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Towards an Evidence Based Treatment Strategy in Hypertension. Tony Woolley M.D. Park Nicollet Clinic Clinical Associate Professor of Medicine, University of Minnesota [email protected] My First Lesson In Hypertension. CIRCA 1980, first Internal Med clinical rotation

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Towards an evidence based treatment strategy in hypertension l.jpg

Towards an Evidence Based Treatment Strategy in Hypertension

Tony Woolley M.D.

Park Nicollet Clinic

Clinical Associate Professor of Medicine, University of Minnesota

[email protected]


My first lesson in hypertension l.jpg

My First Lesson In Hypertension

CIRCA 1980, first Internal Med clinical rotation

Begin Treatment if BP>140/90

Start thiazide diuretic, 50mg qd


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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)?

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)


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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


Evidence hierarchy l.jpg

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)?


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Current Recommendations for BP Goals

JNC 7 (Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood) Pressure

Goal BP <140/90

Goal with Diabetes or CKD <130/80

JNC 8 Expected Mid 2011

Hypertension. 2003;42:1206


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Current Recommendations for BP Goals

JNC VII <140/90, in Diabetes or CKD <130/80

AHA/ACC 2007 <130/80 “high risk”;CVD, CKD, DM or Framingham 10 yr risk score >10%

ADA DM <130/80

WHO/ISH <140/90, in DM, CVD or CKD <130/80 “seems appropriate”

N/DOQI 2004 CKD <130/80

BHS <140/90, <130/80 DM,CVD or CKD

ESH-ESC “at least” <130/80 DM, CVD or CKD


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Hypertension in Diabetes

Guidelines say: Treat to <130/80

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 <120

Lipids: Fibrate added to Statin

BP arm 4,773 randomized to SBP<120 or <140

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

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)


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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

  • † Symptom experienced over past 30 days from HRQL sample of

  • N=969 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 <130, 130-139, 140+

JAMA July 7,2010;304(1)61-68


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Hypertension in Diabetes

Guidelines say: Treat to <130/80

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: <140/85 (consider <130/80 in patients with proteinuria)


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Hypertension in Coronary Artery Disease and “High Risk” Groups

AHA/ACC Guidelines say: Treat to <130/80

High risk includes any vascular disease, Framingham risk score >10%

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 358:1547-1559

I-PRESERVE Diastolic CHF

JAMA July 7,2010;304(1)61-68,

NEJM 358:1547-1559

N Engl J Med 2008;359:2456–67


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Hypertension in Coronary Artery Disease and “High Risk” Groups

AHA/ACC Guidelines say: Treat to <130/80

High risk includes any vascular disease, Framingham risk score >10%

Evidence says: No renal or cardiovascular benefit demonstrated in this overall group

2010 ICSI guideline: <140/90


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Hypertension in the Elderly

JNC7 and other Guidelines say:

Treat to <140/90

High Risk Conditions:

Treat to <130/80


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Hypertension in the ElderlyMeta-analysis RCTs in Patients ≥60 years

15 trials n=24,055

Frail elderly excluded from trials

Results similar for isolated systolic and BP trials

No trials have recruited patients with Isolated Systolic Hypertension and SBP<160

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 (>80)

Oates et al.Journal of the American Geriatrics Society Volume 55, Issue 3, pages 383–388, March 2007

Epidemiologic population studies show better survival with higher BP

STOP-2 Worse survival in treated hypertensives with SBP<140


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Hypertension in the ElderlyMetaanalysis RCTs in Patients ≥80 years

9 trials n=6,798

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

N=3850 mean age 83 mean SBP 173

Goal SBP<150, 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 <140/90

High Risk Conditions:Treat to <130/80

Evidence Suggests:

Initiate Treatment at 160 with SBP goal


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Hypertension in CKD

Guidelines say: Treat to <130/80

ACE or ARB preferred in patients with proteinuria


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Hypertension in CKD

Relevant clinical trials

MDRD 1994 N=884 pt with GFR 13-55

RCT MAP< 93 vs < 107 (<125/75 vs <140/90)

Overall result No benefit in CV or renal outcomes

Post hoc Subgroup analysis; 54 pts with >3g/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 MAP<93 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 <130/80

Evidence says: No renal or cardiovascular benefit in this overall group

Long term renal benefit in patients with proteinuria (>300mg/dl)

New ICSI guideline: <140/90, consider <130/80 in patients with proteinuria


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Evidence Based Goals

<140/90 for almost everybody

Perhaps <130/80 in patients with proteinuric renal disease at risk for ESRD

Perhaps a bit higher (<150 systolic) in older patients with isolated systolic HTN


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The gap between what we know and what we think we know or…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


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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


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My Latest Lesson In Hypertension

CIRCA 2010

Begin Treatment if BP>140/90

Start thiazide , Break it in half


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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


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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


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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, n=58,040

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

The Cochrane Library 2009, issue 3.

http//www.thecochranelibrary.com


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ALLHAT

.2

.16

.12

Cumulative CHD Event Rate

.08

.04

0

0

1

2

3

4

5

6

7

Years to CHD Event

Cumulative Event Rates for the Primary Outcome (Fatal CHD or Nonfatal MI) by ALLHAT Treatment Group

Chlorthalidone

Amlodipine

Lisinopril


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ALLHAT

Total

0.98 (0.90, 1.07)

Total

0.99 (0.91, 1.08)

Age <65

0.99 (0.85, 1.16)

Age < 65

0.95 (0.81, 1.12)

Age>=65

0.97 (0.88, 1.08)

Age >= 65

1.01 (0.91, 1.12)

Men

0.98 (0.87, 1.09)

Men

0.94 (0.85, 1.05)

Women

0.99 (0.85, 1.15)

Women

1.06 (0.92, 1.23)

Black

1.01 (0.86, 1.18)

Black

1.10 (0.94, 1.28)

Non-Black

0.97 (0.87, 1.08)

Non-Black

0.94 (0.85, 1.05)

Diabetic

0.99 (0.87, 1.13)

Diabetic

1.00 (0.87, 1.14)

Non-Diabetic

0.97 (0.86, 1.09)

Non-Diabetic

0.99 (0.88, 1.11)

0.50

1

2

0.50

1

2

Amlodipine Better Chlorthalidone Better

Lisinopril Better Chlorthalidone Better

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 antihypertensivesOutcome RR w/beta blockers95% CI

Stroke 1.161.04-1.30

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

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 CL<30

Spironolactone works well for many who don’t 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 N=17,118 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%, P<0.001), syncope (0.3% vs. 0.2%, P=0.03), and renal dysfunction (13.5% vs. 10.2%, P<0.001)

Similar findings in CHF trials

NEJMVolume 358:1547-1559, 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. 2004;292(18):2217-2222 NEJM 2008 359:2417-2428

JAMA. 2002;288:2981-2997 NEJM. 1999;340:677-684


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Dihydropyridine CCBs: The Swiss Army Knife of BP meds

Amlodipine2.5-20 mg qd

Felodipine 2.5-20 mg qd

Isradipine5-20 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 Proposal:3 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 Proposal:3 Drug Step-Care in Most Patients

Step Care example:

Step IStart Thiazide 12.5 mg; Start Lisinopril/HCT 20/12.5 if >160

Step 2If close to goal increase thiazide to 25mg (Lisinipril 20/25)

Otherwise add second drug (Lisinopril 20mg, amlodipine 2.5-5mg)

Step 3Add 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


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