11-1 INSULINOTROPIC MEGLITINIDE ANALOGUES: Repaglinide (Prandin); A New Oral Drug
      New oral insulinotropic drugs are coming on the market. They act quickly to release insulin into the portal circulation and liver when given shortly before meals. They reduce hyperglycemia by an immediate action on the liver which impairs glucose output. They are less likely to produce hypoglycemia. Dosing schedules may be more flexible.

11-2 CLINICAL INERTIA
      Medicine has traditionally focused on relieving patient symptoms. However, maintaining good health increasingly involves management of such problems as hypertension, dyslipidemia, and diabetes, which often have no symptoms. Abnormal BP, lipid, and glucose values are generally sufficient to warrant treatment without further diagnostic maneuvers. These commentators focus on limitations in managing such problems in everyday practice. They term this "clinical inertia"-- recognition of the problem but failure to act -- failure of clinicians to initiate or intensify therapy when indicated.

11-3 WHY GENERAL PRACTITIONERS DO NOT IMPLEMENT EVIDENCE
      "General practitioners seem to regard clinical evidence as a square peg to fit a round hole in the patient's life." The process of implementation of evidence-based medicine is complex, fluid, and adaptive.
      Decisions are influenced by the doctor's personal and professional experience as well as by their knowledge of and relationship with the patient.

11-4 IMPACT OF HIGH-NORMAL BLOOD PRESSURE ON THE RISK OF CARDIO-VASCULAR DISEASE.
      High normal BP (130-139/85-89) was associated with an increased risk of cardiovascular disease.
      Practical point: Would not lowering "high normal" BP (130-139/85-89) in individuals at high risk due to a combination of factors seem reasonable? Certainly, life style measures are indicated. Drug therapy should be reserved for those with multiple risk factors, addressing all factors at the same time.

11-5 ASSESSMENT OF FREQUENCY OF PROGRESSION TO HYPERTENSION IN NON-HYPERTENSIVE PARTICIPANTS IN THE FRAMINGHAM HEART STUDY
      Normal (120-129/80-85) and high normal (130-139/85-89) frequently progressed to hypertension >140/90) over 4 years, especially in older overweight adults. This supports the recommendation for monitoring those with high normal BP every year, those with normal BP every 2 years.
      Control of weight and weight gain is important for primary prevention.
      Practical point: regular screening for hypertension is a major responsibility of primary care clinicians. Weight control is also a major challenge. Development of systolic hypertension seems almost inevitable as age progresses. When to treat isolated systolic hypertension is another major challenge.

11-6 SIMVASTATIN AND NIACIN, ANTIOXIDANT VITAMINS, OR THE COMBINATION FOR THE PREVENTION OF CORONARY DISEASE.
      Compared with placebo, combined niacin-statin (simvastatin) provided marked clinical and angiographic benefits in patients with established coronary disease and low HDL levels. (Secondary prevention). The decrease in LDL related to combined statin-niacin was greater than the average decrease reported from statin therapy alone. The increase in HDL was much more than usually reported from statins alone. The rate of major clinical events was reduced by 90% in the simvastatin + niacin group.
      Antioxidants did not benefit. "Unless more compelling evidence appears, we see little justification for
      the use of antioxidant vitamins for the prevention of cardiovascular events."

11-7 THE SAFETY OF INACTIVATED INFLUENZA VACCINE IN ADULTS AND CHILDREN WITH ASTHMA.
      "Influenza vaccine does not worsen asthma." Current guidelines for the immunization of patients
      with asthma are safe. In a large diverse group of adults and children with asthma, adverse effects were no more common in those receiving flu vaccine than in those receiving placebo injections.
      Practical point: Health care providers should urge patients with asthma to be immunized and thus reduce the morbidity associated with influenza. Patients may be reassured by referring them to this study.

11-8 PYRAZOLOPYRIMIDINES
      Zaleplon (Sonata) has many attributes of the ideal hypnotic agent — rapid absorption, rapid onset, adequate duration of action, minimum or no residual effect on daytime performance, and no evidence of pharmacological tolerance or withdrawal. "It provides another very helpful option in the management of patients with insomnia."

11-9 ANTIOXIDANTS AND ZINC TO PREVENT PROGRESSION OF AGE-RELATED MACULAR DEGENERATION
      Persons older than 55 years should have dilated eye examinations to determine the risk of developing advanced ARMD.
      Practical point: Those with extensive intermediate size drusen, at least one large druse, non-central geographic atrophy in one or both eyes, or advanced ARMD or vision loss, and without contraindications such as smoking (which may increase adverse effects of beta carotene) should consider taking a supplement of antioxidants plus zinc such as used in this study.

11-10 LEGUME CONSUMPTION AND RISK OF CORONARY HEART DISEASE IN US MEN AND WOMEN
      A significant benefit in reducing incidence of cardiovascular disease was associated with increased legume consumption of at least 4 servings weekly.

11-11 DECREASED RATE OF CORONARY RESTENOSIS AFTER LOWERING OF PLASMA HOMOCYSTEINE LEVELS.
      Treatment with a combination of folic acid (400ug), vitamin B12 (400 ug) and B6 (pyridoxine 10 mg) was associated with a significant reduction in the rate of restenosis after PTCA.

11-12 A COMPARISON OF WARFARIN AND ASPIRIN FOR THE PREVENTION OF RECURRENT ISCHEMIC STROKE.
      Over a 2 year period, there was no difference between aspirin and warfarin in prevention of recurrent non-cardiac stroke or death. For more than 50 years, physicians have prescribed warfarin for patients with non-cardioembolic stroke in the hope that subsequent strokes could be prevented. This treatment was based on a mixture of clinical experience, observational studies, and inferences about the pathophysiology of stroke.
      "Aspirin alone, or in combination with some other antiplatelet agents appears to be a well-justified choice for the prevention of recurrent ischemic stroke"
      Practical point: This simplifies secondary prevention.

11-13 THE PATIENT WITH HYPOCHONDRIASIS
      Although there is no definitive therapy, physicians can effectively care for patients with hypochondriasis by acknowledging that somatic symptoms without a medical basis can be as distressing as those resulting from demonstrable disease. The goal of treatment should be to improve coping with symptoms rather than their elimination, as in the management of chronic physical illness. This approach minimizes the frustration of both the patient and the physician.
      Patients with hypochondriasis are a subgroup of patients who somatize — namely those whose medically unexplained symptoms are accompanied by an unshakable conviction that they have a serious disease. Overlap exists.
      There is good evidence that vigorous treatment of psychiatric disorders that frequently co-exist are responsive to drugs. Drug treatment may help resolve hypochondriacal symptoms associated with major depression, panic disorder, and obsessive-compulsive disorder.

11-14 HORMONE REPLACEMENT THERAPY AND DRY EYE SYNDROME
      Postmenopausal women who used HRT had a higher prevalence of dry eye syndrome compared with never-users. Those using estrogen alone are more affected.

11-15 A SIMPLE RISK INDEX FOR RAPID INITIAL TRIAGE OF PATIENTS WITH ST-ELEVATION MYOCARDIAL INFARCTION
      A simple risk index based on age, heart rate, and systolic BP captured most of the information from more complex tools. Risk rose sharply after age 60, after a pulse rate of 80, and when systolic BP fell below 120. The index is likely to be useful in rapid triage of patients with ST-elevation acute MI.
      Practical point: This assessment could be a useful indicator for immediate use of a new bolus fibrinolytic agent at the primary encounter site.

11-16 CHOOSING A PARENTERAL ANTICOAGULANT AGENT
      Fondaparinux is derived from the activated factor X (Xa) binding moiety of unfractionated heparin.
      Two studies 1,2 report that once-daily treatment initiated early in the postoperative period was more effective than LMWH in preventing venous thromboembolism after hip and knee surgery.
      Fondaparinux has been approved by the FDA for prevention of thromboembolism after orthopedic surgery. (Arixtra)

11-17 NONSTEROIDAL ANTIINFLAMMATORY DRUGS AND THE RISK OF ALZHEIMER'S DISEASE
      Long-term use of NSAIDs may have a beneficial effect in preventing AD. "Primary-prevention trials should be undertaken to confirm this finding and show whether the benefits of such therapy outweigh the risks."
      Practical point; None at this time. We need more information on the benefit/harm-cost. Primary care clinicians should be aware of this putative linkage. Patients may be asking about it.

1. Qualitative study of 19 general practitioners in 3 focus groups asked participants to discuss their behavior in individual cases.
2. Each meeting focused around case notes of a particular patient, the doctor-patient relationship, and the feelings that were generated.
3. Group members were asked to present details of a case in which he or she had knowingly not followed evidence-based practice. The group discussed the case and explored implementation issues arising from it, as well as the doctor's feelings about these issues.
4. The main clinical areas discussed included hypertension, ischemic heart disease, and anticoagulation.

1. Six main themes emerged that indicated barriers to implementation:

   A.	Personal and professional experience: Enthusiasm for the evidence and the way it was implemented varied. The process of implementing clinical evidence was affected by the personal and professional experience of the doctor. Mishaps or spectacular successes had a direct influence on subsequent practice. (Eg., a severe bleeding episode resulting from warfarin use for a patient with non-rheumatic atrial fibrillation might make the clinician somewhat reluctant to prescribe it again.)
   B.	Doctor's relationship with individual patients: Evidence, even if extremely good, was interpreted in the context of the individual patient. (Eg, patients may resist taking certain drugs because of a history of adverse effects in family members.) The views of the patient modified how and when doctors applied the evidence.
   C.	Perceived tension between primary and secondary care: General practitioners approached evidence-based practice differently than specialists. GPs treat patients rather than diseases. They considered specialist care much more controlled than the "real life" of general practice. (Eg, hypertensive patients often feel well. They are just running a risk. "We give them a drug with a side-effect which changes the quality of their life." )
   D.	Clinical evidence can evoke feelings among doctors and patients: For the doctors in the study, clinical evidence was not just an intellectual commodity that is lifted from medical journals and transferred to a patient. Applying EBM, as well as failing to act on EMB, may cause anxiety in both doctor and patient. Nevertheless, they recognized that EBM can change practice within a week.
   E.	Words by doctors can influence patients' decisions: Doctor's choice of words can sway patients to either accept or reject clinical evidence. Doctors realize this and can use it to pre-empt patients' decisions. The way doctors present the evidence to patients may effectively limit the options patients may choose while seeming to invite the patient to make the decision. The semantics used affect the way in which evidence is implemented by swaying the patient in a particular direction. There is a tension between encouraging autonomy and effectively limiting options by a slanted presentation.
   F.	Logistics of general practice: EBM comes up against logistical problems which affect how EBM is applied. Starting a new treatment may be considered a "hassle", "risky", or "hard work" for both doctors and patients. Changing medications may create anxiety and entail frequent visits to try to reassure the patient. Knowing the patient's personal situation influences implementation.

2. Implementation of EBM by primary care clinicians is a complex and fluid process.
3. Scientific research and general practice have been described as being parallel universes. The doctors in this study were exploring personal importance — that is, the "key to transfer of an idea to, and the evaluation and interpretation of an idea by, the doctor and patient together". Evidence is not implemented in a simple linear way as some definitions of EBM imply. It is an evolving process whereby reciprocal contributions by the doctor and the patient over time influence how evidence ultimately is used.
4. Although there was plenty of evidence that the doctors were implementing evidence and were happy to do so, sometimes sticking strictly to the rules of guidelines is not appropriate.

1. The Framingham Heart Study followed over 6800 patients (mean age = 48) . All were free of hypertension (all below 140/90), and cardiovascular disease at baseline.
2. At baseline determined the association between BP category (optimal; normal; and high-normal — the Joint National Committee classification) and incidence of cardiovascular disease on follow up of 10 years.
3. Subjects in the high-normal group were not treated with antihypertension medication.

1. Baseline characteristics:

   	Optimal BP	Normal	High normal
   	(< 120/80) (N = 2900)	(120-129/80-84) (N = 2200)	(130-139/85-89) (N = 1800)
   Mean BP
   Women	108/70	122/72	132/81
   Men	111/71	122/78	131/83

2. Age-adjusted cumulative incidence (10 year) of first cardiovascular event (%):

   	Optimal	Normal	High normal
   Women	1.9	2.9	6.4
   Men	5.8	7.6	10.3

3. The 10-year cumulative incidence of cardiovascular disease in subjects with high normal BP:

   Ages 35-64	Women = 4%	Men = 8%
   Ages 65-90	Women = 18%	Men = 25%

4. Compared with those with optimal BP, a high-normal BP was associated with a risk ratio for cardiovascular disease of 2.5 for women and 1.6 for men.

1. Persons with high-normal BP (130-139/85-89) at baseline had a higher incidence of cardiovascular disease over 10 years follow-up than those with optimal BP (<120/80). A continuous gradient across the 3 non-hypertensive BP categories (optimal; normal: high normal) was observed.
2. Risks persisted after adjustment for other cardiovascular risk factors.
3. The rate of cardiovascular events was low among persons with optimal BP.
4. Whether lowering BP from high-normal to normal or optimal will improve prognosis is not known.
5. We need additional research to determine if persons with high-normal BP who are at high risk (eg, elderly, diabetes, multiple risk factors) will benefit from lowering high-normal BP.

1. Periodically measured BP in over 9500 individuals without hypertension (< 140/90). Mean age = 52; primarily Caucasian.
2. Defined optimum BP as > 120/80; normal as 120-129/80-85, and high normal as 130-139/85-89
3. Determined development of hypertension (=160/100, and use of antihypertension medication) over 4 years.

1. A stepwise increase in incidence of hypertension occurred across 3 non-hypertensive categories:

   A.	Participants below age 65 BP at baseline Developed hypertension Optimum 5% Normal 18% High normal 37%
   B.	Participants over age 65 progressed more frequently: 16%; 26%; and 50%.

2. Obesity and weight gain contributed to progression. A 5% weight gain over 4 years was associated with a 20-30% increased odds of developing hypertension.
3. Progress to hypertension was determined on the basis of an increase in systolic alone in 45%; diastolic alone in 11%; increase in both in 12%; use of antihypertension drugs in 32%.

1. Over 4 years, after a mean age of 52, a stepwise increase occurred in incidence of hypertension across 3 non-hypertensive BP categories (optimum, normal, and high normal).
2. Older individuals and those with high normal BP were more likely to progress. Sex was not an important determinant.
3. Baseline body-mass index (BMI) and weight gain were important determinants of progression
4. Development of isolated systolic hypertension was, by far, the most common.
5. A substantial proportion of those in the high normal group developed hypertension within 1 year of follow-up. This suggests a yearly screening in this group.
6. Less frequent monitoring night be appropriate in younger persons with optimum BP.

1. Randomized, double-blind trial entered 160 patients. All had documented coronary disease. (Ie, a secondary prevention trial.)
2. All had low HDL levels (> 35 mg/dL in men and < 40 mg/dL in women) as well as "normal" LDL levels, defined as below 145 mg/dL). 1
3. Randomized to one of four regimens:

   A.	Simvastatin (Zocor) + niacin (slow release [Slo-Niacin] or crystalline [Niacor] ). (See text p. 1584 for protocol) Mean dose of simvastatin = 13 mg/d. Mean dose of niacin = 2.4 g/d.
   B.	Antioxidants (Vitamin C, vitamin E, carotene, and selenium).
   C.	Simvastatin + niacin + antioxidants.
   D.	Placebos.

4. End-points = change in coronary stenosis by angiography, and the occurrence of a first coronary event (death, non-fatal MI, cerebral infarction, revascularization, hospitalization for ischemia).
5. Follow-up = 3 years.

1. In the simvastatin + niacin group, LDL was lowered by 42% and HDL was raised by 26% .
2. Antioxidants actually reduced benefits when added to simvastatin + niacin. The protective increase in HDL was blunted by addition of antioxidants. (+ 9 mg/dL vs + 6; a surprise finding. )
3. Average coronary stenosis (by angiography) progressed by 4% with placebos, 2% with antioxidants, 0.7% with the simvastatin + niacin + antioxidants, and regressed by 0.4% in the simvastatin + niacin group.
4. Frequency of clinical end-points over 3 years: placebo — 24%; antioxidants alone — 21%; simvastatin + niacin + antioxidants — 14%; simvastatin + niacin — 3%.
5. Adverse effects: Compliance ranged from 80% to 95%. Combined simvastatin + niacin was related to small increases in aspartate aminotransferase, creatine kinase, homocysteine, and insulin. Flushing was reported in 30%. Four of 80 discontinued niacin because of flushing.

1. The rate of major clinical events was reduced by 90% in the simvastatin + niacin group.
2. Antioxidants provided no benefit. (Actually blunted the HDL-raising effect of simvastatin + niacin.)
3. The regression of stenosis in the simvastatin + niacin group was more than that expected from statins alone.
4. Statins principally reduce LDL; niacin principally increases HDL. (The decrease in LDL related to combined statin-niacin was somewhat greater than the average decrease reported from statin therapy alone. The increase in HDL was much more than usually reported from statins alone. RTJ )
5. These findings apply to the many patients with coronary disease who have low HDL levels.
6. The results discourage use of antioxidants (which are frequently used based on unsupported perceptions) "Unless more compelling evidence appears, we see little justification for the use of antioxidant vitamins for the prevention of cardiovascular events."

1. Multicenter, randomized, double-blind, placebo-controlled, cross-over trial in over 2000 patients with asthma — age from 3 to 64.
2. For 2 weeks prior to study, all had stable asthma defined by absence of emergency room visits, hospitalizations, increased doses of corticosteroids, or urgent visits to a health care provider.
3. Randomized, cross over to:

   A.	Inactivated trivalent flu vaccine followed in 3 weeks with placebo injection, or
   B.	Placebo injection followed in 3 weeks with flu vaccine.

4. Primary outcome = an exacerbation of asthma in the 2 weeks following the injections. This was determined by measurement of peak expiratory flow rates, unscheduled visits to heath care, use of asthma medications, and asthma-related absence from school or work.

1. Frequency of exacerbations was similar in the 2 groups in the 2 weeks following the injections: 29% after placebo and 28% after flu.
2. Exacerbation rates were similar in subgroups. Only body aches, headache, and chills were, as expected, slightly more frequent after flu vaccine.

1. "Influenza vaccine does not worsen asthma." Current guidelines for the immunization of patients with asthma are safe.
2. There was no difference in rates of exacerbation in the first 3 days after flu vaccine.
3. The high rate of spontaneous exacerbations, as well as the high rate of symptoms even after placebo shots, may explain the oft-held belief that immunization induces asthma.
4. Patients with more severe symptoms of asthma before either injection was given were more likely to experience an exacerbation after the injection. "Therefore we consider that inactivated influenza vaccine is safe in patients with more severe asthma."
5. The findings cannot be extrapolated to the cold-attenuated live influenza vaccines that may become available in the future. (Ie, the nasal vaccine.)
6. Fewer than 10% of patients with asthma are vaccinated against asthma. Programs that emphasize the importance of flu vaccine should be promoted.

1. Multicenter, double-blind study entered over 3600 patients age 55 to 80. Divided into 4 groups having increasing severity of ARMD:

   A.	"No ARMD" — a few small drusen. (This group was eliminated from the study since the risk of developing progression over 6 years was small ~ 1.3% in 5 years).
   B.	"Early ARMD" — extensive small drusen, a few intermediate drusen, extensive intermediate drusen, or pigment abnormalities.
   C.	"Intermediate ARMD" — large drusen, extensive intermediate drusen, non-central geographic atrophy
   D.	"Advanced ARMD" — treatment of choroidal neovascularization ("wet ARMD") or photographic documentation of geographical atrophy involving the center of the macula, or with vision loss in one eye due to ARMD but not in the other, or extensive maculopathy from ARMD (At least one eye had best-corrected vision to 20/32 or better. )

2. Randomized to daily administration of:
   1. Vitamin C 500 mg; vitamin E 400 IU; beta carotene 15 mg. (Antioxidants)
   2. Zinc oxide 80 mg and copper 2 mg as cupric oxide. (Zinc)
   3. Antioxidants + zinc
   4. Placebo.
3. Follow-up = 6 years for evidence of progression.

1. Incidence of progression from early ARMD and intermediate ARMD. to advanced ARMD was reduced significantly in the antioxidants + zinc group compared with placebo. Odds ratio = 0.66.
2. Odds ratios of developing advanced ARMD were reduced also for zinc alone (OR = 0.71) and antioxidants alone (OR = 0.76)
3. The only statistically significant reduction in rates of at least moderate visual acuity loss occurred in persons assigned to receive antioxidants + zinc.
4. No significant serious adverse events occurred.

1. Compared with placebo, both 1) combination of antioxidants + zinc and 2) zinc alone reduced the odds of developing advanced ARMD in persons at risk of progression.
2. When only those participants with the greatest risk of progression to advanced ARMD and visual loss were considered, the combination of zinc + antioxidants had the most consistent treatment benefit, reducing the risk of development of moderate visual loss and development of advanced ARMD. (Odds ratio = 0.7)
3. "Based on the consistency of the data, and the general lack of any clinically significant serious adverse effects from these treatments, it is reasonable to conclude that persons found to have advanced ARMD in one eye of intermediate ARMD and who do not have contraindications should consider supplements with a combination of these antioxidants and zinc."
4. "This is the first treatment shown to slow the progression of ARMD and is a very important advancement in this field, one that could delay or prevent vision loss in many patients."
5. The value of these supplements in persons at low risk remains uncertain.

1. Prospective cohort study Entered over 9500 men and women who participated in the First National Health and Nutrition Examination Survey (NHEFS). All were free of known cardiovascular disease at baseline.
2. Estimated frequency of legume intake by a 3-month food frequency questionnaire. Foods included dry beans, peas, pinto beans, black-eyed peas; and peanuts and peanut butter.
3. Obtained incidence of coronary heart disease (CHD) and cardiovascular disease (CVD) from medical records and death certificates.
4. Follow-up = an average of 19 years.

1. Over 19 years over 1800 incident cases of CHD and over 3600 incident cases of CVD were documented.
2. Legume consumption was significantly and inversely associated with risk of CHD and CVD after adjustment for established risk factors. Consumption of legumes 4 times a week or more, compared with less than once a week, was associated with a 22% lowering of CHD and a 11% lowering of CVD. However, significant benefit was limited to those over age 60 at baseline. In this older group, those with an intake of at least 4 times weekly had a 38% lower risk of CHD and a 27% lower risk of CVD.
3. Persons with more frequent legume intake had less hypertension, less hypercholesterolemia, less diabetes, and lower body mass index than those consuming legumes less often.

1. "Our study found a strong and independent inverse association between dietary intake of legumes and risk of CHD in a representative sample of non-institutionalized adult US population." The findings are highly generalizable.
2. "Increasing legume intake may be an important part of dietary interventions to reduce heart disease."

1. Prospective, double-blind, placebo-controlled trial entered over 200 patients with coronary disease. All underwent a successful PTCA. (A secondary prevention trial.)
2. Randomized to:

   A.	Vitamin supplementation regimen: folic acid — 400ug; pyridoxine 10 mg; and vitamin B12 400 ug daily. (My vitamin supplement contains 400 ug of folic acid, 2 mg B6, and 6 ug of B12. Additional supplementation is needed to reach the levels of B6 and B12 used in the study. RTJ)
   B.	Placebo

3. Followed at 6 months by repeat coronary angiography.
4. Primary end point = restenosis.

1. The vitamin treatment was associated with a significantly lowered plasma homocysteine level ( from 11 to 7 umol/L).
2. In the treatment group at 6 months, luminal diameter was larger and degree of stenosis lower.
3. Rate of restenosis = 37% in the placebo group vs 20% in the folate group. Need for revascularization: placebo = 22%; vitamin group = 11% [NNT(benefit one patient over 6 months) = 9]

1. The study provides evidence that folate, B12, B6 treatment, lowers homocysteine levels and is associated with a significantly reduced rate of restenosis after PTCA.
2. The folate combination is inexpensive and safe.

1. Double-blind randomized trial compared warfarin with aspirin in over 2000 patients (mean age = 63). All had a non-cardiac ischemic stroke within 30 days of randomization. (Those with atrial fibrillation were excluded.)
2. Randomized to: 1) warfarin to achieve an INR of 1.4 to 2.8, or 2) aspirin 325 mg daily.
3. Primary end point = recurrent ischemic stroke or death from any cause. Follow-up = 2 years.

1. No significant differences in outcomes between groups. Primary end point occurred in 18% of warfarin group vs 16% in the aspirin group.
2. Rates of major hemorrhage were low— 2.2 pre 100 patient-years in the warfarin group vs 1.49 in the aspirin group
3. No difference in time to primary end point.

1. There was no significant difference between treatment with warfarin vs aspirin in prevention of recurrent non-cardiac stroke of death, or the occurrence of serious adverse effects.
2. Actually, warfarin was associated with a non-significant 13% higher increase in risk of recurrent stroke.
3. Aspirin, either alone, or in combination with some other antiplatelet agent, appears to be a well-justified choice for the prevention of recurrent ischemic stroke.

Cognitive-behavioral therapy:

Is promising. However, studies of effectiveness tend to be small and lack controls.
It requires a special program with multiple sessions, and trained therapists.

Pharmacotherapy:

There is good evidence that vigorous treatment of psychiatric disorders that frequently co-exist are responsive to drugs. Drug treatment may help resolve hypochondriacal symptoms associated with major depression, panic disorder, and obsessive-compulsive disorder. (See table 2 p 1397)

Relation to the doctor:

Brief, and frequent regular visits should be advised rather than "as needed" visits. Diagnostic procedures, surgery, lab tests, consultations, should be performed only when clearly indicated. Explicitly acknowledge that the patient' symptoms are real and not imaginary or fabricated.
      Successful long-term management requires a durable and trusting doctor-patient relationship in which access to the doctor is not predicated on an as-needed basis. Try not to vary the frequency of appointments when the number or severity of symptoms increases or decreases. At the same time be alert to the possibility of an organic basis. Regular visits, careful physical examinations, and attentive listening are useful approaches to therapy. Search for evidence of other psychiatric disorders — major depression, panic disorders, and obsessive-compulsive disorder. Treatment of the co-existent psychiatric disorder typically ameliorates hypochondriacal symptoms.

Benign remedies:

Lotions, vitamins, elastic bandages, and heating pads can be helpful because they provide tangible evidence of the patient's distress and the doctor's ongoing interest.

1. At baseline, a large cohort of women (25 000) provided information about use of HRT.
2. Continued inquiry about HRT at 12 and 36 months.
3. Inquired about dry eye syndrome at 48 months.

1. Prevalence of DYS at 4th year:

   Women who had never used HRT — 5.9%.
   Women who had used estrogen alone — 9.1% (NNT harm = 31)
   Women who had used estrogen-progesterone — 6.7% (NNT harm = 125)

2. Each 3-year use was associated with a significant 15% elevation in risk .

1. Most epidemiological studies conclude that dry eye syndrome is more common in women.
2. Postmenopausal women who used HRT had a higher prevalence of DES than never users.
3. Estrogen-alone users had a higher prevalence of DES than users of combined estrogen-progesterone. (+ 69% vs +29% compared with never-users.)
4. The longer the use, the higher the risk.
5. Postmenopausal women who never used HRT had the same prevalence as premenopausal women.
6. Estrogens have an inhibitory effect on sebaceous glands. The authors speculate that estrogens have a drying effect on the meibomian1 and lacrimal glands.

1. Developed and assessed a risk index on the basis of observed risk relations among over 13 000 patients with ST-elevation MI.
2. The risk index included age, systolic BP and heart rate to develop a formula to predict mortality over 30 days.
3. The formula -- heart rate x (age/10)2 / systolic BP.
4. Divided the cohort into quintiles for convenient clinical use.

1. The risk index was a strong and independent predictor of mortality.
2. The index was also a robust predictor of very early events, including death within 24 hours.
3.  

   Risk index (quintiles)	Death in 24 hours	Death within 30 days
   < 12	0.2%	1%
   12-17	0.4%	2%
   18-22	1%	3%
   23-30	2.4%	8%
   > 30	7%	17%

1. A combination of the 3 strongest clinical predictors of mortality risk into a single risk index provided an effective and simple tool for rapid risk assessment.
2. Pre-hospital ECG and assessment of eligibility for reperfusion therapy has been shown to reduce time to treatment and could be associated with improved survival.

1. Prospective, population-based cohort study of almost 7000 patients over age 55. All were free of dementia at baseline.
2. Estimated risk of AD in relation to use of NSAIDs.
3. Sixteen NSAIDs were documented, the most common being diclofenac, ibuprofen, and naproxin.
4. Determined four categories of use: non-use; short-term use (1 month or less); intermediate-term use ( one months to 2 years of cumulative use); and over 2 years of cumulative use.
5. Determined incidence of dementia over a 7-year follow-up.

1. Dementia occurred in 5.6% of patients:

   AD	4.2%
   Vascular dementia	0.8%
   Other	0.6%

2. Relative risk of AD according to length of use compared with no use:

   Less than 1 month	0.98
   One month to 2 years	0.8
   Over 2 years	0.2 (Only 3 of 233 patients developed AD.)

3. Risk did not vary with age.
4. No reduction in incidence of vascular dementia.

1. "In this prospective, population-based study, we found a significantly reduced risk of Alzheimer's disease in subjects who had taken NSAIDs for a cumulative period of 24 months of more."
2. The results are compatible with the hypothesis that inflammatory mechanisms may play a part in AD.
3. The study emphasizes that the information about NSAID use was taken from pharmacy records which in the Netherlands are very complete.
4. At baseline a number of patients were already taking NSAIDs. Thus the period of use may have been longer.