Domenic A. Sica

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

Resistant hypertension is a common clinical problem faced by both primary care clinicians and specialists. While the exact prevalence of resistant hypertension is unknown, clinical trials suggest that it is not rare, involving perhaps 20% to 30% of study participants. As older age and obesity are 2 of the strongest risk factors for uncontrolled hypertension, the incidence of resistant hypertension will likely increase as the population becomes more elderly and heavier. The prognosis of resistant hypertension is unknown, but cardiovascular risk is undoubtedly increased as patients often have a history of long-standing, severe hypertension complicated by multiple other cardiovascular risk factors such as obesity, sleep apnea, diabetes, and chronic kidney disease. The diagnosis of resistant hypertension requires use of good blood pressure technique to confirm persistently elevated blood pressure levels. Pseudoresistance, including lack of blood pressure control secondary to poor medication adherence or white coat hypertension, must be excluded. Resistant hypertension is almost always multifactorial in etiology. Successful treatment requires identification and reversal of lifestyle factors contributing to treatment resistance; diagnosis and appropriate treatment of secondary causes of hypertension; and use of effective multidrug regimens. As a subgroup, patients with resistant hypertension have not been widely studied. Observational assessments have allowed for identification of demographic and lifestyle characteristics associated with resistant hypertension, and the role of secondary causes of hypertension in promoting treatment resistance is well documented; however, identification of broader mechanisms of treatment resistance is lacking. In particular, attempts to elucidate potential genetic causes of resistant hypertension have been limited. Recommendations for the pharmacological treatment of resistant hypertension remain largely empiric due to the lack of systematic assessments of 3 or 4 drug combinations. Studies of resistant hypertension are limited by the high cardiovascular risk of patients within this subgroup, which generally precludes safe withdrawal of medications; the presence of multiple disease processes (eg, sleep apnea, diabetes, chronic kidney disease, atherosclerotic disease) and their associated medical therapies, which confound interpretation of study results; and the difficulty in enrolling large numbers of study participants. Expanding our understanding of the causes of resistant hypertension and thereby potentially allowing for more effective prevention and/or treatment will be essential to improve the long-term clinical management of this disorder.

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

Resistant hypertension is a common clinical problem faced by both primary care clinicians and specialists. While the exact prevalence of resistant hypertension is unknown, clinical trials suggest that it is not rare, involving perhaps 20% to 30% of study participants. As older age and obesity are 2 of the strongest risk factors for uncontrolled hypertension, the incidence of resistant hypertension will likely increase as the population becomes more elderly and heavier. The prognosis of resistant hypertension is unknown, but cardiovascular risk is undoubtedly increased as patients often have a history of long-standing, severe hypertension complicated by multiple other cardiovascular risk factors such as obesity, sleep apnea, diabetes, and chronic kidney disease. The diagnosis of resistant hypertension requires use of good blood pressure technique to confirm persistently elevated blood pressure levels. Pseudoresistance, including lack of blood pressure control secondary to poor medication adherence or white coat hypertension, must be excluded. Resistant hypertension is almost always multifactorial in etiology. Successful treatment requires identification and reversal of lifestyle factors contributing to treatment resistance; diagnosis and appropriate treatment of secondary causes of hypertension; and use of effective multidrug regimens. As a subgroup, patients with resistant hypertension have not been widely studied. Observational assessments have allowed for identification of demographic and lifestyle characteristics associated with resistant hypertension, and the role of secondary causes of hypertension in promoting treatment resistance is well documented; however, identification of broader mechanisms of treatment resistance is lacking. In particular, attempts to elucidate potential genetic causes of resistant hypertension have been limited. Recommendations for the pharmacological treatment of resistant hypertension remain largely empiric due to the lack of systematic assessments of 3 or 4 drug combinations. Studies of resistant hypertension are limited by the high cardiovascular risk of patients within this subgroup, which generally precludes safe withdrawal of medications; the presence of multiple disease processes (eg, sleep apnea, diabetes, chronic kidney disease, atherosclerotic disease) and their associated medical therapies, which confound interpretation of study results; and the difficulty in enrolling large numbers of study participants. Expanding our understanding of the causes of resistant hypertension and thereby potentially allowing for more effective prevention and/or treatment will be essential to improve the long-term clinical management of this disorder.

Diabetes and hypertension in severe obesity and effects of gastric bypass-induced weight loss.

ObjectiveTo evaluate the preoperative relationships of hypertension and diabetes mellitus in severe obesity and the effects of gastric bypass (GBP)-induced weight loss. Summary Background DataSevere obesity is associated with multiple comorbidities, particularly hypertension and type 2 diabetes mellitus, that may affect life expectancy. MethodsThe database of patients who had undergone GBP by one general surgeon at a university hospital between September 1981 and January 2000 was queried as to weight, body mass index (BMI), pre- and postoperative diabetes, hypertension, and other comorbidities, including sleep apnea, hypoventilation, gastroesophageal reflux, degenerative joint disease, urinary incontinence, venous stasis, and pseudotumor cerebri. ResultsOf 1,025 patients treated, 15% had type 2 diabetes mellitus and 51% had hypertension. Of those with diabetes, 75% also had hypertension. There was a progressive increase in age between patients who had neither diabetes nor hypertension, either diabetes or hypertension, or both diabetes and hypertension. At 1 year after GBP (91% follow-up), patients lost 66 ± 18% excess weight (%EWL) or 35 ± 9% of their initial weight (%WL). Hypertension resolved in 69% and diabetes in 83%. Patients who resolved their hypertension or diabetes had greater %EWL and %WL than those who did not. African-American patients had a higher risk of hypertension than whites before GBP and were less likely to correct their hypertension after GBP. There was significant resolution of other obesity comorbidity problems. At 5 to 7 years after GBP (50% follow-up), %EWL was 59 ± 24 and %WL was 31 ± 13; resolution of hypertension was 66% and diabetes 86%. ConclusionsThese data suggest that type 2 diabetes mellitus and hypertension may be indirectly related to each other through the effects of obesity, but not directly as to cause and effect. The longer a person remains severely obese, the more likely he or she is to develop diabetes, hypertension, or both. GBP-induced weight loss is effective in correcting diabetes, hypertension, and other comorbidities but is related to the %EWL achieved. Severely obese African-Americans were more likely to have hypertension and respond less well to GBP surgery than whites. These data suggest that GBP surgery for severe obesity should be provided earlier to patients to prevent the development of diabetes and hypertension and their complications.

Baroreflex Activation Therapy Lowers Blood Pressure in Patients With Resistant Hypertension Results From the Double-Blind, Randomized, Placebo-Controlled Rheos Pivotal Trial

OBJECTIVES We sought to determine the effect of baroreflex activation therapy (BAT) on systolic blood pressure (SBP) in patients with resistant hypertension. BACKGROUND The Rheos Pivotal Trial evaluated BAT for resistant hypertension in a double-blind, randomized, prospective, multicenter, placebo-controlled Phase III clinical trial. METHODS This was a double-blind randomized trial of 265 subjects with resistant hypertension implanted and subsequently randomized (2:1) 1 month after implantation. Subjects received either BAT (Group A) for the first 6 months or delayed BAT initiation following the 6-month visit (Group B). The 5 coprimary endpoints were: 1) acute SBP responder rate at 6 months; 2) sustained responder rate at 12 months; 3) procedure safety; 4) BAT safety; and 5) device safety. RESULTS The trial showed significant benefit for the endpoints of sustained efficacy, BAT safety, and device safety. However, it did not meet the endpoints for acute responders or procedural safety. A protocol-specified ancillary analysis showed 42% (Group A) versus 24% (Group B) achieving SBP ≤140 mm Hg at 6 months (p = 0.005), with both groups achieving over 50% at 12 months, at which point Group B had received 6 months of BAT. CONCLUSIONS A clinically meaningful measure, those achieving a SBP of ≤140 mm Hg, yielded a significant difference between the groups. The weight of the overall evidence suggests that over the long-term, BAT can safely reduce SBP in patients with resistant hypertension. Future clinical trials will address the limitations of this study and further define the therapeutic benefit of BAT.

Rationale for Fixed-Dose Combinations in the Treatment of Hypertension

Single-drug therapy remains the preferred way to begin treatment of hypertension, although in many patients this is unable to bring blood pressure (BP) to goal levels. Single-drug therapy, even when maximally titrated, is at best only modestly effective in normalising BP in Stage-I or II hypertension, which represents the majority of the hypertensive population. It is increasingly appreciated that the elusive goal of a ‘normal’ BP is achieved only if multi-drug therapy is employed. This is especially so when considered in the context of today’s lower BP goals. The options for multi-drug therapy are quite simple: either fixed-dose combination therapy or drugs added sequentially one after another to then arrive at an effective multi-drug regimen. Advocates exist for both approaches.A considerable legacy, dating to the 1950’s, exists for fixed-dose combination therapies. The rationale to this approach has remained constant. Fixed-dose combination therapy successfully reduces BP because two drugs, each typically working at a separate site, block different effector pathways. In addition, the second drug of such two-drug combinations may check counter-regulatory system activity triggered by the other. For example, a diuretic and β-blocker combination may find the diuretic correcting the salt-and-water retention which occasionally accompanies β-blocker therapy. The pattern of adverse effects also differs with fixed-dose combination therapy, in part, because less drug is generally being given. In addition, one component of a fixed-dose combination therapy can effectively counterbalance the tendency of the other to produce adverse effects. For example, the peripheral oedema, that accompanies calcium channel antagonist therapy, occurs less frequently when an ACE inhibitor is co-administered. ACE inhibitors improve, if not eliminate, the peripheral oedema associated with calcium channel antagonists because of their proven ability to cause venodilation. In addition, diuretic therapy-induced volume contraction may generate a state of secondary hyperaldosteronism and thereby electrolyte abnormalities such as hypokalaemia and/or hypomagnesaemia. In many cases, the co-administration of either an ACE inhibitor or an angiotensin II receptor blocker with a diuretic corrects the aforementioned electrolyte disturbances.Fixed-dose combination therapy has a proven record of reducing BP. This form of treatment has been available for close to a half-century. Over that period of time, many physicians have taken advantage of this therapeutic approach even when academic opinion was less than charitable to this concept. Academic opinion is rarely immutable and occasionally irrelevant to prescription practice. Prescription practice is driven by many considerations including ease of use, cost and tolerance of a therapy. Most importantly, the therapeutic pathway taken should successfully result in goal BP being reached in a large number of those treated. Unfortunately, despite the simplicity of the concept behind fixed-dose combination therapy, its success will ultimately rest on cost. If made truly cost-competitive, it will gain an increasing share of the hypertensive market. If not, market forces will relegate it to a secondary role for hypertension treatment.

Chronic Vagus Nerve Stimulation Improves Autonomic Control and Attenuates Systemic Inflammation and Heart Failure Progression in a Canine High-Rate Pacing Model

Background—Autonomic dysfunction, characterized by sympathetic activation and vagal withdrawal, contributes to the progression of heart failure (HF). Although the therapeutic benefits of sympathetic inhibition with &bgr;-blockers in HF are clear, the role of increased vagal tone in this setting has been less studied. We have investigated the impact of enhancing vagal tone (achieved through chronic cervical vagus nerve stimulation, [VNS]) on HF development in a canine high-rate ventricular pacing model. Methods and Results—Fifteen dogs were randomized into control (n=7) and VNS (n=8) groups. All dogs underwent 8 weeks of high-rate ventricular pacing (at 220 bpm for the first 4 weeks to develop HF and another 4 weeks at 180 bpm to maintain HF). Concomitant VNS, at an intensity reducing sinus rate ≈20 bpm, was delivered together with the ventricular pacing in the VNS group. At 4 and 8 weeks of ventricular pacing, both left ventricular end-diastolic and -systolic volumes were lower and left ventricular ejection fraction was higher in the VNS group than in the control group. Heart rate variability and baroreflex sensitivity improved in the VNS dogs. Rises in plasma norepinephrine, angiotensin II, and C-reactive protein levels, ordinarily expected in this model, were markedly attenuated with VNS treatment. Conclusions—Chronic VNS improves cardiac autonomic control and significantly attenuates HF development in the canine high-rate ventricular pacing model. The therapeutic benefit of VNS is associated with pronounced anti-inflammatory effects. VNS is a novel and potentially useful therapy for treating HF.

Drug dosing consideration in patients with acute and chronic kidney disease—a clinical update from Kidney Disease: Improving Global Outcomes (KDIGO)

Drug dosage adjustment for patients with acute or chronic kidney disease is an accepted standard of practice. The challenge is how to accurately estimate a patients kidney function in both acute and chronic kidney disease and determine the influence of renal replacement therapies on drug disposition. Kidney Disease: Improving Global Outcomes (KDIGO) held a conference to investigate these issues and propose recommendations for practitioners, researchers, and those involved in the drug development and regulatory arenas. The conference attendees discussed the major challenges facing drug dosage adjustment for patients with kidney disease. In particular, although glomerular filtration rate is the metric used to guide dose adjustment, kidney disease does affect nonrenal clearances, and this is not adequately considered in most pharmacokinetic studies. There are also inadequate studies in patients receiving all forms of renal replacement therapy and in the pediatric population. The conference generated 37 recommendations for clinical practice, 32 recommendations for future research directions, and 24 recommendations for regulatory agencies (US Food and Drug Administration and European Medicines Agency) to enhance the quality of pharmacokinetic and pharmacodynamic information available to clinicians. The KDIGO Conference highlighted the gaps and focused on crafting paths to the future that will stimulate research and improve the global outcomes of patients with acute and chronic kidney disease.

Effect of increased renal venous pressure on renal function.

OBJECTIVE Acute renal failure is seen with the acute abdominal compartment syndrome (AACS). Although the cause of acute renal failure in AACS may be multifactorial, renal vein compression alone has not been investigated. This study evaluated the effects of elevated renal vein pressure (RVP) on renal function. METHODS Two groups of swine (18-22 kg) were studied after left nephrectomy and placement of a renal artery flow probe to measure renal artery blood flow, renal vein catheter, and ureteral cannula. Two hours were allowed for equilibration and an inulin infusion was begun to calculate inulin clearance for measurement of glomerular filtration rate. Group 1 animals (n = 4) had RVP elevated by 30 mm Hg for 2 hours with renal vein constriction. RVP was then returned to baseline for 1 hour. In group 2 (n = 4), the RVP was not elevated. The cardiac index (2.9 +/- 0.5 L/min/m2) and mean arterial pressure (101 +/- 9 mm Hg) remained stable. Plasma renin activity and serum aldosterone were measured every 60 minutes. RESULTS Elevation of RVP (0-30 mm Hg above baseline) in the experimental group showed a significant decrease in renal artery blood flow index (2.7 to 1.5 mL/min per g) and glomerular filtration rate (26 to 8 mL/min) compared with control. In addition, there was significant elevation of plasma serum aldosterone (14 to 25 microng/dL) and plasma renin activity (2.6 to 9.5 microng/mL per h) as well as urinary protein leak in the experimental animals compared with control. These changes were partially or completely reversible as RVP returned toward baseline. CONCLUSION Elevated RVP alone leads to decreased renal artery blood flow and glomerular filtration rate and increased plasma renin activity, serum aldosterone, and urinary protein leak. These changes are consistent with the renal pathophysiology seen in AACS, morbid obesity, and preeclampsia. The changes are partially or completely reversed by decreasing renal venous pressure as occurs with abdominal decompression for AACS.

Elevated Intra-abdominal Pressure Increases Plasma Renin Activity and Aldosterone Levels

OBJECTIVE To study the effects of elevated intra-abdominal pressure upon renal function and the renin-angiotensin-aldosterone system. MATERIALS AND METHODS Two groups of anesthetized, ventilated swine were studied. Intra-abdominal pressure was increased in experimental animals (n = 6) by incrementally instilling an isosmotic ethylene glycol solution into the peritoneal cavity until intra-abdominal pressure was 25 mm Hg above baseline. The intravascular volume was then expanded until cardiac index returned to baseline. Lastly, the solution was drained to decompress the abdomen. Control animals underwent surgical preparation but did not have their intra-abdominal pressure raised. Changes in systemic and pulmonary hemodynamic parameters, renal venous pressure, and urine output were recorded. Venous samples for plasma renin activity, aldosterone, and atrial natriuretic factor were drawn after each change in either intra-abdominal pressure or intravascular volume in experimental animals, and at the same time points in control animals. MEASUREMENTS AND MAIN RESULTS Elevated intra-abdominal pressure significantly (p < 0.05, analysis of variance) increased renal venous pressure, pleural pressure, wedge pressure, and pulmonary artery pressure compared to both baseline and control animals; whereas cardiac index and urine output decreased significantly. Both plasma renin and aldosterone levels increased significantly compared with baseline and controls. Intravascular volume expansion significantly increased urine output and decreased significantly both plasma renin activity and aldosterone levels. Abdominal decompression further significantly decreased both plasma renin activity and aldosterone levels. There were no significant changes in atrial natriuretic factor at any time point. CONCLUSIONS Elevated intra-abdominal pressure decreases urine output and significantly up-regulates the hormonal output of the renin-angiotensin-aldosterone system. Intravascular volume expansion in combination with abdominal decompression reverses the effects of acutely elevated intra-abdominal pressure upon renal function and the renin-angiotensin-aldosterone system.

Role of Prescription Omega-3 Fatty Acids in the Treatment of Hypertriglyceridemia

A prescription form of omega‐3 fatty acids has been approved by the United States Food and Drug Administration as an adjunct to diet for the treatment of very high triglyceride levels. The active ingredients of omega‐3 fatty acids are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are responsible for the triglyceride lowering. The prescription product contains a total of 0.84 g of these two active ingredients in every 1‐g capsule of omega‐3 fatty acids. The total EPA and DHA dose recommended for triglyceride lowering is approximately 2–4 g/day Fish oil products containing EPA and DHA are available without a prescription, but the American Heart Association advises that therapy with EPA and DHA to lower very high triglyceride levels should be used only under a physicians care. In patients with triglyceride levels above 500 mg/dl, approximately 4 g/day of EPA and DHA reduces triglyceride levels 45% and very low‐density lipoprotein cholesterol levels by more than 50%. Low‐density lipoprotein cholesterol levels may increase depending on the baseline triglyceride level, but the net effect of EPA and DHA therapy is a reduction in non–high‐density lipoprotein cholesterol level. Alternatively, patients may receive one of the fibrates (gemfibrozil or fenofibrate) or niacin for triglyceride lowering if their triglyceride levels are higher than 500 mg/dl. In controlled trials, prescription omega‐3 fatty acids were well tolerated, with a low rate of both adverse events and treatment‐associated discontinuations. The availability of prescription omega‐3 fatty acids, which ensures consistent quality and purity, should prove to be valuable for the medical management of hypertriglyceridemia.