1-1 WHY DO GENERAL PRACTITIONERS PRESCRIBE ANTIBIOTICS FOR SORE THROAT?
      Describing the difference between “Evidence Based Medicine” and the “Real World” of practice. Despite the power of EBM, there are many instances and reasons for deviation.

1-2 ADVERSE EVENTS ASSOCIATED WITH DIETARY SUPPLEMENTS
      “Dietary supplements” are associated with adverse effects that include all organ systems, age groups, and levels of severity,
      Associations between adverse effects and ingredients are difficult to verify. Information systems are incomplete.
      Our strong message should be:”. “You do not know what you are taking”. “You do not know if it is safe”.

1-3 MULTIFACTORIAL INTERVENTION AND CARDIOVASCULAR DISEASE IN PATIENTS WITH TYPE 2 DIABETES
      A targeted long-term intensive intervention aimed at multiple risk factors (hypertension, dyslipidemia, microalbuminuria) in patients with DM-2 and microalbuminuria reduced the risk of cardiovascular and microvascular events by about 50%.

1-4 GLYCEMIC EFECTS OF POSTMENOPAUSAL HORMONE THERAPY:
      In women with established coronary heart disease, hormone therapy reduced the incidence of type 2 diabetes by 3.3% compared with those taking placebo. NNT (4 years to prevent one case) = 30.
      And reduced incidence of diabetes by 12% in those with impaired glucose tolerance at baseline.

1-5 PREMENSTRUAL DYSPHORIC DISORDER
      Selective serotonin reuptake inhibitors (SSRI) are first-line agents for PDD. Several trials have demonstrated they are superior to placebo for treatment of the emotional and physical symptoms.
      Fluoxitine (Prozac) and Sertraline (Zoloft) are the most studied. A 20 mg dose of fluoxitine is as effective as the 60 mg and has fewer adverse effects and fewer dropouts. SSRIs may be given continuously or for two weeks before the expected period. Luteal phase administration has been effective.

1-6 IMPACT OF CHANGING DIAGNOSTIC CRITERIA ON INCIDENCE, MANAGEMENT, AND OUTCOME OF ACUTE MYOCARDIAL INFARCTION
      Adding troponin levels as criterion for the diagnosis identified many more patients as having an acute myocardial infarction.

1-7 DIRECT-TO-CONSUMER ADVERTISING AND SHARED LIABILITY FOR PHARMACEUTICAL MANUFACTURERS
      Marketing of prescription drugs has undergone substantial change facilitated by the regulatory environment governing direct-to-consumer advertising. (DTCA). Physicians who write prescriptions on the request of patients who have been influenced by DTCA, do not relinquish any of their traditional control over prescribing

1-8 ESCALATION OF DRUG USE IN EARLY-ONSET CANNABIS USERS VS CO-TWIN CONTROLS.
      Associations between early cannabis use and later drug use and abuse/dependence cannot be explained solely by common predisposing genetic or environmental factors. Early initiation of cannabis (before age 17) was associated with significantly increased risk of other drug use and abuse/dependence later in life. This is consistent with early use of marijuana having a causal role as a risk factor.
      Regardless of the mechanisms underlying the associations, it is apparent that young people who initiate cannabis at an early age are at heightened risk of progressing to other drug use and drug abuse/dependence.

1-9 PROPHYLACTIC TREATMENT OF MIGRAINE WITH AN ANGIOTENSIN-II RECEPTOR BLOCKER
      In this study, the angiotensin II blocker, candesartan, provided effective migraine prophylaxis with tolerability comparable to that of placebo. Physicians need to be more aware of the risks associated with early use.

1-10 OBESITY AND ADULTHOOD AND ITS CONSEQUENCES FOR LIFE EXPECTANCY
      Obesity in adulthood is associated with decreases in life expectancy among men, women, smokers and non-smokers. (Up to 7 years of life lost.) Combined smoking/obesity doubles risk.

1-11 PRESCRIBING ORAL CONTRACEPTIVES FOR WOMEN OLDER THAN 35 YEARS OF AGE.
      OC can be safely prescribed to many women over age 35.
      There are many risks and absolute contraindications. Primary care clinicians should review risks before prescribing.

1-12 PRIMARY ANGIOPLASTY VERSUS INTRAVENOUS THROMBOLYTIC THERAPY FOR ACUTE MYOCARDIAL INFARCTION.
      Primary PTCA is more effective than thrombolytic therapy for treatment of ST-elevation AMI.

1-13 ROLE OF DRINKING PATTERN AND TYPE OF ALCOHOL CONSUMED IN CORONARY HEART DISEASE IN MEN
      Among men, consumption of alcohol at least 3 to 4 times per week reduced risk of MI. Neither the type of beverage, nor the proportion consumed with meals substantially altered the association.
      Men who increased their alcohol consumption by a moderate amount during the follow-up had a decreased risk of MI.

1-14 OUTDATED DRUGS MAY BE USEFUL
      This letter to the editor brings up an important practical point. Should we discard all drugs when they become outdated?
      The correspondent believes that many drugs maintain potency long after expiration date. In developing countries and “free” clinics in the USA, the choice may be “outdated” or “none at all”.

1-15 DRUG ELUTING STENTS IN VASCULAR INTERVENTION
      Immunosuppressive agents (which inhibit tumor-cell growth) may also inhibit the benign tissue proliferation characterizing intimal hyperplasia. Several immunosuppressants have been tested for potential to inhibit restenosis. Stents coated with the agents are becoming available. Local drug delivery achieves higher tissue concentrations of drugs, while producing no systemic effects. This is associated with a marked reduction in the risk of re-stenosis.
      “The clinical impact of the elimination of restenosis may influence the approach to coronary artery disease, the future of cardiac surgery, and health-care economics.”

1-16 COMBINATION TREATMENT OF ANGIOTENSIN-II RECEPTOR BLOCKER AND ANGIOTENSIN-CONVERTING-ENZYME INHIBITOR IN NON-DIABETIC RENAL DISEASE (COOPERATE)
      Combined ACE-I and A II-I therapy safely retarded progression of non-diabetic renal disease more effectively than either drug alone.

1-17 OPIOID ADDICTION
      In early February 2003, the SAMHSA sent a “Dear Physician” letter outlining a new, office-based approach to opioid addiction. It represents a new era in addiction treatment.
      The new treatment option is based on buprenorphine, a partial opiate agonist/antagonist recently approved by the FDA. Physicians can now provide opioid addiction treatment in their own offices. It also provides access to a supportive network of treatment specialists who can address the psychosocial needs of patients undergoing detoxification or maintenance. Buprenorphine has a lower potential for abuse, a lower level of physical dependence, and weaker opioid effects than other drugs such as methadone.

1. Interviewed 40 general parishioners in the UK. Questions included opinions and beliefs about antibiotic prescribing for sore throat, management of patients, and awareness of research and policy about antibiotic prescribing, and how these influenced practice.

1. All GPs agreed that antibiotics are unnecessary for most patients with sore throat. They identified research, local prescribing advisers and national reports as influencing them to reduce antibiotic prescribing. Indeed, all claimed to have reduced prescribing in response to pressures to do so.
2. They estimated that they prescribed antibiotics from less than 1 in 10 to a maximum of half of patients with sore throat. Only one GP said he prescribed to half and he believed he was a high prescriber.
3. All believed that antibiotics are beneficial to some patients. Specific signs and symptoms and contexts were identified in which they would or would not prescribe antibiotics:

   Prescribed:
   

   If the sore throat lasts for 4 to 5 days and is getting worse.
   If the patient appears toxic. (Ie, high fever, headache, myalgia, looks “awful”, and feels ill when they walk in).
   If lymph nodes are swollen, and throat looks red raw with dilated blood vessels “just like raw meat”.
   If there is concern for complications.
   

   Do not prescribe:
   

   If sore throat began within 48 hours of consultation.

4. Some will tell the patient there is not strong evidence of efficacy of penicillin and give the patient the option to take or not to take the antibiotic.
5. The patient’s appearance, and the duration and severity of symptoms influenced GPs about the cause and likelihood of complications. And influenced prescribing.
6. One high prescriber explained his willingness to prescribe because he had withheld antibiotics from a patient who subsequently developed septicemia. (Individual and reported anecdotal experience are still powerful motivators.. RTJ )
7. Other GPS said their antibiotic prescribing was influenced by previous patients.
8. Some mentioned that if patients take the trouble to consult with a sore throat, they are more likely to be ill. They probably had managed other sore throats at home before.
9. Only one GP took throat swabs when the patients appeared toxic. She found most improved while waiting for the results. However, she would prescribe if the culture grew group A streptococci, even if the patient had improved and even when she suspected the finding was probably co-incidental. No other GP experienced discomfort when prescribing under these contexts.
10. Adverse social factors lowered threshold for prescribing. (eg, poor diet and suboptimal immune function.)
11. GPs in one practice agreed to change practice policy and stopped prescribing antibiotics to all patients with sore throat. Subsequently, they saw an unprecedented rise in the number of patients with quinsy. They then returned to prescribing for severest sore throat symptoms.
12. One GP posted a notice—“Please do not ask the doctor for antibiotics as refusal often offends”.
13. One GP said he formerly was very strict about not prescribing, Later he prescribed more frequently when he felt under pressure or if he was running late and it was too much to go through the detained process of saying sore throats are caused by viruses and will get better anyhow, etcetera. He also prescribed when he knew the patient would not be satisfied unless she received a prescription for antibiotic. “People aren’t always as research would have them.” (An honest MD. RTJ)
14. Delayed prescribing—giving a prescription and asking the patient not to fill it unless she got worse, or was no better in 2 to 3 days. On the whole it was regarded positively as a way to manage uncertainty, to reassure the patient, to prevent re-attendance, and to shorten the consultation. One GP said it had the potential to reduce antibiotic use, and was an indicator of patient-centered consulting. But, not all GPS used delayed prescribing.
15. GPs agreed that overuse of antibiotics would lead to development of resistance. But many were skeptical that prescribing penicillin for sore throat contributed to this significantly. “Tell me why penicillin still works in the community”.
16. Prescribing antibiotics is relevant to maintaining the doctor-patient relationship, but not the most important. Patients “know that I base my advice by considering their story alongside the medical evidence. The sore throat does not exist in isolation—often I’ve seen the same person with blood pressure, depression, diabetes, the list goes on—so, no, my relationship with my patients isn’t that fragile.”
17. Communicating that the science does not support the patient’s beliefs can be difficult. “If I think I am treating the whole patient and not just the virus, then I feel better about giving the antibiotic because of my holistic duty here.”
18. None of the GPs interviewed described feeling very uncomfortable when prescribing antibiotics for sore throat. Most felt they had reduced their prescribing in response to external pressure to a level they felt comfortable with. Many felt there were more pressing issues.

      GPs did not describe appreciable discomfort in prescribing antibiotics for sore throat.
      Maintaining the doctor-patient relationship was not the primary reason for prescribing. They did not believe that withholding antibiotics greatly undermined or damaged the doctor-patient relationship.
      Overall, GPs prescribed antibiotics by taking into account biomedical evidence, policy statements, and social context. But, they had difficulty in distinguishing individuals at most risk of complications.
      GPs who questioned the relevance of research evidence for real life practice said that research was not conducted in comparable settings and with comparable populations.
      Clinical experience and personal knowledge of their patients were other factors that led to bypassing evidence.
      GPs questioned the notion that prescribing penicillin V for sore throat in the community was important as a threat to development of antibiotic resistance. Evidence accumulated in individual practices by individual GPs was given priority over research evidence.

1. Eleven poison control centers recorded details of over 1400 ingestions of DS. Of these, over 700 described symptoms.
2. Assessed the effects of multiple ingredients and long-term use and collated data for patterns of use.

1. Treatment of disease was the reason for use in over ¼ of reports.
2. One third of events were of greater than mild severity.
3. Both new and previously reported associations were reported:

   Neurological (coma, seizures, cerebral bleed)
   Cardiovascular (chest pain, conduction disturbances, arrhythmia, myocardial infarction)
   Hematological (bleeding with raised INR comment, hepatotoxicity, increased live enzymes)
   Metabolic (electrolyte abnormalities, metabolic acidosis)
   Hypersensitivity ( bronchospasm, angio-edema, anaphylaxis)
   Respiratory (dyspnea, respiratory depression)
   Genitourinary (urinary retention)
   Death
   

4. Pediatric exposures were often unintentional.
5. Most products and ingredients were not identified in the information data base of the poison control centers.

1. Some persons take DS to treat disease, contrary to the avowed principle underlying their approval by the government.
2. The regulatory distinction between prescription drugs and DS may not be clear or relevant to consumers. Confusion exists between DS and prescription drugs.
3. Packaging that is not child-proof leads to unintentional ingestion of DS.
4. Serious adverse effects occurred among users of aphrodisiacs, herbal abortifacients, body builders, and among those wishing to enhance athletic performance.
5. Adulteration of products and inadvertent plant substitution may enhance inherent toxicity.
6. Severity of toxicity increased with long-term use. This contradicts the expectation that symptoms would develop only if large amounts of DS were consumed in a suicide attempt. Repeated use allows attainments of steady state pharmacokinetics (about 4 half-lives) and increases toxicity to tissues.
7. Adverse events associated with DS are most certainly under-reported.
8. “Formulation and use of multiple ingredients not only confound the establishment of cause and effect, but could cause interactive fixed supplement effects (analogous to fixed drug effects) because of the number of possible cause and effect combination is enormous.”

1. Randomized, open, parallel trial entered 160 patients with DM-2 (mean age = 55). All had microalbuminuria.1
2. Half of the patients were randomized to conventional treatment; half to intensive treatment targeting hyperglycemia, hypertension, dyslipidemia, and microalbuminuria.
3. The intensive group received behavioral (lifestyle) modifications and a stepwise introduction of pharmacologic therapy. They received individual consultations about every 3 months.
4. Interventions included:

   Dietary (30% or less of fat; less than 10% saturated).
   Light to moderate exercise up to 5 times weekly
   Attempts at smoking cessation
   Prescribed angiotensin II receptor antagonist equivalent to 50 mg captopril twice daily, irrespective of BP level.
   Daily vitamin supplement.
   Drug therapy:
   

   All received low-dose aspirin
   Blood glucose control: Goal = glycosylated hemoglobin < 6.5%
   

   Oral hypoglycemic agents if Glycosylated hemoglobin remained over 6.5%:
   

   Metformin (Glucophage) if overweight; gliclazide (a sulfonylurea) if not overweight; combination if not controlled.
   Insulin (NPH) if Glycosylated hemoglobin remained over 7.0% despite maximal oral therapy.
   

   Dose adjusted on basis of morning blood glucose. If daily dose exceeded 80 U, switched to regular + NHP 2 to 4 times daily.

   Hypertension: Goal = systolic < 130; diastolic < 80
   

   All received an ACE inhibitor or an angiotensin II blocker for microalbuminuria at baseline regardless of BP.
   Thiazides, calcium=blockers, and beta-blockers added if needed.

   Dyslipidemia: Goal= total cholesterol < 175 mg/dL and triglycerides < 150 mg/dL
   

   Statins usually; fibrates occasionally if triglycerides exceeded 350 mg/dL; or both.

5. Primary end point = composite of death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stoke, revascularization, and amputation, Mean follow-up = 8 years.

1. Glycosylated hemoglobin, systolic and diastolic BP, total cholesterol, LDL-cholesterol, triglycerides, and urinary albumin excretion were all significantly lower in the intervention group than in controls.
2. These beneficial changes were maintained or increased over the 8 years.
3. Patients in the intervention group had a significantly lower risk of complications:

   	Hazard ratio compared with controls
   Cardiovascular disease	0.47
   Nephropathy	0.39
   Retinopathy	0.42
   Autonomic neuropathy	0.37

   (All were reduced by over half. All clinically significant. RTJ)

1. A targeted long-term intensified intervention involving multiple risk factors reduced risk of cardiovascular disease in patients with DM-2 who had microalbuminuria.
2. Five patients need to be treated for 8 years to prevent one cardiovascular event. NNT (8 y to benefit one) = 5
3. Serious adverse effects were few.
4. Could not determine which treatment component was most critical in producing the benefit.

1. Randomized, double-blind, placebo-controlled trial entered over 2700 postmenopausal women. (Mean age = 67) All had a history of CHD.
2. At baseline, 26% had diabetes; 8% had impaired fasting glucose levels; 68% were normoglycemic.
3. Diabetes defined as fasting plasma glucose (FPG) 126 mg/dL or greater, or initiation of therapy for diabetes.
4. The 1811 women (74%) without diabetes were randomized to:
   1) Conjugated estrogen 0.625 mg + medroxyprogesterone 2.5 mg daily, or 2) Placebo.
5. Followed up = 4 years,

1. FPG levels increased significantly in the placebo group; did not change in the PHT group.
2. Incidence of diabetes: PHT group = 6.2%; placebo group = 9.5% [Absolute difference = 3.3%]
   (Number needed to treat to prevent one case of diabetes over 4 years = 30.)
3. Of those with impaired fasting glucose (plasma glucose 110 to 125 mg/dL) 25% assigned to PHT vs 37% of those assigned to placebo progressed to diabetes in 4 years. [Absolute difference = 12%]
   (Number needed to treat to prevent one case of diabetes over 4 years = 8.)

1. The comparative risk was lower in those taking PHT because they were less likely than the placebo patients to experience a rise in their fasting glucose over the 4 years. Women in the PHT group were more likely to maintain their glucose levels; those in the placebo group were more likely to progress.
2. Characteristics commonly associated with diabetes (eg, changes in weight or abdominal girth) were not responsible for this association in the PHT women.
3. These effects of estrogen + progestin regimens on glucose metabolism are generally consistent with results of estrogen-alone regimens.
4. Estrogens may have a beneficial effect on hepatic gluconeogenesis. (Ie, a suppression of glucose production by the liver.)
5. The study did not measure 2-hour post-prandial glucose. Thus, no effect on peripheral glucose metabolism was measured. But fewer of the group taking PHT progressed to diabetes than those in the placebo group.
6. Trials in women with type-2 diabetes have reported lower fasting glucose and glycosylated hemoglobin levels in those taking hormone therapy.
7. The investigators comment that the patients included in the study were likely to have a higher risk of diabetes because of older age, higher body weight, and less physical activity.
8. “Postmenopausal patients at high risk of diabetes, such as those with impaired fasting glucose, may benefit from hormone therapy.” But. because of the increased risk of coronary events, breast cancer, and venous thromboembolism in those taking long-term PHT, PHT is not a viable approach to diabetes prevention.”

Reducing intake of caffeine, refined sugars, and sodium.
Exercise
Vitamin B6
Calcium carbonate
Spironolactone (Generic)
(There are no randomized trials to confirm the benefits. But the author suggests a trial of vitamin B6 and calcium carbonate.)

These are first-line agents for PDD. Several trials have demonstrated they are superior to placebo for treatment of the emotional and physical symptoms.
Fluoxitine (Prozac) and Sertraline (Zoloft) are the most studied. A 20 mg dose of fluoxitine is as effective as the 60 mg and has fewer adverse effects and fewer dropouts. SSRIs may be given continuously or for two weeks before the expected period. Luteal phase administration has been effective. Some data support the use of intermittent therapy.

1. Followed all patients admitted with chest pain. (n = 2637). Measured Troponin T in all.
2. Identified patients with a principal diagnosis of AMI according to the old criteria.
3. Identified patients with chest pain who had raised troponin T (> 0.1 ng/mL).

1. The new criteria raised admissions for acute MI by 58% -- from 1671 to 2637.
2. The “new” patients were older. A higher percentage were women.
3. Thrombolysis was given to only 13 (1%) of the additional patients, compared with 40% of those who met the old criteria.
4. The additional patients had a higher 30 day mortality. This increased over one year.

1. The new criteria identified additional patients who were significantly different from those formerly classified as having AMI. The new criteria could increase admissions for AMI by about 160 000 additional cases in the UK every year.
2. Few received thrombolysis because ST segments were not raised.
3. The poorer survival may have been due in part to the older age, as well as ineligibility for thrombolysis.
4. Recent evidence suggests that these patients might benefit from early revascularization.
5. These observations have serious implications for epidemiology and treatment.

“Although the physician writes the prescription, the physician’s role in deciding which prescription drug is selected has been altered by pressure from patients.”
Arguments about the physician’s superior position for the communication of risk information no longer apply in the age of managed care, in which physicians have considerably less time to inform patients of risks and benefits.
The success of DTCA belies manufacturers claim that they lack effective means to communicate directly with patients.

The current undertreatment of conditions that could be treated with advertised pharmaceuticals.
The amount of appropriate and inappropriate prescribing that might be stimulated by DTCA.
The amount of benefit and harm accruing to undertreated and overtreated patients.

1. The Australian Twin Register obtained information on twins born between 1964 and 1971.
2. Conducted telephone interviews during 1996-2000 when the median age of the twins was 30. Determined whether cannabis was used before age 17. Obtained data on self-reported non-medical use of prescription sedatives, hallucinogens, cocaine/other stimulants, and opioids; and abuse or dependence on these dugs (including cannabis abuse/dependence) and alcohol dependence and tobacco use.
3. A total of 14% of the entire twin register (n = 2765 pairs) reported initiating cannabis use before age 17.
   Of these, 622 individuals were from same-sex twin pairs in which the twins were discordant for use of cannabis before age 17. (Ie, one used, and one did not.) 136 were monozygotic discordant twin pairs and 175 were same-sex dizygotic discordant twin pairs.

1. Individual twins who used cannabis by age 17 were more likely to report other drug use and drug abuse/dependence by age 30 at a rate 2 to 5 times higher than the co-twin who did not use cannabis before age 17.
2. Controlling for known risk factors (early-onset alcohol or tobacco use, parental conflict, childhood sexual abuse, conduct disorder, major depression, and social anxiety) had only negligible effects on these results.
3. The associations did not differ significantly between monozygotic and dizygotic twins.
4. The majority of subjects reporting both cannabis and other illicit drug use initiated cannabis before initiating use of other drugs.
5. Early regular use of tobacco and alcohol was also strongly associated with later illicit drug use.

1. Relative to their co-twin who had not used cannabis by age 17, the twin who had used cannabis by this age had elevated lifetime rates of other drug use, illicit drug abuse/dependence, and alcohol dependence.
2. The study provides evidence that inherited factors are not responsible for abuse. If inheritance were a major factor, one would expect that there would be little discordance between the monozygotic twins in illicit drug use. This was found not to be the case. For monozygotic discordant twins, there was no difference in the risk of the non-user twins to later use of illicit drugs than was the case for dizygotic twins.
3. The study also provides evidence that environmental factors do not play a major part in later illicit drug use. Twins raised in the same household would be expected to be highly concordant for environmental experiences. If the association between early use is explained by the environment, then a twin who did not use cannabis at an early age would be at equal risk for developing later drug-related problems as their co-twin who initiate cannabis at an early age. This was not the case.
4. Why might early use of cannabis predispose to later use of illicit drugs and alcohol?

   Exposure to cannabis may induce subtle biochemical changes that encourage drug-taking behavior.
   Cannabis and heroin have similar effects on dopamine transmission.
   Initial experiences with cannabis are frequently rated as pleasurable. This may encourage future use and broader experimentation.
   Seemingly safe experiences with cannabis may reduce the perceived risk of, and barriers to, the use of other drugs.
   Experience with, and subsequent access to, cannabis may provide access to other drugs as individuals more easily come in contact with the hard drug market.
   

5. The authors state, however, that it is not possible to draw strong conclusions solely on the basis of the associations shown. But, regardless of the mechanisms underlying the associations, it is apparent that young people who initiate cannabis an early age are at heightened risk of progressing to other drug use and drug abuse/dependence. Physicians need to be more aware of the risks associated with early use.

1. Randomized, double-blind, placebo-controlled crossover study entered 60 outpatients (age 18 to 65). All had frequent migraine attacks. (2 to 6 per month).
2. Randomized to: 1) candesartan cilexetil (Atacand), one 16-mg tablet daily, or 2) placebo for 12 weeks.
3. Then crossed over to the other group for another 12 weeks after a 4 week wash out period.

1. In the 12 weeks of active treatment, the mean number of days with headache was reduced from 18 to 14.
2.  

   Outcomes over 12 weeks (means)	Candesartan	Placebo
   Hours with headache	59	92
   Days with migraine	10	13
   Headache severity index	191	293
   Level of disability	14	21
   Days of sick leave	1.4	3.9

3. Adverse events were similar in both groups.
4. There was a substantial placebo effect.

1. Beta-blockers, calcium channel blockers, and ACE-I are also first-line prophylactic agents.
2. The mechanism of action of candesartan as a migraine prophylactic is not known. The main rationale for its use in this trial was the observed benefit of ACE inhibitors in other trials. Angiotensin II has several effects which may be relevant: direct vasoconstriction, increased sympathetic discharge, and increased adrenal medullary catecholamine discharge. Angiotensin II also modulates cerebral blood flow and has effects on fluid and electrolyte homeostasis, blocking both potassium channels and calcium activity in cells. It also may have an influence on dopamine and serotonin metabolism in the brain. Blocking these activities may lead to lessening of migraine attacks.
3. The adverse effects of candesartan were similar to placebo. It has no significant drug interactions. In contrast to beta-blockers, it does not affect pulse rate, and is not associated with sexual dysfunction. It can be safely used in patients with asthma. The incidence of cough is low.

1. Prospective cohort study entered over 3400 participants age 30 to 49 at baseline.
   (About half male and half female.)
2. Definitions according to BMI:

   Normal weight	18.5 to 24.9
   Overweight	25 to 29.9
   Obese	30 or over

   (Underweight persons were not considered in the study.)
3. Determined mortality rates related to age and body mass index in over 40 years follow-up calculated according to weight at age 40.

1. Years-of-life lost compared to a 40 year old non-smoker; non-overweight, and non-obese:

   Females	Non-smoker	Smoker
   Overweight	3
   Obese	7	13
   Male
   Overweight	3
   Obese	5	14

2. Mortality rates began to diverge at about 5 years after age 40.

1. The effect of obesity and overweight at age 40 on future life expectancy is striking. Among 40-year old non-smokers without previously diagnosed cardiovascular disease, overweight was associated with a decrease in life expectancy of 3 years, and obesity with a 6 to 7-year decrease. (Compared with normal weight persons at age 40.)
2. Smokers had a similar loss of years-of-life.
3. Obesity plus smoking resulted in a double burden of risk.
4. Mortality rates have improved greatly over the past 50 years. These results may now represent a relative rather than an absolute reduction in life expectancy in today’s population, They are a robust estimation of the relative magnitude of lost life-years. However, obesity is much more prevalent in the USA now than 50 years ago.
5. The investigators did not make conclusions regarding any benefits made possible from weight loss.
6. The study strongly supports prevention as a first-line public health action.

Postpartum up to 6 weeks and breastfeeding
Age over 35 and heavy smoker
Systolic BP over 160 and diastolic 100 or over
Hypertension with vascular disease
Diabetes with micro- or macro vascular disease
History of deep vein thrombosis or pulmonary embolism
Major surgery with immobilization
History of ischemic heart disease
Severe headaches with focal neurological signs
Current breast cancer
Hepatitis, cirrhosis

1. Systematic search identified 23 randomized trials which together assigned over 7700 patients. All had acute ST elevation MI.
2. Patients were randomized to: 1) primary PTCA or 2) thrombolysis. Primary PTCA is not accompanied by thrombolysis.
3. Some patients received streptokinase; most received accelerated tissue plasminogen activator (t-PA).
4. Stents were used in 12 trials; glycoprotein IIb/IIIa inhibitors in 8.
5. Some patients were transferred to primary PTCA sites from sites that could not perform PTCA.

1. Primary PTCA was more effective than thrombolytic therapy:

   	Primary PTCA (%)	Thrombolysis (%)
   Short-term death	7	9
   Non-fatal reinfarction	3	7
   Stroke	1	2
   Combined death, non-fatal MI, stroke	8	14 (NNT = 17)
   Major bleed	7	5

2. Benefits of PTCA were independent of the type of thrombolytic therapy.
3. Benefits of PTCA were maintained in patients who were transferred for primary PTCA.
4. Benefits of PTCA remained during long-term follow-up.

1. These findings indicate that primary PTCA is better than thrombolytic therapy at reducing short-term major adverse cardiac events in patients with ST elevation AMI.
2. The favorable results were sustained during long-term follow up. (6 months.)
3. Favorable results were maintained even when reperfusion was delayed because of transfer to another center for primary PTCA as compared with on-site thrombolysis.
4. More recent trials addressed important questions with respect to safety and efficacy of emergent hospital transfer for primary PTCA and for PTCA done in hospitals without surgical backup.
5. Variation in individual operator experience and hospital volume of primary PTCA implies that this procedure is applicable to a wide range of hospitals. However, the favorable results from PTCA are applicable only to hospitals with well-established primary PTCA programs, and dedicated and experienced teams of operators.
6. Bleeding complications were more common in the PTCA groups. Most bleeding was localized to the access site. Now, with use of lower doses of heparin, smaller sheath sizes, and improved operator technique, the rate of bleeding complications will decrease.
7. What about the longer delay in transferring patients to the catheterization laboratory? Previous studies reported that, despite delay, outcomes were more favorable in the PTCA groups.

1. Assessed the association of alcohol consumption with risk of MI in over 38 000 male health professionals, age 40 to 75 at baseline. All were free of cardiovascular disease at baseline.
2. Determined consumption of beer, red wine, white wine, and liquor every 4 years by questionnaire.
   Standardized portions; one can of beer; one 4 oz glass of wine; one shot of liquor.
   Considered ethanol content to be 12.8 g for beer; 11 g for wine; 14 g for liquor.
   Categorized average daily alcohol intake in grams into 7 categories: 0.1 to 4.9; 5 to 9.9; 10 to 14.9; 15 to 29.9; 30 to 49.9; and 50 or more
3. At baseline, increasing alcohol consumption was positively associated with smoking, hypertension, and hypercholesterolemia.
4. Documented cases of non-fatal MI and fatal coronary disease over 12 years. Related incidence with amount of alcohol consumed.

1. During 12 years follow-up there were 1418 cases of MI. A graded, inverse relation between alcohol and risk of MI was observed. As compared with men who consumed alcohol less than once a week, men who consumed alcohol 3 to 4, or 5 to 7 days per week had decreased risk. (Relative risks = 0.68 and 0.63.)
2. Risk was similar between very light drinkers (0.1 to 5 g daily) and abstainers. (Ie, no protective effect.)
3. The risk reduction was similar among those who consumed 10 g alcohol per drinking day and those who consumed 30 g or more.
4. Alcohol consumption was also inversely associated with risk of undergoing a coronary revascularization procedure. Lowest risk was among those who consumed 50 g or more daily. (RR =0.59)
5. More frequent use (3 or more drinks per week) was associated with lower risk compared with use on fewer than 3 days per week. (RR between 0.66 and 0.77 varying with amount drunk.)
6. The inverse association was evident in all decades of life.
7. Use of aspirin, body mass index, exercise, blood pressure, diabetes, family history, did not modify the association.
8. No single type of beverage conferred additional benefit.
9. Consumption with meals conferred no additional benefit.
10. For men who increased their intake by 10 g during the follow-up period, the relative risk of MI decreased to 0.55 compared with those who did not increase their intake.

1. Alcohol consumption was consistently associated with a lower risk of coronary heart disease, regardless of the type of beverage, the proportion consumed with meals, or the type of coronary outcome.
2. The drinking pattern had an important effect, with a lower relative risk among men who consumed alcohol 3 or more days per week, even if the amount consumed per drinking day was small to moderate.
3. Episodic consumption of large amounts of alcohol (binge drinking) has been associated with a high risk of coronary heart disease.
4. The results of this study emphasize that the frequency of alcohol consumption is the primary determinant of the inverse association.
5. Although there was a decreased risk among frequent drinkers age 40-50, the absolute benefits of moderate drinking will be most apparent in older adults because they are at increased risk of coronary heart disease.

1. Randomized-controlled study entered 301 patients with NDRD. During a run in period, 38 were excluded, mainly for dry cough. 256 followed to completion.

   Almost all had hypertension.
   Glomerular disease (IgA nephropathy, focal segmental sclerosis, membranous proliferative glomerulonephritis) was the most common causes. Some had hypertensive renal disease, some polycystic disease.
   Mean glomerular filtration rate at baseline = 38 mL/min; urinary protein 2.5 g/d.

2. Randomized to:

   1) Losartan 100 mg daily (A II-I)
   2) Trandolapril 3 mg daily (ACE-I)
   3) Both in equivalent doses.
   

   (Doses were gradually increased to these levels.)
3. Primary endpoint = doubling of serum creatinine or end-point renal disease.
4. Follow-up = 3 years.

1. Outcomes:

   	Losartan	Trandolapril	Both
   Reached combined endpoint at 3 years:	23%	23%	11%

2. Only one patient in the combined group required dialysis vs 3 and 7 in the other groups.
3. Blood pressure response was similar between groups (to a mean 128/80).
4. The combined drugs produced a greater fall in urinary protein excretion:

   Losartan - 42%
   Trandolapril - 44%
   Both - 76% (From about 2.5.g /d to about 0.6 g/d)

5. In the small group with nephrosclerosis benefits were less evident.
6. Adverse effects were similar between groups. No serious adverse reactions were reported even in patients with advanced renal disease.

1. In non-diabetic patients with moderately reduced renal function and moderate daily protein excretion, the combination of drugs was significantly better in producing renal survival than either drug alone.
2. Proteinuria has been shown to have a causal role in progression of renal dysfunction in various renal diseases. The most striking difference between groups was the antiproteinuric effect of the combined drug group. “The 3-year renal survival is mainly attributable to this effect.” The antiproteinuric effect in the combined drug group was more evident in those with higher baseline excretion.
3. This study lends support to the theory that the RAAS system has a role in progression of renal disease.
4. Even with maximum doses of two drugs, many patients progressed to end-stage disease. Further strategies are required to improve prognosis.