Journal of the American Society of Hypertension 11(1) (2017) 35
Hypertension Highlights
MEDICATION ADHERENCE AS A POTENTIAL
CONFOUNDER IN DEVICE TRIALS OF
RESISTANT HYPERTENSION
Previous randomized controlled clinical trials in patients
with resistant hypertension have demonstrated conflicting re-
sults with catheter-based renal artery denervation. The Renal
Denervation for Hypertension (DENERHTN) trial was a pro-
spective, open-label, randomized controlled clinical trial per-
formed at 15 French hypertension specialty centers.1 It was
designed to test whether or not renal denervation would lead
to significant additional blood pressure reduction in patients
with resistant hypertension who were concomitantly treated
with a prespecified escalating drug titration regimen. Eligible
patients had confirmed treatment resistance on ambulatory
blood pressure monitoring after treatment with indapamide
1.5 mg daily, ramipril 10 mg daily (or irbesartan if ramipril
was not tolerated), and amlodipine 10 mg daily as background
therapy. Patients were then randomized to receive either step-
ped care antihypertensive treatment with renal denervation or
stepped care antihypertensive treatment without renal denerva-
tion. No sham intervention was performed; as such, subjects
were not blinded to treatment allocation. Whether or not sub-
jects received renal denervation, they were treated with spirono-
lactone 25 mg a day, bisoprolol 10 mg a day, prazosin 5 mg per
day, and rilmenidine 1 mg daily added sequentially. After
6 months, data from 101 patients were analyzed. The mean
change in daytime ambulatory systolic blood pressure was
approximately 6 mm Hg lower in patients who received renal
denervation plus stepped care medical therapy as compared
to those who were treated with stepped care medication therapy
alone. There was no difference in the overall number of medi-
cations, approximately five on average, used in the two groups.
Although the DENERHTN study demonstrated a significant
reduction in blood pressure with renal denervation, since sub-
jects were not blinded to treatment allocation, there was concern
that differences in medication adherence may have accounted
for the difference in achieved blood pressure. During the initial
study, adherence was measured by a well-validated patient
recall instrument (French version of the 8-item Morisky Medi-
cation Adherence Scale-8) and was found to be no different be-
tween the two groups; however, measuring adherence in this
manner is subject to potential recall bias. Given the interest in
determining the effect of adherence to medications in studies
of renal denervation, post hoc, the investigators used stored
urine samples to assess adherence by drug screening in urine
and plasma samples. Data were analyzed for 85 patients.2 In
this analysis, the number of fully adherent, partially not
adherent, or completely nonadherent was not different in the
renal denervation and control groups, respectively. The change
in daytime ambulatory systolic blood pressure from baseline to
6 months was similar in patients who are adherent and not
adherent, 6.7 mm Hg in fully adherent patients, and
7.8 mm Hg in partially or completely nonadherent patients.
First, these data do not support the hypothesis that adherence
rates confounded the primary results of the trial. However, an
additional important finding was that nonadherence was very
common in this patient population. Approximately 50% of pa-
tients were either partially or fully nonadherent based upon this
methodology, with 13% of patients completely nonadherent.
The overall ratio of drugs detected to drugs prescribed was
only 75%. And, based on analyses presented in this manuscript,
it appears that adherence may be responsible for much of the be-
tween patient variability in achieved blood pressure seen in
resistant hypertension trials.
The high rate of poor adherence in DENERHTN occurred
despite the fact that these patients were given all of the ben-
efits of being in a clinical trial, including: frequent follow-up
with clinicians, no cost medications, use of once daily formu-
lations, use of home blood pressure monitoring, and frequent
reminders about the importance of medication adherence and
blood pressure control. It seems likely that rates of nonadher-
ence are higher in routine clinical practice, even when
directed by clinical hypertension specialists. Certainly,
adherence is an issue for all patients with hypertension, but
seems to be particularly so in patients with resistant hyperten-
sion who are often on complex multidrug regimens. Not only
is this a significant issue clinically, but it is also likely to be a
significant confounding issue in all studies of patients with
resistant hypertension, including those that are evaluating
an increasing array of potential investigational devices,
including renal denervation catheters. These data highlight
the importance of carefully measuring adherence, most
effectively with urine or blood samples, in clinical trials of
resistant hypertension, both during the run-in and treatment
phases. These findings also reaffirm the importance of study-
ing these interventions in patients not on any antihyperten-
sive medication (known as off-drug studies) in order to
4 Hypertension Highlights / Journal of the American Society of Hypertension 11(1) (2017) 35
truly prove the concept that these strategies lower blood pres-
sure without the confounding issue of medication adherence.
In routine clinical practice, the importance of careful
screening for pseudoresistance cannot be stressed enough.
The discrepancy between reported adherence and measured
adherence suggests that we need better technology for easily
and accurately assessing adherence both in research and clin-
ical practice.
Michael J. Bloch, MD, FACP, FASH, FNLA, FSVM
Department of Medicine
University of Nevada School of Medicine
Reno, NV, USA
Department of Vascular Care
Renown Institute of Heart and Vascular Health
Reno, NV, USA
http://dx.doi.org/10.1016/j.jash.2016.11.006
References
1. Azizi M, Sapoval M, Gosse P, Monge M, Bobrie G,
Delsart P, et al. Optimum and stepped care standardized
antihypertensive treatment with or without renal dener-
vation for resistant hypertension (DENERHTN): a
multicenter, open-label, randomized controlled trial.
Lancet 2015;385:195765.
2. Azizi M, Pereira H, Hamdidouche I, Gosse P, Monge M,
Bobrie G, et al. Adherence to antihypertensive treatment
and the blood pressure lowering effects of renal denerva-
tion in the renal denervation for hypertension (DE-
NERHTN) trial. Circulation 2016;134(12):84757.
DOES SPRINT SUPPORT A CHANGE IN BLOOD
PRESSURE TARGETS? THE IMPORTANCE OF
TWO IMPLICIT ASSUMPTIONS AND BLOOD
PRESSURE MEASUREMENT METHODS
The Systolic Blood Pressure Intervention Trial (SPRINT)
is a landmark study, which was designed to determine if a
systolic blood pressure (SBP, mm Hg) <120 was better
than a SBP target of <140 for reducing a composite cardio-
vascular outcome.1 In fact, the primary outcome of myocar-
dial infarction, other acute coronary syndrome, stroke, heart
failure, and cardiovascular death was reduced (hazard ratio,
0.75; 95% confidence interval: 0.640.89; P < .0001). The
authors stated that SPRINT now provides evidence of
benefits for an even lower SBP target than that currently
recommended in most hypertensive patients. An editorial
written by key editors of the NEJM stated that This clin-
ical trial (SPRINT) will change practice.2
These disruptive conclusions rest upon two implied
assumptions. First, standard treatment with a SBP goal
<140 mm Hg in SPRINT led to SBP values comparable
to those of treated hypertensives in the United States. If
standard treatment led to a higher SBP than usual care,
then the impact of SPRINT intensive treatment could be
overestimated. Since the authors expanded SPRINT find-
ings to most hypertensive patients, it seems appropriate to
compare SBP values with SPRINT standard treatment to
all treated hypertensives in the United States. In NHANES
20092012, mean SBP for all treated adults with hyperten-
sion was 130.1, which is 6.1 mm Hg lower than SPRINT
standard treatment mean at 1 year and 4.5 mm Hg lower
than the trial mean.3 The higher mean SBP with SPRINT
standard treatment than with usual treatment in the United
States is most likely explained by the study protocol, which
required reducing antihypertensive medications if SBP was
<130 on any single visit or <135 on consecutive visits in
standard treatment participants. This protocol is not typical
of usual care. In fact, 87% of patients in SPRINT standard
treatment had antihypertensive medications reduced at least
once.4
The second key implied assumption is that intensive treat-
ment led to a lower SBP than that in adults with treated hyper-
tension who attained a SBP <140 mm Hg. If this is not true,
then the rationale for lowering target SBP to <130 or <120
is weakened and the rationale for controlling a greater percent-
age of treated hypertensives to SPB <140 strengthened. Adults
in the United States with treated hypertension and SBP <140
attained a mean SBP of 120.9 in 20092012,3 which is slightly
lower than the 1-year mean of 121.4 and the all trial mean of
121.5 with SPRINT intensive treatment.
The blood pressure (BP) measurement method in
SPRINT was rigorous but not representative of usual care
or most clinical trials in hypertension. SPRINT measured
BP after subjects rested 5 minutes alone in the examination
room, that is, unattended automated office BP (AOBP). As
noted,3 a previous ambulatory BP monitoring (ABPM)
study showed that unattended AOBP after 5-minute rest
produces SBP values w7 mm Hg lower than daytime
ABPM values, which is comparable to findings in the
SPRINT APBM substudy among intensively treated pa-
tients. If we assume that NHANES-attended BP measure-
ments approximate daytime ABPM values, then the
superiority of SBP in all treated hypertensive adults to stan-
dard treatment and all treated adults with controlled hyper-
tension to intensive treatment is even greatera difference
further magnified if NHANES-attended BP values are
higher than daytime ABPM.
SPRINT remains a landmark study which provides ev-
idence for a SBP goal <140, particularly in older adults
where the evidence for SBP <140 versus <150 was
debated.1 If future guidelines lower the SBP goal based
on SPRINT, then it would seem prudent to recommend