Med 2014
Potential Limitations
• Drug adherence not measured by blood levels, but adherence was measured by patient diaries at baseline and 6 months.
• Medication changes did occur, but results unchanged even when these patients were censored.
• Duration of primary endpoint may have been too short, but prior studies had found benefit by 6 months.
• Operator learning curve is always a possibility, but we found no relationship with procedural volume in the trial.
• Biological confirmation of denervation did not occur, as there is no accepted measure, but appropriate energy delivery was confirmed.
Bhatt DL, Kandzari DE, O’Neill WW, et al...Bakris GL. N Engl J Med 2014
希望
LONG-TERM SURVIVAL WITH CARDIAC RESYNCHRONIZATION THERAPY IN
MILD HEART FAILURE PATIENTS
LONG-TERM SURVIVAL WITH CARDIAC RESYNCHRONIZATION THERAPY IN
MILD HEART FAILURE PATIENTS
Ilan Goldenberg, MD, Valentina Kutyifa, MD, Ilan Goldenberg, MD, Valentina Kutyifa, MD, PhD, Helmut Klein, MD, Scott McNitt, MA, Mary PhD, Helmut Klein, MD, Scott McNitt, MA, Mary Brown, MA, Arthur J. Moss, MD; and the MADIT-Brown, MA, Arthur J. Moss, MD; and the MADIT-CRT LTFU Executive CommitteeCRT LTFU Executive CommitteeFrom the Cardiology Division of the Department of From the Cardiology Division of the Department of Medicine (I.G., VK, HK, SM, AJ.M) University of Medicine (I.G., VK, HK, SM, AJ.M) University of Rochester Medical Rochester Medical Center, Rochester, N.Y.; and Leviev Center, Rochester, N.Y.; and Leviev Heart Center, Sheba Medical Center and Tel Aviv Heart Center, Sheba Medical Center and Tel Aviv University, Israel (I.G.)University, Israel (I.G.)
共识共识
BACKGROUND: MADIT-CRTBACKGROUND: MADIT-CRT
1820 ICM/NICM pts:1820 ICM/NICM pts: EF ≤ 30%EF ≤ 30% QRS ≥ 130 msecQRS ≥ 130 msec NYHA I/IINYHA I/II
Randomization:Randomization: CRT-D vs. ICD-onlyCRT-D vs. ICD-only 3:2 ratio3:2 ratio
Mean Follow-up:Mean Follow-up: 2.4 yrs2.4 yrs
Outcome:Outcome: HR=0.66 (p=0.001)HR=0.66 (p=0.001)
MADIT-CRT: SUBGROUP ANALYSISMoss et al. NEJM, 2009
MADIT-CRT: SUBGROUP ANALYSISMoss et al. NEJM, 2009
Differential Differential clinical clinical response:response: GenderGenderQRS durationQRS duration
STUDY PURPOSESTUDY PURPOSE
We hypothesized that the pronounced We hypothesized that the pronounced reduction in heart failure events reduction in heart failure events associated with CRT during the in-trial associated with CRT during the in-trial period of MADIT-CRT would translate into period of MADIT-CRT would translate into a long-term survival benefita long-term survival benefit
FOLLOW-UP DATAFOLLOW-UP DATA
Follow-up time:Follow-up time: In-trial: 2.4 yrs (IQR = 1.8 – 3.2)In-trial: 2.4 yrs (IQR = 1.8 – 3.2) Post-trial: 5.6 years (IQR = 5.1 – 6.4)Post-trial: 5.6 years (IQR = 5.1 – 6.4)
Device change:Device change: ICD to CRT-D: 9%ICD to CRT-D: 9% CRT-D to ICD: 5%CRT-D to ICD: 5%
Clinical events: Clinical events: 292 pts died (16%)292 pts died (16%) 442 pts experienced a non-fatal HF event 442 pts experienced a non-fatal HF event
(24%)(24%)
LBBB: ALL-CAUSE MORTALITYLBBB: ALL-CAUSE MORTALITY
NNT = 9NNT = 9
LBBB: NON-FATAL HF EVENTSLBBB: NON-FATAL HF EVENTS
NLBBBNLBBB
ALL-CAUSE MORTALITYALL-CAUSE MORTALITY NON-FATAL HF EVENTSNON-FATAL HF EVENTS
LBBB: SUBGROUP ANALYSISLBBB: SUBGROUP ANALYSIS
NLBBB: SUBGROUP ANALYSISNLBBB: SUBGROUP ANALYSIS
CONCLUSIONSCONCLUSIONS
In patients with heart failure symptoms, In patients with heart failure symptoms, left ventricular dysfunction, and LBBB, left ventricular dysfunction, and LBBB, early intervention with CRT is associated early intervention with CRT is associated with a significant long-term survival with a significant long-term survival benefitbenefit
No clinical benefit in heart failure No clinical benefit in heart failure patients without LBBBpatients without LBBB
Dr Adeel ShahzadDr Rod Stables (PI)
Liverpool Heart and Chest HospitalLiverpool, UK
How Effective areAntithrombotic Therapies in PPCI
争议
1917 patients scheduled for emergency angiography
29 (1.5%) already randomised in the trial59 (3.0%) met one or more other exclusion criteria
1829 eligible for recruitment
1829 Randomised
Representative ‘Real-World’ Population
Assigned to Heparin 914
Included in analysis 907
915 Assigned to Bivalirudin
905 Included in analysis
Consent not available in surviving patients
Consent not available in surviving patients
7 10
Received allocated Rx 900 Received no study drug 14
Treatment cross-over 0LMWH pre-procedure 3
907 Received allocated Rx7 Received no study
drug1 Treatment cross-over 4 LMWH pre-procedure
Characteristic Bivalirudin Heparin
Median age (years) 62.9 63.6
Female sex (%) 28.5 26.9
Caucasian race (%) 95.8 95.9
Diabetes mellitus (%) 12.6 15.1
Previous MI (%) 13.5 10.3
eGFR (ml/min/1.73m2) 80.0 80.0
Haemoglobin (g/dl) 13.6 13.7
Characteristic Bivalirudin (%) Heparin (%)
P2Y12 use - Any 99.6 99.5
- Clopidogrel 11.8 10.0
- Prasugrel 27.3 27.6
- Ticagrelor 61.2 62.7
GPI use 13.5 15.5
Radial arterial access 80.3 82.0
PCI performed 83.0 81.6
Characteristic Bivalirudin (%) Heparin (%)
Thrombectomy 59.1 57.6
Single vessel Tx 93.2 90.3
Any stent implant 92.8 92.2
DES implantation 79.8 79.9
TIMI III flow - post PCI 93.3 92.7
Event curve shows first event experienced
Bivalirudin Heparinn % % n
Death 46 5.1 % v 4.3 % 39
CVA 15 1.6% v 1.2% 11
Reinfarction 24 2.7% v 0.9% 8
TLR 24 2.7% v 0.7% 6
Any MACE 79 8.7 % v 5.7 % 52
Bivalirudin Heparinn % % n
Definite 23 3.3 % v 0.7 % 5
Probable 1 0.1 % v 0.1 % 1
Acute 20 2.9 % v 0.9 % 6
Subacute 4 0.6% v 0% 0
ARC definite or probable stent thrombosis events
Bivalirudin Heparinn % % n
Major Bleed 32 3.5 % v 3.1 % 28
Relative risk = 1.15 (95% CI 0.7 - 1.9) P=0.59
Major Bleed BARC grade 3-5
• Single centre
• Open label
• Potential impact minimised by:
• Complete follow-up - No ‘lost’ cases
• Outcome measures were overt clinical events
• Most MI events involved angiographic imaging
• Independent blinded adjudication
• Open label used in HORIZONS and EUROMAX
•在失望中带来希望•在争议中达成共识
xiexie !