The Ins and Outs of Combination Therapy

December 31, 2003

Q:Which combinations of antihypertensivemedications are most effective-and which arebest avoided?

Q:Which combinations of antihypertensivemedications are most effective--and which arebest avoided?A:Clinical trials continue to demonstrate the benefitsof aggressive blood pressure (BP) reduction. As aresult, therapeutic BP targets have been lowered for hypertensivepatients with comorbid conditions, such as diabetes,renal disease, and congestive heart failure (CHF).1Increased efforts have been directed toward the achievementof goal BPs in clinical practice in an attempt to reducecardiovascular morbidity and mortality. Yet, despitethe publication of hypertension treatment guidelines andthe growing number of effective antihypertensive agents,overall BP control rates are poor worldwide.In most hypertensive patients, aggressive BP goalscannot be achieved with single-drug therapy. Fifty-fourpercent of patients with isolated systolic hypertensionwho participated in the Systolic Hypertension in theElderly Program (SHEP)2 and 40% of patients in theSystolic Hypertension in Europe (Syst-Eur) trial,.3required more than 1 drug, despite the fact that targetsystolic BPs were considerably higher than the currentgoal of 140 mm Hg. In the Hypertension Optimal Treatment(HOT) trial, 67% of patients required 2 or moreagents to achieve the aggressive diastolic BP goalestablished for this study.4 In patients with diabetes andrenal insufficiency, an average of more than 3 drugsmay be required to achieve the recommended goalof 130/80 mm Hg.ADVANTAGES OFCOMBINATION REGIMENSLong-term clinical studies have compared β-blockerswith diuretics and with newer drugs, including angiotensin-converting enzyme (ACE) inhibitors, calcium antagonists,and angiotensin II receptor blockers. No single drugor drug class has demonstrated clear-cut superiority in reducingcardiovascular morbidity and mortality.5-7 However,the addition of a diuretic to almost any other class of agentprovides further BP reduction.Certain fixed combinations offer specific advantages.For example, in hypertensive patients with renal insufficiencywho are at risk for hyperkalemia, the addition of adiuretic may facilitate control of serum potassium throughconcomitant kaliuresis. The combination of an ACE inhibitorand a dihydropyridine calcium antagonist significantlyreduces the incidence of pedal edema associated with the latter class of drugs. The Table lists the approvedfixed-dose combinations.An additive effect can generally be expected when2 agents from different classes are combined. Moreover,use of combination regimens may lower individual drugdosages, thus reducing the potential for adverse reactionsfrom higher dosages of single agents. Combination therapycan also simplify the regimen, improve compliance,and lower the cost of treatment.COMBINATIONS TO BE WARY OFThe following combinations are to be avoided orused only in certain settings:

  • β-Blocker plus α2-agonist. This combination does notprovide additive antihypertensive effects and may inducea paradoxic increase in BP. The risk of rebound hypertensionfrom an α2-agonist, such as clonidine, may be increasedby concurrent β-blockade.
  • β-Blocker plus ACE inhibitor. Although this combinationis not absolutely contraindicated, the effect may notbe additive because agents from both classes block therenin-angiotensin system. Nevertheless, a patient withcoronary artery disease and CHF derives benefit from anACE inhibitor and may also benefit from the secondarycardioprotective effects of a β-blocker.
  • β- Blocker plus nondihydropyridine calcium antagonist.Drugs from both classes have negative inotropic effects.In patients with impaired cardiac function, the combinationmay result in extreme bradycardia, advancedheart block, or systolic heart failure.
  • α 2-Agonist plus α1-blocker. No additive effect isprovided.
  • Angiotensin II receptor blocker plus α 1-blocker, calciumblocker, or αblocker. Although these combinationsare not absolutely contraindicated, there are no good datathat show additive reductions in BP. However, they areoften used in patients who require a 3- or 4-drug regimento control BP.

References:

REFERENCES:


1.

The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation,and Treatment of High Blood Pressure

. Rockville, Md: National Institutes ofHealth; November 1997. NIH publication 98-4080.

2.

Prevention of stroke by antihypertensive drug treatment in older personswith isolated systolic hypertension. Final results of the Systolic Hypertension inthe Elderly Program (SHEP). SHEP Cooperative Research Group.

JAMA

.1991;265:3255-3264.

3.

Staessen JA, Fagard R, Thijs L, et al. Randomised double-blind comparison ofplacebo and active treatment for older patients with isolated systolic hypertension.The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators.

Lancet

.1997;350:757-764.

4.

Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-pressurelowering and low-dose aspirin in patients with hypertension: principal resultsof the Hypertension Optimal Treatment (HOT) randomised trial.

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5.

Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: theAntihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial(ALLHAT).

JAMA

. 2002;288:2981-2997.

6.

Hansson L, Lindholm LH, Ekbom T, et al. Randomised trial of old and newantihypertensive drugs in elderly patients: cardiovascular mortality and morbidity.The Swedish Trial in Old Patients with Hypertension-2 study.

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.1999;354:1751-1756.

7.

Brown MJ, Palmer CR, Castaigne A, et al. Morbidity and mortality in patientsrandomised to double-blind treatment with a long-acting calcium-channel blockeror diuretic in the International Nifedipine GITS study: intervention as a Goalin Hypertension Treatment (INSIGHT).

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