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Blood Pressure Targets in Nephrology

Is it time to reassess our goals ?

Dominique Guerrot

Nephrology Department & INSERM U1096 - Rouen University Hospital

Actualités Néphrologiques - Paris - April 24th, 2017

U1096

@dguerrot

COI Disclosure – D.Guerrot

• Travel & accommodation support

Roche, Amgen, Servier, Daiichi Sankyo,

Otsuka, Shire, Alexion, Sanofi, Vifor-Fresenius

• Industrial research funding

Amgen

• Honoraria

0

Hypertension : 1st modifiable cause of mortality

Ezzati et al. Lancet 2002

Blood pressure and CV mortality

Meta analysis

61 obs. studies

N = 958074

Perspective studies collaboration, Lancet 2002

Framingham: BP and CV mortality

Vasan et al. NEJM 2001

Observational studies

Interventional trials

Meta analysis - 2015

Ettehad et al. Lancet 2015

Expected effects of a decrease in BP

The lower the better … or not?

Staessen et al. Lancet 2001

Is there an optimal target ?

Arguedas et al. Cochrane 2009

Arguedas et al. Cochrane 2009

Conclusion…

Arguedas et al. Cochrane Database Syst 2009

Landmark studies

Design

• Open RCT

• 2 SBP targets

– « Standard » < 140 mm Hg

– « Intensive » < 120 mm Hg

• Objectives

– Primary : Composite / MI, angina, stroke, HF, CV mortality

– Secondary

Inclusion criteria (n=3)

Main exclusion criteria (n=20)

• Standing SBP < 110 mmHg

• Diabetes mellitus

• Stroke

• LVEF < 35% or instable HF

• eGFR < 20 ml/min

• Proteinuria > 1g/24h, GN, ADPKD

• Frail elderly patients

Systolic Blood Pressure

Study stopped

Mean follow-up 3.26 y

Primary outcome (composite)

Secondary outcomes : all-cause mortality

Which practical conclusion does SPRINT suggest ?

High CV risk patients + SBP > 130 mmHg

Antihypertensive therapy

SBP target < 120 mmHg

Even if > 75-80 yo …

If we decided to broadly apply SPRINT results …

• Redefinition of uncontrolled hypertensive pts :

• Addition of 1-2 treatments

– Compliance ?

– Tolerance ?

– Potential complications ?

• Closer follow-up unquestionable … feasible ?

If we decided to broadly apply SPRINT results …

Bress et al. JACC 2016

Normandie ? 400 000

In contradiction with the guidelines …

ESH/ESC 2013

In contradiction with the guidelines …

Analysis

• Benefit

– Mainly related to CV mortality and HF

– Not on stroke

– Idem HYVET / SHEP / SYST-Eur

• Direct impact of the target or role of the medications independently of BP ? …

SPRINT : A methodological exception

SPRINT : A methodological exception

Kjeldsen SE et al, Hypertension 2016

Unattended AOBP = Manual office SBP -15 mmHg

Filipovsky et al, Blood Pressure 2016

SPRINT : All-cause death / median SBP reached

Himes B et al. The SPRINT Data Analysis Challenge, NEJM 2017

BP targets in diabetic patients : ACCORD study

ACCORD Study Group, NEJM 2010

SPS3 Study

Benavente OR et al, Lancet 2013

• RCT : 3020 patients with prior stroke

• Follow-up 3.7 y

• Comparison btw SBP <140 mmHg & < 130 mmHg

• Primary objective : recurrence of stroke / cerebral hemorrhage

SPS3 : Main results

Benavente OR et al, Lancet 2013

• Main outcome : NS (HR 0.81, p=0.08)

• MI + CV mortality : NS (HR 0.84, p=0.32)

• Rare adverse effects

HOPE-3 : Patients with milder CV risk

Lonn EM et al., NEJM 2016

• RCT 12705 patients

– Intermediate CV risk (1%/y) (CV mortality 2.2%/y in SPRINT)

– No HTN, or HTN controlled without ACEi/ARB/HCTZ

• Candesartan+HCTZ vs placebo (& Rosuvastatine vs plac)

• 2 composite primary objectives :

– CV mortality, MI, stroke

– Idem + heart arrest, HF, coronary angioplasty

HOPE-3

Lonn EM et al., NEJM 2016

HOPE-3 : Main result

Lonn EM et al., NEJM 2016

• Significant increase in non-severe adverse effects

• Conclusion : No point in treating if initial BP < 140 without prior CV event

NS

HTN & progression of CKD

Klag MJ et al, NEJM 1996

• MRFIT study

• Incidence of ESRD according to initial BP

Hypertension

Chronic Kidney Disease

Prevented by antihypertensive Rx ?

X

Questioning the link … « Hypertensive Nephropathy » ?

International Consortium for Blood Pressure GWAS, Nature 2011

• 200000 caucasian patients

• SNPs associated with HTN

Questioning the link … « Hypertensive Nephropathy » ?

NS

International Consortium for Blood Pressure GWAS, Nature 2011

SPS3 : Effects on eGFR

Peralta et al, Circulation 2016

CKD patients in SPRINT

Aggarwal R et al. The SPRINT Data Analysis Challenge, NEJM 2017

CKD patients in SPRINT : Renal Outcomes

The SPRINT Research Group, NEJM 2015

CKD patients in SPRINT

Aggarwal R et al. The SPRINT Data Analysis Challenge, NEJM 2017

MDRD 1994 • PAS 125 vs 140

• 100% patients IRC ≥ 3

• Négatif / DFG si Pu<1g/j

Positif / DFG si Pu>1g/j

Négatif / Critère CV

AASK 2002 • PAS 128 vs 141

• 100% patients IRC ≥ 3

• Négatif / DFG

Négatif / Critère CV

REIN-2 2005 • PA 130/80 vs PAD 90

• 100% patients IRC ≥ 3

• Négatif / DFG

Négatif / Critère CV

HOPE-3 2016 • PAS 128 vs 134

• 3% patients IRC ≥ 3

• Négatif / DFG

Négatif / Critère CV

SPRINT 2015 • PAS 120 vs 140

• 28% patients IRC ≥ 3

• Négatif / DFG

Positif / Critère CV

SPS3 2013 • PAS 130 vs 140

• 16% patients IRC ≥ 3

• Négatif / DFG

Négatif / Critère CV

ADVANCE 2007 • PAS 135 vs 140

• 19% patients IRC ≥ 3

• Négatif / DFG

Positif / AlbU

ACCORD 2010 • PAS 120 vs 140

• 9% patients IRC ≥ 3

• Négatif / DFG

Négatif / Critère CV

1995 2000 2005 2010 2015 2017

General BP Targets in CKD : Updated EBM in 2017

Tsai WC et al, JAMA Int Med 2017

• 9 RCTs (MDRD, AASK, REIN-2, SPRINT, …)

• 8127 CKD patients

• SBP difference 4-13 mmHg

• Mean follow-up 3.3 y

Rate of GFR decline : NS

Tsai WC et al, JAMA Int Med 2017

ESRD : NS

Tsai WC et al, JAMA Int Med 2017

General recommendations & in CKD

Individualized BP targets in 2017 ?

• Insufficient EBM for a lower general target in CKD

– For renal outcomes

– For CV outcomes & mortality

• Patient-specific target according to ?

– CV risk / age / initial BP

– Diabetes / ADPKD / proteinuria

– Target organ damage

– Rx side-effects

– Patient’s choice & compliance to reinforced follow-up

– ...

En conclusion

Blood Pressure Targets in Nephrology

Is it time to reassess our goals ?

Dominique Guerrot

Nephrology Department & INSERM U1096 - Rouen University Hospital

Actualités Néphrologiques - Paris - April 24th, 2017

U1096

@dguerrot