Updated European Society of Cardiology guidelines: opportunities and risks for clinical trials

This blog is part of The Regulatory Navigator series, where we explore the evolving regulatory landscape with actionable insight from Parexel's experts, sharing their experience to maximize success for clinical development and patient access.

Clinical practice guidelines for the diagnosis and management of hypertension are foundational to the development of effective anti-hypertensive drugs. 

In October 2024, the European Society of Cardiology (ESC) issued updated guidelines for the management of elevated blood pressure (BP) and hypertension, reflecting a comprehensive approach to addressing the prevalent health concern of inadequately controlled BP1. These guidelines emphasize a more nuanced and personalized BP management strategy and represent a significant change from recommendations provided in guidelines from organizations such as the European Society of Hypertension (ESH), International Society of Hypertension (ISH), American College of Cardiology (ACC), and American Heart Association (AHA).  

The European Medicines Agency (EMA) and US Food and Drug Administration (FDA) guidance for clinical trials of antihypertensive medicines closely align with the recommendations from clinical practice guidelines. Consequently, an understanding of the implications of the updated ESC guidelines is important for the design and conduct of clinical trials in this area. 

ESC’s new approach to pharmacologic treatment of hypertension   

Elevated BP 

One of the most notable changes to the ESC Guidelines is the introduction of a category of BP abnormalities called "elevated BP," which falls between the normal BP range and hypertension (i.e., office systolic BP of 120–139 mmHg or diastolic BP of 70–89 mmHg). This identification of a pre-hypertensive state allows for earlier intervention and potentially better long-term outcomes. The concept of elevated BP is not new per se – it has existed in the ACC/AHA guidelines since 20172. In those guidelines, initial pharmacologic treatment is not recommended for elevated BP patients; rather patients are to be reassessed in three to six months.

In contrast, the updated ESC guidelines advocate for a risk-based approach to pharmacologic treatment, considering not just BP readings but also the patient’s overall cardiovascular risk, which is consistent with other cardiology and hypertension society guidelines. This holistic view seeks to ensure that patients receive appropriate care based on their individual health profiles.

Under the updated ESC recommendations, pharmacologic treatment is to be initiated in patients who have both elevated BP and a 10-year risk of fatal or nonfatal cardiovascular (CV) event >10% risk as measure by the systematic coronary risk evaluation (SCORE-2) or SCORE-older person (SCORE2-OP3,4). Additionally, treatment can be considered for patients with elevated BP and other high-risk conditions such as high-risk ethnicity, family history of premature cardiovascular disease (CVD), or autoimmune disease. It can be also advised due to sex-specific modifiers which include: (1) gestational diabetes, (2) gestational hypertension, or (3) pre-eclampsia, even if the CV risk is <10%. 

BP target

The ESC’s recommended target BP for most adults on anti-hypertensive medication has been refined to 120-129/70-79 mmHg, provided the medication is well-tolerated. This more aggressive target, even in older adults, reflects the growing body of evidence supporting tighter BP control for improved cardiovascular outcomes. 

The ESC recommendation for treating to the lower BP level is based on meta-analysis of individual participant-level data (344 716 participants) from 48 randomized trials. The meta-analysis demonstrated that a 5 mm Hg reduction of systolic BP reduced the risk of major cardiovascular events by about 10%, irrespective of previous diagnoses of cardiovascular disease, and even at normal or high–normal blood pressure values.5   

Out-of-office blood pressure measurement

The updated ESC guidelines place emphasis on out-of-office BP measurements, recognizing the limitations of in-office readings and the value of home or ambulatory monitoring. Except for patients with atrial fibrillation (for whom manual measurements may be required) home or ambulatory BP monitoring is preferred and considered best practice because it provides a more accurate picture of a patient's BP over time and in various settings.   

Combination therapy 

In view of the clinical trial evidence showing more effective BP control compared to monotherapy, the updated ESC guidelines recommend combination therapy as the initial treatment for most patients with confirmed hypertension, moving away from the traditional stepwise approach to BP management.  Patients with moderate-severe frailty, symptomatic hypertension, and who are aged > 85 years with a BP of 120-139/70-89 mm Hg are excluded from this recommendation.

Initiating BP treatment with a combination of medications aims to achieve faster and more effective BP control within 3 months. Patients who are uncontrolled on dual therapy should be stepped up to three antihypertensive agents rather than increasing to maximal doses of the dual therapy, which contrasts with the ESH and ISH Global Hypertension Practice guidelines5. The ESH guideline recommends patients not adequately controlled should receive an additional antihypertensive agent with a different mechanism of action even if the patient has not been titrated to the maximal levels of their background medication, whereas the ISH Global Hypertension Practice guidelines recommend an initial titration to maximal tolerated doses of the current treatment before adding any new antihypertensive agents.

Regulatory considerations 

As there are different guidelines and definitions from ESC and ESH/ISH standards, these new guidelines may not be accepted in different regions or by regulatory authorities. Current EMA guidance for developing antihypertensive medicines and FDA consumer statements state BP<140/90 mmHg as normal in healthy adults. 

While the updated ESC guideline recommends a more intensive earlier treatment of patients, sponsors conducting studies in a monotherapy setting could find it challenging, as it is more likely that for longer-term trials, a new treatment will need to be added to standard of care. This may also be of concern for older people or frail populations. 

There are several published FDA and EMA guidances available for sponsors developing antihypertensives as a monotherapy or as a combination treatment. Current FDA and EMA guidelines recommend superiority over placebo or standard of care and recognize the importance of blood pressure control in prevention of cardiovascular disease (CVS).

Since 2005, FDA favors labeling changes to briefly describe the clinical benefits related to cardiovascular outcomes expected from lowering blood pressure with any antihypertensive drug. The EMA or FDA guidance do not mention treatment of patients specifically with lower baseline BP (i.e. 120–139 mmHg or diastolic BP of 70–89 mmHg range), or prehypertension. In the absence of actuarial data and epidemiological studies demonstrating benefit in treating patients with lower baseline BP, long term cardiovascular outcome studies may be needed to support a positive benefit risk for authorization. Additionally, potential safety of treatment in patients with lower baseline BP (i.e. 120–139 mmHg or diastolic BP of 70–89 mmHg range) would need to be considered.

It is not envisioned that regulatory guidance for sponsors will be updated soon, therefore, further discussion with regulatory authorities would be advised if a marketing authorization in this earlier BP population is planned for.

However, there are opportunities for sponsors to develop combination therapies for patients with lower baseline blood pressure, demonstrate importance of earlier treatment overall or in specific populations such as diabetes, or those at higher risk of CVS disease. The updated ESC guideline may, over time, be reflected in other guidelines mentioned previously.

Clinical trials risks and opportunities

The updated ESC guidelines offer new opportunities for clinical trials of investigational anti-hypertensive drugs but there are also some risks to be assessed. 

If combination drug treatment becomes initial standard of care for the first line setting, it may be more difficult to recruit for monotherapy, placebo-controlled trial – especially if a longer-term study is needed. A potential alternative is a non-inferiority study design. However, predefining a non-inferiority margin may be challenging to justify, as differences by a few mmHG over a prolonged time could result in an increased CV risk for patients. Additionally, the non-inferiority margin may have to be based on both systolic and diastolic BP, since systolic and diastolic hypertension have been shown to independently influence the risk of adverse cardiovascular events, regardless of the definition of hypertension (≥140/90 mm Hg or ≥130/80 mm Hg)5. 

The ESC guidelines recommendation for pharmacologic treatment of patients with elevated BP and CV risk, as well as control of BP to lower levels also have implications for study design. For patients who have elevated BP, lowering of BP could be due to changes in body weight or cardiovascular fitness or other factors. Therefore, these aspects would need to be closely controlled in the clinical trial (as the margin to demonstrate the antihypertensive effect is small).

Short-term trials could be considered for examining the additional pharmacodynamic effect in patients who are not in need of immediate combination therapy. The new medication could be tested as a monotherapy or in combination with patients’ current medication or the standard of care over a short duration. However, if patients’ background hypertensive medication is being amended, there should be a period of stabilization introduced. This is to ensure no further changes in BP occur before commencing the trial and any confounding aspects (such as diet exercise, alcohol intake etc.) are controlled for.

Implementing the updated ESC guidelines would mean medically treating BP abnormalities earlier and perhaps in a younger patient population without co-morbidity. In these populations, medication compliance may become an issue as treatments are usually taken daily and patients are without symptoms. However, this also raises opportunities for development products that have a prolonged duration of action and therefore require less frequent administration. Additionally, medical devices that issue a reminder or enable controlled drug release can also aid patient compliance or improve patient outcomes. For example, novel treatments in development (such as GalNAc–siRNAs) have demonstrated promising results by achieving a sustained and prolonged antihypertensive effect for up to 24 weeks after a single subcutaneous administration. Such treatments offer the potential for sustained reduction of blood pressure in mild-to-moderate hypertension over a 24-hour period, with twice-yearly or quarterly subcutaneous administration and may lead to further changes in the management of hypertension. 

Next steps for the drug developers

Since the updated ESC guidelines diverge from other current clinical practice guidelines in Europe and USA, it is important to be aware of potential challenges in conduct of antihypertensive trials that may arise due to differences in standard of care, treat-to-target aims between the two regions and even across clinical trial sites. 

Over time, other clinical practice guidelines may align with the ESC on recommendations for pharmacologic treatment of patients with elevated BP and hypertension, which presents additional opportunities but also risks for drug developers. For example, in developing medications for use in patients with lower resting BP or with lower cardiovascular risks, developers should demonstrate a positive benefit-risk ratio with chronic treatment. Therefore, we advise developers of new antihypertensives to maintain a global clinical development plan, even if the initial commercialization plan is regional. 

As a leading global phase I-IV clinical research organization, Parexel leverage the breadth of our clinical, regulatory and therapeutic expertise to optimize your clinical development programs and to help you navigate the regulatory agency requirements. Parexel’s Regulatory Consulting group interprets evolving regulatory requirements, prepares robust submissions, and effectively manages interactions with regulatory agencies, ultimately helping to bring innovative therapies to patients more efficiently and effectively. Please contact us  to further discuss on how we can support your drug development.
 

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References

1. John William McEvoy, Cian P McCarthy, Rosa Maria Bruno et al , ESC Scientific Document Group , 2024 ESC Guidelines for the management of elevated blood pressure and hypertension: Developed by the task force on the management of elevated blood pressure and hypertension of the European Society of Cardiology (ESC) and endorsed by the European Society of Endocrinology (ESE) and the European Stroke Organisation (ESO), European Heart Journal, Volume 45, Issue 38, 7 October 2024, Pages 3912–4018, https://doi.org/10.1093/eurheartj/ehae178
2. Colantonio LD, Booth JN 3rd, Bress AP, et al. 2017 ACC/AHA Blood Pressure Treatment Guideline Recommendations and Cardiovascular Risk. J Am Coll Cardiol. 2018 Sep 11;72(11):1187-1197. doi: 10.1016/j.jacc.2018.05.074. PMID: 30189994; PMCID: PMC6346270.
3. SCORE2 working group and ESC cardiovascular risk collaboration. SCORE2 risk prediction algorithms: new models to estimate 10-year risk of cardiovascular disease in Europe. Eur Heart J 2021;42:2439–2454. 
4. SCORE2-OP working group and ESC Cardiovascular group. SCORE2-OP risk prediction algorithms: estimating incident cardiovascular event risk in older persons in four geographical risk regions. Eur Heart J 2021;42:2455–2467
5. Rahimi, Kazem et al. Pharmacological blood pressure lowering for primary and secondary prevention of cardiovascular disease across different levels of blood pressure: an individual participant-level data meta-analysis. The Lancet, Volume 397, Issue 10285, 1625 - 1636
6. Thomas Unger, Claudio Borghi, Fadi Charchar, et al. 2020 International Society of Hypertension Global Hypertension Practice Guidelines. Hypertension Volume 75, Issue 6, June 2020; Pages 1334-1357 https://doi.org/10.1161/HYPERTENSIONAHA.120.15026
7. Alexander C. Flint, M.D., Ph.D., Carol Conell, Ph.D., Xiushui Ren, M.D. et al, Effect of Systolic and Diastolic Blood Pressure on Cardiovascular Outcomes, N Engl J Med 2019;381:243-51. DOI: 10.1056/NEJMoa1803180
    

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