Letter to the editor Are There Gaps in the Evidence on the Treatment of Mild Hypertension in Patients With Low Cardiovascular Risk?

To the Editor,

I read with great interest the articles on the new European guidelines for the management of arterial hypertension.^1,2 One of the changes with respect to the previous guidelines is that the recommendation to start drug treatment in patients with grade 1 hypertension (140-159/90-99 mmHg) and low to moderate cardiovascular (CV) risk after a reasonable period of lifestyle measures has been upgraded from a class IIa level B recommendation to a class I level A recommendation.^1,2 This change would appear to indicate that there is ample evidence from randomized controlled trials (RCTs) or meta-analyses to support this recommendation and that the medical community agrees that antihypertensive drug treatment is beneficial, useful, and effective in this setting.¹

Drug therapy for grade 1 hypertension in patients with a low CV risk profile is one of the most controversial topics in the area of cardiovascular prevention.³ The aim of this article was to briefly address the question of whether there are still gaps in the evidence on the treatment of mild hypertension in this subgroup of patients.⁴

Apart from the general biases associated with RCTs,³ studies analyzing low CV risk and mild hypertension typically use different definitions of what constitutes low risk.³ If we consider the CV risk categories established in the European hypertension guidelines,¹ then representative studies of low CV risk should include individuals with a less than 1% risk of a fatal cardiovascular event over a 10-year period.¹ Likewise, studies of moderate and high CV risk should include samples with a 10-year risk of ≥ 1% to < 5% and ≥ 5% to < 10%, respectively. One of the criticisms of using CV mortality as a marker of CV risk is that the relationship of major CV events to CV mortality varies with risk and age.³ This bias, however, is minimized in studies of patients with a mean age younger than 60 years and a 10-year CV mortality risk of less than 1%. Because age has such a strong influence in the CV risk continuum,³ several prediction models automatically classify mildly hypertensive men aged 55 years or older and women aged 60 years or older in at least the moderate CV risk category, even in the absence of concomitant risk factors.³ This would appear to particularly apply to regions with a higher-risk population for CV disease.

Under the above premises, let us now consider the 3 meta-analyses and the RCT forming the basis of the new evidence level for the recommendation to treat grade I hypertension in patients with low CV risk.¹ Mean patient age was 63.5 years in the meta-analysis by Sunstrom et al.⁵ and 63.0 in that by Brunstrom et al.⁶ and the respective 10-year CV mortality risks were 6.2% and 8.5%. Tomopoulos et al.,⁷ by contrast, reported a 10-year mortality risk of 4.5%.

In the HOPE-3 (Heart Outcomes Prevention Evaluation) trial, the patients had a mean age of 65.7 years and a 10-year CV mortality risk of 4.8%.⁸

Despite the scant evidence on how to manage grade 1 hypertension in patients with low CV risk,^1–3 the European guidelines also recommend antihypertensive treatment in this population¹ due to the linear relationship observed between blood pressure and CV events in several cohort studies with a B level of evidence.^1–3

Finally, there are 4 additional issues that need highlighting: a) treatment of mild hypertension in patients with low CV risk should be individualized, as these patients are not a homogeneous group; b) delayed initiation of drug treatment can put patients at risk because of poor adherence and obstacles impeding the implementation of healthy lifestyle changes and because of the increased risk of a CV event occurring during this period³; c) the recommendation to allow a reasonable period for the implementation of lifestyle measures is not supported by direct evidence from RCTs or meta-analyses³; and d) studies of hypertension in patients with low CV risk should exclude hypertensive patients with asymptomatic organ damage, diabetes mellitus, markedly elevated risk factors, and established CV or renal disease.¹ These patients have not been excluded in any of the studied performed to date.

In conclusion, it would appear that there are still gaps in the evidence on the treatment of mild hypertension in patients with low CV risk. The recommendation to start antihypertensive drug treatment in these patients is a class B recommendation. Cardiovascular mortality and age are useful variables for identifying suitable studies of mildly hypertensive patients with low CV risk.