Hypertension Treatment

Treatment Goals

• To manage hypertension
  • To achieve and maintain BP goal based on age and presence/absence of comorbidities (eg DM and chronic kidney disease)
• To prevent complications through identification and management of all other identified risk factors for CVD (DM or glucose intolerance, lipid disorders, obesity, smoking)
  • Identification and treatment of all reversible risk factors
  • Management of concomitant disorders (eg DM, established CV or renal disease)
• To prevent progression or recurrence of CVD in hypertensive patients with established CVD

Target BP¹

• Reduce BP to <140/90 mmHg in all patients
• If therapy is well tolerated, a treated BP goal of ≤130/80 mmHg is recommended for:
  • Patients with clinical CVD or ≥10% ASCVD risk in 10 years
  • Patients without clinical CVD and <10% ASCVD risk in 10 years
  • Patients with comorbidities such as DM, CKD, heart failure, stable ischemic heart disease, atrial fibrillation on anticoagulation, peripheral vascular disease and for secondary stroke prevention  
• An SBP goal of 130-139 mmHg is recommended for patients ≥70 years old receiving antihypertensive therapy
  • In patients ≥80 years old, an SBP goal of <150 mmHg is advised though it should be adjusted to individual tolerability in frail elderly patients
• An SBP goal of 120-130 mmHg in most patients ≤69 years old receiving antihypertensive therapy is recommended  
• A DBP goal of <80 mmHg should be considered in all patients regardless of risk level and comorbidities

¹Recommendations for BP target goals may vary between countries. Please refer to available guidelines from local health authorities.

General Principles

Initiating Treatment²

• Decision to initiate therapy is based on the untreated BP level and presence of TOD or concomitant disorders
  • CVD risk stratification may be done at or after treatment initiation but only when it is feasible and will not delay treatment
• Primary prevention is recommended for patients:  
  • Without prior history of CVD but with a ≥10% estimated 10-year ASCVD risk and SBP ≥130 mmHg or DBP ≥80 mmHg
  • Without prior history of CVD but with a <10% estimated 10-year ASCVD risk and SBP ≥140 mmHg or DBP ≥90 mmHg
• Secondary prevention of recurrent CVD events is recommended in patients with existing clinical CVD and SBP ≥130 mmHg or DBP ≥80 mmHg  
• Implement lifestyle changes throughout management
  • A defined time period of lifestyle changes may be considered in patients with medication intolerance and <10% 10-year ASCVD risk   
  • Medication is started together with lifestyle changes in patients with elevations in SBP of >20 mmHg or DBP of >10 mmHg above BP goal, those with TOD on screening and in fit patients 65-80 years old with SBP 140-159 mmHg if therapy is well tolerated  
  • In patients with BP ≥140/90 mmHg at low-moderate risk and no target organ damage, pharmacological therapy can be started if still hypertensive despite lifestyle changes for 3-6 months   
• If with high-normal BP, consider initiating drug treatment in very high-risk patients with CVD, especially coronary artery disease (CAD) 
• Pharmacological therapy is recommended in fit patients >80 years old with an SBP of ≥160 mmHg and have not received BP treatment provided therapy is well tolerated
• Start drug treatment promptly in all patients for whom it is necessary to achieve a more rapid control of BP

²Recommendations for treatment initiation may vary between countries. Please refer to available guidelines from local health authorities.

Treatment Regimen

• Assessment of BP and adjustment of treatment regimen is continuous until BP goal is reached 
• Different initial strategies may be considered based on individual circumstances, preferences of physician and patient:
  • Monotherapy
    • Though most patients will need >1 drug to achieve BP control, it is reasonable to start with a single antihypertensive agent in low-risk patients with low baseline BP that is close to recommended goal (SBP <150 mmHg), high-risk patients with high-normal BP, frail or old patients who need gentle BP reduction, or those who have a history or are at risk of hypotension or drug-associated side effects  
    • Dosage titration and sequential addition of other agents may be done to achieve target BP  
  • Combination therapy
    • Two 1st-line agents from separate drug classes, either separately or in a fixed-dose or single-pill combination 
      • Recommended in patients with an average BP of >20/10 mmHg above their target  
      • It has been shown in the general population of individuals with hypertension that combination therapy at low dose is more effective than monotherapy at maximal dose
    • If goal BP cannot be achieved using 2 drugs, increase treatment to a 3-drug combination therapy (preferably in a single-pill combination)
• Initial doses of drugs should be at least half the maximum dose so only one dose adjustment is needed to be done thereafter
• In general, an effective regimen is expected to be reached within 6-8 weeks, regardless whether 1, 2 or 3 drugs were employed
  • Consider stepping down therapy if patient's BP remains controlled after 1-2 years of therapy and is without symptoms related to hypertension or TOD
• Referral to a hypertension specialist may be necessary when goal BP cannot be achieved despite above strategies or when managing patients for whom additional consultation is warranted

Choice of Antihypertensive Agents

• Choice is influenced by the following factors:
  • Patient’s age, ethnicity/race
  • Patient’s previous history with antihypertensive medications
    • Monitor for adverse reactions to avoid patient’s noncompliance to medications
  • Presence of other medical conditions
    • Eg coronary diseases, DM, renal disease, pregnancy, thiazide
  • Possibility of drug interactions with drugs used for other conditions
  • Patient preference
  • Cost (affordability) and availability of the drugs
    • Cost consideration should not predominate efficacy and tolerability
• Long-acting drugs or preparations providing 24-hour efficacy that can be given once daily are preferred
  • Improves compliance and minimizes BP variability
  • Once-daily drugs can be taken at any time during the day (either morning or evening)
• When >1 drug is needed, the use of a combination product (≥2 appropriate medications in a single tablet) can simplify the regimen and improve adherence of patients

• The World Health Organization (WHO) recommends the use of medications from any of the following 3 drug classes as 1st-line antihypertensive agents: Angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), calcium antagonists and thiazide and thiazide-like diuretics

ACE Inhibitors

• Block the conversion of angiotensin I to angiotensin II by inhibiting ACE
• ACE inhibitors are suitable for initiation and maintenance of therapy
• Have established clinical outcome benefits in patients with chronic heart failure (CHF) and post myocardial infarction (MI) patients with reduced LV ejection fraction; also effective in reducing LV hypertrophy and preserving kidney function
• Given as 1st-line agents at maximally tolerated doses to CKD patients with urinary albumin-to-creatinine ratio of ≥30 mg/g (or equivalent)
• Are well-tolerated; most common side effect is dry cough (most common in women and among Asian and African patients) related to effects of bradykinin or prostaglandin metabolism
• There is a risk of hypotension when starting treatment with ACE inhibitors in patients who are already on diuretics, or are on low-salt diet or are dehydrated
  • For patients on diuretics, skipping a dose prior to starting ACE inhibitor may help prevent this sudden drop in BP
• Should not be combined with ARBs or direct renin inhibitors
• Drug effects do not seem to have dose-dependent effects, except for hyperkalemia which may occur more frequently with high doses
  • Allows patient to initiate treatment using medium or even approved high doses

Alpha-Blockers

• Reduce BP by blocking arterial alpha-adrenergic receptors, in effect, preventing the vasoconstrictor actions of these receptors
• Less widely used as first-line agents due to limited evidence for their clinical outcome benefits
• Are useful in treating resistant hypertension when used in combination with other agents such as beta-blockers, diuretics and ACE inhibitors
• Are beneficial part of treatment regimens for older hypertensive men with benign prostatic hypertrophy
• Have favorable effects on blood glucose and lipid levels

Angiotensin II Antagonists (also called ARBs)

• Act by blocking the action of angiotensin II on its AT1 receptors, preventing the vasoconstrictor effects of this receptor
• Provide the same CV and renal benefits as ACE inhibitors
• Recommended as 1st-line agents at maximally tolerated doses to CKD patients with urinary albumin-to-creatinine ratio of ≥30 mg/g
• Should not be combined with ACE inhibitors or direct renin inhibitors
• Are well tolerated; do not cause cough and only rarely cause angioedema
• Drug effects do not appear to have dose-dependent effects
  • Allows patient to start with medium or even maximum approved doses
• For patients on diuretics, skipping a dose of the diuretic prior to starting ARBs may help prevent sudden drop in BP
• Can be used to prevent recurrence of atrial fibrillation

Beta-Blockers

• Beta-blockers may be combined with any of the other major drug classes at any step of the hypertension treatment when indicated (eg post MI, heart failure, angina, atrial fibrillation, or young women planning to get pregnant or are pregnant) 
  • For patients without conditions warranting beta-blockade, beta-blockers should not be used as initial therapy
• Drug of choice in patients with history of MI and heart failure
  • Useful in patients with effort angina, tachyarrhythmia and have been shown to reduce CV morbidity and mortality in post-MI patients and risk of exacerbations and mortality in patients with chronic obstructive lung disease
  • Specified beta-blockers for heart failure include Bisoprolol, Carvedilol, Metoprolol succinate and Nebivolol
• Studies show that Celiprolol, Carvedilol and Nebivolol (3rd generation of beta-blockers) can reduce central pulse pressure and aortic stiffness as compared to Metoprolol and Atenolol (2nd generation of beta-blockers); Nebivolol has less effects on insulin sensitivity than Metoprolol
• Act as competitive antagonists of the effects of catecholamines at beta-adrenergic receptor sites
  • Beta₂-blockade can increase bronchial resistance and inhibition of catecholamine-induced glucose metabolism
  • Beta-blockers have different affinities for beta₁- or beta₂-blockade but as doses are increased, activity of beta₂ receptors can become apparent in beta₁-selective inhibitors
• Combination with thiazide diuretic is shown to have dysmetabolic effect and increased incidence of new onset diabetes among patients and is therefore, not recommended in patients at risk for diabetes

Calcium (Ca) Antagonists

• Act by blocking the inward flow of calcium ions through the L channels of arterial smooth muscle cells
• Ca antagonists are powerful antihypertensive agents, especially when given in combination with ACE inhibitors or with ARBs
• Main side effect is peripheral edema, most especially at high doses; though a clinical rather than a laboratory approach most often is enough to eliminate a renal or hepatic etiology for the edema
  • Reduced by combining with ACE inhibitors or ARBs

Dihydropyridine Ca Antagonists

• Eg Amlodipine, Cilnidipine, Felodipine, Isradipine, Manidipine, Nicardipine, Nifedipine, Nisoldipine
• Usually used for their antihypertensive and anti-anginal effects
• Dihydropyridines have shown beneficial effects on stroke and CV outcomes in hypertension trials
• Dihydropyridines (but not nondihydropyridines) can be safely combined with beta-blockers
• Have greater selectivity for vascular smooth muscle than for myocardium and their main effect is vascular relaxation
  • They have little or no effect at the SA or AV nodes and negative inotropic activity is not typical at therapeutic doses

Benzothiazepine and Phenylalkylamine Ca Antagonists (Non-dihydropyridine Ca Antagonists)

• Eg Diltiazem, Verapamil
• Typically used for their antiarrhythmic, anti-anginal and antihypertensive properties
• Tend to have less selective vasodilatory activity than dihydropyridine Ca antagonists
  • They have direct effect on myocardium causing depression of SA and AV conduction
• Nondihydropyridines are preferred in patients with fast heart rates and rate control for atrial fibrillation patients who cannot tolerate beta-blockers
• A randomized controlled trial revealed that Verapamil + Trandolapril was as clinically effective as Atenolol + Hydrochlorothiazide in hypertensive patients with CAD
• Preferred in patients with proteinuria due to the additional antiproteinuric effect in Diltiazem and Verapamil

Direct Renin Inhibitors

• Eg Aliskiren
• Found to be as effective as ARBs and ACE inhibitors without dose-related increase in side effects in the elderly; combination with ACE inhibitor or ARB is not recommended
• Current available data show that Aliskiren:
  • As monotherapy, lowers systolic BP and diastolic BP in younger and elderly hypertensive patients
  • Has a greater BP lowering effect when used in combination with a thiazide diuretic, a renin angiotensin blocker or a Ca antagonist
  • Prolonged use in combination treatment can have a favorable effect on asymptomatic organ damage
• Appears well tolerated among patients >75 years of age, including those with renal disease (with estimated GFR ≥30 mL/min/1.73 m²)
• Main side effect is mild diarrhea

Diuretics

• Use of diuretics has been well-established in the treatment of hypertension and diuretics are suitable for initiation and maintenance of therapy
  • When used in combination, diuretics may enhance the efficacy of concurrently used antihypertensive drug
  • Reduce the risk of fatal and nonfatal stroke and have been shown to reduce CV morbidity and mortality and all-cause mortality
  • Drug of choice in the elderly with no comorbid conditions
• Combination treatment with potassium-sparing diuretics (eg Amiloride, Triamterene), mineralocorticoid antagonists (eg Spironolactone, Eplerenone), and epithelial sodium transport channel antagonists with other agents are useful in treating hypertension by reducing vascular stiffness and SBP

Aldosterone Antagonists or Mineralocorticoid Receptor Antagonists

• Eg Spironolactone, Eplerenone
• Preferred therapeutic agents for resistant hypertension and primary aldosteronism 
• Have recently been part of standard treatment of heart failure
• Can be effective in lowering BP when added to standard 3-drug regimens (ACE inhibitor or ARB/Ca antagonist/diuretic) in treatment-resistant hypertension after excluding secondary hypertension

Loop Diuretics

• Eg Furosemide, Torasemide, Bumetanide
• Preferred agents in patients with symptomatic heart failure
• Loop diuretics are preferred over thiazide diuretics in patients with renal insufficiency

Thiazide and Thiazide-like Diuretics

• Eg Chlorthalidone, Hydrochlorothiazide, Indapamide, Metolazone
• Act by increasing elimination of sodium by kidneys and may have some vasodilator effects
• Most effective in BP reduction when combined with ACE inhibitors or ARBs
  • Also effective when combined with Ca antagonists
• With proven clinical outcome benefits in reducing strokes and major CV events
  • Chlorthalidone has a longer duration of action and proven reduction of CVD risk
• It was suggested by some meta-analyses and a large randomized controlled trial comparing first-step agents that diuretics, especially the long-acting thiazide-like agent Chlorthalidone, may provide an optimal choice for initial treatment of hypertension 
• Main side effects (metabolic, such as hypokalemia, hyponatremia, hyperuricemia, hyperglycemia) are reduced by lowering the doses or combining them with ACE inhibitors
  • Used also in combination with potassium-sparing diuretic to prevent thiazide-induced hypokalemia

Other Antihypertensives

Centrally-Acting Agents

• Eg Clonidine, Methyldopa
• More often used nowadays as part of multiple drug combinations
• Act by reducing sympathetic outflow from the central nervous system
• Methyldopa may be considered in resistant hypertension in combination with other antihypertensive agents
  • Safe to use in pregnancy

Direct Vasodilators

• Eg Hydralazine, Minoxidil 
• Are most effective in reducing BP when combined with diuretics and beta-blockers or sympatholytic agents
• Usually used only as 4th line or later additions to treatment regimens

Effective Antihypertensive Combinations

Combination therapy can be initiated in hypertension stage 2 and above or hypertension within those at higher risk for CVD. In 15-20% of hypertensive patients, BP control cannot be achieved with a two-drug combination; in this case, a three-drug combination may be used, preferably in a fixed-dose or single-pill combination

• ACE inhibitor or angiotensin II antagonist + Ca antagonist and/or diuretic  
• ACE inhibitor or angiotensin II antagonist + Ca antagonist and/or beta-blocker  
• Ca antagonist + beta-blocker or diuretic  
• Beta-blocker + diuretic

Many antihypertensive combinations are available. Please see the latest MIMS for specific formulations and prescribing information.

• Target BP not achieved and patient treated with ≥3 drugs at optimal doses (including a diuretic) or BP <130/80 mmHg but patient treated with ≥4 drugs  
  • For patients not controlled on 3 drugs, maximizing diuretic therapy and adding an aldosterone antagonist (eg Spironolactone), a beta-blocker, a centrally acting agent, an alpha-blocker, or a direct vasodilator will often be helpful
  • If patient is intolerant to Spironolactone, consider additional diuretic therapy, eg Amiloride, Eplerenone, a loop diuretic or a higher-dose thiazide or thiazide-like diuretic
• If BP is still uncontrolled after 3 drugs at near-max doses, consider the following:
  • Inaccurate BP measurements  
  • Noncompliance to treatment regimen
  • White coat hypertension
  • Nonadherence to lifestyle modifications
  • Drug interactions
  • Secondary hypertension
  • Complications of long-standing hypertension (eg nephrosclerosis)
• Consider referral to a hypertension specialist if after 6 months of therapy, BP remains uncontrolled

• Evidence demonstrates that the risk for severe COVID-19 is increased in the presence of hypertension
• Continue home BP monitoring; if required, telehealth services (eg phone or video consultation) may be used to access healthcare providers during the COVID-19 pandemic 
• Antihypertensive therapy should follow current guideline recommendations  
  • Risk of COVID-19 infection or risk of developing severe COVID-19 complications is not increased with prior or current treatment with ACE inhibitors or ARBs thus treatment should be continued as prescribed  
  • Treatment may be withdrawn temporarily in patients who develop hypotension or acute kidney injury from severe COVID-19 infection  
  • Parenteral antihypertensive medications are necessary for patients previously treated for hypertension who developed persistent severe hypertension requiring invasive ventilation   
• Monitor for arrhythmias in hypertensive patients with cardiac disease and for hypokalemia in those with severe COVID-19 infection