A Network Meta-Analysis of Clinical Management Strategies for Treatment-Resistant Hypertension: Making Optimal Use of the Evidence
KEY WORDS: treatment-resistant hypertension; network meta-analysis;
MRAs.
J Gen Intern Med
A Network Meta-Analysis of Clinical Management Strategies for Treatment-Resistant Hypertension: Making Optimal Use of the Evidence
Peter Makai 1
Joanna IntHout 1
Jaap Deinum 1
Kevin Jenniskens
Gert Jan van der Wilt 1
0 Julius Center, University Medical Center Utrecht , Utrecht , The Netherlands
1 Department for Health Evidence, Health Technology Assessment Group, Radboud Institute for Health Sciences, Radboud University Medical Center , Nijmegen , The Netherlands
BACKGROUND: With the addition of surgical interventions to current medicinal treatments, it is increasingly challenging for clinicians to rationally choose among the various options for treating patients with apparent treatment-resistant hypertension (ATRHTN). This study aims to establish the comparative effectiveness of mineralocorticoid receptor antagonists (MRA), renal denervation (RDN), darusentan and central arteriovenous anastomosis (CAA) for patients with ATRHTN by performing a network meta-analysis. METHODS: Data Sources: Studies from recent meta-analyses for RDN and placebo effect were supplemented with a systematic search for MRAs in ATRHTN in the Pubmed, EMBASE, CINAHL and Cochrane databases through November 2016. Study Selection: Randomized controlled trials comparing treatment options for patients with ATRHTN. Data Extraction and Synthesis: Data were extracted using predefined data extraction forms, including the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria. A Bayesian random effects model was used to conduct a network meta-analysis. Spironolactone was used as the main comparator. Main Outcomes and Measures: Reduction in 24-h ambulatory blood pressure measurement (ABPM). RESULTS: Twenty articles met our inclusion criteria, and seven treatment alternatives were compared. Compared to MRA, CAA had the highest probability of being more effective, further reducing 24-h SBP (−4.8 mmHg [−13.0, 3.7]) and 24-h DBP (−9.7 mmHg [−18, -0.63]). This difference is likely to be clinically meaningful, with a probability of 78 and 96% at a threshold of a 2-mmHg reduction in blood pressure. CONCLUSIONS: When compared to MRA as anchor, darusentan, CAA and RDN are not more effective in achieving a clinically significant reduction in ambulatory blood pressure in individuals with apparent treatmentresistant hypertension.
INTRODUCTION
Hypertension (HTN) is the most common condition seen in
primary care,1 with a global prevalence of 41% in the general
population.2 Uncontrolled HTN is a risk factor for
cardiovascular and renal disease, sources of significant morbidity and
cost to society, and is therefore an important public health
target.1,3,4 An estimated 14–16% of hypertensive patients have
apparent treatment-resistant hypertension (ATRHTN).5 This
proportion will be even higher if more stringent criteria are
adopted for adequate blood pressure control.6–9 ATRHTN is
defined as inadequately controlled blood pressure despite
receiving three or more adequately dosed hypertensive
medications, of which at least one is a diuretic.10 Adherence is a key
factor in ATRHTN, and according to some estimates, 50% of
patients with ATRHTN do not adhere to their medication.11–13
The most common fourth-line treatment is the addition of a
mineralocorticoid receptor antagonist (MRA) to the treatment
regimen.14 In recent years, other pharmacological
interventions have been developed, including darusentan,15 an
endothelin receptor antagonist, as well as various
devicebased strategies such as renal denervation (RDN) and central
arteriovenous anastomosis (CAA).16
A lack of data on the comparative effectiveness of these
new treatment strategies poses challenges to the production
and interpretation of relevant clinical evidence and to choosing
optimal treatment strategies for patients. Direct comparison
trials and conventional pairwise meta-analyses have
demonstrated different conclusions regarding the efficacy of RDN,
likely because of the heterogeneity in control treatments. Trials
of RDN, for example, have compared RDN with standard
medication therapy (no additional treatment),17 with a sham
procedure (mimicking RDN without actually performing the
intervention)18 and with MRA as add-on therapy.19 While a
recent medium-sized trial showed that RDN was superior to
MRA,19 another trial of the same size failed to show a
difference in the primary endpoint.20 Among direct comparisons of
RDN with other active treatments, results have been mixed.
Three conventional pairwise meta-analyses show RDN to be
superior,17,21,22 while a fourth meta-analysis, based
exclusively on randomized controlled trials (RCTs), casts doubt on
these conclusions.23
Conventional pairwise meta-analysis is unable to deal with
heterogeneity in control interventions. A more appropriate
approach in such cases is a network meta-analysis.24 In a
network-meta analysis, effect sizes associat (...truncated)