Cardiovascular Risk in Patients with Diabetes

Transcription

1 PL Detail-Document # This PL Detail-Document gives subscribers additional insight related to the Recommendations published in PHARMACIST S LETTER / PRESCRIBER S LETTER May 2011 Cardiovascular Risk in Patients with Diabetes Background Decisions regarding interventions to reduce cardiovascular events (e.g., starting a statin or aspirin) are based on patient cardiovascular event risk. For example, U.S. guidelines categorize patients with coronary heart disease (CHD) or a 10-year event risk over 20% as being at high risk of an event. In these high-risk patients, a goal LDL of less than 100 mg/dl (2.6 mmol/l) is recommended. 1 And in patients considered to be very high risk an LDL goal less than 70 mg/dl is an option. 2 Similarly, Canadian Cardiovascular Society guidelines set the LDL to under 2 mmol/l (77 mg/dl) for patients with CHD or a 10-year event risk of 20% or higher. 3 U.S. and Canadian guidelines also recommend that most patients with type 2 diabetes should be managed as though they have CHD. 1,3 However, this categorization may not be warranted in all patients with diabetes. This article presents information to help clarify which patients with diabetes should receive interventions aimed at primary prevention of cardiovascular events. Pathophysiology High blood glucose alone is not sufficient to raise cardiovascular event risk to that of a patient with CHD. 1 Indeed, tight glycemic control has not been proven to significantly reduce cardiovascular event risk. 4 However, patients with type 2 diabetes have other metabolic abnormalities (e.g., dyslipidemia, insulin resistance, hypertension, prothrombotic and proinflammatory state) that together with hyperglycemia convey a higher risk. Although patients with type 1 diabetes do have increased risk of CHD, these patients are not assumed to have CHD risk equivalent. Most data suggesting that diabetes is a CHD risk equivalent come from patients with type 2 diabetes. 1 Rationale for Diabetes as CHD Equivalent Treating diabetes as a coronary heart disease equivalent was first suggested over ten years ago. 5 Population studies (e.g., Organization to Assess Strategies for Ischemic Syndromes [OASIS]), as well as major clinical trials (e.g., United Kingdom Prospective Diabetes Study [UKPDS], Heart Outcomes Prevention Evaluation [HOPE]) have shown that cardiovascular event risk in patients with type 2 diabetes is similar to that of people with CHD who do not have diabetes. Furthermore, people with diabetes who develop CHD have a worse prognosis than CHD patients without diabetes. People with diabetes also have a higher mortality rate than nondiabetics if they do suffer an event. In one study, 45% of men with diabetes died within one year after a heart attack. In addition, statins reduced CHD events in patients with diabetes (with and without CHD) in the AFCAPS/TexCAPS, 4S, and LIPID studies. These data suggest aggressive primary and secondary prevention strategies are warranted in patients with type 2 diabetes. 1 Fine-Tuning Risk in Patients with Diabetes Young patients with diabetes and few other risk factors may not have a high 10-year Framingham Risk Score. In fact, in UKPDS, the 10-year risk of hard CHD (heart attack or CHD death) was only 15% to 20%. The patients in UKPDS had newly diagnosed diabetes and were not as obese as most persons with diabetes in the U.S. But among the participants with BMI over 30 kg/m 2, 10-year risk was over 20%. This information suggests that patients with diabetes are not uniform in regard to cardiovascular event risk. However, most patients with diabetes will hit a 10-year risk of over 20% by the time they reach In the Strong Heart study, a cohort of over 4000 Native Americans, only those patients with diabetes who had multiple risk factors had an event risk equivalent to CHD patients. However, most of the participants did have a 10-year risk over 20%. 6 So they would still be categorized and treated as high-risk patients per current lipid guidelines. 1,3 Copyright 2011 by Therapeutic Research Center P.O. Box 8190, Stockton, CA ~ Phone: ~ Fax: ~ ~

2 In a cohort of over 4000 men 60 to 79 years of age, those diagnosed with diabetes before age 60 with a mean diabetes duration of 16.7 years had a cardiovascular event risk similar to patients with a history of a heart attack. But men with a diabetes diagnosis at age 60 or older and a mean diabetes duration of about five years had only half the risk. This study suggests that diabetes duration is an important determinant of risk. 7 Clinical Decision-Making Categorizing all patients with diabetes as high risk simplifies prescribing. But this assumption means that in some patients risk (e.g., statin myopathy, aspirin-associated bleeding) will outweigh benefit. Consider individualizing therapy in young patients with diabetes and/or patients newly diagnosed with diabetes [Evidence level B; clinical cohort study]. 6 As stated previously, U.S. guidelines recommend a goal LDL of less than 100 mg/dl for most patients with diabetes. But in young patients with diabetes and no additional risk factors, consideration can be given to waiting to start lipid-lowering medications until LDL reaches 130 mg/dl [Evidence level C; consensus]. 1 Canadian guidelines recommend an LDL under 2 mmol/l for men over 45 years old with diabetes, women over 50 years old with diabetes, and younger patients with diabetes and additional risk factors. 3 Patients with a 10-year risk of over 20% per Framingham (Canada: 20% or higher per Framingham or Reynolds Risk Score) should also be treated the same as CHD patients. 1,3 Daily aspirin 81 to 325 mg is recommended for secondary prevention of cardiovascular events in patients with diabetes. 8,9 The Canadian guidelines continue to recommend daily aspirin 81 to 325 mg for primary prevention in patients with diabetes based on individual clinical judgment. 9 New U.S. recommendations for aspirin use for primary prevention in patients with diabetes is based on 10-year event risk. Aspirin 81 to 162 mg daily is reasonable in patients with diabetes who have a 10-year event risk over 10% without bleeding risk (e.g., peptic ulcer disease, previous GI bleed, NSAID use, warfarin use). This will include the following patients with diabetes: most men over 50 and women over 60 with at least one additional CV risk factor (i.e., smoking, hypertension, dyslipidemia, family history of premature heart disease, albuminuria). (PL Detail-Document #270516: Page 2 of 3) Low-dose aspirin can also be considered for patients with a 10-year risk of 5% to 10%. Consider using a risk calculator designed for patients with diabetes to clarify event risk [Evidence level C; consensus]: 10 UKPDS Risk Engine Atherosclerosis Risk in Communities [ARIC] American Diabetes Association [ADA] Risk Assessment Tool Canadian Diabetes Association tool for identifying diabetes patients at high risk for a vascular event The use of risk calculators has not been shown to alter clinical outcomes, but it can help with prescribing. Because age is a strong risk determinant, calculators can underestimate risk in young patients and can misidentify elderly patients as targets for pharmacotherapy. Also keep in mind that the elderly were underrepresented in the cohorts from which the calculators were derived. Clinical judgment is therefore important in using the results of the calculators. 11 Another intervention to reduce cardiovascular event risk in patients with diabetes is blood pressure control. Current guidelines recommend a goal of <130/80 mmhg in diabetes patients. 12,13 But the recent ACCORD blood pressure study suggests that an average systolic blood pressure of about 119 mmhg doesn t reduce overall cardiovascular outcomes compared to an average systolic blood pressure of about 133 mmhg [Evidence level A; high-quality RCT]. 14 However, this lower blood pressure was associated with a reduced risk of stroke and macroalbuminuria. 14 Conclusion In the U.S., new JNC 8 hypertension and NCEP IV cholesterol guidelines will be out later this year. Look for them to provide more guidance for individualizing treatment decisions to reduce cardiovascular event risk in patients with diabetes. Copyright 2011 by Therapeutic Research Center P.O. Box 8190, Stockton, CA ~ Phone: ~ Fax: ~ ~

3 (PL Detail-Document #270516: Page 3 of 3) Users of this PL Detail-Document are cautioned to use their own professional judgment and consult any other necessary or appropriate sources prior to making clinical judgments based on the content of this document. Our editors have researched the information with input from experts, government agencies, and national organizations. Information and internet links in this article were current as of the date of publication. Levels of Evidence In accordance with the trend towards Evidence-Based Medicine, we are citing the LEVEL OF EVIDENCE for the statements we publish. Level Definition A High-quality randomized controlled trial (RCT) High-quality meta-analysis (quantitative systematic review) B Nonrandomized clinical trial Nonquantitative systematic review Lower quality RCT Clinical cohort study Case-control study Historical control Epidemiologic study C Consensus Expert opinion D Anecdotal evidence In vitro or animal study Adapted from Siwek J, et al. How to write an evidence-based clinical review article. Am Fam Physician 2002;65: Project Leader in preparation of this PL Detail- Document: Melanie Cupp, Pharm.D., BCPS References 1. National Cholesterol Education Program. Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Final Report. September full.pdf. (Accessed April 6, 2011). 2. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110: Genest J, McPherson R, Frohlich J, et al Canadian Cardiovascular Society/Canadian guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease in the adult-2009 recommendations. Can J Cardiol 2009;25: National Institutes of Health. Press release. June 6, ACCORD clinical trial publishes results. srelease.aspx?id=2573. (Accessed April 13, 2011). 5. Haffner SM, Lehto S, Ronnemaa T, et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998;339: Howard BV, Best LG, Galloway JM, et al. Coronary heart disease risk equivalence in diabetes depends on concomitant risk factors. Diabetes Care 2006;29: Wannamethee SG, Shaper AG, Whincup PH, et al. Impact of diabetes on cardiovascular disease risk and all-cause mortality in older men: influence of age at onset, diabetes duration, and established and novel risk factors. Arch Intern Med 2011;171: Colwell JA, American Diabetes Association. Aspirin therapy in diabetes. Diabetes Care 2004;27(Suppl 1):S Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Vascular protection in people with diabetes. Can J Diabetes 2008;32(Suppl 1):S Pignone M, Alberts MJ, Colwell JA, et al. Aspirin for primary prevention of cardiovascular events in people with diabetes: a position statement of the American Diabetes Association, a scientific statement of the American Heart Association, and an expert consensus document of the American College of Cardiology Foundation. Circulation 2010;121: PL Detail-Document, Common Cardiovascular Risk Calculators. Pharmacist's Letter/Prescriber's Letter. November American Diabetes Association. Standards of medical care in diabetes Diabetes Care 2011;34(Suppl 1):S Canadian Diabetes Association 2008 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes 2008;32(Supp 1):S1-S ACCORD Study Group, Cushman WC, Evans GW, et al. Effects of intensive blood pressure control in type 2 diabetes mellitus. N Engl J Med 2010;362: Cite this document as follows: PL Detail-Document, Cardiovascular Risk in Patients with Diabetes. Pharmacist s Letter/Prescriber s Letter. May Evidence and Recommendations You Can Trust 3120 West March Lane, P.O. Box 8190, Stockton, CA ~ TEL (209) ~ FAX (209) Copyright 2011 by Therapeutic Research Center Subscribers to the Letter can get Detail-Documents, like this one, on any topic covered in any issue by going to or

4 PL Detail-Document # This PL Detail-Document gives subscribers additional insight related to the Recommendations published in PHARMACIST S LETTER / PRESCRIBER S LETTER January 2014 Common Cardiovascular Risk Calculators Risk calculators are used to target therapies toward patients who will get the most benefit from them. They can also help spare low-risk patients from adverse effects and costs of unnecessary therapy. 1 The American Heart Association states that adults 40 to 79 years of age should generally have their heart disease risk calculated every four to six years. 2,16 Risk influences decisions to institute primary prevention interventions such as daily low-dose aspirin and statins. 2,3 Use of risk calculators has not been shown to alter clinical outcomes, but it can improve prescribing and motivate patients. You can show the benefits of the lifestyle changes and drug therapies you re recommending. Consider presenting risk as percentages as well as numbers of persons per 1000 over a specific time period; some patients comprehend numbers per 1000 better. 4 Risk calculators are better at predicting events than just counting risk factors, 5 but they have limitations. For example, because age is a strong risk determinant, calculators may underestimate risk in young patients. 4,11,12 To the other extreme, risk calculators can misidentify elderly patients as targets for aggressive pharmacotherapy. 12 Most calculators can be used in older individuals, but keep in mind that those 65 years and older may have been underrepresented in the cohorts from which the calculators were derived. 13 Clinical judgment is therefore especially important in making treatment decisions in the elderly. 12 In addition, some calculators are more or less appropriate for certain populations than others (e.g., patients with diabetes). The following chart provides links to several risk calculators for North Americans, and provides information to help you choose the most appropriate calculator for a given patient. Calculator/Assessment Tools ASCVD Risk Estimator Plus A list of websites with cardiovascular risk cal culator apps for smartphones follows this chart Comments Incorporates the original ASCVD Risk Estimator plus the 2016 Million Hearts Longitudinal ASCVD Risk Assessment Tool and new guideline recommendations. 17 Maintains the core functionality of the original ASCVD Risk Calculator; users can still calculate the patient s 10-year ASCVD risk and get guideline-based recommendations for statin therapy. Can be used to project the benefit of specific risk-lowering interventions (statins, antihypertensives, aspirin, etc), and update and track change in risk over time based on the patient's actual response to interventions. Provides recommendations from multiple ACC/AHA guidelines (e.g., blood pressure, lifestyle, etc). Initial 10-year ASCVD risk is calculated via the Pooled Cohort Equation. The updated 10-year ASCVD risk at follow-up visits and projected 10 -year ASCVD risk values are derived from the 2016 Million Hearts Longitudinal Risk Assessment Tool. Therapy advice is derived from ACC/AHA guidelines regarding cholesterol, lifestyle, and high blood pressure, and is supplemented by the Million Hearts Longitudinal Risk Assessment User Guide.

5 (PL Detail-Document #300102: Page 2 of 6) Calculator/Assessment Tools 2013 Pooled Cohort Equations Cardiovascular Risk Calculator (ASCVD Risk Calculator) (See the updated version of this calculator above [ASCVD Risk Estimator Plus].) Comments Part of the 2013 ACC/AHA cholesterol guidelines to determine the need for statin therapy. 15 Calculates 10-year risk of atherosclerotic cardiovascular disease (myocardial infarction or stroke). Based on data from men (white and African American) and women, with or without diabetes, 40 to 79 years of age. To determine need for statin therapy, use for primary prevention only, for patients ages 40 to 75 with LDL 70 to 189 mg/dl (1.8 to 4.9 mmol/l). Individuals with LDL 190 mg/dl (5 mmol/l) or established heart disease already qualify for statin therapy. 16 Estimates lifetime risk of atherosclerotic cardiovascular disease in individuals 20 to 59 years of age. 15 May underestimate lifetime risk. 15 May overestimate risk (Mexican Americans, Asian Americans of East Asian ancestry) or underestimate risk (American Indians, Puerto Ricans, Asian Americans of South Asian ancestry). Not intended for use with statin-treated cholesterol. (If used with patients already on a statin, use pretreatment cholesterol value.) Replaces Framingham risk assessment. Framingham Coronary Heart Disease 10-year Risk Calculates 10-year risk of coronary heart disease. Based on data from whites 30 to 74 years of age without heart disease. Also validated in African Americans and Hispanic women. May over- or underestimate risk in other ethnic groups. 7 Less precise in patients under 30 or over 65 years of age, and in patients with diabetes, severe hypertension, or left ventricular hypertrophy. 5 Framingham General Cardiovascular Disease 10-year Risk Calculates 10-year risk of cardiovascular disease (i.e., coronary death, myocardial infarction, coronary insufficiency, angina, ischemic stroke, transient ischemic attack, peripheral artery disease, heart failure). Based on data from predominantly whites 30 to 74 years of age without CVD at baseline. 14 Separate calculators for men and women.

6 (PL Detail-Document #300102: Page 3 of 6) Calculator/Assessment Tools National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) risk assessment tool based on Framingham Heart Study Reynolds Risk score American Diabetes Association s Diabetes My Health Advisor risk assessment tool S.html?loc=dorg-mha Comments Calculates 10-year risk for myocardial infarction and coronary death. For adults 20 years and older without heart disease or diabetes. Not recommended for patients with diabetes because ATP III considered diabetes a coronary disease equivalent. 5 However, current thinking is that not all patients with diabetes are high-risk. 6 Omits family history. Classifies 15% of adults into different risk groups than Framingham (10% higher risk, 5% lower risk). 8 Calculates 10-year risk of heart attack, stroke, or other major heart disease. For healthy patients without diabetes 45 to 80 years of age. Separate calculators for women and men. Based on data from Women s Health Study and Physicians Health Study II. 1 Includes family history and hs-crp. Reclassifies 30% of intermediate risk women and 20.2% of intermediate risk men into lower or higher risk categories vs Framingham. 1 Not validated in Canadian population. 9 Calculates 10-year risk of heart attack or stroke and 8-year risk of diabetes. Also calculates risk of diabetes complications. 10 Can be used for people with or without diabetes. Can be used for people with or without cardiovascular disease. Patients can use on their own. Designed to show how changes in lifestyle or medication can affect risk. Good choice if contemplating aspirin for primary prevention in patients with diabetes. 6 ARIC CHD Risk Calculator RC1.html Calculates 10-year risk of heart attack or coronary heart disease risk in adults. Can be used for people with or without diabetes. For people 45 to 65 years of age. Good choice if contemplating aspirin for primary prevention in patients with diabetes. 6

7 (PL Detail-Document #300102: Page 4 of 6) Calculator/Assessment Tools UKPDS Risk Engine Diabetes Canada tool for identifying diabetes patients who require vascular protective medication Comments Based on data from the UK Prospective Diabetes Study. For patients with diabetes without known heart disease. Calculates 10-year risk estimates for fatal and nonfatal coronary heart disease, fatal coronary heart disease, fatal and nonfatal stroke, and fatal stroke. Good choice if contemplating aspirin for primary prevention in patients with diabetes. 6 For patients with diabetes. Not a quantitative tool; identifies high-risk patients for whom certain pharmacologic interventions are recommended (e.g., ACEI, ARB, statin). n/riskassessment McGill Cardiovascular Health Improvement Program for assessing a patient s Cardiovascular Age (Canada) Use to explain the patient s cardiovascular risk to them and how it can be improved. Can be used to show patients how risk improves with treatment. Some Cardiovascular Risk Calculator Apps for Smartphones Statcoder ( provides 2013 Pooled Cohort Equations CV Risk Calculator, ATP III, Framingham, and Reynolds for iphone, ipod Touch, and ipad (free). Calculate ( includes Framingham and Reynolds for iphone, ipod Touch, ipad, Blackberry, and Android (free). Archimedes 360 ( provides over 200 medical calculators including Framingham and ATP III for iphone, ipod Touch, ipad, Blackberry, Android, and Windows Mobile Smartphone (less than $25) Pooled Cohort Equations CV Risk Calculator ( for iphone, ipod Touch, ipad (free). ClinCalc ( includes a number of online calculators, as well as 2013 Pooled Cohort Equations CV Risk Calculator for iphone/ipad and Android (free). ScyMed ( has 2013 Pooled Cohort Equations CV Risk Calculator for Android ($1.00).

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9 (PL Detail-Document #300102: Page 6 of 6) Users of this PL Detail-Document are cautioned to use their own professional judgment and consult any other necessary or appropriate sources prior to making clinical judgments based on the content of this document. Our editors have researched the information with input from experts, government agencies, and national organizations. Information and internet links in this article were current as of the date of publication. Project Leader in preparation of this PL Detail- Document: Melanie Cupp, Pharm.D., BCPS (Original November 2010); Stacy A. Hester, R.Ph., BCPS, Assistant Editor (January 2014 update); last modified May References 1. Sisson E, Van Tassell BW. Dyslipidemias: updates and new controversies. In: Richardson M, Chant C, Cheng JWM, et al., editors. Pharmacotherapy selfassessment program, 7 th ed. Cardiology. Lenexa, KS: American College of Clinical Pharmacy; p Pearson TA, Blair SN, Daniels SR, et al. American Heart Association Science Advisory and Coordinating Committee. AHA guidelines for primary prevention of cardiovascular disease and stroke: 2002 update: consensus panel guide to comprehensive risk reduction for adult patients without coronary or other atherosclerotic vascular diseases. Circulation 2002;106: National Cholesterol Education Program. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Final Report. September ll.pdf. (Accessed December 3, 2013). 4. Viera AJ, Sheridan SL. Global risk of coronary heart disease: assessment and application. Am Fam Physician 2010;82: Sheridan S, Pignone M, Mulrow C. Framinghambased tools to calculate the global risk of coronary heart disease: a systematic review of tools for clinicians. J Gen Intern Med 2003;18: Pignone M, Alberts MJ, Colwell JA, et al. Aspirin for primary prevention of cardiovascular events in people with diabetes: a position statement of the American Diabetes Association, a scientific statement of the American Heart Association, and an expert consensus document of the American College of Cardiology Foundation. Circulation 2010;121: D Agostino RB, Grundy S, Sullivan LM, et al. Validation of the Framingham Coronary Heart Disease Prediction Scores. JAMA 2001;286: Gordon WJ, Polansky JM, Boscardin WJ, et al. Coronary risk assessment by point-based vs equation-based Framingham models: significant implications for clinical care. J Gen Intern Med 2010;25: Genest J, McPherson R, Frohlich J, et al Canadian Cardiovascular Society/Canadian guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease in the adult-2009 recommendations. Can J Cardiol 2009;25: Stern M, Williams K, Eddy D, Kahn R. Validation of prediction of diabetes by the Archimedes model and comparison with other predicting models. Diabetes Care 2008;31: Berry JD, Lloyd-Jones DM, Garside DB, Greenland P. Framingham risk score and prediction of coronary heart disease death in young men. Am Heart J 2007;154: Grundy SM, Pasternak R, Greenland P, et al. Assessment of cardiovascular risk by use of multiplerisk-factor assessment equations: a statement for healthcare professionals from the American Heart Association and the American College of Cardiology. Circulation 1999;100: Cooney MT, Dudina AL, Graham IM. Value and limitations of existing scores for the assessment of cardiovascular risk: a review for clinicians. J Am Coll Cardiol 2009;54: D Agostino RB, Vasan RS, Pencina MJ, et al. General cardiovascular risk profile for use in primary care: the Framingham Heart Study. Circulation 2008;117: 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 2013 Nov 12 [Epub ahead of print];doi: /01.cir /- /DC 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 2013 Nov 12 [Epub ahead of print];doi: /01.cir a. 17. American College of Cardiology. ASCVD Risk Calculator Plus. practice-support/mobile-resources/features/2013- prevention-guidelines-ascvd-risk-estimator. (Accessed April 17, 2018).

10 (PL Detail-Document #300102: Page 7 of 6) Cite this document as follows: PL Detail-Document, Common Cardiovascular Risk Calculators. Pharmacist s Letter/Prescriber s Letter. January Evidence and Recommendations You Can Trust 3120 West March Lane, Stockton, CA ~ TEL (209) ~ FAX (209) Copyright 2014 by Therapeutic Research Center Subscribers to the Letter can get PL Detail-Documents, like this one, on any topic covered in any issue by going to or