The Growing Need for Combination Rx in Hypertension

The era of controlling blood pressure with monotherapy (ie, with only a single antihypertensive) may well be a thing of the past. A recent American Society of Hypertension position paper on combination therapy in hypertension summarized the following pertinent observations in this regard.¹

 A meta-analysis of 354 randomized, double blind trials demonstrated that monotherapy provided an average 9.1 and 5.5 mm/hg reduction in systolic and diastolic pressures, respectively.² For those many contemporary patients who present with pressures at or above 180/105 mm/hg, this simply won’t cut it. In the Hypertension Trial “biggies”¹ (ALLHAT, HOT, and LIFE), monotherapy achieved goal BP in only 26% of enrollees in ALLHAT and in 33% of enrollees in HOT. Of those studied in LIFE, 90% required at least 2 agents to reach target BP.

So what antihypertensives go well with others when we prescribe combinations?
  
Gradman and colleagues¹ chose potential 2-drug combinations that have been proven to reduce cardiovascular end points. Let’s select some of their recommendations for further commentary.

1. A renin-angiotensin-aldosterone system inhibitor (RAAS-I) and a calcium channel blocker (CCB): This combination (for example, lisinopril, an ACEI, with amlodipine) provides a fully additive blood pressure reduction.

The ACCOMPLISH Trial³ compared an ACEI plus a diuretic with the same ACEI (benazepril) plus a CCB. Despite comparable blood pressure reductions in both treatment limbs, the combined end points of cardiovascular death, heart attack, or stroke were reduced 20% more by the ACEI plus CCB. ARB and CCB combinations are considered equivalent. 

2. In contrast, a CCB plus a diuretic only provides partially additive effects. As a result, this specific combination is classified as only “acceptable.”

3. Likewise, although beta-blockers reduce cardiovascular end points, they are less effective than diuretics, ACEIs, ARBS, and CCBs in doing so. Beta-blockers and a diuretic are an acceptable combination, accompanied by heavy caveats. Glucose intolerance, frank diabetes, fatigue, and sexual dysfunction may accompany this combination.

4. Combining a RAAS-I and a beta-blocker produces little synergistic antihypertensive effects. This is a “less effective” combination.

5. In a previous article, I discussed - - and dismissed -- the combination of an ACEI and ARB for blood pressure control.⁴ Additional reductions in blood pressure were minimal and the risk of hyperkalemia was added. 
  
The Gradman article discusses more efficacious and inefficacious combinations.¹ Since target blood pressures are necessitating multiple drugs, this position paper is a great place to start reading.  

References:
1. Gradman AH, Basile J, Carter BL, Bakris GL, (on behalf of the American Society of Hypertension Writing Group). Combination Therapy in Hypertension. J Clin Hypertension. 2011;13:146-154.
2. Law MR., Wald NJ, Norris JK, et al. Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomized trials. BMJ. 2003; 326:1427-1435.
3. Jamerson K, Weber MA, Bakris GL, et al for the ACCOMPLISH Trial Investigators. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med.2008;359:2417-2428. 
4. Rutecki GW. What’s new in hypertension? A contemporary primer. http://www.consultantlive.com/hypertension/content/article/10162/1904168 Accessed July 28, 2011.