ACCEL | Given the well-established increased CV risk associated with elevated blood pressure (BP), hypertension poses a growing challenge for health policy-makers and physicians worldwide. A high-tech approach to the problem recently stumbled with the results of Symplicity-III (HTN-3), the first blinded, randomized, multicenter study on the efficacy of renal denervation for the treatment of resistant hypertension. There was no significant reduction of BP in patients with resistant hypertension after renal-artery denervation (neither at 6 months or 3 years) compared with controls.^1,2

Consequently, attention has refocused on drug therapy. Secondary forms of hypertension and associated conditions such as obesity, sleep apnea, and primary aldosteronism are common in patients with apparent treatment-resistant hypertension (aTRH). True, resistant hypertension is associated with a high risk of CV and renal events, so it’s important to identify patients with aTRH.

Roland E. Schmieder, MD, is a professor of internal medicine, nephrology and hypertension, and he is head of the Clinical Research Center of Hypertension and Vascular Medicine at the University Hospital, Erlangen, Germany. He emphasizes that uncontrolled hypertension is not synonymous with resistant hypertension. Patients with true treatment resistance comprise a much smaller share of the population of patients who lack BP control on treatment, including those on inadequate treatment regimens, those with poor adherence, and those with undetected secondary hypertension. He adds that before it can be declared aTRH, “the treatment plan must include attention to lifestyle measures.”

Dr. Schmieder also noted that prognosis is “severe” in patients with aTRH: various studies suggest an all-cause death rate in these individuals of 2% to 4% per year and a major adverse cardiac and cerebrovascular event rate of 4% to 6% per year.

Definition and Incidence

There are some variations in the definition of aTRH, but the core definition seems to be: failure to reach BP goal in patients who are adhering to full doses or “optimal” doses of an appropriate three-drug regimen that includes a diuretic.

The most detailed definition comes from Europe: aTRH occurs when appropriate lifestyle measures plus a diuretic and two other antihypertensive drugs belonging to different classes at adequate doses (but not necessarily including a mineralocorticoid receptor [MR] antagonist) fails to lower systolic (SBP) and diastolic (DBP) values to <140 and <90 mm Hg, respectively.³

Depending on the population examined and the level of medical screening, the prevalence of aTRH ranges from 5% to 30%of the overall hypertensive population, with estimates of <10% probably representing the true prevalence.

In the U.S., one often-cited estimate comes from the National Health and Nutrition Examination Survey (NHANES) from 2003 through 2008. Published in 2011,⁴ the analysis covered nonpregnant adults with hypertension whom were classified as resistant if their blood pressure was ≥140/90 mm Hg and they reported using antihypertensive medications from three different drug classes or drugs from ≥4 antihypertensive drug classes regardless of blood pressure. The NHANES data indicated that 8.9% of U.S. adults with hypertension met the criteria for resistant hypertension, which translated to 12.8% of the antihypertensive drug-treated population. These figures suggest an increasing number of the U.S. population has treatment resistant hypertension, based on 1988-1994 and 1999-2004 NHANES data (p<0.01for trend across these time periods versus 2005-2008).

Two aspects to stress regarding the NHANES data:

1. Most (85.6%) of the individuals with resistant hypertension used a diuretic. Still, 15% did not; that’s important given that most definitions of true resistance indicate that one of the trio of drugs used should be a diuretic.
2. Of this group on diuretic therapy, 64.4% used the relatively weak thiazide diuretic hydrochlorothiazide. Again, if the definition requires optimization of antihypertensive therapy, then some of these NHANES patients considered ‘resistant’ might actually fail the definition.

The NHANES data suggest some clinical determinants of resistant hypertension (all p<0.001): these individuals were all more likely to have albuminuria, reduced renal function, and self-reported medical histories of coronary heart disease, HF, stroke, and DM.

aTRH: Is it Really What it Seems?

Let’s face it: secondary causes and other ‘issues’ are often missed in patients wherein resistant hypertension seems to be the problem. Verloop and colleagues from the Netherlands found a sizable number of patients referred for renal denervation who had secondary causes of hypertension that had been missed or other problems that argue against intervention.⁵

At the University Medical Center, Utrecht, Netherlands, for example, patients referred for renal denervation undergo a step-wise screening protocol consisting of:

• 24-hour ambulatory blood pressure measurement
• 24-hour urinary collection
• serum analysis, including sampling of aldosterone and plasma renin activity
• magnetic resonance angiography of the renal arteries and adrenals.

They analyzed data from 11 specialty centers who had 731 patients referred for renal denervation.5 The number of BP-lowering drugs being taken at the time of referral was 4.1 and specialists referred fully three-quarters of the patients.

However, the majority of patients were not deemed eligible for renal denervation, mostly due to normalization of BP after treatment adjustment (46.9%), unsuitable renal arterial anatomy (17.0%), and previously undetected secondary causes of hypertension (11.1%). (Secondary causes included primary hypoaldosteronism, significant renal artery stenosis, primary hyperthyroidism, glycyrrhetinic acid, and coarctation of the aorta.) After careful screening and treatment adjustment at hypertension expert centers, only approximately 40% of patients referred for renal denervation—and, again, mostly referred by specialists—were actually eligible for the procedure.

The authors noted that extensive screening can reveal secondary causes of hypertension or other ‘issues’ that would explain why the problem is not really resistant hypertension.

When it Really Is Resistant Hypertension

The pivotal role of aldosterone in the pathogenesis of aTRH is, in many cases, well recognized. For patients with aTRH, the Joint National Committee-8, the European Society of Hypertension, and a recent consensus conference recommend that a diuretic, ACE-I (or angiotensin receptor blocker [ARB]), and calcium channel blocker combination be used to maximally tolerated doses before starting a ‘fourth-line’ drug such as an MR antagonist. (Although the best fourth-line drug for aTRH has not been extensively investigated, a number of studies suggest that an MR antagonist is effective in reducing BP when added to the standard multi-drug regimen.⁶)

A new Scientific Statement from the ACC/AHA titled, “Treatment of Hypertension in Patients With Coronary Artery Disease,” notes that spironolactone or eplerenone may be used with a thiazide or thiazide-like diuretic, particularly in patients with resistant hypertension (Class I; Level of Evidence: A).⁷

Finally, no matter the definition of resistant hypertension, the emphasis is on providing patients “optimal” therapy before concluding they have aTRH. So, how often is such optimal therapy achieved? A 2013 paper presented the results of a community-based network of nearly half a million hypertensive patients, about one-third of whom were uncontrolled.⁸ Approximately one in seven of all uncontrolled hypertensives and one in two with uncontrolled aTRH are prescribed ≥3 BP medications in optimal regimens. Prescribing more optimal pharmacotherapy for uncontrolled hypertensives, including aTRH, confirmed with out-of-office BP (to detect white-coat hypertension), could greatly improve hypertension control.

Take-Aways

• Hypertension resistant to lifestyle interventions and antihypertensive medications is a common problem encountered by physicians in everyday practice.
• Whether it’s true or not, resistant hypertension may be a challenge, but given the ‘severe’ prognosis of such patients, it’s worth the effort to get a clear diagnosis.
• Optimizing antihypertensive therapy is critical before determining a patient is truly resistant, as is checking for secondary causes of high blood pressure or other ‘issues’ that might make BP control difficult but not treatment resistant.

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References

1. Bhatt DL, Kandzari DE, O’Neill WW, et al. New Engl J Med. 2014;370:1393-401.
2. Esler MD, Böhm M, Sievert H, et al. Eur Heart J. 2014;35:1752-9.
3. Mancia G, Fagard R, Narkiewicz K, et al. J Hypertens. 2013;31:1281-357.
4. Persell SD. Hypertension. 2011;57:1076-80.
5. Persu A, Jin Y, Baelen M, et al. Hypertension. 2014;63:1319-25.
6. Glicklich D, Frishman WH. Drugs. 2015;75:473-85.
7. Rosendorff C, Lackland DT, Allison M, et al. J Am Coll Cardiol. 2015;[online before print]. http://content.onlinejacc.org/article.aspx?articleID=2212514.
8. Egan BM, Zhao Y, Li J, et al. Hypertension. 2013;62:691-7.

Keywords: CardioSource WorldNews, ACC Publications, Blood Pressure, Health Policy, Risk, Hypertension, Renal Artery

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