It is expected that health care professionals continually update their knowledge and clinical practice through research and continuing education. Because elderly patients typically consume more medications than younger populations, drug research may be of particular interest to clinicians who interact with elderly individuals. During the past year, several clinical trials were published that provide new information about drugs commonly used in older adults. In this review those articles, their major findings, and their potential effect on geriatric clinical practice are discussed. A glossary of terms is in the Appendix on page 11. Sections are divided by topic: Cardiology, Hematology, Neurology, and Rheumatology. Conclusions and implications for geriatric clinical practice for each of the studies are listed in the Sidebar on pages 5 and 6.
The Antihypertensive and LipidLowering Treatment to Prevent Heart Attack Trial
During 2002 and 2003, two large clinical trials were published that examined treatments for hypertension and their effectiveness in lowering cardiovascular disease endpoints. The first, The Antihypertensive and LipidLowering Treatment to Prevent Heart Attack (ALLHAT) trial, included 33,357 participants 55 and older who had hypertension and 1 or more coronary heart disease (CHD) risk factors (The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group, 2002). The objective of the study was to determine whether treatment with a calcium channel blocker (CCB) or angiotensin-converting enzyme inhibitor (ACE-I) lowered the incidence of CHD or other cardiovascular disease events compared to diuretic treatment. In this prospective, double-blinded study, participants were randomized to and titrated up one of three drug regimens: chlorthalidone 12.5 to 25 mg per day (diuretic), amlodipine 2.5 to 10 mg per day (CCB), or lisinopril 10 to 40 mg per day (ACE-I). (Previous data were published related to the doxazosin arm, which was stopped early because of increased mortality compared to chlorthalidone [The ALLHAT Officers and Coordinators for the ALLHAT Coilaborative Research Group, 2000].)
Participants were followed for a mean of 4.9 years with a goal blood pressure (BP) of less than 140/90 mmHg and a primary endpoint of combined fatal CHD or non-fatal myocardial infarction (MI). Participants were 47% women and 47% White, with a mean age of 67 years (57% 3* 65 years), and a mean baseline BP of 146/84 mmHg. Primary endpoint event rates were approximately 9% in each treatment group. Lisinopril and amlodipine were not statistically superior to chlorthalidone in preventing this endpoint. In a subgroup analysis of adults 65 or older, the results remained the same.
Second Australian National Blood Pressure Study
Published in 2003, the Second Australian National Blood Pressure Study (ANBP2) compared ACE-I and diuretic therapy in the treatment of hypertension in healthy, elderly Australian adults (Wing et al., 2003). This prospective, open-label study randomized 6,083 participants (51% women) to either diuretic or ACE-I treatment. The individual drug itself was selected by the participant's family practitioner. Participants ranged in age from 65 to 84, with a mean baseline age of 72 years and a mean baseline BP of 168/91 mmHg. They were followed for a median of 4.1 years with a goal BP of less than 140/80 mmHg and a combined primary endpoint of all cardiovascular events or death from any cause.
Overall, the primary endpoint occurred slightly more frequently in the diuretic group, resulting in a trend for 11% reduction (hazard ratio [HR] .89, 95% confidence interval [CI] .79 to 1.00, p = .05) in the ACE-I group compared to the diuretic group. In a subgroup analysis of men, ACE-I treatment significantly reduced the primary endpoint compared to diuretic treatment (HR .83, 95% CI .71 to .97, p = .02). No difference in outcomes between ACE-I and diuretic treatment in women was identified. The ANBP2 study differs from the ALLHAT study in many ways: it was unblinded, participants were older but healthier, mean baseline systolic and diastolic BPs were higher, race was not noted but participants were likely all White, approximately 70% of participants consumed alcohol, and the primary endpoints were slightly different and occurred at different rates. These differences make it very difficult to compare the results and clinical significance of ALLHAT and ANBP2. Nevertheless, both studies are included in the latest recommendations for the treatment of hypertension (Chobanian et al., 2003).
Heart Protection Study
Two large lipid-lowering trials were also published in 2002. The Heart Protection Study (HPS) was designed to demonstrate that simvastatin therapy lowers all-cause mortality and cardiovascular death in participants at high risk for coronary morbidity and mortality (HPS Collaborative Group, 2002b). The study enrolled 20,536 adults ages 40 to 80 with a total cholesterol greater than 135 mg/dL and a history of coronary disease, occlusive disease of non-coronary arteries, diabetes, or high-risk, treated hypertension. This study included a large number of older adults (28% ages 70 to 80), women (25%), and those with a lower range of low-density Hpoprotein (LDL) measurements (mean baseline LDL 131 mg/dL).
Based on entry criteria, most participants were recommended by the National Cholesterol Education Program Adult Treatment Panel III recommendations to have a goal LDL of less than 100 mg/dL (Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, 2001). The study was designed as a prospective, double-blinded trial, and participants were randomized to fixed-dose simvastatin 40 mg per day or placebo for a mean follow-up period of 5 years. Primary endpoints evaluated were all-cause mortality, CHD death, and death from other causes. Compared to placebo, simvastatin significantly reduced all-cause mortality by 13% (p = .0003) and CHD death by 18% (p = .0005). In a subgroup analysis, the first major vascular event in those older than 70 was reduced in the simvastatin group by 18% compared to placebo. Additionally, the rate of first stroke was significantly decreased in the simvastatin group by 25% (p < .001).
Heart Protection Antioxidant Study
In addition to randomization to lipid-lowering therapy, HPS participants were also randomized to a combination antioxidant or placebo to prospectively assess antioxidant effects on coronary events (HPS Collaborative Group, 2002a). The double-blinded HPS antioxidant study evaluated the same 20,536 participants, but initiated them on placebo or a combined 600 mg vitamin E, 250 mg vitamin C, and 20 mg beta-carotene. Major coronary events (i.e., non-fatal MI, CHD death) were evaluated as a primary outcome after a mean follow-up of 5 years. Results showed that this combination antioxidant treatment did not significantly reduce major coronary events (p = .7) or first major vascular events in adults 65 or older compared to placebo.
Prospective Study of Pravastatin in the Elderly at Risk
The first prospective, controlled lipid-lowering trial in older adults was published later in 2002 (Shepherd et al., 2002). The objective of the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) was to demonstrate that the lipid-lowering agent, pravastatin, would reduce coronary and cerebrovascular morbidity and mortality in elderly participants at risk. Prior to this study, it was not known definitively if elderly patients benefited from lipid-lowering therapy. The double-blinded trial included 5,804 participants ages 70 to 82 with vascular disease or risk factors for vascular disease (e.g., smoking, hypertension, diabetes) and a baseline total cholesterol concentration of 155 to 348 mg/dL.
Participants were randomized to fixed-dose pravastatin 40 mg per day or placebo and were followed for a mean of 3.2 years. They had a mean baseline LDL of 147 mg/dL, and 52% were women. The primary endpoint was combined CHD death, non-fatal MI, and stroke. Pravastatin therapy significantly reduced the primary endpoint by 15% compared to placebo (HR .85, 95% CI .74 to .97, p = .014). Analyzed separately, stroke was not significantly reduced in participants taking pravastatin compared to those taking placebo, but a trend for significant reduction in transient ischemie attacks did exist (HR .75, 95% CI .55 to 1.00, p = .051).
A subgroup analysis evaluated the primary outcome in men compared to women, and secondary prevention compared to primary prevention. Significant reductions were found only in men and secondary prevention participants. Overall, it was noted that pravastatin therapy was effective in preventing vascular morbidity and mortality in elderly individuals. It is possible that a difference in stroke may be evident after a longer pravastatin treatment period.
Hydrochlorothiazide and Lipids Study
In early 2003, a study was published to increase knowledge related to thiazide diuretic effects on lipid profiles (Ott, LaCroix, Ichikawa, Scholes, Si Barlow, 2003). The purpose of this prospective, double-blinded, placebo-controlled trial was to confirm previous data that low-dose thiazides do not alter cholesterol levels. The study enrolled 320 healthy older adults (mean age 67) with normal BP and a LDL concentration of less than 190 mg/dL (mean baseline LDL ranged from 120 to 130 mg/dL). Participants were randomized to hydrochlorothiazide 12.5 mg per day, hydrochlorothiazide 25 mg per day, or placebo for 3 years. The primary endpoints were differences in fasting lipid profiles at year 3. No significant change in any lipid measurement was detected with either hydrochlorothiazide dose compared to placebo. Additionally, no differences were found after adjustment for diet.
Women's Health Initiative
One of the most controversial clinical trials published in 2002 was the Women's Health Initiative (WHI) study (Writing Group for the Women's Health Initiative, 2002). Prior to this study, controversy existed about the health risks and benefits of long-term estrogen/progestin treatment. Consequently, the WHI study aimed to demonstrate more clearly those risks and benefits. The double-blinded trial enrolled 16,608 healthy, post-menopausal women ages 50 to 79 (mean age 63) with an intact uterus, and randomized them to receive conjugated equine estrogen .625 mg per day plus medroxyprogesterone acetate 2.5 mg per day or placebo.
In May 2002, the trial was stopped early after a mean of 5.2 years follow-up (planned duration 8.5 years) because of increased risk of invasive breast cancer. The primary outcomes were CHD (i.e., nonfatai MI, CHD death) and invasive breast cancer. A global index was also evaluated and included the two primary outcomes plus stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, and death caused by other causes.
Based on nominal 95% confidence intervals, invasive breast cancer, CHD, and the global index were significantly increased in the estrogen/progestin group compared to placebo (HR 1.26, 95% CI 1.00 to 1.59; HR 1.29, 95% CI 1.02 to 1.63; and HR 1.15, 95% CI 1.03 to 1.28, respectively). However, when adjusted confidence intervals were used, these endpoints did not reach statistical significance. Reduced fracture was the only benefit found as a result of estrogen/progestin therapy that remained significant with adjusted confidence intervals (HR .76, adjusted 95% CI .63 to .92).
The discrepancy between nominal and adjusted confidence intervals makes it difficult to make firm conclusions about the results of the WHI study. However, most clinicians and patients are able to use the results of the WHI study to aid in making a decision related to their preference for the use of long-term estrogen/progestin therapy. In general, the individual risk of invasive breast cancer and CHD are relatively low. During 1 year, 10,000 women taking estrogen/progestin therapy compared with placebo might experience seven additional CHD events and eight more invasive breast cancer events (Writing Group for the Women's Health Initiative, 2002). Regardless, if a patient is using estrogen/progestin therapy solely for osteoporosis prevention or treatment, other options, such as bisphosphonates, can be used without the associated risks. Additionally, clinicians could recommend estrogen/progestin therapy only for the short-term treatment of menopausal vasomotor symptoms. The estrogen-only WHI trial is currently ongoing and will be completed in 2005.
Atrial Fibrillation Follow-up Investigation of Rhythm Management
Prior to 2002, rhythm-control for the treatment of atrial fibrillation was considered first-line therapy for many patients, but no prospective data existed comparing rate-control and rhythm-control treatment. In late 2002, the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial compared mortality outcomes with ratecontrol and rhythm-control treatment for atrial fibrillation (AFFIRM Investigators, 2002). The study enrolled 4,060 participants (mean age 70) with atrial fibrillation and randomized them to either rate-control with beta-blockers, diltiazem, verapamil, or digoxin; or rhythmcontrol with various antiarrhythmic agents. Participants were followed for a mean of 3.5 years to evaluate the primary endpoint of overall mortality. The results of the study indicated a trend for increased deaths in the rhythm-control group (HR 1.15, 95% CI .99 to 1.34, p = .08). Additionally, adverse effects (except congestive heart failure) and hospitalizations were significantly increased in the rhythm-control group (p < .001).
Digitalis Investigation Group Study with Women
In 1997, the Digitalis Investigation Group (DIG) reported the results of a randomized, double-blinded trial comparing digoxin to placebo in the treatment of systolic heart failure (The Digitalis Investigation Group, 1997). A post-hoc analysis of the DIG trial published in 2002 indicates gender-based differences exist in the effect of digoxin for the treatment of systolic heart failure without atrial fibrillation (Rathore, Wang, & Krumholz, 2002). Results from 6,800 participants (1,519 women, 5,281 men) with stable heart failure and an ejection fraction of less than 45% were analyzed.
Participants were randomized to either placebo or nomogram-adjusted digoxin. All-cause mortality, comparing men and women to placebo, was the primary endpoint after a mean follow-up period of 3 years. Compared to men, women were older (median age 66 versus 64), had a shorter duration of heart failure (median 12 versus 18 months), higher ejection fraction (36.5% versus 27.8%), but more severe heart failure (higher percentage of participants in New York Heart Association (NYHA) Class III and IV).
After multivariable adjustment, the women in the study taking digoxin had an increased risk of allcause mortality compared to placebo (HR 1.23, 95% CI 1.02 to 1.47,/? = .014). There was no overall increase in mortality among men taking digoxin compared to placebo. Possible explanations for increased mortality in women may include gender-based differences in the pharmacokinetics of digoxin or gender-based differences in the pathophysiology of heart failure (Rathore et al., 2002). Further investigation is necessary to clarify the results found in women.
Serum Digoxin Concentrations Study
An additional post-hoc analysis of the DIG trial was published in 2003 and evaluated the association of serum digoxin concentrations and mortality (Rathore, Curtís, Wang, Bristow, & Krumholz, 2003). This study included 2,611 men from the original trial randomized to placebo and 1171 men randomized to digoxin who had serum digoxin concentrations measured 1 month after randomization. More than 50% of the men were staged as NYHA Class II heart failure and none had atrial fibrillation. Participants were randomized to placebo or nomogramadjusted digoxin, accounting for the participant's age, gender, weight, and renal function. Participants randomized to digoxin were then further separated into three groups based on their serum digoxin concentration at 1 month: .5 to .8 ng/mL, .9 to 1.1 ng/mL, and greater than or equal to 1.2 ng/mL.
The primary endpoint at 3 years was all-cause mortality, comparing each serum digoxin concentration group to placebo. Crude and adjusted hazard ratios indicated that participants with a serum digoxin concentration of .5 to .8 had significantly lower all-cause mortality compared to placebo (crude HR .72, 95% CI .61 to .85 and adjusted HR .80, 95% CI .68 to .94). In contrast, participants in the highest serum digoxin concentration group (5= 1.2 ng/mL) had increased all-cause mortality compared to placebo (crude HR 1 .34, 95% CI 1.12 to 1.61 and adjusted HR 1.16, 95% CI .96 to 1.39).
Prevention of Recurrent Venous Thromboembolism Trial
The Prevention of Recurrent Venous Thromboembolism (PREVENT) trial provides new evidence related to the treatment of idJopathic venous thromboembolic events (VTE) with warfarin. This prospective, double-blinded, placebo-controlled study enrolled 508 participants with at least one recent idiopathic VTE (Ridker et al., 2003). The median age was 53, 47% were women, and approximately 40% of participants had two or more previous idiopathic VTE. After completing at least 3 months of full-intensity warfarin (internationally normalized ratio [INR] 2.0 to 3.0) participants were initiated on low-intensity warfarin (INR 1.5 to 2.0) or placebo. Participants in the warfarin group completed a median of 6.7 months full-intensity warfarin prior to the study, and participants in the placebo group completed a median of 6.4 months.
After enrolling in the study, participants were followed for a mean of 2.1 years before the study terminated early because of obvious benefit in the warfarin group. The primary objective of this study was to compare low-intensity warfarin to placebo in preventing recurrent VTE. Primary endpoints were recurrent VTE and a composite end point of recurrent VTE, major hemorrhage, and death from any cause. Overall, recurrent VTE was reduced by 64% and the composite endpoint was reduced by 48% in the warfarin group compared to placebo (HR .36, 95% CI .19 to .67, p < .001 and HR .52, 95% CI -31 to .87, p = .01, respectively). In a subgroup analysis, both participants with only one previous idiopathic Vl1E and participants with two or more idiopathic VTE had reduced VTE recurrence when taking warfarin (HR .25, 95% CI .08 to .74 and HR .43, 95% CI .20 to .90, respectively).
Minor bleeding was significantly higher in the warfarin group (HR 1.92, 95% CI 1.26 to 2.93, p = .002), but major bleeding was not statistically different than placebo (HR 2.53, 95% CI .49 to 13.03, p = .25). Current anticoagulation guidelines suggest 6 or more months of fullintensity warfarin following one idiopathic VTE and 12 months to lifetime of full-intensity warfarin following recurrent events (Hyers et al., 2001). At the time of manuscript submission, data were not published regarding the difference in safety or efficacy between low-intensity and full- intensity warfarin for the treatment of idiopathic VTE. Because participants benefited from longterm low-intensity warfarin treatment compared to placebo, this study may extend the standard treatment for those patients with one idiopathic VTE to include longterm, low-intensity warfarin. In contrast, PREVENT results would not change the standard of care for patients with two or more previous idiopathic VTE, as long-term fullintensity warfarin is indicated.
Coenzyme Q10 in Early Parkinson's Disease Study
With many elderly participants taking herbal or alternative therapies to treat medical conditions, it is important to have data to support their safety and efficacy. The Effects of Coenzyme Q10 in Early Parkinson's Disease study was designed to determine what range of coenzyme Q10 dosages is safe and tolerable, and if coenzyme Q10 can slow functional decline in individuals with Parkinson's disease (PD) (Shults et al., 2002). Eighty untreated, early PD participants were enrolled in this prospective, doubleblinded, placebo-controlled trial. Participants were randomized to placebo or coenzyme Q10 300 mg per day, 600 mg per day, or 1,200 mg per day. Participants were followed for 16 months with a primary endpoint of change in the Unified Parkinson's Disease Rating Scale (UPDRS) from baseline to final visit. At all doses, coenzyme Q10 was well tolerated and increased plasma levels greater than placebo. Adverse events were not different than placebo in any group. However, only 1,200 mg per day demonstrated a reduction in UPDRS score worsening compared to placebo (p = .04), and the greatest effect was in activities of daily living.
Opioids Versus Antidepressants in Postherpetic Neuralgia Study
Because postherpetic neuralgia (PHN) affects many elderly patients, research in this area is important. Current first-line treatment usually consists of antidepressant therapy, especially tri-cyclic antidepressants (TCAs), but the role of opioids in PHN remains unclear. The Opioids Versus Antidepressants in Postherpetic Neuralgia study has provided evidence related to effectiveness and tolerability of opioids compared to TCAs to treat PHN (Raja et al-, 2002). This prospective, double-blinded, placebo-controlled, cross-over trial enrolled 76 participants with moderate PHN pain and a mean age of 71. Participants were randomized to a titration of placebo 1 to 16 tablets a day, nortriptyline 10 to 160 mg per day, or long-acting morphine 15 to 240 mg per day; and were then crossed-over for a total of three separate treatment periods of approximately 8 weeks each.
Participants were followed for a total of 6 months with endpoints of pain intensity, pain relief, and cognitive function. Mean maintenance doses of placebo, nortriptyline, and morphine were 9.4 capsules per day, 89 mg per day, and 91 mg per day, respectively. Both opioid and TCA therapy decreased pain intensity and increased pain relief significantly compared to placebo (p < .001 for each endpoint). However, the results indicated a trend for greater reduction in pain intensity with opioids than with TCAs (p = .06). Compared to TCA treatment, opioid treatment had significantly higher reports of constipation, nausea, drowsiness, and loss of appetite (all ? < .01). In contrast, TCA treatment significantly worsened cognitive function (f < .01 for symbol substitution and non-dominant hand grooved pegboard tests). More participants preferred opioids to TCAs (54% versus 30%, p = .02).
Glucosamine Sulfate Use and Delay of Progression of Knee Osteoarthritis Study
Many elderly patients suffer from osteoarthritis (OA) and may be taking glucosamine to treat it. Previous data indicate that glucosamine is effective in delaying the long-term progression of knee OA symptoms and joint structure changes (Reginster et al-, 2001); however, this data has not been confirmed. In October 2002, the Glucosamine Sulfate Use and Delay of Progression of Knee Osteoarthritis study was published to provide additional prospective evidence of safety and efficacy (Pavelka et al., 2002). The study enrolled 202 participants with mild to moderate knee OA (mean duration approximately 10 years) and randomized them to placebo powder or glucosamine sulfate powder 1,500 mg once daily. Participants ranged in age from 45 to 70 (approximate mean age 62), and approximately 70% were women. Follow-up was for 3 years with the primary endpoint of joint space width changes. Symptom indexes (Lequesne and Western Ontario and McMaster Universities [WOMAC] scales) were also evaluated.
An intent-to-treat analysis comparing glucosamine to placebo showed a significant difference in joint space narrowing with glucosamine at the end of each year of treatment, with Year 3 showing the greatest difference (difference .23 mm, 95% CI .09 to .37, p = .001). Significant differences also existed between glucosamine and placebo in both the Lequesne and WOMAC indexes at Year 3, favoring glucosamine (difference .91, 95% CI .34 to 1.5,p = .002 and 3.1, 95% CI .77 to 5.5, p = .01, respectively). Sixty-four percent of participants taking placebo and 66% of participants taking glucosamine reported adverse events. No significant differences existed between groups in the proportion or pattern of events.
The purpose of this review is to educate health professionals by providing summaries of recent clinical trials and how the results apply to geriatric patients. It is essential that health professionals know what drugs their patients are taking and are educated about those drugs. Evaluation and dissemination of new evidence is integral in this education process; only then can practitioners clinically apply new information to their practice.
- Chobanian, A.V., Bakris, G.L., Black, H.R., Cushman, W.C., Green, L.A., Izzo, J.L., Jr., Jones, D.W., Materson, BJ., Oparil, S., Wright, J.T., Jr., Rocella, E.J., & The National High Blood Pressure Education Program Coordinating Commuée. (2003). The seventh repon of the Joint National Commuée on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 report. JAMA, 289(19), 2560-2571.
- Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. (2001). Executive summary of the third report of the national cholesterol education program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA, 285(19), 2486-2497.
- Heart Protection Study Collaborative Group. (2002a). MRC/BHF heart protection study of antioxidant vitamin supplementation in 20,536 high-risk individuals: A randomized placebo-controlled trial. Lancet, 360(9326), 23-33.
- Heart Protection Study Collaborative Group. (2002b). MRC/BHF heart protection study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: A randomized placebo-controlled trial. Lancet, 360(9326), 7-22.
- Hyers, T.M., Agnelli, G., Hull, R.D., Morris, T.A., Samama, M., Tapson, V., & Weg, J.G. (2001). Antithrombotic therapy for venous thromboembolic disease. Chest, 119(Suppl. 1), 176S-193S.
- Ott, S.M., LaCroix, A.Z., Ichikawa, L.E., Scholes, D., & Barlow, W.E. (2003). Effect of low-dose thiazide diuretics on plasma Iipids: Results from a double-blind, randomized clinical trial in older men and women. Journal of the American Geriatrics Society, 51(3), 340-347.
- Pavelka, K-, Gatterova, J., Olejarova, M., Machacek, S., Giacovelli, G., & Rovati, L.C. (2002). Glucosamine sulfate use and delay of progression of knee osteoarthritis: A 3-year, randomized, placebo-controlled, double-blind study. Archives of Internal Medicine, 162(18), 2113-2123.
- Raja, S.N., Haythornthwaite, J.A,, Pappagallo, M., Clark, M.R., Travison, T.G., Sabeen, S., Royall, R.M., & Max, M.B. (2002). Opioids versus antidepressants in postherpetic neuralgia: A randomized, placebo-controlled trial. Neurology, 59(7), 1015-1021.
- Rathore, S.S., Curtís, J.P., Wang, Y., Bristow, M.R., & Krumholz, H.M. (2003). Association of serum digoxin concentration and outcomes in patients with heart failure. JA MA, 289(7), 871-878.
- Rathore, S.S., Wang, Y., & Krumholz, H.M. (2002). Sex-based differences in the effect of digoxin for the treatment of heart failure. New England Journal of Medicine, 347(18), 1403-1411.
- Reginster, J.Y., Deroisy, R., Rovati, L.C., Lee, R.L., Lejeune, E., Bruyère, O-, Giacovelli, G., Henrotin, Y., Dacre, J.E., K Gossett, C. (2001). Long-term effects of glucosamine sulphate on osteoarthritis progression: A randomized, placebo-controlled clinical trial. Lancet, 357(9252), 251-256.
- Ridker, P.M., Goldhaber, S.Z., Danielson, E-, Rosenberg, Y, Eby, C.S., Deitcher, S.R., Cushman, M. Moll, S., Kessler, C.M., Elliott, C.G., Paulson, R., Wong, T., Bauer, K.A., Schwanz, B.A., MUetich, J.P., Bounameaux, H., & Glynn, RJ. for the PREVENT Investigators. (2003). Longterm, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism [comment]. New England Journal of Medicine, 348(\5), 1425-1434.
- Shepherd, J., Blauw, G-J. , Murphy, M.B., Bollen, E.L., Buckley, B.M., Gobbe, S.M., Ford, I-, Gaw, A., Hyland, M., Jukema, J.W., Kamper, A.M., Macfarlane, P.W., Meinders, A.E., Nome, J., Packard, C.J., Perry, IJ., Stott, D.J., Sweeny, B.J., Twomey, C., Westendorp, R.G.J. on behalf of the PROSPER Study Group. (2002). PravaStatin in elderly individuals at risk of vascular disease (PROSPER): A randomized controlled trial. Lancet, 360(9346), 1623-1630.
- Shults, C.W., Oakes, D., Kieburtz, K., Beai, M.F., Haas, R., Plumb, S., Juncos, J.L., Nutt, J., Shoulson, I. Carter, J., Kompoliti, K., Perlmutter, J.S., Reich, S., Stern, M., Watts, R.L., Kurlan, R., Molho, E. Harrison, M., Lew, M., & the Parkinson Study Group. (2002). Effects of coenzyme Q10 in early Parkinson disease: Evidence of slowing of the functional decline. Archives of Neurology, 59(10), 1541-1550.
- The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. (2000). Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: The antihypertensive and lípid-lowering treatment to prevent heart attack trial (ALLHAT). ALLHAT Collaborative Research Group. JAMA, 2SJ(IS), 1967-1975.
- The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. (2002). Major outcomes in highrisk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) JAMA, 288(23), 2981-2997.
- The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators. (2002). A comparison of rate control and rhythm control in patients with atrial fibrillation. New England Journal of Medicine, 347(23), 1825-1833.
- The Digitalis Investigation Group. (1997). The effect of digoxin on mortality and morbidity in patients with heart failure. New England Journal of Medicine, 336(9), 525-533.
- Wing, L.M., Reid, C.M., Ryan, P., Beilin, L.J., Brown, M.A., Jennmgs, G.L., Johnston, CL, McNeil, J.J., Macdonald, GJ., Marley, J.E., Morgan, TO., & West, MJ. for the Second Australian National Blood Pressure Study Group. (2003). A comparison of outcomes with angiotensin-converting - Enzyme inhibitors and diuretics for hypertension in the elderly. New England Journal of Medicine, 348(7), 583-592.
- Writing Group for the Women's Health Initiative. (2002). Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women's Health Initiative randomized controlled trial. JAMA, 288(3), 321-333.