The higher the better? The J shaped
curve of blood pressure
16th May 2017
RCP London
Adrian J.B. Brady MD, FRCP(Glasg), FRCPE, FBHS, FESC, FAHA
Associate Professor, University of Glasgow
Consultant Cardiologist
Glasgow, UK
President, British and Irish Hypertension Society
European Society of Cardiology Global Spokesperson for Hypertension
British Cardiovascular Society Council
Disclosures:
Research grants from: AstraZeneca, Bayer,
Boehringer Ingelheim, Merck,
Roche, Servier
Honoraria/Consultancy:
AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Pfizer, Servier
Question: Which risk factor accounts for the most CV disease
according to the World Health Organisation?
• 1. Smoking
• 2. Dyslipidaemia
• 3. Family History of
CVD
• 4. Obesity
• 5. Diabetes
• 6. Hypertension
• 7. Low birth Weight
• 8. Urban pollution
Which risk factor accounts for the most CV disease according to
the World Health Organisation?
How much conference time does ESC Congress allow for
Hypertension?
•
•
•
•
•
5%
10%
12%
15%
19%
How much conference time does ESC Congress allow for
Hypertension?
•
•
•
•
•
5%
10%
12%
15%
19% correct answer
Blood Pressure Study 1939
The J shaped curve
Cruickshank JM Lancet 1987
902 patients treated for 10 years with
atenolol and other agents. 91 deaths
(40 MI) J curve confined to IHD
patients below 85 mmHg
‘Physiological’ Basis
• CAUSES
CONSEQUENCES
↓Myocardial capillary density → Ischaemia
↓Autoregulation and perfusion → Infarction
↓Cerebral perfusion →
Stroke
↓Renal perfusion
→
↓Renal function
Pharmacotherapy for hypertension in the elderly
Vijaya M Musini1,*, Aaron M Tejani2, Ken Bassett1, James M Wright1
Editorial Group: Cochrane Hypertension Group
Published Online: 7 OCT 2009
Cerebrovascular mortality in the very elderly
patients with hypertension
Coronary heart disease mortality
in the very elderly

Case report: Mrs PC 76
HT 15y

Atenolol 100 mg, Enalapril 20 mg,
Amlodipine 10 mg, Doxazosin 8 mg,
Bendroflumethiazide 2.5 mg, Amiloride 5 mg.
Referred for specialist opinion
177/79 mm Hg
Heart sounds normal; heart rate 88, regular



Case report: Mrs PC
76 HT 15y

Admitted as day case
– given her own
medication
Collapse in hospital
shop
 BP 70/40 mm Hg


48 y.o man
134/93 mm Hg on Losartan 100 mg o.d.

GP added Diltiazem 180 mg S/R o.d.



Occasionally dizzy
10 kg wt loss

3/52 later:
10 Km run at 13.00
17.00 hypotensive blackout while driving

ABPM off therapy 100/70 mm Hg


JAMA Intern Med. doi:10.1001/jamainternmed.2013.14764
Published online February 24, 2014.
JAMA Intern Med. doi:10.1001/jamainternmed.2013.14764
Published online February 24, 2014.
On-treatment DBP and prognosis in
Syst-Eur
 On-Treatment Diastolic Blood Pressure
and Prognosis in Systolic Hypertension
 Fagard et al.
 Arch Intern Med 2007; 167: 1884-1891
SYST-EUR Trial
1. Inclusion criteria
•
•
•
•
•
Age: >60 years
Sitting SBP: 160-219 mmHg*
Sitting DBP: <95 mmHg*
Standing SBP: >140 mmHg*
Follow-up feasible: informed consent/stable
living conditions
* Averge of 6 readings, i.e. 2 at each of 3 run-in visits
Staessen J. et al. Lancet 1997; 350:757-764
SYST-EUR Trial
2. Patient population = 4695 randomised patients
12 Western and 10 Eastern European countries (% of patients)
Finland
Bulgaria
Russia
Belgium
Italy
Israel
UK
France
26.9
22.2
6.8
5.8
4.8
4.5
4.5
3.7
Staessen J et al. Lancet 1997; 350:757-764
Estonia
Lithuania
Spain
Poland
Romania
Netherlands
Greece
Ireland
3.4
3.3
3.0
2.7
2.2
1.4
1.3
0.8
Portugal
Belorussia
Czech Rep.
Slovakia
Slovenia
Germany
Croatia
0.7
0.5
0.4
0.4
0.4
0.2
0.1
SYST-EUR Trial
7. End-points
Events per 100 patients
Fatal and non-fatal stroke
6
Active treatment
5
Placebo
Fatal and non-fatal
myocardial infarction
4
3
2
1
0
0
1
2
3
4
0
1
Time since randomisation (years)
Staessen J et al. Lancet 1997; 350:757-764
2
3
4
Adjusted hazard ratio for CV events in relation
to on-treatment diastolic BP in Syst-Eur

Arch Intern Med
2007; 167: 18841891


On-treatment DBP and prognosis in
Syst-Eur
Conclusions
Antihypertensive treatment can be intensified for the
prevention of cardiovascular events when systolic BP
is not under control in older patients with systolic
hypertension, at least until diastolic BP reaches 55
mmHg.
However, a prudent approach is warranted in
patients with concomitant coronary heart disease in
whom diastolic BP should probably not be lowered to
less than 70 mmHg.
Arch Intern Med 2007; 167: 1884-1891
Canadian Hypertension Education
Program 2014
 New Recommendation: ‘When
decreasing SBP to target levels in
patients with established CHD (especially
if systolic hypertension is present) be
cautious when the DBP is ≤ 60mmHg
because of concerns that myocardial
ischaemia might be exacerbated.
 (Grade D) – weakest evidence based on
low power, imprecise studies or expert
opinion alone
A.The effects of reducing coronary perfusion pressure by intravenous
infusion of nitroprusside on coronary blood flow (measured in the great
cardiac vein) in hypertensive patients with and without left ventricular
hypertrophy (LVH).
Mancia G , and Grassi G Hypertension. 2014;63:29-36
INVEST trial:
systolic blood pressure (SBP) remained ≥140 mm Hg or was reduced to between 130
and 139 mm Hg and <130 mm Hg (left).
Mancia G , and Grassi G Hypertension. 2014;63:29-36
Unadjusted (A) and adjusted (B) relation between achieved (average in-treatment) diastolic blood
pressure and risk of primary outcome in hypertensive patients with coronary artery disease enrolled
in the International Verapamil-Trandolapril Study.
Verdecchia P et al. Hypertension. 2014;63:37-40
Copyright © American Heart Association, Inc. All rights reserved.
Background
POSITION STATEMENT
DIABETIC PATIENTS:
current HTN treatment
guidelines
SBP <130 mm Hg
“there is no threshold
value for BP, and risk
continues to decrease
well into the normal
range”
Evidence supporting
SBP <130 mm Hg is
lacking, particularly in
diabetic patients with
CAD
Diabetes Care. 2010;33 Suppl 1:S11-61, Hypertension. 2003;42(6):1206-1252, Diabetes Care. 2002;25(1):199-201
Results – BP Reduction
Mortality – DBP US Diabetics
(floating absolute risk and 95% CI)
IHD Mortality
Ischemic Heart Disease Mortality Rate in Each Decade
of Age vs Usual BP at the Start of that Decade
Age at Risk:
80-89
256
Age at Risk:
256
80-89
70-79
70-79
60-69
32
32
60-69
50-59
50-59
40-49
4
4
0
0
120
140
160
Usual SBP (mmHg)
Prospective Studies Collaboration, Lancet, v.360, Dec. 14, 2002
180
40-49
70
80
90
100
Usual DBP (mmHg)
110
(floating absolute risk and 95% CI)
IHD Mortality
Ischemic Heart Disease Mortality Rate in Each Decade
of Age vs Usual BP at the Start of that Decade
Age at Risk:
80-89
256
Age at Risk:
256
80-89
70-79
70-79
60-69
32
32
60-69
50-59
50-59
40-49
4
4
0
0
120
140
160
Usual SBP (mmHg)
Prospective Studies Collaboration, Lancet, v.360, Dec. 14, 2002
180
40-49
70
80
90
100
Usual DBP (mmHg)
110
INVEST Subanalysis: BP and Risk: 22,576 patients with HT and CHD
DBP: Risk for Primary Outcome
6
Nadir = 84.1 mm Hg
Hazard Ratio
Primary Outcome
40
5
4
30
3
20
2
10
1
0
0
DBP (mm Hg)
Total patients
176
2239
11306
7376
1230
248
Estimated
Ratio
Hazard Ratio
Estimated Hazard
Incidence (%) of Primary Outcome
50
INVEST Subanalysis: BP and Risk
SBP/DBP: Risk for Primary Outcome
6
6
Nadir = 84.1 mm Hg
Nadir = 119.2 mm Hg
4
2
2
0
0
Hazard Ratio
4
105
115 125 135
145 155 165
SBP (mm Hg)
55
65
75
85
DBP (mm Hg)
95
105
INVEST Subanalysis: BP and Risk
DBP: Risk for All-Cause Death
Nadir = 85.8 mm Hg
All-Cause Death
Mortality (%)
40
66
Hazard Ratio
5
44
30
3
20
22
10
1
0
00
DBP (mm Hg)
Total patients
176
2253
11339
7367
1201
240
Hazard Ratio
EstimatedHazard
Ratio
Estimated
50
INVEST Subanalysis: BP and Risk
Stroke / MI and DBP Strata
20
Incidence (%) of MI/Stroke
MI
Stroke
15
10
5
0
DBP (mm Hg)
J-Curve HOT Study
Non-Ischemic
MI per 1000 Patient Years
10
Ischemic
9
8
7
6
5
4
3
2
1
0
< 80
< 85
< 90
DBP (mmHg)
CruickshankJM, Hannson L,CV Drugs Therapy
2000;14,373.
Valsartan Antihypertensive Long-Term Use Evaluation
15,313 randomised at 942 sites in 31 countries
Average follow up 4.2 years
Julius S et al. Lancet. June 2004;363.
CV events by BP in Coronary artery disease studies
INVEST
(CAD pts)
50
40
30
20
3
(high risk pts, mainly with CAD)
CV events (%)
CV events (%)
ONTARGET
30
20
2
10
1
Adjusted HR
60
10
110
0
>110 >120 >130 >140 >150 >160
to 120 to 130 to 140 to 150 to 160
0
1 12
On-treatment SBP (mmHg)
30
1 26 13 0
13 3
13 6
14 0 1 44
1 49
1 60
On- treatment SBP (mmHg)
VALUE
TNT
35
(High risk pts)
5
(CAD pts)
30
CV events (%)
Cardiac events (%)
1 21
20
10
4
25
3
20
15
2
10
1
5
0
< 120
>120 >130 >140 >150 >160 >170 = 180
to 130 to 140 to 150 to 160 to 170 to 180
On-treatment SBP (mmHg)
14276 M
0
0
= 60
61-70
71-80
81-90
91-100
On-treatment DBP (mmHg)
> 100
Adjusted HR
0
Ropsomaniki et al (Lancet 2014)
 1.25 million patients
 5.2 years median follow up – 83,098 CV
presentations
 Lowest risk 90-114/60-74mmHg
 NO J-shaped increased risk at low
pressures
9361 persons with SBP of 130mmHg or
higher and increased CV risk,
but without diabetes
N Engl J Med 2015; 373: 2103-16
Study stopped early due to
benefit of intensive Rx
3.3 years of the planned 5 years
N Engl J Med 2015; 373: 2103-16
SPRINT Inclusion and Exclusion Criteria
Major Inclusion Criteria
Major Exclusion Criteria
•
≥50 years old
• Stroke
•
SBP: 130 – 180 mm Hg (treated or untreated)
• Diabetes mellitus
•
Additional CVD risk:
– Clinical or subclinical CVD (excluding stroke)
– Chronic kidney disease (eGFR 20 – <60 l/min/1.73m2)
– Framingham 10-year CVD risk ≥ 15%
• Polycystic kidney disease
• Congestive heart failure (symptoms or EF < 35%)
• Proteinuria >1g/d
• CKD with eGFR < 20 mL/min/1.73m2 (MDRD)
• Adherence concerns
– Age ≥ 75 years
14,692 screened
9,361 randomized
High participation rate (loss to follow-up, withdrawal of consent, and discontinuation of intervention less than expected)
Selected Baseline Characteristics
Distribution almost identical in the two treatment groups
Total (N=9361)
Mean age, years (% ≥ 75 y)
Female, %
African-American, %
Taking antihypertensive meds, % (Mean # meds)
Mean Systolic/Diastolic BP, mm Hg
67.9 (28.2%)
35.6%
29.9%
90.6% (1.8)
139.7/78.1
Prevalence of CVD, %
20.1%
Mean 10-year Framingham CVD risk, %
20.1%
Mean eGFR (% eGFR<60), ml/min/1.73m2
71.7 (28.3)
Screening SBP = 130 mmHg
Intensive Rx
Standard Rx
More Rx to 120mmHg
Rx withdrawn at 140mmHg
N Engl J Med 2015; 373: 2103-16
SBP, systolic blood pressure
Drugs Average 2.8 v 1.8
35
30
% Taking Drugs
25
20
15
10
5
0
0 Drugs
1 Drug
Intensive
N Engl J Med 2015; 373: 2103-16
2 Drugs
Standard
3 Drugs
4 Drugs+
Achieved BP 122 v 135 mmHg
N Engl J Med 2015; 373: 2103-16
SPRINT Benefits after 1 year:
primary end point
N Engl J Med 2015; 373: 2103-16
SPRINT All-cause Mortality
Cumulative Hazard
Hazard Ratio = 0.73 (95% CI: 0.60 to 0.90)
Standard
deaths)
Adapt from Figure 2B in the(210
N Engl
J Med manuscript
Intensive
(155 deaths)
Include
NNT
During
Trial (median follow-up = 3.26 years)
Number Needed to Treat (NNT)
to Prevent a death = 90
Number of
Participants
N Engl J Med 2015; 373: 2103-16
Experience in the Six Pre-specified Subgroups of Interest
Primary Outcome (CVD Composite)
All Cause Mortality
(Treatment by subgroup interaction)
*
The SPRINT Research Group. N Engl J Med. 2015;373:2103-2116
*p=0.34, after Hommel adjustment for multiple comparisons
SPRINT Primary Outcome by Frailty Status
Participants ≥75 years: Kaplan-Meier Survival Curves
HR: 0.47 (95% CI: 0.13 to 1.39)
HR: 0.63 (95% CI: 0.43 to 0.91)
HR: 0.68 (95% CI: 0.45 to
1.01)
p for interaction = 0.84
SPRINT Research Group. SPRINT Research Group. JAMA.2016;315:2673-2682.
Generalizing from SPRINT
•
Always challenging to generalize from “efficacy” trials to clinical practice
•
In US, lower BP than currently recommended seems sensible in many “high risk” adults
– Especially in those with a profile like the participants in SPRINT
– Clinical judgement and patient preference central to treatment intensity decisions
•
Meta-analyses (and SPRINT experience) suggest lower BP may be appropriate during treatment of
high CVD risk patients with hypertension in other populations with an ischemic pattern of CVD
•
Canadian BP GL recommends SPRINT BP target in high-risk patients ≥50 y with SBP ≥130 mm Hg
Leung AA et al. Can J Cardiol. 2016;32:569-588 & and Padwal R et al. Hypertension. 2016;68:3-5
•
US ACC/AHA BP Guideline expected in early 2017
•
UK: new NICE/BHS guidance 2017
META-ANALYSIS OF VASCULAR EVENTS IN
MAJOR BP LOWERING TRIALS
The Lancet 2016 387, DOI: (10.1016/S0140-6736(16)30366-X)
Copyright © 2016 Elsevier Ltd Terms and Conditions
Xie et al Lancet June 4th 2016
A
6 (131)
B
C
1
5 (530)
Standard Arm
Intensive Arm
2
3 (866)
Primary (N=478)
MI (N=193)
Non MI ACS (N=7
Stroke (N=108)
Heart Failure (N=
CVD death (N=65
Death (N=242)
Primary/death
(N=606)
3
2
1
3
4 (3924)
4
6
5
2 (225)
1
(346
6)
5
*
4
6
1
H
5
P Value < 0.05
Detrimental effect of four or more drug classes to achieve blood pressure control in
SPRINT – unpublished, Padmanhaban S, et al.
Published Online April 2, 2016 DOI: 10.1056/NEJMoa1600175
Clarify registry; 22672 Pat, stable angina, treated hypertension
3. Conclusions
 There is probably a J-Curve at around 60
mmHg diastolic BP
 The data suggest excess mortality and
morbidity is going to occur in frail elderly
and these individuals may not benefit as
much from aggressive risk reduction
programmes
 We should monitor diastolic pressure
closely when < 65mmHg