Orthostatic hypotension is defined as a fall of at least 20 mm Hg in systolic blood pressure or a fall of at least 10 mm Hg in diastolic blood pressure within 3 minutes of standing.¹ All older persons being treated with antihypertensive drugs routinely should have their blood pressure measured in the sitting position and within 3 minutes of standing.¹ Their blood pressure should not be taken immediately after eating to avoid postprandial hypotension being confused with orthostatic hypotension. Autonomic dysfunction contributes to orthostatic hypotension.¹ Risk factors that contribute to orthostatic hypotension include older age, systemic hypertension, treatment with antihypertensive medications, and diabetes mellitus.

Orthostatic hypotension may cause postural instability, falls, and syncope.¹ Orthostatic hypotension has also been associated with an increased incidence of all-cause mortality, coronary events, heart failure, and stroke.^1-5

A meta-analysis included 13 prospective studies with 121,913 persons.² At 5-year follow-up of 65,174 persons, orthostatic hypotension increased all-cause mortality (relative risk 1.50; 95% CI, 1.24 to 1.81).² At 6.4-year follow-up of 49,512 persons, orthostatic hypotension increased the incidence of coronary heart disease (relative risk 1.41; 95% CI, 1.22 to 1.62).² At 6.8 to 24-year follow-up of 50,096 persons, orthostatic hypotension increased the incidence of heart failure (relative risk 2.25; 95% CI, 1.52 to 3.33).² At 6.8-year follow-up of 58,300 persons, orthostatic hypotension increased the incidence of stroke (relative risk 1.64; 95% CI, 1.13 to 2.37).²

The prevalence of orthostatic hypotension in 2,786 community-dwelling Italians, mean age 76 years, was 9.3%.³ At 4.4-year follow-up, orthostatic hypotension was associated with an increased incidence of all-cause mortality (hazard ratio 1.23; 95% CI, 1.02-1.39), with an increased incidence of cardiovascular mortality (hazard ratio 1.41; 95% CI, 1.08-1.74), and with an increased incidence of non-cardiovascular mortality (hazard ratio 1.19; 95% CI, 1.01-1.60).³

The Atherosclerosis Risk in Communities (ARIC) study included 12,363 persons free of heart failure at baseline.⁴ At 17.5-year follow-up, orthostatic hypotension was associated with an increased incidence of heart failure (hazard ratio 1.54; 95% CI, 1.30-1.82).⁴ Incident heart failure developed in 11% of persons who had orthostatic hypotension versus 4% in persons who did not have orthostatic hypotension.⁴

The Cardiovascular Health Study (CHS) included 5,273 persons, mean age 74 years, free of heart failure at baseline.⁵ At 13-year follow-up, we reported with the use of propensity analysis that the incidence of heart failure was 25% in matched persons with orthostatic hypotension versus 21% in matched persons without orthostatic hypotension (hazard ratio 1.24; 95% CI, 1.06-1.45; p = 0.007).⁵ The hazard ratio for incident heart failure in persons with symptomatic orthostatic hypotension was 1.57; 95% CI, 1.16-2.11; p = 0.003).5 The hazard ratio for incident heart failure in persons with asymptomatic orthostatic hypotension was 1.17; 95% CI, 0.99-1.39; p = 0.069).⁵

The Orthostatic Hypotension in Diabetics in the Action to Control Cardiovascular Risk in Diabetes Blood Pressure (ACCORD BP) trial investigated the prevalence, incidence, and prognostic significance of orthostatic hypotension in the ACCORD BP trial.⁶ The persons in this trial had a mean age of 62.1 years and were at high risk for having orthostatic hypotension because all of the participants had type 2 diabetes mellitus, had systemic hypertension, and were treated with antihypertensive drugs. The participants were also randomized to treatment with antihypertensive drugs to reduce the systolic blood pressure to less than 120 mm Hg or to less than 140 mm Hg. After 1 year, the systolic blood pressure was 119.3 mm Hg with intensive blood pressure control versus 133.5 mm Hg with standard antihypertensive drug therapy.

Orthostatic blood pressure measurements were made in 1,321 participants at baseline, in 2,625 participants at 12 months, in 3,702 participants at 48 months, and in 926 participants at all three visits. The smaller number of orthostatic blood pressure measurements at baseline and at 12 months was due to this investigation not beginning until 44 months after the ACCORD BP trial began. The prevalence of orthostatic hypotension at a specific visit was defined based on the occurrence of consensus orthostatic hypotension at that visit, regardless of whether orthostatic hypotension had been previously diagnosed. The incidence of orthostatic hypotension at a specific follow-up visit was defined as the occurrence of consensus orthostatic hypotension at that visit in participants previously examined who had not been found to have orthostatic hypotension.⁶

The prevalence of orthostatic hypotension in the ACCORD BP trial was 17.8% at baseline, 10.4% at 12 months, 12.8% at 48 months, and 20% at one or more visits.⁶ At baseline, the prevalence of orthostatic hypotension was 19.3% in hypertensive diabetics treated to a systolic blood pressure below 120 mm Hg versus 16.1% in hypertensive diabetics treated to a systolic blood pressure below 140 mm Hg (p not significant). At 12 months, the prevalence of orthostatic hypotension was 9.5% in hypertensive diabetics treated to a systolic blood pressure below 120 mm Hg versus 11.4% in hypertensive diabetics treated to a systolic blood pressure below 140 mm Hg (p not significant). At 48 months, the prevalence of orthostatic hypotension was 12.2% in hypertensive diabetics treated to a systolic blood pressure below 120 mm Hg versus 13.5% in hypertensive diabetics treated to a systolic blood pressure below 140 mm Hg (p not significant).

At 12 months, the incidence of orthostatic hypotension was 8.0% in hypertensive diabetics treated to a systolic blood pressure below 120 mm Hg versus 9.9 % in hypertensive diabetics treated to a systolic blood pressure below 140 mm Hg (p not significant). At 48 months, the incidence of orthostatic hypotension was 9.9% in hypertensive diabetics treated to a systolic blood pressure below 120 mm Hg versus 11.0% in hypertensive diabetics treated to a systolic blood pressure below 140 mm Hg (p not significant). Dizziness upon standing for the blood pressure measurements was similar for both treatment groups at baseline and at 6 months but was higher with a systolic blood pressure below 120 mm Hg at 48 months (5.7%) than with a systolic blood pressure below 140 mm Hg at 48 months (4.1%) (p = 0.02).⁶ Therefore, many hypertensive diabetics with orthostatic hypotension in this study were asymptomatic. Regression analysis showed that female gender, higher systolic blood pressure and hemoglobin A1c, current smoking, and use of beta blockers, alpha blockers, and insulin were associated with an increased likelihood of having orthostatic hypotension and black race with a lower likelihood of having orthostatic hypotension.

This very important study also demonstrated that orthostatic hypotension was associated with increased all-cause mortality (hazard ratio 1.62; 95% CI, 1.10 to 2.36; p = 0.02) and with heart failure death or hospitalization (hazard ratio = 1.85; 95% CI, 1.17 to 2.93; p = 0.01) but not with nonfatal myocardial infarction, stroke, cardiovascular death, or their composite.⁶

In conclusion, a randomized clinical trial using a similar number of participants and design used in the SPRINT (Systolic Blood Pressure Intervention) trial needs to be performed in older hypertensive diabetics to investigate whether the systolic blood pressure goal should be less than 120 mm Hg or less than 140 mm Hg in these persons. On the basis of the available data, I recommend reducing the systolic blood pressure in older hypertensive diabetics at increased cardiovascular risk to less than 130 mm Hg or to less than 120 mm Hg with more intensive monitoring for serious adverse events. The excellent Orthostatic Hypotension in ACCORD BP study reassures us that hypertensive diabetics treated to a systolic blood pressure goal of less than 120 mm Hg will not have a higher prevalence or incidence of orthostatic hypotension than hypertensive diabetics treated to a systolic blood pressure goal of less than 140 mm Hg.

Table 1: OH ACCORD BP Trial⁶

At baseline, the prevalence of orthostatic hypotension (OH) was 19.3% in hypertensive diabetics treated to a SBP <120 mm Hg vs 16.1% treated to a SBP <140 mm Hg (pNS) At 12 months, the prevalence of OH was 9.5% in hypertensive diabetics treated to a SBP <120 mm Hg vs 11.4% treated to a SBP <140 mm Hg (p NS) At 48 months, the prevalence of OH was 12.2% in hypertensive diabetics treated to a SBP <120 mm Hg vs 13.5% treated to a SBP <140 mm Hg (p NS) At 12 months, the incidence of OH was 9.5% in hypertensive diabetics treated to a SBP <120 mm Hg vs 11.4% treated to a SBP <140 mm Hg (p NS) At 48 months, the incidence of OH was 9.9% in hypertensive diabetics treated to a SBP <120 mm Hg vs 11.0 % treated to a SBP <140 mm Hg (p NS) OH was associated with increased all-cause mortality (HR 1.62; 95% CI, 1.10-2.36; p = 0.02) and with heart failure hospitalization or death (HR 1.85; 95% CI, 1.17-2.93; p = 0.01) but not with nonfatal myocardial infarction, stroke, cardiovascular death, or their composite

Appendix:

Learning Objectives

1. How do you diagnose orthostatic hypotension?
2. What is the prevalence of orthostatic hypotension in hypertensive diabetics randomized to a systolic blood pressure of less than 120 mm Hg versus less than 140 mm Hg?
3. What is the incidence of orthostatic hypotension in hypertensive diabetics randomized to a systolic blood pressure of less than 120 mm Hg versus less than 140 mm Hg?
4. What is the prognosis of orthostatic hypotension in hypertensive diabetics?

Questions

1. Orthostatic hypotension is present if the systolic blood pressure within 3 minutes of standing is:
   a. reduced by 5 mm Hg
   b. reduced by 10 mm Hg
   c. reduced by 15 mm Hg
   d. reduced by 20 mm Hg
   Correct answer is d (see references 1 and 6).
   
   
2. The prevalence of orthostatic hypotension at 1 or more visits in the Orthostatic Hypotension ACCORD BP trial was
   a. 5%
   b. 20%
   c. 10%
   d. 15%
   Correct answer is b (see reference 6)
   
   
3. The incidence of orthostatic hypotension at 48 months in hypertensive diabetics treated to a systolic blood pressure below 120 mm Hg in the Orthostatic Hypotension ACCORD BP trial was:
   a. 9.9%
   b. 20%
   c. 15%
   d 25%
   Correct answer is a (See reference 6)
   
   
4. Which statement is incorrect?
   a The Orthostatic Hypotension ACCORD BP trial showed that orthostatic hypotension was associated with increased mortality
   b. The Orthostatic Hypotension ACCORD BP trial showed that orthostatic hypotension was associated with increased heart failure death or hospitalization
   c. The Orthostatic Hypotension ACCORD BP trial showed that orthostatic hypotension was associated with stroke
   d. The Orthostatic Hypotension ACCORD BP trial showed that orthostatic hypotension was not associated with nonfatal myocardial infarction
   Correct answer is c (see reference 6)

References

1. Aronow WS, Fleg JL, Pepine CJ, et al. ACCF/AHA 2011 expert consensus document on hypertension in the elderly: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents developed in collaboration with the American Academy of Neurology, American Geriatrics Society, American Society for Preventive Cardiology, American Society of Hypertension, American Society of Nephrology, Association of Black Cardiologists, and European Society of Hypertension. J Am Coll Cardiol 2011;57:2037-114.
2. Ricci F, Fedorowski A, Radico F, et al. Cardiovascular morbidity and mortality related to orthostatic hypotension: a meta-analysis of prospective observational studies. Eur Heart J 2015;36:1609-17.
3. Veronese N, De Rui M, Bolzetta F, et al. Orthostatic changes in blood pressure and mortality in the elderly: the Pro.V.A study. Am J Hypertens 2015;28:1248-56.
4. Jones CD, Loehr L, Franceschini N, et al. Orthostatic hypotension as a risk factor for incident heart failure: the Atherosclerosis Risk in Communities study. Hypertension 2012;59:913-8.
5. Alagiakrishnan K, Patel K, Desai RV, et al. Orthostatic hypotension and incident heart failure in community-dwelling older adults. J Gerontol A Biol Sci Med Sci 2014;69:223-30.
6. Fleg JL, Evans GW, Margolis KL, et al. Orthostatic hypotension in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) Blood Pressure trial: prevalence, incidence, and prognostic significance. Hypertension 2016;68:888-95.

Keywords: Antihypertensive Agents, Atherosclerosis, Blood Pressure, Blood Pressure Determination, Cardiovascular Diseases, Coronary Artery Disease, Diabetes Mellitus, Type 2, Heart Failure, Hemoglobins, Hypertension, Hypotension, Hypotension, Orthostatic, Insulin, Myocardial Infarction, Regression Analysis, Risk Factors, Smoking, Stroke, Syncope, Metabolic Syndrome

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