JNC 8: Shortcomings in Process and Treatment Recommendations

The treatment strategies that are the centerpiece of the Eighth Joint National Committee (JNC 8) Report on Detection and Treatment of Hypertension differ little from those listed in the 7 previous JNC reports.1 The most noted change was to raise the systolic blood pressure treatment goal from 140 to 150mm Hg—a recommendation from which a minority of the committee publicly dissented in a separate publication.2 Although no longer carrying the National Heart, Lung, and Blood Institute imprimatur, JNC 8 will likely maintain its importance to both clinicians and public health authorities. Previous JNC reports have contributed to increased awareness, detection, and treatment of hypertension so that most hypertensive Americans are now receiving care. However, blood pressure control among treated patients remains disappointingly ineffective. Despite 40 years of encouragement by healthcare providers, industry, and public and private health agencies, nearly half of treated patients still fail to achieve blood pressure goals. Moreover, control rates are significantly below 50% for important subgroups including those at increased cardiovascular risk and minority groups.3 More recently, there has been substantially increased scrutiny of the guideline development process.4,5 Rigorous analyses uncovered flaws within writing committees and their deliberative process. Committee members may introduce unrecognized biases, reflecting personal financial or intellectual commitments, or professional conflicts. These biases can adversely impact guideline content. Our purpose in this article is to assess the process of JNC 8 guideline preparation; present strengths and weaknesses of the 2 JNC 8 treatment options; and make the case for a third option. Properly developed clinical practice guidelines provide an opportunity for authoritative dissemination of well-considered information to clinicians and public health authorities. While the rates of detection, treatment, and control have improved since the first JNC report was published, there is no direct evidence to assess the specific contribution of all JNC reports to these results. Moreover, different organizations continue to generate less rigorously developed guidelines that often lead to conflicting recommendations. One explanation for these discrepancies is the influence of various biases in their preparation. Efforts have recently been made to identify or diminish conflicts of interest (COI) from guidelines. Regrettably, these attempts have had little effect. Lenzer4,5 reviewed the specific nature of COI, both financial and professional. As many as 71% of guideline panel chairs and 91% of co-chairs had financial conflicts according to a recent survey. This troubling observation is confounded by so-called committee stacking, whereby committee leaders select panelists known to support their desired outcome regarding specific tests, procedures, or treatments. There are 2 major types of COI, financial and professional. Both should be avoided in the preparation of treatment guidelines. The majority of guideline panel members should be experts at reviewing scientific evidence and should have no COI. Content experts such as hypertension specialists could be involved as consultants or in an advisory capacity. The Lenzer panel identified 7 circumstances that are “red flags”4,5 that should alert readers to potential biases (Table 1). Red flags in the Eighth Joint National Committee Red flags in the Eighth Joint National Committee The JNC 8 report meets the criteria for 6 of the 7 red flags, a disappointing report card. JNC 8 recommends drugs for both general use as well as for specific groups of patients, defined by demography (e.g., diuretics for blacks, anti-renin agents for younger men) and/or comorbidity (e.g., anti-renin drugs for diabetics). When blood pressure exceeds an arbitrary level, according to age and comorbidity, treatment generally begins with monotherapy. Then, if blood pressure is not controlled, drugs are to be added sequentially. Currently available drugs will succeed in roughly half of patients. However, each drug will produce a different set of responders. A drug that is effective for one patient may either be ineffective or might even provoke an increase in blood pressure in another.6 As a result, many patients are prescribed at least 2 drugs in combination initially, thus denying them an opportunity for successful monotherapy. Patients with comparable levels of blood pressure elevation often differ in their pathophysiology and, consequently, in their response to treatment.7,8 Drug trials usually identify differences in blood pressure responses; however, these are reported as group averages and, thus, do not predict the blood pressure response of an individual patient. For example, all blacks, the elderly, or persons with comorbid conditions are advised to receive the same initial therapy based on trial results. However, these subgroups are composed of individuals with very different blood pressure control mechanisms.9,10 JNC 8 provides a second treatment option—initiate therapy with 2 drugs rather than 1. The pharmaceutical industry has provided, and JNC has recommended, fixed-dose combination pills that generally include both a naturetic (diuretic and/or calcium channel blocker) and an anti-renin drug (angiotensin converting enzyme inhibitor and/or angiotensin receptor blocker).1 By combining an antivolume drug with an anti-renin drug, this approach implicitly recognizes that blood pressure is modulated by altering volume and/or vasoconstriction. Combination drugs are believed to produce greater blood pressure reduction than can be achieved by a single drug. However, no placebo controlled randomized trial is available to provide precise estimates of the additive effect of the 2 agents. Advocates also believe that because lower doses of both drugs are feasible, adverse side effects might be reduced and adherence improved. However, dual-drug treatment exposes patients to additional risk of adverse effects. However, the net effect—the sum of adverse effects prevented and caused—is not known. Finally, because some single pill combinations include patented agents, treatment costs may be increased.11,12 It is worth noting that the JNC options have never been compared with any other treatment strategy in appropriately designed large clinical trials. Nevertheless, a broad consensus generated by succeeding JNC reports favoring empiric selection of antihypertensive drugs may have suppressed development of a more effective treatment strategy. JNC reports have not considered or reflected on the potential of a physiologically based approach to individualized drug treatment that targets pathophysiological mechanisms. We believe that an alternate approach, designed to match treatment to the underlying mechanism of blood pressure control, will provide more effective and cost-efficient antihypertensive treatment for each patient than does JNC option 1 or 2.13,14 Other pathophysiological profiling systems may also provide opportunities to individualize drug selection. However, no other approach has been explored in such detail or provides a tested practical method for clinical application as has renin-guided therapy. Long-term control of blood pressure in everyone, including hypertensive patients, reflects the interaction of just 2 components—volume and vasoconstriction.14 Renin–angiotensin system activity exposes the contribution of each component. Low-renin patients have relative volume excess, whereas high-renin patients have excess angiotensin II–mediated vasoconstriction. Plasma renin activity (PRA), a readily available and inexpensive blood test, identifies, in each patient, the relative contribution of these 2 components. All antihypertensive agents are either primarily naturetic or anti-renin agents. High-PRA patients respond best to anti-renin, and low-renin patients to naturetic agents. At the mid PRA level (>.0.65 to <4.5ng/ml/hr), both drug types can be very effective. We believe, however, that in all except low-renin patients, therapy should begin with an anti-renin agent to avoid volume depletion and a consequent increase in PRA, which is associated with increased cardiovascular mortality in hypertensive patients.15 Moreover, in contrast to either a calcium channel blocker or a diuretic, an anti-renin agent will reduce “effective renin.” A PRA test quantifies the circulating activity of the renin–angiotensin system by measuring the rate of angiotensin I (Ang I) production in plasma. The PRA test overestimates the true activity of the circulating renin–angiotensin system in patients taking angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin-receptor blockers (ARBs) because these drugs block the system distal to the enzymatic release of Ang I by plasma renin. The residual “effective” PRA (ePRA) in response to clinical doses of ACEIs will convert about 10% of Ang I to Ang II, whereas ARBs allow about 10% of Ang II to bind to Ang II type 1 receptors. Therefore, the ePRA is about 10% of the PRA value in patients taking 1 of these agents and about 1% in patients taking both agents. In contrast, PRA, per se, truly reflects the circulating renin–angiotensin system activity in patients taking either calcium channel blockers or diuretics.16,17 This may be of value since cardiovascular events occur with greater frequency in hypertensive patients with elevated PRA.18 Renin-guided treatment may also be useful when selecting the best add-on drugs, particularly for patients who appear to be drug resistant.18 PRA levels during treatment are influenced by drug use but, nevertheless, can identify how to modify antivolume or anti-renin therapy.19 Thus, in contrast to options 1 and 2, PRA-guided treatment provides a pathophysiological and pharmacological rationale that guides every step of blood pressure treatment in each patient. While PRA-directed therapy has not been compared with either option 1 or 2 in randomized clinical trials, we believe that available evidence does justify its inclusion as an option that is of at least equal value to those recommended in JNC 8. The drugs used in the PRA-guided strategy are standard therapies documented to reduce cardiovascular complications and are acceptable choices in JNC 8. Randomized clinical trials have demonstrated that blood pressure reduction is superior when a high-renin patient is matched to an anti-renin drug, as well as when a low-renin patient is matched with a naturetic.10 Since blood pressure reduction contributes to cardiovascular disease prevention, it seems reasonable that a renin-based treatment strategy should be superior to drug selection assigned without reference to the mechanism of blood pressure control. We believe that PRA-guided selection of antihypertensive drug treatment (option 3) that is based on underlying pathophysiology will provide more effective and cost-efficient treatment than either JNC option. The immediate research tasks are to establish whether PRA-guided treatment delivers blood pressure control that is superior to that identified in JNC 8 and will also yield superior cardiovascular outcomes. The authors declared no conflict of interest.