Towards an Evidence Based Treatment Strategy in Hypertension

1
Towards an Evidence Based Treatment Strategy in
Hypertension

• Tony Woolley M.D.
• Park Nicollet Clinic
• Clinical Associate Professor of Medicine,
  University of Minnesota
• Woolla_at_parknicollet.com

2
My First Lesson In Hypertension
CIRCA 1980, first Internal Med clinical
rotation Begin Treatment if BPgt140/90 Start
thiazide diuretic, 50mg qd
3
Towards an Evidence Based Treatment Strategy in
Hypertension

• What should our goal BP be, especially for
  special populations ( Diabetes, Renal disease,
  Coronary disease, other high risk populations)?
• What medication strategies are best supported by
  evidence, especially for special populations?
• How does the gap between clinical practice and
  clinical evidence grow? ( Analysis of Bias)

4
Evidence Based PracticeMajor Principles

• Hierarchy of Evidence
• Level 1 evidence Systematic Reviews or
  Meta-analysis of RCTs or Single high quality RCTs
  (like ALLHAT or ACCORD)
• Tempered by
• Clinical Judgment and
• Patient Preferences

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Evidence Hierarchy
More of This
And less of This
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Towards an Evidence Based Treatment Strategy in
Hypertension

• What should our goal BP be, especially for
  special populations ( Diabetes, Renal disease,
  Coronary disease, other high risk populations)?

7
Current Recommendations for BP Goals

• JNC 7 (Joint National Committee on Prevention,
  Detection, Evaluation, and Treatment of High
  Blood) Pressure
• Goal BP lt140/90
• Goal with Diabetes or CKD lt130/80
• JNC 8 Expected Mid 2011

Hypertension. 2003421206
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Current Recommendations for BP Goals

• JNC VII lt140/90, in Diabetes or CKD lt130/80
• AHA/ACC 2007 lt130/80 high riskCVD, CKD, DM or
  Framingham 10 yr risk score gt10
• ADA DM lt130/80
• WHO/ISH lt140/90, in DM, CVD or CKD lt130/80 seems
  appropriate
• N/DOQI 2004 CKD lt130/80
• BHS lt140/90, lt130/80 DM,CVD or CKD
• ESH-ESC at least lt130/80 DM, CVD or CKD

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Hypertension in Diabetes

• Guidelines say Treat to lt130/80
• ADA Recommends ACE/ARB first

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Action to Control Cardiovascular Risk in Diabetes
(ACCORD) Trial

• NHLBI 10,251 Type 2 diabetics
• Three Trial arms
• Glycemic control
• BP lt120
• Lipids Fibrate added to Statin
• BP arm 4,773 randomized to SBPlt120 or lt140

www.nejm.org March 14, 2010
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Mean Meds Intensive 3.2
3.4 3.5
3.4 Standard
1.9 2.1
2.2 2.3
Average after 1st year 133.5 Standard vs. 119.3
Intensive, Delta 14.2
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Primary Secondary Outcomes
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 (HR0.94,
p0.67), a composite of fatal coronary events,
nonfatal MI and unstable angina (HR0.94, p0.50)
and a composite of the primary outcome,
revascularization and unstable angina
(HR0.95, p0.40)
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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
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Adverse Events
Intensive N () Standard N () P
Serious AE 77 (3.3) 30 (1.3) lt0.0001
Hypotension 17 (0.7) 1 (0.04) lt0.0001
Syncope 12 (0.5) 5 (0.2) 0.10
Bradycardia or Arrhythmia 12 (0.5) 3 (0.1) 0.02
Hyperkalemia 9 (0.4) 1 (0.04) 0.01
Renal Failure 5 (0.2) 1 (0.04) 0.12
eGFR ever lt30 mL/min/1.73m2 99 (4.2) 52 (2.2) lt0.001
Any Dialysis or ESRD 59 (2.5) 58 (2.4) 0.93
Dizziness on Standing 217 (44) 188 (40) 0.36
Symptom experienced over past 30 days from
HRQL sample of N969 participants assessed at
12, 36, and 48 months post-randomization
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• The ACCORD BP trial evaluated the effect of
  targeting a SBP goal of 120 mm Hg, compared to a
  goal of 140 mm Hg, in patients with type 2
  diabetes
• The results provide no conclusive evidence that
  the intensive BP control strategy reduces the
  rate of a composite of major CVD events in such
  patients.

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INVEST Study

• International Verapamil-Trandolapril Study
• Diabetic Subgroup 6400, all with CAD
• Achieved SBP lt130, 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 7,2010304(1)61-68
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(No Transcript)
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Hypertension in Diabetes

• Guidelines say Treat to lt130/80
• Evidence says No renal or cardiovascular benefit
  with lower BP
• ACE/ARB therapy do improve renal outcomes in
  patients with proteinuria including
  microalbuminuria
• New ICSI guideline lt140/85 (consider lt130/80 in
  patients with proteinuria)

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Hypertension in Coronary Artery Disease and High
Risk Groups

• AHA/ACC Guidelines say Treat to lt130/80
• High risk includes any vascular disease,
  Framingham risk score gt10
• Evidence Level 5 (Expert Opinion)

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Framingham 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.
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Hypertension in Coronary Artery Disease and High
Risk Groups

• No Intent to Treat RCT addresses this
• Lower Achieved BP has been associated with no
  benefit or worsened outcomes in post hoc analysis
  of trials
• INVEST DM and CAD
• ONTARGET Vascular disease or DM NEJM
  3581547-1559
• I-PRESERVE Diastolic CHF

JAMA July 7,2010304(1)61-68,
NEJM 3581547-1559
N Engl J Med 2008359245667
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Hypertension in Coronary Artery Disease and High
Risk Groups

• AHA/ACC Guidelines say Treat to lt130/80
• High risk includes any vascular disease,
  Framingham risk score gt10
• Evidence says No renal or cardiovascular benefit
  demonstrated in this overall group
• 2010 ICSI guideline lt140/90

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Hypertension in the Elderly

• JNC7 and other Guidelines say
• Treat to lt140/90
• High Risk Conditions
• Treat to lt130/80

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Hypertension in the ElderlyMeta-analysis RCTs in
Patients 60 years

• 15 trials n24,055
• Frail elderly excluded from trials
• Results similar for isolated systolic and BP
  trials
• No trials have recruited patients with
  Isolated Systolic Hypertension and SBPlt160
• Total CV Morbidity reduced RR .68, ARR 4.3 NNT
  23
• Total Mortality reduced RR .90 ARR 1.2
• Citation Musini VM, Tejani AM, Bassett K,
  Wright JM. Pharmacotherapy for hypertension in
  the elderly. Cochrane Database of Systematic
  Reviews 2009, Issue 4. Art. No. CD000028. DOI
  10.1002/14651858.CD000028.pub2.

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Issues in Treatment of the Very Elderly (gt80)

• Epidemiologic population studies show better
  survival with higher BP
• STOP-2 Worse survival in treated hypertensives
  with SBPlt140

Oates et al.Journal of the American Geriatrics
Society Volume 55, Issue 3, pages 383388, March
2007
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Hypertension in the ElderlyMetaanalysis RCTs in
Patients 80 years

• 9 trials n6,798
• Frail elderly excluded from trials
• Achieved SBP 143-148
• Stroke benefit RR .67 ARR 4 NNT 25
• Total Mortality No benefit RR .97
• Citation Musini VM, Tejani AM, Bassett K,
  Wright JM. Pharmacotherapy for hypertension in
  the elderly. Cochrane Database of Systematic
  Reviews 2009, Issue 4. Art. No. CD000028. DOI
  10.1002/14651858.CD000028.pub2.

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HYVET

• Only HTN RCT in Patients 80 years
• N3850 mean age 83 mean SBP 173
• Goal SBPlt150, mean achieved SBP 143
• Placebo vs perendipril/indapamide
• 18 month BP separation -15/6 mmHg

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HYVET Results
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Hypertension in the Elderly

• JNC7 and other Guidelines say
• Treat to lt140/90
• High Risk Conditions Treat to lt130/80
• Evidence Suggests
• Initiate Treatment at 160 with SBP goal

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Hypertension in CKD

• Guidelines say Treat to lt130/80
• ACE or ARB preferred in patients with proteinuria

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Hypertension in CKD

• Relevant clinical trials
• MDRD 1994 N884 pt with GFR 13-55
• RCT MAPlt 93 vs lt 107 (lt125/75 vs lt140/90)
• Overall result No benefit in CV or renal outcomes
• Post hoc Subgroup analysis 54 pts with gt3g/24h
  proteinuria had renal outcome benefit

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Hypertension in CKD

• Relevant clinical trials AASK 2002
• RCT 1094 African American patients with
  hypertensive nephropathy assigned to MAPlt93 vs
  102-107
• Achieved BP 130/78 vs 141/86
• 4 year result no benefit
• 10 year Cohort followup No benefit overall
• Protenuric subgroup 27 reduction in doubling of
  GFR at 10 years

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Hypertension in CKD

• Guidelines say Treat to lt130/80
• Evidence says No renal or cardiovascular benefit
  in this overall group
• Long term renal benefit in patients with
  proteinuria (gt300mg/dl)
• New ICSI guideline lt140/90, consider lt130/80 in
  patients with proteinuria

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Evidence Based Goals

• lt140/90 for almost everybody
• Perhaps lt130/80 in patients with proteinuric
  renal disease at risk for ESRD
• Perhaps a bit higher (lt150 systolic) in older
  patients with isolated systolic HTN

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The gap between what we know and what we think we
know orHow 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

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The gap between what we know and what 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

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Evidence Hierarchy
More of This
And less of This
38
My Latest Lesson In Hypertension
CIRCA 2010 Begin Treatment if BPgt140/90 Start
thiazide , Break it in half
39
Selected References
ICSI Hypertension Guideline 2010 revision
http//www.icsi.org/guidelines_and_more/... Treat
ment Blood Pressure Targets for Hypertension
Cochrane Review 2009 http//onlinelibrary.wiley.c
om/o/cochrane/clsysrev/articles/CD004349/frame. ht
ml 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
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Selected References
Hypertension in the Very Elderly Trial (HYVET)
2008 N Engl J Med 2008 358(18)1887-98. Pharmaco
therapy of Hypertension in the Elderly Cochrane
Review 2010 http//onlinelibrary.wiley.com/o/coch
rane/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 363918-929 First
Line Drugs for Hypertension Cochrane Review
2009 http//onlinelibrary.wiley.com/o/cochrane/cl
sysrev/articles/CD001841/frame. html
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Additional Slides, Treatment

• These will not be discussed in the presentation

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Drug Rx for HTN

• Where is the evidence pointing us?

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Drug Rx for HTN

• JNC 7
• Thiazides for most
• Other First line drugs
• ACE/ARB
• Beta Blockers
• CCB

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Cochrane Review, Drugs for HTN

• 57 trials, n58,040
• Conclusion Low dose thiazides reduce all
  morbidity and mortality outcomes. ACEI and
  Calcium blockers may be similarly effective but
  the evidence is less robust.
• Beta blockers and high dose thiazides are
  inferior to low dose thiazides

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Cochrane 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
ß 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
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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
Chlorthalidone Amlodipine Lisinopril
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Nonfatal MI CHD Death Subgroup Comparisons
RR (95 CI)
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Beta blockers What Happened to My Atenolol?

• Meta-analysis of trials comparing beta blockers
  with other antihypertensives Outcome RR
  w/beta blockers 95 CI
• Stroke 1.16 1.04-1.30
• MI 1.020 .93-1.12
• All-cause mort. 1.030 .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
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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




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Beta Blockers Are Now 3rd Line Therapy

• After diuretic, ACE/ARB, CCB
• Benefit in clinical trials demonstrated mainly in
  combination therapy
• Appear less effective than other classes at
  preventing stroke
• Are less effective in older patients
• Monotherapy mainly in patients with compelling
  indications (like angina, post-MI,
  tachyarrhythmias)

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The Big 3 Concept

• Thiazides, ACEI and CCBs
• All appear about equally effective
• Work well together

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Diuretics in HTN

• Thiazides are most effective optimal dose
  6.25-25mg
• Metolazone can be used if Cr CLlt30
• Spironolactone works well for many who dont
  tolerate thiazide
• Loop diuretics (except torsemide) need to be
  given twice a day

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ACE Inhibitors/ARBs Special Roles

• In a broad range of patients ACE/ARBs appear to
  contribute to improved endpoints beyond
  antihypertensive effects
• LV Systolic Dysfunction (CHF)
• Diabetes with microalbuminuria
• Proteinuric renal
• ? Post MI
• Not in diastolic CHF, diabetes without
  proteinuria or non-proteinuric renal disease.

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ACEI/ARBs One or the other, not bothThe
ONTARGET Study

• RCCT N17,118 high risk patients with DM or
  vascular disease
• Ramipril, Telmisartan or both for 56 months
• No additional benefit in combined vascular events
• Combination therapy caused higher rate of adverse
  events (hypotensive symptoms (4.8 vs. 1.7,
  Plt0.001), syncope (0.3 vs. 0.2, P0.03), and
  renal dysfunction (13.5 vs. 10.2, Plt0.001)
• Similar findings in CHF trials

NEJMVolume 3581547-1559, April 10, 2008
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Dihydropyridine CCBs The Swiss Army Knife of BP
meds

• No contraindicating medical conditions (CHF,
  diabetes, CKD, arrhythmias etc)
• Effective in all age and ethnicity groups
• Good dose response curve
• Can be used with any other drug class, including
  non-dihydropyridine CCBs

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Dihydropyridine CCBs Clinical Trials

• Equivalent to Thiazide and ACE in ALLHAT
  (including 15,297 diabetics)
• Outperformed thiazide in combination with ACE
  (ACCOMPLISH)
• Superior to ACE in African Americans (ALLHAT)
• Superior to ACE in pts with CAD (CAMELOT)
• Highly effective in elderly isolated systolic
  HTN, including 76 reduction in CV mortality in
  diabetic subgroup (Syst-Eur)

JAMA. 2004292(18)2217-2222 NEJM 2008
3592417-2428 JAMA. 20022882981-2997 NEJM.
1999340677-684
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Dihydropyridine CCBs The Swiss Army 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

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A Modest Proposal3 Drug Step-Care in Most
Patients

• Thiazides, ACEI and CCBs work well together
• Clinical Trials utilizing medication titration by
  algorithm routinely achieve superior control
  rates
• Combination therapy is needed for most patients

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Multidrug Therapy Needed to Achieve Target Blood
Pressure
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A Modest Proposal3 Drug Step-Care in Most
Patients

• Step Care example
• Step I Start Thiazide 12.5 mg Start
  Lisinopril/HCT 20/12.5 if gt160
• Step 2 If close to goal increase thiazide to
  25mg (Lisinipril 20/25)
• Otherwise add second drug (Lisinopril 20mg,
  amlodipine 2.5-5mg)
• Step 3 Add 3rd drug
• Step 4 Titrate Amlodipine to 10-20 mg

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Big 3 Add-ons

• Spironolactone 25 mg
• Aldactazide 25/25 if already on HCTZ
• Monitor K, especially with ACE/ARB
• Beta Blockers
• ?Advantage of vasodilating drugs like labetalol,
  carvedilol, nebivolol
• Central agents
• Ex Guanfacine 1-4 mg qhs. Easier to use than
  clonidine
• Dose Titration (vs adding additional medication)

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Treating to Goal- More Drugs to Consider

• Example additions
• Doxazosin 2-10 mg qhs
• Guanfacine 1-4 mg qhs
• Minoxidil
• Reserpine 0.05-.25mg qhs
• Diltiazem or Verapamil 120-480 qd)
• Direct renin inhibitor (Aliskerin)

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Newer Drugs

• Aliskerin (Tekturna)
• Direct Renin Inhibitor, ACEI like
• Nebivolol (Bystolic)
• Vasodilating Beta Blocker

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Refractory Hypertension

• Failure to control BP with 3-4 drugs including a
  diuretic. Assess for subtle volume overload
• Consider 24 hr Ambulatory BP monitor
• Consider Referral
• Consider differential diagnosis