This article reviews recent advances in resistant hypertension: poor therapy adherence, undertreatment with chlorthaladone and spironolactone, precise patient selection for renal nerve denervation (knowledge of accessory renal arteries and possible reinnervation), baroreflex activation therapy via unilateral carotid sinus stimulation, and refractory hypertension (a severe form, defined as uncontrolled blood pressure in spite of using ≥5 agens, including the long-acting thiazide and aldosterone antagonist).
Resistant hypertension is thought to be from salt-sensitivity upregulation (renal), while refractory HTN from sympathetic overdrive (neurogenic). Both types of severe hypertension increase the risk of clinical events strikingly; heart failure, stroke, coronary heart disease, end-stage nephropathy, and all-cause mortality.
An estimated 10-30% of hypertensive patients can be considered to be resistant to treatment defined as controlled or uncontrolled blood pressure (BP) with use of ≥4 medications, including a diuretic. A large number of cross-sectional and longitudinal studies have demonstrated that patients with treatment-resistant hypertension compared with patients with more easily controlled hypertension have increased cardiovascular risk, including coronary artery disease, congestive heart failure, stroke, and chronic kidney disease (CKD).
Since publication of the first Scientific Statement on the Diagnosis, Evaluation, and Treatment of Resistant Hypertension by the American Heart Association in 2008, which coincided with development of device-based strategies for treating resistant hypertension, resistant hypertension has become a major focus of intensive experimental and clinical investigation. In that context, this review highlights scientific advances specific for resistant hypertension that have occurred in the last 2 years, including important findings related to prognosis, medication adherence, clinical use of aldosterone antagonists, and application of device-based therapies.
Multiple cross-sectional studies have related resistant hypertension to prevalent cardiovascular and renal diseases. Recent analyses have strengthened those associations with use of longitudinal or prospective assessments. From a secondary analysis of the ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) results, which included 1870 participants with resistant hypertension, Muntner et al reported that compared with study participants without resistant hypertension,
participants with resistant hypertension had a 44% (cad), 57% (stroke), 23% (pvd), 88% (hf), 95% (esrd), and 30% (mort) higher risk of incident coronary heart disease, stroke, peripheral artery disease, heart failure, end-stage renal disease, and all-cause mortality, respectively, during the almost 5-year duration of the study,
after adjustment for multiple traditional risk factors, such as age, smoking, diabetes mellitus, and low-density lipoprotein cholesterol. Because of the ALLHAT study design, diuretic use in this analysis was not required to define resistant hypertension; however, in the sensitivity analysis, which was restricted to subjects with diuretic treatment, resistant hypertension remained significantly associated with the specified clinical outcomes, except for stroke and all-cause mortality.
Epidemiological studies have shown that CKD patients have a much higher prevalence of resistant hypertension than general hypertensive populations and that CKD patients with resistant hypertension have an increased prevalence of cardiovascular diseases compared with patients without resistant hypertension.
Recently, two large multicenter, prospective studies further delineated the prognostic significance of resistant hypertension in CKD populations. de Beus et al evaluated 788 CKD patients with a mean eGFR 38. Around 34% of these patients met the diagnostic criteria for having resistant hypertension. After a median follow-up of 5.3 years, nearly 17% of the subjects with resistant hypertension had experienced a cardiovascular complication, including myocardial infarction, ischemic stroke, or death, and 27% had developed end-stage renal disease. Compared with subjects without resistant hypertension, those with resistant hypertension had a 1.5-fold and 2.3-fold higher risk of composite cardiovascular events and end-stage renal disease, respectively.
Analysis of data from the CRIC (Chronic Renal Insufficiency Cohort) Study indicated that among the 3367 CKD patients with an eGFR 20-70, the prevalence of resistant hypertension was 40.4%. Every 5 decrease in eGFR was associated with a 14% higher risk of having resistant hypertension. Compared with those without resistant hypertension, subjects with resistant hypertension had a poorer prognosis, with a 38%, 28%, 66%, and 24% higher risk of experiencing a cardiovascular complication, renal complication, incident heart failure, or death, respectively.
Drug Adherence and Optimal Treatment
Prior studies have demonstrated that poor adherence is common in patients with presumed resistant hypertension. In that regard, the study by Jung et al, which used liquid chromatography–mass spectrometry to assay the presence of prescribed antihypertensive medications or their corresponding metabolites in urine, was pivotal in finding that among 76 patients with presumed resistant hypertension, the majority (53%) were in fact nonadherent, including 30% of whom were taking none of the prescribed medications. Other studies have indicated that undertreatment is also common in patients with apparent resistant hypertension such that poor adherence and suboptimal therapy likely represent the 2 most important reasons for lack of BP control as opposed to true antihypertensive treatment resistance.
Undertreatment and poor adherence
Using population-based data of participants enrolled in a large, healthcare organization in Israel, Weitzman et al reported that among the 172 432 hypertensive patients, the proportion of patients with uncontrolled hypertension was 35.9%. Of these, almost all were undertreated because of either receiving less than maximal dosages of prescribed medications (21%), not receiving a diuretic (9%), having been dispensed <3 agents (48%), or having been dispensed none of the prescribed agents (20%). Having excluded these patients, it was estimated that only ≈2.2% of the patients with uncontrolled hypertension met the strict criteria for resistant hypertension. These findings, combined with the demonstrations that poor adherence is common among patients with presumed resistant hypertension, suggest that lack of BP control in treated patients is much more likely attributable to the combination of undertreatment and poor adherence vs. true treatment resistance.