Apparent treatment resistant hypertension and the risk of recurrent cardiovascular events and mortality in patients with established vascular disease

https://doi.org/10.1016/j.ijcard.2021.04.047Get rights and content

Highlights

  • In hypertensive patients with vascular disease, aTRH is associated with a higher risk of (vascular) death

  • Moreover, aTRH in these patients resulted in a substantial reduction in median life expectancy (free of recurrent MACE)

  • These findings support the need for greater efforts to improve BP control in patients with aTRH and vascular disease

Abstract

Aim

To quantify the relation between apparent treatment resistant hypertension (aTRH) and the risk of recurrent major adverse cardiovascular events (MACE including stroke, myocardial infarction and vascular death) and mortality in patients with stable vascular disease.

Methods

7455 hypertensive patients with symptomatic vascular disease were included from the ongoing UCC-SMART cohort between 1996 and 2019. aTRH was defined as an office blood pressure ≥140/90 mmHg despite treatment with ≥3 antihypertensive drugs including a diuretic. Cox proportional hazard models were used to quantify the relation between aTRH and the risk of recurrent MACE and all-cause mortality. In addition, survival for patients with aTRH was assessed, taking competing risk of non-vascular mortality into account.

Results

A total of 1557 MACE and 1882 deaths occurred during a median follow-up of 9.0 years (interquartile range 4.8–13.1 years). Compared to patients with non-aTRH, the 614 patients (8%) with aTRH were at increased risk of cardiovascular mortality (HR 1.27; 95% CI 1.03–1.56) and death from any cause (HR 1.25; 95% CI 1.07–1.45) but not recurrent MACE (HR 1.13; 95% CI 0.95–1.34). At the age of 50 years, patients with aTRH after a first cardiovascular event on average had a 6.4 year shorter median life expectancy free of recurrent MACE than patients with non-aTRH.

Conclusion

In hypertensive patients with clinically manifest vascular disease, aTRH is related to a higher risk of vascular death and death from any cause. Moreover, patients with aTRH after a first cardiovascular event have a 6.4 year shorter median life expectancy free of recurrent cardiovascular disease.

Introduction

Globally, hypertension affects an estimated 31% (1.4 billion) of the adult population and is an important treatable risk factor for cardiovascular disease (CVD) and mortality [1,2]. Although awareness and treatment have improved considerably, still about 50% of patients medically treated for hypertension do not reach the blood pressure (BP) targets recommended by guidelines [1].

Treatment resistant hypertension (TRH), a particularly severe form of hypertension, has been extensively studied during the last decades. The European Society of Hypertension (ESH) and the European Society of Cardiology (ESC) define TRH as when patients treated with optimal or best-tolerated doses of three or more antihypertensive drugs, which should include a diuretic, fail to achieve office systolic BP and diastolic BP values of <140 mmHg and/or <90 mmHg, respectively [3]. A more liberal definition has been adopted by the American College of Cardiology (ACC) and American Heart Association (AHA) who consider patients resistant when office BP is greater than or equal to 130/80 mmHg despite use of three antihypertensive drugs with complementary mechanisms of action (a diuretic should be 1 component) or when BP control is achieved but requires ≥4 medications [4]. The diagnosis of TRH requires exclusion of pseudo-resistance, including medication non-adherence, improper BP measurement, white coat hypertension, and treatment inertia [5]. After exclusion of pseudo-resistance, the true prevalence of TRH is likely to be <10% of treated patients [3]. Population-based studies often use the term apparent TRH (aTRH) to clarify that pseudo-resistance was not excluded [[6], [7], [8], [9], [10]].

Previous studies among patients with hypertension have shown that patients with resistant hypertension are almost 50% more likely to experience outcomes such as death, myocardial infarction, heart failure, stroke, or chronic kidney disease (CKD) compared with treated hypertensive patients with controlled BP [7,8,10,[11], [12]]. Also, in hypertensive patients with coronary artery disease (CAD) the presence of aTRH was associated with a 27–77% higher risk of all-cause mortality, nonfatal myocardial infarction, and nonfatal stroke compared with treated hypertensive patients with controlled BP [9,13,14].

Although considerable amount of data on the relative risk of (recurrent) major adverse cardiovascular events (MACE) is available, there remains a paucity of data regarding the impact of aTRH on life expectancy (LE) with and without CVD [15,16]. Especially in patients with clinically manifest vascular disease, insight and quantification of the potential gain in life years could be of great value in motivating patients with aTRH to adhere to their risk factor management.

Therefore, the aim of the present study is twofold. First, to examine the risk of aTRH on recurrent MACE and all-cause mortality in patients with established CVD. Second, to evaluate the difference in life expectancy free of recurrent MACE in patients with and without aTRH in a large cohort of hypertensive patients with manifest vascular disease.

Section snippets

Study population

The population in this study originated from the Utrecht Cardiovascular Cohort – Second Manifestations of ARTerial disease (UCC-SMART), a single-center, ongoing prospective cohort study. Since September 1996, patients aged 18–80 referred to the University Medical Center Utrecht (UMCU), the Netherlands with a clinically stable manifestation of arterial disease (coronary artery disease (CAD), cerebrovascular disease (CeVD), peripheral arterial disease (PAD), or abdominal aortic aneurysm (AAA)) or

Clinical characteristics

The study population consisted of 7455 patients, of whom 614 (8%) had aTRH. Compared to patients without aTRH, patients with aTRH had a higher mean age (63.7 ± 9.3 versus 60.7 ± 9.8 years), diabetes mellitus was more prevalent (34% versus 17%) and the average eGFR was lower (68 ± 21 versus 77 ± 18 mL/min/1.73 m2) (Table 1). Baseline cholesterol levels were similar in both groups. Mean number of antihypertensive medications prescribed in patients with aTRH was 3.5 (SD 0.8) compared to 1.5 (SD

Discussion

The present study shows that in patients with a recent manifestation of vascular disease aTRH, based on the ESH/ESC definition, was associated with an increased risk of cardiovascular death and all-cause mortality. At the age of 50 years, compared to patients without aTRH, patients with aTRH, on average had a 4.1 year shorter median life expectancy and a 6.4 year shorter median life expectancy free of recurrent cardiovascular disease.

Results of the present study correspond to results of a

Acknowledgements

We gratefully acknowledge the contribution of the research nurses; R. van Petersen (data-manager); B. van Dinther (study manager) and the members of the Utrecht Cardiovascular Cohort-Second Manifestations of ARTerial disease-Studygroup (UCC-SMART-Studygroup): F.W. Asselbergs and H.M. Nathoe, Department of Cardiology; G.J. de Borst, Department of Vascular Surgery; M.L. Bots and M.I. Geerlings, Julius Center for Health Sciences and Primary Care; M.H. Emmelot, Department of Geriatrics; P.A. de

Conflicts of interest

Folkert Asselbergs is supported by UCL Hospitals NIHR Biomedical Research Centre. The other authors report no conflicts of interest.

Funding

The UCC- SMART study was financially supported by a grant of the University Medical Center Utrecht.

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