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Isser HS, et al
18. Akhras F, Dubrey S, Gazzard B, et al. Emerging patterns of
heart disease in HIV-infected homosexual subjects with and
without opportunistic infections: A prospective colour flow
D o p p l e r e c h o c a r d i o g r a p h i c s t u d y. E u r H e a r t J .
1994;15(1):68–75.
Review Article
19. Vemuri DN, Robbins MJ, Boals BH. Does human
immunodeficiency virus infection alter the course of infective
endocarditis? J Am Coll Cardiol. 1990;15:183A.
Address for correspondence:
Is there a J-curve for hypertension and cardiovascular disease?
How low can one go?
Dr. Isser HS
Email ID: [email protected]
Dr. Iyengar SS, DM Cardiology
Consultant in Cardiology, Manipal Hospital, Bangalore
Abstract
Guidelines on management of hypertension have
laid down the blood pressure levels at which one
should start treating hypertension and what
should be the goals. There is an ongoing debate
whether the relationship between BP levels and
cardiovascular events is a linear one or J-shaped.
There are studies to support either side. While
some argue that lower is better, some advocate
caution that beyond a particular point of low BP,
there is an increased risk of cardiovascular
events. J-curve probably exists for diastolic blood
pressure in an elderly patient with hypertension
and coronary artery disease. However, recent
studies published this year seem to counter the
concept of J-curve phenomenon.
In the field of hypertension, we are going to look at the
relationship between the blood pressure (BP) levels and
cardiovascular (CV) event rates. The J-curve
phenomenon is a paradoxical increase in morbidity and
mortality with an excessive decrease in BP.
BP treatment guidelines have recommended BP
thresholds to commence treatment and also the BP goals
have been defined. However, there is a debate as to how
low one can go to achieve optimal benefit from treatment.
There is a concern that the therapeutic harm/benefit
equation might tilt towards harm if there is aggressive BP
lowering in certain individuals, in certain situations and
in certain organs. The debate of J-curve phenomena
started in 1979 and there is still no definitive answer.
Factors supporting the J-curve phenomenon
• Hypertension
Though there is no undisputable evidence for the
existence of the J-curve phenomenon, it is supported by
common sense (BP value below which organ perfusion is
compromised is bound to exist), physiological data, and
observational studies.
• J-curve
J-curve may have different pathophysiological
mechanisms such as:
 Key Words
• CVD
 Introduction
The term J-curve is commonly used in the world of
economics, where the openness of the economy of the
nation shows a J-shaped relationship with the political
stability of the country and many believe that the J-curve
is a new way to understand why nations rise and fall!
• It may be an epiphenomenon of a more severe
underlying disease, low BP being a marker of the
illness, thereby increasing mortality
• Low BP may be due to underlying impaired cardiac
function
Received: 16-11-2015; Revised: 18-11-2015; Accepted: 20-11-2015
Disclosures: This article has not received any funding and has no vested commercial interest
Acknowledgments: None
826
J. Preventive Cardiology Vol. 5
No. 2
Nov 2015
J. Preventive Cardiology Vol. 5
No. 2
Nov 2015
827
This also has a clinical correlation where studies have
shown that the CV event rates have a J-shaped
relationship with diastolic BP levels in patients with
coronary artery disease (CAD) who did not undergo
coronary revascularization compared with those who
were revascularized (Figure 1).2
A
HT without LVH
HT with LVH
Flow (mL/min)
Data from the ONTARGET trial showed that patients
who showed BP reduction to less than 130/80, more
often exhibited J-shaped response during their visits
3
(Figure 2).
In the INVEST study, the data on 6400 patients of
diabetes compared the outcome in subjects in whom
systolic BP remained 140 mmHg or more, with those
where systolic BP was reduced to between 130 and 139
and less than 130 mmHg. The all-cause mortality
increased in patients with systolic BP less than 120
mmHg.4
The PRoFESS trial studied 20,332 patients with a
5
history of stroke. The group with on-treatment BP
values between 130 and 139 mmHg was taken as
reference. The patients with systolic BP more than 150
mmHg showed decreasing risk of CV events up to the
reference level of 130 to 139. Systolic BP levels falling
below the reference levels again showed an increase in
risk of CV events.
160
140
120
100
80
In TNT study on 10,001 patients with CAD, low BP
(110–120/60–70) portends an increased risk of future
6
CV events (other than stroke) (Figure 2).
60
60
80
70
90
100
110
Coronary pertusion pressure (mmHg)
Evidence against the J-curve phenomenon:
B
With revascularization
Without revascularization
6
Hazard ratio
5
In a study of 61 prospective trials involving one million
adults in the age group of 40 to 89 years with no
previous vascular disease, it was clearly shown that
systolic blood pressure (SBP) and diastolic blood
pressure (DBP) are strongly and directly related to
vascular and overall mortality without evidence of
7
threshold down to 115/75 mmHg.
4
3
2
1
8
0
50
60
70
80
90
100
DBP (mmHg)
110
120
Figure 1: 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
828
In the UKPDS trial, effect of BP control was studied
between patients with tight (BP 144/82 mmHg) vs. less
tight (154/87 mmHg) control. These were 1148 Type II
diabetic patients with 9 years follow up. Patients with
tight control of BP showed significant risk reduction in
stroke, heart failure, micro-vascular disease, any
diabetic-related endpoint, and diabetes-related deaths.
J. Preventive Cardiology Vol. 5
No. 2
Nov 2015
Relative hazard, x 800 000
In the INVEST study, 22,576 patients of hypertension
with CAD were studied and the incidence of
myocardial infarction (MI) clearly showed the J-curve
phenomenon (almost U-shaped), whereas incidence of
stroke did not show the J-curve.2
(high risk pts, mainly with CAD)
20
2
10
1
0
112 121 126 130 135 136 140 144 149 160
On treatment SBP [mmHg]
100
80 Unadjusted
60
40
20
0
0
50
60
70
80
90
100
110
120
DBP, mmHg
B 35
B
5
TNT
(CAD patients)
30
4
25
20
3
15
2
10
1
5
0
60
61-70
71-80
81-90
91-100
>100
0
100
Relative hazard, x 2200
The effects of reducing coronary perfusion pressure by
intravenous infusion of nitroprusside on coronary
blood flow (measured in the great cardiac vein) were
studied in hypertensive patients with and without left
ventricular hypertrophy (LVH). In hypertensive
patients without LVH, there is no decrease in coronary
blood flow till the coronary perfusion pressure of 70
mmHg. Whereas in patients with LVH, the coronary
flow showed significant fall with coronary perfusion
pressure at 90 mmHg (Figure 1).1
A
3
Adjusted HR
Clinical studies
ONTARGET
Adjusted HR
Physiological data
A 30
CV events [%]
• J-curve phenomenon may truly be existing
without LVH;1 B) the CV event incidence at different
achieved diastolic blood pressure (DBP) levels in
patients with coronary artery disease (CAD) who did
not undergo coronary revascularization compared with
those who had the procedure.2
• J-curve may be seen in patients with increased
arterial stiffness, low BP being a marker of high
pulse pressure, and hence, the increase in mortality
Is there a J-curve for hypertension and cardiovascular disease? How low can one go?
CV events [%]
Iyengar SS, et al
80
60
40
After adjustment for age, sex, ethnicity, smoking
previous MI, heart failure, BMI, renal failure,
stroke/TIA, peripheral vascular disease,
coronary revascularization, dyslipidemia, cancer,
aspirin use, average blood pressure,
left ventricular hypertrophy, arrhythmia,
residency in US.
20
0
50
60
70
80
90
100
110
120
On treatment DBP [mmHg]
DBP, mmHg
Figure 2: J-curve in the (A) ONTARGET and (B) TNT
studies
Figure 3: Unadjusted (A) and adjusted (B) relation
between achieved (average in-treatment) DBP and risk
of primary outcome in hypertensive patients with
coronary artery disease enrolled in the International
Verapamil-Trandolapril Study
Though there was 21% risk reduction in MI, it was not
statistically significant.
In the HOT study, 18,790 patients from 26 countries in
the age group of 50 to 80 years were studied.9 Intensive
lowering of BP in hypertensive patients was associated
with a low rate of CV events. The study showed the
benefit of lowering DBP down to 82.6 mmHg. The
diabetes subgroup showed similar results.
Wang et al., in an analysis of different trials, studied the
effects of treatment on CV events in three different age
groups, namely, 30–49, 60–79, and ≥80.10 SBP and DBP
lowering clearly showed significant benefit in lowering
the risk of all CV events, fatal and nonfatal stroke, and
fatal and nonfatal MI.
In the INVEST study, the unadjusted data showed the Jcurve phenomenon. But after adjustment for age, gender,
ethnicity, smoking, previous MI, heart failure, BMI,
renal failure, stroke/TIA, peripheral vascular disease,
coronary revascularization, dyslipidemia, cancer,
aspirin use, arrhythmia, and LVH, the J-curve
phenomenon disappeared (Figure 3).2
J. Preventive Cardiology Vol. 5
No. 2
Nov 2015
Limitations of the studies supporting the J-curve
Following are limitations of the studies supporting Jcurve
• Lack of randomization: In the INVEST study,
compared to patients with DBP 81–90 mmHg, those
with less than 60 mmHg were 10 years older, had
previous MI, stroke, heart failure, diabetes, and
cancer.
• There were a small number of patients with low or
very low achieved BP, i.e., a small number of patients
in the ascending limb of J-curve. In the INVEST
study, a DBP of less than 60 mmHg was seen in 176
patients of 22,576 patients, and in TNT study, a BP of
110/60 or less was seen in 396 patients out of 10,001
patients.
• Most of the studies are observational data and post
hoc analysis. Some of the results were unadjusted for
confounding variables.
829
This also has a clinical correlation where studies have
shown that the CV event rates have a J-shaped
relationship with diastolic BP levels in patients with
coronary artery disease (CAD) who did not undergo
coronary revascularization compared with those who
were revascularized (Figure 1).2
A
HT without LVH
HT with LVH
Flow (mL/min)
Data from the ONTARGET trial showed that patients
who showed BP reduction to less than 130/80, more
often exhibited J-shaped response during their visits
(Figure 2).3
In the INVEST study, the data on 6400 patients of
diabetes compared the outcome in subjects in whom
systolic BP remained 140 mmHg or more, with those
where systolic BP was reduced to between 130 and 139
and less than 130 mmHg. The all-cause mortality
increased in patients with systolic BP less than 120
mmHg.4
The PRoFESS trial studied 20,332 patients with a
history of stroke.5 The group with on-treatment BP
values between 130 and 139 mmHg was taken as
reference. The patients with systolic BP more than 150
mmHg showed decreasing risk of CV events up to the
reference level of 130 to 139. Systolic BP levels falling
below the reference levels again showed an increase in
risk of CV events.
160
140
120
100
80
In TNT study on 10,001 patients with CAD, low BP
(110–120/60–70) portends an increased risk of future
CV events (other than stroke) (Figure 2).6
60
60
80
70
90
100
110
Coronary pertusion pressure (mmHg)
Evidence against the J-curve phenomenon:
B
With revascularization
Without revascularization
6
Hazard ratio
5
In a study of 61 prospective trials involving one million
adults in the age group of 40 to 89 years with no
previous vascular disease, it was clearly shown that
systolic blood pressure (SBP) and diastolic blood
pressure (DBP) are strongly and directly related to
vascular and overall mortality without evidence of
threshold down to 115/75 mmHg.7
4
3
2
1
8
0
50
60
70
80
90
100
DBP (mmHg)
110
120
Figure 1: 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
828
In the UKPDS trial, effect of BP control was studied
between patients with tight (BP 144/82 mmHg) vs. less
tight (154/87 mmHg) control. These were 1148 Type II
diabetic patients with 9 years follow up. Patients with
tight control of BP showed significant risk reduction in
stroke, heart failure, micro-vascular disease, any
diabetic-related endpoint, and diabetes-related deaths.
J. Preventive Cardiology Vol. 5
No. 2
Nov 2015
Relative hazard, x 800 000
In the INVEST study, 22,576 patients of hypertension
with CAD were studied and the incidence of
myocardial infarction (MI) clearly showed the J-curve
phenomenon (almost U-shaped), whereas incidence of
stroke did not show the J-curve.2
(high risk pts, mainly with CAD)
20
2
10
1
0
112 121 126 130 135 136 140 144 149 160
On treatment SBP [mmHg]
100
80 Unadjusted
60
40
20
0
0
50
60
70
80
90
100
110
120
DBP, mmHg
B 35
B
5
TNT
(CAD patients)
30
4
25
20
3
15
2
10
1
5
0
60
61-70
71-80
81-90
91-100
>100
0
100
Relative hazard, x 2200
The effects of reducing coronary perfusion pressure by
intravenous infusion of nitroprusside on coronary
blood flow (measured in the great cardiac vein) were
studied in hypertensive patients with and without left
ventricular hypertrophy (LVH). In hypertensive
patients without LVH, there is no decrease in coronary
blood flow till the coronary perfusion pressure of 70
mmHg. Whereas in patients with LVH, the coronary
flow showed significant fall with coronary perfusion
pressure at 90 mmHg (Figure 1).1
A
3
Adjusted HR
Clinical studies
ONTARGET
Adjusted HR
Physiological data
A 30
CV events [%]
• J-curve phenomenon may truly be existing
without LVH;1 B) the CV event incidence at different
achieved diastolic blood pressure (DBP) levels in
patients with coronary artery disease (CAD) who did
not undergo coronary revascularization compared with
those who had the procedure.2
• J-curve may be seen in patients with increased
arterial stiffness, low BP being a marker of high
pulse pressure, and hence, the increase in mortality
Is there a J-curve for hypertension and cardiovascular disease? How low can one go?
CV events [%]
Iyengar SS, et al
80
60
40
After adjustment for age, sex, ethnicity, smoking
previous MI, heart failure, BMI, renal failure,
stroke/TIA, peripheral vascular disease,
coronary revascularization, dyslipidemia, cancer,
aspirin use, average blood pressure,
left ventricular hypertrophy, arrhythmia,
residency in US.
20
0
50
60
70
80
90
100
110
120
On treatment DBP [mmHg]
DBP, mmHg
Figure 2: J-curve in the (A) ONTARGET and (B) TNT
studies
Figure 3: Unadjusted (A) and adjusted (B) relation
between achieved (average in-treatment) DBP and risk
of primary outcome in hypertensive patients with
coronary artery disease enrolled in the International
Verapamil-Trandolapril Study
Though there was 21% risk reduction in MI, it was not
statistically significant.
In the HOT study, 18,790 patients from 26 countries in
the age group of 50 to 80 years were studied.9 Intensive
lowering of BP in hypertensive patients was associated
with a low rate of CV events. The study showed the
benefit of lowering DBP down to 82.6 mmHg. The
diabetes subgroup showed similar results.
Wang et al., in an analysis of different trials, studied the
effects of treatment on CV events in three different age
groups, namely, 30–49, 60–79, and ≥80.10 SBP and DBP
lowering clearly showed significant benefit in lowering
the risk of all CV events, fatal and nonfatal stroke, and
fatal and nonfatal MI.
In the INVEST study, the unadjusted data showed the Jcurve phenomenon. But after adjustment for age, gender,
ethnicity, smoking, previous MI, heart failure, BMI,
renal failure, stroke/TIA, peripheral vascular disease,
coronary revascularization, dyslipidemia, cancer,
aspirin use, arrhythmia, and LVH, the J-curve
phenomenon disappeared (Figure 3).2
J. Preventive Cardiology Vol. 5
No. 2
Nov 2015
Limitations of the studies supporting the J-curve
Following are limitations of the studies supporting Jcurve
• Lack of randomization: In the INVEST study,
compared to patients with DBP 81–90 mmHg, those
with less than 60 mmHg were 10 years older, had
previous MI, stroke, heart failure, diabetes, and
cancer.
• There were a small number of patients with low or
very low achieved BP, i.e., a small number of patients
in the ascending limb of J-curve. In the INVEST
study, a DBP of less than 60 mmHg was seen in 176
patients of 22,576 patients, and in TNT study, a BP of
110/60 or less was seen in 396 patients out of 10,001
patients.
• Most of the studies are observational data and post
hoc analysis. Some of the results were unadjusted for
confounding variables.
829
Iyengar SS, et al
Organ heterogeneity
ONTARGET study included 25620 high or very high
CV risk hypertensive patients. The unadjusted risk of
CV events and MI showed a J-curve phenomenon but
not the risk of stroke.11
Again there is no evidence of the J-curve phenomenon
for renal events when the BP was lowered in type II
diabetic patients after adjusting for age, gender,
duration of diabetes, glycosylated hemoglobin,
currently treated hypertension, ECG abnormalities,
dyslipidemia, BMI, smoking, alcohol use, and study
drug.12
Cerebral autoregulation is probably more effective
than the coronary autoregulation. Moreover, coronary
circulation occurs mostly during diastole.
New studies
There are three new studies available and it is to be seen
whether these contribute to clarity or confusion to the
present debate.
• SPRINT: In this study, 9300 patients were
randomized into two treatment strategies of
intensive BP control (SBP of 120 mmHg or less) vs.
standard BP control (SBP target of less than 140
mmHg).13 Patients with diabetes, those with a
history of stroke, and subjects less than 50 years of
age were excluded. The study was prematurely
stopped because there was a statistically significant
30% reduction in the primary composite endpoint
and 25% reduction in all-cause mortality with
intensive BP control. The benefit in primary
endpoint was mostly driven by decrease in the risk
of heart failure and mortality. There was no
significant benefit in the risk of stroke, MI, or acute
coronary syndrome (ACS). However, this came at
the cost of increased incidents of syncope,
electrolyte abnormalities, and acute kidney injury.
• New ACCORD Data (ACCORDIAN): The main
ACCORD trial after 4.9 years of follow up had
shown a nonsignificant 12 % reduction in
composite CV events and a significant effect on
stroke with intensive BP control.14 Further, 3957
patients were followed for an additional 54 to 60
months. There was a 9% nonsignificant reduction in
primary CV events. There was a benefit of intensive
BP lowering in patients randomized to standard
glycemic therapy. These results fit well with
SPRINT study, and support SBP lowering to 120
830
mmHg in patients with high CV risk or diabetes.
Is there a J-curve for hypertension and cardiovascular disease? How low can one go?
• Coronary circulation is unique with its dependency
on diastole. Here, probably a J-curve phenomenon
is likely to play a role, particularly in hypertensive
patients who are old and not completely
revascularized. Caution is to be exercised not to
lower DBP below 60 mmHg.
• A meta-analysis of 19 trials involving 45,000
patients showed that intensive BP lowering ( BP
achieved 133/76 mmHg) significantly reduced
major CV events, stroke, MI, albuminuria, and
retinopathy progression.15 But there was no benefit
in heart failure, CV death, total mortality, or endstage renal disease compared with less intensive BP
lowering strategy(BP achieved 140/81). The BP
levels are different and the benefits are different
compared to SPRINT.
• The concern about J-curve phenomenon should not
discourage clinicians from following guidelines in
controlling hypertension and reach reaching targets
recommended because, currently, BP control in the
hypertensive population is dismally low.
What should we do?
 References
In patients with elevated DBP and CAD with evidence
of myocardial ischemia, the BP should be lowered
slowly, and caution is advised in inducing decreases in
DBP to <60 mmHg in any patient with diabetes or who
is more than 60 years of age.
1. Polese A, De Cesare N, Montorsi P, et al. Upward shift of the
lower range of coronary flow autoregulation in hypertensive
patients with hypertrophy of the left ventricle. Circulation.
1991;83:845–53.
2. Messerli FH, Mancia G, Conti CR, et al. Dogma disputed: Can
aggressively lowering blood pressure in hypertensive patients
with coronary artery disease be dangerous? Ann Intern Med.
2006;144:884–93.
3. Mancia G, Schumacher H, Redon J, et al. Blood pressure targets
recommended by guidelines and incidence of cardiovascular
and renal events in the Ongoing Telmisartan Alone and in
Combination With Ramipril Global Endpoint Trial
(ONTARGET). Circulation. 2011;124:1727–36.
4. Cooper-DeHoff RM, Gong Y, Handberg EM, et al. Tight blood
pressure control and cardiovascular outcomes among
hypertensive patients with diabetes and coronary artery disease.
JAMA. 2010;304:61–8.
5. Ovbiagele B, Diener HC, Yusuf S, et al. Level of systolic blood
pressure within the normal range and risk of recurrent stroke.
JAMA. 2011;306:2137–44.
6. Bangalore S, Messerli FH, Wun CC, et al. J-curve revisited: An
analysis of blood pressure and cardiovascular events in the
Treating to New Targets (TNT) Trial. Eur Heart J.
2010;31:2897–908.
7. Lewington S, Clarke R, Qizilbash N, et al. Age-specific relevance
of usual blood pressure to vascular mortality: a meta-analysis of
individual data for one million adults in 61 prospective studies.
Lancet. 2002;360:1903–13.
8. UK Prospective Diabetes Study Group. Tight blood pressure
control and risk of macrovascular and microvascular
complications in type 2 diabetes: UKPDS 38. Br Med J.
In older hypertensive individuals with wide pulse
pressures, lowering SBP may cause low DBP values
(less than 60 mmHg). This should alert the clinicians to
assess carefully any untoward signs or symptoms,
especially those resulting from myocardial ischemia
(Class IIa, C). 16
The BP targets recommended for patients with CAD are
as follows:
• General CAD prevention: <140/90 mmHg
• High CAD risk: <130/80 mmHg
• Stable angina: <130/80 mmHg
• ACS: <130/80 mmHg
• LV dysfunction: <120/80 mmHg
In patients with stroke/TIA, it is reasonable achieve a
SBP of less than 140 and DBP of less than 90
(Class IIa, B).
1998;317:703–13.
9. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive
blood-pressure lowering and low-dose aspirin in patients with
hypertension: Principal results of the Hypertension Optimal
Treatment (HOT) randomised trial. Lancet 1998;351:1755–
62.
10. Wang JG, Staessen JA, Franklin SS, et al. Systolic and diastolic
blood pressure lowering as determinants of cardiovascular
outcome. Hypertension. 2005;45:907–13.
11. Mancia G, Schumacher H, Redon J, et al. Blood pressure targets
recommended by guidelines and incidence of cardiovascular and
renal events in the Ongoing Telmisartan Alone and in
C o m b i n a t i o n Wi t h R a m i p r i l G l o b a l E n d p o i n t Tr i a l
(ONTARGET). Circulation. 2011;124:1727–36.
12. de Galan BE, Pekovic V, Ninomiya T, et al. Lowering blood
pressure reduces renal events in type 2 diabetes. J Am Soc
Nephrol. 2009;20:883–92.
13. SPRINT Research Group, Wright JT Jr, Williamson JD, et al. A
randomized trial of intensive versus standard blood-pressure
control. N Engl J Med. 2015;373(22):2103–16.
14. Cushman WC, Evans GW, Cutler JA. Long-term cardiovascular
effects of 4.9 years of intensive blood pressure control in type 2
diabetes mellitus: The action to control cardiovascular risk in
diabetes follow-on blood-pressure study. American Heart
Association 2015 Scientific Sessions; November 10, 2015;
Orlando, FL
15. Xinfang Xie, Emily Atkins, Jicheng LV. Effects of intensive blood
pressure lowering on cardiovascular and renal outcomes: updated
systematic review and meta-analysis. 2015 Nov 6 [Epub ahead of
print]. doi:5http://dx.doi.org/10.1016/S0140-6736(15)00805.
16. Rosendorff C, Lackland DT, Allison M, et al. Treatment of
hypertension in patients with coronary artery disease: A scientific
statement from the American Heart Association, American
College of Cardiology, and American Society of Hypertension. J
Am Coll Cardiol 2015;65:2000–26.
17. Moser M, Wright JT, Victor RG, et al. How to treat hypertension
in patients with coronary heart disease. J Clin Hypertens
(Greenwich). 2008:10(5):390–7.
Address for correspondence:
Dr. S S Iyengar
Email ID: [email protected]
In patients with a recent lacunar stroke, it is reasonable
to target a SBP of less than 130 mmHg.17
Summary
If one ventures to summarize the available data, the
following points emerge.
• J-curve phenomenon may be an epiphenomenon
(“reverse causality” as in comorbid conditions, poor
LV function, or arterial stiffness states) or in certain
situations, a reality.
J. Preventive Cardiology Vol. 5
No. 2
Nov 2015
J. Preventive Cardiology Vol. 5
No. 2
Nov 2015
831
Iyengar SS, et al
Organ heterogeneity
ONTARGET study included 25620 high or very high
CV risk hypertensive patients. The unadjusted risk of
CV events and MI showed a J-curve phenomenon but
11
not the risk of stroke.
Again there is no evidence of the J-curve phenomenon
for renal events when the BP was lowered in type II
diabetic patients after adjusting for age, gender,
duration of diabetes, glycosylated hemoglobin,
currently treated hypertension, ECG abnormalities,
dyslipidemia, BMI, smoking, alcohol use, and study
drug.12
Cerebral autoregulation is probably more effective
than the coronary autoregulation. Moreover, coronary
circulation occurs mostly during diastole.
New studies
There are three new studies available and it is to be seen
whether these contribute to clarity or confusion to the
present debate.
• SPRINT: In this study, 9300 patients were
randomized into two treatment strategies of
intensive BP control (SBP of 120 mmHg or less) vs.
standard BP control (SBP target of less than 140
13
mmHg). Patients with diabetes, those with a
history of stroke, and subjects less than 50 years of
age were excluded. The study was prematurely
stopped because there was a statistically significant
30% reduction in the primary composite endpoint
and 25% reduction in all-cause mortality with
intensive BP control. The benefit in primary
endpoint was mostly driven by decrease in the risk
of heart failure and mortality. There was no
significant benefit in the risk of stroke, MI, or acute
coronary syndrome (ACS). However, this came at
the cost of increased incidents of syncope,
electrolyte abnormalities, and acute kidney injury.
• New ACCORD Data (ACCORDIAN): The main
ACCORD trial after 4.9 years of follow up had
shown a nonsignificant 12 % reduction in
composite CV events and a significant effect on
14
stroke with intensive BP control. Further, 3957
patients were followed for an additional 54 to 60
months. There was a 9% nonsignificant reduction in
primary CV events. There was a benefit of intensive
BP lowering in patients randomized to standard
glycemic therapy. These results fit well with
SPRINT study, and support SBP lowering to 120
830
mmHg in patients with high CV risk or diabetes.
Is there a J-curve for hypertension and cardiovascular disease? How low can one go?
• Coronary circulation is unique with its dependency
on diastole. Here, probably a J-curve phenomenon
is likely to play a role, particularly in hypertensive
patients who are old and not completely
revascularized. Caution is to be exercised not to
lower DBP below 60 mmHg.
• A meta-analysis of 19 trials involving 45,000
patients showed that intensive BP lowering ( BP
achieved 133/76 mmHg) significantly reduced
major CV events, stroke, MI, albuminuria, and
retinopathy progression.15 But there was no benefit
in heart failure, CV death, total mortality, or endstage renal disease compared with less intensive BP
lowering strategy(BP achieved 140/81). The BP
levels are different and the benefits are different
compared to SPRINT.
• The concern about J-curve phenomenon should not
discourage clinicians from following guidelines in
controlling hypertension and reach reaching targets
recommended because, currently, BP control in the
hypertensive population is dismally low.
What should we do?
 References
In patients with elevated DBP and CAD with evidence
of myocardial ischemia, the BP should be lowered
slowly, and caution is advised in inducing decreases in
DBP to <60 mmHg in any patient with diabetes or who
is more than 60 years of age.
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aggressively lowering blood pressure in hypertensive patients
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3. Mancia G, Schumacher H, Redon J, et al. Blood pressure targets
recommended by guidelines and incidence of cardiovascular
and renal events in the Ongoing Telmisartan Alone and in
Combination With Ramipril Global Endpoint Trial
(ONTARGET). Circulation. 2011;124:1727–36.
4. Cooper-DeHoff RM, Gong Y, Handberg EM, et al. Tight blood
pressure control and cardiovascular outcomes among
hypertensive patients with diabetes and coronary artery disease.
JAMA. 2010;304:61–8.
5. Ovbiagele B, Diener HC, Yusuf S, et al. Level of systolic blood
pressure within the normal range and risk of recurrent stroke.
JAMA. 2011;306:2137–44.
6. Bangalore S, Messerli FH, Wun CC, et al. J-curve revisited: An
analysis of blood pressure and cardiovascular events in the
Treating to New Targets (TNT) Trial. Eur Heart J.
2010;31:2897–908.
7. Lewington S, Clarke R, Qizilbash N, et al. Age-specific relevance
of usual blood pressure to vascular mortality: a meta-analysis of
individual data for one million adults in 61 prospective studies.
Lancet. 2002;360:1903–13.
8. UK Prospective Diabetes Study Group. Tight blood pressure
control and risk of macrovascular and microvascular
complications in type 2 diabetes: UKPDS 38. Br Med J.
In older hypertensive individuals with wide pulse
pressures, lowering SBP may cause low DBP values
(less than 60 mmHg). This should alert the clinicians to
assess carefully any untoward signs or symptoms,
especially those resulting from myocardial ischemia
(Class IIa, C). 16
The BP targets recommended for patients with CAD are
as follows:
• General CAD prevention: <140/90 mmHg
• High CAD risk: <130/80 mmHg
• Stable angina: <130/80 mmHg
• ACS: <130/80 mmHg
• LV dysfunction: <120/80 mmHg
In patients with stroke/TIA, it is reasonable achieve a
SBP of less than 140 and DBP of less than 90
(Class IIa, B).
1998;317:703–13.
9. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive
blood-pressure lowering and low-dose aspirin in patients with
hypertension: Principal results of the Hypertension Optimal
Treatment (HOT) randomised trial. Lancet 1998;351:1755–
62.
10. Wang JG, Staessen JA, Franklin SS, et al. Systolic and diastolic
blood pressure lowering as determinants of cardiovascular
outcome. Hypertension. 2005;45:907–13.
11. Mancia G, Schumacher H, Redon J, et al. Blood pressure targets
recommended by guidelines and incidence of cardiovascular and
renal events in the Ongoing Telmisartan Alone and in
C o m b i n a t i o n Wi t h R a m i p r i l G l o b a l E n d p o i n t Tr i a l
(ONTARGET). Circulation. 2011;124:1727–36.
12. de Galan BE, Pekovic V, Ninomiya T, et al. Lowering blood
pressure reduces renal events in type 2 diabetes. J Am Soc
Nephrol. 2009;20:883–92.
13. SPRINT Research Group, Wright JT Jr, Williamson JD, et al. A
randomized trial of intensive versus standard blood-pressure
control. N Engl J Med. 2015;373(22):2103–16.
14. Cushman WC, Evans GW, Cutler JA. Long-term cardiovascular
effects of 4.9 years of intensive blood pressure control in type 2
diabetes mellitus: The action to control cardiovascular risk in
diabetes follow-on blood-pressure study. American Heart
Association 2015 Scientific Sessions; November 10, 2015;
Orlando, FL
15. Xinfang Xie, Emily Atkins, Jicheng LV. Effects of intensive blood
pressure lowering on cardiovascular and renal outcomes: updated
systematic review and meta-analysis. 2015 Nov 6 [Epub ahead of
print]. doi:5http://dx.doi.org/10.1016/S0140-6736(15)00805.
16. Rosendorff C, Lackland DT, Allison M, et al. Treatment of
hypertension in patients with coronary artery disease: A scientific
statement from the American Heart Association, American
College of Cardiology, and American Society of Hypertension. J
Am Coll Cardiol 2015;65:2000–26.
17. Moser M, Wright JT, Victor RG, et al. How to treat hypertension
in patients with coronary heart disease. J Clin Hypertens
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Address for correspondence:
Dr. S S Iyengar
Email ID: [email protected]
In patients with a recent lacunar stroke, it is reasonable
17
to target a SBP of less than 130 mmHg.
Summary
If one ventures to summarize the available data, the
following points emerge.
• J-curve phenomenon may be an epiphenomenon
(“reverse causality” as in comorbid conditions, poor
LV function, or arterial stiffness states) or in certain
situations, a reality.
J. Preventive Cardiology Vol. 5
No. 2
Nov 2015
J. Preventive Cardiology Vol. 5
No. 2
Nov 2015
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