Practical Pointers

Statin drugs may have effects in addition to their effect on lipids. These include modulation of inflammation, inhibition of platelet function and thrombosis, and enhancement of endothelial function. The ability of statins to immediately affect basic pathophysiologic mechanisms has increased interest in their potential role in acute coronary syndromes. (ACS)

This study examined the association between previous and early in-hospital statin therapy and outcomes of ACS.

Patients who presented with an ACS who were already taking statins were less likely to present with ST-segment elevation MI, experience a large infarct, and have important clinical complications, or die.

Much of the observed effect was lost if statin therapy was not continued during hospitalization. Such patients had death rates similar to patients who had never received statins. Withdrawal of statins reduces the protective effect of statin pretreatment.

In statin-naïve patients, early statin therapy was associated with an improvement in outcomes.

Should primary care clinicians act on these conclusions? Primary care clinicians often act on inconclusive evidence if the putative benefit/harm-cost ratio of the intervention is high. Although the outcomes of the study require confirmation and further experience, I believe the benefit/harm-cost ratio of immediate statin therapy (as of immediate aspirin therapy) for patients with ACS is potentially high. The benefit is potentially life-saving.

The harm and cost of short-term therapy is very low. I would give a high-dose statin immediately on presentation of a patient with presumed ACS.

Those on statins long-term should be continued on statins when admitted for ACS. Those not on statins should start them immediately. And,. of course, continue after discharge.

A study “Lipid-Lowering Therapy And In-Hospital Mortality Following Major Non-Cardiac Surgery” (See Practical Pointers May 2004) also presents evidence of immediate protective effects of statins given within the first 2 days after major surgery. RTJ

6-2 THE SEARCH FOR THE “HOLY GRAIL” OF CLINICALLY SIGNIFICANT CORONARY ATHEROSCLEROSIS.

In some individuals, coronary atherosclerosis (CA) is stable for years, and in others it is very unstable, with rapidly progressive lesions that result in sudden death or an acute coronary syndrome. The diagnostic “Holy Grail” of coronary atherosclerosis is not to be able to identify coronary atherosclerosis (which almost all Americans have eventually) but to identify individuals with unstable coronary atherosclerotic lesions.

The editorialist describes the evolution of our understanding the pathophysiology of CA—from the concept of a gradual process that over decades narrows the arteries, to silent CA diagnosed by treadmill exercise testing, to coronary angiography, and finally to efforts to detect unstable plaques.

More myocardial infarctions occur in the larger sub-population with negative results on a treadmill test than in those with positive results. More myocardial infarctions are caused by hemodynamically insignificant lesions than from high grade stenosis.

This editorial was written in response to a meta-analysis in this issue of Archives (pp 1285-92) which concluded that the coronary artery calcium score detected by electron-beam computed tomography is an independent predictor of coronary events.

The point of the editorial was to state that the clinical utility of fast computed tomography is not ready for prime time. While scanning may reveal calcification, individuals with unstable coronary disease are not always identified. A patient with potentially unstable coronary atherosclerotic lesions may have mildly calcified or non-calcified arteries. Patients with stable and unstable coronary atherosclerosis may have similar calcium scores.

Prevention of an essentially universal disease must be universal. Must we wait for screening tests to detect “higher risk”, and only then encourage patients to change his or her lifestyles?

6-3 NATURAL HISTORY OF EARLY, LOCALIZED PROSTATE CANCER

Even without any initial treatment, only a small proportion of patients diagnosed with PC at an early stage die of the disease within 10 to 15 years following diagnosis.

This observational study of the long-term natural history of localized PC (diagnosed at a mean age 72) assessed disease progression and mortality over years of watchful waiting.

Over 21 years, most patients died, mainly of causes other than PC. Only 9% survived.

Poor differentiation (in only 4% of the cohort) was a strong predictor of cancer-specific death. This became evident within the first 5 years.

Further follow-up after 15 years revealed a substantial worsening of the cancer. The cause-specific mortality from PC increased by 3-fold during years 15 to 20 after diagnosis. .

“If our data reflect a real phenomenon, they would imply that the probability of progression from localized and indolent to metastatic and mortal disease increases markedly after long-term follow-up.”

This would support radical treatment, notably among patients with an estimated life expectancy of over 15 years.

This would argue for greater screening of younger men; less aggressive screening in older men. Long-term follow-up may be necessary to observe the full benefits of early diagnosis and definitive treatment in younger men. Older men likely die of other causes.

According to these data, even if your PC is highly differentiated, you still run a risk of about 2 in 100 of developing metastatic disease each year, and about 1 to 2 chances in 100 of dying of PC each year. If you survive over 15 years, these chances are increased by 300%.

Prostate cancer is never cured spontaneously.

If you live long enough and are not treated, your chance of developing metastatic disease (requiring orchiectomy or estrogen therapy) and fatal PC is high, even if you have a highly differentiated PC. If you have a poorly differentiated grade PC and are not treated, you will likely die of it within 5 years.

No doubt some lives are saved by radical treatment. Who to treat and when to treat remains a dilemma. RTJ

6-4 ABSENCE OF AN EFFECT OF LIPOSUCTION ON INSULIN ACTION AND RISK FACTORS FOR CORONARY HEART DISEASE.

Abdominal obesity (increased abdominal subcutaneous fat, and increased visceral fat) is associated with insulin resistance and other risk factors for coronary heart disease (CHD).

This study asked: Which of these fat deposits is associated with insulin resistance and increased risk of CHD?

Liposuction in 15 grossly obese women reduced volume of subcutaneous abdominal fat by 44%. Weight loss = 10 kg; total body fat decreased by 18%. Liposuction did not significantly alter insulin sensitivity (assessed by stimulation of glucose uptake in muscle); did not suppress glucose production by the liver; and did not suppress lipolysis of adipose tissue.

Levels of C-reactive protein and other indicators of inflammation did not change.

Other risk factors for CHD were unchanged (BP, plasma glucose, insulin, and lipid concentrations).

Large-volume reduction in subcutaneous abdominal fat mass did not have any beneficial metabolic effects despite a considerable decrease in body weight, waist circumference, and plasma leptin concentrations

This provides insight into the mechanism by which conventional weight loss improves insulin sensitivity.

Induction of a negative energy balance, not simply a decrease in the mass of fat tissue, is critical for achieving the metabolic benefits of weight loss. Even small amounts of weight loss induced by a negative energy balance affect many variables pertaining to body-fat composition and lipid metabolism—variables that contribute to metabolic abnormalities associated with obesity. Conventional weight loss decreases visceral fat mass, intrahepatic fat, fat-cell size, and the rate of release of fatty acids from intra-abdominal adipose tissue. Liposuction does not.

Adipose tissue is now recognized as an important endocrine organ that produces several bioactive proteins. Fat loss by conventional obesity treatment decreases plasma concentrations of C-reactive protein, interleukin-6, and tumor necrosis factor. It improves insulin sensitivity and inhibits vascular inflammation.

I abstracted this article mainly to point out the risks associated with intra-abdominal fat accumulation. Visceral fat drains directly into the portal circulation and into the liver; subcutaneous fat drains into the general circulation. There is a vast metabolic difference. RTJ

6-5 THERMODYNAMICS, LIPOSUCTION, AND METABOLISM

Hyperglycemia improves rapidly during caloric restriction. It outpaces the rate of weight loss. About half of the improvements in glycemic control are achieved during the first week of a negative energy balance, although the actual fat loss is typically quite small. Substantial proportions of the early benefits of weight loss on insulin resistance and hyperglycemia in type 2 diabetes may be attributed to a negative energy balance.

Similar observations have been made concerning hypertension. Much of the decrease in BP occurs fairly rapidly in response to a negative energy balance. There is, however, a return toward hypertensive levels once weight has reached a plateau.

Visceral adiposity is strongly associated with insulin resistance. In animals, surgical resection of visceral fat tissue yields marked and nearly immediate reduction in insulin resistance. The removal of an equivalent amount of subcutaneous fat has little effect. The relation may be related, at least in part, to the release of fatty acids into the portal circulation.

Adipose tissue has endocrine functions—synthesizing leptin, adiponectin, and cytokines such as tumor necrosis factor, interleukin-6, and C-reactive protein.

During World War II type 2 diabetes practically disappeared in the Netherlands. This was related to the near starvation conditions produced by the invasion by Germany. RTJ

6-6 COMPARISON OF SURGERY AND COMPRESSION WITH COMPRESSION ALONE IN CHRONIC VENOUS ULCERATION (ESCHAR study)

Multilayered elastic compression bandaging, leg elevation, and exercise achieve healing in up to 80% at 24 weeks. However, despite continued use of elastic compression stockings, the 12-month recurrence rate is high. .

Simple superficial venous surgery (saphenous vein ablation) theoretically removes the underlying venous incompetence in legs in patients with isolated superficial reflux.

This randomized study reported that healing over 24 weeks was similar between groups. Recurrence of the ulcer within 1 year was much less likely in the surgery group. [NNT = 6]

The investigators state that about a quarter of patients with venous ulcers will refuse surgery. Primary care clinicians then deal with these individuals as best they can. RTJ

6-7 FREQUENCY OF SYMPTOMS OF OVARIAN CANCER IN WOMEN PRESENTING TO PRIMARY CARE CLINICS.

Ovarian cancer (OC) has been called the “silent killer” because symptoms are thought not to develop until advanced stages when chance of cure is poor. Standard textbooks state that symptoms do not occur until the disease is advanced. However, several retrospective studies have indicated that the majority of patients with OC do have early symptoms, although not necessarily gynecologic in nature.

Identification of early symptoms may have important clinical implications because the 5-year survival for early stage disease is 70% to 90% compared with 20% to 30% for advanced-stage disease.

This study compared the frequency, severity, and duration of symptoms typically associated with OC vs typical symptoms of women attending primary care clinics.

Women with OC described differences in symptoms compared with the typical women presenting for care. Symptoms in patients with OC were more frequent, more severe, and more often had an onset within 6 months. Patients were much more likely to have a combination of abdominal bloating, increased abdominal size, and urinary urgency.

These symptoms warrant further diagnostic intervention because they are more likely to be associated with ovarian tumors.

This requires the patient to carefully recall and describe her symptoms. And requires the physician to be especially alert about fully understanding the onset, severity, and duration of the symptoms. Clarity may be achieved only after several visits.

Physicians should ask women presenting with relatively new-onset symptoms specifically about bloating, abdominal size and urinary symptoms. RTJ

6-8 EFFECT OF LIFESTYLE CHANGES ON ERECTILE DYSFUNCTION IN OBESE MEN

Erectile dysfunction (ED) is common, even in young men. Several modifiable lifestyle factors are associated with maintenance of erectile function. Men with a body mass index over 28 have a 30% higher risk of ED. The prevalence of overweight and obesity in men reporting ED may be as high as 79%, although vascular factors associated with obesity may play an important role.

This study of obese men with ED determined if a long-term reduction in BMI and an increase in physical activity would positively affect erectile functions.

At 2 years an intensive dietary-fitness program led to over 10% loss of body weight and an increase in physical fitness. About 1/3 of the men regained erectile function.

For many patients, ED is a manifestation of more generalized pathology. Hypertension, hyperglycemia, and dyslipidemia are common co-morbidities. Endothelial dysfunction is likely a pathogenic mechanism common to these co-morbid states, risk of cardiovascular disease, and ED. The study demonstrated improvements in endothelial function related to weight loss..

This is not, however, a practical application. Few patients in primary care practice would be able to complete such a program

The main message is—maintain a healthy lifestyle, don’t wait to repair damage until after it is done. RTJ

6-9 WAITING FOR PLAN B—THE FDA AND NONPRESCRIPTION ON EMERGENCY CONTRACEPTION

The proposal to switch to levonorgestrel emergency contraception (EC; Plan B) to over-the-counter status is in limbo. In May, the FDA rejected the application for non-prescription sales. The acting director wrote that the company had “not provided adequate data to support a conclusion that Plan B can be used safely by young adolescent women for emergency contraception without the professional supervision of a practitioner licensed by law to administer the drug”. In rejecting the application, the FDA also rejected the advice of its medical review-staff. (A vote of 23 to 4 in favor of nonprescription status.)

I would be willing to wager that this decision will be reversed. RTJ

6-10 FONDAPARINUX OR ENOXAPARIN FOR THE INITIAL TREATMENT OF SYMPTOMATIC DEEP VENOUS THROMBOSIS

Fondaparinux is a selective inhibitor of activated factor X (Xa). Once-daily injections produce a predictable anticoagulant effect.

This randomized, double-blind multicenter study entered over 2200 patients (mean age 61) with established acute symptomatic DVT of the lower extremity. Randomized to fondaparinux once-daily, or the low-molecular-weight heparin enoxaparin twice-daily. Many received injections at home. All were started on oral anticoagulant therapy within 72 hours.

Double-blind subcutaneous injections were continued for at least 5 days, or until the warfarin-induced INR reached 2.0 or greater. Oral therapy was continued for 3 months

Over 3 months, outcomes were very similar between groups: recurrent thromboembolic events, pulmonary embolism, recurrent DVT, major bleeding, and death.

“This study adds to the growing body of evidence that inhibitors of activated factor X are effective, safe, and easy-to-use antithrombotics.”

There are several cautions about at-home treatment with either LMWH or fondaparinux: 1) concern about undertreatment of DVT and resultant pulmonary embolism, and 2) the need for careful laboratory monitoring of oral anticoagulation status during the first days of treatment.

Should fondaparinux be considered a “me too” drug? For a new drug to be adopted into primary care practice to replace an old effective drug, important attributes must be established—must be established as just as effective, or more effective; must be established as just as safe or safer; must be more convenient to administer and require fewer doses; must be less costly.

Study sponsored by Sanofi-Synthelabo and MV Organon. I always look for “spin” in drug-company sponsored studies. This study looks straightforward. We look for confirmation. RTJ

6-11 LONG TERM DONEPEZIL (Aricept) TREATMENT IN 565 PATIENTS WITH ALZHEIMER’S DISEASE (AD 2000)

All three available cholinesterase inhibitors produce small improvements in cognitive and global assessments in selected patients mild-to-moderate AD over 3-12 months. Little is known about long-term effectiveness, or their usefulness in patients with severe AD. Nonetheless, the demand from clinicians and patients remains strong.

This study asked whether the cholinesterase inhibitor donepezil (Aricept) is cost effective and produces worthwhile clinical and social improvements .

In absolute terms, donepezil group achieved a slightly higher score on the mini-mental-examination within the first 36 weeks (about 1 point above baseline on a 30-point scale). Thereafter, scores deteriorated back to baseline at 48 weeks and to minus 4 points at 112 weeks. The placebo group lost points continuously

during the 112 weeks.

Comparatively, over 112 weeks, donepezil group (compared with placebo) maintained a slightly better score (a fraction of one point) despite declining in absolute terms.

Donepezil was associated with no improvement in activities-of-daily living scale at any time up to 2 years, although, compared with placebo, decline in ADL score was slightly slower.

No significant benefits were seen vs placebo in institutionalization, progression of disability, behavioral and psychological symptoms, psychopathology of carers, formal care costs, adverse events, or deaths.

No evidence that costs of caring for patients with Alzheimer’s disease in the community are reduced by

donepezil. Any effect of donepezil on informal caregiver time is likely to be small.

Benefits of the acetylcholinesterase inhibitor, donepezil, are “below minimally relevant thresholds”. It is not cost effective “The disappointingly little overall benefit from donepezil cannot be taken lightly.” Clinicians can validly question whether other uses of scarce resources allocated for dementia would provide better value than routine prescription of cholinesterase inhibitors.

I believe many patients are continuing to receive CIs far beyond the time of any hope of benefit.

COST: about $1600 per year quoted by drugstore.com. As is often the case, the 10 mg dose costs just a few dollars more per year than the 5 mg dose. A pill cutter may cut cost in half. There is no statistically significant difference in effects of 10 mg vs 5 mg. Adverse effects (eg, gastrointestinal) are greater with the 10 mg dose. RTJ

6-12 AD 2000: DONEPEZIL IN ALZHEIMER’S DISEASE

Patients seen in everyday practice differ from those selected for inclusion in drug-company-sponsored trials. Drug companies use highly refined selection criteria; often include specialized tests to aid diagnosis; restrict allowable comorbidity and concomitant medications; and the extent of behavioral or functional impairment. They pay for all protocol-related care, including medications. “Typical selection criteria for industry sponsored trials would exclude over 90% of out-patients with mild-to-moderate Alzheimer’s disease in California who would otherwise be eligible to receive treatment. The controversy about effectiveness, costs, and the clinical meaning of trial results has been fueled by the use of participants who do not represent typical patients.”

In the trial, donepezil and placebo were both associated with a worsening over time. The mean differences on the MMSE and activities of daily living scale represent a delay in symptom-worsening of about 3 months.

This commentary presents a clinically important point. It emphasizes the gulf which may separate results of randomized controlled trials from benefits evident in primary care practice. There may be a large difference between results reported by a clinical trial for AD and clinical benefits for Mr. Jones, whose family brings him into your office because of memory loss. A practical office-based, “real world” trial is more meaningful and convincing. Beware of “spin”.

6-13 TACKLING THE NEXT INFLUENZA PANDEMIC

“We must now hasten the preparations for another inevitable influenza pandemic.”

A recent systemic review concluded that the prophylactic use of neuraminidase inhibitors (NIs) could lead to a reduction of 70-90% in risk of symptomatic flu. These drugs have shown efficacy in preventing transmission of influenza in institutions and community setting. The availability of a highly effective supplement to vaccination opens to debate the appropriate role of NIs and other antiviral drugs in the control of pandemic influenza.

What might be an alternative strategy? It is known that “ring” vaccination, which has been used in the past, will quell smallpox outbreaks. The strategy entails post-exposure vaccination of close contacts. For smallpox, this approach has provided a wide safety net of prevention, while focusing vaccination where it was needed most. Ring prophylaxis may be applicable to the initial management of an influenza pandemic. NI treatment of influenza cases with the infection and prophylactic use for their contacts may decrease attack rates substantially. It limits usage of the drug to where it is needed most.

Antiviral ring prophylaxis for flu has proved to be effective in family settings. It requires only short term daily treatment for a period of 5-10 days, and targets a relatively limited proportion of the population. Used in this way, NIs may be dispensed more rapidly and require less of a stockpile.

COST: Tamiflu, 75 mg cost about $6 each capsule— $60 for a treatment course; $42 for 7-day prophylaxis. I believe most patients would consider this a bargain.

Healthcare workers should be the first in line to receive “ring” prophylaxis, and to continue it until assured that the current vaccine is effective.

Primary care clinicians will likely use NIs freely to unvaccinated family members during an epidemic of flu. RTJ

6-14 DANGERS OF ROSUVASTATIN (Crestor) IDENTIFIED BEFORE AND AFTER FDA APPROVAL

The lipid-lowering drug rosuvastatin (Crestor; Astra-Zeneca) is currently in the midst of the most heavily financed launch of a prescription drug ever.

The correspondent presents available pre–marketing and post-marketing evidence of the adverse effects of the drug. The preapproval document stated that 80 mg is associated with a high frequency of creatine kinase elevations (CK 10 times upper normal). Crestor was approved with the belief that lower doses would be much safer. The 80 mg dose was subsequently discontinued.

Since marketing of rosuvastatin, there have been 18 additional cases of rhabdomyolyis. Two patients were using 40 mg; five using 20 mg; 11 using 10 mg.

The 10, 20, and 40 mg doses have been associated with a risk of renal toxicity. There have been 8 reported cases of acute renal failure and 4 of renal insufficiency since marketing began. Nine were using 10 mg; two using 40 mg. “By now, the number of reported cases of rhabdomyolyis and renal insufficiency or renal failure—20 of which have occurred in people using 10 mg—is certain to have increased substantially from the number filed by April 13, 2004.”

A statistical review of comparative efficacy found no significant difference in LDL-cholesterol lowering between 5, 10, and 20 mg of rosuvastatin and 20, 40 and 80 mg of atorvastatin. (This surrogate laboratory finding does not indicate comparative clinical effectiveness.)

Comment:

These letters raise an important clinical point. When should primary care clinicians add a new drug to their practice?

Is Crestor a unique and important addition to therapeutics? Or is it just a “me-too” drug? Should primary care clinicians prescribe it a the present time?

1. Is Crestor more effective in lowering LDL? No. Other statins lower LDL just as much, although they might require a higher dose. Remember, this is a laboratory endpoint, not a clinical endpoint. Clinical efficacy has not been established.

2. Is Crestor as safe as other statins? This is the dispute. That the 80 mg dose has been withdrawn because of toxicity raises caution. It will take several years of general use in the USA for the FDA to determine toxicity. Certainly, Crestor is not safer.

3. Is Crestor more convenient to administer. Does it require fewer doses? No

4. Is Crestor less costly? No. Costs are comparable.

The first letter may raise an entirely unwarranted red flag. I do not know. I abstracted these letters mainly to reinforce the long-honored and oft-repeated admonishment to primary care clinicians not to be the first to prescribe a new drug, no matter how highly touted, unless it is known to be safe and carry unique and important benefits. Regardless of the question of toxicity, I do not believe the benefits of Crestor are unique or comparatively important.

I would not prescribe Crestor at this time. If it proves equally or less toxic, maintains its reported comparative efficacy in reducing LDL-c, and has a significant cost benefit, I would consider prescribing it.

I have faced (as have most older clinicians) the embarrassment of having a drug I had prescribed suddenly withdrawn from the market. The patient will ask for an explanation. RTJ

Statin drugs may have important benefits if given immediately for acute coronary syndrome

6-1 ASSOCIATION OF STATIN THERAPY WITH OUTCOMES OF ACUTE CORONARY SYNDROMES: The GRACE Study

This study examined the association between previous and early in-hospital statin therapy and outcomes of ACS.

Conclusion: Statin therapy can modulate early pathophysiologic processes in patients with ACS.

STUDY

1. Multicountry observational study enrolled over 19 500 patients with ACS from 1999 to 2002.

2. All had symptoms of acute ischemia, and at least one of the following: ECG changes consistent with ACS, serial increases in biochemical markers of myocardial necrosis, documentation of coronary artery disease.

3. Treatments were defined as: no statin use; long-term use at home and within 7 days of the presenting event (but not in hospital); use in hospital only (not before hospitalization); and use both before and during hospitalization.

4. Determined hospital complications, and hospital deaths related to statin use. The composite end-point included death, in-hospital MI, and stroke.

RESULTS

1. 21% (4056) of the patients with ACS were already taking statins when they presented to the hospitals. Patients who were already taking statins when they presented to the hospital were less likely to have ST-segment elevation. (Odds ratio = 0.79); myocardial infarction (OR = 0.78); and other complications.

2. Incidence of hospital outcomes according to previous statin therapy:

Long-term use (%) No long term use (%)

Creatine phosphokinase > 2 times normal 28 45

MI after 24 hours or recurrent MI 7 10

Congestive heart failure 12 15

Cardiogenic shock 2 5

Cardiac arrest 3 6

Death 3 7

Final diagnosis:

ST-elevation MI 18 38

Non-ST-elevation MI 30 30

Unstable angina 52 32

3. Hospital outcomes according to statin groups (%):

No statin Long-term only In hospital only Long-term and hospital

Cardiogenic shock 6.5 8.7 2.5 1.6

Cardiac arrest 7.5 8.2 3.4 1.9

Ventricular tachycardia or fibrillation 5 6.2 4.1 2.8

Death 9.9 11.6 2.1 2.1

Death, stroke, or in-hospital MI 17.9 17.3 15.3 9.2

(Note that the 2 groups receiving statins in hospital had better outcomes than those who received no statins or received them long-term and discontinued on admission.)

DISCUSSION

1. Results suggest that previous statin therapy significantly affects severity of hospital presentation and hospital outcomes. Patients who presented with an ACS who were already taking statins were less likely to present with ST-segment elevation MI, experience a large infarct, and have important clinical complications, or die.

2. Much of the observed effect was lost if statin therapy was not continued during hospitalization. Such patients had death rates similar to patients who had never received statins. Withdrawal of statins reduces the protective effect of statin pretreatment

3. Previous studies have reported that statins (eg, atorvastatin) results in early (within 48 hours) decrease in C-reactive protein and augmentation of endothelium-dependent blood flow. Discontinuation in the hospital after admission for an ACS may cause a rebound phenomenon in which the protective pathophysiologic mechanisms are rapidly reversed.

4. “These findings are similar to the results of studies that have examined the effects of previous aspirin therapy on acute coronary syndrome presentation.” No reason why aspirin, beta-blockers, and ACE inhibitors cannot be used concomitantly with statins.

5. Some data suggests that initiation of lipid-lowering therapy during hospitalization in patients with acute MI is associated with long-term adherence and better post-discharge outcomes.

6. The authors state that their observational study cannot exclude possible multiple confounding factors.

CONCLUSION

This large observational study suggests that patients who are taking statins when they present with an ACS have less severe presentations, fewer in-hospital complications, and lower hospital death rates.

The observed beneficial effect on outcomes is less apparent in those who did not continue statins during hospitalization.

In statin-naïve patients, early statin therapy was associated with an improvement in outcomes.

Annals Int Med June 1, 2004; 140: 857-66 Original investigation by the GRACE (Global Registry of Acute Coronary Events) investigators, first author Frederick A Spencer, University of Massachusetts Medical School, Worcester.

Comment:

The harm and cost of short-term therapy is very low. I would give a high-dose statin immediately on presentation of a patient with presumed ACS.

Those on statins long-term should be continued on statins when admitted for ACS. Those not on statins should start them immediately.

A study “Lipid-Lowering Therapy And In-Hospital Mortality Following Major Non-Cardiac Surgery” (See Practical Pointers May 2004 ) also presents evidence of immediate protective effects of statins given within the first 2 days after major surgery. RTJ

More myocardial infarctions are caused by hemodynamically insignificant lesions than from high grade stenosis.

6-2 THE SEARCH FOR THE “HOLY GRAIL” OF CLINICALLY SIGNIFICANT CORONARY ATHEROSCLEROSIS.

In some individuals, coronary atherosclerosis is stable for years, and in others it is very unstable, with rapidly progressive lesions that result in sudden death or an acute coronary syndrome. The diagnostic “Holy Grail” of coronary atherosclerosis is not to be able to identify coronary atherosclerosis (which almost all Americans have eventually) but to identify individuals with unstable coronary atherosclerotic lesions.

Shortly after World War II, it became apparent that the greatest threat to the lives of Americans was not from without, but from within. Our greatest threat was cardiovascular disease, with 50% of Americans dying from it.

The medical profession’s initial concept was that coronary atherosclerosis was characterized by a process that gradually, over decades, narrows the coronary arteries. We systematically looked for silent coronary disease with “executive physicals” that emphasized the treadmill exercise test. We were surprised to find that more myocardial infarctions occurred in the larger sub-population with negative results than in those with positive results.

These observations led to the era of coronary angiography, during which we assumed that angiography was the gold standard for identifying clinically significant coronary artery disease. Again, we found that, although a high grade coronary lesion was more likely to occlude, more myocardial infarctions were caused by hemodynamically insignificant lesions than from high grade stenosis. And there were many more of the hemodynamically insignificant lesions. When plaques in hemodynamically insignificant lesions ruptured, coronary artery thrombosis might occur with subsequent sudden death or an acute coronary syndrome. Most often the rupture is clinically silent. An estimated one in 100 plaque ruptures actually results in an acute coronary syndrome. The healing process leads to progressive coronary stenosis.

More recently, coronary intravascular ultrasound demonstrated that early atherosclerosis often results in “positive remodeling” of the coronary artery and does not narrow the lumen until the process is far advanced. As a result, minimal lesions detected by coronary angiography may reflect advanced disease. These minimal lesions, if unstable, can result in plaque rupture and major acute coronary events.

How can we identify these unstable plaques? They are characterized by inflammation. The inflammatory cells produce cytokines that stimulate the liver to produce C-reactive proteins (CRP) and other acute phase reactants. High-sensitivity CRP appears to be a marker for more unstable coronary disease. Increasing levels of high-sensitivity CRP and an increasing ratio of total cholesterol to high density lipoprotein cholesterol can identify increased risk.

Scanning the coronary arteries for calcium, and assuming that one is identifying unstable coronary disease, or the risk for developing unstable coronary disease, is like scanning an egg and trying to assess the composition and stability of the yoke by the amount of calcium in the shell. Unstable coronary atherosclerosis undoubtedly develops before calcification.

The search for the “Holy Grail”, a fail-safe method for detecting clinically significant coronary atherosclerotic disease, must continue.

Archives Int Med June 28, 2004; 164: 1266-67 Editorial by Gordon A Ewy, University of Arizona, Tucson.

Comment:

Prevention of an essentially universal disease must be universal. Must we wait for screening tests to detect “higher risk”, and only then encourage patients to change lifestyles? RTJ

“The probability of progression from localized to metastatic increases markedly after long-term follow-up.”

6-3 NATURAL HISTORY OF EARLY, LOCALIZED PROSTATE CANCER

The challenge of prostate cancer (PC) is to maximize the possibilities of survival without extensive over- treatment. Even without any initial treatment, only a small proportion of patients diagnosed at an early stage die from PC within 10 to 15 years following diagnosis.

No study has hitherto adequately analyzed whether patients who escaped metastases and death without treatment during 10 to 15 years after diagnosis continue to have an indolent, nonfatal disease course, or whether in the long-term tumor progression takes a more aggressive turn.

Because it takes several years after operation for any benefit to emerge, age at diagnosis, comorbidity, and long-term natural history will determine the potential advantage from radical primary treatment.

This observational study of the long-term natural history of PC assessed disease progression and mortality after years of watchful waiting.

Conclusion: Although most PCs diagnosed at an early stage have an indolent course, local recurrence and aggressive metastatic disease may occur in the long term.

STUDY

1. Population-based cohort study followed 223 untreated patients (age range at diagnosis 41-91; mean = 72) with PC over a mean of 21 years. All had early stage PC: T1, T2; NX; M0.

[T1-T2 = PC confined within gland; T1 = nodule surrounded by normal tissue, not palpable; T2 = palpable disease with a large nodule or multiple nodules; NX (no nodes involved); M0 (no metastases).]

2. The great majority of PCs were highly differentiated; only 4% were poorly differentiated.

3. None received a PSA determination. The test was not available when the study began. About half were diagnosed by histopathologic examinations of specimens obtained at operation for suspected benign prostatic hyperplasia.

4. All were followed up from diagnosis until death, or until September 2001, when the study was terminated. All were followed by clinical examinations, laboratory tests, and bone scans. If the PC progressed to symptomatic disease, estrogens or orchiectomy were prescribed. Local progression was defined as tumor growth through the prostate capsule (T3) as judged by digital rectal examination. Development to metastases (M1) was classified as generalized disease.

5. Main outcome = progression-free, cause-specific, and overall survival.

RESULTS

1. Over the 21 years, most patients died (mainly of causes other than PC) Only 9% survived.

2. Poor differentiation was a strong predictor of cancer-specific death. This became evident within the first 5 years.

3. Most cancers had an indolent course during the first 10 to 15 years. Cancer progression and mortality remained fairly constant during the first 15 years following diagnosis. Progression to metastatic disease was 18 per1000 person-years; PC mortality rate = 15 per 1000 person-years. In contrast, after 15 years, an approximately 3-fold higher rate occurred in both progression and mortality.

4. During the entire 21-year observation, PC was considered the cause of death in 16%. Among patients under age 70 at diagnosis, 22% died from PC. At higher ages at diagnosis, the mortality from PC decreased markedly.

5. Further follow-up after 15 years (n = 49 patients) revealed a substantial worsening of the cancer. Progression-free survival decreased from 45% to 36%; survival without metastases from 77% to 51%; and prostate cancer specific survival from 79% to 54%. PC mortality rate increased from 15 per 1000 person-years during the first 15 years to 44 per 1000 beyond 15 years.

DISCUSSION

1. This study revealed an unexpected change in prognostic outlook after 15 years of observation. The cause-specific mortality from PC increased by 3-fold after this time as compared with the first 15 years.

2. The increase occurred consistently across stage and grade except for poorly differentiated cancers in which excess mortality became manifest during the first 5 years.

3. Mortality rates were mirrored closely by rates of disease progression to metastatic disease.

4. “If our data reflect a real phenomenon, they would imply that the probability of progression from localized and indolent to metastatic and mortal disease increases markedly after long-term follow-up.”

5. PC mortality was slightly higher among patients whose cancer was diagnosed at age 70 or younger.

CONCLUSION

Most PCs diagnosed at an early stage have an indolent course. Local tumor progression and aggressive metastatic disease may develop long-term (after 15 years). This would support radical treatment, notably among patients with an estimated life-expectancy of over 15 years.

JAMA June 9, 2002; 291: 2713-19 Original investigation, first author Jan-Erik Johansson, Orebro University Hospital, Orebro Sweden.

Comment:

The study is unique. It will never be repeated.

This would argue for greater screening of younger men; less aggressive screening in older men. Long term follow-up may be necessary to observe the full benefits of early diagnosis and treatment in younger men.

Prostate cancer is never cured spontaneously.

If you live long enough and are not treated, your chance of eventually developing metastatic disease (requiring orchiectomy or estrogen therapy) and fatal PC is high, even if you have a highly differentiated PC. If you have a poorly differentiated grade PC and are not treated, you will likely die of it within 5 years.

No doubt some lives are saved by radical treatment. Which ones? RTJ

Adipose tissue is an important endocrine organ that produces several bioactive proteins

6-4 ABSENCE OF AN EFFECT OF LIPOSUCTION ON INSULIN ACTION AND RISK FACTORS FOR CORONARY HEART DISEASE.

Abdominal obesity (increased abdominal subcutaneous fat, and increased visceral fat) is associated with insulin resistance and other risk factors for coronary heart disease (CHD).

This study asked: Which of these fat deposits is associated with insulin resistance and increased risk of CHD?

Conclusion: Removal of subcutaneous abdominal fat does not alleviate insulin resistance.

STUDY

1. Followed 15 sedentary obese women (mean age 42) with increased abdominal circumference (mean = 108 cm; mean body mass index = 38). All had been scheduled for abdominal liposuction for cosmetic reasons.

2. Evaluated insulin sensitivity of liver, skeletal muscle and adipose tissue with a euglycemic-hyperinsulinemic clamp procedure (see text) before and after liposuction.

3. Also determined levels of inflammatory mediators and other risk factors for CHD.

RESULTS

1. Liposuction reduced volume of subcutaneous abdominal fat by 44%. Weight loss = 10 kg; total body fat decreased by 18%.

2. Liposuction did not significantly alter insulin sensitivity (assessed by stimulation of glucose uptake in muscle); did not suppress glucose production by the liver; and did not suppress lipolysis of adipose tissue.

3. Levels of C-reactive protein and other indicators of inflammation did not change.

4. Other risk factors for CHD were unchanged (BP, plasma glucose, insulin, and lipid concentrations).

DISCUSSION

1. Large-volume reduction in subcutaneous abdominal fat mass did not have any beneficial metabolic effects despite a considerable decrease in body weight, waist circumference, and plasma leptin concentrations.

2. The amount of fat removed was equivalent to weight loss achieved by optimal behavioral and pharmacological treatments. (about 12% of body weight). This amount of weight loss by these methods usually results in marked improvements in the metabolic abnormalities associated with obesity (insulin sensitivity, BP, and lipids), and reduces levels of circulating markers of inflammation.

3. “It is striking that the amount of fat loss achieved by liposuction…did not improve any of these metabolic variables.”

4. This provides insight into the mechanism by which conventional weight loss improves insulin sensitivity. Induction of a negative energy balance, not simply a decrease in the mass of fat tissue, is critical for achieving the metabolic benefits of weight loss. Even small amounts of weight loss induced by a negative energy balance affect many variables pertaining to body-fat composition and lipid metabolism—variables that contribute to metabolic abnormalities associated with obesity. Weight loss decreases visceral fat mass, intrahepatic fat, fat-cell size, and the rate of release of fatty acids from adipose tissue. Liposuction does not.

5. Adipose tissue is an important endocrine organ that produces several bioactive proteins, including interleukin-6, tumor necrosis factor, and adiponectin. Interleukin-6 and tumor necrosis factor can cause insulin resistance and atherosclerosis by impairing insulin signaling, stimulating lipolysis and fatty acid release, increasing hepatic synthesis of C-reactive protein, and increasing systemic inflammation, whereas the production of adiponectin by adipose tissue can improve insulin sensitivity and inhibit vascular inflammation. Fat loss by conventional obesity treatment decreases concentrations of C-reactive protein, interleukin-6, and tumor necrosis factor. Conversely, it increases concentration of adiponectin. .

6. Liposuction did decrease plasma leptin concentrations, a marker of adipose-tissue mass.

7. Liposuction may have cosmetic benefits, but no other.

8. “The effects of a negative energy balance on specific endogenous triglyceride depots and inflammation, which are not altered by liposuction, may be necessary to achieve the clinical benefits of therapy for obesity.”

CONCLUSION

Abdominal liposuction does not improve obesity-associated metabolic abnormalities. It does not achieve the metabolic benefits of conventional weight loss.

NEJM June 17, 2004; 350: 2549-57 Original investigation, first author Samuel Klein, Washington University School of Medicine, St. Louis, MO.

Comment:

I abstracted this article mainly to point out the risks associated with intra-abdominal fat accumulation. Visceral fat depots drain directly into the portal circulation and into the liver; subcutaneous fat depots drain into the general circulation. There is a vast metabolic difference.

I suspect the investigators really did not believe subcutaneous abdominal liposuction would improve metabolic functions. It is important, nevertheless, to have objective data.

C- reactive protein is a favored marker of inflammation because a high-sensitivity determination is available at modest cost.

Liposuction is the most common aesthetic procedure performed in the USA. New techniques make it possible to remove considerable amounts of subcutaneous fat tissue. RTJ

Some adipose tissue has endocrine functions

6-5 THERMODYNAMICS, LIPOSUCTION, AND METABOLISM

(This editorial comments and expands on the preceding study.)

The regulation of body weight adheres to the principle of thermodynamics: a positive energy balance causes weight gain, and a negative balance weight loss. (Calories still count.) There is good evidence that a moderate amount of weight loss plus increased physical activity reduces the likelihood of progression from impaired glucose tolerance to type 2 diabetes.

The editorialist comments on two important metabolic benefits that are directly related to effect of a negative energy balance: 1) rapid improvement in hyperglycemia, and hypertension, and 2) benefits on metabolic risk factors related to loss of visceral adiposity.

1) Hyperglycemia improves rapidly during caloric restriction. It outpaces the rate of weight loss. About half of the improvements in glycemic control are achieved during the first week of a negative energy balance, although the actual fat loss is typically quite small during short periods of caloric restriction. Substantial proportions of the early benefits of weight loss on insulin resistance and hyperglycemia in type 2 diabetes may be attributed to a negative energy balance.

Weight loss by liposuction has no comparable beneficial effects.

2) Visceral adiposity is strongly associated with insulin resistance. In animals, surgical resection of visceral fat tissue yields marked and nearly immediate improvement in insulin resistance. The removal of an equivalent amount of subcutaneous fat has little effect.

The relation may be related, at least in part, to the release of fatty acids into the portal circulation.

Adipose tissue has endocrine functions—synthesizing leptin, and cytokines such as tumor necrosis factor, interleukin-6, and C-reactive protein.

It may well be that a negative energy balance permits a rapid improvement in fat content within liver and muscle, depots of stored energy that affect the severity of insulin resistance.

NEJM June 17, 2004; 350: 2542-44 Editorial by David E Kelley. University of Pittsburgh, PA.

Comment:

During World War II type 2 diabetes practically disappeared in the Netherlands. This was related to the near starvation conditions produced by the invasion by Germany. RTJ

Surgery prevents recurrence

6-6 COMPARISON OF SURGERY AND COMPRESSION WITH COMPRESSION ALONE IN CHRONIC VENOUS ULCERATION (ESCHAR study)

Chronic venous ulceration affects 1-2% of the population. It usually has a protracted course of healing and can recur many times.

Conservative measures do little to address the underlying abnormal venous function. About 50% of patients with ulceration have reflux in the superficial system of veins alone; about 40% in the superficial and deep venous systems; and about 10% reflux in the deep system alone.

Simple superficial venous surgery (saphenous vein ablation) theoretically removes the underlying venous incompetence in legs in patients with isolated superficial reflux. Surgery to correct venous reflux in the deep veins is complex and of unproven value.

This study assessed the effect of surgery + compression vs compression alone on healing and recurrence of ulcers.

Conclusion: Surgery reduced 12-month recurrence. It did not hasten healing.

STUDY

1. Performed venous Doppler ultrasound imaging of ulcerated or recently healed legs in 500 consecutive patients (mean age 73).

2. Randomized those with isolated superficial venous reflux and mixed superficial-deep reflux to:

1) Compression alone, or 2) Compression + surgery of superficial veins.

3. Compression consisted of multilayer compression bandaging every week until healing occurred. Then continued compression with below-knee support stockings.

4. Primary endpoints = 24-week healing rates and 12-month recurrence rates.

RESULTS

1. Healing rates over 24 weeks were similar between groups

Surgery-compression Compression alone

Isolated superficial 65% 66%

Superficial and segmental deep 56% 57%

2. Twelve month ulcer recurrence was significantly reduced in the surgery + compression group (12% vs 28%).

Surgery-compression Compression alone NNT

Isolated superficial 12% 28% 6

Superficial and segmental deep 9% 25% 6

3. Adverse events: few surgical patients developed deep vein thrombosis, wound infection, hematoma, and phlebitis.

DISCUSSION

1. Postoperative ultrasound has shown that segmental reflux in the deep veins is reversed in about 50% of cases by ablative superficial venous surgery.

2. Healing is not enhanced at 24 weeks by superficial vein surgery. This is probably because the hemodynamic benefits of compression are as great as surgery.

3. Superficial vein surgery significantly reduced recurrence of ulcer at one year.

CONCLUSION

Surgical correction of superficial venous reflux reduced 12-month recurrence of leg ulcers. It did not hasten healing.

Lancet June 5, 2004; 363: 1854-59 Original investigation, first author Jamie R Barwell, Cheltenham General Hospital, Cheltenham, UK

ESCHAR Effect of Surgery and Compression on Healing And Recurrence

Comment:

The investigators state that about a quarter of patients with venous ulcers will refuse surgery. Primary care clinicians then deal with these individuals as best they can. RTJ

“Ovarian cancer is not a silent disease.”

6-7 FREQUENCY OF SYMPTOMS OF OVARIAN CANCER IN WOMEN PRESENTING TO PRIMARY CARE CLINICS.

Identification of early symptoms may have important clinical implications because the 5-year survival for early stage disease is 70% to 90% compared with 20% to 30% for advanced-stage disease.

Distinguishing symptoms of OC from those that typically occur in women seeking medical advice remains problematic.

This study compared the frequency, severity, and duration of symptoms associated with OC with symptoms in a typical population of women presenting to primary care clinics.

Conclusion: Suspicion of OC may be increased if symptoms occur more frequently, are more severe, and have begun within the past 6 months. Combined abdominal bloating, increased abdominal size, and urinary symptoms occur much more frequently in OC patients. .

STUDY

1. Prospective case-control study of women attending primary care clinics. All voluntarily completed a survey of symptoms experienced over the past year. Symptoms severity was rated on a 5-point scale. Duration was recorded, and frequency indicated as the number of episodes per month.

A. Cases: 128 women with a pelvic mass who were about to undergo surgery (84 benign; 44 malignant). (Median age of OC patients = 55)

B. Controls: Over 1700 women (median age 45) actively seeking medical care who visited a clinic for a total of about 12 000 times.