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Stemming the Tide of Cardiovascular Disease: Transitioning from OI to CVD Prophylaxis

Stemming the Tide of Cardiovascular Disease: Transitioning from OI to CVD Prophylaxis



Tyler Lonergan, MD, of the UC San Diego Owen Clinic, presents "Stemming the Tide of Cardiovascular Disease: Transitioning from OI to CVD Prophylaxis" for AIDS Clinical Rounds at UC San Diego

Tyler Lonergan, MD, of the UC San Diego Owen Clinic, presents "Stemming the Tide of Cardiovascular Disease: Transitioning from OI to CVD Prophylaxis" for AIDS Clinical Rounds at UC San Diego

Clinical Professor
UC San Diego Owen Clinic



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    Stemming the Tide of Cardiovascular Disease: Transitioning from OI to CVD Prophylaxis Stemming the Tide of Cardiovascular Disease: Transitioning from OI to CVD Prophylaxis Presentation Transcript

    • AIDS CLINICAL ROUNDS The UC San Diego AntiViral Research Center sponsors weekly presentations by infectious disease clinicians, physicians and researchers. The goal of these presentations is to provide the most current research, clinical practices and trends in HIV, HBV, HCV, TB and other infectious diseases of global significance. The slides from the AIDS Clinical Rounds presentation that you are about to view are intended for the educational purposes of our audience. They may not be used for other purposes without the presenter’s express permission.
    • Stemming the Tide of Cardiovascular Disease in HIV-infected Persons: Transitioning from OI Prophylaxis to CVD Prevention Tyler Lonergan, MD Clinical Professor of Medicine
    • Case Presentation • 51 year old male w/ HIV (CD4=406/20%, VL<20 on ART) and HTN who presented to Owen Clinic complaining of epigastric pain • Pt experienced extreme dizziness on the night before, while getting out of the jacuzzi at the gym. It was followed by a dull epigastric pain, which he suspected to be due to indigestion. The pain progressed overnight, became sharp in quality, radiated to the L side of his chest, back, and L arm. It was accompanied by nausea, non-bloody emesis, and loose stools • In the following morning, he called the Owen Clinic and scheduled an appointment to be seen in the afternoon despite their advice to go to the UCSD Hillcrest ED • At around 14:30 while standing in line to check into the clinic, he became weak, lightheaded, diaphoretic, and developed L hand numbness
    • Case Presentation • PMHx: HIV Dx 2002 (CD4 nadir 29), Herpes Zoster, LTBI, hypogonadism, depression/ anxiety, osteoporosis, s/p appy, HTN, dyslipidemia (TC 197, HDL 37, LDL 109, TG 253) • Meds: efavirenz, abacavir, lamivudine, testosterone gel, losartan, paroxetine, alendronate, Vit D, Ca • ScHx: single, lives alone, homosexual (not sexually active), smokes 1-2 ppw x 12 years, no etoh or illicit drug abuse • FmHx: mother MI @ 82 yo; uncle, aunt & GF CVA in late 60s • PEx: thin, anxious, ill appearing, T: 97.8 , BP: 88/58, HR: 87 HEENT: no icterus, no oral lesions, JVP <5 cm, no lad CV: RRR, nl s1,2, no m,r,g Lungs: CTAB Abd: nabs, soft, ttp over epigastric area, no HSM Ext: no edema • DDx: PUD, pancreatitis, acute MI • Sent to ED via ambulance
    • ED Course • Upon arrival in ED at 16:12, he was hypotensive at 80s/50s, HR 80s, and had abnormal ECG. A STEMI code was called, and cath lab was emergently activated. Serum cardiac markers (CPK, CK-MB and index, Troponin T) were all elevated. Heparin bolus and drip, prasugrel, ASA, atorvastatin and oxygen given
    • ED and Cath Lab • Developed 3rd degree AV block, bradycardia in 30-40s. Atropine given and external, transcutaneous pacing initiated. Pt then went into VT/VF and was shocked once at 150J and converted back into sinus bradycardia. Also received a dose of Amiodarone • In the cath lab, his RCA was found to be 100% occluded and 2 DES were placed. He continued dopamine drip to sustain SBP in the 70s-80s
    • Hospital Course • Echocardiogram: inferior and posterior wall hypokinesis, EF 48% • Peak CPK: 6306 • Pressure on the chest, sob, dizziness slowly improved over the week • New onset of dry cough morning HD#2. Found to have pulmonary edema on CXR. Edema resolved w/ diuresis • Pt was in persistent sinus bradycardia but it slowly converted to a normal rate over the week • His hemodynamic status was initially grossly unstable w/ low BP, requiring dopamine infusion for 5 days. Unable to start BB or ACEI due to borderline BP and bradycardia
    • Question #1 • For this patient which of the following is not a risk factor for CVD? – – – – – – – – HIV CD4 Abacavir Lipids Age Smoking HTN None of the above (all RFs)
    • Question #2 • Prior to his MI which lipid lowering medication would you have prescribed? – Statin – Niacin – Fibrate – Omega 3 Fatty Acids – None of the above
    • Question #3 • Prior to his MI would you have prescribed aspirin? – Yes – No – Uncertain
    • Leading Causes of Death among All Americans Age>9yo, 2009
    • Prevalence of CHD by Age and Gender National Health and Nutrition Examination Survey: 2007-2010 Source: National Heart, Lung and Blood Institute
    • AMI rates in HIV vs non-HIV VA patients • More than 80,000 veterans with nearly 6 years of follow-up had 871 acute myocardial infarctions (AMIs) • Across 3 decades of age, mean AMIs per 1000 person-years was consistently higher for PLHIV than HIV negative people • Hazard ratio was 1.5 after adjusting for Framingham risk factors, comorbidities, and substance use
    • Meta-analysis: Relative Risk of CHD in HIV vs nonHIV Islam FM et al. HIV Medicine 2012
    • Increased Rates of other CVD in PLHIV • Sudden cardiac death - SF clinic: 4.5 fold increased risk of SCD compared to expected city-wide rate1 • Heart Failure – VA cohort: compared with HIV-uninfected veterans, those who were HIV infected had an increased risk of HF (adjusted HR, 1.81). Those with baseline HIV RNA>500 had increased risk of HF while those with baseline or most recent HIV RNA<500 did not2 • Atrial Fibrillation – VA Cohort: lower CD4(+) cell count (<200 compared with >350; HR: 1.4) and higher viral load (>100,000 compared with <500 copies/ml; HR: 1.7) were independently associated with increased risk of AF. Additional RFs: older age, White race, CAD, CHF, etoh, proteinuria, reduced kidney function, and hypothyroidism3 • Stroke – Boston Cohort: HR of ischemic stroke 1.21 in HIV vs non-HIV. Increased HIV RNA was associated with an increased risk of IS4 – In US from 1997 to 2006 stroke hospitalizations with coexisting HIV infection rose 60% (888 to 1425)5 • PAD6 1 Tseng ZH er al. J Am Coll Cardiol 2012, 2 Butt AA et al. Arch Intern Med 2011, 3 Hsu JC et al. J Am Coll Cardiol 2013, 4 Chow FC et al. JAIDS 2012, 5 Ovbiagele B et al. Neurology 2011, 6 Ye Y et al. JAIDS 2010
    • Age Distribution by Year: Swiss HIV Cohort Hasse B, et al. CID 2011
    • Aging of Owen Clinic Patients
    • Distribution of Owen Clinic Patients by Age Group and Year
    • Life Expectancy at Age 20 among Treated HIV+ North Americans • Estimate temporal changes in life expectancy among HIV+ adults on ART from 2000-2007 in US and Canada • 22,937 participants from NA-ACCORD Cohort • 1622 deaths; crude mortality rate 19.8/1000 py • Life expectancy was lower for individuals with a history of IVDU, non-whites, and in patients with baseline CD4 counts <350 cells/mm3 Samji J, et al. PLOS ONE 2013
    • Causes of Death in PLHIV on ART • Retrospective classification of deaths in 39,272 European and NA patients who initiated ART from 1996-2006 and were enrolled in one of 13 HIV cohort studies • 1597/1876 deaths a definitive cause of death identified Antiretroviral Therapy Cohort Collaboration CID 2010
    • Traditional CVD Risk Factors in HIV vs Non-HIV a statistically significant comparison of HIV and non-HIV proportions, with X2 (P<0.0001) Triant VA, et al. J Clin Endocrinol Metab 2007
    • Other Risk Factors for CVD in PLHIV • Low CD4 count: – HOPS COHORT: Baseline CD4<500 was an independent RF for CVE and risk of CVE attributable to baseline CD4<500 was comparable to smoking and dyslipidemia1 • Detectable Viral load – SMART TRIAL: Hazard Ratio for risk of CVD events for DC vs VS was 1.57 (95% CI 1.00 – 2.46; P=0.05)2 1Lichtenstein KA, et al. CID 2010, 2Phillips N, et al. Antiviral Therapy 2007
    • Antiretrovirals and MI Risk • Abacavir: – Meta-analysis of observational studies indicate increased risk of MI with <6 months of exposure to abacavir (RR 1.92, 95% CI 1.51-2.42) – Meta-analysis of RCTs found no association between abacavir use and MI • Protease inhibitors: – Meta-analysis of observational studies found increase in risk of MI with recent PI exposure (OR 2.13, 95% CI 1.06 – 4.28) and cumulative exposure to indinavir (RR 1.11, 95% CI 1.05 – 1.17) and lopinavir (RR 1.22 (95% CI 1.01 – 1.47) – Meta-analysis of RCTs failed to demonstrate an association between PI use and MI C Bavinger PLOS One 2013
    • Causes and Consequences of HIVassociated Inflammation S Deeks et al. The Lancet. 2013
    • Primary Prevention of CHD • Non-modifiable RF (age, gender, family history) • Modifiable RF (via lifestyle changes +/- meds) – – – – – – – – – • Poor diet Smoking Hypertension Dyslipidemia Physical inactivity Obesity Diabetes mellitus Heavy alcohol consumption HIV Additional adjunctive medication intervention: aspirin
    • Mortality attributable to Smoking in PLHIV • Danish cohort • 2921 HIV+ patients, 10,642 HIVcontrols • Among PLHIV 47.4%, 17.7%, 34.9% were current, former and never smokers and among HIVcontrols corresponding rates were 20.6%, 32.8%, 46.6% • Among PLHIV relative MR from CVD in smokers 4.3 higher than in never smokers • Excess mortality of smokers is tripled (17.6 vs 4.8/1000 py) and population-attributable risk of death associated with smoking is doubled (61.5% vs 34.2%) among HIV+ patients compared to HIVcontrols Helleberg, M et al. CID 2013
    • Smoking Cessation Reduces Risk for Cardiovascular Events • D:A:D Cohort • More than 27,000 patients had a total of 1778 CVEs or mortality • Adjusted incidence rate ratio of CVD in patients who stopped smoking decreased from 2.3 within the first year of stopping to 1.5 after > 3 years compared with those who never smoked. Similar trends were observed for the MI and CHD endpoints Petoumenos et al, HIV Medicine 2011
    • Question #4 • Which guidelines do you use to determine who should go on lipid lowering therapy? – 2013 ACC-AHA – NECP ACT III – IDSA/ACTG – Other – Do not use any
    • 2003 IDSA/ACTG Dyslipidemia Guidelines for HIV+ Persons Dube MP, et al. CID 2003
    • NCEP ATP III Cholesterol Guidelines http://my.americanheart.org/professional/StatementsGuidelines/PreventionGuidelines/Prevention-Guidelines_UCM_457698_SubHomePage.jsp
    • NCEP ATP III Guidelines TLC: low saturated fat diet, increase physical activity and weight management Consider drug simultaneously with TLC for CHD and CHD equivalents Consider adding drug to TLC after 3 months for other risk categories. http://my.americanheart.org/professional/StatementsGuidelines/PreventionGuidelines/Prevention-Guidelines_UCM_457698_SubHomePage.jsp
    • NCEP ATP III Cholesterol Guidelines If TG>500 treat TG first Non-HDL goal 30 mg/dL higher than LDL goal http://my.americanheart.org/professional/StatementsGuidelines/PreventionGuidelines/Prevention-Guidelines_UCM_457698_SubHomePage.jsp
    • 2013 ACA-AHA Cholesterol Guidelines
    • High and Moderate-Intensity Statin Therapy according to ACC-AHA Cholesterol Guidelines
    • 2013 ACC/AHA CV Risk Calculator http://my.americanheart.org/professional/StatementsGuidelines/PreventionGuidelines/Prevention-Guidelines_UCM_457698_SubHomePage.jsp
    • D:A:D 5 year Estimated Risk Calculator* • BMI, lipodystrophy, TGs, CD4 and VL were assessed and excluded based on nonsignificance • Risk of CHD over 5 year period: – – – – Low (<1%) moderate (1-5%) high (6-10%) very high (>10%) • DAD model better predicted CVE than an older FRAM equation (one used did not include variable for treated HTN and had differences in outcomes measured) • Not validated externally *http://www.cphiv.dk/TOOLS/DADRiskEquations/tabid/437/Default.aspx Friis-Moller N, et al. Eur J Cardiovasc Prev & Rehabil 2010
    • Updated D:A:D risk models • Additional 80,000 PY of follow-up (total 180,000 PY) • One outcome only: Global CVD risk • Based on baseline rather than time-updated risk parameters (Cox Model) • Full and Reduced D:A:D models (+/- ARVs) • Updated Models will be available at www.CPHIV.DK (updated models still currently unavailable) N Friis Moller et al. 14th European AIDS Conference 2013
    • 3 CVD Risk Models N Friis Moller et al. 14th European AIDS Conference 2013
    • 5-year CVD risk by Age and Diabetes N Friis Moller et al. 14th European AIDS Conference 2013
    • UpToDate Treatment of Lipids in Primary Prevention Guidelines • Counsel all patients to exercise, eat a prudent diet and lose weight as appropriate • Calculate pt’s baseline risk for CVE (using FRC) and treating with statin in pts for whom 20-30% reduction in events translates into absolute reduction in events worth costs and burdens of daily therapy • Do not recommend specific LDL target or calculated CV risk cutoff to determine use of statin • If decision made to treat then use moderate statin dose (eg, pravastatin 40 mg, atorvastatin 20 mg, rosuvastatin 5-10 mg)
    • UpToDate Cholesterol Guidelines • Recommend measuring LDL 6 weeks after starting statin and every 6-12 months thereafter to assess med adherence only • Do not recommend monitoring LDL response to therapy or intensifying dose to achieve any particular LDL goal • Do not recommend nonstatin lipid-lowering therapy in pts who do not tolerate statins or adding them in pts who do not achieve a particular LDL level on a statin alone.
    • 2013 Cochrane Review of Statins for primary prevention of CVD Incidence of cancers, myalgia, rhabdomyolysis, LFT elevation, renal dysfunction, or arthritis and rates of adverse events (17%) and stopping treatment (12%) did not differ between statin and placebo groups. An increase risk of incident of diabetes (RR 1.18 [95% CI, 1.01-1.39], NNT 198) found in 1/2 trials reporting this outcome. No long term data on health related QOL outcomes. Taylor F, et al. Cochrane Database Syst Rev. 2013
    • Statin Affects on Inflammatory Markers in PLHIV • Retrospective cohort study • 151 HIV+, dyslipidemic pts on stable ART who were started on a statin and followed for ≥12 mo Calza L, et al. HIV Cin Trials 2012
    • Statin Affects on Immune Activation in PLHIV • Randomized, double-blind, placebo-controlled crossover trial to investigate effect of statin on HIV RNA and cellular markers of immune activation • 24 untreated HIV+ pt randomized to receive 8 weeks of atorvastatin 80 mg or placebo daily. After 4-6 week washout phase, participants switched treatment assignments Ganesan A, et al. JID 2011
    • Affect of Rosuvastatin on cIMT and lipids in PLHIV • 36 adult (30 M) HIV+ pts, mean age 49 yr, mean duration of ART 38 mo, mean 10 yr risk of MI 18.5%. • Rosuvastatin 10 mgdaily x 24 months • Well tolerated, no adverse events Calza L, et al. AIDS Res Hum Retroviruses 2013
    • Association between Statins and Mortality in PLHIV • JH HIV Cohort • 238/1538 pt fully suppressed on ART were also taking a statin • 85 deaths (7 on statins) – 12 cardiovascular (2 on statin) • Statin use associated with relative hazard of 0.33 (95% CI: 0.14-0.76; P=0.0009) of all cause mortality after adjusting for multiple factors Moore RD, et al. PloS One 2011
    • Aspirin • Aspirin has been shown to be effective in the primary and secondary prevention of AMI in the general population • No study looking at the effect of aspirin in prevention of CVD in PLHIV • Decrease cardiovascular events via: – Antiplatelet effects – Increased nitric oxide formation – Anti-inflammatory effects • Heightened platelet activation and immune activation in treated HIV-infected patients were attenuated by 1 week of aspirin therapy (325 mg loading dose followed by 81 mg daily)1 1 O’Brien M, et al. JAIDS 2013
    • Aspirin Primary Prevention of CVD • Pooled data from RCT in general population suggest aspirin is associated with: – ~20% relative risk reduction in non-fatal MI – No significant effect on non-fatal stroke (including hemorrhagic stroke) – ~12% relative risk reduction in cancer incidence – ~50% increase in relative risk of major non-fatal extracranial bleed – ~6% reduction in relative risk in overall mortality
    • Estimated Absolute Benefits and Risks of Aspirin for Primary Prevention • Daily aspirin use in a thousand 60 yo HIV negative pts with avg risk (10-20%) for CAD and malignancy (~12%) over 10 yr period: – 6 fewer deaths – 6 fewer cancers – 17 fewer non-fatal MI – No significant reductions in non-fatal strokes – 16 more major bleeding events (IC, GI or other requiring hospitalization +/- transfusion)
    • Caveats of Aspirin Use • Low dose as effective as higher dose with possibly less side effects • Do not use concurrently with warfarin • Avoid concurrent use of NSAIDs (reduces anticardioprotective effects and increases risk of GIB) • Avoid use in patients with history of PUD or other risk factors of GIB
    • Guidelines for Aspirin Use • UTDOL: individualize assessment of patient’s risk for MI, cancer and bleeding and discuss results with patient to determine patient’s preference. For individuals age ≥50 yr without excess bleeding risk, suggest low dose daily aspirin • ACCP 2012: suggest low-dose aspirin (75-100 mg) daily over no aspirin therapy for persons ≥50 yr without symptomatic CVD • European Society of Cardiology 2012: advise against use of aspirin in individuals without CVD due to risk of major bleeding • USPTF 2009: recommends for men 45-79 yo for MI prevention and women 55-79 for stroke prevention if benefits outweigh risks • No specific guidelines for HIV+ patients
    • USPSTF Aspirin for Primary CVD Prevention Guidelines Does not apply to adults taking NSAIDs (4x GIB risk), have upper GI pain or Hx of GI ulcers (2-3x GIB risk) USPSTF Ann Intern Med 2009;150:396-404
    • Underutilization of Aspirin for primary prevention of CVD in qualifying PLHIV • UAB HIV Clinic: 66/397 (17%) patients who qualified to receive ASA were prescribed it1 • Spanish Cohort: 2/37 patients who met criteria for aspirin for primary prevention of CVD were prescribed it2 1 Burkholder GA, et al. CID 2012, 2 Tornero CA, et al. JAIDS 2010
    • Undertreatment of CVD RFs • Multicenter German Cohort: Almost half of patients with DM and HTN were untreated. LDL appropriately treated <50% in patients at moderate CHD risk and <70% at high risk 1 • VACS: 39% of HIV+ vs 62% of HIV- vets (OR 0.45) received appropriate lipid lowering therapy2 • HOPS: 81%-87% treated for elevated LDL but only 2-11% for low HDL (NCEP ATP III guidelines) and 46-59% for HTN3 1Reinsch N, et al. Eur J Prev Cardiol 2012, 2 Freiberg MS, et al. J Gen Intern Med 2009 3Lichenstein KA, et al. Preventing Chronic Disease 2013
    • Case: Statin/ASA for primary MI prevention? • • • • PreMI lipids: TC 197, HDL 37, LDL 109, TG 253, nonHDL 160 Traditional RFs: HTN, Smoker, Low HDL, Age HIV related RFs: CD4<500, abacavir NCEP ATP III: – 10-year risk: 16% – 2+RF, 10-yr risk ≤20%: LDL goal <130, nonHDL goal<160 – At goal LDL, slightly above nonHDL goal, initiate TLC and consider drug therapy • ACC/AHA 10-year risk: 12.6% – Recommend high-intensity statin therapy • D:A:D 5 year risk: 7.4% (high risk) • USPSTF Guidelines: – 10-year risk: 17% – Recommend aspirin
    • First MI among Owen Clinic Patients 2012+2013 • 11 patients • All male • Race: 6 W, 3 L, 1 Asian, 1B • Mean Age: 49 (range: 3857), 2<45 yo • 8/11 on ART • Mean CD4: 488 (1601253) • Viral Load: 8/11<100 • Mean TC: 188 (126-241) • Mean HDL: 39 (21-52), 6/11<40 • Mean LDL: 107 (61-175), 3/11<70, x/11<100 • Current Smoker: 6/11 • Hypertension: 4/11 • DM: 2/11 • ACC/AHA Calculator: mean (range): 7.4% (2.9%-16.2%) • UTDOL FRAM Calculator: 16.5% (6.7%-33.8%)
    • First MI at Owen Clinic • Prescribed Aspirin prior to MI: 2/11 – 8/11 met USTSPF criteria – Of 3 who did not meet criteria: • 1 calculated risk below threshold • 2 <45 yr • Prescribed Statin prior to MI: 1/11 – 4/11 met ACC-AHA criteria – Of 7 who did not meet criteria: • 3 had LDL<70 • 4 risk <7.5% • 10/11 patients had stents – 8 DES, 2 BMS – 4 had 1 stent, 6 had 2 stents • 1 CABG • All survived MI and are still alive
    • Summary • Due to advances in ART, the life expectancy of PLHIV is approaching that of the general population • PLHIV are at greater risk for developing CVD due to HIV-associated inflammation and immune activation and higher rates of traditional CVD RFs • Encourage all patients to adopt a healthy life style • Treat HIV and identify and manage modifiable traditional CVD RFs
    • Summary II • Use of interventions for primary prevention of CVD are underutilized • Aspirin and statins provide anti-inflammatory and immune deactivation effects that may provide additional benefits for PLWH • Current guidelines for use of aspirin and statin therapy for primary prevention of CVD in the general population use risk calculators that do not account for the deleterious effect of HIV and therefore likely underestimate the CVD risk for PLWH • In 2012 and 2013 most Owen Clinic patients did not meet current guideline criteria for aspirin or statin use due to young age, low LDL or low calculated risk prior to their MIs. Consider the following for PLWH: – account for HIV-related risk factors (e.g, CD4 count, viral load) when determining risk – start statins and aspirin at younger ages than currently recommended for general population – use statins at lower doses in high risk patients with LDL<70 – use new D:A:D HIV risk calculator when available or if using ACC-AHA calculator then multiply determined risk by 1.5