I. Section One: IM Cardiology
CAPRIE
"A Randomized, blinded, trial of copidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE)"
Lancet. 1996 Nov 16;348(9038):1329-39.
BACKGROUND: Many clinical trials have evaluated the benefit of long-term use of antiplatelet drugs in reducing the risk of clinical thrombotic events. Aspirin and ticlopidine have been shown to be effective, but both have potentially serious adverse effects. Clopidogrel, a new thienopyridine derivative similar to ticlopidine, is an inhibitor of platelet aggregation induced by adenosine diphosphate.
METHODS: CAPRIE was a randomised, blinded, international trial designed to assess the relative efficacy of clopidogrel (75 mg once daily) and aspirin (325 mg once daily) in reducing the risk of a composite outcome cluster of ischaemic stroke, myocardial infarction, or vascular death; their relative safety was also assessed. The population studied comprised subgroups of Hier finden Sie die versautesten Livegirls online die sehr gerne live Ficken. Unsere heissen Erotik Girls stehen live vor der Sexchat, hol Dir einfach den echten gratis und kostenlos Zugang zu den Fickgirls. Bei uns gibt es wirklich echte Cam Sex Erlebnisse, und wenn Du das auch magst kannst Du auch Toilettensex mit unseren Cam Girls erleben und genissen. patients with atherosclerotic vascular disease manifested as either recent ischaemic stroke, recent myocardial infarction, or symptomatic peripheral arterial disease. Patients were followed for 1 to 3 years.
FINDINGS: 19,185 patients, with more than 6300 in each of the clinical subgroups, were recruited over 3 years, with a mean follow-up of 1.91 years. There were 1960 first events included in the outcome cluster on which an intention-to-treat analysis showed that patients treated with clopidogrel had an annual 5.32% risk of ischaemic stroke, myocardial infarction, or vascular death compared with 5.83% with aspirin. These sexcamrates reflect a statistically significant (p = 0.043) relative-risk reduction of 8.7% in favour of clopidogrel (95% Cl 0.3-16.5). Corresponding on-treatment analysis yielded a relative-risk reduction of 9.4%. There were no major differences in terms of safety. Reported adverse experiences in the clopidogrel and aspirin groups judged to be severe included rash (0.26% vs 0.10%), diarrhoea (0.23% vs 0.11%), upper gastrointestinal discomfort (0.97% vs 1.22%), intracranial haemorrhage (0.33% vs 0.47%), and gastrointestinal haemorrhage (0.52% vs 0.72%), respectively. There were ten (0.10%) patients in the clopidogrel group with significant reductions in neutrophils (< 1.2 x 10(9)/L) and 16 (0.17%) in the aspirin group.
INTERPRETATION: Long-term administration of clopidogrel to patients with atherosclerotic vascular disease is more effective than aspirin in reducing the combined risk of ischaemic stroke, myocardial infarction, or vascular death. The overall safety profile of clopidogrel is at least as good as that of medium-dose aspirin.
--------------------
CHARISMA
"Clopidogrel and Aspirin versus Aspirin Alone for the Prevention of Atherothrombotic Events (The CHARISMA trial)"
N Engl J Med. 2006 Apr 20;354(16):1706-17
BACKGROUND: Dual antiplatelet therapy with clopidogrel plus low-dose aspirin has not been studied in a broad population of patients at high risk for atherothrombotic events.
METHODS: We randomly assigned 15,603 patients with either clinically evident cardiovascular disease or multiple risk factors to receive clopidogrel (75 mg per day) plus low-dose aspirin (75 to 162 mg per day) or placebo plus low-dose aspirin and followed them for a median of 28 months. The primary efficacy end point was a composite of myocardial infarction, stroke, or death from cardiovascular causes.
RESULTS: The rate of the primary efficacy end point was 6.8 percent with clopidogrel plus aspirin and 7.3 percent with placebo plus aspirin (relative risk, 0.93; 95 percent confidence interval, 0.83 to 1.05; P=0.22). The respective rate of the principal secondary efficacy end point, which included hospitalizations for ischemic events, was 16.7 percent and 17.9 percent (relative risk, 0.92; 95 percent confidence interval, 0.86 to 0.995; P=0.04), and the rate of severe bleeding was 1.7 percent and 1.3 percent (relative risk, 1.25; 95 percent confidence interval, 0.97 to 1.61 percent; P=0.09). The rate of the primary end point among patients with multiple risk factors was 6.6 percent with clopidogrel and 5.5 percent with placebo (relative risk, 1.2; 95 percent confidence interval, 0.91 to 1.59; P=0.20) and the rate of death from cardiovascular causes also was higher with clopidogrel (3.9 percent vs. 2.2 percent, P=0.01). In the subgroup with clinically evident atherothrombosis, the rate was 6.9 percent with clopidogrel and 7.9 percent with placebo (relative risk, 0.88; 95 percent confidence interval, 0.77 to 0.998; P=0.046).
CONCLUSIONS: In this trial, there was a suggestion of benefit with clopidogrel treatment in patients with symptomatic atherothrombosis and a suggestion of harm in patients with multiple risk factors. Overall, clopidogrel plus aspirin was not significantly more effective than aspirin alone in reducing the rate of myocardial infarction, stroke, or death from cardiovascular causes. (ClinicalTrials.gov number, NCT00050817.).
-------------------------
PROFESS
Telmisartan to Prevent Recurrent Stroke and
Cardiovascular Events
Yusuf S, Diener HC, Sacco RL, et al., on behalf of the
PRoFESS Study Group. NEJM 2008;359:1225-1237
High blood-pressure is known to be an important risk factor for development of
stroke. Lowering of blood-pressure with renin angiotensin system blockers in patients with ischemic stroke has been shown to reduce risk of recurrent stroke in previous studies. However, in these studies, the
majority of patients were enrolled several months or years after a stroke which
precluded assessment of the potential benefit of these agents initiated soon after a
stroke.
The PROFESS trial randomized 20,332 patients in a 2 x 2 factorial design to twicedaily,
fixed-dose combination of aspirin (25 mg) with extended-release dipyridamole
(200 mg) or once a day clopidogrel (75 mg) and to either once a day telmisartan (80
mg) or placebo. All patients were enrolled and randomized within 4 months after
experiencing an ischemic stroke. The primary outcome was recurrent stroke.
The mean duration of follow-up was 2.5 years. At study completion, the use of
diuretics, angiotensin-converting enzyme inhibitors, calcium-channel blockers and
beta-blockers was more frequent in the placebo group compared with the
telmisartan group. Blood pressure was lower in the telmisartan group (average
difference 3.8/2.0 mm Hg throughout the study). No significant difference was noted
in the incidence of recurrent strokes in the two groups (8.7% in the telmisartan group
vs. 9.2% in the placebo group) compared with the controls (8.7% vs. 9.2%). A similar
pattern was observed for the secondary outcome;
It was concluded that telmisartan started soon after ischemic stroke did not
significantly lower the rate of recurrent stroke, major cardiovascular events or
development of diabetes. However, there were several factors which could have
contributed to the lack of beneficial effect with telmisartan such as lower adherence
rates to treatment than reported in other large trials of telmisartan (e.g. ONTARGET),
higher use of non-study blood-pressure-lowering medications in the placebo group
and the too short duration of the trial.
---------------------
I-PRESERVE
Irbesartan in Heart Failure with Preserved Ejection
Fraction Study
Massie BM, et al. N Engl J Med 2008; 359:2456-2467
Heart failure with normal ejection fraction (HFNEF) comprises of nearly half of all
patients with heart failure (HF). In contrast to systolic heart failure, no pharmacologic
therapy has been shown to be effective in improving outcomes in these patients with
HFNEF. Since previous studies have demonstrated increased plasma renin activity
in patients with HFNEF, this study was performed to evaluate the effect of the
angiotensin-receptor blocker irbesartan on cardiovascular outcomes in this patient subset.
In this study, 4128 patients with New York Heart Association class II, III or IV heart
failure and an ejection fraction of at least 45% were randomized to receive 300 mg of
irbesartan or placebo per day. The primary composite outcome was death from any
cause or hospitalization for a cardiovascular cause (heart failure, myocardial
infarction, unstable angina,
arrhythmia, or stroke). The patients were followed up for a mean duration of 49.5
months.
At the end of follow-up, there was no difference between irbesartan and placebo
arms in the primary outcome (hazard ratio 0.95, 95% CI 0.86-1.05, p = 0.35). In
addition, no difference was found in the all-cause mortality (p = 0.98), worsening HF
(p > 0.05) and change in NT-proBNP (p = 0.14) also. Most side effects were similar
between the two groups but the risk of serious hyperkalemia was significantly higher
with irbesartan (3% vs. 2%, p = 0.01).
After previous trials with candesartan (CHARM-preserved) and perindopril (PEPCHF),
this is yet another trial that has demonstrated lack of benefit of inhibitors of the
reninangiotensinaldosterone system on CV outcomes in patients with HFNEF.
-----------------------------
ACCORD
The Action to Control Cardiovascular Risk in Diabetes Study ACCORD Study Group.
N Engl J Med 2008;358:2545-59
Previous observational studies have shown that in patients with diabetes mellitus, an
increase of 1% in the HbA1C level is associated with an increase of 18% in the risk
of CV events. This study was therefore performed to determine whether intensive
therapy to achieve normal HbA1C levels could reduce CV events in patients with type
2 diabetes with either pre-existing CVD or additional CV risk factors.
In this study, 10,251 type 2 diabetes patients were randomized to intensive therapy
(target HbA1C <6%, n = 5,128) versus standard therapy (target HbA1C 7%-7.9%, n =
5,123). Mean age of the patients was 62.2 years and mean HbA1C at baseline was
8.1%. The primary outcome was a composite of nonfatal myocardial infarction,
nonfatal stroke or death from cardiovascular causes. The study was prematurely
terminated after a mean follow-up of 3.5 years.
During follow-up, stable median levels of HbA1C of 6.4% (interquartile range, 6.1 to 7.0) and 7.5% (interquartile range, 7.0 to 8.1) were achieved in the intensive therapy and the standard therapy groups respectively at 1
year and were maintained throughout the follow-up period. Although there was no
significant difference in the primary outcome in the two groups at 3.5 years, intensive
therapy was associated with increased incidence of all-cause mortality (5% vs. 4%, p
= 0.04), CV death (2.6% vs. 1.8% p = 0.02), hypoglycemia requiring assistance
(10.5% vs. 3.5%, p <0.001) and weight gain of more than 10 kg (27.8% vs. 14.1%,
p<0.001).
Thus, contrary to expectations, intensive glucose-lowering therapy in this study was
found to be harmful in diabetic patients with respect to CV event reduction. Rapidity of
glucose lowering, increased frequency of hypoglycemic episodes, possible druginteractions,
adverse effects related to specific drugs were some of the mechanisms
proposed to explain this discrepancy.
----------------------------
ADVANCE
The Action in Diabetes and Vascular Disease:
Preterax and Diamicron Modified Release
Controlled Evaluation
N Engl J Med 2008;358:2560-72
This study had almost similar objectives as the ACCORD trial. However, the patient
profile, strategies used for glucose lowering and the target HbA1C levels were
different in this trial.
In the ADVANCE trial, 11,140 patients with type 2 diabetes were randomized to
receive either standard therapy or intensive therapy with modified release gliclazide
in combination with other drugs as required to achieve an HbA1C level of < 6.5%. The
patients were followed-up for 5 years. Primary end points were composites of major
macrovascular events (death from cardiovascular causes, nonfatal myocardial
infarction or nonfatal stroke), major microvascular events (new or worsening
nephropathy or retinopathy) and a combination of the two.
At the end of follow-up, mean HbA1C level achieved in the intensive-control was 6.5%
as compared to 7.3% in the standard-control group. Incidence of major
microvascular events was significantly reduced by the intensive glucose control
(9.4% vs. 10.9%, p=0.01) but there was no significant difference in the incidence of
major macrovascular events in the two groups (hazard ratio with intensive control,
0.94; 95% CI, 0.84 to 1.06; p=0.32). The beneficial effect on major microvascular
events was achieved primarily through reduction in the incidence of nephropathy
(4.1% vs. 5.2%, p=0.006) with no significant effect on retinopathy (p=0.50). Though
severe hypoglycemia was more frequent in the intensive-control group, there were no
significant effects of the treatment strategy on all-cause or cardiovascular mortality.
Thus this study showed a significant beneficial effect of intensive blood glucose
lowering with a regimen including modified release gliclazide on the risk of
development of nephropathy with no significant effect on retinopathy or major
macrovascular events.
-----------------------
JUPITER
Justification for the Use of Statins in Prevention: An Intervention Trial
Evaluating Rosuvastatin
Ridker PM, et al. NEJM 2008;359:2195-207
Previous studies have shown that elevated levels of high-sensitive C-reactive protein
(hs-CRP) levels are associated with increased risk of adverse CV events and statins
reduce risk of CV events not only by lowering LDL cholesterol but through lowering of
hs-CRP levels also. The present study was conducted to investigate whether statin
therapy in patients with elevated hs-CRP levels but normal LDL cholesterol levels
could reduce risk of CV events.
Apparently healthy individuals (n=17802) with LDL cholesterol <130 mg/dl and hs-
CRP > 2 mg/L were randomized to receive rosuvastatin 20 mg daily or placebo.
Clinical outcomes were compared at a median of 1.9 years when the trial was
stopped prematurely owing to the dramatic beneficial effects of Rosuvastatin in the
treatment arm.
In the treatment group, rosuvastatin reduced LDL cholesterol levels by 50% and highsensitivity
C-reactive protein levels by 37%. Rosuvastatin significantly reduced
incidence of primary end-point (composite of myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina or death from cardiovascular
causes) as well as the component efficacy parameters separately. There was no
significant increase in the incidence of serious adverse events with rosuvastatin but
incidence of physician-reported diabetes was found to be higher in the rosuvastatin
group.
The findings of this study imply that elevated levels of hs-CRP be considered to be
the target for treatment with rosuvastatin, irrespective of LDL cholesterol levels or
other CV risk factors and thus mandate routine measurement of hs-CRP levels in our
clinical practice. These results have major implications on the current clinical
practice and are likely to lead to revisions of the existing guidelines in the near future.
II. Section Two: Peds ID
"Reduction of Maternal-Infant Transmission of Human Immunodeficiency Virus Type 1 with Zidovudine Treatment"
N Engl J Med. 1994 Nov 3;331(18):1173-80.
BACKGROUND AND METHODS. Maternal-infant transmission is the primary means by which young children become infected with human immunodeficiency virus type 1 (HIV). We conducted a randomized, double-blind, placebo-controlled trial of the efficacy and safety of zidovudine in reducing the risk of maternal-infant HIV transmission. HIV-infected pregnant women (14 to 34 weeks' gestation) with CD4+ T-lymphocyte counts above 200 cells per cubic millimeter who had not received antiretroviral therapy during the current pregnancy were enrolled. The zidovudine regimen included antepartum zidovudine (100 mg orally five times daily), intrapartum zidovudine (2 mg per kilogram of body weight given intravenously over one hour, then 1 mg per kilogram per hour until delivery), and zidovudine for the newborn (2 mg per kilogram orally every six hours for six weeks). Infants with at least one positive HIV culture of peripheral-blood mononuclear cells were classified as HIV-infected.
RESULTS. From April 1991 through December 20, 1993, the cutoff date for the first interim analysis of efficacy, 477 pregnant women were enrolled; during the study period, 409 gave birth to 415 live-born infants. HIV-infection status was known for 363 births (180 in the zidovudine group and 183 in the placebo group). Thirteen infants in the zidovudine group and 40 in the placebo group were HIV-infected. The proportions infected at 18 months, as estimated by the Kaplan-Meier method, were 8.3 percent (95 percent confidence interval, 3.9 to 12.8 percent) in the zidovudine group and 25.5 percent (95 percent confidence interval, 18.4 to 32.5 percent) in the placebo group. This corresponds to a 67.5 percent (95 percent confidence interval, 40.7 to 82.1 percent) relative reduction in the risk of HIV transmission (Z = 4.03, P = 0.00006). Minimal short-term toxic effects were observed. The level of hemoglobin at birth in the infants in the zidovudine group was significantly lower than that in the infants in the placebo group. By 12 weeks of age, hemoglobin values in the two groups were similar.
CONCLUSIONS. In pregnant women with mildly symptomatic HIV disease and no prior treatment with antiretroviral drugs during the pregnancy, a regimen consisting of zidovudine given ante partum and intra partum to the mother and to the newborn for six weeks reduced the risk of maternal-infant HIV transmission by approximately two thirds.
--------------------