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Corpus/written/non-fiction/rybczynski-ch3.txt view on Meta::CPAN
The transparent railings of I. M. Pei’s East Building are understated, elegant, and luxurious—like the building. “Beauty will result from the form and correspondence of the whole with respect to the several parts,†taught Palladio, “of the ...
The house that Robert Venturi built for his mother in 1964 shook the foundations of the International Style; much of this effect was the result of details. Although Venturi obviously was working in a Modernist idiom—there is a strip window and a st...
Coming through the front door of the Vanna Venturi House one immediately senses that it is an unusual place. A broad stair rises beside the fireplace, then peters out to almost nothing. The fireplace looks like an abstract sculpture, but it has a tra...
Whether one is looking up at the tall dome of the Pantheon, descending the spiraling vortex of Wright’s Guggenheim Museum, or standing in the living room of Venturi’s small house, the experience of architecture is above all the experience of bein...
•••
The Postmodern movement that followed the Vanna Venturi House was relatively short-lived but it had an important consequence: it broke the stranglehold of Modernism, leaving designers free to explore other forms of expression. The profusion of styles...
Allan Greenberg is a confirmed Classicist. He does not consider this an anomaly. “To be truly modern,†he writes, “means finding the dynamic balance between eternal human values and the specific demands of the present. Classical architecture pr...
Early in his career, after emigrating to the United States from South Africa, Greenberg was employed writing design standards for courthouses, which led to an unusual commission: the conversion of an empty supermarket into a courthouse. He gave the c...
One of my favorite Greenberg houses is a cottage set among windblown dunes on the eastern seaboard. Completed in 1992, the low-lying building is shingled, but it is not exactly Shingle Style. Recent Shingle Style buildings are often broken down into ...
Hugh Newell Jacobsen studied at Yale under Louis Kahn, worked for Philip Johnson, and opened his own office in 1958. He established himself as a premier residential architect, winning commissions in the United States and abroad and receiving numerous...
The Palmedo House, built in 1988, reinterprets the American Colonial architecture of its location—Long Island. At first glance, the six pavilions resemble a little village, a little Amish village, judging from the austere white wood siding, the pri...
Jacobsen reacts to the collapse of Modernism by seeking a compromise position, while Greenberg anchors himself in the certainties of Classicism. Enrique Norten, the youngest of the three, takes a different course—he is trying to put Modernism back ...
In 1994, Norten built a house for himself and his family on a tight urban site in Mexico City. The three-story street façade is mostly a blank concrete wall; the wall facing the interior walled patio is entirely glass. The main living floor is open,...
Like Greenberg and Jacobsen, Norten reflects on the past. Although his house has little to do formally with the International Style of the flat-roofed stucco villas of the 1920s—except for the white-painted circular steel columns—it shares that p...
Whether one prefers the work of Greenberg, Jacobsen, or Norten is a matter of taste (I happen to like all three). The buildings are different, yet the three architects have something in common. They are serious about what they are doing, that is, the...
Greenberg, Jacobsen, and Norten do not describe what they do in terms of style. I think that there are a number of reasons that architects are uncomfortable talking about the subject. A suspicion of style is a heritage of the Modern Movement, which p...
Coda
Richard Morris Hunt was the most celebrated American architect of the late nineteenth century. His preeminence is reflected by his appointment as the architect of two important national works: the centerpiece building of the Chicago World’s Columbi...
No pair of architects could be more dissimilar than this distinctly odd couple, the proper High Society favorite of the Gilded Age and the untidy bohemian from Santa Monica. Yet they bear comparison. They were both late bloomers. Gehry was 48 when he...
Hunt was 43 when he came into his own. He had established an architectural practice in New York in 1855, almost immediately on his return from the Ecole des Beaux-Arts. He was moderately successful, achieving local renown for the Tribune Building, an...
Corpus/written/technical/1468-6708-3-3.txt view on Meta::CPAN
The problem
Three published [ 1 2 3 ] and one recently presented [ 4
] randomized placebo-controlled clinical trial have
unequivocally demonstrated that 3-Hydroxy-3-methylgluatryl
coenzyme A (HMG CoA) reductase inhibitors (statins) reduce
the morbidity and mortality associated with coronary
disease. These trials found that when compared with
placebo, statins significantly reduced the incidence of
death, myocardial infarction, unstable angina, percutaneous
and surgical coronary revascularization, and stroke in
persons with
stable coronary disease. Because
patients who had experienced an acute coronary syndrome
within three to six months of enrollment were excluded,
these trials did not assess the effect of lipid-lowering
therapy on adverse cardiovascular events in those with
recently
unstable coronary disease. Whether
lipid-lowering therapy would provide incremental benefit if
initiated immediately following an acute coronary syndrome
is an important issue as the risk of a recurrent adverse
cardiac events is much greater in patients with unstable
coronary disease than in the stable setting. The Myocardial
Ischemia Reduction with Aggressive Cholesterol Lowering
(MIRACL) trial set out to answer this question.
The answer?
MIRACL enrolled 3,086 patients within 24-96 hours (mean
63 hours) of admission for unstable angina or a non-Q-wave
myocardial infarction and randomized them to 16 weeks of
atorvastatin 80 mg or placebo once daily [ 5 ] . The major
exclusion criteria were: total cholesterol level greater
than 270 mg/dL; Q-wave myocardial infarction on admission
or during the previous month; and, coronary
revascularization in the months before admission, during
the index hospitalization or anticipated following hospital
discharge. The primary efficacy endpoint was a composite of
death, non-fatal myocardial infarction, resuscitated sudden
cardiac death or emergent rehospitalization for worsening
symptomatic myocardial ischemia. Secondary endpoints
included stroke, worsening heart failure, need for coronary
revascularization and change in lipid levels throughout the
study. On average, patients were 65 years of age,
approximately 65% were men, 86% Caucasian and the mean
baseline low density lipoprotein (LDL) cholesterol level
was 124 mg/dL. Atorvastatin treatment was associated with a
2.6% absolute reduction in the risk of the primary endpoint
(14.8% vs. 17.4%; RR relative risk [RR] 0.84, 95%
confidence interval [CI] 0.70-1.00, p = 0.048). This
reduction was primarily driven by the 2.2% absolute
reduction in incidence of emergent rehospitalization for
symptomatic myocardial ischemia (6.2% vs. 8.4%; RR 0.74,
95% CI 0.57-0.95, p = 0.02). The risk of death, nonfatal
myocardial infarction and resuscitated sudden cardiac death
were each no different between the two groups. While there
were no significant differences in the incidence of
worsening heart failure or need for coronary
revascularization, atorvastatin did reduce the incidence of
fatal or non-fatal stroke by 0.8% (0.8% vs. 1.6%; RR 0.50,
95% CI 0.26-0.99, p = 0.045). Atorvastatin also
significantly reduced total and LDL cholesterol and
triglyceride levels but did not significantly change high
density lipoprotein (HDL) cholesterol by 16 weeks. By 16
weeks, the adjusted mean LDL cholesterol decreased to 72
mg/dL in atorvastatin-treated patients but increased to 135
mg/dL among placebo-treated patients. No serious adverse
events occurred as the result of treatment with
atorvastatin, although reversible liver transaminase
elevation more than three times the upper limit of normal
occurred in 2.5% of atorvastatin-treated versus 0.6% of
placebo-treated patients (p < 0.001).
The MIRACuLous
The efficacy and safety findings from MIRACL were unique
for a number of reasons. Although lipid-lowering therapy
was associated with a significantly lower mortality when
initiated early after an acute coronary syndrome in two
large observational studies [ 6 7 ] , MIRACL was the first
randomized trial to suggest that statins confer clinical
benefits in this setting. It was also the first trial to
identify a short-term (ie, within 16 weeks) clinical
benefit from statin therapy; in previous secondary
prevention trials, the benefit of statin therapy was not
evident for one to two years. And, while clinical trial
safety endpoints may be considered less glamorous, MIRACL's
most important contribution may have been that high-dose
statin therapy was not associated with serious harm,
despite its use in the unstable setting. Earlier secondary
prevention statin trials had excluded patients with
unstable coronary syndromes largely out of theoretical
concern that statin-mediated reductions in vascular smooth
muscle cell proliferation might destabilize healing plaque.
That no harm resulted from this aggressive treatment
strategy should allay theoretical fears and by doing so
remove a major obstacle to the inpatient initiation of
lipid-lowing therapy after coronary events.
The not so MIRACuLous
Despite these unique and important findings, there were
a number of inherent study limitations worth noting. First
and foremost, the possibility of a null treatment effect
cannot be ignored given the wide confidence intervals (and
hence marginally significant p value of 0.048) for the
effect of atorvastatin on the primary efficacy endpoint.
Furthermore, while the number of patients lost to follow up
was small, if adverse events had occurred in those treated
with atorvastatin (n = 3) but not placebo (n = 8), the
overall trial results may have been neutral rather than
positive.
The types of events prevented in MIRACL are also worth
noting. While rehospitalization for recurrent myocardial
ischemia is an important determinant of quality of life and
health care costs, other important endpoints were not
significantly affected (eg, death, myocardial infarction,
resuscitated sudden cardiac death, worsening heart failure,
need for coronary revascularization, etc). The question of
whether statins can prevent these and other adverse events
when initiated soon after an acute coronary syndrome will
require further study.
The short duration of follow-up is also particularly
troubling. While it is impressive that a clinical benefit
was realized after only 16 weeks of statin therapy, the
increased risk of adverse clinical events persists
throughout the year following an acute coronary syndrome.
Without longer clinical follow up, it is not possible to
assess the intermediate-term effect (if any) of
atorvastatin on hard endpoints such as death or myocardial
infarction. To do so would be critical in light of the lack
of effect on these important endpoints at 16 weeks.
Unfortunately, no late clinical follow up is planned.
There were also a number of limitations that may have
hampered the study's generalizability. First, patients who
underwent recent revascularization or in whom it was
planned were excluded. Specifically, patients who underwent
percutaneous transluminal coronary angioplasty (PTCA) or
coronary artery bypass graft (CABG) surgery within the
previous three or six months respectively were not eligible
for inclusion. The investigators reasoned that recurrent
ischemic events in this population were likely to result
from restenosis or bypass graft closure and that statins
would be less likely to affect these processes [ 8 ] .
Nevertheless, a number of trials have established the
benefits of statin therapy
early after coronary
revascularization [ 9 10 11 ] . Furthermore, a number of
recent trials have suggested that higher risk patients with
non-ST elevation acute coronary syndromes fair better when
an early invasive strategy is applied [ 12 13 14 ] and it
is not uncommon for patients to be treated in this fashion.
Second, patients with Q-wave myocardial infarction were not
eligible for enrollment because it was felt that statins
would not influence the development of important prognostic
determinants such as left ventricular systolic dysfunction,
ventricular arrhythmias or mechanical complications [ 5 ] .
Nevertheless, patients who develop electrocardiographic
Q-waves represent a substantial proportion of all patients
with myocardial infarction. While their short-term risk
following hospital discharge is lower relative to those
with a non-Q-wave myocardial infarction, it is still much
greater than in patients with stable coronary disease, and
the need for secondary prevention in this population is
equally important. Third, despite the high risk nature of
enrolled patients (ie, electrocardiogram [ECG] changes
and/or other objective evidence of ischemia), the rate of
platelet glycoprotein IIb/IIIa inhibitor utilization was
quite low (1.1%). Such therapy appears to be cost effective
[ 15 16 ] , especially among high risk patients and is
recommended under current American College of
Cardiology/American Heart Association guidelines [ 17 ] .
Fourth, it may not be possible to ascertain whether these
findings apply to all patients with recent acute coronary
syndromes regardless of baseline lipid levels. The small
difference in number of primary endpoint events between
atorvastatin and placebo groups make it difficult to
dissect the relationship between baseline lipid levels and
treatment effect further. Consequently, it remains
uncertain whether one can extrapolate the MIRACL trial
results to those who undergo coronary revascularization
shortly before or after a coronary event, who present with
a Q-wave myocardial infarction, who are treated with
platelet glycoprotein IIb/IIIa inhibitors, or who have
relatively low admission LDL cholesterol levels.
Time to change current practice
Although MIRACL and the two aforementioned cohort
studies suggest that lipid-lowering agents exert short-term
clinical benefits when initiated soon after an acute
coronary syndrome, this remains an open question. Even if
these findings are not confirmed after further study, one
could still make a compelling argument that lipid-lowering
therapy (barring contraindications) should be initiated
early and universally in patients who present with an acute
coronary syndrome: First, the long-term safety and
effectiveness of statins for the secondary prevention of
stable coronary disease is
well-established [ 1 2 3 ] ; Second, as evidenced by
MIRACL, these agents are safe when initiated at the time of
hospitalization for an acute coronary syndrome; Third, the
in-hospital initiation of lipid-lowering therapy appears to
promote greater long-term utilization of these agents [ 18
19 20 21 ] . Finally, although lipid levels may be
unreliable in the setting of an acute coronary syndrome
(excepting total :HDL and LDL:HDL cholesterol ratios [ 22 ]
) the overwhelming majority of patients with coronary
disease will ultimately require both pharmacologic and
non-pharmacologic lipid-lowering interventions to attain
recommended cholesterol targets [ 23 24 25 ] ; newer
guidelines are even more stringent [ 26 ] . Furthermore,
data from the recently presented Heart Protection Study
suggest that clinical benefits may accrue independent of
baseline cholesterol level [ 4 ] . Thus, to withhold
lipid-lowering therapy from patients who present with an
acute coronary syndrome would be to accept the status quo,
and to date our efforts at cholesterol lowering in the
secondary prevention setting have been dismal [ 27 28 ]
.
More MIRACLes ahead?
The ascertainment and quantification of any incremental
benefit conferred by statin therapy initiated early after
an acute coronary syndrome will require confirmation. There
is currently only one ongoing randomized placebo-controlled
trial of early versus delayed statin therapy in this
setting, A-2-Z (Aggrastat to Zocor, Merck) [ 29 ] . The
A-2-Z study is evaluating the efficacy of early treatment
with simvastatin in 4,500 patients following an episode of
unstable angina or a non-Q wave myocardial infarction. In
the first four months, patients will be randomized to
simvastatin 40 mg daily or placebo. Thereafter, those
patients treated with simvastatin in the first phase will
receive 80 mg of simvastatin daily and those treated with
placebo, 40 mg of simvastatin daily. The primary composite
endpoint is the occurrence of cardiovascular death,
non-fatal myocardial infarction, or rehospitalization for
an acute coronary syndrome (ACS) at one year. If A-2-Z
demonstrates significant reductions in the incidence of
adverse events during the first four months, it would
suggest an incremental clinical benefit from initiating
these agents early after an acute coronary syndrome. If
benefits accrue, but do so later during follow up, it would
be difficult to discriminate between the effects of more
aggressive vs. earlier lipid lowering therapy.
The Pravastatin or Atorvastatin Evaluation and Infection
Therapy (PROVE IT) trial is looking at 4,000 patients
within 10 days of an acute coronary syndrome and
randomizing them to either pravastatin 40 mg or
atorvastatin 80 mg daily [ 29 ] . Patients will be observed
over at least 1.5 years for the occurrence of myocardial
infarction or other cardiovascular events. Unlike, MIRACL
and the A-2-Z trials, this study will not assess the
efficacy of early statin therapy after an acute coronary
syndrome; rather, it will examine the role of
more vs.
less aggressive lipid-lowering in
this setting.
In 2002, many would consider it unethical to withhold
statins from patients with established coronary disease.
This makes it unlikely that additional placebo-controlled
trials will be carried out in this area. Future secondary
prevention studies should look at patients with stable
or unstable disease and will need to
address the comparative efficacy of different statins (or
newer agents), assess the incremental benefit of
combination therapy [ 30 ] and determine whether there is a
serum cholesterol 'floor' below which reductions are
unlikely to provide further clinical benefit.
Corpus/written/technical/1468-6708-3-3.txt view on Meta::CPAN
Dr Aronow has received honoraria as a speaker and
advisory board member for Pfizer and as a speaker for
Merck.
Abbreviations
HMG CoA = 3-Hydroxy-3-methylgluatryl coenzyme A; MIRACL
= Myocardial Ischemia Reduction with Aggressive Cholesterol
Lowering; LDL = low density lipoprotein; RR = relative
risk; CI = confidence interval; HDL = high density
lipoprotein; PTCA = percutaneous transluminal coronary
angioplasty; CABG = coronary artery bypass graft; ECG =
electrocardiogram; A-2-Z = Aggrastat to Zocor; ACS = acute
coronary syndrome; PROVE IT = Pravastatin or Atorvastatin
Evaluation and Infection Therapy.
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