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Treating Obstructive Sleep Apnea: Is There More to the Story Than 2 Millimeters of
Mercury?
John S. Floras and T. Douglas Bradley
Hypertension. 2007;50:289-291; originally published online June 4, 2007;
doi: 10.1161/HYPERTENSIONAHA.107.092106
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Editorial Commentary
Treating Obstructive Sleep Apnea
Is There More to the Story Than 2 Millimeters of Mercury?
John S. Floras, T. Douglas Bradley
O
bstructive sleep apnea (OSA), a common disorder,
increases the 4-year risk of developing hypertension by
⬇3-fold.1 In an uncontrolled trial, treatment of OSA when
present in drug-resistant hypertension by nasal continuous
positive airway pressure (CPAP) achieved substantial reductions in both nighttime and daytime blood pressure (BP).2
However, in controlled and uncontrolled studies involving
small cohorts of patients with OSA with stage 1 hypertension,
prehypertension, or normal BP, the short-term use of CPAP
had less or no effect on BP. A meta-analysis in the present
issue of Hypertension3 attempts to estimate the effect of this
intervention on BP.
The authors identified all of the published trials that
reported BP as a primary or a secondary end point in which
adults with OSA diagnosed by polysomnography were randomly allocated to therapeutic CPAP or not for ⱖ2 weeks.
These 16 trials involved 818 participants (86.3% men; mean
age: 51 years; mean apnea-hypopnea index: 36.2 events per
hour) treated for ⱕ24 weeks. From the 15 trials that reported
systolic and diastolic BP, the authors calculated a significant
mean net reduction of 2.46/1.83 mm Hg with CPAP and,
from the 7 trials that reported mean arterial BP, a significant net reduction of 2.22 mm Hg. By comparison, in a
previous meta-analysis restricted to 12 trials in which the
primary variable of interest was 24-hour mean ambulatory
BP, the calculated net decrease was still significant at
1.69 mm Hg.4 In the present analysis by Bazzano et al,3 the
mean net change in systolic BP tended to correlate with the
average nightly CPAP use (Figure 5 in Reference 3;
P⫽0.13). These authors concluded that CPAP decreases
BP among those with OSA, and treating OSA with CPAP
may help prevent hypertension.
There is increasing awareness of the adverse interactions
between OSA and several cardiovascular conditions.5 Consequently, these 2 conclusions are certain to attract attention.
However, they are based on a meta-analysis involving a small
number of subjects treated briefly. Absent are long-term data
confirming that any initial reduction persists, and there has
been no randomized, controlled test of the hypothesis that
The opinions expressed in this editorial are not necessarily those of the
editors or of the American Heart Association.
From the Department of Medicine (J.S.F., T.D.B.), University Health
Network and Mount Sinai Hospital, Toronto, Ontario, Canada; Toronto
Rehabilitation Institute (T.D.B.), Toronto, Ontario, Canada; and the
University of Toronto (J.S.F., T.D.B.), Toronto, Ontario, Canada.
Correspondence to John S. Floras, Suite 1614, 600 University Ave,
Toronto, Ontario M5G 1X5, Canada. E-mail [email protected]
(Hypertension. 2007;50:289-291.)
© 2007 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org
DOI: 10.1161/HYPERTENSIONAHA.107.092106
abolition of OSA in prehypertensive patients will prevent the
subsequent development of hypertension. Only 2 of these
trials recruited specifically hypertensive patients, in whom
hypertension was usually treated. The average BP of all 818
subjects was 131/80 mm Hg. In a subsequent subgroup
analysis, significant BP reductions were identified only in
those with BP ⱖ130/80 mm Hg. Little or no impact on BP
would be anticipated from any intervention in normotensive individuals. The analysis also conflates studies of
people with (afterload-insensitive) normal and (afterloadsensitive) impaired ventricular systolic function. Does this
meta-analysis then truly provide robust and reliable “level
A” evidence for an antihypertensive or hypertensionpreventative effect of CPAP? As we address this question,
we will develop 2 concepts: the distinction between
“effects” and “after effects” of OSA and its treatment and
the impact of negative intrathoracic pressure on cardiac
structure and function.
BP was obtained by ambulatory monitoring in 11 of these
studies and by conventional methods in a clinic or laboratory
setting in 5. Assumed is that nocturnal BP can be measured
reliably by this method. However, in OSA, nocturnal BP is
inherently unstable. Each obstructive apnea during sleep
elicits a 10- to 90-second cycle of apnea, progressive hypoxia
and hypercapnia, efferent sympathetic vasoconstrictor nerve
discharge, and arousal from sleep. Each cycle terminates with
a substantial surge in BP.5 CPAP, which prevents pharyngeal
obstruction, eliminates these oscillations, but once CPAP is
withdrawn, this acute antihypertensive effect disappears.6
The discontinuous noninvasive ambulatory method used in
the studies composing the present meta-analysis will not
reliably detect these recurrent BP surges or the acute damping
effect of CPAP on these oscillations. Thus, the nocturnal
values reported in Table 2 of Reference 3 are unlikely to be
accurate and likely underestimate any hypotensive effect of
CPAP during sleep.
However, the key clinical question is not, “what is the
acute effect of CPAP on BP during sleep in subjects with
OSA?” Because CPAP eliminates acutely the obstructive
pressor stimulus, the finding that its therapeutic application
lowers BP during sleep is obvious. If comparison is made
between 2 sequences of ambulatory BP recordings in the
same individual, 1 obtained during sustained running exercise
and 1 during rest, one might choose to conclude that rest
lowers systolic BP, but it would be difficult to argue that
inactivity is more effective than regular exercise in preventing the development of hypertension.
If the goal is to treat or prevent hypertension, then this
question should be reframed as, “what are the after effects of
obstructive apnea during sleep and therapeutic CPAP on BP
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Hypertension
August 2007
during wakefulness?” The first randomized trial of CPAP in
OSA with sympathetic vasoconstrictor nerve traffic as its
primary end point demonstrated a significant reduction during wakefulness in all of the treated subjects and a parallel
decrease in concurrently measured systolic BP.7 Thus, an
important after effect of OSA is its chronic facilitation of
sympathetically mediated vasoconstriction during wakefulness.8 It is, therefore, noteworthy that the trial in which CPAP
caused the greatest fall in systolic BP involved patients with
OSA with advanced heart failure, individuals with the highest
daytime sympathetic nerve traffic of all of those represented
in this meta-analysis,8 and measured BP shortly after
waking.9
The after effects of therapeutic CPAP are, therefore,
critical to the authors’ conclusions, and here the data presented are ambiguous. In Figure 2 of Reference 3, they present
mean net changes in systolic BP for 15 studies without
indicating whether these represent daytime, nighttime, or
24-hour average measurements, yet their subgroup analyses
according to acquisition time (Table 2 of Reference 3) reports
changes in daytime systolic BP for only 9 trials. We,
therefore, assume that their pooled data represent a combination of values obtained during wakefulness, sleep, or both. If
so, these data do not reveal the actual after effects of CPAP.
As well, none of the mean net reductions in daytime systolic,
diastolic, or mean BP reported in Table 2 of Reference 3 were
in and of themselves significant, a finding that at first glance
appears to contradict both the authors’ first conclusion and
also their speculation that CPAP might be a useful nonpharmacological method of preventing the development of hypertension. However, this apparent lack of efficacy is likely an
issue of statistical power. Had the authors calculated mean
arterial BP from systolic and diastolic changes provided
(approximately ⫺2.07 mm Hg) and added these data to those
from trials that reported only mean BP, a significant reduction
might well have emerged. On the other hand, the authors also
inform us that, in subgroup analysis, the BP-lowering effects
of therapeutic CPAP were restricted to trials in which sham
CPAP was administered as control. Because sham CPAP is
not inert and can raise BP,10 therapeutic CPAP may itself
have no clinically relevant BP-lowering effect in a primarily
nonhypertensive study population.
OSA might well be the most common cause of preventable
and treatable secondary hypertension, but from the limited
information available to and generated by this meta-analysis, it
is premature to recommend, on the basis of level A evidence,
therapeutic CPAP either for the specific treatment of hypertension or for its prevention in those at risk. The importance
of the present statistical exercise is that it highlights the need
for adequately powered, randomized, long-term clinical trials
of therapeutic CPAP involving hypertensive and prehypertensive subjects.
An equally or more important long-term adverse hemodynamic consequence of OSA may be its effect on left-ventricular (LV) transmural pressure, a major component of afterload (Figure). The heart of a patient with OSA will be
subjected to acute increases in LV transmural pressure
several hundred times each night during 6 to 8 hours of sleep
over many years.5 Abrupt increases in negative intrathoracic
An elastic sphere within a glass jar provides a useful conceptual
model for the impact of OSA on LV systolic trans-mural pressure (LV systolic pressure minus intrathoracic pressure). If,
under baseline conditions (left jar), LV systolic pressure is
assumed to be 150 mm Hg and intrathoracic pressure 0 mm Hg,
then LV systolic trans-mural pressure is 150 mm Hg. If a peripheral vasoconstrictor, such as phenylephrine, is infused and
raises systolic LV pressure by 50 mm Hg (middle jar), LV systolic transmural pressure increases to 200 mm Hg. During OSA
(right jar), obstruction of the pharynx (illustrated by the cork)
causes the patient to generate negative intrathoracic pressure
during inspiratory efforts in a futile attempt to restore ventilation.
If, for example, ⫺50 mm Hg is generated, the net effect on LV
trans-mural pressure is equivalent to that induced by phenylephrine (200 mm Hg).
pressure induced by obstructive apneas have the potential to
acutely trigger myocardial ischemia, atrial fibrillation, and
ventricular arrhythmias, and over time impair tonic and reflex
vagal heart rate modulation and stimulate septal and LV
hypertrophy, ventricular remodeling, and thoracic aortic dilation. Therapeutic CPAP abolishes these negative intrathoracic pressure swings and reduces LV and intrathoracic aortic
transmural pressures.6 In a heart failure cohort, 1 month of
therapeutic CPAP reduced daytime sympathetic vasoconstrictor discharge7 and BP9 and improved LV systolic function.9
Thus, abolition of negative intrathoracic swings is a key
mechanism by which treatment of OSA could reduce adverse
stimuli to the heart and intrathoracic vessels, yet one that
cannot be detected by systemic BP recordings. Accordingly,
the very modest BP lowering reported by Bazzano et al3 may
not be the only or even the most important beneficial effect on
cardiovascular risk of treating OSA with CPAP.
Sources of Funding
This work was supported by grants from the Canadian Institutes of
Health Research (MOP 11607) and the Heart and Stroke Foundation
of Ontario (T4938 and PRG5276). J.S.F. holds the Canada Research
Chair in Integrative Cardiovascular Biology and is a Career Investigator of the Heart and Stroke Foundation of Ontario.
Disclosures
None.
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