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Several low-dose drugs better for BP than one pill – Australian meta-analysis

Researchers have found that taking three or four medications – at lower doses – rather than just a single pill, may help people lower their blood pressure without increasing the risk of most negative side effects.

To estimate how much benefit this kind of low-dose combination therapy offers for controlling blood pressure, a team, led by the University of New South Wales, Australia, reviewed seven previous randomised clinical trials, and also combined the results of these studies, using the statistical method known as a meta-analysis, reports Healthline.

Their findings, published in JAMA Cardiology, suggest that combining low doses of three or four blood-pressure-lowering medications is safe and effective as an initial treatment strategy for high blood pressure. Previously, three-drug combinations had been recommended only if people have difficulty keeping their blood pressure under control with two drugs.

The seven randomised clinical trials compared low-dose combinations of three or four blood-pressure-lowering drugs to treatment with a single drug, usual care, or an inactive placebo.

Researchers defined low doses as half or less than half the standard dose.

The clinical trials included 1 918 patients. In five of the trials, participants were followed for four to 12 weeks, and for six to 12 months in the other two trials.

People treated with low-dose drug combinations saw their systolic blood pressure decrease on average by 16 to 28 millimetres of mercury (mm Hg) over four to 12 weeks, the analysis showed.

In contrast, systolic blood pressure decreased 12 to 18mm Hg on average in the group taking one drug or receiving usual care.

At six and 12 months, people receiving low-dose combination therapy continued to have greater reductions in their blood pressure compared with the one-drug or usual care groups. Low-dose combination therapy also lowered blood pressure more than placebo.

In addition, a greater percentage of people receiving low-dose combination therapy lowered their blood pressure below 140/90mm Hg, compared with those receiving one drug or usual care. This was true during the short-term and long-term follow-ups.

According to the American Heart Association, hypertension stage two is when the blood pressure is consistently at or above 140/90mm Hg.

Two-thirds of people in the clinical trials were able to control their blood pressure with low-dose combination therapy, the researchers found. However, that means that one-third would “require treatment intensification to achieve better control rates,” they wrote.

Overall, there was a low risk of adverse effects with low-dose combination therapy, although people taking three or four medications were more likely to experience dizziness than those treated with one drug or usual care.

Not yet the recommendation for hypertension

One limitation of the analysis is that some of the clinical trials included people who were taking blood-pressure-lowering medications at the start of the trial – so low-dose combination therapy was not their initial treatment.

However, the authors of the study found that the results were similar when they compared people who had already been taking medications to those who started on the low-dose combination therapy.

Another limitation was that the analysis included only a few clinical trials, with just two trials following patients for six to 12 months, meaning the researchers might not be able to clearly see if people on the low-dose combination therapy had fewer or more side effects than the other groups.

Dr Michael Broukhim, an interventional cardiologist at Providence Saint John’s Health Centre in Santa Monica, said larger studies would be needed to clearly assess the adverse effects of low-dose combination therapy.

Ideally, he would like to see a larger randomised clinical trial that compares low-dose combination therapy to taking a single pill, focused on people with high blood pressure but no related health conditions.

Increasing the dose can mean more side effects

The study also shows patients tolerate low doses of multiple medications, an approach that may work better than increasing the dose of a single medication to achieve blood pressure control.

With many medications, upping the dosage increases the risk of negative side effects.

Dr Sanjiv Patel, an interventional cardiologist at MemorialCare Heart & Vascular Institute at Orange Coast Medical Centre, agreed.

“The key is multiple medications, but at low doses, because high doses can also cause side effects and problems,” he told Healthline.

However, Broukhim questions whether this particular paper will change how physicians treat high blood pressure – for several reasons.

For example, patients may have other health conditions, like diabetes or heart disease or rheumatoid conditions, that need to be treated alongside high blood pressure.

“There are multiple decisions that make a once-size-fits-all approach for the treatment of hypertension very difficult,” he said.

Is a polypill the answer for high BP?

In addition, it’s more challenging for patients to take several pills every day. “Nobody wants to take multiple medications,” said Patel.

One solution to this is combining several drugs in a single pill, what’s known as a polypill. Patel said this can help patients take their medications regularly.

Research supports this, at least with cardiovascular medications – in the study, patients who had a heart attack adhered better to their medicine regimen if they were given a polypill versus multiple pills.

One challenge with polypills, though, is adjusting the medication to fit the needs of the patient.

“If you have to change one of the medications, then you have to change the whole pill,” said Patel.

Broukhim said polypills for blood-pressure-lowering medications may not be possible with the current state of the pharmaceutical industry.

Medications that would work together may be manufactured by different companies, which would require them to agree to combining their drug with others in a single pill.

Study details

Efficacy and Safety of Low-Dose Triple and Quadruple Combination Pills vs Monotherapy, Usual Care, or Placebo for the Initial Management of HypertensionA Systematic Review and Meta-analysis

Nelson Wang, Phidias Rueter, Emily Atkins.

Published in JAMA Cardiology on 26 April 2023

Key Points

Question What is the efficacy and safety of low-dose combination triple and quadruple antihypertensives for the management of hypertension?

Findings This systematic review and meta-analysis of seven trials enrolling 1918 patients found that low-dose combination antihypertensives were more efficacious than monotherapy, usual care, or placebo in terms of mean blood pressure reduction and achieving blood pressure target. Low-dose combinations were also well tolerated but were associated with higher rates of dizziness than monotherapy or usual care.

Meaning The findings suggest that low-dose combinations with 3 or 4 antihypertensives were effective and well tolerated in the lowering of blood pressure and may be an effective strategy for the early management of hypertension.


Low-dose combination (LDC) antihypertensives consisting of 3 or 4 blood pressure (BP)–lowering drugs have emerged as a potentially important therapy for the initial management of hypertension.

To assess the efficacy and safety of LDC therapies for the management of hypertension.

Study Selection
Randomised clinical trials comparing LDC consisting of 3 or 4 BP-lowering drugs compared to either monotherapy, usual care, or placebo.

Data Extraction and Synthesis
Data were extracted by two independent authors and synthesised using both random and fixed-effects models using risk ratios (RR) for binary outcomes and mean differences for continuous outcomes.

Main Outcomes and Measures
The primary outcome was mean reduction in systolic BP (SBP) between LDC and monotherapy, usual care, or placebo. Other outcomes of interest included the proportion of patients achieving BP less than 140/90 mm Hg, rates of adverse effects, and treatment withdrawal.

Seven trials with a total of 1918 patients (mean [mean range] age, 59 [50-70] years; 739 [38%] female) were included. Four trials involved triple-component LDC and 3 involved quadruple-component LDC. At 4 to 12 weeks follow-up, LDC was associated with a greater mean reduction in SBP than initial monotherapy or usual care (mean reduction, 7.4 mm Hg; 95% CI, 4.3-10.5) and placebo (mean reduction, 18.0 mm Hg; 95% CI, 15.1-20.8). LDC was associated with a higher proportion of participants achieving BP less than 140/90 mm Hg at 4 to 12 weeks compared to both monotherapy or usual care (66% vs 46%; RR, 1.40; 95% CI, 1.27-1.52) and placebo (54% vs 18%; RR, 3.03; 95% CI, 1.93-4.77). There was no significant heterogeneity between trials enrolling patients with and without baseline BP-lowering therapy. Results from 2 trials indicated LDC remained superior to monotherapy or usual care at 6 to 12 months. LDC was associated with more dizziness (14% vs 11%; RR 1.28, 95% CI 1.00-1.63) but no other adverse effects nor treatment withdrawal.

Conclusions and Relevance
The findings in the study showed that LDCs with 3 or 4 antihypertensives were an effective and well-tolerated BP-lowering treatment option for the initial or early management of hypertension.


JAMACardiology article – Efficacy and Safety of Low-Dose Triple and Quadruple Combination Pills vs Monotherapy, Usual Care, or Placebo for the Initial Management of HypertensionA Systematic Review and Meta-analysis (Open access)


Healthline article – Study Finds Using 3 to 4 Drugs for High Blood Pressure May Be More Effective Than Single Pill (Open access)


See more from MedicalBrief archives:


Daily polypill instead of drug trio reduces CVD risk – SECURE randomised trial


Benefits of polypills include preventing heart attacks and strokes


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Stringent diet puts diabetes into remission and cuts need for BP medication

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