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EDITORIAL COMMENT

Lower Is Not Always Better?Blood Pressure TreatmentTargets Revisited*

Charlotte Andersson, MD, PHD,yz Ramachandran S. Vasan, MDyxk

SEE PAGE 588

H ypertension is an important cause of car-diovascular disease (CVD) and mortality.Hypertension is present in approximately

40% of adults in the United States, and it accountsfor 41% of all CVD deaths (1–3), with a similar burdenof disease in the rest of the world (4). Lowering bloodpressure (BP) with medications substantially reducesthe risk of CVD (5,6).

Hypertension is well controlled in about 60%of patients in the United States (i.e., a systolicBP <140 mm Hg and a diastolic BP <90 mm Hg) (3).What should be done for the remaining 40%? Shouldthey be treated more aggressively with medications,or is it enough that they are treated, even if their BPare not “normalized”? Panelists from the Eighth JointNational Committee recently stirred up controversyby relaxing the BP treatment target to <150/90 mm Hgamong people $60 years of age, largely because theyfound little evidence from randomized trials showingthat tighter BP control leads to better outcomes (7).These recommendations have been criticized asrelying too much on trials, without considering otherforms of evidence.

In this issue of the Journal, Sim et al. (8) providemore support for relaxing BP treatment targets. They

*Editorials published in the Journal of the American College of Cardiology

reflect the views of the authors and do not necessarily represent the

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

School of Medicine, Boston, Massachusetts; and the kDepartment of

Epidemiology, Boston University School of Public Health, Boston, Mas-

sachusetts. Dr. Andersson has received a travel grant from AstraZeneca;

and a research grant (#FSS-11-120873) from the Danish Agency for Sci-

ence, Technology and Innovation. Dr. Vasan has reported that he has no

relationships relevant to the contents of this paper to disclose.

analyzed the association of actual, on-treatment BPlevels with the risk of end-stage renal disease andmortality over 3 to 5 years of follow-up in individualswho were diagnosed with hypertension in the KaiserPermanente Southern California health system. Theiranalyses of nearly 400,000 individuals, 19% of whomhad ischemic heart disease and 30% of whom haddiabetes, showed a significant J-shaped associationbetween actual (treated) BP levels and adverse out-comes, mainly driven by the higher mortality associ-ated with lower on-treatment BP levels. Their datasuggest that the lowest risk of the composite outcomewas at systolic BP of 137 mm Hg and a diastolic BPof 71 mm Hg. BP either higher or lower than 130 to139 mm Hg systolic and 60 to 79 mm Hg diastolicwere associated with increased risk of the compositeendpoint.

Epidemiological studies of hypertensive, medicallyuntreated individuals have shown a graded increasein CVD and mortality with higher BP levels, withoutany evidence of any J-shaped curve (9,10). Theseobservations led to the argument that the “lower theblood pressure, the better the outcomes.” However,the associations from untreated individuals mightnot apply to people treated for hypertension, and itis obvious that driving BP too low with medicationscan lead to adverse effects. So, a J-curve relationshipbetween on-treatment BP and mortality is plausible,yet leaves unanswered the question of what levels ofsystolic and diastolic BP are optimal.

There is a physiologic rationale for a J-shapedrelationship between treated BP and outcomes.Hypertension may, to some extent, be a consequenceof high arterial stiffness, so overly aggressive BPlowering can lead to orthostatic hypotension andhypoperfusion of vital organs (11). Furthermore, with

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long-standing uncontrolled or poorly controlledhypertension, autoregulatory mechanisms adapt tohigher BP levels, so the threshold for hypoperfusionof vital organs is shifted upward (12). Coronaryperfusion pressure can fall approximately 30%from the normal value before the autoregulatorymechanisms begin to fail in people without heartdisease (13). Among people with heart disease (suchas significant coronary stenoses, left ventricularhypertrophy, or tachycardia), the coronary artery flowreserve is usually reduced. These people may, there-fore, be more sensitive to BP-lowering interventions.Lowering diastolic BP below 80 to 85 mm Hg (or even90 mm Hg) has been suggested to increase the risk ofmyocardial infarction in some groups (13,14).

Available randomized trials have not convincinglydemonstrated improved mortality rates with aggres-sive antihypertensive treatment (6,15). A collabora-tive meta-analysis of several large, randomizedclinical trials did not demonstrate any significanteffect on mortality from intensive lowering ofBP compared with standard BP-lowering targets(although there were fewer major adverse cardiacevents with the intensive treatment) (6). These ob-servations suggest that optimal BP targets may varywidely for different patient groups, and that theremight be heterogeneity in outcomes associated withtight BP control. Further evidence that tight BP con-trol may be undesirable in some patients is providedby a recent trial that randomized patients with dia-betes and hypertension to a systolic BP target of <140mm Hg versus <120 mm Hg and showed that patientsassigned to intensive treatment had greater declinesin total brain volume over 40 months (16).

Older patients and those with long-standing poorlycontrolled hypertension may be more sensitive tointensive BP-lowering treatment compared withyounger people with less comorbidity. Sim et al. (8)elegantly demonstrated that the optimal BP levelswere lower for younger patients (younger than vs.older than 70 years of age), for individuals with dia-betes, and for patients with low comorbidity burden.

J-shaped curves for CVD and mortality have beenshown for some other risk factors, including alcoholconsumption (17), glycosylated hemoglobin levels for

patients with diabetes (18), and body mass index(19,20). Although these associations are biologicallyplausible, they might be due to “reverse causation”:individuals with very low values of a risk factor mightbe sicker and have advanced disease and hencehigher mortality. Patients with chronic diseases alsomay have spontaneous BP reductions, as their con-ditions worsen. Sim et al. (8) found that systolic BPvalues fell 7 mm Hg in the 60 days before death.Although the J-shaped relation remained evidenteven when these pre-mortality BP values wereomitted from the analysis, a much longer phase ofBP reduction before death would not have beenadequately addressed by the analysis. In an analysisof individual patient data from 7 randomized clinicaltrials of blood pressure lowering, Boutitie et al. (21)also found an increased risk of mortality amongpatients with low blood pressure values, which wasnot related specifically to antihypertensive treat-ment, suggesting that comorbid conditions mightexplain the J-shaped mortality curve.

Ultimately, we need further studies to establishthe optimal BP treatment target for patients withvarious comorbidities. It may make sense to treatyounger people with less comorbidity more aggres-sively than older patients or people with a largeburden of comorbidity, but the exact numerical BPtargets are yet to be determined. Clinical trial resultswould provide a more definitive answer than obser-vational analyses will, even analyses of very largedatasets. The ongoing SPRINT (Systolic Blood PressureIntervention Trial), which randomizes people withhypertension to a systolic BP of <140 mm Hg or <120mm Hg, should provide key data on targets. Trulyuncontrolled hypertension, even on the basis of thelooser targets recommended by the Eighth Joint Na-tional Committee, remains a challenge, and we stillmust be concerned about undertreatment of hyper-tension, even as we sort out the optimal treatmenttarget.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.Charlotte Andersson, Gentofte Hospital, Departmentof Cardiology, Niels Andersens vej 65, 2900 Hellerup,Denmark. E-mail: ca@heart.dk.

RE F E RENCE S

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KEY WORDS blood pressure, epidemiology,hypertension, treatment targets