RECENT ADVANCES IN INTERNAL MEDICINE
From University of California, San Francisco, School of Medicine’s 35th Annual Advances in Internal Medicine
| AMBULATORY MEDICINE: YEAR IN REVIEW — Jeffrey Kohlwes, MD, MPH, Associate Professor of Clinical
Medicine, University of California, San Francisco, School of Medicine, and Director, Veterans Affairs Medical Center
PRIME Program, San Francisco
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| Nonsteroidal anti-inflammatory drugs (NSAIDs) and cardiovascular (CV) risk: until 1997, NSAIDs
16th leading cause of death in United States, due to gastrointestinal (GI) bleeding; led to development of cyclooxygenase-2
(COX-2) inhibitors; rofecoxib (Vioxx) reduced bleeding 66% compared to naproxen (Naprosyn), but associated
with 5-fold increase in CV outcomes (largely ignored); in 2004, adenoma prevention trial found 2-fold
increase in CV mortality in rofecoxib group (similar findings in trial of celecoxib); attributable risk reduction 1.6,
and number needed to harm 62.5 in rofecoxib trial (causing 1 heart attack or stroke in 62.5 low-risk patients), resulting
in ≈160000 strokes and heart attacks; rofecoxib withdrawn from market
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 | How COX system works: COX-1 produced in stomach for GI cytoprotection and causes platelet aggregation (prothrombotic);
COX-2 induced by proinflammatory stimuli; COX system homeostatic; selective inhibition of
COX-2 inhibits COX-2 in endothelium, causing vasoconstriction and decreased platelet inhibition; unopposed
COX-1 leads to platelet aggregation and thrombotic CV events (myocardial infarction [MI] and stroke)
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| Other NSAIDs also problematic: while COX-2 inhibitors increased relative risk (RR) for MI 86% in normal-risk patients,
ibuprofen and diclofenac also increased risk; Danish study—looked at mortality in all patients discharged after
first MI from 1995 to 2002; patients receiving rofecoxib had 5- to 6-fold increased rate of mortality; risk also
increased after exposure to ibuprofen (doubled), and diclofenac (more than doubled), and any other NSAID
(slightly); demonstrates prothrombotic effect of nonselective COX inhibitors (“really pretty scary”); bottom line—
caution required using NSAIDs in patients after MI; number needed to harm for rofecoxib 13, celecoxib ≈13, ibuprofen
(>1200 mg per day) 45; naproxen relatively low risk compared to other nonselective NSAIDs, but not without
risk for thrombotic complications
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| Treatment guidelines from American Heart Association: stepped-care approach for patients with arthritis-type pain
and known coronary artery disease (CAD); step 1—regular exercise; glucosamine (1500 mg per day); acetaminophen
or aspirin; opioids for short-term pain relief; step 2—aspirin and proton pump inhibitor (PPI) or misoprostol
combined with NSAID (naproxen first recommendation; followed by ibuprofen, then diclofenac); to
preserve aspirin’s antiplatelet effect—take aspirin 30 min before or 6 hr after NSAID dose; step 3—COX-2 inhibitors;
speaker’s recommendation—consult with rheumatologist before beginning COX-2 inhibitor
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| Bottom line: prothrombotic effect of NSAIDs dose- and time-related; risk acceptable for 1-wk course of NSAID
for acute injury; avoid NSAIDs in patients with CAD; avoid COX-2 inhibitors “unless really pushed”
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| Saw palmetto: found no better than placebo for prostate symptoms
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| Green tea: contains polyphenols, free radical scavengers shown in vitro to reduce cardiovascular disease (CVD)
and carcinogenesis; large cohort study in Japan found drinking 100 to 200 mL per day can lead to 25% reduction in
RR for CV mortality; reduced risk for diabetes associated with caffeine intake (benefit greater with coffee); green
tea not found to reduce risk for cancer in vivo
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| Influenza update: annual infection rate 10% to 15% worldwide; 30000 to 35000 deaths annually in United States
(fifth leading cause); 90% of deaths in people >65 yr of age; 90% of costs indirect, eg, work days lost; influenza
virus—envelope RNA virus with 3 major proteins on cell surface; neuraminidase (breaks down neuraminic acid
in respiratory mucin, allowing penetration of host defense; causes cell lysis after viral replication); hemagglutinin
(allows virus to stick to respiratory endothelium); M2 protein (only on type A; allows enzymes to enter and
uncoat virus before replication); all treatments based on M2 protein and neuraminidase; subtypes infecting
humans—H1N1; H3N2; ability of body to produce antibodies to previous viral strains affects body’s ability to
resist new viral strain each year; rapid changes in virus require annual change in vaccine
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| Resistance to adamantine derivatives: amantadine and rimantadine effective at reducing influenza symptoms (by 2 days)
and infectivity to others; less expensive than newer drugs; widespread resistance to adamantines began in 2004; 2006
study by Centers for Disease Control and Prevention (CDC) found 92% of H3N2 strains resistant (due to point mutation
in M2 protein); source of resistance—in response to severe acute respiratory syndrome (SARS) epidemic,
adamantine derivatives became widely available over-the-counter, especially in Southeast Asia; change in
recommendation—more expensive drugs (eg, oseltamivir [Tamiflu]) first-line therapy
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| Prevention key: routine annual vaccination recommended for patients >50 yr of age; data show vaccination resulted
in 50% reduction in death from all causes in patients >65 yr of age; encouraging development—although
2004 influenza vaccine poorly matched to annual antigenic drift in influenza virus, vaccination led to 77% reduction
in influenza in patients diagnosed with viral culture; raises possibility that vaccine may be effective against
avian influenza even though virus undergoing antigenic drift
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| Avian influenza: 1918 to 1919 influenza pandemic—avian influenza virus responsible; killed more humans than any
other disease in similar period in world history; ≤90 million died; life expectancy worldwide reduced 13 yr; 25%
of US population infected; avian influenza last year—spread through close contact between humans and birds;
children most likely to encounter bird feces (probable cause of infection); encouraging hygiene essential if virus
appears in United States; point on diagnosis—rapid influenza test ineffective for bird flu
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| Carotid stents: North American Symptomatic Carotid Endarterectomy Trialists (NASCET) found procedure clearly
beneficial in patients with symptomatic unilateral stenosis; 2.5% surgical risk vs 13.1% medical risk; number
needed to treat 8 to prevent bad outcome at 2 yr; level of risk requires <6% rate of surgical side effects; must be
performed at center of excellence; factors increasing risk include triple vessel disease and transient monocular
blindness; Stent-supported Percutaneous Angioplasty of the Carotid vs Endarterectomy (SPACE) Trial showed
stents effective, but even in carotid endarterectomy group, rate of side effects unacceptable; French study presented
contradictory findings (dramatic worsening with stents); overall, studies fail to provide clear guidance
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| Recommendation for carotid stenting: identify center of excellence; refer only patients “you firmly believe” will
not have good outcome with carotid endarterectomy
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| Asthma and long-acting beta2-agonists (LAbeta2As): pathogenesis of asthma—inflammation; smooth muscle
hypertrophy; mucous gland hypertrophy; leads to airway hyperreactivity and wheezing
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| Chronic disease model: suppress symptoms; long-term control with inhaled corticosteroids (ICS); short-term β-agonists
alone increase mortality; step-up approach for breakthrough symptoms
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| Long-term medications for moderate asthma
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| ICS: first-line drugs; 21% reduction in RR for mortality per canister prescribed
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| Anticholinergics: probably ineffective, except in patients with Arg-Arg genetic mutation (mostly in black patients);
consider referral to asthma specialist for black patients refractory to ICS
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| Antileukotrienes: 33% to 50% as effective as ICS overall in preventing exacerbations
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| Mast cell stabilizers: for exercise- and cold-induced asthma
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| LA β2 As: more effective than antileukotrienes
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| Recent findings: head-to-head trial found fewer exacerbations with triamcinolone (6%) vs LA β2 A, salmeterol
(24%); results likely due to large amount of inflammation not suppressed with LA β2 A; increased mortality—
meta-analysis of all placebo-controlled trials of ≥3-mo duration; found odds ratio 2.6 times higher for exacerbations
and 3.5 times higher for death; probably explained by failure of patients to continue ICS use
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| “Absolute take-home message”: restrict LA β2 A use to add-on therapy for patients on ICS; patients must not use
LA β2 A alone, only in combination with ICS; newly published study found pump spray combining LA β2 A and
ICS effective in reducing exacerbations; indicates probable direction of therapy
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| Helmets and head injuries: recommend helmet use by any active patient coming in for routine visit; millions of patients
ski or ride boards; head injuries leading cause of admission to hospital (for observation); 8% of admitted patients
die after skiing head injuries; helmets reduce injuries in—bikers; motorcyclists; skateboarders; skaters (inline
and ice); Norwegian study—found helmets produced 60% RR reduction for head injuries and 55% RR reduction for
severe injuries
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| Questions and answers: surgeon quality—surgeons increasingly pressured to record side effect rates; institutions
encourage practice to increase referral base; Kaiser developed centers of excellence model (eg, for endarterectomy);
glucosamine—meta-analysis found 25% reduction in symptoms in patients taking glucosamine (1500 mg/
day) for ≥3 mo; no benefit for first 3 to 6 mo
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| PREVENTING HPV INFECTION AND CVD IN WOMEN —Judith M. Walsh, MD, Associate Professor of Medicine,
University of California, San Francisco, School of Medicine (UCSF), and UCSF Women’s Health Clinical Research
Center, San Francisco
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| Human papillomavirus (HPV) vaccine: in several studies, found effective against most common cancer-causing
HPV types; two vaccines—quadrivalent (against HPV types 6, 11, 16, and 18) recombinant vaccine (Gardasil)
approved and currently in use; bivalent, against HPV type 16 and 18; administration—3-dose series (at 0, 2,
and 6 mo); cost ≈$360; duration of protection ≤5 yr (more studies needed)
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| Recommendations: routine vaccination for girls 11 to 12 yr of age (≥9 yr of age possible); girls 13 to 18 yr of age to
catch up on missed dose or to complete series; insufficient data to recommend for or against routine vaccination
of women 19 to 26 yr of age; not recommended—for women >26 yr of age or for men; screening for cervical
cancer—continue regardless of vaccination status; HPV testing before vaccination not recommended
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| Condom use and HPV prevention: study analyzed 82 women (average age 19 yr) followed for 34 mo; findings—
after first intercourse in first 12 mo, 37% cumulative incidence of new HPV infection; women whose partners
used condoms 100% of time much less likely to acquire HPV infection than women whose partners used condoms
<5% of time; trends similar for high- vs low-risk HPV types and for cervical vs vulvovaginal infection; no
incidence of cervical squamous intraepithelial lesions during 32 patient-years at risk in women whose partners
used condoms 100% of time vs 14 during 97 patient-years of exposure in women whose partners used condoms
less consistently
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| Conclusion: women and men can be counseled that condom use prevents HPV transmission in addition to other
benefits; may provide protection against HPV types not in vaccine
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| Preventing CVD in women: based on 2007 update of current clinical recommendations; speaker focuses on new
and different aspects since 2004 guidelines
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| Risk assessment: focus shifted from next 10 yr to lifetime risk; based on new categories; high risk—known CVD;
diabetes; end-stage renal disease; Framingham risk >20%; at risk—≥1 major risk factor; evidence of subclinical
disease (eg, calcification on computed tomography); metabolic syndrome; poor exercise capacity on exercise
treadmill test; optimal—Framingham risk <10% and healthy lifestyle with no risk factors
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| Prevention of CVD: lifestyle interventions; major drug interventions
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| Who should get aspirin?
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| High-risk women: 75 to 325 mg/day
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| High-risk and aspirin intolerant: substitute clopidogrel
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| Women >65 yr of age (blood pressure well-controlled; benefits outweigh risks): 81 to 100 mg/day
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| Consider for women <65 yr of age when benefit for ischemic stroke outweighs risk: 81 to 100 mg/day
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| Interventions not recommended: aspirin for healthy women <65 yr of age (to prevent MI); hormone therapy; folic
acid and antioxidant supplements
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| Conclusion: most recommendations similar to those for men (except for aspirin and in women considering pregnancy)
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| Questions and answers: C-reactive protein (CRP)—elevated in people at increased risk for CVD and, eg, in people
with colds; useful in patients already at high risk; possibly useful when patient at intermediate risk and physician
trying to decide whether to start lipid-lowering or antihypertensive medications; makes difference in small group;
antioxidants—not recommended because studies do not show decrease in heart disease or cancer
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Suggested Reading
Antman EM et al: Use of nonsteroidal antiinflammatory drugs: an update for clinicians: a scientific statement
from the American Heart Association. Circulation 115:1634, 2007; Bates ER et al: ACCF/SCAI/SVMB/SIR/
ASITN 2007 Clinical Expert Consensus Document on carotid stenting. Vasc Med 12:35, 2007; Bresalier RS et al:
Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med
352:1092, 2005; Ernst P et al: Safety and effectiveness of long-acting inhaled beta-agonist bronchodilators when
taken with inhaled corticosteroids. Ann Intern Med 145:692, 2006; Kuitert LM et al: Antileukotrienes as adjunctive
therapy in acute asthma. Drugs 67:1665, 2007; Kuriyama S et al: Green tea consumption and mortality due to cardiovascular
disease, cancer, and all causes in Japan: the Ohsaki study. JAMA 296:1255, 2006; Lazarus SC et al:
Long-acting beta2-agonist monotherapy vs continued therapy with inhaled corticosteroids in patients with persistent
asthma: a randomized controlled trial. JAMA 285:2583, 2001; Liang W: Condom use and the risk of HPV infection.
N Engl J Med 355:1388; author reply 1389, 2006; Markowitz LE et al: Quadrivalent Human Papillomavirus Vaccine:
Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 56:1,
2007; Naylor AR: SPACE: not the final frontier. Lancet 368:1215, 2006; Oner AF et al: Avian influenza A
(H5N1) infection in eastern Turkey in 2006. N Engl J Med 355:2179, 2006; Qureshi AI et al: Guidelines for
screening of extracranial carotid artery disease: a statement for healthcare professionals from the multidisciplinary
practice guidelines committee of the American Society of Neuroimaging; cosponsored by the Society of Vascular and
Interventional Neurology. J Neuroimaging 17:19, 2007; Saito R et al: Amantadine-resistant influenza A (H3N2) virus
in Japan, 2005-2006. N Engl J Med 356:312, 2007; Saslow D et al: American Cancer Society Guideline for human
papillomavirus (HPV) vaccine use to prevent cervical cancer and its precursors. CA Cancer J Clin 57:7, 2007;
SPACE Collaborative Group et al: 30 day results from the SPACE trial of stent-protected angioplasty versus
carotid endarterectomy in symptomatic patients: a randomised non-inferiority trial. Lancet 368:1239, (Erratum:
368:1238) 2006.
Educational Objectives
| The goal of this program is to enable internists to employ recent advances in the diagnosis and management of disease.
After hearing and assimilating this program, the clinician will be better able to:
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| 1. Avoid risks of nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with cardiovascular disease (CVD).
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| 2. Prevent and manage influenza infection.
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| 3. Refer patients with indications for carotid stenting or carotid endarterectomy.
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| 4. Manage asthma with appropriately selected medications.
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| 5. Prevent human papillomavirus (HPV) infection and CVD in women.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty members to disclose
relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any
identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary
business or commercial interest. For this program, the faculty reported nothing to disclose.
Acknowledgements
Drs. Kohlwes and Walsh were recorded at 35th Annual Advances in Internal Medicine, May 21-25, 2007, in San Francisco,
CA, and sponsored by the University of California, San Francisco, School of Medicine. The Audio-Digest
Foundation thanks the speakers and the University of California, San Francisco, School of Medicine for their cooperation
in the production of this program.
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