Making the Most of Antihypertensive Drug Combinations

The number of people who require 2 or more antihypertensives to reach target blood pressure is on the increase. So, simply stated, what goes best with what? The 2013 ASH meeting offered some good suggestions under the heading of “Within Class Differences.”

1.) It has become more and more apparent that chlorthalidone (chlr) is superior to hydrochlorothiazide  (hctz). Let us count the ways.

Has any study provided evidence that 12.5 to 25 mg of hctz decreases cardiovascular risk?

The answer is no. Randomized controlled trials (like MRFIT) have however, demonstrated that chlr has.

With a demographic increasing in prevalence-- that is, chronic kidney disease (CKD), does chlr work at lower GFRs than hctz?

Yes, it does. (Hctz no effect below a GFR of 45 mL/min; chlr is okay down to 30 mL/min.). More than these, chrl has pheiotropic effects, including inhibition of platelet carbonic anhydrase, and sympathetic activity; it also causes decreases in vascular permeability. Hctz does not.

 2.) A new trend is “stacking” diuretics. That means using 2 to 4 diuretics that are complementary (more on this shortly) and function at different levels of the nephron.

Let’s tackle complementary.

When spironolactone is add on therapy, hyperkalemia (K+) is the concern, If spironolactone is added to a diuretic that wastes potassium, things go better. So, chlr or furosemide can be stacked with spironolactone. If a patient has a decreased GFR, furosemide plus metazolone increases K+ and volume loss and represents a good stacking maneuver. 

3.) Beta blockers have been “on trial” as antihypertensives since JNC7, especially atenolol (it can increase central blood pressure and the likelihood of DM). Part of the problem within this class is the marked heterogeneity among the agents (selective beta blockade, added effects like alpha blockade, and others). Subgroup analysis has demonstrated that beta blockade can lower systolic BP in blacks 6 mmHg compared with caucasians whose pressures were lowered 12 mmHg. That effect was noted with older, traditional beta blockers, but not with a beta blocker plus like nevbivolol.

More on the future of beta blockers for BP will follow in a separate installment. 

4.)  Most calcium channel blocker (CCB) prescriptions come from the dihydropyridine class with representative drugs like amlodipine and nicardipine. Edema can be a result of amlodipine treatment, which can lead to discontinuation. Edema may not necessitate discontinuation of the dihydropyridine.

The clinician can switch to isradipine, add an ACEI or ARB which helps, or substitute a non-dihydropyridine. CCBs, like diuretics, can be combined (a dihydropyridine + verapamil, for example). Gingival hyperplasia has been described with this class. Caution should be exercised when using diltiazem or verpamil with a beta blocker.

5.)  All ACEIS appear to be created equally in terms of blood pressure lowering. ARBs and ACEIs have comparable effects and are both relatively safe (less angioedema with ARBs; no increased risk of DM with either; ARBs may be better after MIs). Both classes protect after strokes.

There is no evidence to support combining an ACEI and an ARB.

Nothing was said about aliskiren, the direct renin inhibitor.  
     
I will use a number of facts from this review, especially “stacking” diuretics--possibly combining 2 different classes of CCBs, and starting an ARB in preference to an ACEI when either is indicated.