Atherosclerotic Cardiovascular Disease (ASCVD) Primary Prevention Guideline

Transcription

1 Atherosclerotic Cardiovascular Disease (ASCVD) Primary Prevention Guideline Major Changes as of January Preface... 2 Terminology... 4 Overview of Primary Prevention Interventions... 4 Cholesterol Screening... 5 Screening patients without diabetes... 5 Screening patients with diabetes... 6 Screening tests that are not recommended... 7 Considerations with the CVD Risk Calculator... 7 Prevention and Risk Reduction... 8 Goals of primary prevention of ASCVD... 8 Interventions based on CVD risk calculations... 8 Interventions based on LDL cholesterol... 9 Lifestyle modifications for all patients... 9 Pharmacologic Options Statin Therapy for Primary Prevention of ASCVD Statin therapy Cholesterol goals Shared decision making Pharmacologic Options ACE Inhibitor or ARB Therapy Only for Patients with Diabetes ACE inhibitor or ARB therapy only for patients with diabetes Combination therapy is not recommended Pharmacologic Options Antiplatelet Therapy for Primary Prevention of ASCVD Antiplatelet therapy Antiplatelet therapy that is not recommended Pharmacologic Options Lowering Triglycerides to Prevent Pancreatitis Follow-up and Monitoring Medication monitoring that is not recommended Evidence Summary References Guideline Development Process and Team Appendix 1: Q&A on Group Health Recommendations vs. ACC/AHA Recommendations Appendix 2: Questions Asked in Customized CVD Risk Calculator Last guideline approval: January 2014 Guidelines are systematically developed statements to assist patients and providers in choosing appropriate health care for specific clinical conditions. While guidelines are useful aids to assist providers in determining appropriate practices for many patients with specific clinical problems or prevention issues, guidelines are not meant to replace the clinical judgment of the individual provider or establish a standard of care. The recommendations contained in the guidelines may not be appropriate for use in all circumstances. The inclusion of a recommendation in a guideline does not imply coverage. A decision to adopt any particular recommendation must be made by the provider in light of the circumstances presented by the individual patient. Atherosclerotic Cardiovascular Disease (ASCVD) Primary Prevention Guideline 1 Copyright Group Health Cooperative. All rights reserved.

2 Major Changes as of January 2014 New Separate primary prevention guideline (previous guideline was split in two). Previous One guideline, with recommendations for both primary and secondary prevention. Routine screening extended from age 74 to 79. Screen through age 74. Atorvastatin is a valid first-line option. Consider statin therapy for LDL 190, using shared decision making. Daily consumption of fish oil is no longer recommended for primary prevention of ASCVD. Instead, recommend regularly consuming fish as part of a Mediterranean-style eating plan. Maximum recommended dose of aspirin for antiplatelet therapy is 81 mg. Added a shared decision making section on whether to take statins for moderate risk. Added information on the workup and management of elevated triglycerides. Atorvastatin was second-line option. Consider fish oil 800 1,000 mg of EPA and DHA daily for primary or secondary prevention of ASCVD. No maximum provided. Provided only drug treatment information. Preface In November 2013, shortly before this guideline was to be published, the American College of Cardiology (ACC) and the American Heart Association (AHA) published new clinical practice guidelines for assessment of cardiovascular risk, lifestyle modifications to reduce cardiovascular risk, and management of blood cholesterol, overweight, and obesity in adults. Recommendations in the ACC/AHA guidelines have much in common with the recommendations in this guideline and in the ASCVD Secondary Prevention Guideline. But there are differences. Members of the guideline team who developed both ASCVD prevention guidelines discussed the ACC/AHA recommendations before finalizing the Group Health recommendations. Here are some of the key similarities and differences between the ACC/AHA and Group Health recommendations for both primary and secondary prevention. Cardiovascular risk calculator One of the most controversial points of the new ACC/AHA Guideline on the Assessment of Cardiovascular Risk is the adoption of a new risk calculator. At Group Health, we use a customized version of the 2008 Framingham calculator, which estimates 5-year risk of total ASCVD (stroke, MI, CABG/PCI, PAD, HF), and we generally recommend statins at 10% (2%/year). The ACC/AHA calculator estimates 10-year risk of hard ASCVD (stroke, MI), and it recommends statins at 7.5% (0.75%/year). This new calculator leads to many healthy people with favorable lipid values and no apparent disease being recommended for statin therapy on the basis of age alone. We believe at this point that the estimates from the 2008 version of the calculator are more clinically meaningful, and we recommend continuing to use them. Who to treat ACC/AHA recommends treating four distinct groups of patients with statins. A simplified list of these is: Clinical ASCVD No question about this one. Atherosclerotic Cardiovascular Disease (ASCVD) Primary Prevention Guideline 2

3 Diabetes ages years We certainly agree with this as well. Treatment beyond age 75 is reasonable in most cases; it s shared decision making with the patient, as in all cases of statin treatment. LDL 190 There isn t great evidence behind this, but we believe treatment should be considered in these cases, based on expert opinion and standard of care. This does not mean it s necessary, however, to screen everyone s LDL! A good proxy for this LDL level is a non-hdl cholesterol (total cholesterol minus HDL) of 220 or above. CVD 10-year risk 7.5% As explained above, we recommend sticking with our existing calculator. Intensity of statin therapy The ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults is now stressing the importance of starting statins with at least moderate-intensity therapy (e.g., simvastatin 40 mg or atorvastatin 20 mg). Depending on the situation, they sometimes recommend high-intensity therapy (atorvastatin mg). Their recommendations are a bit difficult to remember, and we believe somewhat arbitrary. By contrast, our recommendation is simpler, and we believe more evidence based generally treat primaryprevention patients with moderate-intensity therapy, and secondary-prevention patients with highintensity therapy. For primary-prevention patients, we have actually recommended starting with at least moderateintensity therapy for years, so this is not really a change. The point was not stressed much, however, so it may feel new. In practice, this means generally starting primary-prevention patients on 40 mg of simvastatin, not 10 or 20 mg, unless there is a reason (e.g., age, drug interaction, hepatic/renal dysfunction, etc.) that they can t handle the 40 mg. For secondary-prevention patients, we have changed the guideline to recommend starting with high-intensity therapy, consistent with ACC/AHA. We believe the evidence has been mounting for this change, and that it is evidence based. In particular, we recommend starting with the highest dose i.e., atorvastatin 80 mg, unless, again, there is some reason that you suspect that the patient will not be able to safely tolerate that dose (e.g., age, drug interactions, hepatic/renal dysfunction, etc.). The best evidence is behind this highest dose of atorvastatin, not 40 mg, even though both are considered high-intensity therapy. LDL targets One of the most significant changes in the ACC/AHA guideline is that it discarded the use of LDL targets. There is some logic to this, in that if you routinely start with moderate- to high-intensity statin therapy, you will achieve the LDL target in the majority of cases even without checking and adjusting. We do believe, however, that it is still important to recognize those cases where even those higher doses of statins have not achieved the targets, and where patients might therefore benefit from a change to their medication. The best way to identify these cases is to continue checking the LDL annually, and to have a low threshold to increase the dose when targets are not comfortably achieved. Be aware that ACC/AHA also still recommends checking LDL annually as well, largely to ensure compliance with the medication. Liver function tests Our guidelines have not changed regarding LFTs. We recommend against both baseline and routine LFT testing for patients on statin monotherapy. ACC/AHA now agrees that routine LFT testing is not necessary but still recommends baseline testing. Studies have shown, however, that statins do not generally increase LFTs, and are safe even in patients with LFTs that are elevated at the start of therapy. The downside of checking them is that it is common to find slight, clinically meaningless elevations that worry providers and patients unnecessarily going forward. Some patients then even end up stopping or not starting their statins, due to fear caused by these lab tests. Atherosclerotic Cardiovascular Disease (ASCVD) Primary Prevention Guideline 3

4 Hemodialysis/CHF patients The ACC/AHA guidelines do not recommend for or against statin therapy for patients on maintenance hemodialysis or who have congestive heart failure (NYHA classes II IV). This is because studies done with these subgroups have failed to show significant benefit of statins; patients in such studies were at a very high risk of all-cause mortality at baseline, so it s harder to demonstrate a benefit overall. It is not known if statins would work any less well for patients on HD or with CHF who have a prolonged life expectancy. So, our recommendation is to generally treat such patients with statins whenever you would any other patient, unless with shared decision making you decide not to treat because of a shortened life expectancy as you might do for any patient with a shortened life expectancy. For a Q&A by Group Health cardiologist Art Resnick, MD, FACC, that further compares the Group Health and ACC/AHA guidelines, see Appendix 1 on page 29. Terminology ASCVD, or atherosclerotic cardiovascular disease, is caused by plaque buildup in arterial walls and refers to the following conditions: Coronary heart disease (CHD), such as myocardial infarction (MI), angina, and coronary artery stenosis greater than 50%. Cerebrovascular disease, such as transient ischemic attack (TIA), ischemic stroke, and carotid artery stenosis greater than 50%. Peripheral artery disease, such as claudication. Aortic atherosclerotic disease, such as abdominal aortic aneurysm (AAA) and descending thoracic aneurysm. Primary prevention refers to the effort to prevent or delay the onset of ASCVD disease. Secondary prevention refers to the effort to treat known, clinically significant ASCVD disease, and to prevent or delay the onset of disease manifestations. Overview of Primary Prevention Interventions This guideline addresses the primary prevention of ASCVD in general. It does not attempt to address any potential screening or treatment of specific manifestations of ASCVD. Group Health uses CVD risk calculations to help determine which patients might benefit from primary prevention interventions. These CVD risk calculations returned with cholesterol screen results or by using a SmartLink in Epic are generated by a modified version of the Framingham CVD risk calculator. Note: There are many different versions of the Framingham calculator. Group Health s customized version approximates the absolute risk of ASCVD (as defined in the Terminology section, above) and of congestive heart failure in the next 5 years, instead of the 10 years used most often by other calculator versions. (For more information on how the Group Health customized calculator differs from others, see the Considerations with CVD Risk Calculator section on page 7.) Atherosclerotic Cardiovascular Disease (ASCVD) Primary Prevention Guideline 4

5 Table 1. Overview of intervention considerations for primary prevention of ASCVD See individual therapy sections for details. Population Low CVD risk calculation (<5% over 5 years) Moderate CVD risk calculation (5 10% over 5 years) High CVD risk calculation (>10% over 5 years) LDL cholesterol 190 Statin therapy Not recommended Can be considered; use shared decision making Antiplatelet therapy Not recommended Use shared decision making ACE inhibitor therapy ONLY for patients with diabetes See recommendations in ACE inhibitor section See recommendations in ACE inhibitor section Lifestyle modifications Recommended Recommended Recommended Recommended Recommended Recommended Should be considered; use shared decision making Use shared decision making Recommended Cholesterol Screening Screening patients without diabetes Within Group Health, the results of a cholesterol screen total cholesterol, HDL cholesterol, and total cholesterol/hdl ratio ordered through Epic include the patient s 5-year risk calculation for cardiovascular disease. A lipoprotein panel measures triglycerides and LDL cholesterol, in addition to total cholesterol, HDL cholesterol, and total cholesterol/hdl ratio. In general, do not use the lipoprotein panel as the screening test for patients without diabetes, because it requires fasting and because LDL and triglycerides are not necessary for risk stratification. A very small number of patients do have very high LDL (190 or above) and may require treatment (shared decision making), but it is possible to screen for such patients by looking at the non-hdl cholesterol (total cholesterol minus HDL). If that is 220 or above, the LDL is likely to be above 190. In that case, a fasting lipoprotein panel can be ordered as a follow up. Atherosclerotic Cardiovascular Disease (ASCVD) Primary Prevention Guideline 5

6 Table 2. Cholesterol screening for patients without diabetes Eligible population Men Under age 35 Test Frequency Routine screening is not recommended unless patient has a major cardiovascular risk factor Aged Cholesterol screen Every 5 years if low CVD risk 1 Every 2 4 years if moderate CVD risk 1 Annually if high CVD risk 1 Over age 79 Routine screening is not recommended Upon patient request or based on other ASCVD risk factors Women Under age 45 Routine screening is not recommended unless patient has a major cardiovascular risk factor Aged Cholesterol screen Every 5 years if low CVD risk 1 Every 2 4 years if moderate CVD risk 1 Annually if high CVD risk 1 Over age 79 Routine screening is not recommended Upon patient request or based on other ASCVD risk factors 1 As estimated in lab results, using customized version of Framingham calculator. Screening patients with diabetes For patients with diabetes, use the direct LDL test or fasting lipoprotein panel and not the cholesterol screen as the screening test because LDL is reported in our HEDIS measures for diabetes. Table 3. Cholesterol screening for patients with diabetes Eligible population Test Frequency Patients with diabetes not taking a statin Fasting lipoprotein panel 1 Annually Patients with diabetes taking a statin Fasting lipoprotein panel 1 1 or Direct LDL 1 Annually Within Group Health, the direct LDL cholesterol and fasting lipoprotein panel do not return a 5-year risk calculation for cardiovascular disease with test results. Use the.fram SmartLink in Epic to determine a patient s CVD risk calculation. Atherosclerotic Cardiovascular Disease (ASCVD) Primary Prevention Guideline 6

7 Screening tests that are not recommended Biomarker tests Testing for the biomarkers of inflammation and the lipid-related markers in Table 4 are not recommended. Although they may be independently associated with cardiovascular disease risk, they have only a minimal prognostic value when added to conventional risk markers. Table 4. Biomarker tests that are not recommended Marker Fibrinogen Lipoprotein(a) Phospholipase A 2 3 NNS 1 over 10 years 973 Apolipoprotein B and A-1 combined 3 4, Number needed to screen or use marker to assess individuals at medium CVD risk to prevent an additional cardiovascular event. Analysis performed by Emerging Risk Factors Collaboration (Kaptoge et al 2012). Analysis performed by Emerging Risk Factors Collaboration (Di Angelantonio et al 2012). For information on the hs-crp test, see the Patients at moderate risk section on page 8 under Interventions based on CVD risk calculations. Coronary artery calcium scoring Coronary artery calcium scoring generally is not recommended because it has not been proven to add significantly to clinical decision making in a way that improves outcomes. If available, the score can be used to help decide whether someone in the moderate risk category should receive statins. See Group Health Clinical Review Criteria for CT Angiography and CT Cardiography: Screening & Calcium Scores for more information ( Considerations with the CVD Risk Calculator Group Health s customized version of the Framingham CVD risk calculator is different from other Framingham versions that clinicians and patients will likely encounter in an internet search. Descriptions of the differences are listed below and include issues to consider when using risk calculations to inform intervention decisions: Risk time frame The Group Health version calculates risk for 5 years out instead of the usual 10. This is a Group Health specific customization. We do this because most of the evidence in trials is for 5 years. ASCVD definition The Group Health version is based on the 2008 Framingham calculator (D Agostino et al), which calculates the risk of not only hard ASCVD (stroke, MI) but also of peripheral artery disease and heart failure. The 2002 ATP III version is common in internet search results that calculator, by contrast, is essentially calculating the risk of hard CVD (MI). So partly because of this, the risk per year is significantly higher with the Group Health calculator for any given patient than it will be with the ATP III calculator. The new calculator released in 2013 as part of the ACC/AHA guidelines calculates the risk of hard ASCVD alone (stroke, MI), so it produces yet different numbers and can lead to healthy people with favorable lipid values and no apparent disease being recommended for statin therapy. Atherosclerotic Cardiovascular Disease (ASCVD) Primary Prevention Guideline 7

8 The guideline team continues to recommend using the Group Health version of the 2008 calculator because its risk estimates are more clinically meaningful. Family history The Group Health calculator adds 5 percentage points for family history of heart disease. This is another Group Health specific customization. Be aware that this is a rough estimate. For younger patients (<50 years) and for patients with less clear-cut family history, the full 5-percentage-point value is likely to be an overestimate of added risk. Diabetes Some risk calculators ask about diabetes, and some do not. The Group Health calculator does ask for this information, as does the 2013 calculator from ACC/AHA. Newer or well-controlled diabetes has a minimal effect on a patient s cardiovascular risk (compared with long-standing and/or poorly controlled diabetes). So for such patients, clinicians will likely want to adjust the risk calculation downward to account for the new or well-controlled diabetes. CVD risk calculators can provide only an estimate of risk. Interpretation of CVD risk calculations should always reflect informed clinical judgment. The following versions of the customized Group Health calculator are all the same: On ghc.org for use by clinicians, contracted providers, and members: ghc.org/tools/heart/. Through the Epic SmartLinks.framinghamscore and.fram, which pull information from a patient s record to calculate the risk. In the Health Profile interactive online tool for members. In the Clinical Lab s cholesterol screen. See Appendix 2 on page 33 for the list of questions asked in the Group Health CVD risk calculator. Prevention and Risk Reduction Goals of primary prevention of ASCVD Modify risk factors or prevent their development with the aim of delaying or preventing new-onset ASCVD. Interventions based on CVD risk calculations Patients at low risk (<5%) Rescreen total cholesterol/hdl in 5 years. Update CVD risk calculation if new risk factors develop. Patients at moderate risk (5 10%) Use shared decision making regarding daily antiplatelet therapy. (See the Pharmacologic Options Antiplatelet Therapy for Primary Prevention of ASCVD section on page 15.) Statin therapy can be considered it may be reasonable for some patients. Use shared decision making. (See the Pharmacologic Options Statin Therapy for Primary Prevention of ASCVD section on page 11.) If undecided about statin therapy, consider other factors that might affect risk (e.g., family history, smoking history, overweight, sedentary lifestyle, glucose level, treated blood pressure). Also consider testing hs-crp. Recommend statin therapy if CRP and/or other factors confirm elevated risk. hs-crp test Testing a patient s hs-crp may provide minimal prognostic value when added to the CVD risk calculation. (NNS = 440. Analysis performed by Emerging Risk Factors Collaboration. Kaptoge et Atherosclerotic Cardiovascular Disease (ASCVD) Primary Prevention Guideline 8

9 al 2012.) Test hs-crp once to adjust the risk calculation (similar to how family history and other factors are used to adjust risk). Table 5. Interpreting hs-crp test result Result Less than 1 mg/l Interpretation Risk is lower than the CVD risk calculation. 1 3 mg/l Risk is close to the CVD risk calculation mg/l Risk is higher than the CVD risk calculation. 10 mg/l and higher These elevations are associated with a nonspecific inflammatory process. Cardiac risk CRP should be reevaluated after the inflammatory condition has resolved. Patients at high risk (>10%) Recommend statin therapy. (See the Pharmacologic Options Statin Therapy section on page 11.) Recommend ACE inhibitor therapy ONLY for patients with diabetes. (See the Pharmacologic Options ACE Inhibitor or ARB Therapy section on page 15.) Recommend daily antiplatelet therapy. (See the Pharmacologic Options Antiplatelet Therapy section on page 15.) Interventions based on LDL cholesterol If LDL cholesterol is 190 or above: Statin treatment should be considered (expert opinion); use shared decision making. In such cases, familial hypercholesterolemia is a high possibility. If this is not the case, consider testing for secondary causes (e.g., diabetes, obesity, albuminuria). Use shared decision making regarding daily antiplatelet therapy. Younger patients with low shortterm but high lifetime risk of ASCVD may not need aspirin; this decision is independent of the decision on statin treatment. Lifestyle modifications for all patients Tobacco cessation Ask patients about tobacco use at every office visit. Advise tobacco users to quit. Advise patients at every office visit to avoid exposure to environmental tobacco smoke at home, work, and in public places. See the Tobacco Use Guideline for additional information. Healthy diet All patients should strive to: Make smart choices from every food group to meet caloric needs. Get the most and best nutrition from the calories consumed. Note that the PREDIMED study provides strong evidence that adhering to a Mediterranean-style eating plan reduces the incidence of major cardiovascular events in people at high risk for CVD (Estruch, Ros, Salas-Salvado, et al 2013). Adhering to a DASH eating plan can be an alternative. Both eating plans Atherosclerotic Cardiovascular Disease (ASCVD) Primary Prevention Guideline 9

10 provide similar key elements: an emphasis on plant foods (fruits, vegetables, whole-grain breads or other forms of cereals, beans, nuts, and seeds), minimally processed foods, and seasonally fresh foods; inclusion of fish; and minimal intake of red meat. The SmartPhrases.avsmediterraneandiet,.avsdash, and.avsnutrition are available for after-visit summaries. There is some evidence from observational studies that fish consumption of an average of 2 servings per week may reduce CHD mortality. Moderation of alcohol consumption Table 6. Recommended drinking limits 1 Population Healthy men aged 18 through 65 Healthy men aged 66 and older Healthy women of any age 1 Maximum number of drinks 4 or fewer in 1 day and 14 or fewer in 1 week 3 or fewer in 1 day and 7 or fewer in 1 week 3 or fewer in 1 day and 7 or fewer in 1 week Drinking levels defined by the National Institute on Alcohol Abuse and Alcoholism. Physical activity The American Heart Association recommends the following physical activity goals: At least 30 minutes of moderate-intensity aerobic activity 5 or more days per week. Moderate- to high-intensity muscle-strengthening activity 2 or more days per week. An example of moderate-intensity aerobic activity is walking at a pace that makes a patient feel slightly out of breath but still able to maintain a conversation. For patients who have been inactive for a while, recommend that they start slowly and work up to at least 30 minutes per day at a pace that is comfortable. If they are unable to be active for 30 minutes at one time, suggest accumulating activity over the course of the day in 10- to 15-minute sessions. Weight management Encourage getting to or maintaining a healthy weight through an appropriate balance of caloric intake and physical activity. See the Weight Management Guideline for additional information. Blood pressure management For patients aged 79 or younger, the blood pressure goal is less than 140/90 mm Hg. For patients aged 80 or older, the blood pressure goal is less than 150/90 mm Hg. Consider using this goal for frail elderly patients under age 80 who are not tolerating pharmacologic treatment. If a patient s BP is higher than goal, see the Hypertension Guideline for management recommendations. Dietary supplements Calcium and vitamin D If a patient is taking a calcium supplement for the prevention of osteoporosis, recommend that it be taken in combination with vitamin D and that its dose not exceed 1,200 mg per day. There is some evidence that calcium supplementation may be associated with increased risk of cardiovascular events, particularly myocardial infarction. The co-administration of Atherosclerotic Cardiovascular Disease (ASCVD) Primary Prevention Guideline 10

11 vitamin D with the calcium supplement may weaken the observed adverse effects of calcium supplementation. The literature indicates that intake of calcium from whole foods is not associated with an increased CVD risk. Dietary supplements that are not recommended Multivitamins There is evidence that daily intake of a multivitamin does not reduce major cardiovascular events, MI, stroke, or CVD mortality. Folic acid, vitamin B12, and vitamin E There is evidence of no benefit and/or possible harm with the use of these supplements/vitamins in the primary prevention of ASCVD. Beta-carotene There is good evidence that supplemental doses of beta-carotene do not improve cardiovascular outcome and that they may be associated with increased cardiovascular deaths and overall mortality. Vitamin C There is evidence that vitamin C supplementation has no benefit in the primary prevention of ASCVD. Fish oil There is some evidence that fish oil supplementation has no significant benefit in reducing cardiovascular events or mortality among individuals with no history of CVD. Pharmacologic Options Statin Therapy for Primary Prevention of ASCVD Statin therapy Use a statin as described in Table 7a or Table 7b for the following patients: With a CVD risk calculation greater than 10%. With diabetes and aged 40 and older. For patients with a moderate CVD risk calculation (5 10%), statin therapy can be considered. For patients with LDL cholesterol 190 or above, statin therapy should be considered. In both cases, use shared decision making. Attention to adherence is important for patients to be successful in lowering their cholesterol. Approximately half of the patients who start on statin drugs stop them on their own within 1 year. Use clinical judgment before escalating medication levels. Note The statins in Table 7a start out at what is considered moderate-intensity therapy (defined as lowering LDL cholesterol on average by approximately 30% to <50%). Patients should generally be on lower doses only if there are concerns about their ability to tolerate moderate-intensity therapy (e.g., elderly/frail, hepatic/renal impairment, untreated hypothyroidism, taking interacting drugs). For such cases, see Table 7b for reduced dosing. Table 7a. Standard dosing: Statins for lowering cholesterol for primary prevention of ASCVD Table 7b. Reduced dosing: Statins for lowering cholesterol for primary prevention of ASCVD Atherosclerotic Cardiovascular Disease (ASCVD) Primary Prevention Guideline 11

12 Table 7a. Standard dosing: Statins for lowering cholesterol for primary prevention of ASCVD Standard dosing applies to patients for whom there are no concerns about their ability to tolerate moderate-intensity statin therapy. Line Medication Initial dose Maximum dose 1 st Simvastatin 40 mg daily at bedtime 1 40 mg 1 daily at bedtime Atorvastatin 20 mg daily 80 mg daily For patients already on simvastatin 80 mg daily, it is acceptable to maintain the dose if they have been taking the drug for 12 months or longer, are not taking interacting medications, are at LDL goal, and are without myopathy. Table 7b. Reduced dosing: Statins for lowering cholesterol for primary prevention of ASCVD Reduced dosing applies to patients whose ability to tolerate moderate-intensity statin therapy may be in question, e.g., those who are elderly/frail, who have hepatic/renal impairment or untreated hypothyroidism, or who are taking interacting drugs. Line Medication Initial dose Maximum dose 1 st Simvastatin mg daily at bedtime 40 mg daily at bedtime Atorvastatin 10 mg daily 80 mg daily 2 nd Pravastatin 1 (Alternative in cases of drug interactions or side effects) mg daily at bedtime 80 mg daily at bedtime Pravastatin has about half the potency of simvastatin; however, it is less likely to interact with other medications, particularly medications that are strong CYP3A4 inhibitors. If a patient cannot tolerate a statin or the medication is not working, see Table 12b, Follow-up for patients on statin therapy, on page 19. Cholesterol goals We do recommend continuing to check LDL annually, but the intensity of statin therapy is the most critical factor in appropriate treatment. Assuming a patient is on at least moderate-intensity therapy (Table 7a, Standard dosing, above), it makes sense to consider increasing to high-intensity statin therapy (defined as lowering LDL cholesterol on average by approximately 50%) if the patient is above the goals in Table 8. Similarly, it may make sense to lower the intensity of statin therapy if the resulting LDL is very low. Expert opinion is that it is reasonable to consider lowering the intensity level if LDL is below 40 for 2 measurements in a row. A low HDL level is an independent risk factor for CVD, but there is no evidence that increasing HDL levels reduces cardiovascular risk. Evidence has shown, at most, a weak association between elevated triglycerides (TG) and health outcomes. Neither the threshold nor target of therapy is known. Although there is no direct evidence, there is consensus that TG levels of 500 mg/dl or greater warrant treatment to prevent pancreatitis. (See the Pharmacologic Options Lowering Triglycerides to Prevent Pancreatitis section on page 16.) Treatment/investigation at higher than 1,000 mg/dl would also be reasonable. Use shared decision making. Atherosclerotic Cardiovascular Disease (ASCVD) Primary Prevention Guideline 12

13 Table 8. Goals for cholesterol levels in patients on statin therapy Population LDL cholesterol 1 Goal Patients with moderate or high CVD risk LDL lower than 130 2,3 Patients with diabetes LDL lower than 100 2,3 HDL cholesterol All patients Triglycerides No specific HDL target for therapy. All patients TG less than 500 mg/dl Encourage patients to increase HDL levels through lifestyle measures, e.g., increased physical activity, weight loss if overweight, and tobacco cessation. Medications generally are not recommended. Generally, LDL is measured only as follow-up for patients on statin therapy to assess response and adjust dose if needed. (See also the Follow-up and Monitoring section on page 18.) This LDL goal may not fit all patients. An alternate goal is a 30 40% reduction from the previous LDL measure. Once a patient is on a high dose of a statin, use clinical judgment before escalating medication levels. LDL values can come from either a fasting lipoprotein panel or a direct LDL test. The lipoprotein panel indirectly calculates LDL cholesterol by using the Friedewald equation (LDL = TC HDL TG/5). In general, either test can be used, but be aware that the Friedewald equation tends to underestimate LDL when LDL is low (~70) or triglycerides are high (> ). In these cases, the true LDL value can be points higher. So, in such cases, consider using a direct LDL test or ensuring that the patient is well below the target. A goal of less than 1,000 mg/dl would also be reasonable. Use shared-decision making. Shared decision making Making a decision to initiate long-term lipid lowering with medication requires knowledge of the patient s absolute risk of CVD in the next 5 years. Benefits of statin therapy Statins decrease major vascular events by approximately 25%. The overall benefit is therefore dependent on the baseline risk. Numbers are expressed in number needed to treat (NNT) for 5 years. CV risk Absolute risk reduction NNT/ 5 years 2% 0.5% 200 4% 1.0% 100 6% 1.5% 67 8% 2.0% 50 10% 2.5% 40 12% 3.0% 33 14% 3.5% 29 16% 4.0% 25 Keep in mind that the benefits of therapy likely do extend beyond 5 years, especially for relatively young patients. So the actual NNT is likely lower than this at each risk level. This needs to be weighed against the known risks (summarized below). Atherosclerotic Cardiovascular Disease (ASCVD) Primary Prevention Guideline 13

14 Risks of statin therapy Cognitive impairment Per the U.S. Food and Drug Administration (FDA), rare post-marketing reports of cognitive impairment (e.g., memory loss/impairment, forgetfulness, amnesia, confusion) have been reported with statin use, with time to onset ranging from 1 day to years after starting statin therapy (FDA 2012). The incidence of cognitive-related adverse events reported to the FDA for statins (1.9 per 1 million prescriptions) was similar to those reported for losartan (1.6 per 1 million prescriptions) and clopidogrel (1.9 per 1 million prescriptions) (Richardson 2013). If cognitive impairment occurs, discontinue the statin (median time to symptom resolution was 3 weeks upon statin discontinuation). Diabetes risk The FDA added warnings to all statins (except pravastatin) that statin use can increase HbA1c and fasting serum glucose levels. The absolute excess risk of new-onset diabetes is very low, approximately 0.1% per year (number needed to harm [NNH] 255 over 4 years; Sattar 2010). The FDA (2012) also analyzed this data, and stated that the cardiovascular benefits of statins in clinically appropriate patients outweigh this risk. The Group Health guideline team agrees and recommends against routine screening for diabetes in patients taking statins. Myalgias/musculoskeletal injuries/decreased benefits of exercise In a recent meta-analysis of 55 placebo-controlled RCTs (N=43,531), there was no significant increase in myalgia with statins compared with control (Naci 2013), whereas observational studies have reported myalgia incidence varying from 1 to 25% (Sathasivam 2012, Parker 2013). Keep in mind, however, that many of the RCTs had a run-in period of 30 days, where patients who were intolerant of the statins were excluded from the study. A recent retrospective, propensity-matched cohort study (N=13,934) reported a 0.6% per-year risk of dislocation/strain/sprain with statin use (NNH 38 over 4.7 years; Mansi 2013). Other small RCTs have reported conflicting results of whether statin use decreases muscle strength or exercise capacity (Parker 2013, Mikus 2013). Rhabdomyolysis Very rare. A large (N=473,343) observational cohort study reported that for commercially available statins, rates of hospitalized rhabdomyolysis events were approximately per 10,000 person-years of statin use (NNH 6250 to 33,334 per year) (Cziraky 2013). Acute kidney injury (AKI) Rare. A large (N=2,067,639) retrospective observational analysis reported that in non-ckd patients on low-dose statins, hospitalizations for acute kidney injury at 6 months ranged from 1.0 to 3.5 per 1,000 patients in those younger than 65 years old and per 1,000 patients in those aged 65 years and older (Dormuth 2013). Non-CKD patients on high-potency statins versus low-potency statins were 34% more likely to be hospitalized for acute kidney injury, but incidence remained rare, with NNH 1,700 over 120 days. Hepatotoxicity Per the FDA, statins have a very low risk of serious liver injury (reported at a rate of 2 per 1 million person-years), and routine liver function monitoring is not recommended, as ALT monitoring does not appear to detect or prevent serious liver injury (FDA 2011). Atherosclerotic Cardiovascular Disease (ASCVD) Primary Prevention Guideline 14

15 Pharmacologic Options ACE Inhibitor or ARB Therapy Only for Patients with Diabetes ACE inhibitor or ARB therapy only for patients with diabetes Use an ACE inhibitor as described in Table 9 for ONLY the following patients with diabetes: Aged with a high CVD risk calculation (>10%). Aged 55 and older at any risk calculation level. For ONLY the following patients with diabetes, using an ACE inhibitor can be considered; use shared decision making: Aged with a moderate CVD risk calculation (5 10%). Younger than 40 years of age, regardless of CVD risk calculation. Table 9. ACE inhibitor or ARB therapy ONLY for patients with diabetes Line Medication Initial dose Maximum dose 1 st ACE inhibitor 2 nd ARB 1 Lisinopril or 5 10 mg daily 40 mg daily (target dose is 20 mg daily) Ramipril mg daily 20 mg daily (target dose is 10 mg daily) 1 Losartan mg daily 100 mg daily Use an ARB (Losartan) for patients who cannot tolerate an ACE inhibitor because of cough, rash, or angioedema (rather than because of renal failure, hyperkalemia, or hypotension). In a patient who previously developed angioedema with an ACE inhibitor, an ARB is less likely to cause angioedema, but there is still a risk of cross-reactivity. In the CHARM-Alternative study, the ARB group had 2.6% ACE-ARB cross-reactivity versus 0% in the placebo group (Granger 2003). Combination therapy is not recommended ACE inhibitor and ARB combination therapy is not recommended. There is evidence that there is harm and no additional benefit in combining an ACE inhibitor and an ARB. Numbers needed to harm (NNH) are 33 for hypotensive symptoms, 1,000 for syncope, 250 for diarrhea, and 250 for renal impairment. Pharmacologic Options Antiplatelet Therapy for Primary Prevention of ASCVD Antiplatelet therapy Use antiplatelet therapy as described in Table 10 for the following patients: With a high CVD risk calculation (>10%). For patients with a moderate CVD risk calculation (5 10%) or with LDL cholesterol 190 or above, use shared decision making. For patients with a low CVD risk calculation (<5%), antiplatelet therapy is not recommended. (Group Health recommendations differ from USPSTF recommendations [ in that the Group Health guideline Atherosclerotic Cardiovascular Disease (ASCVD) Primary Prevention Guideline 15

16 team agreed to focus on level of risk as determined by the CVD risk calculator rather than by patient age/gender.) Note that patients who need to take an NSAID should continue taking it during antiplatelet therapy. Table 10. Antiplatelet therapy for primary prevention of ASCVD Line Medication Initial dose Maximum dose 1 st Aspirin 81 mg daily 81 mg daily 2 nd Clopidogrel 1 75 mg daily 75 mg daily 1 Clopidogrel may be an option for patients who have aspirin intolerance and a high CVD risk calculation (>10%). The decision on daily antiplatelet therapy should be based on individualized risk, which includes assessment of both the risk of a first cardiovascular event and the risk of major bleeds. Factors that increase GI bleeding risk (Bhatt 2008): Patient has one of the following risk factors: history of ulcer disease, history of GI bleeding, current dual antiplatelet therapy (clopidogrel plus daily NSAID/aspirin), or current concomitant anticoagulant therapy (warfarin, enoxaparin, etc.). Patient has more than one of the following risk factors: aged 60 years or older, concomitant systemic corticosteroid use, or dyspepsia or GERD symptoms. Antiplatelet therapy that is not recommended NSAIDs alone are not appropriate substitutes for aspirin as antiplatelet agents. Pharmacologic Options Lowering Triglycerides to Prevent Pancreatitis Triglycerides do not require investigation or treatment unless they are higher than 500 mg/dl. (Treatment/investigation at higher than 1,000 mg/dl would also be reasonable. Use shared-decision making.) If a patient has elevated triglycerides, consider the following workup: HbA1c, TSH, protein/creatinine ratio, and pregnancy test (if applicable). Review other items that can cause triglyceride elevations: o Obesity (review diet). o Alcohol intake. o Medications estrogen replacement, oral contraceptives, tamoxifen, HIV antiretroviral regimens, beta blockers (excluding carvedilol), retinoids, and immunosuppressive agents such as glucocorticoids and cyclosporine. Consult with Endocrinology if: Cause of elevated triglycerides cannot be identified. You are not able to get triglyceride level lower than 500 mg/dl with treatment. You have any other questions about elevated triglycerides. See also the prescribing notes that follow Table 11. Atherosclerotic Cardiovascular Disease (ASCVD) Primary Prevention Guideline 16

17 Table 11. Medications for lowering triglyceride levels to prevent possible pancreatitis Line Medication Initial dose Maximum dose 1 st Atorvastatin 80 mg daily 80 mg daily If TG still not <500 mg/dl Add Fenofibrate (preferred) mg daily 160 mg daily or If TG still not <500 mg/dl Add Niacin Niacin IR 100 mg twice daily 1,000 mg 3 times daily Niacin SR (Slo-Niacin) 250 mg twice daily 1,000 mg twice daily Fish oil (if LDL is at goal) 2,000 mg DHA/EPA in divided doses daily 4,000 mg DHA/EPA in divided doses daily OR 1 st Gemfibrozil monotherapy 600 mg twice daily 600 mg twice daily Prescribing notes Atorvastatin Weigh risks and benefits of using maximum dose (80 mg). Use maximum dose with caution in patients who are elderly, have kidney disease (CKD 3 5), have untreated hypothyroidism, or are taking interacting drugs. Fenofibrate For patients with CKD 3 (creatinine clearance ml/min), do not exceed fenofibrate 54 mg per day. Do not use for patients with CKD 4 5. Niacin Use niacin with care in patients on a statin. When niacin at doses of 1,000 mg daily or higher is combined with a statin, patients are at increased risk of myalgia and rhabdomyolysis. Avoid use if ALT/AST is greater than 2 3 times upper limit of normal or if persistent severe cutaneous symptoms, persistent hyperglycemia, acute gout, or gastrointestinal symptoms occur. Niacin IR is the preferred form of niacin. If niacin SR is to be used, Slo-Niacin is the brand used at Group Health. Trials with niacin SR made by other manufacturers showed an increased risk of hepatotoxicity, so caution is advised if other brands of niacin SR are used. See Niacin IR or Niacin SR (Slo-Niacin) patient dosing instructions for information on dosing escalation (Group Health internal staff website only). Gemfibrozil Gemfibrozil is contraindicated with statin therapy. Use caution for patients with mild to moderate renal impairment (CKD 2 3). Atherosclerotic Cardiovascular Disease (ASCVD) Primary Prevention Guideline 17

18 Do not use for patients with severe renal impairment (serum creatinine greater than 2 mg/dl or CKD 4 5). Follow-up and Monitoring Table 12a. Medication monitoring Table 12b. Follow-up for patients on statin therapy Table 12a. Medication monitoring Eligible population Test(s) Frequency Patients on statin Patients on ACE inhibitor or ARB Patients on fenofibrate therapy Patients on niacin 1 Fasting lipoprotein panel 1 or Direct LDL cholesterol Potassium and Creatinine Creatinine and ALT/AST (Only for patients on combo therapy with a statin) ALT/AST and Fasting blood glucose or HbA1c and Uric acid At minimum 4 6 weeks after initiating therapy and Annually At baseline and 2 4 weeks after initiating therapy or increasing dose and Annually At baseline and 3 months after initiating therapy and Every 6 months At baseline and 4 6 weeks after initiating therapy and Annually At baseline and 2 4 weeks after increasing dose and Every 6 months LDL values can come from either a fasting lipoprotein panel or a direct LDL test. The lipoprotein panel indirectly calculates LDL cholesterol by using the Friedewald equation (LDL = TC - HDL - TG/5). In general, either test can be used, but be aware that the Friedewald equation tends to underestimate LDL when LDL is low (~70) or triglycerides are high (> ). In these cases, the true LDL value can be points higher. So, in such cases, consider using a direct LDL test or ensuring that the patient is well below the target. Atherosclerotic Cardiovascular Disease (ASCVD) Primary Prevention Guideline 18

19 Table 12b. Follow-up for patients on statin therapy Population Statin intolerance Patients with moderate CVD risk calculation (5 10%) Patients with high CVD risk calculation (>10%) Statin not working Patients with moderate CVD risk calculation (5 10%) Patients with high CVD risk calculation (>10%) Action First, consider decreasing dose. If still intolerant, use shared decision making to decide whether or not to consider switching to another statin. If still intolerant, stop statin; do not prescribe further medications. First, consider decreasing dose. If still intolerant, use shared decision making to decide whether or not to consider switching to another statin. Consider a virtual consult with Cardiology. If still intolerant, stop statin; do not prescribe further medications. First, assess adherence to therapy. Patients often are not taking their medication regularly. If they are taking regularly, consider increasing dose (if not already at maximum). If still not working, use shared decision making to decide whether or not to consider switching to another statin. If still not working, stop statin; do not prescribe further medications. First, assess adherence to therapy. Patients often are not taking their medication regularly. If they are taking regularly, consider increasing dose (if not already at maximum). If still not working, use shared decision making to decide whether or not to consider switching to another statin. Consider a virtual consult with Cardiology. Medication monitoring that is not recommended ALT/AST For patients on statin monotherapy, routine baseline and periodic ALT or AST monitoring are not recommended. Liver function tests are recommended only if clinically indicated to work up symptoms of liver disease. Asymptomatic transaminase elevations with statin use are common but usually mild, transient, and reversible. They do not indicate liver dysfunction. Progression to liver toxicity is exceedingly rare and is likely due to idiosyncratic or immunoallergic reactions. The presence of chronic liver disease other than cirrhosis is not a contraindication for statin use. However, virtual consultation with Gastroenterology first is recommended. CK Routine CKs are not helpful and often are misleading. Check creatine kinase only if patient has symptoms of myopathy, an extremely rare side effect. Atherosclerotic Cardiovascular Disease (ASCVD) Primary Prevention Guideline 19

20 Evidence Summary Group Health developed the ASCVD Primary Prevention Guideline using an evidence-based process, including systematic literature search, critical appraisal, and evidence synthesis. CVD risk estimation A new Framingham CVD prediction model, also referred to as general CVD risk function, was developed by D'Agastino and colleagues (2008). The new model includes age, total cholesterol, HDL cholesterol, systolic blood pressure, antihypertensive medication used, current smoking, and diabetes status. When compared with the traditional Framingham risk stratification calculator after calibration, the new model was found to be superior in estimating CVD risk, with a net reclassification improvement of 6.65% (p <0.001) for men, and 7.95% (p = 0.003) for women. Other new risk models developed in the United States include Reynolds Risk Score (RRS) for women and for men. The Reynolds Risk Score added both high-sensitivity C-reactive protein and parental history of early MI (<60 years) to the traditional Framingham calculator risk score variables. European risk estimators such as the PROCAM equation (Germany), ASSIGN (Scotland), and QRISK and QRISK 2 (United Kingdom) also added family history and other variables to the classic risk factors to estimate CHD or CVD risk. Screening Lipid screening There is no direct evidence to determine the optimal age for screening men and women for lipid disorders, the appropriate interval for screening, or the appropriate age to stop screening. In 2008, the U.S. Preventive Services Task Force (USPSTF) strongly recommended screening all men 35 years of age or older, and screening women 45 years or older if they are at increased risk for CHD. The USPSTF also recommended screening men aged years and women aged years if they are at increased risk for CHD. The USPSTF made no recommendation for or against routine screening of men aged years or of women aged 20 years or older who are not at increased risk for CHD. The USPSTF indicated that screening may be appropriate in older people who were never screened but that repeated screening is less important in older people, as lipid levels are less likely to increase after age 65. However, because older adults have an increased baseline risk for CHD, they would gain greater absolute benefit from the treatment of dyslipidemia compared with younger adults. Serum triglycerides There is insufficient evidence to recommend for or against triglyceride measurement as part of routine screening for lipid disorders. Large observational studies and a meta-analysis that pooled data from 29 studies (Sarwar et al 2007) indicate that hypertriglyceridemia is independently associated with CHD. However, there is insufficient evidence to determine that this association is causal, that including triglyceride values would add incremental value to the traditional variables used to estimate CHD or CVD risk, or that lowering isolated serum triglyceride levels would reduce future CHD events. ASCVD emerging risk markers There are multiple published studies and meta-analyses on novel biomarkers used as risk predictors of CVD. Among these are CRP, fibrinogen, homocysteine, lipoproteins, LP-PLA2, and many others. The studies are relatively large, prospective, and have long-term event follow-up. However, the majority were nested case-cohort studies, and CRP levels as well as other markers' levels were measured only once at baseline. In addition, the blood samples were stored for up to 10 years before analysis. Moreover, there were several possible uncontrolled risk factors and confounders unadjusted for in the analysis. Many of the studies did not report on the results of cerebrovascular and coronary events separately. The authors mainly presented the results in hazard ratios comparing the lowest with the highest tertile, quartile, or Atherosclerotic Cardiovascular Disease (ASCVD) Primary Prevention Guideline 20

21 quintile values. The results may indicate a statistical association but do not show that the marker or test adds to the risk prediction. The association observed, however, is purely statistical and depends on the variables included in the analysis. An independent risk factor does not imply causality, and vice versa. Biomarkers of inflammation (CRP and fibrinogen) The Emerging Risk Factors Collaboration (Kaptoge et al 2012) analyzed individual records of 52 prospective cohort studies with 246,669 participants without a history of CVD to investigate the value of adding CRP or fibrinogen levels to conventional risk factors for the prediction of cardiovascular risk. The analysis showed that adding information of an inflammation biomarker to the standard risk factors used to predict 10-year risk of first cardiovascular event leads to a very small but statistically significant increase in the C-statistics ( for CRP and for fibrinogen). Based on the results of the analysis, the authors estimated that targeted CRP assessment of individuals at an intermediate risk could help prevent one additional cardiovascular event over a period of 10 years for every 440 individuals screened, as a result of 23 additional people starting statin therapy. Lipid-related markers The Emerging Risk Factors Collaboration (Di Angelantonio et al 2012) used individual records for 165,544 participants without baseline CVD from 37 prospective cohorts to determine whether adding information on apolipoprotein, A-1, B, lipoprotein(a), or lipoprotein associated phospholipase A 2, to total cholesterol and HDL-C would improve CVD risk prediction. The results of the analysis showed a minimal improvement in the C-index (change ranged from to for the different markers with a <1% net classification improvement with the addition of each of these markers to the conventional risk factors). The authors estimated that in order to prevent one extra CVD outcome over 10 years, 4,500 people need to be additionally screened with a combination of apo B and apo A-1, or about 1,000 people need to be screened with lipoprotein associated phospholipase A 2 mass, or about 800 people need to be screened with lipoprotein(a). Pharmacologic prophylaxis Aspirin/antiplatelet chemoprophylaxis There is good evidence from multiple primary prevention of ASCVD studies and meta-analyses that aspirin is associated with a significant reduction in MI among men and ischemic stroke among women, and that it is also associated with a significant increase in bleeding in men and women. Three recent meta-analyses (Raju et al 2011; Bartolucci, Tendera and Howard 2011; and Seshasai et al 2012) pooled the results of nine trials enrolling just over 100,000 participants (the six original primary prevention trials British Doctors Study, Physicians Health Study, Hypertension Optimal Treatment trial, Thrombosis Prevention Trial, Primary Prevention Project, and Women s Health Study and the Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes trial, Prevention of Progression of Asymptomatic Diabetic Arterial Disease trial, and Aspirin for Asymptomatic Atherosclerosis study) to examine the effect of aspirin in the primary prevention of CVD. All three meta-analyses had generally valid methodology and analysis. Seshasai and colleagues calculated NNT and NNH, and the results of their analysis showed that after a mean follow-up years aspirin reduced total CVD events by 10% (OR 0.90; 95% CI ), with a number needed to treat=120; this was driven primarily with the reduction in nonfatal MI (NNT=162). There was an increased risk of total bleeds and nontrivial bleeds. The odds ratio for nontrivial bleeds was 1.31 (95% CI ) with a NNH of 73. Aspirin use for the primary prevention of cardiovascular events in patients with diabetes Several published meta-analyses have focused on primary prevention of cardiovascular events with aspirin in diabetic patients. The findings of these meta-analyses are consistent despite slightly different designs and sizes. The overall results show that aspirin use is associated with nonsignificant reduction in major cardiovascular events (MACE) and a nonsignificant increase in the risk of major bleeds. Atherosclerotic Cardiovascular Disease (ASCVD) Primary Prevention Guideline 21

22 The most recent of these meta-analyses (Butalia 2011) included 7 trials (N=11,618 patients) that reported on the use of aspirin on the primary prevention of MACE in patients with diabetes. The pooled results showed insignificant benefit of aspirin in reducing MACE, MI, stroke, cardiovascular deaths, or all-cause mortality, and an insignificant increase in bleeding and major bleeds. The authors concluded that the results indicate that for every 10,000 patients treated with aspirin, approximately 109 MACE may be prevented at the expense of 19 major bleeding events with no overall mortality benefit (duration of ASA therapy ranged between studies from 3.6 to 10.1 years). Statin monotherapy There is good evidence from multiple RCTs and meta-analyses of RCTs that statin treatment reduces the risk of major cardiovascular events and cardiovascular mortality even among individuals at low risk. The recent report from the Cholesterol Treatment Trialists (CTT) Collaborators (Mihaylova et al 2012) meta-analysis showed that statins reduced the risk of major vascular events by 21% per 1 mmol/l (38.67 mg/dl) of LDL cholesterol reduction. (RR 0.79; 95% CI ), i.e., it might prevent 11 major cardiovascular events per 1,000 treated patients over 5 years. The analysis showed that the 5 years statin of therapy was associated with a small increased risk of myopathy (excess incidence of 0.5/1,000), and more rarely of rhabdomyolysis (excess incidence of 0.1/1,000). Statin therapy may also be associated with an increased risk of hemorrhagic stroke (excess risk 0.5/1,000 people treated over 5 years; which could be higher in Asian populations) and of diabetes (excess incidence 0.1% per year). A more recent Cochrane review and meta-analysis (Taylor E et al 2013) calculated a NNT with statin of 96 (95% CI ) for all-cause mortality, and 56 (95% CI 46 75) for fatal and nonfatal CHD events over 5 years. Target LDL cholesterol level There is no direct evidence on the optimal target lipid level for primary prevention. Monitoring statin therapy There is no direct evidence to determine the benefits and harms of routine monitoring of LFTs in patients receiving statin therapy, or the optimal management of elevated liver enzymes with statin therapy. Lifestyle modifications Diet There is new good supporting evidence from the PREDIMED trial (Estruch 2013) that adhering to the Mediterranean diet reduced the risk of cardiovascular disease among high-risk adults. The trial randomized 7,447 men and women at high risk of CVD to one of 3 groups: Two groups received advice on Mediterranean diet (Med-Diet) and were provided with either extra virgin olive oil or mixed nuts, and the third group received advice to reduce dietary fat. The primary outcome was a composite of major cardiovascular events, and the secondary outcomes were the components of the primary outcome. Participants were followed up for a median of 4.8 years before the trial was terminated due to the benefits observed with the Med-Diet. During follow-up, participants in the 2 Mediterranean diet groups significantly increased their consumption of extra virgin olive oil and nuts, and increased their weekly servings of fish and legumes. On the other hand, participants in the low-fat diet group did not significantly lower their fat intake. Participants in the latter group started out with a diet that averaged 39% fat, and during the study period they decreased fat intake to just 37%. Thus the study was in fact comparing Mediterranean diet with usual modern diet. The results of the study shows that participants randomized to the 2 Mediterranean diet groups combined had a 30% lower incidence of the composite cardiovascular events versus the controls (NNT 105). This Atherosclerotic Cardiovascular Disease (ASCVD) Primary Prevention Guideline 22

23 was more evident for stroke, most probably due to the reduction in blood pressure (reported reduction in blood pressure at 3 months after randomization). The Mediterranean diet does not have a single dietary pattern but has emphasis on fruits and vegetables, legumes, grains (mostly whole), beans, nuts, seeds, olive oil, fish and seafood, limiting red meat, and eating fish and poultry at least twice a week. Omega-3 fatty acid supplements There is some evidence that fish oil supplementation has no significant benefit in reducing cardiovascular events or mortality among individuals with or without a history of CVD. A recent meta-analysis (Rizos et al 2012) that pooled the results of 20 primary and secondary prevention trials showed no significant benefit on major cardiovascular events or mortality with omega-3 supplementation. Efficacy of omega-3 polyunsaturated fatty acid supplements* Outcomes N studies Weighted event rate % RR Omega 3 Control (95% CI) All-cause mortality % 10.2% 0.96 ( ) Cardiac death % 6.4% 0.91 ( )** Sudden death 7 2.3% 2.6% 0.87 ( ) Myocardial % 3.2% 0.89 ( ) infarction Stroke 9 2.9% 2.8% 1.05 ( ) * Excluding DART 1&2 trials where omega-3 PUFA was provided through diet. ** The authors indicate that this was not significant after correction for multiple comparisons. Fish consumption A meta-analysis of 17 cohort studies with a total of 315,812 participants (Zheng et al 2011) and an average follow-up of 15.9 years (range 6 30 years) showed that fish consumption of at least 1 and no more than 4 servings a week was associated with significantly lower CHD mortality. The results should be interpreted with caution due to the nature of observational studies, method of assessment, variations in patient characteristics, and amounts of fish consumed, source, and method of cooking, as well as other potential confounders. Vitamin E There is evidence from the Physicians Health Study II (PHS II, Sesso et al 2008) a double-blind RCT that evaluated the effect of vitamins C (500 mg daily) and E (400 IU every other day) supplementation on the risk of major cardiovascular events among 14,641 healthy male physicians aged 50 years and older that vitamin E supplementation did not reduce the risk of major cardiovascular events when compared with placebo. However, vitamin E supplementation was associated with a slightly higher incidence of hemorrhagic stroke in middle-aged and older men as compared with placebo. There is also good evidence from several RCTs and meta-analyses that vitamin E supplementation does not lower cardiac event rates in patients with coronary artery disease (GISSI-Prevenzione Investigators Heart Protection Study [HPS] and others). Vitamin C There is good evidence that vitamin C supplementation has no benefit in the primary or secondary prevention of ASCVD (HPS study and PHS II). Atherosclerotic Cardiovascular Disease (ASCVD) Primary Prevention Guideline 23

24 Beta-carotene There is good evidence that supplemental doses of beta-carotene do not improve cardiovascular outcome (HPS study), and that it may be associated with increased cardiovascular deaths and overall mortality (Vivekananthan et al 2003). Folic acid and B vitamins There is evidence from two large, well-conducted, randomized double-blind trials that combination therapy of folic acid, vitamin B6, and vitamin B12 was associated with a significant reduction in plasma homocysteine concentration. The combination did not reduce the risk of major cardiovascular events in patients with vascular disease (Lonn 2005) or after an acute myocardial infarction (Bonaa 2006). There was an observed trend toward more harm associated with the combination therapy. Ebbing and colleagues (2009) pooled data from 2 double-blind vitamin intervention RCTs conducted in Norway (N=6,837) to determine the effects of treatment with B vitamins on cancer and all-cause mortality. The objective of the 2 trials (NORVIT and WENBIT) was to assess whether homocysteine-lowering treatment with folic acid and B12 could improve cardiovascular morbidity and mortality in patients with ischemic heart disease. Patients were followed up for a median of 39 months during treatment and for an additional 38 months after the trial ended (91.6% of the study population participated in the post-trial follow-up). The meta-analysis had some limitations, among which are the lack of data on patients characteristics and cancer risk. It was also assumed that all patients assigned to folic acid treatment also received vitamin B12. The overall results show that treatment with folic acid plus vitamin B12 was associated with increased cancer incidence, cancer mortality, and all-cause mortality. The association with vitamin B6 with cancer incidence and mortality was not significant. Multivitamins There is evidence from the PHS II (Sesso et al 2012) that taking a daily multivitamin does not reduce major cardiovascular events. The trial randomized 14,641 male physicians aged 50 years and older to receive a daily multivitamin or placebo to determine whether long-term multivitamin supplementation would decrease the risk of major cardiovascular events. During a median follow-up of 11.2 years, there were 1,732 confirmed major cardiovascular events and 19% of the participants died. The adjusted hazard ratio for multivitamin use was 1.02 (95% CI ) in those without baseline cardiovascular disease. The trial had valid methodology and analysis, but it included only a highly educated group of predominantly white, healthy, nonsmoking, male physicians, which may limit generalization of the results. Physical activity The Health Professionals Follow-up Study (Chiuve 2006) that followed a cohort of more than 50,000 male health professionals aged years, and free of diseases at baseline, for 16 years showed that the healthy lifestyle score was significantly inversely associated with the risk of CHD. It is to be noted, however, that the study included only male physicians, and follow-up data were obtained from a selfadministered questionnaire, all of which may be potential sources of bias. Atherosclerotic Cardiovascular Disease (ASCVD) Primary Prevention Guideline 24

25 References Bartolucci AA, Tendera M, Howard G. Meta-analysis of multiple primary prevention trials of cardiovascular events using aspirin. Am J Cardiol. 2011;107(12): Bhatt DL, Scheiman J, Abraham NS, Antman EM, et al. ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol. 2008;52: Bonaa KH, Njolstad I, Ueland PM, et al; NORVIT Trial Investigators. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med. 2006;354(15): Butalia S, Leung AA, Ghali WA, Rabi DM. Aspirin effect on the incidence of major adverse cardiovascular events in patients with diabetes mellitus: a systematic review and meta-analysis. Cardiovasc Diabetol. 2011;10:25. Chiuve SE, McCullough ML, Sacks FM, Rimm EB. Healthy lifestyle factors in the primary prevention of coronary heart disease among men: benefits among users and nonusers of lipid-lowering and antihypertensive medications. Circulation. 2006;114(2): Cziraky MJ, Willey VJ, McKenney JM, et al. Risk of hospitalized rhabdomyolysis associated with lipidlowering drugs in a real-world clinical setting. J Clin Lipidol. 2013;7(2): D'Agostino RB Sr, Vasan RS, Pencina MJ,et al. General cardiovascular risk profile for use in primary care: the Framingham Heart Study. Circulation. 2008;117(6): Di Angelantonio E, Gao P, Pennells L, et al for the Emerging Risk Factors Collaboration. Lipid-related markers and cardiovascular disease prediction. JAMA. 2012;307(23): Dormuth CR, Hemmelgarn BR, Paterson JM, et al. Use of high potency statins and rates of admission for acute kidney injury: multicenter, retrospective observational analysis of administrative databases. BMJ. 2013;346:f880. Ebbing M, Bønaa KH, Nygård O, et al. Cancer incidence and mortality after treatment with folic acid and vitamin B12. JAMA. 2009;302(19): Eckel RH, Jakicic JM, Ard JD, et al AHA/ACC Guideline on Lifestyle Management to Reduce Cardiovascular Risk: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation Nov 12. [Epub ahead of print] Estruch R, Ros E, Salas-Salvadó J, et al; PREDIMED Study Investigators. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med. 2013;368(14): Goff DC Jr, Lloyd-Jones DM, Bennett G, et al ACC/AHA Guideline on the Assessment of Cardiovascular Risk: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation Nov 12. [Epub ahead of print] Granger CB, McMurray JJ, Yusuf S, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet. 2003;362(9386): Kaptoge S, Di Angelantonio E, Pennells L, et al for Emerging Risk Factors Collaboration. C-reactive protein, fibrinogen, and cardiovascular disease prediction. N Engl J Med. 2012;367(14): Atherosclerotic Cardiovascular Disease (ASCVD) Primary Prevention Guideline 25

26 Lonn E, Bosch J, Yusuf S, et al for the HOPE and HOPE-TOO Trial Investigators. Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA. 2005;293(11): Mansi I, Frei CR, Pugh MJ, Makris U, Mortensen EM. Statins and musculoskeletal conditions, arthropathies, and injuries. JAMA Intern Med. 2013;173(14):1-10. Mihaylova B, Emberson J, Blackwell L et al for the Cholesterol Treatment Trialists' (CTT) Collaborators. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: metaanalysis of individual data from 27 randomised trials. Lancet. 2012;380(9841): Mikus CR, Boyle LJ, Borengasser SJ, et al. Simvastatin impairs exercise training adaptations. J Am Coll Cardiol. 2013;62(8): Epub 2013 Apr 10. Naci H, Brugts J, Ades T. Comparative tolerability and harms of individual statins: a study-level network meta-analysis of 246,955 participants from 135 randomized, controlled trials. Circ Cardiovasc Qual Outcomes. 2013;6(4): Parker BA, Capizzi JA, Grimaldi AS, et al. Effect of statins on skeletal muscle function. Circulation. 2013;127(1): Epub 2012 Nov 26. Raju N, Sobieraj-Teague M, Hirsh J, O'Donnell M, Eikelboom J. Effect of aspirin on mortality in the primary prevention of cardiovascular disease. Am J Med. 2011;124(7): Richardson K, Schoen M, French B, et al. Statins and cognitive function: a systematic review. Ann Intern Med. 2013;159(10): Rizos EC, Ntzani EE, Bika E, Kostapanos MS, Elisaf MS. Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis. JAMA. 2012;308(10): Sarwar N, Danesh J, Eiriksdottir G, et al. Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 Western prospective studies. Circulation. 2007;115(4): Sathasivam S. Statin induced myotoxicity. Eur J Intern Med. 2012;23(4): Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. 2010;375(9716): Seshasai SR, Wijesuriya S, Sivakumaran R, et al. Effect of aspirin on vascular and nonvascular outcomes: meta-analysis of randomized controlled trials. Arch Intern Med. 2012;172(3): Sesso HD, Buring, JE, Christen, WG, et al. Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians Health Study II randomized controlled trial. JAMA. 2008;300(18): Sesso HD, Christen WG, Bubes V, et al. Multivitamins in the prevention of cardiovascular disease in men: the Physicians' Health Study II randomized controlled trial. JAMA. 2012;308(17): Stone NJ, Robinson J, Lichtenstein AH, et al ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation Nov 12. [Epub ahead of print] Taylor F, Huffman MD, Macedo AF, Moore TH, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2013;1:CD doi: / cd pub5. Atherosclerotic Cardiovascular Disease (ASCVD) Primary Prevention Guideline 26

27 U.S. Food and Drug Administration. FDA Drug Safety Communication: Important safety label changes to cholesterol-lowering statin drugs. Announced February Last updated July Accessed July U.S. Food and Drug Administration. FDA Drug Safety Communication: New restrictions, contraindications, and dose limitations for Zocor (simvastatin) to reduce the risk of muscle injury. Announced June Last updated December Accessed July U.S. Preventive Services Task Force. Screening for lipid disorders in adults: U.S. Preventive Services Task Force recommendation statement. Rockville (MD): Agency for Healthcare Research and Quality (AHRQ); June Vivekananthan DP, Penn MS, Sapp SK, Hsu A, Topol EJ. Use of antioxidant vitamins for the prevention of cardiovascular heart disease: meta-analysis of randomised trials. Lancet. 2003;361(9374): Zheng J, Huang T, Yu Y, Hu X, Yang B, Li D. Fish consumption and CHD mortality: an updated metaanalysis of seventeen cohort studies. Public Health Nutr. 2012;15(4): Atherosclerotic Cardiovascular Disease (ASCVD) Primary Prevention Guideline 27

28 Guideline Development Process and Team Development process Group Health developed the ASCVD Primary Prevention Guideline using an evidence-based process, including systematic literature search, critical appraisal, and evidence synthesis. For details, see Evidence Summary and References. This edition of the guideline was approved for publication by the Guideline Oversight Group in January Team The ASCVD Primary Prevention Guideline development team included representatives from the following specialties: cardiology, family medicine, nursing, nutritional services, pharmacy, clinical laboratory. Clinician lead: Chris Thayer, MD, Medical Director, Clinical Knowledge Support, Guideline coordinator: Avra Cohen, MN, Clinical Improvement & Prevention, Chris Amante, Clinical Publications, Clinical Improvement & Prevention Jodi Augustine, RD, Nutritional Services Paul Brock, RPh, Pharmacy Administration Alan Golston, MD, Cardiology Scott Haugen, MD, Cardiology Sarah Matthews, DNP, ARNP, Nursing Operations Chuck McQuinn, MD, Vascular Surgery Lisa Nguyen, PharmD, BCPS, Pharmacy Administration Kathryn Ramos, Patient Health Education Resources, Clinical Improvement & Prevention Art Resnick, MD, Cardiology Kim Riddell, MD, Clinical Lab Nadia Salama, MD, PhD, Epidemiologist, Clinical Improvement & Prevention Kevin Touney, MD, Family Medicine Disclosure of conflict of interest Group Health Cooperative requires that team members participating on a guideline team disclose and resolve all potential conflicts of interest that arise from financial relationships between a guideline team member or guideline team member's spouse or partner and any commercial interests or proprietary entity that provides or produces health care related products and/or services relevant to the content of the guideline. Team members listed above have disclosed that their participation on the ASCVD Primary Prevention Guideline team includes no promotion of any commercial products or services, and that they have no relationships with commercial entities to report. Atherosclerotic Cardiovascular Disease (ASCVD) Primary Prevention Guideline 28

29 Appendix 1: Q&A on Group Health Recommendations vs. ACC/AHA Recommendations By Art Resnick, MD Cardiology, Capitol Hill Campus, Seattle Wouldn t you know it right as we d finalized the latest revised version of Group Health s ASCVD prevention guidelines, the announcement of the new ACC/AHA cholesterol guideline exploded with the sort of media circus usually reserved for Kardashians (or possibly Sarkisians). This was the first full national guideline update since the original 2001 ATP3 report, and the first with a solid evidence-based format. It has a lot in common with the Group Health guidelines, and quite a few differences. Even if we won t make any local headlines, this seems like a good opportunity to highlight the issues raised by the Group Health guidelines and the ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults. ACC/AHA switched to high-intensity statin Rx for all secondary prevention, and then threw out the whole concept of LDL targets in their guideline. Group Health kept the targets in. Is there new evidence that explains the difference? Sorry to break the news, but there s never been any evidence that treating to a target was useful. The targets have been a construct and not evidence based from the start, and they have differed in the United States and elsewhere (where SI molar units make a target of 100 mg/dl into an odd number). There s never been an RCT that treated to a target (including the Treating to New Targets trial!). All the trials simply compared a potent high-dose statin with something less potent, or with the same statin at a lower dose. Throwing out targets and substituting put almost everybody on 80 mg atorvastatin as in the new ACC/AHA guideline does make some sense, but it leaves you with a different set of conundrums especially if you require an evidence basis for your practice decisions, as we prefer to do. What are we to do with the coronary patient with a low baseline LDL (say, <70), or the vascular patient with an LDL of 80 prior to therapy, and potentially interacting drugs (such as diltiazem or amlodipine)? These situations are not uncommon in the treated population, and using high-dose atorvastatin is likely to reduce LDL to very low levels. We certainly don t have any large-scale RCTs of patients like this, so we have reason to be worried about high-dose statins or on-treatment LDLs of 25, which are the inevitable result of the one-size-fits-all strategy. Although the ACC/AHA guideline includes 40 mg atorvastatin as an option for secondary prevention, only one trial (IDEAL) used this as an option for patients with LDL <39, and this applied to only 13% of the high-dose treated patients in that trial, hardly a robust evidence basis for concluding that this is an equivalent dose to 80 mg in terms of outcomes. Even the ACC bows to the reality of sensible management at the expense of a truly evidence-based strategy here. So, if there is a problem with using a fixed maximal dose, and no evidence basis for the targets, why did we keep the targets? Lesser of two evils? Well, first, we ve never slavishly adhered to the targets in the Group Health guideline, and we have consistently emphasized that the goals mattered only if you achieved them with statins alone. We have avoided the widespread use of secondary agents (ezetimibe, in particular) that s been seen elsewhere with no evidence basis whatsoever that it improved outcomes. Still, we felt that the targets were an important measure for our patients. They approximated what was demonstrated to be beneficial in the randomized trials (i.e., the 3 high-dose atorvastatin trials achieved on-treatment LDLs between 68 and 78), and they would usually result in high-dose statin being prescribed in patients with average to slightly lower-than-average baseline LDLs. At Group Health, we didn t have the problem of excessive add-on therapy motivated by the LDL targets which is what motivated the ACC/AHA guideline writers to eliminate the targets. Atherosclerotic Cardiovascular Disease (ASCVD) Primary Prevention Guideline 29

30 Furthermore, the targets to some degree reinforce regular follow-up of lipids, which is still an important part of the ACC/AHA guideline and sensible clinical care. (Also, HEDIS hasn t quit requiring the attainment of LDL targets as a quality metric.) If there is a take-home message to be gleaned from the ACC/AHA guideline, it is that at Group Health, we often don t push statin dosing high enough in many secondary-prevention patients, and instead satisfy ourselves with an LDL just barely below 100 on a lower-dose statin. And that s a strategy that is not supported by the clinical trials evidence. This is particularly true as we gain a better appreciation of the inaccuracy of the LDL measurements in our labs using the Friedewald calculation (an industry standard), which tends to underestimate actual LDL, particularly in patients with triglycerides over about 150. If we are systematically underestimating LDL, we particularly don t want to be cutting back on statin dosing unless the LDL is well below our target thresholds. So, we shouldn t fear pushing the atorvastatin dose to 80 mg in most secondary-prevention patients under age 75, who have ontreatment LDLs >40. And achieving a target LDL <70 in a patient getting low- to moderate-intensity statin (i.e., something less potent than atorva 40 mg) does not mean you ve prescribed adequate statin therapy. At the same time, we probably don t need to be sending out the guideline police if your patient has an LDL in the 50s on 20 mg of pravastatin or some similarly low-potency regimen. The ACC/AHA guideline suggests an alternative approach of using a 50% reduction in baseline LDL, rather than using a target. Should we try that? We did try that, in the 1990s, and it proved impractical. We had far too many patients who simply didn t have a baseline LDL in any available database. Furthermore, no trials have ever used a percentage reduction in LDL to target therapy, so it doesn t really satisfy our need to apply an evidence-based approach. What should be the threshold for primary prevention of coronary disease with statin Rx? The new ACC/AHA guideline suggests a 7.5% 10-year risk level, which seems far below the Group Health recommendation to treat patients with a 10% 5-year risk, with consideration to treat in the 5 10% range after appropriate shared decision making. The differences are not as large as they seem. First, the ACC/AHA calculator uses only hard end points, such as nonfatal MI, stroke, and cardiac death. The Group Health calculator includes unstable angina and bypass surgery/pci as undesirable end points to be prevented, if possible, with therapy. So, the Group Health calculator comes up with a result about twice as high as the ACC/AHA calculator. As the critics have pointed out in their tirades regarding the statinization of America, both calculators suggest treating a very large proportion of the population in their 60s and 70s, even without elevated LDL. Still, in an evidence-based world, the trial basis for this recommendation is fairly strong JUPITER showed a benefit of statin treatment in reducing major cardiovascular-event rates in a population with a total cardiac event rate of 1.36% per year, and AFCAPS/TexCAPS reported the same in 1998 in a low- HDL, primary-prevention population with a 5.4% event rate over 5 years. Meta-analysis in primaryprevention trials now confirms a mortality benefit for statin therapy compared with placebo, and outcomes appear the same in both men and women. So, it s settled, then, all our patients at that level of risk need a statin? No, it s never settled. Primary prevention of CHD with statins is a prime topic for shared decision making (a point which the ACC/AHA guideline finally stepped up and strongly recommended). Although the evidence basis is fairly robust in terms of risk reduction in the randomized trials, the reality is that nobody s ever done a trial that used a risk calculator in its entry criteria they ve used either very high LDL (WOSCOPS) or reduced HDL (AFCAPS/TexCAPS), or a combination of risk factors including elevated CRP (JUPITER). Not all patients (or their physicians!!) will favorably view treating almost everybody in their 60s with a statin, regardless of whether they have an elevated LDL or not. Furthermore, there remain concerns (blown up in the popular press, but real nevertheless) about underreporting of statin side effects. In Atherosclerotic Cardiovascular Disease (ASCVD) Primary Prevention Guideline 30

31 particular, the clinical mega-trials haven t focused on quality of life as an end point, and smaller studies have reported adverse outcomes for fatigue and energy in statin-naïve patients randomized to statins compared with placebo. The larger trials (HPS, TNT, IDEAL) used statin-tolerance run-in periods or excluded statin-intolerant patients those patients who couldn t tolerate a statin for a month weren t even randomized into the trials. So perhaps it s not surprising that our real-world clinical experience with statin intolerance doesn t match that seen in these trials. Still, in patients who tolerate statins for a month, we don t see any differences at all in major morbidity or organ injury between statin- and placebo-treated patients, or any significant difference in frequency of myalgia, memory difficulty, or other nuisance side effects. What about the ACC/AHA risk calculator controversy? Does the new calculator grossly overestimate risk? There will be endless arguments here, but the data is mixed. If, for example, you plug in a typical JUPITER patient (BP 134/80, TC/HDL=186/49, nonsmoker, nondiabetic) into the Group Health (another Framingham-based) calculator, you get a projected yearly risk of 1.36% (adjusted for a population that was 38% female). This is frighteningly close to the actual value seen in the trial, though it doesn t account for the fact that all the JUPITER patients had elevated CRP. (It also doesn t account for the fact that clinical trial patients often are healthier in unmeasurable ways compared with the general population.) Not all databases perform this way when subjected to similar calculations, and literally hundreds of calculators have been proposed, some including family history (like ours) or CRP (which we suggest using as a tie-breaker in cases of uncertainty, and is included in the Reynolds calculator directly). The important point is that these calculators are really risk estimators and should serve as a starting point for a discussion. Actual risk is going to be affected by many other factors (how long has a patient been diabetic or hypertensive; is family history completely negative, or really borderline positive at a slightly older age; what s the fitness level/sedentariness; remote cigarette use; glucose intolerance, etc). In the end, the Group Health guideline team decided to stick with the prior recommendation, based on data that we ve had since the last millennium, to discuss treatment options in patients with risks in the 5 10%/5-year range and to recommend treatment for patients in the 10%/5-year range. So, which statin therapy for primary prevention? High intensity or moderate intensity? The ACC/AHA suggests high-intensity statin therapy for everybody with a Group Health calculated risk equivalent >1.5%/yr (or ~7.5%/5yr). There is no actual evidence basis for this, unlike the evidence basis in secondary prevention, and the Group Health guideline team does not share the ACC/AHA enthusiasm for the aggressive approach. There are too many unknowns with respect to the uncertainty of adverse events to be certain that a high-intensity approach is better. If the patient places a high value on prevention and is willing to take a small risk of adverse effects, which may not yet be fully enumerated (this despite the fact that statins are the best-studied drugs in the history of the planets, including Earth, SATURN and JUPITER) high-intensity statin therapy is a reasonable (and reasonably inexpensive) option. Doses should take comorbidities, drug interactions, and patient preferences into account. Any further take-away lessons from the ACC/AHA guideline that I should attend to, that aren t part of the Group Health guideline? Treating 21-year-olds with LDL 190 might be reasonable, but it s certainly not evidence based, as it is made out to be in the ACC/AHA guideline. Though lifetime risk of ASCVD will be high, short-term risk is very low to negligible. The lifetime risk concept is discussed early on in the guideline, and generally (for LDL <190) relegated to the not-evidence-based, so we can t say anything about it category. But ACC/AHA apparently couldn t help themselves for the extremes of LDL elevation. The Group Health view is that this is actually pretty reasonable given the markedly increased lifetime CAD risk, but it s definitely a matter for shared decision making. Unfortunately, at this point it s unlikely to ever be subject to controlled clinical trials, and we ll certainly never have a trial that compares starting Rx at 20 versus 30 versus 40 years of age. Many of these patients will be motivated to start treatment early, particularly with a family history of early coronary events. On the other hand, treatment can be delayed until the patient is Atherosclerotic Cardiovascular Disease (ASCVD) Primary Prevention Guideline 31

32 prepared to make an informed decision, which is often well after the age of 21. Use of the risk calculator, which looks at short-term clinical risk, is probably inappropriate to inform decision making at the extremes of LDL elevation. The ACC/AHA guideline makes a particular point that secondary-prevention recommendations apply to patients with clinical CAD, i.e., angina, MI, revascularization. The Group Health guideline isn t so specific. If a patient with LV dysfunction, no prior MI, and no angina has severe three-vessel disease that can t be revascularized, he/she won t meet the ACC/AHA definition. That really makes very little sense to us. But we all agree that patients with mild coronary atherosclerosis (as assessed by CT scan or other angiographic study) won t be included with the secondary-prevention patients. Atherosclerotic Cardiovascular Disease (ASCVD) Primary Prevention Guideline 32

33 Appendix 2: Questions Asked in Customized CVD Risk Calculator The Group Health customized CVD risk calculator asks the following questions: What is your age? What is your gender? Do you have heart disease or cardiovascular disease? This includes being diagnosed with angina, a heart attack, a stroke, a mini-stroke (TIA), or peripheral artery disease (PAD). Did your father or a brother have heart disease before the age of 55? Did your mother or sister have heart disease before the age of 60? What were the results of your most recent cholesterol test? o Total cholesterol o HDL cholesterol What is your blood pressure? Do you take medicine for high blood pressure? Do you have diabetes? Do you smoke? Answer "yes" if you've had a cigarette in the last month. The calculator is available at Atherosclerotic Cardiovascular Disease (ASCVD) Primary Prevention Guideline 33