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expected to decrease during sleep by 10%–20% relative to daytime BP.878 Night-time dipping patterns are classified into four groups:879,880 • Inverse dipping (riser): nocturnal increase in BP (night-to-day ratio of >1.0). • Non-dipper: reduced night-time BP dip of <10% (or night-to-day ratio of >0.9 and ≤1.0). • Normal dipping: fall in night-time BP of >10% and <20% (or night-to-day ratio of 0.8 to 0.9). • Extreme dipping: marked fall in night-time BP of >20% (or night-to-day ratio of <0.8). Patients with nocturnal hypertension may be dippers or non-dippers. Of note, the long-term reproducibility of dipping patterns appears to be low.881,882

9.12.2 Epidemiology

Nocturnal hypertension has been observed in up to half of patients with hypertension,883–886 and is associated with increased HMOD,883 impaired renal function, and diabetes mellitus.887 Nocturnal hypertension appears to be more prevalent in black888–890 and Asian891,892 populations. Masked uncontrolled hypertension, which occurs in 30% of patients treated for hypertension, is more often due to poorly controlled nocturnal BP than daytime BP on ABPM.893 Environmental factors, including sleep duration and higher humidity,894 nocturia,895 OSAS,896 obesity, high salt intake in salt-sensitive patients,897 orthostatic hypotension, autonomic dysfunction, CKD,898–900 diabetic neuropathy/diabetes,901 and old age62 are associated with nondipping. Moreover, nocturnal hypertension and absent night-time dipping pattern are more common in secondary hypertension.902,903

9.12.3 Night-time blood pressure as a cardiovascular

disease risk factor Nocturnal hypertension is a risk factor for adverse CVD events,904 cerebrovascular disease, including stroke,905 and cardiovascular mortality.891,906,907 Night-time BP may provide more prognostic information than daytime BP, perhaps as it is less dependent on physical activities. Non-dipping908–910 and reverse dipping (nocturnal rise in BP) may also be associated with increased CVD risk.62,910–913 A nocturnal rise in BP is associated with an increased risk of dementia and Alzheimer’s disease in older men.914 There is also some evidence that extreme dipping, particularly in untreated patients, is associated with an increased risk for CVD events.35,886

9.12.4 Treatment of nocturnal hypertension

There is no reliable evidence that BP-lowering medication should be routinely dosed at bedtime. The diurnal timing of drug administration is discussed in Section 8.3.4. In patients with secondary hypertension, the underlying cause (OSAS, primary aldosteronism) should be treated as discussed in Section 9.14.

9.13 Resistant hypertension

9.13.1. Definition of resistant hypertension Resistant hypertension is defined as BP remaining above goal despite three or more BP-lowering drugs of different classes at maximally tolerated doses, of which one is a diuretic (Table 11).915 Resistant hypertension should be managed at specialized centres with the expertise and resources to exclude pseudo-resistant hypertension (adherence testing) and causes of secondary hypertension.916 9.13.2 Non-pharmacological interventions

The Treating Resistant Hypertension Using Lifestyle Modification to Promote Health (TRIUMPH) trial demonstrated significant clinic and ambulatory BP reductions in patients with resistant hypertension participating in a 4-month lifestyle intervention comprising diet and exercise interventions delivered within a cardiac rehabilitation programme.917

9.13.3 Pharmacological interventions

BP-lowering treatment of resistant hypertension with single-pill combinations is recommended to reduce the pill burden, thereby increasing drug adherence and persistence.492 As resistant hypertension often, and especially in CKD,918 represents a state of salt retention and volume expansion secondary to relative aldosterone excess,516,919,920 BP control may be improved by switching hydrochlorothiazide to long-acting thiazide-like diuretics, such as chlorthalidone.921,922 However, a recent trial of chlorthalidone vs. hydrochlorothiazide—which probably included a sizeable proportion of adults with resistant hypertension—did not demonstrate any difference in systolic BP or CVD outcomes between the two medications. In the subgroup of patients with prior CVD, there was a strong trend of benefit with chlorthalidone on CVD outcomes.447 Of note, the risk of hypokalaemia was higher in the chlorthalidone group than in the hydrochlorothiazide group.447 In patients with eGFR < 30 mL/min/1.73 m2, an adequately uptitrated loop diuretic is necessary to define resistant hypertension. Most patients with resistant hypertension require the addition of non-first-line BP-lowering drugs (Figure 22). Of these, low-dose spironolactone (25–50 mg daily) should be considered first.459,515,923–925 In patients with resistant hypertension and type 2 diabetes, spironolactone (25–50 mg daily) reduced BP and albuminuria.926 The use of spironolactone can be precluded by limited tolerability due to anti-androgenic side effects resulting in breast tenderness or gynaecomastia (in about 6%), impotence in men, and menstrual irregularities in women.927 The efficacy and safety of spironolactone for treating resistant hypertension have not yet been established in patients with significant renal impairment. Moreover, spironolactone, especially in addition to RAS inhibitors, increases the risk of hyperkalaemia.927,928 Therefore, spironolactone should be restricted to patients with an eGFR of ≥30 mL/min/1.73 m2 and a plasma potassium concentration of ≤4.5 mmol/L.459 Steroidal MRAs are contraindicated in patients with an eGFR of <30 mL/min/1.73 m2. Serum electrolytes and kidney function should be monitored soon after initiation and frequently thereafter. In patients with resistant hypertension and CKD (eGFR of 25–45 mL/min/1.73 m2), the oral potassium binder patiromer enabled more patients to continue treatment with spironolactone.929 If spironolactone is not tolerated due to anti-androgen side effects, eplerenone may be used. If eplerenone is used, higher doses (i.e. 50–200 mg daily) and twice-daily dosing may be necessary to achieve a BP-lowering effect.503 Of note, eplerenone is not licensed for hypertension treatment in many countries. When not already prescribed for a compelling indication, betablockers should be considered in the treatment of resistant hypertension, though their BP-lowering effects appear to be less potent than spironolactone in the setting of resistant hypertension.459 Amiloride and clonidine have data suggesting they are as effective as spironolactone for BP lowering, though they lack outcomes data. A non-exhaustive list of additional medications sometimes used for BP-lowering purposes includes other centrally acting BP-lowering medications (e.g. methyldopa), hydralazine, aliskiren, minoxidil, triamterene, and loop diuretics (Figure 22).515,516 As noted earlier, minoxidil use is often limited by side effects. Downloaded from academic.oup.com/eurheartj/article/45/38/3912/7741010 by guest on 07 October 2026