Why use one drug when four will do just fine? Safety and efficacy of quarter-dose antihypertensive therapy.

You know I’ve been busy when my login to the site timed out. It’s been so long since that happened that I actually  had to look up my password. But! I moved to New York, I turned 30, and IM HEAT is back and ready to bring you some scalding hot trials. Let’s start with HYPERTENSION WEEK. It’s bold so you know it’s cool. When’s the last time something uncool was bolded? Never, that’s when.

Today, we’re going to catch up on some research that has flown under my personal radar. When it comes to treating blood pressure, treatment guidelines are almost all expert opinion. Most of us follow the recommendations of the Eighth Joint National Comittee (JNC-8) when it comes to selecting our treatments, but that document is pretty upfront that most of their guidelines don’t have much evidence to back them up. In the absence of a clearly superior strategy, I and most of the physicians I know tend to pick one of the recommended agents for initial therapy and titrate to maximum dose before adding a second drug. However, there’s been a growing body of research over the last few years regarding the use of multiple drugs at lower doses rather than immediately maximizing the first agent. Multiple trials, and here I am all in the dark about it! So it was quite kind of Alexander Bennett and colleagues to collate the existing data for me in a metanalysis. Let’s see what there is to see.

If You’re Only Going to Read One Paragraph

In a systematic review and metanalysis, authors found that therapy with “quarter-dose” antihypertensive medications consistently produced blood pressure reduction better than placebo. Compared to standard monotherapy, relative BP was +3.7/+2.6 (P<0.001) on quarter-dose monotherapy, +1.3/−0.3 (NS) on quarter-dose dual therapy, and −13.1/−7.9 (P<0.001) when four drugs were used at quarter-doses. Rates of adverse effects with quarter-dose meds were similar to placebo, and significantly better than standard monotherapy. These comparisons are limited by the fact that only one quadruple quarter-dose vs monotherapy study was included (which had only 18 patients), by the lack of patient-level data for review, and by short on-treatment periods (4-12 weeks, with a median of 7 weeks of therapy). Using multiple agents at low doses as the preferred therapy may offer similar results and a better adverse effect profile than fewer agents at higher doses —while concerns remain about adherence given higher pill burden, these findings merit further investigation, especially of quadruple quarter-dose therapy.

A Bit of Context

We are doing a bad job of controlling hypertension. As the authors point out, while 88% of patients with a diagnosis of hypertension are on some kind of therapy, only 34% of those on therapy have actually achieved recommended BP targets. This is not necessarily because everyone has terrible resistant hypertension, but rather because most of them are on monotherapy, even though combination therapy is required to get most patients to goal.

The law of the land when it comes to the treatment of hypertension is JNC-8. Compared to the sweeping prose of it’s beautifully written predecessor, JNC-7 (seriously, read it some time, I’m a fan), JNC-8 is a choppy list of 9 recommendations regarding the management of hypertension. Of these 9 recommendations, 6 of them are grade E, expert opinion. This is to say, if it seems like every physician has his own approach to antihypertensive pharmacotherapy, that’s because the only thing that the guidelines feel strongly about is that patients with CKD should get an ACE or ARB (grade B). OK, and that 150 is just too high for anyone’s blood pressure to be (grade A). But beyond its lack of comprehensive guidance, at this point, JNC-8 is three years old. That doesn’t sound like all that long, but consider what isn’t included in that trial — the SPRINT trial, PATHWAY-2 (spironolactone as the 4th line agent for resistant hypertension), and too many others to name.

When it comes to the strategy of drug titration, JNC-8 is explicitly vague, noting that no data exists regarding the efficacy of strategies with regard to cardiovascular endpoints and declaring that either titration of one drug or the early addition of a second are both reasonable ways to get patient to target.

So, there is certainly room for new and different investigations into the treatment of hypertension. Low-dose combination therapy has been under investigation for a while. A 2003 BMJ metanalysis of blood pressure trials paved the way for such investigation — in their analysis of 354 double-blind RCTs of various classes of antihypertensives, they note that halving the standard dose does not halve its efficacy, but rather only dropped the total BP reduction by around 20%. It did, however, roughly halve the rate of dose-dependent adverse effects. Conversely, adding a second drug at low-dose did have an additive effect, while the increase in adverse events was less than additive when doing so. Note that I wrote the word “dose” right next to the word “does” a few sentences ago — rest assured I have done that only in an effort to give all of you an aneurysm, especially my copy editor.

So, reasonable to assume that a few meds at lower dose might be a better option than one med at a higher dose. To change this “might” to “is,” numerous studies performed dedicated comparisons of low-dose therapy to placebo, and more specifically combination therapy at low dose to monotherapy at standard dose. However, since that first metanalysis, nobody has taken the time to gather and analyze the dedicated trials of low-dose therapy in aggregate. That’s where Bennett and company pick up.

So What Did They Do?

The authors searched for English-language RCTs of low-dose antihypertensive therapy versus either placebo or standard monotherapy. As you might imagine, this resulted in a wide variety of comparisons — included trials range from single-arm low vs standard dose comparisons to a 4×3 factorial dose-response trial (i.e. 12 separate patient groups). The paper goes into a fair amount of detail about how the authors picked apart these studies and selected their groups for inclusion, but it all makes fairly intuitive sense. The only caveat is that, given multiple analyses of quarter-dose versus standard dose and quarter-dose versus placebo, some patients were included in multiple analyses. This does not present a problem on its face, given that the results of one analysis are not reliant on the results of the other.

So what is a quarter dose? Authors searched various “pharamacoeias” (fancy word for reference books) and chose the most often reported dose, with the WHO standard dose used to break a tie. This results in fairly intuitive “standard” doses, which importantly do not sound like “max” doses — 5mg of amlodipine, 20 mg of lisinopril, or 25mg of hydrochlorothiazide, to pick out the usual suspects. As the name implies, a “quarter dose” is 1/4 of this standard dose. If you’re wondering where the investigators got 1.25mg of amlodipine, great question! But seriously, those are the doses in question. HCTZ was studied at both 5mg and 6mg doses. Certainly we don’t usually have access to those doses in clinical practice, but it’s not unreasonable to extend the general idea of “more meds and lower doses” to the lowest commercially available dose.

Authors lumped together data about various classes of antihypertensives, including ACE-Is, ARBs, thiazides, beta blockers, and calcium channel blockers, but in breaking the individual classes out the significant associations (though not their magnitudes) were preserved.

The last important thing to mention is that study-level rather than patient-level data I’ve enticed you with my enthralling discourse on the merits of patient-level data before, so I won’t belabor the point except to invite you to review that article about NSAIDs and MIs if you’re of a mind.

And What Did They Find?

42 studies met the authors’ criteria for inclusion, which yielded 20,284 participants. Patients had a mean age of 54 years, were 61% male, and had mean baseline blood pressure of 154/101 mmHg.

I’ll bottom line the results: some blood pressure medication is better than none, as every quarter dose med beat placebo except for calcium channel blockers (which had a trend towards superiority in 5 trials with 364 patients, so grain of salt). More is better: whereas monotherapy in the aggregate resulted in a BP change of −4.7/−2.4 mmHg, dual therapy moved the needle by −6.7/ −4.4 mmHg, and the single quadruple quarter-dose study observed a blood pressure reduction of −22.4/−13.1 mmHg versus placebo (P<0.001).

And compared to monotherapy, what I’ve been doing to date? Compared to standard-dose monotherapy, relative BP was +3.7/+2.6 (P<0.001) on quarter-dose monotherapy, +1.3/−0.3 (NS) on quarter-dose dual therapy, and −13.1/−7.9 (P<0.001) when four drugs were used at quarter-doses (ARB, CCB, thiazide, and beta blocker, because I know you were curious).

The last piece of the puzzle is adverse events. There was no significant difference between quarter-dose meds as either monotherapy or dual-therapy and placebo, and both of these regimens had significantly fewer events than standard-dose monotherapy. Quadruple quarter-dose, or “quad-quarter” therapy (my term, not theirs, but © Bill Fuller 2017 just in case it catches on) had no meaningful data for comparison of adverse events.

So, we have comparable efficacy with overall lower rates of adverse events. Not a bad place to be! The accompanying editorial is sunny on the whole about the prospects suggested here. They note, for example, that the BP reduction of four quarter-dose meds is similar to that seen in SPRINT, with its much-lauded reduction in cardiovascular events. In the same breath, they note the study’s chief limitation — its headline finding, that quad-quarter therapy gives a great blood pressure reduction with adverse effects better than standard dose monotherapy, is based on one trial. With 18 patients. Other limitations include the lack of patient-level data and the fact that the studies included only covered 4-12 weeks of treatment. Given that duration of antihypertensive therapy tends to be necessary for years rather than weeks, we would certainly like to base any practice-changing recommendations on a longer follow-up period.

One more thing that nobody is keen to talk about — adherence. Patients in clinical trials are well-known to adhere to medications better than patients in the wild. Adding more medications might worsen this disparity, resulting in more nonadherence than might titrating up a single medication. Then again, perhaps a lower rate of adverse effects might actually produce the opposite effect, resulting in less patient discontinuation. A good question for future studies to answer. And you can be certain that they will try to do so — the quad-quarter dosing, for example, was a pilot study of Quadpill, a formulation custom-built for the purpose (and thus likely patentable).

So how does this change my practice? Well, my current strategy for hypertension tends to be to maximize the dose of one medication before adding a second. I’m all about decreasing pill burden, because many of my patients have trouble with compliance already and I don’t need to make that problem worse. However, the reduction in adverse effects seems to be real, and makes intuitive sense. Given the ready availability of combo pills for blood pressure control, some of which are generic and available at low cost, I’m strongly considering starting patients on low-dose combo pills rather than a single agent at anything other than the lowest dose. The data isn’t there for this strategy yet, but if I can get additive efficacy with non-additive adverse effects, it seems like something I should probably do! Besides, the hardest part of titrating patients to goal is always adding the second drug when you hit the therapeutic ceiling for the first (dose titrations are one thing, but my patients tend to push back if I try to add another med). Being on a combo pill increases your odds of being controlled without having to add a second pill.

What do you guys think? This is more of a suggestive than a conclusive piece in my opinion, so I’d love to get some comments on this. If you’re one of the lovely people prone to e-mailing me comments, drop them down in the box instead and maybe we can get some conversation going. Think of it as a warm-up for our next discussion: the SPRINT trial. I’m sure you’ll alllllll have something to say about that.

Read the original study here.

Coming Up on IM HEAT

On Thursday we are going to have a post heavily inspired by Dr. Joshua Uy of Penn geriatrics going over everyone’s favorite (read: most vexing) blood pressure reduction trial, SPRINT. When the New York Times editorial predates the NEJM paper, you know you’re in for a good time.

Follow along!

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