Treatment of Hypertension

Full update January 2023

For antihypertensive dosing information and more, see our charts, ACE Inhibitor Antihypertensive Dose Comparison, Comparison of Angiotensin Receptor Blockers, Comparison of Commonly Used Diuretics, Comparison of Calcium Channel Blockers, and Comparison of Oral Beta-Blockers. Note that blood pressure control in hypertensive crises, and acute ischemic stroke are covered in our charts, Drug Options for Hypertensive Emergency, and Acute Ischemic Stroke Pharmacotherapy Checklist.

Question

Answer/Pertinent Information

What lifestyle changes are recommended?

  • Maintain healthy body weight.3 Weight loss of 1 kg can reduce SBP by 1 mm Hg.6
  • Consume a heart-healthy diet (e.g., DASH dietary pattern).3,6,16 The DASH dietary pattern can reduce SBP by 11 mm Hg).6
    • Dietary sodium reduction.
      • Hypertension Canada: reduce sodium reduction toward 2,000 mg/day.
      • Cutting sodium by 25% or 1,000 mg/day can reduce SBP by 5 mm Hg.6
      • Avoid adding salt when cooking or at the table. Avoid fast food, processed foods, and other high sodium foods (e.g., soy sauce, certain breads and cereals).16
    • Increased dietary potassium (e.g., 4 to 5 servings of fruits and vegetables/day), if not at risk of hyperkalemia (e.g., eGFR <45 mL/min/1.73 m2, taking meds that cause hyperkalemia, or baseline potassium >4.5 mmol/L.3,6,16
    • Increased whole grains, fiber, and plant protein (e.g., nuts, legumes, tofu).3,16
    • Eight to ten fruit/vegetable servings daily.3
    • Two to three low-fat dairy servings daily.3
  • Exercise. Aerobic activity for 150 min/week can reduce SBP by 5 mm Hg.6
    • ACC/AHA: structured exercise program.
    • Hypertension Canada: moderate exercise for 30 to 60 minutes/day, four to seven days/week.3
    • Int Soc HTN: moderate exercise for 30 minutes per day, five to seven days/week, plus strength/resistance training two to three days/week.16
  • Reduced alcohol intake recommendations:
    • ACC/AHA: one (women) or two (men) drinks daily.6
    • Hypertension Canada: two drinks daily.3
    • Int Soc HTN: 1.5 (women) or two (men) drinks daily.16
  • Reduce stress with cognitive behavioral therapy (Hypertension Canada), or daily mindfulness or meditation (Int Soc HTN).3,16 ACC/AHA guidelines do not recommend stress reduction due to paucity of evidence.6

How should BP be measured?

  • Patients should avoid exercise, nicotine, and caffeine for at least 30 min before measurement (Hypertension Canada: no nicotine or caffeine 60 minutes before measurement).5,6,16 (Note that caffeine probably has little effect in chronic users.49)
  • BP should be measured after the patient has emptied their bladder and bowels, and has been seated for ~5 minutes with back supported and legs resting on the floor (not crossed).5,6,16
  • Arm should be supported (e.g., resting on table) at heart level.5,6,48
  • Position correct-size cuff (i.e., inner bladder encircles at least 75% of the arm, or per automated device instructions) at the level of the right atrium (midpoint of sternum).5,6,16 Use a validated device.See ValidateBP.org.
  • Patient should not talk or move during measurement.5,16
  • Take two readings one to two minutes apart and average the readings (AHA/ACC).Int Soc HTN: take three readings at one-minute intervals, discard the first, and average the other two.16 Hypertension Canada: except for patients presenting with hypertensive urgency or emergency, at least two readings should be averaged at the same visit. If not automated, take three readings and discard the first.3
  • ACC/AHA: measure BP in both arms at initial evaluation. Use the higher reading for measurements thereafter.6
  • Change in BP from seated to standing position should be measured to detect orthostatic hypotension (a decline >20 mm Hg in SBP or >10 mm Hg in DBP after 1 minute is abnormal).6
  • For more information see our Measuring Blood Pressure Checklist. An AHA patient resource on Monitoring Your Blood Pressure at Home is available at https://www.heart.org/en/health-topics/high-blood-pressure/understanding-blood-pressure-readings/monitoring-your-blood-pressure-at-home.

How is hypertension diagnosed?

  • In general, use an average of ≥2 measurements taken ≥2 separate visits.6
  • Patients who present with hypertensive urgency or emergency (Hypertension Canada), or BP ≥180/≥110 mm Hg (Int Soc HTN: with evidence of CV disease) should be diagnosed with HTN.3,16
  • Out-of-office BP monitoring (i.e., home BP monitoring or ambulatory BP monitoring) is used:***
    • ACC/AHA: if white coat HTN is suspected in adults with untreated SBP >130 mm Hg but <160 mm Hg or DBP >80 mm Hg but <100 mm Hg.For other patients, make the diagnosis based on two or three visits one to four weeks apart.16
    • Int Soc HTN: ideally, to confirm the diagnosis.16,***
    • Hypertension Canada: before visit 2 for confirmation if office BP is ≥140/90 mm Hg (≥135/85 mm Hg if automated [preferred method]).3
  • Hypertension Canada: if out-of-office measurement is not performed, patients can be diagnosed at the second visit if the average of all office measurements across visits is >140 mm Hg SBP or >90 mm Hg DBP and patient has DM, macrovascular target organ damage, or CKD.3
    • Without target organ damage, etc., HTN is diagnosed if:3
      • at visit three, mean office BP measurements averaged across all visits is ≥160 mm Hg SBP of ≥100 mm Hg DBP.3
      • at visits four or five the mean office BP measurement averaged across all visits I ≥140 mm Hg SBP or ≥90 mm Hg DBP.3

***On ABPM, mean awake BP ≥135/≥85 mm Hg, or mean 24-hr BP ≥130/80 mm Hg, is high. Using HBPM, the patient should average two readings each morning and evening for seven days and discard the first day’s measurements. Mean BP ≥135/85 mm Hg is high.3,16 These metrics are not validated in US populations, and should be interpreted cautiously.6

What are some other roles for out-of-office BP monitoring?

  • Home (HBPM) or ambulatory BP monitoring (ABPM) can be used:
    • to identify white-coat effect in patients with BP not at goal despite multiple BP meds (Canada: use ABPM).3,50
    • symptoms of hypotension (Canada: use ABPM).3
    • inconsistent office readings (Canada: use ABPM).3
    • in patients with known white-coat HTN, to catch transition to sustained HTN.16,50
    • to identify masked HTN if suspected (e.g., in patients high-normal office readings, or normal BP and target organ damage or CV risk factors).3,16,50
    • on a regular basis (HBPM) in patients with HTN and DM, CKD, suspected nonadherence, or known masked or white coat HTN.3

Who should be treated with pharmacotherapy based on the ACC/AHA guidelines?

  • Clinical CV disease (e.g., stable ischemic heart disease, peripheral artery disease) or 10-year atherosclerotic CV disease risk of 10% or higher: start pharmacotherapy at 130/80 mm Hg.6
  • HF: start pharmacotherapy at 130/80 mm Hg.6
  • Stroke:
    • Post-stroke, BP 140/90 mm Hg or higher, but without previously diagnosed or treated HTN: start pharmacotherapy 72 hours after symptom onset and stable neurological status or TIA (benefit of pharmacotherapy not established if BP <140/90 mm Hg).6
    • Post-stroke or TIA, with previously diagnosed or treated HTN: restart pharmacotherapy 72 hours after symptom onset and stable neurological status or TIA.6
  • No history of CV disease and 10-year atherosclerotic CV disease risk of <10%: start pharmacotherapy at 140/90 mm Hg.6
  • 65 years of age and older, community-dwelling, ambulatory: start pharmacotherapy at SBP 130 mm Hg.6
  • DM: start pharmacotherapy at 130/80 mm Hg.6
  • CKD (including post-kidney transplant): start pharmacotherapy at 130/80 mm Hg.6

Who should be treated with pharmacotherapy based on the JNC 8 guidelines?

  • Patients <60 years of age: start pharmacotherapy at 140/90 mm Hg.1
  • Patients with DM: start pharmacotherapy at 140/90 mm Hg.1
  • Patients with CKD: start pharmacotherapy at 140/90 mm Hg.1
  • Patients 60 years of age and older: start pharmacotherapy at 150/90 mm Hg.1

Who should be treated with pharmacotherapy based on the Hypertension Canada guidelines?

  • For patients without CV risk factors or macrovascular target organ damage, start pharmacotherapy if the average in-office BP is ≥160/100 mm Hg.3
  • For patients with CV risk factors or macrovascular target organ damage, strongly consider pharmacotherapy if the average in-office BP is ≥140/90 mm Hg.3
  • For high CV-risk patients ≥50 years of age meeting SPRINT criteria (see footnote a), consider pharmacotherapy if SBP ≥130 mm Hg.3
  • For patients with DM, start pharmacotherapy if average in-office BP is ≥130/80 mm Hg.3
  • For all other adults, start pharmacotherapy if average in-office BP is ≥140/90 mm Hg.3
  • For high CV-risk patients ≥50 years of age meeting SPRINT criteria (see footnote a), consider pharmacotherapy if SBP ≥130 mm Hg.

Who should be treated with pharmacotherapy based on the Int Soc HTN guidelines?

  • For patients with BP ≥160/100 mm Hg, start pharmacotherapy immediately.16
  • For patients with DM, CV disease, CKD, target organ damage, and BP ≥140/90 mm Hg, start pharmacotherapy immediately.16
  • For other patients with BP 140-159/90-99 mm Hg, start pharmacotherapy after a three- to six-month trial of lifestyle interventions alone.16

What are BP goals based on ACC/AHA guidelines?

For goals in patients with diabetes, see the DIABETES section, below.

  • Most patients: <130/80 mm Hg6
  • Elderly:
    • 65 years of age and older, community-dwelling, ambulatory: SBP <130 mm Hg.6
    • Use clinical judgement and consider patient preference in patients with multiple comorbidities, falls, dementia, inability to live independently, orthostasis, Parkinson’s disease, or limited life expectancy.6
  • Stroke:6
    • Post-stroke or TIA, BP ≥140/90 mm Hg, but without previously diagnosed or treated HTN: <130/80 mm Hg.6
    • Post-stroke, with previously diagnosed or treated HTN: <130/90 mm Hg.
    • Lacunar stroke: SBP <130 mm Hg.6
  • NOTE: lower goals vs JNC 8 influenced by results of SPRINT.

What are BP goals based on JNC 8 guidelines?

  • Patients <60 years of age: <140/90 mm Hg1
  • Patients with CKD: <140/90 mm Hg1
  • Patients 60 years of age and older: <150/90 mm Hg [Evidence Level B-1].51,52 But no need to back off on tolerated treatment if lower SBP (e.g., <140 mm Hg) achieved.1
  • Use clinical judgment; consider risk/benefit of treatment for each individual when setting goal.1

What are BP goals based on Hypertension Canada guidelines?

  • Without target organ damage or CV risk factors: <140/90 mm Hg.
  • Post-ischemic stroke (after the acute phase [i.e., after the first 72 hours]): <140/90 mm Hg.
  • CKD (nondiabetic): SBP <140/90 mm Hg.
    • With shared decision-making, consider <120 mm Hg.*
      • Hypertension Canada guidelines base this recommendation on SPRINT, which showed reduced mortality.7 See footnote a regarding SPRINT criteria.
      • SPRINT was not designed to detect benefits on kidney outcomes.18 Secondary analysis of other studies (MDRD, AASK) suggest that lower BP goals may improve kidney outcomes (e.g., <130/80 mm Hg for patients with proteinuria >0.3 g/day or <125/75 mm Hg for patients with proteinuria >1 g/day).18
    • With shared decision-making, consider <110 mm Hg for polycystic kidney disease to slow disease progression, per the HALT-PKD trial of patients15 to 49 years of age.17
  • Patients meeting SPRINT criteria (see footnote a): SBP target <120 mm Hg.*

*Target SBP <120 mm Hg is not appropriate for patients with secondary HTN, adherence problems, or standing SBP <110 mm Hg, or if SBP cannot be measured accurately. There is limited or no evidence for this target in patients with LVEF <35%, MI within the past three months, patients with an indication for but not receiving a BB, or institutionalized elderly. Evidence is inconclusive for this target for patients with DM, history of stroke, or eGFR <20 mL/min/1.73 m2. Consider risk of side effects (e.g., orthostatic hypotension, acute kidney injury, electrolyte disturbances), and life expectancy (patients with less than three years were excluded from SPRINT).7

What are BP goals based on the Int Soc HTN guidelines?

  • At minimum, reduce BP by at least 20/10 mm Hg, ideally to <140/90 mm Hg. If ≥65 years of age, consider individualizing target based on tolerability and functional status. For patients <65 years of age, target <130/80 mm Hg, but >120/70 mm Hg, if tolerated.16
  • CAD: <130/80 mm Hg (if elderly, <140/80 mm Hg).16
  • HF: <130/80 mm Hg but >120/70 mm Hg.16
  • CKD: <130/80 mm Hg (if ≥65 years, <140/80 mm Hg).16
  • Stroke history: <130/80 mm Hg (if elderly, <140/80 mm Hg).16

How can BP goals be individualized?

Age

  • There is limited evidence to support a SBP goal of ≤120 mm Hg in institutionalized elderly in long term care.3
  • Age itself does not preclude a lower goal. Almost 30% of the patients randomized to intensive treatment in SPRINT were 75 years of age or older.7
  • Although there is less evidence to determine an optimal target in type 1 vs type 2 DM patients, DBP could be targeted in younger adults because DBP seems to be a more important CV event predictor in patients <50 years of age. Also, young patients with type 1 DM might more easily/safely reach a lower target and derive benefit over the long-term.15

Comorbidities

  • The higher the baseline CV risk, the greater the absolute benefit from lower goals.4
  • Patients with DM with multiple comorbidities or polypharmacy may be less suited to a lower target.15
  • There is limited or no evidence to support a SBP goal of ≤120 mm Hg in patients with left ventricular ejection fraction <35% or a MI within the last three months.3
  • Only inconclusive evidence supports a SBP goal ≤120 mm Hg in patients with prior stroke or eGFR <20 mL/min/1.73m2.3

Other considerations

  • Choose a target using shared decision-making, especially if there are opposing health concerns (e.g., fall risk vs high CV risk), limited life expectancy, or unclear benefit of a lower treatment goal.3,15
  • Consider patient motivation and socioeconomic resources when choosing a BP target.3,15 Canadian guidelines recommend against a SBP goal <120 mm Hg in patients unwilling or unable to take multiple antihypertensives.3

What pharmacotherapy is recommended for uncomplicated hypertension?

For treatment options for patients with diabetes, see DIABETES section, below.

  • First-line agents include ACEI (nonblack) or ARB, thiazideb, (long-acting3) CCB,BB (Hypertension Canada; not for patients ≥60 years of age).1,3,6
    • Most adults will need at least two antihypertensives to reach <130/80 mm Hg, especially Black patients.Can initiate with two agents, especially if SBP >20 mm Hg above goal or DBP >10 mm Hg above goal.1,6
    • Single-pill combinations (first- or second line) include ACEI/CCB, ARB/CCB, ACEI/diuretic, ARB/diuretic.3
      • Combination examples: nonblack, low-dose ACEI or ARB plus dihydropyridine CCB.16 Black, low-dose ARB plus dihydropyridine CCB, dihydropyridine CCB plus thiazide.b.
      • Use caution in the elderly.Consider monotherapy in low-risk patients ≥80 years of age or other frail elderly.16
  • Second-line: after optimizing doses, add another first-line agents3,16 Don’t use ACEI plus ARB.3,16 Use caution with nondihydropyridine CCB plus BB.3
  • Third-line: add spironolactone (preferred), amiloride, doxazosin, eplerenone, clonidine, or BB.16

What pharmacotherapy is recommended for hypertension based on patient-specific compelling indications?

  • Stable ischemic heart disease: first-line, evidence-based BB, ACEI, or ARB.3.6 If needed, add a dihydropyridine CCB (especially for angina despite BB), thiazide, and/or mineralocorticoid blocker.6
    • Can continue BB and/or CCB beyond three years post-MI or ACS for treatment of HTN without HFrEF.6
    • BB choices include carvedilol, metoprolol, nadolol, bisoprolol, propranolol, or timolol. Avoid atenolol; it does not reduce CV events.6
  • CAD: ACEI or ARB.3 Int Soc HTN: ACEI or ARB plus BB with or without CCB.16 For stable angina, a BB or CCB.3 For recent MI, BB (long-acting CCB if BB cannot be used or is ineffective) and ACEI (preferred over ARB).3
    • Do not use short-acting nifedipine.3 Do not use a nondihydropyridine CCB (diltiazem, verapamil) in patients with HF with evidence of pulmonary congestion.3
    • Second-line: combination of first-line drugs.3 For high-risk patients, give preference to an ACEI plus dihydropyridine CCB.3 Do NOT use an ACEI plus ARB.3
    • Use caution reducing DBP to ≤60 mm Hg, especially in left ventricular hypertrophy.3
  • HFrEF: ACEI (Hypertension Canada: preferred over ARB) or sacubitril/valsartan titrated to evidence-based target dose and BB.3,16 Add aldosterone antagonist for recent CV hospitalization, MI, elevated brain natriuretic peptide (BNP), or N-terminal pro-B-type natriuretic peptide (NT-proBNP) level, or New York Heart Association (NYHA) class II to IV.3 Can add a diuretic for volume overload.3,16
    • Preferred BBs are metoprolol succinate, bisoprolol, and carvedilol.
    • A CCB can be added.16 Do not use a non-dihydropyridine CCB (diltiazem, verapamil).Amlodipine or felodipine can be used.6
    • Monitor potassium closely if combining RAAS inhibitors.3
  • HFpEF: Optimal strategy unknown.16 HFpEF is treated with cautious diuresis. Consider an ARB, sacubitril/valsartan (do not combine with ARB), spironolactone, or BB for patients with a history of MI, CAD, or A-Fib, if exercise tolerance allows.19
  • CKD: regimen should include an ACEI or ARB (including African Americans).1,3,6
    • Second-line for CKD: dd a CCB or a diuretic (loop diuretic if eGFR <30 mL/min/1.73 m2.3,16
  • Thoracic aortic disease:BB.6
  • Stroke or TIA: thiazide, ACEI, or ARB, or thiazide plus ACEI, but consider comorbidities.Post-ischemic stroke: ACEI plus thiaizide.b
  • Stroke history:ACEI or ARB, CCB, diuretics.16
  • Atrial fibrillation: ARB.6
  • Kidney transplant: CCB.6
  • Isolated systolic HTN: thiazideb, ARB, long-acting dihydropyridine CCB3
    • Second-line for isolated systolic HTN: combine first-line agents.3
  • Left ventricular hypertrophy: ACEI, ARB, long-acting CCB, thiazideb.3 Do not use hydralazine or minoxidil.3
    • Second-line for left ventricular hypertrophy: combine first-line agents.Do not combine an ACEI plus ARB.6

Notes:

  • Choose once-daily or combination products to simplify the regimen.16
  • Pivotal studies showing clinical benefits of treating HTN included a thiazide.1 Chlorthalidone or indapamide are preferred over hydrochlorothiazide due to longer duration of action and better evidence of benefit.3,6,16
  • For Black patients, an ARB may pose a lower risk of cough and angioedema than an ACEI.Black patients have high stroke risk.16 CCBs provide better stroke prevention and BP reduction in Black patients vs ACEIs.Thiazidesb produce better CV outcomes (including reduced stroke risk) than ACEIs in Black patinets.For Black patients without HF or CKD, first-line treatment should include a thiazide (chlorthalidone) and/or CCB for optimum endpoint protection.1,6 However, treatment should include an ACEI or ARB for Black patients with diabetic nephropathy or other CKD.6,16 Black and nonblack patients have similar antihypertensive responses to combination therapy (i.e., thiazide plus ARB; CCB plus ARB).6
  • For HTN, beta- and alpha-blockers have worse CV outcomes data than the recommended agents.
  • Do not use an ACEI plus an ARB and/or aliskiren; no added benefit, more side effects (e.g., hyperkalemia).6
  • Avoid antihypertensives that slow the heart rate in patients with chronic aortic valve insufficiency.6

Treatment of HTN in Patients With Diabetes

What is the goal BP in patients with DM?

  • ACC/AHA: <130/80 mm Hg.6
  • ADA: <130/80 mm Hg if it can be achieved safely.4
  • JNC 8: <140/90 mm Hg.1
  • Int Soc HTN: <130/80 mm Hg.16
  • Hypertension Canada: <130/80 mm Hg.3
  • Diabetes Canada: <130/80 mm Hg.10

What are the ACC/AHA BP goals for patients with DM based on?

  • ACCORD: high-risk DM patients did not attain greater benefit from a lower target (<120 mm Hg vs <140 mm Hg) for a composite outcome of nonfatal MI, nonfatal stroke, and CV death.2 The study may have been underpowered.4,6 The event rate was low, and the composite endpoint may have been insensitive to the effect of BP reduction.4,6 The lower target <120 mm Hg reduced stroke in at the expense of increased SCr, hypotension, bradycardia, and hyper- and hypokalemia, but not end stage kidney disease or stroke.3,6 A secondary analysis demonstrated a reduction in LVH with a SBP goal of <120 mm Hg.6
  • SPRINT: comparing a SBP target of <140 mm Hg to a target of <120 mm Hg. SPRINT did NOT include patients with DM. A SPRINT sub study that showed that patients with prediabetes attained CV benefit (composite of MI, coronary syndromes, stroke HF, death) from a target of <120 mm Hg vs <140 mm Hg.4,7 
  • Three meta-analyses, two of which included only studies in which patients were randomized to different BP goals.6

Treatment of HTN in Patients With Diabetes

What are ADA BP goals for patients with DM based on?

  • STEP: a reduction in CV events with a target of <130 mm Hg.This study included patients 60 to 80 years of age, ~20% of whom had DM.4
  • ADVANCE: enrolled patients with type 2 DM and high CV risk.12 Patients were randomized to perindopril/indapamide or placebo. Mean BP achieved in the treatment group was 136/73 mm Hg, which led to reduction in a composite endpoint of macro- or microvascular events and reduce mortality. This study supports a goal of <140/80 mm Hg, although it was not a “treat-to-target” study.
  • ACCORD (described above).4
  • SPRINT (described above), because the evidence of benefit was strong, despite not including patients with DM.4
  • HOT (described below).4

What are Hypertension Canada BP goals for patients with DM based on?

  • DM subgroup of HOT (a treat-to-target study): there was a 51% relative reduction in CV events in patients assigned to a target DBP ≤80 mm Hg vs ≤90 mm Hg.3
  • SPRINT (described above).3
  • Meta-analyses.3

What are the Diabetes Canada BP goals for patients with DM based on?

  • UKPDS-38: an RCT comparing a goal of <150/85 mm Hg to <180/105 mm Hg.8
  • UKPDS-36: a prospective observational study showing an approximately linear association between SBP reduction and reduction in diabetic complications.9
  • HOT, ADVANCE, ACCORD, and SPRINT (described above).10
    • They maintain that the results of ACCORD and SPRINT, taken together, support lower targets for high-risk patients, DM or not.10
  • ABCD: patients were randomized to a DBP goal of 80 to 89 mm Hg or 10 mm Hg below baseline (intensive treatment).In ABCD, patients in the intensive group reached a BP of 128/75 mm Hg and had a lower incidence of stroke, and slower progression to retinopathy and overt nephropathy.11

What are the Diabetes Canada BP goals for patients with DM based on?

  • SHEP, UKPDS, and Syst-EUR RCTs: showed evidence of benefit of SBP goal <150 mm Hg. There are no RCTs comparing a goal of <150 mm Hg to a goal of <140 mm Hg.ADVANCE (described above) did not meet the panel’s inclusion criteria due to lack of randomization to different BP goals.
  • ACCORD: supports a SBP goal of <140 mm Hg.1
  • Lack of quality RCTs with mortality as an a priori outcome measure that support a DBP goal of <90 mm Hg.1
  • The JNC 8 authors point out that the positive outcome measure in the HOT study used by some to support a DBP goal of <80 mm Hg was a subgroup analysis. In regard to UKPDS, they argue that because a DBP of <85 mm Hg was compared to a DBP goal of <105 mm Hg, the results do not prove that a goal of <80 mm Hg is better than a goal of <90 mm Hg. The JNC 8 authors also feel that having one goal for patients with or without DM will facilitate guideline adherence.1

Treatment of HTN in Patients With Diabetes

What are the Int Soc HTN BP goals for patients with DM based on?

  • The Int Soc HTN follows ADA guidance.16

Why doesn’t intensive BP reduction show clear benefit in patients with DM?

  • Lack of clear benefit may be a result of study limitations. For example, ACCORD (described above) had a low event rate, included patients who had low CV risk, may have been underpowered to detect a benefit, and used hydrochlorothiazide. Only indapamide and chlorthalidone (which was used in SPRINT, described above) have shown benefit in diabetes.13
  • DM affects arteriolar function and blood flow as it relates to BP, such that reducing BP below a point that might be tolerated in a nondiabetic might significantly reduce blood flow to end organs in patients with DM.13
  • DM may potentiate vascular damage such that vascular structure and function may not be amenable to the benefits of a lower SBP.14

Which antihypertensives are recommended for patients with DM?

  • Choose an agent shown to reduce CV events in patients with DM: ACEI or ARB, dihydropyridine CCB, or thiazideb.1,3,6,10,16
    • Hypertension Canada, Diabetes Canada, and Int Soc HTN give preference to chlorthalidone or indapamide due to evidence supporting CV benefit with these longer-acting diuretics.3,10
    • Note that JNC 8, ACC/AHA, and Int Soc HTN do not specify “dihydropyridine,” and ACC/AHA does not specify “thiazide.”1,6,16
    • Int Soc HTN states treatment should include an ACEI or ARB, plus a CCB and/or thiazideb.16
    • Hypertension Canada and Diabetes Canada recommend a dihydropyridine CCB as the preferred add-on to an ACEI or ARB.3,10
  • Some guidelines recommend specific agents for comorbidities in the context of DM.
    • Albuminuria: ACEI or ARB (ACC/AHA, ADA, Diabetes Canada, Hypertension Canada).3,4,6,10
      • Diabetes Canada and Hypertension Canada include kidney disease or microalbuminuria (e.g., persistent albumin to creatinine ratio ≥2 mg/mmol).3,10
      • ACC/AHA specifies ≥300 mg/day, or ≥300 mg/g albumin-to-creatinine ratio or equivalent in first morning void.ACEI preferred.6
      • ADA specifies urine albumin-to-creatinine ratio ≥300 mg/g creatinine (strongly recommended) or 30 to 299 mg/g creatinine (suggested).4
      • Both Black and nonblack patients should get an ACEI or ARB first line for proteinuria.16
    • Fluid overload (chronic kidney failure): loop diuretic (Hypertension Canada).3
  • CV disease or CV risk factors: ACEI or ARB (Diabetes Canada, Hypertension Canada).3,10

Treatment of Resistant HTN

What is resistant hypertension?

  • Resistant HTN can be defined as BP higher than goal despite optimal dosing of three antihypertensives from different classes (preferably a diuretic, and normally a CCB and an ACE inhibitor or ARB),20,21 or BP that is controlled with four antihypertensives.20
  • Hypertension Canada recommends specialist referral for patients not at goal with three agents.21

What are some causes of resistant hypertension?

  • Pseudoresistance due to:
    • nonadherence.20
    • BP measurement error. Ensure an average of two separate readings on two separate occasions, using proper technique, cuff size, patient prep, and environment.20 For details, see our Measuring Blood Pressure Checklist.
    • white coat HTN. Confirm resistant HTN using ambulatory BP monitoring (if available), or home BP monitoring using a cuff.20,21
  • Secondary HTN due to:
    • primary hyperaldosteronism (AHA guidelines recommend screening all patients)20
    • obstructive sleep apnea (very common)22
    • CKD20
    • renal artery stenosis20
    • chromaffin cell tumors (e.g., pheochromocytoma)20
    • coarctation of the aorta (even post-repair)20
    • Cushing’s disease20
    • rare endocrine disorders20

What nondrug interventions can be recommended to address resistant hypertension?

  • Identify nonadherence.20,21 Our toolbox, Medication Adherence Strategies, provides practical tips and resources to improve adherence.
  • Consider discontinuation or dose reduction of drugs or substances that may increase BP. See the chart below (Meds That Can Increase BP) for help.
  • Optimize lifestyle interventions (e.g., healthy diet, exercise, weight loss, sodium restriction [e.g., 2,400 mg/day], increased dietary potassium [if appropriate], sleep hygiene, alcohol restriction, stress reduction).20,21

How do you optimize first-line antihypertensives in the treatment of resistant hypertension?

  • Diuretics:
    • Consider use of indapamide or chlorthalidone (e.g., switch from hydrochlorothiazide).20.21
      • Chlorthalidone and indapamide are longer-acting and have better evidence for affecting CV outcomes than hydrochlorothiazide.20,21,23
      • Chlorthalidone is more effective for BP control than hydrochlorothiazide and is about twice as potent as hydrochlorothiazide.20,23
      • Chlorthalidone is available alone or in combination with azilsartan (Edarbyclor). Azilsartan may be more effective than other ARBs or ACE inhibitors.20
      • Effective to an eGFR 30 mL/min/1.73m2.20
    • Use a loop diuretic for volume overload or if eGFR <30 mL/min/1.73m2.20
  • CCBs:
    • Consider use of long-acting nifedipine over amlodipine for potentially better BP control; however, nifedipine may cause more edema than amlodipine.20
    • For patients on cyclosporine or tacrolimus, consider a dihydropyridine CCB to offset vasoconstrictive effects.20
    • There is little information on the use of diltiazem or verapamil in resistant HTN, but they can be considered for heart rate control (e.g., once-daily diltiazem).20
  • Consider use of once daily antihypertensives (to improve adherence), giving at least one at bedtime, since patients with resistant HTN often have BP that doesn’t “dip” at night like it should.20,24

Does treatment of resistant hypertension lead to better outcomes?

  • Resistant HTN has been associated with a higher risk of CV events, CKD, and death.20
  • Evidence that BP reduction improves CV outcomes in resistant HTN is lacking.21 Therefore, adverse effects are an important consideration when choosing an add-on.21

What add-on antihypertensives (i.e., fourth-line, etc) can be considered for resistant hypertension?

  • Aldosterone antagonist. Spironolactone is very effective for BP reduction, has been studied for BP control in resistant HTN (though often underutilized), and is a first-line add-on.20,21,25 Eplerenone is an alternative if hormonal effects (gynecomastia, erectile dysfunction, irregular menses) are a concern, but it is dosed twice daily.20 Amiloride is another alternative.21
  • Sympathetic blocker. If heart rate is ≥70 beats/minute, consider a BB (e.g., bisoprolol, metoprolol succinate [U.S]), or alpha/beta-blocker (e.g., carvedilol; may be more effective), especially for patients with comorbidities that could benefit from an appropriate BB (e.g., migraine, angina, HF, post-MI).3,20,26If a BB can’t be used, consider:
    • diltiazem or verapamil (once-daily formulation)20 OR
    • alpha-blocker, usuallydoxazosin (consider for patients with benign prostatic hypertrophy). Orthostatic hypotension and dizziness may limit use.21,22,27 OR
    • central alpha-2 agonist
      • clonidine patch (tablets require multiple doses/day, and nonadherence can cause rebound HTN).20 CNS adverse effects (e.g., sedation) and dry mouth may limit use.28 If discontinued, taper to limit rebound HTN.28 OR
      • guanfacine at bedtime.20 CNS adverse effects (e.g., sedation) and dry mouth may limit use.28 If discontinued, taper to limit rebound HTN.28
  • Vasodilator. The next step is hydralazine or minoxidil.20
    • Use with a BB and diuretic to counteract reflex tachycardia and fluid retention.20
    • Requires multiple doses daily.20
    • For patients with HFrEF, use hydralazine plus a nitrate.20 Limit hydralazine dose to 50 mg three times daily to reduce the risk of drug-induced lupus.20,28
    • Minoxidil may not be acceptable to some patients due to hirsutism.20
  • AVOID combining an ACEI plus an ARB; clonidine plus a BB; or diltiazem or verapamil plus a BB due to potentially dangerous drug interactions.29

Note: Although not indicated for HTN, SGLT2 inhibitors (e.g., dapagliflozin) reduce BP and could be added at any time in appropriate patients with DM, CKD, or HF.25

 

 

Meds that Can Increase Blood Pressure

Drug/Drug Class

Pertinent Information

Acetaminophen

  • Mechanism unclear, but acetaminophen may reduce prostaglandins via some COX-2 inhibition.35
  • Short-term studies have shown acetaminophen may raise BP.32-34 For example, scheduled doses (1,000 mg PO four times daily for ~2 weeks) in patients with HTN increased BP ~5 mm Hg vs placebo [Evidence Level B-1].34
  • It is not known if this increase in BP is seen in patients without HTN; when using lower doses, shorter durations, or with as-needed dosing (e.g., treating acute pain in hospitalized patients); if changes in BP persist with long-term acetaminophen use; or if increase in BP translates into increased CV risk.35

Alcohol

  • Potential mechanisms include stimulation of sympathetic nervous system, activation of the RAAS, inducing calcium-mediated vasoconstriction.30
  • Effects on BP appear to be more common with excessive alcohol consumption (e.g., ≥14 to 21 drinks/week).30,45
  • In patients with existing HTN, alcohol may initially lower BP within the first few hours of consumption, but then lead to increased BP 10 to 15 hours later.30

Antidepressants

Bupropion

  • Though product labeling cautions against possible drug-induced HTN with bupropion, data are conflicting.
    • Some studies indicate bupropion may lower BP by about 4 to 6 mm Hg.30
    • BP elevations may be more common when used with nicotine replacement therapy for smoking cessation.28

Monoamine oxidase inhibitors (MAOIs [e.g., phenelzine, tranylcypromine])30,31

  • Though rarely used, it is important to be aware of risk for significant elevations in BP, including hypertensive crisis, with ingestion of tyramine-containing foods (e.g., aged cheese, smoked meats, pickled fish).28,30 Tyramine amounts of 15 mg combined with phenelzine can increase BP by 30 mm Hg.30

Selective serotonin-norepinephrine reuptake inhibitors (SNRIs)

  • Impact on BP may vary among available SNRIs.
    • Biggest effect on BP: venlafaxine.37
      • Dose-dependent. May increase BP by up to DBP by up to 15 mm Hg.28 Risk is higher with immediate-release than extended-release formulations.37
    • Least effect on BP: duloxetine (risk is very low with therapeutic doses)37

Selective serotonin reuptake inhibitors (SSRIs)

  • Unlikely to significantly increase BP.37

Tricyclic antidepressants

  • May increase SBP and DBP by about 8 mm Hg [Evidence Level C].38
  • Increases in BP occur more commonly in patients with an anxiety or panic disorder.39

Caffeine

  • Increases sympathetic activation, catecholamine release, and blocks adenosine (naturally occurring vasodilator).30
  • Caffeine intake of 200 and 300 mg (e.g., about 1 to 2 cups of coffee) may increase BP by about 8 mm Hg (SBP) and 6 mm Hg (DBP).30
  • Effects may be more evident within 2 to 3 hours of periodic use, as tolerance to BP elevations seems to occur with regular caffeine intake (e.g., drinking coffee every day).30

Calcineurin inhibitors

(e.g., cyclosporine, tacrolimus)

  • BP elevations may be more common with cyclosporine than with tacrolimus.30,42
  • Dihydropyridine CCBs (e.g., amlodipine, felodipine) may be preferred to counteract effects on BP.42

Cyclosporine

  • BP elevations are associated with both single doses and chronic therapy.43
  • Dose-dependent
    • Doses of 1 to 4 mg/kg/day may increase BP by about 5 mm Hg.43
    • Doses ≥10 mg/kg/day may increase BP by about 11 mm Hg.43
  • More common in transplant patients than for other indications (e.g., psoriasis, rheumatoid arthritis).28

Tacrolimus

  • Associated with systemic therapy, not with topical use.28

Cocaine

  • In addition to arrhythmias, cocaine use is associated with acute increases in BP of about 8 mm Hg.28,30,39
  • Cocaine’s effects appear to be dose dependent.30
  • Route of administration may affect BP elevations.
    • Injection seems to have a lesser effect on BP compared to intranasal administration.30
  • Management of cocaine-induced HTN can be complex, involving several medications (e.g., benzodiazepines, nitroglycerin, phentolamine).30Avoid BBs.
    • BBs can further increase BP and possibly lead to death, from unopposed alpha-adrenergic stimulation.30

Corticosteroids

  • Effect on BP appears to be dose-dependent.30
  • May be more common in patients not taking any antihypertensives.30
  • May be more likely with short courses, as some studies show no increase with prolonged use (e.g., >1 month).30
  • If additional therapy is needed to counteract corticosteroid-induced HTN, consider a diuretic, or ACEI or ARB.30

Decongestants

Phenylephrine: unlikely to raise BP at recommended doses [Evidence Level C].40

  • BP elevations are more common with intravenous compared to ocular or oral administration.28
  • Poor oral absorption, but acetaminophen (e.g., in many combination cold and flu products) may increase absorption.30

Pseudoephedrine: may raise BP by about 1 to 2 mm Hg [Evidence Level C].41

  • Short-term use of pseudoephedrine in patients with controlled HTN is unlikely to significantly increase BP.30
    • Sustained-release products may be less likely to increase BP compared to immediate-release products.30,41
    • Higher doses may be associated with larger BP increases compared to lower doses.41
  • Nasal saline and/or a topical decongestant (e.g., oxymetazoline) can be used in patients at high-risk or with uncontrolled BP, as they are not associated with BP elevations.28

Dietary supplements

  • Several dietary or herbal supplements have been associated with elevated BPs. Examples include:45-47
    • Blue cohosh (Caulophyllum thalictroides)
    • Bitter orange (Citrus aurantium)
    • Ephedra (ma-huang)
    • Hoodia (Hoodia gordonii)
    • Black licorice (Glycyrrhiza glabra)
  • May increase BP by up to 10 mm Hg.44
  • Discontinuation can be considered based on continued risk versus benefit before adding another med to control BP.44

Erythropoietin

  • HTN occurs in up to 20% to 30% of patients taking erythropoietin.30
  • Can take weeks to a few months for elevations in BP to occur.30
  • BP may return to normal without intervention, despite correction of hemoglobin and hematocrit.30
  • Increasing the dose of existing antihypertensives or adding a diuretic (for patients not already on one) or increasing ultrafiltration in dialysis patients can be considered to counteract erythropoietin-induced HTN.30,44

Estrogen

  • May raise BP by about 8 mm Hg.30
  • Occurs in about 5% of women taking oral contraceptives and resolves within a few weeks after discontinuation.30
  • Certain conditions may increase risk of hormone-induced elevations in BP.28,30,31
    • age >35 years
    • dose (more common with higher doses [e.g., ≥50 mcg of estrogen], still possible with lower doses [e.g., 20 to 35 mcg of estrogen])
    • duration of contraceptive use
    • family history of HTN
    • history of gestational HTN
    • kidney disease
    • smoking
  • Not usually associated with nonhormonal or progesterone-only contraceptives or oral or transdermal estrogen products used for hormone replacement therapy.30
  • If continuing an oral contraceptive is desired and lower-dose products are not feasible or don’t resolve effects on BP, consider using ACEI or ARB to control BP.30
    • Be aware of potential risk to the fetus if women should become pregnant while taking an ACEI or ARB.30

Nonsteroidal anti-inflammatory drugs (NSAIDs)

  • NSAID-induced HTN may be more common in patients with CKD.30
  • Use for ≥1 week can be associated with a BP increase of ~5 mm Hg.30
  • Impact on BP may vary among available NSAIDs.30
    • More likely to cause increase in BP: piroxicam, indomethacin, ibuprofen, and naproxen.30,31
    • Celecoxib risk for BP elevation appears moderate.30
    • Least likely to cause increase in BP: aspirin, sulindac, and diclofenac.30
  • If unable to discontinue the NSAID, try reducing the dose or switching to an NSAID less likely to raise BP.30
  • Acetaminophen or topical therapy can be tried as alternatives to oral NSAID therapy.
  • If additional therapy is needed to counteract NSAID-induced HTN consider the following:30
    • CCBs (e.g., amlodipine, felodipine) may be more effective than other first-line antihypertensives (e.g., ACEI, ARB, BB) when treating NSAID-induced HTN.30,36
    • Diuretics (e.g., chlorthalidone, hydrochlorothiazide) can also be used, but use cautiously to avoid over-diuresis.30

Stimulants, prescription

Attention-deficit-hyperactivity-disorder (ADHD) medications

  • Periodic BP monitoring is recommended with stimulants.30
    • Atomoxetine can increase both DBP and SBP (e.g., up to 15 to 20 mm Hg).28
    • In kids, methylphenidate may increase DBP about 4 mm Hg, without significantly affecting SBP.30
    • In adults, methylphenidate may increase SBP by about 3 to 4 mm Hg and DBP by about 2 mm Hg.30
  • Options to manage stimulant-induced HTN:30
    • Dosage reductions or a drug holiday but be aware this may compromise ADHD symptom control.
    • Centrally acting BP meds can be used to treat BP elevations (e.g., clonidine, guanfacine).
      • Clonidine (Kapvay [US only]) or guanfacine (Intuniv, Intuniv XR [Canada]) may also be beneficial for additional ADHD control.

Weight loss medications

  • Diethylpropion and phentermine (e.g., Adipex-P, Lomaira [US]) are contraindicated in patients with severe or uncontrolled HTN.28
  • Product labeling cautions against use of phentermine in patients with mild or controlled HTN.28

Testosterone

  • Though possible with any testosterone product, risk seems most common with subcutaneous administration of testosterone enanthate (e.g., Xyosted [US only]) or oral administration of testosterone undecanoate (e.g., Jatenzo [US], generic versions of discontinued Andriol [Canada]). In the US, both of these products contain a “Blackbox warning” about the risk for HTN.28
  • May raise BP by about 4 mm Hg.28

Vascular endothelial growth factor inhibitors

(e.g., bevacizumab, sorafenib)

  • HTN has been seen in about 20% of patients and can be severe in about 6% of patients.30
  • An ACEI or dihydropyridine CCB (e.g., amlodipine, felodipine) is a good choice to counteract effects on BP.44

Bevacizumab

  • May take up to 3 months for BP to return to baseline after discontinuation.30

Sorafenib

  • BP rises within 24 hours of administration and may increase by about 11 mm Hg (SBP) and 8 mm Hg (DBP).30
  1. SPRINT criteria: ≥50 years of age and SBP 130 to 180 mm Hg, with CV disease other than stroke, CKD,* 10-year CV risk ≥15%per Framingham, or age ≥75 years. (*Nondiabetic nephropathy, proteinuria <1 g/day, and eGFR 20 to 59 mL/min/1.73 m2 per the MDRD equation. Patients with more advanced CKD, polycystic kidney disease, or glomerulonephritis were excluded from SPRIINT.7
  2. “Thiazide” includes thiazide-like diuretics. Long-acting agents (chlorthalidone, indapamide) are preferred due to positive outcomes data.3,6,16,20,21,23

Abbreviations: ACC = American College of Cardiology; ACEI = angiotensin-converting enzyme inhibitor; ACS = acute coronary syndrome; AHA = American Heart Association; ABPM = ambulatory blood pressure monitoring; ARB = angiotensin receptor blocker; BB = beta-blocker; BP = blood pressure; CAD = coronary artery disease; CCB = calcium channel blocker; CKD = chronic kidney disease; CNS = central nervous system; CV = cardiovascular; DM = diabetes mellitus; eGFR = estimated glomerular filtration rate; DBP = diastolic blood pressure; HBPM= home blood pressure monitoring; HF = heart failure; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; HTN = hypertension; Int Soc HTN = International Society of Hypertension; MI = myocardial infarction; NSAID = nonsteroidal anti-inflammatory drug; JNC 8 = Eighth Joint National Committee; RAAS = renin-angiotensin-aldosterone system; RCT = randomized controlled trial; SBP = systolic blood pressure; SGLT2 = sodium-glucose transporter 2.

Levels of Evidence

In accordance with our goal of providing Evidence-Based information, we are citing the LEVEL OF EVIDENCE for the clinical recommendations we publish.

Level

Definition

Study Quality

A

Good-quality patient-oriented evidence.*

  1. High-quality randomized controlled trial (RCT)
  2. Systematic review (SR)/Meta-analysis of RCTs with consistent findings
  3. All-or-none study

B

Inconsistent or limited-quality patient-oriented evidence.*

  1. Lower-quality RCT
  2. SR/Meta-analysis with low-quality clinical trials or of studies with inconsistent findings
  3. Cohort study
  4. Case control study

C

Consensus; usual practice; expert opinion; disease-oriented evidence (e.g., physiologic or surrogate endpoints); case series for studies of diagnosis, treatment, prevention, or screening.

*Outcomes that matter to patients (e.g., morbidity, mortality, symptom improvement, quality of life).

[Adapted from Ebell MH, Siwek J, Weiss BD, et al. Strength of Recommendation Taxonomy (SORT): a patient-centered approach to grading evidence in the medical literature. Am Fam Physician 2004;69:548-56.  https://www.aafp.org/pubs/afp/issues/2004/0201/p548.html.]

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Cite this document as follows: Clinical Resource, Treatment of Hypertension. Pharmacist’s Letter/Prescriber’s Letter. February 2023. [390127]

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