hypertension and related clinical trials and various guidelines related to hypertension in different countries

1. HYPERTENSION
BY : MANISHA VERMA
16CRM 2488

2. INTRODUCTION
• Hypertension or high B.P. is very common & one of the major contributors of
cardiovascular morbidity and mortality worldwide.
• 50% of the population >60years of age has hypertension
• Worldwide prevalence estimates may be 1 billion individuals &7.1 million deaths
• Major public health concern affecting 26% of adults worldwide
• 1.6 million HTN patients by 2025
• WHO identified HTN – preventable causes of premature mortality & morbidity
• May 14th is world hypertension day
INDIA
Urban- 33%
Rural- 25%
57%- stroke deaths
24%- CHD

3. HYPERTENSION GUIDELINES
JNC 8 EMA
CHEP NICE
ESH
AHA

4. GUIDELINES GOAL BP, mm Hg
JNC <150/90 (patients >60 y)
<140/90 (patients < 60y + compelling indications)
ESH/ESC 2013 <150/90 (patients <80y or >80y)
<140/85 ( compelling indication)
CHEP 2013 <140/90 (patients <80y or CKD)
<150/90 (patients > 80y)
ADA 2013 Diabetes <140/80
KDIGO 2012 CKD (noproteinuria) ≤140/90
CKD + proteinuria ≤130/80
NICE2011 <140/90 (General<80y )
<150/90 (General≥80y)

5. • BP- pressure exerted by the blood on the walls of the blood vessels
while flowing through them
• Normal blood pressure is 120/80 mmHg
• Systolic BP
• Diastolic BP
• Pulse pressure (PP)
BLOOD PRESSURE

6. BP & CARDIOVASCULAR RISK
• The higher the BP, the greater the chance of heart attack, HF, stroke,
and kidney diseases.
• For every 20 mmHg systolic or 10 mmHg diastolic increase in BP,
there is a doubling of mortality from both IHD and stroke.
• SBP is an imp. risk factor for CVD
• DBP is a more potent cardiovascular risk factor than SBP until age 50
after that SBP plays an imp. role

8. REGULATION OF BP

9. SYMPTOMS
• Silent killer
1. Dull headaches
2. Vomiting
3. Dizzy spells
4. Epistaxis

10. TYPES OF
HYPERTENSION

11. CLASSIFICATION OF HYPERTENSION
• Aetiology: essential or primary hypertension vs. secondary
hypertension
• Severity: according to WHO/ISH, JNC 7, or ESC/ESH guidelines
• Type: systolic, diastolic or both;

12. ETIOLOGY OF HYPERTENSION
Primary HTN:
• also known as
essential HTN.
• accounts for 95%
cases of HTN.
• no universally
established cause
known.
Secondary HTN:
• less common cause of
HTN (5%).
• secondary to other
causes.

13. BASIS FOR
RECLASSIFICATION OF
BP

14. JNC 6 category JNC 7 category
SBP/ DBP
Optimal <120/80 Normal
Normal
Borderline
120–129/80–84
130–139/85–89
Prehypertension
Hypertension >140/90 Hypertension
STAGE 1 140–159/90–99 STAGE 1
STAGE 2 160–179/100–109
STAGE 2
STAGE 3 >180/110

15. • MALIGNANT HTN : also known as accelerated HTN
• Characterised by greatly elevated BP (usually >220/120 mmHg)
• Associated with ongoing small vessel damage
• Medical emergency condition requires hospital admission
• WHITE COAT HTN: some people develop excessive &
unrepresentative BP rises when attending the doctor’s clinic

16. • ECLAMPSIA:
- HTN in pregnant women is known as pre-eclampsia
- can progress to a life-threatening condition called eclampsia
-development of protein in the urine, generalized swelling & severe
seizures.

17. PREDISPOSING FACTORS
• Risk factors which can be controlled:
 Obesity
Sedentary life style
Tobacco usage
Unhealthy diet (high in sodium)
Excessive alcohol usage
Stress
Comorbities- diabetes, and hyperlipidemia
• Risk factors which cannot be controlled:
Advancing Age
Family history of cardiovascular disease

18.  DISEASE STATES:
1. Cardiovascular HTN-
-atherosclerosis
-coarctation of aorta
2. Renal HTN-
-renal artery stenosis
-glomerulonephritis
3. Endocrine HTN-
-pheochromocytoma
4. Neurological HTN-
-increased intracranial tension
Causes of secondary HTN

19. TREATMENT
• Goals of therapy
• Pharmacologic treatment
• Lifestyle Modifications

20. GOALS OF THERAPY
 Reduce Cardiac and renal morbidity and mortality.
 Treat to BP <140/90 mmHg or BP <130/80 mmHg in patients
with diabetes or chronic kidney disease.

21. PHARMACOLOGICAL TREATMENT

22. NEW DRUGS
• Byvalson (nebivolol & valsartan) – Jun 2016
• Prestalia- (perindopril arginine & amlodipine besylate)- Jan 2015
• Uptravi (selexipag)- PAH- Dec 2015
• Northera (droxidopa)- treatment of neurogenic orthostatic
hypotension – Feb 2014
• Amturnide (aliskiren + amlodipine +hydrochlorthiazide) – Dec 2010

23. FOLLOWUPAND MONITORING
• At monthly intervals or until BP goal is reached
• More frequent visits
• Serum potassium and creatinine should be monitored at least 1-2 times
per year.
• BP goal is at stable: 3-6 months intervals

24. Modification Recommendation Approximate SBP
Reduction
(Range)
Weight reduction Maintain normal body weight (body mass index 18.5–24.9 kg/m2). 5–20 mmHg/10kg
Adopt DASH eating plan Consume a diet rich in fruits, vegetables, and lowfat dairy products
with a reduced content of saturated and total fat.
8–14 mmHg
Dietary sodium reduction Reduce dietary sodium intake to NMT 100 mmol per day (2.4 g
sodium or 6 g sodium chloride).
2–8 mmHg
Physical activity Engage in regular aerobic physical activity such as brisk walking
(atleast 30 min per day, most days of the week).
4–9 mmHg
Moderation of alcohol
consumption
Limit consumption to NMT 2 drinks (e.g., 24 oz beer, 10 oz wine, or 3
oz 80-proof whiskey) per day in most men, and to no
more than 1 drink per day in women and lighter weight persons.
2–4 mmHg
LIFESTYLE MODIFICATIONS TO PREVENT AND MANAGE
HYPERTENSION

25. Dietary sodium
should be reduced
to NMT 2.4 g
Diet rich in fruits,
vegetables, lowfat
dairy products +
reduced dietary
Chl.
Rich in
calcium &
potassium

26. EMA GUIDELINES

27. 4. ASSESSMENT OF EFFICACY
CRITERIA
4.1 Blood pressure
• goal of treating
hypertension
• valid surrogate
endpoint
4.2. Morbidity
and mortality
• evaluated
properly in large-
scale and long-
term controlled
clinical trials
4.3. Target organ
damage
• target organ damage
of heart, brain, eyes,
kidneys and blood
vessels

28. 5. METHODS TO ASSESS EFFICACY
5.1 Blood pressure:
• SBP preferred efficacy variable & DBP mandatory secondary
endpoint
• Secondary endpoint - Effects on response criteria
• Main endpoint should be blood pressure at trough which is defined as
the residual effect at the end of the dose interval.

29. Methods to measure BP
a) Sphygmomanometry
b) Intra-arterial measurements
c) Non-invasive ambulatory blood pressure monitoring
d) Automatic self (home) measurement

30. a) SPHYGMOMANOMETRY
• Calibrated sphygmomanometer
• Aneroid manometer is not recommended
• Two or more readings separated by 2 minutes should be averaged
• In brachial artery
• Measured in either supine or sitting position or both
• Standing blood pressure
• Blood pressure should be measured under standardised conditions, as
nearly as possible at the same time each day, on the same arm, by the
same personnel, with the same apparatus

33. b) INTRA-ARTERIAL MEASUREMENT
• Phase II studies
• Relation between dose, magnitude, & duration of effect
• Assess changes during exercise & to measure 24-hour efficacy
• complicated and the interpretation of the results is difficult
• It is not considered to be widely applicable in the setting of clinical
pivotal studies.

34. c) NON-INVASIVE AMBULATORY BLOOD
PRESSURE MONITORING
• provides a better insight to blood pressure changes during everyday
activities
• recorders used must fulfil international validation procedures (e.g. AAM-
IBHS)
• Repetitive investigations
• Readings should cover time before drug intake.
• Measurements within one hour and two hours after wake up, respectively,
are recommended.
• At least 8 measurements should be included between 18 and 24 hours after
drug intake.
• Indicated in case of suspected white coat hypertension

35. d) AUTOMATIC SELF (HOME)
MEASUREMENT
• Automatic devices
• Validation of device is necessary
• Home measurement of >135/85 mmHg is generally considered to be
hypertensive

36. INITIAL BP (mm hg) Followup Recommended
Normal Recheck in 2 years
Prehypertension Recheck in 1 year
Stage 1 Hypertension Confirm within 2 months
Stage 2 Hypertension Evaluate or refer to source of care within 1 month. For
those with higher pressures (e.g., >180/110 mmHg),
evaluate and treat immediately or within 1 week
depending on clinical situation and complications
RECOMMENDATIONS FOR FOLLOWUP BASED ON INITIAL
BP MEASUREMENTS FOR ADULTS WITHOUT ACUTE END
ORGAN DAMAGE

37. 5.2 Target organ damage
• Echocardiography
• Tissue Doppler myocardial imaging & echo tracking events
• serum creatinine concentrations, 24-hour creatinine clearance and
urinary protein excretion, eGFR
• Clearance of inulin
• Fundoscopy
• Ultrasound of large vessels/ angiography

38. 5.3 Mortality & morbidity
• Special emphasis on special populations- elderly patients & subjects
with comorbidities
• Patients above 75 yrs

39. 6. SELECTION OF PATIENTS
• Etiology & type of hypertension
• Studies for the evaluation of efficacy or safety of a new
antihypertensive drug
• Patients of both gender in balanced way
• Patients with more severe stages of hypertension need to be included
& add on design is appropriate
• Elderly patients

40. 7. STRATEGY DESIGN
• Patients currently on antihypertensive therapy should be withdrawn
• Sufficient washout & run in period
• Washout period of about 2 weeks to 4 weeks
7.1 Pharmacodynamics
-Evaluation of tolerability, duration of action, haemodynamic
parameters
7.2 Pharmacokinetics
7.3 Interactions

41. 7.4 Therapeutic studies:
Evaluation of efficacy-
• Dose-response studies should be randomised, placebo-controlled and
double blinded using at least 3 dosages to establish the clinically
useful dose-range as well as the optimal dose.
 Patients-
• Generally, patients with mild to moderate essential hypertension, but a
certain proportion of patients with (very) severe hypertension should
be enrolled as appropriate.

42.  Design and study duration-
• Dose response studies- parallel group studies
- alteast 3 months
• Controlled studies with reference agents should last even longer up to
6 months

43. 8. SAFETY ASPECTS
8.1 Hypotension: especially at initiation of therapy or at increase of
dosage
8.2 Rebound hypertension: Withdrawal phenomena
8.3 Effects on cardiac rhythm:
8.4 Pro-ischemic effects
8.5 Effects on target organ damage
8.6 Effects on concomitant diseases
8.7 Immunological reactions

44. CLINICAL TRIALS

46. • OBJECTIVE: whether a combination of aliskiren and amlodipine is superior
to each monotherapy in early control of blood pressure without excess of
adverse events
• METHOD: double blind, randomized, parallel group, superiority trial
- 146 primary and secondary care sites in ten countries
- enrolment from Nov 28, 2008, to July 15, 2009
• INCLUSION CRITERIA:
- patients of both genders
- more than 18 yrs
- seated SBP at the time of random assignment was 150-180
mm Hg & DBP < 110 mm Hg

47. • HYPOTHESIS: initial treatment with two drugs of complementary
mechanisms would achieve earlier, larger, and more sustained
reductions in blood pressure than a sequential add-on regimen
• Stratified randomization ( study centre)
• IVRS
• End points were assessed at end of second phase
• 1:1: 2 ratio
• PRIMARY ENDPOINT: mean reduction from baseline of SBP over weeks
8, 16, and 24, testing for superiority between the aliskiren plus
amlodipine group

48. • SECONDFARY ENDPOINT:
1. reduction in diastolic blood pressure from baseline at 16 and 24
weeks
2. reductions in systolic and diastolic blood pressure at 32 weeks
• Primary analysis- ITT
• Secondary analysis- per protocol

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