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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/advagg_css\/css__ce2QY63WIanKyr8eSq7eavr1XQRRmFD6ZSmwpyJi8lM__zXwFqpqmxrZOXXcd_TpBQpjuELbmIP9wBR5UuTDWAO4__YJWWMMdfCJuAFm5cUEp88OsodhO3ZA-2lzRfoBsSlk4.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003EThis article discusses the renewed focus on treatment-resistant hypertension (RH), which has been sparked by the interest in catheter renal denervation and the somewhat disappointing results with this interventional approach in the SYMPLICITY HTN trial program.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003ERenal Disease\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EInterventional Techniques \u0026amp; Devices\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EHypertension \u0026amp; Kidney Disease\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EHypertensive Disease\u003C\/li\u003E\u003C\/ul\u003E\u003Cul class=\u0022kwd-group clinical-trial\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003ERenal Disease\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EInterventional Techniques \u0026amp; Devices\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EHypertension \u0026amp; Kidney Disease\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EHypertensive Disease\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ECardiology\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003EFour leading hypertension experts voiced their hope for a renewed focus on treatment-resistant hypertension (RH), sparked by the interest in catheter renal denervation (RDN) and the somewhat disappointing results with this interventional approach in the SYMPLICITY HTN trial program.\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003EThe prognosis of RH is severe, stated Roland E. Schmieder, MD, Friedrich Alexander University, Erlangen, Nurnberg, Germany, with associated annual rates of all-cause death ranging from 2% to 4% and major adverse cardiovascular (CV) and cerebrovascular events of 4.6%, on the basis of estimates from retrospective analyses, as there are no prospective, observational, longitudinal data.\u003C\/p\u003E\u003Cp id=\u0022p-4\u0022\u003ERH is defined by the major hypertension guidelines as a blood pressure (BP) that remains above goal despite optimized treatment with \u22653 antihypertensive (AH) drugs from different drug classes, including a diuretic. The European Society of Hypertension (ESH) and European Society of Cardiology (ESC) Guidelines include appropriate lifestyle measures in their definition [Mancia G et al. \u003Cem\u003EJ Hypertens\u003C\/em\u003E 2013].\u003C\/p\u003E\u003Cp id=\u0022p-5\u0022\u003EIn the international Reduction of Atherothrombosis for Continued Health registry, patients identified as having RH (12.7% of 53,530 patients) had an increased risk for CV death, myocardial infarction, or stroke at 4 years compared with patients without RH (HR, 1.11; 95% CI, 1.02 to 1.20; p=0.017) [Kumbhani DJ et al. \u003Cem\u003EEur Heart J\u003C\/em\u003E 2013]. An increased risk was noted for the individual endpoints of nonfatal stroke (HR, 1.26; 95% CI, 1.10 to 1.45; p= 0.0008) and hospitalization for congestive heart failure (p\u0026lt;0.0001).\u003C\/p\u003E\u003Cp id=\u0022p-6\u0022\u003EAdherence to treatment is a key factor to distinguish between uncontrolled hypertension (UH) and true RH. UH is defined as a lack of BP control despite treatment because of inadequate treatment regimens, poor adherence, undetected secondary hypertension, and true RH. One study showed that 23% of patients with RH were only partially adherent and 24% were fully nonadherent to treatment [Strauch B et al. \u003Cem\u003EJ Hypertens\u003C\/em\u003E 2013]. Other studies have investigated whether tandem high-performance liquid chromatography\/mass spectrometry urine analysis could be used to assess medication adherence and differentiate between patients with true RH versus UH due to nonadherence [Tomaszewski M et al. \u003Cem\u003EHeart\u003C\/em\u003E 2014].\u003C\/p\u003E\u003Cp id=\u0022p-7\u0022\u003EAn analysis from a community-based practice network in the United States showed that only 15% of 468,877 patients with hypertension had been prescribed optimal treatment; 31.5% had UH despite \u22653 AH drugs [Egan BM et al. \u003Cem\u003EHypertension\u003C\/em\u003E 2013].\u003C\/p\u003E\u003Cp id=\u0022p-8\u0022\u003EIn the United States, the prevalence of apparent RH rose from 15.9% in the period from 1998 to 2004 to 28.0% in the period from 2005 to 2008 among 13,375 adults treated with \u22653 drugs in the National Health and Nutrition Examination Surveys [Egan BM et al. \u003Cem\u003ECirculation\u003C\/em\u003E 2011]. Clinical characteristics associated with RH were albuminuria, reduced renal function, and signs of target organ damage. Prof. Schmieder stated that this increase in RH reflects improved efforts to treat patients to target BP levels, rather than a sicker population.\u003C\/p\u003E\u003Cp id=\u0022p-9\u0022\u003EIn the Spanish Ambulatory Blood Pressure Monitoring Registry of 68,045 treated patients with UH in usual daily practice, 12.2% had RH on the basis of office BP (OBP) \u2265140\/90 mm Hg despite predefined background therapy, while it was lower (7.6%) on the basis of ambulatory BP monitoring (ABPM) [de la Sierra A et al. \u003Cem\u003EHypertension\u003C\/em\u003E 2011]. The investigators suggested that ABPM may be a way to distinguish between true RH and white-coat hypertension.\u003C\/p\u003E\u003Cp id=\u0022p-10\u0022\u003EThe discordance between OBP and ABPM in distinguishing patients with RH was also found in the 3A Registry and thus requires further investigation, said Prof. Schmieder. Among 14,988 patients with UH enrolled in the registry, 1628 were taking \u22653 AH drugs at 1-year follow-up. Of these, BP was controlled in 49.63% on the basis of OBP and ABPM. However, in 5.65%, BP was controlled on the basis of OBP but not ABPM. Furthermore, 29.3% had UH on the basis of OBP but not ABPM, and 15.42% had controlled hypertension on the basis of ABPM but not OBP.\u003C\/p\u003E\u003Cp id=\u0022p-11\u0022\u003EScreening for secondary forms of hypertension is essential because they are frequent in the setting of RH, stated Michel Azizi, MD, Paris Descartes University, H\u00f4pital Europ\u00e9en Georges Pompidou, Paris, France. Primary aldosteronism is the most frequent cause of RH (20%\u201330%) and may be curable in younger patients with aldosterone-producing adenomas. The screening test is based on the measurement of the plasma aldosterone-to-renin ratio. The diagnosis of aldosterone-producing adenoma is based on additional tests to confirm autonomous aldosterone secretion (saline infusion test) and on imaging procedure (computed tomographic or magnetic resonance angiography [CTA; MRA]), followed by confirmation of the lateralization of aldosterone secretion by adrenal vein sampling in case of indication of adrenal surgery. Other common causes are obstructive sleep apnea (diagnosed by polysomnography), renal artery stenosis (diagnosed by renal duplex ultrasound or, preferentially, by CTA or MRA), and renal parenchymal disease. Uncommon causes of RH include pheochromocytoma (diagnosed by urinary or plasma metanephrine + normetanephrine, followed by imaging including total-body CTA or, preferentially, MRA), Cushing\u0027s disease, hyperparathyroidism, aortic coarctation, and intracranial tumor [Calhoun DA et al. \u003Cem\u003ECirculation\u003C\/em\u003E 2008]. Screening for secondary hypertension also allows the adaptation of treatment regimens (eg, for low-renin hypertension) and to assess, if needed, the feasibility of device-based therapy including RDN or baroreceptor stimulation, which are still in the process of evaluation.\u003C\/p\u003E\u003Cp id=\u0022p-12\u0022\u003EThe pharmacologic treatment of true RH has been poorly studied, and the clinical evidence to guide treatment is clearly suboptimal, stated Bryan Williams, MD, University College London, London, United Kingdom. Drug treatment can be guided by the pathophysiologic basis of RH, that is, whether the phenotype is excess sodium retention, including excess aldosterone production, in which patients have excess volume, or renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system activation, in which patients have increased vascular resistance; diuretics are recommended for the former and RAAS blockers for the latter (\u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E).\u003C\/p\u003E\u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/18\/28\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Pathophysiologic Approach to Drug Treatment of Resistant Hypertension\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-233988821\u0022 data-figure-caption=\u0022Pathophysiologic Approach to Drug Treatment of Resistant Hypertension\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 1.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/18\/28\/F1.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/18\/28\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 1.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/18\/28\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/14635\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 1.\u003C\/span\u003E \n            \u003Cp id=\u0022p-13\u0022 class=\u0022first-child\u0022\u003EPathophysiologic Approach to Drug Treatment of Resistant Hypertension\u003C\/p\u003E\n         \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-1\u0022\u003EGFR=glomerular filtration rate; RAAS=renin-angiotensin-aldosterone system; SNS=sympathetic nervous system.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-14\u0022\u003EThe predominant pathophysiologic cause of RH appears to be excess sodium retention, stated Prof. Williams, as shown by the nearly 67% of patients with RH who have low plasma renin activity despite being on treatment that should raise this level [Eide IK et al. \u003Cem\u003EJ Hypertens\u003C\/em\u003E 2004].\u003C\/p\u003E\u003Cp id=\u0022p-15\u0022\u003EIn patients with excess sodium retention resistant to diuretic therapy, additional approaches include a higher dose thiazide-type diuretic, adding low-dose spironolactone or eplerenone, or adding amiloride. In patients resistant to RAAS blocker therapy, an \u03b1-blocker or \u03b2-blocker can be added. Prof. Williams stated that the evidence for low-dose spironolactone (25 mg\/day) is based on small post hoc analyses or observational studies showing that it lowers BP, but there are no data on clinical outcomes; the data are reviewed in the hypertension clinical practice guidelines of the National Institute for Health Care and Excellence [Krause T et al. \u003Cem\u003EBMJ\u003C\/em\u003E 2011].\u003C\/p\u003E\u003Cp id=\u0022p-16\u0022\u003EThe recommendations from the ESH\/ESC Guidelines for treating RH are based on evidence from subgroups of large-scale trials or observational studies. In patients on \u22653 AH drugs, including a diuretic, a good response has been reported with low-dose spironolactone or eplerenone, the a\u003Csub\u003E1\u003C\/sub\u003E blocker doxazosin, a further increase in the diuretic dose, or replacing thiazides or chlorthalidone with a loop diuretic if renal function is impaired [Mancia G et al. \u003Cem\u003EJ Hypertens\u003C\/em\u003E 2013].\u003C\/p\u003E\u003Cp id=\u0022p-17\u0022\u003EMarkus Schlaich, MD, Baker Heart and Diabetes Institute, Melbourne, Australia, reviewed the 3-year results in 88 patients from the randomized, sham-controlled, open-label SYMPLICITY HTN-1 study of percutaneous RDN [Krum H et al. \u003Cem\u003ELancet\u003C\/em\u003E 2014]. The study patients had a mean age of 57 years, 42% were women, and 28% had diabetes. The mean estimated glomerular filtration rate was 85 mL\/min\/1.73 m\u003Csup\u003E2\u003C\/sup\u003E, and mean BP was 175\/98 mm Hg at baseline.\u003C\/p\u003E\u003Cp id=\u0022p-18\u0022\u003EThe substantial, significant reduction in OBP was sustained at Year 3 (\u201332\/14 mm Hg, p\u0026lt;0.01), without a change in the number of AH drugs. The proportion of patients with controlled BP increased progressively over 3 years, with about 93% having 10% improvements (\u003Ca id=\u0022xref-fig-2-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F2\u0022\u003EFigure 2\u003C\/a\u003E).\u003C\/p\u003E\u003Cdiv id=\u0022F2\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/18\/28\/F2.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Distribution of Changes in Systolic Blood Pressure\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-233988821\u0022 data-figure-caption=\u0022Distribution of Changes in Systolic Blood Pressure\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 2.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/18\/28\/F2.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/18\/28\/F2.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 2.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/18\/28\/F2.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/14636\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 2.\u003C\/span\u003E \n            \u003Cp id=\u0022p-19\u0022 class=\u0022first-child\u0022\u003EDistribution of Changes in Systolic Blood Pressure\u003C\/p\u003E\n         \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-2\u0022\u003EGFR=glomerular filtration rate; RAAS=renin-angiotensin-aldosterone system; SNS=sympathetic nervous system.\u003C\/q\u003E\u003Cq class=\u0022attrib\u0022 id=\u0022attrib-3\u0022\u003EReproduced with permission from Elsevier from Krum H, Schlaich MP, Sobotka PA, et al. Percutaneous renal denervation in patients with treatment-resistant hypertension: final 3-year report of the Symplicity HTN-1 study. \u003Cem\u003ELancet\u003C\/em\u003E 2014;383(9917):622\u2013629.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-20\u0022\u003EThe treatment effect was consistent across subgroups (age, diabetes status, baseline renal function), and the increase in responder rates indicates that some patients respond late to RDN and that there was no loss of treatment effect at 3 years. Because the study patients were at high cardiovascular risk, the results are highly relevant, Dr. Schlaich noted. The procedure was safe, with no major adverse consequences.\u003C\/p\u003E\u003Cp id=\u0022p-21\u0022\u003EAlthough the open-label experience with RDN appeared encouraging, enthusiasm has been tempered by the neutral results of the blinded SYMPLICITY HTN-3 trial. These results demonstrate the importance of blinded, appropriately controlled trials and the need for definitive evidence of benefit before the widespread adoption of novel interventions. Additional studies are needed to define if there is a benefit of RDN and which patients are most appropriate for this therapy.\u003C\/p\u003E\u003Cp id=\u0022p-22\u0022\u003EProf. Schlaich stated that regardless of the role RDN eventually plays in treating RH, it has stimulated new clinical and research interest in RH, and hopefully additional clinical trials will be conducted.\u003C\/p\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2014 MD Conference Express\u00ae\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/14\/18\/28.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_figures.js?nzp1jd\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzp1jd\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}