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While we started clinical trials evaluating the benefit of lowering systolic BP's160 mm Hg and diastolic BPs of130 mm Hg, the latest guideline suggests a target of130/80 mm Hg in those with hypertension. This article summarizes exactly how we got to where we are looking over the last half-century.Our understanding of systolic and diastolic blood pressure targets to improve cardiovascular outcomes has changed substantially over the past 5 decades. Regarding diastolic blood pressure targets to improve cardiovascular outcomes, initially the VA1 in 1967 had set the goal to115 mmHg. Over time, several studies including the VA2, Hypertension Optimal Treatment (HOT), and United Kingdom Prospective Diabetes Study Group 38 (UKPDS38) highlighted even greater cardiovascular benefit with lower diastolic targets80 mmHg, especially in diabetic patients. Of equal importance, multiple studies have focused the attention to systolic blood pressure targets. Starting in 1948 with the Framingham study, passing through the Systolic Hypertension in the Elderly Program (SHEP), Syst-Eur and Syst-China trials, all have set the systolic blood pressure goal150 mmHg. Most recently, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial showed an improved cardiovascular outcome with a systolic blood pressure target140 mmHg in patients with type 2 diabetes, while the Systolic Blood Pressure Intervention Trial (SPRINT) in non-diabetic patients moved it closer to 120 mmHg. There is "no one size fits all" when it comes to blood pressure targets to improve cardiovascular outcomes. To progress our understanding of individual blood pressure goals, future studies might develop a more standardized approach to highlight characteristics such as design and end point definitions while allowing clinical practitioners greater latitude to adapt guideline recommendations to individual patient characteristics and clinical needs.

There is no evidence from randomized trials to support a strategy of lowering systolic blood pressure below 135 to 140 mm Hg in persons with type 2 diabetes mellitus. We investigated whether therapy targeting normal systolic pressure (i.e.,120 mm Hg) reduces major cardiovascular events in participants with type 2 diabetes at high risk for cardiovascular events.A total of 4733 participants with type 2 diabetes were randomly assigned to intensive therapy, targeting a systolic pressure of less than 120 mm Hg, or standard therapy, targeting a systolic pressure of less than 140 mm Hg. The primary composite outcome was nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The mean follow-up was 4.7 years.After 1 year, the mean systolic blood pressure was 119.3 mm Hg in the intensive-therapy group and 133.5 mm Hg in the standard-therapy group. The annual rate of the primary outcome was 1.87% in the intensive-therapy group and 2.09% in the standard-therapy group (hazard ratio with intensive therapy, 0.88; 95% confidence interval [CI], 0.73 to 1.06; P=0.20). The annual rates of death from any cause were 1.28% and 1.19% in the two groups, respectively (hazard ratio, 1.07; 95% CI, 0.85 to 1.35; P=0.55). The annual rates of stroke, a prespecified secondary outcome, were 0.32% and 0.53% in the two groups, respectively (hazard ratio, 0.59; 95% CI, 0.39 to 0.89; P=0.01). Serious adverse events attributed to antihypertensive treatment occurred in 77 of the 2362 participants in the intensive-therapy group (3.3%) and 30 of the 2371 participants in the standard-therapy group (1.3%) (P0.001).In patients with type 2 diabetes at high risk for cardiovascular events, targeting a systolic blood pressure of less than 120 mm Hg, as compared with less than 140 mm Hg, did not reduce the rate of a composite outcome of fatal and nonfatal major cardiovascular events. (ClinicalTrials.gov number, NCT00000620.)

Editor’s Note: The American Society of Hypertension is publishing a series of Position Papers in their official journals throughout the 2008–2011 years. The following Position Paper originally appeared: JASH. 2010;4:42–50. The goal of antihypertensive therapy is to abolish the risks associated with blood pressure (BP) elevation without adversely affecting quality of life. Drug selection is based on efficacy in lowering BP and in reducing cardiovascular (CV) end points, including stroke, myocardial infarction, and heart failure. Although the choice of initial drug therapy exerts some effect on long‐term outcomes, it is evident that BP reduction per se is the primary determinant of CV risk reduction. Available data suggest that at least 75% of patients will require combination therapy to achieve contemporary BP targets, and increasing emphasis is being placed on the practical tasks involved in consistently achieving and maintaining goal BP in clinical practice. It is within this context that the American Society of Hypertension presents this Position Paper on Combination Therapy for Hypertension. It will address the scientific basis of combination therapy, present the pharmacologic rationale for choosing specific drug combinations, and review patient selection criteria for initial and secondary use. The advantages and disadvantages of single‐pill (fixed) drug combinations and the implications of recent clinical trials involving specific combination strategies will also be discussed. J Clin Hypertens (Greenwich). 2011;13:146–154. © 2010 Wiley Periodicals, Inc.

A randomized, double-blind, active-controlled, multicenter trial assigned 32,804 participants aged 55 years and older with hypertension and ≥ 1 other coronary heart disease risk factors to receive chlorthalidone (n=15,002), amlodipine (n=8898), or lisinopril (n=8904) for 4 to 8 years, when double-blinded therapy was discontinued. Passive surveillance continued for a total follow-up of 8 to 13 years using national administrative databases to ascertain deaths and hospitalizations. During the post-trial period, fatal outcomes and nonfatal outcomes were available for 98% and 65% of participants, respectively, due to lack of access to administrative databases for the remainder. This paper assesses whether mortality and morbidity differences persisted or new differences developed during the extended follow-up. Primary outcome was cardiovascular mortality and secondary outcomes were mortality, stroke, coronary heart disease, heart failure, cardiovascular disease, and end-stage renal disease. For the post-trial period, data are not available on medications or blood pressure levels. No significant differences (P.05) appeared in cardiovascular mortality for amlodipine (hazard ratio [HR], 1.00; 95% confidence interval [CI], 0.93-1.06) or lisinopril (HR, 0.97; CI, 0.90-1.03), each compared with chlorthalidone. The only significant differences in secondary outcomes were for heart failure, which was higher with amlodipine (HR, 1.12; CI, 1.02-1.22), and stroke mortality, which was higher with lisinopril (HR, 1.20; CI, 1.01-1.41), each compared with chlorthalidone. Similar to the previously reported in-trial result, there was a significant treatment-by-race interaction for cardiovascular disease for lisinopril vs chlorthalidone. Black participants had higher risk than non-black participants taking lisinopril compared with chlorthalidone. After accounting for multiple comparisons, none of these results were significant. These findings suggest that neither calcium channel blockers nor angiotensin-converting enzyme inhibitors are superior to diuretics for the long-term prevention of major cardiovascular complications of hypertension.

Out-of-hospital sudden cardiac death occurs in approximately 300,000 individuals each year in the United States, a total that represents about half of all annual deaths from coronary heart disease. Beta-blockers were the first class of drugs investigated for the prevention of sudden cardiac arrest because of their ability to reduce ventricular arrhythmias. Numerous randomized, controlled trials have now established the importance of beta-blockade in preventing sudden cardiac death. Clinical evidence reveals the association between beta-blockade and improved survival, and trials explore the role for beta-blockers in the prevention of sudden cardiac death.

Beta-blockers are an established class in the management of hypertension, and numerous randomized, controlled trials have shown that these drugs can prevent cardiovascular events in this population. However, beta-blockers are underutilized in managing the general hypertensive population. This phenomenon may stem in part from concerns about side effects. On the contrary, beta-blockers demonstrate comparable efficacy, safety, and tolerability compared with other classes of antihypertensive drugs. Because beta-blockers offer unique cardiovascular protection, they should be considered an integral part of the treatment regimen for patients with hypertension who are at risk for cardiovascular events.

Antihypertensive drugs with favorable metabolic effects are advocated for first-line therapy in hypertensive patients with metabolic/cardiometabolic syndrome (MetS). We compared outcomes by race in hypertensive individuals with and without MetS treated with a thiazide-type diuretic (chlorthalidone), a calcium channel blocker (amlodipine besylate), an alpha-blocker (doxazosin mesylate), or an angiotensin-converting enzyme inhibitor (lisinopril).A subgroup analysis of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a randomized, double-blind hypertension treatment trial of 42 418 participants. We defined MetS as hypertension plus at least 2 of the following: fasting serum glucose level of at least 100 mg/dL, body mass index (calculated as weight in kilograms divided by height in meters squared) of at least 30, fasting triglyceride levels of at least 150 mg/dL, and high-density lipoprotein cholesterol levels of less than 40 mg/dL in men or less than 50 mg/dL in women.Significantly higher rates of heart failure were consistent across all treatment comparisons in those with MetS. Relative risks (RRs) were 1.50 (95% confidence interval, 1.18-1.90), 1.49 (1.17-1.90), and 1.88 (1.42-2.47) in black participants and 1.25 (1.06-1.47), 1.20 (1.01-1.41), and 1.82 (1.51-2.19) in nonblack participants for amlodipine, lisinopril, and doxazosin comparisons with chlorthalidone, respectively. Higher rates for combined cardiovascular disease were observed with lisinopril-chlorthalidone (RRs, 1.24 [1.09-1.40] and 1.10 [1.02-1.19], respectively) and doxazosin-chlorthalidone comparisons (RRs, 1.37 [1.19-1.58] and 1.18 [1.08-1.30], respectively) in black and nonblack participants with MetS. Higher rates of stroke were seen in black participants only (RR, 1.37 [1.07-1.76] for the lisinopril-chlorthalidone comparison, and RR, 1.49 [1.09-2.03] for the doxazosin-chlorthalidone comparison). Black patients with MetS also had higher rates of end-stage renal disease (RR, 1.70 [1.13-2.55]) with lisinopril compared with chlorthalidone.The ALLHAT findings fail to support the preference for calcium channel blockers, alpha-blockers, or angiotensin-converting enzyme inhibitors compared with thiazide-type diuretics in patients with the MetS, despite their more favorable metabolic profiles. This was particularly true for black participants.

Hypertension affects approximately 50 million individuals in the United States (US) and approximately 1 billion individuals worldwide. Blood pressure (BP) reduction significantly lowers the risk of cardiovascular (CV) disease-the most common cause of death in the US-yet only approximately one third of Americans with hypertension have their disease controlled to the minimum recommended level of140/90 mm Hg. Clinical trials such as the Hypertension Optimal Treatment (HOT) study, and Treatment of Mild Hypertension Study (TOMHS) have shown that control of BP to targets ofor =140/90 mm Hg reduces the likelihood of CV disease and improves quality of life. This appears to be true even in patients at high risk, such as those with diabetes. Furthermore, it has become increasingly recognized that multiple BP-lowering agents are usually necessary to achieve BP control (140/90 mm Hg, or130/80 mm Hg for patients with diabetes or chronic kidney disease). In fact, current hypertension guidelines clearly state that most hypertensive patients will require two or more agents, and recommend initiating treatment with two antihypertensive medications if the BP is20/10 mm Hg above goal BP. A valuable class of drug in the management of hypertension, beta-blockers (betaB) play an important role-whether as initial agents or as add-on therapy. They are especially useful in hypertensive patients with certain comorbidities such as diabetes or heart failure, in patients post-myocardial infarction, or in those generally at high risk for coronary disease. This article explores the cardioprotective role of how betaB may be used to optimize antihypertensive treatment.

Data from large clinical trials indicate that beta-blocker therapy can be successfully initiated and adjusted upward in most patients with stable chronic heart failure who already take standard heart failure therapy. Such therapy typically includes ACE inhibitors, diuretics, and digoxin. With optimal titration and maintenance strategies, beta-blockers are effective and well tolerated in these patients. It is recommened that all patients with clinically stable mild to moderate chronic heart failure (NYHA class II or III), no contraindications to beta-blocker use, and an LVEF less than 40% should be treated with beta-blockers. Based on the results of recent clinical trials on heart failure, beta-blocker therapy should be initiated at a low dose and slowly tirtrated upward as tolerated. A patient's heart failure should be stable for at least 2 weeks before the dose is adjusted upward. Slow titration facilitates maximal tolerability. In primary care practice, physicians should apply titration strategies and target dosed that have been demonstrated to reduce morbidity and mortality in clinical trials. Although worsening heart failure or other adverse events occur in a minority of patients who take beta-blockers, these effects can be managed by adjusting the dose of ACE inhibitor or diuretic, or both, or by temporarily withholding the beta-clocker. Currently, professional treatment guidelines recommend beta-blocker therapy in combination with ACE inhibitors an diuretics as the standard of care in the treatment of heart failure.

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

Elevation of systolic blood pressure predicts the risk of cardiovascular disease better than increases in diastolic blood pressure.1 Although this was observed more than three decades ago, no attempt was made to translate this evidence into practice until in 1993, when a report of the fifth joint national committee of the United States for the detection, evaluation, and treatment of high blood pressure recognised isolated systolic hypertension as an important target for the control of blood pressure.2 Nevertheless it is the elevation in systolic blood pressure that still limits our ability to control blood pressure to the recommended goal of less than 140/90 mm Hg.3 Although associated with more variability in measurement, systolic blood pressure is easier to determine and allows more appropriate risk stratification than diastolic blood pressure. In a recent analysis of the Framingham heart study, knowing only the systolic blood pressure correctly classified the stage of blood pressure in 99% of adults over age 60 whereas knowing the diastolic blood pressure allowed only 66% to be classified correctly.4 Isolated systolic hypertension is defined as a systolic blood pressure more than or equal to 140 …