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Outcomes after hypertensive crisis: Comparison between diabetics and nondiabetics
Outcomes after hypertensive crisis: nondiabetics
Comparison between diabetics and
Rashed Al Bannay, Aysha Husain, Michael B¨ohm, Stefan Wagenpfeil PII: DOI: Reference:
S2214-7624(15)00014-6 doi: 10.1016/j.ijcme.2015.03.003 IJCME 69
To appear in:
International Journal of Cardiology
Received date: Revised date: Accepted date:
27 July 2014 12 December 2014 4 March 2015
Please cite this article as: Al Bannay Rashed, Husain Aysha, B¨ohm Michael, Wagenpfeil Stefan, Outcomes after hypertensive crisis: Comparison between diabetics and nondiabetics, International Journal of Cardiology (2015), doi: 10.1016/j.ijcme.2015.03.003
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Outcomes after hypertensive crisis: comparison between diabetics and nondiabetics.
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Rashed Al Bannay1, Aysha Husain2, Michael Böhm3 , Stefan Wagenpfeil4
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Running title: Outcome of hypertensive crisis
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Address for correspondence:
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Rashed Al Bannay, MD Consultant Adult Cardiology, Cardiology Unit,
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Internal Medicine Department,
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Salmaniya Medical Complex, Bahrain.
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Assistant Professor, Internal Medicine Department Arabian Gulf University.
[email protected] Tel: 0097339669406
Fax: 0097317251303 P.O box 12, Manama, Kingdom of Bahrain 1
Al Bannay R: Consultant Adult Cardiology, Salmaniya Medical Complex, Bahrain, Kingdom of
Bahrain. 2
Husain A: Adult Cardiology fellow, Heart Center, King Faisal Hospital and Research center,
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Riyadh, Kingdom of Saudi Arabia. Böhm M: Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, DE-66424
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3
4
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Homburg, Germany.
Wagenpfeil S: Institut für Medizinische Biometrie, Epidemiologie und Medizinische Informatik,
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Universitätsklinikum des Saarlandes, D-66421 Homburg, Germany.
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The authors of this manuscript declare no conflict of interests.
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Key words: Hypertensive crisis, Hypertensive urgency, Hypertensive emergency, Diabetes
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mellitus, Hypertensive left ventricular failure
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Abstract
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Objective:
To study the long-term cardiovascular and non-cardiovascular outcomes among patients
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admitted with hypertensive crisis.
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Methods:
A total of 297 (145 diabetics, 152 nondiabetics) patients with hypertensive crisis were followed
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up for a median of 30 months. Fatal and nonfatal events were tracked. The traced events
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defined as hypertensive urgency, acute coronary syndrome, left ventricular failure, atrial
Results:
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fibrillation, cerebrovascular or renal failure were consecutively analyzed during the follow-up.
Overall, 140 (47%) patients had nonfatal clinical events (115 diabetics and 25 nondiabetics); 37 (12%) patients had fatal clinical events (26 diabetics and 11 nondiabetics). The rate of fatal and nonfatal events was significantly higher in diabetics. The mean time of survival was 25.7 months, with the shortest periods for stroke and left ventricular failure. For nondiabetic participants, the mean time of survival was 31 months. Cox regression analysis identified diabetes mellitus, acute left ventricular failure, stroke and renal impairment as predictors of mortality. Conclusion
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Hypertensive crisis is associated with a markedly increased risk for subsequent cardiovascular
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morbidity and mortality, especially among diabetics who present with heart failure.
Introduction
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Hypertensive crisis is defined as acute marked elevation of blood pressure, SBP ≥180 mmHg
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and/or DBP ≥ 120 mmHg. Hypertensive emergency is diagnosed, when there is acute target damage and hypertensive urgency when the latter is absent. (1, 2) Previously we studied the
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behavior of hypertensive crisis in our community. (3-6) The clinical presentation of hypertensive
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crisis between diabetics and nondiabetics was compared. (4) Patients with diabetes exhibited higher rates of hypertensive emergency, particularly, left ventricular failure. (4) There is little if
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any knowledge of whether the prognoses and outcomes of hypertensive crisis differ between diabetics and nondiabetics. In this study, we aimed to discover the clinical outcomes of hypertensive crisis in both diabetics and nondiabetics beyond their initial clinical presentation. Methods
All patients age above 18 years, visited the accident and emergency department with hypertensive crisis for a period of 6 months, from 1st June 2010 till 31st December 2010 were consecutively included. Patients with end stage renal failure requiring renal replacement therapy were excluded. Data on 297 patients were collected, 145 patients were diabetics, and 152 were nondiabetics. The initial comparison of their modes of presentation, types of hypertensive crises and associated comorbidities were published earlier. (4)
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These patients were followed for a period of 32 months from their initial presentation. Cardiovascular and cerebrovascular events requiring admission, development or worsening of
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renal failure requiring admission and commencement of renal replacement therapy were tracked
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using electronic data records along with chart retrieval.
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Mortality was documented based on electronic medical records and patient death certificates. Causes of death were retrieved from the official death certificates. To validate the status of
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patients who were lost during follow-up, phone calls at the time of data collection were made to gather meticulous information regarding admissions and deaths. The time from the initial
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hypertensive crisis presentation until the occurrence of each event was documented. Hypertensive crisis was defined based on the Joint National Committee on Prevention,
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Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) and the latest guidelines
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of the European Society of Hypertension (ESH) guidelines of systolic blood pressure ≥ 180
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mmHg and diastolic blood pressure of ≥ 120 mmHg. The presence or absence of acute target organ damage was the basis for defining hypertensive emergency versus urgency, respectively. (1, 2) A patient was considered to have diabetes if two readings of fasting blood glucose, taken on separate occasions, exceeded 7 mmol/L, if symptoms of diabetes occurred with casual plasma glucose concentration ≥200 mg/dl (11.1 mmol/L), or if the 2-hour post-load glucose level was ≥200 mg/dl (11.1 mmol/L) during an oral glucose tolerance test (OGTT). (7) Dyslipidemia (hypercholesterolemia) was diagnosed if the total cholesterol level exceeded 200 mg/dl. (8) Acute stroke was defined if the patient was admitted to the hospital because of neurological deficits for more than 24 hours and the radiology imaging of the brain revealed an ischemic or hemorrhagic area. (9) The definition of acute coronary syndrome was based on typical chest pain with electrocardiogram (ECG) changes with or without elevated cardiac enzymes. We involved patients with unstable angina, non-ST-elevation myocardial infarction (NSTEMI) and
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ST-elevation myocardial infarction (STEMI). (10-12) Left ventricular failure was defined according to the Framingham criteria. The presence of two major criteria or one major and two
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minor criteria were satisfactory for diagnosing left ventricular failure or congestive heart failure.
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(13) Chronic renal impairment was diagnosed when the estimated glomerular filtration rate
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(GFR) was <60 ml/min/1.73 m2. (14) Acute renal failure and worsening kidney function were validated using the RIFLE criteria for acute kidney injury. (15) Patients were also included in the
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study if they had been admitted to commence renal replacement therapy with either hemodialysis or peritoneal dialysis at follow up. New-onset atrial fibrillation requiring admission
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was validated by comparing the ECG conducted during the admission with the patient’s most
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recent ECG. Fast and slow atrial fibrillation ventricular rates were included.
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Statistical analysis:
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Quantitative data are presented as mean and standard deviation or median and range. Categorical variables are given as absolute (counts) and relative frequencies (percentage). For univariate comparison of continuous variables, a t-test for two independent samples or MannWhitney U-test was used. For univariate comparison of categorical data X² tests were utilized. Mean survival times were calculated and compared between diabetic and nondiabetic patients. Survival analyses are due to Kaplan-Meier and log-rank tests. Hazard ratios and respective 95 % confidence intervals were calculated using Cox regression. In univariate survival analyses the following variables were included: presence or absence of diabetes mellitus, age, sex, nationality, systolic blood pressure, diastolic blood pressure, pulse pressure, type of the hypertensive crisis, smoking, renal impairment, alcohol consumption and ejection fraction. If statistically significant in the univariate analysis, variables were included in an additional multiple Cox regression to account for possible confounding. Mortality was the dependent variable and
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the independent variables were diabetes, nationality, type of crisis, and renal impairment. Data
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values are two-sided and subject to a significance level of 0.05.
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processing was performed with MS Excel 2007 for Windows and IBM SPSS 20 for Windows. P
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Results
The demographic data, comorbid conditions, blood pressure at initial presentation, type of
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hypertensive crisis and mortality are shown in (Table 1). Out of the 297 patients who presented
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with hypertensive crisis, 145 were diabetics and 152 were nondiabetics. Diabetics were older
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than 65 years of age and most were Bahrain citizens. Those younger than 45 years were mainly nondiabetics. The median follow-up was 30 months for nondiabetics (1–32) and 24 for diabetics (0–28). (Table 1) Hyperlipidemia was more common among diabetics, and nearly one-third had renal impairment. At initial presentation, diabetics had lower diastolic blood pressure, and hence their pulse pressures were also higher. (Table 1) Diabetics had higher mortality over the followup period, 26 (17.9%) compared with 11(7.2%) among the nondiabetics (P value <0.01). (Table 1) Fatal and nonfatal cardiovascular and non-cardiovascular events. Of the 297 patients in our cohort, 177 events were observed during the follow-up period, 37 fatal and 140 nonfatal. There were 26 fatal events among the diabetics and 11 among the nondiabetics (p value <0.01). (Table 2) Mortality attributed to cerebrovascular events or to ACS
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was comparable between the diabetics and nondiabetics during the follow-up period. Mortality caused by heart failure, however, was much more prevalent among the diabetics upon follow-
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up. (Table 2) There were also significantly more nonfatal events among the diabetics (115 vs.
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25) (P <0.01). Of the nonfatal cardiovascular events, recurrent acute left ventricular failure was
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predominant among the diabetics. Moreover, it was strikingly higher in comparison with nondiabetics (p <0.0001). (Table 2) Of particular note was the development of atrial fibrillation in
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four patients with diabetes but not in any of the nondiabetic patients. (Table 2)
Association between hypertensive crisis and subsequent fatal cardiovascular and non-
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cardiovascular events.
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The Kaplan-Meier plot demonstrating the probability of event-free survival between diabetics
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and nondiabetics is presented in (Figure 1). As seen in the plot, the cumulative survival curve splits within approximately 15 months of follow-up and continues to separate (p value <0.001). The time-to-death intervals in the different hypertensive crisis groups are depicted in (Table 3), with marked differences between the diabetics and nondiabetics. The hazard survival analyses with time to death are shown separately for diabetics and nondiabetics. (Figure 2, 3) Similar plots that compare the probability of survival across the different age groups, types of hypertensive crisis, and normal vs. impaired renal dysfunction are presented. (Figure 1) Univariate Cox regression analysis identified diabetes mellitus, acute left ventricular failure, stroke and renal impairment as independent predictors of mortality. The hazard ratio obtained through univariate Cox regression analysis is shown in (Table 4).
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In the multivariate Cox regression, age above 65 and hypertensive emergency were predictors
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of mortality.
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Discussion
This study compares the clinical outcomes of hypertensive crises between diabetics and
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nondiabetics during almost three years of follow-up. No such analysis has ever been reported in
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the literature. At the initial clinical presentation, the diabetic patients were older and had more comorbidities.
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The mortality rate was 7% in patients without diabetes. Among these patients, the majority of their presentation (75%) was hypertensive urgency (115,), Table 1 Vlcek et al found 2%
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mortality among patients with hypertensive urgency during 5 years of follow-up. (16) There was
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no significant mortality difference with the matched controls. The latter were patients with
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elevated blood pressure and no hypertensive urgency. (16) In the same study, a high number of nonfatal cardiovascular events in patients with hypertensive urgency compared with the controls was observed. (16) Severely elevated blood pressure with no acute target involvement would appear to have a worse prognosis than was previously anticipated. The cautious immediate reduction of blood pressure during hypertensive urgency should not underestimate its serious cardiovascular outcome. Marked elevation in blood pressure with evidence of proteinuria and/or left ventricular hypertrophy stratifies hypertensive urgency as high risk. As shown by Messerli et al (17) , during the blood pressure progression of former US President Franklin Roosevelt, when proteinuria and left ventricular hypertrophy were detected, he died within a year from hypertensive crisis and cerebral hemorrhage. In our study, nondiabetic patients, although hypertensive urgency was their dominant presentation, showed relatively a high mortality rate of 7%. It is likely that their mortality was
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partly driven by the few hypertensive emergencies and the evidence of renal impairment that was observed in 17% of the patients. Diabetic patients with hypertensive crisis exhibited higher
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mortality (17.9%) and morbidity. (Table1) They sustained more cardiovascular and non-
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cardiovascular insults throughout the period of the study. (Table 2) Diabetic patients were older
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and had higher pulse pressure. (Table1) Wide pulse pressure is well documented in diabetics above the age of 50 years. (18-20) Pulse pressure amplification is considered a mechanical
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biomarker and can predict all cause cardiovascular mortality. (21-23) Both fatal and nonfatal clinical outcomes were more prevalent among patients with diabetes.
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Diabetes amplifies individual cardiovascular risk, and hence, its presence is considered equivalent to ischemic heart disease. (24, 25) In our data, hazard ratios and time to death were
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syndrome. (Table 3)
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worse in diabetics with hypertensive urgency than in nondiabetics with acute coronary
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Diabetes augments the relationship between the metabolic derangement and arterial stiffness. The wide pulse pressure is marker of the latter. (26-28) Elevated pulse pressure can predict the development of new-onset non-insulin-dependent diabetes. (29) This emphasizes the bidirectional relationship between arterial stiffness, reflected pressure waves and diabetes. (30) Among the fatalities, there were more deaths from stroke than from any other causes. As seen in the Kaplan-Meier plot, patients with stroke being initial clinical presentation as hypertensive crisis had the highest tendency to die during the first admission. (Figure 5) The presence of elevated pulse pressure during acute stroke carries dismal prognosis. (31, 32) Acute mortality attributed to stroke-related hypertensive emergency was not significant between diabetics and nondiabetics. In regard to nonfatal events, there were more strokes among the diabetic patients beyond the first presentation.
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Hypertensive Left ventricular failure dominated the mortality in diabetics at the initial clinical presentation. (Table 2) Diabetics with hypertensive left ventricular failure sustained a
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progressive decline in survival rate throughout the study. (Figure 2) The distinctive
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pathophysiology of acute heart failure with marked blood pressure remains speculative. Some
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believe that it might represent a distinct vascular disorder. (33, 34) Some evidence favors the presence of prolonged neurohormonal and inflammatory reaction that increases arterial
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stiffness. A steep increase in the afterload ensues, triggering acute left ventricular failure. The evidence of persistent neurohormonal and inflammatory activation beyond the acute episode is
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accumulating. (35-37)
Persistent indolent inflammation can partially explain the sustained high readmission and
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mortality rates observed among our diabetic patients who had left ventricular failure
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hypertensive crises.
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Kidney dysfunction was an independent predictor of mortality in our study. (Figure 1) Patients with renal impairment manifested mortality drift as early as ten months from the initial clinical presentation. The intimate relationship between cardiovascular disease and renal impairment is well-known and is even more intense with heart failure. (38) Diabetic patients with hypertensive crisis had recurrent admissions with worsening renal function. (Table 2) In patients with hypertensive heart failure, the kidney is both victim and offender. Among patients admitted with heart failure, Forman et al identified admission SBP above 160 mg, diabetes mellitus and history of congestive heart failure as predictors of worsening renal function. Hospital deaths, complications, and longer hospital stays were greater among the patients with worsening renal function. (39) In our study, renal impairment was a strong predictor of mortality among patients with hypertensive crisis. This finding is consistent with those of previous studies. Sub-analysis of the
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STAT registry (Studying the Treatment of Acute Hypertension) found chronic kidney disease to
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be a common comorbidity in patients with acute severe hypertension. (40) Moreover, acute kidney injury is associated with a greater risk of mortality and of acute heart
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failure. Patients admitted with malignant hypertension ; if proteinurea was present ,and their
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serum creatinine (>200 µmol/L) at presentation, their median survival time is shortened. (41) Limitations:
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Our study is subject to inherent limitations that should be addressed. The degree of renal
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impairment was not stratified according to severity. However, a large body of evidence stresses that with acute severe hypertension, any degree of acute kidney injury is associated with a
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greater risk of morbidity and mortality. (40) Second, blood pressure medications and degree of
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blood pressure control at follow-up were not studied, and their relationship to the outcomes was not analyzed. It is unknown whether the prognoses might have been altered. This aspect should
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be verified in future studies on hypertensive crisis. With the available evidence, patients with hypertensive urgency whose blood pressure was controlled after their initial clinical presentations yet sustained more cardiovascular events in comparison with their matching controls. (16)
Conclusion Patients with hypertensive crisis are at risk of developing both fatal and nonfatal cardiovascular events. Hypertensive crisis with diabetes is a fatal blend. Hypertensive urgency in a diabetic is the equivalent of hypertensive emergency in non-diabetics. Hypertensive urgency can be a dormant hypertensive emergency. Evidence of left ventricular hypertrophy or renal impairment
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during the urgency conceals hypertensive emergency. The best strategy to ameliorate the poor
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prognosis of hypertensive crisis is to prevent it.
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Non-diabetics (n=152)
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Characteristic
Demography Female sex [no.] (%)
49 (32.2)
p Value
60 (41.4)
0.10 <0.01
49 (32.2)
10 (6.9)
81 (53.3)
84 (57.9)
22 (14.5)
51 (35.2)
83 (54.6)
106 (73.1)
<0.01
Smoker [no.] (%)
52 (34.2)
39 (26.9)
0.17
Alcohol drinker [no.] (%)
13 (8.6)
10 (6.9)
0.59
High lipid [no.] (%)
56 (36.8)
102 (70.3)
<0.01
Renal = 1[no.] (%)
26 (17.1)
46 (31.7)
<0.01
Ejection fraction [mean] (Range)
0.57 (0.20-0.80)
0.54 (0.20-0.80)
0.21
Mortality – dead [no.] (%)
11 (7.2)
26 (17.9)
<0.01
Median follow-up time [months] (Range)
30 (0.5-32)
24 (0.3-28)
<0.01
199.6 (±21.9)
200.8 (±20.6)
0.62
<45 45-65
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>65
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Age [no.] (%)
Diabetics (n=145)
Bahraini nationality [no.] (%) Risk factors
Blood pressure Systolic [mean mmHg] (SD)
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114.1 (±18.0)
108.1 (±17.5)
<0.01
Pulse Pressure [mean mmHg] (SD)
85.5 (±22.4)
92.7 (±21.5)
<0.01
HBA1c [no. >53mmol/l] (%)
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Diastolic [mean mmHg] (SD)
117 (80.7)
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Significant P value <0.05
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Table 1: Characteristics of 297 Patients Included, among two groups.
Diabetics
(n=152)
(n= 145)
115
57
0.001
37
86
0.001
11
26
0.001
Hypertensive urgency
1
4
0.01
Acute coronary syndrome
2
3
NS
Left ventricular failure
3
15
0.001
Cerebrovascular
5
4
NS
3
19
0.001
Hypertensive urgency
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Hypertenisve emergency
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Non- diabetics
Mortality (Total fatal events)
P value
Mortality across initial hypertensive crisis group
Non fatal events Hypertensive urgency
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6
12
0.001
Left ventricular failure
6
34
0.0001
Cerebrovascular
6
26
0.001
Renal failure
4
20
0.001
Atrial Fibrillation
-
4
-
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Acute coronary syndrome
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Table 2: Frequency of fatal and non fatal events across two groups during follow up peroid.
Non- diabetics
Diabetics
(n=152)
(n= 145)
Overall
30.70.4
25.7 0.4
<0.01
Hypertensive Urgency
31.80.1
27.10.5
<0.01
Hypertensive ACS
29.21.8
25.51.0
<0.01
Hypertensive LVF
28.51.7
23.80.8
<0.01
Hypertensive CVA
22.64.6
23.21.8
<0.01
P value
Table 3: Time to death in different hypertensive crisis groups among diabetics and nondiabetics (data expressed as meanSD) ACS: acute coronary syndrome, LVF: left ventricular failure, CVA: cerebrovascular accidents
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Figure 1: Kaplan-Meier curves for the survival rate during study period.
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A: DM patients’ vs nonDM patients P <0.001. B: Three age groups P value <0.01
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C: Initial hypertensive crisis groups P<0.001
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D: Patients with normal renal function vs renal impairment p< 0.01
Figure 2: Hazard survival analysis for diabetic patients across hypertensive crisis groups.
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Figure 3: Hazard survival analysis for nondiabetic patients across hypertensive crisis groups.
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95%confidence interval
P value
Diabetes Mellitus
3.46
1.65- 7.24
<0.01
Age( >65 yr)
10.86
Nationality(Non-Bahraini)
0.14
Hypertenisve LVF
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Hazard ratio
<0.01
0.04-0.45
<0.01
13.63
5.05-36.81
<0.01
Hypertensive ACS
5.23
1.51-18.10
<0.01
Hypertensive CVA
17.09
5.71-51.16
<0.01
0.39
0.21-0.75
<0.01
Dyslipidemia
0.75
0.38-1.44
0.38
Systolic blood pressure
1.00
0.98-1.01
0.92
Diastolic blood pressure
0.99
0.97-1.01
0.26
Pulse pressure
1.01
0.99-1.02
0.42
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Renal Impairment
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2.55-46.32
Table 4: Results from univariate Cox regression analyses to predict fatal events during study period.
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Highlights
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1- We followed diabetic and nondiabetic patients presented with hypertensive crisis for 2.5 years. 2- We compared the cardiovascular and non-cardiovascular clinical outcomes of both groups. 3- Hypertensive crisis carries significant subsequent morbidity and mortality risk especially in diabetics with heart failure. 4- Hypertensive urgency in diabetics is equivalent to hypertensive coronary syndrome in nondiabetics. 5- Hypertensive Urgency conceals an emergency risk if associated with left ventricular hypertrophy or renal impairment.
Comparison between diabetics and
Rashed Al Bannay, Aysha Husain, Michael B¨ohm, Stefan Wagenpfeil PII: DOI: Reference:
S2214-7624(15)00014-6 doi: 10.1016/j.ijcme.2015.03.003 IJCME 69
To appear in:
International Journal of Cardiology
Received date: Revised date: Accepted date:
27 July 2014 12 December 2014 4 March 2015
Please cite this article as: Al Bannay Rashed, Husain Aysha, B¨ohm Michael, Wagenpfeil Stefan, Outcomes after hypertensive crisis: Comparison between diabetics and nondiabetics, International Journal of Cardiology (2015), doi: 10.1016/j.ijcme.2015.03.003
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Outcomes after hypertensive crisis: comparison between diabetics and nondiabetics.
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Rashed Al Bannay1, Aysha Husain2, Michael Böhm3 , Stefan Wagenpfeil4
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Running title: Outcome of hypertensive crisis
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Address for correspondence:
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Rashed Al Bannay, MD Consultant Adult Cardiology, Cardiology Unit,
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Internal Medicine Department,
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Salmaniya Medical Complex, Bahrain.
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Assistant Professor, Internal Medicine Department Arabian Gulf University.
[email protected] Tel: 0097339669406
Fax: 0097317251303 P.O box 12, Manama, Kingdom of Bahrain 1
Al Bannay R: Consultant Adult Cardiology, Salmaniya Medical Complex, Bahrain, Kingdom of
Bahrain. 2
Husain A: Adult Cardiology fellow, Heart Center, King Faisal Hospital and Research center,
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Riyadh, Kingdom of Saudi Arabia. Böhm M: Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, DE-66424
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3
4
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Homburg, Germany.
Wagenpfeil S: Institut für Medizinische Biometrie, Epidemiologie und Medizinische Informatik,
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Universitätsklinikum des Saarlandes, D-66421 Homburg, Germany.
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The authors of this manuscript declare no conflict of interests.
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Key words: Hypertensive crisis, Hypertensive urgency, Hypertensive emergency, Diabetes
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mellitus, Hypertensive left ventricular failure
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Abstract
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Objective:
To study the long-term cardiovascular and non-cardiovascular outcomes among patients
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admitted with hypertensive crisis.
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Methods:
A total of 297 (145 diabetics, 152 nondiabetics) patients with hypertensive crisis were followed
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up for a median of 30 months. Fatal and nonfatal events were tracked. The traced events
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defined as hypertensive urgency, acute coronary syndrome, left ventricular failure, atrial
Results:
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fibrillation, cerebrovascular or renal failure were consecutively analyzed during the follow-up.
Overall, 140 (47%) patients had nonfatal clinical events (115 diabetics and 25 nondiabetics); 37 (12%) patients had fatal clinical events (26 diabetics and 11 nondiabetics). The rate of fatal and nonfatal events was significantly higher in diabetics. The mean time of survival was 25.7 months, with the shortest periods for stroke and left ventricular failure. For nondiabetic participants, the mean time of survival was 31 months. Cox regression analysis identified diabetes mellitus, acute left ventricular failure, stroke and renal impairment as predictors of mortality. Conclusion
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Hypertensive crisis is associated with a markedly increased risk for subsequent cardiovascular
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morbidity and mortality, especially among diabetics who present with heart failure.
Introduction
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Hypertensive crisis is defined as acute marked elevation of blood pressure, SBP ≥180 mmHg
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and/or DBP ≥ 120 mmHg. Hypertensive emergency is diagnosed, when there is acute target damage and hypertensive urgency when the latter is absent. (1, 2) Previously we studied the
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behavior of hypertensive crisis in our community. (3-6) The clinical presentation of hypertensive
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crisis between diabetics and nondiabetics was compared. (4) Patients with diabetes exhibited higher rates of hypertensive emergency, particularly, left ventricular failure. (4) There is little if
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any knowledge of whether the prognoses and outcomes of hypertensive crisis differ between diabetics and nondiabetics. In this study, we aimed to discover the clinical outcomes of hypertensive crisis in both diabetics and nondiabetics beyond their initial clinical presentation. Methods
All patients age above 18 years, visited the accident and emergency department with hypertensive crisis for a period of 6 months, from 1st June 2010 till 31st December 2010 were consecutively included. Patients with end stage renal failure requiring renal replacement therapy were excluded. Data on 297 patients were collected, 145 patients were diabetics, and 152 were nondiabetics. The initial comparison of their modes of presentation, types of hypertensive crises and associated comorbidities were published earlier. (4)
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These patients were followed for a period of 32 months from their initial presentation. Cardiovascular and cerebrovascular events requiring admission, development or worsening of
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renal failure requiring admission and commencement of renal replacement therapy were tracked
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using electronic data records along with chart retrieval.
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Mortality was documented based on electronic medical records and patient death certificates. Causes of death were retrieved from the official death certificates. To validate the status of
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patients who were lost during follow-up, phone calls at the time of data collection were made to gather meticulous information regarding admissions and deaths. The time from the initial
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hypertensive crisis presentation until the occurrence of each event was documented. Hypertensive crisis was defined based on the Joint National Committee on Prevention,
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Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) and the latest guidelines
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of the European Society of Hypertension (ESH) guidelines of systolic blood pressure ≥ 180
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mmHg and diastolic blood pressure of ≥ 120 mmHg. The presence or absence of acute target organ damage was the basis for defining hypertensive emergency versus urgency, respectively. (1, 2) A patient was considered to have diabetes if two readings of fasting blood glucose, taken on separate occasions, exceeded 7 mmol/L, if symptoms of diabetes occurred with casual plasma glucose concentration ≥200 mg/dl (11.1 mmol/L), or if the 2-hour post-load glucose level was ≥200 mg/dl (11.1 mmol/L) during an oral glucose tolerance test (OGTT). (7) Dyslipidemia (hypercholesterolemia) was diagnosed if the total cholesterol level exceeded 200 mg/dl. (8) Acute stroke was defined if the patient was admitted to the hospital because of neurological deficits for more than 24 hours and the radiology imaging of the brain revealed an ischemic or hemorrhagic area. (9) The definition of acute coronary syndrome was based on typical chest pain with electrocardiogram (ECG) changes with or without elevated cardiac enzymes. We involved patients with unstable angina, non-ST-elevation myocardial infarction (NSTEMI) and
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ST-elevation myocardial infarction (STEMI). (10-12) Left ventricular failure was defined according to the Framingham criteria. The presence of two major criteria or one major and two
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minor criteria were satisfactory for diagnosing left ventricular failure or congestive heart failure.
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(13) Chronic renal impairment was diagnosed when the estimated glomerular filtration rate
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(GFR) was <60 ml/min/1.73 m2. (14) Acute renal failure and worsening kidney function were validated using the RIFLE criteria for acute kidney injury. (15) Patients were also included in the
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study if they had been admitted to commence renal replacement therapy with either hemodialysis or peritoneal dialysis at follow up. New-onset atrial fibrillation requiring admission
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was validated by comparing the ECG conducted during the admission with the patient’s most
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recent ECG. Fast and slow atrial fibrillation ventricular rates were included.
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Statistical analysis:
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Quantitative data are presented as mean and standard deviation or median and range. Categorical variables are given as absolute (counts) and relative frequencies (percentage). For univariate comparison of continuous variables, a t-test for two independent samples or MannWhitney U-test was used. For univariate comparison of categorical data X² tests were utilized. Mean survival times were calculated and compared between diabetic and nondiabetic patients. Survival analyses are due to Kaplan-Meier and log-rank tests. Hazard ratios and respective 95 % confidence intervals were calculated using Cox regression. In univariate survival analyses the following variables were included: presence or absence of diabetes mellitus, age, sex, nationality, systolic blood pressure, diastolic blood pressure, pulse pressure, type of the hypertensive crisis, smoking, renal impairment, alcohol consumption and ejection fraction. If statistically significant in the univariate analysis, variables were included in an additional multiple Cox regression to account for possible confounding. Mortality was the dependent variable and
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the independent variables were diabetes, nationality, type of crisis, and renal impairment. Data
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values are two-sided and subject to a significance level of 0.05.
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processing was performed with MS Excel 2007 for Windows and IBM SPSS 20 for Windows. P
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Results
The demographic data, comorbid conditions, blood pressure at initial presentation, type of
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hypertensive crisis and mortality are shown in (Table 1). Out of the 297 patients who presented
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with hypertensive crisis, 145 were diabetics and 152 were nondiabetics. Diabetics were older
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than 65 years of age and most were Bahrain citizens. Those younger than 45 years were mainly nondiabetics. The median follow-up was 30 months for nondiabetics (1–32) and 24 for diabetics (0–28). (Table 1) Hyperlipidemia was more common among diabetics, and nearly one-third had renal impairment. At initial presentation, diabetics had lower diastolic blood pressure, and hence their pulse pressures were also higher. (Table 1) Diabetics had higher mortality over the followup period, 26 (17.9%) compared with 11(7.2%) among the nondiabetics (P value <0.01). (Table 1) Fatal and nonfatal cardiovascular and non-cardiovascular events. Of the 297 patients in our cohort, 177 events were observed during the follow-up period, 37 fatal and 140 nonfatal. There were 26 fatal events among the diabetics and 11 among the nondiabetics (p value <0.01). (Table 2) Mortality attributed to cerebrovascular events or to ACS
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was comparable between the diabetics and nondiabetics during the follow-up period. Mortality caused by heart failure, however, was much more prevalent among the diabetics upon follow-
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up. (Table 2) There were also significantly more nonfatal events among the diabetics (115 vs.
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25) (P <0.01). Of the nonfatal cardiovascular events, recurrent acute left ventricular failure was
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predominant among the diabetics. Moreover, it was strikingly higher in comparison with nondiabetics (p <0.0001). (Table 2) Of particular note was the development of atrial fibrillation in
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four patients with diabetes but not in any of the nondiabetic patients. (Table 2)
Association between hypertensive crisis and subsequent fatal cardiovascular and non-
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cardiovascular events.
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The Kaplan-Meier plot demonstrating the probability of event-free survival between diabetics
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and nondiabetics is presented in (Figure 1). As seen in the plot, the cumulative survival curve splits within approximately 15 months of follow-up and continues to separate (p value <0.001). The time-to-death intervals in the different hypertensive crisis groups are depicted in (Table 3), with marked differences between the diabetics and nondiabetics. The hazard survival analyses with time to death are shown separately for diabetics and nondiabetics. (Figure 2, 3) Similar plots that compare the probability of survival across the different age groups, types of hypertensive crisis, and normal vs. impaired renal dysfunction are presented. (Figure 1) Univariate Cox regression analysis identified diabetes mellitus, acute left ventricular failure, stroke and renal impairment as independent predictors of mortality. The hazard ratio obtained through univariate Cox regression analysis is shown in (Table 4).
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In the multivariate Cox regression, age above 65 and hypertensive emergency were predictors
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of mortality.
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Discussion
This study compares the clinical outcomes of hypertensive crises between diabetics and
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nondiabetics during almost three years of follow-up. No such analysis has ever been reported in
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the literature. At the initial clinical presentation, the diabetic patients were older and had more comorbidities.
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The mortality rate was 7% in patients without diabetes. Among these patients, the majority of their presentation (75%) was hypertensive urgency (115,), Table 1 Vlcek et al found 2%
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mortality among patients with hypertensive urgency during 5 years of follow-up. (16) There was
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no significant mortality difference with the matched controls. The latter were patients with
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elevated blood pressure and no hypertensive urgency. (16) In the same study, a high number of nonfatal cardiovascular events in patients with hypertensive urgency compared with the controls was observed. (16) Severely elevated blood pressure with no acute target involvement would appear to have a worse prognosis than was previously anticipated. The cautious immediate reduction of blood pressure during hypertensive urgency should not underestimate its serious cardiovascular outcome. Marked elevation in blood pressure with evidence of proteinuria and/or left ventricular hypertrophy stratifies hypertensive urgency as high risk. As shown by Messerli et al (17) , during the blood pressure progression of former US President Franklin Roosevelt, when proteinuria and left ventricular hypertrophy were detected, he died within a year from hypertensive crisis and cerebral hemorrhage. In our study, nondiabetic patients, although hypertensive urgency was their dominant presentation, showed relatively a high mortality rate of 7%. It is likely that their mortality was
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partly driven by the few hypertensive emergencies and the evidence of renal impairment that was observed in 17% of the patients. Diabetic patients with hypertensive crisis exhibited higher
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mortality (17.9%) and morbidity. (Table1) They sustained more cardiovascular and non-
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cardiovascular insults throughout the period of the study. (Table 2) Diabetic patients were older
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and had higher pulse pressure. (Table1) Wide pulse pressure is well documented in diabetics above the age of 50 years. (18-20) Pulse pressure amplification is considered a mechanical
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biomarker and can predict all cause cardiovascular mortality. (21-23) Both fatal and nonfatal clinical outcomes were more prevalent among patients with diabetes.
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Diabetes amplifies individual cardiovascular risk, and hence, its presence is considered equivalent to ischemic heart disease. (24, 25) In our data, hazard ratios and time to death were
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syndrome. (Table 3)
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worse in diabetics with hypertensive urgency than in nondiabetics with acute coronary
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Diabetes augments the relationship between the metabolic derangement and arterial stiffness. The wide pulse pressure is marker of the latter. (26-28) Elevated pulse pressure can predict the development of new-onset non-insulin-dependent diabetes. (29) This emphasizes the bidirectional relationship between arterial stiffness, reflected pressure waves and diabetes. (30) Among the fatalities, there were more deaths from stroke than from any other causes. As seen in the Kaplan-Meier plot, patients with stroke being initial clinical presentation as hypertensive crisis had the highest tendency to die during the first admission. (Figure 5) The presence of elevated pulse pressure during acute stroke carries dismal prognosis. (31, 32) Acute mortality attributed to stroke-related hypertensive emergency was not significant between diabetics and nondiabetics. In regard to nonfatal events, there were more strokes among the diabetic patients beyond the first presentation.
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Hypertensive Left ventricular failure dominated the mortality in diabetics at the initial clinical presentation. (Table 2) Diabetics with hypertensive left ventricular failure sustained a
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progressive decline in survival rate throughout the study. (Figure 2) The distinctive
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pathophysiology of acute heart failure with marked blood pressure remains speculative. Some
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believe that it might represent a distinct vascular disorder. (33, 34) Some evidence favors the presence of prolonged neurohormonal and inflammatory reaction that increases arterial
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stiffness. A steep increase in the afterload ensues, triggering acute left ventricular failure. The evidence of persistent neurohormonal and inflammatory activation beyond the acute episode is
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accumulating. (35-37)
Persistent indolent inflammation can partially explain the sustained high readmission and
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mortality rates observed among our diabetic patients who had left ventricular failure
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hypertensive crises.
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Kidney dysfunction was an independent predictor of mortality in our study. (Figure 1) Patients with renal impairment manifested mortality drift as early as ten months from the initial clinical presentation. The intimate relationship between cardiovascular disease and renal impairment is well-known and is even more intense with heart failure. (38) Diabetic patients with hypertensive crisis had recurrent admissions with worsening renal function. (Table 2) In patients with hypertensive heart failure, the kidney is both victim and offender. Among patients admitted with heart failure, Forman et al identified admission SBP above 160 mg, diabetes mellitus and history of congestive heart failure as predictors of worsening renal function. Hospital deaths, complications, and longer hospital stays were greater among the patients with worsening renal function. (39) In our study, renal impairment was a strong predictor of mortality among patients with hypertensive crisis. This finding is consistent with those of previous studies. Sub-analysis of the
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STAT registry (Studying the Treatment of Acute Hypertension) found chronic kidney disease to
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be a common comorbidity in patients with acute severe hypertension. (40) Moreover, acute kidney injury is associated with a greater risk of mortality and of acute heart
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failure. Patients admitted with malignant hypertension ; if proteinurea was present ,and their
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serum creatinine (>200 µmol/L) at presentation, their median survival time is shortened. (41) Limitations:
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Our study is subject to inherent limitations that should be addressed. The degree of renal
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impairment was not stratified according to severity. However, a large body of evidence stresses that with acute severe hypertension, any degree of acute kidney injury is associated with a
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greater risk of morbidity and mortality. (40) Second, blood pressure medications and degree of
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blood pressure control at follow-up were not studied, and their relationship to the outcomes was not analyzed. It is unknown whether the prognoses might have been altered. This aspect should
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be verified in future studies on hypertensive crisis. With the available evidence, patients with hypertensive urgency whose blood pressure was controlled after their initial clinical presentations yet sustained more cardiovascular events in comparison with their matching controls. (16)
Conclusion Patients with hypertensive crisis are at risk of developing both fatal and nonfatal cardiovascular events. Hypertensive crisis with diabetes is a fatal blend. Hypertensive urgency in a diabetic is the equivalent of hypertensive emergency in non-diabetics. Hypertensive urgency can be a dormant hypertensive emergency. Evidence of left ventricular hypertrophy or renal impairment
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during the urgency conceals hypertensive emergency. The best strategy to ameliorate the poor
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prognosis of hypertensive crisis is to prevent it.
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heart failure associated with high admission blood pressure–a distinct vascular disorder? Eur J Heart Fail 2007;9:178-83 34. Gandhi S.K. Powers J.C. Nomier A.M. Fowle K,. Kitzman DW, Rankin KM et al. The pathogenesis of acute pulmonary edema associated with hypertension New Engl J Med 2001 344 17 22.
35. Braunwald E. Heart Failure. JCHF 2013;1(1):1-20. 36. Sato Y. Takaysu Y. Kataoka K. et al. Serial circulating concentrations of C-reactive protein, Interleukin (IL)-4 and IL-6 in-patients with acute left heart decompensation Clin Cardiol 1999;22: 811-813. 37. Milo O. Cotter, G. Kaluski E, Brill A, Blatt A, Krakover R, et al. Inflammatory and neurohormonal activation in cardiogenic pulmonary edema: implications on the pathogenesis and outcome of acute ischemic versus non-ischemic acute heart failure
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Am J Cardiol 2003; 92: 222 - 226. 38. Petrie CJ, Mark PB, Weir RA: Broken pump or leaky filter? Renal dysfunction in heart
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failure a contemporary review. Int J Cardiol 2008;128:154–165.
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39. Forman D.E., Butler J., Wang Y.; Incidence, predictors at admission, and impact of
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worsening renal function among patients hospitalized with heart failure. J Am Coll Cardiol 2004 ;43:61-67.
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40. Szczech LA, Granger CB, Dasta JF, Amin A, Peacock WF, McCullough PA, Devlin JW,
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Weir MR, Katz JN, Anderson FA Jr, et al. Acute kidney injury and cardiovascular outcomes in acute severe hypertension. Circulation 2010;121:2183–2191.
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41. Lip GY, Beevers M, Beevers DG. Complication and survival of 315 patients with
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malignant-phase hypertension. J Hypertens 1995;13:915–924.
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Non-diabetics (n=152)
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Characteristic
Demography Female sex [no.] (%)
49 (32.2)
p Value
60 (41.4)
0.10 <0.01
49 (32.2)
10 (6.9)
81 (53.3)
84 (57.9)
22 (14.5)
51 (35.2)
83 (54.6)
106 (73.1)
<0.01
Smoker [no.] (%)
52 (34.2)
39 (26.9)
0.17
Alcohol drinker [no.] (%)
13 (8.6)
10 (6.9)
0.59
High lipid [no.] (%)
56 (36.8)
102 (70.3)
<0.01
Renal = 1[no.] (%)
26 (17.1)
46 (31.7)
<0.01
Ejection fraction [mean] (Range)
0.57 (0.20-0.80)
0.54 (0.20-0.80)
0.21
Mortality – dead [no.] (%)
11 (7.2)
26 (17.9)
<0.01
Median follow-up time [months] (Range)
30 (0.5-32)
24 (0.3-28)
<0.01
199.6 (±21.9)
200.8 (±20.6)
0.62
<45 45-65
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Age [no.] (%)
Diabetics (n=145)
Bahraini nationality [no.] (%) Risk factors
Blood pressure Systolic [mean mmHg] (SD)
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114.1 (±18.0)
108.1 (±17.5)
<0.01
Pulse Pressure [mean mmHg] (SD)
85.5 (±22.4)
92.7 (±21.5)
<0.01
HBA1c [no. >53mmol/l] (%)
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Diastolic [mean mmHg] (SD)
117 (80.7)
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Significant P value <0.05
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Table 1: Characteristics of 297 Patients Included, among two groups.
Diabetics
(n=152)
(n= 145)
115
57
0.001
37
86
0.001
11
26
0.001
Hypertensive urgency
1
4
0.01
Acute coronary syndrome
2
3
NS
Left ventricular failure
3
15
0.001
Cerebrovascular
5
4
NS
3
19
0.001
Hypertensive urgency
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Hypertenisve emergency
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Non- diabetics
Mortality (Total fatal events)
P value
Mortality across initial hypertensive crisis group
Non fatal events Hypertensive urgency
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6
12
0.001
Left ventricular failure
6
34
0.0001
Cerebrovascular
6
26
0.001
Renal failure
4
20
0.001
Atrial Fibrillation
-
4
-
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Acute coronary syndrome
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Table 2: Frequency of fatal and non fatal events across two groups during follow up peroid.
Non- diabetics
Diabetics
(n=152)
(n= 145)
Overall
30.70.4
25.7 0.4
<0.01
Hypertensive Urgency
31.80.1
27.10.5
<0.01
Hypertensive ACS
29.21.8
25.51.0
<0.01
Hypertensive LVF
28.51.7
23.80.8
<0.01
Hypertensive CVA
22.64.6
23.21.8
<0.01
P value
Table 3: Time to death in different hypertensive crisis groups among diabetics and nondiabetics (data expressed as meanSD) ACS: acute coronary syndrome, LVF: left ventricular failure, CVA: cerebrovascular accidents
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Figure 1: Kaplan-Meier curves for the survival rate during study period.
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A: DM patients’ vs nonDM patients P <0.001. B: Three age groups P value <0.01
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C: Initial hypertensive crisis groups P<0.001
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D: Patients with normal renal function vs renal impairment p< 0.01
Figure 2: Hazard survival analysis for diabetic patients across hypertensive crisis groups.
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Figure 3: Hazard survival analysis for nondiabetic patients across hypertensive crisis groups.
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95%confidence interval
P value
Diabetes Mellitus
3.46
1.65- 7.24
<0.01
Age( >65 yr)
10.86
Nationality(Non-Bahraini)
0.14
Hypertenisve LVF
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Hazard ratio
<0.01
0.04-0.45
<0.01
13.63
5.05-36.81
<0.01
Hypertensive ACS
5.23
1.51-18.10
<0.01
Hypertensive CVA
17.09
5.71-51.16
<0.01
0.39
0.21-0.75
<0.01
Dyslipidemia
0.75
0.38-1.44
0.38
Systolic blood pressure
1.00
0.98-1.01
0.92
Diastolic blood pressure
0.99
0.97-1.01
0.26
Pulse pressure
1.01
0.99-1.02
0.42
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Renal Impairment
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2.55-46.32
Table 4: Results from univariate Cox regression analyses to predict fatal events during study period.
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Highlights
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1- We followed diabetic and nondiabetic patients presented with hypertensive crisis for 2.5 years. 2- We compared the cardiovascular and non-cardiovascular clinical outcomes of both groups. 3- Hypertensive crisis carries significant subsequent morbidity and mortality risk especially in diabetics with heart failure. 4- Hypertensive urgency in diabetics is equivalent to hypertensive coronary syndrome in nondiabetics. 5- Hypertensive Urgency conceals an emergency risk if associated with left ventricular hypertrophy or renal impairment.