Urinary Stones Passage Enhanced by Medical Therapy

ANN ARBOR, Mich., Oct. 2 -- The likelihood of spontaneous urinary stone passage can be increased significantly by treatment with calcium channel blockers or α blockers, according to pooled data on nearly 700 patients with urinary calculi.
A nine-trial meta-analysis found that patients treated with calcium channel blockers or α blockers were 65% more likely to spontaneously pass the stones (95% confidence interval 1.45-1.88 P<0.001), reported John M. Hollingsworth, M.D., of the University of Michigan and the Veterans Affairs Center here, and colleagues, in the Sept.30 issue of The Lancet.
In four studies in which patients were treated with the α blocker Flomax (tamsulosin) the pooled risk ratio was 1.52 (95% CI 1.23-1.86, P<0.001).
In three trials in which corticosteroids were added to calcium channel blockers the pooled risk ratio was 1.90 (95% CI 1.51-2.40 P<0.0001).
The number of patients needed to treat in order to achieve one spontaneous stone expulsion with calcium channel blockers or α blockers was four.
Although the authors included the caveat that the a large confirmatory trial is needed, they concluded that "with the low- risk profile of these drugs and their wide therapeutic window, our results suggest that treating physicians should consider a new algorithm for the management of urolithiasis, in which treatment begins with a course of medical therapy, unless medically contraindicated."
Moreover, they pointed out that medical treatment costs just a fraction of the average cost of ureteroscopy ($2,645) or shock wave lithotripsy ($4,225). The estimated cost for medical treatment ranged from $10 to $74 for a 28-day course of Cardura (doxazosin) to $104 to $141 for a 42-day course of Flomax, the only non-generic drugs included in the meta-analysis.
The analysis included data from 693 patients with ureteral stones. The studies compared treatment with calcium channel blockers and/or α blockers, or standard therapy (control group).
In seven of the nine studies, both treatment and control groups received on-demand nonsteroidal anti-inflammatory drugs for relief of acute renal colic. In three, trials corticosteroids were given along with the calcium channel blocker nifedipine.
The mean age of patients ranged from 34.4 to 46.5 years and number of women in the trials ranged from 25% to 60%. The mean stone size ranged from 3.9 mm to 7.8 mm.
Treatment duration ranged from seven days to six weeks and follow-up ranged from 15 days to 48 days.
Among the findings:
When data from all five studies in which patients were treated with α blockers were pooled the risk ratio was 1.54 (95%CI 1.29-1.85, P<0.001).
In the two studies in which patients were treated with nifedipine without α blockers the risk ratio was 1.51 (95% CI 1.18-1.94 P=0.001).
The risk ratio in a subgroup analysis that pooled data from two studies in which neither treatment nor control group received NSAIDs was 1.74 (95% CI 1.29-2.33 P<0.0001)
Pooled risk in seven studies in which NSAIDs were used in treatment and control arms was 1.63 (1.41-1.88 P<0.001).
The authors noted that their findings might be limited by publication bias, because positive trials are more likely to have been published. Another potential limitation is the possibility of clinical heterogeneity, which they said they have addressed by conducting separate analysis of each drug class.
In a comment that accompanied the study, Margaret S. Pearle, M.D., of the department of urology at the University of Texas Southwestern Medical Center in Dallas said that in "view of the strong endorsement provided by this meta-analysis, patients with ureteral stones measuring less than 1 cm who are candidates for observation, especially those with stones in the distal ureter, deserve a trial of medical expulsive therapy." Primary source: The LancetSource reference: Hollingsworth JM "Medical therapy to facilitate urinary stone passage: a meta-analysis" Lancet 2006; 368:1171-79
Pearle MS "Medical therapy for urinary stone passage" Lancet 2006;368:1138-39.

Blood Clots Linked to Alzheimer's and Vascular Dementias

ReviewMANCHESTER, England, April 28 — Spontaneous cerebral blood clots appear to be a common pathology of Alzheimer's disease and vascular dementia, and they may be targets for prevention or treatment of both disorders, according to researchers here.
In a study comparing patients with each form of dementia with age- and sex-matched controls, surgeon Charles McCollum, M.D., of the University of Manchester and colleagues found that spontaneous cerebral emboli were significantly more frequent in patients with Alzheimer's or vascular dementia.
"The frequency of spontaneous cerebral emboli was similar in Alzheimer's disease and vascular dementia, which may explain the similarity in risk factors between these two dementias with differing final pathology," the investigators wrote in the early online edition of BMJ, formerly theBritish Medical Journal.
The findings lend credence to the theory that some dementias may be caused by silent cerebral infarctions or "mini-strokes."
Both Alzheimer's and vascular dementia are associated with vascular risk factors such as smoking, hypertension, high cholesterol, and diabetes, as well as carotid atherosclerosis, the authors noted.
They speculated that spontaneous cerebral emboli of vascular or cardiac origin--such as atrial fibrillation, valvular heart disease, or a shunt from the venous to the arterial circulation caused by defects such as patent foramen ovale--could be a common feature of both Alzheimer's disease and vascular dementia, which together account for about 80% of all dementia cases.
To test this theory, they used a minimally invasive transcranial Doppler technique to determine the frequency of spontaneous cerebral emboli, carotid artery disease, and venous-to-arterial shunts in 85 patients with Alzheimer's, 85 with vascular dementia, and 150 controls. Some of the patients had been part of a smaller pilot study of the monitoring technique.
The patients with dementia had cardiovascular risk factors similar to those of controls, although patients with vascular dementia were significantly more likely to have had a history of stroke or transient ischemic attacks.
Patients with vascular dementia were also more likely than those with Alzheimer's patients to have a history of stroke, TIA, use of antiplatelet drugs (P for all < 0.001), hypertension (P = 0.01), and lower HDL cholesterol levels (P = 0.03).
"These factors are all likely to lead a clinician to diagnose vascular dementia or, in the case of antiplatelet drugs, a consequence of that diagnosis," Dr. McCollum and colleagues wrote.
During a single hour of transcranial Doppler monitoring, they found that spontaneous cerebral emboli occurred in 40% of the patients with Alzheimer's disease and in 37% of those with vascular dementia, but in only 15% and 14% of the respective controls. The remarkable frequency of spontaneous cerebral emboli during a single hour in patients with dementia raises the possibility that the true prevalence is even higher and that emboli would be detected in many more patients if they were monitored over several hours.
Two or more emboli were seen during the course of monitoring in 21% of patients in each dementia group, compared with 9%-11% of controls.
The odds ratio for spontaneous cerebral emboli was 3.22 (95% confidence interval, 1.52 to 6.81) for Alzheimer's disease and 4.80 (95% CI, 1.83 to 12.58) for vascular dementia.
Even after adjusting for cardiovascular risk factors, the odds ratios for emboli and dementia remained significant, at 2.70 (95% CI, 1.18 to 6.21) for Alzheimer's disease and 5.36 (95% CI, 1.24 to 23.18) for vascular dementia.
When they looked at carotid artery disease, they found that there were no statistically significant differences in moderate or severe stenosis of either internal carotid artery between the dementia groups and controls.
When they looked for shunts from the venous circulation to the arterial circulation, they found that they found clinically significant shunts in 32% of the Alzheimer's patients, 29% of those with vascular dementia, 22% of the controls for Alzheimer's disease and 20% of the controls for the vascular dementia patients.
The odds ratio for shunts was 1.57 (95% CI, 0.80 to 3.07) for Alzheimer's disease and 1.67 (95% CI, 0.81 to 3.41) for vascular dementia. When they excluded from the analysis patients who had taken part in the pilot study, however, they found that the differences between the dementia patients and controls were not statistically significant.
There were also no significant difference in major shunts between the dementia groups and controls.
"As expected, spontaneous cerebral emboli were associated with all the major cardiovascular risk factors in controls," the investigators wrote. "We found no such association in dementia patients, implying that spontaneous cerebral emboli may be universal in dementia."

Acute Coronary Syndrome Deaths Decline If Hospitals Follow Guidelines

DURHAM, N.C., April 26 — Hospital deaths among patients with acute coronary syndromes decreased when care was based on national clinical-practice guidelines, according to an observational study.
As adherence to guidelines increased, mortality decreased, Eric Peterson, M.D., of Duke University reported in the April 26 issue of the Journal of the American Medical Association.
Nine treatment guidelines recommended by the American College of Cardiology and the American Heart Association were followed in 74% of eligible instances at 350 U.S. academic and nonacademic centers included in the analysis.
The data came from 64,775 patients enrolled from Jan. 1, 2001, to Sept. 30, 2003, in the CRUSADE National Quality Improvement Initiative. (CRUSADE stands for Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA guidelines.) Patients had either positive electrocardiographic changes or cardiac enzymes consistent with non-ST-segment elevation acute coronary syndrome.
"To our knowledge our study is among the first to link this variability in hospital process performance with patient outcomes," Dr. Peterson and his team wrote.
Hospitals in the fourth quartile (the highest adherence group) had a median adherence score of 82% (80% to 84%) compared with 63% (59% to 66%) for those in the first (lowest) quartile, the researchers reported.
Furthermore, adherence rates were significantly associated with in-hospital mortality. Observed mortality rates of 6.31% in the lowest adherence quartile contrasted with 4.15% in the highest adherence quartile (P<0.001). Adjusted odds ratio for in-hospital mortality in the highest versus the lowest quartile was 0.81 (95% CI 0.68-0.97), the researchers reported.
After risk adjustment, the researchers calculated that every 10% increase in composite adherence at a hospital was linked to a 10% decrease in its patients' likelihood of dying in the hospital (adjusted odds ratio 0.90; 95% confidence interval, 0.84-0.97; P<0.001).
As might be expected, hospitals with the highest overall adherence scores had higher than average scores on all acute, discharge and lifestyle prevention measures.
In addition, the aspirin message is clearly being delivered—almost all hospitals used aspirin acutely and were still using it at discharge. By contrast, there was a two to threefold difference at discharge for recommended medications such as IV glycoprotein IIb/IIIa inhibitors and Plavix (clopidogrel), the researchers said.
Among individual recommended medications, the highest associations between use and decreased mortality were for acute IV glycoprotein IIb/IIIa inhibitors, discharge Plavix, and discharge lipid-lowering agents.
Use of lifestyle interventions, such as dietary or smoking advice or cardiac rehabilitation referral was 20% to 30% higher among hospitals with the greatest adherence versus those in the lowest quartile, the researchers said.
Patients treated at hospitals with lower composite adherence scores tended to be slightly older, non-white, and had slightly more co-morbid illness.
Although larger hospitals with teaching facilities tended to have higher unadjusted adherence scores, the only multivariable predictors identified were presence of cardiac revascularization facilities and the proportion of patients treated primarily by a cardiologist, the investigators wrote.
The study was limited by its observational, nonrandomized design. Moreover, the researchers noted that observed links between adherence measures and outcomes do not prove causality. Finally, limited the study to a single class of patients makes it difficult to generalize the findings to all heart disease patients.
In conclusion, the researchers wrote, "Our work supports the central hypothesis of hospital quality improvement; namely better adherence with evidence-based care practices will result in better outcomes for patients who are treated."
Dr. Peterson and several colleagues have received support from Schering-Plough, Bristol-Myers Squibb/Sanofi-Aventis, and Millennium Pharmaceuticals. These companies also provided partial funding for the study.

Brain Images Link Strokes to Heart Damage

BOSTON, April 25 - Ischemic strokes in two specific area of the brain appear to send shockwaves through the sympathetic nervous system to cause myocardial injury.
Magnetic resonance imaging studies of patients who had new evidence of myocardial damage following an ischemic stroke indicated that infarctions occurring in the right insula and right inferior parietal lobule regions of the brain might be to blame, researchers here reported in an early online release in Neurology.
"The link between the brain and the heart in stroke patients is fascinating," said A. Gregory Sorensen, M.D., of Massachusetts General Hospital. "For instance, most patients with acute stroke have elevated blood pressure that returns to baseline over three to seven days. The connection is believed to be through the autonomic nervous system, but what the mechanism is has been unclear.
"By finding a specific brain area associated with a dramatically increased risk of heart damage, we can identify at-risk patients when they arrive at the hospital and put them on protective therapy, which should have a direct impact on their care," he continued.
Dr. Sorensen and colleagues at MGH and Harvard Medical School looked at 738 consecutive patients with acute ischemic stroke and identified 50 who had elevated serums levels of cardiac troponin T in the absence of any apparent cardiac cause within three days of the onset of stroke symptoms.
They randomly selected an additional 50 age- and sex-matched patients who had suffered ischemic strokes without apparent myocardial injury as controls.
The groups had similar stroke risk factors, history of coronary artery disease, infarction volume, and frequency of right and left middle cerebral artery territory involvement.
The investigators assembled diffusion-weighted MRI imaging studies taken during initial clinical evaluations of each patient and created outlines of infarctions. They co-registered the images to a template and averaged them to create a detailed brain map. They then used digital subtraction to detect voxels (volume pixels) that differed between the patients with myocardial injury and controls.
"Brain regions that were a priori associated with cardiac troponin T elevation included the right posterior, superior, and medial insula and the right inferior parietal lobule," the authors wrote.
In all, 17 of the patients in the elevated troponin group and 21 of those in the normal troponin group had infarctions in the right middle cerebral artery territory. Among these patients, the insular cluster was involved in 88% of those with evidence of myocardial damage, compared with 33% of those without marker elevation. The odds ratio for heart damage from a stroke in the right insular area was 15.00 (95% confidence interval 2.65 to 84.79).
The authors noted that the insula is the site for integration of sensory, autonomic, and limbic functions, and that studies in animal models have linked the region to cardiac autonomic control.
"We speculate that an infarction in the right posterior insula might cause disinhibition of other centers, such as more anterior insular sites, that in turn leads to enhanced cardiac sympathetic activity and related myocardial injury," they wrote.
They acknowledged, however, that they could not explain the link between myocardial injury and strokes in the right inferior parietal lobule. This region, which shares an arterial supply with the right insula, could be a "bystander," the authors speculated.
"In treating stroke patients, we often raise their blood pressures to try and increase blood flow into the affected areas, but we don't know why that works well for some patients and not for others," said Walter Koroshetz, M.D., a co-author. He is director of the MGH Stroke and Neurointensive Care Service.
"This technique may help us identify which patients will do well with that approach, and it has great potential for helping us get unbiased answers to many other questions regarding localized effects in the brain," Dr. Koroshetz added.
The authors pointed out that "despite the stringent criteria to exclude patients with acute coronary syndromes, in some of our patients, troponin T elevation might have been caused by exacerbation of coincident coronary artery disease. There is currently no available test to be used for such distinction."
However, they wrote that "our data imply that there might be a troponin T threshold that differentiates between neural and cardiac mechanisms of troponin T elevation; most troponin T elevations in the current study were modest, not exceeding 1 ng/mL in 96% of the patients. In contrast, troponin T levels typically increase up to 50 times of the upper reference limit when measured 18 to 24 hours after an acute coronary syndrome."

Coffee by the Tank Car Does Not Increase Risk of Coronary Heart Disease

BOSTON, April 24 — Gallons and gallons of coffee, day in and day out, year after year, decade after decade, do not increase the risk of coronary heart disease, researchers here reported today.
In fact, men and women who drank six or more cups of coffee a day for up to 20 years had a slightly lower relative risk of developing coronary artery disease than men who consumed a cup or less a day (P for trend= 0.41 for men and 0.08 for women) according to a study in the April 25 issue of Circulation, Journal of the American Heart Association.
That observation emerged from a prospective cohort study of 44,005 men enrolled in the Health Professionals Follow-Up Study and 84,488 women enrolled in the Nurses' Health Study, according to lead author Esther Lopez-Garcia, Dr.P.H. of the School of Medicine at the Universidad Autonoma de Madrid in Spain.
After adjusting for age, smoking, and other coronary heart disease risk factors, the relative risks of coronary heart disease among men were 1.0 for men who drank less than a cup of coffee a month and 1.04 for men who drank one cup a month to four cups a week (95% CI 0.91 to 1.17). For those who drank about a cup a day the RR was 1.02 (95 % CI 0.91 to 1.15) and for those who said they drank two to three cups a day the RR was 0.97 (95% CI 0.83 to 1.14).
For those who drank four to five cups daily the RR was 1.07 (CI: 0.88 to 131), while for those who drank six or more cups every day the RR dropped to 0.72 (95% CI 0.49 to 1.07; P for trend= 0.41).
Among women, after adjusting for other known risks, the RR for those who drank less than a cup a month was 1.0 and for those who consumed one cup a month to four a week the RR was 0.97 (95% CI 0.83 to 1.14); for women drinking a cup a day the RR was 1.02 (95% CI 0.90 to 1.17) and for those drinking two to three cups a day the RR was 0.84 (95% CI 0.74 to 0.97).
Women who drank four to five cups a day had an RR of 0.84 (95% CI 0.74 to 0.97) and for those who said that had at least six cups a day 0.87 (95% CI 0.68 to 1.11; P for trend-0.08).
Additionally, stratification of the data by smoking status, alcohol consumption and history of type 2 diabetes and body mass index did not alter the results.
Coffee consumption was, however, strongly correlated with smoking, which may explain why a study using data from Britain's National Health Service reported a link between coffee and risk of coronary heart disease. In this study more than half of the women who drank six or more cups of coffee were smokers as were 30% of the men who consumed at least a half dozen cups of coffee daily.
Other characteristics of heavy coffee drinkers were a greater likelihood of drinking alcohol and the use of aspirin. But they were less likely to drink tea, use multivitamins or vitamin E supplements, and they disdained exercise.
Although the study found no evidence to suggest an increased risk of coronary heart disease based on total caffeine consumption, said co-author Rob van Dam Ph.D., a researcher at the Harvard School of Public Health, he cautioned that in "certain genotypes" caffeine may increase the risk of coronary heart disease but said that remains to be proven.
And he said the findings apply to standard percolator or drip coffee, not to high intakes of unfiltered coffee such as the increasingly popular "French press" coffee, which produces a dark, strong cup. He said published studies have "consistently shown that drinking a lot of French press coffee increases LDL."
Coffee consumption was first measured in the Nurses' Health Study in 1980 and was first assessed in 1986 in the Health Professionals Follow-Up Study, and then reassessed every two to four years through 2000.
During that period there were 2,173 incident cases of coronary heart disease among the men and 2,254 cases among women.
Events in men included 1,449 nonfatal myocardial infarctions and 724 fatal cases of coronary heart disease. Among women there were 1,561 nonfatal MIs and 693 fatal cases of coronary heart disease.