Introduction

Hypertension (HTN) is one of the most common chronic conditions in the United States (US). If a threshold of 130/80 mmHg is used, approximately 45% of US adults have HTN.1 The advent of effective antihypertensive therapies has led to improvements in blood pressure (BP) control and contributed to a reduction in HTN-related mortality.2 However, despite these advances, poorly controlled HTN remains a major health problem with increased risk of damage to vital organs, particularly the heart, brain and kidneys.

Hypertensive crisis (HTNC) is the most extreme form of poorly controlled HTN that can develop in patients with known pre-existing HTN and in individuals who are not aware that they have HTN (i.e. have not yet been diagnosed with HTN). Hypertensive crisis may be an initial manifestation of HTN in those patients.3,4 Hypertensive crisis is defined as a severe and abrupt elevation of BP, which is classified into two types: hypertensive emergency (HTN-E) and hypertensive urgency (HTN-U) based on the presence or absence of acute target organ damage, respectively.5-8 Acute target organ damage is an acute and potentially life-threatening dysfunction affecting cardiovascular, cerebrovascular and renal systems.5,9 A hypertensive emergency is defined as a severe increase in BP associated with potentially life-threatening target organ damage such as myocardial infarction, ischemic stroke, hemorrhagic stroke, pulmonary edema, acute renal injury or aortic dissection.5-8 In this condition, hospitalization, preferably in an intensive care unit, is required for prompt BP control through administration of intravenous antihypertensive medications. Hypertensive urgency, on the other hand, is characterized by equally high BP in the absence of symptoms suggesting acute organ dysfunction.5-8 Hypertensive urgency is a manifestation of uncontrolled HTN that carries little short-term risk,10,11 thus referral to the emergency department (ED), hospitalization and immediate reduction of BP is not necessary.12 These patients can be effectively treated in outpatient settings by institution or intensification of antihypertensive drug therapy.11,12 While HTN-E and HTN-U are often described as two distinct types of HTNC, it still remains unclear whether HTN-E is a more pernicious form of the disease relative to HTN-U or whether they have disparate etiologies.

Historically, "malignant hypertension" described an acute rise in BP accompanied by target organ injuries such as encephalopathy, acute nephropathy and retinopathy (including papilledema and retinal hemorrhages).9 This terminology was listed in the medical lexicon in the 1930s because, at that time, patients with this condition had a prognosis that was similar to patients with many cancers. However, antihypertensive medications that safely lower BP have improved outcomes of severe HTN,13 and, therefore, the term is now considered outdated.

Hypertensive crisis is defined as a severe acute elevation in BP. The levels of BP for the definition of HTNC are not uniformly established. Some studies define HTNC as an elevation of BP to at least 180 mmHg systolic and/or 110 mmHg diastolic,3,14 while others cite higher thresholds (>= 180 and/or >=120 mmHg).15-17 The US guidelines (the 2017 American College of Cardiology/American Heart Association and the Seventh Report of the Joint National Committee) define HTNC as systolic BP >=180 mmHg and/or diastolic BP >=120 mmHg.12,18 However, international guidelines from the 2016 National Heart Foundation of Australia, the 2016 National Institute for Health and Care Excellence, the 2013 and 2018 European Society of Hypertension, and the European Society of Cardiology use >= 180 mmHg systolic and/or >= 110 mmHg diastolic as the definition of the HTNC.19-22 This discrepancy reflects variability in clinical presentations and outcomes of HTNC, as the same degree of blood pressure increase may translate into life-threatening target organ injuries in one patient (HTN-E) or may result in minimal or no symptoms in another patient (HTN-U).5

Hypertensive crisis is relatively common. It is estimated that approximately 1% of patients with hypertension will at some point develop HTNC.13 Acute severe HTN is present in 25% of all ED visits.13 Compared with the frequency of encounters for severely elevated BP, true HTN-E is quite rare. A recent nationwide study demonstrated that the frequency of HTN-E was 0.2% of all adult ED visits in the US.23 Although uncommon, HTN-E accounts for most morbidity and mortality associated with HTNC.

Mortality from HTNC, more precisely from HTN-E, has declined significantly with the widespread use of antihypertensive drugs. The five-year survival rate in patients diagnosed with "malignant HTN" has shown improvement from 37% in 1960 s to 91% in 2000 s.2 Despite this remarkable progress, HTNC carries a significant risk for cardiovascular morbidity and mortality. In a large multi-centered study from the US that included patients with severe acute HTN treated with intravenous therapy, the hospital mortality rate was 6.9%, with a subsequent 90-day mortality of 4.6%.13 More than half of these patients (59%) developed new or worsening end-organ damage, most commonly renal insufficiency, acute heart failure, myocardial ischemia or infarction, and encephalopathy.13 Registry data from Europe revealed 4% mortality (30-day) in patients who required parenteral antihypertensive therapy to control BP, and an overall rate of vital organ injuries of 19%.24

In addition to poor clinical outcomes, hospital admission and readmission rates for patients with HTNC are strikingly high. An analysis of the nationwide inpatient database revealed that there was a 63% increase in the number of admissions for HTN-E from 2002 to 2012 (9511 to 15,479 admissions).25 It was reported that approximately one-third of patients discharged after hospitalization with severe HTN were re-hospitalized within 90 days.13 Rehospitalizations with recurrent severe HTN accounted for 29% of rehospitalizations and tended to occur early (<1 month) after discharge.13 These data suggest that HTNC is responsible for major use of healthcare resources and is a significant economic burden on the system; a large portion of these are directly attributable to recurrent episodes of HTNC.

Hypertensive crisis is associated with adverse patient outcomes and high utilization of healthcare services. In this context, understanding risk factors for the development of HTNC is a first step in improving medical care of hypertensive patients while reducing healthcare burden. Several studies have addressed the effect of non-modifiable (age, sex, ethnicity) and modifiable (medication non-adherence, poor access to medical care, cardiovascular and renal comorbidities) risk factors associated with severely elevated BP. It was reported that male sex, African American race, older age and history of cardiovascular comorbidities increase the likelihood of HTNC.16,17,26-29 Lack of medical insurance and poor access to medical care were found to be the strongest predictors of HNTC in an inner-city minority population where financial barriers to care contribute to the poor control of HTN and subsequent development of HTNC.27 Non-adherence to antihypertensive medications was identified as the most important risk factor for HTNC.3,15,17,30 Patients with comorbid cardiovascular conditions (e.g. coronary artery disease, congestive heart failure), chronic renal failure and obesity had a higher risk for developing HTNC and HTN-E.15,26,31

Despite the growing interest in the risk factors of HTNC and specifically HTN-E, to date no comprehensive appraisal of the evidence has been conducted. A preliminary search of PROSPERO, MEDLINE, the Cochrane Database of Systematic Reviews and the JBI Database of Systematic Reviews and Implementation Reports was conducted and no current or underway systematic reviews on the topic were identified. A systematic review of the available studies will therefore add to the body of knowledge and inform clinicians, healthcare administrators and public health workers on high-risk populations, and assist in creating targeted interventions for these groups.

Review questions

i. What are the modifiable and non-modifiable risk factors for HTNC in adult hypertensive patients?

ii. What are the modifiable and non-modifiable risk factors for HTN-U in adult hypertensive patients?

iii. What are the modifiable and non-modifiable risk factors for HTN-E in adult hypertensive patients?

Inclusion criteria

Population

This review will consider studies that include participants of both sexes who are over 18 years old with the diagnosis of HTN. The review will exclude pediatric, pregnant or immediate postpartum patients as the etiology and risk factors for HTNC are different in these populations.

Exposure of interest

This review will consider studies that explore risk factors for HTNC and hypertensive emergencies. The factors will include non-modifiable (age, sex, ethnicity) and modifiable factors, such as socio-economic factors (e.g. lack of medical insurance, lack of access to medical care), adherence to medical therapies, presence of comorbidities (e.g. diabetes, hyperlipidemia, coronary artery disease, history of stroke, chronic kidney disease, congestive heart failure) and substance abuse.

Outcomes

The primary outcome of interest is incidence of HTNC and its subtypes, HTN-E and HTN-U, measured as odds ratio. The incidence of HTNC, HTN-E and HTN-U will be treated separately, since they are not analogous conditions. Hypertensive crisis will be defined as an acute elevation of BP >= 180 mmHg systolic and/or >= 110 mmHg diastolic. Hypertensive emergency will be defined as an acute elevation of BP >= 180 mmHg systolic and/or >= 110 mmHg diastolic accompanied by acute target organ damage (e.g. myocardial infarction, acute or worsening heart failure, pulmonary edema, ischemic stroke, hemorrhagic stroke, acute kidney injury, aortic dissection, hypertensive encephalopathy, acute hypertensive retinopathy). Hypertensive urgency will be defined as an acute elevation of BP >= 180 mmHg systolic and/or >= 110 mmHg diastolic without evidence of acute target organ damage. The level of BP >= 180 mmHg systolic and/or >= 110 mmHg diastolic will be used since this is the lowest threshold for the definition of HTNC across major guidelines. Studies that do not include these specific BP thresholds will be excluded.

The secondary outcome is the prevalence of non-modifiable and modifiable risk factors measured as an event rate (frequency). Studies that do not report on these specific outcomes of interest will be excluded.

Types of studies

The review will consider epidemiological study designs including prospective and retrospective cohort studies, case control studies and analytical cross-sectional studies.

Methods

The proposed systematic review will be conducted in accordance with the Joanna Briggs Institute methodology for systematic reviews of etiology and risk.32,33

Search strategy

The search strategy aims to find both published and unpublished studies. A three-step search strategy will be utilized in this review. An initial limited search of MEDLINE will be undertaken followed by an analysis of the text words contained in the title and abstract, and of the index terms used to describe each article. A second search using all identified keywords and index terms will then be undertaken across all included databases. The MEDLINE (Ovid) search strategy is shown in Appendix I. Thirdly, the reference lists of all identified reports and articles will be searched for additional studies. Only studies published in English language and available in full text will be considered for inclusion in this review. A search range based on the year of publication will not be set to allow greater sensitivity.

Information sources

The databases to be searched include: MEDLINE (Ovid), Embase, Cochrane Database of Systematic Reviews, Web of Science and CINAHL (EBSCO). The search for unpublished studies will include: ProQuest Dissertation and Theses, the directory of gray literature via the New York Academy of Medicine website, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform (who.int), opengrey.eu, greynet.org, Institute of Medicine reports (nationalacademies.org), Google Scholar/MedNar, websites of World Hypertension League, American Heart Association, American College of Cardiology, International Society of Hypertension, European Society of Hypertension, and American Society of Hypertension.

Study selection

Following the search, all identified citations will be collated and uploaded into EndNote X9 (Clarivate Analytics, PA, USA) and duplicates removed. Titles and abstracts will then be screened by two independent reviewers for assessment against the inclusion criteria for the review. Studies that may meet the inclusion criteria will be retrieved in full and their details imported into JBI System for the Unified Management, Assessment and Review of Information (JBI SUMARI; Joanna Briggs Institute, Adelaide, Australia). The full text of selected studies will be retrieved and assessed in detail against the inclusion criteria. Full-text studies that do not meet the inclusion criteria will be excluded and reasons for exclusion will be provided in an appendix in the final systematic review. The results of the search will be reported in full in the final report and presented in a Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) flow diagram.34 Any disagreements that arise between the reviewers (IB, FAW) will be resolved through discussion or with a third reviewer (YTJ, CH).

Assessment of methodological quality

Selected studies will be critically appraised by two independent reviewers (IB, FAW) at the study level for methodological quality in the review using standardized critical appraisal instruments from the JBI.32 Authors of papers will be contacted to request missing or additional data for clarification, where required. Any disagreements that arise will be resolved through discussion or with a third reviewer (YTJ, CH). The results of critical appraisal will be reported in narrative form and in a table. The assessment of methodological quality will contribute to an evaluation of the quality of the evidence and impact of bias on the findings. No studies will be excluded based on methodological quality.

Data extraction

Data will be extracted from papers included in the review using the standardized data extraction tools in JBI SUMARI32 by two independent reviewers (IB, FAW). The data extracted will include specific details about the exposure of interest including different exposure categories if applicable, populations, study methods and outcomes or dependent variables of significance to the review question and specific objectives. Any disagreements that arise between the reviewers will be resolved through discussion or with a third reviewer (YJT, CH). Authors of papers will be contacted to request missing or additional data, where required.

Data synthesis

Quantitative data will, where possible, be pooled in statistical meta-analysis. All results will be subject to double data entry. Where effect sizes are expressed as odd ratios, relative ratios, correlation coefficients or rates, OpenMeta [Analyst] software will be used for statistical pooling. For studies that report only the results of regression analyses, the authors will aim to extract the maximally adjusted effect sizes for the predictors of interest to facilitate greater comparability of the effect size data across studies. Effect sizes expressed as odds ratio (for categorical data) and their 95% confidence intervals will be calculated for analysis. Heterogeneity will be assessed statistically using Q-statistic, which will provide a test of the null hypothesis that all included studies in the analysis share a common effect size. The I² statistics will be calculated to estimate what proportion of the observed variance reflects differences in true effect sizes rather than a sampling error. All studies that report on HTNC, HTN-E or HTN-U based on the threshold of >= 180 mmHg systolic and/or >= 110 mmHg diastolic pressure will initially be pooled into one meta-analysis, which will provide evidence of the impact of the risk factors on the outcome of HTNC (since both HTN-U and HTN-E meet the threshold of hypertensive crisis). Data from studies that provide detailed definitions for distinguishing between the outcomes of HTN-E versus HTN-U will then be pooled separately using subgroup analysis to determine the association of the risk factors with these two outcomes. The evidence of end-organ damage will be used to determine how to classify studies for the subgroup analyses. Where statistical pooling is not possible, the findings will be presented in narrative form including tables and figures to aid in data presentation where appropriate.

Assessing certainty in the findings

A Summary of Findings (SoF) will be created using the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach to grade the quality of evidence. The SoF will present the following information where appropriate: estimates of relative risk and a ranking of the quality of the evidence based on study limitations (risk of bias), indirectness, inconsistency, imprecision and publication bias. The following outcomes will be included in the SoF: risk of HTNC, risk of HTN-U and risk of HTN-E.

Appendix I: Search strategy for MEDLINE (Ovid)

1. Exp Hypertension, Malignant/

2. Hypertension/co [Complications]

3. malignant hypertension.mp

4. hypertensive emergenc^*.mp

5. hypertensive urgenc^*.mp

6. accelerated hypertens^*.mp

7. severely elevated blood pressure.mp

8. severely elevated hypertens^*.mp

9. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8

10. Exp Risk Factors/

11. Risk Assessment/

12. Exp Population Characteristics/

13. Exp Epidemiology/ cl, do, mt, pc, st, sn, td [classification, diagnosis, methods, prevention, standards, statistics, trends]

14. risk factor^*.mp

15. predict^*.mp

16. characteristic^*.mp

17. epidemiolog^*.mp

18. profile.mp

19. 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18

20. Exp Adult/

21. Young adult/

22. adult^*.mp

23. 20 or 21 or 22

24. 9 and 19 and 23

References