are we nearing the limits of office based cv prevention
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Are We Nearing the Limits of Office-Based CV Prevention?. Thomas G. Allison, PhD, MPH. America the Beautiful?. Continuum of CVD Prevention. Public Health Community Programs. Primary Prevention Clinic-based. Acute Treatment Hospital-based. Secondary Prevention Clinic-based. Case Study.

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continuum of cvd prevention
Continuum of CVD Prevention

Public Health

Community Programs

Primary Prevention

Clinic-based

Acute Treatment

Hospital-based

Secondary Prevention

Clinic-based

case study
Case Study
  • 62-year old white male
  • No known CV disease
  • Former smoker
  • BMI = 32.2 kg/m2
  • Taking ASA 81 mg/day
case study5
Case Study
  • Type II diabetes x 10 years
  • Hemoglobin A1c = 6.5%
  • Diabetic medications
    • Metformin
    • Glimepiride
    • Rosiglitazone
case study6
Case Study
  • Blood pressure = 134/64 mmHg
    • Blood pressure medications:
      • ACE-inhibitor
      • HCTZ
  • Lipids:
    • Total-C = 165 mg/dL HDL-C = 39 mg/dL
    • LDL-C = 95 mg/dL TG = 155 mg/dL
      • Rx = Simvastatin 40 mg/day
questions
Questions
  • Should we intensify diabetic therapy?
    • Add insulin? Add Exenatide? Other?
  • Should we attempt to lower systolic blood pressure?
    • Goal < 130 mg/Hg? < 120 mmHg?
    • Add beta blocker? Ca++ blocker? ARB?
  • Are lipids satisfactory?
    • Higher dose or stronger statin? Add Ezetimibe?
    • Add fibrate? Add niacin?
the accord trial
The ACCORD Trial

The trial with 3 arms but no legs to stand on

slide9

ACCORD Double 2 x 2 Factorial Design

Lipid

BP

Placebo Fibrate

Intensive

Standard

Intensive

Glycemic

Control

1383

1374

1178

1193

5128

Standard

Glycemic

Control

1370

1391

1184

1178

5123

2765

2362

2371

10,251

2753

5518

4733*

  • * 94% power for 20% reduction in event rate, assuming standard group rate of 4% / yr and 5.6 yrs follow-up
accord baseline patient characteristics
ACCORD Baseline Patient Characteristics
  • Number of patients: 10,251
  • Age: 62 years
  • Duration of diabetes: 10 years
  • Macrovascular disease: >35 %
  • HbA1c: 8.1%
accord glucose treatment
ACCORD-Glucose Treatment
  • Glycated hemoglobin: < 6.0% versus < 8.0%
  • Duration of follow-up: Median 3.4 yrs
  • Ending therapy:
    • Sulfonylurea: 78% vs. 68%
    • Repaglinide: 50% vs. 18%
    • Metformin: 74% vs. 67%
    • Rosiglitazone: 91% vs. 58%
    • Exenatide: 12% vs. 4%
    • Insulin: 77% vs. 35%
accord glucose control
ACCORDGlucose control

9.0

8.5

Standard therapy

8.0

7.5

Hba1c (%)

7.0

6.5

6.0

Intensive therapy

0

0

1

2

3

4

5

6

Time (years)

ACCORD Study Group. N Engl J Med.008;358:2545-59.

accord primary outcome cv death mi stroke
ACCORD Primary outcome(CV death, MI, stroke)

25

20

Standard therapy

HR 0.90 (0.78-1.04)P = 0.16

15

Patients with events (%)

10

Intensive therapy

5

0

0

1

2

3

4

5

6

Time (years)

ACCORD Study Group. N Engl J Med.008;358:2545-59.

accord all cause mortality
ACCORDAll-cause mortality

25

20

15

Patients with events (%)

Intensive therapy

HR 1.22 (1.01-1.46)P = 0.04

10

5

Standard therapy

0

0

1

2

3

4

5

6

Time (years)

ACCORD Study Group. N Engl J Med.008;358:2545-59.

accord blood pressure
ACCORD-Blood Pressure
  • N=4733 type 2 diabetics
  • Systolic blood pressure goals
    • < 120 mmHg versus < 140 mmHg
  • Primary outcome (composite):
    • Nonfatal MI / stroke / CV death
  • Mean follow-up: 4.7 years
  • Many drugs/combinations provided to achieve goal BP according to randomized assignment
slide16
Intensive Intervention:

2-drug therapy initiated: thiazide-type diuretic + ACEI, ARB, or b-blocker.

Drugs added and/or titrated at each visit to achieve SBP <120 mm Hg.

Standard Intervention:

Intensify therapy if SBP ≥160 mm Hg @ 1 visit or ≥140 mm Hg @ 2 consecutive visits

Down-titration if SBP <130 mm Hg @ 1 visit or <135 mm Hg @ 2 consecutive visits

systolic pressures mean 95 ci
Systolic Pressures (mean + 95% CI)

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

accord lipid
ACCORD-Lipid
  • N=5518 type 2 diabetics
  • Open label Simvastatin + PBO or fenofibrate
  • Primary outcome (composite):
    • Nonfatal MI / stroke / CV death
  • Mean follow-up: 4.7 years
slide21

4S

HPS

CARDS

other recent negative prevention trials
Other Recent Negative Prevention Trials

Lipids

  • ENHANCE
    • Ezetimibe 10 mg/day or PBO + Simvastatin 80 mg/day in familial hyperlipidemia
  • ILLUMINATE
    • Torcetrapib 600 mg/day or PBO + Atorvastatin in patients with CAD, PVD, or DM
  • Supplements
  • Alpha-Omega Trial
    • Low-dose omega-3 and alpha linolenic acid post-MI
slide23
Diabetes
  • ADVANCE
    • A1c < 6.5% using Gliclazide versus local standard (A1c < 7.0%)
  • VADT
    • Intensive (A1c < 7.0%) versus standard (A1c ~ 8.5%) in military veterans with type 2 DM

Hypertension

  • INVEST
    • SBP < 130 versus 130-140 mmHg in type 2 diabetics
perspective on accord
Was it a poorly designed or conducted trial?

Or does it simply fit in with other recent negative CV prevention trials?

Mostly add-on or titration trials

Background medical therapy is better than in older positive trials

More intensive intervention comes with costs

Are we nearing the limits of office-based CV prevention?

Perspective on ACCORD
slide25

Risk factors are not linear

Achieving a lower goal will have less relative impact

therapies from 4s effects on coronary events
Therapies from 4S: Effects on Coronary Events

28.9

Placebo

Statin only

18.6

Statin+ASA

11.2

Statin+

ASA+BB

8.6

Coronary Event Rate (%)

Kjekshus, J. Am J of CD. 1995, 76:64C-68C.

slide28

There may be a j-curve

Relative risk

95% CI

P(trend)<0.001

Relative risk

Diastolic BP = 55 mm Hg

2

80

60

25

DBP cutoff (mm Hg)

Somes et al: Arch Intern Med 159:2004, 1999

CP1211802-3

pharmacologic therapy statins dose response
Pharmacologic Therapy: Statins—Dose Response

Response to Minimum/Maximum Statin Dose

Fluvastatin

20/80 mg

Pravastatin

20/80 mg

Lovastatin

20/80 mg

Simvastatin

20/80 mg

Atorvastatin10/80 mg

% Reduction in LDL-C

31

37*

40

47

55

Adapted from Illingworth, Med Clin North Am 2000;84:23.

slide30

August 8, 2001

BAYER VOLUNTARILY WITHDRAWS BAYCOL

FDA today announced that Bayer Pharmaceutical Division

is voluntarily withdrawing Baycol (cerivastatin)

from the U.S. market because of reports of sometimes

fatal rhabdomyolysis, a severe muscle adverse reaction

from this cholesterol-lowering (lipid-lowering) product.

The FDA agrees with and supports this decision.

slide31

Fatal rhabdomyolysis reports with Baycol have been

reported most frequently when used at higher doses,

when used in elderly patients, and particularly, when used

in combination with gemfibrozil (LOPID and generics),

another lipid lowering drug. FDA has received reports

of 31 U.S. deaths due to severe rhabdomyolysis

associated with use of Baycol, 12 of which involved

concomitant gemfibrozil use.

summary
Summary
  • Rash of recent negative prevention trials
  • Pushing risk factors to lower levels
    • Yields less in terms of relative risk reduction
    • Requires more drugs at higher doses
      • With increased risk
    • May push the patient onto the J-curve tail
  • Good background medical therapy is required in contemporary studies
    • Lowers global risk; narrows therapeutic window
important points
Important Points
  • We continue to struggle against lifestyles that lead to cardiovascular disease – this is where the largest gains can potentially be achieved
  • There remains an “application gap” – not all patients with cardiovascular disease are taking appropriate medications and do not have risk factors controlled to even minimally acceptable levels
slide35
Questions?
  • Comments?
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