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

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

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  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/m2 • 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/dL HDL-C = 39 mg/dL • LDL-C = 95 mg/dL TG = 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 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

  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. 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.

  13. 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.

  14. 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.

  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 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

  17. 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

  18. Primary and Secondary Outcomes

  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

  20. 4S HPS CARDS

  21. 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

  22. 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

  23. 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

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

  25. 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.

  26. Lipid Trials Comparison

  27. 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

  28. 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.

  29. 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.

  30. 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.

  31. TNT Adverse Events

  32. 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

  33. 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

  34. Questions? • Comments?

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