1. Are We Nearing the Limits of Office-Based CV Prevention? Thomas G. Allison, PhD, MPH

2. America the Beautiful?

3. Continuum of CVD Prevention Public Health Community Programs Primary Prevention Clinic-based Acute Treatment Hospital-based Secondary Prevention Clinic-based

4. Case Study 62-year old white male No known CV disease Former smoker BMI = 32.2 kg/m 2 Taking ASA 81 mg/day

5. Case Study Type II diabetes x 10 years Hemoglobin A1c = 6.5% Diabetic medications –Metformin –Glimepiride –Rosiglitazone

6. Case Study Blood pressure = 134/64 mmHg –Blood pressure medications: ACE-inhibitor HCTZ Lipids: –Total-C = 165 mg/dLHDL-C = 39 mg/dL –LDL-C = 95 mg/dLTG = 155 mg/dL Rx = Simvastatin 40 mg/day

7. 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?

8. The ACCORD Trial The trial with 3 arms but no legs to stand on

9. ACCORD Double 2 x 2 Factorial Design Intensive Glycemic Control 5128 Standard Glycemic Control 5123 LipidBP Placebo FibrateIntensiveStandard 23712362 2753 2765 13831374 13911370 1193 1178 1184 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

10. ACCORD Baseline Patient Characteristics  Number of patients: 10,251  Age: 62 years  Duration of diabetes: 10 years  Macrovascular disease: >35 %  HbA1c: 8.1%

11. 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%

12. ACCORD Glucose control Hba1c (%) Time (years) Standard therapy Intensive therapy 6 9.0 8.5 8.0 7.5 7.0 6.5 6.0 0 012345 ACCORD Study Group. N Engl J Med.008;358:2545-59.

13. ACCORD Primary outcome (CV death, MI, stroke) 25 0 20 15 10 5 0 123456 Standard therapy Intensive therapy Patients with events (%) Time (years) HR 0.90 (0.78-1.04) P = 0.16 ACCORD Study Group. N Engl J Med.008;358:2545-59.

14. ACCORD All-cause mortality ACCORD Study Group. N Engl J Med.008;358:2545-59. Patients with events (%) Time (years) 25 0 20 15 10 5 0 123456 Standard therapy Intensive therapy HR 1.22 (1.01-1.46) P = 0.04

15. 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

16. 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

17. Average after 1 st 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

18. Primary and Secondary Outcomes Intensive Events (%/yr) Standard Events (%/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

19. 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

21. CARDS HPS 4S

22. 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

23. 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

24. 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?

25. Risk factors are not linear Achieving a lower goal will have less relative impact

26. Therapies from 4S: Effects on Coronary Events 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.

27. 4STNT Year published19972005 Number (women)4444 (827 = 19%)10,001 (1902 = 19%) Age (years)58.6 ± 7.060.3 ± 8.8 Beta blocker57%55% ASA37%88% ACE/ARBNR29% Smoker26%13% BP147/85131/78 Diabetes5%15% Baseline LDL-C188 mg/dL98 mg/dL RandomizationPBO vs Simva 20-40Atorva 10 vs 80 Major CV Event29.8% vs 19.4%10.9% vs 8.7% Total Mortality11.5% vs 8.2%5.6% vs 5.7% Lipid Trials Comparison

28. CP1211802-3 Relative risk DBP cutoff (mm Hg) Somes et al: Arch Intern Med 159:2004, 1999 Relative risk 95% CI P (trend) <0.001 Relative risk 95% CI P (trend) <0.001 80 60 25 2 Diastolic BP = 55 mm Hg There may be a j-curve

29. Pharmacologic Therapy: Statins—Dose Response % Reduction in LDL-C Lovastatin 20/80 mg Fluvastatin 20/80 mg Simvastatin 20/80 mg Pravastatin 20/80 mg Atorvastatin 10/80 mg Response to Minimum/Maximum Statin Dose 31 37 * 40 47 55 Adapted from Illingworth, Med Clin North Am 2000;84:23.

30. 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.

31. 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.

32. TNT Adverse Events Adverse Event10 mg80 mgp All289 (5.8%)406 (8.1%).001 Stopped treatment265 (5.3%)360 (7.2%).001 Myalgia234 (4.7%)241 (4.8%)NS Elevated LFT9 (0.2%)80 (1.2%).001 Non-CV death155 (3.1%)183 (3.7%)NS

33. 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

34. 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

35. Questions? Comments?