11-1 INTRATHECAL METHYLPREDNISOLONE FOR INTRACTABLE POST HERPETIC NEURALGIA.
      Intrathecal administration of methylprednisolone was an effective treatment for severe, persistent PHN.

11-2 A NEW TREATMENT FOR POSTHERPETIC NEURALGIA
      The editorialist, an experienced observer of PHN, comments that treatment should start with the simplest and safest approaches (see text). However, he found the results of the trial remarkable. Replication is necessary.
      Primary care clinicians may be willing to consult with expert anesthesiologists to ask their opinion and willingness to try this new procedure in a highly distressed patient.

11-3 RHYTHM OR RATE CONTROL IN ATRIAL FIBRILLATION — Pharmacological Intervention in Atrial Fibrillation (PIAF): A Randomized Trial
      Rate control and rhythm control yielded similar symptomatic improvement.
      Rate control with diltiazem and digoxin had the advantage of fewer adverse effects and fewer hospitalizations; but the disadvantage of continuing warfarin prophylaxis to prevent embolic stroke.
      Rhythm control had the advantage of improving exercise tolerance. But the disadvantages of often requiring electrical conversion and continuing amiodarone prophylaxis. Hospital admissions and withdrawals due to drug adverse effects were more frequent. Almost half failed to maintain normal sinus rhythm over 1 year.
      "It seems appropriate to choose the best therapeutic strategy according to the needs of the individual patient."
      Primary care clinicians may choose the simplest approach — rate control with added aspirin or warfarin.

11-4 SAFETY AND COSTS OF INITIATING ANGIOTENSIN CONVERTING INHIBITORS FOR HEART FAILURE IN PRIMARY CARE: Analysis Of Individual Data From Studies Of Left Ventricular Dysfunction
      ACE inhibitors delay progression and reduce mortality in patients with HF due to left ventricular systolic dysfunction.
      These drugs are underused in primary care practice.
      Fewer than 2% of patients receiving a small test dose of enalapril reported side effects severe enough to discontinue. (More likely in older patients with more severe HF).
      Continuing the drug at gradually increasing doses for prevention or treatment of HF was safe — overall, no difference between enalapril and placebo in withdrawals.
      Primary care clinicians should use ACE inhibitors routinely in patients with HF or a reduced ejection fraction.

11-5 THE ROLE OF COMPLEMENTARY AND ALTERNATIVE MEDICINE
      We should listen less to the opinions of those who either overtly promote or stubbornly reject complementary medicine. The many patients who use CM deserve better. Patients and health care providers need to know which forms of CM are safe and effective. Its future should be determined by unbiased scientific evaluation.
      Meanwhile, "The complete physician must be sensitive to the values and beliefs of those who live in different worlds, working with them, not against them."
      Primary care physicians can learn from some practitioners of CM that there is much more to practice than technical management of disease. We need to concentrate more on the patient as a whole.

11-6 SEVEN LEGAL BARRIERS TO END-OF-LIFE CARE" Myths, Realities, And Grains Of Truth
      "Many legal barriers to end-of-life care are more mythical than real, but sometimes there is a grain of truth. Physicians must know the law of the state in which they practice."
      See text for a discussion of 7 legal myths regarding end--of-life care.
      Primary care clinicians must be equipped to give their terminal patients the best of palliative care.

11-7 USEFULNESS OF ULTRASONOGRAPHY IN THE MANAGEMENT OF THYROID DISEASE.
      Ultrasonography altered the clinical management of 2 out of every 3 patients referred because of detection of a thyroid nodule by physical examination. Clinical examination does not detect all nodules, many of which should have fine-needle aspiration.
      Ultrasound should be routine in patients with thyroid nodules.

11-8 TREATMENT OF WARFARIN-ASSOCIATED COAGULOPATHY WITH ORAL VITAMIN K
      Low oral dose (1 mg) was more effective than placebo for rapidly lowering high INR values (5 to 10) in patients taking warfarin.
      Primary care clinicians must always consider the cause of the increase in the INR.

11-9 ASSOCIATION BETWEEN CIGARETTE SMOKING AND ANXIETY DISORDERS DURING ADOLESCENCE AND EARLY ADULTHOOD.
      Heavy cigarette smoking during adolescence was associated with a higher risk of development of agoraphobia, generalized anxiety disorder, and panic disorder in early adulthood.
      Primary care clinicians should recognize the youths who may be crying out for help.

11-10 SMOKING AND MENTAL ILLNESS: A Population-Based Prevalence Study
      Persons with mental illness were about twice as likely to smoke as persons without mental illness.
      Primary care clinicians should consider smoking a possible marker for mental illness, especially in those who start at an early age.

11-11 RISK OF GASTROINTESTINAL HAEMORRRHAGE WITH LONG TERM USE OF ASPIRIN: Meta-Analysis
      Long-term therapy with aspirin is associated with a clinically significant increase in incidence of GI hemorrhage. No evidence that low dose or enteric coating reduces risk.
      Primary care clinicians should alert patients taking long-term low-dose aspirin of this uncommon, but important adverse effect. On the basis of common sense, many clinicians might continue to use enteric coated aspirin (eg, 80 mg daily) despite the lack of any protective effect reported by this study.

11-12 ASPIRIN, LIKE ALL OTHER DRUGS, IS A POISON
      The hope was that reducing the dose and providing different formulations of aspirin would reduce the risk of hemorrhage. The preceding meta-analysis negates this hope.

11-13 STRATIFIED CARE VS STEP CARE STRATEGIES FOR MIGRAINE.
      Go at once to the most effective therapy based on individual trial and error experience.

11-14 THE IMPORTANCE OF INJECTING VACCINES INTO MUSCLE
      Injecting a vaccine into the layer of subcutaneous fat, where poor vascularity may result in slow mobilization and processing of the antigen, is a cause of vaccine failure. Needles should be long enough to reach muscle.

11-15 STATINS AND THE RISK OF DEMENTIA
      Individuals over age 50 who were prescribed statins had a substantially lowered risk of developing dementia.
      This preliminary report needs replication. Patients who ask about it should be told statins should not be prescribed solely for this purpose. It may be an added benefit.

11-16 A COMPARISON OF ETANERCEPT AND METHOTREXATE IN PATIENTS WITH EARLY RHEUMATOID ARTHRITIS
      "Etanercept ( tumor necrosis factor inhibitor) represents an important new therapeutic option to decrease disease activity and slow joint damage in patients with active rheumatoid arthritis."
      As compared with oral methotrexate alone, subcutaneous etanercept alone acted more rapidly to decrease symptoms and slow joint damage in patients with early active RA.
      "Preventing the damage that occurs early in the course of the disease may be the key to better long-term functional outcomes."

11-17 INFLIXIMAB AND METHOTREXATE IN THE TREATMENT OF RHEUMATOID ARTHRITIS
      In patients with persistently active RA despite methotrexate therapy, repeated doses of infliximab (an antibody against tumor necrosis factor) in combination with methotrexate provided clinical benefit and halted the progression of joint damage.
      At present, primary care clinicians should inform patients with RA of the benefit/harm-cost of TNF inhibitors and refer those interested to a rheumatologist.

11-18 EXERCISE TESTING IN CLINICAL MEDICINE
      "Brief, inexpensive, and done in most cases without the presence of a cardiologist, the exercise test offers the highest value for predictive accuracy of any of the non-invasive tests for coronary artery disease."
      Primary care clinicians may wish to add a treadmill to their practice.

11-19 TREATMENT POSSIBILITIES FOR UNSTABLE ANGINA
      An excellent reference treatment plan is outlined on page 1272.
      Most of the interventions can be prescribed by primary care clinicians.

RECOMMENDED READING

11-5 THE ROLE OF COMPLEMENTARY AND ALTERNATIVE MEDICINE.

REFERENCE ARTICLES

11-6 SEVEN LEGAL BARRIERS TO END-OF-LIFE CARE" Myths, Realities, And Grains Of Truth
11-18 EXERCISE TESTING IN CLINICAL MEDICINE
11-19 TREATMENT POSSIBILITIES FOR UNSTABLE ANGINA

1. Enrolled over 250 patients with intractable PHN — defined as burning and lancinating pain that was accompanied by allodynia1, restricted to the dermatomes involved in the original eruption. Patients with involvement of the cranial nerves were excluded.
2. All had pain lasting over a year.
3. All had pain resistant to conventional treatments: antidepressants; anticonvulsants; epidural local anesthetics; topical anesthetics.
4. Randomized to: 1) intrathecal (lumbar space) methylprednisolone (60 mg) with lidocaine (3 mL of 3%), or 2) lidocaine alone, or 3) no treatment. Injections were given for once a week for up to 4 weeks. (See text for technique of injection.)
5. Follow-up = 2 years

1. Minimal change in degree of pain occurred in the lidocaine-alone and the untreated control groups.
2. 90% of the methylprednisolone group vs 4% to 6% of the other 2 groups reported good or excellent relief. The intensity and area of pain decreased; the use of NSAIDs declined. The pain relief lasted throughout the 2 years of follow-up.
3. Interleukin concentrations in the cerebrospinal fluid decreased by 50% in the methylprednisolone-lidocaine group.
4. No complications were noted.

1. Interleukin 8 is a potent mediator of inflammation. The high concentrations of interleukin 8 in the cerebrospinal fluid indicated a prolonged spinal inflammatory reaction in these patients. The inflammation responded to the methylprednisolone. The degree of decrease in the interleukin 8 concentrations was correlated with the degree of pain relief.
2. The methylprednisolone-lidocaine solution was hyperbaric. When the patient was tilted in a head-down position, the solution which had been injected into the lumbar region spread to the thoracic and cervical regions. This allowed effective treatment of neuralgia in these regions. The risk of injections associated with cervical or thoracic intrathecal injections was avoided.

1. Randomized trial entered over 250 patients with AF of 1 week to 1 year duration.
2. Randomized to:

   Group A) Rate control with diltiazem (Cardizem , a calcium blocker) as first line therapy. No attempt was made to terminate AF. The goal was to control symptoms by rate control alone.
   
   Group B) hythm control: Patients first received pharmacological or electrical cardioversion followed by rhythm control with amiodarone (Cordarone), aimed at prevention of recurrence of AF.
   
   

3. About 75% of patients in both groups were receiving digoxin at baseline. This was continued. The addition of diltiazem led to a small, but significant further decrease in heart rate.
4. All patients were anticoagulated throughout the study period.
5. Primary end-point = improvement in symptoms. (Palpation, dyspnea, dizziness)

1. In the rhythm control group, restoration of sinus rhythm occurred in 23% of patients on amiodarone alone. The remaining required electrical conversion.
2. At 1 year:

   	Rate control (Group A)	Rhythm control (Group B)
   In sinus rhythm	10%	56%
   Hospital admissions	24%	69%
   Adverse drug reactions	15%	25% (Leading to a change in therapy.)

3. Over the year, a similar number of patients (63% vs 58%) reported symptom improvement. There was no difference in reported quality of life.
4. Walk test was better in the rhythm control group.

1. In the rhythm control group many more were in sinus rhythm at 1 year (56% vs 10%) [But note that almost half failed to maintain normal sinus rhythm over 1 year. RTJ]
2. Amiodarone loading in the rhythm control group restored sinus rhythm in 23%. The majority required electroconversion.
3. Neither of the 2 therapeutic strategies was superior to the other in terms of AF symptom control. "The results may have important implications for the care of individual patients who are treated mainly for symptomatic control."
4. Once converted, over half the patients could be maintained in sinus rhythm by continued low-dose amiodarone. However, amiodarone was discontinued in 25% of patients due to presumed side-effects.
5. Any advantage of rate control is counteracted in part by the need for continued anticoagulation.
6. "Careful control of the ventricular rate in atrial fibrillation can result in a substantial benefit for the patient." This includes lower costs related to a reduced rate of hospitalization.
7. "It seems appropriate to choose the best therapeutic strategy according to the needs of the individual patient."

1. Entered about 7500 patients under age 80. All had an ejection fraction below 35%.
2. All were challenged with a dose of enalapril 2.5 mg twice daily for 2 to 7 days.
3. Treatment was continued with gradually increasing dose over one year, either for prevention or treatment of HF.

1. Initial treatment: Initial test dose of 2.5 mg twice daily for one week:
   

   8% reported side effects. (Most common— hypotension, altered taste, and rash. (No mention of cough)
   Only 2% reported the side effects severe enough to discontinue.
   Older patients with severe HF and severely impaired ejection fractions and anemia were more likely to discontinue.
   

2. Continuing treatment: Dose reduction of enalapril in the first year was most likely due to hypotension, although overall there was no difference between enalapril and placebo in withdrawals.

1. Patients should be started on small doses of an ACE inhibitor with the goal of reaching the dose used in large scale trials (eg, enalapril 10 mg twice daily)
2. Older patients should be observed for several hours after the first test dose. BP, renal function, and electrolytes should be monitored. Since many patients seen in primary care with HF are over age 80, special care must be used.
3. "Introduction of ACE inhibitors rarely causes problems. None of 7500 patients in the initiation phase had a lasting or life threatening event." In the first year, withdrawal and dose reduction were similar for enalapril and placebo.
4. The validity of a clinical diagnosis of HF in primary care is low (25%-50% accuracy). Diagnosis requires objective evidence — at least echocardiography. However, an entirely normal electrocardiogram will usually exclude HF.
5. Estimated costs of diagnosis and starting treatment in the UK = equivalent of about $500.
6. "Doctor's perceptions of the risks of these drugs in patients with HF are exaggerated."

1) When CM impedes access to the benefits of western interventions. (Eg, denying or delaying treatment of diabetic keto-acidosis, acute appendicitis, myocardial infarction, meningococcemia.)

2) When the herb is toxic, or incompatible with prescription drugs. (This is a major reason primary care clinicians should keep up with studies of CM.) Primary care clinicians should understand that many of their patients use CM, be uncritical about it, and encourage their patients to openly discuss it. RTJ

1. Forgoing life-sustaining treatment for patients without decision making capacity requires that there be evidence that this was the patient's actual wish.
2. Withholding or withdrawing artificial fluids and nutrition from terminally ill or permanently unconscious patients is illegal.
3. Risk management personnel must be consulted before life-sustaining medical treatment may be terminated.
4. Advance directives must comply with specific forms, are not transferable between states, govern all of a patient's future treatment decisions; oral advance directives are unenforceable.
5. If a physician prescribes or administers high doses of medication to relieve pain or other discomfort in a terminally ill patient and this results in death, the physician will be criminally prosecuted.
6. When a terminally ill patient's suffering is overwhelming despite excellent palliative care, and the patient is requesting a hastened death, there are no legally permissible options to ease suffering.
7. The 1997 Supreme Court decision outlawed physician-assisted suicide.

1. Retrospective chart review of over 150 patients referred to a thyroid nodule clinic.
2. All patients with suspected nodular thyroid disease or suspected recurrent thyroid cancer received ultrasonography and ultrasonographic-guided fine needle aspiration biopsy of nodules at least 1 cm in diameter.
3. Compared ultrasonography findings with the referring physician's findings.

1. A total of 209 fine-needle aspirations were performed in 156 patients.
2. Among 114 patients referred for a solitary nodule:

   A. Ultrasound detected additional non-palpable nodules of at least 1 cm in diameter in 23%.
   B. Ultrasound determined that no nodules required aspiration in 20%.

3. Among 59 patients referred for a diffuse goiter or a multinodular gland, ultrasound detected a discrete nodule of at least 1 cm in diameter in 39, and determined that aspiration was not necessary in 20.

1. "We routinely use ultrasonography and ultrasonography-guided fine-needle aspiration in patients referred to our Thyroid Nodule Clinic for suspected thyroid nodules.
2. Almost half referred for a solitary nodule on physical examination were found to have multiple nodules. Many required aspiration of a non-palpable nodule.
3. More than 50% of those with suspected diffuse or asymmetric goiter had discrete nodules requiring fine needle aspiration.
4. About 25% of patients had no nodule equal or greater than 1 cm, despite abnormal findings on physical examination.
5. "The occurrence of malignancy was similar in patients with solitary and multiple nodules."
6. Non-palpable nodules are often at least 1 cm in diameter. "It is difficult to predict which patients will benefit from ultrasonography on the basis of physical examination."
7. The presence of cancer in thyroid nodules is independent of the number of nodules. In 4 of the 12 patients with thyroid cancer, the malignant nodules were not palpated by the referring physician and would not have been detected at the time of referral without ultrasonography.
8. "Since the prognosis of thyroid cancer is partially dependent on its size at surgery, earlier detection is probably beneficial."

1. Multicenter, double-blind, placebo-controlled randomized trial entered 92 patients (mean age = 65). All were receiving warfarin and had an INR between 4.5 and 10.0 (mean = 5.7)
2. None had an indication for immediate normalization of the INR. Warfarin was withheld.
3. Randomized to: 1) 1 mg vitamin K, or 2) placebo (Note the vitamin K was given orally.)
4. Primary outcome = INR on the day after treatment.

1. Patients given vitamin K had a more rapid decline in INR: 56% had an INR of 1.8 to 3.2 the next day compared with 20% of the placebo patients.
2. Patients receiving vitamin K had a significant decrease in the number of minor bleeding episodes in a follow up of 3 months.
3. One deep-vein thrombotic episode occurred at 22 days in the placebo group; one myocardial infarction at 3 days in the treatment group.

1. Giving the small dose of vitamin K not only brought the INR from 4.5-10.0 to a treatment range more quickly than simply withholding treatment, but did so without causing warfarin resistance.
2. Patients receiving 1 mg vitamin K did not have persistently lower INR values than those who received placebo.
3. The authors state that the inclusion criteria of the study would capture a representative population of patients with this common clinical complication.
4. Many clinicians do not give vitamin K to symptomless patients even with an INR of 8.0, preferring simply to withdrawing warfarin. "Our findings provide a strong case for the routine use of vitamin K in patients with a symptomless increase in INR."

1. "The Children in the Community Study" (1991-92), a prospective longitudinal investigation followed over 650 youths at a mean age of 16 in 1985-86 (adolescents) , and later at a mean age of 22 (young adults).
2. Determined prevalence of cigarette smoking and psychiatric disorders.

1. Heavy cigarette smoking (> 20/d) during adolescence was associated with higher risks of psychiatric disorders during early adulthood

   	Heavy smokers	Non-smokers
   Agoraphobia	10%	2%
   Generalized anxiety disorder	21%	4%
   Panic disorder	8%	0.6%

   
   
2. Anxiety disorders during adolescence were not significantly associated with later chronic use of cigarettes during early adulthood. (15% of participants with, and 15% of participants without, anxiety in adolescence smoked at least 20 cigarettes during early adult hood.)

1. Heavy cigarette smoking during adolescence was associated with an increased risk of agoraphobia, generalized anxiety disorder, and panic disorder during early adulthood.
2. The findings do not support the hypothesis that anxiety in adolescents is related to an elevated risk of smoking later in life.

1. The National Comorbidity Study (1991-92), a nationally representative multistage probability study, analyzed data on over 4400 respondents age 15-54 for presence or absence of mental illness.
2. Defined mental illness as: major depression; bipolar depression; panic disorder; agoraphobia; social phobia; simple phobia; generalized anxiety disorder; alcohol abuse; alcohol dependence; drug abuse; drug dependence; antisocial personality; conduct disorder; or non-affective psychosis such as schizophrenia.
3. Determined rates of smoking according to the type of psychiatric diagnoses.
4. Determined rates of cessation.

1.  

   	Current smoking	Lifetime history of smoking
   No mental illness	23%	39%
   Lifetime mental illness	35%	55%
   Past month mental illness	41%	59%

2. Odds ratios for smoking in persons with mental illness vs respondents without mental illness, adjusted for age, sex, and region of country = 2.7.
3. Self-quit rates = 37% of those with any mental illness; 30% of those with past-month mental illness; 42% of those without mental illness.
4. "Persons with mental illness in the past month consumed approximately 44% of cigarettes smoked by this nationally representative sample."

1. Persons with mental illness were about twice as likely to smoke as persons without mental illness.
2. However, more than one third of those with mental illness had quit smoking at the time of the survey.
3. Except for the group of persons dependant on alcohol and drugs, the quit rates of others with mental illness were similar to those without mental illness.
4. Why do persons with mental illness smoke more? As a means of self-medication for their psychiatric symptoms? This would imply that the mental illness causes smoking. However, there is data suggesting that smoking comes first and may be followed by depression, panic disorder, and anxiety. A recent study found that smoking preceded onset of schizophrenia in the majority of persons with schizophrenia who smoked.
5. Internal documents suggest that the tobacco industry has identified psychologically vulnerable persons as a part of their market.
6. These findings emphasize the importance of focusing on smoking prevention and cessation efforts of the mentally ill.
7. "The fact that smokers with mental illness are able to quit should offer hope."

1. Included 24 randomized, controlled trials (about 66 000 participants; predominantly male and middle-aged. ).
2. All trials compared aspirin with placebo, or no treatment for one year or more. (Mean = 28 months) Doses of aspirin varied from 50-1500 mg/d.
3. Indications for aspirin extended from primary prevention in "healthy" individuals to secondary prevention after stroke.
4. Excluded individuals with history of peptic ulcer, previous GI hemorrhage, or intolerance to aspirin.
5. Main outcome measure = GI hemorrhage.

1.  

   GI hemorrhage	Aspirin	Control	Odds ratio	Odds ratio modified release
   	2.47%	1.42%	1.68	1.93

2. Number needed to harm = 106 over 28 months.
3. No relation between dose of aspirin and hemorrhage. At doses below 163 mg/d, GI hemorrhage occurred in 2.3%
4. No reduction when modified release aspirin was used.

1. Long-term aspirin, even at low dose, carries a risk of GI hemorrhage. (Number to harm = 248 per year).
2. Benefits must be weighed against harms. For secondary prevention of stroke, an estimated 2 recurrent strokes would be prevented at a risk of one hemorrhage. For primary prevention of myocardial infarction (MI) , 2 to 3 GI hemorrhages (depending on baseline risks) would occur for each MI prevented.
3. Since there are relatively few deaths after GI hemorrhage, a trade-off with MI may be worth considering. (Again depending on baseline risk. RTJ )
4. Neither reducing the dose or changing the formulation of aspirin offered clear benefits.

1) Step care across attacks: Patients begin with a non-specific therapy (ie, a simple or combination analgesic). After treating several attacks, if the treatment is not satisfactory, treatment is escalated. The process is continued until a satisfactory treatment result is achieved. (This approach is often advocated by managed care guidelines.)
2) Step care within attacks: Patients begin treatment with a non-specific therapy. At a specific time point (eg, 2 hours) patients assess their response and, if needed, take another medication, often migraine specific.
3) Stratified care: Patients select initial treatment based on their own treatment needs.

1. Multicenter, randomized, controlled parallel -group trial entered over 800 adult patients (mean age = 38). All had an established diagnosis of migraine based on the International Headache Society's criteria . All had 1 to 8 migraine attacks monthly with severity ranging from II, III, and IV.
2. Randomized to:

   1) Step care across attacks:
   

   First 3 attacks treated with aspirin + metoclopramide. If inadequate relief step up to zolmitriptan (Zomig) as first drug for the next 3 attacks.

   2) Step care within attacks:
   

   First treatment = aspirin + metoclopramide for all attacks. If inadequate relief in 2 hours, step up to zolmitriptan. (In practice, step care will include other multiple steps — one simple analgesic, followed by various combinations of analgesics , isometheptene (Midrin), or a barbital-containing agent, and finally a triptan. Thus effective treatment may be delayed.)

   3) Stratified care:
   

   A. Grade II (Mild or infrequent disability) attacks received aspirin 800 to 1000 mg + metoclopramide 10 mg.
   B. Grade III (moderate disability) and IV (severe disability) attacks received zolmitriptan 2.5 mg orally as initial treatment of all attacks.

1. Headache response at 2 hours was clinically better in the stratified care group.
2. Disability time was shorter, but the incidence of adverse events was higher. (Most adverse events were of mild-to-moderate intensity.)

1. Stratified care is based on the principle that patient characteristics (ie, headache disability) can be used to help determine the patient's treatment needs, thereby increasing the chance for successful therapy from the outset.
2. One difficulty with step-care is the delay which can occur in instituting effective treatment.
3. Severity of the headache predicts treatment need. Aspirin-metoclopramide effectively treats only about 25% of patients with severe migraine.

1. Multicenter, population-based, case-control study determined all individuals who had a first-time diagnosis of dementia during the study. (The cases; N = 284; all over age 50)
2. Matched each case with up to 4 controls from the same population base. (N=1080)
3. Determined use of statins and other lipid-controlling drugs in both cases and controls.
4. Duration of use of the drugs for the majority was less than 4 years.

1. After control for confounders:

   	Cases (dementia)	Controls (no dementia)
   Current use of statins	4.6%	9.3%
   Past use of statins	0%	1.4%

   (Ie, use of statins was less common in patients who developed dementia; more common in those who did not develop dementia. Ie, a protective effect of statins)
2. Adjusted relative risk estimate = 0.29 (95% confidence interval = 0.13 to 0.63) (By my calculation, NNT for up to 4 years to be associated with prevention of one case of dementia = 16)
3. People who were prescribed non-statin lipid-lowering agents did not have a reduced risk for dementia. (Ie, the benefit seems to be limited to statin drugs.)

1. People in the UK who are prescribed statins have a risk of dementia estimated as much as 70% lower (but at least 39% lower) than those who are not receiving statins.
2. The authors speculate that statins may have beneficial effects of the microvasculature, including increasing endothelial nitric oxide synthase, and reducing endothelin-1, thereby dilating capillaries and increasing blood flow.
3. The available data did not distinguish between Alzheimer's disease and other forms of dementia.
4. "These findings suggest that the use of statins could substantially reduce the risk of dementia in the elderly, either by delaying its onset, or by opposing . . . age-related changes that result in cognitive impairment."

1. Entered over 600 patients with early RA (no more than 3 years duration; no other important concurrent disease; never treated with methotrexate) These patients were considered at risk for rapidly progressive joint damage.
2. Randomized to: 1) etanercept (10 or 25 mg subcutaneously twice-weekly), or 2) oral methotrexate weekly (mean 19 mg).
3. Follow-up = 1 year.

1. Etanercept 25 mg group (compared with methotrexate group) had a more rapid rate of improvement during the first 6 months.
2. Mean increase in joint erosion score in etanercept group at 1 year was 0.47 vs 1.03 in the methotrexate group. 72% of etanercept patients had no increase in erosion score vs 60% of methotrexate group. Both drugs prevented joint-space narrowing.
3. Both drugs were well tolerated. Most adverse effects were mild or moderate. Fewer adverse events and fewer infections occurred in the etanercept group. The most common adverse effect of etanercept was a reaction at the injection site.

1. Early intervention in slowing or arresting the joint damage is important. "Preventing the damage that occurs early in the course of the disease may be the key to better long-term functional outcomes."
2. Both the clinical benefits and the decrease in the rate of radiographic evidence of progression occurred more rapidly in the group receiving 25 mg etanercept.
3. Other studies have reported that etanercept can be safely administered with methotrexate.
4. "Etanercept represents an important new therapeutic option to decrease disease activity and slow joint damage in patients with active rheumatoid arthritis."

1. Entered over 400 patients with active RA. All continued to have active disease despite continuing methotrexate therapy.
2. Randomized to: 1) Infliximab (Remicade) 3 mg/kg intravenously every 4 or 8 weeks plus continued oral methotrexate ; 2) infliximab 10 mg/kg every 4 or 8 weeks plus continued oral methotrexate; or 3) methotrexate plus placebo.
3. NSAIDs and prednisone were continued as before.
4. Follow-up to 54 weeks.

1. Combination infliximab and methotrexate was well tolerated. It resulted in a greater sustained reduction in symptoms and signs of RA than the effect of methotrexate alone. The lowest dose of infliximab was effective; the higher dose more effective.
2. Radiographic evidence of joint damage did not increase in the combination group; did increase in the methotrexate-alone group. (Mean change in radiographic score = 0.6 vs 7.0)
3. Adverse events were common in all treatment groups — at least one in 9 out of ten treated. Most were minor. Serious adverse effects similar across the 2 groups.

1. Combination of infliximab + methotrexate for 1 year provided sustained clinical benefit in patients with active RA.
2. Quality of life was improved and symptoms and signs of the RA also improved.
3. Progression of joint damage halted, even in those with extensive damage.
4. The frequency of infections requiring antimicrobial-drug therapy was 44% in the combination group vs 35% in the methotrexate-alone group. ("Serious" infections occurred in 8% vs 6%.)