Are We Nearing the Limits of Office-Based CV Prevention?

Thomas G. Allison, PhD, MPH

America the Beautiful?

Continuum of CVD Prevention

Public HealthCommunity Programs

Primary PreventionClinic-based

Acute TreatmentHospital-based

Secondary PreventionClinic-based

Case Study

• 62-year old white male

• No known CV disease

• Former smoker

• BMI = 32.2 kg/m2

• Taking ASA 81 mg/day

Case Study

• Type II diabetes x 10 years

• Hemoglobin A1c = 6.5%

• Diabetic medications– Metformin– Glimepiride– Rosiglitazone

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

• 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 trial with 3 arms but no legs to stand on

ACCORD Double 2 x 2 Factorial Design

IntensiveGlycemicControl 5128

StandardGlycemicControl 5123

Lipid BP

Placebo Fibrate Intensive Standard

237123622753 2765

1383 1374

13911370

1193

11781184

1178

10,251

4733*5518* 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

Number of patients: 10,251 Age: 62 years Duration of diabetes: 10 years Macrovascular disease: >35 % HbA1c: 8.1%

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%

ACCORDGlucose controlH

ba1

c (%

)

Time (years)

Standard therapy

Intensive therapy

6

9.0

8.5

8.0

7.5

7.0

6.5

6.00

0 1 2 3 4 5

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

ACCORD Primary outcome(CV death, MI, stroke)

25

0

20

15

10

5

01 2 3 4 5 6

Standard therapy

Intensive therapy

Pat

ien

ts w

ith

eve

nts

(%

)

Time (years)

HR 0.90 (0.78-1.04)P = 0.16

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

ACCORDAll-cause mortality

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

Patients with events

(%)

Time (years)

25

0

20

15

10

5

01 2 3 4 5 6

Standard therapy

Intensive therapyHR 1.22 (1.01-1.46)P = 0.04

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

• Intensive Intervention:

– 2-drug therapy initiated: thiazide-type diuretic + ACEI, ARB, or -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

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

Primary and Secondary Outcomes

Intensive Events (%/yr)

StandardEvents (%/yr) HR (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

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

CARDS

HPS

4S

Other Recent Negative Prevention TrialsLipids

• 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

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?

MRFIT

0

2

4

6

8

10

12

14

6-Year CHD Deaths/1000

153 175 187 198 208 216 226 238 253 290

Serum Cholesterol by Deciles

Risk factors are not linear

Achieving a lower goal will have less relative impact

Therapies from 4S: Effects on Coronary Events

0 5 10 15 20 25 30 35

Coronary Event Rate (%)

Placebo

Statin only

Statin+ASA

Statin+ ASA+BB

28.9

18.6

11.2

8.6

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

4S TNT

Year published 1997 2005

Number (women) 4444 (827 = 19%) 10,001 (1902 = 19%)

Age (years) 58.6 ± 7.0 60.3 ± 8.8

Beta blocker 57% 55%

ASA 37% 88%

ACE/ARB NR 29%

Smoker 26% 13%

BP 147/85 131/78

Diabetes 5% 15%

Baseline LDL-C 188 mg/dL 98 mg/dL

Randomization PBO vs Simva 20-40 Atorva 10 vs 80

Major CV Event 29.8% vs 19.4% 10.9% vs 8.7%

Total Mortality 11.5% vs 8.2% 5.6% vs 5.7%

Lipid Trials Comparison

CP1211802-3

0123456789

10

80 75 70 65 60 55 50 45 40 35 30 25

Relative risk

Relative risk

DBP cutoff (mm Hg)DBP cutoff (mm Hg)

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

Relative risk95% CIP(trend)<0.001

Relative risk95% CIP(trend)<0.001

80 60 25

2

Diastolic BP = 55 mm HgDiastolic BP = 55 mm Hg

There may be a j-curve

Pharmacologic Therapy: Statins—Dose Response

% R

edu

ctio

n in

LD

L-C

1927 28

35 37

12

10 12

1218

0

10

20

30

40

50

60

Lovastatin20/80 mg

Fluvastatin20/80 mg

Simvastatin20/80 mg

Pravastatin20/80 mg

Atorvastatin10/80 mg

Response to Minimum/Maximum Statin Dose

3137*

40

47

55

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

BAYER VOLUNTARILY WITHDRAWS BAYCOL

August 8, 2001

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.

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.

TNT Adverse Events

Adverse Event 10 mg 80 mg p

All 289 (5.8%) 406 (8.1%) .001

Stopped treatment 265 (5.3%) 360 (7.2%) .001

Myalgia 234 (4.7%) 241 (4.8%) NS

Elevated LFT 9 (0.2%) 80 (1.2%) .001

Non-CV death 155 (3.1%) 183 (3.7%) NS

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

• 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

• Questions?

• Comments?