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 the Journal of the American Medical Association.
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. While 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 two drugs,” Sundström said. “While we know that the four recommended classes of antihypertensives lower blood pressure equally well on average, we don’t know if their efficacy is the same in individual patients.
“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,” he said.
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 four different classes of antihypertensive drugs:
an angiotensin-converting enzyme (ACE) inhibitor, lisinopril
an angiotensin II blocker, candesartan
a thiazide diuretic, hydrochlorothiazide
a calcium channel blocker, amlodipine
There were then repeated treatment periods for two drug classes to try to account for any effect of a particular event that might have affected the blood pressure at one 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 taking 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.
While 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 vs amlodipine and between lisinopril vs 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?
“The million-dollar question is how we identify the best drug for each individual patient,” Sundström said. “This study has opened Pandora’s box. We now need to figure out how to go forward and how we tailor treatment in each patient.”
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 one 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, 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 two 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 as big problem with antihypertensives,” he added. “This approach may allow patients to be more empowered when to comes to choosing the right treatment, which should help adherence in the longer term.”
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.”
He believes 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 currently few phenotypic markers are currently available that would be likely to accurately predict the individual response to a particular therapy.
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. Sundström reported owning stock in Symptoms Europe AB and Anagram Kommunikation AB. Co-author Emil Hagström, MD, PhD, reported receiving grants from Pfizer and Amgen and personal fees from Amgen, Novo Nordisk, Bayer, AstraZeneca, Amarin, and Novartis. Co-author 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. Carey reports no relevant financial relationships.
JAMA. Published online April 11, 2023. Full text, Editorial
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