Resistant Hypertension

Which medications; and which doses?

Dr. Sahar Gamal El-DinNational Heart Institute

© 2008, American Heart Association. All rights reserved.

• Blood pressure remaining above goal in spite of concurrent use of 3 antihypertensive agents of different classes.

• Ideally, 1 of the 3 agents should be a diuretic & all agents should be prescribed at optimal dose amounts.

Resistant Hypertension

Definition Highlights

• Use of diuretic recommended but not required before diagnosing resistant hypertension.

• Doses should be optimal but not necessarily maximal before diagnosing resistant hypertension.

• Controlled resistant hypertension: high blood pressure controlled but with use of 4 of more agents should be considered resistant.

Treatment of Resistant Hypertension

Pharmacologic Recommendations

• Withdrawal or down titration of interfering substances as possible

• Optimize existing drugs • Maximize diuretic therapy.

• Combination therapy.Combination therapy. • Dosing schedule

Interfering Substances•Many exogenous substances

can interfere with BP control by directly raising BP, interfering with the mechanisms of antihypertensive drugs, or both.

• Non-Narcotic Analgesics - Non-steroidal anti-inflammatory agents including aspirin - Selective COX-2 inhibitors

• Sympathomimetic agents- Decongestants- Diet pills- Cocaine

• Stimulants -

Methylphenidate,dexmethylphenidate, - amphetamine, methamphetamine, dextroamphetamine.

• NSAIDs, should be avoided or withdrawn in patients with resistant hypertension. However, as this is often clinically difficult, the lowest effective dose should be used with subsequent down titration whenever possible.

• When initiating treatment with these agents, blood pressure should be monitored closely while recognizing that adjustments to the antihypertensive regimen may become necessary.

• Like other nonnarcotic analgesics, acetaminophen is associated with an increased risk of developing hypertension, although when compared with ibuprofen it was less likely to worsen blood pressure control in treated subjects.

• Therefore, if analgesics are necessary, acetaminophen may be preferable to NSAIDs in subjects with resistant hypertension, recognizing, however, that acetaminophen will provide little if any antiinflammatory benefit.

Hypertension. 2005;46:500–507.

Diuretic therapyDiuretic therapy• A 2008 scientific statement by the

American Heart Association provided treatment recommendations for resistant hypertension.

• A primary recommendation is to maximize diuretic therapy, because fluid retention is a major cause of resistant hypertension.

Maximize diuretic therapy

• This can be accomplished by using :• The preferred thiazide (chlorthalidone).

• Using a loop diuretic in patients with chronic kidney disease (CKD).

• Adding an aldosterone antagonist (spironolactone or eplerenone).

• Hydrochlorothiazide 12.5mg is (often) ineffective dose, but doctors are sometimes unwlling to increase it.

• The most effective thiazide(-like) anytihypertensive drug is chlorthalidone which is dosed at 12.5 or 25mg .

• Daily 12.5mg chlorthalidone is approximately equipotent with 25mg hydrochlorothiazide.

• Chlorthalidone has other advantages over the other drugs though including a much longer ½ life, with the largest difference occurring overnight.

• In contrast to hydrochlorothiazide, chlorthalidone is available in very few fixed-dose combinations and so its use will generally require separate dosing.

• In patients with underlying chronic kidney disease (creatinine clearance 30 mL/min), loop diuretics may be necessary for effective volume and blood pressure control.

• Furosemide is relatively short acting and usually requires at least twice-daily dosing.

• Alternatively, loop diuretics with a longer duration of action, such as torsemide, can be used.

• Diuretics are often inappropriately stopped if a patient develops hypokalemia.

• Potassium supplementation should always be an adjunct to diuretic therapy.

• Potassium itself is a potent vasodilator and, given as a supplement, has been shown to reduce stroke risk in rats.

Adding an aldosterone antagonist

• Spironolactone is a mineralocorticoid receptor antagonist that was shown to lower BP effectively in both general hypertensive patients and patients with primary aldosteronism , as proved by a number of small, uncontrolled trials that showed the positive effect of small doses of spironolactone in lowering BP in patients with resistant arterial hypertension

J Hypertens. 2007;25:891– 894.

Addition of Spironolactone in Patients With Resistant HTN

(ASPIRANT)• A randomized, double-Blind, placebo-

controlled Trial, 117 patients were randomly assigned to receive spironolactone or a placebo as an add-on to their antihypertensive medication, by the method of simple randomization.

• Analyses were done with 111 patients (55 in the spironolactone and 56 in the placebo groups). At 8 weeks, the primary end points, a difference in mean fall of BP on daytime ambulatory BP monitoring (ABPM), between the groups was 5.4 mm Hg for systolic BP (P0.024) and 1.0 mm Hg for diastolic BP (P0.358).

• The APBM nighttime systolic, 24-hour ABPM systolic, and office systolic BP values were significantly decreased by spironolactone (difference of 8.6, 9.8, and 6.5 mm Hg; P0.011, 0.004, and 0.011), whereas the fall of the respective diastolic BP values was not significant (3.0, 1.0, and 2.5 mm Hg; P0.079, 0.405, and 0.079).

• The adverse events in both groups were comparable. In conclusion, spironolactone is an effective drug for lowering systolic BP in patients with resistant arterial hypertension.

Hypertension. 2011;57:1069-1075.

• When using spironolactone, careful attention must be paid to potassium levels, especially in patients who also are taking an ACE inhibitor or ARB.

• Spironolactone can cause gynecomastia in men.

• Eplerenone is an alternative• aldosterone antagonist that does not

cause gynecomastia.

Combination TherapyCombination Therapy

• An abundance of studies demonstrate additive antihypertensive benefit by combining 2 agents of different classes. This is particularly true of thiazide diuretics, which significantly improve blood pressure control when used in combination with most if not all other classes of agents.

Combination Therapy (JNC – VII)Combination Therapy (JNC – VII)

• ACE inhibitors and calcium channel ACE inhibitors and calcium channel blockers (CCBs).blockers (CCBs).

• ACE inhibitors and diureticsACE inhibitors and diuretics• ARBs and diuretics.ARBs and diuretics.• Beta blockers and diuretics.Beta blockers and diuretics.• Centrally acting drug and diuretic.Centrally acting drug and diuretic.• Diuretic and diuretic: e.g. amiloride Diuretic and diuretic: e.g. amiloride

and hydrochlorothiazide.and hydrochlorothiazide.

• Beyond studies of 2-drug combinations, there is little data assessing the efficacy of specific combinations of 3 or more drugs.

• Accordingly, recommendation of specific multidrug combinations is largely empiric .

• Intuitively, it seems most appropriate to continue to combine agents of different mechanisms of action. In that regard, a triple drug regimen of an ACE inhibitor or ARB, calcium channel blocker, and a thiazide diuretic is effective and generally well tolerated.

• This triple regimen can be accomplished with 2 pills with use of various fixed-dose combinations.

• Although α-β-antagonists are indicated in the setting of coronary heart disease or congestive heart failure, combined antagonists, because of their dual combination of action, may be more effective antihypertensives, although head to-head comparisons of maximal doses are lacking.

• Centrally acting agents are effective antihypertensive agents but have a higher incidence of adverse effects and lack outcome data.

• Lastly, potent vasodilators such as hydralazine or minoxidil can be very effective, particularly at higher doses, but adverse effects are common. With minoxidil especially, reflexive increases in heart rate and fluid retention occur such that concomitant use of a β -blocker and a loop diuretic is generally necessary.

• Ultimately, combinations of 3 or more drugs must be tailored on an individual basis taking into consideration prior benefit, history of adverse events, contributing factors, including concomitant disease processes such as CKD or diabetes, and patient financial limitations.

• Treatment recommendations in this setting cannot be overly standardized, particularly when going beyond 3 drugs.

• Recent reports have suggested that the combined use of an ACE inhibitor and ARB or a dihydropyridine and non-dihydropyridine calcium channel blocker provides significant additional antihypertensive benefit compared with monotherapy with the different agents.

• These studies, however, have not generally used maximal doses of either of the combined agents, so it is not possible to know whether the additional blood pressure reduction is really unique to the combination or simply a titration effect. Accordingly, it is premature from a purely blood pressure perspective to recommend the use of same-class combinations over use of agents from different classes.

Some “Wrong” CombinationsBeta blocker + ACE-inhibitorBeta blocker + ARBACE inhibitor + ARB

Some “Right” CombinationsThiazide + ACE inhibitorCalcium channel blocker + ACE inhibitorBeta blocker + alpha blocker

Practical Approach to combination therapy(allow minimum of 2 weeks between dose adjustments)

Thiazide ½ dose (eg chlorthalidone 12.5mg)

Not at target add ACE-inhibitor ½ dose (eg ramipril 2.5mg)

Not at target

Up thiazide to full dose (chlorthalidone 25mg)

Not at targetUp ACE-inhibitor to full dose (ramipril 5mg)

Not at target

Add CCB ½ dose (eg amlodipine 5mg)

Not at targetUp CCB to full dose (eg amlodipine 10mg)

Dosing• A recent cross-sectional analysis of

ambulatory blood pressure control indicated that patients taking at least one of their hypertensive agents at bedtime had better 24-hour mean blood pressure control and, in particular, lower nighttime systolic and diastolic blood pressure values.

• This latter difference may be particularly relevant as recent studies have suggested that nighttime blood pressure levels better predict cardiovascular risk than do daytime valuesHypertension.2005;46:1053–1059.

• It may be that twice-daily dosing of nondiuretic blood pressure medications will improve control rates in patients with resistant hypertension.

• This potential benefit, however, would have to be reconciled with reductions in adherence that would likely occur with use of less convenient and potentially more expensive dosing regimens.

Hypertension. 2005;45:240 –245.

Encourage Adherence to Therapy

• it is important to keep the medication regimen as simple as possible.

• A once-daily regimen improves patients’ adherence to antihypertensive medications.

• Fixed-dose combination pills, also may improve adherence.

Pharmacologic principles

• Suboptimal dosing regimens or inappropriate antihypertensive drug combinations are most common causes of true resistant hypertension.

• As volume expansion is a frequent pathogenic finding in these patients, an appropriate diuretic to decrease volume overload remains a cornerstone of therapy

• Dual renin-angiotensin system blockade is not recommended for patients with true resistant hypertension

• Ultimately, patient characteristics (age, pathogenetic mechanisms involved, and concomitant disease) will determine the best combination of agents needed to achieve the blood pressure goal.

Controlled Resistant Hypertension

• Such patients are at increased risk of reversible and/or secondary causes of hypertension.

• Consider adjustment of the treatment regimen to maintain blood pressure control but with use of fewer medications and/or with use of a regimen that minimizes adverse effects. In this regard, patient preference will be an important consideration.

Experimental drug therapy• Endothelin receptor antagonists are

currently under investigation for the treatment of resistant hypertension.

• The protein endothelin-1 (ET-1) is a potent vasoconstrictor (30–50 times more potent than angiotensin II and norepinephrine) and has a long duration of action.

• ET-1 binds to two receptors with opposing effects:

• ET-A promotes vasoconstriction, and• ET-B promotes vasodilation and clears ET-

1.

• Darusentan, a selective blocker of ET-A,was tested in the phase III DORADO trial, which was discontinued because the initial results did not meet primary outcome measures.

• Initial findings had indicated that it might not be as useful as hoped. Side effects included headache, flushing, and edema.

Cl e v e l a n d c l i n i c j o u r n a l o f m e d i c i n e v o l . 8 0 . f e b r u a ry 2 0 1 3