Cardiac Update: Part 2
Educational Objectives
| The goal of this program is to improve survival in sudden cardiac arrest and improve cardiac care. After hearing
and assimilating this program, the participant will be better able to:
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 | 1. Explain how best to utilize and combine chest compression, mouth-to-mouth breathing, electric shock
defibrillation, ventilation, and therapeutic hypothermia during resuscitation efforts.
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| 2. Review the 3 phases of cardiac arrest and describe appropriate interventions during each.
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| 3. Discuss the role of cardiocerebral resuscitation in improving quality of care and patient outcomes.
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| 4. Identify and discuss the potential heart-related side effects of rosiglitazone and other oral antidiabetic
agents classified as thiazolidinediones (TZDs).
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| 5. Describe the potential side effects of nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors
in individuals at risk for or under treatment for hypertension and heart failure.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning
committee 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 and planning committee reported
nothing to disclose.
Acknowledgements
Dr. Bobrow was recorded at Emergency Medicine 2008—Moving Forward, held March 31 to April 2, 2008, in
Scottsdale, AZ, and sponsored by Mayo Clinic Scottsdale, College of Medicine, Mayo School of Continuing Medical
Education, in cooperation with Maricopa Integrated Health Systems, and endorsed by the Arizona College of Emergency
Physicians. Dr. Paauw was recorded at 2007 Washington Chapter Scientific Meeting, held November 1-3,
2007, in Seattle, WA, and sponsored by the Washington Chapter of American College of Physicians. The Audio-Digest
Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.
| NEW TECHNIQUES IN CARDIOPULMONARY RESUSCITATION (CPR)—Ben J. Bobrow, MD, Assistant Professor,
Department of Emergency Medicine, Mayo Clinic Scottsdale, College of Medicine, Scottsdale, AZ
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| Resuscitation: standardized, goal-directed, evidence-based resuscitation improves survival after cardiac arrest; bringing
new treatment strategies into emergency departments (EDs), hospitals, and communities, and consistently implementing
existing strategies, would likely save tens of thousands of lives annually; success of resuscitation after cardiac arrest functions
as litmus test for effectiveness of emergency medical services (EMS) system, from initial call and bystander intervention,
to dispatch system and response time, to on-scene care, and finally, ED care; opportunity for EDs to evaluate
existing resuscitation efforts, introduce improvements, and improve survival rates
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| Out-of-hospital cardiac arrest (OHCA): ≈1000 cases per day in United States; survival rates only recently improved;
considerations for survival—time to first defibrillation (from time of collapse); timing of defibrillation; bystander
CPR; ratio of ventilations to compressions; interaction of CPR and defibrillation; postresuscitation care
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| Ventricular fibrillation (VF) cardiac arrest: 3 distinct phases; electrical phase—initial arrest (first 3-4 min); ample substrate
remaining in myocardium; shock administered during this phase can result in perfusing rhythm and dramatically
improve survival; circulatory phase—next 5 to 10 min; perfusion to replenish blood to heart and brain, most important
consideration; shock administered during this stage does not improve outcome; may instead shock patient from VF to
asystolic cardiac arrest; metabolic phase—next 10 to 20 min; use of therapeutic hypothermia can improve survival rate
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| Public access to defibrillation: trained use of automatic external defibrillators (AEDs) in public places results in 50% survival
rate; public access to AEDs increasing, but remains limited; home use of AEDs—under study
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| Bystander CPR: nearly triples chance of survival; low rates of bystander response; occurs only about 25% of time; anonymous
surveys reveal reluctance among lay people, nurses, and physicians to perform mouth-to-mouth breathing; chest
compression alone more acceptable
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| Problems with bystander CPR: may delay or interrupt chest compressions; even trained bystanders have trouble remembering
proper CPR techniques in emergencies; gastric inflation—overventilation increases intrathoracic pressure and
decreases important coronary and cerebral perfusion pressure; bystander CPR study in Japan—compared chest compression-only
CPR with standard CPR or none at all; survival rates improved with any CPR, and trended better in chest
compression-only group; animal studies reveal interrupting chest compressions decreases survival; interruption interferes
with coronary perfusion pressure and replenishment of blood to heart and brain
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| CPR before shock: Seattle EMS system— decrease in OHCA survival rates after AEDs installed on all ambulances; attributed
to shocks administered before any attempt at CPR; modified protocols to include 90 sec of CPR before any shock for all
unwitnessed cardiac arrests; survival rate for OHCA subsequently doubled; Norwegian study—specified 3 min of CPR before
any shock; neurologically intact survival rate for those in circulatory phase of cardiac arrest nearly doubled; survival
rate for those in electrical phase remained same, revealing no detrimental effect from attempting CPR before administering
shock
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| Cardiocerebral resuscitation (CCR): in Arizona, led to better survival rates than advanced life support (ALS); highlights
of CCR protocols—bystanders perform continuous-chest-compression CPR; paramedics manage airway with either bag-
valve-mask ventilation or true passive oxygen insufflation (oropharyngeal airway and nonrebreather oxygen mask); paramedics
begin with 200 preshock chest compressions, followed by rhythm analysis and one shock if indicated; follow immediately
with postshock chest compressions before pulse check or rhythm analysis; earlier epinephrine administration
specified; advanced airway delayed until 3 rounds of chest compressions, rhythm analysis and chest compressions completed;
overall effect of CCR protocol to minimize all interruptions to forward blood flow
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| Implementation of CCR protocol (Arizona): trained 3000 emergency medical technicians (EMT) basics and paramedics
in CCR protocols; primary outcome survival to hospital discharge among witnessed arrests with VF upon EMS arrival; examined
>3300 cardiac arrests; 598 received CCR; 1700 received routine ALS; survival rates—among those with any rhythm
upon EMS arrival, survival 3.6% with routine ALS, 9.2% with CCR; among witnessed VF arrests, 10.9% with routine
ALS, 28.1% with CCR; odds ratio for survival 3.1; increased survival rates attributable to—minimized interruptions to
marginal blood flow during resuscitation; minimized hyperventilation; delayed advanced airway; earlier administration of
epinephrine; conclusions—patients who received CCR instead of routine ALS had increased chance for survival; patients
went on to have normal life
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| Remaining questions about CCR: success with witnessed VF cardiac arrests; effect on asystolic and other arrests remains
unknown; other unknowns—most important component of new protocols, optimal training method, appropriate retraining
intervals, and whether training in continuous chest compression CPR improves bystander CPR rates
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| High-proficiency model for CCR: needed in EDs; most important to emphasize high-quality CPR and uninterrupted high-
quality chest compressions; care provided by EDs ideally comparable to model of care provided by first responders, ie,
quality of care should not decrease upon hospitalization
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| Postresuscitation care: therapeutic hypothermia— new paradigm for chain of survival in cardiac arrest; randomized controlled
trials have shown improved survival rates and helpfulness in maintaining neurologic function; cooling methods other
than ice now available; not yet routine in United States
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| Developing cardiac care model: similar to stroke and trauma care models; avoid prognostications during first 24 hr; response
time correlates with survival rate for OHCA, but transport time does not; safe to take 5 to 10 min longer to transport
OHCA patients to hospital centers with standardized protocol for postresuscitation care
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| DRUGS THAT CAN HAVE ADVERSE EFFECTS ON THE HEART —Douglas S. Paauw, MD, Professor of Medicine,
University of Washington School of Medicine, Seattle
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| Meta-analysis of rosiglitazone trials: analyzed Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication
(DREAM) trial, A Diabetes Outcome Progression Trial (ADOPT), and several smaller trials; patients with diabetes
taking rosiglitazone compared to diabetic control group receiving usual care; meta-analysis results revealed statistically
significant increase in incidence of myocardial infarction (MI) in patients taking rosiglitazone, along with statistically insignificant
increase in mortality; actual numbers—of 14371 patients taking rosiglitazone, 86 experienced MI; of 11634
patients in control group, 72 experienced MI; risk for death in rosiglitazone group, 39 in 14371 patients; risk for death in
usual care group, 22 in 11634; media reported—43% increase in MI and 64% increase in risk for death among patients
taking rosiglitazone; media attention driven around these 2 percentages, rather than actual numbers
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| Number needed to harm (NNH): in DREAM trial, NNH 440; in ADOPT, NNH 227; in combined smaller trials, NNH
1470; meta-analysis resulted in slightly lower but still relatively high NNH
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| Rosiglitazone Evaluated for Cardiac Outcomes and Regulation in Glycemia in Diabetes (RECORD) trial: ongoing;
patients on rosiglitazone plus metformin or sulfonylureas vs. patients on sulfonylureas plus metformin; end point hospitalization
or death from cardiovascular causes; 217 patients in rosiglitazone group and 202 patients in control group met
end points; 47 patients in rosiglitazone group vs 22 patients in control group experienced heart failure (HF)
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| DREAM trial: attempt to prevent diabetes in 5000 patients with impaired glucose tolerance; onset of diabetes delayed by 1.5
yr in study group, but no delay in study or control group thereafter; side effects of rosiglitazone included weight gain, fluid
retention, and increased risk for HF; results in rosiglitazone group highly significant for HF and trended toward worse cardiovascular
outcomes; marketing of drug may stress that rosiglitazone reduced development of diabetes by >60%; on other
hand, media could also report rosiglitazone increased development of HF >700%; actual numbers—in DREAM study, 14
patients in study group vs 2 in control group developed HF
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| Pioglitazone: meta-analysis examined whether side effects with rosiglitazone might appear with other drugs in thiazolidinediones
(TZD) class; control group received baseline diabetes therapy; meta-analysis looked at 19 pioglitazone studies;
death, MI, or stroke occurred in 375 of 8554 (4.4%) patients in pioglitazone group vs 450 of 7836 (5.7%) patients in control
group; slight but statistically significant improvement noted in cardiovascular events for group on pioglitazone; use of pioglitazone
and other drugs in TZD class, however, led to fluid retention and increased risk for HF in patients at risk for HF;
200 patients (3.3%) in pioglitazone group developed HF, compared to 139 patients (1.8%) in control group; PROspective
pioglitAzone Clinical Trial in macroVascular Events (PROactive) Study—found increased risk for HF in pioglitazone
study group (5.7% vs 4.1% for control group); no increased mortality
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| Publication bias: only 9 of 35 licensure trials for rosiglitazone (26%) resulted in published findings; unclear what prevented
publication; further information may yet emerge from unpublished findings
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| Reasons to use or not use TZDs: cost— rosiglitazone and pioglitazone $5 to $6 per day, compared to metformin or glyburide
at 13 cents per day; risk for HF increases with rosiglitazone and pioglitazone; patients with diabetes already among
those at increased risk for HF; other side effects of TZDs include edema and weight gain; little discussion in literature of decreased
bone density that occurs with TZDs; separate increased cardiovascular risk may exist with rosiglitazone; reasons to
prescribe may not outweigh risk factors
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| Rosiglitazone: cardiovascular risk attracted attention, despite less than significant risk for mortality; possible benefits, eg,
improved lipid profile, chiefly theoretic; concern in prescribing less about magnitude of harm as fact that theoretic benefits
did not materialize
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| Sulfonylureas: studies in 1970s suggested possible cardiovascular risk; subsequent studies in 1990s compared patients on sulfonylureas
to those on other oral agents; increased risk for death seen with higher doses of sulfonylureas, but not with higher doses
of metformin; other studies have also found metformin safe and effective, with possible cardiovascular and mortality benefits,
compared to some other oral agents for diabetes
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Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
| Hypertension: study in 1990s examined initiation of antihypertensive therapy during ongoing NSAID use, and whether patients
on NSAIDs more likely to develop hypertension; increased likelihood of developing hypertension correlated with
higher NSAID dose; later studies also correlated development of hypertension with longer-acting NSAIDs; British study
concluded that as much as one-third of hypertension among elderly possibly associated with NSAID use
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| Effect on other drugs: study examined effect of ibuprofen use on efficacy of hydrochlorothiazide; at study’s end, supine systolic
blood pressure 144 mm Hg for patients on ibuprofen and 139 mm Hg for those on placebo; cardiovascular drugs most affected by
coadministration of NSAIDs include hydrochlorothiazide and other diuretics, as well as angiotensin-converting enzyme (ACE) inhibitors
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| Heart failure: in study of 365 hospital admissions for HF, using 658 admissions for other reasons as control group, NSAID
users exhibited increased risk for hospital admission for HF; risk for first admission for HF even higher in patients with heart
disease using NSAIDs; increased risk correlated with higher dose and longer-acting NSAIDs; additional study of 10000 patients
on NSAIDs and diuretics revealed higher likelihood of hospitalization for HF among those also taking NSAIDs
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| Mechanism of NSAID side effects and interaction: probably interference with renal prostaglandin biosynthesis by inhibiting
function of cyclooxygenase; interference occurs with NSAIDs as well as cyclooxygenase-2 (COX-2) inhibitors; both
equally likely to precipitate HF and have similar effects on kidneys
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COX-2 Inhibitors
| Vioxx Gastrointestinal Outcomes Research (VIGOR) trial: examined patients taking rofecoxib (Vioxx) or naproxen; patients
on naproxen much less likely to experience cardiovascular events than those on rofecoxib (however, naproxen associated
with more upper gastrointestinal [GI] events); increased risk for thrombotic cardiovascular events also associated
with rofecoxib
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| Celecoxib Long-term Arthritis Safety Study (CLASS) trial: found no difference between cardiovascular event rates between
users of celecoxib and those using NSAIDs
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| Overall safety: COX-2 inhibitors perceived as safer; risk for thrombosis with rofecoxib; help with preventing GI bleeding may
outweigh other risks; one study found little difference in hospitalization rates for GI bleeding between patients on warfarin plus
NSAIDs and those on warfarin plus COX-2 inhibitors; rofecoxib—thrombosis risk originally, but mistakenly, dismissed as occurring
only among patients who could not tolerate aspirin; no difference in mortality rate emerged in VIGOR trial, but increased
risk for MI and thrombotic events caused concern
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Suggested Reading
Bardy GH et al: Home use of automatic external defibrillators for cardiac arrest. N Engl J Med 358:1793, 2008; Berberoglu
Z: Rosiglitazone decreases serum bone-specific alkaline phosphatase activity in postmenopausal diabetic women. J
Clin Endocrinol Metab 92:3523, 2007; Bobrow B: Minimally interrupted cardiac resuscitation by emergency medical services
for out-of-hospital cardiac arrest. JAMA 299:1158, 2008; Gislason GH: Risk of death or reinfarction associated with
the use of selective cyclooxygenase-2 inhibitors and nonselective nonsteroidal antiinflammatory drugs after acute myocardial
infarction. Circulation 113:2906, 2006; Home PD et al: Rosiglitazone evaluated for cardiovascular outcomes: an interim
analysis. N Engl J Med 357:28, 2007; Lago RM: Congestive heart failure and cardiovascular death in patients with
prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomized clinical trials. Lancet 370:1129,
2007; Lincoff AM: Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis
of randomized trials. JAMA 298:1180, 2007; McKee M, McKee D: Public access defibrillation: how to maximise the gain.
Heart 94:349, 2008; Merchant RM et al: Therapeutic hypothermia utilization among physicians after resuscitation from
cardiac arrest. Crit Care Med 34:1935, 2006; Moodley I: Review of the cardiovascular safety of COXIBs compared to
NSAIDS. Cardiovasc J Afr 19:102, 2008; Moore RA et al: Cyclo-oxygenase-2 selective inhibitors and nonsteroidal anti-
inflammatory drugs: balancing gastrointestinal and cardiovascular risk. BMC Musculoskelet Disord 8:73, 2007; Nagao K et
al: Cardiopulmonary resuscitation by bystanders with chest compression only (SOS-KANTO): an observational study. Lancet
369:920, 2007; Nissen SE: Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular
causes. N Engl J Med 356:2457, 2007; Oddo M, et al: From evidence to clinical practice: effective implementation of therapeutic
hypothermia to improve patient outcome after cardiac arrest. Crit Care Med 34:1865, 2006; Salpeter SR: Metformin
treatment in persons at risk for diabetes mellitus. Am J Med 121:149, 2008; Sayre MR et al: Hands-only
(compression only) cardiopulmonary resuscitation: a call to action for bystander response to adults who experience out-of-
hospital sudden cardiac arrest: a science advisory for the public from the American Heart Association Emergency Cardiovascular
Care Committee. Circulation 117:2162, 2008; Singh S: Long-term risk of cardiovascular events with rosiglitazone:
a meta-analysis. JAMA 298:1189, 2007; Solomon DH: Cardiovascular outcomes in new users of coxibs and
nonsteroidal antiinflammatory drugs: high-risk subgroups and time course of risk. Arthritis Rheum 54:1378, 2006; Tannenbaum
H et al: An evidence-based approach to prescribing nonsteroidal antiinflammatory drugs. Third Canadian Consensus
Conference. J Rheumatol 33:140, 2006; Uwaifo GI: Differential effects of oral hypoglycemic agents on glucose control and
cardiovascular risk. Am J Cardiol 99:51B, 2007.
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