8-1 BREAST CANCER AND HORMONE-REPLACEMENT THERAPY IN THE MILLION WOMEN STUDY
      This remarkable, country-wide study confirms that current use of HRT is associated with increased risk of incident and fatal BC. Between 1996 and 2001, one half of the million women age 50-64 in this UK cohort of were using HRT.
      The risk is substantially less for estrogen-alone than for E-P combinations.
      Use of HRT by women aged 50-64 in the UK over the past decade is estimated to have resulted in 20 000 extra cases of BC; 15 000 of these associated with E-P use; 5000 with use of estrogen alone. (Ie, progestins are the major culprit.)
      Women who are presently taking estrogen-progestin may be told there is one additional chance in 150 of an invasive BC over 5 years; and one additional chance in 800 if they are taking estrogen alone.
      Risk increases with duration of use. Past users (5 or more years previously) were not at increased risk.

8-2 ESTROGEN PLUS PROGESTIN AND THE RISK OF CORONARY HEART DISEASE.
      E-P, in standard dose, does not confer cardiac protection. It may slightly increase risk of CHD, especially during the first year of use. Primary care clinicians may consider prescribing low-dose aspirin for primary prevention, at least during the first year. Treatment to improve lipid profiles reduces risk.
      E-P should not be prescribed for the prevention of cardiovascular disease.
      Any possible increase in incidence of CHD (about 6 extra cases per 10 000 patient-years) is minor compared with the risk for breast cancer.

8-3 IS OPPORTUNISTIC DISEASE PREVENTION IN THE CONSULTATION ETHICALLY JUSTIFIABLE?
      Consultations in primary health care have been suggested as an ideal setting for health promotion and disease prevention. Doctors are expected to discuss preventive measures even when they are not among the reasons for the consultation. Opportunistic preventive medicine is considered a part of good medical practice. This article asks. . .Is this ethically justifiable?
      The authors argue that doctors should maintain a clear focus on each patient’s reasons for seeking help rather than be distracted by an increasing list of preventive measures. They maintain that, from a moral point of view, initiatives to improve health among people who are currently free of symptoms is fundamentally different from curative medicine—the condition for which the patient consults.
      Physicians who offer a screening test carry a considerable responsibility. They must offer enough information about risks and benefits in order to enable the patient to give informed consent. Informed consent presupposes an understanding of the limitations of the screening test. Every test carries a chance of misclassification of disease. A false positive test may result in further interventions that do not benefit the patient, and may cause harm.
      “Once medical risk has been passed on to a person, it cannot be retracted. Respect for autonomy should therefore also honor the person’s right not to be opportunistically confronted with knowledge about biomedical risks that are unrelated to his or her reasons for seeing the doctor.”
      “As the list of accessible preventive tests lengthens and thresholds for intervention are lowered, a doctor who adheres to all recommendations for provision of preventive services may ultimately be able to find something abnormal in everybody.”
      Think twice before advising screening tests.

8-4 A RISK SCORE FOR PREDICTION OF STROKE OR DEATH IN INDIVIDUALS WITH NEW-ONSET ATRIAL FIBRILLATION IN THE COMMUNITY: The Framingham Heart Study
      This risk score for embolic stroke was derived from 5 risk predictors: advancing age, female sex, increasing
      systolic BP, prior stroke or TIA, and diabetes. The score can be used to estimate absolute risk of stroke (5% to 75% over 5 years) and help to negotiate treatment decisions with patients with AF at the time they are first diagnosed. . Risk may be stratified into mild, moderate or severe.
      Although some physicians and patients may more readily accept and act on a numerical risk prediction,
      I believe primary care clinicians can just as accurately judge risk without creating a numerical 5-year “risk”. Most patients with AF eventually end up receiving anticoagulation. It is nevertheless important to spare those at low risk from the potential adverse effects of warfarin therapy and use aspirin instead. Patients with AF, but without structural heart disease, (including no hypertension) are at relatively low risk, especially if they are under age 65.
      To anticoagualate or not anticoagualate is a difficult and important decision. It remains a clinical-judgment call. For each patient, clinicians must strike an acceptable balance between risk of ischemic stroke and bleeding. In the absence of an absolute or important relative contraindication, the data seem compelling that warfarin therapy should be offered to most patients with AF. The difficulty is to know what threshold of stroke risk is low enough so that the potential risk of warfarin therapy outweighs its potential benefits. For most patients the potential benefits of stroke prevention will outweigh the potential risks of bleeding secondary to warfarin.
      An article (Annals Internal Medicine April 28 , 2003; 163: 936-43; Practical Pointers April 2003) differs somewhat in suggesting that up to 1/3 of patients with AF can be classified as low-risk and treated with aspirin.

8-5 COMPARISON OF LOW-INTENSITY WARFARIN THERAPY WITH CONVENTIONAL-INTENSITY WARFARIN THERAPY FOR LONG-TERM PREVENTION OF RECURRENT VENOUS THROMBOEMBOLISM
      “The intensity of anticoagulation for patients who have had unprovoked venous thromboembolism should not be reduced after the first three months of treatment.” Such a reduction increases risk of recurrence. INR should remain at 2.0 to 3.0.
      Risk of recurrent VTE was 0.7 per 100 patient-years in the INR 2.0 to 3.0 group vs 2.8 per 100 patient years in the INR 1.5 to 1.9 group.
      In this study, there was no evidence that aiming for an INT of 1.5 to 1.9 (vs 2.0 to 3.0) reduced risk of bleeding.
      I believe that in the “real world” of primary care, aiming for a higher INR will be related to an increased risk of bleeding. Indeed, bleeding risk is increased in patients who aim for the lower INR as compared with placebo.
      An article in NEJM April 10, 2003; 348; 1425-34 reported that a low-level INR (target 1.5 to 2.0; compared with placebo) in patients with unprovoked VTE was highly effective in preventing recurrence. It is likely that a higher target will be slightly more effective in prevention, but will lead to greater risk of bleeding. Again a clinical judgment call based on individual-patient characteristics and preferences.

8-6 D-DIMER LEVELS AND RISK OF RECURRENT VENOUS THROMBOEMBOLISM
      After 3-months of anticoagulation for a first episode of unprovoked VTE, measuring D-dimer levels allowed identification of a subset of patients with very low risk of recurrence. Patients with a level of less than 250 ng/mL 3 weeks after discontinuation of oral anticoagulation were at low risk.
      The cumulative probability of recurrent VTE at 2 years among those with levels < 250 was 3.7%. Among those with higher levels was 11.5%
      A higher D-dimer is likely to be related to ongoing thrombosis-thrombolysis due to a thrombogenic potential.

8-7 PREVALENCE OF CONVENTIONAL RISK FACTORS IN PATIENTS WITH CORONARY HEART DISEASE.
      At least 80% to 90% of patients with CHD have conventional risk factors (cigarette smoking, diabetes, dyslipidemia, and hypertension). This is probably an underestimate. Clinical medicine, public health policies, and research efforts should place significant emphasis on the 4 factors and lifestyle behaviors. Non-traditional risk factors and genetic causes deserve less emphasis.
      “Although widely asserted, the belief that more than 50% of patients with CHD lack conventional risk
      factors is not supported by primary data.” “In essence, patients without conventional risk factors are unlikely to develop CHD.”
      “The true prevalence of conventional risk factors is certainly higher than identified in our study.”
      Many patients with hypertension and diabetes are not aware of their condition. More stringent cutoffs for BP, lipids, and blood glucose have been increasingly recommended.
      “It is increasingly clear that the 4 conventional risk factors and their resulting health risks are largely
preventable by a healthy life-style.”
      Primary care clinicians have their hands full encouraging patients to deal with these conventional risk factors. We don’t need more at this time.

8-8 EMERGING RISK FACTORS FOR ATHEROSCLEROTIC VASCULAR DISEASE.
      This critical review highlights 4 emerging risk predictors: C-reactive protein, Lipoprotein (a), Fibrinogen, and Homocysteine.
      “Their optimal use in routine screening and risk stratification remains to be determined.”
      “The explanatory power of the major established cardiovascular risk factors has been systematically underestimated.” (See previous abstract.)
      Primary care clinicians and their patients have not even begun to assess, prevent, and treat the established major, modifiable risk factors. Until we do, I believe we need no more risk factors.
      We will, with interest, however, follow the basic science investigations aimed at determining the best mix of risk factors on which to base clinical interventions.

8-9 CARDIOVASCULAR RISK FACTORS AND INCREASED CAROTID INTIMA-MEDIA THICKNESS IN HEALTHY YOUNG ADULTS
      Atherosclerosis is a slowly progressive process possibly starting at a young age. Preventive measures taken early in life might postpone the development of atherosclerosis and decrease risk of clinical cardiovascular disease (CVD).
      Unfavorable cardiovascular risk factors (cigarette smoking, diabetes, dyslipidemia, and hypertension) were related to greater CIMT in young adulthood. Effort to change modifiable risk factors early in life may retard development of atherosclerosis and the onset of clinical cardiovascular disease later in life.

8-10 REGRESSION OF CAROTID AND FEMORAL ARTERY INTIMA-MEDIA THICKNESS IN FAMILIAL HYPERCHOLESTEROLEMIA
      High dose simvastatin over 2 years reduced combined carotid/femoral IMT in more than two thirds of patients. The largest effect was on the femoral artery. This degree of reduction of IMT. . . “will likely have a significant clinical impact on the prevention of coronary artery disease”.
      Primary care clinicians might easily extrapolate these results to other patients with high cholesterol levels.
      Atherosclerosis is reversible.

8-11 BULIMIA NERVOSA
      Has 3 key features: 1) Intense preoccupation with body weight and shape; 2) Repetitive episodes of binge eating--uncontrollable eating a large quantity of food in a defined period—usually less than 2 hours; 3) Routinely taking extreme measures to prevent weight gain: self induced vomiting, fasting, exercise, and misuse of laxatives and diuretics. Some patients take up to 50 laxative pills per day. Severe constipation with a laxative-dependence syndrome may result.
      Anorexia nervosa differs. Patients with BN maintain a normal weight.
      The challenge for primary care clinicians is to suspect and recognize BN in select young women who present with vague symptoms, anxiety and depression. The clinical clues cited may help. A metabolic package might very well reveal a metabolic alkalosis.
      “Hypokalemia in an otherwise healthy young woman is highly specific for BN.”

8-12 DIFFERENTIAL ASSOCIATION OF ORAL AND TRANSDERMAL OESTROGEN-REPLACEMENT THERAPY WITH VENOUS THROMBOSIS RISK.
      Oral, but not transdermal ERT, was associated with risk of VTE in postmenopausal women. Transdermal administration avoids the first pass through the liver and blunts production of thrombogenic proteins by the liver.
      A good example of the advantages of transdermal application of drugs.

8-13 ENDOCRINE TREATMENT OF PHYSIOLOGICAL GYNECOMASTIA
      “Physiological” gynecomastia is due to an altered ratio between free estradiol (a stimulant) and testosterone (an inhibitor). Anti-estrogens such as tamoxifen (Nolvadex) have therefore been suggested as non-surgical treatment. Various published studies have used tamoxifen at a dose of 10 to 40 mg daily for several months. Resolution of the lump and pain has been reported in 80% of cases. Only minor and reversible side effects were reported.

8-14 EXPOSURE TO NON-STEROIDAL ANTI-INFLAMMATORY DRUGS DURING PREGNANCY AND RISK OF MISCARRIAGE
      NSAIDs and aspirin were associated with an increased risk of miscarriage. Acetaminophen was not.

8-15 POOR GLYCEMIC CONTROL CAUSED BY INSULIN INDUCED LIPOHYPERTROPHY.
      Prevalence of lipohypertrophy in patients with type 1 diabetes is estimated to be around 20% to 30%. It is due to a cellular response of adipocytes to the local effects of injected insulin. Immunological factors may be important. Frequent injection into the same site is related to incidence.
      Injection repeatedly given into these sites may lead to problems of glycemic control. Insulin absorption can be significantly delayed.

1. Recruited over one million women aged 50-64 in the UK between 1996 and 2001.
2. All provided information about their use of HRT and other personal details.
3. Estrogen-only users were subdivided according to the specific estrogen (equine estrogen, or estradiol), and whether it was administered as on oral, transdermal, or implanted formulation.
4. Users of combined E-P were subdivided into subgroups by the specific progestogen constituents and by sequential or continuous regimens.
5. Determined cancer incidence and death.

1. Half the entire cohort had used HRT.
2. Incident invasive BC was recorded in over 9300 women after an average follow-up of 2.6 years.
3. BC deaths occurred in over 600 women after an average of 4.1 years of follow-up.
4. Current users at recruitment were more likely than never-users to develop BC (Relative Risk = 1.66), and were more likely to die from BC (RR = 1.22).
5. Incident invasive BC over 5 years:

   All never users 2894/392 757 = 0.737%
   Current users of estrogen alone 991/115 383 = 0.858% Absolute difference = 0.121 NNT to harm = 826
   Current users of E-P 1934/142 870 = 1.35% Absolute difference = 0.613 NNT to harm = 159
   (My calculations. About a five-fold higher incidence in the E-P group. RTJ)

6. Use of HRT by women aged 50-64 in the UK over the past decade is estimated to have resulted in 20 000 extra cases of BC; 15 000 of these associated with E-P use.
7. In current users of each type of HRT, the risk increased with increasing total duration of use:10-years of use is estimated to result in 5 additional cancers per 1000 users of estrogen alone and 19 additional cases in users of combined E-P per 1000 users.
8. Past users (5 or more years previously) were not at increased risks of incident or fatal BC.
9. Results varied little between specific estrogens and progestogens and their doses, or between continuous or sequential regimens.
10. The extra deaths cannot yet be reliably estimated.

1. This confirms previous findings of increased risk of BC in current and recent HRT users. There was considerably less risk among users of estrogen alone compared with E-P users.
2. The only factor that modified the RR estimates was the body-mass index. Thinner women had a greater risk than obese women.
3. Incident BC was diagnosed on average 1.2 years after recruitment. Risk increased with increasing duration of use.
4. There was little or no increased risk in past users of HRT.
5. Endometrial cancer risk increased in women with an intact uterus who used estrogen alone. The main reason to use E-P preparations in these women is to prevent endometrial cancer. “However, if the additional breast cancers and endometrial cancers associated with each type of HRT are added together, there seems to be little advantage to using estrogen-progestogen in preference to estrogen alone in women who still have a uterus.”

      A general practitioner would need to give combined HRT to 166 women for 5 years—or 53 women for 10 years—to see one extra case of BC.
      Most women receiving HRT are in primary care. Despite stringent controls of drugs, how is it that heavy promotion of HRT has put millions of women at risk? Any preventive intervention in healthy people must be supported by the strongest evidence of benefit and virtually no evidence of risk. “Digression from this principle could be considered unethical.”
      Primary care is the vital ingredient of clinical research before introduction of a new intervention.
      For many general practitioners, the HRT story must present an all-too-familiar pattern. Those who claim special expertise place a new product in a positive light, overwhelming general practitioners with “evidence” of benefits. The drug industry promoted HRT to physicians and directly to patients, neglecting the risks. Now that the risks are firmly demonstrated, it is left to primary care providers to solve the problem.
      HRT should be discouraged. For post-menopausal-related health problems, women should be well-informed about HRT and use it for no more than 6 months.
      Women who are already using HRT should discontinue use.

1. Randomized, primary-prevention trial entered over 16 000 generally healthy postmenopausal women age 50 to 79.
2. Randomized to: 1) Prempro -- estrogen + progestin (conjugated equine 0.625 mg + medroxyprogesterone 2.5 mg) once daily, or 2) placebo
3. Primary outcome = CHD (non-fatal myocardial infarction or death due to CHD).
4. Mean follow-up = 5 years.

1. Coronary outcomes over 5 years:

   	E-P group (n = 8506)	Placebo (n = 8102)
   CHD	188	147
   Nonfatal MI	151	114
   Death due to CHD	39	34

2. Absolute rates of CHD: 39 cases per 10 000 person-years for E-P group vs 33 cases in the placebo group.
3. No significant differences for coronary revascularization, angina, acute coronary syndrome, or congestive heart failure.
4. The number of cases of CHD was higher in the first year of E-P therapy: 42 vs 23. In following years, risk was less. After year 6, the risk of CHD the E-P group actually fell below the placebo group. (Ie, favoring E-P over placebo). Numbers were small.
5. Patients in the E-P group had improvements in lipids. The increased risk developed despite a lowering of conventional (surrogate) risk factors; total-cholesterol (- 5%); LDL-cholesterol (- 13%); glucose (- 2,.5%); insulin (- 7%) and an increase in HDL-cholesterol (+ 7%). In addition, weight, waist circumference, and waist/hip ratio decreased in the treatment group. (One might assume that reduction of all of these risk factor reductions might reduce incidence of CHD. It did not.)
6. Possible adverse effects on risk factors: triglycerides were raised by +7%; systolic BP increased by 1 mmHg.
7. However, in the E-P group, aspirin users and statin users had a lower risk than non users. Subjects with LDL-cholesterol under 125 mg/dL had a lower risk than those with LDL-c above 125. Those with HDL-cholesterol above 58 mg/dL had lower risk than those with levels below 58. (Ie, some evidence of protection against CHD in these subgroups.) However, in all these subgroups of women, no group except those with a higher LDL-c had evidence of a risk of CHD with E-P that differed significantly for that observed for all women.

1. In addition to the favorable changes in risk factors noted above in the E-P group, E-P favorably improves endothelial vascular function fibrinogen levels, Lp(a) lipoprotein, plasminogen-activator and insulin. This might again lead to the conclusion that hormone therapy would decrease CHD risk.
2. However, estrogen also has adverse physiological effects; increased triglycerides, small-dense LDL particles, and C-reactive protein. It also has prothrombotic effects.
3. The addition of progestin attenuates some of the lipid benefits of estrogen, especially the increase in HDL-c, but does not seem to counter the prothrombotic effects.
4. The Woman’s Health Initiative previously reported that the risks of E-P outweigh the benefits. The combined excess of CHD, stroke, venous thromboembolism, and breast cancer was not offset by a reduced risk of hip fracture and colorectal cancer. Study stopped early because overall risks exceeded benefits.
5. “This treatment is not a viable intervention for primary prevention.”

1. Prospective, community-based observational cohort study identified over 700 patients (mean age = 75) with new-onset AF. None was being treated with warfarin at baseline.
2. New onset AF was diagnosed when AF or atrial flutter was first noted on an EKG obtained from the Framingham clinic visit, hospital charts, or physician office record.
3. Developed risk scores from patient outcomes for embolic stroke or death according to patient characteristics.
   The risk score was derived from 5 risk predictors: advancing age, female sex, increasing systolic BP, prior stroke or TIA (not in the setting of AF) , and diabetes. (The cause of the increased risk in women is not known. It may be due to an increased thrombotic tendency.)
4. Patients were censored once warfarin was started. (Ie, this natural-history study concerned only those who were not taking warfarin.)
5. Mean follow-up = 4 years.

1. During a mean follow-up of 4 years in patients who were not anticoagulated, stroke alone occurred in 83 patients; stroke or death occurred in 383.
2. Crude incidence rates were 3 per 100 person-years for stroke, and 13 per 100 patient-years for stroke or death. (See figures on page 1052 and 1053 www.nhlbi.nih.gov/about/framingham/stroke.htm )
3. Example for risk of stroke within 5 years:

   A. The predicted highest risk (75% in 5 years) was for a female over age 93, with systolic BP over 179, with diabetes, and prior stroke or TIA.
   
   B. The predicted lowest risk (5% in 5 years) was for a male age 55-59, with a systolic BP under 120, without diabetes, and without prior stroke.

4. Risks for stroke or death were higher.

1. These risk scores can be used to estimate the absolute risk of a stroke in individuals diagnosed with new-onset AF. They can be used to stratify patents at particularly high or low risk.
2. Other risk predictors have included heart failure or left ventricular dysfunction.
3. The study did not include patients with prior stroke occurring in the setting of AF because there is broad consensus that these individuals are at high risk of events and should receive anticoagulation. (The study concerned risks following new-onset of AF. Patients with stroke or TIA in the past associated with AF were excluded because the onset of AF was not “new”. Presumably any prior stroke or TIA in the study patients was due to factors other than AF, not thromboembolism associated with AF )
4. Individuals with a 10% or lower risk of stroke over 5 years may not realize additional benefit from warfarin compared with aspirin. Their risk of stroke may not exceed the risk of bleeding due to warfarin.
5. “A potential advantage of the Framingham scheme over existing risk schemes is the greater flexibility provided by a point-scoring system because a given score may be attained by different combinations of patient characteristics.”
6. Some patients in the study were receiving aspirin. Aspirin reduces the risk of thromboembolism in AF. Therefore, the stroke rates derived by the study may underestimate the risk in persons not taking aspirin.
7. The study did not distinguish between paroxysmal and sustained AF or between AF and atrial flutter. Stroke risk associated with paroxysmal AF is similar to that of sustained AF. A large proportion of patients with flutter subsequently develop AF.
8. The risks of thromboembolic complications of AF are highly variable. It is increasingly important to be able to risk-stratify patients. These risk scores enable prediction of the risk of stoke or death over a 5-year period in an individual patient at the time of diagnosis. (Note that there was no indication in the study about the length of time AF existed before it was diagnosed. This will extend to period of risk assessment beyond 5-year. RTJ)
9. “An understanding of absolute risk is fundamental to make clinical decisions involving patients with AF such as the decision to initiate anticoagulant therapy or to temporarily stop anticoagulation for surgical procedures.”

      Prevention of ischemic stroke in patients with AF remains a major challenge. Risk of stroke may be stratified by many factors, including age, previous thromboembolic embolic stroke, hypertension, diabetes, ventricular dysfunction, mitral stenosis, coronary heart disease, female sex, thyrotoxicosis, and cardiomyopathy.
      Risk may be stratified further into mild, moderate or severe. Patients with AF, but without structural heart disease, (including no hypertension) are at relatively low risk, especially if they are under age 65.
      For patients with AF who are at higher risk of ischemic stroke, warfarin is significantly better than aspirin for preventing stroke. The prevalence of AF and risk of AF-associated embolic stroke increase with age. Risk of intracranial bleeding while taking warfarin also increases with age. Risk of bleeding, particularly related to falls, frailty, or forgetfulness is the most noteworthy reason for reluctance to anticoagualate the elderly. “Patients with the greatest risk of ischemic stroke in the face of AF are the ones least likely to receive it.” It is difficult to regulate the INR (between 2.0 and 3.0) in the elderly. One reason is the interaction of warfarin with the large numbers of other drugs they take.
      For each patient, clinicians must strike an acceptable balance between risk of ischemic stroke and bleeding. In the absence of an absolute or important relative contraindication, the data seem compelling that warfarin therapy should be offered to most patients with AF. The difficulty is to know what threshold of stroke risk is low enough so that the potential risk of warfarin therapy outweighs its potential benefits. For most patients the potential benefits of stroke prevention will outweigh the potential risks of bleeding secondary to warfarin.
      The advent of new anticoagulants such as the direct thrombin inhibitor ximelagatran may simplify decision-making.

1. Randomized, double-blind study entered over 700 consecutive patients (mean age = 57). All had one or more episodes of UVTE. All had completed 3 or more months of conventional warfarin therapy (INR target 2.0 to3.0).
2. All episodes were unprovoked deep venous thrombosis or pulmonary embolism. No patient had a major risk factor for VTE (recent trauma, fracture, cancer, hospitalization with confinement to bed, or surgery).
3. Factor V Leiden was present in 171 (26%); prothrombin gene mutation present in 60 (9%).
4. Randomized, after the first 3 months to continued warfarin with 1) a target INR of 2.0 to 3.0 (conventional intensity), or 2) a target INR of 1.5 to 1.9 (low intensity).
5. Follow-up = an average of 2.4 years

1.  

   Outcome	INR 2.0 to 3.0 (n = 369)	INR 1.5 to 1.9 (n = 369)
   Recurrent VTE	6 (1.6%)	16 (4.3% )
   	0.7 per 100 patient years	2.8 per 100 patient-years.
   Major bleeding	8 (2 %)	9 (2 %)

2. No significant difference in frequency of overall bleeding between groups.
3. INR control was excellent. Mean INR in the low-intensity group was 1.8; in the conventional group, 2.4. In the remainder of the patients, INR fell above and below these levels to roughly the same extent. There was no instance where INR exceeded 4.0

1. Conventional-intensity warfarin (INR 2.0 to 3.0) was more effective than low-intensity warfarin (1.5 to 1.9) in preventing recurrence in patients with UVTE
2. The study found no significant increase in bleeding in the INR 2-0 to 3.0 group
3. As in other studies, factor V Leiden and prothrombin mutations were not associated with a higher risk of recurrent VTE when the patients were anticoagulated.

1. Prospective cohort study entered over 600 patients who had a history of a first spontaneous VTE. All had been treated with oral anticoagulation for at least 3 months.
2. Measured D-dimer levels shortly after discontinuation of anticoagulation.
3. Followed frequently for recurrence of VTE over a mean of 38 months.
4. A high percentage of these patients had thrombophilic factors present (factor V Leiden, prothrombin mutation, and high factor VIII).

1. VTE recurred in 79 (13%) of 610 patients. Patients with a recurrence had significantly higher mean D-dimer levels compared with those without recurrence. (553 ng/mL vs 427 ng/mL).
2.  

   D-dimer level (ng/mL)	< 250	250-499	500-749	> 750
   Number of recurrences	16 (8%)	39 (16%)	11 (14%)	13 (19%)
   Relative risk of recurrence	0.3	0.6	0.6	1.0

3. A total of 209 (34%) of 610 patients had D-dimer levels less than 250. VTE recurred in 8% of these patients. They had significantly fewer thrombotic risk factors such as factor V Leiden, and high factor VIII compared with patients with higher D-dimer levels.
4. The cumulative probability of recurrent VTE at 2 years among those with levels < 250 was 3.7%. Among those with higher levels was 11.5%.
   
   

1. Patients with a first spontaneous VTE and a D-dimer level of less than 250 ng/mL 3 weeks after discontinuation of oral anticoagulation were at low risk of recurrence.
2. Extensive screening for thrombophilic factors in patients with unprovoked VTE has become more common. Assessing the overall risk of recurrence is intricate. Many patients carry more than one thrombogenic risk factor. The effect of compound defects tends to be multiplicative rather than additive. Thus, a simple test that measures multifactorial thrombophilia is required.
3. D-dimer allows a global assessment of thrombotic tendency. It allows stratification into high and low-risk with regard to recurrence.

1. Analyzed data from over 122 000 patients with CHD. This included patients with ST-elevation myocardial infarction, with unstable angina, and those undergoing percutaneous coronary intervention (PTCI).
2. Determined prevalence of each CRF and the number of CRFs present among patients with CHD.
3. Main outcome measures = prevalence of each CRF compared between men and women and by age at trial entry.

1. Among patients with CHD, at least one risk factor was present in 85% of women and 81% of men.
2. In younger patients (men , age < 55; women age < 65), and most patients with unstable angina or presenting for PTCI, only 10% to 15% lacked any of the CRFs.
3. Premature CHD was related to cigarette smoking in men, and to cigarette smoking and diabetes in women. Smoking decreased the age at the time of the first CHD event by nearly one decade.
4. Prevalence of CRF:

   	Women	Men
   Current smoking	29%	42%
   Diabetes	23%	15%
   Hyperlipidemia	40%	34%
   Hypertension	56%	38%

5. Number of risk factors

   0	15%	19%
   1	37%	43%
   2	33%	28%
   3	13%	9%
   4	1%	1%

1. In patients with CHD, conventional risk factors were present at a much higher level than commonly believed. Only 15% to 20% lacked any of the factors.
2. Cigarette smoking played a critical role in the development of premature CHD.
3. Overall, the prevalence of risk factors was greater in women than in men. Because CHD typically presents 10 years later in women than in men, higher risk factor prevalence in women is necessary to lead to the development of CHD at the same age as in men. Diabetes virtually negates the usual protection women have against CHD.
4. “Although widely asserted, the belief that more than 50% of patients with CHD lack conventional risk factors is not supported by primary data.”
5. “In essence, patients without conventional risk factors are unlikely to develop CHD.”
6. “The true prevalence of conventional risk factors is certainly higher than identified in our study.” Many patients with hypertension and diabetes are not aware of their condition. More stringent cutoffs for abnormal BP, lipids, and blood glucose have been increasingly recommended. Self-report of risk factors has been shown to systematically underestimate the true prevalence of risk factors as measured objectively.
7. “It is increasingly clear that the 4 conventional risk factors and their resulting health risks are largely preventable by a healthy life-style.”

C-reactive protein
Lipoprotein (a)
Fibrinogen
Homocysteine.

1. Healthy young adults (age 27-30; n = 750; about equally male and female) completed a questionnaire on risk factors. All underwent blood tests and assessment of CIMT by ultrasound.
2. Correlated CIMT with risk factors.

1. Body mass index, age, pulse pressure, male sex, and LDL-cholesterol were independently associated with increased CIMT.
2. Total pack-years of smoking showed a linear trend with increased CIMT.
3. CIMT increased gradually and significantly with the number of risk factors present.
4. The estimated absolute risk for development of coronary heart disease (CHD) within 20 years (based on the Framingham data) was over two times higher in individuals with a CIMT in the highest quartile as compared with those in the lowest quartile.

1. Age, BMI, pulse pressure, LDL-cholesterol, and male sex were independent determinants of CIMT in these young adults.
2. Risk of CHD within 20 years rose gradually with increasing CIMT in these young adults. (As shown previously in older adults.) Men with 3 or more risk factors had 6% thicker CIMT than those with no risk factors. Women had a 4% greater thickness.
3. Modification of risk factors early in life may postpone development and progression of subclinical atherosclerosis, which in turn, would delay the onset of clinical manifestations of CVD later in life. Risk factors in children may be easier to change.

1. Recruited 153 patients with FH (age range, 19 to 79; mean = 46). All patients received simvastatin 80 mg daily for 2 years.
2. Determined IMT of segments of the common carotid artery and femoral artery at baseline and at 2 years.
3. End point = change in the mean combined IMT of carotid and femoral arterial segments at 2 years.

1. Over the 2 years, total cholesterol declined by 36%; LDL-c by 44%, triglycerides by 25%. HDL-cholesterol rose by 7%.
2. The mean baseline arterial IMT was increased by at least twice that of normal controls. In the subset of patients with cardiovascular disease (24%), IMT was increased to a greater degree.
3. After 2 years, mean IMT declined by 0.08 mm. The largest decline was in the femoral artery (-0.3 mm)
4. An actual decrease in IMT occurred in 70% of all patients.
5. In the 30 patients receiving antihypertension drugs (calcium antagonists, ACE inhibitors, or beta-blockers), the mean combined IMT was reduced to a greater extent compared with patients who were not receiving these drugs.

1. Even 1 year of treatment was sufficient to reduce mean IMT.
2. The decrease in IMT of the degree observed is likely to have a significant clinical impact of prevention of coronary artery disease.
3. Other studies reported that beta-blockers, added to statins in hypercholesterolemic patients, have a synergistic effect on decreasing IMT.
4. Safety and tolerability of the statin were excellent.

      1) Intense preoccupation with body weight and shape.
      2) Repetitive episodes of binge eating (uncontrollable eating a large quantity of food in a defined period—usually less than 2 hours.
      3) Routinely taking extreme measures to prevent weight gain: self induced vomiting, fasting, exercise, and misuse of laxatives and diuretics. Some patients take up to 50 laxative pills per day. Severe constipation with a laxative-dependence syndrome may result.

      1) Antidepressants can reduce binge eating and purging, improve depression and attitudes toward food. Fluoxitine (Generic; Prozac) is the only selective serotonin reuptake inhibitor known to be effective treatment. There is insufficient evidence about its role in maintenance therapy.
      2) Cognitive behavior therapy is equally effective. A therapist leads the patient to realize what her eating habits are and to change them. Therapists use many different techniques to help patients understand their problem and change their thinking and behavior.
      3) Combined treatment is more effective than either alone.

1. Multicenter hospital-based case-control study recruited 155 consecutive cases of a first documented episode of idiopathic (unprovoked) VTE (92 with pulmonary embolism and 63 with deep venous thromboembolism):
   

   Cases—VTE present. Women with previous VTE were excluded.
   Controls--381 controls—no VTE, matched for center, age (62), and time of recruitment.

1. Comparison:

   	Cases	Controls
   Current users of oral estrogen	21%	7%

2. Odds ratio for VTE among users of oral ERT compared with non-users was 3.5. Odds ratio for VTE among users of transdermal ERT compared with non-users was 0.9.
3. Likelihood of VTE in oral users was 4 times that of transdermal users.
4. Likelihood of VTE among users of oral VTE increased with duration of use.

1. Risk of VTE was greater in patients receiving current oral ERT than in patient receiving transdermal ERT. Risk was highest in the first year of use of oral ERT.
2. Indeed, there was no association between transdermal ERT use and VTE.
3. Oral, but not transdermal estrogen leads to high hormone concentrations in the liver and promotes hepatic protein synthesis. This increases concentrations of some prothrombin fragments, generates thrombin, lowers antithrombin concentration, and increases resistance to activated protein C.
4. Transdermal estrogen has little or no effect on hemostasis. It causes none of these hemostatic changes.
5. The relation between oral ERT and VTE is biologically plausible.
6. For women at high risk of VTE who have disturbing menopausal symptoms, use of short-term transdermal estrogen might be an important clinical choice.

1. Prospective cohort study recruited over 1000 pregnant women immediately after their positive pregnancy test. Mean gestational age at entry was 40 days.
2. Determined NSAID, aspirin, and acetaminophen use.
3. Main outcome measure = pregnancy outcomes up to 20 weeks of gestation.

1. 53 women (5% of cohort) reported prenatal NSAID and aspirin use around time of conception or during pregnancy.
2. Use around the time of conception and during pregnancy was associated with an adjusted 80% increased risk of miscarriage.
3. Outcomes: miscarriage occurred in 162 women:

   Non-users (n= 980)	149 (15% had a miscarriage)
   Users (n=53)	13 (25% had a miscarriage)

   ( Absolute difference = 10%; NNT (harm one patient) = 10)
4. Of 162 patients with miscarriage, 8% used NSAIDs; of 871 without miscarriage, 5% used NSAIDs.
5. Associations with aspirin were similar.
6. The association was stronger if the initial NSAID or aspirin use was around the time of conception, or if use lasted more than a week.
7. Acetaminophen was not associated with increased risk.

1. NSAIDs and aspirin inhibit prostaglandin biosynthesis in most organ systems. Acetaminophen inhibits prostaglandin synthesis only in the central nervous system.
2. Prostaglandins may be needed for successful implantation of the embryo. Abnormal implantation may predispose to miscarriage.
3. The newer cyclo-oxygenase 2 inhibitors have been reported to increase peri-implantation and post-implantation losses and reduce fetal survival in animals.
4. Suppression of prostaglandin production by NSAIDs may have an adverse effect on placental perfusion and circulation, thus increasing likelihood of fetal loss.
5. These findings require confirmation.