Siddiqui M. Hypertension. 2020 Feb;75(2):510-515.
Refractory hypertension (RfHTN) is a phenotype of antihypertensive therapy failure described as uncontrolled BP (≥130/80 mm Hg), regardless of adequate doses of 5 or more different classes of antihypertensive medications incorporating a long-acting thiazide-like diuretic (chlorthalidone) and a mineralocorticoid receptor antagonist (MRA). Patients with RfHTN are more likely to be female, African-American, and have greater rates of cardiovascular complications as compared to patients with controlled resistant hypertension (RHTN), inclusive of stroke, left ventricular hypertrophy, and congestive heart failure. White coat effect impacting only 6.5% of patients with RfHTN, is unusual in such patients. Medication nonadherence would be inflated in patients with apparent RfHTN, because patients with apparent RfHTN needed at least 5 different antihypertensive class of medications. To test that hypothesis, Siddiqui M et al., conducted a study to analyse antihypertensive medication adherence in patients with apparent RfTHN by estimating urinary drug or drug metabolite levels with high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS).
Patients enlisted between April 2014 and July 2019 was assigned to the UAB Hypertension Clinic for uncontrolled resistant hypertension. Patients were analysed for secondary causes of hypertension, incorporating hyperaldosteronism, pheochromocytoma, and renal artery stenosis as clinically specified. Automated office BP (AOBP) was estimated following at least 5 minutes of quiet rest in a sitting position with the back supported and the arm supported at heart level. The BpTRU device was used to estimate the office BP, which automatically acquires 6 serial BP readings, 1 minute apart, before displaying the average of the last 5 reading. In 24-hour ambulatory blood pressure monitoring (ABPM), 21,22 recordings were made every 20 minutes in the awake (day-time) and every 30 minutes in the night-time (asleep) phases of the 24-hour period. Awake and asleep times were estimated by patient self-report.
Based on uncontrolled AOBP, 54 patients were recruited in the study. Of these, 49 patients had valid 24-hour ABPM readings and 45 patients completed 24-hour urine collections to analyse antihypertensive medication adherence. Out of the 45 patients, 40 (88.9%) patients showed confirmed RfHTN based on an increased AOBP (≥130/80 mm Hg), mean 24-hour ABP (≥125/75 mm Hg), and mean awake (day-time) ABP (≥130/80 mm Hg), while 5 patients showed a white-coat effect. The mean age of patients with RfHTN was 53.0±8.3 years, 65.0% were female and 85.0% were African-American. The mean BMI was 36.0±6.4 kg/m2. The prevalence of dyslipidemia and diabetes mellitus was 52.5% and 50.0%, respectively. The mean serum sodium was 138.3±2.9 mMol/L, serum creatinine was 1.1±0.4 mg/dL, and serum potassium was 4.0±0.5 mMol/L. The mean systolic and diastolic AOBP were 151.1±23.5/89.9±13.8 mmHg. The mean AOBP heart rate were 76.7±12.0 beats/minute. The mean 24-hour systolic and diastolic BP were 157.5±21.4/89.5±13.0 mmHg. The mean 24-hour heart rate was 75.4±11.3 beats/minute. The mean awake (day-time) systolic and diastolic BP were 161.0±21.2/92.4±14.4 mmHg. The mean awake (day-time) heart rate was 76.8±11.4 beats/ minute. The mean asleep (night-time) systolic and diastolic BP were 150.3±23.1/83.7±13.8 mm Hg. The mean asleep (night-time) heart rate was 71.9±12.8 beats/minute. 16 (40.0%) were completely adherent with all of their prescribed antihypertensive medications from the 40 patients with RfHTN who were fully analysed; 18 (45.0%) were partially adherent, taking less than the number of prescribed agents; and 6 (15.0%) were completely nonadherent with any of prescribed medications. From the 18 patients who were partially adherent, 5 (12.5%) were adherent with 5 or more antihypertensive medications, including an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, a calcium channel blocker, chlorthalidone, and MRA. 52.5% patients were adherent with 5 or more antihypertensive medications, inclusive of chlorthalidone and an MRA, accordant with true RfHTN. Altogether, adherence for the different antihypertensive medication classes or agents was 79.2% for angiotensin-converting enzyme inhibitors, 75.0% for angiotensin II receptor blockers, 72.5% for calcium channel blockers, 70.0% for chlorthalidone, 67.5% for MRA (Spironolactone or Eplerenone), 57.1% for α-β blockers, and 64.7% for α-2 agonists. The patients with refractory hypertension were categorised into complete, partial, and nonadherence based on antihypertensive medication adherence. The mean number of antihypertensive medications prescribed was 5.5±0.6, 5.8±0.7, and 6.2±0.8 in the above groups, respectively, while the mean number of antihypertensive medications identifed was 5.5±0.6, 3.8±1.3, and 0 in the above groups, respectively (Figure 1).
Thus, it was concluded that RfHTN is a rare, however true phenotype of antihypertensive treatment failure as 52.5% of patients recognized as having apparent RfHTN, were adherent with at least 5 antihypertensive medications, inclusive of chlorthalidone and a mineralocorticoid receptor antagonist, validating true RfTHN.
Figure 1: Antihypertensive medication adherence in refractory hypertensive patients