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Journal Club
2007年３月１日 8:20-8:50
B棟８階 カンファレンス室
亀田メディカルセンター 糖尿病内分泌内科
Diabetes and Endocrine Department,
Kameda Medical Center
松田 昌文
Matsuda, Masafumi
N Engl J Med 2006;355:2297-307.
The Clopidogrel for High Atherothrombotic Risk and Ischemic
Stabilization, Management, and Avoidance (CHARISMA) trial
Mechanism of action of clopidogrel
Abbreviations: AA, arachidonic acid; ASA, aspirin; cAMP, cyclic AMP; COX-1, cyclo-oxygenase 1; CYP P450,
cytochrome P450; PI3K, phosphatidylionisitol 3-kinase; PLC , phospholipase C ; TP, thromboxane receptor;
TxA2, thromboxane A2; VASP-P, phosphorylated vasodilator-stimulated phosphoprotein.
Gurbel PA and Tantry US (2006) Drug Insight: clopidogrel nonresponsiveness
Nat Clin Pract Cardiovasc Med 3: 387–395 doi:10.1038/ncpcardio0602
Abbildung: CAPRIE: Amplified benefit of clopidogrel in patients with hihger vascular risk In CAPRIE, 8,854 patients had a
prior history of any ischemic event, and of these 4,496 had a history of a major acute event – a myocardial infarction or a
stroke. The annual event rate per 1,000 patients was reduced in the clopidogrel group vs the ASA group by 34 in patients
with a prior history of a major acute event, and by 28 in those with a prior history of any ischemic event, compared with 11
in the overall population. The benefits of clopidogrel over ASA were amplified in the higher vascular risk group
Abbildung 59: CAPRIE: Amplified benefit of clopidogrel in patients with diabetes
In CAPRIE, 3,837 patients had co-existing diabetes. These patients are at higher risk of myocardial infarction, ischemic
stroke, vascular death or hospitalization for ischemic events/bleeding (17.7 % diabetic vs 12.7 % non-diabetic in the ASA
group; 15.6 % diabetic vs 11.8 % non-diabetic in the clopidogrel group). The annual event rate per 1,000 patients was
reduced in the clopidogrel group vs the ASA group: by 38 in patients receiving insulin at baseline, 21 in diabetic patients
who were not receiving insulin, compared with 11 in the overall CAPRIE population. The benefits of clopidogrel over ASA
were amplified in the higher risk, insulin-dependent patients.
Background and Aim
Low-dose aspirin has been shown to reduce ischemic outcomes
in patients above a certain risk threshold.5 However, aspirin
alone in many instances is not sufficient to prevent ischemic
events in patients at high risk. Furthermore, aspirin inhibits only
the cyclooxygenase pathway, leaving the adenosine diphosphate
P2Y12 receptor unaffected. Dual antiplatelet therapy with
clopidogrel (Plavix, Sanofi-Aventis), a P2Y12-receptor antagonist,
plus aspirin has been shown to reduce ischemic events in patients
with unstable angina, myocardial infarction without ST-segment
elevation, or myocardial infarction with ST-segment elevation, as
well as those undergoing angioplasty and stenting.
Accordingly, we tested the hypothesis that longterm treatment
with a combination of clopidogrel plus aspirin may provide
greater protection against cardiovascular events than aspirin
alone in a broad population of patients at high risk.
Inclusion criteria:
45 years of age or older and ;
one of the following conditions:
multiple atherothrombotic risk factors,
documented coronary disease,
documented cerebrovascular disease, or
documented symptomatic peripheral arterial disease.
with multiple risk factors
with established vascular disease
Exclusion criteria:
taking oral antithrombotic medications or
nonsteroidal antiinflammatory drugs on a longterm basis (although
cyclooxygenase-2 inhibitors were permitted).
in the judgment of the investigator, they had established indications for
clopidogrel therapy (such as a recent acute coronary syndrome).
Patients who were scheduled to undergo a revascularization were not
allowed to enroll until the procedure had been completed.
Randomly assigned either to clopidogrel (75 mg per day) plus lowdose aspirin (75 to 162 mg per day) or to placebo plus low-dose
aspirin.
Total 15,603 randamized
End point
The primary efficacy end point :
first occurrence of
myocardial infarction,
stroke (of any cause), or
death from cardiovascular causes (including hemorrhage).
The principal secondary efficacy end point :
the first occurrence of
myocardial infarction,
stroke,
death from cardiovascular causes, or
hospitalization for unstable angina, a transient ischemic attack, or
a revascularization procedure (coronary, cerebral, or peripheral).
Other efficacy end points included :
death from any cause and
death from cardiovascular causes as well as myocardial infarction,
ischemic stroke, any stroke,
and hospitalization for unstable angina, transient ischemic attack, or
revascularization
Safety end point
The primary safety end point :
Severe bleeding, according to the Global Utilization of
Streptokinase and Tissue Plasminogen Activator for
Occluded Coronary Arteries (GUSTO) definition, which
includes fatal bleeding and intracranial hemorrhage, or
bleeding that caused hemodynamic compromise
requiring blood or fluid replacement, inotropic support,
or surgical intervention.
Moderate bleeding according to the GUSTO criteria
(bleeding that led to transfusion but did not meet the
criteria for severe bleeding) was also examined, as
were fatal bleeding and primary intracranial
hemorrhage.
Hazard Ratios for Myocardial
Infarction (MI), Stroke, or Death
from Cardiovascular Causes in
Each of the Subgroups Examined.
Hazard ratios are shown with their 95
percent confidence intervals. The sizes of
the symbols are roughly proportional to the
number of patients in the analysis. Bodymass index is the weight in kilograms
divided by the square of the height in
meters. CABG denotes coronary-artery
bypass grafting, and PCI percutaneous
coronary intervention.
CONCLUSIONS
Data on mortality rates suggest that
dual antiplatelet therapy should not
be used in patients without a history
of established vascular disease.
N Engl J Med 2007; 356: 820-9.
Gastroparesis
Delayed gastric emptying in the absence of mechanical obstruction of the
stomach
Symptom
postprandial fullness (early satiety), nausea, vomiting, and bloating.
Diabetes accounted for almost one third of cases of gastroparesis. Other
causes include previous gastric surgery and neurologic and rheumatologic
disorders; many cases are idiopathic (possibly occurring after a viral
infection).
Symptoms attributable to gastroparesis are reported by 5 to 12% of
patients with diabetes.
In a study of 86 patients with diabetes who were followed for at least 9 years,
gastroparesis was not associated with mortality after adjustment for other
disorders.
Differential Diagnosis
• Vomiting in the morning before eating suggests an
alternative cause (e.g., pregnancy, uremia, or a brain
tumor).
• Heartburn, dyspepsia, or use of nonsteroidal
antiinflammatory drugs suggests peptic ulcer disease,
including pyloric stenosis.
• The physical examination typically shows associated
peripheral and autonomic neuropathy (e.g., pupils that
are responsive to accommodation but not to light and
peripheral sensory neuropathy), background or more
advanced retinopathy, epigastric distention, and the
sound of liquid splashing when the abdomen is shaken
from side to side.
• The absence of a splashing sound on abdominal
succussion 1 hour after a meal suggests normal gastric
emptying of liquids.
Diagnosis
Scintiscans of Residual Gastric Contents.
Scintiscanning at 15-minute intervals for 4 hours after food intake is
considered the gold standard for measuring gastric emptying in detail.
A simplified approach involving hourly scans to quantify residual gastric
content is often used in practice; retention of over 10% of the meal after 4
hours is abnormal.26 As compared with the gold standard, the simplified
approach has a specificity of 62% and a sensitivity of 93%.
A breath test to measure gastric emptying involves ingestion of a meal enriched
with a stable isotope, followed by the collection of breath samples, which are
analyzed for carbon dioxide incorporating the isotope (i.e., 13CO2) at a reference
laboratory. The profile of 13CO2 excretion is used to estimate the half-time of
gastric emptying. As compared with detailed scintiscanning over a period of 4
hours, the breath test has a specificity of 80% and a sensitivity of 86%
Gastric emptying can be evaluated with the use of radiography 6 hours after
the ingestion of nondigestible, radiopaque markers. It assesses the emptying
of nondigestible solids rather than digestible solids, which require a different
type of contraction to be emptied from the stomach.
Intraluminal pressure and surface electrical profiles can be used to assess the
motor function of the stomach.
Echo?
Remove Exacerbating Factors
Avoid medications such as
antihypertensive agents (calcium-channel blockers or clonidine),
Anticholinergic agents (e.g., antidepressants), and exenatide or pramlintide
(used to control postprandial hyperglycemia)
should be discontinued whenever possible.
Although there is a lack of clinical trials showing that the restoration of
euglycemia or correction of electrolyte derangements normalizes gastric
emptying or ameliorates symptoms, clinical experience and observational data
suggest that improved metabolic control is beneficial.
In one study, patients with uremia due to diabetes who underwent kidney and
pancreas transplantation had significant improvement in gastric emptying and
associated gastrointestinal symptoms.
Pharmacologic Therapy
Prokinetic Agents
Antiemetic agents
Nutritional Support
The choice of nutritional support and its route of administration depend on the
severity of disease.
The indications for supplementation of enteral nutrition (infusion of nutrients to
intestines) include :
unintentional loss of 10% or more of the usual body weight during a period of 3
to 6 months,
inability to achieve the recommended weight by the oral route,
repeated hospitalization for refractory symptoms,
interference with delivery of nutrients and medications,
need for nasogastric intubation to relieve symptoms, and
nausea and vomiting resulting in a poor quality of life.
The degree of gastric retention at 4 hours may help guide decisions regarding
nutritional support but should not be used in isolation in the decision making.
Endoscopic or operative placement of gastrostomy tubes (for decompression,
not feeding) or jejunal feeding tubes is reserved for patients with severe
gastroparesis.
A potential disadvantage of gastrostomy is that it might interfere with
subsequent electrode placement for gastric electrical stimulation (see below).
Permanent percutaneous placement of a jejunal tube should be preceded by
successful nasojejunal feeding. In appropriate patients, enteral feeding through
the jejunum maintains nutrition, relieves symptoms, and reduces the frequency
of hospital admissions for acute exacerbation of symptoms.
In one case series, direct percutaneous endoscopic jejunostomy was feasible in
68% of 307 consecutive attempts, though 10% of patients had complications; in
2% of patients, serious complications occurred: bowel perforations, jejunal
volvulus, major bleeding (including one episode of fatal mesenteric bleeding),
and aspiration.
Nonpharmacologic Therapy
Endoscopic Injection of Botulinum Toxin
The results of several uncontrolled studies have suggested that endoscopic
injection of botulinum toxin into the pylorus is efficacious. However, a controlled
trial showed no efficacy.
Gastric Electrical Stimulation
Gastric electrical stimulation involves the use of electrodes, usually placed
laparoscopically in the muscle wall of the stomach antrum, connected to
a neurostimulator in a pocket of the abdominal wall. Limited data suggest that this
approach may control symptoms of gastroparesis. The device (Enterra,
Medtronic) has been approved by the FDA through a humanitarian device
exemption. In the only controlled trial (crossover, with each treatment
administered for 1 month), involving 33 patients with idiopathic or diabetic
gastroparesis, electrical stimulation had no significant effect on symptoms overall
but reduced the weekly frequency of vomiting (P<0.05). Among the 17 patients
with diabetes in the study, the median frequency of episodes of vomiting per
week was 6.0 with the stimulator on and 12.8 with the stimulator off (P = 0.16).48
Long-term open-label studies of gastric stimulation, with mean follow-up periods
of 3.7 and 4.3 years, have reported relief of symptoms and a reduced need for
nutritional support, but no long-term randomized trials have been conducted. The
mechanism by which electrical stimulation improves symptoms is unclear. The
use of different electrical settings for stimulation may improve clinical efficacy, but
this suggestion requires further study.
Surgery
Surgery is rarely indicated for the treatment of gastroparesis, except to rule
out other disorders or to place decompression or feeding tubes. A systematic
review concluded that the data are insufficient to provide support for gastric
surgery in the treatment of patients with diabetic gastroparesis. Concomitant
denervation of the small intestine may result in persistent symptoms in
patients with diabetes, even after gastrectomy.
Summary and Recommendations
The diabetic complications and gastrointestinal symptoms suggest the
diagnosis of gastroparesis.
After obstruction has been ruled out with the use of gastroduodenoscopy, the
diagnosis should be confirmed. I would confirm it by measuring gastric
emptying using scintigraphy hourly for 4 hours (alternatively, a breath test could
be performed).
I would then initiate therapy with a prokinetic agent (I start with metoclopramide,
10 mg three times daily before meals) and an antiemetic agent (either
prochlorperazine, 10 mg, or dimenhydrinate, 50 mg, every 12 hours).
A dietitian should advise the patient on the use of liquid or homogenized
meals to supplement oral nutrition, and control of diabetes should be optimized.
If symptoms persist and weight loss increases despite medical therapy,
nasojejunal feeding should be attempted; if such feeding is tolerated, a
percutaneous endoscopic jejunostomy tube should be placed for enteral
nutrition.