- Email: [email protected]
Lower Is Not Always Better? Blood Pressure Treatment Targets Revisited∗
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
VOL. 64, NO. 6, 2014
ª 2014 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 0735-1097/$36.00
PUBLISHED BY ELSEVIER INC.
http://dx.doi.org/10.1016/j.jacc.2014.04.066
EDITORIAL COMMENT
Lower Is Not Always Better? Blood Pressure Treatment Targets Revisited* Charlotte Andersson, MD, PHD,yz Ramachandran S. Vasan, MDyxk
H
ypertension is an important cause of car-
analyzed the association of actual, on-treatment BP
diovascular disease (CVD) and mortality.
levels with the risk of end-stage renal disease and
Hypertension is present in approximately
mortality over 3 to 5 years of follow-up in individuals
40% of adults in the United States, and it accounts
who were diagnosed with hypertension in the Kaiser
for 41% of all CVD deaths (1–3), with a similar burden
Permanente Southern California health system. Their
of disease in the rest of the world (4). Lowering blood
analyses of nearly 400,000 individuals, 19% of whom
pressure (BP) with medications substantially reduces
had ischemic heart disease and 30% of whom had
the risk of CVD (5,6).
diabetes, showed a significant J-shaped association
Hypertension is well controlled in about 60%
between actual (treated) BP levels and adverse out-
of patients in the United States (i.e., a systolic
comes, mainly driven by the higher mortality associ-
BP <140 mm Hg and a diastolic BP <90 mm Hg) (3).
ated with lower on-treatment BP levels. Their data
What should be done for the remaining 40%? Should
suggest that the lowest risk of the composite outcome
they be treated more aggressively with medications,
was at systolic BP of 137 mm Hg and a diastolic BP
or is it enough that they are treated, even if their BP
of 71 mm Hg. BP either higher or lower than 130 to
are not “normalized”? Panelists from the Eighth Joint
139 mm Hg systolic and 60 to 79 mm Hg diastolic
National Committee recently stirred up controversy
were associated with increased risk of the composite
by relaxing the BP treatment target to <150/90 mm Hg
endpoint.
among people $60 years of age, largely because they
SEE PAGE 588
found little evidence from randomized trials showing that tighter BP control leads to better outcomes (7).
Epidemiological studies of hypertensive, medically
These recommendations have been criticized as
untreated individuals have shown a graded increase
relying too much on trials, without considering other
in CVD and mortality with higher BP levels, without
forms of evidence.
any evidence of any J-shaped curve (9,10). These
In this issue of the Journal, Sim et al. (8) provide more support for relaxing BP treatment targets. They
observations led to the argument that the “lower the blood pressure, the better the outcomes.” However, the associations from untreated individuals might not apply to people treated for hypertension, and it is obvious that driving BP too low with medications
*Editorials published in the Journal of the American College of Cardiology
can lead to adverse effects. So, a J-curve relationship
reflect the views of the authors and do not necessarily represent the
between on-treatment BP and mortality is plausible,
views of JACC or the American College of Cardiology. From yThe Framingham Heart Study, Framingham, Massachusetts; zDepartment of Cardiology, Gentofte Hospital, Hellerup, Denmark; xSections of Preventive Medicine and Cardiology, Boston University
yet leaves unanswered the question of what levels of systolic and diastolic BP are optimal. There is a physiologic rationale for a J-shaped
School of Medicine, Boston, Massachusetts; and the kDepartment of
relationship between treated BP and outcomes.
Epidemiology, Boston University School of Public Health, Boston, Mas-
Hypertension may, to some extent, be a consequence
sachusetts. Dr. Andersson has received a travel grant from AstraZeneca; and a research grant (#FSS-11-120873) from the Danish Agency for Sci-
of high arterial stiffness, so overly aggressive BP
ence, Technology and Innovation. Dr. Vasan has reported that he has no
lowering can lead to orthostatic hypotension and
relationships relevant to the contents of this paper to disclose.
hypoperfusion of vital organs (11). Furthermore, with
Andersson and Vasan
JACC VOL. 64, NO. 6, 2014 AUGUST 12, 2014:598–600
Blood Pressure Treatment Targets Revisited
controlled
patients with diabetes (18), and body mass index
hypertension, autoregulatory mechanisms adapt to
(19,20). Although these associations are biologically
long-standing
uncontrolled
or
poorly
higher BP levels, so the threshold for hypoperfusion
plausible, they might be due to “reverse causation”:
of vital organs is shifted upward (12). Coronary
individuals with very low values of a risk factor might
perfusion
30%
be sicker and have advanced disease and hence
from the normal value before the autoregulatory
higher mortality. Patients with chronic diseases also
mechanisms begin to fail in people without heart
may have spontaneous BP reductions, as their con-
disease (13). Among people with heart disease (such
ditions worsen. Sim et al. (8) found that systolic BP
as significant coronary stenoses, left ventricular
values fell 7 mm Hg in the 60 days before death.
hypertrophy, or tachycardia), the coronary artery flow
Although the J-shaped relation remained evident
reserve is usually reduced. These people may, there-
even when these pre-mortality BP values were
fore, be more sensitive to BP-lowering interventions.
omitted from the analysis, a much longer phase of
Lowering diastolic BP below 80 to 85 mm Hg (or even
BP reduction before death would not have been
90 mm Hg) has been suggested to increase the risk of
adequately addressed by the analysis. In an analysis
myocardial infarction in some groups (13,14). Available randomized trials have not convincingly
of individual patient data from 7 randomized clinical
demonstrated improved mortality rates with aggres-
also found an increased risk of mortality among
sive antihypertensive treatment (6,15). A collabora-
patients with low blood pressure values, which was
tive meta-analysis of several large, randomized
not related specifically to antihypertensive treat-
clinical trials did not demonstrate any significant
ment, suggesting that comorbid conditions might
effect on mortality from intensive lowering of
explain the J-shaped mortality curve.
pressure
can
fall
approximately
trials of blood pressure lowering, Boutitie et al. (21)
BP compared with standard BP-lowering targets
Ultimately, we need further studies to establish
(although there were fewer major adverse cardiac
the optimal BP treatment target for patients with
events with the intensive treatment) (6). These ob-
various comorbidities. It may make sense to treat
servations suggest that optimal BP targets may vary
younger people with less comorbidity more aggres-
widely for different patient groups, and that there
sively than older patients or people with a large
might be heterogeneity in outcomes associated with
burden of comorbidity, but the exact numerical BP
tight BP control. Further evidence that tight BP con-
targets are yet to be determined. Clinical trial results
trol may be undesirable in some patients is provided
would provide a more definitive answer than obser-
by a recent trial that randomized patients with dia-
vational analyses will, even analyses of very large
betes and hypertension to a systolic BP target of <140
datasets. The ongoing SPRINT (Systolic Blood Pressure
mm Hg versus <120 mm Hg and showed that patients
Intervention Trial), which randomizes people with
assigned to intensive treatment had greater declines
hypertension to a systolic BP of <140 mm Hg or <120
in total brain volume over 40 months (16). Older patients and those with long-standing poorly
mm Hg, should provide key data on targets. Truly
controlled hypertension may be more sensitive to
looser targets recommended by the Eighth Joint Na-
intensive BP-lowering treatment compared with
tional Committee, remains a challenge, and we still
younger people with less comorbidity. Sim et al. (8)
must be concerned about undertreatment of hyper-
elegantly demonstrated that the optimal BP levels
tension, even as we sort out the optimal treatment
were lower for younger patients (younger than vs.
target.
uncontrolled hypertension, even on the basis of the
older than 70 years of age), for individuals with diaREPRINT REQUESTS AND CORRESPONDENCE: Dr.
betes, and for patients with low comorbidity burden. J-shaped curves for CVD and mortality have been
Charlotte Andersson, Gentofte Hospital, Department
shown for some other risk factors, including alcohol
of Cardiology, Niels Andersens vej 65, 2900 Hellerup,
consumption (17), glycosylated hemoglobin levels for
Denmark. E-mail: [email protected].
REFERENCES 1. Yang Q, Cogswell ME, Flanders WD, et al. Trends in cardiovascular health metrics and associations with all-cause and CVD mortality among US adults. JAMA 2012;307:1273–83.
and stroke statistics–2014 update: a report from the American Heart Association. Circulation 2014;129: 399–410.
2. Go AS, Mozaffarian D, Roger VL, et al., for the AHA Statistics Committee and Stroke Statistics
3. Olives C, Myerson R, Mokdad AH, Murray CJ, Lim SS. Prevalence, awareness, treatment, and control of hypertension in United States counties,
Subcommittee. Executive summary: heart disease
2001-2009. PloS One 2013;8:e60308.
4. Laslett LJ, Alagona P Jr., Clark BA 3rd, et al. The worldwide environment of cardiovascular disease: prevalence, diagnosis, therapy, and policy issues: a report from the American College of Cardiology. J Am Coll Cardiol 2012;60 Suppl 25:S1–49. 5. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of
599
600
Andersson and Vasan
JACC VOL. 64, NO. 6, 2014 AUGUST 12, 2014:598–600
Blood Pressure Treatment Targets Revisited
cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ 2009;338:b1665. 6. Turnbull F, for the Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet 2003;362:1527–35. 7. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014;311:507–20. 8. Sim JJ, Shi J, Kovesdy CP, Kalantar-Zadeh K, Jacobsen SJ. Impact of achieved blood pressures on mortality risk and end-stage renal disease among a large, diverse hypertension population. J Am Coll Cardiol 2014;64:588–97. 9. Franklin SS, Lopez VA, Wong ND, et al. Single versus combined blood pressure components and risk for cardiovascular disease: the Framingham Heart Study. Circulation 2009;119:243–50.
data for one million adults in 61 prospective studies. Lancet 2002;360:1903–13. 11. Kaess BM, Rong J, Larson MG, et al. Aortic stiffness, blood pressure progression, and incident hypertension. JAMA 2012;308:875–81. 12. Strandgaard S. Autoregulation of cerebral blood flow in hypertensive patients: the modifying influence of prolonged antihypertensive treatment on the tolerance to acute, drug-induced hypotension. Circulation 1976;53:720–7. 13. Cruickshank JM. The role of coronary perfusion pressure. Eur Heart J 1992;13 Suppl D:39–43. 14. Lindblad U, Rastam L, Ryden L, Ranstam J, Isacsson SO, Berglund G. Control of blood pressure and risk of first acute myocardial infarction: Skaraborg hypertension project. BMJ 1994;308: 681–6. 15. Benavente OR, Coffey CS, Conwit R, et al., for the SP3S Study Group. Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial. Lancet 2013;382:507–15.
10. Lewington S, Clarke R, Qizilbash N, et al., for the Prospective Studies Collaboration. Agespecific relevance of usual blood pressure to
16. Williamson JD, Launer LJ, Bryan RN, et al., for the Action to Control Cardiovascular Risk in Diabetes Memory in Diabetes Investigators. Cognitive function and brain structure in persons with type 2 diabetes mellitus after intensive lowering of blood pressure and lipid levels: a randomized clinical
vascular mortality: a meta-analysis of individual
trial. JAMA Intern Med 2014;174:324–33.
17. Mukamal KJ, Maclure M, Muller JE, Sherwood JB, Mittleman MA. Prior alcohol consumption and mortality following acute myocardial infarction. JAMA 2001;285:1965–70. 18. Currie CJ, Peters JR, Tynan A, et al. Survival as a function of HbA(1c) in people with type 2 diabetes: a retrospective cohort study. Lancet 2010; 375:481–9. 19. Kalantar-Zadeh K, Abbott KC, Salahudeen AK, Kilpatrick RD, Horwich TB. Survival advantages of obesity in dialysis patients. Am J Clin Nutr 2005; 81:543–54. 20. Kalantar-Zadeh K, Block G, Horwich T, Fonarow GC. Reverse epidemiology of conventional cardiovascular risk factors in patients with chronic heart failure. J Am Coll Cardiol 2004;43: 1439–44. 21. Boutitie F, Gueyffier F, Pocock S, et al., for the INDANA Project Steering Committee. J-shaped relationship between blood pressure and mortality in hypertensive patients: new insights from a meta-analysis of individual-patient data. Ann Internal Med 2002;136:438–48.
KEY WORDS blood pressure, epidemiology, hypertension, treatment targets
VOL. 64, NO. 6, 2014
ª 2014 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 0735-1097/$36.00
PUBLISHED BY ELSEVIER INC.
http://dx.doi.org/10.1016/j.jacc.2014.04.066
EDITORIAL COMMENT
Lower Is Not Always Better? Blood Pressure Treatment Targets Revisited* Charlotte Andersson, MD, PHD,yz Ramachandran S. Vasan, MDyxk
H
ypertension is an important cause of car-
analyzed the association of actual, on-treatment BP
diovascular disease (CVD) and mortality.
levels with the risk of end-stage renal disease and
Hypertension is present in approximately
mortality over 3 to 5 years of follow-up in individuals
40% of adults in the United States, and it accounts
who were diagnosed with hypertension in the Kaiser
for 41% of all CVD deaths (1–3), with a similar burden
Permanente Southern California health system. Their
of disease in the rest of the world (4). Lowering blood
analyses of nearly 400,000 individuals, 19% of whom
pressure (BP) with medications substantially reduces
had ischemic heart disease and 30% of whom had
the risk of CVD (5,6).
diabetes, showed a significant J-shaped association
Hypertension is well controlled in about 60%
between actual (treated) BP levels and adverse out-
of patients in the United States (i.e., a systolic
comes, mainly driven by the higher mortality associ-
BP <140 mm Hg and a diastolic BP <90 mm Hg) (3).
ated with lower on-treatment BP levels. Their data
What should be done for the remaining 40%? Should
suggest that the lowest risk of the composite outcome
they be treated more aggressively with medications,
was at systolic BP of 137 mm Hg and a diastolic BP
or is it enough that they are treated, even if their BP
of 71 mm Hg. BP either higher or lower than 130 to
are not “normalized”? Panelists from the Eighth Joint
139 mm Hg systolic and 60 to 79 mm Hg diastolic
National Committee recently stirred up controversy
were associated with increased risk of the composite
by relaxing the BP treatment target to <150/90 mm Hg
endpoint.
among people $60 years of age, largely because they
SEE PAGE 588
found little evidence from randomized trials showing that tighter BP control leads to better outcomes (7).
Epidemiological studies of hypertensive, medically
These recommendations have been criticized as
untreated individuals have shown a graded increase
relying too much on trials, without considering other
in CVD and mortality with higher BP levels, without
forms of evidence.
any evidence of any J-shaped curve (9,10). These
In this issue of the Journal, Sim et al. (8) provide more support for relaxing BP treatment targets. They
observations led to the argument that the “lower the blood pressure, the better the outcomes.” However, the associations from untreated individuals might not apply to people treated for hypertension, and it is obvious that driving BP too low with medications
*Editorials published in the Journal of the American College of Cardiology
can lead to adverse effects. So, a J-curve relationship
reflect the views of the authors and do not necessarily represent the
between on-treatment BP and mortality is plausible,
views of JACC or the American College of Cardiology. From yThe Framingham Heart Study, Framingham, Massachusetts; zDepartment of Cardiology, Gentofte Hospital, Hellerup, Denmark; xSections of Preventive Medicine and Cardiology, Boston University
yet leaves unanswered the question of what levels of systolic and diastolic BP are optimal. There is a physiologic rationale for a J-shaped
School of Medicine, Boston, Massachusetts; and the kDepartment of
relationship between treated BP and outcomes.
Epidemiology, Boston University School of Public Health, Boston, Mas-
Hypertension may, to some extent, be a consequence
sachusetts. Dr. Andersson has received a travel grant from AstraZeneca; and a research grant (#FSS-11-120873) from the Danish Agency for Sci-
of high arterial stiffness, so overly aggressive BP
ence, Technology and Innovation. Dr. Vasan has reported that he has no
lowering can lead to orthostatic hypotension and
relationships relevant to the contents of this paper to disclose.
hypoperfusion of vital organs (11). Furthermore, with
Andersson and Vasan
JACC VOL. 64, NO. 6, 2014 AUGUST 12, 2014:598–600
Blood Pressure Treatment Targets Revisited
controlled
patients with diabetes (18), and body mass index
hypertension, autoregulatory mechanisms adapt to
(19,20). Although these associations are biologically
long-standing
uncontrolled
or
poorly
higher BP levels, so the threshold for hypoperfusion
plausible, they might be due to “reverse causation”:
of vital organs is shifted upward (12). Coronary
individuals with very low values of a risk factor might
perfusion
30%
be sicker and have advanced disease and hence
from the normal value before the autoregulatory
higher mortality. Patients with chronic diseases also
mechanisms begin to fail in people without heart
may have spontaneous BP reductions, as their con-
disease (13). Among people with heart disease (such
ditions worsen. Sim et al. (8) found that systolic BP
as significant coronary stenoses, left ventricular
values fell 7 mm Hg in the 60 days before death.
hypertrophy, or tachycardia), the coronary artery flow
Although the J-shaped relation remained evident
reserve is usually reduced. These people may, there-
even when these pre-mortality BP values were
fore, be more sensitive to BP-lowering interventions.
omitted from the analysis, a much longer phase of
Lowering diastolic BP below 80 to 85 mm Hg (or even
BP reduction before death would not have been
90 mm Hg) has been suggested to increase the risk of
adequately addressed by the analysis. In an analysis
myocardial infarction in some groups (13,14). Available randomized trials have not convincingly
of individual patient data from 7 randomized clinical
demonstrated improved mortality rates with aggres-
also found an increased risk of mortality among
sive antihypertensive treatment (6,15). A collabora-
patients with low blood pressure values, which was
tive meta-analysis of several large, randomized
not related specifically to antihypertensive treat-
clinical trials did not demonstrate any significant
ment, suggesting that comorbid conditions might
effect on mortality from intensive lowering of
explain the J-shaped mortality curve.
pressure
can
fall
approximately
trials of blood pressure lowering, Boutitie et al. (21)
BP compared with standard BP-lowering targets
Ultimately, we need further studies to establish
(although there were fewer major adverse cardiac
the optimal BP treatment target for patients with
events with the intensive treatment) (6). These ob-
various comorbidities. It may make sense to treat
servations suggest that optimal BP targets may vary
younger people with less comorbidity more aggres-
widely for different patient groups, and that there
sively than older patients or people with a large
might be heterogeneity in outcomes associated with
burden of comorbidity, but the exact numerical BP
tight BP control. Further evidence that tight BP con-
targets are yet to be determined. Clinical trial results
trol may be undesirable in some patients is provided
would provide a more definitive answer than obser-
by a recent trial that randomized patients with dia-
vational analyses will, even analyses of very large
betes and hypertension to a systolic BP target of <140
datasets. The ongoing SPRINT (Systolic Blood Pressure
mm Hg versus <120 mm Hg and showed that patients
Intervention Trial), which randomizes people with
assigned to intensive treatment had greater declines
hypertension to a systolic BP of <140 mm Hg or <120
in total brain volume over 40 months (16). Older patients and those with long-standing poorly
mm Hg, should provide key data on targets. Truly
controlled hypertension may be more sensitive to
looser targets recommended by the Eighth Joint Na-
intensive BP-lowering treatment compared with
tional Committee, remains a challenge, and we still
younger people with less comorbidity. Sim et al. (8)
must be concerned about undertreatment of hyper-
elegantly demonstrated that the optimal BP levels
tension, even as we sort out the optimal treatment
were lower for younger patients (younger than vs.
target.
uncontrolled hypertension, even on the basis of the
older than 70 years of age), for individuals with diaREPRINT REQUESTS AND CORRESPONDENCE: Dr.
betes, and for patients with low comorbidity burden. J-shaped curves for CVD and mortality have been
Charlotte Andersson, Gentofte Hospital, Department
shown for some other risk factors, including alcohol
of Cardiology, Niels Andersens vej 65, 2900 Hellerup,
consumption (17), glycosylated hemoglobin levels for
Denmark. E-mail: [email protected].
REFERENCES 1. Yang Q, Cogswell ME, Flanders WD, et al. Trends in cardiovascular health metrics and associations with all-cause and CVD mortality among US adults. JAMA 2012;307:1273–83.
and stroke statistics–2014 update: a report from the American Heart Association. Circulation 2014;129: 399–410.
2. Go AS, Mozaffarian D, Roger VL, et al., for the AHA Statistics Committee and Stroke Statistics
3. Olives C, Myerson R, Mokdad AH, Murray CJ, Lim SS. Prevalence, awareness, treatment, and control of hypertension in United States counties,
Subcommittee. Executive summary: heart disease
2001-2009. PloS One 2013;8:e60308.
4. Laslett LJ, Alagona P Jr., Clark BA 3rd, et al. The worldwide environment of cardiovascular disease: prevalence, diagnosis, therapy, and policy issues: a report from the American College of Cardiology. J Am Coll Cardiol 2012;60 Suppl 25:S1–49. 5. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of
599
600
Andersson and Vasan
JACC VOL. 64, NO. 6, 2014 AUGUST 12, 2014:598–600
Blood Pressure Treatment Targets Revisited
cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ 2009;338:b1665. 6. Turnbull F, for the Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet 2003;362:1527–35. 7. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014;311:507–20. 8. Sim JJ, Shi J, Kovesdy CP, Kalantar-Zadeh K, Jacobsen SJ. Impact of achieved blood pressures on mortality risk and end-stage renal disease among a large, diverse hypertension population. J Am Coll Cardiol 2014;64:588–97. 9. Franklin SS, Lopez VA, Wong ND, et al. Single versus combined blood pressure components and risk for cardiovascular disease: the Framingham Heart Study. Circulation 2009;119:243–50.
data for one million adults in 61 prospective studies. Lancet 2002;360:1903–13. 11. Kaess BM, Rong J, Larson MG, et al. Aortic stiffness, blood pressure progression, and incident hypertension. JAMA 2012;308:875–81. 12. Strandgaard S. Autoregulation of cerebral blood flow in hypertensive patients: the modifying influence of prolonged antihypertensive treatment on the tolerance to acute, drug-induced hypotension. Circulation 1976;53:720–7. 13. Cruickshank JM. The role of coronary perfusion pressure. Eur Heart J 1992;13 Suppl D:39–43. 14. Lindblad U, Rastam L, Ryden L, Ranstam J, Isacsson SO, Berglund G. Control of blood pressure and risk of first acute myocardial infarction: Skaraborg hypertension project. BMJ 1994;308: 681–6. 15. Benavente OR, Coffey CS, Conwit R, et al., for the SP3S Study Group. Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial. Lancet 2013;382:507–15.
10. Lewington S, Clarke R, Qizilbash N, et al., for the Prospective Studies Collaboration. Agespecific relevance of usual blood pressure to
16. Williamson JD, Launer LJ, Bryan RN, et al., for the Action to Control Cardiovascular Risk in Diabetes Memory in Diabetes Investigators. Cognitive function and brain structure in persons with type 2 diabetes mellitus after intensive lowering of blood pressure and lipid levels: a randomized clinical
vascular mortality: a meta-analysis of individual
trial. JAMA Intern Med 2014;174:324–33.
17. Mukamal KJ, Maclure M, Muller JE, Sherwood JB, Mittleman MA. Prior alcohol consumption and mortality following acute myocardial infarction. JAMA 2001;285:1965–70. 18. Currie CJ, Peters JR, Tynan A, et al. Survival as a function of HbA(1c) in people with type 2 diabetes: a retrospective cohort study. Lancet 2010; 375:481–9. 19. Kalantar-Zadeh K, Abbott KC, Salahudeen AK, Kilpatrick RD, Horwich TB. Survival advantages of obesity in dialysis patients. Am J Clin Nutr 2005; 81:543–54. 20. Kalantar-Zadeh K, Block G, Horwich T, Fonarow GC. Reverse epidemiology of conventional cardiovascular risk factors in patients with chronic heart failure. J Am Coll Cardiol 2004;43: 1439–44. 21. Boutitie F, Gueyffier F, Pocock S, et al., for the INDANA Project Steering Committee. J-shaped relationship between blood pressure and mortality in hypertensive patients: new insights from a meta-analysis of individual-patient data. Ann Internal Med 2002;136:438–48.
KEY WORDS blood pressure, epidemiology, hypertension, treatment targets