Transcript Are We Nearing the Limits of Office

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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•
•
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
– LDL-C = 95 mg/dL
HDL-C = 39 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
Lipid
BP
Placebo
Fibrate
Intensive
Intensive
Glycemic
Control
1383
1374
1178
1193
5128
Standard
Glycemic
Control
1370
1391
1184
1178
5123
2765
2362
2371
10,251
2753
5518
Standard
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
 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%
ACCORD
Glucose control
9.0
Hba1c (%)
8.5
Standard therapy
8.0
7.5
7.0
6.5
6.0
0
Intensive therapy
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)
Patients with events (%)
25
20
Standard therapy
HR 0.90 (0.78-1.04)
P = 0.16
15
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
25
20
Patients
with events
(%)
15
Intensive therapy
10
HR 1.22 (1.01-1.46)
P = 0.04
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
• 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 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
Mean # Meds
Intensive:
Standard:
3.2
1.9
3.4
2.1
3.5
2.2
3.4
2.3
Average after 1st year: 133.5 Standard vs. 119.3 Intensive, Delta = 14.2
Primary and Secondary Outcomes
Intensive
Events
(%/yr)
Standard
Events
(%/yr)
HR (95% CI)
p
208 (1.87)
237 (2.09)
0.88 (0.73-1.06)
0.20
Total Mortality
Cardiovascular
Deaths
Nonfatal MI
150 (1.28)
144 (1.19)
1.07 (0.85-1.35)
0.55
60 (0.52)
58 (0.49)
1.06 (0.74-1.52)
0.74
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
Primary
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
4S
HPS
CARDS
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
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?
Risk factors are not linear
MRFIT
14
12
10
6-Year CHD 8
Deaths/1000 6
4
2
0
153 175 187 198 208 216 226 238 253 290
Serum Cholesterol by Deciles
Achieving a lower goal will have less relative impact
Therapies from 4S: Effects on
Coronary Events
28.9
Placebo
Statin only
18.6
Statin+ASA
Statin+
ASA+BB
11.2
8.6
0
5
10
15
20
Coronary Event Rate (%)
Kjekshus, J. Am J of CD. 1995, 76:64C-68C.
25
30
35
Lipid Trials Comparison
4S
TNT
1997
2005
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%
147/85
131/78
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%
Year published
Number (women)
BP
Diabetes
There may be a j-curve
10
9
8
7
6
Relative
5
risk
4
3
2
1
0
Relative risk
95% CI
P(trend)<0.001
Diastolic BP = 55 mm Hg
80 75 70 65 60 55 50 45 40 35 30 25
DBP cutoff (mm Hg)
Somes et al: Arch Intern Med 159:2004, 1999
CP1211802-3
Pharmacologic Therapy:
Statins—Dose Response
Response to Minimum/Maximum Statin Dose
% Reduction in LDL-C
0
10
Fluvastatin Pravastatin Lovastatin Simvastatin Atorvastatin
10/80 mg
20/80 mg
20/80 mg
20/80 mg
20/80 mg
19
27
28
20
35
37
12
30
31
40
50
60
10
37*
12
40
12
18
47
55
Adapted from Illingworth, Med Clin North Am 2000;84:23.
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.
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?