A “quadpill” containing quarter doses of four blood stress (BP)-reducing medications used to be extra efficient than monotherapy for initial therapy of hypertension, with same tolerability, in the 1-year, piece 3 QUARTET randomized, active-like watch over trial.
Clara Chow, MD, PhD, academic director of the Westmead Utilized Study Centre, College of Sydney, Australia, equipped the findings in a gradual-breaking trial session on the European Society of Cardiology (ESC) Congress 2021. The gaze used to be simultaneously published in The Lancet.
The distinguished , imply unattended place of job BP at 12 weeks, dropped from 142/86 mm Hg to 120/71 mm Hg in sufferers who got the day after day quadpill — a pill containing irbesartan, amlodipine, indapamide, and bisoprolol — and fell from 140/83 mm Hg to 127/79 mmHg in sufferers who got a day after day full dose of irbesartan.
This 6.9 mm Hg bigger tumble in systolic BP at 12 months is clinically meaningful, Chow advised theheart.org | Medscape Cardiology. “If maintained, it would be expected to confer about a 15% to 20% reduction” in coronary heart disease, stroke, and coronary heart failure.
In the SPRINT gaze, she popular, the final phrase systolic BP used to be 120 mm Hg in the intervention staff and 134 mm Hg in the like watch over staff, and the difference used to be associated to a 27% reduction in the composite cardiovascular (CV) .
The outcomes of QUARTET suggest that “even in these with stage 1 hypertension, we can safely minimize BP to a critical diploma by this straightforward approach, when put next to frequent care,” Salim Yusuf, MD, DPhil, a long-time advocate of a polypill approach, advised theheart.org | Medscape Cardiology in an email.
Importantly, Chow identified, at 12 months, 81% of sufferers handled with the quadpill versus 62% of sufferers handled with monotherapy had BP like watch over (< 140/90 mm Hg). Patients who received monotherapy did not "catch up," even though a higher percentage received stepped-up therapy.
The quadpill dosing strategy aligns with the latest 2018 ESC/European Society of Hypertension guidelines, which recommend starting antihypertensive treatment with more than one drug, session co-chair Thomas Kahan, MD, PhD, Karolinska Institute, Danderyd Hospital, Department of Clinical Sciences, Stockholm, Sweden, commented.
“How many drugs should be in the initial step?” he asked. “Is four better than three or two, or should we have even more drugs at low doses?”
The trial was not designed to answer these questions, Chow replied. “We were really comparing [the quadpill] against what the majority of people around the planet are still doing, which is starting on one drug and slowly but surely stepping it up,” she said.
The quadpill was actually a capsule, she clarified, that contained four generic BP medications available in half doses in Australia. The half doses were cut in half and the medications were encapsulated. The control drug was prepared in an identical-looking capsule.
It is important to note that “the time to BP control was shorter in patients who received the quadpill versus monotherapy,” session co-chair Felix Mahfoud, MD, Internal Medicine and Cardiology, Saarland University Hospital, Hamburg, Germany, pointed out, because “in clinical practice we aim to get patients to BP control as quickly as possible.”
“What is new here is the use of four drugs, each given at quarter doses,” Yusuf, director of the Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada, said. Although a few questions remain, “this study emphasizes the importance and potential benefits and simplicity of using combination BP-lowering drugs at low doses.”
For guidelines to be changed, he observed, the findings would have to be replicated in independent studies, and the quadpill would likely have to be shown to be superior to the dual pill.
“It took about 20 years [to change guidelines] after the first evidence that combinations of two pills were preferable to single drug combinations,” he noted.
“I hope that in most people with elevated BP, at least a two-drug combination plus a statin plus aspirin will be prescribed,” Yusuf said. “This can reduce the risk of CVD events by 50% or more — a big impact both for the individual and for populations. The quad pill may have a role in this approach.”
Worldwide, hypertension control is poor, Chow said, due to the need for multiple medications, treatment inertia, and concerns about adverse events.
The researchers hypothesized that initial antihypertensive treatment with a four-in-one pill with quarter doses of each medication would minimize side effects, maximize BP lowering, and overcome these treatment barriers and concerns. A pilot study of this strategy published by the group in 2017 showed promise.
QUARTET randomized 591 adults with hypertension, seen at clinics in four states in Australia, from June 2017 through August 2020.
Patients were either receiving no antihypertensive medication and had an unattended standard office BP of 140/90 to 179/109 mm Hg or daytime ambulatory BP > 135/95 mm Hg, or they had been on BP-reducing monotherapy and had a BP of 130/85 to 179/109 mm Hg or daylight hours ambulatory BP > 125/80 mm Hg. Sufferers who had been taking antihypertensive therapy entered a washout length earlier than the trial.
The researchers randomized 291 participants to win 150 mg irbesartan day after day (frequent care or like watch over staff).
The opposite 300 participants got a day after day quadpill containing 37.5 mg irbesartan, 1.25 mg amlodipine, 0.625 mg indapamide, and 2.5 mg bisoprolol. The distinguished three pills are essentially the most in most cases prescribed angiotensin II receptor blocker, calcium channel blocker, and thiazide or thiazide-admire diuretic in Australia, and the last drug, a beta-blocker, has a long length of action, the gaze protocol explains.
Sufferers in both groups had same baseline characteristics. They had been a median age of 58 years, 40% had been ladies folk, and 82% had been White. In addition they had a median body mass index of 31 kg/m2. About 8% had been recent smokers, and about 54% weren’t taking a BP-reducing drug.
Contributors had health center visits at baseline, 6 weeks, and 12 weeks, and if they continued the gaze, at 26 weeks and 52 weeks.
If a affected person’s blood stress used to be > 140/90 mg, clinicians may well well well add one other medication, starting with amlodipine 5 mg.
At 12 weeks, 15% of sufferers in the intervention staff and 40% in the like watch over staff had stepped up therapy.
Despite bigger up-titration in the same outdated care staff, BP like watch over remained bigger in the quadpill staff, Chow identified. That is, sufferers in the quadpill staff had been extra likely than sufferers in the same outdated care staff to love a BP < 140/90 mm Hg (76% vs 58% respectively; P < .0001).
Sufferers in the quadpill staff also had decrease daylight hours and middle of the evening ambulatory systolic BP.
At 12 months, amongst the 417 sufferers who continued therapy, sufferers in the quadpill staff had a 7.7 mm Hg bigger tumble in systolic BP when put next with sufferers in the like watch over staff, (P < .001).
There had been no critical variations in unfavorable events, which had been most in most cases dizziness (31% and 25%) or muscle cramps, gastrointestinal complaints, headache, or musculoskeletal complaints.
At 12 weeks, there had been seven extreme unfavorable events in the intervention staff versus three in the like watch over staff. There had been 12 therapy withdrawals in the intervention staff versus seven in the like watch over staff (P = .27).
Final Questions, Upcoming Segment 3 US Look
“Whereas the [QUARTET] outcomes are impressive, we’re left with a sequence of questions,” Yusuf said.
Would the implications be the same with a 3-drug combo and even a two-drug combo at half doses? In the HOPE 3 trial, a two-drug combo at half doses equipped same outcomes to the recent gaze, over a distinguished longer imply apply-up of 5.6 years, he popular.
Additionally, is the quadpill associated to bigger charges of diabetes or bigger creatinine phases in the atomize? “Provided that we blueprint not like any files on long-term scientific outcomes from a four-drug combination,” Yusuf said, “warning must be utilized.”
Would the lowered risk of CVD be bigger with a combination of low doses of two BP-reducing pills plus a statin plus aspirin? That may well well well be superior, he said, “based on recent knowledge published on the polypill indicating a 50% relative risk reduction in CVD events.”
The associated piece 2 QUARTET US trial ought to shed additional light on a quadpill approach. Sufferers with hypertension are being randomized to a day after day quadpill containing 2 mg candesartan, 1.25 mg amlodipine besylate, 0.625 mg indapamide, and 2.5 mg bisoprolol, or to frequent care, 8 mg candesartan day after day.
Investigators thought to impress up 87 participants in the Chicago house, with estimated gaze completion by March 31, 2023.
The gaze used to be supported by an Australian National Health and Scientific Study Council grant. The George Institute for Global Health has submitted patent functions for low mounted-dose combination merchandise to manage with CV or cardiometabolic disease. Chow and coauthor Kris Rogers are listed as inventors, but they blueprint not like explain monetary interests in these patent functions.
European Society of Cardiology (ESC) Congress 2021.
The Lancet. Revealed online August 28, 2021. Abstract