9-1 EFFECT OF INTENSITY OF ORAL ANTICOAGULATION ON STROKE SEVERITY AND MORTALITY IN ATRIAL FIBRILLATION
      Emboli of atrial origin are larger than average. The brain infarcts they produce are more disabling and lethal.
      Among patients with non-valvular AF, the degree of anticoagulation at admission for stroke was associated with risk of disability and death. Anticoagulation that resulted in an INR of 2.0 or greater reduced frequency and severity of ischemic stroke and risk of death. This is evidence against INR targets below 2.0
      Risk of hemorrhagic stroke did not increase until INR was 4.0 or above.
      INR below 2.0 and aspirin protect against stroke less effectively than INR 2.0 to 3.0, but are superior to use of no anticoagulant. Aspirin is adequate prophylaxis in patients considered at low risk for thromboembolic stroke. Eventually almost all patients with AF will become high risk due to age and co-morbidity. As age progresses, risk of bleeding from warfarin increases. This dilemma must be solved on an individual basis. Patients accepting warfarin must be carefully controlled at a stable INR around 2.5.
      “Our results provide further support for anticoagulation to achieve an INR of 2.0 or greater (eg, 2.5) in patients with non-valvular atrial fibrillation.”

9-2 ORAL XIMELAGATRAN FOR SECONDARY PROPHYLAXIS AFTER MYOCARDIAL INFARCTION
      In patients with a recent MI, long term treatment with ximelagatran, combined with aspirin, was more effective than aspirin alone in reducing frequency of major cardiovascular events. [NNT (for 6 months to benefit one) = 33]
      Ximelagatran is the first of a new class of oral direct-thrombin inhibitors under investigation. It is rapidly metabolized to its active form, melagatran. It is stable over time. Its metabolism is unaffected by age, sex, body weight, or ethnic origin. It is not affected by the hepatic cytochrome P450 enzyme system, thus providing a low potential for drug-drug interactions. There are no relevant food or alcohol interactions. “Melagatran’s pharmacokinetics are unchanged and the pharmacodynamic properties show only minor additive effects when oral ximelagatran and acetylsalicylic acid are given concomitantly.”
      Ximelagatran has undergone extensive assessment in patients with venous thromboembolism and atrial fibrillation. It has a rapid onset of action, achieves a peak level within 2 hours, and has a half-life of 4 hours. It is administered twice daily. There is no need of monitoring and dose adjustments. (Monitoring of liver and kidney function is required. RTJ) Ximelagatran is primarily excreted by the kidney. Data on patients with kidney dysfunction are limited.
      With the 24 mg BID dose, the bleeding rate was low, and high concentrations of alanine amino transferase occurred less frequently (7%).
      “It is good news that the more than half century wait of new and improved oral antithrombotics finally appears to be ending.”

9-3 EFFICACY OF PERINDOPRIL IN REDUCTION OF CARDIOVASCULAR EVENTS AMONG PATIENTS WITH STABLE CORONARY ARTERY DISEASE
      Among patients with stable CAD without apparent heart failure, the angiotensin converting enzyme inhibitor, perindopril (Aceon) improved outcomes. This was in addition to use of other preventive drugs. [NNT(4 years to benefit one) = 50]
      ACE inhibitors have been shown to have the broadest impact of any drugs in cardiovascular medicine, reducing the risk of death, myocardial infarction, stroke, diabetes, and renal impairment. They benefit patients with heart failure, post myocardial infarction left ventricular dysfunction, peripheral vascular disease, diabetes, stroke, and transient ischemic attacks.
      As long-term therapy, perindopril is expensive. It has not been compared with less expensive ACE inhibitors (eg, enalapril) which may be just as effective.
      ACE inhibition is underused in primary care practice.

9-4 LIFETIME RISK OF CORONARY HEART DISEASE BY CHOLESTEROL LEVELS AT SELECTED AGES.
      For persons of all ages, lifetime risk of CHD increases as total cholesterol levels rise from under 200 to over 240.
      This supports the important role of cholesterol screening at all ages.
      This article is of considerable clinical importance even though it provided no outcomes from lifestyle or drug interventions. Patients, old and young, now have a reasonable prediction of lifetime risk according to total cholesterol levels. (And cholesterol subfractions.) Old, and young should be screened periodically. The data may convince some younger persons to intervene to reduce their lifetime risk
      Guidelines suggest lipid screening begin at age 20.

9-5 SOCIAL ANXIETY DISORDER
      The hallmark of social anxiety disorder (SAD) is extreme and persistent fear of embarrassment and humiliation. People with SAD (also known as social phobia) avoid participating in social and public activities such as public speaking, social gatherings, and meetings. The intense symptoms of SAD interfere with functioning and cause marked distress.
      It is the third most prevalent psychiatric disorder in the USA. Paroxitine and sertraline are effective drug therapy.
      SAD can be differentiated from panic disorder by its consistent relation to social issues.
      Less severe, and more common symptoms can benefit from beta-blockers.

9-6 EFFECTS OF CANDESARTAN ON MORTALITY AND MORBIDITY IN PATIENTS WITH CHRONIC HEART FAILURE
      ACE inhibitors have been shown to have the broadest impact of any drug in cardiovascular medicine, reducing the risk of death, myocardial infarction, stroke, diabetes, and renal impairment. They benefit patients with heart failure, left ventricular dysfunction, peripheral vascular disease, diabetes, stroke, and transient ischemic attacks.
      Candesartan, blocks angiotensin II at the cellular level. Given to patients with heart failure in addition to other drugs (including ACE inhibitors) it was associated with reduced cardiovascular deaths and hospital admissions for heart failure.
      Reducing angiotensin II levels is a basic therapy in cardiovascular disease. ACE inhibitors have been the standard. Addition of an angiotensin II blocker may benefit slightly. They should be used when the patients cannot tolerate ACE inhibitor.

9-7 POLYPHARMACY AND COMORBIDITY IN HEART FAILURE
      Primary care clinicians are responsible for reviewing medication lists with a goal of eliminating medications that are not known to provide clear benefits. Little evidence is available to guide polypharmacy in patients with heart failure and other common conditions
      Too many patients, especially the elderly, are taking too many drugs.
      Primary care clinicians should insist that their patients bring to the office for review all medications they use, including those prescribed by other physicians, standard drugs bought over the counter, and herbal nostrums used as “alternative” medicines. This seems difficult for patients to do, but is most important.

9-8 ABILITY OF EXERCISE TESTING TO PREDICT CARDIOVASCULAR AND ALL-CAUSE DEATH IN ASYMPTOMATIC WOMEN: A 20-YEAR FOLLOW-UP OF THE LIPID RESEARCH CLINICS PREVALENCE STUDY
      Exercise capacity and heart rate responses were strong, graded, and independent predictors of cardiovascular and all-cause mortality. Not achieving target heart rate and slow return of the rapid heart rate induced by exercise toward normal predicted future mortality in younger women.
      ST segment depression, while predictive in men, had no value in women.
      The benefit of exercise testing in asymptomatic women is in determining their cardiovascular fitness.
      Women need more fitness exercise independent of their weight, blood pressure, or lipid levels.

9-9 ALCOHOL USE DISORDERS IN ELDERLY PEOPLE: Redefining An Age Old Problem In Old Age
      Be vigilant for the role of alcohol when older people present with physical and psychiatric illness, cognitive impairment, and social problems. Use disorders may be more common in the elderly than you think .
      Primary care clinicians should include sensitive questions about alcohol use in their systemic review of the patient history.

9-10 SELF ESTEEM AND HEALTH
      There are two basic human needs—health and autonomy. Autonomy is closely linked with self esteem and the earning of respect. “Low levels of autonomy and low self esteem are likely to be related to worse health.” Increasing pride in one’s identity may have a more favorable effect on health behaviors and risks than focusing on how to change the risks themselves. There is a link between low self esteem and ill health. “All people have a basic need for autonomy and self esteem.”
      Primary care clinicians can enhance the self-esteem of patients with low esteem by listening carefully to their problems and showing respect and concern.

9-11 RISK OF ADENOCARCINOMA IN BARRETT’S ESOPHAGUS
      “Patients with Barrett’s oesophagus are at low risk of oesophageal adenocarcinoma. This risk is almost exclusively in patients with specialized intestinal metaplasia.”
      “Up to 8 years after diagnosis we found no increased risk of malignancy with time.”
      Surveillance of patients with BE at a risk of malignant transformation of 1% per year may be cost effective, but only in men over age 70. This questions the value of universal endoscopic screening for cancer in patients with BE.
      Primary care clinicians in the USA refer patients with BE to gastroenterologists. They will usually advise periodic endoscopic screening .

9-12 ASSESSING THE SUCCESS OF SUCCESSFUL AGING
      Clinicians must learn what their patients expect and value, and develop treatment plans that balance longevity with other facets of life. We should determine what social roles patients most value, what features of functioning are most important, and which strategies of treatment and prevention will optimize the chances of success as the patient defines it.
      Successful aging is possible despite disease and disability. If our concept of successful aging includes dignity, autonomy, social engagement, and the absence of suffering, we will be better positioned to configure our system of care to address the needs of the elderly. Pursuing the myth of the Fountain of Youth is not the answer.
      Success in aging is “what I say it is” and what I make it. I will not depend on my clinician or on the public health service to define it.

9-13 PATIENTS PUT THEIR RELATIONSHIP WITH THEIR DOCTORS AS SECOND ONLY TO THAT OF THEIR FAMILIES
      A new international study given at the World Medical Association annual assembly reported that, although the doctor-patient relationship has become less paternalistic, it still holds a central and trusted place in society. The authors warn that, to keep this status, doctors will need to measure up to patients’ higher expectations of care.
      “The patient-physician relationship is part of the critical underpinnings of stable societies.”
      It is still a privilege to be a physician.

9-14 EFFECT OF ST JOHN’S WORT ON DRUG METABOLISM BY INDUCTION OF CYTOCHROME P450 3A4 ENZYME
      Long-term dosing of St John’s wort results in induction of the liver enzyme cytochrome P450 3A4. This hastens metabolism of many drugs and diminishes their plasma levels and clinical effectiveness. This leads to increased dosage requirements of the 50% of drugs metabolized by this liver enzyme.
      St. John’s wort can significantly alter the effectiveness and dosing of a wide range of medications.
      Patients’ use of herbal nostrums continues undiminished. “Natural” is considered harmless even by the most sophisticated patients. This is another good reason for primary care clinicians to insist that patients “brown bag” all medications they take at each office visit.

9-15 EFFECT OF MAGNETIC VS SHAM-MAGNETIC INSOLES ON PLANTAR HEEL PAIN: A RANDOMIZED CONTROLLED TRIAL
      Magnetic insoles did not benefit any more than sham insoles. Many patients who use them will not be convinced despite this well-controlled study.

9-16 METHYLXANTHINES FOR EXACERBATIONS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE
      When given in conjunction with other standard treatments, methylxanthines did not confer statistically significant benefits for lung function, clinical outcomes, and symptoms in patients with exacerbations of COPD. They significantly increase nausea and vomiting.

9-17 PARATHYROID HORMONE PLUS ALENDRONATE—A Combination That Does Not Add Up
      It would be plausible to assume that the effect of a bisphosphonate + parathyroid hormone would be additive, since their mechanisms of action differ. Unfortunately, this is not the case. Disappointing !
      Apparently, alendronate impairs the anabolic activity of parathyroid hormone.

1. Followed over 13 500 patients (mean age 78) with non-valvular AF discovered on routine physician-visits.
2. Determined incidence of stroke on follow-up.
3. In those experiencing stroke, determined INR at admission, use of warfarin, aspirin, and no antithrombotic related to severity of stroke according to a stroke-scale, and 30-day mortality from stroke.
4. Follow-up = 30 days

1. 596 ischemic strokes occurred during follow-up . At the time of the stroke:

   188 (32%) occurred during warfarin therapy
   160 (27%) occurred during aspirin therapy;
   248 (42%) occurred in those who were receiving neither.

   (Note that there were fewer strokes in patients on aspirin. The investigators did not assign individuals in the cohort to high, moderate, or low risk of stroke. Note that 4 of 10 were not receiving any prophylactic therapy RTJ.)
2. Median INR of those taking warfarin was 1.7; 62% had levels less than 2.0
3. Intensity of anticoagulation associated with incidence of death or severe stroke (%):

   INR 2.0 or greater	5
   INR less than 2.0	15
   Aspirin	13
   On no antithrombotic	22

4. Proportion of those with severe or fatal stroke did not differ significantly between those with an admission INR 1.5 to 1.9 and those with an INR less than 1.5
5. Intensity of anticoagulation and 30-day mortality (%):

   INR 2.0 and greater	6
   INR less than 2.0	16
   INR 1.5 to 1.9	18
   INR less than 1.5	15
   Aspirin	15
   None	24

   (Low dose warfarin and aspirin conferred some protection.)
6. Incidence of ischemic stroke and intracranial hemorrhage.

   	Stroke ( per 100 person –years)	Intracranial hemorrhage (per 100 person-years)
   INR < 1.5	8	0.5
   1.5-1.9	1.9	0.3
   2.0-2.5	0.4	0.3
   2.6 to 3.0	0.9	0.5
   3.1 to 3.5	0.7	0.6
   3.6 to 3.9	0.4	0.4
   4.0-4.5	1.4	2.7
   > 4.5	2.6	9.4

   (Note the large jump in risk of hemorrhagic stroke at 4.0 and above. RTJ)

1. Incidence of ischemic stroke among patients with AF is greatly reduced when INR reaches 2.0 or above.
2. Strokes that occur among patients with adequate anticoagulation (2.0 to 3.0) are far less likely to result in severe disability or death. For those with an INR less than 2.0 who had an ischemic stroke, risk of death within 30 days was more than 3 times the risk among those with INR of 2.0 or greater.
3. Outcomes were equally poor among warfarin users with an INR of 1.5 to 1.9 at admission as those with an INR of less than 1.5. Outcomes were even worse for those who received no antithrombotic therapy.
4. Outcomes for those taking aspirin when they had a stroke were similar to that of patients with INR less than 2.0, but better than those taking no anticoagulation.
5. The American Heart Association suggests the use of lower INR target for certain patients with AF who are older than age 75. The data in this study indicate that this will likely increase disability and death.
6. In the study, there was little additional risk of intracranial hemorrhage until INR exceeded 3.9. These findings weigh against use of target INR less than 2.0.

1. Placebo-controlled, double blind dose-guided phase II trial assessed over 1800 patients who had a recent ST-elevation MI, or non-ST elevation MI.
2. Randomized within 14 days (mean = 7) of the MI to: 1) oral ximelagatran, twice daily, at doses of 24 mg, 36 mg, 48 mg, or 60 mg + aspirin 160 mg once daily; or 2) aspirin alone--160 mg once daily for 6 months.
3. Ximelagatran was begun within 6-12 hours after the end of heparin as a protection against rebound events, and as added secondary prevention.
4. Primary efficacy outcome = all-cause death, non-fatal MI, and severe recurrent ischemia.
5. Follow-up = 6 months

1. Oral ximelagatran combined with aspirin significantly reduced risk of the primary endpoint from 16% to13%. [NNT (for 6 months to benefit one) = 33]
2. There was no indication of a dose response. (Ie, 24 mg just as effective as 60 mg.)
3. Major bleeding events overall: 1.8% vs 0.9% for aspirin alone. [NNT (to harm one patient over 6 months) = 100]
4. No other adverse outcomes related to the ximelagatran.

1. After an acute MI, oral ximelagatran combined with aspirin was more effective than aspirin alone in preventing a composite endpoint of death, non-fatal MI, and severe recurrent ischemia. Absolute difference was 3.6 % (NNT = 28) There was no dose response relation for efficacy—24 mg as effective as 60 mg.)
2. “The findings would support a hypothesis of a benefit . . . in prevention of other thromboembolic events such as stroke.”
3. The benefits of ximelagatran seem to be of the same magnitude as clopidogrel in non-ST-elevation MI, or with warfarin after initial heparin treatment in all patients with MI. .
4. Elevated alanine transferase levels were dose related—much less pronounced rises occurred with the 24 mg dose.
5. In this trial there was no indication of difference in efficacy between the four doses of ximelagatran given in addition to aspirin. “These findings suggest that ximelagatran is effective at a wide range of doses with a low risk of bleeding.”
6. Total bleeding rates (major and minor) were 1% higher with ximelagatran plus aspirin than with aspirin alone.
7. In the 24 mg dose group there was no difference in the rate of discontinuation from that seen with placebo.
8. Ximelagatran has been reported to be efficacious for prevention of venous thromboembolism and to be as effective as warfarin for stroke prevention in patients with atrial fibrillation.

1. Followed over 12 000 patients (mean age 60; almost all males) with established CAD. (History of myocardial infarction, angiographic evidence of CAD, coronary revascularization, or a positive stress test.) None had evidence of heart failure
2. Mean systolic BP = 137 mm Hg; 27% had hypertension
3. Randomized to: 1) perindopril 8 mg once daily, or 2) placebo.
4. Many were taking platelet inhibitors, beta-blockers, and lipid-lowering therapy.
5. Primary outcome = cardiovascular death, myocardial infarction, or cardiac arrest.
6. Follow-up—up to 5 years.

1.  

   Outcome—5-years	Perindopril	Placebo	NNT
   Primary endpoint	8%	10%	50

2. Secondary endpoints also benefited by perindopril treatment: 1% to 2% reductions occurred in heart failure requiring hospitalization, unstable angina, and MI (fatal and non-fatal).
3. “Perindopril was well tolerated.” But 2.7% withdrew from perindopril (mainly for cough) vs 0.5% with placebo.

1. Perindopril was chosen because it is long-acting, has documented BP-lowering properties, and anti-ischemic and anti-atherogenic properties, as well as an effect of cardiovascular remodeling.
2. “We show a substantial benefit with perindopril in a broad population of patients with stable coronary artery disease and with no evidence of heart failure or notable hypertension. Cardiovascular death, myocardial infarction, cardiac arrest, acute coronary syndromes, and development of heart failure were all reduced.”
3. Almost a third of patients in this study were younger than age 55.
4. Benefits of perindopril were evident when added to other secondary prevention drugs--platelet inhibitors, beta-blockers, and lipid-lowering agents.
5. Treatment effect was similar among patients with treated hypertension and those without hypertension.
6. The reduction in cardiovascular events was greater than may be expected for the 5/2 mm mean reduction in BP achieved by perindopril
7. Benefits began after one year of treatment. The gradual onset of effect and the progressive benefit over time is consistent with the anti-atherosclerotic and anti-hypertensive properties of ACE inhibition.
8. An estimated 50 patients need to be treated with perindopril for a period of 4 years to prevent one major cardiovascular event.

1. Included all Framingham participants examined from 1971 through 1996 who did not have CHD and were not receiving lipid-lowering therapy.
2. Participants were stratified by total cholesterol levels at index ages of 40, 50, 60, 70, and 80 years.
3. Calculated lifetime risk of CHD with death free of CHD as a competing event over the next 25 years.

1. During follow-up, among over 3200 men and over 4000 women, 1120 died of CHD and 1365 died free of CHD.
2. At each index age, lifetime risk of CHD (fatal and non-fatal) increased with higher cholesterol levels, and the time to event decreased. Lifetime risk of CHD (%):

   Index age	Total cholesterol (men)			Total cholesterol (women)
   	< 200	200-239	>239	< 200	200-239	> 239
   40*	31	43	57	15	26	33
   50**	40	42	63	19	30	39
   60#	34	41	51	20	24	36
   70#	27	36	42	14	20	29
   80#	17	23	34	17	17	21

   (* lifetime risk through age 80 ** lifetime risk through age 90 # lifetime risk through age 94)
3. These long-term risks can be compared with short-term risks. For young participants, short-term risk of CHD is exceedingly low, even with elevated cholesterol levels, whereas life-time risks are high, especially for those with elevated cholesterol. At age 40, the 10-year risk of CHD for men: Cholesterol < 200 3% Cholesterol 200 to 239 5% Cholesterol > 239 12%

1. In men and women across the age spectrum who were free of CHD at baseline, total cholesterol levels were extremely effective at stratifying the remaining life-time risk of CHD.
2. There was a 1.5- to 2-fold higher absolute remaining lifetime risk of CHD for men and women with elevated, compared with desirable cholesterol levels. (Eg, at age 40, the lifetime risk of CHD through age 80 was 31% for men with desirable levels, and 57% for men with elevated levels.
3. Even at age 80, elevated total cholesterol levels conferred substantially higher remaining lifetime risk.
4. The remaining lifetime risk diminishes with advancing age, likely reflecting both depletion of susceptible individuals and increasing risk of death from other causes.
5. It is clear that cholesterol levels do not account for all the lifetime risk of CHD. Other risk factors contribute—smoking, hypertension, and diabetes.
6. The present study has the advantage of accounting for non-fatal coronary events, which are associated with substantial morbidity.
7. The current national guidelines recommend that all adults 20 years and older have a complete lipoprotein profile at least once every 5 years. (Determination of LDL-c and HDL-c and their ratios may sharpen the predictive value.)
8. “Our data highlight the utility of total cholesterol measurement in young adults (both men and women) for stratifying remaining lifetime risk of CHD and for identifying remaining lifetime risk.”
9. In younger individuals with elevated cholesterol and low short-term risk, informing them of their high lifetime risk might be more useful in motivating lifestyle modifications.
10. Hypercholesterolemic participants have a markedly shorter time-to-event to reach a threshold of 20% for the cumulative lifetime risk of CHD.
11. In older individuals (70s and 80s) with higher cholesterol levels the increased risk of CHD indicates the near-term importance of interventions to control lipids.

1. Randomized, double-blind, controlled trial of over 7600 patients with HF (45% with NYHA class II, 52% with class III, 3% class IV; mean age = 66), compared candesartan with placebo.
2. It involved 3 distinct populations of patients with HF:

   Patients with left ventricular ejection fraction (LVEF) less than 40% who were not taking ACE inhibitors.
   Patients with LVEF less than 40% who were taking ACE inhibitors.
   Patients with LVEF higher than 40%.

3. Randomized to: 1) candesartan titrated up to 32 mg once daily, or 2) placebo. Other drugs were continued.
4. Primary outcome = all-cause mortality, cardiovascular death and hospital admissions for HF.
5. Median follow-up = 38 months.

1.  

   Outcomes (3 groups combined)	Candesartan	Placebo	NNT 3 years to benefit one patient
   All-cause deaths	23%	25%	50
   Cardiovascular deaths	18%	20%	50
   Hospital admissions for HF	20%	24%	25

2. More patients discontinued candesartan (21%) than placebo (17%) because of concerns about renal function, hypotension, and hyperkalemia. [NNT(harm to one patient over 3 years) = 25
3. Benefits were strongly affected by left ventricular systolic function. In the group with LVEF over 40%, candesartan did not improve survival. (Ie, no definitive benefit in patients with “normal” ejection fraction--those with “diastolic” HF)
4. In the two groups with low LVEF there was a clear prolongation of survival and a 16% lower rate of cardiovascular death. This was complemented by a significant reduction in hospital admission for HF.
5. Beneficial effects were similar irrespective of other drug use at baseline—ACE, beta-blockers, spirinolactone, diuretic, digitalis, aspirin, and/or statins.
6. There was a reduction in the number of candesartan patients developing diabetes over the trial duration (6% vs 7.4% in the placebo group).

1. Treatment of a broad spectrum of patients with symptomatic HF with candesartan was associated with a reduction in deaths (albeit of borderline statistical significance), notably because of a significant reduction in cardiovascular deaths.
2. Blockade of angiotensin II at the cell-receptor level, given in addition to the partial inhibition of angiotensin II production by ACE inhibitors, can result in more complete inhibition of the adverse cardiovascular effects of angiotensin II. It may leave unopposed potentially desirable effects of angiotensin II on other receptors. AIIRBs effectively reduce important clinical events in hypertensive patients with diabetes and neuropathy, hypertensive patients with EKG evidence of left ventricular hypertrophy, elderly patients with hypertension, and those with HF and depressed ejection fraction.
3. The reduction in cardiovascular death with candesartan was similar in 2 groups: 1) those taking ACE inhibitors and those not taking ACE inhibitors. Benefits from candesartan were also present irrespective of beta-blocker use. The added efficacy on top of beta blockers is particularly noteworthy.
4. Patients who are intolerant to ACE inhibitors should not be denied the benefits of angiotensin-receptor blockade.
5. Patients who have symptomatic heart failure will derive important clinical benefits from candesartan.”

1. Entered over 2900 asymptomatic women age 30-80 (Mean = 42). None had known cardiovascular disease. Exercised all using Bruce protocol. Test terminated at 90% predicted maximum heart rate; or if hypotension, EKG changes of ischemia, or significant arrhythmia occurred.
2. At baseline, determined exercise test variables related to ischemia, fitness, and autonomic function:

   A. ST segment depression defined as >1.0 mm depression at 0.08 seconds after J point.
   B. Arrhythmia defined as multifocal pvcs, >10% pvcs, or ventricular tachycardia.
   C. Heart rate recovery (HRR) determined by subtracting pulse rate after 2 minutes rest from maximal heart rate during exercise.
   D. Exercise capacity—not able to achieve target rate.

3. Patients were followed annually for 20 years.
4. Main outcome = cardiovascular and all-cause deaths.

1. Fourteen percent of the cohort died during follow-up of an average 20 years; 34% of all deaths were cardiovascular.
2. Low exercise capacity, not achieving target heart rate on exercise, and low heart rate recovery were all independently associated with increased cardiovascular and all-cause mortality. Women who exceeded average exercise capacity (7.5 METS) and had a HRR of 55/minute or more had fewer cardiovascular deaths and all-cause deaths.
3. There was a graded increase in mortality for decreasing quintiles of exercise capacity and HRR.
4. There was no increased cardiovascular death risk associated with exercise-induced ST segment depression.
5. Multivariable-adjusted risk of deaths according to exercise test variables:

   Variable	CV deaths (Hazard ratio)
   Exercise capacity < median (7.5 METS)	1.9
   Heart rate recovery < median (55 beats per minute)	2.2
   Target heart rate not achieved	1.5
   Ventricular arrhythmia	1.7
   ST depression > 1.0 mm	0.88

6. Women below the median for both exercise capacity and HRR had a 3.5-fold increased risk of cardiovascular death compared with those above the median for both.

1. Exercise capacity and heart rate responses were strong, graded, and independent predictors of cardiovascular and all-cause mortality.
2. ST segment depression, while predictive in men, had no value in women.
3. Women need more fitness exercise independent of weight, blood pressure, or lipid levels.

1. Examined the pathology reports related to all esophageal biopsies in Northern Ireland between 1993 and 1999.
2. Included every adult identified as having columnar epithelium, excluding those taken from the esophageal-gastric junction.
3. Identified BE as the presence of columnar metaplasia in the esophagus irrespective of whether Barrett’s mucosa was reported. Further subdivided biopsies if the pathologist specifically stated that specialized intestinal metaplasia, or goblet cells, were definitely present or absent.
4. Identified patients in the cohort and followed them up for death and esophageal malignancy.

1. Between 1993 and 1999, over 15 000 esophageal biopsies from almost 3000 patients met criteria for BE. Mean follow-up = 3.7 years.
2. 29 esophageal malignancies were discovered in over 11 000 person years of follow up. Esophageal malignancy rate was 0.26% a year overall and 0.4% a year for patients with specialized intestinal metaplasia. Only in men over age 70 with specialized intestinal metaplasia was the incidence greater than 1% per year.

1. “Patients with Barrett’s oesophagus are at low risk of oesophageal adenocarcinoma. This risk is almost exclusively in patients with specialized intestinal metaplasia.”
2. Surveillance of patients with BE at a risk of malignant transformation of 1% per year may be cost effective, but only in men over age 70.
3. “Up to 8 years after diagnosis we found no increased risk of malignancy with time.”

1) The psychosocial school primarily defines successful aging as a mental state (for example, acceptance of death, life satisfaction).
2) The biomedical school defines it as the avoidance of disease and disability.

1) Successful aging means something beyond health and longevity. It is rooted in a broader definition of “the good life” in late-life. It refers to the capacity to function across many domains, including the cognitive, social, and emotional.
2) Successful aging is in large part what older adults value in the quality of their life and death.
3) Successful aging implies aging that is better than “usual aging”, which many envision as lock-step declines in capacity and health. Herein lies both the promise and the danger of the concept. The promise comes from envisioning exceptional functioning as possible; the danger is concluding that sickness and dependency constitute a “failure” in aging.

1) Many interventions aimed at maximizing successful aging have not worked.
2) Interventions that work have not been implemented.
3) Existing health care systems in the USA are not well designed for the purpose of successful aging.

1. Open-label study involved 12 healthy volunteers, age 22 to 38.
2. At baseline, assessed cytochrome P450 (CYP) activity by two probe drugs: 1) 30 mg dextromethorphan [Robitussin] and 2) 2 mg alprazolam [Xanax; Generic]. Alprazolam is predominantly metabolized by CYP 3A4; dextromethorphan by CYP 2D6.
3. Subjects were then given 14 days of St John’s wort (trade name, Kira) 300 mg three times daily.
4. At 14 days, participants were again given the two probe drugs to establish effect of St John’s wort on their metabolism. The St John’s wort was continued for another 2 days.

1. Metabolism of alprazolam after the second administration was greatly increased from baseline. Plasma clearance was increased two-fold. Half life was shortened from 12 hours to 6 hours. The increased degradation of the drug was attributed to induction of CYP 3A4. At 48 hours, no participant had measurable concentrations of alprazolam after St. John’s administration, compared with 11 of 12 participants at baseline.
2. St. John’s wort did not affect CYP 2D6 activity according to dextromethorphan metabolism.

1. Approximately 50% of all currently used medications are metabolized by cytochrome P450 3A4.
2. Long-term administration of St John’s wort may diminish clinical efficacy and increase dosage requirements for a large and diverse group of medications. In this study, St John’s wort substantially hastened metabolism of alprazolam by inducing activity of CYP 3A4
3. Single or short-term doses (less than 3 days) of St. John’s wort have little effect of CYP 3A4.
4. Repeated dosing of St John’s wort variably altered activity of CYP 2D6. In some patients plasma levels of dextromethorphan were increased , in some were decreased. The authors conclude that effects of St John’s wort on CYP 2D6 are not likely to be of clinical significance.

1. Randomized, double-blind, placebo-controlled trial of 101 volunteer patients with plantar fasciitis of at least 30 days duration.
2. Randomized to daily use of 1) static magnets vs 2) sham magnets placed on insoles
3. Daily pain diaries were kept for at least 8 weeks.
4. Trial magnets were similar to those available on the market.

1. Comparison at 4 and 8 weeks showed no difference in a variety of pain assessment scores.
2. 44% of the nonmagnetic group versus 31% of the magnetic group were all or mostly better at 4 weeks. At 8 weeks, the numbers were 33% and 35%, respectively.
3. Morning pain intensity (range on 0 to 10 visual-analogue scale):

   Follow-up interval	Non-magnetized	Magnetized
   Baseline	6.9	6.9
   4-week	4.2	4.4
   8-week	3.9	3.9

4. Participants who believe a priori that magnets would be beneficial trended toward categorical improvement no matter which group they were actually in. This same group of participants (both non-magnetized and magnetized) had significantly more improvement in morning pain intensity at 8 weeks.

1. The strength of these magnets was comparable to widely available devices.
2. Although participants could have tested their insoles for magnets, they signed an agreement they would not. At the end of study an equal number guessed their correct group, which was no different than chance.

1. Meta-analysis found 4 randomized trials meeting inclusion criteria (169 patients). COPD exacerbations were considered moderately severe—FEV1 range 0.6 to 0.8.
2. All were treated in the emergency department or on admission to the hospital. Co-interventions were permitted—beta-agonists, ipratropium, antibiotics, corticosteroids, and oxygen.
3. Trials compared add-on oral theophylline and intravenous aminophylline with placebo.
4. Patients with asthma were excluded.
5. Main outcomes = mean change in spirometry, clinical end points, symptom scores, and adverse events.

1. Mean change in FEV1 and at 2 hours were similar between groups.
2. Non-significant reductions in admissions and length of stay were offset by non-significant increases in relapses at one week.
3. Changes in symptom scores did not reach significance.
4. Methylxanthines caused more nausea and vomiting than placebo (odds ratio = 4.6) and non-significant increases in tremor, palpitations, and arrhythmias.