9-1 DIET, LIFESTYLE, AND THE RISK OF TYPE 2 DIABETES MELLITUS IN WOMEN.
      Most cases of type 2 diabetes could be prevented by a healthy lifestyle: weight control, regular exercise, modification of diet, abstinence from smoking, and limited consumption of alcohol.
      Weight control would appear to offer the greatest benefit.

9-2 EFFECTS OF EXERCISE ON GLYCEMIC CONTROL AND BODY MASS INDEX IN TYPE 2 DIABETES MELLITUS
      Exercise programs per se, both resistance and aerobic, over a 4 month period resulted in a reduction in HbA1c of a magnitude likely to be of clinical significance.
      Practical points:

A.	Exercise improved HbA1c, not dependent on weight loss.
B.	Resistance exercise was also of value, especially applicable to patients who cannot walk.
C.	Patients can be told as little as 4 months of consistent exercise 3 to 4 times weekly will benefit.
D.	Exercise per se is likely to be beneficial in preventing development of type 2 diabetes in patients with impaired glucose tolerance or elevated fasting glucose levels not now considered as having type 2 diabetes.

9-3 INSULINS TODAY AND BEYOND
      "Insulin glargine (Lantus) as the basal insulin combined with rapid acting analogues (Humalog) is probably the most physiological insulin substitution therapy and will therefore be the basis for future comparisons."
      Practical point: In difficult-to-control diabetics, the combination will more likely reduce the HbA1c toward normal.

9-4 PERIPHERAL ARTERIAL DISEASE DETECTION, AWARENESS, AND TREATMENT IN PRIMARY CARE.
      PAD is prevalent in older Americans. It is associated with a high risk of cardiovascular complications. Many patients are not diagnosed before occurrence of a morbid event.
      PAD is easily detected with the ankle/brachial index (ABI) in primary care.
      Treatment of hypertension, lipid disorders, and diabetes are as important in patients with PAD as in patients with coronary disease. Smoking cessation is essential.
      Practical point: Should all primary care clinicians make ABI available? Yes, but nor necessarily in their own offices. But, primary care clinicians should institute preventive measures far before the ABI becomes abnormal.

9-5 ASPIRIN USE AND ALL-CAUSE MORTALITY AMONG PATIENTS BEING EVALUATED FOR KNOWN OR SUSPECTED CORONARY ARTERY DISEASE. A Propensity Analysis
      Aspirin use among patients suspected of CAD was independently associated with reduced long-term all-cause mortality, particularly among older patients, those with known CAD, and those with impaired exercise capacity.
      Practical point: Prophylactic low-dose aspirin will benefit individuals at higher risk of CVD. For those at low risk, harms outweigh benefits. The challenge for primary care clinicians is to judge the risk.

9-6 CHALLENGE OF CULTURE, CONSCIENCE, AND CONTRACT TO GENERAL PRACTITIONER'S CARE OF THEIR OWN HEALTH: Qualitative Study
      Doctors perceive that their professional position and training adversely influence their attitudes to illness in themselves and their colleagues..
      The list of doctor's duties begins with "make the care of your patient your first concern". The authors of this study suggest that a duty of self knowledge and self care should underpin this. Organizational changes within practice must take account of the barriers experienced in accessing physician health care. Medical education and culture should strive to promote appropriate self care among doctors.
      Practical point: "Physician, heal thyself."

9-7 HELICOBACTER INFECTION AND THE DEVELOPMENT OF GASTRIC CANCER
      Gastric cancer developed in patients infected with H pylori, but not in uninfected patients.
      Gastric cancer did not develop in any of the infected patients who received eradication therapy.
      Patients with duodenal ulcers were not at risk.
      Evidence is accumulating that eradication therapy is effective in prevention of gastric cancer. "Gastric cancer may in the future be viewed, like colon cancer, as largely a preventable disease." "We may need to view H pylori less as a beneficial commensal organism, and more as something akin to tobacco."
      Practical point: H pylori infections should be eradicated.

9-8 RANDOMIZED TRIAL OF A PERINDOPRIL-BASED BLOOD-PRESSURE-LOWERING REGIMEN AMONG 6105 INDIVIDUALS WITH PREVIOUS STROKE OR TRANSIENT ISCHAEMIC ATTACK.
      In patients with previous stroke or TIA, a combination of an ACE inhibitor and a diuretic lowered mean BP from about 148/86 to about 125/75 and resulted in a large reduction in risk of recurrence of stroke.
      "Treatment . . . should be considered routinely for patients with a history of stroke or TIA, irrespective of their BP."
      Importantly, benefit for BP lowering was evident in patients not usually considered to be hypertensive — ie, those with "high normal" BP in whom BP was lowered from a mean of 136/79 to 127/75.
      Practical point: A reduction to about 125/75 would benefit without causing harm.

9-9 THE EFFECT OF IRBESARTAN ON THE DEVELOPMENT OF DIABETIC NEPHROPATHY IN PATIENTS WITH TYPE 2 DIABETES.
      In patients with type 2 diabetes, microalbuminuria, and hypertension, the angiotensin II blocker, irbesartan, was renoprotective, independent of its blood pressure lowering effect
      Choice of an ACE inhibitor vs an angiotensin II blocker would depend on adverse effects (eg, cough) and cost.
      Practical point: All patients with diabetes should be tested for microalbuminuria. Treatment with an ACE inhibitor or an angiotensin blocking drug should be started early.

9-10 BENEFICIAL EFFECTS OF POTASSIUM: Clinical Review
      There is good evidence that potassium (K) intake is important in regulating blood pressure. Increasing K intake lowers BP in both hypertensive and normotensive patients.
      This review article discusses other probable benefits of increased K intake: Lowering risk of stroke; prevention of renal vascular, glomerular, and tubular damage; reduction of urinary calcium excretion, possibly reducing stone formation and preventing bone demineralization; and reduction in risk of ventricular arrhythmias in patients with ischemic heart disease, heart failure, and left ventricular hypertrophy.
      Practical point: The best way to increase K intake is to eat more fresh fruit and vegetables.

9-11 BLOOD LIPID CONCENTRATIONS AND RISK OF MYOCARDIAL INFARCTION
      As in the West, Algerians who survived a MI, had higher total cholesterol and LDL-cholesterol, and lower HDL-cholesterol than controls. However, concentrations rarely reached the levels usually considered when instituting treatment in Western countries. The ratio of total-c/HDL-c, and of LDL-c/HDL-c, as in the West were similarly elevated. These ratios are therefore good predictors of risk, irrespective of nationality.
      Practical point: A ratio has greater predictive value than total-cholesterol or LDL-cholesterol alone. Total cholesterol levels alone may be very misleading.

9-12 TINZAPARIN IN ACUTE ISCHEMIC STROKE (TAIST): A Randomized, Aspirin-controlled Trial
      Treatment with the low-molecular weight heparin, tinzaparin, within 48 hours of acute ischemic stroke did not improve functional outcome compared with aspirin. It was associated with increased intracerebral hemorrhage.
      Practical point: Rely on aspirin alone

9-13 LONG-TERM WEIGHT LOSS WITH SIBUTRAMINE
      Sibutramine administered for 48 weeks resulted in clinically relevant weight loss compared with placebo.
      Practical point: Although possibly of long term benefit, this therapy should be left to specialists.

9-14 METFORMIN IN NON-ALCOHOLIC STEATOHEPATITIS
      In patients with steatohepatitis, metformin given over 4 months reduced ALT, increased insulin sensitivity, and decreased liver size.
      Practical point: Primary care clinicians will encounter patients with steatohepatitis. Most will be secondary to alcoholism, obesity, or diabetes. Metformin may benefit a subset.

9-15 EFFECT OF LEVODOPA IN COMBINATION WITH PHYSIOTHERAPY ON FUNCTIONAL MOTOR RECOVERY AFTER STROKE
      The brain is plastic. It is pliable and capable of being reformed. Specific transmitters are involved. Enhancement of functional motor recovery seems to rely on an increased concentration of norepinephrine at the synapses.
      Levodopa is converted to dopamine in the brain. Small amounts are then converted to norepinephrine.
      Combined with physiotherapy, levodopa was an effective and safe method for improving motor recovery after stroke. In view of its minimal side effects, it will be a possible add-on during stroke rehabilitation.
      Practical point: None at this time. I abstracted this study because it is so provocative. Watch for follow-ups.

9-16 ROLE OF INFLAMMATORY BIOMARKERS IN PREDICTION OF CORONARY HEART DISEASE.
      C-reactive protein, is a strong and independent predictor of future vascular events. Measurement of this inflammatory marker adds to the predictive value of standard lipid screening, particularly in primary prevention. The greater prognostic utility of C-reactive protein reflects the long half-life and stability of the molecule. This is coupled with a lack of circadian variation and low coefficients of variation when measured by high sensitivity assays.
      Practical point: CRP has not yet been included in the usual risk markers. CRP is of potential future interest. We await clarification. Primary care clinicians — keep it in mind.

9-17 PEGINTERFERON ALFA-2B PLUS RIBAVIRIN COMPARED WITH INTERFERON ALFA-2B PLUS RIBAVIRIN FOR INITIAL TREATMENT OF CHRONIC HEPATITIS C
      The most effective therapy for patients with chronic hepatitis C was peginterferon (a new compound of interferon with polyethylene glycol) once weekly combined with oral ribavirin. The benefit was mainly in patients with type 1 infection.
      Practical point: The prevalence of hepatitis C is high. Primary care clinicians should be able to refer patients for the best therapy.

9-18 SEVERE PULMONARY EMBOLISM ASSOCIATED WITH AIR TRAVEL
      The greater the distance and time traveled in airflights the greater the risk. The absolute incidence is low.
      Almost all patients had high and moderate risk of thromboembolic disease.
      The sitting position is associated with venous stasis. The double 90-degree angle bends at the knee and hip impede flow.
      Practical point: Simple behavioral and mechanical prophylaxis should be considered to prevent air-travel associated PE and DVT, especially in patients with risk factors.

9-19 SPIRONOLACTONE IN ADDITION TO ACE INHIBITION TO REDUCE PROTEINURIA IN PATIENTS WITH CHRONIC RENAL DISEASE
      The study entered eight patients with various renal diseases and persistent proteinuria despite treatment with enalapril (Vasotec) for 12 months. Spironolactone 25 mg daily was then added.
      After treatment, there was a mean 54% reduction in protein excretion. There was no significant reduction in BP or creatinine clearance.
      "Spironolactone therapy may be useful in patients with proteinuria and renal impairment who still have proteinuria after treatment with ACE inhibitors."
      Practical point: Spirinolactone add-on may be helpful in some patients with renal disease as well as in some with heart failure.

1. The Nurses' Health Study followed over 84 000 female nurses from 1980 to 1996. All were free of diagnosed cardiovascular disease, diabetes, and cancer at baseline.
2. Obtained information about diet and lifestyle, updated regularly, and development of type 2 diabetes.
3. Defined a low-risk group according to a combination of variables: 1) body mass index less than 25;
4. 2) diet high in cereal fiber and polyunsaturated fat, low in trans fat, and low in glycemic load (effect of specific foods on the blood glucose level); 4) engagement in moderate-to-vigorous physical activity for at least 1/2 hour a day; 5) no current smoking; and 6) consumption of at least half a drink of alcoholic beverage per day.

1. Documented 3300 new cases of type 2 diabetes during 16 years of follow-up.
2. Overweight was the single most important predictor of diabetes. Relative risk of diabetes was 39 for women with a BMI over 35, and 20 for those with a BMI 30-35. A BMI at the high end of the normal range (23 to 25) was associated with a risk of 2.7 relative to those with BMI < 23.
3. Lack of exercise, a poor diet, current smoking, and abstinence from alcohol use were all associated with significantly increased risk, even after adjustment for body mass index.
4. Of interest, the association between diabetes and diet, physical activity, smoking, and alcohol use was generally similar among overweight and obese women as among those with a normal BMI.
   (Ie, risk factors increased risk of development of type 2 diabetes even in those not considered obese.)
5. Compared with the rest of the cohort, women in the low-risk group (3.4% of women) had a relative risk of diabetes of 0.09. (Ie, those with no risk factors were at extremely low risk.)
6. The population "attributable risk" in this population was 87% — ie, 87% of new cases might have been prevented if all women had been in the low risk category. The population attributable risk increased to 91% when abstinence from smoking and use of small amounts of alcohol were included.
7. Individual components of the diet were independently and significantly associated with risk.
   (Ie, increased cereal-fiber intake and increased polyunsaturated fat/saturated fat ratio reduced RR; increased trans fat and increased glycemic load both increased risk.)
8. Women in the low risk of 3 categories (BMI, diet, and exercise) has a RR of 0.12 compared with all women.
9. The reduction in risk associated with the low risk factors was similar in women with a family history as well as for those without.
10. Even among obese women (BMI > 35) a combination of a healthy diet and regular exercise was associated with a 24% reduction in risk. (Ie, even if weight was maintained.)
11. If a BMI of 23 were to be adopted as the high end of the normal range, the population attributable risk of developing diabetes would have been reduced to 2.3%.

1. In middle-aged women, a combination of favorable lifestyle factors was associated with an incidence of type 2 diabetes that was about 90% lower than incidence in women without these factors. "The majority of cases of type 2 diabetes could be avoided by behavior modification."
2. Weight control would be the most effective way to reduce risk. "The public does not recognize the connection between overweight and diabetes." Greater educational efforts are needed.
3. Adoption of diet and exercise by obese women would result in an absolute reduction in incidence of diabetes even if they do not lose weight.

1. Literature search systematically selected and reviewed 14 trials on the effect of exercise in adults with type 2 diabetes. Studies that included drug co-interventions were excluded.
2. Types of exercise:

   A.	Aerobic training studies (n = 12): Moderate exercise sessions for a mean of 50 minutes, three to 4 times a week for 18 weeks
   B.	Resistance training studies (n = 2): Mean of 10 exercises with 13 repetitions 3 times weekly for 15 weeks.

3. Compared baseline and post-intervention data in intervention and control groups.

1. At 4 months, mean HbA1c was lowered in the intervention groups to 7.65% vs 8.31% in controls .
2. Aerobic and resistance exercise reduced HbA1c similarly.
3. Difference in post-intervention body mass in the exercise groups vs control groups was not statistically significant (83.02 kg vs 82.48 kg). (Ie, essentially little or no weight loss.)

1. Exercise was associated with a significant reduction in HbA1c. Body mass was not changed. The improvement in HbA1c was not dependent on weight loss. “The finding that exercise does not need to reduce body weight to have a beneficial impact on glycemic control is clinically important.”
2. The investigators believe a reduction in HbA1c of this magnitude (0.66%) is related to a significant reduction in diabetes-related clinical endpoints.
3. Unlike insulin and sulfonylureas, exercise is associated with other cardioprotective benefits without causing weight gain.
4. Exercise training decreases hepatic and muscle insulin resistance and increases glucose disposal. This would not necessarily depend on weight change.
5. It is possible that one reason for the maintenance of weight might be a result of increased muscle mass and decreased fat mass.
6. These results are widely generalizable to middle-aged patients with type 2 diabetes.

1. Multicenter, cross-sectional study conducted at 27 sites in the US entered over 6900 individuals.
2. All were over age 70 or age 50-69 with a history of cigarette smoking or diabetes.
3. Measured ankle/brachial index (ratio of systolic blood pressure at the ankle to systolic blood pressure at the brachial artery). Systolic blood pressures were recorded with the aid of Doppler ultrasound at both brachial arteries and all 4 ankle-foot arteries. Sensitivity of ABI of 0.9 or less is 90% and specificity is 98% for an angiographically defined stenosis of 50% or more in a major leg artery. (Ie, of all persons with arterial stenosis, 90 out of 100 will have an abnormal ABI; for all persons without arterial stenosis, only 2 out of 100 will have an abnormal ABI.)
4. Subjects were considered to have PAD if their ABI was 0.9 or less. (Eg, brachial systolic = 150; ankle systolic = 135. 150/135 = 0.9) A systolic under 135 would indicate an abnormal ABI when present in either ankle or foot.

1. PAD was present in 29% of the cohort of 6000. Of these, 44% had PAD only without evidence of cardiovascular disease (CVD); 56% had combined PAD and CVD. A high percentage were women, almost all postmenopausal. Mean ABI in patients with PAD was 0.78
2. Overall:

   PAD only	13%
   PAD + CVD	16%
   CVD only	24%
   Neither	47%

3. In almost half of the patients PAD was newly diagnosed. Only about half of their physicians were aware of the PAD.
4. Classic intermittent claudication was distinctly uncommon.
5. Patients with PAD had similar atherosclerotic risk factors compared with those with CVD.
6. Antiplatelets were not often prescribed.

1. PAD is prevalent in primary care settings and confers a high risk of associated fatal and non-fatal cardiovascular ischemic events.
2. It is easily detected by ABI measurement during routine office visits. (History and physical examination are inaccurate detectors of PAD.)
3. Clinicians who rely on intermittent claudication to diagnose PAD will miss most patients with PAD.
4. Even in patients without established CVD, an ABI of 0.78 portends an approximate 30% 5-year risk of MI, stroke, and vascular death.
5. Smoking cessation reduces disease progression and mortality risk in PAD patients.
6. The diagnosis of diabetes is adequate to initiate prophylactic treatment in almost all patients regardless of evidence of PAD.
7. Guidelines for treatment of hypertension recognize that if PAD is present, drug therapy for all stages of hypertension is required.
8. Antiplatelet therapy is recommended for secondary prevention (ie, in those with ABI < 0.9). 1

1. Prospective, nonrandomized observational trial entered 6174 patients. All had been referred for echocardiography because of known or suspected CAD.
2. Over 2310 (37%) were taking aspirin regularly. After excluding patients with significant valvular disease, documented contraindications to aspirin (including peptic ulcer), renal insufficiency, and NSAID use, 1351 subjects remained.
3. Of the 3864 non-aspirin users (controls), 1351 were selected on the basis of being the most comparable to the aspirin users. 30 clinical characteristics were used in the match.
   (Table 3, p 1191)
4. Determined all-cause mortality according to aspirin use (n = 1351), or non-use (n = 1351), over 3-year follow-up.

1. Over 3 years, 276 (4.5%) of the cohort died.
2. In a simple univariate analysis (ie comparing all aspirin users with all non-aspirin users) there was no association between aspirin use and mortality. (4.5% vs 4.5%)
3. Comparing the two groups selected by propensity analysis, the 1351 patients taking aspirin had a mortality of 4%; 1351 non-aspirin users had a mortality of 8%.
4. The patient characteristics associated with the greatest aspirin-related reductions in mortality were: older age, known CAD, and impaired exercise capacity.

1. Among consecutive patients referred because of suspected CAD, aspirin use was associated with a substantial reduction in all-cause mortality.
2. The consecutive patients in this study may represent a more representative sample of real world patients than those selected to enter into a randomized, controlled trial.
3. The findings provide additional support for recommending the routine use of aspirin in patients at risk for cardiovascular disease.

1. Qualitative study of 27 primary care physicians used focus groups and in depth interviews seeking views about their own health and that of colleagues.

1. Doctors were concerned about the current level of illness within the profession.
2. They described their need to portray a healthy image to both patients and colleagues. This hindered acknowledgement of personal illness and willingness to engage in health screening.
3. Embarrassment in adopting the role of patient and concerns about confidentiality also influenced their reaction to personal illness.
4. These attitudes can impede access to appropriate health care for themselves, their families, and their colleagues.
5. Almost all reported working through illness and expecting their colleagues to do likewise. This included illnesses they would not expect their patients to work through. A sense of conscience toward patients and colleagues and the working arrangements of the practice were cited as reasons.
6. Participants were reluctant to declare themselves ill, but readily shared anxieties about the health of the profession. "We are seeing increasing illness in doctors that's quite scary. It used to be 50 year olds with MIs, now they are seen in physicians in their 30s, along with various other stress-related illnesses."
7. There is pressure to appear well. This reflects the perception that patients believe a doctor's health reflects medical competence. The attitude affects their approach to screening. "Nobody wants to go and see a doctor who is sick."
8. Acknowledging psychological illness was extremely difficult. It was regarded as a weakness. Concerns about confidentiality emerged as a factor in use of psychiatric services. Embarrassment was a barrier to consulting other primary care physicians. "Doctors feel they shouldn't be sick. You don't want to go see your local psychiatrist in case one of your patients is sitting beside you."
9. Comments indicated a reluctance to accept treatment and an underlying assumption that the roles of patient and doctor were incompatible. "We think we're superhuman and that we don't get ill and that if we do, we can cope with it." Some reported that, in medical school and hospital, illness was not tolerated. "You were expected to do the job." Self care was not adequately taught. Several reported their medical knowledge made them prone to swing between panic and denial when they experienced symptoms. Similar stresses were described regarding illness in their family.
10. A sense of obligation to colleagues emerged. "You don't stay off work because you're not going to earn money, you continue to work because of your partners." "A terrible sense of duty of letting your partners down if you don't go in."
11. Most agreed that they did not take an active interest in their partner's health and played down evidence of colleagues being unwell.
12. The authors propose an "Informal Shadow Contract" (page 730) between individual clinicians and their partners which outlines how clinicians and partners should not respond to their illnesses.

1. Prospectively studied over 1500 Japanese patients who had duodenal ulcers, gastric ulcers, gastric hyperplasia, or non-ulcer dyspepsia at the time of enrollment. None were taking NSAIDs.
   All underwent endoscopy with biopsy.
2. Of these, 81% had H pylori infection demonstrated by positive results of any one of 3 tests: serology, rapid urease, and histologic examination.
3. Follow up for a mean of 8 years in untreated patients; and a mean of 5 years after eradication in the treated patients.

1. Among 1526 patients, 1246 (81%) were H pylori positive. Gastric cancer developed in 3% of the infected patients; in none of the uninfected patients.
2. All those with active gastric ulcer, all those with gastric hyperplastic polyps, and all those with active duodenal ulcer were infected with H pylori.
3. Risks differed among those with various clinical conditions at baseline:

   Of 445 patients with non-ulcer dyspepsia, 21 (4.7%) developed gastric cancer over 8 years:
   Of 297 patients with gastric ulcers, 10 (3.4%) developed cancer.
   Of 229 patients with gastric hyperplastic polyps, 5 (2.2%) developed cancer.
   Of 275 patients with duodenal ulcer, none developed cancer.

4. Among the infected patients, those with severe gastric atrophy, corpus-predominant gastritis, and intestinal metaplasia were at significantly higher risk for gastric cancer.
5. About 40% of those with non-ulcer dyspepsia were not infected. This was the only group that contained patients without infection.
6. Gastric cancer did not develop in any of 253 infected patients who received eradication therapy.

1. H pylori infection was associated with severe atrophic gastritis, corpus-predominant gastritis, and gastric intestinal metaplasia.
2. Gastric ulcer was associated with a high risk of gastric cancer; duodenal ulcer with low risk. Patients with gastric ulcers typically had corpus-predominant atrophic gastritis. Patients with duodenal ulcer had few atrophic changes and had antrum predominant gastritis. This may be the reason duodenal ulcer patients are at low risk of gastric cancer.
3. The authors previously had shown that in patients with early gastric cancer treated with endoscopic mucosal resection, eradication of H pylori prevents the development of a new cancer .

1. Randomized, double-blind, multicenter, secondary prevention study entered over 6100 patients (mean age = 64). All had a history of stroke (11% hemorrhagic), or TIA within the past 5 years. All were clinically stable.
2. All underwent a 2-week run in open-label period of 2 mg perindopril then 2 weeks of 4 mg. Those who adhered to, and tolerated, the run in were randomized.
3. Randomized to: 1) An active treatment flexible regimen based on the ACE inhibitor perindopril (Aceon) 4 mg daily alone [single therapy] , or with addition of 2.5 mg of the non-thiazide diuretic indapamide (Generic) [dual therapy] at the discretion of the treating physician, or 2) Placebo(s).
4. Most also received aspirin.
5. Primary outcome = total recurrent stroke (fatal and non-fatal). Follow-up = 4 years.

1. At baseline mean BP = 146/86. About half of the cohort was classified as "hypertensive" (BP = 160 and/or = 90)
2. Effect on BP overall ( n = 6105):

   Active treatment with perindopril alone (compared with placebo) reduced mean BP from 146/86 to 141/83.
   Active treatment with perindopril plus indapamide reduced mean BP from 146/86 to 134/81.
   These differences were maintained over the 4 years.

3. Effect on BP in subjects considered hypertensive [BP = 160/90; n = 2916] Dual therapy reduced BP from a mean of 159/94 to 149/80
4. Effect on BP in subjects considered non-hypertensive [BP =160/90; n = 3189] Dual therapy reduced mean baseline BP from 136/79 to 127/75
5. Effect on risk of recurrent stroke:

   Dual therapy (perindopril + diuretic) reduced risk of recurrent stroke by 43%.
   But, single therapy with perindopril alone was associated with no discernable reduction of risk of recurrent stroke.1
   Both groups (hypertensive and non-hypertensive) achieved about equal benefit from dual therapy in reducing risk of recurrent stroke.

6. Dual therapy also was associated with a 26% reduction in major vascular events.

1. Dual therapy reduced annual stroke incidence from 3.8% to 2.4% (NNT 1 year = 71).
   Results suggest that 5 years treatment with combination drugs would result in avoidance of one fatal or major non-fatal vascular event among every 11 patients. Absolute benefits of this size greatly exceed the estimated benefits of BP lowering for prevention of initial stroke in patients with uncomplicated hypertension.
2. There was a reduction in both recurrent fatal and disabling strokes (ischemic and hemorrhagic).
3. Importantly, benefit for BP lowering was evident in patients not usually considered to be hypertensive. Incidence of recurrent stroke was reduced not only among those with mean baseline BP 159/94, but also among those with a mean baseline BP of 136/79.
4. Benefits were achieved in the context of low withdrawal rate for adverse effects after initial screening for intolerance.
5. These results should resolve the clinical uncertainty that has existed about benefits and safety of BP lowering for patients with a history of stroke or TIA.
6. The HOPE study 2 also reported clear benefits with ACE inhibitor ramipril (Altace) for treatment of high risk, non-hypertensive patients as well as for those with hypertension.
7. The greater reduction in BP achieved by dual therapy would indicate that dual therapy is usually required for adequate BP reduction and that a reduction to about 130/80 would benefit without causing harm.
8. Treatment was safe across a broad range of patients irrespective of BP, type of qualifying cerebrovascular event, time since last event, or geographic region.. For patients presenting with an acute stroke or TIA, physicians should consider starting treatment early. Although treatment may commence with a single agent, the objective should be to move patients onto combination therapy as soon as possible.

1. Randomized, double-blind, placebo-controlled trial enrolled over 550 patients (mean age 58).
   All had type 2 diabetes (WHO criteria). All had microalbuminuria (mean = 55 ug albumin / min) and hypertension (BP > 135/85; mean = 153/90). None had elevated creatinine levels.
2. Randomized to:
         A. Irbesartan (Avapro) 300 mg daily, or
         B. Placebo.
3. Primary end point = incidence of persistent albuminuria over 200 ug/min (diabetic nephropathy).
4. Follow-up = 2 years.

1. Five % of irbesartan group reached primary endpoint vs 15% in the placebo group.
2. Average BP = 141/83 in the irbesartan group vs 144/83 in the placebo group.
3. Serious adverse effects and withdrawals were less frequent in the irbesartan group than in the placebo group.

1. Treatment with irbesartan significantly reduced the risk of progression to clinical albuminuria, the hallmark of overt diabetic nephropathy.
2. The benefit appeared to be independent of blood pressure.
3. Kidney function remained well preserved in all groups.
4. Persistent albuminuria heralds progressive kidney disease ultimately leading to end-stage renal disease. An initial and sustained reduction in albuminuria during antihypertensive treatment is associated with a diminished rate of decline in the glomerular filtration rate and an improved prognosis.
5. The goal of delaying or preventing development of diabetic nephropathy can be achieved if high-risk patients are identified early and given appropriate renoprotective therapy.
6. ”Routine screening for microalbuminuria should be performed in all patients with diabetes.”
7. In the present study, there was no difference in glycemic control between groups. Metabolic factors cannot be considered to have played a part in the benefits of "sartan" therapy. Nevertheless, it must be emphasized that improvement in glycemic control slows the increase in the level of albuminuria and postpones the development of overt diabetic nephropathy.

1. Randomized, double-blind study followed over 800 private patients (mean age = 43) for 48 weeks. All had a BMI of 30 to 40 kg/m2. (Mean = 34) All were otherwise in good health. All had previously unsuccessfully attempted weight loss by dietary measures.
2. Prior to randomization patients were enrolled in a 4-week run-in period with 15 mg of sibutramine daily. Those achieving at least a 2 kg weight loss were then randomized for 44 weeks to: 1) sibutramine 15 mg daily; 2) sibutramine 15 mg intermittently during weeks 1-12, 19-30, and 37-48; or 3) placebo.

1. About 3/4 of subjects completed the trial.
2. Mean weight change:

   	Weeks 5 to 48	Overall (48 weeks)
   Continuous sibutramine	- 3.8 kg (4.0%)	- 7.9 kg
   Intermittent sibutramine	- 3.3 kg 93.5%)	- 7.8 kg
   Placebo (after 4 weeks drug therapy)	+ 0.2 kg (weight gain)	- 3.8 kg

   (Ie, considerable weight loss in the first 4 weeks, the run-in period.)
3. There was a tendency for weight re-gain after the 4-week run-in period in the group assigned to placebo.
4. Abdominal circumference and lipids improved in the sibutramine groups.
5. Blood pressures were stable across all 3 groups. (See figure 4 p 1336.) Mean BP at baseline was 132/82. In all 3 groups, BP did not change over 48 weeks. (The investigation entered only normotensive patients.)
6. Adverse effects occurred at similar frequencies across all 3 groups. The proportion was lowest in the intermittent group. 14% experienced adverse events classified as drug related: dry mouth, constipation, increased sweating, and headache. Withdrawals due to adverse events: intermittent = 3.3%; continuous = 6.2%; placebo = 4.5%.

1. Patients receiving sibutramine over 48 weeks lost significantly more weight than patients receiving placebo.
2. Even a moderate weight loss of about 5% unquestionably provides benefits. More than 60% of patients in the active groups achieved 5% or more loss compared with 35% of the placebo group.
3. Weight loss reached a maximum at 3 months. Thereafter slowed, but was maintained up to month 12.
4. Patients who do not lose during a first 4 weeks of therapy are not likely to be successful long-term. Long-term treatment should be avoided in this group.
5. Concerning effects on BP, the authors comment that sibutramine gives rise to 2 opposing effects: 1) weight loss results in a decrease; 2) the sympathomimetic effect results in a rise. Generally the effects neutralize each other. (Note these patients were normotensive.)

1. Enrolled 53 patients with hemiplegia in a randomized, placebo-controlled, double-blind trial. All had radiologically verified thromboembolic brain infarctions. All strokes had occurred within 3 weeks to 6 months before the start of the study.
2. For the first 3 weeks randomized to: 1) levodopa 100 mg daily by mouth + physiotherapy, or 2) placebo + physiotherapy. For the second 3 weeks they received only physiotherapy to monitor the stability of effects.
3. Assessed motor progress quantitatively by a motor function assessment scale. The goal-oriented approach focused on transfers, control of posture, independent walking, reduction in motor tone, and on increasing range of motion and function of the arms.

1. In the drug intervention group, motor recovery was significantly improved after 3 weeks.
   (Motor function improved by 6 points on a 10 point scale compared with 4 points for placebo.)
2. Benefit was independent of initial degree of impairment.
3. The advantage of levodopa was maintained during the following 3 weeks after levodopa was stopped.

1. "Our finding that motor recovery is improved by a combination of levodopa and physiotherapy accords with results of other work in animals and clinical trials done with amphetamines."
2. Recovery of motor function was not affected by initial severity of hemiparesis.
3. Several hypotheses may account for the mechanism by which brain plasticity is enhanced. (See text p 789.)

1. Randomized trial entered over 1500 patients with chronic hepatitis C. None had been treated previously. Liver biopsy was consistent with chronic hepatitis in all. All had serum alanine aminotransferase above normal. None had decompensated cirrhosis.
2. Randomized to: 1) peginterferon once weekly intramuscularly + oral ribavirin daily, or 2) interferon three times weekly + oral ribavirin daily for 48 weeks.
3. Primary endpoint — a sustained virological response rate (undetectable hepatitis C virus RNA) at 24 weeks after end of therapy.

1. The SVR rate 24 weeks after end of therapy was significantly higher in the peginterferon + ribavirin group. (54% vs 47%).
2. Among those with type 1 HCV response rates were 42% and 33%.
3. The response rates for genotypes 2 and 3 were about 80% for both groups.
4. Adverse effects were frequent but similar between groups. Dose reductions were necessary in up to 18%. Discontinuation rates were 14% and 13%.

1. Patients receiving peginterferon + ribavirin given for 48 weeks achieved a significantly higher SVR rate. The benefit was associated with a decrease in hepatic inflammation.
2. The response rate in the subset of patients with type 1 HCV was substantially improved over those receiving interferon + ribavirin.
3. Response rates in type 2 and 3 were similar and uniformly high with both groups. The benefit of peginterferon in these groups may be one of convenience and ease of administration.

1. Systematically reviewed all cases of PE requiring medical treatment on arrival at the busiest airport in France.
2. Obtained data on geographic origins of all flights and the numbers of passengers in order to evaluate the incidence of PE per million passenger-arrivals as a function of distance traveled.
3. PE was suspected if the passenger, within one hour after arrival, experienced chest pain, malaise, syncope, of shortness of breath. Diagnosis was confirmed by ventilation-perfusion scans, angiography, or high resolution CT.

1. In over 135 million passengers arriving from 145 countries, 56 cases of PE occurred. All patients met at least one criterion for PE — syncope, right ventricular dysfunction, shock, tachycardia, and cardiac arrest.
2. Incidence of PE was much higher in passengers traveling more than 3000 miles (1.5 per million passengers) than in those traveling less than 3000 miles (0.01 cases per million).
3. Incidence of PE was 5 cases per million passengers among those traveling more than 6000 miles.
4. Only 5% of patients reported they had left their seats during the flight; 75% reported they were completely immobile during the flight.
5. Almost all patients had high and moderate risk of thromboembolic disease. (Mainly varicose veins, use of estrogens or progesterones, age over 40.) Several individuals reported immobilization before the flight, recent surgery and trauma, and previous deep vein thrombosis.
6. In no case did the primary manifestation of PE extend beyond the jetway — all occurred inside the airport.

1. PE was related to duration of air travel. Incidence was much higher in those traveling more than 3000 miles or spending more than about 6 hours in flight.
2. The study probably underestimated the incidence of PE because of inability to detect mild cases or incidence beyond the airport. All cases in this report were severe. Several reports have suggested that PE may develop several weeks after air travel.
3. The incidence of deep venous thrombosis (DVT) was not studied. It probably is much higher than PE.
4. The sitting position is associated with venous stasis.1 The double 90 degree angle bends at the knee and hip impede flow. It is also suggested that compression of the lower extremities by the seat may be a risk factor
5. Simple behavioral and mechanical prophylaxis should be considered to prevent air-travel associated PE and DVT. This includes fluids, avoidance of alcohol and smoking, avoidance of restrictive clothing, avoidance of leg crossing. Physical activity such as walking in the aisle and movement of the legs and frequent changes in position while seated should be encouraged. Support stockings may be reasonable advice for those at high risk.