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 ！