Treatment-resistant hypertension (HTN) has been defined in various ways in clinical research. Some definitions go so far as to say which medications should be used before classifying patients as having resistant HTN. Regardless of the definition, the overriding theme of treatment-resistant HTN is that it occurs when several anti-hypertensive drugs are needed to control blood pressure (BP). Studies suggest that treatment-resistant HTN is present in 20% to 30% of patients with HTN. Its prevalence has more than doubled over the past 25 years, and research has linked it to an increased risk of cardiovascular events when compared with patients without treatment-resistant HTN.

“The topic of treatment-resistant HTN has gained attention in recent years,” says Rhonda M. Cooper-DeHoff, PharmD, MS, FAHA, FACC. “The condition increases long-term risk for poor outcomes, regardless of whether or not HTN is controlled or uncontrolled. Unfortunately, we’re lacking important data on the long-term effects of treatment-resistant HTN.” Coronary artery disease (CAD) is among the leading causes of mortality, and treatment-resistant HTN is more common in patients with CAD than without CAD. Little is known, however, about the impact that treatment-resistant HTN has on cardiovascular outcomes in patients with CAD. Such data may inform clinicians on strategies to aggressively manage risk factors.

Identifying Predictors & Impact

In the Journal of Hypertension, Dr. Cooper-DeHoff and colleagues published a study that described the prevalence, predictors, and impact on adverse cardiovascular outcomes of resistant HTN among patients with CAD and HTN. More than 17,000 study participants were divided into three groups according to achieved BP: 1) controlled (BP<140/90 mm Hg on three or fewer drugs); 2) uncontrolled (BP≥140/90 mm Hg on two or fewer drugs); or 3) resistant (BP≥140/90 mm Hg on three drugs or any patient on at least four drugs).

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“We found that resistant HTN occurred in 38% of patients with CAD and HTN,” says Dr. Cooper-DeHoff. “Those with resistant HTN were at increased risk for having poorer outcomes.” Several characteristics were associated with an increased risk of resistant HTN, including a history of heart failure, diabetes, and renal insufficiency, among others (Figure 1). Overall, 13 independent predictors of resistant HTN were identified. Many of these characteristics can be obtained noninvasively and help clinicians recognize these patients in the clinic.

“The prevalence of resistant HTN in people with CAD and the level of risk were important findings in our analysis,” says Dr. Cooper-DeHoff. “Our results confirm the findings of previous studies and extend them to patients with concomitant CAD and HTN who were well managed. Regardless of how resistant HTN is defined, the condition portends an increased risk of major cardiovascular outcomes, especially non-fatal stroke and mortality.”

With the exception of non-fatal stroke, adverse outcomes did not differ significantly in patients with resistant HTN when compared with those with uncontrolled HTN. The overall prevalence of resistant HTN increased as the number of risk factors increased, ranging from about 25% in participants with no risk factors to higher than 75% in participants with at least eight risk factors (Figure 2). The prevalence of resistant HTN was at least 50% in participants with five or more risk factors. In addition, female sex, increasing age, and BMI were associated with a classification of resistant HTN.

Important Implications

Risk factors for resistant HTN appear to be comparable in patients with HTN with and without established cardiovascular disease. This underscores the need to recognize patients with CAD who are at risk for resistant HTN, Dr. Cooper-DeHoff says. “Many clinicians do not believe in the concept of resistant HTN,” she says. “They may think the phenomenon relates to a lack of patient adherence to therapy. Others believe that resistant HTN results from physician inertia, in which the prescribing of medications or dose titration of these drugs is inadequate. Regardless of how or why these patients become classified with resistant HTN, our data show that these individuals have poor outcomes.”

Clinicians may want to consider alternate therapies, such as renal denervation, as they become available for patients with resistant HTN, says Dr. Cooper-DeHoff. “Particular attention should be paid to those with comorbid cardiovascular diseases, diabetes, and renal insufficiency,” she says. “These characteristics are associated with the greatest risk of developing resistant HTN.”

The findings also have important implications for future research, according to Dr. Cooper-DeHoff. “Within the same dataset from this analysis, we’re currently examining the genetic makeup of patients to spot genetic and pharmacogenetic predictors of resistant HTN,” she says. “This information may help us improve how we target specific drug therapies for patients early in the process of treating their HTN.”

References

Smith SM, Gong Y, Handberg E, et al. Predictors and outcomes of resistant hypertension among patients with coronary artery disease and hypertension. J Hypertens. 2014;32:635-643. Available at: http://journals.lww.com/jhypertension/Fulltext/2014/03000/Predictors_and_outcomes_of_resistant_hypertension.24.aspx.

Calhoun DA, Jones D, Textor S, et al. Resistant hypertension: diagnosis, evaluation, and treatment. A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Hypertension. 2008;51:1403-1419.

Smith SM. Epidemiology, prognosis, and treatment of resistant hypertension. Pharmacotherapy. 2013;33:1071-1086.

Daugherty SL, Powers JD, Magid DJ, et al. Incidence and prognosis of resistant hypertension in hypertensive patients. Circulation. 2012;125:1635-1642.

Messerli FH, Mancia G, Conti CR, et al. Dogma disputed: can aggressively lowering blood pressure in hypertensive patients with coronary artery disease be dangerous? Ann Intern Med. 2006;144:884-893.

Weber MA, Julius S, Kjeldsen SE, et al. Cardiovascular outcomes in hypertensive patients: comparing single agent therapy with combination therapy. J Hypertens. 2012;30:2213-2222.