3-1 INFLUENZA VACCINATION AND REDUCTION IN HOSPITALIZATIONS FOR CARDIAC DISEASE AND STROKE AMONG THE ELDERLY
      In the elderly, vaccination against influenza was associated with large reductions in numbers of hospitalizations from heart disease, cerebrovascular disease, as well as pneumonia and influenza. Risk of death was reduced by about 50%.
      Flu vaccination is one of the most cost-effective health interventions. Primary care clinicians bear responsibility for increasing uptake by the general population.

3-2 LONG-TERM, LOW-INTENSITY WARFARIN THERAPY FOR THE PREVENTION OF RECURRENT VENOUS THROMBOEMBOLISM.
      Long-term, low-intensity warfarin therapy with a target INR of 1.5 to 2.0 was highly effective in preventing recurrent VTE in patients with a history of idiopathic VTE, including patients with thrombophilia due to factor V Leiden and prothrombin mutations.
      For patients with acute VTE, low-dose warfarin is appropriate after a 3-month course of conventional-dose warfarin. How long should therapy be continued? No definite answer, but probably long-term.

3-3 CEREAL, FRUIT, AND VEGETABLE FIBER INTAKE AND THE RISK OF CARDIOVASCULAR DISEASE IN ELDERLY INDIVIDUALS.
      Cereal fiber consumption (equivalent to 2 slices of whole grain bread) in later life was associated with lower risk of incident CVD.

3-4 EFFECT OF FOUR MONTHLY ORAL VITAMIN D3 (CHOLECALCIFEROL) SUPPLEMENTATION ON FRACTURES AND MORTALITY IN MAN AND WOMEN LIVING IN COMMUNITY.
      Vitamin D supplements of 100 000 IU given orally every 4 months for primary prevention was associated with a lower risk of fractures (and without adverse effects) in older men and women living in the community.
      This is equivalent to our usual dose of 800 IU daily. Calcium supplements would have lowered ris even more.

3-5 SILENT BRAIN INFARCTS AND THE RISK OF DEMENTIA AND COGNITIVE DECLINE
      Silent brain infarcts are common in the elderly. Persons with silent brain infarcts had an increased risk of dementia, and a steeper decline in cognitive function than persons without such lesions.
      In clinical practice—How can we intervene to benefit the patient? The hope is that treatment directed at vascular disease will reduce the burden of dementia. We should optimize cardiovascular health by established means: control of hypertension; lipid control; weight control; exercise; smoking-avoidance.
      Other possible beneficial interventions: low-dose aspirin; one alcoholic drink daily; and folic acid supplementation to reduce homocysteine levels.

3-6 SUDDEN ACUTE RESPIRATORY SYNDROME (SARS)
      “Plagues are as certain as death and taxes. The optimism of the 1960s and 1970s has given way to a mature realism that relationship between human beings and microbes is neither completely predictable nor biased in favor of humans.” Is SARS a rehearsal for the next pandemic of influenza.?
      The disease represents a sudden jump from animal species to humans. The virus probably evolved in animals for eons and for some reason suddenly became able to infect humans.
      The SARS story has been astounding! In a short period of 2 months, the world-wide epidemiology has been described, the virus identified, its genetic code determined, and control measures instituted and found effective. As of the end of April 2003, the epidemic has been declared to be controlled in Vietnam and in Toronto Canada because no new cases were reported over a 3 week period. How would the history of the 20th century have changed if we had the technology, control measures, and world-wide instantaneous communication available during the 1918 influenza epidemic?
      The ability of the virus to spread and cause serious illness and death in healthy persons increases the alarm.
      Is SARS a rehearsal for the next pandemic of influenza.?

3-7 MOVING BEYOND SINGLE AND DUAL DIAGNOSIS IN GENERAL PRACTICE.
      “The awkward phrase ‘multiple morbidity’ describes the common predicament of the many patients who have more than one health problem.” Poor health is inextricably linked to low income, unemployment, poor housing, and inadequate social support as well as old age.
      The trend towards more specialization tends to disadvantage people with multiple morbidity. The effective management of such patients depends heavily on primary care practice.
      “As general practitioners it is our job to manage all of a patient’s health problems by drawing on help for specialists where we can.”

3-8 EARLY INTERVENTION WITH BUDESONIDE IN MILD PERSISTENT ASTHMA
      Long-term, once-daily low-dose inhaled budesonide decreased the risk of severe exacerbations and the need for systemic corticosteroids and improved asthma control in patients with mild, persistent asthma of recent onset.

3-9 INHALED GLUCOCORTICOIDS VERSUS LEUKOTRIENE RECEPTOR ANTAGONIST AS SINGLE AGENT ASTHMA TREATMENT
      Anti-leukotrienes as single agents were less effective than inhaled corticosteroids in the treatment of adults with mild to moderate asthma.

3- 10 ACCESSIBILITY, ACCEPTABILITY, AND EFFECTIVENESS OF ROUTINE TELEPHONE REVIEW OF ASTHMA: Pragmatic, Randomized, Trial
      Telephone consultations enabled more patients with asthma to be reviewed. There was no apparent clinical disadvantage or loss of satisfaction. They may be an efficient option for primary care practice.

3-11 A RANDOMIZED TRIAL OF ASPIRIN TO PREVENT COLORECTAL ADENOMAS IN PATIENTS WITH PREVIOUS COLORECTAL CANCER
      Compared with placebo, a daily dose of 325 mg aspirin reduced risk of adenoma development in patients with a history of surgery for CRC. (High risk patients.)

3-12 A RANDOMIZED TRIAL OF ASPIRIN TO PREVENT COLORECTAL ADENOMAS
      Low-dose aspirin had a moderate chemoprotective effect on adenoma formation.

3-13 ASPIRIN AND PREVENTION OF COLORECTAL CANCER
      Among persons with a history of adenomas or CRC the number of recurrences of adenomas prevented by aspirin (secondary prevention) would be higher than the number of episodes of bleeding. However, the cumulative clinical importance of bleeding probably exceeds that of surrogate neoplasm-related outcomes, especially when the effect of colonoscopic surveillance is taken into account.
      If aspirin is used for primary prevention of CRC, it would have to be given for 10 to 20 years, the time it takes for CRC to develop. The cumulative adverse effects of aspirin over this time outweigh any benefit in prevention of CRC, particularly when prevention by screening for CRC is considered. Long-term use of aspirin for primary prevention of CRC is not cost-effective. It does not obviate the need for screening and surveillance.
      Aspirin does reduce risk of recurrent colorectal neoplasia. Whether aspirin has a role in preventing colorectal cancer and whether it can be used to decrease the required frequency of screening or surveillance must await results of clinical trials.

3-14 PLASMA HOMOCYSTEINE AND RISK FOR CONGESTIVE HEART FAILURE IN ADULTS WITHOUT PRIOR MYOCARDIAL INFARCTION
      An increased plasma homocysteine level independently predicted risk of development of CHF in adults without prior myocardial infarction. Another indication for supplementation with folate?

3-15 OUTCOME OF ELDERLY PATIENTS WITH CHRONIC SYMPTOMATIC CORONARY ARTERY DISEASE WITH INVASIVE VS OPTIMIZED MEDICAL TREATMENT STRATEGY.
      After one year, there was no difference in quality-of-life between optimized medical therapy vs early invasive therapy. However, about half of the medical group needed hospitalization and later revascularization during the year. Death and non-fatal MI occurred at similar rates.
      Elderly patients with severe angina have a difficult choice.

3-16 PROGNOSTIC IMPORTANCE OF WEIGHT LOSS IN CHRONIC HEART FAILURE AND THE EFFECT OF TREATMENT WITH ANGIOTENSIN-CONVERTING-ENZYME INHIBITORS
      Cardiac cachexia is common in chronic HF. It independently predicts a poor outcome. This may assist decisions for Hospice care.

3- 17 APOLIPOPROTEINS VERSUS LIPIDS AS INDICES OF CORONARY RISK AND AS TARGETS FOR STATIN TREATMENT.
      Apo-lipo-protein B (APO-B) is a measure of the total number of atherogenic particles. APO-B is a risk factor, as is LDL-cholesterol. The higher the ABO-B, the higher the risk. In contrast, APO-A1 is a protective factor, as is HDL-c. The higher the APO-A1, the lower the risk. Many studies show that APO-B is a better marker of risk of vascular disease and a better guide to the adequacy of statin treatment than any cholesterol index.
      We are still pursuing the search for the best, most accurate, most reproducible, least costly risk factor for cardiovascular disease. LDL-cholesterol remains the choice at present. Other candidates are forthcoming, including C-reactive protein and APO-B. It will be interesting to follow the search. RTJ

1. Observational study included over 140 000 subjects from three large, managed-care organizations in each of two influenza seasons (1998-1999 and 1999-2000). All were over age 65 (mean age = 74) and were living in the community. Many had co-existing conditions (heart disease, lung disease, cancer, hypertension, diabetes).
2. Between 56% and 60% were immunized for influenza. Patients in the vaccinated group were, on average, sicker and had higher rates of care than those in the non-vaccinated group.
3. Determined hospitalizations and deaths from cardiac disease, and cerebrovascular disease as well as from pneumonia.

1. As expected, vaccination was associated with a reduction in hospitalization for pneumonia and influenza by about 30%.
2. Risk of death was reduced by about 50%
3. Vaccination was also associated with a reduction in hospitalization for cardiac disease (-19%) in both seasons; and cerebrovascular disease (-16% and -23%).
4.  

   Outcomes 1998-1999 season:	Odds ratio	NNT
   	(Vaccinated vs non-vaccinated)	(To prevent one outcome in one season)
   Cardiac disease	0.81	329
   Ischemic heart disease	0.80	556
   Congestive heart failure	0.81	585
   Cerebrovascular disease	0.84	893
   Pneumonia or influenza	0.68	347
   Death	0.52	95

5. Outcomes were similar in all age groups, co-existing risks, and site of study.

1. Possible mechanisms for increased risk of cardiovascular and cerebrovascular disease associated with influenza include: alterations in clotting factors, platelet aggregation, concentrations of inflammatory response proteins, and alterations in cytokine concentrations. Thrombotic tendencies, impaired vasodilation, and endothelial injury may result.
2. Influenza vaccination of elderly persons was associated with substantial reductions in risk of hospitalizations for cardiac and cerebrovascular disease. This was even though the vaccinated group was, on average, sicker and were receiving higher rates of care than the non-vaccinated. As expected, risk of hospitalization for pneumonia and influenza was also reduced.
3. The reduction in risk of death was remarkable.
4. The authors believe that these results can be generalized.
5. Vaccination protects the many elderly persons with high-risk co-existing conditions as well as healthy elderly. Many high-risk patients receive care from subspecialty physicians. Subspecialists are less likely than primary care clinicians to recommend vaccination.

1. 1. Randomized, double-blind, placebo-controlled trial followed over 500 patients (mean age = 53). All patients had a history of one or more episodes of previous idiopathic VTE. All patients had been on full-dose warfarin for a median of 6.5 months. (At least 3 months)
2. 2. About 1/3 had a positive family history of VTE, about 25% had Factor V Leiden present, 5% had prothrombin mutation. Patients with cancer were excluded.
3. 3. All participated in a 30-day open-label run-in phase during which their dose of warfarin was titrated to a stable level that achieved an INR between 1.5 and 2.0.
4. 4. Randomized to: 1) low-intensity warfarin, or 2) matching placebo.
5. 5. Checked prothrombin time every 2 months and adjusted warfarin dose if necessary.
6. 6. End point = confirmed recurrent VTE (positive venographic study or clear evidence of pulmonary embolism).

1. The trial was terminated early at a mean of 2 years therapy because effectiveness and safety were considered established.
2. Median dose of warfarin = 4 mg (range 0.5 to 10 mg daily). Median INR was 1.7 in the warfarin group.
3.  

   Outcomes	Warfarin (n = 255)	Placebo (n = 253)
   Recurrent VTE (per 100 person years)	2.6	7.2
   Major hemorrhage	5 patients	2 patients
   Death	4 patients	8 patients
   NNT (to prevent one recurrence in one year) = 46

4. Outcomes were more favorable in women than in men. Hazard ratio of recurrent VTE: women = 0.20; men = 0.47
5. Recurrent events per 100 person-years of the 77 patients with either factor V Leiden, or prothrombin mutations:
   Placebo -- 8.6; Low-dose warfarin – 2.2 NNT(to prevent one event per year) = 16
6. Bleeding episodes necessitating hospitalization per 100 person-years:
   Placebo—0.4; Warfarin—0.9 [NNT(harm) = 200]
7. Minor bleeding or bruising occurred about twice as often in the warfarin group.
8. The rate of the composite end-point (recurrent VTE, major hemorrhage, or death from any cause) favored warfarin. (Hazard ratio = 0.52)

1. “Long-term low-intensity warfarin therapy given with a target INR of 1.5 to 2.0 results in a large and significant reduction in the risk of recurrent venous thrombosis.”
2. Benefit was achieved with little evidence of any increase in the risk of hemorrhage or stroke, despite the infrequency of monitoring anticoagulant therapy. (Every 2 months)
3. Low-dose long-term therapy can be implemented easily in primary care practice.
4. Importantly, this therapy was equally effective in patients with idiopathic DVT associated with thrombophilia (factor V Leiden and prothrombin mutations). Patients with anti-phospholipid antibody syndrome were not studied.

1. Population-based multicenter study followed over 3500 men and women--all over age 65 (mean age = 72). All were free of known CVD at baseline.
2. At baseline, determined usual dietary fiber consumption by a food frequency questionnaire. Average consumption of cereal fiber was 4.2 grams per day; fruit fiber – 5.2 grams/day; and vegetable Fiber--6.9 grams/ day.
3. The main foods contributing to the cereal fiber were dark breads and bran cereals. The intake of persons in the highest quintile of cereal fiber was 8 grams per day; the lowest quintile was 0.8 grams. (One slice of whole grain bread contains about 4 grams of fiber. Two slices would contain the 8 grams consumed by the highest quintile.)
4. Determined incident CVD over a 9 year period as related to quintiles of intake of fiber.

1. Over follow-up there were 811 incident CVD events.
2. After adjustment for multiple other risk factors, incidence of CVD was 21% lower in the highest quintile vs the lowest quintile of cereal fiber intake. Associations of cereal fiber consumption with CVD risk appeared to be graded and continuous.
3. Benefit was not evident for intake of vegetable or fruit fiber, only in relation to cereal fiber.
4. When CVD events were separately evaluated, higher cereal fiber intake was associated with lower incidence of stroke. Hazard ratio for ischemic stoke = 0.76. There was also a trend toward lower incidence of ischemic heart disease.
5. The lower risk appeared predominantly related to fiber intake from dark breads (whole wheat, rye, pumpernickel), rather than to fiber from bran or granola cereals and other cold or cooked cereals.

1. Consumption of cereal fiber (approximately equal to 2 slices of whole grain bread daily) was inversely associated with risk of incident CVD (especially stroke) in elderly people.
2. The difference in risk was modest¹, but the benefit/harm-cost ratio is high. Benefits on a population or public health level may be substantial
3. Cereal fiber consumption may also reduce risk by a substitution effect, replacing intake of other foods having potential detrimental effects.
4. No benefits from fruit and vegetable fiber were noted. This is consistent with prior observations.

1. Randomized, double-blind controlled trial followed over 2600 persons (over 2000 men and over 600 women) living in the general community in the UK. All were between ages 65 and 85.
2. Randomized to: 1) 100 000 IU oral cholecalciferol every 4 months, or 2) placebo. (Fifteen doses total)
3. Mean calcium intake at 4 years = 742 mg/d.
4. Observed for fracture incidence.
5. Follow-up = 5 years.

1. After 5 years, 268 men and women had incident fractures—147 in common osteoporotic sites (hip, wrist, forearm, of vertebra).

2. Incidence of fractures 5 years	Vitamin D	Placebo	Absolute difference
   Overall--hip wrist, forearm, vertebra	60/1345 (4.5%)	87/1341 (6.5%)	2.0%
   Men – hip wrist, forearm, vertebra	36/1019 (3.5%)	50/1018 (4.9%)	1.4%
   Women – hip wrist, forearm, vertebra	24/326 (7.4%)	37/323 (11.5%)	4.1%

3. Number needed to treat with vitamin D for 5 years to prevent one fracture:
   Men = 71; women = 24
4.  

   Relative risks (intention to treat)	Vitamin D	Placebo
   Any first fracture	0.78	1.00
   First fracture at osteoporotic sites	0.67 (~ a 30% reduction)
   Mortality	0.88 (not significant statistically)

5. Differences in fracture rate were evident at one year into the study.
6. No difference between groups on mortality, or incidence of cancer or cardiovascular disease.

1. The 100 00 IU dose every 4 months is equivalent to 800 IU daily.
2. No calcium supplements were prescribed.
3. This pragmatic (“real world”) primary prevention trial maximized generalizability. Subjects were similar to the general practice population in the UK and in the USA. Most fractures do not occur in persons with severe osteoporosis, but in the large numbers at moderately increased risk.¹ Indeed, population-wide preventive interventions have been proposed for all elderly people. “The clinical dilemma for primary prevention is that whereas the population-attributable risk is large, the absolute individual risk is still low.” The risk-benefit balance for community based prevention (and overall costs) differs from that for intervention in clinically defined groups. Safety, feasibility, and cost effectiveness are crucial. Side effects are less acceptable in a healthy group in which the risk of fracture is not high.”
4. Cost of vitamin D is low. The investigators quote a price of less than $2 for a year of treatment. (In the USA, supplements of calcium + vitamin D given daily cost less than $10 per year. RTJ)
5. “The results indicate that isolated vitamin D supplementation prevents fractures.”

I enjoyed this article. It suggests several important, potentially clinically applicable applications:
1) Vitamin D is a useful and effective preventive therapy. Its benefit/harm-cost ratio is very high.
2) It brings potential benefit to men as well as women. Prevention and treatment of osteoporosis has been a neglected subject in men. It is important.
3) Primary prevention can be effective even in old age. The age group in the study was 65 to 85. (The mean age was not mentioned. It must have been greater than 65.)
4) The absolute risk of osteoporosis is very high, almost universal as we age. Prophylaxis should be started at an early age (in the teen years). If not started early in life, it may be started much later with considerable benefit. Osteoporosis in older age brings great disability. We should prevent it as much as possible. RTJ

1. A prospective population-based cohort study (The Rotterdam Scan Study) was designed to study the causes and consequences of brain changes in the elderly.
2. In 1995-1996, randomly selected over 1000 participants (mean age = 71; range 60 to 90). All were free of dementia and stroke at baseline.
3. Conducted neuropsychologic testing and cerebral MRI at baseline and again in 3 to 4 years; 619 of the cohort underwent the second MRI for SBI. SBI was defined as one or more areas of focal hyperintensity at least 3 mm in diameter without a history of a corresponding stroke or TIA Infarcts on both the baseline and second MRI were graded with respect to location and size.
4. Monitored all for development of dementia throughout the study and any history of stroke or transient ischemic attacks (TIA).
5. Also analyzed for the presence or absence of subcortical atrophy and white-matter lesions.
6. Follow-up = mean of 3.6 years.

1. Baseline characteristics all participants (n = 1015)

   Mean age	72 years
   Hypertension	51%
   Diabetes	7%
   Use of aspirin	11%
   Silent brain infarcts	21% (The great majority lacunar)

   (Note that at mean age 72, in this study, about 1/5 of all asymptomatic individuals had already experienced a SBI. This requires confirmation. RTJ)
2. Presence of SBI at baseline more than doubled the risk of dementia during follow-up of 3.6 years. Of 798 subjects without SBI at baseline, 16 (2%) developed dementia; of 217 with SBI at baseline, 14 (6%) developed dementia. (My calculation, RTJ)
3. Greater severity of periventricular white-matter lesions was associated with greater risk.
4. Greater subcortical atrophy of the brain was also associated with greater risk.
5. Nineteen of the 30 patients who developed dementia underwent a second MRI. Of these 3 (16%) experienced a symptomatic infarct, and a new SBI was found in 4 (21%). Of the 618 without dementia at follow-up, 1% had a symptomatic infarct and 11% had a new SBI. Global cognitive function declined more in those with SBI at baseline who developed an additional infarct during follow-up.
6. Subjects with SBI at baseline experienced steeper decline in cognitive function over 3.6 years. This was especially evident in those with multiple SBI.

1. The presence of SBI on MRI in elderly persons without dementia at baseline, more than doubled the risk of developing dementia (majority of the Alzheimer’s type) over the next 3.6 years
2. There is increasing evidence that vascular factors may contribute to the development of Alzheimer’s disease. After a symptomatic stroke, dementia (including Alzheimer’s disease) develops in approximately 30% of patients. .
3. A greater severity of periventricular white-matter lesions (thought to result from small-vessel disease) was associated with increased risk of dementia.
4. Persons with SBI are at greater risk for additional infarcts, both symptomatic and silent.

1. World-wide, randomized, double-blind trial followed over 7000 patients (age 5 to 66; mean = 24) to completion of a 3-year trial.
2. All had mild persistent asthma of less than 2-years duration. All had symptoms in the 3 months before entry. None had previous regular treatment with corticosteroids.
3. Mild persistent asthma defined as wheezing, cough, dyspnea, or chest tightness at least once a week , but not \ as often as daily. All had reversible airway obstruction (increase in FEV1 of more than 12% after a short-acting bronchodilator, a fall in FEV1 of more than 15% on exercise testing, or a variation of more than 15% between the two highest and two lowest peak expiratory flow rates during 14 days.)
4. Randomized to: 1) once daily inhaled budesonide (400 micrograms [two inhalations]for adults; 200 ug for children under age 11), or 2) inhaled lactose. [In the USA, Pulmicort turbohaler delivers 200 mcg of budesonide with each activation.]
5. The primary outcome was time to first severe asthma-related event, defined as one which required admission or emergency treatment for worsening asthma, or as death due to asthma.
6. Other asthma treatments were continued as before.

1.  

   Outcomes over 3 years:	Budesonide (n = 3568)	Placebo (n = 3597)
   At least one severe exacerbation	117 (3.3%)	198 (5.5%)
   [Absolute difference = 2.2%; NNT (to benefit one patient over 3 years) = 45]
   Treated patients had fewer courses of systemic corticosteroids and more symptom free days.
   Treatment benefited all age groups.
   Compared with placebo, post-bronchodilator FEV1 increased by 1.5% after one year and by 0.9% after three years (expressed as percent of the predicted value).

2. In younger children, 3-year growth was reduced by 1.3 cm; the greatest reduction in the first year.
3. “Both treatment regimens were well tolerated with a similar rate of non-asthma related adverse effects.”

1. Substantial morbidity is associated with mild asthma.
2. Early once-daily inhalations of low-dose budesonide reduced risk of having a severe asthma exacerbation “by almost half”¹ and even more so for life-threatening exacerbations.
3. Treatment also resulted in more symptom-free days, and a reduced need for systemic corticosteroids.
4. The effectiveness of budesonide was independent of lung function or medications at baseline.
5. The small change in growth noted in children was expected. Despite the reported initial effect on growth, other studies reported children attained normal adult height while continuing treatment with budesonide for 10 years.

1. Systematic review of randomized-controlled trials found 13 trials (12 in adults; 1 in children) meeting inclusion criteria. All were in patients with mild to moderate asthma.
2. Compared anti-leukotriene receptor antagonists montelukast (Singulair) 10 mg once daily; and zafirlukast 20 mg twice daily) with inhaled glucocorticoids equivalent to beclomethasone (Beclovent; Vanceril) 400-450 micrograms daily.
3. Main outcome = rate of exacerbations requiring treatment with systemic glucocorticoids.
4. Follow-up = as long as 37 weeks.

1. Leukotriene receptor antagonists were more likely to suffer an exacerbation requiring systemic glucocorticoids; 11.6% vs 6.1%. (NNT = 18)
2. Inhaled glucocorticoids provided greater improvement in FEV1, in morning peak expiratory flow rate, nocturnal awakenings, use of rescue beta-agonists, and days without symptoms.
3. Side effects did not differ between groups according to a priori definition of equivalence. However, treatment period was limited and adverse effects typical of inhaled corticosteroids were not measured.
4. Anti-leukotrienes were associated with more withdrawals due to poor control of asthma.

1. In patients with mild to moderate asthma, use of anti-leukotrienes was more likely to require systemic glucocorticoid therapy.
2. The effect was not influenced by the type of anti-leukotriene or the inhaled corticosteroid used, by disease severity, or intention to treat analysis.
3. There was a higher rate of withdrawals of anti-leukotrienes due to lack of efficacy.
4. The superiority of inhaled glucocorticosteroids was evident within 4 to 6 weeks, and persisted for up to 37 weeks.

1. Pragmatic (real world), randomized controlled trial in 4 general practices in the UK followed 278 adults (mean age 55) with asthma. None had received a routine asthma review in the past 11 months.
2. Randomized to: 1) telephone reviews with a specialist nurse trained in asthma treatment., or 2) office consultations
3. Patients randomized to telephone were sent a letter informing them that they would receive a telephone review and that they should expect a call from an asthma nurse within the month.
4. Nurses followed their normal practice made appropriate to each patient’s individual clinical need.
5. Nurses arranged any follow-up office consultations they felt necessary. Patients were free to arrange any consultations they wished.
6. Patients in the control group were sent a written invitation to make an appointment to see the asthma nurse within a month.
7. Outcomes—change in asthma symptoms and related quality-of-life determined by questionnaire.

1. Telephone consultations were shorter than office visits (mean duration 11 min vs 22 min).
2. The 2 types of consultation addressed similar aspects of asthma care. Peak flow measurements were more likely to be discussed in the office.
3. Quality-of-life scores and symptom scores measured within 3 months of randomization were similar in the two groups.
4. The number of acute asthma exacerbations and use of health resources did not differ.

1. Telephone consultations enabled 26% more people with asthma to be reviewed as compared with office visits, without any apparent clinical disadvantage or loss of satisfaction.
2. Because of their shorter duration, telephone consultations may be an efficient option in primary care for routine review of patients with asthma.
3. All practices were “asthma interested”—they all had specialist nurses experienced in providing asthma care.
4. Content of the telephone consultations was similar to office consultations, apart from peak flow measurements.
5. Telephone reviews can take as long or as short a time as necessary. The time limits imposed on office visits do not apply. However, nurses observed that telephone consultations were more “focused”. This may reflect the tendency of telephone consultations to be more goal oriented, with fewer digressions.
6. Despite the shorter time, there was no evidence of dissatisfaction with the time spent.
7. There may be some cost advantages to patients.

1. Randomized, double-blind trial assessed the effect of aspirin on incidence of adenomas in 635 persons. All had a history of previous CRC. All had undergone surgery aimed at cure.
2. Participants were considered at relatively low risk for recurrence of cancer. Most had Dukes’ stage A or B1 and had no metastatic spread. Some patients with higher grades of CRC were entered if they had received surgery aimed at cure and had been free of disease for more than 5 years.
3. Before study entry, all received colonoscopy within 4 months, with removal of all polyps.
4. Randomized to: 1) enteric-coated aspirin 365 mg daily, or 2) placebo.
5. During follow-up, (median of 31 months) repeat colonoscopy determined the proportion of patients with adenomas, the number of recurrent adenomas, and the time of development of adenomas between randomization and subsequent colonoscopic examinations.

1. A total of 517 patients had at least one colonoscopy after randomization.
2.  

   Outcomes	Aspirin (n = 259)	Placebo (n = 258)
   One or more new adenomas found	43 (17%)	70 (27%)
   (Absolute difference = 10%; NNT(to benefit one patient) = 10.)

3. Median size of adenomas and proportion of subjects with advanced adenomas was the same in both groups.
4. Incidence and type of adverse effects were similar in the two groups.

1. Previous trials have reported that patients with familial adenomatous polyposis treated with celecoxib (Celebrex) and sulindac (Generic; Clinoril) developed fewer adenomas.
2. It is difficult, however, to show that NSAIDs prevent CRC because of the long latency period of progression from benign adenoma to CRC. Because most CRCs develop from adenomas, adenomas have been used as surrogate endpoints in prevention trials.
3. The present trial was based on the premise that patients with a history of CRC might constitute a group at higher risk for adenomas and thus be particularly suitable for a study of chemopreventive effects of NSAIDs.
4. Support for the hypothesis that aspirin protects against colorectal neoplasia comes from other studies that have used either cancer or adenomas as endpoints. “These studies have had remarkably consistent results, with benefits irrespective of age, race, sex, location of the study centers, and location of the tumor in the colon or rectum, and have generally shown a 40 to 50 percent reduction in the risk of colorectal neoplasia.”
5. This present study is important because it demonstrates a protective effect of aspirin in a population at higher risk.
6. A recent study that used rectal mucosal prostaglandin E2 levels as a biologic marker found that, as compared with placebo, an 81-mg dose of aspirin significantly suppressed prostaglandin levels to an extent equivalent to that of higher doses.
7. Aspirin cannot be viewed as a replacement for surveillance colonoscopy.

1. Community-based prospective cohort study entered over 2400 adults (mean age 72) who participated in the Framingham Heart Study. All were free of CHF and prior myocardial infarction at baseline.
2. Divided homocysteine levels into quartiles for women (in umol/L) 1) 3.5 to 8.9; 2) 9.0 to 11.0; 3) 11.1 to 13.6; 4) 13.7 to 65. Mean = 12.0. In men levels were slightly higher.
3. Main outcome = incidence of a first episode of CHF during an 8-year follow-up.

1. During follow-up 156 subjects developed CHF.
2. Development of CHF according to quartiles of plasma homocysteine;

   Quartile	1	2	3	4
   Women developing CHF	10/386 (2.6%)	16/389 (4.1%)	20/385 (5.2%)	42/387 (10.9%)

   [Absolute difference between quartile 1 and 4 = 8.3%. NNT(8 years to benefit one) = 12 ]
3. Results for men – NNT = 17
4. After controlling for established risk factors for CHF, including the occurrence of MI, plasma homocysteine levels higher than the median values (over 11 umol/L in women and over 12 umol/L in men) were associated with an adjusted hazard ratio for CHF of 1.9 for women, and 1.8 for men.
5. The relation between plasma homocysteine in those without coronary heart disease at baseline and risk of future CHF was maintained in both men and women.

1. In older adults without prior myocardial infarction, elevated plasma homocysteine was related positively and strongly with risk of CHF.
2. In women, the risk of CHF doubled at the second quartile. A 4-fold risk was observed for those with values in the top quartile vs those in the lowest quartile.
3. In men, the risk of CHF became evident only at values exceeding the median.
4. In a small subgroup of individuals who underwent echocardographic evaluation within 30 days of their first CHF hospitalization, homocysteine levels above the median were associated with both systolic and diastolic CHF.
5. What might the mechanisms be for the association?

   The myocardium might be uniquely susceptible to homocysteine-induced injury.
   Homocysteine is a risk factor for coronary atherosclerosis and MI.
   Homocysteine may lead to myocardial ischemia by promoting endothelial dysfunction of coronary resistance vessels.
   Homocysteine levels in patients with coronary syndromes are associated with greater myocardial injury as evidenced by higher troponin levels.
   Homocysteine may have a critical role as a source of oxidative stress, a factor known to promote myocardial dysfunction.

6. “Our study design would support the importance of non-ischemic mechanisms in addition to the well-recognized ischemic mechanisms.”
7. “Our findings are consistent with the hypothesis that elevated plasma homocysteine levels are important risk factor for CHF.”
8. Folic acid, alone or in combination with vitamins B6 and B12, lowers homocysteine levels, and may reduce risk of CHF.

1. Prospective, randomized trial entered 282 patients (mean age = 80). All had class 2 or higher chronic angina despite treatment with 2 or more anti-anginal drugs. Comorbidity and risk factors were universal in these patients.
2. Randomized to: 1) coronary angiography followed by revascularization (if feasible), or 2) optimized medical therapy.
3. Optimized medical therapy was not described fully. The number of anti-anginal drugs was increased and the dosages were increased.
4. Main outcomes = quality of life assessed by standardized questionnaire, and major adverse cardiac events (death, non-fatal MI, or hospitalization for acute coronary syndrome).
5. Follow-up = one year.

1. Intervention group (n = 155 assigned):

   PCI	79
   CABG	39

   (Not all patients in the intervention group actually received an intervention.)

2. At one year:	Invasive ( n = 140)	Medical (n = 142)
   Later revascularization	10%	46%
   Mortality	11%	8%
   Death or non-fatal MI	17%	20%
   Overall major adverse cardiovascular events
   At 6 months	19%	49%
   At one year	25%	64%

   (Note that half of the patients assigned to medical therapy underwent revascularization within the year.)
3. There was a persistent and marked relief of symptoms and improvement in quality of life in both groups. The improvements were greater in the intervention group in the first 6 months, but the difference disappeared at one year.

1. Previous short-term trials in elderly patients reported greater benefits from invasive therapy, but at a risk of excess early mortality.
2. In this trial, the early unfavorable mortality observed in the intervention group disappeared during late follow-up.
3. The advantage of invasive therapy regarding symptom relief and improvement in quality-of-life noted after 6 months also disappeared during late follow-up.
4. Significantly more optimized medical patients needed to be hospitalized for uncontrolled symptoms, and significantly more received late revascularization for that reason.
5. In this study, rates of death, and death or non-fatal MI, were similar after one year and there was no longer a significant difference in angina relief or improvement in quality-of-life between treatment groups. Thus, would it not be reasonable to wait until revascularization becomes urgently necessary? If symptoms are acceptably controlled by optimized medical therapy, they may not have to undergo the risks of revascularization.
6. However, if medically treated individual patients cannot accept the 50% chance of hospitalization with later revascularization, they can choose early revascularization.

1) “Optimal” medical therapy is difficult to achieve in primary care practice, and brings adverse side-effects. The investigators were expert.
2) An 80 year old patient may welcome the early relief of symptoms and be willing to accept the chance of intervention-related death in order to achieve some degree of comfort, albeit temporary.
3) That an individual patient faces a 50% chance of intervention within a year (and its risk) might tilt him or her toward earlier intervention.
4) I believe it more likely now, with the advent of sirolimus-coated stents, that outcomes from PTCA will be more favorable than outcomes in the study. RTJ

1. Investigated weight changes in over 1900 patients (mean age 61) with chronic HF randomized to 1) enalapril vs 2) placebo. ¹
2. At baseline, all patients had an ejection fraction less than 35%, were clinically stable, and were included only if they were free of edema. .
3. Determined prognostic effect of weight loss at cut points of 5%, 7.5%, 10%, and 15%.
4. Mean follow-up = 35 months. During follow-up 39% died.

1. Effects of weight loss:

   A. Over follow-up, 42% of patients had weight loss from baseline of 5% or more.
   B. Weight loss was independently related to reduced survival. All cutpoints for weight loss were significantly associated with impaired survival after adjustment for age, sex, NYHA class, and left ventricular ejection fraction.
   C. 29% of all deaths occurred on the background of newly developed weight loss of 7.5%or more; 38% of the people who died had a weight loss of 6% or more. These deaths were in a population of patients judged clinically stable and non-cachectic at baseline.
   D. Weight loss of 6% or more at any time during follow-up occurred in 36%. This was the strongest predictor of death (adjusted hazard ratio compared with no weight loss = 2.1)
   E. Over 4 months, patients who lost more than 15% of their original weight had 3.3 times the risk of death as persons who maintained their original weight.

2. Effect of enalapril:
   

         Patients taking enalapril had a lower hazard of weight loss . Over 36 months, the hazard ratio of those taking enalapril vs those taking placebo gradually widened. The delay in weight loss associated with enalapril was such that a 30% cumulative proportion of patients with weight loss of 6% or more was reached after 24 months in the placebo group vs 32 months in the enalapril group. (By my calculation from their figure 2 page 1080, at 36 months enalapril(as compared with placebo) was related to a reduction in risk of weight loss-- from over 40% in placebo group to 30% in enalapril group. RTJ)
         However, enalapril was not protective of survival in those with severe cachexia (weight loss over 15%)

1. Substantial weight loss is a common event in persons with chronic HF. It is a gradual and graded process. Spontaneous reversal is a rare event. In chronic HF, the wasting process affects muscle, fat, bone, and heart. Contributing factors include: anorexia, malabsorption, mental depression, and upregulation of catecholamine levels. ACE have a favorable blunting effect on catecholamine levels.
2. Weight loss was independently linked to impaired survival.
3. “We suggest that weight loss of 6% or more should be the cutpoint to define the presence of cachexia in chronic heart failure.” At 9 months, patients with weight loss 6% or more had up to a 100% higher subsequent death rate.
4. Enalapril delayed the development of cardiac cachexia by about 8 months, and delayed death by 6 months.

1) Optimum medical treatment with diuretics and vasodilators (usually ACE inhibitors). OR, angina pectoris at rest, resistant to standard nitrate therapy. AND
2) Significant symptoms of recurrent congestive heart failure at rest (NYHA Class IV)