1. Towards an Evidence BasedTowards an Evidence Based
Treatment Strategy in HypertensionTreatment Strategy in Hypertension
Tony Woolley M.D.Tony Woolley M.D.
Park Nicollet ClinicPark Nicollet Clinic
Clinical Associate Professor ofClinical Associate Professor of
Medicine, University of MinnesotaMedicine, University of Minnesota
Woolla@parknicollet.comWoolla@parknicollet.com

2. My First Lesson In HypertensionMy First Lesson In Hypertension
CIRCA 1980, first Internal Med clinical
rotation
Begin Treatment if BP>140/90
Start thiazide diuretic, 50mg qd

3. Towards an Evidence BasedTowards an Evidence Based
Treatment Strategy in HypertensionTreatment Strategy in Hypertension
•What should our goal BP be, especially forWhat should our goal BP be, especially for
special populations ( Diabetes, Renal disease,special populations ( Diabetes, Renal disease,
Coronary disease, other high risk populations)?Coronary disease, other high risk populations)?
•What medication strategies are best supportedWhat medication strategies are best supported
by evidence, especially for special populations?by evidence, especially for special populations?
•How does the gap between clinical practice andHow does the gap between clinical practice and
clinical evidence grow? ( Analysis of Bias)clinical evidence grow? ( Analysis of Bias)

4. Evidence Based PracticeEvidence Based Practice
Major PrinciplesMajor Principles
• Hierarchy of EvidenceHierarchy of Evidence
– Level 1 evidence= Systematic Reviews orLevel 1 evidence= Systematic Reviews or
Meta-analysis of RCTs or Single high qualityMeta-analysis of RCTs or Single high quality
RCTs (like ALLHAT or ACCORD)RCTs (like ALLHAT or ACCORD)
• Tempered byTempered by
–Clinical JudgmentClinical Judgment andand
–Patient PreferencesPatient Preferences

5. Evidence HierarchyEvidence Hierarchy
More of This
And less of This

6. Towards an Evidence BasedTowards an Evidence Based
Treatment Strategy in HypertensionTreatment Strategy in Hypertension
•What should our goal BP be, especially forWhat should our goal BP be, especially for
special populations ( Diabetes, Renal disease,special populations ( Diabetes, Renal disease,
Coronary disease, other high risk populations)?Coronary disease, other high risk populations)?

7. Current Recommendations for BPCurrent Recommendations for BP
GoalsGoals
• JNC 7 (JNC 7 (Joint National Committee on Prevention,Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High Blood)Detection, Evaluation, and Treatment of High Blood)
PressurePressure
– Goal BP <140/90Goal BP <140/90
– Goal with Diabetes or CKD <130/80Goal with Diabetes or CKD <130/80
• JNC 8 Expected Mid 2011JNC 8 Expected Mid 2011
Hypertension. 2003;42:1206

8. Current Recommendations for BPCurrent Recommendations for BP
GoalsGoals
• JNC VII <140/90, in Diabetes or CKD <130/80JNC VII <140/90, in Diabetes or CKD <130/80
• AHA/ACC 2007 <130/80 “high risk”;CVD, CKD, DMAHA/ACC 2007 <130/80 “high risk”;CVD, CKD, DM
or Framingham 10 yr risk score >10%or Framingham 10 yr risk score >10%
• ADA DM <130/80ADA DM <130/80
• WHO/ISH <140/90, in DM, CVD or CKD <130/80WHO/ISH <140/90, in DM, CVD or CKD <130/80
“seems appropriate”“seems appropriate”
• N/DOQI 2004 CKD <130/80N/DOQI 2004 CKD <130/80
• BHS <140/90, <130/80 DM,CVD or CKDBHS <140/90, <130/80 DM,CVD or CKD
• ESH-ESC “at least” <130/80 DM, CVD or CKDESH-ESC “at least” <130/80 DM, CVD or CKD

9. Hypertension in DiabetesHypertension in Diabetes
• Guidelines say: Treat to <130/80Guidelines say: Treat to <130/80
• ADA Recommends ACE/ARB firstADA Recommends ACE/ARB first

10. Action to Control CardiovascularAction to Control Cardiovascular
Risk in Diabetes (ACCORD) TrialRisk in Diabetes (ACCORD) Trial
• NHLBI 10,251 Type 2 diabeticsNHLBI 10,251 Type 2 diabetics
• Three Trial armsThree Trial arms
– Glycemic controlGlycemic control
– BP <120BP <120
– Lipids: Fibrate added to StatinLipids: Fibrate added to Statin
• BP arm 4,773 randomized to SBP<120 orBP arm 4,773 randomized to SBP<120 or
<140<140
www.nejm.org March 14, 2010

11. Average after 1st
year: 133.5 Standard vs. 119.3 Intensive, Delta = 14.2
Mean # Meds
Intensive: 3.2 3.4 3.5 3.4
Standard: 1.9 2.1 2.2 2.3

12. Intensive
Events (%/yr)
Standard
Events (%/yr) RR (95% CI) P
Primary 208 (1.87) 237 (2.09) 0.88 (0.73-1.06) 0.20
Total Mortality 150 (1.28) 144 (1.19) 1.07 (0.85-1.35) 0.55
Cardiovascular
Deaths
60 (0.52) 58 (0.49) 1.06 (0.74-1.52) 0.74
Nonfatal MI 126 (1.13) 146 (1.28) 0.87 (0.68-1.10) 0.25
Nonfatal Stroke 34 (0.30) 55 (0.47) 0.63 (0.41-0.96) 0.03
Total Stroke 36 (0.32) 62 (0.53) 0.59 (0.39-0.89) 0.01
Also examined Fatal/Nonfatal HF (HR=0.94, p=0.67), a composite of fatal
coronary events, nonfatal MI and unstable angina (HR=0.94, p=0.50) and a
composite of the primary outcome, revascularization and unstable angina
(HR=0.95, p=0.40)

13. PatientswithEvents(%)
0
5
10
15
20
Years Post-Randomization
0 1 2 3 4 5 6 7 8
PatientswithEvents(%) 0
5
10
15
20
Years Post-Randomization
0 1 2 3 4 5 6 7 8
Primary Outcome
Nonfatal MI, Nonfatal Stroke or CVD Death Total Stroke
HR = 0.88
95% CI (0.73-1.06)
HR = 0.59
95% CI (0.39-0.89)
NNT for 5 years = 89

14. IntensiveIntensive
N (%)N (%)
StandardStandard
N (%)N (%)
PP
Serious AESerious AE 77 (3.3)77 (3.3) 30 (1.3)30 (1.3) <0.0001<0.0001
HypotensionHypotension 17 (0.7)17 (0.7) 1 (0.04)1 (0.04) <0.0001<0.0001
SyncopeSyncope 12 (0.5)12 (0.5) 5 (0.2)5 (0.2) 0.100.10
Bradycardia orBradycardia or
ArrhythmiaArrhythmia 12 (0.5)12 (0.5) 3 (0.1)3 (0.1) 0.020.02
HyperkalemiaHyperkalemia 9 (0.4)9 (0.4) 1 (0.04)1 (0.04) 0.010.01
Renal FailureRenal Failure 5 (0.2)5 (0.2) 1 (0.04)1 (0.04) 0.120.12
eGFR ever <30eGFR ever <30
mL/min/1.73mmL/min/1.73m22 99 (4.2)99 (4.2) 52 (2.2)52 (2.2) <0.001<0.001
Any Dialysis or ESRDAny Dialysis or ESRD 59 (2.5)59 (2.5) 58 (2.4)58 (2.4) 0.930.93
Dizziness on StandingDizziness on Standing††
217 (44)217 (44) 188 (40)188 (40) 0.360.36
† Symptom experienced over past 30 days from HRQL sample of
N=969 participants assessed at 12, 36, and 48 months post-randomization

15. • The ACCORD BP trial evaluated theThe ACCORD BP trial evaluated the
effect of targeting a SBP goal of 120 mmeffect of targeting a SBP goal of 120 mm
Hg, compared to a goal of 140 mm Hg, inHg, compared to a goal of 140 mm Hg, in
patients with type 2 diabetespatients with type 2 diabetes
• The results provide no conclusiveThe results provide no conclusive
evidence that the intensive BP controlevidence that the intensive BP control
strategy reduces the rate of a compositestrategy reduces the rate of a composite
of major CVD events in such patients.of major CVD events in such patients.

16. INVEST StudyINVEST Study
International Verapamil-Trandolapril StudyInternational Verapamil-Trandolapril Study
•Diabetic Subgroup 6400, all with CADDiabetic Subgroup 6400, all with CAD
•Achieved SBP <130, 130-139, 140+Achieved SBP <130, 130-139, 140+
OUTCOME
%
TIGHT
CONTROL
USUAL
CONTROL
UNCONTROLLED
Death, MI,
Stroke
12.7 12.6 19.8 *
CI 1.01-1.31
Mortality
11.0 10.2 15.4
JAMA July 7,2010;304(1)61-68

18. Hypertension in DiabetesHypertension in Diabetes
• Guidelines say: Treat to <130/80Guidelines say: Treat to <130/80
• Evidence says: No renal or cardiovascularEvidence says: No renal or cardiovascular
benefit with lower BPbenefit with lower BP
• ACE/ARB therapy do improve renalACE/ARB therapy do improve renal
outcomes in patients with proteinuriaoutcomes in patients with proteinuria
including microalbuminuriaincluding microalbuminuria
• New ICSI guideline: <140/85 (considerNew ICSI guideline: <140/85 (consider
<130/80 in patients with proteinuria)<130/80 in patients with proteinuria)

19. Hypertension in Coronary ArteryHypertension in Coronary Artery
Disease and “High Risk” GroupsDisease and “High Risk” Groups
• AHA/ACC Guidelines say: Treat toAHA/ACC Guidelines say: Treat to
<130/80<130/80
• High risk includes any vascular disease,High risk includes any vascular disease,
Framingham risk score >10%Framingham risk score >10%
• Evidence Level 5 (Expert Opinion)Evidence Level 5 (Expert Opinion)

20. Framingham Risk Calculation, ExFramingham Risk Calculation, Ex..
Age: 65
Gender: male
Total Cholesterol: 200 mg/dL
HDL Cholesterol: 40 mg/dL
Smoker: No
Systolic Blood Pressure: 140 mm/Hg
On medication for HBP: Yes
Risk Score* 19%
* The risk score shown was derived on the basis of an equation. Other NCEP
materials, such as ATP III print products, use a point-based system to calculate a
risk score that approximates the equation-based one. ATP III Executive
Summary and ATP III At-a-Glance.

21. Hypertension in Coronary ArteryHypertension in Coronary Artery
Disease and “High Risk” GroupsDisease and “High Risk” Groups
• No Intent to Treat RCT addresses thisNo Intent to Treat RCT addresses this
• Lower Achieved BP has been associatedLower Achieved BP has been associated
with no benefit orwith no benefit or worsenedworsened outcomes inoutcomes in
post hoc analysis of trialspost hoc analysis of trials
– INVESTINVEST DM and CADDM and CAD
– ONTARGETONTARGET Vascular disease or DMVascular disease or DM NEJMNEJM 358:1547-1559358:1547-1559
– I-PRESERVEI-PRESERVE Diastolic CHFDiastolic CHF
JAMA July 7,2010;304(1)61-68, NEJM 358:1547-1559
N Engl J Med 2008;359:2456–67

22. Hypertension in Coronary ArteryHypertension in Coronary Artery
Disease and “High Risk” GroupsDisease and “High Risk” Groups
• AHA/ACC Guidelines say: Treat toAHA/ACC Guidelines say: Treat to
<130/80<130/80
• High risk includes any vascular disease,High risk includes any vascular disease,
Framingham risk score >10%Framingham risk score >10%
• Evidence says: No renal or cardiovascularEvidence says: No renal or cardiovascular
benefit demonstrated in this overall groupbenefit demonstrated in this overall group
• 2010 ICSI guideline: <140/902010 ICSI guideline: <140/90

23. Hypertension in the ElderlyHypertension in the Elderly
JNC7 and other Guidelines say:JNC7 and other Guidelines say:
Treat to <140/90Treat to <140/90
High Risk Conditions:High Risk Conditions:
Treat to <130/80Treat to <130/80

24. Hypertension in the ElderlyHypertension in the Elderly
Meta-analysis RCTs in Patients ≥60 yearsMeta-analysis RCTs in Patients ≥60 years
15 trials n=24,05515 trials n=24,055
Frail elderly excluded from trialsFrail elderly excluded from trials
Results similar for isolated systolic and BPResults similar for isolated systolic and BP
trialstrials
No trials have recruited patients withNo trials have recruited patients with
Isolated Systolic Hypertension and SBP<160Isolated Systolic Hypertension and SBP<160
Total CV Morbidity reduced RR .68, ARR 4.3% NNTTotal CV Morbidity reduced RR .68, ARR 4.3% NNT
2323
Total Mortality reduced RR .90 ARR 1.2%Total Mortality reduced RR .90 ARR 1.2%
Citation: Musini VM, Tejani AM, Bassett K, Wright JM. Pharmacotherapy for hypertension in the elderly.Citation: Musini VM, Tejani AM, Bassett K, Wright JM. Pharmacotherapy for hypertension in the elderly. CochraneCochrane
Database of Systematic Reviews 2009, Issue 4. Art. No.: CD000028. DOI: 10.1002/14651858.CD000028.pub2.Database of Systematic Reviews 2009, Issue 4. Art. No.: CD000028. DOI: 10.1002/14651858.CD000028.pub2.

25. Issues in Treatment of the VeryIssues in Treatment of the Very
Elderly (>80)Elderly (>80)
• Epidemiologic population studiesEpidemiologic population studies
show better survival with higher BPshow better survival with higher BP
• STOP-2 Worse survival in treatedSTOP-2 Worse survival in treated
hypertensives with SBP<140hypertensives with SBP<140
Oates et al.Journal of the American Geriatrics Society
Volume 55, Issue 3, pages 383–388, March 2007

26. Hypertension in the ElderlyHypertension in the Elderly
Metaanalysis RCTs in Patients ≥80 yearsMetaanalysis RCTs in Patients ≥80 years
9 trials n=6,7989 trials n=6,798
Frail elderly excludedFrail elderly excluded
from trialsfrom trials
Achieved SBP 143-148Achieved SBP 143-148
Stroke benefit:Stroke benefit: RR .67 ARRRR .67 ARR
4% NNT 254% NNT 25

27. HYVETHYVET
• Only HTN RCT in Patients ≥80Only HTN RCT in Patients ≥80
yearsyears
• N=3850 mean age 83 mean SBP 173N=3850 mean age 83 mean SBP 173
• Goal SBP<150, mean achieved SBPGoal SBP<150, mean achieved SBP
=143=143
• Placebo vs perendipril/indapamidePlacebo vs perendipril/indapamide
• 18 month BP separation -15/6 mmHg18 month BP separation -15/6 mmHg

28. HYVET ResultsHYVET Results

29. Hypertension in the ElderlyHypertension in the Elderly
•JNC7 and other Guidelines say:JNC7 and other Guidelines say:
• Treat to <140/90Treat to <140/90
• High Risk Conditions:High Risk Conditions: Treat to <130/80Treat to <130/80
•Evidence Suggests:Evidence Suggests:
• Initiate Treatment at 160 with SBP goalInitiate Treatment at 160 with SBP goal

30. Hypertension in CKDHypertension in CKD
• Guidelines say: Treat to <130/80Guidelines say: Treat to <130/80
• ACE or ARB preferred in patients withACE or ARB preferred in patients with
proteinuriaproteinuria

31. Hypertension in CKDHypertension in CKD
• Relevant clinical trialsRelevant clinical trials
– MDRD 1994 N=884 pt with GFR 13-55MDRD 1994 N=884 pt with GFR 13-55
– RCT MAP< 93 vs < 107 (<125/75 vs <140/90)RCT MAP< 93 vs < 107 (<125/75 vs <140/90)
– Overall result No benefit in CV or renalOverall result No benefit in CV or renal
outcomesoutcomes
– Post hoc Subgroup analysis; 54 pts withPost hoc Subgroup analysis; 54 pts with
>3g/24h proteinuria had renal outcome benefit>3g/24h proteinuria had renal outcome benefit

32. Hypertension in CKDHypertension in CKD
• Relevant clinical trials: AASK 2002Relevant clinical trials: AASK 2002
– RCT 1094 African American patients withRCT 1094 African American patients with
hypertensive nephropathy assigned tohypertensive nephropathy assigned to
MAP<93 vs 102-107MAP<93 vs 102-107
– Achieved BP 130/78 vs 141/86Achieved BP 130/78 vs 141/86
– 4 year result no benefit4 year result no benefit
– 10 year Cohort followup: No benefit overall10 year Cohort followup: No benefit overall
– Protenuric subgroup 27% reduction inProtenuric subgroup 27% reduction in
doubling of GFR at 10 yearsdoubling of GFR at 10 years

33. Hypertension in CKDHypertension in CKD
• Guidelines say: Treat to <130/80Guidelines say: Treat to <130/80
• Evidence says: No renal or cardiovascularEvidence says: No renal or cardiovascular
benefit in this overall groupbenefit in this overall group
• Long term renal benefit in patients withLong term renal benefit in patients with
proteinuria (>300mg/dl)proteinuria (>300mg/dl)
• New ICSI guideline: <140/90, considerNew ICSI guideline: <140/90, consider
<130/80 in patients with proteinuria<130/80 in patients with proteinuria

34. Evidence Based GoalsEvidence Based Goals
• <140/90 for almost everybody<140/90 for almost everybody
• Perhaps <130/80 in patients withPerhaps <130/80 in patients with
proteinuricproteinuric renal disease at risk for ESRDrenal disease at risk for ESRD
• Perhaps a bit higher (<150 systolic) inPerhaps a bit higher (<150 systolic) in
older patients with isolated systolic HTNolder patients with isolated systolic HTN

35. The gap between what we know andThe gap between what we know and
what we think we know or…what we think we know or…
How Do We Get It so Wrong?How Do We Get It so Wrong?
•Theraputic Optimism
•The bias that the benefit of treatment exceeds the
risk/harm
•Authority Bias
•Overvaluing the opinions of experts
•Influence of Industry
•More treatment/diagnosis is usually good for
business, and sponsorship of research and
education tends to support more rather than less
treatment

36. The gap between what we know andThe gap between what we know and
what we think we knowwhat we think we know
•Confirmation Bias
•We are much more likely to seek information that
confirms rather than refutes what we believe to be
true
•Forgetting the asymmetry of epidemiology and
treatment
•In many (?most) instances, correcting a causal
risk factor does not fully resolve associated risk

37. Evidence HierarchyEvidence Hierarchy
More of This
And less of This

38. My Latest Lesson InMy Latest Lesson In
HypertensionHypertension
CIRCA 2010
Begin Treatment if BP>140/90
Start thiazide , Break it in half

39. Selected References
ICSI Hypertension Guideline 2010 revision
http://www.icsi.org/guidelines_and_more/...
Treatment Blood Pressure Targets for Hypertension: Cochrane Review 2009
http://onlinelibrary.wiley.com/o/cochrane/clsysrev/articles/CD004349/frame.
html
ACCORD BP Study, March 14 2010
The Effects of Intensive Blood Pressire Control in Type 2 Diabetes Mellitus
http://www.nejm.org/doi/pdf/10.1056/NEJMoa1001286
INVEST Diabetes Subgroup
Tight Blood Pressure Control and Cardiovascular Outcomes Among
Hypertensive Patients with Diabetes and Coronary Artery Disease
JAMA, Vol 304, 1, 61-67

40. Selected References
Hypertension in the Very Elderly Trial (HYVET) 2008
N Engl J Med 2008; 358(18):1887-98.
Pharmacotherapy of Hypertension in the Elderly: Cochrane Review 2010
http://onlinelibrary.wiley.com/o/cochrane/clsysrev/articles/CD000028/frame.
html
AASK 10 year follow up 2010
Intensive Blood-Pressure Control in Hypertensive Chronic Kidney
Disease
N Engl J Med 2010; 363:918-929
First Line Drugs for Hypertension: Cochrane Review 2009
http://onlinelibrary.wiley.com/o/cochrane/clsysrev/articles/CD001841/frame.
html

41. Additional Slides, Treatment
• These will not be discussed in the
presentation

42. Drug Rx for HTNDrug Rx for HTN
Where is the evidenceWhere is the evidence
pointing us?pointing us?

43. Drug Rx for HTNDrug Rx for HTN
• JNC 7JNC 7
– Thiazides for mostThiazides for most
– Other First line drugsOther First line drugs
• ACE/ARBACE/ARB
• Beta BlockersBeta Blockers
• CCBCCB

44. Cochrane Review, Drugs for HTNCochrane Review, Drugs for HTN
• 57 trials, n=58,04057 trials, n=58,040
• Conclusion: Low dose thiazides reduce allConclusion: Low dose thiazides reduce all
morbidity and mortality outcomes. ACEImorbidity and mortality outcomes. ACEI
and Calcium blockers may be similarlyand Calcium blockers may be similarly
effective but the evidence is less robust.effective but the evidence is less robust.
• Beta blockers and high dose thiazides areBeta blockers and high dose thiazides are
inferior to low dose thiazidesinferior to low dose thiazides

45. Cochrane Review, Drugs for HTNCochrane Review, Drugs for HTN
#RCT Mortality Stroke CHD CV events
Thiazides 19 .89 .63 .84 .70
low dose 8 .72
high dose 11 1.01 ns
β Blocker 5 .96 ns .83 .90 ns .89
ACEI 3 .83 .65 .81 .76
CCB 1 .86 ns .58 .77 ns .71
The Cochrane Library 2009, issue 3.
http//www.thecochranelibrary.com

46. Years to CHD Event
0 1 2 3 4 5 6 7
CumulativeCHDEventRate
0
.04
.08
.12
.16
.2
Number at Risk:
Chlorthalidone 15,255 14,477 13,820 13,102 11,362 6,340 2,956 209
Amlodipine 9,048 8,576 8,218 7,843 6,824 3,870 1,878 215
Lisinopril 9,054 8,535 8,123 7,711 6,662 3,832 1,770 195
Cumulative Event Rates for the Primary
Outcome (Fatal CHD or Nonfatal MI) by
ALLHAT Treatment Group
RR (95% CI) p value
A/C 0.98 (0.90-1.07) 0.65
L/C 0.99 (0.91-1.08) 0.81
ALLHAT
Chlorthalidone
Amlodipine
Lisinopril

47. Nonfatal MI + CHD Death – Subgroup
Comparisons – RR (95% CI)
Amlodipine Better Chlorthalidone Better
0.50 1 2
Non-Diabetic 0.97 (0.86, 1.09)
Diabetic 0.99 (0.87, 1.13)
Non-Black 0.97 (0.87, 1.08)
Black 1.01 (0.86, 1.18)
Women 0.99 (0.85, 1.15)
Men 0.98 (0.87, 1.09)
Age>=65 0.97 (0.88, 1.08)
Age <65 0.99 (0.85, 1.16)
Total 0.98 (0.90, 1.07)
Lisinopril Better Chlorthalidone Better
0.50 1 2
Non-Diabetic 0.99 (0.88, 1.11)
Diabetic 1.00 (0.87, 1.14)
Non-Black 0.94 (0.85, 1.05)
Black 1.10 (0.94, 1.28)
Women 1.06 (0.92, 1.23)
Men 0.94 (0.85, 1.05)
Age >= 65 1.01 (0.91, 1.12)
Age < 65 0.95 (0.81, 1.12)
Total 0.99 (0.91, 1.08)
ALLHAT

48. Beta blockers: What Happened toBeta blockers: What Happened to
My Atenolol?My Atenolol?
• Meta-analysis of trials comparing betaMeta-analysis of trials comparing beta
blockers with other antihypertensivesblockers with other antihypertensives
OutcomeOutcome RR w/beta blockersRR w/beta blockers 95% CI95% CI
•
StrokeStroke 1.161.16 1.04-1.301.04-1.30
•
MIMI 1.0201.020 .93-1.12.93-1.12
•
All-cause mort.All-cause mort. 1.0301.030 .99-1.08.99-1.08
Lindholm LH, Carlberg B, and Samuelsson O. Should blockers remain first
choice in the treatment of primary hypertension? A meta-analysis. Lancet 2005;
366(9496):1545-1553

49. Atenolol vs other antihypertensives
Outcome Relative risk with atenolol 95% CI
Stroke 1.26 1.15-
1.38
MI 1.05 0.91-
1.21
All-cause
mortality
1.08 1.02-
1.14
Lindholm LH, Carlberg B, and Samuelsson O. Should
blockers remain first choice in the treatment of primary
hypertension? A meta-analysis. Lancet 2005;
366(9496):1545-1553

50. Beta Blockers Are Now 3Beta Blockers Are Now 3rdrd
LineLine
TherapyTherapy
• AfterAfter diuretic, ACE/ARB, CCB…diuretic, ACE/ARB, CCB…
• Benefit in clinical trials demonstratedBenefit in clinical trials demonstrated
mainly in combination therapymainly in combination therapy
• Appear less effective than other classes atAppear less effective than other classes at
preventing strokepreventing stroke
• Are less effective in older patientsAre less effective in older patients
• Monotherapy mainly in patients withMonotherapy mainly in patients with
compelling indications (like angina, post-compelling indications (like angina, post-
MI, tachyarrhythmias…)MI, tachyarrhythmias…)

51. The Big 3 ConceptThe Big 3 Concept
• Thiazides, ACEI and CCBsThiazides, ACEI and CCBs
• All appear about equally effectiveAll appear about equally effective
• Work well togetherWork well together

52. Diuretics in HTNDiuretics in HTN
• Thiazides are most effective; optimal doseThiazides are most effective; optimal dose
6.25-25mg6.25-25mg
• Metolazone can be used if Cr CL<30Metolazone can be used if Cr CL<30
• Spironolactone works well for many whoSpironolactone works well for many who
don’t tolerate thiazidedon’t tolerate thiazide
• Loop diuretics (except torsemide) need toLoop diuretics (except torsemide) need to
be given twice a daybe given twice a day

53. ACE Inhibitors/ARBs: SpecialACE Inhibitors/ARBs: Special
RolesRoles
• In a broad range of patients ACE/ARBs appearIn a broad range of patients ACE/ARBs appear
to contribute to improved endpoints beyondto contribute to improved endpoints beyond
antihypertensive effectsantihypertensive effects
– LV Systolic Dysfunction (CHF)LV Systolic Dysfunction (CHF)
– Diabetes with microalbuminuriaDiabetes with microalbuminuria
– Proteinuric renalProteinuric renal
– ? Post MI? Post MI
• NotNot in diastolic CHF, diabetes without proteinuriain diastolic CHF, diabetes without proteinuria
or non-proteinuric renal disease.or non-proteinuric renal disease.

54. ACEI/ARBs: One or the other, not bothACEI/ARBs: One or the other, not both
The ONTARGET StudyThe ONTARGET Study
– RCCT N=17,118 high risk patients with DM orRCCT N=17,118 high risk patients with DM or
vascular diseasevascular disease
– Ramipril, Telmisartan or both for 56 monthsRamipril, Telmisartan or both for 56 months
– No additional benefit in combined vascularNo additional benefit in combined vascular
eventsevents
– Combination therapy caused higher rate ofCombination therapy caused higher rate of
adverse events (adverse events (hypotensive symptoms (4.8% vs.hypotensive symptoms (4.8% vs.
1.7%, P<0.001), syncope (0.3% vs. 0.2%, P=0.03),1.7%, P<0.001), syncope (0.3% vs. 0.2%, P=0.03),
and renal dysfunction (13.5% vs. 10.2%, P<0.001)and renal dysfunction (13.5% vs. 10.2%, P<0.001)
• Similar findings in CHF trialsSimilar findings in CHF trials
NEJMVolume 358:1547-1559,
April 10, 2008

55. Dihydropyridine CCBs: The SwissDihydropyridine CCBs: The Swiss
Army Knife of BP medsArmy Knife of BP meds
• No contraindicating medical conditions (CHF,No contraindicating medical conditions (CHF,
diabetes, CKD, arrhythmias etc)diabetes, CKD, arrhythmias etc)
• Effective in all age and ethnicity groupsEffective in all age and ethnicity groups
• Good dose response curveGood dose response curve
• Can be used with any other drug class, includingCan be used with any other drug class, including
non-dihydropyridine CCBsnon-dihydropyridine CCBs

56. Dihydropyridine CCBs:Dihydropyridine CCBs:
Clinical TrialsClinical Trials
• Equivalent to Thiazide and ACE in ALLHATEquivalent to Thiazide and ACE in ALLHAT
(including 15,297 diabetics)(including 15,297 diabetics)
• Outperformed thiazide in combination with ACEOutperformed thiazide in combination with ACE
(ACCOMPLISH)(ACCOMPLISH)
• Superior to ACE in African Americans (ALLHAT)Superior to ACE in African Americans (ALLHAT)
• Superior to ACE in pts with CAD (CAMELOT)Superior to ACE in pts with CAD (CAMELOT)
• Highly effective in elderly isolated systolic HTN,Highly effective in elderly isolated systolic HTN,
including 76% reduction in CV mortality inincluding 76% reduction in CV mortality in
diabetic subgroup (Syst-Eur)diabetic subgroup (Syst-Eur)
JAMA. 2004;292(18):2217-2222 NEJM 2008 359:2417-2428
JAMA. 2002;288:2981-2997 NEJM. 1999;340:677-684

57. Dihydropyridine CCBs: The SwissDihydropyridine CCBs: The Swiss
Army Knife of BP medsArmy Knife of BP meds
• Amlodipine 2.5-20 mg qd
• Felodipine 2.5-20 mg qd
• Isradipine 5-20 mg qd
• Nicardipine SR 30-120 mg qd
• Nifedipine ER 30-120 mg qd
• Nisoldipine 20-60 mg qd

58. A Modest Proposal:A Modest Proposal:
3 Drug Step-Care in Most Patients3 Drug Step-Care in Most Patients
• Thiazides, ACEI and CCBs work wellThiazides, ACEI and CCBs work well
togethertogether
• Clinical Trials utilizing medication titrationClinical Trials utilizing medication titration
by algorithm routinely achieve superiorby algorithm routinely achieve superior
control ratescontrol rates
• Combination therapy is needed for mostCombination therapy is needed for most
patientspatients

59. Multidrug Therapy NeededMultidrug Therapy Needed
to Achieve Target Blood Pressureto Achieve Target Blood Pressure

60. A Modest Proposal:A Modest Proposal:
3 Drug Step-Care in Most Patients3 Drug Step-Care in Most Patients
• Step Care example:Step Care example:
• Step IStep I Start Thiazide 12.5 mg; StartStart Thiazide 12.5 mg; Start
Lisinopril/HCT 20/12.5 if >160Lisinopril/HCT 20/12.5 if >160
• Step 2Step 2 If close to goal increase thiazideIf close to goal increase thiazide
to 25mg (Lisinipril 20/25)to 25mg (Lisinipril 20/25)
Otherwise add second drugOtherwise add second drug
(Lisinopril 20mg, amlodipine 2.5-5mg)(Lisinopril 20mg, amlodipine 2.5-5mg)
• Step 3Step 3 Add 3Add 3rdrd
drugdrug
• Step 4Step 4 Titrate Amlodipine to 10-20 mgTitrate Amlodipine to 10-20 mg

61. Big 3 Add-onsBig 3 Add-ons
• Spironolactone 25 mgSpironolactone 25 mg
– ““Aldactazide 25/25” if already on HCTZAldactazide 25/25” if already on HCTZ
– Monitor K+, especially with ACE/ARBMonitor K+, especially with ACE/ARB
• Beta BlockersBeta Blockers
– ?Advantage of vasodilating drugs like labetalol,?Advantage of vasodilating drugs like labetalol,
carvedilol, nebivololcarvedilol, nebivolol
• Central agentsCentral agents
– Ex Guanfacine 1-4 mg qhs. Easier to use thanEx Guanfacine 1-4 mg qhs. Easier to use than
clonidineclonidine
• Dose Titration (vs adding additional medication)Dose Titration (vs adding additional medication)

62. Treating to Goal- More Drugs toTreating to Goal- More Drugs to
ConsiderConsider
• Example additionsExample additions
– Doxazosin 2-10 mg qhsDoxazosin 2-10 mg qhs
– Guanfacine 1-4 mg qhsGuanfacine 1-4 mg qhs
– MinoxidilMinoxidil
– Reserpine 0.05-.25mg qhsReserpine 0.05-.25mg qhs
– Diltiazem or Verapamil 120-480 qd)Diltiazem or Verapamil 120-480 qd)
– Direct renin inhibitor (Aliskerin)Direct renin inhibitor (Aliskerin)

63. Newer DrugsNewer Drugs
• Aliskerin (Tekturna)Aliskerin (Tekturna)
– Direct Renin Inhibitor, ACEI likeDirect Renin Inhibitor, ACEI like
• Nebivolol (Bystolic)Nebivolol (Bystolic)
– Vasodilating Beta BlockerVasodilating Beta Blocker

64. Refractory HypertensionRefractory Hypertension
• Failure to control BP with 3-4 drugsFailure to control BP with 3-4 drugs
including a diuretic. Assess for subtleincluding a diuretic. Assess for subtle
volume overloadvolume overload
• Consider 24 hr Ambulatory BP monitorConsider 24 hr Ambulatory BP monitor
• Consider ReferralConsider Referral
• Consider differential diagnosisConsider differential diagnosis