New Hypertension Approach Hits Multiple Targets at Low Dose

LONDON — Single-pill combinations that include three or four antihypertensive medications are the way forward for the management of patients with elevated blood pressure, according to experts evaluating the new approach.

This multidrug strategy — in which ultralow-dose triple combinations can be used as a starting treatment and four full-dose combinations can be used to treat resistant hypertension — has shown an impressive ability to lower blood pressure in several new studies.

But will it catch on as a routine treatment recommendation in current practice?

Studies of treatment strategies that involve an ultralow quarter dose of three drugs that lower blood pressure and then escalation to a half-dose triple combination and then to a full-dose triple combination, all given as a single pill, were presented at the European Society of Cardiology (ESC) Congress 2024. Another strategy presented involves a four-drug full-dose combination in patients with resistant hypertension.

Start With Low Doses of Three Drugs

The triple-combination pill contains telmisartan (an angiotensin blocker), amlodipine (a calcium channel blocker), and indapamide (a diuretic). The three medications are used at three doses: Quarter, half, and standard.

“The idea is to start treatment with a little bit of the three main drug classes instead of the full dose of one drug and then to increase the triple-combination doses as required to get to blood pressure goal,” said Anthony Rodgers, PhD, from the team at The George Institute for Global Health, Sydney, Australia, that is developing this triple-combination product.

“Using three different mechanisms right from the beginning covers all the bases and leads to improved blood pressure reduction while just using very small doses of each agent. This represents a completely new approach that could transform the management of hypertension,” he reported.

Single-pill triple-combination antihypertensive formulations exist already, but the component drugs are all at standard doses. Such combinations were designed to improve adherence in patients with hard-to-control blood pressure who need more than two full-dose medications, he explained.

“We are suggesting a completely different concept using much lower doses of the triple combination right from the beginning of treatment,” Rodgers explained. “Convenience and adherence will be an added advantage, but there’s more to it than that. It’s about combining the different mechanisms of three separate drug classes to get a better antihypertensive effect and being able to do this right from the start of treatment in patients with mildly elevated blood pressure, as well as those with higher levels.”

Proof-of-concept trials of this approach have been conducted, but no commercial low-dose triple-combination product has been available.

The George Institute is now developing such a product — through George Medicines, its commercial arm — with the aim of bringing the triple-combination pill to market in both high- and low-income countries. An approval submission has been filed in the United States.

Rodgers presented two studies that assessed the triple combination. One showed that the quarter dose reduced blood pressure significantly better than placebo in patients with mildly elevated blood pressure. The second showed that half and standard doses of the three medications were more effective at lowering blood pressure than three dual combinations at the same doses.

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, 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,” 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,” 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.”

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 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, 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,” 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.

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 in 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,” 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 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,” 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 QUADRA 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 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 Taub.

“For years, such single-pill combinations have been viewed as ‘bad medicine’ in hypertension,” 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.”