Preventing Atherosclerotic Vascular Disease

1. Preventing Atherosclerotic Vascular Disease

2. Recommendations for Antiviral Treatment of H1N1 • For patients with confirmed or strongly suspected infection with influenza pandemic (H1N1) 2009, when antiviral medications for influenza are available, specific recommendations regarding use of antivirals for treatment of pandemic (H1N1) 2009 influenza virus infection are as follows: • Oseltamivir should be prescribed, and treatment started as soon as possible, for patients with severe or progressive clinical illness (strong recommendation, low-quality evidence). Depending on clinical response, higher doses of up to 150 mg twice daily and longer duration of treatment may be indicated. This recommendation is intended for all patient groups, including pregnant women, neonates, and children younger than 5 years of age. • Zanamivir is indicated for patients with severe or progressive clinical illness when oseltamivir is not available or not possible to use, or when the virus is resistant to oseltamivir but known or likely to be susceptible to zanamivir (strong recommendation, very low quality evidence). • Antiviral treatment is not required in patients not in at-risk groups who have uncomplicated illness caused by confirmed or strongly suspected influenza virus infection (weak recommendation, low-quality evidence). Patients considered to be at risk are infants and children younger than 5 years of age; adults older than 65 years of age; nursing home residents; pregnant women; patients with chronic comorbid disease including cardiovascular, respiratory, or liver disease and diabetes; and immunosuppressed patients because of malignancy, HIV infection, or other diseases. • Oseltamivir or zanamivir treatment should be started as soon as possible after the onset of illness in patients in at-risk groups who have uncomplicated illness caused by influenza virus infection (strong recommendation, very low quality evidence).

3. Recommendations for Chemoprophylaxis of H1N1 • Specific recommendations regarding the use of antivirals for chemoprophylaxis of pandemic (H1N1) 2009 influenza virus infection are as follows: • When risk for human-to-human transmission of influenza is high or low, and the probability of complications of infection is high, either because of the influenza strain or because of the baseline risk of the exposed group, use of oseltamivir or zanamivir may be considered as postexposure chemoprophylaxis for the affected community or group, for individuals in at-risk groups, or for healthcare workers (weak recommendation, moderate-quality evidence). • Individuals in at-risk groups or healthcare personnel need not be offered antiviral chemoprophylaxis if the likelihood of complications of infection is low. This recommendation should be applied independent of risk for human-to-human transmission (weak recommendation, low-quality evidence). • For treatment of mild to moderate uncomplicated clinical presentation of infection with multiple cocirculating influenza A subtypes or viruses with different antiviral susceptibilities, patients in at-risk groups should be treated with zanamivir or oseltamivir plus M2 inhibitor (noting that amantadine should not be used in pregnant women). Otherwise-healthy patients with this presentation need not be treated. • When the clinical presentation of infection with multiple cocirculating influenza A subtypes or viruses with different antiviral susceptibilities is severe or progressive, all patients should be treated with oseltamivir plus M2 inhibitor, or zanamivir. • For treatment of mild to moderate uncomplicated clinical presentation of infection with sporadic zoonotic influenza A viruses including H5N1, the at-risk population should be treated with oseltamivir or zanamivir, and the otherwise-healthy population with oseltamivir. All patients, regardless of risk status, with severe or progressive presentation of infection with sporadic zoonotic influenza A viruses including H5N1 should be treated with oseltamivir plus an M2 inhibitor.

4. Smoking Cessation from FP Audio Digest 362 • 20% of the US population smokes cigarettes • At least 70% of individuals who smoke see a physician each year. • Approximately 70% of individuals who smoke want to quite • Only 25 to 33% report receiving guidance or follow-up related to smoking cessation.

5. Health Behavior: Smoking Cessation • A 3 minute intervention can increase the likelihood of quitting • A 4 to 30 minute intervention can almost double quite rates • A 31 to 90 minute intervention can almost double quit rates • Rates are compared with no discussion or tobacco use.

6. Helping patients quit • The 2008 Treating Tobacco Use and Dependence guidelines encourage the use of the 5 A’s • Ask, ask every patient at every visit about tobacco use status. • Advise, every tobacco user should be advised to quit. Tell them you are willing to help them quit. Quitting tobacco is the most important thing you can do to protect you health. Even light smoking is dangerous. Whenever you’re ready to quit let me know and we will do everything we can to help you to be successful.

7. Continuing the 5 A’s • Assess • Try to determine patient willingness to quite • Assist • Target the habits and behaviors, thoughts and emotions and physiologic factors that contribute to tobacco use. • Establish a quit plan with a time and date. • Prepare for a quit date, by not buying tobacco in bulk and make clean areas in which tobacco is not to be used. Smoke outside. It will reduce the effects of tobacco on any of those who are exposed to the smoke. • Eliminate materials associated with tobacco use like lighters and ashtrays.

8. Assist • Ask patients to think about past quit experiences • Identify a support system. • Determine if avoiding certain individuals will help in quitting cigarettes • Ask others to help you quite, also known as quite buddies • Encourage others in household to quite smoking. • Behavioral techniques. • Nicotine fading • Gradually decreasing the amount of nicotine consuming over time. Tapering the frequency of tobacco use over time. Switching to a brand of tobacco that contains less nicotine.

9. Assist • Aversive tobacco use • Rapid consumption of tobacco, intended • to make the last experience with • tobacco unpleasant to decrease the • likelihood of relapse. • Brand switching • Consumption of a different brand of tobacco • that is stronger to make the last experience • with tobacco unpleasant to decrease relapse • Aversive or rapid smoking techniques increase the likelihood of success by 1.5 to 2 times.

10. Pharmacotherapy • 2008 treating tobacco use and dependence guidelines recommend seven first-line treatments • Rive nicotine replacement therapies • Transdermal nicotine • Nicotine gum • Nicotine inhaler • Nicotine lozenge • Nicotine nasal spray • Two non-nicotine replacement therapies which include Bupropion SR (Zyban) and Varenicline (Chantix) • Most effective treatment combines behavioral counseling and pharmacotherapy • Every individual who smokes should be offered drug treatment to assist with quitting.

11. Assist • Help the patient develop skill to manage challenges after the quit date. • Total abstinence is the goal • Main reasons for relapse are 1. Stress 2. Withdrawal symptoms 3. Cravings • Determine what to do in response to tobacco use urge. • 4 A’s • Avoid situations associated with tobacco use • Alter the habits • Alternative include gum, mints, and cinnamon sticks. • Activity, increasing it helps with everything

12. Assist • Encourage patients to consider themselves individuals who do not smoke • When they encounter increased urges to use tobacco have them ask themselves “What would a nontobacco user do?” • Ask patients what they will do when they believe they must use tobacco. • Briefly discuss methods to challenge beliefs that they must use tobacco. • I would like to have a cigarette but I don’t need or I don’t have to have one now”. • Distract themselves with another activity.

13. Assist • Stress management • Determine current methods beside tobacco use to manage stress. • Brief relaxation techniques. • Cognitive strategies. • Increased physical activity. • Lapses and relapses • Most lapses occur within the first 5 to 10 days after quitting • 90% of lapses lead to relapses • Meeting with a patient within the first week of the quit date may help decrease the likelihood of lapse

14. Assist • Quit lines • http://www.smokefree.gov. • 1-800-QUITNOW (1-800-784-8669). • 1-800-NOBUTTS (1-800-662-8887). • Arrange • Praise successful quit attempts • Review benefits of quitting • Discuss problems associated with quitting • If a patient experiences a lapse or relapse • Discuss recommitting to quit effort • Set a new quit date

15. A man, 48 yr of age, presents with acute chest pain. Evaluation reveals evidence of acute myocardial ischemia and existing cardiovascular disease. What target level of low-density lipoprotein cholesterol (LDL-C) is recommended? A) <130 mg/dL B) <100 mg/dL C) <70 mg/dL D) <40 mg/dL

16. Answer •  C) <70 mg/dL

17. Which of the following statins are metabolized via the cytochrome P450 3A4 system?AtorvastatinFluvastatinLovastatinPravastatinRosuvastatinSimvastatin A) 1,6 B) 1,3,6 C) 4,5 D) 2,4,5

18. Answer • Atorvastatin • Lovastatin • Simvastatin •   B) 1,3,6

19. Which of the following statins has the highest relative efficacy? A) Atorvastatin B) Pravastatin C) Rosuvastatin D) Simvastatin

20. Answer •  C) Rosuvastatin

21. Which of the following statements about statin-associated myalgia is true? A) It is responsible for the increased rate of discontinuation that occurs with higher doses B) Biopsy reveals pathologic changes in muscle tissue in some patients with myalgia C) Discontinuation of the statin is recommended only if creatine kinase levels are elevated D) There is good evidence that supplementation with coenzyme Q10reduces risk for myalgia

22. Answer •  B) Biopsy reveals pathologic changes in muscle tissue in some patients with myalgia

23. The goal for non-high-density lipoprotein cholesterol (non-HDL-C) is _______ higher than the goal for LDL-C. A) 30 mg/dL B) 40 mg/dL C) 50 mg/dL D) 60 mg/dL

24. Answer •  A) 30 mg/dL

25. Raising levels of HDL-C without changing other lipid parameters is independently associated with reduced cardiovascular (CV) risk. A) True B) False

26. Answer •  B) False

27. Niacin monotherapy has been associated with significantly decreased risks for coronary death and nonfatal myocardial infarction. A) True B) False

28. Answer •  A) True

29.  All the following statements about triglyceride levels are true, except: A) Independently predictive of CV disease B) Higher predictive value among men than among women C) Elevated levels associated with production of small, dense LDL particles D) Significantly decreased with niacin therapy

30. Answer •  B) Higher predictive value among men than among women

31.  The level of non-HDL-C: A) Can be measured easily and inexpensively B) Requires fasting for accurate measurement C) Is a poorer predictor of atherosclerosis than level of LDL-C D) Is predictive of risk in adults but not in children or adolescents

32. Answer • A) Can be measured easily and inexpensively

33. Which of the following drug combinations has/have been shown to be significantly more effective than statin monotherapy at lowering CV risk?Bile acid resin plus statinBile acid resin plus niacinStatin plus fibrateStatin plus antioxidants A) 1 B) 1,2 C) 1,3 D) 1,4

34. Answer • Bile acid resin plus statin • Bile acid resin plus niacin •   B) 1,2

35. Trends • coronary heart disease (CHD) remains leading cause of death in United States • prevalence expected to increase • Some improvements in trends (eg, total cholesterol levels), but 48% of adults have total cholesterol levels above 200 mg/dL • 33% have elevated levels of low-density lipoprotein cholesterol (LDLC) • 17% have low levels of high-density lipoprotein cholesterol (HDL-C)

36. Risk assessment: • Framingham risk calculator—calculates risk • based on levels of LDL-C and HDL-C, systolic blood pressure, smoking, age, and gender • estimates 10-yr risk for nonfatal myocardial infarction (MI) or fatal CHD • Coronary equivalents—diabetes; abdominal aortic aneurysm greater than 3.5 cm; peripheral vascular disease; carotid disease or history of transient • ischemic attack (TIA) • Lower LDL targets recommended for patients with coronary equivalents • identifying at-risk patients—important to identify patients with multiple risk factors who have not yet had cardiac event • risk calculators available online • document calculated risk and discuss implications with patients

37. LDL goals • target less than 100 mg/dL for high-risk patients • target less than 70 mg/dL recommended if patient has cardiovascular (CV) disease and multiple risk factors (eg, diabetes, metabolic syndrome, acute coronary syndrome [ACS]) • best evidence for patients with CV disease and ACS • for patients with ACS or unstable angina, initiate lipid-lowering therapy within 24 hr or before discharge, unless contraindicated • management— lifestyle interventions; statins as first-line medical therapy • adjunctive therapies include bile acid resins, ezetimibe, and niacin

38. Statins • effects—LDL-C level lowered; endothelial function restored; • decreased level of high-sensitivity C-reactive protein (hsCRP) • fewer ischemic episodes on exercise stress tests • plaques stabilized • decreased risk for cardiac events • Decreased mortality rate options—6 agents available; potencies, • pharmacokinetics, drug interactions, and metabolic pathways differ • generic simvastatin available; atorvastatin, • lovastatin, and simvastatin metabolized via cytochrome P450 3A4 system (interact with azole antifungal agents, HIV medications, or macrolide antibiotics • decrease dose, withhold statin, or switch to other statin with no interaction)

39. Statins • Efficacy: strategies for increasing efficacy—double dose (results in additional 6% reduction in level of LDL-C) • Switch to more potent statin • add adjunctive therapy (eg, ezetimibe, bile acid resin) • relative efficacies—trial showed 20 mg rosuvastatin produced reduction in LDL-C similar to that seen with 80 mg atorvastatin • measuring markers of risk—clinical trial showed combination • agent (simvastatin plus ezetimibe [Vytorin]) associated with additional reductions in levels of LDL-C and hsCRP (compared to simvastatin alone) • but no additional improvement in carotid intima-medial thickness • finding led to concernabout extrapolating effects on markers of risk (eg, hsCRP) to CV outcomes (new study will analyze effect on CV end points)

40. Statins • Safety and tolerability: although generally safe and well-tolerated, • over-the-counter formulations not recommended by • monitoring important • also important to know when (and why) patients discontinue taking statins • Trials comparing different statins and different dosing regimens • conclude that lowering LDL-C levels to less than 40 mg/dL improves outcomes without compromising safety • Higher doses associated with higher rate of discontinuation (related mostly to elevated liver enzymes, not to increased myalgias) • hepatotoxicity—generally low • risk increases with alcohol use and drug interactions • myalgia—relatively low incidence, but one study showed pathologic changes on muscle biopsy in some patients • consider discontinuing or switching to different statin, even if creatine kinase level not elevated • most trial data do not support supplementation with agents like CoEnzyme Q, but some patients report improvement with 100 to 200 mg/day

41. High-sensitivity CRP • independent marker of CV risk • Optional component of coronary risk assessment in adults without known CV disease • most useful for patients at intermediate risk • elevated CRP (1-3 mg/L) may be reason to decrease LDL goal to less than 100 mg/dL • Framingham Heart Study identified hsCRP as predictor of CV disease

42. Primary prevention • Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) • double blind, randomized trial comparing 20mg rosuvastatin to placebo for primary prevention of CV events among adults with LDL-C less than 130 mg/dL and hsCRP greater than 2 mg/L, but no history of CV disease or diabetes • data monitoring board stopped study early because of benefit seen with active treatment • treatment associated with improved LDL, hsCRP, and all CV outcomes, except for hospitalization for unstable angina • clinical implications—in JUPITER, hsCRP measured as marker of risk, not as means of guiding therapy • data support expanding use of statins for primary prevention • considerations include potential benefits, long-term safety, and cost-effectiveness

43. Risk-based management • Heart Protection Study (HPS) 20,000 participants, 40 to 80 yr of age, with high CV risk, randomized to 40 mg simvastatin or placebo • simvastatin associated with 34% reduction in mortality and CV events, regardless of baseline LDL-C (including patients with baseline • LDL-C 80 mg/dL) • results suggest that overall CV risk (instead • of LDL-C level alone) should guide therapy • American Diabetes Association recommendations—statins indicated for diabetic patients 40 yr of age (unless contraindication present), regardless of LDL-C level

44. Non–HDL-C • clinical trials of statin therapy show that residual CV risk exists after LDL-C target met • residual risk associated with other atherogenic lipoproteins • calculating non–HDL-C—subtract HDL-C from total cholesterol • goal—30 mg/dL higher than goal for LDL-C • clinical relevance—correlates closely with obesity, visceral adiposity, and metabolic syndrome • Predicts CV risk more strongly than does LDL-C • includes LDL-C, intermediate-density lipoproteins, chylomicrons and chylomicron remnants • in Framingham Heart Study, little association found between level of LDL-C and risk for CHD, after controlling for level of HDL-C • but HDL-C strongly associated with risk, even after controlling for level of LDL-C • Strong Heart Study—non–HDL-C predicted CV risk as well as LDL-C among American Indian men and women • ratio of total cholesterol to HDL-C also good predictor (target ratio less than 3.5) • guidelines—non–HDL-C recommended as secondary target of therapy for patients with triglyceride levels 200 mg/dL and above.

45. Raising HDL-C • agents—nicotinic acid (niacin; considered most effective agent) • Fibrates • fish oils • benefits—low level of HDL-C associated with increased risk for CV events • but no good evidence that raising level (independent of other changes in lipid profile) improves outcomes • Except Helsinki heart study 1987 with Gemfibricil • Every 1% rise in HDL-C had 2% reduction in coronary events

46. Beyond statins • niacin—Coronary Drug Project showed monotherapy associated with significantly decreased risks for coronary death and nonfatal MI (compared to placebo) • gemfibrozil—monotherapy shown beneficial for secondary prevention in population with underlying CHD • take-home point—patients unable to take statins have options including • bile acid resins, ezetimibe, niacin, and fibrates

47. Combination therapies • insufficient evidence that specific combinations result in improved risk reduction • niacin, fibrates, and omega-3 fatty acids suggested as possible combination therapies • statin plus niacin—HDL-Atherosclerosis Treatment Study (HATS) • 160 patients with known coronary • disease, low level of HDL-C, and LDL-C less than 145 mg/dL at baseline baseline • randomized to simvastatin plus niacin, antioxidants alone • combination of simvastatin, niacin, and antioxidants, or placebo; • simvastatin plus niacin associated with improvements in lipid profiles and significant reductions in risks for coronary death, MI, stroke, and revascularization and in regression of coronary stenosis • no benefit seen with antioxidants • Adding antioxidants appeared to reduce efficacy of combination therapy • larger study (in progress) comparing simvastatin monotherapy • with simvastatin plus niacin • statin plus fibrate—no clinical trial has compared combination to statin monotherapy • gemfibrozil should not be combined with higher doses of statins, because of increased risk for rhabdomyolysis • Fenofibrate safe to combine with statins • arm of Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial (in progress) • will compare simvastatin alone to simvastatin plus fenofibrate in patients with type 2 diabetes

48. Questions and answers • statins for primary prevention in premenopausal women • decision to treat based on CV risk generally, • premenopausal women have low risk • Statins recommended for women with underlying CV disease, diabetes, or others with high risk • statins as effective in women as in men • statins and risk for diabetes—trial showed treatment with rosuvastatin increased risk for new-onset diabetes but decreased mortality • significance unclear • myalgias—discontinue statin • measure creatine kinase (if normal, consider other causes) • myalgia should resolve in 1 to 2 wk after discontinuation (if not, consider other causes) • Augmentative medications (eg, ezetimibe) also may cause myalgias • Elevated liver enzymes—reduce dose or discontinue statin if aspartate aminotransferase or alanine aminotransferase 3 times upper limit of normal (ULN) • moderate elevations (eg, up to 4 times ULN) of creatine kinase acceptable as long as patient remains asymptomatic • fish oil—good adjunctive therapy • Evidence for use in patients with underlying CV disease • for primary prevention, benefit unclear

49. Beyond LDL Cholesterol • Dyslipidemia and CV risk: statin therapy effectively reduces level of LDL-C • patients with high triglycerides and low levels of HDL-C have residual risk for atherosclerosis; important to address all aspects of dyslipidemia • triglycerides—independent predictor of CV disease • Framingham study found triglyceride level and HDL-C level more predictive in women than men • another study showed that, among individuals with premature heart disease and family history of CV disease, triglyceride level associated with increased risk (11-fold higher when 500 mg/dL vs 100 mg/dL • 17-fold higher when triglyceride level 300 mg/dL and HDL-C level 30 mg/dL)

50. Lipoprotein interactions • when triglycerides elevated, cells produce abnormal forms of cholesterol (especially in patients with abdominal obesity) • triglycerides transiently inserted into LDL particle, then removed by cholesterol-ester transfer protein, creating small, dense LDLs • these small LDLs oxidize easily and penetrate arteries more rapidly than larger LDL particles • standard lipid profile does not detect small LDLs • Situation common among patients with abdominal obesity, high triglycerides, and low level of HDL • individuals with low levels of triglycerides do not produce small LDLs • production of small LDLs substantially increases when triglyceride level reaches 80 to 100 mg/dL • by 150 mg/dL, almost all LDL particles are small LDLs • guidelines list triglyceride level of 150 mg/dL as risk factor (cutoff may change to 100 mg/dL in next version of guidelines)