Steep BP Drop Using 'Quadpill' in Untreated HTN: Pilot Study

Patrice Wendling

February 20, 2017

SYDNEY, AUSTRALIA — A small randomized trial reports sharp blood-pressure reductions in untreated hypertensives using a single pill combining four BP-lowering drugs at one-quarter the usual dose[1].

Among 18 patients, mean 24-hour systolic BP fell 18.7 mm Hg and office BP 22.4/13.1 mm Hg (P<0.0001 for all three) after 4 weeks of treatment with irbesartan 37.5 mg, amlodipine 1.25 mg, hydrochlorothiazide 6.25 mg, and atenolol 12.5 mg.

All 18 patients achieved an office BP <140/90 mm Hg, compared with six of the 18 patients while on crossover placebo treatment after a 2-week washout period (risk ratio [RR] 3.01, 95% CI 1.54-5.89; P=0.0013).

"The message should be that this is exciting that we can get such blood-pressure control with four quarters of these tablets, but this is a small trial despite being backed by a systematic review and needs to be looked at in larger studies," lead author Dr Clara K Chow (University of Sydney, Australia) told heartwire from Medscape.

Dr George Bakris (University of Chicago, IL) told heartwire what's novel about the pilot study is the finding of blood-pressure reduction "when none of the individual components by themselves pass muster for lowering blood pressure."

He added, "Not surprisingly, the side-effect profile is minimal, if at all, and it's a single pill, and all of the drugs used are generic. So there are potential positives to this, but it's not ready for prime time."

Not the Same Old Polypill

Chow said their quadpill is different from polypills of the past that combined BP-lowering drugs with statins or blood thinners and that the data bear out their theory of an additive effect when combining four quarter-dose BP-lowering meds: a diuretic, angiotensin-receptor blocker, calcium-channel inhibitor, and beta-blocker.

They conducted a systematic review of 36 quarter-dose trials, in which quarter-dose BP-lowering drugs reduced systolic BP by 4.7 mm Hg and diastolic BP by 2.4 mm Hg, with no increase in adverse events over placebo (RR 1.0; 95% CI 0.88-1.10).

The results, reported in the same paper, "are consistent with our finding of a large benefit with minimum side effects," the investigators write.

Bakris observed that the combination of drugs used in the quadpill "makes beautiful pharmacologic sense" and that "they do have complementary mechanisms.

"So I'm not shocked that you got blood-pressure reduction, but I am shocked at the magnitude of that blood-pressure reduction and with all due respect, I would challenge that."

Devil in the Details

In an invited commentary[2], Dr Alan H Gradman (Temple University School of Medicine, Philadelphia, PA) writes, "There are many limitations to this new study."

He notes that the sample size is small and "represents only a tiny fraction of patients with hypertension worldwide."

The study also lacked an active comparator, despite the availability of two- and three-drug combinations that deliver similar BP reductions when used as initial treatment.

Similar protests were lodged on Twitter, with one tweet chiding that the study's 24 investigators outnumber the 18 patients.

Where Chow, Bakris, and Gradman do agree is on the need for further study on the quadpill concept and for an antihypertensive therapy that will improve adherence, which has been shown in three studies now to be just 45%.

"A lot of people just end up stuck on monotherapy, and we know clearly that with more drugs, the more likely they are to be nonadherent," Chow said. "So if there's just one drug that fixes their problem it would be much easier; and the other advantage here is the lack of need for uptitration."

Dr Steven Chrysant (University of Oklahoma, Oklahoma City) told heartwire in an email, however, that "the problem with a polypill is the loss of flexibility, and according to my previous research on the subject, doctors are hesitant to adopt a polypill for the treatment of their patients."

He added, "Different polypills have been approved by several countries outside the US, but their use is very limited for these reasons."

In the coming weeks, the investigator plan to launch the QUARTET study comparing a quarter-dose quadpill at 12 weeks and 12 months with standard-dose irbesartan in patients with grade 1 and 2 hypertension. Chow said two changes will be made to the pill, swapping out atenolol for bisoprolol and hydrochlorothiazide for indapamide.

She added, "Blood-pressure control is a problem globally and if we can do something with our existing drugs by using them in a different way, we should look at it."

The study was funded by Australia's National Heart Foundation (NHF), the University of Sydney, and the National Health and Medical Research Council (NHMRC) of Australia. Chow is supported by an NHMRC career development fellowship and cofunded by an NHF future leader fellowship and the Sydney Medical Foundation. Disclosures for the coauthors are listed in the paper. Gradman reports unrelated consultancy fees from Allergan and Servier; investigator fees from Allergan; and speaking fees from Glenmark, Pfizer, and Servier. Bakris reports serving on the steering committee for trials sponsored by Janssen Pharmaceuticals and Bayer and consulting for Relypsa.

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