Influence of treatment-time regimen of hypertension medications on ambulatory blood pressure in patients with resistant hypertension

Resumo

By current definition, hypertension is considered resistant to treatment when lifestyle measures plus ingestion of ¿3 hypertension medications, one preferably a diuretic unless contraindicated, in therapeutic doses fail to reduce systolic (SBP) and diastolic (DBP) blood pressure (BP) to recommended clinic BP threshold criteria. Patients with resistant hypertension are at greater risk for stroke, renal insufficiency, and cardiovascular disease (CVD) events than are those for whom BP is responsive to and well controlled by therapeutic interventions. The diagnosis of hypertension (including resistant hypertension) and clinical decisions regarding its treatment typically are based on a limited number of daytime clinic BP measurements obtained in the physician¿s office. However, the correlation between BP level and target organ damage, CVD risk, and long-term prognosis is greater for ambulatory BP monitoring (ABPM) than clinic BP measurements. In particular, independent prospective studies have reported that the asleep BP mean determined by ABPM is a better predictor of CVD events than the awake or 24h BP means. Most individuals, including those under hypertension therapy, show a ¿white-coat effect¿ that could cause an overestimation of their real BP. The prevalence and clinical characteristics of ¿white-coat¿ or isolated-office resistant hypertension, however, has always been evaluated by comparing clinic BP values with either daytime home BP measurements or the awake BP mean obtained from ABPM, therefore including patients with either normal or elevated asleep BP mean. In resistant hypertension, the currently recommended therapeutic strategies entail prescription of additional medications or exchange of one for another in an attempt to achieve enhanced synergy of effects when ingested most typically in the morning. However, current information from several clinical trials clearly substantiates enhancement of BP-lowering efficacy by a bedtime treatment schedule of both hypertension monotherapies and fixed combinations. For example, because the high-amplitude circadian rhythm of the renin-angiotensin-aldosterone system activates during nighttime sleep, bedtime versus morning ingestion of angiotensin-converting enzyme inhibitors and angiotensin-II receptor blockers better controls the asleep BP mean, with additional benefit, independent of medication terminal half-life, of converting the 24h BP profile into more normal dipper patterning. While all reported chronotherapy trials have compared the effects on BP regulation of full daily doses of medications when ingested in the morning versus at bedtime, prescription of the same medications in divided doses twice-daily (BID) is frequent. Accordingly, we investigated: (i) the impact of including asleep BP mean as a requirement for the definition of hypertension on the prevalence, clinical characteristics, and estimated CVD risk of isolated-office resistant hypertension; and (ii) the influence of hypertension treatment-time regimen on the circadian BP pattern, degree of BP control, and relevant clinical and laboratory medicine parameters of patients with true resistant hypertension. For the first objective, we evaluated 3042 patients treated with ¿3 hypertension medications and evaluated by 48h ABPM (1707 men/1335 women), 64.2±11.6 (mean±SD) years of age, enrolled in the Hygia Project, designed to evaluate prospectively CVD risk by 48h ABPM in primary care centers of Northwest Spain. Among the participants, 522 (17.2%) had true isolated-office resistant hypertension (elevated clinic BP and controlled awake and asleep ambulatory BP while treated with 3 hypertension medications), 260 (8.6%) had false isolated-office resistant hypertension (elevated clinic BP, controlled awake SBP/DBP means, but elevated asleep SBP or DBP means while treated with 3 hypertension medications), and the remaining 2260 (74.3%) had true resistant hypertension (elevated awake or asleep SBP/DBP means while treated with 3 medications, or any patient treated with ¿4 medications). BP was automatically assessed every 20 minutes between 07:00 and 23:00h and every 30 minutes during the night for 48 consecutive hours. Participants kept a diary listing the time of retiring to bed at night, awakening in the morning, consumption of meals, participation in exercise, and episodes of atypical physical activity, mood/emotional states, and other events that might affect BP. ABPM was considered controlled if the awake and asleep SBP/DBP means were <135/85 and <120/70 mmHg, respectively. Patients with false, relative to those with true isolated-office resistant hypertension, had higher prevalence of albuminuria and chronic kidney disease (CKD), significantly higher albumin/creatinine ratio (P<0.001), a significantly higher 48h SBP/DBP means by 9.6/5.3 mmHg (P<0.001), significantly lower sleep-time relative SBP and DBP decline (P<0.001), and significantly greater prevalence of a non-dipper BP profile (96.9 vs. 38.9%; P<0.001). Additionally, the prevalence of the riser BP pattern, which is associated with highest CVD risk, was much greater, 40.4 vs. 5.0% (P<0.001), among patients with false isolated-office resistant hypertension. The estimated hazard ratio of CVD events, using a fully adjusted model including the significant confounding variables of sex, age, diabetes, CKD, asleep SBP mean, and sleep-time relative SBP decline, was significantly greater for patients with false compared to those with true isolated-office resistant hypertension (2.13, [95%CI: 1.95-2.32]; P<0.001). Patients with false isolated-office hypertension and true resistant hypertension, however, were equivalent for the prevalence of obstructive sleep apnea, metabolic syndrome, obesity, diabetes, albuminuria, and CKD, and they had an equivalent estimated hazard ratio of CVD events (1.04, [95%CI: .97-1.12]; P=0.265). These findings document a significantly elevated prevalence of a blunted nighttime BP decline in patients here categorized as either false isolated-office resistant hypertension and true resistant hypertension, jointly accounting for 82.8% of the studied sample. Previous reports of much lower prevalence of true resistant hypertension plus a non-significant increased CVD risk of this condition compared with isolated-office resistant hypertension are misleading by disregarding asleep BP mean for classification. Our results further indicate that classification of patients with resistant hypertension into categories of isolated-office, masked, and true resistant hypertension cannot be based on the comparison of clinic BP with either daytime home BP measurements or awake BP mean from ABPM, as so far customary in the available literature, totally disregarding the highly significant prognostic value of sleep-time BP. Accordingly, ABPM should be regarded as a clinical requirement for proper diagnosis of true resistant hypertension. For the second objective, we evaluated 2899 patients with resistant hypertension (1701 men/1198 women), 64.2±11.8 (mean±SD) years of age, including the 260 patients with false isolated-office resistant hypertension and the 2260 with true resistant hypertension mentioned above. Among these 2520 participants, 1084 were ingesting all hypertension medications upon awakening (awakening-regimen) and 1436 patients were ingesting the full daily dose of ¿1 of them at bedtime (bedtime-regimen). For comparative purposes, we additionally evaluated a third group of 379 patients with resistant hypertension who were ingesting split doses of ¿1 medications BID upon awakening and at bedtime (BID-regimen). Patients of the bedtime compared to the other two treatment-time regimens had: lower likelihood of albuminuria and CKD; significantly lower albumin/creatinine ratio, glucose, total cholesterol, and LDL-cholesterol; plus higher estimated glomerular filtration rate and HDL-cholesterol. The bedtime-regimen was also significantly associated with lower asleep SBP and DBP means than the upon-awakening and BID regimens. The sleep-time relative SBP and DBP decline was significantly attenuated by the awakening- and BID regimens (P<0.001), resulting in significantly higher prevalence of non-dipping in these two treatment-time regimen groups (80.5 and 77.3%, respectively) than in the bedtime-regimen (54.4%; P<0.001 between groups). Additionally, the prevalence of the high-risk riser BP pattern was much greater, 31.0 and 29.8%, respectively, among patients of the upon-awakening and BID-treatment regimens, compared to the bedtime-regimen (17.6%; P<0.001 between groups). Patients of the bedtime-regimen also showed significantly higher prevalence of properly controlled ambulatory BP (P<0.001) as a result of a greater proportion of them who were showing complete control of asleep SBP and DBP means. These findings demonstrate significantly lower asleep SBP and DBP means and attenuated prevalence of blunted nighttime BP decline, i.e., lower prevalence of CVD risk markers, in patients with resistant hypertension ingesting the full daily dose of ¿1 hypertension medications at bedtime than in those ingesting all of them upon awakening or ¿1 of them as split doses BID. In resistant hypertension, ingesting the same medications BID neither improves ambulatory BP control nor reduces the prevalence of non-dipping, and cannot be considered a proper chronotherapeutic approach. Collectively, the findings of this study indicate a bedtime hypertension medication regimen, in conjunction with proper patient evaluation by ABPM to corroborate the diagnosis of true resistant hypertension and avoid treatment-induced nocturnal hypotension, should be the therapeutic scheme of choice for patients who, by conventional cuff methods (and in the absence of ABPM) and the morning-treatment regimen have been mistakenly judged to be resistant to therapy.