1. State University of New York
High Blood Pressure, towards optimal control: What are the current opportunities?
Slides prepared and presented at CDMC on April 20, in Hanoi, Vietnam by
Michael Weber, MD
State University of New York
USA

2. Recent Hypertension Trials that will Affect JNC 8
Aggressive BP reduction, but how aggressive?
Benefit of treating patients aged over 80
Growing use of single-pill combinations
Benefits of blocking the renin-angiotensin system with ACE inhibitors and angiotensin receptor blockers
Concern over older beta blockers, focus on new vasodilatory agents
Chlorthalidone: will it replace hydrochlorothiazide?
In CV and renal protection, are CCBs better partners than diuretics in combination therapy?
Resistant hypertension: new interest in spironolactone

3. What Made Traditional Antihypertensive Therapy Traditional: Initial Placebo-Controlled VA Studies
On assigned
meds at
study end:
VA-1 92%
VA-2 85%
CV Event Rate (%)
Active treatment: HCTZ mg, reserpine mg, hydralazine mg.
JAMA 1967;202: and JAMA 1970;213:

4. CHD Rates by SBP, DBP and Age
A: Systolic Blood Pressure
B: Diastolic Blood Pressure
Age at risk:
Age at risk:
256
80-89 Years
256
80-89 Years
70-79 Years
70-79 Years
128
128
60-69 Years
60-69 Years 64 64
50-59 Years
50-59 Years 32 32
IHD Mortality (Floating Absolute Risk and 95% CI) 16
IHD Mortality (Floating Absolute Risk and 95% CI) 16
40-49 Years
40-49 Years 8 8 4 4
For every 20 mm Hg systolic or 10 mm Hg diastolic increase in BP, there is a doubling of mortality from both ischemic heart disease and stroke.
Data from observational studies involving more than 1million individuals have indicated that death from both ischemic heart disease and stroke increases progressively and linearly from BP levels as low as 115 mm Hg systolic and 75 mm Hg diastolic upward. The increased risks are present in all age groups ranging from 40 to 89 years old. 2 2 1 1
120
140
160
180 70 80 90
100
110
Usual Systolic Blood Pressure (mm Hg)
Usual Diastolic Blood Pressure (mm Hg)
Adapted from Lewington et al. Lancet. 2002; 360:

5. VALUE: Analysis of Results Based on BP Control at 6 Months
Patients Treated With Valsartan
Patients Treated With Amlodipine
Odds Ratio
Odds Ratio
Fatal/Non-fatal cardiac events **
0.76 (0.66–0.88) **
0.73 (0.63–0.85)
Fatal/Non-fatal stroke
0.60 (0.48–0.74) ** **
0.50 (0.39–0.64) **
0.79 (0.69–0.91) **
0.79 (0.69–0.92)
All-cause death
0.91 (0.71–1.17)
Myocardial infarction
0.83 (0.66–1.03)
Heart failure hospitalisations **
0.62 (0.50–0.77) **
0.64 (0.52–0.79)
The benefits of blood pressure control at 6 months were closely similar in patients who received both the valsartan-based regimen and the amlodipine-based regimen.1
Early blood pressure control was a powerful determinant of almost all endpoints (except myocardial infarction) in both treatment groups.1
1. Weber MA et al. Blood pressure dependent and independent effects of antihypertensive treatment on clinical values in the VALUE trial. Lancet. 2004;363:
0.4
0.6
0.8
1.0
1.2
0.4
0.6
0.8
1.0
1.2
Controlled patients*
(n = 5253)
Non-controlled patients
(n = 2396)
Controlled patients*
(n = 5502)
Non-controlled patients
(n = 2094)
Hazard Ratio 95% CI
Hazard Ratio 95% CI
*SBP < 140 mmHg at 6 months.
**P < 0.01.
Weber MA et al. Lancet. 2004;363:2047–49.

6. Effects of Intensive Blood Pressure Control on Cardiovascular Events in Type 2 Diabetes Mellitus: The Action to Control Cardiovascular Risk in Diabetes (ACCORD) Blood Pressure Trial
William C. Cushman, MD, FACP, FAHA
Veterans Affairs Medical Center, Memphis, TN
For The ACCORD Study Group

7. Systolic Pressures (mean + 95% CI)
Mean # Meds
Intensive:
Standard:
Average : Standard vs Intensive, Delta = 14.2 7

8. The HYpertension in the Very Elderly Trial
N. Beckett, R. Peters, A. Fletcher, C. Bulpitt
on behalf of the HYVET committees and investigators
ClinicalTrials.gov: NCT

9. Baseline data Placebo (n= 1912) Active (n= 1933) Age (years) 83.5 83.6
Female
60.3%
60.7%
Blood Pressure:
Sitting SBP (mmHg)
173.0
Sitting DBP (mmHg)
90.8
Orthostatic Hypotension‡
8.8%
7.9%
Isolated Systolic Hypertension
32.6%
32.3%
‡ Fall in SBP ≥ 20mmHg and/or fall in DBP ≥ 10mmHg

10. Blood pressure separation
15 mmHg
Median follow-up 1.8 years
6 mmHg

11. Total Mortality (21% reduction)
P=0.019

12. What is the optimal target for BP?
Current BP target of 140/90 mmHg exists by default
Stroke reduction improves with lower systolic BPs, down as low as 115 mmHg
MI reduction is not as clearly BP dependent; achieving values below 140 mmHg may not be necessary
CV death reduction appears to follow the MI pattern
Older patients (80+) benefit if systolic BP < 160 mmHg; no evidence that below 150 mmHg is justified
No evidence of benefit with lower targets (<130/80) in patients with diabetes or CKD
International Society for Hypertension in Blacks (ISHIB) has recently recommended < 135/85 mmHg in black patients due to their high risk status

13. Multiple antihypertensive agents are needed to reach BP goal
Trial (SBP achieved)
MDRD (132 mmHg)
HOT (138 mmHg)
RENAAL (141 mmHg)
AASK (128 mmHg)
ABCD (132 mmHg)
IDNT (138 mmHg)
UKPDS (144 mmHg)
ASCOT-BPLA (136.9 mmHg)
ALLHAT (138 mmHg)
ACCOMPLISH (132 mmHg)
Major clinical trials have demonstrated that patients typically needed treatment with multiple antihypertensive agents to get to, and stay at, BP goal. The number of antihypertensive agents required for BP control in many patients typically averages 24, with co-morbid conditions (such as kidney disease or diabetes mellitus) imposing greater drug requirement.1,2
A number of well-known clinical trials have supported the need for patients to be treated with at least 3 concomitant drugs. For example, in the Hypertension Optimal Treatment (HOT) study, an average of 3.3 drugs were required to attain a diastolic BP goal of <80 mmHg. In the United Kingdom Prospective Diabetes Study (UKPDS), patients in the tight BP control group required a greater number of antihypertensive therapies than patients in the less tightly controlled group.2 In the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA), most patients were taking ≥2 antihypertensive agents by the end of the trial.2,3
In the Avoiding Cardiovascular Events Through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial, patients were receiving initial treatment with single-pill combinations of antihypertensive agents. Excellent BP control rates were obtained with both the single-pill combinations used in the study.4
References
1. Sica DA. Rationale for fixed-dose combinations in the treatment of hypertension. The cycle repeats. Drugs 2002;62:44362
2. Bakris GL, et al. The importance of blood pressure control in the patient with diabetes. Am J Med 2004;116:30S–8S
3. Dahlöf B, et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 2005;366:895906
4. Jamerson K, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med 2008;359:241728
Initial 2-drug combination therapy
Average no. of antihypertensive medications
Bakris et al. Am J Med 2004;116:30S–8; Dahlöf et al. Lancet 2005;366:895–906 Jamerson et al. Blood Press 2007;16:806; Jamerson et al. N Engl J Med 2008;359:2417–28

14. Single Pill Combination Therapy Compliance in Hypertensive Patients
Retrospective Study
Risk ratio
(95% CI)
% Weight
Taylor et al
0.74 (0.67, 0.81)
27.1
Dezii
0.74 (0.65, 0.84)
13.9
NDC dataset
0.81 (0.77, 0.86)
46.4
Dezii
0.71 (0.62, 0.80)
12.6
The study shown on this slide was a meta-analysis evaluating the effects of FDC therapy compared with the individual drug components prescribed separately on improving medication compliance1
A subgroup analysis of 4 studies on hypertension showed that FDC agents improve medication compliance by 23% compared with the individual drug components prescribed separately (relative risk = 0.77, 95% confidence interval , P<.0001)
Reference
Bangalore S, Kamalakkannan G, Panjrath G, Parkar S, Messerli FH. Fixed-dose combinations improve medication compliance: a meta-analysis. Data from poster presented at: American Society of Hypertension 21st Annual Scientific Meeting and Exposition: May 2006; New York, NY.
Overall (95% CI)
0.77 (0.73, 0.80)
P<.0001
0.1 1 10
Risk Ratio
Favors SPC Agent
Favors Individual Agents Given Separately
Retrospective Study
SPC – fixed dose combination
Bangalore S, Am J Med 2007;120:713-9. 14

15. Chlorthalidone vs. Hydrochlorothiazide
Recent retrospective analysis of MRFIT indicates both CTD (by 49%) and HCTZ (by 35%) reduced CV events (Dorsch et al, Hypertension 2011; 57:689)
CTD more effective in event reduction than HCTZ, but other interventions differed between groups; also, CLD more effective in reducing BP
CTD used in SHEP and ALLHAT; HCTZ in VA studies
CTD longer acting and more potent than HCTZ
British Guidelines (NICE) now prefer CTD ( or indapamide) to HCTZ

16. bendroflumethiazide-K additional drugs, eg, moxonidine/spironolactone
Treatment Algorithm to BP Targets < 140/90 mm Hg or < 130/80 mm Hg in Patients with Diabetes
amlodipine 5-10 mg
atenolol mg
add
add
bendroflumethiazide-K mg
perindopril 4-8 mg
add
doxazosin GITS 4-8 mg
add
additional drugs, eg, moxonidine/spironolactone
ACC – March 8, 2005 3

17. Favors Amlodipine/Perindopril Favors Atenolol/Bendroflumethiazide
ASCOT: Primary and Secondary End Points –Amlodipine/Perindopril vs atenolol/Bendroflumethiazide
End point
Hazard Ratio
P Value
All-cause mortality
Primary end point: nonfatal MI and fatal CHD
Total coronary end point: primary end point + new-onset angina + fatal and nonfatal heart failure
Fatal and nonfatal stroke
All CV events and revascularization procedures
CV mortality
0.005
0.12
0.0048
0.0007
<0.0001
0.0017
0.5 1
1.5
Favors Amlodipine/Perindopril
Favors Atenolol/Bendroflumethiazide
ASCOT = Anglo-Scandinavian Cardiac Outcomes Trial; MI = myocardial infarction; CHD = cardiovascular heart disease; CV = cardiovascular.
Sever PS, Dahlöf B. American College of Cardiology 2005 Scientific Sessions; March 6-9, 2005; Orlando, FL.

18. RESISTANT HYPERTENSION: DEFINITION PER JNC 7 (2003)
Failure to reach goal BP (<140/90 mm Hg, <130/80 mm Hg with diabetes, chronic renal disease and CAD)
At least a three-drug regimen, one of which is a diuretic…
that the patient is taking
Chobanian AV, et al. Hypertension. 2003;42: 18

19. Resistant Hypertension: Spironolactone Efficacy
Baseline
First visit on spironolactone
Second visit on spironolactone
182 * *
161
158
BP (mm Hg) * * 95 86 85
SBP
DBP
* P< vs baseline.
Lane et al. J Hypertens. 2007;25:891.

20. Azilsartan has greater selective affinity for AT1 receptor versus olmesartan, telmisartan, valsartan, irbesartan
This graph shows the inhibition of the specific binding of 125I-Sar1-Ile8-AII to human AT1 receptors by AZL, olmesartan, telmisartan, valsartan, and irbesartan.
Membranes of CHO cells expressing AT1 receptor were preincubated for 90 min with each compound and further incubated with 125I-Sar1-Ile8-AII for 5 h with or without washout.
Results shown are in presence of compounds (A) and after washout of compounds (B).
Azilsartan selectively and competitively blocks angiotensin II-induced activation of AT1 receptors in an insurmountable fashion
A potent inhibitory effect of AZL at AT1 receptors was maintained even 5 h after washout with an IC50 value of 7.4 nM (Fig. B).
In contrast, the inhibitory effects of olmesartan, telmisartan, irbesartan, and valsartan were markedly attenuated after washout.
Ref: Ojima M, et al. JPET 2011;336:801–808.
Ref: Ojima M, et al. JPET 2011;336:801–808.

21. Study 1: Reductions in 24-Hour Mean Ambulatory SBP at Week 6
Comparison of azilsartan medoxomil with valsartan and olmesartan:
Effects on Systolic BP by ABPM
Study 1: Reductions in 24-Hour Mean Ambulatory SBP at Week 6
N=1291
Clinic SBP differences between EDARBI and active comparators were consistent with mean ambulatory results
Similar results were observed in Study 2 and Study 3
Placebo lowered 24-hour mean ambulatory SBP by 0.25 mm Hg. Data shown are placebo- corrected.
Change in SBP, mm Hg
-10.0
mm Hg
EDARBI 80 mg was statistically superior to the highest doses of Diovan and Benicar in Study 1 as measured by 24-hour ABPM
FDA-approved PI includes statistical superiority in 24-hour mean ambulatory SBP with EDARBI 80 mg compared with Diovan 320 mg and Benicar 40 mg
These data are from Study 1 of 3 studies investigating EDARBI superiority over Diovan and Benicar
Patient numbers in each study arm: Diovan (n=282); Benicar (n=290); EDARBI 80 mg (n=285)
-11.7 mm Hg
valsartan 320 mg
olmesartan 40 mg
azilsartan 80 mg
-14.3 mm Hg
P<0.001 vs Diovan 320 mg
P=0.009 vs Benicar 40 mg
Mean baseline 24-hour mean ambulatory SBP: mm Hg
1. EDARBI (azilsartan medoxomil). Package Insert. Deerfield, IL: Takeda Pharmaceuticals America, Inc.; Data on File; 3. White WB, et al. Hypertension. 2011;57:
For Internal Use Only

22. Sustained Efficacy at Each Hour Over 24 Hours in a 6-Week Study
Study 1: Mean Ambulatory SBP at Each Hour With EDARBI 80 mg at Week 6
Treatment Group:
azilsartan 80 mg (N=285)
olmesartan 40 mg (N=290)
valsartan 320 mg (N=282)
Placebo (N=154)
SBP, mm Hg
The efficacy of EDARBI 80 mg was sustained over 24 hours
Data shown here are from Study 1. Study 1 design was previously reviewed.
Studies 2 and 3 showed similar 24-hour ambulatory blood pressure profiles.
Hour Post Dose
Mean baseline 24-hour mean ambulatory SBP: mm Hg
1. EDARBI (azilsartan medoxomil). Package Insert. Deerfield, IL: Takeda Pharmaceuticals America, Inc.; 2011; 2. White WB, et al. Hypertension. 2011;57:
For Internal Use Only

23. Recent Hypertension Trends that will Affect JNC 8
Aggressive BP reduction, but how aggressive?
140/90 mmHg will remain, 150/90 mmHg in elderly, no more 139/80 mmHg
Benefit of treating patients aged over 80
Growing use of single-pill combinations
Use of ACE inhibitors and angiotensin receptor blockers
Chlorthalidone: will it challenge hydrochlorothiazide?
In CV and renal protection, are CCBs equal to diuretics in combination therapy?
Resistant hypertension: new interest in spironolactone and other more powerful drugs