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Which Target Blood Pressure in Year 2018? Evidence from Recent Clinical Trials

  • Sondre Heimark
  • Julian E. Mariampillai
  • Krzysztof Narkiewicz
  • Peter M. Nilsson
  • Sverre E. Kjeldsen
Review Article

Abstract

The Systolic Blood Pressure Intervention Trial (SPRINT) suggested a favourable effect of lowering blood pressure to < 120/80 mmHg in high-risk hypertensive patients; however, new American guidelines in 2017 have not followed SPRINT but lowered its recommended treatment target to < 130/80 mmHg. We aimed to review the latest research from large randomised controlled trials and observational analyses in order to investigate the evidence for new treatment targets. We assessed recent data from the Action to Control Cardiovascular Risk in Diabetes Blood Pressure (ACCORD) study, the International Verapamil-Trandolapril Study (INVEST), the Telmisartan, Ramipril or Both in Patients at High Risk for Vascular Events trial (ONTARGET)/the Telmisartan Randomised AssessmenNt Study in aCE iNtolerant participants with cardiovascular Disease (TRANSCEND) study and The Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) study. These studies confirm a positive effect on cardiovascular protection with blood pressure lowering treatment to between 120–140 mmHg in patients with and without diabetes, but no additional effect of lowering blood pressure to < 120 mmHg; possibly too aggressive treatment may increase both cardiovascular morbidity and mortality. Thus, a target blood pressure < 130/80 mmHg appears appropriate in most high-risk hypertensive patients. Additionally, early and sustained BP control below this target is required for optimal cardiovascular protection.

Keywords

Antihypertensive drug-treatment Antihypertensive therapy Blood pressure measurement Blood pressure target Cardiovascular disease Hypertension Randomized controlled trial 

1 Introduction

Recent studies have led to regained attention regarding blood pressure (BP) treatment targets, and the debate on whether an aggressive or a conservative approach is most favourable is yet again under scrutiny. In the aftermath of the publication of the Systolic Blood Pressure Intervention Trial (SPRINT) study in the fall of 2015 [1], the tendency towards more aggressive BP control grew stronger. The results of SPRINT, apparent target BP of 120/80 mmHg in high-risk hypertensive patients, gained widespread attention upon its publication [2, 3], both within the academic community [4, 5] and in the tabloid press [6, 7], but the SPRINT results has also met considerable criticism [8], amongst several aspects (Table 1), due to its unattended BP measurement method [9]. Still, latest American guidelines recently published [10], lowered its recommended treatment target from previous guidelines to ≤ 130/80 mmHg, but not to 120/80 mmHg. We have recently published a comprehensive review of the most important clinical trials and observational studies in hypertension research where we recommended early and sustained blood pressure control rather than too aggressive treatment, though a target BP of 130/80 mmHg appears prudent in light of the trial outcomes [11]. There is now need for an update, and the aim of this review is to assess the latest analyses from the major clinical trials and observational studies in hypertension research in light of the recent American guidelines of 2017 and the SPRINT publication and the extensive debate which followed.
Table 1

Overview of the Systolic Blood Pressure Intervention Trial (SPRINT)—(a) findings reported by the investigators, (b) data taken from their main publication, (c) our comments or concerns, and d) results from the Latest Observational Analyses of Interventional Trials (study acronyms, findings and characteristics of patients)

(a) Findings reported by the investigators

(b) Data in the main publication

(c) Our comments or concerns

The primary endpoint: 25% reduction

76 less patients in < 120 vs. < 140 mmHg arm

Caused by including heart failure

The heart failure finding: 33% reduction

38 less patients in 120 vs. 140 mmHg arm

Should not be part of primary endpoint

The total mortality finding: 27% reduction

55 less patients in 120 vs. 140 mmHg arm

CV n = 28, non-CV n = 27; non specific finding

The side effect: no difference in “serious”

Hypotension: 65 more patientsa

Large number of adverse events—typical aggressive diuretic treatment versus diuretic withdrawal

 

Syncope: 50 more patientsa

 
 

Orthostatic hypotension: 80 more patientsa

 
 

Acute renal failure: 84 more patientsa

 
 

Se-Na+ below 130 mmol/L: 80 more patientsa

 
 

Se-K+ below 3.0 mmol/L: 40 more patientsa

 

Blood pressure taken after 5 minutes of quiet rest

Automated measurement with Omron 907

Unattended, staff left the room for 5 min—a method not validated against endpoints

 

At year 1 achieved BP 121 vs. 136 mmHg

Corrected to be 132 vs. 144 mmHg

(d) Study acronym new analyses

Findings

Characteristics of patients

ACCORDb

 

Patients with diabetes mellitus

 

Optimal target SBP between 120 and 140 mmHg

 
 

SBP < 120 mmHg shows no increase in CV risk or benefit

 

INVESTb

  
 

Optimal target SBP between 120 and 140 mmHg

Patients with coronary heart disease

 

SBP < 120 mmHg shows increased mortality

 

ONTARGETb/TRANSCENDb

 

Patients with “high risk”

 

Optimal target SBP between 120 and 140 mmHg

 
 

SBP < 120 mmHg shows increased risk

 

LIFEb

 

Patients with left ventricular hypertrophy

 

Optimal target SBP above 130 mmHg

 
 

SBP < 130 mmHg shows increased mortality with higher baseline SBP

 

HOPE-3b

Benefit of drug treatment if baseline SBP > 143.4 mmHg

Intermediate risk without CV disease

CV cardiovascular, SBP systolic blood pressure

aIn intensive treatment arm vs. standard treatment arm

bAcronyms are defined in “Methods” section

2 Methods

We assessed the following major studies to assess for new evidence concerning standard or intensive blood pressure treatment regarding cardiovascular disease (CVD) risk: the SPRINT study, the Action to Control Cardiovascular Risk in Diabetes Blood Pressure (ACCORD) study, the International Verapamil-Trandolapril Study (INVEST), the Telmisartan, Ramipril or Both in Patients at High Risk for Vascular Events trial (ONTARGET)/ the Telmisartan Randomised AssessmenNt Study in aCE iNtolerant participants with cardiovascular Disease (TRANSEND) study and The Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) Study. These are the most important interventional and observational studies in the field that have performed additional analyses aimed to investigate the optimal BP targets in high-risk hypertensive patients. The scope of this review is the newest analyses from these studies, as previous results have been reported and reviewed earlier [11].

3 ACCORD BP

The ACCORD trial included 4733 patients in an open-label, multi-centre randomised controlled trial with the aim of investigating optimal BP treatment target in patients with diabetes mellitus (DM) and established CVD or high risk of CVD. Patients were randomised to a standard treatment arm with target BP < 140 mmHg or an intensive treatment arm with target BP < 120 mmHg, and the results showed a non-significant reduction in the primary endpoint in the intensive treatment arm (p = 0.20). Concerning the secondary outcome, fatal and non-fatal stroke, the intensive treatment arm did show a significant risk reduction, p = 0.03 and p = 0.01, for fatal stroke and stroke of any kind, respectively. To further investigate the possibly beneficial effect of standard or intensive blood pressure treatment, Hartaigh et al. grouped the patients in the two treatment arms according to whether or not they achieved their BP goals [12]. During a median follow up of 5.0 years, 1939 (82%) and 2038 (86%) achieved their BP targets in the intensive and standard treatment arms, respectively. Achieving target BP was defined as having had three consecutive BP measurements below their respective targets, and the primary endpoint was a composite of major adverse cardiovascular events (MACE) that consisted of CV mortality, nonfatal myocardial infarction (MI) and nonfatal stroke. All-cause mortality was assessed as a secondary outcome. In univariate Cox regression models, achieving target BP compared to not achieving target BP reduced all-cause mortality, risk of MACE and all of its components except non-fatal MI in the standard group. In the intensive group, only risk of MACE and non-fatal stroke was significantly reduced in the same model. When adjusting for age, education, diastolic BP, glycosylated haemoglobin, intensive glycemic arm, low density lipoprotein (LDL)- and high density lipoprotein (HDL)-cholesterol and urine albumin/creatinine-ratio in multivariate Cox regression models, there was no risk reduction in the intensive arm, and significant reduction in MACE, all-cause death and non-fatal stroke in the standard arm. With the same adjusted analysis, achieving BP < 120 mmHg and between 120 and 140 mmHg in the intensive arm resulted in a non-significant HR of 0.91 and 0.70, respectively, compared to BP > 140 mmHg. In the standard treatment arm, having BP between 120 and 140 mmHg resulted in a significant 35% reduction in adjusted risk of MACE, while BP < 120 mmHg resulted in a non-significant 5% increase in MACE, compared to BP > 140 mmHg. For the overall study population, achieving SBP between 120–140 mmHg resulted in the lowest risk of MACE (HR 0.66, 95% CI 0.52–0.84).

4 INVEST

The INVEST study randomised 17,131 patients aged at least 50 years with essential hypertension and stable coronary artery disease (CAD) to either verapamil- or atenolol-based regimens in order to achieve BP control and found no statistically significant difference between the two drug regimens [13]. Wokhlu et al. recently published an analysis of diastolic BP (DBP) in relation to different SBP categories to investigate whether lower DBP increased risk of all-cause mortality in the same cohort [14]. Patients from the INVEST trial were first categorised in four different SBP categories: < 120, 120 to < 130, 130 to < 140, and ≥ 140 mmHg. For each SBP category, they further subdivided the participants into tertiles of DBP: low, middle or high. Chi-square tests were used to compare cumulative all-cause mortality between groups, and HR were calculated using a Cox regression model adjusting for average heart rate, age, sex, race, and history of MI, DM, congestive heart failure, renal insufficiency and stroke. Among patients with SBP < 120 mmHg, concomitant low DBP (≤ 69 mmHg) was significantly associated with increased mortality (HR 1.60, CI 1.33–1.91, p ≤ 0.0001), compared to SBP 120 to ≤ 130 mmHg, and DBP ≥ 79 mmHg as reference. In the SBP range 120–140 mmHg there was no significant increase in mortality across all tertiles of DBP, but among patients with SBP > 140 mmHg there was higher risk of mortality across all DBP tertiles, however, only significant in the highest tertile (HR 1.46, CI 1.28–1.66, p ≤ 0.0001). Similar results were found using the middle DBP tertile within each SBP group as reference. Within the SBP < 120 mmHg group, the low DBP tertile remained significantly associated with increased risk of mortality (HR 1.40, CI 1.10–1.79, p = 0.0064). No increase in risk of mortality across the DBP tertiles was found in patients with SBP 120–140 mmHg, and with SBP > 140 mmHg. The highest DBP tertile remained significantly associated with increased risk (HR 1.21, CI 1.10–1.37, p = 0.0002).

5 ONTARGET/TRANSCEND

In the ONTARGET study more than 25,000 patients with CVD or high-risk DM were randomised to telmisartan (angiotensin II receptor antagonist), ramipril (angiotensin converting enzyme inhibitor), or a combination of the two, but no significant superiority where found regarding CVD events [15]. Böhm et al. have recently reviewed data from both ONTARGET and TRANSCEND, where 5810 patients intolerant to ACE-inhibitors were assigned to telmisartan or placebo, providing a total of more than 30,000 patients in a post-hoc observational analysis [16]. They aimed to investigate associations between different baseline BPs, mean achieved BPs and time-updated BPs (BP value from last measurement before an event or at the end of the study) for risk of a composite outcome of cardiovascular death, MI, stroke and hospital admission for heart failure, as well as its individual components and the secondary outcome all-cause mortality. As there was no difference in outcome between the groups in the original trials, all patients were pooled in the analyses by Böhm et al., and split in to SBP categories; < 120, 120 to < 140, 140 to < 160, and ≥ 160 mmHg, and DBP categories; < 70, 70 to < 80, 80 to < 90, and ≥ 90 mmHg. Yearly event rates and Kaplan-Meier curves were analysed by SBP categories and tested for differences using a Cox regression model adjusted for heart rate, age, sex, body-mass index, renal function, physical activity, education, alcohol consumption, tobacco use, history of hypertension, history of DM, MI, stroke or transient ischemic attack, heart rhythm, concomitant medications, and study medications. Patients with higher baseline SBP were older, had higher body-mass index, and higher prevalence of hypertension, diabetes mellitus or history of stroke. SBP ≥ 120 to < 140 mmHg and DBP ≥ 70 to < 80 mmHg was used as reference. The lowest risk of the primary endpoint, all of its components and all-cause mortality was observed with mean achieved SBP between 120 and 140 mmHg. Reduction of mean achieved SBP to less than 120 mmHg was associated with significantly increased risk of CV mortality, hospital admission for heart failure and all-cause mortality. Similar patterns were observed with DBP, in which DBP < 70 mmHg was associated with a higher risk of MI and hospital admission for heart failure. Baseline values did not reveal a significant difference in SBP < 120 mmHg, and the highest risk was observed with baseline DBP < 70 mmHg for all outcomes except stroke. Further analysis using SBP as a continuous variable with cubic spline regression revealed a non-linear relationship between endpoints and baseline SBP, as well as achieved SBP. Risk of the primary endpoint increased from 140 mmHg, used as reference point, to lower mean achieved SBP, but not for MI or stroke. However, lower DBP showed increased risk of the primary endpoint, MI, hospital admission for heart failure and all-cause death both with baseline and achieved, but no significant increase in risk of stroke.

6 LIFE

The LIFE Study was a randomised, triple-blinded, parallel study to investigate the effect of losartan versus atenolol on the reduction of morbidity and mortality in hypertensive patients with left ventricular hypertrophy on electrocardiogram [17]. In the original study, there was a significantly lower risk of mortality and morbidity in the losartan group compared to the atenolol group, indicating an effect of losartan beyond the blood pressure reduction per se. Okin et al. found that SBP < 130 mmHg was associated with a significantly increased risk of death and a trend towards higher CV mortality [18], differing from most recent research, and SPRINT in particular. In a recent analysis, Okin et al. aimed to assess possible implications of high baseline SBP on CV risk [19], as mean baseline SBP in SPRINT was 140 mmHg and one third of the patients had 132 mmHg or less at baseline while LIFE included patients with higher baseline SBP.

As participants with diabetes were excluded in the present analysis, the study included about 8000 participants with left ventricular hypertrophy and baseline BP at 160–200/95–115 mmHg. Participants were divided at the 25-percentile of baseline SBP (164 mmHg) and again in tertiles of on-treatment SBP, used in Cox regression analyses. The study showed a relation between all-cause mortality and baseline SBP, as participants in the lowest on-treatment tertile had reduced risk of all-cause mortality if belonging to the group with baseline SBP in the lowest 25-percentile (multivariate adjusted HR 0.60, CI 0.36–0.99) when comparing to the highest on-treatment tertile in a multivariate Cox regression analysis. However, among the 75% of participants with the highest baseline SBP (above 164 mmHg), participants in the lowest on-treatment tertile (< 142 mmHg) had increased risk of all-cause mortality (multivariate adjusted HR 1.32, CI 1.01–1.65). The participants with baseline SBP above 25-percentile were older, had higher total cholesterol and greater albuminuria. The results of the study indicated that in older patients with left ventricular hypertrophy and with high baseline SBP, too intensive BP reduction might lead to increased mortality.

7 Discussion

In the present overview, we have reviewed the newest evidence on blood pressure treatment target derived from the latest research in 2017, assessing post-hoc observational analyses of prospective interventional studies (Fig. 1). Being post-hoc analyses is thus the limitation of this approach. Nonetheless, the studies provide important indications for optimal treatment targets. In ACCORD, achieving SBP < 140 mmHg significantly reduces CV risk, compared to not achieving target, whereas whether or not patients achieve target < 120 mmHg or not, had no impact on CV risk. Analyses of all patients pooled showed that the optimal target SBP was 120–140 mmHg, but with no further increase in risk reduction with SBP < 120 mmHg among all patients. Similar results were established by Brunström and Carlberg [20] in a systematic review and meta-analysis where the greatest risk reduction for all-cause mortality among patients with DM was achieved with SBP between 130-140 mmHg.
Fig. 1

Arrows indicate optimal systolic blood pressure treatment target, mmHg, based on results from the respective studies, as well as recommended treatment target from American guidelines from 2017. Acronyms are defined in “Methods” section. SPRINT, corr: treatment target when translating blood pressure results into standard office measurement technique

With the abovementioned analysis in mind, “the lower-the better” strategy for hypertensive patients with DM might not be supported [21]. Still, the authors from the recent ACCORD analysis state that this is a matter in need of further studies [12], and that these results, however, must be interpreted in light of the fact that ACCORD was statistically underpowered in event rates and had an open-label design.

The recent analysis from the INVEST database also supports SBP treatment target between 120 and 140 mmHg, finding increased mortality with both SBP < 120 and > 140 mmHg and concomitant low DBP (≤ 69 mmHg) in older patients with CAD. Between 120 and 140 mmHg, concomitantly low DBP does not show increased risk. There are limited randomised controlled trials on equally low DBP and mortality, but low DBP has been observed in multiple studies to be associated with increased CV risk and mortality, although the evidence is conflicting [22, 23, 24, 25, 26, 27, 28]. The underlying mechanism(s) as to why there may be a J-shaped risk curve concerning DBP remains unknown, but the fact that coronary blood flow is dependent on DBP may play a significant role. However, a limitation in several studies is the possibility that the combination of low SBP and DBP could be a marker of co-morbidity, thus reverse causality could not be ruled out and further research is needed. Although the recent analysis from INVEST is limited to being observational, these results showed no further reduction in mortality with SBP < 120 mmHg, and warrant careful consideration in older patients with CAD when choosing intensity of target BP. On the contrary, the observations from the ONTARGET and TRANSCEND trials indicate increased risk of cardiovascular and all-cause mortality with SBP < 120 mmHg, at least in patients with known CV disease and a high prevalence of hypertension. The lowest risk for the primary endpoint and all of its components were observed at SBP between 120–140 mmHg, with a nadir at approximately 130 mmHg. Interestingly, risk of stroke was not significantly reduced with lower baseline or mean achieved either SBP or DBP, consistent with the observations by Verdecchia et al. [29] when risk of stroke related to changes in systolic BP and diastolic BP was investigated.

Regardless of the results of the abovementioned studies, most attention has been drawn towards the results from SPRINT, suggesting reduced CV risk with SBP treatment target < 120 mmHg [2]. The major issue regarding SPRINT is the new blood pressure measurement method introduced, performing measurements with a semi-automated device without staff in the room (Table 1). The automated measurements have been known to average significantly lower than standard office or 24-h ambulatory BP measurements [30, 31], and even in a sub-group analysis in SPRINT, the unattended measurements averaged below 24-h ambulatory measurements [32]. When translating SPRINT measurements to standard office measurements, the treatment targets in clinical practice are more likely 132 vs. 144 mmHg [32]. It is important to remember that we are not treating office BP, but rather an increased risk of CV disease reflecting the everyday BP variation. Office BP is only a surrogate for this, though an extremely well validated one, and by altering the premises completely as in the SPRINT study, one must find new references for our surrogate. In the future, the unattended measurement might reveal itself to be a better marker for disease, but presently there is not enough evidence, hardly any, to make conclusions on the SPRINT study measurement technique.

In SPRINT, there were only 76 participants more in the standard treatment arm having an event of the primary endpoint, of which 50% had incident heart failure (Table 1), possibly contributing to the apparent superiority of intensive BP lowering [8]. The study design may also have contributed to de-masking compensated heart failure, as some participants were down-titrated on diuretics in order to achieve treatment arm BP target. In a properly blinded study, this may have had no impact, but it is reasonable to question this effect in an open-label study as SPRINT.

There were 55 less cases of mortality in the intensive treatment arm compared to the standard treatment arm, divided in 28 cardiovascular and 27 non-cardiovascular cases (Table 1). There were 25% more visits in the intensive treatment arm in order to titrate BP medication, and differences in mortality data may be due to non-specific effect of intervention, leading to possibly false conclusions.

SPRINT results also showed significantly higher rates of treatment-related adverse events in the intensive treatment arm, actually outnumbering patients with the primary endpoint (Table 1). In a post-hoc analysis from Ireland, patients older than 75 years who met the inclusion criteria for SPRINT had a five-fold higher rate of serious adverse effect than the standard treatment arm in SPRINT [33], visualising the potential harm that could follow a more aggressive treatment recommendation, especially in the elderly. Increasing rates of side effects could lead to discontinuation of medications and it is well known that poor compliance is a major cause for not achieving BP control [34, 35], possibly promoting less intensive treatment as a consequence of preventing extensive side effects. Also, a recent post-hoc analysis from SPRINT even indicates increased CV risk when aggressively lowering SBP in patients with high baseline BP [36].

Mean baseline SBP in SPRINT was 140 mmHg, and one third of the patients had baseline SBP < 132 mmHg. In light of this, the question has been raised on whether the results from SPRINT in part could be explained by a selection of patients with low baseline SBP in whom intensive BP lowering is well tolerated compared to patients with higher baseline SBP. Okin et al. recently addressed this issue in an analysis on patient data from the LIFE study [19], indicating that risk of all-cause mortality with on-treatment SBP < 142 mmHg was significantly related to baseline SBP, and that patients with high baseline BP did not tolerate intensive BP lowering. Such findings could not be demonstrated in SPRINT, however, the results are not directly comparable to the findings from LIFE, as initial BP levels in SPRINT were analysed on-treatment and > 90% were already receiving anti-hypertensive medications, thus having significantly lower BP levels at baseline than LIFE. It should be noted that no patients with diabetes were included in the SPRINT study; for this reason the findings of this trial do not apply to diabetic patients.

Finally, results of the Heart Outcomes Prevention Evaluation (HOPE)-3 trial could be mentioned in this discussion [37]. The HOPE-3 investigators compared candesartan/hydrochlorothiazid combination with placebo in 12,705 people with intermediate risk but without established cardiovascular disease. The blood pressure lowering medication did not lower CV complications in the overall population which had average blood pressure at baseline of 138.1/81.9 mmHg; however, CV complications were lowered in the pre-specified subgroup of upper one third of blood pressure (> 143.5 mmHg) at baseline. Though the HOPE-3 population was healthier than the other study populations discussed above, this is an additional argument against antihypertensive drug treatment of people with normal blood pressure below 140 mmHg.

8 Summary

In summary, recent analysis from large databases of hypertensive patients in which standard office BP measurements have been used, in contrast to the unattended automated measurements in SPRINT, continue to indicate either increased risk or no further benefit with SBP < 120 mmHg. Optimal treatment targets from ACCORD, INVEST and ONTARGET appear to be between 120 and 140 mmHg. Correspondingly, a comprehensive meta-analysis [38] of 17 trials including SPRINT, aiming at assessing optimal BP targets, concluded that 130 mmHg achieved the optimal balance with respect to efficacy and safety. In 2017, the American College of Cardiologist/American Heart Association (ACC/AHA) updated their hypertension clinical guidelines recommending BP target of < 130/80 mmHg across all patient groups where BP lowering is indicated, with both general indications and recommendations regarding patient groups with specific comorbidities only differing in the strength of recommendations [10]. In addition to the abovementioned meta-analysis, evidence originates from other updated systematic reviews and meta-analyses [38, 39, 40, 41, 42]. Still, European latest hypertension guidelines from European Society of Hypertension (ESH) and European Society of Cardiology (ESC) from 2013 recommend a treatment target of < 140/90 mmHg, which in our opinion and according to published data should change to < 130/80 mmHg in the 2018 edition, thus harmonizing guidelines recommendations across the Atlantic [43].

9 Conclusion

In conclusion, data from new analyses from large BP trials, though observational and post-hoc in design, continue to disclose either increased risk or no-benefit with more intensive BP treatment strategies, and show that the overall nadir in risk reduction occurs between 120 and 140 mmHg in systolic BP. Considering the results from the large meta-analysis [18, 34, 35, 36, 37, 38], there seems to be little evidence in support of further reduction in BP to < 120/80 mmHg. Additionally we persistently emphasise early and sustained BP control [9] rather than too aggressive BP reduction for optimal cardiovascular prevention.

Notes

Compliance with Ethical Standards

Funding

No funding has been received in support of writing this article.

Conflict of interest

The two first authors have no conflict of interest to disclose. Peter M Nilsson has received speaking honoraria from Novo Nordisk, Merck, AstraZeneca and Boehringer-Ingelheim over past 3 years. Krzysztof Narkiewicz has received speaking honoraria from Berlin-Chemie/Menarini, Egis, Gedeon Richter, Krka and Servier. Sverre E. Kjeldsen has within the past 3 years received speaking honoraria from Bayer, MSD, Sanofi and Takeda.

Ethical approval

This article does not contain data derived by any current studies with human participants performed by any of the authors. The clinical studies mentioned were provided with specific ethical approval.

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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Sondre Heimark
    • 1
  • Julian E. Mariampillai
    • 2
  • Krzysztof Narkiewicz
    • 3
  • Peter M. Nilsson
    • 4
  • Sverre E. Kjeldsen
    • 5
    • 6
  1. 1.Department of MedicineDiakonhjemmet HospitalOsloNorway
  2. 2.Department of Emergency MedicineUllevaal University HospitalOsloNorway
  3. 3.Department of Hypertension and DiabetologyMedical University of GdanskGdańskPoland
  4. 4.Department of Clinical SciencesSkåne University HospitalMalmöSweden
  5. 5.Department of CardiologyUllevaal University HospitalOsloNorway
  6. 6.Institute of Clinical Medicine, Medical FacultyUniversity of OsloOsloNorway

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