QUADRO: Four-Drug Combo in Resistant Hypertension
Another scenario in which single-pill antihypertensive combinations could be particularly useful is at the other end of the spectrum: The treatment of patients with resistant hypertension.
The QUADRO study showed that a single pill containing perindopril, indapamide, amlodipine, and bisoprolol is better at lowering blood pressure than the triple combination of perindopril, indapamide, and amlodipine.
The primary endpoint — office sitting systolic blood pressure at 16 weeks — was 8 mm Hg lower with the quadruple combination than with the triple combination. And mean ambulatory 24-hour systolic blood pressure was 7.5 mm Hg lower with the four-drug combination.
This was the first study of a single-pill quadruple combination in patients with resistant hypertension, which is a “difficult-to-treat condition demanding a high number of pills with not enough safe and practical options,” said Stefano Taddei, MD, from the University of Pisa, Italy, when he presented the study at the ESC meeting.
Using “four well-established drugs in a single-combination pill may improve adherence and should be an innovative solution for resistant and difficult-to-treat hypertensive patients,” he said.
Nonadherence is a big problem in patients with resistant hypertension. “It is really difficult to get patients to take three or four antihypertensive agents along with all the other medications they have for other comorbidities,” Dr. Taub pointed out. “We really need to think about combination formulations that reduce the pill burden for our patients.”
Around 10% patients with hypertension may require a fourth drug, so a four-drug single-pill combination therefore makes good sense, said Dr. Poulter.
But the choice of the fourth drug is the subject of debate. The PATHWAY trial showed spironolactone to be the most effective fourth agent, but it can cause side effects, such as gynecomastia and hyperkalemia.
“The beta-blocker in the four-drug combination product used in the QUADRO study may not be as effective as spironolactone at lowering blood pressure,” Dr. Poulter explained, noting that beta-blockers have known side effects. However, “they are often already recommended for patients with very common comorbidities, such as arrhythmias, history of MI, heart failure, angina. In that regard, it makes sense to have a beta-blocker in there.”
The four-drug combination used in the QUADRO study led to a bigger reduction — by 8 mm Hg — than the three-drug combination. “That’s pretty good. I thought this was a very useful and interesting study,” he said.
There could be a role for a four-drug combination product in resistant hypertension. “Whatever we can do to improve adherence and reduce blood pressure is good thing,” said Dr. Yang.
However, a mineralocorticoid receptor antagonist (such as spironolactone) might be better as the fourth drug; that is what is recommended in the resistant hypertension algorithm.
Lower Blood Pressure, Better Outcomes
“What we are seeing in these trials is that across a wide spectrum of patients with hypertension or resistant hypertension, combination pills are superior to standard practice for BP lowering, and that will lead to improved outcomes,” said Dr. Taub.
“For years, such single-pill combinations have been viewed as ‘bad medicine’ in hypertension,” Dr. Poulter added. “That is clearly not the case, as these studies are showing. And single-pill combination therapies are used extensively in practically every other area of medicine. We are starting to accept them now in the blood pressure community, and I think the use of triple and quadruple combinations, as in these studies, has a real logic to it. But for this approach to be useful, these single-pill combinations must be made available, cheaply, across the world, especially in low- and middle-income countries where hypertension rates are a particular problem.”
A version of this article appeared on Medscape.com.