Practical Pointers - March 2004

This article defines the “actual” causes of death as underlying-modifiable-behavioral risk factors which predispose to the “disease” which is labeled as the cause of death

About half of all deaths could be attributed to a limited number of largely preventable behaviors: tobacco, poor diet and physical inactivity, alcohol, firearms, sexual behavior, and illicit drug use.

Interventions to prevent and increase cessation of smoking, improve diet, and increase physical activity must become a much higher priority in the public health and health care systems.

The most striking finding is the substantial increase (to about 400 000) in the number of estimated deaths attributable to poor diet and physical inactivity. The gap between deaths due to poor diet and inactivity and those due to smoking has narrowed substantially. “It is clear that if the increasing trend of overweight is not reversed over the next few years, poor diet will likely overtake tobacco as the leading cause of mortality.”

In addition to premature death, years of lost life, diminished productivity, and decreased quality of life are strongly associated with the actual causes.

One important cause of death not directly related to obesity is the deficiency of calcium and vitamin D in the American diet. This leads eventually to death and disability as a complication of hip and other fractures.

Primary care clinicians bear a responsibility and opportunity to: 1) follow a healthy lifestyle themselves as an example to patients, and 2) to constantly encourage patients to do likewise. RTJ

3-2 THE IMMEDIATE VS THE IMPORTANT

“One of the most difficult challenges is to ensure that the urgent does not crowd out the important. That challenge is especially difficult because urgent matters can be so riveting.”

Every death has a definable history that usually can be traced back to decades and sometimes even generations. Reporting of deaths, diseases and disabilities in traditional diagnostic categories tend to obscure the importance of factors that often play determinant antecedent roles in the occurrence of reported conditions. When it comes to ranking health problems and committing resources, attention seems more naturally drawn to the conditions most proximate to serious illness or death.

3-3 EVALUATION OF CARDIOVASCULAR EVENT RATES WITH HORMONE THERAPY IN HEALTHY, EARLY POSTMENOPAUSAL WOMEN

Two large randomized trials have evaluated effects of hormone replacement therapy (HRT) in postmenopausal women.

The average age of the subjects in these two studies was 63 years, well past onset of the menopause. Overall, the studies concluded that HRT results in net harms. The greatest risk of adverse effects occurred in the first year.

This was contrary to older observational studies which reported considerable benefit in reducing cardiovascular morbidity and mortality. It led to reevaluation of the use of HRT.

It is important to determine if adverse events occur in younger women. Most women with menopausal symptoms take HRT at an earlier age, relatively soon after the menopause. This article reviewed 2 other large clinical trials of younger women (mean age 54). It asks—What is the risk of adverse events at this age?

Conclusion: In young, healthy postmenopausal women, the adverse effects of HRT in the first year of use were no greater than the expected harms in women not taking HRT.

What should primary care clinicians advise their patients about HRT?

A. Risks of adverse events during the first few perimenopausal years are low in younger, healthier women taking combined HRT, and even lower in those taking estrogen alone.

B. These risks can be further reduced by therapy aimed at reducing cardiovascular risk: smoking cessation, low-dose aspirin; lipid, weight, and BP control; and using the lowest effective dose of estrogen and progesterone. Indeed, I believe it likely that women who, at the age of 50 adopt these protective measures and take HRT will be less likely to experience cerebrovascular events than women who do not take HRT and do not adopt these protective measures.

I believe that recent reports overemphasized the adverse effects of HRT, and that many women who would benefit by symptom relief are being denied treatment. RTJ

3-4 CARDIOVASCULAR PROGNOSIS OF ”MASKED HYPERTENSION” DETECTED BY BLOOD PRESSURE SELF-MEASUREMENT IN ELDERLY TREATED HYPERTENSIVE PATIENTS.

There are numerous criticisms of clinical BP measurement. Major inter- and intra-observer variability exist. There are difficulties with standardization of the measurement conditions, and insufficiency in the number of measurements. Office BP fails to recognize the patient’s average daily BP.

In this study, home BP self-measurement defined the prognosis in terms of cardiovascular morbidity and mortality better than office measurement. This was due in part to the poor performance of office BP measurements.

The study reported a high prevalence of two classes of patients with hypertension not recognized by BP measurements confined to the office: 1) “White coat” hypertension (office BP higher than home BP);

2) “Masked” hypertension (the opposite - home BP higher than office BP). “The frequency of this double error, which is both diagnostic (with respect to the control of hypertension), and prognostic (with respect to the incidence of cardiovascular events), suggests that monitoring of patients being treated for hypertension must include home BP self measurement.”

“Masked” hypertension was associated with a statistically significant increase in risk of adverse cardiovascular events. Indeed, the risk over 3 years was about the same as the group with uncontrolled hypertension. It remains to be seen, however, that adaptation of treatment to the results of home BP self-measurement allows better cardiovascular prevention than treatment based on office BP.

Although, as the authors state, there are no data reporting outcomes of patients treated for “masked hypertension”, I believe it would be reasonable to treat them. What about “white coat”? Previous observations suggest that these patients are subject to development of sustained hypertension. They should be carefully observed. Some would advocate treatment.

I believe home BP will become more standardized as a method for following patients treated for hypertension. RTJ

3-5 SMOKING AND BLINDNESS

Age-related macular degeneration (MD) is related to smoking.

Three cross-sectional studies of over 12 000 patients reported that current smoking leads to a 3- to 4-fold incidence of MD compared with non-smokers. Indeed, the relative risk of smoking associated with MD is higher than the relative risk with ischemic heart disease. A dose-response relationship has been established.

Observational studies show a protective effect of smoking cessation on development of MD.

I was unaware of this association. Informing patients may be a powerful incentive to quit. RTJ

3-6 EFFECT OF INTENSIVE COMPARED WITH MODERATE LIPID-LOWERING THERAPY ON PROGRESSION OF CORONARY ATHEROSCLEROSIS. (REVERSAL)

Is there any benefit in lowering LDL-cholesterol below the recommended 100 mg/dL?

This study, in patients with established coronary atherosclerosis, compared the effect of moderate lipid-lowering by 40 mg pravastatin (Pravachol) with intensive lowering by 80 mg atorvastatin (Lipitor). Final mean LDL-c was 110 in the Pravachol group and 79 in the Lipitor group.

The main outcome (progression of coronary atherosclerosis as determined by intracoronary ultrasound) favored atorvastatin. Over 18 months, the atherosclerotic burden in the Pravachol group increased by +2.7% compared with – 0.4% in the atorvastatin group.

“These findings have considerable implications for treatment guidelines for patients with dyslipidemia and established CAD.”

Note this was a study of lipid-lowering and atherosclerotic progression in patients with established CHD (a high risk group). It did not report any clinical benefits.

The larger problem of primary prevention is unanswered.

The benefit/harm-cost ratio of intensive statin therapy is not known.

We are becoming a nation of statin takers. Should the recommended dose be the highest demonstrated to produce surrogate end-point benefits? Should primary care clinicians now recommend 80 mg of atorvastatin for all? I believe not. The excess cost would be considerable. And, despite the report that the drug “was well tolerated”, there will be serious adverse effects.

Note that LDL-c reached a level below 100 mg/dL in 65% of the group receiving 40 mg Pravachol. I believe it reasonable to start with a moderate dose and gradually increase if needed.

3-7 EFFECTS OF CHOLESTEROL-LOWERING WITH SIMVASTATIN ON STROKE AND OTHER MAJOR VASCULAR EVENTS IN 20 536 PEOPLE WITH CEREBROVASCULAR DISEASE OR OTHER HIGH-RISK CONDITIONS

In a large group of patients at high risk of vascular disese, statin therapy rapidly reduced risk of ischemic stroke with no apparent increase in risk of hemorrhagic stroke. Benefits occurred even among those who did not have high cholesterol concentrations. Statin therapy also reduced the risk of major vascular events among people who had previously experienced a stroke or other cerebrovascular event.

A reduction in LDL-cholesterol from about 154 mg/dL to about 115 mg/dL reduced risk of stroke and other major vascular events by about one-quarter. Lowering it from about 115 mg/dL to about 77 mg/dL also reduced risk by about one quarter. “Current guidelines could, therefore, lead to substantial undertreatment of high-risk patients who present below, or close to, particular targets for LDL reduction.”

“These results have important implications for revising treatment guidelines which do not currently take into account cerebrovascular disease risk reduction when considering the nitiation of statin therapy.”

“Statin therapy should now be considered routinely for all patients at high risk of stroke, irrespective of their initial cholesterol concentrations.”

This study confirms the widely-held belief that statin therapy reduces risk of stroke as well as coronary disease. It also strengthens the observation that lowering LDL-cholesterol below levels usually considered “satisfactory” will further reduce risk of atherosclerotic disease.

The risk of events associated with cardiovascular risk factors increases linearly. There are no artificial cut-points dividing “satisfactory” levels vs “unsatisfactory” levels. RTJ

3-8 TEN YEAR’S EXPERIENCE WITH ALENDRONATE FOR OSTEOPOROSIS IN POSTMENOPAUSAL WOMEN

How long is the benefit of bisphosphonates sustained? This article reports results of a trial of postmenopausal women with osteoporosis who were treated for 10 years with alendronate (Fosamax).

Bone mineral density (BMD) continued to increase throughout the 10-year period. Lumbar spine density was increased by doses of 5 mg and 10 mg daily (+ 9% and +14%). The density of the femoral neck was increased by +3 and + 5%.

Even when alendronate is discontinued, the increased BMD persists for some time.

The drug was well tolerated over 10 years. There is some concern that bone may become more brittle as BMD increases due to prolonged therapy. No evidence, however, of an increase in fracture rate in this study.

The study reported a low calcium intake in these women. Deficient intake of calcium and vitamin D is common in the USA. Providing adequate calcium and vitamin D will retard development of osteoporosis. Women (and men) should maintain adequate intake of calcium and vitamin D throughout their lives. This can usually be attained only by supplementation. RTJ

3-9 A RANDOMIZED TRIAL OF EXEMESTANE AFTER TWO OR THREE YEARS OF TAMOXIFEN THERAPY IN POSTMENOPAUSAL WOMEN WITH PRIMARY BREAST CANCER

Aromatase is the enzyme that catalyses the conversion of androgens to estrogens in females. Exemestane is a 3^rd generation aromatase inhibitor. It inhibits aromatization almost completely.

Exemestane therapy, after 2 or 3 years of tamoxifen therapy, significantly reduced risk of metastatic recurrence and contralateral breast cancer as compared with continued tamoxifen.

[NNT (3 years exemestane to benefit one patient) = 21]

This is consistent with the hypothesis that BC frequently becomes resistant to tamoxifen within 5 years.

I included this abstract because I believe therapy with these aromatase inhibitors will continue to improve BC survival. Primary care clinicians should be aware of developments even though they may not be directly involved in this therapy. RTJ

3-10 PURINE-RICH FOODS, DAIRY AND PROTEIN INTAKE, AND RISK OF GOUT IN MEN.

This study prospectively investigated the association between dietary factors and new cases of gout.

Higher intakes of meats and seafoods were associated with increased risk of gout. Higher consumption of low-fat dairy products was associated with decreased risk. Those in the highest quintile of meat intake (beef, pork, and lamb as main dishes), compared with the lowest quintile, had an elevated risk of developing gout (relative risk = 1.4). Each additional daily serving of meat was associated with a 21% increase in risk.

Corresponding RR associated with seafood was 1.5. Each additional weekly serving was associated with a 7% increase in risk.

Higher intake of total protein and higher intake of purine-rich vegetables were not associated with increased risk.

The investigators speculate that the risk associated with increased meat and seafood may be greater in men who already have gout because they have impaired renal clearance of uric acid and the absorption of dietary purines causes a steeper increase in blood uric acid levels than in persons with normal uric acid concentrations. (Ie, diet is likely to be a secondary prevention measure.)

This was essentially a primary prevention study. It provides no information on risk of exacerbations due to dietary factors in men with established gout. The authors, however, speculate that increased intake of meat and seafood may increase risk of recurrence of acute gouty arthritis, and low-fat dairy products may decrease risk. I believe it prudent for primary care clinicians to advise these dietary limitations in patients with established gout. RTJ

3-11 URIC ACID AND DIET—INSIGHTS INTO THE EPIDEMIC OF CARDIOVASCULAR DISEASE.

The effects of diet are relevant to the epidemiology of hyperuricemia and gout. Gout and obesity have become epidemic among native people, such as the Maori of New Zealand, since the introduction of Western culture and diets. The immigration of non-Western peoples to Western countries—for example that of Filipino and Japanese to North America—has been associated with increases in the incidence of gout in parallel with the shift in diet to higher intakes of meat and saturated fats. Gout was rare among blacks in the USA until the 1940s when changes in diet led to the rapid development of obesity, diabetes, and hypertension. Now, gout is more common among blacks than in whites. It is also becoming more common in urban communities of Africa in association with an increasing frequency of hypertension and cardiovascular disease.

Gout is thus no longer a disease of the wealthy; rather its appearance reflects a worldwide increase in fatty meats and a decrease in intake of dairy products associated with Westernization.

Gout should be considered a part of the current epidemic of obesity, hypertension, and diabetes.

The preceding articles convincingly reinforce the view that lifestyle is indeed important in the pathogenesis of gout.

3-12 TAMSULOSIN (FLOMAX) IS EFFECTIVE FOR RENAL COLIC

In patients with renal colic due to juxtavesical stone, tamsulosin (Flomax) 0.4 mg given 3 times daily was associated with greater chance of passing the stone. And fewer hours to expulsion, fewer number of injections of diclofenac, lower hospitalization rate, and reduced need for endoscopic stone removal.

A therapeutic measure worth keeping in mind.

The major adverse effect of Flomax is postural hypotension. The PDR suggests the highest dose should be 0.8 mg daily. A daily dose of 1.2 mg (0.4 mg 3 times daily) will likely be associated with greater likelihood of hypotension. RTJ

3-13 THE BODY-MASS INDEX, AIRFLOW OBSTRUCTION, DYSPNEA, AND EXERCISE CAPACITY INDEX IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE: The BODE Index

A simple multidimensional grading system predicted risk of death better than the FEV1 alone.

B Body mass index (Low BMI— weight in kg/height in meters ²; cutpoint under 21)

O FEV1 as a percentage of predicted (Obstruction)

D Score on a dyspnea scale (Dyspnea scale 0 to 4)

E Distance walked in 6 minutes. (Exercise)

This simple grading system is a better predictor of death from any cause and death from respiratory causes than the FEV1 alone. Mortality increased progressively with quartiles of the score. The highest quartile (score = 7 to 10) was associated with a mortality of 80% over 4 years.

Despite its importance as a public health problem, COPD is vastly underappreciated. It is underdiagnosed, and when diagnosed, is commonly undertreated. Although it is not a single entity, all patients share a common physiological abnormality—limitation of expiratory airflow. It is a complex disorder, affecting far more than a single organ system. Patients with a similar FEV1 can have obvious and marked differences in body habitus, exercise performance, and oxygenation. Additional information complements the assessment by spirometry alone.

I believe primary care clinicians will rarely calculate this index. They will rely for prognosis on their general assessment of the patient. A patient who is wasted down from his normal weight to a BMI under 21 (probably, in old parlance, a “pink puffer”), who can do little without dyspnea, and who cannot walk even slowly for 6 minutes without stopping, has a very dim prognosis indeed. Assessment of the general condition may lead primary care clinicians to advise oxygen at an earlier stage, to treat more vigorously with inhalation therapy, and to use antibiotics earlier and more frequently. RTJ

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About Half Of All Deaths Can Be Attributed To A Limited Number Of Preventable Behaviors.

3-1 ACTUAL CAUSES OF DEATH IN THE UNITED STATES, 2000

This article defines the “actual” causes of death as underlying-modifiable-behavioral risk factors which predispose to the “disease” which is labeled as the cause of death .

A literature search identified epidemiological, clinical, and laboratory studies linking risk behaviors and mortality. The authors used a formula which calculated ‘actual” causes of death from the percentage of deaths in those engaged in the risk behavior and the percentage not engaging in the risk behavior. (Eg, estimated the percentage of smokers dying of heart disease vs the percentage of non-smokers dying of heart disease. Then compared the relative risks of death in the two groups.)

Causes of death as reported in death certificates

(No. per 100 000 population)

Heart disease 258

Malignant neoplasms 200

Cerebrovascular disease 61

Chronic lower respiratory disease 44

Unintentional injuries 36

Diabetes 25

Influenza and pneumonia 24

Alzheimer disease 18

“Actual” causes of death No. in 1990 (thousands) No. in 2000 (thousands)

Tobacco 400 435

Poor diet and physical inactivity 300 400

Alcohol 100 85

Microbial agents 90 75

Toxic agents 60 55

Motor vehicle 25 43

Firearms 35 29

Sexual behavior 30 17

Illicit drug use 20 17

About half of all deaths could be attributed to a limited number of largely preventable behaviors.

Interventions to prevent and increase cessation of smoking, improve diet, and increase physical activity must become a much higher priority in the public health and health care systems.

The most disappointing finding may be the slow progress in reducing tobacco-related mortality.

In addition to premature death, years of lost life, diminished productivity, and decreased quality of life are strongly associated with the actual causes.

JAMA March 10, 2004; 291: 1238-45 “Special Communication”, commentary, first author Ali H Mokdad, Centers for Disease Control and Prevention, Atlanta. GA. www.jama.com

Comment:

One important cause of death not directly related to obesity is the deficiency of calcium and vitamin D in the American diet. This leads eventually to death and disability due to hip and other fractures.

Primary care is the specialty which bears the greatest responsibility and opportunity to reduce prevalence of unhealthy lifestyles. Clinicians must: 1) follow a healthy lifestyle themselves as an example to patients, and 2) to constantly encourage patients to do likewise. RTJ

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The Urgent Crowds Out The Important

3-2 THE IMMEDIATE VS THE IMPORTANT

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

“One of the most difficult challenges is to ensure that the urgent does not crowd out the important. That challenge is especially difficult because urgent matters can be so riveting.”

At the policy level, medical care expenditures often drive decisions in which cost cutting is aimed at discretionary investments, such as those in prevention and public health, that offer the greatest prospects for overall health improvement.

Every death has a definable history that usually can be traced back for decades, and sometimes even generations. Reporting of deaths, diseases and disabilities in traditional diagnostic categories tend to obscure the importance of factors that often play determinant antecedent roles in the occurrence of the reported conditions. When it comes to ranking health problems and committing resources, attention seems more naturally drawn to the conditions most proximate to serious illness or death.

Another important category not included in the articles is medical error, which, according the Institute of Medicine, are estimated to account for 44 000 to 98 000 deaths annually.

Refining insights into the root causes of illness and injury, presenting those insights in a fashion that can motivate and guide effective action, and marshalling the effort to monitor the results of these actions will require steady improvements in the knowledge base and commitment at the policy level.

JAMA March 10, 2004; 291: 1263-64 Editorial, first author J Michael McGinnis, Robert Wood Johnson Foundation, Princeton, NJ www.jama.com

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HRT Is Safer In Younger Postmenopausal Women

3-3 EVALUATION OF CARDIOVASCULAR EVENT RATES WITH HORMONE THERAPY IN HEALTHY, EARLY POSTMENOPAUSAL WOMEN

Two large randomized trials ^1,2 have evaluated effects of hormone replacement therapy (HRT) in postmenopausal women with and without established cardiovascular disease (CVD). HRT consisted of oral conjugated equine estrogens + medroxyprogesterone acetate (CEE; Premarin—0.625 daily + MPA; Provera – 2 .5 mg daily). The average age of the subjects was 63 years, well past onset of the menopause. The greatest risk of adverse effects occurred in the first year.

Overall, the studies concluded that HRT results in net harms. This was contrary to older observational studies which reported considerable benefit in reducing cardiovascular morbidity and mortality. It led to reevaluation of the use of HRT.

It is important, however, to determine if adverse events occur in younger women. Most women with menopausal symptoms take HRT at an earlier age relatively soon after the menopause. This article asks - What is the risk of adverse events at this age?

Conclusion: In young, healthy postmenopausal women, the adverse effects of HRT in the first year of use were low.

STUDY

1. Evaluated results of 2 large clinical trials ^3,4 of over 3500 healthy women, mean age 53. They were an average of 5 years past their last menstrual period.

2. Some received varying doses of CEE—0.3 mg to 0.625 mg, with and without MPA at varying doses. Some received placebo.

3. Determined adverse effects during the first year of use, and compared them with expected risks in women not taking HRT.

RESULTS

1. In the first year of treatment with HRT no cardiovascular deaths occurred. No myocardial infarct was diagnosed.

2. There were 7 vascular events among HRT treated women: stroke (3); TIA (1); pulmonary embolism and venous thrombosis (3).

3. Overall incidence of vascular events in women using HRT for the first year = 2/1000 patient-years. This compares with the expected annual rate of events (4/1000) in women not taking HRT.

DISCUSSION

1. During the first year of HRT use, the incidence of vascular events in healthy women age 50-60 (mean age = 53) was low.

2. This contrasts markedly with the risks reported by the Woman’s Health Initiative (WHI). Women in the WHI, however, were older and not as close to the menopause as women in this study.

3. “The CHD and stroke data suggest that there is no increased risk in young symptomatic women compared with reported annual rates.”

4. “The data seem to suggest that the results of early CHD risk observed in the WHI may not be applicable to healthy, younger postmenopausal women who seek treatment for menopausal symptoms.” Indeed, in the WHI, women who had experienced menopause within the past 10 years, the hazard ratio of HRT was only 0.89, compared with 1.22 and 1.71 respectively for women who had experienced menopause between 10 to 19 years previously, and women who had experienced it more than 20 years previously.

CONCLUSION

“For patients who seek HRT for symptoms early in the menopause, these data suggest that the benefits may outweigh the risks.”

Archives Int Med March 8, 2004; 164: 482-84 Commentary by Rogerio A Lobo, Columbia University College of Physicians and Surgeons, New York www.archinternmed.com

1 The Heart and Estrogen/progestin Replacement Study (HERS) JAMA 1998; 280: 605-13

2 The Women’s Health Initiative (WHI) Risks and Benefits of Estrogen plus Progestin in Healthy Postmenopausal Women JAMA 2002; 288: 321-33

3 Relief Of Vasomotor Symptoms And Vaginal Atrophy With Lower Doses Of Conjugated Equine Estrogens And Medroxyprogesterone Acetate Fertil Steril 2001; 75: 1065-79

4 Bleeding Patterns In Postmenopausal Women Taking Continuous Combined Or Sequential Regimens Of Conjugated Equine Estrogens With Medroxyprogesterone Obstet Gynecol 1994; 83:686-92

Comment:

Practical Pointers has abstracted 6 reports relating HRT to vascular complications over the past 2 years. I will try to clarify and condense important points:

1. The main message is that HRT does not lower risks, and that it should not be used for that purpose. HRT does not protect against vascular disease. This is a complete reversal of past observational studies which suggested a large protective effect.

2. HRT is more risky in women with established vascular disease than in women free of vascular disease.

3. Risks are higher in elderly women than in perimenopausal women.

4. Estrogen alone is safer than estrogen/progestin.

5. Risks are especially high in the first year of use. (I believe these risks can be reduced by smoking cessation, low dose aspirin, lipid and BP control, and by using lowest effective dose of estrogen and progesterone. Indeed, I believe it likely that women who, at the age of 50 adopt these protective measures and take HRT will be less likely to experience vascular events than women who do not take HRT and do not adopt these protective measures.)

6. There is some evidence that, once the 1-year period of increased vulnerability is past, and HRT is continued, risk of vascular disease is reduced to match that of women who do not take HRT.

7. Risks should not be overemphasized. They are less than 1 in 1000 women per year.

8. HRT does improve lipid profiles. The increased risk of vascular disease is likely due to an increased thrombotic potential.

What about breast cancer?

Reports are consistent. HRT over time does increase risk. But estrogen alone carries less risk than estrogen/progestin.

I believe that recent reports overemphasized the adverse effects of HRT, and that many women who would benefit by symptom relief are being denied treatment. Individual informed consent should be obtained after explanation of the risk/benefit ratio. RTJ

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Monitoring Of Patients Being Treated For Hypertension Must Include Home BP Self Measurement.”

3-4 CARDIOVASCULAR PROGNOSIS OF ”MASKED HYPERTENSION” DETECTED BY BLOOD PRESSURE SELF-MEASUREMENT IN ELDERLY TREATED HYPERTENSIVE PATIENTS.

The reference method for BP measurement is the auscultatory method with a mercury sphygmomanometer. This has demonstrated the relationship between BP and cardiovascular risk. For each increase of 10 mm Hg in systolic BP (SBP), or 5 mm HG of diastolic BP (DBP), the average risk of cerebrovascular mortality increases by 40%, and the risk of mortality from ischemic heart disease increases by 30%.

But, there are numerous criticisms of clinical BP measurement. Major inter- and intra-observer variability exist. There are difficulties with standardization of the measurement conditions, and insufficiency in the number of measurements. It fails to recognize “masked” hypertension (home hypertension) as well as “white-coat” hypertension (office hypertension).

Many guidelines recommend replacement of the office BP measurement with physician-independent methods (ambulatory 24-hour BP monitoring or self-measurement at home). Home BP has a high degree of quality and is cheaper and better accepted by patients than ambulatory (24 hour) monitoring.

This cohort study evaluated the prognostic value of home BP measurement vs office BP measurement in a population being treated for hypertension.

Conclusion: Home BP measurement had better prognostic value than office BP measurement.

It uncovered masked hypertension as well as white coat hypertension.

STUDY

1. Prospective study entered over 4900 patients (mean age 70). All had treated hypertension. The study was designed to compare the prognostic value of home BP vs office BP.

2. The first phase measured office BP by a mercury sphygmomanometer 3 times on two separate visits over 2 weeks. (Average of 6 readings.) Home BP was determined over a 4-day period by 3 measurements of BP in the AM and 3 in the PM with an Omron 705 CP device. (Average of 24 determinations.) The device had been previously validated against a mercury sphygmomanometer.

3. The second phase periodically measured both office and home BP at intervals for 3 years.

4. The mean of all home BP measurements was used for comparison with the mean office BP. The threshold defining uncontrolled hypertension was 140/90 for office BP and 135/85 for home BP.

5. Primary end point = cardiovascular mortality. Secondary end points = total mortality, and the combination of cardiovascular mortality, nonfatal myocardial infarction, nonfatal stroke, transient ischemic attack, hospitalization for angina or heart failure, and coronary angioplasty or coronary bypass surgery.

6. There were no specific recommendations concerning management of hypertension, including frequency of visits, drug treatment, or BP goal.

RESULTS

1. At 3 years, at least one cardiovascular event occurred in 324 patients. (6.5%)

2. For home BP, each 10 mm increase in systolic increased risk of a cardiovascular event by 17%; each 5 mm increase in diastolic increased risk by 12%.

3. 3-year hazard ratios for cardiovascular outcomes: HR Number of patients

A. Both home and office normal 1.00 (referent) 685 (14%)

B. Both high (Uncontrolled hypertension) 1.96 3125 (64%)

C. Normal office; high home* (“Masked” hypertension) 2.06 462 (9%)

D. High office; normal home (“White-coat” hypertension) 1.18 656 (12%)

(* Note the main conclusion of the study: Masked hypertension was associated with a statistically significant increase in risk. Indeed, the risk over 3 years was about the same as the group with uncontrolled hypertension.)

DISCUSSION

1. In this study, home BP self-measurement defined the prognosis in terms of cardiovascular morbidity and mortality better than office measurement.

2. Home BP identified a subgroup of 9% who had poor control at home, but apparently controlled in the office. (“White coat hypertension”). And a group of 12% with apparently controlled BP in the office, but not controlled at home. (“Masked” hypertension).

3. Home BP is the mean BP trough (morning) and peak (evening) values. Since office BP was obtained during normal working hours, it is likely that every possible timing of measurement is represented in this sample.

4. The large number of morbidity and mortality events demonstrated the prognostic superiority of standardized home BP measurements. Superiority was related to the reduced variability of home BP compared with the office BP measurement. This was due, in part, to the increased number of measurements (24), which defined home BP, compared with only 6 measurements which defined office BP.

5. This is also due in part to the poor performance of office BP measurement.

6. The study confirms the high prevalence of the “white coat” effect.

7. The new element of the study relates to “masked hypertension” (elevated home BP; normal office BP).

8. The authors state home BP has excellent feasibility and is the method preferred by patients. It remains to be seen, however, that adaptation of treatment to the results of home BP self-measurement allows better cardiovascular prevention than treatment based on office BP.

CONCLUSION

Home BP self measurement had a better prognostic value than office BP. Office BP failed to identify patients with elevated BP in the office, but not at home (“white coat hypertension”) and those with elevated BP at home but not in the office (“masked hypertension”).

“The frequency of this double error, which is both diagnostic (with respect to the control of hypertension), and prognostic (with respect to the incidence of cardiovascular events), suggests that monitoring of patients being treated for hypertension must include home BP self measurement.”

JAMA March 17, 2004; 291: 1342-49 Original investigation by the “Self Measurement of Blood Pressure at Home in the Elderly: Assessment and Follow-up” (SHEAF) Study, first author Guillaume Bobrie, Hopital Europeen Georges Pompidou, Paris France. www.jama.com

Comment:

An article abstracted in the February 2004 issue of Practical Pointers (2-1) reported that self-measured home BP (SMHBP) led to less intensive drug therapy and to discontinuation of drug therapy in twice as many patients as office BP measurement. It mentioned that SMHBP will detect patients with “masked hypertension”.

Although, as the authors state, there are no data reporting outcomes of patients treated for “masked hypertension”, I believe it would be reasonable to treat them.

I believe home BP will become more standardized as a method for following patients treated for hypertension. RTJ

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Smoking Is The Prime Modifiable Risk Factor

3-5 SMOKING AND BLINDNESS

Patients (and physicians) remain largely unaware of the link between smoking and blindness. Smoking is a risk factor for age-related macular degeneration (MD).

Three cross-sectional studies of over 12 000 patients reported that current smoking leads to a 3- to 4-fold incidence of MD compared with non-smokers. Indeed, the relative risk of smoking associated with MD is higher than the relative risk with ischemic heart disease.

A dose-response relationship has been established. The risk of early MD increases with the number of pack years. MD develops about 10 years earlier in smokers. About ¼ of all cases of age-related MD are attributable to smoking.

The relationship is biologically plausible. Age-related MD may reflect accumulated oxidative damage in the retina. Smoking is known to impede the protective effects of antioxidants and to reduce macular pigment density. The editorialist estimates that over 50 000 residents in the UK older than age 69 may have visual impairment because of MD attributable to smoking, and over 17 000 are blind.

Observational studies show a protective effect of smoking cessation on development of MD. Former smokers have only a slightly increased risk compared to never smokers. In patients with MD in one eye, cessation may prevent development of MD in the other eye. Smoking is associated with poorer outcomes after photocoagulation.

Primary smoking prevention is even more important.

BMJ March 6, 2004; 32 8: 537-38 Editorial, fist author Simon P Kelly, Bolton Hospital, Bolton UK www.bmj.com

Comment:

I was unaware of this association. Informing patients may be a powerful incentive to quit. RTJ

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Intensive Lipid-Lowering Therapy Stopped Progression of Coronary Atherosclerosis

3-6 EFFECT OF INTENSIVE COMPARED WITH MODERATE LIPID-LOWERING THERAPY ON PROGRESSION OF CORONARY ATHEROSCLEROSIS. (REVERSAL)

The optimal approach to lipid control in patients with established coronary heart disease (CHD) remains uncertain.

This study compared the effect of moderate lipid-lowering with pravastatin (Pravachol) with intensive lowering with atorvastatin (Lipitor). Is there any benefit in lowering LDL-cholesterol below the recommended 100 mg/dL?

Conclusion: High dose atorvastatin was associated with lower LDL-c levels, and stopped progression of coronary atherosclerosis. There was no data on clinical benefits.

STUDY

1. Double-blind, randomized trial entered over 650 patients (mean age 56). All had established CHD which required coronary angiography for a clinical indication. All had a luminal narrowing of more than 50% in a “target” segment of an artery.

2. Measured coronary atherosclerotic progression with a miniaturized ultrasound transducer which generates detailed images of the vessel wall. This allows precise quantification of the atherosclerotic burden.

3. Randomized to: 1) pravastatin 40 mg daily, or 2) atorvastatin 80 mg daily.

4. Primary efficacy parameter was percentage change in atheroma volume. Follow-up = 18 months.

RESULTS

1. Lipid changes (means) Total cholesterol LDL-c HDL-c Triglycerides

Baseline 232 150 42 197

Final pravastatin 187 110 45 166

Final atorvastatin 151 79 43 148

2. LDL-c reached levels under 100 mg/dL in 65% of the pravastatin group vs 97% in the atorvastatin group.

3. C-reactive protein and apolipoprotein levels were decreased much more in the atorvastatin group (-36% vs – 5%; and – 39% vs – 22%)

4. Progression of coronary atherosclerosis occurred in the pravastatin group (+2.7%); but did not occur in the atorvastatin group (-0.4%). Significant differences favoring atorvastatin occurred in total atheroma volume.

5. Both regimens were well tolerated. About 6% withdrew in each group.

DISCUSSION

1. In comparison with moderate lipid control, intensive control resulted in significantly reduced progression of coronary atherosclerosis. “These findings have considerable implications for treatment guidelines for patients with dyslipidemia and established CAD.”

2. The clinical significance of the large reduction in C-reactive protein by atorvastatin is not known. The reduction in triglycerides and apolipoprotein B may add to the benefit in reducing atherosclerotic burden.

3. The clinical benefits of high-dose atorvastatin are not known. The authors believe, however, that halting progression of the atherosclerotic process will translate into clinical benefit.

CONCLUSION

High-dose atorvastatin in patients with established CHD halted progression of atherosclerosis, whereas moderate therapy with pravastatin was associated with significant disease progression.

“A more intensive lipid-lowering therapy is required than is currently recommended by the national guidelines to obtain maximal reduction in the progression of coronary atherosclerosis.”

JAMA March 3, 2004; 291: 1071-80 Original investigation by the REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering) study, first author Steven E Nissen, Cleveland Clinic Foundation, Cleveland, Ohio www.jama.com

Cost: www.mydrugstore.com quotes $95 for 30 tablets of 80 mg Lipitor; $120 for 30 tablets 40 mg Pravachol

Comment:

Note this was a study of lipid-lowering and atherosclerotic progression in patients with established CHD (a high risk group). It did not report any clinical benefits. ( Ie, the benefit of intensive LDL-c lowering in secondary prevention of CHD events was not known.)

The larger problem of primary prevention is unanswered as well.

The benefit/harm-cost ratio of intensive statin therapy is not known.

Note that LDL-c reached a level below 100 mg/dL in 65% of the group receiving 40 mg Pravachol. I believe it reasonable to start with a moderate dose and gradually increase if needed. RTJ

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Statin Therapy Rapidly Reduced The Risk Of Ischemic Stroke.

3-7 EFFECTS OF CHOLESTEROL-LOWERING WITH SIMVASTATIN ON STROKE AND OTHER MAJOR VASCULAR EVENTS IN 20 536 PEOPLE WITH CEREBROVASCULAR DISEASE OR OTHER HIGH-RISK CONDITIONS

Lower cholesterol concentrations have consistently been found to be strongly associated with lower risks of coronary disease, but not stroke. Previous small trials, have suggested, however, that statin therapy does reduce risk of stroke. This large prospective study was designed to provide confirmation of the association.

Conclusion: Statin therapy rapidly reduced the risk of ischemic stroke.

STUDY

1. Entered over 3200 adults (mean age = 65) with established cerebrovascular disease, and another 17 000 with other occlusive arterial diseases or diabetes. (Ie, high risk groups.)

2. Randomized to: 1) 40 mg simvastatin (Zocor) daily, or 2) matching placebo.

3. Outcomes: first “major vascular event” (non-fatal MI or coronary death, stroke of any type, or any revascularization procedure).

4. Follow-up = 5 years.

RESULTS

1. Overall, there was a highly significant 25% reduction in rate of stroke (simvastatin 4.3% vs placebo 5.7%). (Absolute differences = 1.4%; NNT (5 years to prevent one stroke) = 71.

2. The benefits were limited to ischemic stroke; no difference in hemorrhagic stroke.

3. In addition, simvastatin was associated with a reduction in transient ischemic attacks (2.0% vs 2.4%), and those requiring carotid endarterectomy or angioplasty (0.4% vs 0.8%)

4. The reduction in risk did not occur until the 2nd year. Continuation of therapy beyond 5 years would eventually produce an even larger absolute reduction in risk.

5. In the subset with preexisting cerebrovascular disease there was no apparent reduction in stroke rate, but a highly significant reduction in rate of other vascular events (24.7% vs 29.8%).

6. Risk of stroke was reduced by about ¼ in subcategories of patients: those with coronary disease; diabetes; age over 70; and those with different levels of lipids and blood pressure. Benefit was evident even in those with a baseline LDL-cholesterol below 116 mg/dL.

7. There was no evidence of an excess risk of hemorrhagic stroke.

DISCUSSION

1. In these high risk groups, statin therapy rapidly produced a substantial reduction in risk of ischemic stroke regardless of the patient’s age, sex, or lipid concentrations. “These results have important implications for revising treatment guidelines which do not currently take into account cerebrovascular disease risk reduction when considering the initiation of statin therapy.”

2. Statin therapy also reduced the risk of major vascular events among people who have previously had a stroke or other cerebrovascular event.

3. When published results of large-scale randomized trials of statins are considered together, an average reduction of LDL-cholesterol of 39 mg/dL is associated with a 21% reduction in incidence of stroke.

4. A reduction in LDL-cholesterol from about 154 mg/dL to about 115 mg/dL reduced risk of stroke and other major vascular events by about one-quarter. Reducing it from about 115 mg/dL to about 77 mg/dL also reduced risk by about one quarter. “Current guidelines could, therefore, lead to substantial undertreatment of high-risk patients who present below, or close to, particular targets for LDL reduction.”

5. The lack of observed benefit in the subgroup with history of ischemic stroke at baseline could be due to the play of chance. (Numbers of subjects with pre-existing cerebrovascular disease were small.)

6. “Statin therapy should now be considered routinely for all patients at high risk of stroke, irrespective of their initial cholesterol concentrations.”

CONCLUSION

In a large group of patients at high risk of vascular disese, statin therapy rapidly reduced risk of ischemic stroke with no apparent increase in risk of hemorrhagic stroke even among those who did not have high cholesterol concentrations.

Lancet March 6, 2004; 363: 757-67 Original investigation by the Heart Protection Study Collaborative Group, correspondence to Heart Protection Study, Clinical Trials Service Unit and Epidemiological Studies Unit, Radcliffe Infirmary, Oxford, UK. www.thelancet.com

Comment:

The risk of events associated with risk factors increases linearly. There are no artificial values dividing “satisfactory” levels vs “unsatisfactory” levels. RTJ

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Therapeutic Benefits Were Sustained Over A 10-Year Period.

3-8 TEN YEAR’S EXPERIENCE WITH ALENDRONATE (FOSAMAX) FOR OSTEOPOROSIS IN POSTMENOPAUSAL WOMEN

Postmenopausal osteoporosis is a chronic, progressive disorder in which bone resorption exceeds bone formation. The resultant decrease in bone strength increases susceptibility to fractures.

Previous trials reported that the increased bone mineral density (BMD) resulting from bisphosphonate therapy is associated with a substantially reduced risk of fracture.

How long is the benefit sustained? This article reports results of a trial of women with osteoporosis who were treated for 10 years with alendronate (Fosamax).

Conclusion: Therapeutic benefit was sustained over a 10-year period.

STUDY

1. Double-blind study followed 78 women receiving alendronate 5 mg daily and 86 receiving 10 mg daily for 10 years. Mean age of women = 63 at baseline. Daily calcium intake averaged below 850 mg daily.

(The study included several sub-groups of subjects receiving placebo and varying doses of alendronate for varying durations. This abstract is limited to the groups receiving alendronate daily for 10 years. RTJ)

2. Determined bone mineral density at baseline and at 10 years.

RESULTS

1. Outcomes at 10 years compared with baseline:

Alendronate 5 mg Alendronate 10 mg.

Changes in bone mineral density

Lumbar spine + 9% +14%

Trochanter +5% + 10%

Femoral neck + 3% + 5%

Total hip +3% +7%

Total body +1% +3%

Distal forearm -1% +1%

2. Bone mineral density at the lumbar spine continued to increase throughout the 10-year period.

3. Non-vertebral fracture rate and loss of height were less in the 10 mg group. The groups were too small to permit detection of rate of vertebral fracture.