Michael J. Bloch

New British Guidelines Mandate Ambulatory Blood Pressure Monitoring to Diagnose Hypertension in All Patients: Not Ready for Prime Time in the United States

BRITISH RECOMMEND ABPM FOR ALL NEWLY DIAGNOSED WITH HYPERTENSION In May 2011, the United Kingdom (UK) National Clinical Guideline Centre (NCGC) published their most recent guideline for the clinical management of primary hypertension in adults. As an update to the National Institute for Clinical Excellence (NICE) guideline report, this 332-page document covers a wide range of issues worthy of discussion. However, the main subject that caught our attention was the recommendation calling for routine use of ambulatory blood pressure monitoring (ABPM) to make the initial diagnosis of hypertension. According to these guidelines, clinic blood pressure (BP) measurement is recommended as a screening tool, and if the mean clinic BP is 140 ⁄ 90 mm Hg, the clinician is instructed to ‘‘offer ABPM to confirm the diagnosis of hypertension.’’ Specifically, the guidelines recommend that ABPM be performed by measuring at least two readings per hour during usual waking hours and that a minimum of 14 readings be obtained. A diagnosis of hypertension is thereby made in patients with a mean daytime ambulatory BP of at least 135 ⁄ 85 mm Hg. Of note, this means that patients do not necessarily need to wear the ABPM monitor for a full 24 hours or in the evenings. Home BP self-monitoring is only recommended as an alternative method for making the diagnosis of hypertension when ABPM is not tolerated. In the setting of ‘‘severe’’ clinic hypertension, antihypertensive medications can be started while waiting for the results of ABPM, but in other cases, the clinician is instructed to await the results of ABPM (as well as screening for target organ damage) prior to initiating antihypertensive therapy.

The diagnosis and management of renovascular disease: a primary care perspective. Part I. Making the diagnosis.

Renovascular disease is a complex disorder, the most common causes of which are fibromuscular dysplasia and atherosclerotic disease. It usually presents in one of three forms: asymptomatic renal artery stenosis, renovascular hypertension, or ischemic nephropathy. This complexity often makes diagnostic and management decisions difficult. This review will be presented in two parts. In Part I, the authors will discuss when to consider and how to go about making the diagnosis. In Part II (in a future issue of The JCH), the authors discuss the management of renovascular disease. The clinical index of suspicion remains paramount in setting the diagnostic strategy. Although it is subject to certain limitations, conventional contrast angiography is usually considered the gold standard in confirming the diagnosis. In addition, there are a number of available noninvasive tests that can aid in decision making. These tests can be divided into those that detect the anatomic presence of a stenosis and those that identify the functional consequences of the renal artery obstruction.

Cardiovascular Outcomes According to Systolic Blood Pressure in Patients With and Without Diabetes: An ACCOMPLISH Substudy

To evaluate the effects of achieved systolic blood pressure (SBP) during treatment on cardiovascular (CV) outcomes, the authors measured event rates of a composite primary endpoint (CV death or nonfatal myocardial infarction or stroke) at on‐treatment SBPs of ≥140 mm Hg and the 10 mm Hg intervals of <140 mm Hg, <130 mm Hg, and <120 mm Hg in 6459 patients with diabetes (mean age, 67) and 4246 patients without diabetes (mean age, 69) from the Avoiding Cardiovascular Events in Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial. In the diabetic cohort, the primary endpoint was 49% lower (P<.001) at <140 mm Hg than at ≥140 mm Hg, and the separate components of this endpoint were also significantly reduced. Further SBP reductions did not improve outcomes, and at <120 mm Hg they were no longer different (except for stroke) from ≥140 mm Hg. In contrast, in the nondiabetic cohort, the primary endpoint event rate fell steadily (although not significantly) through the decreasing SBP categories until it was reduced by 45% (P=.0413) at <120 mm Hg. Total stroke rates for both the diabetic (−56%, P=.0120) and nondiabetic (−68%, P=.0067) cohorts were lowest at <120 mm Hg, and adverse renal events (serum creatinine increase ≥50%) were significantly lowest in the range of 130 mm Hg to 139 mm Hg for both cohorts. Diabetic patients (<140 mm Hg or <130 mm Hg) and nondiabetic patients (<120 mm Hg) may require different SBP targets for optimal CV protection, although stroke and renal considerations should also influence the selection of blood pressure targets.

Analysis of Recent Papers in Hypertension Jan Basile, MD, Senior Editor

THREE STRIKES AND YOU’RE OUT: BLOCKADE OF THE RENIN-ANGIOTENSIN SYSTEM DOES NOT BENEFIT PATIENTS WITH HEART FAILURE AND PRESERVED EJECTION FRACTION Blockade of the renin-angiotensin-aldosterone system (RAAS) improves outcomes in patients with chronic heart failure (HF) and decreased left ventricular (LV) ejection fraction (EF). While many experts have continued to recommend RAAS blockade in patients with HF and normal (or preserved) EF, there has been no clinical trial evidence to support this recommendation. The Irbesartan in Heart Failure With Preserved Ejection Fraction Study (I-PRESERVE) was an industry-sponsored, investigator-designed trial to evaluate the effect of the angiotensin receptor blocker (ARB) irbesartan on mortality and cardiovascular (CV) morbidity in patients with chronic HF and preserved EF. To be eligible for I-PRESERVE, patients had to be at least 60 years of age, have symptoms of HF (New York Heart Association [NYHA] class II, III, or IV), and have an LVEF >45%. In addition, patients had to either have been hospitalized for HF within the previous 6 months with some corroborating evidence supporting the diagnosis of chronic HF or, if they had not been hospitalized for HF, have NYHA class III or IV symptoms with corroborating evidence of HF. Corroborating evidence could include findings of pulmonary congestion on radiologic studies, evidence of LV hypertrophy (LVH) or left atrial enlargement on echocardiography, or evidence of LVH or left bundle branch block (LBBB) on electrocardiography (ECG). Exclusion criteria included previous intolerance to an ARB; an alternative probable cause of the patient’s symptoms; any previous history of documented LVEF <40%; acute coronary syndrome, coronary revascularization, or stroke within the previous 3 months; substantial valvular disease; hypertrophic or restrictive cardiomyopathy; pericardial disease; cor pulmonale or other cause of isolated right HF; a systolic BP <100 mm Hg or <160 mm Hg despite antihypertensive therapy or a diastolic BP >95 mm Hg despite antihypertensive therapy; a life expectancy of <3 years; or substantial laboratory abnormalities including a hemoglobin level <11 g ⁄dL, liver function abnormalities, or a serum creatinine level >2.5 mg ⁄dL. Treatment with an angiotensin-converting enzyme (ACE) inhibitor was permitted when the investigator considered its use to be essential for an indication other than uncomplicated hypertension. Per protocol, the absolute number of patients who were taking an ACE inhibitor at baseline was capped at 33% at each site. Potentially eligible patients were treated with single-blind placebo therapy for 1 to 2 weeks prior to randomization. Subsequent to the single-blind runin phase, those patients who still met entry criteria were randomized in a double-blind fashion to therapy with irbesartan or matching placebo in addition to other therapy. Randomization was stratified according to site and ACE inhibitor use at baseline. Irbesartan or matching placebo was started at a dose of 75 mg once daily. As tolerated, the dose was increased by a forced-titration protocol to 150 mg daily after 1 to 2 weeks and to 300 mg From the Division of General Internal Medicine ⁄ Division of Cardiology, University of Nevada School of Medicine; the Risk Reduction Center, Saint Mary’s Regional Medical Center, Reno, NV; the Primary Care Service Line, Ralph H. Johnson VA Medical Center; and the Division of General Internal Medicine ⁄ Geriatrics, Medical University of South Carolina, Charleston, SC Address for correspondence: Michael J. Bloch, MD, Risk Reduction Center, Saint Mary’s Regional Medical Center, 645 North Arlington Street, Suite 460, Reno, NV 89503 E-mail: mbloch@aol.com

Diagnosis and management of renovascular disease and renovascular hypertension.

Renovascular disease is a common but complex disorder, the most common causes of which are fibromuscular dysplasia and atherosclerosis. Clinically, it can present as asymptomatic renal artery stenosis, renovascular hypertension, or ischemic nephropathy. Assessing the clinical index of suspicion remains essential in determining an appropriate diagnostic strategy. For diagnosis in patients with suspected fibromuscular disease, it may be reasonable to proceed directly to renal angiography; however, for most patients with suspected atherosclerotic disease, there are a number of noninvasive tests available that can aid in decision making. The choice of the most appropriate initial test should be based on patient characteristics, clinical presentation, and local expertise. Treatment options include medical, surgical, or percutaneous approaches. Generally, in patients with fibromuscular disease, percutaneous intervention provides durable improvement or cure of hypertension. In patients with atherosclerotic disease, the data are less consistent, and there does appear to be a group of patients who will respond well to medical management alone. As technology advances, the diagnostic and treatment paradigms will continue to evolve.

UK Guidelines Call for Routine 24‐Hour Ambulatory Blood Pressure Monitoring in All Patients to Make the Diagnosis of Hypertension—Not Ready for Prime Time in the United States

In May 2011, the UK National Clinical Guideline Centre (NCGC) published their most recent guideline for the clinical management of primary hypertension in adults. As an update to the National Institute for Clinical Excellence (NICE) guideline report, this 332page document covers a wide range of issues worthy of discussion. However, the main subject that caught our attention was the recommendation calling for routine use of ambulatory blood pressure monitoring (ABPM) to make the initial diagnosis of hypertension. According to these guidelines, clinic blood pressure (BP) measurement is recommended as a screening tool, and if the mean clinic BP is 140 ⁄90 mm Hg, the clinician is instructed to ‘‘offer ABPM to confirm the diagnosis of hypertension.’’ Specifically, the guidelines recommend that ABPM be performed by measuring at least 2 readings per hour during usual waking hours and that a minimum of 14 readings be obtained. A diagnosis of hypertension is thereby made in patients with mean daytime ambulatory BP of at least 135 ⁄85 mm Hg. Of note, this means that patients do not necessarily need to wear the ABPM monitor for a full 24 hours or in the evenings. Home BP self-monitoring is only recommended as an alternative method for making the diagnosis of hypertension when ABPM is not tolerated. In the setting of ‘‘severe’’ clinic hypertension, antihypertensive medications can be started while waiting for the results of ABPM, but in other cases, the clinician is instructed to await the results of ABPM (as well as screening for target organ damage) prior to initiating antihypertensive therapy. ABPM is not widely available in primary care practice and in the United States is usually offered only by centers that specialize in hypertension or cardiovascular medicine. Advantages of ABPM include the ability to detect white-coat or masked hypertension, determine the presence or absence of normal nocturnal dipping status, and assess the adequacy BP control in patients taking complex antihypertensive medication regimens. While it makes intuitive sense to use ABPM in these situations, it has been hard to obtain evidence of improved clinical outcome to support these indications. While numerous observational studies have demonstrated ABPM to be superior to clinic measurements in predicting target organ damage and other clinical outcomes associated with hypertension, definitive evidence that this is a superior management strategy is still lacking. To date, ABPM is most commonly used to determine the presence or absence of an exaggerated alerting response (white-coat effect), and this is generally the only indication for which it is covered by payers in the United States. Now, the NCGC is recommending ABPM in all patients suspected of having hypertension. As part of the basis for its recommendation, the NCGC performed a rigorous cost-effective analysis that demonstrated that ABPM would not only be a more effective means of making the diagnosis of hypertension, but also would provide a more costeffective approach than either the current approach (clinic BP) or use of home BP monitoring. Compared with making the diagnosis with clinic or home BP monitoring, not only was ABPM determined to be the most cost-effective approach in all age and sex subgroups, it also led to an improvement in quality health outcomes and was cost-saving when long-term costs were taken into account. The key driver of cost savings in this analysis was the cost of hypertension treatment that would be avoided due to improved specificity in making an accurate diagnosis with ABPM. The model suggested that antihypertensive therapy would be required in about 25% fewer patients than if the diagnosis was made based on clinic BPs alone. The pharmacy cost savings overwhelmed the cost increases associated with ABPM itself. According to the NICE publication, the conclusions of this analysis were generally stable regardless of a wide range of sensitivity analyses that were performed. But, cost-effective analyses require that the investigators make important assumptions about the future. Even with the best of intentions, these assumptions may prove inaccurate. We believe that while such analyses may play a supportive role in developing guidelines, they should not be the primary driver in determining clinical utility. Unfortunately, it can be very difficult for outside observers to confirm the methodology of a costeffective analysis, and they are probably most helpful when they can be independently externally validated. In any event, the assumptions made in the NCGC costeffective analysis are based on the UK model of health care delivery and should not be considered valid for use in the United States or other countries. Regardless of the validity of the UK cost-effective analysis, the requirement for routine ABPM in order From the Department of Internal Medicine, University of Nevada School of Medicine, Medical Director, Risk Reduction Center, Saint Mary’s Regional Medical Center, Reno, NV; and The Seinsheimer Cardiovascular Health Program, Division of General Internal Medicine ⁄Geriatrics, Medical University of South Carolina, Ralph H. Johnson VA Medical Center, Charleston, SC

Combination Angiotensin Receptor Blocker‐Neutral Endopeptidase Inhibitor Provides Additive Blood Pressure Reduction Over Angiotensin Receptor Blocker Alone

COMBINATION ANGIOTENSIN RECEPTOR BLOCKER–NEUTRAL ENDOPEPTIDASE INHIBITOR PROVIDES ADDITIVE BLOOD PRESSURE REDUCTION OVER ANGIOTENSIN RECEPTOR BLOCKER ALONE Hypertension continues to be the single most important cause of morbidity and mortality worldwide. The most recent United States National Health and Nutrition Examination Survey (NHANES) data suggests that blood pressure (BP) control continues to improve in all demographic groups, with 50% of all persons with hypertension and more than 65% of persons also being treated for hypertension currently controlled to the minimum goal of <140 ⁄90 mm Hg. Despite these successes, the pathogenesis of hypertension remains extremely heterogeneous and, since most patients require 2 antihypertensive agents to control BP, the hypertension community continues to look for new and innovative pathophysiologic approaches for BP control. Vasopeptidase inhibitors simultaneously block 2 key enzymes involved in the regulation of cardiac function: (1) neprilysin (neutral endopeptidase [NEP]), which increases concentrations of natriuretic peptides and also inhibits the renin-angiotensin-aldosterone and sympathetic nervous system, and (2) angiotensin-converting enzyme (ACE). The most widely studied vasopeptidase inhibitor, omapatrilat, has been found to be a potent BP-lowering agent; however, since its use was associated with an increased risk for angioedema, believed to occur as a result of bradykinin upregulation, it was never approved for clinical use. Because angiotensin receptor blockers (ARBs) are believed to have less effect on bradykinin metabolism, agents that combine NEP inhibition with agents that block the angiotensin II receptor (ARBs) might be associated with the cardiac benefits of vasopeptidase inhibition without the increased risk for angioedema. Developed using a radiographic crystallographic technique, LCZ696 is a first-in-class dual-acting angiotensin II receptor and NEP inhibitor (ARNI) that combines the ARB valsartan with AHU377, its NEP inhibitor moiety. The present industry sponsored proof-of-concept trial was designed to establish whether LCZ696 leads to greater reduction of BP compared with the ARB valsartan. Recruited from 134 sites in 18 countries (including the United States) between September 2007 and March 2008, eligible patients had to be aged between 18 and 75 years and have uncomplicated essential hypertension (mean sitting diastolic BP 90–109 mm Hg after antihypertensive drug washout or 95–109 mm Hg if untreated). Exclusion criteria included severe hypertension (mean sitting systolic BP 180 mm Hg), history of angioedema or allergy to an ARB or NEP inhibitor, type 1 or 2 diabetes, secondary hypertension, a serious structural or functional cardiac disorder, significant hepatic or renal disease, clinically important anemia, or abnormal serum sodium or potassium concentrations. In addition, use of certain medications were prohibited, including antihypertensives other than those specified in the protocol, antiarrhythmics, tricyclic antidepressants and monoamine oxidase inhibitors, systemic corticosteroids, nonsteroidal anti-inflammatory drugs, chronic sympathomimetic use, bile acid resins, a-blockers, and phosphodiesterase inhibitors taken within 48 hours of scheduled visits. From the Department of Internal Medicine, University of Nevada School of Medicine, Medical Director, Risk Reduction Center, Saint Mary’s Regional Medical Center; and the Seinsheimer Cardiovascular Health Program, Division of General Internal Medicine ⁄ Geriatrics, Medical University of South Carolina, Ralph H. Johnson VA Medical Center, Charleston, SC Address for correspondence: Michael J. Bloch, MD, Risk Reduction Center, Saint Mary’s Regional Medical Center, 645 North Arlington Street, Suite 460, Reno, NV 89503 E-mail: mbloch@aol.com

Overcoming Racial and Ethnic Disparities in Blood Pressure Control: A Patient‐Centered Approach to Cross‐Cultural Communication

“It is much more important to know what sort of a patient has a disease than what sort of a disease a patient has.”—William Osler 1

Exposure to Air Pollution Increases the Incidence of Hypertension and Diabetes in Black Women Living in Los Angeles

COMMENTS Multiple epidemiological studies have established a statistical association between exposure to air pollutants and incident cardiovascular (CV) disease. As part of the Black Women’s Health Study (BWHS), investigators examined the association between chronic exposure to air pollution and the risk of incident diabetes mellitus and hypertension. This analysis suggests that exposure to chronic air pollutants, particularly those associated with automobile traffic, is related to an increased risk of both type 2 diabetes mellitus and hypertension. Although the explanation for the apparent association between air pollution and CV disease remains unknown, most previous research has focused on the hypothesis that short-term exposure to air pollution may lead to acute increases in platelet activation, vascular reactivity, and potential plaque rupture. Another intriguing possibility is that there may also be a longterm effect on traditional CV risk factors such as diabetes and hypertension. This appears to be the first study that examined the potential relationship between hypertension and ambient air pollution. While this analysis is clearly not definitive, the results suggest that ambient air pollutants, particularly those caused by automobile traffic, may be an unrecognized risk factor for the development of hypertension. Given the fact that hypertension is present in nearly 1 in 3 adult Americans, even if exposure to air pollution produces only a modest increase in the relative risk for hypertension, the absolute population attributable risk may be substantial.

Is There Accord in ACCORD? Lower Blood Pressure Targets in Type 2 Diabetes Does Not Lead to Fewer Cardiovascular Events Except for Reductions in Stroke

Approximately 8% of the US population—or 24 million people—have diabetes, with type 2 diabetes mellitus (T2DM) making up 90% to 95% of the cases. Cardiovascular (CV) disease remains the number one cause of death in T2DM, and CV risk is increased 2to 3-fold at every level of systolic blood pressure (BP). In those with versus without T2DM, optimal management of diabetes consists of controlling the major associated CV risk factors of hyperglycemia, hyperlipidemia, and hypertension, but which specific glycosylated hemoglobin, lipid, or BP goal is associated with optimal event reduction continues to be unclear. Recent guideline recommendations of the Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) and the American Diabetes Association (ADA) recommend a target BP of <130 ⁄ 80 mm Hg in patients with T2DM, even though there is no randomized clinical trial data to support this particular recommendation. Many would argue that the best available evidence suggests the goal BP should be <140 ⁄ 80 mm Hg. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) BP trial, part of the overall ACCORD trial program, was designed to determine whether a target systolic BP of <120 mm Hg would lead to a reduction in major CV events when compared with a target of <140 mm Hg among patients with T2DM.