Controlling Hypertension: We Have the Tools—We Just Need to Use Them
Controlling Hypertension: We Have the Tools-We Just Need to Use Them
David J. Hyman 0
Valory Pavlik 0
0 Baylor College of Medicine , Houston, TX , USA
B been improving in recent decades. Poor control in the
lood pressure control among treated hypertensives has
past was largely attributed to Bclinical inertia^—i.e., clinicians
not increasing or adding antihypertensives in the face of
uncontrolled blood pressure (BP), with nonadherence
accounting for only 13% of the poor control.1 Physicians are
now much more likely to add a second or third drug to reach
the BP treatment target of less than 140/90 mmHg. Although
BP control is usually achieved with three-drug therapy, some
studies have suggested that many patients on three drugs,
including a diuretic, were not controlled, and therefore
potentially met criteria for resistant hypertension. Several studies
published between 2003 and 2008 found that about 10% of all
treated hypertensives on three or more drugs had uncontrolled
BP.2 Thus, with over 80 million treated hypertensives in the
US alone, there appeared to be a vast number of people who
could benefit from further intervention and a huge market for
new drugs or technologies that were proven to be effective.
In this issue of JGIM, Makai and colleagues3 present a
network meta-analysis that compares the potential new interventions
tested for patients who need something more than the three
standard BP drugs to achieve BP control. Without delving into
the complexities of the methodology, the conclusion that none of
the options reviewed was clearly superior to mineralocorticoid
receptor antagonists (MRAs)—spironolactone and
eplerenone—is reassuring, as, unlike MRAs, none of the other
interventions included in the meta-analysis have been proven safe
and effective in their own right, and are not available outside of
research settings in this country. Furthermore, it is unlikely that
we will know enough about their long-term effectiveness and
safety to envision them as part of our therapeutic arsenal in the
Developing new drugs and especially new devices for
resistant hypertension has engendered much excitement in the
hypertension field since about 2000. Unfortunately, the results
to date have been disappointing. New drug development has
always been expensive and risky. The success of Gilead
Sciences’ hepatitis C drug, sofosbuvir, was not replicated with
darusentan, the company’s drug for resistant hypertension.
Darusentan’s side effect profile was a bit worrisome in its
most successful trial, and it failed to beat placebo for the
prespecified primary endpoint of office BP in a larger trial; the
sponsor stopped development in 2009.4
Several types of devices for controlling BP—including
renal denervation (RDN), carotid baroreceptor modulation,
median nerve modulation, deep brain stimulation, and creation
of arteriovenous (AV) anastomosis—have been developed and
are in various phases of testing.5 The most widely used and
evaluated are the renal denervation devices. Although many
promising studies have been reported around the world, they
were not blinded. The field experienced a significant setback
when the highly anticipated results from the sham-controlled
Symplicity 3 trial were negative. The evidence-based observer
is likely to have reached the same conclusions as those
recently reported in a Cochrane review of renal denervation: 1)
based on low-quality evidence, renal denervation has no effect
on major cardiovascular events or renal function; 2)
moderatequality evidence shows no effect on BP; and 3) based on
lowquality evidence, renal denervation caused an increase in
bradycardia episodes.6 Nevertheless, much was learned from
the early trials, and new trials are underway with better devices
and study designs to address some of the challenges in patient
selection, adherence monitoring, and BP measurement.
The ROX Coupler—the AV device that was shown in the
network meta-analysis to be superior to MRAs for 24-h
diastolic blood pressure (DBP) control—has been tested in one
unblinded trial of 88 patients, 44 of whom received the
device.7 The ROX Coupler was initially designed to improve
oxygenation in patients with chronic obstructive pulmonary
disease (COPD), but was also noted to reduce BP. The device
was inserted in a femoral vein, and pushed through to create an
openable and closable fistula between the iliac vein and artery.
The follow-up time in the trial was 6 months. The impressive
drop in systolic blood pressure (SBP) reported in the single
unblinded trial was accompanied by a 29% incidence of
venous stenosis, which was treated with venous stenting
procedures. The multi-year risks and benefits of this novel therapy
are unknown, and further trials are ongoing.
Luckily, although it might not have been clear over a decade
ago when the newer interventions began testing, there is now
little doubt in the hypertension community as to the next line of
therapy in most cases for resistant hypertension after three
standard drugs. In this role, MRAs have been shown to be superior to
other BP drugs as the fourth drug in randomized controlled
trials.8, 9 The MRA was found to reduce SBP an average of
7.4 mmHg versus active comparators such as beta-blockers,
improving BP in almost all patients, and bringing over half of
patients into full control. Most of the evidence regarding MRAs
as a class is with spironolactone, usually at doses of 25–50 mg.
Spironolactone is a Bfour-dollar^ drug in many pharmacies. Its
feared side effect, gynecomastia, occurs in about 5% of men who
take it for resistant hypertension. Eplerenone, which is also
generic, does not cause gynecomastia, but it is more expensive
and less potent than spironolactone. Although the package insert
limits the maximum dose to 100 mg per day, recent work
suggests that to obtain the equivalent effect, eplerenone has to
be dosed at 4.5 times the dose of spironolactone.10 As most
patients will also be on an angiotensin-converting enzyme
(ACE) inhibitor or angiotensin receptor blocker (ARB),
potassium does need to be monitored. Despite the strong evidence to
support the efficacy of MRAs, national databases suggest that
less than 6% of hypertensives on four drugs are on an MRA.11
This may be another example of very slow diffusion of
evidencebased interventions to medical practitioners in the community,
e s p e c i a l l y w h e n g e n e r i c d r u g s a r e n o t h e a v i l y
promoted—something that teachers of primary care try to correct.
In interpreting the findings of the network meta-analysis by
Makai et al., we must not lose sight of other important
considerations in addressing resistant hypertension. The definition
of resistant hypertension includes 1) treatment with three or
more adequately dosed antihypertensives, 2) confirmation that
the patient is taking the medications as described, and 3)
documentation that the BP is uncontrolled outside the office.
As resistant hypertension has received increasing attention
from the research community and industry groups, it has
become clear that it is not always easy to establish whether
all three criteria have been met. To solve this problem, the term
Bapparent treatment-resistant hypertension^ has gained
currency. The number of resistant hypertensives who truly need
more effective therapies than are currently available is likely a
function of how much effort is made to identify them. In one
US sample, of those who appeared to be resistant on the basis
of office BP and prescribed regimen, 29% had controlled BP
on 24-h monitoring and 29% were non-adherent based on
electronic bottle cap monitoring. In this study, as in others that
describe resistant hypertension samples, even when patients
are on a three-drug regimen that includes a diuretic, the
combination of drugs and dosing is frequently suboptimal.
Diuretics are the principal tool for reducing difficult-to-control
BP. Many experts believe that chlorthalidone should be the
preferred diuretic, but it is rarely used in practice.
Hydrochlorothiazide is almost never used at doses greater than 25 mg per
day.11 This dose is much less potent than chlorthalidone 25 mg
and may not be adequate for resistant hypertension. One large
Israeli study with good medication and refill records found
that only 0.8% of hypertensives who were 85% adherent to
three medications, including a diuretic, had uncontrolled BP.12
The most useful technological innovations for managing
resistant hypertension may be in the areas of adherence
promotion and monitoring and in more accurate BP measurement.
As mentioned earlier, it is reassuring that in the general
hypertension population, treatment non-adherence is not the
overwhelming problem. However, in populations with
resistant hypertension referred to hypertension specialty centers or
for device intervention, this is not the case. There have been
several recent studies in these populations that used serum or
urine drug levels to ascertain adherence. These studies have
shown very high levels of complete or partial
non-adherence.13 Interventions in this very small but high-risk
population will likely need to be multifactorial, including behavioral
approaches. The growing appreciation of the importance of
out-of-office BP measurement will help with accurate
classification of resistant hypertension. If we adopt new
technologies and protocols to move away from the problematic
officebased BP measurements that are now the norm, we could also
improve the recognition and management of resistant
We do not know precisely how many Breal’ resistant
hypertensives would remain after accounting for adherence and
outof-office BP, assuming widespread use of chlorthalidone, or
even requiring that four drugs including an MRA be included
in the new definition of resistant hypertension. Even if it is 1%,
given 80 million-plus hypertensives in the US, and over one
billion worldwide, there is still a potential need for new drugs
or devices. With further development and testing, device
therapy could conceivably be safe and inexpensive enough to
provide a lifestyle choice similar to LASIK eye surgery instead
of glasses or contacts. There may be a few patients with very
high-risk hypertension who are not amenable to improved
adherence, in whom device therapy could be lifesaving. The
immediate challenge is for primary care physicians and health
systems to use the existing drug arsenal, along with behavioral
interventions and BP measurement technologies, to further
reduce uncontrolled BP. If the already available tools were
properly deployed, it is likely that BP control in the US
population could reach 98%.
Corresponding Author: David J. Hyman, MD, MPH; Baylor College
of Medicine, Houston, TX, USA (e-mail: ).
Compliance with ethical standards:
Conflict of Interest: The authors have no confilicts of interest.
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