3-1 RAPID ANTIBIOTIC DELIVERY AND APPROPRIATE ANTIBIOTIC SELECTION REDUCE LENGTH OF HOSPITAL STAY IN PATIENTS WITH COMMUNITY-ACQUIRED PNEUMONIA
      Rapid delivery of the appropriate antibiotic in the ED was associated with a shorter length of stay in hospitalized patients with community-acquired pneumonia.
      Practical point: Primary care clinicians who see very ill patients with infectious disease should administer a full dose of the reasonably appropriate antibiotic immediately in the home, office or emergency department. Do not wait for delivery from the pharmacy or the long door- to-antibiotic time in the hospital. This will improve prognosis.

3-2 PREVALENCE OF IMPAIRED GLUCOSE TOLERANCE AMONG CHILDREN AND ADOLESCENTS WITH MARKED OBESITY
      Impaired glucose tolerance is highly prevalent among children and adolescents with severe obesity. It is associated with insulin resistance while beta-cell function is still relatively preserved.
      Overt DM2, which occurred in a few adolescents, was linked to beta-cell failure.
      Impaired glucose tolerance (2 h pc glucose 126-200) is a more sensitive marker of risk of DM2 than elevated fasting glucose (110-125). This is an important clinical point.
      Practical point: Primary care clinicians should maximize efforts to reduce obesity in their adolescent patients.

3-3 EXERCISE CAPACITY AND MORTALITY AMONG MEN REFERRED FOR EXERCISE TESTING
      Exercise capacity was a more powerful predictor of increased risk of death than established risk factors such as hypertension, smoking, and diabetes.
      Poor fitness is a modifiable risk factor. Improvements in fitness over time have been demonstrated to improve prognosis.
      Practical point: Health professionals should incorporate into their practices strategies to promote physical activity at all stages of life. The greatest health benefits are achieved by increasing physical activity among the least fit, including persons without, as well as persons with, cardiovascular disease. Fitness will overcome some of the risks of established risk factors. If you can’t stop smoking, at least get fit!

3-4 IMPROVED CARDIORESPIRATORY ENDURANCE FOLLOWING 6 MONTHS OF RESISTANCE EXERCISE IN ELDERLY MEN AND WOMEN
      Resistance exercise led to significant improvements in muscle strength, aerobic capacity, and treadmill time in older adults. It is a clinically applicable means of improving fitness. The principal finding of the study was that peak O2 consumption and treadmill time increased in a low-intensity exercise group.
      Practical point: Almost all older, non-fit patients, even those with localized muscle weakness, could be instructed to perform some resistance exercises. A program could easily be designed with little equipment and applied at convenient times for variable duration. A formal machine-based program as described in the article would not be necessary. Problems would be motivation and consistency. A successful program would likely enhance balance, and reduce risk of falling.

3-5 BETA-BLOCKERS AND REDUCTION OF CARDIAC EVENTS IN NON-CARDIAC SURGERY
      Use of beta blocker therapy perioperatively significantly reduces cardiac morbidity and mortality in patients at high risk.
      Practical point: This is an important clinical consideration for primary care clinicians whose patients are contemplating high risk surgery.

3- 6 PARTICIPATION IN COGNITIVELY STIMULATING ACTIVITIES AND RISK OF INCIDENT ALZHEIMER’S DISEASE
      Frequent participation in cognitively stimulation activities was associated with reduced risk of cognitive decline and AD.
      The frequency of cognitive activity is associated not only with the level of cognition at baseline, but also with the rate of cognitive decline.
      (Ie, the rate of cognitive decline even after first stages of AD may be slowed by continuing cognitive activity.)

      If cognitive activity is protective, reduced cognitive activity should be an early sign of disease.
      Practical point: Use it, or you will lose it!

3-7 MODERN WORRIES, NEW TECHNOLOGY, AND MEDICINE
      Historically, the introduction of new technologies has frequently been accompanied by new complaints, fears, and illness. Currently, the adoption of new technologies is accelerating and is occurring in a climate of suspicion and mistrust in medical evidence. Distrust of experts is now commonplace. At its extreme it can merge into the conspirational thinking that is part of a modern paranoid style. Well publicized crises have clearly dented confidence. Mismanaged environmental incidents and examples of the fallibility of experts are easily recalled.
      “It is difficult to feel optimistic.” Despite all the evidence of the extraordinary improvements in public health during the past century, surveys show that we experience more symptoms and feel worse than our ancestors.” The rapid introduction of new technologies, while improving quality of life, has been accompanied by important adverse effects in the way people make sense of illness and present with health complaints.
      Controversy in “scientific” medicine itself compounds the public confusion. Expressions of differences in opinions and conflicting studies published in medical journals quickly reach the media. Is mammography really effective in reducing breast cancer death? Is PCA screening helpful or harmful? What about all the confusion about benefits and harms of hormone replacement therapy? How common are the harms associated with drug therapy and hospitalization?
      Practical point: Do you agree? If so, what is to be done?

3-8 STATIN USE, BONE MINERAL DENSITY, AND FRACTURE RISK
      Over 2 years, statin use was associated with a 4% absolute reduction in fracture risk . (NNT to benefit one over 2 y = 26)
      The protective effect was greater than would be expected from increases in BMD. The mechanism of action is not clear.
      Practical point: Many elderly persons will be taking statins for lipid control. Is this an added bonus? Watch for developments.

3-9 HMG COA REDUCTASE INHIBITOR (STATIN) AND AORTIC VALVE CALCIUM
      Statin therapy may retard progression of calcific aortic valve disease.
      Practical point: Another added bonus?

3-10 LONG-TERM EFFECTS OF MAMMOGRAPHY SCREENING: UPDATED OVERVIEW OF THE SWEDISH RANDOMISED TRIALS
      The effect of BC screening in terms of BC mortality reduction persists after long-term follow up. The benefit is highest in women age 55-69 at randomization. The recent criticism against the Swedish trial is misleading and unfounded.
      (By my calculation, screening in the Swedish trial was associated with one death from BC prevented each year for every 1000 women screened. RTJ)
      Practical point: Mammography is so engrained in our society, it would be difficult for primary care clinicians to deny it to their patients.

3-11 PROSPECTIVE STUDY OF MODERATE ALCOHOL CONSUMPTION AND RISK OF HYPERTENSION IN YOUNG WOMEN
      The association between alcohol consumption and risk of chronic hypertension in young women followed a J-shaped curve. Light drinkers demonstrated a modest decrease in risk. Regular, more heavy drinkers demonstrated increased risk.
      Practical point: The epidemiological evidence for benefits of light drinking is strong and consistent.

3-12 USE OF RAMIPRIL IN PREVENTING STROKE
      The ACE inhibitor, ramipril, was associated with a reduced incidence of stroke despite a modest reduction in BP.
      Practical point: This is a good example of the “spin” investigators sometimes place on their studies. Their abstract states the relative risk of fatal stroke was reduced by 61%. (In absolute terms this actually amounted to 0.6%; NNT = 166 for 4.5 years to prevent one fatal stroke)

3-13 CARDIOVASCULAR MORBIDITY AND MORTALITY IN LOSARTAN INTERVENTION FOR ENDPOINT REDUCTION IN HYPERTENSION STUDY (LIFE): A Randomized Trial Against Atenolol
      The angiotensin II blocker losartan prevented more combined cardiovascular morbidity and death and stroke than the beta-blocker atenolol for a similar reduction in BP. “Losartan seems to confer benefits (in relation to stroke) beyond reduction in BP.”
      Practical point: Another example of “spin” . The benefit of losartan applied to only one person out of 59 over 5 years. This may be “highly significant” statistically, but hardly significant clinically. Primary care clinicians should beware! I believe the conclusions of this study may mislead clinicians who do not have the time to judge the study in detail. Putting a favorable “spin” on conclusions of studies seems to be occurring more frequently.

3-14 DECONSTRUCTING THE PLACEBO EFFECT
      The authors of this article present a new perspective to what has been known as the "placebo effect". The most recent serious attempt to try logically to define the placebo effect failed utterly. One definition: "A placebo is a substance or procedure without specific activity for the condition being treated. The placebo effect is the therapeutic effect produced by a placebo." This makes no sense whatsoever. It flies in the face of the obvious. "The one thing of which we can be absolutely certain is that placebos do not cause placebo effects. Placebos are inert and don't cause anything."
      The editorialists suggest thinking about this issue in a new way. "Although placebos clearly cannot do anything themselves, their meaning can."

3-15 NONSPECIFIC MEDICATION SIDE EFFECTS AND THE NOCEBO PHENONEMON
      This article used the nocebo phenomenon to explore the occurrence of adverse, nonspecific effects in patients taking active medications and suggest ways in which clinicians can deal more effectively with them.
      Practical point: Nocebo and placebo effects accompany all medical interventions. Primary care clinicians accept them even if they do not understand them.

1. Selected 700 adult patients with pneumonia presenting to Eds. All were judged to require hospitalization. Patient had to be admitted from the home or a nursing home. Direct to the floor admissions were excluded.
2. The majority had co-morbid conditions.
3. Determined 3 quality-of-care measures: 1) site of initial antibiotic administration (ER or after admission on the floor); 2) door to needle time (apparently all were treated with intravenous antibiotics); 3) appropriate antibiotic selection. (Guidelines defined by the Infectious Disease Society of America [IDSA] in 1998.)
4. Determined associations between length of stay in hospital and these variables.

1. All three quality-of-care variables were associated with length of stay. Initial antibiotic given in ED; appropriate antibiotic selection; 1 and shorter door-to-needle time were associated with shorter length-of-stay by a mean of 2 days (7 vs 9).
2. The mean door-to-needle time in the ED was 3.5 hours; on the floor was 9.5 hours.
3. The appropriate choice of antibiotic was especially significant for patients with comorbid conditions.

1. Implementation of short door-to-needle time; choice of an appropriate antibiotic; and initial treatment in the ED were associated with shorter hospital stays.
2. A more rapid antibiotic delivery time may hasten the establishment of clinical stability and earlier discharge. This is particularly true of the many elderly high-risk patients with co-morbid conditions who are admitted to the hospital with pneumonia.
3. The choice of optimum antibiotic(s) is important and also may shorten hospital stay. What is the proper choice of antibiotic in patients with community-acquired pneumonia who are judged sick enough to be admitted to the hospital? The article quotes the guidelines issued by the IDSA: 1
4. In this study many patients were not treated expeditiously in the ED. And many were not treated with an appropriate antibiotic (as defined by the IDSA) in the hospital.

1. Flouroqinolone (alone):
   Levofloxacin [Levaquin] 500 mg IV or PO daily for 7 to 10 days. or,
   Gatifloxacin [Tequin] 400 mg IV/PO daily for 7 to 10 days
2. Ceftriaxone [Rocephin; 1 g IV daily] or cefotaxime [Claforan 1 g IV q 8h] plus a macrolide

   A.	(Azithromycin [Zithromax] 500 mg IV or PO for 5-10 days daily, or
   B.	Clarithromycin [Biaxin ] 500 mg PO bid , or
   C.	Erythromycin 500 mg to 1 g IV q 6h, or 500 mg PO qid

1. Recruited 55 obese children (age 4 to 10) and 112 adolescents (age 11 to 18). All had a body mass index (BMI) higher than the 95th percentile for their age and sex. [Mean BMI children = 32; adolescents = 35.]
2. Approximately 40% of the 58 adolescent girls had hirsutism, oligomenorrhea, acne, and increased testosterone, suggesting polycystic ovary syndrome. 1
3. Administered an oral glucose tolerance test with a dose of 1.75 g per kg up to a maximum of 75 g. Determined plasma glucose, insulin, and C-peptide every 30 minutes for 2 hours. Defined IGT as fasting glucose less than 126 mg/dL and a 2-h glucose between 140 and 200. Defined DM2 as fasting glucose 126 or higher, or 2-h glucose more than 200. [Impaired fasting glucose is defined as between 110 and 125. RTJ]

1. IGT was detected in 25% of the children and 21% of the adolescents.
2. Insulin and C-peptide were markedly elevated in those with IGT. But not in the adolescents with DM2.
3. Insulin resistance was greater in those with IGT.
4. Silent DM2 was identified in 4 adolescents.

1. In these obese children and adolescents, there was a high prevalence of IGT. Frank DM2 was discovered in a few adolescents. (Ie, DM2 can occur in childhood.)
2. Risk factors for IGT included insulin resistance, marked hyperinsulinemia fasting, and after a glucose challenge, and hyper pro-insulinemia. 2
3. Look for signs of polycystic ovary syndrome in adolescent girls with IGT.
4. The onset of IGT was clearly associated with development of insulin resistance while beta-cell function was still relatively preserved.
5. In the 4 with DM2, insulin secretion declined and disproportionate hyper-pro-insulinemia was present. "Disproportionate hyper-pro-insulinemia is a clear marker of beta-cell dysfunction in overt type 2 diabetes." "The vigorous hyper-pro-insulinemic response to glucose found in the pre-diabetic stage in obese children and adolescents may reflect an up-regulation of beta-cell function caused by chronic severe insulin resistance."
6. In these obese children and adolescents with IGT, prevalence of impaired fasting glucose (110 to 125 mg/dL) was low (less than1%). "Fasting hyperglycemia is indicative of a more advanced stage of clinical diabetes and the determination of its presence represents a very insensitive method for detecting impaired glucose tolerance." 3

1. Studied over 6000 consecutive men referred for treadmill exercise testing for clinical reasons. (Mean age = 58)
2. Classified them into 2 groups: 1) those with an abnormal exercise test or a history of cardiovascular disease, or both; 2) those with a normal exercise test and no history of cardiovascular disease. (N over 2500)
3. Follow-up = a mean of 6 years. End-point = overall mortality.

1. There were over 1200 deaths during follow-up (20% of cohort).
2. Men who died were older, had a lower maximal heart rate, lower maximal systolic and diastolic BP, and lower exercise capacity measured as metabolic equivalents (METs).
3. After adjustment for age, the peak maximal exercise capacity measured in METs was the strongest predictor of the risk of death among normal men as well as those with cardiovascular disease. Each MET increase in exercise capacity conferred a 12% improvement in survival.
4. Among subsets of patients with hypertension, COPD, diabetes, smokers, obesity, and elevated total cholesterol, those with the highest exercise capacity (> 8 METS) had about a 50% lower risk of death from any cause than those with capacity < 5 METS. A near linear reduction in death occurred as fitness levels increased.
5. For each quintile of exercise capacity, the relative risk of death increased as the METs achieved decreased.
6. There was no interaction between the use of beta-blockers and the predictive power of exercise capacity.

1. The study afforded the opportunity to assess normal subjects as well as those with cardiovascular disease. Exercise capacity was a similarly important marker of risk in both groups.
2. The maximal exercise testing used in this study provided an objective measure of physical fitness.
3. In healthy subjects (as well as those with cardiovascular disease) the peak exercise capacity achieved was a stronger predictor of increased risk of death than established risk factors such as hypertension, smoking, and diabetes.
4. Poor fitness is a modifiable risk factor. Improvements in fitness over time have been demonstrated to improve prognosis. Health professionals should incorporate into their practices strategies to promote physical activity. The greatest health benefits are achieved by increasing physical activity among the least fit, including both persons without, as well as persons with, cardiovascular disease.
5. Outcomes were not affected by beta-blockade. Among those taking beta-blockers, the most fit were the most likely to survive.

1. Followed 62 men and women volunteers aged 60 to 83 (mean = 68) to completion of a six month course of resistance exercise.
2. One third were controls; 1/3 assigned to low-intensity resistance exercise; 1/3 to high-resistance exercise. (I omit the high-intensity group because compliance with this degree of effort would not be routinely acceptable to primary care patients in this age group. RTJ )
3. Subjects were tested by determining their maximum strength in 8 resistance exercises beginning with light weight lifting and incrementally increasing the load up to a maximum. The low-intensity group then exercised at 50% of this maximum.
4. Over 6 months, eight different resistance exercises were performed on an exercise machine in single sets of 13 repetitions with a 2 minute rest between. All attended at least 85% of the thrice-weekly sessions.

1. At 6 months, maximum strength increased significantly in low-intensity group.
2. Aerobic capacity (peak O2 consumption tested on a treadmill) increased by 24% compared to controls.
3. Treadmill time to exhaustion increased by 26%.

1. The principal finding of the study was that peak O2 consumption and treadmill time increased in the low-intensity exercise group.
2. It is reasonable to conclude that endurance performance during submaximal activities of daily living would also benefit.
3. Resistance training may be a viable means of improving cardiorespiratory endurance in elderly persons. Improvement might be greater in those who are more deconditioned and frail, or when recovering from an illness.

1. Performed literature search related to perioperative cardiac complications and beta-blockade.
   Selected 5 prospective randomized studies which assessed the impact of beta-blockade on cardiac ischemia, MI, and mortality in patients undergoing major non-cardiac surgery.
2. Beta-blockers included atenolol, bisoprolol, esmolol, and labetolol.
3. All sought to achieve beta-blockade before induction of anesthesia by titrating dose to a target heart rate.
4. The studies included patients with evidence of prior coronary disease, risk factors for CHD, and untreated hypertension

1. For prevention of myocardial ischemia, the number needed to treat (NNT) to prevent one event varied between 3 and 7. For mortality, cardiac or all cause, the NNT was 3 to 8.
2. The most marked benefits were seen in patients at high risk. For those at highest risk the NNT was as low as 3.
3. Adverse effects: One study reported a high rate of bradycardia which required atropine therapy.
   Patients who discontinued perioperative use immediately after surgery had a marked increase in MI after surgery. "Discontinuing beta-blocker use in patients who have a longstanding indication for adrenergic blockade may lead to adverse outcomes perioperatively, and worsen survival.
4. Who should receive beta-blockers perioperatively?
   Patients at low risk can be excluded, especially those undergoing low-risk procedures. Harms may outweigh benefits. Patients at high risk should receive beta-blockade:
   

   High risk surgical procedure — intraperitoneal, intrathoraccic or suprainguinal vascular procedure.
   History of ischemic heart disease
   History of cerebrovascular disease
   Chronic renal insufficiency (creatinine > 2.0 mg/dL)
   Diabetes requiring insulin
   Congestive heart failure is a high risk, but not an indication for immediate perioperative beta-blockade.
   

   For the many patients taking beta-blockers long before the immediate perioperative period, including those with congestive failure, it is important to continue.
   Beta-blockade may have additional benefits in elderly patients.

1. Longitudinal cohort study followed over 700 Catholic nuns, priests, and brothers older than age 65.
2. None had dementia at baseline.
3. Participants rated frequency of participation in common cognitive activities. At baseline asked about 7 common activities which involve information processing: viewing TV, listening to radio, reading newspapers, reading magazines, reading books, playing games (eg, checkers, cards, crossword and other puzzles), and going to museums.
4. Rated frequency of participation in each activity on a 5-point scale: daily – 5 points; several times a week – 4 points; several times a month - 3 points; several times a year – 2 points; once a year or less – 1 point.
5. Repeatedly tested for cognition over a mean of 4.5 years. At each evaluation, administered 20 tests of cognition. (See text p 743) Criteria for diagnosis of AD required a history of cognitive decline, and impairment of memory and at least one other cognitive domain.
6. A neurologist made a clinical diagnosis of AD based on national standard criteria, assessed change in global and specific measures of cognitive function, and compared cognitive activity score change with baseline.

1. Baseline scores on the composite measure of cognitive activity ranged from 1.6 to 4.7. (Higher scores indicate more frequent activity.)
2. During follow-up, 111 persons developed AD.
3. After controlling for age, sex, and education, a 1-point increase in cognitive activity score was associated with a 33% reduction in risk of AD.
4. A 1-point increase in cognitive activity score was associated with a 30% to 60% slower decline in global cognition, working memory, and perceptional speed.
5. Physical activity was not related to rate of decline of cognition.

1. On average, during 4.5 years, a person reporting frequent cognitive activity at baseline had about half the risk of developing AD as a person with little cognitive activity.
2. “These results suggest that frequent cognitive activity in old age is associated with reduced risk of incident AD.”
3. This study found, as have others, that the frequency of cognitive activity is associated not only with the level of cognition at baseline, but also with the rate of cognitive decline. (Ie, the rate of cognitive decline even after first stages of AD may be slowed by continuing cognitive activity.)
4. If cognitive activity is protective, reduced cognitive activity should be an early sign of disease.

1. Cross-sectional study in Australia evaluated association between statin use and BMD in over 1300 women (age 50-95; mean = 70).
2. Determined current statin use in over 550 women who developed fracture during a 2-year period and over 800 women who did not experience a fracture.
3. Self-reported questionnaire assessed diet and lifestyles and statin use.
4. Determined BMD.

1. There were 16 statin users in the fracture group (2.7%) and 53 statin users in the non-fracture group (6.6%).
2. Absolute fracture difference between groups = 3.9%. (NNT to benefit one over 2 y = 26)
3. BMD at the femoral neck was 3% greater in statin users.
4. BMD also tended to be greater in the spine and whole body (not statistically significant).

1. Statin use was associated with a reduction in risk of fracture. The reduction was not wholly explained by the effects on BMD. (The increases in BMD were too small to account for the effect.)
2. Other case-control studies in different populations have also reported a reduction in risk among statin users. There is an exception: pravastatin (Pravachol) has been reported to have no effect on fracture. It may have less effect on increasing BMD.
3. The mechanism of action remains unclear.

1. The 5 trials included over 247 000 population-based women — 129 000 invited to receive mammography, and a control group of 117 000. Age at entry varied between 38 to 75. Attendance rate varied from 74% to 89%.
2. Followed up by the Swedish Cancer and Cause of Death Registers. Calculated the relative risks (RR) for BC death between groups.

1. The median time from randomization to the end of follow-up was 16 years.
2. Breast cancer deaths occurred in 511 women (1 864 770 women-years) in the mammography group and 584 (1 688 440 women-years) in the control group. (By my calculation, this is equivalent to 2.7 women per year per 1000 screened and 3.5 per year per1000 women in the control group. RTJ)
3. This was a significant 21% reduction in BC mortality in the screened group. (RR = 0.79).
4. Reduction was greatest in the age group 60-69 at entry. Significant reductions occurred in all groups 55-69. There was a small effect in women 50-55 at randomization (RR = 0.95). Benefit was also present in the 40-49 decade.
5. The benefit in terms of cumulative BC mortality began to emerge at about 4 years after randomization and continued to increase to about 10 years. Thereafter the benefit in absolute terms was maintained throughout the period of observation,.

1. “Our main observation was that the benefit of screening was maintained for several years after the trials had been closed. In general the benefit in absolute terms increased up to 12 years after randomization and thereafter it was maintained.”

1. The Nurses' Health Study prospectively examined the association between alcohol consumption and incident hypertension among over 70 000 women age 25 to 42 (mean = 35) at baseline.
2. Questionnaires every 2 years asked about average alcohol intake (beer, wine, or liquor) during the past year.
3. They were asked about development of physician-diagnosed hypertension (> 140/90).
4. Follow-up = 8 years.

1. During 8 years over 4000 cases of incident hypertension (6% of cohort) were reported.
2. After adjustment, the association between alcohol consumption and risk of hypertension followed a J-shaped curve.
3. Compared with abstainers, the relative risk of developing hypertension according to number of drinks consumed per day:

   0.25 or less	0.96
   0.26 to 0.50	0.86
   0.51 to 1.00	0.92
   1.01 to 150	1.00
   1.51 to 2.00	1.20
   More than 2	1.31

4. Among women in the highest category of consumption, the increased risk occurred regardless of the type of alcohol consumed.
5. Binge drinking (consumption of more than 10 drinks over 3 or fewer days per week) was not associated with increased risk of hypertension.

1. "In this study of 70891 women, the association between alcohol intake and risk of hypertension followed a J-shaped curve."
2. Among women who consumed 0.26 to 0.5 drinks daily the risk was lower by 14% compared to abstainers. Among women who consumed 1 drink daily the risk was lower by 8% compared to abstainers.
3. An increased risk of hypertension was evident beyond consumption of 1.5 drinks per day.
4. No beverage-specific effect was noted.
5. Although episodic (binge) drinking may have been associated with acute elevation of BP, in this study it was not associated with chronic hypertension unless heavier consumption extended to most days of the week.
6. Among women who consumed up to 25 or more drinks per week before onset of the study, no noticeable elevated risk of hypertension was evident during the study. This suggests that the ill effects of heavy past drinking do not persist.

1. Randomized controlled trial entered over 9000 patients. All were over age 55 (mean = 66) and considered at high risk for cardiovascular events because of history of cardiovascular disease and continuing risk factors and diabetes.
2. Mean BP at baseline = 139/79. (46% were considered to have hypertension.)
3. The majority (76%) were taking aspirin; 28% taking lipid-lowering agents.
4. Randomized to:

   1)	Ramipril 10 mg daily
   2)	Vitamin E 400 IU daily (I omit this data — not beneficial. RTJ)
   3)	Both
   4)	Placebo

5. Outcome measures: stroke, TIA, cognitive function. (The primary endpoint in the original study was a composite of myocardial infarction, stroke, or cardiovascular death.) This subset of the study focuses on stroke.
6. Follow-up - 4.5 years.

1. Reduction in BP was modest (mean of 3.8/2.8 mm Hg)
2.  

   Absolute risk reductions:	NNT 4.5 years to benefit one
   Any stroke = 1.5%	66
   Fatal stroke = 0.6%	166
   Combined risk of stroke and TIA = 1.9%	53
   Change in cognition = 0.5%	200

1. "Our results show that prolonged treatment with ramipril is effective in reducing fatal and non-fatal stroke and transient ischemic attack in a broad group of patients at high risk of stroke but with a relatively normal blood pressure."
2. Benefit was independent of the modest reduction in BP with ramipril.
3. Benefit was seen in all values of BP including patients with an initial BP less than 120/70. Benefit was not confined to those with "high BP".
4. “Our results indicate that patients who are at high risk of stroke should be treated with ramipril irrespective of their initial blood pressure and in addition to other preventive measures.” 1

1. Double-blind randomized, parallel trial entered over 9000 participants age 55-80 (mean = 67).
2. All had hypertension (160-200/95-115; mean = 175/97)
3. All had LVH determined electrocardiographically. (Ie, patients were at high risk.)
4. Randomized to:

   A.	Losartan 50 mg daily – increasing to 100 mg if needed to control BP, or
   B.	Atenolol 50 mg daily – increasing to 100 mg if needed

   Patients also received added hydrochlorothiazide (HCTZ) up to 25 mg daily (some also a third drug) trying to achieve a BP of less than 140/90.
5. Follow-up = 4.8 years.

1. Mean BP fell to a mean of 146/79 in the losartan group, and to 148/79 in the atenolol group.
2. To try to achieve target BP, the majority were increased to the 100 mg dose of both drugs, and had a third drug added.
3.  

   Outcomes (4.8 years)	Losartan	Atenolol	Difference	NNT 4.8 y
   Primary composite endpoint (death, myocardial infarction, or stroke)	11 %	12.8%	1.8%	56
   Death due to cardiovascular disease	4.4%	5.1%	0.7%	143
   Stroke	5%	6.7%	1.7%	59
   Myocardial infarction	4.3%	4.1%	-0.2%	500 (Harm)

4. Left ventricular hypertrophy decreased by about 5% in losartan group more than in the atenolol group.
5. Adverse effects were lower in the losartan group.

1. Losartan was more effective than atenolol in reducing frequency of composite endpoint of cardiovascular death, stroke, and myocardial infarction. (Note that myocardial infarction was more common in the losartan group. RTJ ) Losartan was associated with a “significant” 13% reduction in the composite endpoint compared to the atenolol group. The reduction in death, and myocardial infarction was not significant. The difference was due to a “significant” reduction in stroke.
2. The mean BP in both groups was reduced by the same amount.
3. Losartan substantially reduced the rate of fatal and non-fatal stroke by 25%. 1
4. The losartan group experienced a lower rate of adverse effects. 2
5. “Our results are directly applicable to clinical practice and should affect future guidelines.” 3

      In a controlled study, 1000 subjects were given “placebo”. Five hundred of them took the placebo religiously; 500 complied poorly. Outcomes in the first 500 were much better.
      The individual response to care and suggestion is basic to a favorable placebo response. RTJ