EvidenceSupporting ClinicalPractice Activities: Antiplatelet Therapy, EyeCare,FootCare

Dr. Palmer disclosed no relevant financial relationships with any commercial interests.

Elissa J. Palmer, MD, FAAFP Professor and Chair Department of Family and Community Medicine University of Nevada School of Medicine

Complete management of our patients with cardiometabolic risk includes preventing, and if necessary, treating the myriad of comorbidities and complications associated with the components of cardiometabolic syndrome.

Review current recommendations for antiplatelet therapy, eye care, foot care, vitamin D, and hormones for patients with cardiometabolic risk Outline the evidence for the clinical practice recommendations Assess your clinical practice activities and set up future goals to improve outcomes for patients with cardiometabolic risk

POINTS AGE years M 6 F 0 9 22

Janine BP mm Hg 0 <120 120-139 140 TC/HDL Ratio

POINTS

Janine

Janine is your 41-year-old, married Caucasian patient who comes in today to discuss labs you ordered after she had a prior first HbA1c of 7.0%. Janine is a nonsmoker. BP = 140/68 mm Hg; P = 68 Reg (no hx arrhythmias); Wt = 185 lbs
TC LDL HDL HbA1C Urine Microalbumin

<60

0 1 4 4 (140/68)

60-74.9 20 >75 41 DM years <5 5-9.9 >10 HbA1c <7 % 7%-7.9% >8% 0 2 6 0 2 5

<4.0 4-5.9 6.0 Smoker No

0 6 10 6 (5.57)

195 mg/dL 98 mg/dL 35 mg/dL

Diagnosis = DM type 2

7.5%

40 mcg/min

0 2

Cardiac risk assessment: UKPDS Risk Engine

(predicts risk of CHD in patients with diabetes)
HbA1c = hemaglobin A1c; BP = blood pressure; TC = total cholesterol; LDL = low-density lipoprotein; HDL = highdensity lipoprotein; DM = diabetes mellitus; UKPDS = UK Prospective Diabetes Study; CHD = coronary heart disease.

2 (7.5%) Microalbumin <30 mcg/min

Yes

0 1 1 (40)

http://www.dtu.ox.ac.uk/index.php?main doc=/riskengine

30 mcg/min

EvidenceSupporting ClinicalPractice Activities: Antiplatelet Therapy, EyeCare,FootCare

Janine 13 SCORE Points 0-17 18-31 32-69

Risk Average Elevated High

10-Year CHD Risk <15% 15%-30% >30%

With her UKPDS score of 13 points, indicating a 10-year risk <15%, and her diagnosis of DM type 2, should you recommended that Janine take one aspirin 81 mg a day?

1. Yes 2. No

University of Oxford. Diabetes Trials Unit. http://www.dtu.ox.ac.uk/index.php?maindoc=/riskengine. Accessed July 23, 2012.

Secondary prevention of CVD (macrovascular disease) Acute MI Occlusive stroke Transient ischemic attack Stable angina Coronary artery bypass surgery In acute ischemic syndromes Acute MI Unstable angina In acute occlusive stroke or a recurrent stroke Primary prevention of a first CVD event Individuals at moderate to high risk
MI = myocardial infarction; CVD = cardiovascular disease. Hennekens CH, et al. Circulation. 1997;96:2751.

No
DM + Low CVD 10-Year Risk (Evidence Level C)

DM + Major Risk Factor 10-Year Risk (Evidence Level C) If >10%: Men >50 Years Women >60 Years 75 to 162 mg/day DM + CVD Secondary Prevention 75-162 mg/day (Evidence Level A)

Yes

Maybe
Clinical Judgment DM + 10-Year Risk (Evidence Level E)

If 5%: Men <50 Years Women <60 Years

If 5%-10% and other risk factors: Men <50 Years Women <60 Years

American Diabetes Association. Diabetes Care. 2012:35(Suppl 1).

Use in DM
DM + CVD: 75-162 mg/day (Evidence Level A)

Population-based cohort study1

Comparison to

thienopyridine1,2

Aspirin preferred (Evidence grade 2B) for benefit to risk and cost Slightly > efficacy, so thienopyridine if no cost issue

186,425 individuals with new prescription for low-dose aspirin (300 mg) 186,425 propensity-matched controls, identified January 2003 to December 2008 Hospitalization for major GI bleeding or cerebral hemorrhage compared for aspirin users and non-users Followed 5.7 years

CONCLUSION
Overall incidence of hemorrhagic events Significantly higher for aspirin users than for those without aspirin use
(5.58 vs 3.6 per 1000 person-years; IRR 1.55)

Cessation of aspirin high risk? continue3 ACE inhibitors no issues4 NSAIDs problematic5
ACE = angiotensin-converting-enzyme; NSAIDs = nonsteroidal anti-inflammatory drugs. 1. A randomised, blinded, trial of clopidogrel versus aspirin (CAPRIE). Lancet. 1996;348:1329-1339. 2. De Berardis G, et al. JAMA. 2012;307(21):2286-2294. 3. Hennekens C, et al. Benefits and Risks of Aspirin. Up To Date. April 2012. 4. Teo KK, et al. Lancet. 2002;360:1037-1043. 5. Capone ML, et al. J Am Coll Cardiol. 2005; 45:1295-1301.

Diabetes correlated independently with an increased risk of major bleeding, regardless of aspirin use (IRR 1.36)

Risk bleeding may outweigh benefit2

Low cardiovascular risks <20% over 10 years Older patients >70 years

Consider proton pump inhibitors

GI = gastroentestinal; IRR = incidence ratio rate. 1. De Berardis G, et al. JAMA. 2012;307(21):2286-2294. 2. De Berardis, G, et al. BMJ. 2009;339:b4531.

EvidenceSupporting ClinicalPractice Activities: Antiplatelet Therapy, EyeCare,FootCare

RESISTANCE Occurrence of cardiovascular events despite aspirin at recommended doses Lack of evidence to support clinical relevance of aspirin "resistance" in the CVD events that occur

SENSITIVITY Minority of patients Symptoms

Respiratory tract disease
Rhinitis Asthma Urticaria/angioedema

Desensitization Alternative: clopidogrel 75 mg/day (Evidence Level B) Randomized studies lacking

Antithrombotic Trialists' Collaboration1 75 to 325 mg/day Post-hoc subset from CHARISMA trial2 Efficacy same comparing doses of 75 to 150 mg/day (lowdose) and 160 to 325 mg/day (medium (medium-dose) dose) United States Food and Drug Administration 75 to 325 mg/day American College of Cardiology/American Heart Association3
75 to 162 mg/day

American College of Chest Physicians 3

75 to 100 mg/day
1. Antithrombotic Trialists' Colaboration. BMJ. 2002; 324:71-86. 2. Steinhubl SR, et al. Ann Intern Med. 2009; 150:379-386. 3. American Heart Association. J Am Coll Cardiol. 2006;47:2130-2139.

Stevenson DD. Immunol Allergy Clin North Am. 2004;24:491-505. Gollapudi RR, et al. JAMA. 2004;292:3017-3023.

Which one of the following statements is correct regarding aspirin?

1. 2. 3. 4. In studies, enteric-coated aspirin protects against the clinically relevant end point of GI bleeding. Studies show that women who take aspirin have a better response to lowering CVD risk than men who are study matched controls. Aspirin is underutilized in prevention of CVD. Based on evidence from large-scale primary prevention trials of men and women without established CVD, aspirin produces a statistically significant and clinically important reduction in the risk of a first MI, stroke, and cardiovascular death.

Enteric coated
Lack of protection against end point of GI bleeding1 Crush or chew in acute vascular events

Enteric versus plain2

Some studies show enteric less effective

1. Kelly JP, et al. Lancet. 1996; 348:1413-1416. 2. Cox D, et al. Stroke. 2006; 37:2153-2158.

Study
Physicians Health Study (PHS) British Doctors Trial (BDT) Thrombosis Prevention Trial (TPT) Primary Prevention Project (PPP) Hypertension Optimal Treatment Trial (HOT) Women's Health Study (WHS) Aspirin for Asymptomatic Atherosclerosis trial (AAAT) Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) Prevention of Progression of Arterial Disease and Diabetes (POPADAD)

Aspirin Dose
325 mg qod 500 mg qd 75 mg + warfarin at INR 1.5 Enteric 100 mg qd 75 mg qd 100 mg qd x 10 years 100 mg qd

Reference
N Engl J Med. 1988;318:262 Br Med J (Clin Res Ed). 1988; 296:313 Lancet. 1998; 351:233. Lancet. 2001; 357:89 Lancet. 1998; 351:1755 N Engl J Med. 2005;352:1293 JAMA. 2010;303:841 JAMA. 2008;300:2134. BMJ. 2008;337:a1840

AGE 6 large-scale randomized trials

Over 90,000 subjects 40 to 89 years yea so of age Average 10-year risk of a first CHD event is less than 5%

GENDER 2002 meta-analysis

Trials of secondary prevention

2009 meta-analysis
22 trials of primary and secondary prevention About 135,000 patients Conclusion: No difference in the response to aspirin between men and women

ARRIVE and ASPREE

Patients at moderate to high risk Average risk of a first CHD event of 10% to 19%

81-100 mg qd 100 mg qd for patients with DM

Antithrombotic Trialists' Collaboration. Lancet. 2009;373:1849-1860. Antithrombotic Trialists' Collaboration. BMJ. 2002; 324:71-86.

EvidenceSupporting ClinicalPractice Activities: Antiplatelet Therapy, EyeCare,FootCare

Underutilized in
Patients with prior occlusive vascular diseases Acute MI Improving Unstable angina in hospital Outpatients with CVD Outpatients with DM

Anticoagulation and then adding aspirin

Not shown to improve outcomes (Grade 2C) Risk of bleeding increased Possible use with prior MI or <1 year after stenting If no significant bleeding episodes Risk of future bleeding is low
Flaker GC, et al. Am Heart J. 2006;152:967-973.

In discussing with Janine initial recommendations for care related to her DM, she should have an initial dilated and comprehensive eye examination upon diagnosis (Evidence Level B). For prevention of diabetic retinopathy, optimal control of which of the following should occur? 1. Weight 2. Hypertension 3. Hyperglycemia 4. Severe hypoglycemic events 5. Both 2 and 3

Few symptoms
Spots of flashes of light Examination important

Glaucoma and cataracts earlier and more frequent Patient concern - blindness

Important Contributors Hyperglycemia Hypertension Duration of DM (>5 years in type 1 DM)

Management Hyperglycemia BP control Laser treatment

AGE 40-64 years >65 years 28.0 % 29.5% Male

GENDER 31.6% 25.7%

ETHNICITY Caucasian African American Mexican American Other 26.8% 38.8%

UKPDS study
Glucose control ACCORD trial: subgroup analysis Glucose control FIELD study: subgroup analysis Fenofibrate DCCT BP control
ACCORD = Action to Control Cardiovascular Risk in Diabetes; FIELD = Fenofibrate Intervention and Event Lowering in Diabetes; DCCT = Diabetes Control and Complications Trial. UKPDS. BMJ. 1998;317:708-713. Estacio RO, et al. Diabetes Care. 2000;23 (Suppl 2):B54-B64. ACCORD. N Engl J Med. 2008;358:2545-2559. DCCT. N Engl J Med. 1993;329:977-986.

Female

34.0%

19.7%

NHANES. JAMA. 2010;304(6):649-656.

EvidenceSupporting ClinicalPractice Activities: Antiplatelet Therapy, EyeCare,FootCare

Sudden monocular loss of vision in a patient with diabetic retinopathy is most commonly due to: 1. 1 2. 3. 4. 5. Acute glaucoma. A l Vertebrobasilar stroke. Vitreous hemorrhage. Central retinal vein occlusion. Episcleritis.

Duration of DM
Type 1 patients:
25% rate of retinopathy after 5 years 80% at 15 years

Type 2 patients:
Around A d 21% 21%, retinopathy ti th at t diagnosis di i

Potential increased risk of retinopathy

Puberty Pregnancy NOTE: Retinopathy is not a contraindication to aspirin therapy
American Diabetes Association. Diabetes Care. 2012:35(Suppl 1).

Type of DM
Screen

Type 1
Within 3-5 years of diagnosis for > age 10 years Annually (can consider less frequent, Level E)

Type 2
At time of diagnosis Annually (can consider less frequent, Level E)

Pregnancy (pre-existing DM)

Before conception and first trimester

Follow-up Method Retinopathy Signs Evidence Level B

At 1 year

Dilated indirect ophthalmoscopy with fundus photography More frequent screenings for all categories

American Diabetes Association. Diabetes Care. 2012:35(Suppl 1).

Janines father has type 2 DM with neuropathy. She would like to know what risk factors she could modify to prevent the development of neuropathy. Of the following, which is the biggest risk factor for developing diabetic neuropathy?

Recommendation

Type

Method 10 g monofilament PLUS one: 128 Hz tuning fork Pinprick sensation Ankle reflexes Vibration perception All patients with DM Multidisciplinary Foot care specialist Consider ankle-brachial index Older than 50 years of age Younger than 50 years of age with risk factors

Evidence

Inspection Pulses Annual Examination Loss sensation Self care, shoes High risk/ulcers Smokers, high-risk Sensation loss Claudication Peripheral pulses

Education

B B B

1. 2. 3. 4. 5.

Coronary artery disease Retinopathy Smoking Uncontrolled high blood sugars over time Uncontrolled high BP over time

Referral

Screen PAD

PAD = peripheral arterial disease. American Diabetes Association. Diabetes Care. 2012:35(Suppl 1). American Diabetes Association. Diabetes Care 2008;26:3333-3341.

EvidenceSupporting ClinicalPractice Activities: Antiplatelet Therapy, EyeCare,FootCare

Clean daily Lubricate

Avoid alcohol-based, avoid between toes

Callus debridement (reduce plantar pressure by 25%)

Emory E b board, d pumice i stone t nothing thi sharp h

Janine asks why the nurse always has her father remove his shoes and socks before you see him. You explain that multiple research studies have demonstrated that the a socks off examination can reduce amputation rates by:

Nail trim No bare feet Exercise

If neuropathy, bicycling, swimming

Optimal footwear

1. 10%. 2. 25%. 3. 50%. 4. 75%.

DCCT. N Engl J Med. 1993;329:977-986. UKPDS. Lancet. 1998;352(9131):837-853. ACCORD-EYE. N Engl J Med. 2010;363:233-244. ADVANCE. N Engl J Med. 2008;358:2560-2572. VADT. N Engl J Med. 2009;360:129-139.

Group 0 1

Description No evidence of neuropathy Neuropathy present but no evidence of foot deformity or peripheral vascular disease Neuropathy with evidence of deformity or peripheral vascular disease History of foot ulceration or lower extremity amputation

Developed Ulcers 5.1% 14.3%

Amputation 0.0% 0.0%

2 3

18.8% 55.8%

3.1% 20.9%

Peters E, et al. Diabetes Care. 2001;24(8):1442-1447.

Janines father, a diabetic with poor control and diagnosed neuropathy, comes in complaining of a sensation of burning in his feet. Which one of the following has the closest correlation with amputations of f the h lower l extremity? ?
1. 2. 3. 4. 5. Pins and needles sensation on feet Loss of ankle reflex Burning sensation on feet Inability to feel pressure with monofilament test Pale and blotchy skin on lower ankles and feet

Device 10-gram (5.07 Semmes-Weinstein) nylon filament standardized to deliver a 10 gram force Use for <100 applications per 24 hours then rest for 24 hours (filament fatigue lessens force) If feel 10 gram force risk ulcer development Prevalenceinsensatefeet: 30%>40years 50% are asymptomatic for 50%>60years
neuropathic symptoms

Rith-Najarian SJ, et al. J Family Practice. 2000;49(11 Suppl):S30-S39. Rith-Najarian SJ, et al. Diabetes Care. 1992;15(10):1386-1389.

EvidenceSupporting ClinicalPractice Activities: Antiplatelet Therapy, EyeCare,FootCare

Test characteristics Negative predictive value = 90% - 98% Positive predictive value = 18% - 36% Prospective Observational Study 80% of ulcers and 100% of amputations occur in insensate feet Superior predictive value compared to other test modalities
Rith-Najarian SJ, et al. J Family Practice. 2000;49(11 Suppl):S30-S39. Rith-Najarian SJ, et al. Diabetes Care. 1992;15(10):1386-1389.

Tuning Fork (128 Hz) Testing at each hallux Can use in conjunction with monofilament Inexpensive Avoid calluses Document as (+) or (-)

Biosthesiometer Quantitatively assesses vibration sense Can use in conjunction with monofilament Expensive Electrical tuning fork

American Diabetes Association. Diabetes Care. 2012:35(Suppl 1). Miranda-Palma B, et al. Diabetes Res Clin Pract. 2005;70(1):8-12.

Which one of the following is NOT suggestive of autonomic neuropathy? 1. 1 2. 3. 4. 5. Dizziness Third nerve palsy Resting tachycardia Exercise intolerance Constipation

1. Focal 2. Sensorimotor (peripheral) 3. Autonomic

Autonomic Increased morbidity and mortality Resting tachycardia (>100 bpm) Exercise intolerance Orthostatic hypotension (>20 mm Hg fall in BP with standing) Constipation Gastroparesis Erectile dysfunction Brittle diabetes Hypoglycemic autonomic failure

American Diabetes Association. Diabetes Care. 2012:35(Suppl 1).

Glucose
Good control and minimize fluctuations

Class

Evidence

Medication Carbamazepine

Dosage 200-400 mg 3 x day 300-1200 mg 3 x day 100 mg 3 x day 60-120 mg daily Controlled-release 10-40 mg 2 x day 0.025%-0.075% applied 3 or 4 x day 10-75 mg at night 25-75 mg at night 25-75 mg at night

Smoking
Encourage patient to quit

Anticonvulsants 5-Hydroxytryptamine and norepinephrine uptake inhibitor Opioids Substance P inhibitor

Gabapentin Pregabalin Duloxetine

Peripheral p vasculature
Screen for PAD

Feet
Evaluate for plantarpressure Erythema, warmth, callus, or measured pressure Shoes Extrawide,custommolded Accommodatebonydeformities
American Diabetes Association. Diabetes Care. 2012:35(Suppl 1). Seaquist ER, et al. J Clin Endocrinol Metab. 2010;95:3103-3110.

2 2

Oxycodone Capsaicin cream Amitriptyline

Tricyclic drugs

Imipramine Nortriptyline

American Diabetes Association. Diabetes Care. 2012:35(Suppl 1). Watson CP, et al. Pain. 2003;105(1-2):71-78.

EvidenceSupporting ClinicalPractice Activities: Antiplatelet Therapy, EyeCare,FootCare

Michael is a 57-year-old, married African American patient with DM in for a 3-month follow-up visit. BP = 122/68 mm Hg; P = 66 Reg (no hx arrhythmias); BMI = 33
TC 198 mg/dL LDL 120 mg/dL HDL 39 mg/dL HbA1c 6.1% Vitamin D <30 ng/ml

True or False: Deficiency of vitamin D is associated with hypertension, DM, and metabolic syndrome. 1.True
BMI = body mass index.

2. False

Deficiency in 25 (OH) D levels

18, 000 healthy men followed for 10 years <30 ng/ml for Vitamin D associated with risk MI1 Vitamin D deficiency: associated with hypertension, DM, and metabolic syndrome2 Prevalence of hypertension, DM, and hypertriglyceridemia higher in those with lowest 25(OH)D [15,000 patients; National Health & Nutrition Examination Survey III]2

Vitamin D status and cardiometabolic outcome

Uncertain

Trials
13 observational studies (14 cohorts) and 18 trials No clinically significant effect of vitamin D supplementation at the dosages given

1. Giovannucci E, et al. Archives Int Med. 2008;168(11). 2. Wang TJ, et al. Circulation. 2008;117:503-511.

Pittas AG, et al. Ann Intern Med. 2010;152(5):307-314.

Conclusions: Calcium and vitamin D are 2 essential nutrients for bone health Little evidence of f other health benefit f

Life Stage Infants 0-6 Months Infants 6-12 months Children 1 to 8 years Adults 9-70 years Adults >70 years

Estimated Average Requirement 400 IU (10 ug) 400 IU (10 ug) 400 IU (10 ug) 400 IU (10 ug) 400 IU (10 ug)

Recommended Dietary Allowance

Tolerable Upper Intake Level 1000 IU (25 ug) 1500 IU (38 ug) 2500-3000 IU (63-75 ug) 4000 IU (100 ug) 4000 IU (100 ug)

600 IU (15 ug) 600 IU (15 ug) 800 IU (20 ug)

Dietary Reference Intakes for Calcium and Vitamin D. Institute of Medicine Consensus Report. November 30, 2010.

Ross AC, et al, eds. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press;2011:345-402.

EvidenceSupporting ClinicalPractice Activities: Antiplatelet Therapy, EyeCare,FootCare

Michael is your 57-year-old, married African American patient who comes in today to discuss labs you ordered.
BP = 122/68 mm Hg; P = 66 Reg (no hx arrhythmias); BMI = 33
TC 198 mg/dL LDL 120 mg/dL HDL 39 mg/dL HbA1C 7.1% T t t Testosterone 215 ng/ml

Your lab normal is 270-1070 ng/dL. You would: 1. Diagnose Michael with androgen deficiency. 2. Start Michael on testosterone. 3. Both 1 and 2. 4. None of the above

Statistics
25% of Med 5.6% sx 50% of DM >30 years, 1% a year

Manifestations
Bone loss Fractures Lose Muscle Lethargy Depression

Metabolic Syndrome, Insulin Resistance, Low T

Replacement ? Corrects Resistance No RCTs with Benefit Unless Deficient

Routine testosterone levels

Not recommended

Diagnosis
Need consistent symptoms Unequivocally low serum testosterone levels

Measure
Morning total testosterone level Confirm by repeating the measurement Possibly measure free or bioavailable testosterone level

Treat only symptomatic men with androgen deficiency

Improve their sexual function Sense of well-being Muscle mass and strength Bone mineral density

RCTs = randomized control trials. Dhindsa S, et al. J Clin Endocrinol Metab. 2004;89:5462-5468.

The Endocrine Society. Testosterone Therapy in Adult Men with Androgen Deficiency Syndromes: An Endocrine Society Clinical Practice Guideline. http://www.endo-society.org/guidelines/final/upload/FINAL-Androgens-in-MenStandalone.pdf. Accessed July 23, 2012.

Recommend against testosterone in patients with:

Breast or prostate cancer Palpable prostate nodule or prostate-specific antigen greater than 3 ng/ml without further urological evaluation Erythrocytosis (hematocrit >50%) Untreated obstructive sleep apnea IPSS greater than 19 Class III or IV heart failure

Treatment
Aim for testosterone levels in mid-normal range Any approved formulation Choose based on
Patient's preference Consideration of pharmacokinetics Treatment burden Cost

IPSS = International Prostate Symptom Score. The Endocrine Society. Testosterone Therapy in Adult Men with Androgen Deficiency Syndromes: An Endocrine Society Clinical Practice Guideline. http://www.endo-society.org/guidelines/final/upload/FINAL-Androgens-in-MenStandalone.pdf. Accessed July 23, 2012.

The Endocrine Society. Testosterone Therapy in Adult Men with Androgen Deficiency Syndromes: An Endocrine Society Clinical Practice Guideline. http://www.endo-society.org/guidelines/final/upload/FINAL-Androgens-in-MenStandalone.pdf. Accessed July 23, 2012.

EvidenceSupporting ClinicalPractice Activities: Antiplatelet Therapy, EyeCare,FootCare

Antiplatelet
Recommendations vary depending upon risks and with newest data, risk/benefit discussion around GI bleeding needs to occur

Retinopathy
Control Co o BP and a d blood b ood sugar suga

Neuropathy
Control blood sugar

Vitamin D
Contributes to bone health

Testosterone
Treat symptomatic men