- Email: [email protected]
No Such Thing as Ideal Blood Pressure
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
VOL. 67, NO. 25, 2016
ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 0735-1097/$36.00
PUBLISHED BY ELSEVIER
http://dx.doi.org/10.1016/j.jacc.2016.05.005
EDITOR’S PAGE
No Such Thing as Ideal Blood Pressure A Case for Personalized Medicine Valentin Fuster, MD, PHD
“The practice of making a sharp division
(i.e.,
angiotensin-converting
enzyme
inhibitors),
between normal and pathologically high blood
edema (i.e., calcium-channel blockers), and so on.
pressure is entirely arbitrary and is in the nature
We also need to determine whether the level of BP
of artifact. Essential hypertension represents the
achieved is too low for a given patient, resulting
upper end of a distribution curve showing
in lightheadedness, dizziness, or fainting. Thus,
continuous variation, with no definite evidence
personalized pharmacotherapy, a model that tailors
of two populations.”
specific medication to the individual patient and that
A
—G.W. Pickering (1) pproximately 80 million American adults (29%) have hypertension—1 of every 3 adults in the United States (2)—and it remains a
leading risk factor for stroke and heart disease. Unfortunately, >50% of the hypertensive population remains untreated or has blood pressure (BP) that is only partially under control (2,3), which is a critical
problem of adherence. In fact, in a recent study of patients with hypertension who were monitored with electronic pill boxes, 42% were not adherent, which was defined as taking <80% of prescribed antihypertensive medication (4). Furthermore, the total costs associated with hypertension in 2011 in the United States were $46 billion in health care services, medications, and missed days of work (5). When faced with these statistics, such issues related to hypertension and BP control appear to be quite challenging. We, as general internists or cardiovascular specialists, have the responsibility of helping each of our individual patients achieve the ideal BP. However, in addition to the problem of adherence, this decisionmaking is complex, as we weigh the not infrequent side effects of medications in each of our patients. The medications, for example, can cause fatigability (i.e.,
beta-blockers),
gastrointestinal
difficulties
has proved successful in oncology, is becoming a huge challenge in the cardiovascular field because of, on the one hand, the well-recognized low adherence of patients to cardiovascular medications in general and antihypertensive agents in particular (6,7), and on the other hand, the frequent side effects including the targeting of a BP that is too low for a given patient. Focusing on the lowest possible objective BP target is generating confusion among general internists and cardiovascular specialists (8). Although some authors have suggested that the target should be as low as possible, this pathway unfortunately ignores an important clinical consideration. That is, the physician needs to establish a BP target as low as can be tolerated by the patient. We cannot negate the side effects associated with antihypertensive agents, which are different depending on the unique biology of each patient. In other words, there is not such a thing as ideal BP, again, unless we take into account what is the target that our patient can tolerate. Perhaps, in the cardiovascular field, this is the first obvious evidence for personalized medicine or pharmacotherapy. Let us elaborate on this concept further and in more detail. There is a great deal of misinformation circulated in the mainstream media and among our patients, largely due to the statistical presentation of recent, large-scale trials. As I have written about before (9),
From the Zena and Michael A. Wiener Cardiovascular Institute, Icahn
the authors of the landmark SPRINT (Systolic Blood
School of Medicine at Mount Sinai, New York, New York.
Pressure Intervention Trial) wrote: “Trial participants
Fuster
JACC VOL. 67, NO. 25, 2016 JUNE 28, 2016:3014–5
Editor’s Page
assigned to the lower systolic BP target (intensive-
hypotension, dizziness, and light-headedness but not
treatment group), as compared with those assigned to
syncope. In a separate arm of that study, the re-
the higher target (standard-treatment group), had a
searchers randomly assigned rosuvastatin at a dose of
25% lower relative risk of the primary outcome” (10)
10 mg/day or placebo to 12,705 participants in 21
(italics in quotation marks included for emphasis).
countries who did not have cardiovascular disease
In actuality, this was an absolute risk reduction in a
and were at intermediate risk (12). Although the
primary outcome, from 6.8% to 5.2%, over a median
rosuvastatin arm did experience a lower risk of car-
3.26-year follow-up. As I wrote at the time, it is our
diovascular events compared with the placebo arm—
charge as investigators to assess both the efficacy and
3.7% versus 4.8%—those patients in the treatment
the safety of therapies for our patients. Indeed, we
arm had a higher incidence of cataract surgery and
need to be very clear when presenting adverse out-
muscle symptoms. Despite these findings, the main-
comes. When reporting on the serious adverse events,
stream press spoke to the benefits of placing more
the authors wrote that 4.7% of the intensive-
patients on BP and lipid-lowering medications.
treatment group and 2.5% of the standard-treatment
In the cardiovascular field, there are some similar
group had serious adverse events that were classi-
outcomes between antihypertensive and statin med-
fied as possibly or definitely related to the interven-
ications; thus, a lower targeted level leads to not only
tion (10), which was a relative risk increase of 88% by
a greater benefit but also a greater chance of side ef-
applying similar presentation of the data on efficacy
fects, particularly with the antihypertensive agents.
and safety. In the treatment of our patients, the
On the basis of a recent systematic review and meta-
trade-off between efficacy and safety (benefits and
analysis of 123 studies with >600,000 participants,
side effects) is essential in achieving a cautious,
regardless of the baseline systolic BP (from <130
balanced therapeutic approach as clinicians.
mm Hg to any higher level), for every 10-mm Hg
More recently, the impressive, 3-arm HOPE-3
decrease in systolic BP there was a relative 20% sig-
trial
nificant reduction of major cardiovascular events;
randomly assigned 12,705 participants in 21 countries
thus, a higher baseline BP led to a higher absolute
(Heart
Outcomes
Prevention
Evaluation-3)
at intermediate risk who did not have cardiovascular
beneficial effect (13). But, as discussed, a critical issue
disease to receive either candesartan at a dose of
is what magnitude drop in BP may be tolerated by a
16 mg/day plus hydrochlorothiazide at a dose of
given patient. In other words, the answer is, there is
12.5 mg/day or placebo (11). At baseline, the mean BP
no such thing as an ideal BP, but rather, a personal-
in the entire trial population was 138.1/81.9 mm Hg.
ized approach should be applied to each individual
The mean decreases from baseline during the trial
patient.
were 10.0 13.1 mm Hg in the active treatment group and 4.0 12.9 mm Hg in the placebo group, with an
ADDRESS
average difference between the groups of 6.0 13.0
Fuster, Zena and Michael A. Wiener Cardiovascular
CORRESPONDENCE
mm Hg, which was not significant (11). Yet, as
Institute, Icahn School of Medicine at Mount Sinai,
compared with placebo, the active treatment arm was
One
associated with a slightly higher risk of symptomatic
York 10029. E-mail: [email protected].
Gustave
L.
Levy
Place,
TO:
New
Dr.
Valentin
York,
New
REFERENCES 1. Rothstein WG. Readings in American Health Care: Current Issues in Socio-historical Perspective. Madison, WI: University of Wisconsin Press,
6. Yusuf S, Islam S, Chow CK, et al. Use of secondary prevention drugs for cardiovascular disease in the community in high-income, middle-income, and low-
10. The SPRINT Research Group. A randomized trial of intensive versus standard bloodpressure control. N Engl J Med 2015;373:
1995;94.
income countries (the PURE Study): a prospective epidemiological survey. Lancet 2011;378:1231–43.
2103–16.
2. Go AS, Bauman MA, Coleman King SM, et al. An effective approach to high blood pressure control. Hypertension 2014;63:878–85. 3. Kotchen TA, Cowley AW, Liang M. Ushering hypertension into a new era of precision medicine. JAMA 2016;315:343–4. 4. Gallagher BD, Muntner P, Moise N, Lin JJ, Kronish IM. Are two commonly used self-report questionnaires useful for identifying antihypertensive medication nonadherence? J Hypertens 2015;33:1108–13.
7. Castellano JM, Sanz G, Fernandez Ortiz A, et al. A polypill strategy to improve global secondary
11. Lonn EM, Bosch J, López-Jaramillo P, et al. Blood-pressure lowering in intermediate-risk persons without cardiovascular disease.
cardiovascular prevention: from concept to reality. J Am Coll Cardiol 2014;64:613–21.
N Engl J Med 2016 Apr 2 [E-pub ahead of print].
8. Krakoff LR, Gillespie RL, Ferdinand KC, et al. 2014 hypertension recommendations from the
12. Yusuf S, Bosch J, Dagenais G, et al. Cholesterol lowering in intermediate-risk persons without
Eighth Joint National Committee Panel Members raise concerns for elderly black and female populations. J Am Coll Cardiol 2014;64:394–402.
cardiovascular disease. N Engl J Med 2016 Apr 2 [E-pub ahead of print].
5. Mozzafarian D, Benjamin EJ,Go AS, et al. Heart disease
9. Fuster V. Unraveling the complexities of sta-
13. Ettehad D, Emdin CA, Anderson SG, et al. Blood pressure lowering for prevention of cardiovascular
and stroke statistics—2015 update: a report from the American Heart Association. Circulation 2015:e29–322.
tistical presentation: why it is important. J Am Coll Cardiol 2015;66:2909–10.
disease and death: a systematic review and metaanalysis. Lancet 2016;387:957–67.
3015
VOL. 67, NO. 25, 2016
ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 0735-1097/$36.00
PUBLISHED BY ELSEVIER
http://dx.doi.org/10.1016/j.jacc.2016.05.005
EDITOR’S PAGE
No Such Thing as Ideal Blood Pressure A Case for Personalized Medicine Valentin Fuster, MD, PHD
“The practice of making a sharp division
(i.e.,
angiotensin-converting
enzyme
inhibitors),
between normal and pathologically high blood
edema (i.e., calcium-channel blockers), and so on.
pressure is entirely arbitrary and is in the nature
We also need to determine whether the level of BP
of artifact. Essential hypertension represents the
achieved is too low for a given patient, resulting
upper end of a distribution curve showing
in lightheadedness, dizziness, or fainting. Thus,
continuous variation, with no definite evidence
personalized pharmacotherapy, a model that tailors
of two populations.”
specific medication to the individual patient and that
A
—G.W. Pickering (1) pproximately 80 million American adults (29%) have hypertension—1 of every 3 adults in the United States (2)—and it remains a
leading risk factor for stroke and heart disease. Unfortunately, >50% of the hypertensive population remains untreated or has blood pressure (BP) that is only partially under control (2,3), which is a critical
problem of adherence. In fact, in a recent study of patients with hypertension who were monitored with electronic pill boxes, 42% were not adherent, which was defined as taking <80% of prescribed antihypertensive medication (4). Furthermore, the total costs associated with hypertension in 2011 in the United States were $46 billion in health care services, medications, and missed days of work (5). When faced with these statistics, such issues related to hypertension and BP control appear to be quite challenging. We, as general internists or cardiovascular specialists, have the responsibility of helping each of our individual patients achieve the ideal BP. However, in addition to the problem of adherence, this decisionmaking is complex, as we weigh the not infrequent side effects of medications in each of our patients. The medications, for example, can cause fatigability (i.e.,
beta-blockers),
gastrointestinal
difficulties
has proved successful in oncology, is becoming a huge challenge in the cardiovascular field because of, on the one hand, the well-recognized low adherence of patients to cardiovascular medications in general and antihypertensive agents in particular (6,7), and on the other hand, the frequent side effects including the targeting of a BP that is too low for a given patient. Focusing on the lowest possible objective BP target is generating confusion among general internists and cardiovascular specialists (8). Although some authors have suggested that the target should be as low as possible, this pathway unfortunately ignores an important clinical consideration. That is, the physician needs to establish a BP target as low as can be tolerated by the patient. We cannot negate the side effects associated with antihypertensive agents, which are different depending on the unique biology of each patient. In other words, there is not such a thing as ideal BP, again, unless we take into account what is the target that our patient can tolerate. Perhaps, in the cardiovascular field, this is the first obvious evidence for personalized medicine or pharmacotherapy. Let us elaborate on this concept further and in more detail. There is a great deal of misinformation circulated in the mainstream media and among our patients, largely due to the statistical presentation of recent, large-scale trials. As I have written about before (9),
From the Zena and Michael A. Wiener Cardiovascular Institute, Icahn
the authors of the landmark SPRINT (Systolic Blood
School of Medicine at Mount Sinai, New York, New York.
Pressure Intervention Trial) wrote: “Trial participants
Fuster
JACC VOL. 67, NO. 25, 2016 JUNE 28, 2016:3014–5
Editor’s Page
assigned to the lower systolic BP target (intensive-
hypotension, dizziness, and light-headedness but not
treatment group), as compared with those assigned to
syncope. In a separate arm of that study, the re-
the higher target (standard-treatment group), had a
searchers randomly assigned rosuvastatin at a dose of
25% lower relative risk of the primary outcome” (10)
10 mg/day or placebo to 12,705 participants in 21
(italics in quotation marks included for emphasis).
countries who did not have cardiovascular disease
In actuality, this was an absolute risk reduction in a
and were at intermediate risk (12). Although the
primary outcome, from 6.8% to 5.2%, over a median
rosuvastatin arm did experience a lower risk of car-
3.26-year follow-up. As I wrote at the time, it is our
diovascular events compared with the placebo arm—
charge as investigators to assess both the efficacy and
3.7% versus 4.8%—those patients in the treatment
the safety of therapies for our patients. Indeed, we
arm had a higher incidence of cataract surgery and
need to be very clear when presenting adverse out-
muscle symptoms. Despite these findings, the main-
comes. When reporting on the serious adverse events,
stream press spoke to the benefits of placing more
the authors wrote that 4.7% of the intensive-
patients on BP and lipid-lowering medications.
treatment group and 2.5% of the standard-treatment
In the cardiovascular field, there are some similar
group had serious adverse events that were classi-
outcomes between antihypertensive and statin med-
fied as possibly or definitely related to the interven-
ications; thus, a lower targeted level leads to not only
tion (10), which was a relative risk increase of 88% by
a greater benefit but also a greater chance of side ef-
applying similar presentation of the data on efficacy
fects, particularly with the antihypertensive agents.
and safety. In the treatment of our patients, the
On the basis of a recent systematic review and meta-
trade-off between efficacy and safety (benefits and
analysis of 123 studies with >600,000 participants,
side effects) is essential in achieving a cautious,
regardless of the baseline systolic BP (from <130
balanced therapeutic approach as clinicians.
mm Hg to any higher level), for every 10-mm Hg
More recently, the impressive, 3-arm HOPE-3
decrease in systolic BP there was a relative 20% sig-
trial
nificant reduction of major cardiovascular events;
randomly assigned 12,705 participants in 21 countries
thus, a higher baseline BP led to a higher absolute
(Heart
Outcomes
Prevention
Evaluation-3)
at intermediate risk who did not have cardiovascular
beneficial effect (13). But, as discussed, a critical issue
disease to receive either candesartan at a dose of
is what magnitude drop in BP may be tolerated by a
16 mg/day plus hydrochlorothiazide at a dose of
given patient. In other words, the answer is, there is
12.5 mg/day or placebo (11). At baseline, the mean BP
no such thing as an ideal BP, but rather, a personal-
in the entire trial population was 138.1/81.9 mm Hg.
ized approach should be applied to each individual
The mean decreases from baseline during the trial
patient.
were 10.0 13.1 mm Hg in the active treatment group and 4.0 12.9 mm Hg in the placebo group, with an
ADDRESS
average difference between the groups of 6.0 13.0
Fuster, Zena and Michael A. Wiener Cardiovascular
CORRESPONDENCE
mm Hg, which was not significant (11). Yet, as
Institute, Icahn School of Medicine at Mount Sinai,
compared with placebo, the active treatment arm was
One
associated with a slightly higher risk of symptomatic
York 10029. E-mail: [email protected].
Gustave
L.
Levy
Place,
TO:
New
Dr.
Valentin
York,
New
REFERENCES 1. Rothstein WG. Readings in American Health Care: Current Issues in Socio-historical Perspective. Madison, WI: University of Wisconsin Press,
6. Yusuf S, Islam S, Chow CK, et al. Use of secondary prevention drugs for cardiovascular disease in the community in high-income, middle-income, and low-
10. The SPRINT Research Group. A randomized trial of intensive versus standard bloodpressure control. N Engl J Med 2015;373:
1995;94.
income countries (the PURE Study): a prospective epidemiological survey. Lancet 2011;378:1231–43.
2103–16.
2. Go AS, Bauman MA, Coleman King SM, et al. An effective approach to high blood pressure control. Hypertension 2014;63:878–85. 3. Kotchen TA, Cowley AW, Liang M. Ushering hypertension into a new era of precision medicine. JAMA 2016;315:343–4. 4. Gallagher BD, Muntner P, Moise N, Lin JJ, Kronish IM. Are two commonly used self-report questionnaires useful for identifying antihypertensive medication nonadherence? J Hypertens 2015;33:1108–13.
7. Castellano JM, Sanz G, Fernandez Ortiz A, et al. A polypill strategy to improve global secondary
11. Lonn EM, Bosch J, López-Jaramillo P, et al. Blood-pressure lowering in intermediate-risk persons without cardiovascular disease.
cardiovascular prevention: from concept to reality. J Am Coll Cardiol 2014;64:613–21.
N Engl J Med 2016 Apr 2 [E-pub ahead of print].
8. Krakoff LR, Gillespie RL, Ferdinand KC, et al. 2014 hypertension recommendations from the
12. Yusuf S, Bosch J, Dagenais G, et al. Cholesterol lowering in intermediate-risk persons without
Eighth Joint National Committee Panel Members raise concerns for elderly black and female populations. J Am Coll Cardiol 2014;64:394–402.
cardiovascular disease. N Engl J Med 2016 Apr 2 [E-pub ahead of print].
5. Mozzafarian D, Benjamin EJ,Go AS, et al. Heart disease
9. Fuster V. Unraveling the complexities of sta-
13. Ettehad D, Emdin CA, Anderson SG, et al. Blood pressure lowering for prevention of cardiovascular
and stroke statistics—2015 update: a report from the American Heart Association. Circulation 2015:e29–322.
tistical presentation: why it is important. J Am Coll Cardiol 2015;66:2909–10.
disease and death: a systematic review and metaanalysis. Lancet 2016;387:957–67.
3015