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Common Office Medical Problems

Common Office Medical Problems . Christian Wagner, MD Clinical Assistant Professor Department of Family Medicine University of Illinois College of Medicine at Urbana-Champaign June 2010. Hyperlipidemia Hypertension Diabetes Congestive Heart Failure. Hyperlipidemia. Types:

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Common Office Medical Problems

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  1. Common Office Medical Problems Christian Wagner, MD Clinical Assistant Professor Department of Family Medicine University of Illinois College of Medicine at Urbana-Champaign June 2010

  2. Hyperlipidemia • Hypertension • Diabetes • Congestive Heart Failure

  3. Hyperlipidemia

  4. Types: • heterozygous form - associated with total cholesterol level > 300 mg/dL (7.7 mmol/L), high risk of coronary artery disease by 30-40, 50% reduction in LDL receptor activity • homozygous form - associated with total cholesterol of 600-1000 mg/dL (15.5-26 mmol/L), rare, myocardial infarction by age 10 and death by age 20 is common, total deficiency of LDL receptor activity • familial hypercholesterolemia • Fredrickson Type IIa hyperlipoproteinemia • hyperbetalipoproteinemia • group A hyperlipidemia • LDL hyperlipoproteinemia

  5. Incidence/Prevalence: • hypercholesterolemia is eleventh most common diagnosis made during family physician visits; analysis of patient visits to family physicians in United States 1995-1998 in National Ambulatory Medical Care Survey; hypercholesterolemia diagnosis coded in 2.8% of visits (Ann Fam Med 2004 Sep-Oct;2(5):411full-text) • estimated risk for developing dyslipidemia by age 50 years • > 80% for "borderline-high" LDL cholesterol (≥ 130 mg/dL [3.4 mmol/L]) • 50% for "high" LDL cholesterol (≥ 160 mg/dL [4.1 mmol/L]) • 25% women and 65% men for "low" HDL cholesterol (< 40 mg/dL [1 mmol/L]) • Reference - based on 4,701 Framingham Offspring study participants (Am J Med 2007 Jul;120(7):623) • prevalence of elevated cholesterol in children and adolescents • based on cohort of 9,868 children aged 6-17 years from National Health and Nutrition Examination Survey 1999-2006 • prevalence of elevated total cholesterol (cut point 200 mg/dL or 5.2 mmol/L) 10.7% • mean total cholesterol 163 mg/dL (4.2 mmol/L) • prevalence of elevated LDL cholesterol in 2,724 adolescents aged 12-17 years (cut point 130 mg/dL or 3.4 mmol/L) 6.6% • mean LDL cholesterol in adolescents 90.2 mg/dL (2.3 mmol/L) • estimated only 0.8% of adolescents exceed LDL threshold for considering for pharmacological treatment by current AAP guideline • Reference - Circulation 2009 Mar 3;119(8):1108

  6. Causes: • autosomal dominant LDL receptor defect (heterozygous), inherited as autosomal codominant trait, else polygenic hyperlipidemia • Likely risk factors: • diet • hypothyroidism • nephrotic syndrome • obstructive liver disease • hepatoma • Cushing's syndrome • anorexia nervosa • Werner's syndrome • acute intermittent porphyria

  7. Complications: • very high risk of CAD, premature atherosclerosis • elevated cholesterol clearly shown to be a risk factor for cardiovascular mortality in men 40-64 • elevated cholesterol in younger men (35-39) shown to be associated with increased long-term risk for cardiovascular and total mortality; study of 64,205 men 35-39 followed 16 years plus 2 other studies of 12,283 men 18-39 followed 25-34 years; increasing total cholesterol level associated with strong graded independent risk for total mortality and cardiovascular disease; total cholesterol > 240 mg/dL (6.2 mmol/L) compared with cholesterol < 200 mg/dL (5.2 mmol/L) associated with significantly increased risk for total mortality, corresponding to reduce life expectancy of 3.8-8.7 years (JAMA 2000 Jul 19;284(3):311), editorial can be found in JAMA 2000 Jul 19;284(3):365 • Associated conditions: • association with subclinical hypothyroidism controversial • hypercholesterolemia associated with subclinical hypothyroidism, based on study of 1,191 patients 40-60, 10.3% prevalence of subclinical hypothyroidism among patients with total cholesterol > 309 mg/dL (8 mmol/L) (Clin Endocrinol (Oxf) 1999 Feb;50(2):217 in QuickScan Reviews in Fam Pract 1999 Sep;24(6):21) • subclinical hypothyroidism not associated with abnormal lipid levels after adjusting for confounding factors in US population-based study of 8,218 adults > 40 years old (Ann Fam Med 2004 Jul-Aug;2(4):351full-text) • smoking associated with elevated LDL cholesterol in study of 492 persons aged 26-66 with hypercholesterolemia (Clin Exp Med 2002 Jul;2(2):83)

  8. Diagnosis Rule out: • hypothyroidism • nephrotic syndrome • diabetes • obstructive liver disease • hypercholesterolemia secondary to diet • anorexia nervosa • Testing to consider: • TSH, blood glucose, creatinine • fasting lipid profile • LDL = total cholesterol - HDL - TG/5 • not valid if TG > 400 • cardiovascular risk by lipid panel appears similar in patients fasting and non-fasting • based on data from 302,430 people without initial vascular disease • Reference - JAMA 2009 Nov 11;302(18):1993

  9. chemistry - cholesterol/triglyceride > 1.5 (high TG if IIb) • high cholesterol - 300-600 mg/dL (800-1000 homozygous) • electrophoresis - increased beta (increased pre-beta if IIb) • ultracentrifugation - high LDL, normal TG (high VLDL if IIb) • apolipoprotein B may help guide statin therapy in subgroup analysis of Collaborative Atorvastatin Diabetes Study (CARDS) (Clin Chem 2009 Mar;55(3):473), editorial can be found in Clin Chem 2009 Mar;55(3):391)

  10. Prognosis: • homozygous - myocardial infarction in teens, heterozygous - MI in 40's • about 40% persons with familial hypercholesterolemia have normal lifespan, based on study of large family pedigree (BMJ 2001 Apr 28;322(7293):1019full-text)

  11. Treatment overview: • diet low in cholesterol and total fat, increased polyunsaturated-to-saturated fat ratio • statins are drug of choice • target LDL cholesterol levels • "high risk" if coronary heart disease, diabetes, peripheral arterial disease, stroke, or 10-year cardiovascular risk > 20% • LDL goal < 100 mg/dL (2.6 mmol/L) • optional goal < 70 mg/dL (1.8 mmol/L) encouraged if very high risk • "moderately high risk" if 2 or more major risk factors • LDL goal < 130 mg/dL (3.4 mmol/L) • optional goal < 100 mg/dL (2.6 mmol/L) if 10-year risk of cardiovascular disease 10-20% • "lower risk" if 0 or 1 major risk factor • LDL goal < 160 mg/dL (4.1 mmol/L) • Reference - 2004 update to NCEP/ATP III guidelines (Circulation 2004 Jul 13;110(2):227full-text) • see Cholesterol screening and management for cardiovascular disease prevention for details

  12. Diet: • diet low in cholesterol and total fat, increased polyunsaturated-to-saturated fat ratio • adherence to diet may result in 10-15% reduction in cholesterol level • insufficient evidence to evaluate cholesterol-lowering diet or other dietary interventions for familial hypercholesterolemia • based on Cochrane review • systematic review of 11 short-term randomized and quasi-randomized trials evaluating cholesterol-lowering diet in 331 children and adults with familial hypercholesterolemia • all trials of short duration and no primary outcomes evaluated ischemic heart disease, number of deaths and age at death) • no significant differences in most secondary outcomes • Reference - Cochrane Database Syst Rev 2010 Jan 20;(1):CD001918

  13. Activity: • moderate intensity walking may reduce total cholesterol/HDL ratio in men with hypercholesterolemia (level 3 [lacking direct] evidence) • based on randomized trial without clinical outcomes • 67 men (mean age 55.1 years) with hypercholesterolemia randomized to brisk walking (burning ≥ 300 kcal/walk) vs. control for 12 weeks • walking group had significant reduction in total cholesterol/HDL and weight and borderline reduction in triglycerides • Reference - Prev Med 2008 Jun;46(6):545

  14. use of medications depend on patient's risk factors for atherosclerotic disease • secondary prevention (treatment for patients with atherosclerotic disease) typically targeted at LDL cholesterol level < 100 mg/dL (2.6 mmol/L) • for help in determining need for medications in primary prevention of atherosclerotic disease, see Revised Sheffield table for determining risk of coronary artery disease • evidence-based assessment finds that lipid-lowering therapy generally indicated for patients with diabetes or diagnosis of coronary artery disease (JAMA 1999 Dec 1;282(21):2051), summary can be found in Am Fam Physician 2000 May 15;61(10):3133 • statins would be agents of first choice

  15. bile acid sequestrants - cholestyramine (Questran), colestipol (Colestid), colesevelam (Cholestagel) • decreases LDL (and cholesterol) up to 25% • second line drugs, large doses three times daily, start at low dose • side effects - constipation, fullness, discomfort, increases TGs if type IIb, interferes with drug absorption

  16. nicotinic acid • side effects often occur > 1 year after initiating drug therapy; follow-up of 110 individuals taking nicotinic acid (133 drug exposures), 63 took regular nicotinic acid (target dose 3,000 mg/day), 65 took SR nicotinic acid (1500 mg/day); 42-43% of each group discontinued the drug due to side effects, most commonly abnormal liver function tests (11 reg, 9 SR), flushing (7 reg, 5 SR), abdominal pain (6 reg, 7 SR), nausea/emesis (6 reg, 4 SR), rash (4 reg, 4 SR), hyperuricemia (6 reg, 1 SR), and hyperglycemia (4 reg, 2 SR); other side effects included fatigue, ankle swelling, headache, itching, and arrhythmias; patients took nicotinic acid an average of 16.7 (reg) and 14.9 (SR) months prior to developing the symptoms resulting in drug cessation (Am J Med 1995 Oct;99(4):378 in QuickScan Reviews in Fam Pract 1996 Mar;14)

  17. in children • review of dietary therapy in children can be found in Am Fam Physician 2000 Feb 1;61(3):675, editorial can be found in Am Fam Physician 2000 Feb 1;61(3):633 • if cholesterol remains < 300 mg/dL (7.8 mmol/L), bile acid-binding resins (cholestyramine, colestipol) are safe and efficacious • little experience with other lipid-lowering drugs in children • homozygous form very resistant to treatment - consider repeated exchange transfusion, portocaval shunting, liver transplantation • cholesterol-lowering treatments not associated with increased risk for non-illness mortality; no significant associations between cholesterol-lowering treatments (diet, drugs, partial ileal bypass) and non-illness mortality (suicide, accident, trauma) in meta-analysis of 19 randomized controlled trials lasting at least 1 year; non-significant trend observed in trials of dietary interventions and non-statin drugs, no increase with statins (BMJ 2001 Jan 6;322(7277):11full-text)

  18. Screening: • see updated NCEP guidelines • cardiac risk factors - male > 45, female > 55, FH premature CHD, smoking, hypertension, HDL < 35; negative risk factor if HDL > 60

  19. United States Preventive Services Task Force (USPSTF) screening recommendations • USPSTF guidelines for screening for lipid disorders in adults • strongly recommend routine screening in men ≥ 35 years old and women ≥ 45 years old (USPSTF Grade A recommendation) • recommend screening men aged 20-35 years and women aged 20-45 years if at increased risk for coronary heart disease (USPSTF Grade B recommendation) • no recommendation for or against routine screening in men aged 20-35 or women ≥ 20 years old who are not at increased risk for coronary heart disease (USPSTF Grade C recommendation) • Reference - USPSTF 2008 Jun or at National Guideline Clearinghouse 2008 Jul 28:12634, previous version can be found in Am J Prev Med 2001 Apr;20(3 Suppl):73 • USPSTF concludes there is insufficient evidence to recommend for or against routine screening for lipid disorders in children (USPSTF Grade I recommendation) (Pediatrics 2007 Jul;120(1):e215 or at National Guideline Clearinghouse 2007 Oct 15:10865), supporting systematic review can be found in Pediatrics 2007 Jul;120(1):e189 • United States Preventive Services Task Force (USPSTF) grades of recommendation • grade A - USPSTF recommends the service with high certainty of substantial net benefit • grade B - USPSTF recommends the service with high certainty of moderate net benefit or moderate certainty of moderate to substantial net benefit • grade C - USPSTF recommends against routinely providing the service with at least moderate certainty that net benefit is small, but in individual patients considerations may support providing the service • grade D - USPSTF recommends against providing the service with moderate to high certainty of no net benefit or harms outweighing benefits • grade I - insufficient evidence to assess balance of benefits and harms • see USPSTF Grade Definitions for more detail

  20. Reviews: • review can be found in BMJ 2008 Aug 21;337:a993, commentary can be found in BMJ 2008 Sep 3;337:a1493, BMJ 2008 Sep 16;337:a1681 • review of treatment of cholesterol abnormalities can be found in Am Fam Physician 2005 Mar 15;71(6):1137, commentary can be found in Am Fam Physician 2006 Mar 15;73(6):973 • Applied Evidence review of treatment of hyperlipidemia can be found in J Fam Pract 2002 Apr;51(4):370 • review of dyslipidemia can be found in Am Fam Physician 1998 May 1;57(9):2192 • review of drug treatment of lipid disorders can be found in N Engl J Med 1999 Aug 12;341(7):498 (author may have conflict of interest [N Engl J Med 2000 Feb 24;342(8):586]), commentary can be found in N Engl J Med 1999 Dec 23;341(26):2020 • review of lifestyle, diet, dietary supplements and botanicals in management of hyperlipidemia can be found in Altern Ther Health Med 2003 May-Jun;9(3):28

  21. Guidelines: • synthesis of 3 guidelines (UMHS 2009, USPSTF 2008, VA/DoD 2006) on screening for lipid disorders in adults can be found at National Guideline Clearinghouse 2010 Mar 8:LIPSCREEN7 • United States Preventive Services Task Force (USPSTF) guidelines for screening for lipid disorders in adults can be found in USPSTF 2008 Jun or at National Guideline Clearinghouse 2008 Jul 28:12634, previous version can be found in Am J Prev Med 2001 Apr;20(3 Suppl):73 • USPSTF guidelines for screening for lipid disorders in children can be found in Pediatrics 2007 Jul;120(1):e215 or at National Guideline Clearinghouse 2007 Oct 15:10865, supporting systematic review can be found in Pediatrics 2007 Jul;120(1):e189 • American Academy of Pediatrics (AAP) clinical report on lipid screening and cardiovascular health in childhood (grade C recommendation [lacking direct evidence]) • recommendations include • increased physical activity and dietary changes for children at risk of overweight or obesity • screening between age 2-10 years in children with family history of dyslipidemia or premature cardiovascular disease or dyslipidemia (or if unknown family history or those with other cardiovascular disease risk factors) • consider pharmacologic intervention in patients ≥ 8 years old with LDL level ≥ 190 mg/dL (4.9 mmol/L) (≥ 160 mg/dL [4.1 mmol/L] with family history of early heart disease or 2 other risk factors present or ≥ 130 mg/dL [3.4 mmol/L] if diabetes mellitus) • limitations of recommendations • no data to predict risk of cardiovascular disease as an adult based on cholesterol levels in children • insufficient data to support specific evidence-based recommendation for cholesterol screening in children • insufficient data to support specific evidence-based recommendation for specific age to implement pharmacologic treatment • Reference - Pediatrics 2008 Jul;122(1):198 or at National Guideline Clearinghouse 2009 May 18:13438, commentary can be found in BMJ 2008 Jul 23;337:a886 • previous American Academy of Pediatrics statement on cholesterol levels in children can be found in Pediatrics 1998 Jan (Am Fam Physician 1998 May 1;57(9):2266full-text) • commentary stating that childhood cholesterol screening is not justified can be found in Pediatrics 2000 Mar;105(3):637 and in Pediatrics 2001 May;107(5):1229 • parent history screening criteria not much better than random population screening in cohort of 2,475 Quebec youths ages 9-16 years; parent history had 41% sensitivity, 75% specificity, 8% positive predictive value and 96% negative predictive value for identifying high LDL cholesterol (Pediatrics 2004 Jun;113(6):1723), commentary can be found in Pediatrics 2005 Jan;115(1):195, summary can be found in Am Fam Physician 2005 Mar 15;71(6):1203

  22. Hypertension

  23. Hypertension • stage 1 hypertension if SBP 140-159 mm Hg or DBP 90-99 mm Hg • stage 2 hypertension if SBP > 160 mm Hg or DBP > 100 mm Hg • stages of hypertension in children and adolescents • stage 1 hypertension if blood pressure 95th percentile to 99th percentile plus 5 mm Hg, based on charts for gender, age and height • stage 2 hypertension if blood pressure > 99th percentile plus 5 mm Hg, based on charts for gender, age and height • Reference - Pediatrics 2004 Aug;114(2 Suppl 4th Report):555full-text, commentary can be found in Pediatrics 2005 Mar;115(3):826

  24. Types of Hypertension • types of hypertension based on renin-angiotensin system • type 1 hypertension is vasoconstrictor, high renin • renin secretion inappropriately high for blood pressure, exaggerated renal elimination of sodium • common in young white people • responds better to ACE inhibitors, angiotensin receptor blockers and beta blockers • type 2 hypertensin is sodium dependent, low renin • renin secretion suppressed by kidney's detection of excessive sodium reabsorption • common in young black people • responds better to diuretics and calcium channel blockers • Reference - BMJ 2006 Apr 8;332(7545):833, commentary can be found in BMJ 2006 Apr 22;332(7547):974

  25. Causes • unknown • 90%-95% hypertension is essential hypertension

  26. Pathogenesis • volume expansion, vasoconstriction - increased total peripheral resistance • resistant hypertension associated with elevated aldosterone and natriuretic peptide levels • based on case-control study • 279 consecutive patients with resistant hypertension (nonresponsive to 3 antihypertensive drugs) were compared to 53 controls with normal pressure or controlled hypertension • resistant hypertension associated with higher levels of aldosterone, brain-type natriurietic peptide and atrial natriuretic peptide • Reference - Arch Intern Med 2008 Jun 9;168(11):1159 • bosentan, endothelin receptor antagonist, shown to reduce blood pressure in 4-week randomized trial with effect similar to enalapril; adverse effects included headache, flushing, leg edema and elevated transaminases (N Engl J Med 1998 Mar 19;338(12):784), commentary can be found in N Engl J Med 1998 Jul 30;339(5):346 • review of pathogenesis of hypertension can be found in BMJ 2001 Apr 14;322(7291):912 • review of pathogenesis of hypertension can be found in Ann Intern Med 2003 Nov 4;139(9):761

  27. review of role of aldosterone in pathogenesis of metabolic syndrome and resistant hypertension can be found in Ann Intern Med 2009 Jun 2;150(11):776 • review of role of endothelin in pathogenesis of hypertension can be found in Mayo Clin Proc 2005 Jan;80(1):84 • review of sodium and potassium in pathogenesis of hypertension can be found in N Engl J Med 2007 May 10;356(19):1966, commentary can be found in N Engl J Med 2007 Aug 23;357(8):827

  28. patients with normal and high-normal blood pressure at significant risk for developing hypertension over 4 years • based on 9,845 men and women with blood pressure < 140/90 mm Hg in Framingham Heart Study • 4-year risk for hypertension in persons < 65 years old • 5.3% for those with optimum blood pressure (< 120/80 mm Hg) • 17.6% with normal blood pressure (120-129/80-84 mm Hg) • 37.3% with high-normal blood pressure (130-139/85-89 mm Hg) • 4-year risk for hypertension in persons > 65 years old • 16% for those with optimum blood pressure • 25.5% with normal blood pressure • 49.5% with high-normal blood pressure • Reference - Lancet 2001 Nov 17;358(9294):1682, editorial can be found in Lancet 2001 Nov 17;358(9294):1659

  29. light-to-moderate alcohol use associated with increased risk of hypertension in men but not women • based on 2 prospective cohort studies • 28,848 women from Women's Health Study followed for 10.9 years and 13,455 from Physicians' Health Study followed for 21.8 years • all were without hypertension at baseline • 8,680 women and 6,012 men developed hypertension • adjusted relative risks for developing hypertension in women (compared to rare/never drinkers) • 0.98 (95% CI 0.91-1.05) for 1-3 drinks monthly • 0.96 (95% CI 0.87-1.06) for 1 drink daily • 1.1 (95% CI 0.97-1.25) for 2-3 drinks daily • 1.84 (95% CI 1.36-2.48) for ≥ 4 drinks daily • adjusted relative risks for developing hypertension in men (compared to rare/never drinkers) (p < 0.0001) • 1.11 (95% CI 1-1.23) for 1-3 drinks monthly • 1.26 (95% CI 1.15-1.37) for 1 drink daily • 1.29 (95% CI 1.08-1.53) for ≥ 4 drinks daily • in women, relative risks similar with specific alcohol types compare to total alcohol intake • relative risks remained similar after adjusting for baseline blood pressure in women and men • Reference - Hypertension 2008 Apr;51(4):1080 • alcohol intake > 2 drinks/day associated with increased blood pressure in men but not women in cross-sectional study of 5,448 adults > 20 years old (J Hypertens 2007 May;25(5):965)

  30. dyslipidemia modestly associated with subsequent hypertension in prospective study of 16,130 women > 45 years old followed for 10.8 years (Arch Intern Med 2005 Nov 14;165(20):2420) • time urgency/impatience and hostility significantly associated with developing hypertension in 15-year prospective follow-up of 3,308 black and white United States adults aged 18-30 years at baseline; no consistent associations with depression, anxiety, or achievement striving/competitiveness (JAMA 2003 Oct 22-29;290(16):2138), editorial can be found in JAMA 2003 Oct 22-29;290(16):2190, commentary can be found in JAMA 2004 Feb 11;291(6):692 • smaller retinal arteriolar diameters associated with development of hypertension • in cohort of 2,451 normotensive persons aged 43-84 years followed for 10 years (BMJ 2004 Jul 10;329(7457):79), correction can be found in BMJ 2004 Aug 14;329(7462):384, commentary can be found in BMJ 2004 Aug 28;329(7464):514 and reply

  31. Factors increasing risk of Hypertension • higher salt intake may be associated with increased risk for hypertension • urinary sodium levels strongly associated with systolic blood pressure in 10,074 men and women ages 20-59 years in 32 countries (BMJ 1996 May 18;312(7041):1249full-text), editorial can be found in BMJ 1996 May 18;312(7041):1241, commentary can be found in BMJ 1996 Jun 29;312(7047):1659 and BMJ 1997 Aug 23;315(7106):484 • some evidence supports international consensus of lower risk of hypertension when salt intake is lower; 24-hour urinary sodium excretion associated with systolic blood pressure, diastolic blood pressure and hypertension over range of sodium excretion rates from 70-400 mmol/day (Arch Intern Med 1997 Jan 27;157(2):234)

  32. red meat intake may be associated with risk of hypertension in women ≥ 45 years old • based on prospective cohort study • 28,766 women ≥ 45 years old followed for 10 years • frequency of red meat intake assessed by food surveys and diagnosis of hypertension identified in annual follow-up questionnaires • incidence of hypertension in women who consumed (p = 0.008 for trend) • no red meat 21.7% • < 0.5 servings daily 29.2% (relative risk [RR] 1.24) • 0.5-1 servings daily 29.8% (RR 1.25) • 1-1.5 servings daily 33.1% (RR 1.32) • ≥ 1.5 servings daily 35.6% (RR 1.35) • Reference - J Hypertens 2008 Feb;26(2):215

  33. association of caffeine intake with hypertension may depend on beverage type • coffee intake over years associated with small increase in blood pressure • 1,017 white male former medical students (mean age 26) followed for median 33 years • consumption of 1 cup of coffee a day raised adjusted systolic blood pressure by 0.19 mm Hg (95% CI 0.02-0.35) and diastolic pressure by 0.27 mm Hg (95% CI 0.15-0.39) • coffee drinkers had increased risk for hypertension compared with nondrinkers at baseline (28.3% vs. 18.8%, p = 0.03), drinking 5 or more cups/day associated with 1.35-1.6x relative risk for hypertension; none of these associations were statistically significant after adjusting for other variables • Reference - Arch Intern Med 2002 Mar 25;162(6):657, commentary can be found in Arch Intern Med 2003 Feb 10;163(3):370

  34. oral contraceptives may increase risk of hypertension • based on prospective cohort study of 68,297 healthy female nurses aged 25-42 years followed for 4 years • 1,567 developed hypertension • 1.5 times relative risk of hypertension with current use of oral contraceptives, increased to 1.8 times when adjusted for other factors • no increased risk from past use of oral contraceptives • absolute risk of hypertension due to oral contraceptives was only 41.5 cases/10,000 person-years • Reference - Circulation 1996 Aug 1;94(3):483

  35. some prospective cohorts find increased risk of hypertension with frequent analgesic use • higher daily doses of acetaminophen and NSAIDs associated with hypertension in 2 prospective cohort studies of women ages 51-77 years and women ages 34-53 years (Hypertension 2005 Sep;46(3):500) • frequent analgesic use, based on Nurses Health Study with 80,020 women ages 31-50 years followed for 2 years (Arch Intern Med 2002 Oct 28;162(19):2204), commentary can be found in Arch Intern Med 2003 May 12;163(9):1113 • aspirin, acetaminophen and ibuprofen use each associated with increased risk of incident hypertension in Nurses' Health Study (Hypertension 2002 Nov;40(5):604 in CMAJ 2003 May 27;168(11):1445)

  36. Short sleep duration: • sleep duration < 5 hours/night associated with 2.1 times risk of hypertension in cohort of 4,810 United States persons aged 32-59 years followed for 8-10 years of whom 647 were diagnosed with hypertension (Hypertension 2006 May;47(5):833) • sleep duration ≤ 5 hours/night associated with about 2 times risk of hypertension for women (but not in men) in cross-sectional analysis of 5,766 British persons aged 35-55 years, but results not statistically significant in longitudinal analysis (3,691 participants normotensive at baseline and followed mean 5 years) after adjusting for cardiovascular risk factors and psychiatric comorbidities (Hypertension 2007 Oct;50(4):693) • shorter sleep duration associated with increasing risk of hypertension • based on prospective cohort of 535 participants aged 33-45 years who had objective sleep duration and maintenance measurements and followed for 5 years • incident hypertension in 14% over 5-year follow-up • 37% increase in odds of incident hypertension associated with each hour of reduction in sleep duration • Reference - Arch Intern Med 2009 Jun 8;169(11):1055

  37. elevated C-reactive protein levels associated with increased risk of developing hypertension • based on 2 cohort studies • elevated C-reactive protein levels associated with increased risk of developing hypertension in dose-dependent fashion in prospective cohort study of 20,525 United States nurses > 45 years old followed median 7.8 years (JAMA 2003 Dec 10;290(22):2945), editorial can be found in JAMA 2003 Dec 10;290(22):3000, commentary can be found in Am Fam Physician 2004 Jun 15;69(12):2924 • elevated C-reactive protein levels associated with incident hypertension in 7-year follow-up of 3,919 young adults ages 25-37 years, but no significant association after adjusting for body mass index (Arch Intern Med 2006 Feb 13;166(3):345), commentary can be found in Arch Intern Med 2006 Jul 24;166(14):1526

  38. various single nucleotide polymorphisms in CYP19A1 gene associated with essential hypertension • based on case-control study with 218 patients with essential hypertension and 225 matched controls • Reference - Int J Med Sci 2008 Feb 7;5(1):29full-text • low ghrelin levels associated with type 2 diabetes and hypertension • based on case-control study with 1,045 subjects • Reference - Diabetes 2003 Oct;52(10):2546 • high levels of trait anger associated with increased risk for hypertension in men but not in women • based on cohort of 2,334 men and women aged 45-64 years with prehypertension but without heart disease or stroke at baseline and followed for 4-8 years • risk of progression to hypertension • 59.9% with low trait anger • 55.6% with medium trait anger • 66.7% with high trait anger • association significant in men but not in women

  39. Factors not associated with increased risk: • modifiable low-risk factors associated with decreased risk in healthy women • based on prospective cohort study • 83,882 women aged 27-44 years in second Nurses Health Study without hypertension, cardiovascular disease, diabetes, or cancer, and with normal reported blood pressure were followed for 14 years • incident hypertension in 14.7% • modifiable low-risk factors independently associated with risk of hypertension • body mass index (BMI) < 25 kg/m2 • daily vigorous exercise (mean 30 minutes) • high score on Dietary Approaches to Stop Hypertension (DASH) diet based on responses to food frequency questionnaire • modest alcohol intake (≤ 10 g/day) • use of nonnarcotic analgesics < 1/week • intake of supplemental folic acid ≥ 400 mcg/day

  40. high job stress not associated with developing hypertension in 5-year follow-up of 292 healthy adults (mean age 38 years) (Hypertension 2003 Dec;42(6):1112) • job strain associated with modest increases in systolic blood pressure in prospective study of 8,395 white-collar workers followed 7.5 years (Am J Public Health 2006 Aug;96(8):1436) • vitamin D intake not associated with risk of hypertension in 3 cohorts with 209,313 nurses and physicians followed for at least 8 years (Hypertension 2005 Oct;46(4):676) • high levels of anxiety and depression appear associated with lower systolic blood pressure 11 years later • based on cohort study in Norway • 36,530 persons aged 20-78 years followed for 11 years • Reference - Br J Psychiatry 2008 Aug;193(2):108

  41. birth weight does not appear to significantly affect adult blood pressure • systematic review found that birth weight has little effect on blood pressure later in life • 55 studies that reported regression coefficients found weaker associations with larger studies • studies with > 3,000 participants found inverse association of birth weight and blood pressure of only 0.6 mm Hg/kg • only 25 of 48 studies that did not report regression coefficients found inverse association • Reference - Lancet 2002 Aug 31;360(9334):659, commentary can be found in Lancet 2002 Dec 21-28;360(9350):2072 • low birth weight has been suggested as risk factor for hypertension, but likely a confounding factor as maternal hypertension associated with low birth weight and parental hypertension increases risk of hypertension (BMJ 1998 Mar 14;316(7134):834), commentary can be found in BMJ 1998 Sep 5;317(7159):680 and in BMJ 1999 Apr 3;318(7188):943

  42. Complications of Hypertension • Hypertension is a risk factor for: • Coronary artery disease (CAD) • Heart failure • Chronic kidney disease • Stroke • Intracerebral hemorrhage • Transient ischemic attack (TIA) • Peripheral arterial disease (PAD) • Aortic regurgitation • Atrial flutter

  43. Mortality associated with Hypertension • usual blood pressure directly related to vascular mortality at all pressures above 115/75 mm Hg and at all ages above 40 years • based on meta-analysis of individual patient data from 1 million adults in 61 prospective studies • Reference - Lancet 2002 Dec 14;360(9349):1903, correction can be found in Lancet 2003 Mar 22;361(9362), commentary can be found in Lancet 2003 Apr 19;361(9366):1389, Evidence-Based Medicine 2003 Jul-Aug;8(4):122 • increased blood pressure associated with increased all-cause and cardiovascular mortality • based on prospective cohort study in China • 169,871 Chinese adults ≥ 40 years old examined in 1991 and followed up 1999-2000 • hypertension and prehypertension associated with increased all-cause and cardiovascular mortality (p < 0.0001) • estimated deaths attributable to increased blood pressure in China in 2005 • 2.33 million cardiovascular deaths • 1.27 million premature (< 72 years old in men and < 75 years in women) cardiovascular deaths • 1.86 million blood pressure-related deaths attributed to cerebrovascular diseases • Reference - Lancet 2009 Nov 21;374(9703):1765, editorial can be found in Lancet 2009 Nov 21;374(9703):1728

  44. elevated blood pressure associated with increased long-term mortality in young men • study of 10,874 men aged 18-39 years followed for 25 years • blood pressure above normal associated with increased long-term mortality due to coronary heart disease, cerebrovascular disease, and all causes • Reference - Arch Intern Med 2001 Jun 25;161(12):1501, commentary can be found in Arch Intern Med 2002 Mar 11;162(5):610 • systolic (but not diastolic) blood pressure is a strong, positive, continuous and independent indicator of mortality risk in the elderly; 10-year follow-up of 3,858 outpatients > 65, 74 patients (1.9%) were lost to follow-up and 1,561 (41.3%) died, 709 (45.4% all deaths) died from cardiovascular causes; positive continuous, graded, strong and independent association observed with both total (P < 0.001) and cardiovascular (P < 0.001) mortality for systolic blood pressure (SBP) but not for diastolic blood pressure (DBP), no J-shaped mortality curve in subjects with lowest SBP and DBP (Arch Intern Med 1999 Jun 14;159(11):1205) • Stroke:

  45. Stroke • hypertension and type 2 diabetes increase risk of stroke independently based on 19-year prospective follow-up of 49,582 Finnish persons ages 25-74 years (Stroke 2005 Dec;36(12):2538) • stroke risk correlates with diastolic blood pressure (Lancet 1995 Dec 23-30;346(8991-8992):1647 in J Watch 1996 Jan 15;16(2);14) • midlife blood pressure associated with late-life stroke risk (Arch Intern Med 2001 Oct 22;161(19):2343), summary can be found in Am Fam Physician 2002 Mar 1;65(5):963 • blood pressure important determinant of stroke risk in eastern Asian populations, whereas cholesterol concentration less important; association between blood pressure and stroke seems stronger than in western populations; population-wide reduction of 3 mm Hg in diastolic blood pressure should eventually decrease number of strokes by about 1/3 (Lancet 1998 Dec 5;352(9143):1801)

  46. Cognitive decline: • midlife hypertension associated with late-life cognitive dysfunction (JAMA 1995 Dec 20;274:1846 in J Watch 1996 Jan 15;16(2):14) • hypertension associated with cognitive decline in 20-year follow-up of 529 persons aged 18-83 years (Hypertension 2004 Nov;44(5):631 in BMJ 2004 Nov 20;329(7476):1246) • End-stage regnal disease: • elevated blood pressure is a strong risk factor for the development of end-stage renal disease (N Engl J Med 1996 Jan 4;334(1):13 in QuickScan Reviews in Fam Pract 1996 Aug;21(5):9, Arch Intern Med 2005 Apr 25;165(8):923)

  47. Perinatal mortality: • maternal chronic hypertension associated with increased perinatal mortality in male infants • based on prospective cohort study of 866,188 women with singleton pregnancies • 4,749 (0.55%) were diagnosed with chronic hypertension • chronic hypertension in mothers associated with • intrauterine death odds ratio 3.07 for males • neonatal death odds ratio 2.99 for males • intrauterine death odds ratio 0.98 for females (not significant) • neonatal death odds ratio 1.88 for females (not significant) • Reference - BJOG 2008 Oct;115(11):1436

  48. Associated Conditions • obstructive sleep apnea • sleep disordered breathing and sleep apnea syndrome associated with hypertension • based on cross-sectional study of 6,132 middle aged or older individuals • association weak after adjustment for obesity • Reference - JAMA 2000 Apr 12;283(14):1829, correction can be found in JAMA 2002 Oct 23/30;288(16):1985 • editorial states that hypertension alone does not warrant testing for sleep apnea (JAMA 2000 Apr 12;283(14):1880 • strong association between hypertension and obstructive sleep apnea • based on cohort of 2,677 adults ages 20-85 years referred to sleep clinic for suspected sleep apnea • Reference - BMJ 2000 Feb 19;320(7233):479full-text, commentary can be found in BMJ 2000 Jul 22;321(7255):237full-text • sleep-disordered breathing associated with hypertension • based on study of 1,741 persons ages 20-100 years selected as those with higher risk for sleep-disordered breathing from interviews of 16,583 persons • Reference - Arch Intern Med 2000 Aug 14/28;160(15):2289, commentary can be found in Arch Intern Med 2001 Nov 26;161(21):2634 • sleep-disordered breathing associated with increased risk for hypertension • based on prospective study of 709 persons who had polysomnography and were followed 4 years • dose-response relationship found even after adjustment for known confounding factors • Reference - N Engl J Med 2000 May 11;342(19):1378, commentary can be found in N Engl J Med 2000 Sep 28;343(13):966 • drug-resistant hypertension may be associated with high rate of sleep apnea • based on case series of 41 patients on 3 or more antihypertensive medications • 83% found to have AHI > 10/hour on overnight polysomnography • Reference - J Hypertens 2001 Dec;19(12):2271 • see Cardiovascular disease and obstructive sleep apnea for details

  49. higher blood pressure associated with higher rate of bone loss in 3,676 elderly white women followed mean 3.5 years, even among women not taking antihypertensive agents (Lancet 1999 Sep 18;354(9183):971) • increased prevalence of panic attacks and panic disorder among hypertensive patients; 351 hypertensive patients compared with normotensive controls, 17-19% vs. 11% had panic attacks within 6 months, 33-39% vs. 22% had history of panic attacks, 13% vs. 8% had panic disorder (Am J Med 1999 Oct;107(4):310 in JAMA 2000 Jan 5;283(1):29)

  50. hypertension is a risk factor for type 2 diabetes • prospective study of 12,550 persons 45-64 in Atherosclerosis Risk in Communities (ARIC) study who did not have diabetes at baseline and were evaluated at 3 years and 6 years • diabetes defined at all time points as fasting glucose > 125 mg/dL (7 mmol/L), nonfasting glucose > 200 mg/dL (11 mmol/L), use of insulin or oral hypoglycemic agent, or physician's diagnosis of diabetes • overall incidence of diabetes was 16.6 cases per 1,000 person-years • hypertension increased risk by relative risk of 2.43 (95% CI 2.16-2.73) • incidence of diabetes was 12 per 1,000 person-years in 8,746 subjects with normal blood pressure • incidence of diabetes was 29.1 per 1,000 person-years in 3,804 subjects with hypertension • among 3,804 subjects with hypertension • subgroup analysis performed to examine risk differences between different classes of antihypertensives and no treatment • classification of use of medications based on asking patient whether the medication had been prescribed to treat high blood pressure • thiazide diuretics, ACE inhibitors and calcium channel blockers were not shown to increase risk of diabetes {significance of this finding is that "risk" of diabetes is not a valid reason to withhold thiazide diuretics} • no significant differences upon comparing drug classes • beta blockers associated with statistically significant increased risk for diabetes compared to no treatment for hypertension with relative risk of 1.28 (95% CI 1.04-1.57, number needed to harm [NNH] with use of beta blockers if this association is true is 122 patients per year) • Reference - N Engl J Med 2000 Mar 30;342(13):905, editorial can be found in N Engl J Med 2000 Mar 30;342(13):969,

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