The VERONICA Trial
The triple combination was also assessed in the VERONICA study, which showed that among Black adults in Nigeria with uncontrolled hypertension, blood pressure was lower and control was better with the low-dose triple-combination pill than with standard care, and tolerability was good.
In VERONICA, recently published in JAMA, 300 patients with a mean baseline blood pressure of 151/97 mm Hg at home and 156/97 mm Hg in the clinic were randomly assigned to receive the triple-combination pill or standard care.
In the triple-combination group, patients started with the quarter-dose pill, then accelerated, as necessary, to the half-dose and standard-dose pills.
In the standard care group, patients started with amlodipine (5 mg), which was stepped up at monthly intervals so patients could achieve a target blood pressure < 140/90 mm Hg as follows: Amlodipine (5 mg) plus losartan (50 mg); then amlodipine (10 mg) plus losartan (100 mg); then amlodipine (10 mg), losartan (100 mg), plus hydrochlorothiazide (25 mg); and finally referral to a specialist if the target blood pressure was still not achieved.
At month 6, mean home systolic blood pressure was, on average, 31 mm Hg lower in the triple-combination group and 26 mm Hg lower in the standard care group (adjusted difference, −5.8 mm Hg; P < .001).
More patients in the triple-combination group than in the standard care group achieved clinic blood pressure control, defined as blood pressure < 140/90 mm Hg (82% vs 72%), and more patients achieved home blood pressure control, defined as blood pressure below 130/80 mm Hg (62% vs 28%).
No participants discontinued treatment due to adverse events, and adverse events of special interest were reported by just 2% and 3% patients in the triple-combination and standard care groups, respectively.
At month 6, however, more participants in the triple-combination group than in the standard care group had serum potassium levels < 3.5 mmol/L (34% vs 18%), although fewer participants in both the groups had potassium levels < 3.0 mmol/L (10% vs 5%).
Hypokalemia may be the consequence of low dietary potassium intake in Africa, and co-administration with potassium-enriched salt substitution should be evaluated, said Dike Ojji, MBBS, PhD, University of Abuja, Nigeria, who was the lead investigator of VERONICA.
“These findings have broad clinical and public health implications, given that improved hypertension control is a priority in Africa and globally. The results underscore the need for combination therapy to be the cornerstone of effective treatment regimens,” Dr. Ojji said.
Missed Targets
“It has taken a long time for the penny to drop as to why the existing antihypertensive treatment paradigm does not work so well,” Dr. Rodgers pointed out. “What tends to happen in clinical practice is that people start on one drug and blood pressure falls a bit, then no further action is taken. But this is not usually enough to get to target. With our approach of using three drugs at low doses straight away, we can often get the blood pressure controlled to target much more quickly with one tablet.”
Low doses of the triple-combination pill should also have a favorable adverse-effect profile and fewer drug interactions, as these issues are generally seen much more frequently with higher doses of drugs, he explained.
This low-dose triple-combination approach could help manage the current epidemic of hypertension and cardiometabolic disease, said Pam Taub, MD, director of preventive cardiology at UC San Diego Health System.
“We are in a new era of cardiometabolic disease, and one of the fundamental drivers of atherosclerotic cardiovascular disease is hypertension, which is prevalent in patients with diabetes, in those with obesity, and is a contributor to chronic kidney disease,” she said.
“We really need to be addressing hypertension very early to prevent this end-organ damage, but because hypertension tends to occur alongside multiple other comorbidities, patients are often on many different medications and are overwhelmed by the burden of polypharmacy.”
Dr. Taub described this triple-combination approach as “looking at hypertension treatment through a new lens.”
“We’ve always been taught to maximize the dose of one agent before we go to a new agent,” she said. “These studies are fundamentally challenging that paradigm. From a pathophysiological and mechanistic perspective, we are seeing that lower doses of different medications can really harness some unique synergistic mechanisms, which can be beneficial for patients.”
But not all experts are convinced that this approach will be a popular option in all countries.
Although this approach makes sense, in that the different agents work synergistically to give a better antihypertensive effect, many physicians could be uncomfortable with the idea of giving multiple medications straight off as the first step of treatment, said Eugene Yang, MD, from the University of Washington in Seattle.
If the patient develops a side effect, it will not be clear which medication is causing it, making it difficult to know which one to stop, he pointed out.
“These studies confirm that a low-dose multidrug-combination pill is effective at lowering blood pressure, but we already have previous studies showing this,” he added. “The issue is how we translate this into patient care. It would be great if we could get people to use it, but I think concerns from both clinicians and patients about identifying the source of any side effects may be a stumbling block.”
The approach is more likely to be adopted in low- to middle-income countries, where there is limited access to healthcare and where the population-wide control of blood pressure makes sense, said Dr. Yang.
Most current guidelines now recommend initiating therapy with two agents, ideally, as a single-pill combination product. “We have finally acknowledged that the vast majority of patients need two drugs. That’s a good starting point. This low-dose triple combination could be an interesting new approach,” said Neil Poulter, MD, professor of preventive cardiovascular medicine at Imperial College London, England.
This approach is in line with the idea that single-pill combinations are the way forward for hypertension therapy, he added.
“The triple combination is attractive, in that you are never quite sure which particular mechanism is driving an individual’s elevated blood pressure, so if you can target three different mechanisms at the same time, you’ve got more chance of a good hit,” Dr. Poulter said.
“The VERONICA trial showed a very good result on lowering BP using this low-dose triple combination as a starting point and increasing quickly to single-pill combinations of triple half doses, then triple full doses, as required. But I think we need more evidence on how this compares to current practice than just this one study in Africa to make this an acceptable routine approach on a global level,” he said.