Treatment-resistant hypertension requires a multi-drug treatment strategy

For many patients, successful antihypertensive therapy requires a combination of drugs from different classes working by complementary mechanisms to reduce blood pressure (BP).1,2

The agents most commonly used fall into 4 classes:

  • Renin-angiotensin-aldosterone system (RAAS)-targeted agents
    • Includes angiotensin-converting enzyme inhibitors (ACEIs), antgiotensin-receptor blockers (ARBs), direct renin inhibitors, β-blockers, and diuretics
    • Target various components of the RAAS, which controls sodium and blood-volume homeostasis
  • Calcium channel blockers (CCBs)
    • Dilate the arteries and reduce peripheral resistance
  • α-blockers
    • Lower postsynaptic vasoconstrictor effects of norepinephreine
  • Centrally-acting agents
    • Act on the hypothalamus and reduce sympathetic outflow3

Figure 1 depicts preferred combinations of antihypertensive agents. Solid lines indicate preferred combinations. Note that α-blockers have not been proven beneficial in controlled trials.2 The combination of an ACEI and an ARB may cause increased side effects without added benefit and therefore is not recommended.


POP - star-chart

*Not proven beneficial in controlled trials.
Reproduced with permission from Mancia G, et al. Eur Heart J. 2007;28:1462-1536.

Optimizing combination therapy

An effective treatment regimen should target multiple mechanisms responsible for BP control, including:4

  • Volume overload (diuretics and aldosterone antagonists)
  • Sympathetic overactivity (β-blockers and centrally acting agents)
  • Vascular resistance, which can be targeted via
    • Inhibition of the RAAS (ACE inhibitors or ARBs)
    • Promotion of smooth-muscle relaxation (CCBs or α-blockers)

While 3-drug combinations have not been extensively studied, the combination of an ACE inhibitor or ARB, a CCB, and a thiazide-like diuretic is effective and well-tolerated5

If BP control is not achieved, dosages should be titrated to the maximum tolerated or in-label dose4,5

Optimization of diuretic regimen

Diuretics are a cornerstone of therapy for treatment-resistant hypertension. Optimizing diuretic therapy will help many patients achieve BP control.

Optimization strategies:

  • Adding a drug
  • Increasing a dosage
  • Changing diuretic class

When managing diuretic therapy, treatment should be chosen based on kidney function.6

Aldosterone antagonists

The aldosterone antagonist spironolactone is a mineralocorticoid receptor antagonist. It provides significant additional antihypertensive benefits in patients with treatment-resistant hypertension when added to a multidrug treatment regimen.7,8

  • In the ASCOT study, addition of spironolactone to a multidrug antihypertensive regimen at a median dose of 25 mg reduced BP by an average of 21.9/9.5 mm Hg7
  • In the ASPIRANT study, in patients with treatment-resistant hypertension despite treatment with 3 classes of antihypertensive drugs including a diuretic, the addition of 25 mg spironolactone once-daily resulted in an average decrease of 9.3/4.2 mm Hg at 8 weeks vs placebo, which resulted in an average decrease of 3.9/3.2 mm Hg8

Common side effects were gynecomastia in 5%-6% of males, and hyperkalemia in 2%-4% of patients.7

Eplerenone, another mineralocorticoid receptor antagonist, blocks aldosterone with high selectivity. It is, therefore, associated with a favorable tolerability profile, with low rates of gynecomastia, impotence, and menstrual-cycle abnormalities. In a prospective, open-label trial of eplerenone, patients with treatment-resistant hypertension underwent 12 weeks of eplerenone therapy (50 mg to 100 mg daily, titrated to effect), added to their current antihypertensive regimen. At the end of the 12 week period9:

  • Change from baseline in clinic BP was a reduction of 17.6/7.9 mm Hg (P <0.0001 for both systolic and diastolic BP)
  • The mean number of antihypertensive agents decreased from 3.7 ± 0.8 to 3.3 ± 0.9

Eplerenone therefore represents an additional option for aldosterone blockade in the management of treatment-resistant hypertension.

A CCB may not be suitable for some patients—for example, those with edema or known CCB intolerance. If a CCB is not suitable, or if there is evidence of or high risk of heart failure, a thiazide-like diuretic should be offered.


  1. Chobanian AV, Bakris GL, Black HR, et al. Hypertension. 2003;42:1206-1252.
  2. Mancia G, De BG, Dominiczak A, et al. Eur Heart J. 2007;28:1462-1536.
  3. Hypertension Primer: The Essentials of High Blood Pressure. 4th ed. Philadelphia, Pa.: Lippincott Williams & Wilkins; 2008.
  4. Moser M, Setaro J. N Eng J Med. 2006;355:385-392.
  5. Calhoun D, Jones D, Textor S, et al. Circulation. 2008;117:e510-e526.
  6. Sarafidis PA, Bakris GL. J Am Coll Cardiol. 2008;52:1749-1757.
  7. Chapman N, Dobson J, Wilson S, et al. Hypertension. 2007;49:839-845.
  8. Václavík J, Sedlák R, Plachý M, et al. Hypertension. 2011;57:1069-1075.
  9. Calhoun DA, White WB. J Am Soc Hypertens. 2008;2:462-468.

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