9-1 EVIDENCE FROM RANDOMIZED TRIALS ON THE LONG-TERM EFFECTS OF HORMONE REPLACEMENT THERAPY
      Over 5 years of use by 1000 healthy post-menopausal women HRT was estimated to cause:
      In women age 50-59: 6 extra strokes, 6 breast cancers, and 6 extra pulmonary emboli.

Prevent 2 colorectal cancers and 2 fractured femurs.
In women age 60-69: 12 extra strokes, breast cancers, and pulmonary emboli.
Prevent 5 colorectal cancers and 5 fractured femurs.

Women age 50-59: 1 per 230 users
Women age 60-69: 1 per 150 users

9-2 HORMONE REPLACEMENT THERAPY AND ASSOCIATED RISK OF STROKE IN POSTMENOPAUSAL WOMEN.
      Cardiovascular risks may be greater in the first year of HRT use.
      Lower doses of estrogen may be safer.

9-3 A RANDOMIZED TRIAL COMPARING RADICAL PROSTATECTOMY WITH WATCHFUL WAITING IN EARLY PROSTATE CANCER
      In a select group of generally healthy men mean age 65 with moderately-well, or well-differentiated PC, the study found a statistically significant difference in the risk of death over 6 years due to PC after radical prostatectomy as compared with watchful waiting (surgery – 5%; waiting – 9%).
      Local progression and distant metastases were much less common in the surgery group.
      No difference in overall mortality.

9-4 QUALITY OF LIFE AFTER RADICAL PROSTATECTOMY OR WATCHFUL WAITING
      Assignment of patients to watchful waiting or radical prostatectomy entails different risks, but on average, the choice has little if any influence on well-being and or subjective quality of life after 4 years.

9-5 SURGERY AND THE REDUCTION OF MORTALITY FROM PROSTATE CANCER.
      Should all undergo radical prostatectomy? The answer is a categorical “no”.
      Should no one be followed by watchful waiting? The answer is a categorical “no”.
      In a young man with localized mild- to moderate-PC who is otherwise in good health, surgery performed by an experienced surgeon, is an excellent option. And his subsequent quality of life should be more satisfactory.

9-6 MANAGING ACUTE APPENDICITIS
      The simple expedient of close observation and repeated re-evaluation has been shown to reduce the unnecessary exploration rate. The single greatest change in surgical practice has been the widespread introduction of laparoscopy. It has been quickly applied to the problem of acute appendicitis. A systematic review reported that laparoscopic appendectomy halves the number of wound infections, reduces pain, and shortens hospital stay and time to return to work. This is at a cost of a three-fold increase in the number of postoperative intra-abdominal abscesses.

9-7 WALKING COMPARED WITH VIGOROUS EXERCISE FOR THE PREVENTION OF CARDIOVASCULAR EVENTS IN WOMEN
      Walking and vigorous exercise were associated with similar risk reductions.
      Both walking and vigorous exercise were associated with substantial reductions in incidence of cardiovascular events among postmenopausal women, irrespective of race, ethnic group, age and body mass index. Prolonged sitting increased risk.

9-8 SPLINTING VS SURGERY IN THE TREATMENT OF CARPAL TUNNEL SYNDROME
      Treatment with open carpal tunnel release surgery resulted in better outcomes than treatment with wrist splinting for patients with CTS.

9-9 EFFICACY, TOLERABILITY AND UPPER GASTROINTESTINAL SAFETY OF CELECOXIB FOR TREATMENT OF OSTEOARTHRITIS AND RHEUMATOID ARTHRITIS: Systematic Review
      Celecoxib was as effective as other NSAIDS for relief of symptoms of arthritis, and had significantly improved gastrointestinal safety and tolerability even when aspirin was co-administered.

9-10 OBSERVATIONAL STUDY OF UPPER GASTROINTESTINAL HAEMORRHAGE IN ELDERLY PATIENTS GIVEN SELECTIVE CYCLO-OXYGFENASE-2 INHIBITORS OR CONVENTIONAL NON-STEROIDAL ANTI-INFLAMMATORY DRUGS.
      This population-based observational study found a lower short-term risk of upper gastrointestinal hemorrhage associated with selective COX-2 inhibitors compared with non-selective.
      But, risk of hemorrhage in those taking celecoxib was not increased compared with non-takers.

9-11 EFFICACY AND SAFETY OF COX-2 INHIBITORS
      “At present, it is still difficult to give patients an honest, accurate, and understandable account of the balance between relief of pain and improved function on one hand and the likelihood of serious adverse effects on the other.”
      More information is required for prescribers to be able to make rational decisions about the use of these agents, particularly in older people in whom co-morbidity is common.
      They may be safer, but they are not safe.

9-12 SPONTANEOUS TALKING TIME AT START OF CONSULTATION IN OUTPATIENT CLINIC.
      The average patient visiting a doctor in the USA gets 22 seconds for his initial statement, then the doctor takes the lead. Doctors may assume that patients will mess up the time schedule if allowed to talk as long as they wish.
      This study asked – How long will patients actually talk, at least initially, if they are not interrupted? How long would it take outpatients to indicate they have completed their story?
      Mean talking time was 92 seconds. About 3 out of 4 patients completed their statement within 2 minutes. Few patients talked more than 5 minutes.

9-13 PATIENTS’ PERCEPTIONS OF ENTITLEMENT TO TIME IN GENERAL PRACTICE FOR DEPRESSION.
      Patients’ self-imposed restraint in taking up doctors’ time. This has important consequences for the recognition and treatment of depression. Doctors need to have a greater awareness of patients’ anxieties about time and should move to allay such anxieties by preemptive reassurance and reinforcing patients’ sense of entitlement to time.

9-14 PATIENT’S VIEWS OF THE GOOD DOCTOR
      ”Technical Skill, Humaneness, Competence, Time For Care, Listening, Involving Patients In Decisions, Communication, Trust, Support, Reassurance” Quite An Order. Nevertheless, “Most doctors are good doctors in the eyes of most patients.”

9-15 EFFECTS OF LOSARTAN ON CARDIOVASCULAR MORBIDITY AND MORTALITY IN PATIENTS WITH ISOLATED SYSTOLIC HYPERTENSION AND LEFT VENTRICULAR HYPERTROPHY
      Therapy based on the angiotensin II blocker, losartan, was more effective than a beta-blocker-based therapy with atenolol in preventing CV morbidity and mortality (especially stroke) in patients with isolated systolic BP and left ventricular hypertrophy.
      However, the NNT for one year is over 100. Additional cost is over $400 a year.

9-16 PLASMA NATRIURETIC PEPTIDES FOR COMMUNITY SCREENING FOR LEFT VENTRICULAR HYPERTROPHY AND SYSTOLIC DYSFUNCTION: The Framingham Heart Study
      In a large community-based sample, the performance of BNP and ANP for detection of elevated LV mass and LVSD was suboptimal. Natriuretic peptides are of limited usefulness as mass screening tests.

9-17 PEGINTERFERON ALFA-2a PLUS RIBAVIRIN FOR CHRONIC HEPATITIS C VIRUS INFECTION
      In patients with chronic hepatitis C, peginterferon alfa-2a once weekly + ribavirin daily offered significantly enhanced sustained virologic responses in all patients regardless of HCV genotype and viral load. The combination was tolerated as well as other regimens.

9-18 FONDAPARINUX VS ENOXAPARIN FOR THE PREVENTION OF VENOUS THROMBOEMBOLISM IN MAJOR ORTHOPEDIC SURGERY.
      In patients undergoing orthopedic surgery, fondaparinux (a factor Xa inhibitor) once daily, starting 6 hours post surgery, showed major benefit over enoxaparin (a low-molecular weight heparin) in reducing DVT at the expense of a slightly increased risk of bleeding.
      Fondaparinux may be a valuable addition to anticoagulant therapy.

9-19 PEPTIC-ULCER DISEASE
      A review of the remarkable progress in our understanding over the past 20 years.
      Many questions answered; more questions arise.

1. Population-based case-control study assessed whether HRT was associated with incidence of stroke.
2.  

   A.	Cases: All post-menopausal women enrolled in a health maintenance organization (~ 570 000 enrollees; mean age = 69) who sustained an incident ischemic (n = 726) or hemorrhagic (n = 213) stroke. (Total = 949)
   B.	Controls: Randomly selected matched patients without a stroke. (n= 2525)

3. Determined HRT use in both groups. Follow-up = 10 years.

1. Over the follow-up period, after risk factor adjustment, ischemic and hemorrhagic stroke were not associated with current use of estrogen with progestin or with estrogen alone, compared with never-use:
   

   Adjusted odds ratio of ischemic stroke
   Never-use	1.00 (Reference)
   Current use estrogen + progestin	0.97
   Current use estrogen only	0.94
   Past use estrogen + progestin	0.90

2. However, the risks of stroke were increased 2-fold during the first 6 months of hormone use.
         Incidence of stroke in the first 6 months of HRT use: Compared with never-users, adjusted odds ratio of stroke in the first six months of HRT use was 1.7.
         (Note these are small numbers of stroke. Suggestive, not definitive evidence RTJ .)
3. Over a mean of 7 years use, stroke was less common in those taking estrogen equivalent to 0.3 mg conjugated estrogen compared with those taking 0.625 or more:
        

   Adjusted odds ratio of ischemic stroke.
   0.3 mg	1.00 (referent)
   0.625	1.44
   > 0.625	2.41

1. Overall, in this case-control study, ever use of estrogen, past use of estrogen, current use of estrogen, and current use of estrogen/progestin were not associated with risk of stroke after adjustment for cardiovascular risk factors.
2. But, incidence of both ischemic and hemorrhagic stroke appeared to increase transiently in the first 6 months of use.
3. Use of lower doses of estrogen (0.3 mg) appeared to be safer regarding incidence of stroke than higher doses. This is in agreement with previous studies.
4. The authors admit the small numbers of subjects was a weakness of the study.

1.       Followed over 650 men (mean age = 65; all under age 75) with clinical stage T1b, T1c, and T2.
         All had newly diagnosed adenocarcinoma of the prostate. All were in a generally good physical condition and mental status expected to permit a radical prostatectomy and a follow-up of at least 10 years.
         All cancers were in early stages, either clinically inapparent, or confined to the prostate.
         Some were diagnosed by needle biopsy performed because of an elevated prostate-specific antigen. (Had to be less than 50 ug/mL)
         The tumor had to be well differentiated or moderately well differentiated. Men with poorly differentiated PC were excluded. ¹
         Those diagnosed by an extended biopsy protocol were accepted if less than 25% of the tumor was Gleason grade 4, and less than 5% was Gleason grade 5.
         None had metastasis seen on bone scan. None had evidence of upper urinary tract obstruction.
   
   
2. Randomized to: 1) watchful waiting, or 2) radical prostatectomy.
3. Primary end point = death due to PC. Secondary endpoints = overall mortality, metastasis-free survival, and local progression.
4. Follow-up a median of 6 years.

1. Outcomes over a median of 6 years:

   	Surgery (n=348)	Watchful waiting (n = 347)	Absolute Difference	NNT(to benefit one over 6 y)
   Death (all causes)	53 (15%)	62 (18%) 2	3%	33
   Death due to PC	16 (5%)	31 (9%)	4%	25

2. Outcomes at 8 years  

   Death due to PC	7%	14%	7%	14
   Local progression	19%	61%	42%	2.4
   Distant metastases	13%	27%	14%	7
   Overall mortality	28%	22%	6%	16 *

   (* Favors ww; not statistically significant. The differences in favor of surgery in PC death, local progression, and distant metastases are impressive. RTJ )
3. Overall, 116 in the watchful waiting group (25%) and 80 (17%) in the surgery group received hormonal treatment.
4. The cumulative hazard for death from PC increased over time with a difference favoring surgery. Absolute difference at 5 years = 2%; at 8 years = 6%.

1. The study found a statistically significant difference in the risk of death over 6 years due to PC after radical prostatectomy as compared with watchful waiting (surgery – 5%; waiting – 9%)
2. All who died of PC had clinically verified metastases, and all received palliative hormonal therapy. There was no significant difference in overall mortality.
3. The authors stress that results were obtained in a group of men with well-differentiated or moderately well differentiated PC.
4. Surgical removal of the primary tumors will prevent spread and provide cure only in men with localized disease at diagnosis. This effect will be tangible beyond 5 years after surgery.
5. Any benefit from surgery must be weighed against the side effects of surgery – erectile dysfunction and urinary leakage (and surgical mortality). And the side effects of watchful waiting – obstructed voiding and possibly fecal leakage. The level of distress varies considerably among subjects. Men give different priorities to survival and to avoidance of therapy-induced distress.
6. The choice in early PC is complex. Patients need complete information about alternatives. Physicians need to know about individual patients’ concerns.
7. Outcomes may differ with elapse of more time.

1. Randomly assigned and followed 326 men (mean age = 64) with localized PC.
2. Detailed questionnaire obtained information about various physical and psychological changes in quality of life.

1. Outcomes at mean of 4 years:

   	Surgery (%)	Waiting (%)
   Erectile dysfunction	80	45
   Urinary leakage	49	21
   Urinary obstruction	28	44

2. Bowel function, anxiety, depression, well-being, and subjective quality of life were similar in the 2 groups.

1. Men who underwent surgery had a higher prevalence of erectile dysfunction, and urinary leakage, but a lower prevalence of obstructive voiding problems.
2. The data were consistent with no difference between the 2 groups regarding psychological symptoms, well-being, subjective quality of life.
3. There was no data concerning the extent to which surgeons attempted to preserve erectile nerves.
4. The study leaves little doubt that bladder emptying function is improved by radical prostatectomy.
5. There was no evidence of disturbance in bowel function. Radiotherapy is undoubtedly associated with this risk.
6. “We cannot say that radical prostatectomy is better than watchful waiting for all men with localized prostate cancer.” “Each man must judge for himself.”

Should all undergo radical prostatectomy? The answer is a categorical “no”.
Should no one be followed by watchful waiting? The answer is a categorical “no”.

1. Prospectively examined: walking, vigorous exercise, total physical-activity score. and hours spent sitting as predictors of total cardiovascular events among over 73 000 postmenopausal women age 50 to 79.
2. All were free of diagnosed cardiovascular disease and cancer at baseline.
3. Questionnaire asked for detailed data about physical activity. Divided participants into quintiles of total metabolic equivalent hour (MET-Hr per week) categories of walking and vigorous activity.
4. Follow-up = 6 years.

1. Documented 345 newly diagnosed cases of coronary heart disease (CHD), and 1551 total cardiovascular disease (CVD) events.
2. An increasing physical-activity score had a strong, graded inverse association with risk of both CHD and CVD.
3. Results were similar between white and black women.
4. Age-adjusted relative risk according to quintiles of increasing energy expenditure:

   Coronary heart disease	1.00, 0.73, 0.69, 0.68, 0.47
   Total cardiovascular disease	1.00, 0.89, 0.81, 0.78, 0.72

5. Risks of cardiovascular disease over 6 years according to quintiles of MET-hours per week:

   Quintile	1	2	3	4	5
   Total exercise
   Total MET-hr/wk (median)	0	4.2	10	17	33
   CHD (No. of cases)	92	70	68	70	45
   Total CVD (No. of cases)	396	342	304	281	228
   Walking
   Total MET-hr/wk (median)	0	1.5	4	8	17
   CHD (No. of cases)	133	64	52	47	48
   Total CVD (No. of cases)	550	322	249	236	194
   Vigorous exercise
   Total min strenuous exercise /wk	0	30	90	140	210
   CHD (No. of cases)	269	35	13	14	14
   Total CVD (No. of cases)	1220	125	78	61	67

6. Walking and vigorous exercise were associated with similar risk reductions.
7. Results did not substantially vary according to race, age, and body mass index.
8. A brisker walking and fewer hours spent sitting predicted lower risk. As walking speed increased – casual, brisk, very brisk – risk was reduced.
9. Relative risk of CVD between hours sitting and lying down increased as the time increased. Among women who spent 12 to 15 hours per day lying down or sleeping relative risk was 1.4 compared with more active women. Among women who spent at lest 16 hours per day sitting, relative risk of CVD was 1.7 compared with women who spent less than 4 hours per day sitting.

1. In this cohort of post-menopausal women, both walking and vigorous exercise were associated with substantial reeducations in cardiovascular events.
2. Prolonged time spent sitting or lying down predicted increased risk.
3. Results were similar among white and black women, among different age groups, and categories of body mass index.
4. This study lends support to the current federal guidelines that endorse moderate-intensity exercise for at least 30 minutes daily.
5. “Evidence of the applicability of these guidelines to non-white women is of particular importance because of the high prevalence of sedentary lifestyles, obesity and related conditions minority populations.”
6. The strong dose-response gradient observed between physical activity and reduced risk and the consistency of the findings across strata of age, race, and body-mass index lend credence to a causal relationship in women.
7. Physical activity has also been linked to improvement in emotional well being.

1. Randomized, controlled trial followed 147 outpatients. All had clinical CTS confirmed electrophysiologically.
2. Randomized to: wrist splinting during the night for at least 6 weeks, or 2) open release surgery.
   The splint was custom made. It immobilized the wrist in a neutral position. (Both extension and flexion of the wrist can increase pressure on the nerve. RTJ) Surgery consisted of release of the transverse carpal ligament
3. Main outcome (intention to treat) = general improvement and number of nights waking up due to symptoms.
4. Final follow-up assessment = 18 months.

1. Surgery was more effective:
   General improvement at 3 months 80% vs 54% (Absolute difference = 26%; NNT one patient = 4)
   At 18 months, success rates increased to 90% in the surgery group vs 75% in the splinting group. However, by that time, 41% of the splint group had also received surgery.
2. Adverse effects in both groups were generally mild and of short duration. One patient who underwent surgery developed reflex sympathetic dystrophy.

1. Surgery was more effective than splinting at 3, 6, 12, and 18 months.
2. A large number of patients originally assigned to splinting crossed over to surgery.
3. The least severe and the most severe cases were probably not included in this trial. These patients and their physicians typically have a strong preference for splinting or surgery.
4. The American Academy of Neurology recommends treatment of CTS with non-invasive options (eg, splinting) first and surgery only if the non-invasive approach fails. A splint might be used while a patient waits for surgery.
5. A recent randomized controlled trial reported that splinting offered more relief than no treatment.

1. Systematic review of 9 randomized trials comparing use of celecoxib with other NSAIDs in over 15 000 patients. Use was continued for at least 12 weeks.
2. Compared effectiveness, tolerability safety, and withdrawal rates.
3. Compared safety of celecoxib alone with celecoxib + aspirin.

1. Celecoxib was equally effective as other NSAIDs for relief of symptoms.
2. Tolerability at 12 weeks:

   Celecoxib vs placebo:	Celecoxib	Placebo	Absolute diff	NNT (To withdraw one patient)
   Withdrawal due to any adverse effect	9%	6%	3%	33
   Withdrawal due to any GI adverse effect	3%	2%	1%	100
   (Withdrawals more common than with placebo.)
   Celecoxib vs other NSAIDs
   Withdrawals due to any adverse effect	8%	10%	2%	50
   Withdrawals due to any GI adverse effect	3%	6%	3%	33
   (Withdrawals less common than with other NSAIDs.)

3. Tolerability at 24 weeks:

   Withdrawals due to bleeding, symptomatic	Celecoxib	NSAIDs	Absolute difference
   ulcers, perforation, and obstruction	0.76%	1.23%	0.47%
   (Celecoxib is safer, but far from safe!)

4. What is the impact of celecoxib added to prophylactic aspirin?

   Ulcers detected by routine endoscopy at 12 weeks:	Celecoxib	NSAIDs	Absolute difference
   No prophylactic aspirin	6%	23%	17%
   Prophylactic aspirin	12%	26%	14%

   (Celecoxib + aspirin safer than NSAIDs + aspirin; but not safe!)

1. Observational cohort study identified over 43 000 patients over age 65 who were taking a variety of NSAIDs: [non-selective NSAIDS; diclofenac (Generic) plus misoprostol (Cytotec); rofecoxib (Vioxx); celecoxib (Celebrex) and a randomly selected cohort of over 100 000 subjects not taking NSAIDs.]
2. All patients were NSAID-naïve and had started NSAID use in the years 2000 and 2001.
3. Main outcome = rates of hospital admissions for upper gastrointestinal hemorrhage, as adjusted for potential confounders.

1. Relative to controls, there was an increased short-term risk of hemorrhage for users of:

   Non-selective NSAIDs	Rate ratio =	4
   Diclofenac plus misoprostol		3
   Rofecoxib		1.9
   Celecoxib		1.0

2. The NNT to cause hemorrhage = 403 for non-selective NSAIDs; 592 for diclofenac-misoprostol; 1389 for rofecoxib. (Users of rofecoxib had a significantly reduced risk of hemorrhage compared with the other 2 groups.)
3. But, risk of hemorrhage in those taking celecoxib was not increased compared with non-takers. (Rate ratio = 1.0) (The risk of rofecoxib was higher that that for celecoxib.).
4. “The differences in unobserved covariates between rofecoxib and celecoxib groups are probably minimal and would not explain the difference in upper gastrointestinal hemorrhage between the two drugs.”

1. Recruited a sample of 32 general practice patients with recently diagnosed mild to moderate depression.
2. Interviewed them to assess their perceptions of entitlement to time in the consultation.

1. An intense sense of time pressure and a self-imposed rationing of time in consultations were key concerns among the patients.
2. Anxiety about time affected their freedom to talk about their problems.
3. Patients took upon themselves part of the responsibility for managing time in the consultation to relieve the burden they perceived their doctors to be working under.
4. There was often a mismatch between patients own sense of time entitlement and the doctors’ capacity to respond flexibly and constructively in offering extended consultation time when this was necessary. There was often a disparity between patients’ sense of time shortage and the amount of time their doctors were willing to and able to provide.
5. Patients valued time to talk and would often have liked more, but they did not necessarily associate length of time with quality.
6. The impression the doctor gave in handling time in the consultation sent strong messages about legitimizing the patients’ illness and their decision to consult.

1. “It is the patients rather than doctors who take the initiative in rationing consultation time.” In effect, the patients in this study often failed to capitalize on the resource that was on offer, feeling unable to use the time their doctors were willing to provide. Consequently, they left with questions unasked and issues unexplored.
2. This inhibits the development of more patient-centered and concordant consultations. Paradoxically, it may be patients’ concern to keep within their perceived time entitlement that causes time to be “wasted” in ineffective and superficial consultations from which they derive little benefit. Patients with depression feel under such acute pressure of time that they are often inhibited from fully disclosing their problems.
3. Despite their anxieties about time, patients quite commonly reported receiving more time than they expected, especially during the first consultation for depression. When patients presented with severe distress, some doctors managed to find up to an hour or more to extend the consultation. Patients were deeply appreciative of this kind of response.
4. The scope for flexible and creative use of time still obtains (though doubtless reinforcing the stress of other patients in the waiting room). There is a wide range of consultation times.
5. The quality of patients’ relationships with their doctors is fashioned over a series of consultations, it is important to take account of the extension of time across these consultations as well as what happens in discrete episodes. “Perhaps the preoccupation the average length of consultation is misplaced. Doctors’ ability to allocate time flexibly and according to individual need is what is really critical.”
6. Doctors should be more aware of patients’ anxieties about time and allay these anxieties by providing pre-emptive reassurance as a means of reinforcing patients’ sense of entitlement to consultation time.

1. Double-blind, randomized, parallel-group study entered over 1300 patients (mean age = 70).
2. All had systolic hypertension (160-200 mmHg), and diastolic pressure < 90. (Mean = 174/83)
3. All had LVH by ECG criteria based on QRS duration and voltage. (See p 1492) This subset of hypertensive patients is at higher risk of cardiovascular complications than those without LVH.
4. Randomized to: 1) losartan (50 mg) or atenolol (50 mg) . Used hydrochlorothiazide as a secondary agent in both arms. Losartan and atenolol were increased to 100 mg, and a third drug was added if needed to reduce systolic BP to < 140
5. Main outcome = composite endpoint of cardiovascular death, stroke, or myocardial infarction.
6. Follow-up – 4.7 years.

1. Fewer than 10% of patients were controlled by the original dose of 50 mg. Most required an increase in dose of losartan or atenolol, and addition of hydrochlorothiazide. . About 20% required three drugs. '
2. Over 25% in both groups discontinued therapy. Drug-related withdrawals – 7% for losartan; 13% for atenolol.
3. BP was reduced equally in both groups. (- 28/9)
4.  

   Outcomes per 100 patient years:	Losartan (%)	Atenolol (%)	Absolute difference	NNT(losartan to benefit one/y)
   Main composite outcome	2.5	3.5	1%	100
   Cardiovascular mortality	0.87	1.69	0.82%	122
   Stroke	1.06	1.89	0.83%	120
   New onset diabetes	1.26	2.02	0.75%	133
   Total mortality	2.12	3.02	0.90%	111

5. No difference in reduction of myocardial infarction.
6. Losartan regimen was associated with a greater decrease in LVH. Voltage reduction of 3.9 mm vs 2.3 mm
7. And was better tolerated. Drug related withdrawals – losartan = 15%; Atenolol = 22%

1. This confirms the hypothesis that losartan is more effective than atenolol in reversing LVH.
2. This study “showed that losartan treatment resulted in a 25% reduction in the main outcome, the predefined primary composite endpoint of CV death, stroke, and myocardial infarction vs atenolol.” ¹
3. This occurred without any difference in the degree of BP reduction.
4. “A further reduction in stroke with losartan-based therapy, as demonstrated in this study, is an important finding because stroke is a major cause of death and disability.” ¹
5. Losartan regimen was better tolerated and resulted in fewer withdrawals.
6. It is not known if losartan is superior to diuretic or calcium-blocker regimens.

1. Community-based prospective cohort study entered over 3100 participants from the Framingham Heart Study who attended routine examinations 1995-98. Patients with a history of heart failure were excluded.
2. All underwent echocardiography:

   Determined left ventricular internal dimensions, thickness of LV walls, and calculated left ventricular mass.
   Estimated left ventricular ejection fraction. [Defined as normal >55%; borderline 51%-55%; mildly reduced 41% -50%; moderately diminished 31% - 40%; severely impaired < 30%]
   Elevated let ventricular mass was defined as greater than or equal to the sex-specific 90th percentile for the entire sample.
   LVSD defined as a fractional shortening of less than 29%.

3. Measured natriuretic peptides by an immuno-radiometric assay.
4. Used a statistical analysis to compare various levels of BNP and ANP with echocardographic LSVD. (Those more expert in statistical analysis than I am, see the text. RTJ )

1. Overall, 70 (2%) subjects had moderate to severe LVSD.
2. BNP levels were in general higher in individuals with elevated LV mass and in subjects with LVSD.
3. But, various determinations of BNP and ANP concentrations identified less than 1/3 of subjects who had elevated LV mass and LVSD.

1. BNP discrimination limits (cutpoints) have limitations. They vary considerably. This is in part related to referral bias (inclusion of symptomatic and asymptomatic subjects, post-myocardial infarction patients, varying definitions of LVSD, and different NP assays.
2. In the case on NP screening for asymptomatic LVSD or elevated LV mass, because of the size of the screened population and the low prevalence of the condition, the false-positive rate of the screening test must be low to reduce the burden of expensive follow-up tests.
3. The performance of NPs for detection of LV mass and LVSD in the community was only fair in men and poor in women. The low sensitivity combined with the low prevalence of LVD may offset any potential usefulness of screening.

1. Followed over 1100 patients with chronic hepatitis C. All had at least 2000 copies of HCV-RNA per milliliter of serum by polymerase chain reaction, elevated alanine aminotransferase levels, and a liver biopsy consistent with chronic hepatitis.
2. Randomized to: 1) peginterferon alfa-2a once weekly + ribavirin once daily, 2) pegylated interferon alfa-2b + daily ribavirin, and 3) weekly pegylated interferon alfa-2a alone.
3. Defined sustained virological response as absence of detectable HCV RNA at 24 weeks after cessation of therapy.
4. Drugs were administered for 48 weeks.

1. Significantly more patients who received peginterferon alfa-2a + ribavirin had a sustained virologic response: 1) 56%; vs 2) 44%: vs 3) 29%.
2. More patients with a high viral load and those with HCV genotype 1 (more likely to be resistant) responded to peginterferon alfa-2a + ribavirin
3. Overall safety and withdrawals were similar between groups. Incidence of influenza-like symptoms and depression was higher in the peginterferon alfa-2a + ribavirin group.
4. If there was no virologic response at 12 weeks, there was almost no chance of a sustained response.

1. Peginterferon alfa-2a + ribavirin was more effective than the other 2 regimens.
2. Ability to predict response after 12 weeks of therapy is a useful clinical tool.

1. Meta-analysis of 4 double-blind trials in over 5200 patients (mean age = 68) undergoing elective knee surgery and surgery for hip fracture.
2. Compared fondaparinux (2.5 mg subcutaneously daily) with the LMWH enoxaparin (3 different preparations) 30 mg twice daily or 40 mg once daily. Fondaparinux was started 6 hours after surgery.
3. Primary efficacy outcome defined as VTE up to day 11 detected by bilateral venography, documented symptomatic deep vein thrombosis, or pulmonary embolism.

1. Fondaparinux was superior in preventing VTE:

   Outcome at day 11:	Fondaparinux	Enoxaparin	Absolute difference	NNT (benefit one patients)
   Incidence of VTE	7%	14%	7%	14
   Proximal deep vein thrombosis	1.3%	2.9%	1.6%	62

2. Benefit was consistent across all types of surgery and all subgroups.
3. Incidence of major bleeding was higher in the fondaparinux group (2.7% vs 1.7%) NNT (harm one patient = 100)
4. Incidence of bleeding (fondaparinux vs enoxaparin) leading to death (0 vs 1 patient), reoperation (12 vs 8 patients) or occurring in a critical organ (0 vs 1) did not differ statistically between groups.