The treatment of atherosclerosis and its related diseases is undergoing a
tremendous revolution. Specific treatments have evolved largely through a
better understanding of the pathophysiology of the disease. Much of this ground
breaking research is the result of discoveries made by pathologists.
| PROGNOSIS AND TREATMENT |
CHARACTERIZATION |
| BETA-BLOCKERS |
|
Beta-Blockers and Reduction of Cardiac Events in Noncardiac Surgery
Scientific Review
Andrew D. Auerbach, MD, MPH; Lee Goldman, MD
nical approach while definitive trials are awaited.
JAMA. 2002;287:1435-1444
|
JAMA. 2002;287:1435-1444 Abstract quote
Context
Recent studies suggest that perioperatively administered -blockers may
reduce the risk of adverse cardiac events in patients undergoing major
noncardiac surgery.
Objective
To review the efficacy of perioperative -blockade in reducing myocardial
ischemia, myocardial infarction, and cardiac or all-cause mortality
from randomized trials.
Data Sources
A MEDLINE and conventional search of English-language articles published
since 1980 was performed to gather information related to perioperative
cardiac complications and -blockade. Reference lists from all relevant
articles and published recommendations for perioperative cardiac risk
management were reviewed to identify additional studies.
Study Selection and Data Extraction
Prospective randomized studies (6) were included in the analysis if
they discussed the impact of -blockade on perioperative cardiac ischemia,
myocardial infarction, and mortality for patients undergoing major noncardiac
surgery. Articles were examined for elements of trial design, treatment
protocols, important biases, and major findings. These elements were
then qualitatively compared.
Data Synthesis
We identified 5 randomized controlled trials: 4 assessed myocardial
ischemia and 3 reported myocardial infarction, cardiac, or all-cause
mortality. All studies sought to achieve -blockade before the induction
of anesthesia by titrating doses to a target heart rate. Of studies
reporting myocardial ischemia, numbers needed to treat were modest (2.5-6.7).
Similarly modest numbers needed to treat were observed in studies reporting
a significant impact on cardiac or all-cause mortality (3.2-8.3). The
most marked effects were seen in patients at high risk; the sole study
reporting a nonsignificant result enrolled patients with low baseline
risk. As a group, studies of perioperative -blockade have enrolled relatively
few carefully selected patients. In addition, differences in treatment
protocols leave questions unanswered regarding optimal duration of therapy.
Conclusions
Despite heterogeneity of trials, a growing literature suggests a benefit
of -blockade in preventing perioperative cardiac morbidity. Evidence
from these trials can be used to formulate an effective clinical approach
while definitive trials are awaited. |
|
Preoperative beta-Blocker Use and Mortality and Morbidity Following
CABG Surgery in North America.
Ferguson TB Jr, Coombs LP, Peterson ED.
Departments of Surgery and Physiology, Louisiana State University
Health Sciences Center, 1542 Tulane Ave, 7th Floor, New Orleans, LA
70012-2822. |
JAMA 2002 May 1;287(17):2221-7 Abstract quote
CONTEXT: beta-Blockade therapy has recently been shown to convey a
survival benefit in preoperative noncardiac vascular surgical settings.
The effect of preoperative beta-blocker therapy on coronary artery bypass
graft surgery (CABG) outcomes has not been assessed.
OBJECTIVES: To examine patterns of use of preoperative beta-blockers
in patients undergoing isolated CABG and to determine whether use of
beta-blockers is associated with lower operative mortality and morbidity.
DESIGN, SETTING, AND PATIENTS: Observational study using the Society
of Thoracic Surgeons National Adult Cardiac Surgery Database (NCD) to
assess beta-blocker use and outcomes among 629 877 patients undergoing
isolated CABG between 1996 and 1999 at 497 US and Canadian sites.
MAIN OUTCOME MEASURE: Influence of beta-blockers on operative mortality,
examined using both direct risk adjustment and a matched-pairs analysis
based on propensity for preoperative beta-blocker therapy.
RESULTS: From 1996 to 1999, overall use of preoperative beta-blockers
increased from 50% to 60% in the NCD (P<.001 for time trend). Major
predictors of use included recent myocardial infarction; hypertension;
worse angina; younger age; better left ventricular systolic function;
and absence of congestive heart failure, chronic lung disease, and diabetes.
Patients who received beta-blockers had lower mortality than those who
did not (unadjusted 30-day mortality, 2.8% vs 3.4%; odds ratio [OR],
0.80; 95% confidence interval [CI], 0.78-0.82). Preoperative beta-blocker
use remained associated with slightly lower mortality after adjusting
for patient risk and center effects using both risk adjustment (OR,
0.94; 95% CI, 0.91-0.97) and treatment propensity matching (OR, 0.97;
95% CI, 0.93-1.00). Procedural complications also tended to be lower
among treated patients. This treatment advantage was seen among the
majority of patient subgroups, including women; elderly persons; and
those with chronic lung disease, diabetes, or moderately depressed ventricular
function. Among patients with a left ventricular ejection fraction of
less than 30%, however, preoperative beta-blocker therapy was associated
with a trend toward a higher mortality rate (OR, 1.13; 95% CI, 0.96-1.33;
P =.23).
CONCLUSIONS: In this large North American observational analysis, preoperative
beta-blocker therapy was associated with a small but consistent survival
benefit for patients undergoing CABG, except among patients with a left
ventricular ejection fraction of less than 30%. This analysis further
suggests that preoperative beta-blocker therapy may be a useful process
measure for CABG quality improvement assessment. |
| CONGESTIVE HEART FAILURE |
|
|
Intravenous nesiritide vs nitroglycerin for treatment of decompensated
congestive heart failure: a randomized controlled trial.
Publication Committee for the VMAC Investigators (Vasodilatation
in the Management of Acute CHF).
|
JAMA 2002 Mar 27;287(12):1531-40 Abstract quote
CONTEXT: Decompensated congestive heart failure (CHF) is the leading
hospital discharge diagnosis in patients older than 65 years.
OBJECTIVE: To compare the efficacy and safety of intravenous nesiritide,
intravenous nitroglycerin, and placebo.
DESIGN, SETTING, AND PATIENTS: Randomized, double-blind trial of 489
inpatients with dyspnea at rest from decompensated CHF, including 246
who received pulmonary artery catheterization, that was conducted at
55 community and academic hospitals between October 1999 and July 2000.
INTERVENTIONS: Intravenous nesiritide (n = 204), intravenous nitroglycerin
(n = 143), or placebo (n = 142) added to standard medications for 3
hours, followed by nesiritide (n = 278) or nitroglycerin (n = 216) added
to standard medication for 24 hours.
MAIN OUTCOME MEASURES: Change in pulmonary capillary wedge pressure
(PCWP) among catheterized patients and patient self-evaluation of dyspnea
at 3 hours after initiation of study drug among all patients. Secondary
outcomes included comparisons of hemodynamic and clinical effects between
nesiritide and nitroglycerin at 24 hours.
RESULTS: At 3 hours, the mean (SD) decrease in PCWP from baseline was
-5.8 (6.5) mm Hg for nesiritide (vs placebo, P<.001; vs nitroglycerin,
P =.03), -3.8 (5.3) mm Hg for nitroglycerin (vs placebo, P =.09), and
-2 (4.2) mm Hg for placebo. At 3 hours, nesiritide resulted in improvement
in dyspnea compared with placebo (P =.03), but there was no significant
difference in dyspnea or global clinical status with nesiritide compared
with nitroglycerin. At 24 hours, the reduction in PCWP was greater in
the nesiritide group (-8.2 mm Hg) than the nitroglycerin group (-6.3
mm Hg), but patients reported no significant differences in dyspnea
and only modest improvement in global clinical status.
CONCLUSION: When added to standard care in patients hospitalized with
acutely decompensated CHF, nesiritide improves hemodynamic function
and some self-reported symptoms more effectively than intravenous nitroglycerin
or placebo. |
|
Short-term intravenous milrinone for acute exacerbation of chronic heart
failure: a randomized controlled trial.
Cuffe MS, Califf RM, Adams KF Jr, Benza R, Bourge R, Colucci WS,
Massie BM, O'Connor CM, Pina I, Quigg R, Silver MA, Gheorghiade M; The
Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations
of Chronic Heart Failure (OPTIME-CHF) Investigators.
Northwestern University Medical School, Division of Cardiology,
201 E Huron St, Galter 10-240, Chicago, IL 60611, USA. |
JAMA 2002 Mar 27;287(12):1541-7 Abstract quote
CONTEXT: Little randomized evidence is available to guide the in-hospital
management of patients with an acute exacerbation of chronic heart failure.
Although intravenous inotropic therapy usually produces beneficial hemodynamic
effects and is labeled for use in the care of such patients, the effect
of such therapy on intermediate-term clinical outcomes is uncertain.
OBJECTIVE: To prospectively test whether a strategy that includes short-term
use of milrinone in addition to standard therapy can improve clinical
outcomes of patients hospitalized with an exacerbation of chronic heart
failure.
DESIGN: Prospective, randomized, double-blind, placebo-controlled trial
conducted from July 1997 through November 1999.
SETTING: Seventy-eight community and tertiary care hospitals in the
United States.
PARTICIPANTS: A total of 951 patients admitted with an exacerbation
of systolic heart failure not requiring intravenous inotropic support
(mean age, 65 years; 92% with baseline New York Heart Association class
III or IV; mean left ventricular ejection fraction, 23%).
INTERVENTION: Patients were randomly assigned to receive a 48-hour
infusion of either milrinone, 0.5 microg/kg per minute initially (n
= 477), or saline placebo (n = 472).
MAIN OUTCOME MEASURE: Cumulative days of hospitalization for cardiovascular
cause within 60 days following randomization. RESULTS: The median number
of days hospitalized for cardiovascular causes within 60 days after
randomization did not differ significantly between patients given milrinone
(6 days) compared with placebo (7 days; P =.71). Sustained hypotension
requiring intervention (10.7% vs 3.2%; P<.001) and new atrial arrhythmias
(4.6% vs 1.5%; P =.004) occurred more frequently in patients who received
milrinone. The milrinone and placebo groups did not differ significantly
in in-hospital mortality (3.8% vs 2.3%; P =.19), 60-day mortality (10.3%
vs 8.9%; P =.41), or the composite incidence of death or readmission
(35.0% vs 35.3%; P =.92)
CONCLUSION: These results do not support the routine use of intravenous
milrinone as an adjunct to standard therapy in the treatment of patients
hospitalized for an exacerbation of chronic heart failure. |
| CORONARY ARTERY BYPASS GRAFT SURGERY |
|
Cognitive Outcome After Off-Pump and On-Pump Coronary
Artery Bypass Graft Surgery
A Randomized Trial
Diederik Van Dijk, MD; Erik W. L. Jansen, MD, PhD; Ron Hijman, PhD; Arno
P. Nierich, MD, PhD; Jan C. Diephuis, MD; Karel G. M. Moons, PhD; Jaap
R. Lahpor, MD, PhD; Cornelius Borst, MD, PhD; Annemieke M. A. Keizer,
MSc; Hendrik M. Nathoe, MD; Diederick E. Grobbee, MD, PhD; Peter P. T.
De Jaegere, MD, PhD; Cor J. Kalkman, MD, PhD; for the Octopus Study Group
|
JAMA. 2002;287:1405-1412 Abstract quote
Context
Coronary artery bypass graft (CABG) surgery is associated with a decline
in cognitive function, which has largely been attributed to the use
of cardiopulmonary bypass (on-pump procedures). Cardiac stabilizers
facilitate CABG surgery without use of cardiopulmonary bypass (off-pump
procedures) and should reduce the cognitive decline associated with
on-pump procedures.
Objective
To compare the effect of CABG surgery with (on-pump) and without (off-pump)
cardiopulmonary bypass on cognitive outcome.
Design and Setting
Randomized controlled trial conducted in the Netherlands of CABG surgery
patients enrolled from March 1998 through August 2000, with 3- and 12-month
follow-up.
Participants and Intervention
Patients scheduled for their first CABG surgery (mean age, 61 years;
n = 281) were randomly assigned to off-pump surgery (n = 142) or on-pump
surgery (n = 139).
Main Outcome Measures
Cognitive outcome at 3 and 12 months, which was determined by psychologists
(blinded for randomization) who administered 10 neuropsychological tests
before and after surgery. Quality of life, stroke rate, and all-cause
mortality at 3 and 12 months were secondary outcome measures.
Results
Cognitive outcome could be determined at 3 months in 248 patients. Cognitive
decline occurred in 21% in the off-pump group and 29% in the on-pump
group (relative risk [RR], 0.65; 95% confidence interval [CI], 0.36-1.16;
P = .15). The overall standardized change score (ie, improvement of
cognitive performance) was 0.19 in the off-pump vs 0.13 in the on-pump
group (P = .03). At 12 months, cognitive decline occurred in 30.8% in
the off-pump group and 33.6% in the on-pump group (RR, 0.88; 95% CI,
0.52-1.49; P = .69). The overall standardized change score was 0.19
in the off-pump vs 0.12 in the on-pump group (P = .09). No statistically
significant differences were observed between the on-pump and off-pump
groups in quality of life, stroke rate, or all-cause mortality at 3
and 12 months.
Conclusion
Patients who received their first CABG surgery without cardiopulmonary
bypass had improved cognitive outcomes 3 months after the procedure,
but the effects were limited and became negligible at 12 months. |
| ELUTING STENT THERAPY |
|
| Sirolimus-Eluting Stents vs Paclitaxel-Eluting Stents in Patients With Coronary Artery Disease
Meta-analysis of Randomized Trials
Adnan Kastrati, MD; Alban Dibra, MD; Sonja Eberle, Dipl Stat; Julinda Mehilli, MD; José Suárez de Lezo, MD; Jean-Jacque Goy, MD; Kurt Ulm, PhD; Albert Schömig, MD
|
JAMA. 2005;294:819-825. Abstract quote
Context Placement of sirolimus-eluting stents or paclitaxel-eluting stents has emerged as the predominant percutaneous treatment strategy in patients with coronary artery disease (CAD). Whether there are any differences in efficacy and safety between these 2 drug-eluting stents is unclear.
Objective To compare outcomes of sirolimus-eluting and paclitaxel-eluting coronary stents on the basis of data generated by randomized head-to-head clinical trials.
Data Sources PubMed and the Cochrane Central Register of Controlled Trials, conference proceedings from major cardiology meetings, and Internet-based sources of information on clinical trials in cardiology from January 2003 to April 2005.
Study Selection Randomized trials comparing the sirolimus-eluting stent with the paclitaxel-eluting stent in patients with CAD reporting the outcomes of interest (target lesion revascularization, angiographic restenosis, stent thrombosis, myocardial infarction [MI], death, and the composite of death or MI) during a follow-up of at least 6 months.
Data Extraction Two reviewers independently identified studies and abstracted data on sample size, baseline characteristics, and outcomes of interest.
Data Synthesis Six trials, including 3669 patients, met the selection criteria. No significant heterogeneity was found across trials. Target lesion revascularization, the primary outcome of interest, was less frequently performed in patients who were treated with the sirolimus-eluting stent (5.1%) vs the paclitaxel-eluting stent (7.8%) (odds ratio [OR], 0.64; 95% confidence interval [CI], 0.49-0.84; P = .001). Similarly, angiographic restenosis was less frequently observed among patients assigned to the sirolimus-eluting stent (9.3%) vs the paclitaxel-eluting stent (13.1%) (OR, 0.68; 95% CI, 0.55-0.86; P = .001). Event rates for sirolimus-eluting vs paclitaxel-eluting stents were 0.9% and 1.1%, respectively, for stent thrombosis (P = .62); 1.4% and 1.6%, respectively, for death (P = .56); and 4.9% and 5.8%, respectively, for the composite of death or MI (P = .23).
Conclusions Patients receiving sirolimus-eluting stents had a significantly lower risk of restenosis and target vessel revascularization compared with those receiving paclitaxel-eluting stents. Rates of death, death or MI, and stent thrombosis were similar.
|
-
Sirolimus-eluting stent or paclitaxel-eluting stent vs balloon angioplasty for prevention of recurrences in patients with coronary in-stent restenosis: a randomized controlled trial.
Kastrati A, Mehilli J, von Beckerath N, Dibra A, Hausleiter J, Pache J, Schuhlen H, Schmitt C, Dirschinger J, Schomig A; ISAR-DESIRE Study Investigators.
Deutsches Herzzentrum, Technische Universitat, Munich, Germany.
|
-
| JAMA. 2005 Jan 12;293(2):165-71. Abstract quote |
|
CONTEXT: In patients with de novo coronary lesions, drug-eluting stents have drastically reduced restenosis risk compared with bare metal stents and conventional balloon angioplasty. It is less clear whether drug-eluting stents are superior to conventional balloon angioplasty for the treatment of patients with in-stent restenosis.
OBJECTIVES: To assess if drug-eluting stents are a more effective treatment of in-stent restenosis than conventional balloon angioplasty, and to assess the relative merits of 2 drug-eluting stents, a sirolimus-eluting stent and a paclitaxel-eluting stent.
DESIGN, SETTING, AND PARTICIPANTS: Randomized, open-label, active-controlled trial conducted among 300 patients with angiographically significant in-stent restenosis in 2 tertiary German centers from June 1, 2003, to October 20, 2003.
INTERVENTIONS: After pretreatment with 600 mg of clopidogrel for at least 2 hours before intervention, all patients were randomly assigned to 1 of 3 treatment groups: sirolimus stent, paclitaxel stent, or balloon angioplasty (100 patients in each group).
MAIN OUTCOME MEASURES: Primary end point: angiographic restenosis (diameter stenosis > or =50%) at 6-month follow-up angiography based on "in-segment" analysis. Primary analysis was comparison between stent groups and balloon angioplasty groups; a secondary analysis compared sirolimus and paclitaxel stents.
RESULTS: Follow-up angiography was performed in 275 (92%) of 300 patients. The incidence of angiographic restenosis was 44.6% (41/92) in the balloon angioplasty group, 14.3% (13/91) in the sirolimus stent group (P<.001 vs balloon angioplasty), and 21.7% (20/92) in the paclitaxel stent group (P = .001 vs balloon angioplasty). When compared with balloon angioplasty, receiving a sirolimus stent had a relative risk (RR) of angiographic restenosis of 0.32 (95% confidence interval [CI], 0.18-0.56); a paclitaxel stent had an RR of 0.49 (95% CI, 0.31-0.76). The incidence of target vessel revascularization was 33.0% (33/100) in the balloon angioplasty group, 8.0% (8/100) in the sirolimus stent group (P<.001 vs balloon angioplasty), and 19.0% (19/100) in the paclitaxel stent group (P = .02 vs balloon angioplasty). The secondary analysis showed a trend toward a lower rate of angiographic restenosis (P = .19) and a significantly lower rate of target vessel revascularization (P = .02) among sirolimus stent patients compared with paclitaxel stent patients.
CONCLUSIONS: In patients with in-stent restenosis, a strategy based on sirolimus- or paclitaxel-eluting stents is superior to conventional balloon angioplasty for the prevention of recurrent restenosis. Sirolimus-eluting stents may be superior to paclitaxel-eluting stents for treatment of this disorder.
|
| FIBRINOLYTIC THERAPY |
|
|
Indications for fibrinolytic therapy in suspected acute myocardial
infarction: collaborative overview of early mortality and major morbidity
results from all randomised trials of more than 1000 patients.
Fibrinolytic Therapy Trialists' (FTT) Collaborative Group.
|
Lancet 1994 Feb 5;343(8893):311-22 Abstract quote
Large randomised trials have demonstrated that fibrinolytic therapy
can reduce mortality in patients with suspected acute myocardial infarction
(AMI). The indications for, and contraindications to, this treatment
in some categories of patient are disputed, examples being late presentation,
elderly patients, and those in cardiogenic shock.
This overview aims to help resolve some of the remaining uncertainties.
From all trials of fibrinolytic therapy versus control that randomised
more than 1000 patients with suspected AMI, information was sought and
checked on deaths during the first 5 weeks and on major adverse events
occurring during hospitalisation.
The nine trials included 58,600 patients, among whom 6177 (10.5%) deaths,
564 (1.0%) strokes, and 436 (0.7%) major non-cerebral bleeds were reported.
Fibrinolytic therapy was associated with an excess of deaths during
days 0-1 (especially among patients presenting more than 12 h after
symptom onset, and in the elderly) but this was outweighed by a much
larger benefit during days 2-35. This "early hazard" should
not obscure the very clear overall survival advantage that is produced
by fibrinolytic therapy. Benefit was observed among patients presenting
with ST elevation or bundle-branch block (BBB)--irrespective of age,
sex, blood pressure, heart rate, or previous history of myocardial infarction
or diabetes--and was greater the earlier treatment began. Among the
45,000 patients presenting with ST elevation or BBB the relation between
benefit and delay from symptom onset indicated highly significant absolute
mortality reductions of about 30 per 1000 for those presenting within
0-6 h and of about 20 per 1000 for those presenting 7-12 h from onset,
and a statistically uncertain benefit of about 10 per 1000 for those
presenting at 13-18 h (with more randomised evidence needed in this
latter group to assess reliably the net effects of treatment).
Fibrinolytic therapy was associated with about 4 extra strokes per
1000 during days 0-1: of these, 2 were associated with early death and
so were already accounted for in the overall mortality reduction, 1
was moderately or severely disabling, and 1 was not. This overview indicates
that fibrinolytic therapy is beneficial in a much wider range of patients
than is currently given such treatment routinely. |
Mortality at 1 Year With Combination Platelet Glycoprotein IIb/IIIa
Inhibition and Reduced-Dose Fibrinolytic Therapy vs Conventional Fibrinolytic
Therapy for Acute Myocardial Infarction: GUSTO V Randomized Trial.
Lincoff AM, Califf RM, Van De Werf F, Willerson JT, White HD,
Armstrong PW, Guetta V, Gibler WB, Hochman JS, Bode C, Vahanian A, Steg
PG, Ardissino D, Savonitto S, Bar F, Sadowski Z, Betriu A, Booth JE,
Wolski K, Waller M, Topol EJ.
Department of Cardiovascular Medicine, Cleveland Clinic Foundation,
9500 Euclid Ave, Cleveland, OH 44195. |
JAMA 2002 Nov 6;288(17):2130-5 Abstract quote
CONTEXT: Among patients with acute myocardial infarction, combination
reperfusion therapy with a platelet glycoprotein IIb/IIIa receptor inhibitor
(abciximab) and a half dose of a plasminogen activator (reteplase) did
not significantly reduce mortality at 30 days compared with a full dose
of reteplase. Rates of nonfatal ischemic complications were significantly
diminished.
OBJECTIVE: To determine if the beneficial effects of abciximab and
reteplase (combination therapy) on early nonfatal complications would
translate into a reduction in the risk of death by 1 year.
DESIGN, SETTING, AND PATIENTS: One-year follow-up of a randomized controlled
trial (Global Use of Strategies To Open Coronary Arteries [GUSTO] V).
Of 16 588 patients who had been treated in 820 community and referral
hospitals in 20 countries between July 1999 and February 2001, mortality
data were available for 16 453 (99.2%).
INTERVENTION: Patients were randomly assigned to receive (intravenously)
a standard dose of reteplase (two 10-U boluses, 30 minutes apart) or
the combination of a standard dose of abciximab (0.25 mg/kg bolus, 0.125
micro g/kg per minute infusion [maximum 10 micro g/min for 12 hours])
and a half dose of reteplase (two 5-U boluses, 30 minutes apart).
MAIN OUTCOME MEASURE: One-year all-cause mortality rates.
RESULTS: All-cause mortality at 1 year occurred in 692 (8.38%) of 8260
patients in the reteplase group and 698 (8.38%) of the 8328 patients
in the combination therapy group (hazard ratio [HR], 1.00; 95% confidence
interval [CI], 0.90-1.11; P>.99). Reinfarction within the first 7
days occurred in 3.5% of patients in the reteplase group and 2.3% of
patients in the combination therapy group, and was significantly associated
with 1-year mortality (22.6% in patients with reinfarction vs 8.0% in
patients without reinfarction; HR, 3.08; 95% CI, 2.53-3.75; P<.001).
However, treatment assignment did not significantly influence time of
mortality regardless of reinfarction status.
CONCLUSION: Combination therapy (abciximab and reteplase) did not reduce
mortality over 1 year compared with fibrinolytic therapy with reteplase
alone. |
|
Early and sustained dual oral antiplatelet therapy following percutaneous
coronary intervention: a randomized controlled trial.
Steinhubl SR, Berger PB, Mann JT 3rd, Fry ET, DeLago A, Wilmer
C, Topol EJ.
Division of Cardiology, University of North Carolina, CB#7075,
338 Burnett-Womack Bldg, Chapel Hill, NC 27599. |
JAMA 2002 Nov 20;288(19):2411-20 Abstract quote
CONTEXT: Following percutaneous coronary intervention (PCI), short-term
clopidogrel therapy in addition to aspirin leads to greater protection
from thrombotic complications than aspirin alone. However, the optimal
duration of combination oral antiplatelet therapy is unknown. Also,
although current clinical data suggest a benefit for beginning therapy
with a clopidogrel loading dose prior to PCI, the practical application
of this therapy has not been prospectively studied.
OBJECTIVES: To evaluate the benefit of long-term (12-month) treatment
with clopidogrel after PCI and to determine the benefit of initiating
clopidogrel with a preprocedure loading dose, both in addition to aspirin
therapy.
DESIGN, SETTING, AND PARTICIPANTS: The Clopidogrel for the Reduction
of Events During Observation (CREDO) trial, a randomized, double-blind,
placebo-controlled trial conducted among 2116 patients who were to undergo
elective PCI or were deemed at high likelihood of undergoing PCI, enrolled
at 99 centers in North America from June 1999 through April 2001.
INTERVENTIONS: Patients were randomly assigned to receive a 300-mg
clopidogrel loading dose (n = 1053) or placebo (n = 1063) 3 to 24 hours
before PCI. Thereafter, all patients received clopidogrel, 75 mg/d,
through day 28. From day 29 through 12 months, patients in the loading-dose
group received clopidogrel, 75 mg/d, and those in the control group
received placebo. Both groups received aspirin throughout the study.
MAIN OUTCOME MEASURES: One-year incidence of the composite of death,
myocardial infarction (MI), or stroke in the intent-to-treat population;
28-day incidence of the composite of death, MI, or urgent target vessel
revascularization in the per-protocol population. RESULTS: At 1 year,
long-term clopidogrel therapy was associated with a 26.9% relative reduction
in the combined risk of death, MI, or stroke (95% confidence interval
[CI], 3.9%-44.4%; P =.02; absolute reduction, 3%). Clopidogrel pretreatment
did not significantly reduce the combined risk of death, MI, or urgent
target vessel revascularization at 28 days (reduction, 18.5%; 95% CI,
-14.2% to 41.8%; P =.23). However, in a prespecified subgroup analysis,
patients who received clopidogrel at least 6 hours before PCI experienced
a relative risk reduction of 38.6% (95% CI, -1.6% to 62.9%; P =.051)
for this end point compared with no reduction with treatment less than
6 hours before PCI. Risk of major bleeding at 1 year increased, but
not significantly (8.8% with clopidogrel vs 6.7% with placebo; P =.07).
CONCLUSIONS: Following PCI, long-term (1-year) clopidogrel therapy significantly
reduced the risk of adverse ischemic events. A loading dose of clopidogrel
given at least 3 hours before the procedure did not reduce events at
28 days, but subgroup analyses suggest that longer intervals between
the loading dose and PCI may reduce events. |
| PERCUTANEOUS CORONARY THERAPEUTIC INTERVENTION
(PCTA) |
|
Thrombolytic Therapy vs Primary Percutaneous Coronary Intervention
for Myocardial Infarction in Patients Presenting to Hospitals Without
On-site Cardiac Surgery
A Randomized Controlled Trial
Thomas Aversano, MD; Lynnet T. Aversano, RN, BSN; Eugene Passamani, MD;
Genell L. Knatterud, PhD; Michael L. Terrin, MD; David O. Williams, MD;
Sandra A. Forman, MA; for the Atlantic Cardiovascular Patient Outcomes
Research Team (C-PORT)
|
JAMA. 2002;287:1943-1951 Abstract quote
Context
Trials comparing primary percutaneous coronary intervention (PCI) and
thrombolytic therapy for treatment of acute myocardial infarction (MI)
suggest primary PCI is the superior therapy, although they differ with
respect to the durability of benefit. Because PCI is often limited to
hospitals that have on-site cardiac surgery programs, most acute MI patients
do not have access to this therapy.
Objective
To determine whether treatment of acute MI with primary PCI is superior
to thrombolytic therapy at hospitals without on-site cardiac surgery
and, if so, whether superiority is durable.
Design
The Atlantic Cardiovascular Patient Outcomes Research Team (C-PORT)
trial, a prospective, randomized trial conducted from July 1996 through
December 1999.
Setting
Eleven community hospitals in Massachusetts and Maryland without on-site
cardiac surgery or extant PCI programs.
Patients
Four hundred fifty-one thrombolytic-eligible patients with acute MI
of less than 12 hours' duration associated with ST-segment elevation
on electrocardiogram.
Interventions
After a formal primary PCI development program was completed at all
sites, patients were randomly assigned to receive primary PCI (n = 225)
or accelerated tissue plasminogen activator (bolus dose of 15 mg and
an infusion of 0.75 mg/kg for 30 minutes followed by 0.5 mg/kg for 60
minutes; n = 226). After initiation of assigned treatment, all care
was determined by treating physicians.
Main Outcome Measures
Six-month composite incidence of death, recurrent MI, and stroke; median
hospital length of stay.
Results
The incidence of the composite end point was reduced in the primary
PCI group at 6 weeks (10.7% vs 17.7%; P = .03) and 6 months (12.4% vs
19.9%; P = .03) after index MI. Six-month rates for individual outcomes
were 6.2% vs 7.1% for death (P = .72), 5.3% vs 10.6% for recurrent MI
(P = .04), and 2.2% vs 4.0% for stroke (P = .28) for primary PCI vs
thrombolytic therapy, respectively. Median length of stay was also reduced
in the primary PCI group (4.5 vs 6.0 days; P = .02).
Conclusions
Compared with thrombolytic therapy, treatment of patients with primary
PCI at hospitals without on-site cardiac surgery is associated with
better clinical outcomes for 6 months after index MI and a shorter hospital
stay. |
| RALOXIFENE |
|
Raloxifene and Cardiovascular Events in Osteoporotic Postmenopausal Women
Four-Year Results From the MORE (Multiple Outcomes of Raloxifene Evaluation)
Randomized Trial
Elizabeth Barrett-Connor, MD; Deborah Grady, MD; Andreas Sashegyi, PhD;
Pamela W. Anderson, MD; David A. Cox, PhD; Krzysztof Hoszowski, MD; Pentti
Rautaharju, MD; Kristine D. Harper, MD; for the MORE Investigators |
JAMA. 2002;287:847-857 Abstract quote
Context
Raloxifene, a selective estrogen receptor modulator, improves cardiovascular
risk factors, but its effect on cardiovascular events is unknown.
Objective
To determine the effect of raloxifene on cardiovascular events in osteoporotic
postmenopausal women.
Design
Secondary analysis of data from the Multiple Outcomes of Raloxifene
Evaluation trial, a randomized, double-blind, placebo-controlled trial
conducted between November 1994 and September 1999.
Setting
Outpatient and community settings at 180 sites in 25 countries.
Participants A total of 7705 osteoporotic postmenopausal women (mean
age, 67 years).
Intervention
Patients were randomly assigned to receive raloxifene, 60 mg/d (n =
2557), or 120 mg/d (n = 2572), or placebo (n = 2576) for 4 years.
Main Outcome Measures
Cardiovascular events, including coronary events (myocardial infarction,
unstable angina, or coronary ischemia) and cerebrovascular events (stroke
or transient ischemic attack), collected as safety end points and subsequently
adjudicated by a cardiologist blinded to therapy. Cardiovascular risk
at study entry was determined by the presence of multiple cardiovascular
risk factors or prior coronary events or revascularization procedure.
Results
In the overall cohort, there were no significant differences between
treatment groups in the number of combined coronary and cerebrovascular
events: 96 (3.7%) with placebo, 82 (3.2%) with 60 mg/d of raloxifene,
and 94 (3.7%) with 120 mg/d of raloxifene. Relative risks (RRs) were
0.86 (95% confidence interval [CI], 0.64-1.15) and 0.98 (95% CI, 0.74-1.30)
for 60 mg/d and 120 mg/d of raloxifene, respectively. Similar results
were obtained when coronary and cerebrovascular events were analyzed
separately. Among the subset of 1035 women with increased cardiovascular
risk at baseline, those assigned to raloxifene had a significantly lower
risk of cardiovascular events compared with placebo (RR, 0.60; 95% CI,
0.38-0.95 for both raloxifene groups). The number of cardiovascular
events during the first year was not significantly different across
groups in the overall cohort (P = .94), or among women at increased
cardiovascular risk (P = .86) or with evidence of established coronary
heart disease (P = .60).
Conclusions
Raloxifene therapy for 4 years did not significantly affect the risk
of cardiovascular events in the overall cohort but did significantly
reduce the risk of cardiovascular events in the subset of women with
increased cardiovascular risk. There was no evidence that raloxifene
caused an early increase in risk of cardiovascular events. Before raloxifene
is used for prevention of cardiovascular events, these findings require
confirmation in trials with evaluation of cardiovascular outcomes as
the primary objective. |
| STATIN THERAPY |
|
|
Effects of a Dietary Portfolio of Cholesterol-Lowering Foods vs Lovastatin
on Serum Lipids and C-Reactive Protein.
Jenkins DJ, Kendall CW, Marchie A, Faulkner DA, Wong JM, De
Souza R, Emam A, Parker TL, Vidgen E, Lapsley KG, Trautwein EA, Josse
RG, Leiter LA, Connelly PW.
Clinical Nutrition and Risk Factor Modification Center, St
Michael's Hospital, and Departments of Nutritional Sciences, Medicine,
Biochemistry, and Laboratory Medicine and Pathobiology, Faculty of Medicine,
University of Toronto, Toronto, Ontario.
|
JAMA. 2003 Jul 23;290(4):502-10 Abstract quote
CONTEXT: To enhance the effectiveness of diet in lowering cholesterol,
recommendations of the Adult Treatment Panel III of the National Cholesterol
Education Program emphasize diets low in saturated fat together with
plant sterols and viscous fibers, and the American Heart Association
supports the use of soy protein and nuts.
OBJECTIVE: To determine whether a diet containing all of these recommended
food components leads to cholesterol reduction comparable with that
of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins).
DESIGN: Randomized controlled trial conducted between October and December
2002.
Setting and PARTICIPANTS: Forty-six healthy, hyperlipidemic adults (25
men and 21 postmenopausal women) with a mean (SE) age of 59 (1) years
and body mass index of 27.6 (0.5), recruited from a Canadian hospital-affiliated
nutrition research center and the community.
INTERVENTIONS: Participants were randomly assigned to undergo 1 of 3
interventions on an outpatient basis for 1 month: a diet very low in
saturated fat, based on milled whole-wheat cereals and low-fat dairy
foods (n = 16; control); the same diet plus lovastatin, 20 mg/d (n =
14); or a diet high in plant sterols (1.0 g/1000 kcal), soy protein
(21.4 g/1000 kcal), viscous fibers (9.8 g/1000 kcal), and almonds (14
g/1000 kcal) (n = 16; dietary portfolio).
MAIN OUTCOME MEASURES: Lipid and C-reactive protein levels, obtained
from fasting blood samples; blood pressure; and body weight; measured
at weeks 0, 2, and 4 and compared among the 3 treatment groups.
RESULTS: The control, statin, and dietary portfolio groups had mean
(SE) decreases in low-density lipoprotein cholesterol of 8.0% (2.1%)
(P =.002), 30.9% (3.6%) (P<.001), and 28.6% (3.2%) (P<.001), respectively.
Respective reductions in C-reactive protein were 10.0% (8.6%) (P =.27),
33.3% (8.3%) (P =.002), and 28.2% (10.8%) (P =.02). The significant
reductions in the statin and dietary portfolio groups were all significantly
different from changes in the control group. There were no significant
differences in efficacy between the statin and dietary portfolio treatments.
CONCLUSION: In this study, diversifying cholesterol-lowering components
in the same dietary portfolio increased the effectiveness of diet as
a treatment of hypercholesterolemia. |
|
Fluvastatin for prevention of cardiac events following successful first
percutaneous coronary intervention: a randomized controlled trial.
Serruys PW, De Feyter P, Macaya C, Kokott N, Puel J, Vrolix M, Branzi
A, Bertolami MC, Jackson G, Strauss B, Meier B.
Interventional Cardiology, Thoraxcenter, Bd 418, Academic Hospital,
Dr Molewaterplein 40, 3015 GD Rotterdam, the Netherlands. |
JAMA 2002 Jun 26;287(24):3215-22 Abstract quote
CONTEXT: Percutaneous coronary intervention (PCI) is associated with
excellent short-term improvements in ischemic symptoms, yet only three
fifths of PCI patients at 5 years and one third of patients at 10 years
remain free of major adverse cardiac events (MACE).
OBJECTIVE: To determine whether treatment with fluvastatin reduces
MACE in patients who have undergone PCI.
DESIGN AND SETTING: Randomized, double-blind, placebo-controlled trial
conducted at 77 referral centers in Europe, Canada, and Brazil.
PATIENTS: A total of 1677 patients (aged 18-80 years) recruited between
April 1996 and October 1998 with stable or unstable angina or silent
ischemia following successful completion of their first PCI who had
baseline total cholesterol levels between 135 and 270 mg/dL (3.5-7.0
mmol/L), with fasting triglyceride levels of less than 400 mg/dL (4.5
mmol/L).
INTERVENTIONS: Patients were randomly assigned to receive treatment
with fluvastatin, 80 mg/d (n = 844), or matching placebo (n = 833) at
hospital discharge for 3 to 4 years.
MAIN OUTCOME MEASURE: Survival time free of MACE, defined as cardiac
death, nonfatal myocardial infarction, or reintervention procedure,
compared between the treatment and placebo groups.
RESULTS: Median time between PCI and first dose of study medication
was 2.0 days, and median follow-up was 3.9 years. MACE-free survival
time was significantly longer in the fluvastatin group (P =.01). One
hundred eighty-one (21.4%) of 844 patients in the fluvastatin group
and 222 (26.7%) of 833 patients in the placebo group had at least 1
MACE (relative risk [RR], 0.78; 95% confidence interval [CI], 0.64-0.95;
P =.01). This result was independent of baseline total cholesterol levels
(above [RR, 0.76; 95% CI, 0.56-1.04] vs below [RR, 0.77; 95% CI, 0.57-1.02]
the median). In subgroup analysis, the risk of MACE was reduced in patients
with diabetes (n = 202; RR, 0.53; 95% CI, 0.29-0.97; P =.04) and in
those with multivessel disease (n = 614; RR, 0.66; 95% CI, 0.48-0.91;
P =.01) who received fluvastatin compared with those who received placebo.
There were no instances of creatine phosphokinase elevations 10 or more
times the upper limit of normal or rhabdomyolysis in the fluvastatin
group.
CONCLUSION: Fluvastatin treatment in patients with average cholesterol
levels undergoing their first successful PCI significantly reduces the
risk of major adverse cardiac events. |
|
Long-term persistence in use of statin therapy in elderly patients.
Benner JS, Glynn RJ, Mogun H, Neumann PJ, Weinstein MC, Avorn J.
Division of Pharmacoepidemiology & Pharmacoeconomics, Department
of Medicine, Brigham and Women's Hospital and Harvard Medical School,
221 Longwood Ave, Suite 341, Boston, MA 02115, USA. |
JAMA 2002 Jul 24-31;288(4):455-61 Abstract quote
CONTEXT: Knowledge of long-term persistence with 3-hydroxy-3-methylglutaryl
coenzyme A reductase inhibitor (statin) therapy is limited because previous
studies have observed patients for short periods of time, in closely
monitored clinical trials, or in other unrepresentative settings.
OBJECTIVE: To describe the patterns and predictors of long-term persistence
with statin therapy in an elderly US population.
DESIGN, SETTING, AND PATIENTS: Retrospective cohort study including
34 501 enrollees in the New Jersey Medicaid and Pharmaceutical Assistance
to the Aged and Disabled programs who were 65 years of age and older,
initiated statin treatment between 1990 and 1998, and who were followed
up until death, disenrollment, or December 31, 1999.
MAIN OUTCOME MEASURES: Proportion of days covered (PDC) by a statin
in each quarter during the first year of therapy and every 6 months
thereafter; predictors of suboptimal persistence during each interval
(PDC <80%) were identified using generalized linear models for repeated
measures.
RESULTS: The mean PDC was 79% in the first 3 months of treatment, 56%
in the second quarter, and 42% after 120 months. Only 1 patient in 4
maintained a PDC of at least 80% after 5 years. The proportion of patients
with a PDC less than 80% increased in a log-linear manner, comprising
40%, 61%, and 68% of the cohort after 3, 12, and 120 months, respectively.
Independent predictors of poor long-term persistence included nonwhite
race, lower income, older age, less cardiovascular morbidity at initiation
of therapy, depression, dementia, and occurrence of coronary heart disease
events after starting treatment. Patients who initiated therapy between
1996-1998 were 21% to 25% more likely to have a PDC of at least 80%
than those who started in 1990.
CONCLUSIONS: Persistence with statin therapy in older patients declines
substantially over time, with the greatest drop occurring in the first
6 months of treatment. Despite slightly better persistence among patients
who began treatment in recent years, long-term use remains low. Interventions
are needed early in treatment and among high-risk groups, including
those who experience coronary heart disease events after initiating
treatment. |
Effects of atorvastatin on stroke in patients with unstable angina or
non-Q-wave myocardial infarction: a Myocardial Ischemia Reduction with
Aggressive Cholesterol Lowering (MIRACL) substudy.
Waters DD, Schwartz GG, Olsson AG, Zeiher A, Oliver MF, Ganz
P, Ezekowitz M, Chaitman BR, Leslie SJ, Stern T; MIRACL Study Investigators.
|
Circulation 2002 Sep 24;106(13):1690-5 Abstract quote
BACKGROUND: This report describes the effect of intensive cholesterol
lowering with atorvastatin on the incidence of nonfatal stroke, a secondary
end point, in a randomized, placebo-controlled trial of patients with
unstable angina or non-Q-wave myocardial infarction. The primary end
point, a composite of death, nonfatal myocardial infarction, resuscitated
cardiac arrest, or recurrent symptomatic myocardial ischemia with objective
evidence requiring emergency rehospitalization, was reduced from 17.4%
in the placebo group to 14.8% in the atorvastatin group over the 16
weeks of the trial (P=0.048).
METHODS AND RESULTS: Strokes were adjudicated by a blinded end-point
committee using standard clinical and imaging criteria. The outcomes
of nonfatal stroke and fatal plus nonfatal stroke were analyzed by time
to first occurrence during the 16-week trial. Of 38 events (in 36 patients)
adjudicated as fatal or nonfatal strokes, 3 were classified as hemorrhagic,
one as embolic, and 29 as thrombotic or embolic; 5 could not be categorized.
Nonfatal stroke occurred in 9 patients in the atorvastatin group and
22 in the placebo group (relative risk, 0.40; 95% confidence intervals,
0.19 to 0.88; P=0.02). Fatal or nonfatal stroke occurred in 12 atorvastatin
patients and 24 placebo patients (relative risk, 0.49; 95% confidence
intervals, 0.24 to 0.98; P=0.04). All 3 hemorrhagic strokes occurred
in the placebo group.
CONCLUSION: Intensive cholesterol lowering with atorvastatin over 16
weeks in patients with acute coronary syndromes reduced the overall
stroke rate by half and did not cause hemorrhagic stroke. These findings
need to be confirmed in future trials.
|
