What are the latest guidelines for managing hypertension and resistant hypertension?

Management of Hypertension and Resistant Hypertension

Blood Pressure Targets and Initial Treatment

For most adults with hypertension, target a systolic BP of 120-129 mmHg to reduce cardiovascular risk, provided treatment is well tolerated. 1

• If this target cannot be achieved due to poor tolerance, apply the "as low as reasonably achievable" (ALARA) principle rather than abandoning treatment 1
• For adults with confirmed BP ≥140/90 mmHg, initiate both lifestyle measures and pharmacological treatment promptly, regardless of cardiovascular risk level 1
• For adults with elevated BP (120-139/70-89 mmHg) and high cardiovascular risk (≥10% over 10 years), start pharmacological treatment after 3 months of lifestyle intervention if BP remains ≥130/80 mmHg 1
• Continue BP-lowering treatment lifelong, even beyond age 85 years, if well tolerated 1

Accurate Diagnosis and Measurement

Use out-of-office BP readings (ambulatory or home monitoring) to confirm the diagnosis and exclude white-coat hypertension, which accounts for approximately 50% of apparent resistant cases. 1, 2

• Ambulatory BP monitoring (ABPM) is more sensitive than home BP monitoring (HBPM) for detecting masked hypertension 1
• HBPM is the most practical method for documenting BP during medication titration 1
• Ensure proper measurement technique using appropriate cuff size—large arms require large cuffs to avoid falsely elevated readings 1, 3

First-Line Pharmacological Treatment

Initiate combination therapy with two drugs for most patients with confirmed hypertension (BP ≥140/90 mmHg) rather than monotherapy. 1

• Preferred combinations: RAS blocker (ACE inhibitor or ARB) + dihydropyridine calcium channel blocker OR RAS blocker + thiazide/thiazide-like diuretic 1
• Use fixed-dose single-pill combinations to improve adherence 1
• Exceptions to dual therapy: patients ≥85 years, symptomatic orthostatic hypotension, moderate-to-severe frailty, or elevated BP (120-139/70-89 mmHg) with specific indications 1
• First-line drug classes with proven CVD event reduction: ACE inhibitors, ARBs, dihydropyridine calcium channel blockers, and thiazides/thiazide-like diuretics 1

Escalation to Three-Drug Therapy

If BP remains uncontrolled on two drugs, escalate to a three-drug combination: RAS blocker + dihydropyridine calcium channel blocker + thiazide/thiazide-like diuretic, preferably as a single-pill combination. 1

• Never combine two RAS blockers (ACE inhibitor + ARB) 1
• Add beta-blockers when compelling indications exist: angina, post-myocardial infarction, heart failure with reduced ejection fraction, or heart rate control 1

Lifestyle Modifications (Essential at All Stages)

Implement intensive lifestyle modifications as they produce additive BP-lowering effects and improve medication effectiveness. 1

• Sodium restriction: Limit intake to <2400 mg/day, as high sodium significantly contributes to treatment resistance 4, 2
• Weight management: Target BMI 20-25 kg/m² and waist circumference <94 cm (men) or <80 cm (women) 1
• Diet: Adopt Mediterranean or DASH diet patterns 1
• Alcohol: Limit to <100 g/week of pure alcohol; preferably avoid completely for best outcomes 1
• Sugar: Restrict free sugar to maximum 10% of energy intake; discourage sugar-sweetened beverages 1
• Exercise: Engage in 150 minutes/week of moderate-intensity aerobic activity, complemented by resistance training 2-3 times/week 1
• Tobacco: Complete cessation with supportive care and referral to cessation programs 1
• Each intervention is effective individually, but concurrent use of multiple interventions produces additive effects 1

Definition and Diagnosis of Resistant Hypertension

Resistant hypertension is defined as BP ≥130/80 mmHg despite adherence to ≥3 antihypertensive medications from different classes at maximum tolerated doses (including a diuretic), or BP <130/80 mmHg requiring ≥4 drugs. 1

Exclude Pseudo-Resistance First:

1. Confirm with 24-hour ABPM to exclude white-coat effect (accounts for ~50% of cases) 4, 2
2. Verify medication adherence through direct questioning, pill counts, or pharmacy records (nonadherence responsible for ~50% of resistance) 4, 2
3. Check BP measurement technique and cuff size 4
4. Assess for interfering substances: NSAIDs, stimulants, oral contraceptives, certain antidepressants, decongestants 4, 3

Screen for Secondary Causes:

• Primary aldosteronism: Screen all adults with difficult-to-control or resistant hypertension using aldosterone-to-renin ratio, even with normal potassium 1, 4
• If aldosterone-to-renin ratio is low but plasma renin is also low, measure 24-hour urine aldosterone during salt loading 1
• Obstructive sleep apnea: Screen systematically 1, 4
• Renal artery stenosis: Consider, especially in younger patients where revascularization may be beneficial 1, 4
• Chronic kidney disease: Assess baseline eGFR 4
• Thyroid dysfunction: Check TSH 4

Management of Resistant Hypertension

Step 1: Optimize the Three-Drug Regimen

Switch from hydrochlorothiazide to chlorthalidone (12.5-25 mg daily) or indapamide (1.5-2.5 mg daily) for superior 24-hour BP control. 4, 2

• Thiazide-like diuretics are significantly more effective than hydrochlorothiazide for resistant hypertension 4
• If eGFR <30 mL/min/1.73m² or clinical volume overload is present, use loop diuretics instead of thiazides, as thiazides become ineffective at lower GFR 4, 2
• Volume overload from insufficient diuretic therapy is a common but unappreciated cause of treatment failure 1, 3
• Ensure the regimen includes a RAS blocker, long-acting calcium channel blocker, and appropriate diuretic at maximal tolerated doses 4

Step 2: Add Spironolactone as Fourth-Line Agent

Add low-dose spironolactone (25-50 mg daily) as the most effective fourth-line agent, provided serum potassium is <4.5 mEq/L and eGFR >45 mL/min/1.73m². 4, 2

• Start with 25 mg once daily; increase to 50 mg daily if BP remains uncontrolled and medication is well-tolerated 4
• Approximately 70% of adults with resistant hypertension are candidates for mineralocorticoid receptor antagonists based on potassium and eGFR criteria 4
• Spironolactone provides significant additional BP reduction when added to multidrug regimens 1
• Monitor serum potassium and renal function regularly after initiation, especially in patients on RAS blockers 1, 4

Step 3: Alternative Fourth-Line Agents (If Spironolactone Contraindicated or Not Tolerated)

If spironolactone cannot be used, consider these alternatives in order of preference:

1. Eplerenone (50-200 mg daily): Less gynecomastia and sexual side effects than spironolactone, but requires higher dosing for equivalent BP reduction 4, 2

   • May need twice-daily dosing due to shorter duration of action 4

2. Amiloride: One placebo-controlled trial found it more effective than spironolactone for resistant hypertension 1, 4

3. Beta-blockers (vasodilating types): Safest option for patients who cannot undergo regular laboratory monitoring, as they don't require potassium checks 4

   • Prefer labetalol, carvedilol, or nebivolol over traditional beta-blockers 4
   • Less potent than spironolactone for BP lowering 4

4. Doxazosin or clonidine 1

Step 4: Fifth-Line and Beyond

If BP remains uncontrolled after optimizing four-drug therapy:

• Hydralazine: Add only after other agents prove ineffective; start 10 mg four times daily for 2-4 days, increase to 25 mg four times daily for first week, then 50 mg four times daily for maintenance 4
• Minoxidil: Reserve as last resort due to multiple side effects and poor tolerability, but effectively lowers BP when other agents fail 4

Step 5: Specialist Referral

Refer to a hypertension specialist if BP remains >130/80 mmHg after optimizing the four-drug regimen with lifestyle modifications, or if complications arise (severe hyperkalemia, progressive renal dysfunction, difficulty managing regimen). 4, 2

Monitoring Strategy

• Reassess BP response within 2-4 weeks of any medication adjustment 4
• Target BP achievement within 3 months of initiating or adjusting therapy 4
• Use home BP monitoring to guide medication titration and improve adherence 1, 4
• Check serum potassium and renal function regularly, particularly after adding spironolactone 4

Critical Pitfalls to Avoid

• Do not continue hydrochlorothiazide in resistant hypertension—switch to chlorthalidone or indapamide 4
• Do not combine ACE inhibitor + ARB 1
• Do not withhold or down-titrate treatment for asymptomatic orthostatic hypotension, as it is not associated with higher rates of CVD events, syncope, injurious falls, or acute renal failure 1
• Do not delay screening for primary aldosteronism—autonomous aldosterone production may play a role even in Stages 1 and 2 hypertension 1
• Do not overlook medication adherence—it accounts for approximately half of treatment resistance 4, 2
• Do not ignore volume overload—insufficient diuretic therapy is a common unrecognized cause of treatment failure 1, 3

Special Populations

Older Adults

• Intensive BP lowering may prevent or partially arrest cognitive decline 1
• Intensive BP control is not associated with increased hospitalization or orthostatic hypotension risk 1
• Continue treatment beyond age 85 if well tolerated 1

Young Adults with Hypertension

• Have earlier onset of CVD events compared to those with normal BP 1
• For those with target organ damage, manage with lifestyle modification for 6-12 months, then add antihypertensive drugs if BP remains above goal 1

Chronic Kidney Disease

• Target systolic BP 120-129 mmHg if eGFR >30 mL/min/1.73m² 2
• Use loop diuretics if eGFR <30 mL/min/1.73m² 4, 2

Implementation Strategies

Multilevel, multicomponent implementation strategies, including team-based care, are the most effective methods for BP control. 1

• Incorporate nurse case managers, pharmacists, and nutritionists for a multidisciplinary approach 2
• Simplify medication regimens using long-acting combination products to improve adherence 2
• Implement home BP self-monitoring and telemonitoring to facilitate drug titration 1