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True resistant hypertension must be distinguished from apparent resistant hypertension, of which important causes include medication nonadherence, illicit drug use, and alcoholism. Ambulatory blood pressure monitoring should be considered to rule out white coat hypertension. The pathogenesis is multifactorial, but the 2 pivotal factors include volume excess and the myriad effects of aldosterone. Aldosterone increases vascular tone because of endothelial dysfunction and enhances the pressor response to catecholamines. It also plays a crucial role in vascular remodeling of small and large arteries. Aldosterone also promotes collagen synthesis, which leads to increased arterial stiffness and elevation of blood pressure. Because aldosterone has been demonstrated to modulate baroreflex resetting, in cases of severe hypertension, there would be fewer compensatory mechanisms available to offset the blood pressure elevation.
Volume excess and the myriad actions of aldosterone are pivotal factors in the pathogenesis of true resistant hypertension.
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Spironolactone is the most effective add-on drug for the treatment of resistant hypertension.
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The risk of mineralocorticoid receptor antagonist-induced hyperkalemia is increased in chronic kidney disease, diabetes mellitus, and elderly patients.
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Renal denervation system and carotid baroreceptor stimulation are not ready for clinical application for the treatment of resistant hypertension.
Resistant hypertension is a common medical disorder encountered by all clinicians. Demographic trends, including the aging of our adult population and the increasing prevalence of obesity, indicate that resistant hypertension will become even more common. The past few years have witnessed increased clinical and investigative attention to this disease entity that informs an appropriate clinical management.
Resistant hypertension: diagnosis, evaluation, and treatment. A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research.
Moreover, clinical studies have focused increasingly on the overriding importance of aldosterone and mineralocorticoid signaling in the pathogenesis and maintenance of resistant hypertension.
This review will focus on the clinical features of resistant hypertension and consider the importance of several risk factors undergoing reappraisal and clinical investigation, as well as the pivotal pathogenic role of aldosterone in both promoting and sustaining resistant hypertension.
Definition
Resistant hypertension is defined as failure to attain the goal blood pressure of <140/90 mm Hg despite adherence to 3 different antihypertensive medications at reasonable dosages, one of which must be a diuretic.
Resistant hypertension: diagnosis, evaluation, and treatment. A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research.
Detection, evaluation, and treatment of severe and resistant hypertension: proceedings from an American Society of Hypertension Interactive forum held in Bethesda, MD, U.S.A., October 10th 2013.
For patients with diabetes or renal failure (defined as a serum creatinine >1.5 mg/dL or 133 μmol/L and/or proteinuria >300 mg in 24 hours), the definition is modified as a failure to reach a goal blood pressure of <135/85 mm Hg with the stated criteria.
Scope of the Problem
Increased Cardiovascular/Renal Morbidity and Mortality
Hypertension is a major independent risk factor for cardiovascular disease and mortality, and patients with resistant hypertension represent a more severe subset with an even greater increased cardiovascular risk compared with patients without resistant hypertension.
Compared with patients with controlled hypertension, patients with resistant hypertension develop greater target end-organ damage, including increased left ventricular hypertrophy, retinal changes, and microalbuminuria.
Data from the National Health and Nutrition Examination Survey, 2011-2012 reported that the age-adjusted prevalence of hypertension among US adults aged 18 years or more was 29.1% in 2011-2012, similar to the prevalence in 2009-2010.
Among adults with hypertension, approximately 83% were aware of it, approximately 76% were taking medication to lower their blood pressure, but only 52% had controlled hypertension, and the control rates failed to increase from 2009-2010 to 2011-2012. The failure to control blood pressure exists across all socioeconomic and ethnic groups and is likely multifactorial, including sociologic factors, such as health care access; patient factors, such as lack of understanding and financial burden; and provider factors, such as prescribing inappropriate combinations of medications or inadequate dosages despite poorly controlled blood pressure.
Of great importance, some studies suggest that the most common reason for poor blood pressure control is the failure of providers to prescribe optimal antihypertensive therapy and that rational titration of diuretics and increasing the number of blood pressure-lowering medications were the most likely interventions to achieve the target blood pressure.
High rates of non-adherence to antihypertensive treatment revealed by high-performance liquid chromatography-tandem mass spectrometry (HP LCMS/MS) urine analysis.
Thus, truly resistant or difficult-to-control hypertension explains only a part of the huge public health problem of uncontrolled blood pressure. In all probability, the problem will be magnified after the publication of the results of the recent Systolic blood PRessure INterventional Trial (SPRINT), which provided evidence that in a large hypertensive population the target blood pressure of 120/80 mm Hg is more beneficial than 140/90 mm Hg.
Table 1 lists the common causes of resistant hypertension. A large portion of patients have “apparent” resistant hypertension that must be distinguished from true resistant hypertension. Causes of “apparent resistant hypertension” include improper blood pressure measurements, pseudo-hypertension, medication nonadherence, and white coat hypertension.
Resistant hypertension: diagnosis, evaluation, and treatment. A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research.
The patient should be seated for at least 5 minutes, and blood pressure should be measured with an appropriately sized cuff that encircles 80% of the arm. Blood pressure should be confirmed in both arms, with the arms supported at heart level.
Some patients exhibit pseudo-hypertension in which sclerotic arteries are incompressible and therefore have falsely elevated cuff blood pressures. Pseudohypertension can be distinguished from resistant hypertension by the Osler maneuver, in which the radial artery is still palpable after compression of the brachial artery with the blood pressure cuff.
Only an intra-arterial blood pressure can provide a true measurement of blood pressure in these patients.
Medication Nonadherence
Medication nonadherence or noncompliance is an extremely important cause of both “apparent” resistant hypertension and poorly controlled hypertension. Adherence is usually defined as taking the medication regimen correctly ≥80% of the time. The World Health Organization reports 7 estimates that at least 50% of hypertensive patients do not adhere to the prescribed medication regimen.
Noncommunicable diseases: a major health challenge of the 21st century. In: World Heath Statistics 2012, ed. World Health Organization:34-37. Available at: www.who.int/gho/publications/world_health_statistics/2012/en/. Accessed January 27, 2016.
The term “noncompliance” is no longer favored because of its negative connotation that the patient is a passive recipient of the doctor's order; therefore, the preferred term is “nonadherence.” Because the definition of resistant hypertension is contingent on patients adhering to their multidrug antihypertensive regimens, medication nonadherence does not constitute a cause of true resistant hypertension, but rather a form of apparent resistant hypertension, often due to multiple causes.
Clinical Relevance of Obstructive Sleep Apnea
Several studies have reported an extremely high prevalence of obstructive sleep apnea in patients with resistant hypertension.
Activation of the sympathetic nervous system plays a crucial role in the pathogenesis of hypertension in patients with obstructive sleep apnea. Aldosterone seems to be the other significant player in this field. Increased aldosterone levels have been documented in patients with obstructive sleep apnea with resistant hypertension.
The exact nature of the association between obstructive sleep apnea and aldosterone excess remains to be elucidated. Whether obstructive sleep apnea results in aldosterone excess or aldosterone excess contributes to obstructive sleep apnea or another underlying factor (eg, obesity) promoting both aldosterone excess and obstructive sleep apnea remains to be clarified.
Treatment-Resistant Hypertension
In treating resistant hypertension, a major step is lifestyle change emphasizing weight loss, a heart healthy diet, salt restriction, cessation of smoking, and reduction of alcohol intake. Because these interventions usually do not suffice, then the next step is pharmacologic treatment. The underlying pathophysiologic basis of resistant hypertension is incompletely understood.
Pharmacologic Management of Resistant Hypertension
Knowledge of the pathophysiology of resistant hypertension provides the rationale for the effective management of this clinical entity (Figure). The combination of increased systemic vascular resistance, together with marked volume expansion in many cases, renders the triple combination of a drug inhibiting the renin-angiotensin axis (an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker) with a calcium antagonist and a long-acting diuretic as an attractive combination for the majority of patients, unless these drugs are contraindicated or not tolerated, or other drugs are indicated because of comorbidities.
Resistant hypertension: diagnosis, evaluation, and treatment. A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research.
However, reliable data confirming the superiority of this combination over other combinations are not available. We emphasize the importance of maximizing the dose of diuretics or switching to loop diuretics in patients with low glomerular filtration rate (<35 mL/min/1.73 m2). Because of the importance of the increase in sympathetic tone, beta-blockers, alpha-blockers, and centrally acting antihypertensive drugs (clonidine, alpha-methyldopa) may be of potential benefit in many patients when added to previous therapy.
We will now consider emerging treatment paradigms for the management of resistant hypertension. Many lines of evidence indicate that mineralocorticoid receptor antagonists, such as spironolactone, are the drugs of choice in the treatment of resistant hypertension (Table 2). Several studies revealed impressive blood pressure reductions in patients with resistant hypertension when spironolactone was added to the therapeutic regimen.
Low dose spironolactone reduces blood pressure in patients with resistant hypertension and type 2 diabetes mellitus: a double blind randomized clinical trial.
A meta-analysis of randomized and nonrandomized studies of mineralocorticoid receptor antagonists in patients with resistant hypertension disclosed that spironolactone is a safe and effective therapy in resistant hypertension.
The recent publication of the PATHWAY-2 study is the first randomized controlled trial to compare different blood pressure-lowering treatments in rigorously assessed patients with resistant hypertension and the first comparison of mineralocorticoid receptor antagonist blockade with alternative recommended classes that block the sympathetic nervous system: α-blockers (doxazosin) and β-blockers (bisoprolol).
Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial.
Spironolactone unequivocally was shown to be the most effective add-on drug for the treatment of resistant hypertension.
There are less data with eplerenone in the treatment of resistant hypertension. Eplerenone demonstrated substantial efficacy and is well tolerated with modest changes in plasma potassium.
The most recently developed mineralocorticoid receptor antagonist finerenone has not been studied in resistant hypertension, but the pharmacokinetic profile is promising.
Safety and tolerability of the novel, selective mineralocorticoid receptor antagonist finerenone - results from first-in-man and relative bioavailability studies.
Fundam Clin Pharmacol.2015 Nov 25; ([Epub ahead of print])
Chronic kidney disease is the most frequent of several patient factors or comorbidities associated with resistant hypertension. In resistant hypertension complicating chronic kidney disease, the use of mineralocorticoid receptor antagonists in patients already receiving a triple antihypertensive therapy can constitute a challenge because of the risk of hyperkalemia. New therapeutic innovations for resistant hypertension are under investigation, especially in patients with advanced chronic kidney disease. Renin-angiotensin-aldosterone inhibitors are preferred drugs for resistant hypertension because they reduce blood pressure and chronic kidney disease progression. However, hyperkalemia is a frequent complication in clinical practice and a cause for renin-angiotensin-aldosterone inhibitor down-titration or discontinuation. Chronic treatment with the new polymer resin potassium binder, patiromer, has been demonstrated to lower serum potassium sufficiently for periods exceeding 52 weeks, thereby preventing down-titrations and discontinuations of renin-angiotensin-aldosterone inhibitor therapy due to hyperkalemia in this population of patients with resistant hypertension. In essence, they are “enablers” facilitating mineralocorticoid receptor antagonist therapy.
Newer Drugs for the Management of Resistant Hypertension
A few years ago, selective endothelin antagonists were potentially considered to be a novel treatment for hypertension and particularly for resistant hypertension. The results of a double-blind placebo-controlled trial with darusentan demonstrated an additional reduction in blood pressure in patients with resistant hypertension already taking 3 antihypertensive drugs.
A selective endothelin-receptor antagonist to reduce blood pressure in patients with treatment-resistant hypertension: a randomised, double-blind, placebo-controlled trial.
One of the major side effects of darusentan was significant fluid retention. Consequently, the future of darusentan remains unclear.
Interventional Management of Resistant Hypertension
There has been a growing perception that controlling blood pressure in resistant hypertension is beyond the reach of existing drug therapies, leading to the emergence of device-based therapies, such as renal denervation and baroreceptor stimulation (Table 3).
This development was based on the pathophysiologic findings that carotid baroreceptors and renal sympathetic overdrive play a significant role in blood pressure regulation.
The Rheos Pivotal Trial evaluated carotid baroreceptor activation therapy for resistant hypertension in a double-blind, randomized, prospective, multicenter, placebo-controlled phase III clinical trial.
Baroreflex activation therapy lowers blood pressure in patients with resistant hypertension: results from the double-blind, randomized, placebo-controlled Rheos Pivotal Trial.
The subjects received carotid baroreceptor activation therapy for the first 6 months or delayed carotid baroreceptor activation therapy initiation after the 6-month visit. The 5 co-primary end points were (1) acute systolic blood pressure responder rate at 6 months; (2) sustained responder rate at 12 months; (3) procedure safety; (4) carotid baroreceptor activation therapy safety; and (5) device safety. The trial showed significant benefit for the end points of sustained efficacy, carotid baroreceptor activation therapy safety, and device safety. In contrast, it did not meet the end points for acute responders or procedural safety. After completion of the randomized Rheos Pivotal Trial, patients participated in open-label, nonrandomized follow-up to assess the safety and efficacy of carotid baroreceptor activation therapy. Blood pressure reductions were measured relative to a preimplant baseline as the results achieved at the completion of 1 year of follow-up in the randomized phase.
Baroreflex activation therapy provides durable benefit in patients with resistant hypertension: results of long-term follow-up in the Rheos Pivotal Trial.
Blood pressures of all active patients remained stable from completion of the randomized phase through long-term follow-up. Carotid baroreceptor activation therapy substantially reduced arterial pressure for most patients participating in the Rheos Pivotal Trial. Additional studies are required to ascertain who constitute the best candidate patients for this therapy, because a large number of these patients with resistant hypertension have neuropathy due to diabetes or chronic renal insufficiency.
Renal Nerve Denervation
The publication of data from the SYMPLICITY HTN-1 trial in 2009 initially appeared to be a watershed event for patients with resistant hypertension.
The trial reported on the first experience using a catheter-based renal denervation system for the treatment of resistant hypertension. It is regrettable that the recent multicenter SYMPLICITY-3 trial failed to meet its primary efficacy end point.
several problems confounded the conduct of the SYMPLICITY-3 clinical trial, including questions as to whether the study appropriately included study patients who had “verifiable” resistant hypertension, and operator inexperience; although the proceduralists were experts in the field of interventional cardiology, the majority of trialist were novices in the renal denervation procedure. The original SYMPLICITY catheter had design flaws that precluded its complete ablation of adventitial sympathetic nerves with a single short treatment time for each renal artery. We hope that the imminent availability of newer multicathode catheter-based renal denervation system devices that allow 4 ablations to be performed simultaneously with a single short treatment time, with energy delivery into the distal renal artery and its divisions, will allow for a true assessment of the potential role of catheter-based renal denervation system as an acceptable treatment for resistant hypertension.
The Prague Study is the first randomized, multicenter study that compared the relative efficacy of catheter-based renal denervation system with pharmacotherapy alone in patients with true resistant hypertension and assessed the effect of spironolactone addition.
A total of 106 patients with true resistant hypertension were enrolled in this study; 52 patients were randomized to catheter-based renal denervation system, and 54 patients were randomized to the spironolactone addition. During a period of 12 months, a catheter-based renal denervation system in the setting of true resistant hypertension with confirmed compliance was not superior to intensified pharmacologic treatment. The addition of spironolactone was more effective in 24-hour ambulatory systolic blood pressure reduction.
Conclusions
Resistant hypertension remains a major diagnostic and even more a therapeutic challenge in the global spectrum of management of arterial hypertension. The issue of tailoring antihypertensive therapy within the scope of the comorbidities constitutes a must. The benefit of adding mineralocorticoid receptor antagonists to the antihypertensive regimen in resistant hypertension is clear-cut. There is often hesitation, underdosing, and fear of adding a mineralocorticoid receptor antagonist in these cases, especially in the presence of renal disease, diabetes, and heart failure. The newly available potassium binders may facilitate add-on of a mineralocorticoid receptor antagonist by the ability to achieve sustained normokalemia long term in patients with resistant hypertension, despite treatment with concomitant angiotensin-converting enzyme inhibitor/angiotensin receptor blocker. A dialogue with a cardio-renal team may be the solution in the final decision of bringing a mineralocorticoid receptor antagonist on board.
References
Calhoun D.A.
Jones D.
Textor S.
et al.
Resistant hypertension: diagnosis, evaluation, and treatment. A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research.
Detection, evaluation, and treatment of severe and resistant hypertension: proceedings from an American Society of Hypertension Interactive forum held in Bethesda, MD, U.S.A., October 10th 2013.
High rates of non-adherence to antihypertensive treatment revealed by high-performance liquid chromatography-tandem mass spectrometry (HP LCMS/MS) urine analysis.
Noncommunicable diseases: a major health challenge of the 21st century. In: World Heath Statistics 2012, ed. World Health Organization:34-37. Available at: www.who.int/gho/publications/world_health_statistics/2012/en/. Accessed January 27, 2016.
Low dose spironolactone reduces blood pressure in patients with resistant hypertension and type 2 diabetes mellitus: a double blind randomized clinical trial.
Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial.
Safety and tolerability of the novel, selective mineralocorticoid receptor antagonist finerenone - results from first-in-man and relative bioavailability studies.
Fundam Clin Pharmacol.2015 Nov 25; ([Epub ahead of print])
A selective endothelin-receptor antagonist to reduce blood pressure in patients with treatment-resistant hypertension: a randomised, double-blind, placebo-controlled trial.
Baroreflex activation therapy lowers blood pressure in patients with resistant hypertension: results from the double-blind, randomized, placebo-controlled Rheos Pivotal Trial.
Baroreflex activation therapy provides durable benefit in patients with resistant hypertension: results of long-term follow-up in the Rheos Pivotal Trial.
Conflict of Interest: ME served as a consultant and received consultant fees from Relypsa Inc, OPKO Health, Bayer Health Care, Rockwell Medical, and Medscape. DAD has received research grants from Sanofi, Regeneron, and Pfizer, and honoraria for consulting and speaking for Lundbeck and Amgen.
Authorship: Both authors had access to the data and played a role in writing this manuscript.
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