Clinical Context

In hypertension, numbers are quite important. Maintaining the blood pressure in a healthy range is a mainstay of treatment, yet many patients demonstrate substantial variability in their blood pressure values. Bell and colleagues examined this issue by performing a meta-analysis of data from 7 randomized controlled trials of angiotensin-converting enzyme (ACE) inhibitors. Their results were published in the July 12, 2010, issue of Hypertension.^[1]

The between-person variation in response to ACE inhibitors was large, with an average standard deviation of 15.2/8.5 mm Hg. However, the respective within-person variability was similar: 14.9/8.45 mm Hg. Using these data, the study authors estimated that the true between-person response to ACE inhibitors was trivial: 2.6/1.0 mm Hg, or 3% of systolic blood pressure and 1% of diastolic blood pressure.

Before concluding that the variability in hypertension treatment response is entirely a result of within person blood pressure variability, a study needs to address that issue as a potential confounding factor. The current study does just that.

Study Synopsis and Perspective

A new study has shown a substantial variation in the blood pressure response to various antihypertensive medications between individuals, raising the possibility of future personalized therapy.

“We found that using the optimal antihypertensive drug for a particular patient resulted in an average of a 4.4 mm Hg greater reduction of blood pressure compared with a random choice of the other drugs. That is quite a substantial difference, and could be equivalent to adding in another drug,” lead author Johan Sundström, MD, Uppsala University Hospital, Uppsala, Sweden, told theheart.org | Medscape Cardiology.

“These preliminary findings suggest that some people may be better treated with one antihypertensive drug rather than another. This is opening up the field of hypertension for personalized medicine,” he added.

The study was published online April 11 in JAMA.^[2]

The authors note that despite global access to multiple classes of highly effective blood pressure-lowering drugs, only 1 in 4 women and 1 in 5 men with hypertension reach treatment targets. Although most hypertension guidelines advocate combination pharmacotherapy, many patients in routine care continue to be treated with monotherapy, with adverse effects and nonadherence being important clinical problems.

“One drug often does not give enough blood pressure reduction, but patients are often reluctant to up-titrate to 2 drugs,” Dr Sundström said. “We wondered whether there could be different optimal drugs for different people, and if we could identify the optimal drug for each person then maybe more patients could get to target levels with just one drug.”

The researchers conducted a randomized, double-blind, repeated crossover trial at an outpatient research clinic in Sweden, studying 280 men and women with grade 1 hypertension at low risk for cardiovascular events.

Each participant was scheduled for 2 months’ treatment, in random order, with each of 4 different classes of antihypertensive drugs:

• an ACE inhibitor, lisinopril
• an angiotensin II blocker, candesartan
• a thiazide diuretic, hydrochlorothiazide
• a calcium channel blocker, amlodipine

There were then repeated treatment periods for 2 drug classes to try to account for any effect of a particular event that might have affected the blood pressure at 1 point in time. Ambulatory daytime systolic blood pressure was measured at the end of each treatment period.

Results showed that variation in systolic blood pressure was large between treatments on average, between participants on average, within participants receiving the same treatment, and between treatments in the same participant.

Overall, personalized treatment using the optimal single-drug therapy led to a 4.4 mm Hg lower systolic blood pressure in the trial population than a random choice of any of the other drug classes.

Taking into consideration that lisinopril was found to be on average the most efficacious of the drugs at the selected doses, personalized treatment compared with lisinopril still led to a 3.1 mm Hg improvement in systolic blood pressure.

The researchers note that the mean additional blood pressure reduction achievable by using the optimal agent was of a magnitude twice that achieved by doubling the dose of a first drug, and more than half that of adding a second drug on average.

Although there were only small differences between certain drugs (eg, candesartan vs lisinopril; amlodipine vs hydrochlorothiazide), for all other comparisons tested the choice was important, with particularly large gains to be made by personalizing the choice between candesartan and amlodipine and between lisinopril and amlodipine.

In addition, some people showed very large differences in response to different drugs, whereas others did not have much difference at all.

How to Identify the Optimal Drug?

In the study, the researchers suggest that personalizing therapy could be achieved either by identifying the phenotypic characteristics that are associated with enhanced response to 1 treatment vs another or by directly measuring the individual’s responses to a series of treatments to ascertain which is most effective.

Addressing the first scenario, Dr Sundström explained: “We can analyze the characteristics of patients who did best on each drug. There are many variables we can look at here, such as age, diet, baseline blood pressure, exercise levels, smoking status, race, body weight, salt intake, and findings from genetic tests. We are going to try to look into these to see if we can find any predictors of response to various different drugs.”

For the second strategy, he suggested that patients starting pharmacologic therapy could try a few different treatments. “For example, we could give patients 2 different drugs and ask them to alternate treatment periods with each of them and measure their blood pressure with a home monitoring kit and record adverse effects.”

Nonadherence “is such a big problem with antihypertensives,” he added. “This approach may allow patients to be more empowered [when choosing] the right treatment, which should help adherence in the longer term.”

“Proof-of-Principle”

Commenting on the study in an accompanying editorial, Robert Carey, MD, University of Virginia Health System, Charlottesville, writes: “At this stage, the findings are more theoretical than immediately practical for the implementation of personalized antihypertensive drug therapy, but the study does provide proof-of-principle and the authors suggest a few scenarios in which a personalized approach could be used in the future.”^[3]

He believes that the practical ramifications of personally targeted therapy remain unclear, given that determination of an individual’s response to a series of short test treatments before selecting long-term therapy may be considered too cumbersome, and that at this time, few phenotypic markers are currently available that would be likely to accurately predict the individual response to a particular therapy.

Dr Carey concludes that the results of this study “encourage the further pursuit of larger randomized trials using similar repeated crossover designs to validate this concept and eventually in trials with longer follow-up data to determine whether there is improvement in long-term clinical outcomes compared with current strategies.”

He adds that the results also support the possibility that personalized medical treatment of hypertension “may ultimately supplement or even supplant the current method of antihypertensive drug decision-making in the future.”

This study was supported by the Swedish Research Council, Kjell and Märta Beijer Foundation, and Anders Wiklöf. Dr Sundström reported owning stock in Symptoms Europe AB and Anagram Kommunikation AB. Coauthor Emil Hagström, MD, PhD, reported receiving grants from Pfizer and Amgen and personal fees from Amgen, Novo Nordisk, Bayer, AstraZeneca, Amarin, and Novartis. Coauthor Ollie Östlund, PhD, reported fees from Uppsala University paid to his institution, Uppsala Clinical Research Center, for its participation in the PHYSIC trial during the conduct of the study. Dr Carey has disclosed no relevant financial relationships.

JAMA. Published online April 11, 2023.

Implications for the healthcare team

• A previous study found that the degree of between-person variability in the blood pressure response to ACE inhibitors was similar to that of regular within-person blood pressure variability.
• In the current study, lisinopril was associated with the greatest reduction in systolic blood pressure compared with candesartan, amlodipine, and hydrochlorothiazide. Personalized therapy to the most effective antihypertensive drug for each individual participant could reduce systolic blood pressure by an additional 4.4 mm Hg.
• The healthcare team should understand that certain patients may respond differently to different forms of antihypertensive treatment.

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