# Presentation: 199835

## How Should One Decide Whom to Treat for Hypertension?

***Jay N. Cohn, M.D.***
*Professor of Medicine*
*Director, Rasmussen Center for Cardiovascular Disease Prevention*
*University of Minnesota Medical School*
*Minneapolis, MN*

## CV Mortality Risk Doubles withEach 20/10 mm Hg BP Increment*

- *Individuals aged 40-69 years, starting at BP 115/75 mm Hg.
- CV, cardiovascular; SBP, systolic blood pressure; DBP, diastolic blood pressure
- Lewington S, et al. *Lancet*. 2002; 60:1903-1913.
- JNC VII. *JAMA.* 2003.

- CVmortalityrisk

- SBP/DBP (mm Hg)

- 0

- 1

- 2

- 3

- 4

- 5

- 6

- 7

- 8

- 115/75

- 135/85

- 155/95

- 175/105

## Impact of “High-Normal” BP on CV RiskData from the Framingham Heart Study

- 16

- 12

- 8

- 4

- 0

**Optimal BP**

**Normal BP**

- 12

- 8

- 4

- 0

- 0

- 2

- 4

- 6

- 8

- 10

- 12

**Years**

**Optimal BP**

**Normal BP**

**High-normal BP**

**Women**

**Men**

**Cumulative **

**incidence of **

**CV events**

**(%)**

**High-normal BP**

- Vasan et al. *N Engl J Med.* 2001;345:1291-7.

- Optimal BP: <120/80
- Normal BP: 120-129/80-84
- High-normal BP: 130-139/85-89

## Lower Is BetterIHD Rates by SBP, DBP, and Age

**A: Systolic Blood Pressure**

**40-49 years**

**50-59 years**

**60-69 years**

**70-79 years**

**80-89 years**

**Age at risk:**

**IHD Mortality**

**(Floating Absolute Risk and 95% CI)**

**256**

**128**

**64**

**32**

**16**

**8**

**4**

**2**

**1**

**120**

**140**

**160**

**180**

**Usual SBP (mm Hg)**

**B: Diastolic Blood Pressure**

**IHD Mortality**

**(Floating Absolute Risk and 95% CI)**

**256**

**128**

**64**

**32**

**16**

**8**

**4**

**2**

**1**

**70**

**80**

**90**

**100**

**110**

**Usual DBP (mm Hg)**

- Lewington et al. *Lancet.* 2002;360:1903-1913.

**Age at risk:**

## Hypothesis

*	**The apparent linear relationship between blood pressure and ischemic disease events as well as age and ischemic disease events does not necessarily mean that age or blood pressure cause events but that both markers capture a progressively higher proportion of people with early disease. *

## Blood Pressure and Likelihood of Disease

- 		**100**
**Frequency in**
**Population (%)**
- 		 **50**
- 		   **0**
**	****	****	****75****	****100****	****125****	****150****	****175****	****200**
- 			**Systolic Blood Pressure (mmHg)**

**No Disease**

**Possible Disease**

**Likely Disease**

## Systolic BP Reduction and CVD Mortality 

****** ****Systolic BP (control - experimental, mm Hg)**

**Cardiovascular Mortality Odds Ratio**

- Staessen JA et al. *Lancet.* 2001;358:1305 -1315.

## SBP Reductions as Little as 

- 2 mm Hg Reduce the Risk of CV Events by Up to 10%

- Meta-analysis of 61 prospective, observational studies
- 1 million adults
- 12.7 million person-years

- Lewington S et al.  *Lancet.* 2002;360:1903-1913.

**2 mm Hg decrease in mean SBP**

**10% reduction in risk of stroke mortality**

**7% reduction in risk of ischemic heart disease mortality**

## Benefits of Intensive BP ReductionHOT Study

*****Mean BP from 6 months of follow-up to end of study.
-   Hansson L et al. *Lancet.* 1998;351:1755-1762.

**Achieved DBP* ****(mm Hg)**

**85.2**

**83.2**

**81.1**

*P*=0.05 for trend

**Number of MIs**

- 90	143.7	85.2
- 85	141.4	83.2
- 80	138.7	81.1

**Target****DBP****(mm Hg)**

**Achieved****SBP****(mm Hg)**

**Achieved****DBP*****(mm Hg)**

## Hypothesis

*	**The apparent linear relationship between the magnitude of drug-induced BP fall and the reduction of morbid events does not necessarily indicate that blood pressure reduction prevents events but that the drugs protect the arteries and heart (while also lowering blood pressure).  A corollary: the greater the BP reduction from a drug the less the vascular disease - i.e., BP fall identifies a low-risk population. *

## Antihypertensive Drugs that Slow Disease Progression in Known Doses

- 		_*Vascular*_			_*Cardiac*_
- 		Ramipril			Enalapril
- 		Perindopril			Captopril
- 		?other ACEIs			Carvedilol
- 	           Amlodipine			Metoprolol
- 		Valsartan			Bucindolol
- 		Losartan			Valsartan
- 		Hydrochlorothiazide		Candesartan
- 						Spironolactone
- 						Eplerenone
- 						ISDN/hydralazine

## Old Paradigm

- 	       *BP*				*Cholesterol*
- Disease			          Disease
- 		       Treatment			         Treatment
- Normal			           Normal
_***GOAL***_**: Target Response**

## Current Paradigm

- _DISEASE_
- 	BP		   Cholesterol
_***GOAL***_**: ?Target Response**

**TREATMENT**

## Pathophysiology of CV Continuum

*	*
*	*_*Genes*_*	**	*				_*Environment*_
- 	Ethnicity						Diet
- 	Family Hx					Exercise
- 	Polymorphisms					Stress
- 	Proteomics					Smoking
- Blood Vessel/ Heart
- 						Angiotensin
- 						Nitric Oxide
- 		 	Progression		Aldosterone
- 						Norepinephrine
- 						Cytokines
- Structural Remodeling
- 			CAD			Cerebrovascular Disease
- 			Heart Failure		Renal Failure
- 			PVD			Dementia

## Genes, Ethnicity, Diet, Exercise, Smoking, Obesity, Lipids

-     _**Small Artery**_** ****	****  **_**Arterial Structural**_** ****	**_**Cardiac**_** **
**    **_**Elasticity**_** ****	****	****  **_**Abnormalities**_** ****	****	**_**Abnormalities**_
-    (*Endothelial*	   Microalbumin		  LVM
*   **Dysfunction*)	     IMT			  BNP
-       BP			    Retinal Vasculopathy	  ECG
-       PNE		     Large Artery Elasticity
-       AngII		     Exercise BP
- 			     Resting BP
**	****	****	****	****         ****Disease**
- 			      	     _*Drug Therapy*_
*	**	**	**RAAS Blockade**	**Statins*
*	**	**	**NO Enhancers**	**Antihypertensives **	**	**	**	**Antioxidants**	**	**?Antiinflammatories*

## ASH Writing Group: Proposed New Definition of Hypertension

- Hypertension is a progressive cardiovascular
- syndrome arising from complex and interrelated
- etiologies. Early markers of the syndrome are often
- present before blood pressure elevation is
- sustained; therefore, hypertension cannot be
- classified solely by discrete blood pressure
- thresholds. Progression is strongly associated with
- functional and structural cardiac and vascular
- abnormalities that damage the heart, kidneys, brain,
- vasculature and other organs and lead to premature
- morbidity and death.

- ASH Writing Group 2005.

## ASH Writing Group Definition and Classification of Hypertension

- †CVD designation is determined by the constellation of risk factors, early disease markers, and target-organ disease.
- CVD, cardiovascular disease.

| Classification | Normal | Stage 1 
hypertension | Stage 2 
hypertension | Stage 3 
hypertension |
| --- | --- | --- | --- | --- |
| Descriptive 
Category | Normal BP or rare 
blood pressure 
elevations
AND
No identifiable 
CVD† | Occasional or 
intermittent BP
elevations
OR
Early 
CVD† | Sustained BP
elevations
OR
Progressive 
CVD† | Marked and 
sustained BP
elevations
OR
Advanced 
CVD† |
| Cardiovascular 
Risk Factors  | None or few | Several | Many | Many |
| Early Disease 
Markers  | None  | Usually present | Overtly present | Overtly present 
with progression |
| Target-organ 
Disease  | None | None | Early signs 
present | Overtly present 
with or without 
CVD events |

- ASH Writing Group 2005.

## Early Markers for Hypertensive Vascular Disease

**  **_**Blood Pressure**_
- 	*-Exaggerated response to exercise*
*	**-Widened pulse pressure*
**  **_**Vascular**_
- 	*-Reduced small artery elasticity*
*	**-Reduced large artery elasticity*
*	**-Endothelial dysfunction*
*	**-Increased pulsewave velocity*
*	**-Increased carotid intima-medial thickness*
*	**-Retinal vascular changes*
*	**-Microalbuminuria*
**  **_**Cardiac**_
- 	*-Increased LV wall thickness**	**	**-Increased LV volume*
*	**-Increased LV mass**	**	**	**-Abnormal ECG*
*	**-B-type natriuretic peptide**	**	**	**	*

## R  A  S  M  U  S  S  E  NC  E  N  T  E  RforCARDIOVASCULARDISEASE PREVENTION

## RASMUSSEN CENTER

- Screening Tests for Early Detection

-  Arterial Elasticity (Pulse Contour Analysis)
- 	- Small Artery (C2)
- 	- Large Artery (C1)
-  Rest and exercise BP (3-minute treadmill)
-  Retinal digital photograph
-  Urine for microalbumin/creatinine ratio
-  Carotid intimal-medial thickness

**Vascular Evaluation**

## RASMUSSEN CENTER

**Screening Tests for Early Detection**

**Cardiac Evaluation**

-   Electrocardiogram
-   Cardiac ultrasound (LVID & LVWT)
-   Plasma BNP (Biosite)

## RASMUSSEN CENTER

**Screening Tests for Early Detection**

**Modifiable Disease Contributors**

-   Fasting lipids (LDL, HDL, Trig)
-   Fasting blood sugar
-   hsCRP
-   Homocysteine

## Results of Rasmussen Center Screening

**Frequency**

**Rasmussen Score**

**Low Risk**

**33%**

**Modest Risk**

**36%**

**High Risk**

**31%**

## Patient: 60-year-old female registered nurse
Past History: negative except high cholesterol
Family History: both parents smoked, no significant CV disease

Physical Exam: 	Height 5’4”		Weight 126 lb.
			HR 64 b/min		BP 132/66 mmHg

Screening Results:	C1 = 8.5 ml/mmHg x10 (abnormal)
			C2 = 2.4 ml/mmHg x100 (abnormal)
			Exercise BP = 173/64 mmHg (abnormal)
			Retinal photo = A:V nicking (abnormal)
			Microalbumin = 0.86 mg/mmol (abnormal)
			LV ultrasound = increased mass (abnormal)
			Rasmussen score = 12 points		

Blood Chemistry: LDL 187 mg/dl; HDL 70 mg/dl

Interpretation: Advanced CV Disease
Treatment: Antihypertensive, statin

_**Past History**_: negative except high cholesterol
_**Family History**_: both parents smoked, no significant CV disease
_**Physical Exam**_: 	Height 5’4”		Weight 126 lb.
- 			HR 64 b/min		BP 132/66 mmHg
_**Screening Results**_:	C1 = 8.5 ml/mmHg x10 (abnormal)
- 			C2 = 2.4 ml/mmHg x100 (abnormal)
- 			Exercise BP = 173/64 mmHg (abnormal)
- 			Retinal photo = A:V nicking (abnormal)
- 			Microalbumin = 0.86 mg/mmol (abnormal)
- 			LV ultrasound = increased mass (abnormal)
- 			Rasmussen score = 12 points
_**Blood Chemistry**_: LDL 187 mg/dl; HDL 70 mg/dl
_***Interpretation***_**: ***Advanced CV Disease*
_***Treatment***_***: ****Antihypertensive, statin*

## Patient: 62-year-old female florist
Past History:	Asymptomatic, plays tennis and golf
		Elevated cholesterol: Atorvastatin, 10 mg
Family History: Negative

Physical Exam: 	Height 5’5”		Weight 128 lb.
			HR 74 b/min		BP 140/80 mmHg

Screening Results:	C1 = 8.7 ml/mmHg x10 (abnormal)
			C2 = 1.6 ml/mmHg x100 (abnormal)
			Exercise BP = 182/80 mmHg (abnormal)
			Retinal photo = decreased A:V ratio (borderline)
			Microalbumin = 1.98 mg/mmol (abnormal)
			Rasmussen score = 9 points		

Blood Chemistry: LDL 137 mg/dl; HDL 129 mg/dl; CRP 0.13 mg/dl

Interpretation: Advancing CV Disease
Treatment: ACE/ARB; BP Control; Increase atorvastatin

_**Past History**_:	Asymptomatic, plays tennis and golf
- 		Elevated cholesterol: Atorvastatin, 10 mg
_**Family History**_: Negative
_**Physical Exam**_: 	Height 5’5”		Weight 128 lb.
- 			HR 74 b/min		BP 140/80 mmHg
_**Screening Results**_:	C1 = 8.7 ml/mmHg x10 (abnormal)
- 			C2 = 1.6 ml/mmHg x100 (abnormal)
- 			Exercise BP = 182/80 mmHg (abnormal)
- 			Retinal photo = decreased A:V ratio (borderline)
- 			Microalbumin = 1.98 mg/mmol (abnormal)
- 			Rasmussen score = 9 points
_**Blood Chemistry**_: LDL 137 mg/dl; HDL 129 mg/dl; CRP 0.13 mg/dl
_***Interpretation***_**: ***Advancing CV Disease*
_***Treatment***_***: ****ACE/ARB; BP Control; Increase atorvastatin*

## Patient: 49-year-old male executive
Past History:	Overweight, elevated BP, asymptomatic, no therapy

Family History: Hypertension, coronary disease

Physical Exam: 	Height 5’8”		Weight 240 lb.
			HR 76 b/min		BP 144/84 mmHg

Screening Results:	C1 = 16.1 ml/mmHg x10 (normal)
			C2 = 6.4 ml/mmHg x100 (normal)
			Exercise BP = 154/74 mmHg (normal)
			All other tests normal
			Rasmussen score = 2 points (BP only)		

Blood Chemistry: 	LDL 172 mg/dl; HDL 38 mg/dl; 
			FBS 108 mg/dl; CRP 1.0 mg/dl

Interpretation: No CV Disease
Treatment: Diet, ?statin

_**Past History**_:	Overweight, elevated BP, asymptomatic, no therapy
_**Family History**_: Hypertension, coronary disease
_**Physical Exam**_: 	Height 5’8”		Weight 240 lb.
- 			HR 76 b/min		BP 144/84 mmHg
_**Screening Results**_:	C1 = 16.1 ml/mmHg x10 (normal)
- 			C2 = 6.4 ml/mmHg x100 (normal)
- 			Exercise BP = 154/74 mmHg (normal)
- 			All other tests normal
- 			Rasmussen score = 2 points (BP only)
_**Blood Chemistry**_: 	LDL 172 mg/dl; HDL 38 mg/dl;
- 			FBS 108 mg/dl; CRP 1.0 mg/dl
_***Interpretation***_**: ***No CV Disease*
_***Treatment***_***: ****Diet, ?statin*

## Strategies for Aggressive Treatment

- _PRIMARY PREVENTION_
*Primary Prevention* (global)
- Polypill
- Everyone >55 years old
- Impractical
- Inefficient
- Benefit: risk ratio untested
*Primary Prevention* (targeted)
- Risk factor identification
- Treatment targets risk factor
- Misses many at-risk
- Risk factor levels?
- Benefit: risk?

## Strategies for Aggressive Treatment

- _SECONDARY PREVENTION_
*Secondary Prevention* (early)
- Detect markers for early disease
- Treat disease not risk factor
- Sensitivity/specificity of detection?
- Benefit: risk better?
- Prolonged event-free survival
- Reduced health care costs
*Secondary Prevention* (late)
- Patients with symptomatic disease
- Treatment can prevent events/prolong life
- Increased burden of health care costs

## Risk Factors

**Biomarkers**

**Cardiac and Vascular**
**Structural Abnormalities**

**Death**

**Non-Fatal**
**Morbid**
**Events**

**Recurrence**
**Progression**

**Primary Prevention**

**Secondary Prevention**

**Tertiary Prevention**

## Who to Treat with Antihypertensives (Pressure Orientation)

- SBP>160 mmHg most of the time
- SBP>140 mmHg most of the time & evidence for vascular or cardiac functional/structural abnormalities
- SBP>130 mmHg with symptomatic vascular or cardiac disease or diabetes
- ?SBP>130 mmHg with evidence for vascular or cardiac functional/structural abnormalities
_***GOAL***_**: Lower Blood Pressure**

## Who to Treat with Antihypertensives (Pathophysiologic Orientation) 

- Anyone with symptomatic atherosclerotic vascular or cardiac disease
- ?Anyone with vascular or cardiac functional/structural abnormalities and BP >120/80 mmHg
_***GOAL***_***: Slow Disease Progression***

## Future Paradigm

- 			  **Early Disease**
- 					*Statin*
*	**	**	**	**	**RAAS Blockade*
*	**	**	**	**	**Antihypertensives*
*	**	**	**	**	**NO donor/enhancer*
- 					*Innovative Therapy*
- 			  **Slow Progression**
**	****	****	**
**	****	****	**_***GOAL***_**: ?Target Dose****	**

## Strategies to Identify At-Risk Population

- Blood pressure level
- Which measurement?
- What level?
- Cholesterol level
- Which fraction?
- Reproducibility?
- Blood pressure + cholesterol (BP + Ch)
- Sensitivity, specificity
- BP + Ch + other “risk factors”
- Sensitivity, specificity
- Early disease detection
- Endothelial dysfunction
- Vascular functional/structural abnormalities
- Cardiac functional/structural abnormalities