Background Story

The groundwork for the first United States hypertension guideline began with the first randomized trial of hypertension treatment in U.S. veterans, which was directed by Dr. Ed Freis, a Veterans Administration Physician. The trial was conducted by the Veterans Administration Cooperative Trial Study Group on Antihypertensive Agents. Two seminal publications resulted from this early effort. The first part of this landmark trial, published in 1967, involved 143 men with diastolic blood pressures (DBP) of 115 to 129 mm Hg of whom 73 were treated with active medication, and 70 received placebos. After about 2 years there were 27 terminating events in the placebo group, and 2 in the active treatment group. This demonstrated for the first time that, although both groups were basically asymptomatic at enrollment, men with significant hypertension benefitted dramatically from antihypertensive drug therapy in a relatively short period of time. Three years later, the second portion of the VA Cooperative Trial was published. This segment randomized men with DBP of 90 to 114 mm Hg of whom 186 were treated with active medication, and 194 received placebos. After about 2 years there were 76 assessable events in the placebo group, and 22 in the active treatment group over the 5 years of the study. Those with DBP of 105 to 114 mm Hg were about twice as likely to benefit, compared with men with similar diastolic pressures in the placebo group, from active treatment when they compared with those within the active treatment group who had diastolic values of 90 to 104 mm Hg at randomization. The trial investigators again stressed the value of antihypertensive therapy, but readers were left with a bit of residual uncertainty over those with DBP in the 90 to 104 mm Hg group.

Despite the dramatic results of these two studies, and their publication in a high profile journal (JAMA), physicians were sluggish to act on these findings and treatment rates remained low ( Table 50.1 ). As a result of this ‘inertia’ the philanthropist and medical research proponent Mary Lasker, with the lead VA Cooperative Study Group Investigator Dr. Ed Freis, Dr. Thomas Rudeshan, and Deeda Blair (the current Vice President of the Albert and Mary Lasker Foundation) visited Elliot Richardson, who was at that time, Secretary of the Department of Health Education and Welfare. During that meeting Dr. Freis reviewed the VA Cooperative Study data emphasizing the declines in morbidity and mortality from lowering BP with drug treatment. Mr. Richardson’s father had been a surgeon at the Massachusetts General Hospital whose career came to an end from a stroke related to his hypertension. Mr. Richardson convinced the Director of the National Heart and Lung Institute (NHLI; this was before ‘Blood’ was added to the Institute name), Dr. Theodore Cooper, who directed the Institute from 1968 to 1974 to work on a strategy to promote hypertension awareness and treatment. During the Nixon and Ford administrations Dr. Cooper was appointed the Assistant Secretary for Health at the Department of Health, Education, and Welfare (HEW), and he worked in that position, as well as during his Directorship at the National Institutes of Health (NIH), to enable the initiative that became known as the National High Blood Pressure Education Project (NHBPEP). In the beginning, the focus of the NHBPEP was on developing Task Forces to publish papers on aspects such as screenings for blood pressure (BP). Task Force I was devoted to treatment and was chaired by Dr. H. Mitchell Perry Jr. The output of Task Force I was the precursor for the first U.S. guideline. (The author would like to acknowledge the input of Dr. Edward J. Roccella [also from NIH/National Heart, Blood, and Lung Institute {NHLBI}/NHBPEP] in the history covered herein.)

As clamor on the part of patients for more attention to their BP became more audible, the desire to “know your number” and participate in community BP screenings grew. Consequently an early objective of the NHBPEP was to reach consensus on a definition for hypertension. A substantial challenge in this endeavor was to choose between options such as “100 + age” for the ‘normal’ systolic BP, whereas others favored using only the diastolic BP, and a value such as 105 mm Hg seemed an attractive cut point based on VA Cooperative data. Detection of hypertension, a key to selecting those who need further evaluation, as well as treatment remained active areas of discussion. The NHBPEP formed a Coordinating Committee to provide guidance on the detection, evaluation, and treatment of hypertension. Stakeholders in this Committee included representatives from the American Academy of Family Practice, American College of Cardiology (ACC), American College of Physicians, American Heart Association (AHA), American Medical Association, the National Kidney Foundation, the National Medical Association, the Veterans Administration, and the United States Public Health Service. The goal was to speak with a single voice about managing hypertension using consensus methodology in the formation of recommendations. The Coordinating Committee was chaired by Dr. Marvin Moser and its publication became the first Joint National Committee (JNC) Report.

A Short History of the United States of America Joint National Committee Guidelines

The first guideline on hypertension was published in the USA in 1977. This first Joint National Committee (JNC) Report spanned seven printed journal pages, made six recommendations, and cited a single reference ( Table 50.2 ). It made the term “stepped-care approach” common parlance in hypertension, and provided guidance on how to evaluate and manage high BP using consensus from input provided by the nine major stakeholder groups cited previously. The Report was accompanied by a half page editorial in the same issue of JAMA, written by William Barclay. In that brief space Barclay makes the following prescient observations:

“Although the report was sponsored by the National Heart and Lung Institute, it is not a government directive on how to practice medicine. The report should be viewed as a useful guide and not as a rigid directive on how to manage high blood pressure. One should be aware that such reports are compromises and do not necessarily reflect the conviction of individual committee members.”

In the ensuing decades after the first JNC Report, high BP advanced from fourth place on the World Health Organization (WHO) listing of factors responsible for premature death and disability in 1990, to first place in 2010. In the ensuing decades, new antihypertensive agent classes, new clinical trial results, and redirection in thinking about the importance of systolic pressure have prompted repeated revision of the U.S. hypertension guidelines.

The second JNC Report was issued following the completion of the Hypertension Detection and Follow-up Program (HDFP) and the United States Public Health Service’s 10 year intervention trial for hypertension. It introduced a classification system for DBP levels, and was responsible for the terms ‘mild’ (DBP 90 to 104 mm Hg), ‘moderate’ (DBP 105 to 114 mm Hg), and ‘severe’ hypertension (DBP ≥ 115 mm Hg) and recommended initiating antihypertensive therapy with a diuretic because chlorthalidone (a thiazide-type of diuretic) was the initial step in the stepped care (SC) arm of HDFP. Although not often mentioned today, the HDFP made several important contributions in addition to being a major reason for the second JNC Report. First, with an enrollment of 10,940 participants it had enough power to establish the significant benefit of treating diastolic values of 90 to 104 mm Hg in the SC compared with the Referred Care (RC) group, reducing the uncertainty left in the wake of the first JNC Report which did not have enough basis in treatment success to recommend this target. Second, HDFP enrolled participants with preexisting target organ damage and showed there was still benefit in treating their hypertension, but those without prior cardiovascular disease experienced greater benefit, emphasizing the importance of primary over secondary prevention of hypertensive target organ damage. Finally, the HDFP investigators observed that those with a serum creatinine value higher than 1.7 mg/dL at enrollment had more than three-fold greater risk of mortality compared with those who had lower values establishing the importance of kidney disease in hypertensives.

In 1984, the third JNC Report appeared updated based on the results of hypertension trials outside the U.S. and recommended initial therapy with either beta-adrenergic blockade (in younger patients, or those with faster heart rates) or diuretic therapy. The expansion to beta-blocker therapy was driven, in part, because of the emerging findings of reduced death after a myocardial infarction when beta-blockade was employed. The classification scheme of BP based on diastolic values remained; however, the 1984 Report introduced the concept of “high normal” blood pressure (DBP 85 to 89 mm Hg) and expanded the classification system to include levels of systolic pressure when the DBP was less than 90 mm Hg.

The fourth JNC Report was published in 1988. The most significant events that transpired between the 1984 and 1988 reports included the growing popularity of two new classes of antihypertensive agents following the approval of the three original calcium channel blockers (verapamil, diltiazem, and nifedipine) in 1981, and the angiotensin-converting enzyme (ACE) inhibitor captopril in 1981, followed by enalapril in 1986. Added to this was the publication of several landmark European trials including the Medical Research Council study and the European Working Party for Hypertension in the Elderly. In a previous understanding of “personalized medicine” the 1988 Report laid emphasis on quality of life, cost of care, and the need to consider ways to prevent hypertension. The main legacies of the 1988 Report were an expansion of the recommendation for treatment to the use of any of the four classes of popular antihypertensives (diuretic, beta-blocker, ACE-inhibitor, or calcium channel blocker), the use of nondrug therapy as foundational to the subsequent drug usage steps, and incorporating mechanisms to step down antihypertensive drug therapy in select cases.

The fifth JNC Report (JNC V) appeared in 1993 and was noteworthy for returning to the emphasis of using a diuretic or a beta-blocker as the initial antihypertensive therapy. The staging system for BP reached its zenith in JNC V which defined stage 1 hypertension as a DBP of 90 to 99 mm Hg or a systolic blood pressure (SBP) of 140 to 159 mm Hg. Stage 2 was defined as a DBP of 100 to 109 mm Hg or an SBP of 160 to 179 mm Hg. Stage 3 hypertension was defined as a DBP of 110 to 119 mm Hg or an SBP of 180 to 219 mm Hg. Stage 4 was defined as a DBP higher than 120 mm Hg or an SBP higher than 220 mm Hg. JNC V emphasized that if the BP fell into discordant categories, such as stage 2 by DBP but a stage 3 by SBP, the higher stage was the category to use in that patient. They also defined an “optimal” category as less than 120/80 mm Hg. The fifth JNC also proposed reasons for doing an Ambulatory Blood Pressure Monitoring (ABPM) test.

JNC VI appeared in 1997 and was noteworthy for its classification of the papers (e.g., “cohort study,” “randomized trial,” etc.) used in the preparation of the Report, and for simplifying the classification system from four stages to three stages. The most innovative aspect of JNC VI was the incorporation of nonhypertensive risk factors for cardiovascular disease into the classification system, using a scale ranging from Group A (no cardiovascular [CV] risk factors, target organ damage [TOD], or concomitant cardiovascular disease [CVD]) to Group B which had one or more CV risk factor (not including diabetes mellitus [DM]), but no TOD or concomitant CVD) and designated the highest Risk Group as C defined as the presence of TOD. JNC VI also introduced the term “compelling indications” recommending specific classes of antihypertensive drug therapy in patients with specific comorbidities (e.g., the use of an ACE inhibitor in type 1 diabetes with proteinuria). JNC VI also included the term “Prevention” in the title of the Report for the first time. Drug recommendations per JNC VI continued to recommend diuretic or beta-blocker as initial therapy, and they hinted that low dose combination therapy may be appropriate is some patients.

JNC 7 appeared in 2003 and reduced further the classification system to stage 1 (140 to 159/90 to 99 mm Hg) or stage 2 (≥160/≥ 100 mm Hg). The JNC VI appeared in the Archives of Internal Medicine which allowed the usage of Roman Numerals in the article title. JAMA, the site of initial publication of JNC 7 did not allow the use of Roman Numerals, thus the change to “7.” JNC 7 was published in two stages. The first article was published in May 2003, followed about 6 months later by a “Complete Version” published in December in Hypertension. JNC 7 was remarkable for several things. It proposed treatment goals lower than 140/90 mm Hg in diabetes and chronic kidney disease (CKD). One of the most discussion-promoting aspects of JNC 7 was the promotion of a new category of blood pressure called “prehypertension” based on having either an SBP of 120 to 139 mm Hg or a DBP of 80 to 89 mm Hg. This was done to emphasize the opportunity for clinicians to intervene and perhaps prevent the progression to established hypertension through the use of, for example, weight loss and exercise programs that could have greater impact on patients when based upon a label or diagnosis such as Prehypertension. JNC 7 also gave concrete recommendations for using combination drug therapy when the starting BP is more than 159/99 mm Hg (either the SBP of the DBP). The next guideline, the Management of Hypertension in Adults (empaneled as JNC 8) took no issue with the classification scheme of JNC 7 and had no reason to update it.

2014 Expert Panel Report

The Report of the group empaneled as JNC 8 appeared in the same journal as the first JNC Report (JAMA), in February 2014. In an ironic fashion the response to this Report was very much predicted in the words of Barclay written almost 4 decades previously. The Expert Panel was careful to point out in the Abstract and the concluding paragraph that guidelines are not a substitute for clinical judgment. When the three panels that were initially commissioned in September 2008 to undertake updates to the lipid (ATP 1-3), obesity (a single prior report in 1998), and the Hypertension guidelines the emphasis placed upon the three panels was principally driven by the Institute of Medicine Report “Crossing the Quality Chasm” which underscored the need to have recommendations for health care based on evidence. When the Expert Panel was empaneled the NHLBI (at that time the sponsor) emphasized strongly the need to produce an evidence-based guideline citing, for example, the experience with the AHA/ACC recommendations in which about 1 in 9 recommendations (11%) made in the management of a variety of cardiovascular disorders had “A” level evidence to support it. Unlike the previous JNC Reports, the Expert Panel Report (JNC 8) was comprised of 18 people, representing a broad range of hypertension expertise, and including two employees of NIH (one from NHLBI and one from the National Institute of Diabetes and Digestive and Kidney Diseases [NIDDK]). Early in the process one panel member left academia for Industry and the number was reduced to 17.

The largest hurdle faced by the Expert Panel was the challenge to use evidence in the formulation of “evidence-based recommendations.” It was necessary first to construct an evidence base. This required several preparatory steps. The primary focus of the Expert Panel, determined early in the process, was the primary care practitioner. Every evidence statement that was developed, and each of the 9 main recommendations, was crafted with careful attention to the mission of assembling a guidance document that would be useful, and clear, in a primary care practice.

The first step was the development of the critical questions. Initially the panel members identified 23 separate critical questions that were felt to be important for primary care practitioners managing hypertension patients. These were winnowed down to five critical questions, two of which were not addressed in the Expert Panel Report. The fourth critical question asked whether it was better to start with two antihypertensive agents compared with one agent. We could find no data on that question. The fifth question asked whether it mattered where BP was measured (home, office, ABPM, kiosk, or other location). Limitations in time and funding precluded answering critical question five.

Once critical questions were framed it was necessary to develop a search strategy. This meant defining limits on what constituted acceptable “evidence” to include in the evidence base. We used the PICOTSS (population, intervention/exposure, comparison group, outcome, time, setting, and study design) strategy for this as outlined in supplement of the Expert Panel Report. One of the most time-consuming aspects at this stage was defining “important health outcomes.” When treating a patient with hypertension using drug therapy, what are the important health benefits? Also, what level of BP reduction does one need to target to achieve these benefits? This area generated controversy after the manuscript first appeared as an e-publication in JAMA. For example, we defined doubling of the serum creatinine concentration, halving of glomerular filtration rate (GFR), or the development of end-stage renal disease as the kidney-related important health outcomes. We did not use the slope of GFR change over time. Consequently, the Expert Panel felt that the original Modification of Diet in Renal Disease (MDRD) study report did not demonstrate a benefit in the more aggressive compared with the standard level of BP in patients with moderate and advanced nondiabetic chronic kidney disease. The MDRD investigators stated as much in their original report, but did note that the slope of GFR change was favorably reduced in those in the more aggressive BP target group when the magnitude of urinary protein loss was more than 1 g but less than 3 g a day, and more so if it was more than 3 g a day. After careful review of the African American Trial of Kidney Disease and Hypertension and the Ramipril Efficacy in Nephropathy II trials, both of which compared more intensive to standard BP goals, the Expert Panel agreed that it could not find evidence fitting its definition of an important health outcome in a randomized controlled trial supporting a value lower than 140/90 mm Hg in the management of patients with CKD. This is supported further by a systematic review of BP goals in CKD which reached the same conclusion.

The circumstances underpinning the approach to guideline development become a challenging and confusing issue for practitioners who try to understand, reconcile, and incorporate the various BP targets recommended by different BP guideline writing groups in diverse subsets of hypertensive patients. In the execution of the search strategy the Expert Panel felt it was important to use only prospective randomized clinical trials of antihypertensive therapy that enrolled only hypertensive patients. This excluded trials like the Heart Outcome Prospective Evaluation (HOPE) which, although it was a randomized trial and included hypertensive patients, it also included high cardiovascular risk patients who did not have hypertension.

Once the investigations identified by the search criteria were identified it was necessary to have two independent raters categorize the trial as good, fair, or poor using a 14-point set of predefined criteria. After this process, which often reduced 1 to 2000 articles down to about 20 to 25 papers that fit our definition, it was necessary to summarize the data in a fashion that made clear what the benefits were, at what level of BP (systolic and diastolic were treated separately), with what agent(s), and in which subgroups (e.g., general population, self-declared Black, diabetic, or CKD). The Expert Panel did not review the evidence for important health outcomes accrued to patients with preexisting heart disease or stroke from BP management because that was being done in parallel by the American Heart Association/American College of Cardiology (AHA/ACC).

The final steps were the formation of evidence statements which are in the JAMA online supplement, and then crafting recommendations based on the evidence. The recommendations, all 9 of them, are visible within the algorithm in the Expert Panel Report. Equipped with the knowledge of the patient’s age (in years), ethnicity (African American, non-African American), diabetic status (Yes/No), and CKD status (Yes/No), the algorithm walks the viewer through what agent to use, what BP target to use, how soon to follow up, and when to refer. After years of poring over the existing evidence, the Expert Panel came to the conclusion that 140/90 mm Hg was the definition of hypertension, and the treatment goal in most patients (with the exception of those over 59 years of age where we recommended <150 mm Hg as the SBP goal). This recommendation, with its Corollary Recommendation, was perhaps the most controversial aspect of the Expert Panel Report. The Expert Panel did not recommend step-down therapy. Moreover it did support continuing therapy even if it achieved a blood pressure substantially lower than 150 mm Hg if therapy was well tolerated.

In the later part of 2015 the AHA and the ACC chose a new hypertension guideline panel. The release of the SPRINT (Systolic blood PRessure INtervention Trial) results in November of 2015 provided crucial evidence for managing those over 59 years of age and it is likely that the next guideline will lower the BP target for many hypertension subgroups, including the elderly.

Which Guideline?

High BP is a very common finding in the USA. It is not surprising, then, that several groups have issued guidelines for high BP. What is disconcerting to a practitioner is that despite having access to the same evidence, guideline writing groups can differ in their target BP goals recommendations, particularly within subgroups such as diabetes and chronic kidney disease. Choosing which guideline to follow is a daunting task.

Not Covered in Depth

It would be a disservice to the NHBPEP to leave the reader with the impression that hypertension guidelines via the JNC process was the only impact of the Coordinating Committee for the NHBPEP. Also published, under the auspices of the NHBPEP, were guidelines for managing BP:

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  In pregnancy

  
  
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  In children

  
  
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  In renovascular disease

  
  
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  Re: prevalence, awareness, treatment, and control updates

  
  
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  In the elderly

  
  
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  Ambulatory blood pressure monitoring

  
  
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  In chronic kidney disease and

  
  
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  Primary prevention of hypertension

In the U.S. we owe a large debt of gratitude to the NHBPEP for their unflagging efforts in the area of high BP, particularly the value of screening, the definition of elevated BP, the evaluation of hypertensive patients, and the management of hypertension. Although the profusion of guidelines on hypertension in the last few years generated a great deal of confusion and frustration, there are actually many similarities between the various recommendations made. Given the prevalence of high BP, and the catastrophic nature of hypertensive end-organ damage, it is vital that every practitioner caring for a hypertensive patient has a clear idea of how to measure, evaluate, and manage high BP in their practice.