7-1 TEN YEARS OF LIFE
      Life-style choices regarding diet, exercise, smoking, body weight, and hormone replacement singly and in combination appeared to lengthen life-expectancy by many years.
      Practical point: Primary care clinicians should adopt these lifestyles themselves. Then they can encourage patients to do likewise. Publication of this study might motivate some patients.

7-2 BOLUS FIBRINOLYTIC THERAPY IN ACUTE MYOCARDIAL INFARCTION
      Given the ease of administration and the similar outcomes compared with recombinant tPA, it is likely that a key component of reperfusion will include a bolus fibrinolytic. The simple bolus administration should shorten the time between onset of symptoms and treatment (onset-to-needle time). It should facilitate pre-hospital fibrinolysis and improve prognosis.
      Practical point: Primary care clinicians who do not have immediate access to emergency department consultations should be able to administer the newer bolus fibrinolytics in the office.

7-3 ALBUMINURIA AND RISK OF CARDIOVASCULAR EVENTS, DEATH, AND HEART FAILURE IN DIABETIC AND NON-DIABETIC INDIVIDUALS.
      Any degree of albuminuria is a robust, independent risk factor for future cardiovascular events in individuals without DM who have increased risk factors for CVD, as well as those with DM. The risk increases as the albumin/creatinine ratio increases, starting well below the cutoff for microalbuminuria.
      Practical point: Primary care clinicians should screen for albuminuria (both dipstick positive and below) in diabetic patients and high risk patients without diabetes. It is an inexpensive and rewarding prognostic indicator which calls for early intervention.

7-4 ANGIOTENSIN-CONVERTING ENZYME INHIBITORS AND PROGRESSION OF NON-DIABETIC RENAL DISEASE: Meta-analysis of Patient-Level Data
      Antihypertension regimens which include ACE inhibitors are more beneficial in slowing the progression of non-diabetic renal disease than regimens that do not contain ACE.
      Practical point: Chronic renal insufficiency is under-diagnosed and under-treated. Opportunities for prevention are lost. The presence of proteinuria in chronic renal disease is a strong indication for treatment with ACE. ACE inhibitors should be the antihypertensive agents of first choice in nondiabetic renal disease as well as in diabetic renal disease.

7-5 PATIENT-INITIATED TREATMENT OF UNCOMPLICATED RECURRENT URINARY TRACT INFECTIONS IN YOUNG WOMEN
      Motivated and adherent young women can accurately self-diagnose and self-treat recurrent UTIs.
      Practical point: Primary care clinicians should make this option available to select patients.

7-6 THE EFFECT OF HORMONE REPLACEMENT THERAPY ON CARDIOVASCULAR RISK FACTORS IN TYPE 2 DIABETES.
      There is compelling evidence that HRT exerts beneficial effects on a number of cardiovascular risk factors in non-diabetic women. This study demonstrated its beneficial effect on women with type 2 diabetes.
      Practical point: This may reassure those of us who believe HRT ultimately improves risk of CHD.
      All patients with diabetes must be especially vigilant in reducing risk factors for cardiovascular disease. This includes routine use of low-dose aspirin. Use of aspirin during the first few months of HRT use, when there is increased risk of cardiovascular events, may be a reasonable strategy for non-diabetic patients as well as diabetic patients.

7-7 POSTMENOPAUSAL HORMONE USE AND SECONDARY PREVENTION OF CORONARY EVENTS IN THE NURSES’ HEALTH STUDY
      The risk of recurrent major coronary events seems to be increased among short-term hormone users with previous coronary disease. With continued use beyond 1 year, risk decreases to a level below the risk in non-users.
      Practical point:
           I believe primary care clinicians can reasonably give the following advice:

1. HRT should be started early in the premenopausal or immediate postmenopausal time period when women, because of their younger age, will have less risk of coronary events.
2. HRT might be avoided if possible even at an early age in women at high risk (eg, smokers, those with lipid disorders, hypertension).
3. Women with troublesome menopausal symptoms might be started on low dose estrogen (eg, 0.3 mg Premarin) until the danger period of 1 year is passed. Low-dose aspirin prophylaxis should be given.

7-8 RISK OF RECURRENT CORONARY EVENTS IN RELATION TO USE AND RECENT INITIATION OF POSTMENOPAUSAL HORMONE THERAPY
      After a first myocardial infarction, use of HRT suggested a transient rise in risk of recurrent coronary events in the first 60 days. Thereafter, use of HRT (compared with non-use) suggested a reduction in risk (ie, a benefit).
      Practical point: I do not believe HERS and other studies should deter primary care clinicians from prescribing HRT for most patients who opt to take them. These results reinforce the preceding study. Starting HRT at or before the menopause when women are younger, and avoiding use by those with many CVD risk factors would be prudent.
      With due care, and concomitant use of aspirin for its anti-platelet effect, any increased risk in the first months would be avoided and thereafter a reduction of cardiovascular events would be likely as women grow older.

7-9 ANALGESIC USE AND RENAL FUNCTION IN MEN
      This provides reassurance that there is not a strong relationship between chronic (up to 4 years) moderate use of acetaminophen, aspirin, and other NSAIDs and development of renal disease in persons with normal renal function.
      This does not provide reassurance among those with initial renal dysfunction. NSAIDs in these patients may lead to further kidney dysfunction.
      Primary care clinicians must remember that NSAIDs can have a deleterious effect on patients with heart failure and hypertension through their pharmacological effect on the kidney.

7-10 A PROSPECTIVE STUDY OF PHYSICAL ACTIVITY AND COGNITIVE DECLINE IN ELDERLY WOMEN.
      Elderly women with higher levels of baseline physical activity were less likely to develop cognitive decline over the next 6 to 8 years.
      Practical point: Another point for clinicians to encourage fitness over a lifetime.

7-11 ACUTE EFFECTS OF PASSIVE SMOKING ON THE CORONARY CIRCULATION IN HEALTHY YOUNG ADULTS.
      Passive smoking substantially reduced coronary blood flow reserve in healthy non-smokers. Passive smoking may cause endothelial dysfunction in the coronary circulation in non-smokers.
      This should convince the diehards who still maintain that harms of passive smoking are not proven. It strengthens the resolve of those who oppose smoking in public places

7-12 MANAGEMENT OF SUSPECTED DEEP VENOUS THROMBOSIS IN OUTPATIENTS USING CLINICAL ASSESSMENT AND D-DIMER TESTING
      The combination of a low pretest probability of DVT and a negative D-dimer test rules out DVT.
      Practical point: Primary care clinicians may use a D-dimer test to help rule out DVT in select low probability patients. D-dimer is not useful in ruling in DVT. It is not useful in patients with moderate or high probability of DVT.

7-13 SUBCLINICAL HYPOTHYROIDISM
      Routine screening, especially of older women, has been advocated, although not endorsed unanimously. The benefits of subsequent therapy have not been established in prospective trials. However, a decision and cost-effectiveness model calculated that screening women over age 35 every 5 years would be beneficial. Half the benefit would be from prevention of subsequent overt hypothyroidism, 30 percent for improved symptoms, and a smaller benefit from improvement in serum lipids.
      Prevention of progression to overt hypothyroidism has been found to be about 4% per year in women with both an elevated TSH and antithyroid antibodies. (38 times that of women with normal values.) The NNT to prevent one patient from developing overt hypothyroidism = 4 to 14.
      Practical point: Primary care clinicians must decide on long-term thyroxine supplementation or continued observation. I believe cautious supplementation is the best choice.

7-14 CAM RESEARCH ATTEMPTS TO SEPARATE WHEAT FROM CHAFF
      The National Center for Complementary and Alternative Medicine (part of the NIH) is attempting to develop a more thorough understanding of how herbs react in the body.
      Several multicenter, randomized trials are being conducted. Primary care clinicians should watch for developments.

7-15 HERBAL MEDICINES AND PERIOPERATIVE CARE.
      Many potential adverse effects may occur in patients taking herbal medicines before surgery.
      During the perioperative evaluation, physicians should explicitly elicit and document a history of herbal medicine use.
      Practical point: Primary care clinicians should be familiar with potential adverse effects of complementary-alternative medicines in order to recognize, prevent, and treat serious problems associated with their use.

7-16 EXTENDED-DURATION PROPHYLAXIS AGAINST VENOUS THROMBOEMBOLISM AFTER TOTAL HIP OR KNEE REPLACEMENT
      Among patients undergoing elective hip and knee replacement, outpatient LMW heparin continued for 4 to 6 weeks after discharge reduced the frequency of DVT.
      Practical point: For the many patients for whom extended heparin or warfarin is not feasible, aspirin should be considered an option.

7-17 THREE MONTHS VERSUS ONE YEAR OF ORAL ANTICOAGULANT THERAPY FOR IDIOPATHIC DEEP VENOUS THROMBOSIS.
      In patients with acute idiopathic DVT, continuing anticoagulation for 1 year reduced recurrence during that year. However, after discontinuing anticoagulation, thrombosis recurred at a rate similar to the rate in those who discontinued after 3 months.
      Practical point: Primary care clinicians face the decision – continue or discontinue anticoagulation? I believe the answer depends on the severity of the DVT, the preference of the patient, and the local availability of logistic support for anticoagulation. If discontinued, recurrence is likely. We should search for underlying thrombogenic factors in these patients. If the decision is made not to continue warfarin, these patients should be placed on continuous aspirin.

7-18 A 28-YEAR OLD WITH PANIC DISORDER
      A clinical review article defining panic attack and panic disorder. Comments on diagnosis and treatment. "The cause is not known, but treatment is almost always successful."

7-19 PROPHYLAXIS WITH SINGLE-DOSE DOXYCYCLINE FOR THE PREVENTION OF LYME DISEASE AFTER AN IXODES SCAPULARIS TICK BITE
      A single dose of doxycycline given within 3 days of a recognized tick bite prevented development of Lyme disease.
      Who should receive prophylactic doxycycline?
           Persons bitten by ticks in endemic areas.
           The tick is at least partially engorged.
           The tick is a nymphal deer tick.
      Practical point: This applies to only a few primary care clinicians. The application is important to them and their patients.

1. Enrolled a cohort of over 34 000 California Seventh-Day Adventists (75% of those eligible) and followed up from 1976 to 1988.
2. Extensive lifestyle questionnaire determined medical history, diet, physical activity, and a few psychosocial variables.
3. Ascertained mortality of all subjects.

1. Percentage of the cohort who adopted various lifestyles:

   Vegetarian	30%
   Eat nuts at least 5 times weekly 1	23%
   Exercise vigorously for 15 minutes at least 3 times weekly	40%
   Ever use of hormone therapy (HRT by women)	53%
   Smokers (current)	Nil
   Body mass index (mean)	25

2. Except for abstinence from smoking, more than half Adventists did not adhere to these lifestyle variables; fewer than half complied. Compared with adherers, those that did not comply lost more than 4 years of life.
3. Each variable (eg, vegetarian vs non-vegetarian; high exercise vs low; high nut consumption vs low; low BMI vs high; never smoker vs past smoker; HRT ever vs HRT never) resulted in an approximate 1.5 to 2.5 years gain in life expectancy, compared with the corresponding high risk variables.

1. California Adventists have higher life expectancy at age 30 than other white Californians. (Females + 7 years; males + 4 years; expected ages at death — men = 83, women = 86). This is the highest life expectancy of any formally described population.
2. Behavioral choices extended the expected age at death by several years, even as much as a decade.
3. "Evidence of the benefits associated with these behaviors can be used to motivate change."
4. "Adventist women can anticipate fewer years of widowhood, assuming their husbands are also Adventist."
5. Substantial gains in life expectancy would be worthwhile only if they are accompanied by a longer period of good-quality life. It was previously shown that vegetarian Adventists took less medication, and had fewer hospital stays, surgical procedures and X-ray examinations. They also had reduced prevalence of several chronic diseases.
6. The vegetarian diet provides greater intakes of unsaturated fat; lower saturated fat; higher fiber, and antioxidant vitamins. Those that consume more nuts have been shown to have lower rates of coronary events. 1

1. Literature search selected 38 studies which evaluated the pharmacokinetics and pharmacodynamics of the 3 BFs.

1. Alteplase (the original tissue plasminogen activator — tPA) is given by bolus + infusion over 90 minutes.
2. Reteplase (rPA) is derived from tPA. It is produced in E coli cells.
3. Lanoteplase (nPA) is derived from tPA by deleting one amino-acid chain and mutating one amino-acid substitution.
4. Tenecteplase (TNK-tPA) is produced by altering tPA at 3 sites.
5. nPA and TNK-tPA are administered as a single bolus; rPA as a double bolus 30 minutes apart.
6. rPA is excreted by both kidney and liver; the other two by liver.
7. All three have a prolonged half-life compared with tPA. All are given with aspirin and heparin.
8. TNK-tPA is the most fibrin-specific. It reduces systemic fibrinogen and plasminogen levels to a lesser extent than the other 2.
9. rPA and nPA also degrade factor V and factor VIII. They may lead to a greater potential for bleeding.
10. TNK-tPa and rPA are comparable with tPA in terms of efficacy and safety. They are more convenient to administer.
11. nPA is effective, but the rate of intracranial hemorrhage is higher.

1. The simple bolus administration should shorten the time between onset of pain and treatment (onset-to-needle time). It should facilitate pre-hospital fibrinolysis.
2. The less complicated regimens will likely reduce medication errors and reduce mortality.
3. Intracranial bleeding is the most serious complication of fibrinolysis. It is a major disadvantage when compared with percutaneous coronary intervention. Reduced doses of heparin may lower the risk without compromising efficacy. The difference in risk of intracranial bleeding between the drugs awaits further investigation.
4. The thrombus obstructing the artery in ST-segment-elevation acute MI consists of several elements — platelets and thrombin in addition to fibrin mesh. Fibrinolytic agents target the fibrin, but are also associated with heightened thrombin activity and platelet activation. The glycoprotein platelet inhibitor, GPIIb/IIIa might be a logical addition to fibrinolytic therapy. A recent study reported equal efficacy of half dose rPA + the platelet inhibitor abciximab compared with full dose rPA. This combination may be safer.

1. The Heart Outcomes Prevention Evaluation study (HOPE)1, a cohort study, followed over 5500 individuals.
2. All were over age 55. All had: 1) a history of CVD, or 2) DM with at least 1 additional CVD risk factor. None had dipstick-positive albuminuria or established diabetic nephropathy.
3. Measured albumin/creatinine ratio (ACR) in a first morning urine specimen at baseline, at 1 year, and at study end.
4. Defined microalbuminuria as an albumin/creatinine ratio of 2mg/mmol or more, provided the dipstick was negative for proteinuria. (Microalbuminuria has also been defined as excretion of 30 to 300 mg daily, and as 20 to 200 ug/min.)
5. Follow-up = 4.5 years.

1. Microalbuminuria as defined was detected in 33% of patients with DM and 15% of those at high risk but without DM.
2. Microalbuminuria increased the adjusted relative risks (RR):

   Major CVD events	1.8
   All cause death	2.1
   Hospitalization for CHF	3.2

3. Results were similar for participants with and without DM. Those with MA were older, had higher BPs, a lower ankle/brachial systolic BP ratio, and a higher serum creatinine concentration.
4. Relative risk of the aggregate endpoint (cardiovascular events, all-cause death, and hospitalization for congestive heart failure) rose in a graded manner from the lowest quartile of MA (the lowest a/c ratio) to the highest quartile of MA (the highest a/c ratio). Quartiles of relative risk:

   First (<0.22)	Second (0.22-0.57)	Third (0.58-1.62)	Fourth (>1.62)
   1.0	1.1	1.4	2.0

1. MA was a strong independent risk factor for future CVD events, hospitalization for heart failure, and all-cause mortality in patients with diabetes and in those individuals without diabetes who have increased risk factors at baseline.
2. The risk extends well below the currently accepted screening threshold for diagnosis of MA.
3. These results support the suggestion that albuminuria reflects underlying vascular disease.
4. Patients with a higher absolute risk of CVD will experience a greater absolute risk reduction when given preventive interventions.
5. Albuminuria reveals increased renal endothelial permeability and may be an easily measured marker of diffuse endothelial dysfunction, and likely reflects underlying macrovascular and microvascular disease.
6. Cost of determining the albumin/creatinine ratio in urine is relatively inexpensive.

1. Performed literature search of studies (pooled individual patients = 1900; mean age = 52) evaluating effects of ACE on non-diabetic renal disease. Mean baseline values: BP = 148/86; creatinine = 2.3 mg/dL; urinary protein = 1.8 g/d
2. Worldwide, many cases of renal failure are not due to diabetes. This study included glomerular diseases, polycystic kidney disease, and hypertensive nephrosclerosis.
3. Determined differences in effects on renal function of antihypertension regimens containing ACE vs non-ACE regimens over a mean of 2.2 years. Non-ACE included diuretics, beta-blockers, calcium blockers, and alpha adrenergics.

1. Patients in the ACE groups had a greater decrease in mean BP (4.5/2.3 mm Hg).
2. And a lower excretion of protein by 0.5 g/d.
3. After adjustments, relative risks in the ACE group were 0.7 for end-stage renal disease, and 0.7 for the combined outcome of doubling of baseline creatinine concentrations and end stage renal disease.
4. Patients with greater urinary protein excretion at baseline benefited more.

1. "Our pooled analysis . . . reveals strong and consistent effects of ACE inhibitors in slowing progression of nondiabetic renal disease."
2. As in diabetic renal disease, ACE decreased BP, decreased urinary protein excretion, slowed the increase in serum creatinine, and reduced incidence of end-stage renal disease.
3. As in diabetic renal disease, a greater decrease in BP and urinary protein excretion was associated with lower risk of progression, but the beneficial effect of ACE was mediated by factors in addition to their effect on BP.
4. Chronic renal insufficiency is under-diagnosed and under-treated. Opportunities for prevention are lost. The presence of proteinuria in chronic renal disease is a strong indication for treatment with ACE.
5. "ACE inhibitors should be the antihypertensive agents of first choice in nondiabetic renal disease."
6. If BP and proteinuria remain elevated despite maximal ACE administration, other agents should be added.

1. Uncontrolled, prospective trial entered 172 women over 18 years of age (mean = 23). All had a history of at least 2 UTIs in the past year. All were highly motivated and adherent.
2. They self-diagnosed recurrent UTI on the basis of symptoms, and self-treated with ofloxacin (Floxin ) or levofloxacin (Levoquin) for 3 days.
3. Pretherapy urinalysis determined accuracy of self-diagnosis by culture, or sterile pyuria, or no alternative diagnosis probable.
4. Post-therapy interviews and urine cultures assessed clinical and microbiological cure rates, adverse effects, and patient satisfaction.

1. During a 12-month period, 50% self-diagnosed at least one episode of UTI .
2. In most cases culture showed a uropathogen. Some had only pyuria or bacteriuria. A few had no bacteriuria or pyuria and were diagnosed on the basis of no reasonable alternative diagnosis. Overall, the great majority (94%) of self-diagnosed episodes were UTIs reasonably requiring antimicrobial therapy.
3. Over 90% had clinical and microbiological cures from self-initiated therapy.
4. Almost all participants preferred this method of management. Few significant adverse events occurred.

1. Previous studies reported that each episode of UTI results in 6 symptomatic days as well as time lost from work.
2. In this study, over 90% of suspected UTIs met criteria for definite or probable UTI.
3. In primary care practice a urine culture would not be necessary. Young women with a history of recurrent UTIs would usually be treated empirically.

1. Randomized, controlled cross-over study enrolled 61 postmenopausal women. (Mean age = 64)
2. Each subject received continuous HRT or placebo of 6 months, and then was crossed over. HRT consisted of conjugated equine estrogens (Premarin ) 0.625 mg daily, and medroxyprogesterone (Provera) 2.5 mg daily. To minimize possible early acute adverse effects, HRT was started at a low dose and gradually increased to these levels over one month.
3. Excluded patients with established coronary disease, severe diabetes, and very high total cholesterol levels.
4. Measured lipid profiles fibrinogen, and HbA1c.

1. After 6 months (mean levels):

   	HRT	Placebo
   Total cholesterol (mg/dL)	224	243
   LDL-cholesterol "	139	158
   HDL-cholesterol "	46	42 (not significant)
   Triglyceride "	212	204 (not significant)
   Lipoprotein (a) (U/L)	149	173
   Glucose (mg/dL)	154	171
   HbA1c (%)	7.6	7.6
   Fibrinogen (mg/dL)	350	370

2. The reduction in total cholesterol was accounted for mainly by the reduction in LDL.

1. Combined HRT was associated with reduced levels of total cholesterol, LDL-cholesterol, Lp(a), and fibrinogen.
2. The reduction in LDL was comparable to effects of regimens using only estrogen. This suggests that medroxyprogesterone does not attenuate the LDL-lowering effect of estrogen.
3. Studies using estrogen alone have demonstrated a HDL-elevating effect. In this study, there was no significant increase in HDL. This may be due to an attenuating effect of the progestin.
4. Triglycerides were not increased significantly by combined HRT. This is contrary to effects of estrogen in non-diabetic women. The lack of increase may be due to an improvement in insulin sensitivity. Other studies have reported that estrogen increases insulin sensitivity.
5. No evidence in this study that risk of cardiovascular events increased during the HRT phase.

1. The prospective observational Nurses’ Health Study began in 1976 entering over 121 000 women. Information was updated every 2 years for 20 years.
2. At onset, 248 postmenopausal women reported CHD. Over the years, over 2200 women who reported coronary disease were added.
3. Determined hormone replacement therapy (HRT) relating time of onset of HRT with time of the CHD event.

1. Short-term users of hormone therapy (< 1 year) had a 25% increase in recurrent coronary events. (Relative risk 1.25 compared with never users.)
2. Long-term users had a decreased risk compared with never users:

   	Relative risk
   Never users	1.0 (referent)
   < 1 year	1.25
   1-2 years	0.55
   > 2 years	0.38
   All current users (overall)	0.65

3. Calculating the absolute risk:
   If 100 000 women age 60-75 with coronary heart disease at baseline received hormone therapy, one would expect 420 additional recurrent coronary events in the first year of use. But 1040 fewer events per year during longer term use.
4. Short term risk (1 year) of an event was largely limited to the subset of women who originally began HRT after a first coronary event. (Relative risk = 2.1 compared with never users.) Risk of a second event after the first year declined (RR = 0.5) indicating a protective effect of hormones.
5. No clear difference between users of estrogen alone vs estrogen/progestin.

1. In this cohort of postmenopausal women who had established coronary disease, there was an apparent increased risk of a second major coronary event during the first year of use of hormone therapy.
2. During the 2nd year and after, risk declined to below that of never users.

1. HRT should be started early in the premenopausal or immediate postmenopausal time period when women, because of their younger age, will have less risk of coronary events.
2. HRT might be avoided if possible even at an early age in women at high risk (eg, established coronary disease, smokers, lipid disorders, hypertension).
3. Women with troublesome menopausal symptoms who choose HRT might be started on low dose estrogen. (eg, 0.3 mg Premarin) augmented with low-dose prophylactic aspirin until the danger period of 1 year is passed.

1. Population-based cohort study followed over 950 postmenopausal women. All had survived hospital discharge after their first MI. [A secondary prevention study.]
2. Obtained information on use of HRT and recurrent coronary events.
3. Follow-up = 3.5 years.

1. 186 recurrent coronary events occurred.
2. Overall, after 3.5 years and adjustment for possible confounders, there was no difference in risk of recurrent events between current hormone users and non-users. (RH = 0.96)
3. Comparing users with non-users, there was a suggestion of an increased risk of a recurrent event during the first 60 days after starting HRT. (RH = 2.2). For most of these women, this was the first recorded HRT use. (Ie, they were not receiving HRT at the time of their MI.)
4. Risk was slightly reduced among current HRT users during days 60 to 365. (RH = 0.92)
5. And a further reduction after 1 year. (RH = 0.76)

1. "In this 3.5 year observational study of women who survived to hospital discharge after a first myocardial infarction, there was no overall difference in the adjusted risk of recurrent coronary events between current users and current non-users of hormones."
2. There was a suggestion of increased risk during the first 60 days after starting or restarting HRT.
3. Compared with non-users, there was a suggestion of a decreased risk after 1 year of use. (Ie, possible benefit.)

1. Cohort study of over 10 000 men in the Physician's Health Study1 lasted over 14 years. All were considered healthy at baseline.
2. Conducted annual follow-ups. Determined self-reported use of acetaminophen (Tylenol) aspirin, and other NSAIDs.
3. Main outcome measures: 1) elevated creatinine defined as 1.5 mg (133 umol/L) or higher, or 2) creatinine clearance of 55 mL/min (0.9 mL/s) or lower.

1. A total of 460 men (4%) developed elevated creatinine levels; 11% developed reduced creatinine clearance.
2. Mean creatinine levels and creatinine clearances were similar among men who used analgesics vs those who did not.
3. Even at a total of 2500 or more pills, there was no difference in risk of kidney damage.

   Relative risk acetaminophen	0.83
   aspirin	0.98
   other NSAIDs	1.07

4. No association between analgesic use and reduced creatinine clearance.

1. "In this large cohort study of initially healthy male physicians followed for an average of 14 years, we found no significant associations between the use of acetaminophen, aspirin, and other NSAIDs and either elevated creatinine levels of reduced creatinine clearance."
2. There was no association in men who used over 2500 pills (mean of 3 to 4 a week).
3. There was no increased risk among higher-risk groups such as those over age 60, or those with hypertension or diabetes.
4. This result contrasts with some previous case-control studies.

1. Entered 6000 community-dwelling women all over age 65. None had cognitive impairment or physical limitations at baseline.
2. Measured cognitive performance using a modified Mini-Mental State Examination.
3. Measured daily activities and recreational activities by self-reported blocks walked per week and by total kilocalories expended per week in recreation (blocks walked and stairs climbed).
4. Repeated mental examination 6 to 8 years later.

1. Women with greater physical activity at baseline were less likely to experience cognitive decline. 17% of women in the greatest activity quartile had a 3-point decline of cognition vs 24% of those in the lowest quartile.
2. After adjustment for possible confounders, the odds ratio for cognitive decline in the highest physical activity group was 0.7 compared with those in the lowest activity group.

1. Women who had greater baseline physical activity, whether measured by blocks walked or total kilocalories expended per week, were less likely to develop cognitive decline over 6 to 8 years.
2. Moderate, as well as strenuous physical activity was associated with decreased risk.
3. The association was not explained by differences in baseline function or health status.
4. Although the exact mechanism is not known, regular physical activity may reduce serum-lipid levels and hypertension, and increase cerebral blood flow, all of which could reduce risk of vascular dementia and Alzheimer's disease.

1. Cross sectional study of 30 Japanese men (mean age 27) entered 15 healthy non-smokers and 15 asymptomatic active smokers. The non-smokers had no history of exposure to tobacco smoke.
2. Measured coronary blood flow velocity reserve (CBFVR) in the left anterior descending artery. CBFVR is the ratio of hyperemic to basal coronary flow velocity when the hyperemia is induced by intravenous adenosine. (This is a measure of endothelial function. Adenosine causes dilation of the coronary arteries, increasing blood flow velocity. The study did not actually measure coronary blood flow.)
3. Measured each participant before and after a 30 minutes exposure to environmental tobacco smoke.

1. Heart rate and BP were not affected by the adenosine in either group.
2. Before passive smoke:
         At baseline, CBFVR (increase in velocity after adenosine) was significantly lower in the smokers vs the non-smokers. (Ie, smokers had less capacity to dilate when given adenosine.)
3. After passive smoking:
         Passive smoke exposure significantly reduced mean CBFVR in non-smokers but not in smokers. (In non-smokers, the 30 minute exposure to smoke reduced the capacity of the coronary artery to dilate. The CBFVR in smokers did not decrease at all after passive smoke inhalation. They were already at a state where the passive smoke had no effect in addition to the effect of recent smoking.)
4. Carbon monoxide levels rose in the non-smokers, did not rise in smokers. It was already at a high baseline level.

1. Temporary passive smoke inhalation abruptly reduced coronary blood flow reserve in non-smokers, but did not affect active smokers. (Their system is saturated.) This provides direct evidence of a harmful effect of passive smoking on the coronary circulation.
2. Impaired coronary flow reserve has been suggested as a surrogate measure of subclinical coronary atherosclerosis. It provides an integrated measure of both vascular endothelial function and smooth muscle relaxation.
3. After exposure to passive smoke, the CBFVR in non-smokers was reduced to the same level as in active smokers.
4. Carbon monoxide levels rose after passive smoke exposure in non-smokers, but was unchanged in smokers. This is likely to increase the harmful effects on non-smokers.

1. Prospective cohort of 445 symptomatic patients referred for suspected first episode of DVT.
2. Categorized patients initially as low, moderate, or high probability of having DVT.
3. Clinical factors included in the assessment of DVT (pretest): 1       Objective leg swelling
         Pain on palpation of deep vein regions
         Elevated pulse rate (> 100)
         Immobilization
         Recent surgery
         Previous DVT or pulmonary embolism
         Malignancy
4. Correlated results of bedside D-dimer test 2 (positive or negative) with clinician's assessment of pretest probability.
5. Presence or absence of DVT was established by venography and ultrasound. Follow-up = 3 months.

1. Prevalence of DVT

   D-dimer	Pretest probability
   	Low	Moderate	High
   Negative	1 of 177	7 of 120	2 of 8
   Positive	4 of 29	17 of 68	33 of 41

2. Patients who had a low pretest probability and a negative D-dimer were highly unlikely to have DVT on a 3-month follow-up. Only one of 177 such patients developed DVT during follow-up. These patients did not receive anticoagulation.

1. "This study shows that it is safe to withhold further diagnostic testing and anticoagulant therapy in patients with 1) a low pretest probability of DVT and 2) a negative D-dimer test."
2. The likelihood of false negative and false positive D-dimer tests make the test unhelpful in the other categories of pretest probability.

1. Literature search selected studies addressing the safety and pharmacology of 8 most commonly used herbal medications for which pertinent safety information was available.
2. These include: echinacea, ephedra, garlic, ginkgo, ginseng, kava, St. John's wort, and valerian.
3. Non-herbal dietary supplements were excluded (vitamins, hormones, amino acids). Also excluded nonherbal medicines such as chondroitin and glucosamine which appear to be safe.

1. Complications in the perioperative period can arise from these herbs — direct actions as well as pharmacodynamic or pharmacokinetic effects.
2. Direct effects include bleeding from garlic, ginkgo, and ginseng; cardiovascular instability from ephedra; and hypoglycemia from ginseng.
3. Pharmacokinetic herb-drug interactions include potentiation of the sedative effect of anesthetics by kava and valerian.
4. Pharmacodynamic herb-drug interactions include increased metabolism of many drugs used in the perioperative period by St. John's wort.
5. (See table 1 p 213)

1. In 1997, about 12% of the US population used herbal medicines. "Patients undergoing surgery appear to use herbal medicines significantly more frequently than the general population." Most fail to disclose their use.
2. "Empirical evidence from a long history of herbal medication use supports the notion that most are safe. Nevertheless, some have been associated with serious harm."
3. The prevention, recognition, and treatment of complications begin with explicitly eliciting and documenting history of use. Familiarity with adverse effects as documented in the scientific literature is necessary because current US regulations for commercial preparations sold in the US do not protect the population against undesirable effects. Adverse effects are underreported.
4. A history of herbal medicine use should prompt physicians to suspect the presence of undiagnosed disorders causing symptoms that lead to self-medication. This includes children whose caretakers may prescribe herbs.
5. These herbs should be discontinued before surgery. There is a potential danger of adverse effects.
6. The task of caring for patients who use herbal medicines is an evolving challenge. The limited evidence-based information about their safety and efficacy and the absence of standard regulatory mechanisms for approval and surveillance, and improper patients assumptions, represent important medical issues. Physicians should be familiar with all medications, herbal or conventional, patients are taking in order to prevent, recognize, and treat potential serious problems associated with their use.
7. The article lists several sites on the World Wide Web relating to herbal medicines and supplements.

1. Herbs are not standardized. They may contain multiple active components the effects of which are not known.
2. Potency may vary from batch to batch, and from manufacturer to manufacturer.
3. They may be misidentified or deliberately mislabeled or replaced with cheaper and more readily available alternatives.
4. May be adulterated with toxic substances or even conventional drugs.
5. Adverse effects may occur when combined with standardized drugs.
6. There is no mechanism for postmarketing surveillance.

1. Meta-analysis of randomized trials included 4000 patients. Nine trials met the authors’ inclusion criteria. Eight used low molecular weight heparin; one, unfractionated heparin.
2. Out-of-hospital antithrombosis was continued for 30 to 42 days.
3. Compared incidence of DVT in patients receiving heparin vs placebo or no antithrombotic therapy.

1. Incidence of DVT during out-patient follow-up of 30-42 days:

   	Heparin	Placebo	Absolute difference	NNT
   Symptomatic DVT	1.3%	3.3%	2%	50
   Asymptomatic DVT	10%	20%	10%	10

   (By venography, ultrasound, or impedance plethysmography. )
2. No increase in major bleeding; 3.7% vs 2.5% incidence of minor bleeding. [Number needed to treat to harm 1 patient = 83.]

1. Extending duration of prophylaxis with heparin after hip or knee replacement for 4 to 6 weeks after hospitalization significantly reduced risk of DVT over a subsequent month.
2. There was an increase in the risk of minor, not major bleeding.
3. The risk of DVT in patients undergoing knee replacement was greater than those undergoing hip replacement possibly because of more extensive disruption of soft tissue and bone, and greater release of prothrombotic tissue factors.
4. Most DVT remains symptomless.
5. The authors estimate that routine use of extended-duration prophylaxis would prevent about 20 episodes of symptomatic DVT for every 1000 elective surgeries and one fatal case of pulmonary embolism for every 1000.
6. Low-molecular-weight heparin costs about $25 per day.
7. There is emerging data that aspirin might be effective for prevention of DVT after hip fracture.

1. Followed patients with a first episode of idiopathic DVT (n = 267 ). All had been treated with a 3 month course of oral anticoagulation.
2. Randomly assigned to: 1) discontinuation of anticoagulation, or 2) continuation for an additional 9 months.
3. Follow-up for an additional 2 years to determine recurrence of symptomatic DVT.

1. Recurrence of DVT over an average follow-up of 38 months:

   After additional 9 months of therapy	Therapy discontinued after 3 months
   16%	16%

2. Of the 134 patients who continued anticoagulation, only 1 patient had a recurrence of DVT while receiving oral anticoagulants during months 4 to 12. Of the 133 who discontinued after 3 months, 11 had a recurrence during months 4 to 12. (Ie, continuing anticoagulation did prevent DVT during the treatment period.)
3. Three % of patients experienced major bleeding during the extended period of anticoagulation.

1. In patients with idiopathic DVT, continuing anticoagulation for 1 year after an episode of DVT decreased incidence of DVT during that time. However, after discontinuing anticoagulation, the recurrence rate of DVT was similar to that of patients who discontinued after 3 months. Prolonged anticoagulation in patients with idiopathic DVT simply delayed recurrence until after anticoagulation therapy was stopped.
2. Most recurrences occurred within the first year after discontinuation.
3. These results apply only to patients with idiopathic (apparently spontaneous) DVT.
4. All recurrences were also idiopathic. More than half involved the initially unaffected leg. This suggests a persistent underlying hypercoagulable state.
5. The recurrent events likely could be prevented by continuing anticoagulation indefinitely. This would bring a continuing risk of bleeding and costs of therapy.

1. Randomized, double-blind, placebo-controlled trial conducted in a hyperendemic area of New York entered 482 subjects. All had removed an attached Ixodes tick from their bodies within the previous 72 hours. The species and stage of the ticks were determined by a medical entomologist.
2. Randomized to 1) a single 200 mg dose of doxycycline, or 2) placebo.
3. Primary endpoint = development of erythema marginatum at the site of the tick bite.
   Secondary endpoints = development of erythema migrans at a site different from the area of the bite, and serological evidence of infection.

1. Characteristics

   Nymphal ticks

   Partially engorged — 16%
   Mean estimated duration of attachment — 30 hours

   Adult ticks

   Partially engorged — 6%
   Estimated duration of attachment — 14 hours.

2. Erythema migrans developed in 1% of those receiving doxycycline vs 3.2% of those receiving placebo.
3. Erythema migrans developed more frequently after untreated bites from nymphal ticks than from adult bites (6% vs 0%).
   Only ticks partially engorged with blood were associated with development of erythema migrans. This may have been related to the shorter period of attachment of the better recognized adults.
4. Objective extracutaneous manifestations of Lyme disease did not occur in any subject. There were no seroconversions.

1. Prophylaxis with a single dose of doxycycline given within 72 hours of a recognized bite from Ixodes was highly effective in preventing development of Lyme disease.
2. Erythema migrans at the site of the bite is the most common clinical manifestation.
3. Subsequent tick bites are common, reported by 18% of the subjects questioned.
4. Nausea and vomiting were common in the doxycycline group. Taking the drug with food may improve tolerability.

An editorial in this issue of NEJM (pp 133-34) by Eugene Shapiro, Yale University School of Medicine comments:

The study confirms that the risk of Lyme disease is low (in this study 3%) after a deer tick bite even in a region where incidence is among the highest in the world.
Ticks must be at least partially engorged with blood (ie, must feed for hours) before B burgdorferi is transmitted. Incidence of erythema migrans was about 10% if the tick was partially engorged. If the tick had fed for over 3 days, the risk of Lyme disease rose to about 25%.
Prophylaxis might be stratified according to risk. If the risk of Lyme disease is about 3%, it would be necessary to give doxycycline to about 40 patients to prevent one case. (If the absolute benefit is 3.2% - 1% = 2.2%) And this would apply only to areas of high endemicity. Most tick bites in the US are due to the Lone star tick Amblyomma americanum and others that do not transmit Lyme disease.

      However, in normal practice, it is difficult to know the species, stage, and degree of engorgement of the tick. "Ticks" identified by physicians may in fact be beetles, bugs, lice, spiders, or even just debris.
      Anxiety about Lyme disease may be the most potent factor for demands for chemoprophylaxis. Publicity in the media and on the Internet has increased fears of Lyme disease out of proportion to its actual morbidity. This is compounded by the high frequency of misdiagnosis of Lyme disease in persons with chronic symptoms from other causes.

Who should receive prophylactic doxycycline?

Persons bitten by ticks in endemic areas.
The tick is at least partially engorged.
The tick is a nymphal deer tick.

In far more common circumstances, the risk of Lyme disease is so low that prophylaxis is not indicated.
"There is substantial evidence that in the vast majority of patients with Lyme disease conventional treatment with antimicrobials is very effective, and the long-term outcomes are excellent." Patients should be so advised.
The potential risks and benefits should be discussed with the patient, who should be involved in making the decision about prophylaxis. In any case, patients should be instructed to seek treatment if an expanding erythematous rash develops.