Under Pressure:The Disease of Hypertension vs Blood Pressure, Its Biomarker
Case Presentation:
Patient 1: SPRINT
A 68 year old nondiabetic male with stage 3 CKD, who had a coronary stent placed in his LAD 1 year ago for stable angina presents to his primary care provider to establish care after moving into the area. His office blood pressure is 138/84 mm Hg. His nephrologist had placed him on HCTZ years ago for his CKD and his cardiologist placed him on low dose metoprolol succinate following his stent.
What makes this patient vulnerable?
This patient fits the inclusion criteria and in some ways represents the typical SPRINT trial participant: Over age 50 (mean age 68) with established CAD or CKD (has both) on ~ 2 drugs for hypertension.
Patient 2: White Coat Hypertension
A 36 year old female marathon runner with BMI of 20 presents to her PCP office for evaluation of bunions. She has no other chronic medical problems except for mild anxiety - mostly in social situations. She takes occasional propranolol prior to public speaking but otherwise no other medications.
She ran 10 miles earlier that day but cut it short because it was hot outside and her foot was acting up. She apologizes for being 5 minutes late to the appointment.
Her blood pressure in the office is 147/92 mm Hg with a HR of 87 bpm. Her last office visit 6 months ago for plantar fasciitis showed a BP of 142/91 mm Hg and HR of 78 bpm. She states her BP is always high in the office but she doesn’t check it at home. She is surprised by her HR since her Apple Watch typically shows it in the mid 50s when resting at home.
Her PCP informs her that she has Stage 2 Hypertension and by the latest guidelines she should be treated aggressively with 2 different agents. She places her on hydrochlorothiazide because it is a first line agent and a low dose beta blocker since her HR has gone up so much and it might help with her anxiety.
What makes this patient vulnerable?
First of all, it’s highly unlikely this patient actually has hypertension. Again, hypertension is a disease. It usually keeps close company with many other cardiometabolic diseases such as obesity, sedentary lifestyle, diabetes or prediabetes, CKD, cardiovascular diseases and aging. She has none of those.
This patient is a young, athletic and otherwise healthy individual, with an optimal BMI. As a marathon runner, she no doubt has a high vagal tone (parasympathetic nervous system) but also a robust sympathetic response to stress (doctor’s office, pain, dehydration, anxiety). The relatively high HR and BP are more likely a reflection of her adrenergic state, than a true representation of the disease of hypertension. Furthermore, (this should come as no surprise) the doctor’s office rarely has the time to check BP’s in accordance with guideline recommendations.
In this setting the biomarker is not being employed and interpreted correctly.
Treating this particular patient - an endurance athlete - with a diuretic (yikes) and a beta blocker is a recipe for disaster. Yet it happens. At best she will feel miserable trying to get her HR up when she runs. But more likely she will have worsening dehydration, electrolyte abnormalities (low sodium, high/low potassium, low magnesium), kidney impairment (from thiazide diuretic) and risk for syncope (passing out) with the combination of both.
Patient 3: Masked hypertension
A 58 year-old male smoker is seen in the primary clinic for his annual follow up visit. His blood pressure is 132/83 mmHg. Similar to last year and the year before that. He typically fasts and doesn’t drink any water prior to his office visits in the event he has to do lab work.
He has a high stress job selling cars at the local dealer. He hates drinking water and prefers coffee during the day and then several alcoholic beverages nightly to help him relax after work. He doesn’t feel he has time to exercise but his wife, who accompanies him to the visit, occasionally forces him to go for evening walks with her but at a casual pace. She also checks his blood pressure at home and reports that more often than not it is in the 140-150’s/80-90s mmHg.
What makes this patient vulnerable?
The precise cause of masked hypertension is not entirely known but is typically seen in those with untreated risk factors of smoking, alcohol abuse, sedentary lifestyle and job stress. There may be many reasons why the office based blood pressures tend to be normal, while the out of office measures are elevated. Chronic dehydration, alcohol consumption, poor eating behaviors, disrupted sleep patterns and lack of exercise/activity all have unpredictable influences on blood pressure as an accurate biomarker for hypertension recognition and for gauging its severity.
Hypertension, in many ways, is a “gateway” disease to other cardiometabolic disease states. When hypertension fails to be diagnosed and treated, so too do the other cardiometabolic diseases which accompany it.
Vital signs are just that - they are “vital.” When the most important “vital” sign, blood pressure, is “normal” in the office, the patient may be overlooked despite demonstrating numerous warning signs of uncontrolled metabolic syndrome. This represents a high risk patient at greater risk for stroke, heart attack and heart failure when left untreated year after year.
Flying Under the Radar
Hypertension is a disease, best characterized as a derangement in the body’s ability to deliver nutrients to a tissue bed and extract waste products.
Blood pressure (BP) is the biomarker of that disease. It is a very good biomarker, but it is not perfect. Like many biomarkers, it must be employed, measured and utilized correctly; in the appropriate clinical setting.
One can have high office based blood pressures, yet not have the disease of hypertension. So-called “White Coat Hypertension” is the classic example most commonly seen in the clinic and referred to in hypertension guidelines.
For example, if blood pressure is measured while in a physically stressful setting or circumstance such as while anxious, while running on the treadmill, while engaged in an argument, while battling an infectious illness, following a poor night’s sleep, while dehydrated following bouts of diarrhea, while in acute abdominal pain, chances are the blood pressure will be elevated. An elevated blood pressure measurement in such settings may not be a reflection of an uncontrolled disease or represent any disease at all. Rather, it more likely represents an appropriate and in fact necessary adrenergic physiologic response to that particular environmental and situational stress. Measuring blood pressure under times of stress is not how hypertension is diagnosed, nor is it how we utilize blood pressure as a biomarker to gauge the effectiveness of any sort of treatment for the disease of hypertension. We do not “treat” appropriate physiological reflexes with antihypertensive therapies that are FDA approved for the treatment of a disease. In other words, we employ medical interventions such as diet, lifestyle and pharmacotherapy to treat the disease of “hypertension,” not necessarily “blood pressure” as an isolated biomarker.
Over-treatment of “office-based” or other “catecholamine-driven” blood pressures runs the risk of adverse consequences and side effects of antihypertensive drugs. To be clear, all antihypertensive drugs have adverse consequences and are the major pitfall of all clinical trials of these antihypertensive drugs.
On the other hand, one can have normal office based blood pressures, yet have hypertension. “Masked Hypertension” is the classic example in this case. A patient may happen to have a normal blood pressure in the office that day, but the more accurate home BP readings demonstrate a trend of blood pressures consistent with the diagnosis of hypertension. These patients are therefore missed and undertreated.
CardioAdvocate Checklist:
Purchase an automated blood pressure cuff
Use an appropriately sized arm cuff (wrist cuffs are not recommended)
Sitting relaxed, for AT LEAST 5 minutes, in a comfortable chair, back supported, feet flat, legs not crossed, arm at the same height as the heart
Take 2-3 measurements and average them
Bring in 10-15 samples of home blood pressures to your next visit
For those with White Coat Hypertension, or to avoid this diagnosis, take your blood pressure at home on the morning of your office visit (a bit of a cheat but at our clinic we will use this value in our vitals for the day…it is well established that home BP’s are more accurate than office based BPs)
Come to the office well hydrated
Get plenty of sleep the night(s) before your visit
Deep Dive
As early as the 1920’s it’s been observed that with higher blood pressures there exists a strong direct correlation with greater clinical complications and death. Subsequent observational trials have demonstrated that for every 20 mm Hg higher SBP and 10 mm Hg DBP there is a doubling of the risk of death from stroke, heart disease and vascular disease.
The disease of hypertension represents a common frustration in medicine: It’s one thing to link a biomarker to adverse health outcomes, but it’s much harder to develop interventions that, when reducing that biomarker, leads to a lowering in those adverse events.
Demonstrating benefits from the pharmacologic treatment of high blood pressure, particularly to intense targets of < 120 mm Hg has been challenging. Recently, the SPRINT trial showed benefits of an “intensive-treatment” in reducing MACE, but only in those at high risk, without diabetes. Previous trials such as the ACCORD-BP (Effects of Intensive Blood-Pressure Control in Type 2 Diabetes Mellitus | New England Journal of Medicine), which looked at diabetic patients - a particular patient population known to have a high risk of ASCVD - failed to show a benefit.
Diagnosing Hypertension
It is worth repeating that blood pressure is a “biomarker” which needs to be distinguished from hypertension, which is a disease.
Therefore, it is absolutely critical that BP is measured appropriately and accurately before making a diagnosis of hypertension.
The following method is recommended:
At least 2 measurements, preferably in both arms, 1 minute apart, on 2 separate visits
Sitting relaxed, for AT LEAST 5 minutes, in a comfortable chair, back supported, feet flat, legs not crossed, arm at the same height as the heart, with an appropriately sized arm cuff and automated BP machine
Spurious elevations in BP, at random clinic visits, particularly in the setting of acute or chronic pain, anxiety or other “adrenalin” provoking situations, does not make the diagnosis of hypertension
2020 International Society of Hypertension Global Hypertension Practice Guidelines:
“Whenever possible, the diagnosis should not be made on a single office visit”
“Usually 2-3 office visits at 1-4 week intervals are required to confirm the diagnosis of hypertension”
“The diagnosis might be made on a single visit if BP is >/= 180/110 mmHg and there is evidence of cardiovascular disease (CVD)”
Slide deck found here: 2020 ISH Global Hypertension Practice Guidelines
Classifying Hypertension
Contemporary Guidelines differ on the definitions and classification of Hypertension. Guidelines are just that - they are “guidelines.” They may differ, sometimes very significantly, on key aspects. The totality of evidence to include societal guidelines, expert consensus documents, opinion papers and community best practices are what dictate local, regional, national and international standards of care.
The latest American College of Cardiology (ACC)/American Heart Association (AHA) guidelines revised previous guidelines, with more “intense” or strict definitions and thresholds for hypertension, based upon new data from the SPRINT trial: A Randomized Trial of Intensive versus Standard Blood-Pressure Control | New England Journal of Medicine. The ACC/AHA guidelines recommend calculating risk in primary prevention patients and starting medical therapy at a lower BP threshold for patients at high risk.
However, many other reputable guidelines chose not to follow suit. The 2018 ESC/ESH Guidelines for the management of arterial hypertension | European Heart Journal | Oxford Academic recommends a threshold of > 140/90 mmHg (grade 1) for the diagnosis of hypertension. Same with the 2020 International Society of Hypertension Global Hypertension Practice Guidelines: a BP of 130-139/85-89 is defined as “high normal”. “High normal” BP is “intended to identify individuals who could benefit from lifestyle interventions and who would receive pharmacological treatment if compelling indications are present.”
There is a lack of consistency in the definition and classification of hypertension among various guidelines. This reflects the controversy and uncertainty which remains after evaluating the totality of evidence from a relatively sparse collection of clinical trials devoted to cardiovascular event reduction from the pharmacologic (drug) treatment of mildly to moderately elevated blood pressures and the pitfalls of extrapolating the findings from the SPRINT trial to a broader population.
Breaking Down the SPRINT Trial
Importantly, the SPRINT trial enrolled “high risk” patients, which included nondiabetic patients over age 50 with cardiovascular disease, or those with a 10 year CVD risk (using Framingham Risk Calculator) of 15% or more. The mean age was 68 years of age. More than 25% were over age 75.
Benefits in treating hypertension largely depend on baseline risk. The higher the baseline risk, the greater the benefits of pharmacologic intervention. The treatment of hypertension is not without adverse events. The “intense” treatment arm of the SPRINT trial suffered statistically significantly more adverse events such as Emergency Room visits, syncope (passing out), electrolyte abnormalities requiring additional intervention, than the “standard” therapy arm.
Such heterogeneity of the effect of strict BP control was exemplified in a comparable clinical trial called the ACCORD BP trial: Effects of Intensive Blood-Pressure Control in Type 2 Diabetes Mellitus, where higher risk diabetic patients greater than 40 years of age were enrolled and subjected to “intense” treatment. However this patient population did not show a benefit to intense blood pressure lowering compared to standard thresholds, despite their high risk.
Therefore, caution is advised when extrapolating the benefits seen in one high risk patient population to even other high risk patient populations, let alone lower risk patient populations – as this runs the risk of inheriting all of the side effects of the intervention without any of the benefits seen in the clinical trials.
The importance of baseline risk as well as using accurate biomarkers is best summarized in this editorial accompanying the publication of SPRINT Redefining Blood-Pressure Targets — SPRINT Starts the Marathon: “The ability to generalize the SPRINT results to clinical practice requires accurate assessment of BP and evidence of high CV risk.”
