Jeffrey Probstfield - Academia.edu (original) (raw)
Papers by Jeffrey Probstfield
Journal of Investigative Medicine, Apr 1, 2004
Background Angiotensin-converting enzyme (ACE) inhibitor use is presumed to be contraindicated in... more Background Angiotensin-converting enzyme (ACE) inhibitor use is presumed to be contraindicated in patients with aortic stenosis (AS). We determined the hemodynamic effects of ACE inhibitors in patients with mild to moderate aortic stenosis (AS) and preserved left ventricular function. Methods Thirteen elderly patients (mean [SD] age = 65 [17] years), with mild to moderate AS (aortic jet velocity 2.5–4.0 m/s), normal left ventricular and renal function, and no clinical coronary artery disease, were enrolled in a single-center, open-label trial comparing the hemodynamic effects at baseline and following titration of ramipril to a maximum dose of 7.5 mg twice daily. Patients were identified from echocardiography laboratory logs. Despite a presumed contraindication to ACE inhibitor use in AS patients, 30% (71 of 235) of patients otherwise meeting inclusion or exclusion criteria were excluded owing to current ACE inhibitor use. Patients were monitored with weekly clinic visits, biweekly laboratory tests, and monthly echocardiograms. Results There were no significant changes from baseline to week 8 in echocardiographic parameters, including mean (SD) aortic jet velocity [2.9 (0.4) vs 2.9 (0.4) m/s], calculated aortic transvalvular gradient [18 (6) vs 18 (6) mm Hg], or cardiac output [5.5 (1.2) vs 6.0 (2.1) L/min], or significant changes in blood pressure or heart rate. Early discontinuations were for asymptomatic low blood pressure (one patient) or a reversible creatinine increase of 0.3 mg/dL (one patient). Conclusions Short-term treatment with up to 7.5 mg twice daily of ramipril was well tolerated in patients with mild to moderate AS and preserved left ventricular function. A surprisingly high proportion of patients with documented AS were already receiving ACE inhibitors.
Current Hypertension Reports, 2003
The American Journal of Cardiology, 1990
Social Science Research Network, 2023
Journal of Investigative Medicine, Apr 1, 2004
Evidence-based Cardiovascular Medicine, 1998
The Journal of family practice, 2009
American Journal of Hypertension, 1995
TOMHS is an NHLBl supported \ ' Udy whichexamlned lifestyle and Iifesty~e ph,J.j active dmg thera... more TOMHS is an NHLBl supported \ ' Udy whichexamlned lifestyle and Iifesty~e ph,J.j active dmg therapieJ for rreatiPr, Stage I diastolic hypertenslion (DDP 9O-S'~ml,~,gi. The trial was carried Ol't over ,1••6 years in9U2 1 ,''len and women, Poges;J5•69, initially free ofevidence ofclinical CHD. Particlpents were randomized tooneof six groups: 1) placebo; 2) beta blocker (acebutolol): 3) calcium blocker (amlodipine); 4) diuretic (chlorthalidoneh5f alpha blocker (doxazosln); or6) ACIi inhibitor (enalapril), All groups received lifestyle intervention. Measureawe.re carried outon BP, side effects. quality ofijf~;')lochemistries. llpoproteins, resting and ambulatory BCGs, m-rnode echocardiograms and cardiovascular events. Follow-up ranged from 4 to5.5 years, average follow-up was 4.4 years. Thestcdy group was 38% female (0-34.5), 62% male (n-55.1), 20% were AmtanAmerican. Significant l.ifestyle changes were achieved in all groups. Greater weight loss was associated Wli'iJ favorable changes in BP. lipids, and qualhy oflife. Updeted results will bepresented onside effects, fasting. serum insulin. quality of life. and other study endpoints.
Arthritis & Rheumatism, 1989
Adherence in clinical trials is a consistent problem regardless of the disease process or organ s... more Adherence in clinical trials is a consistent problem regardless of the disease process or organ system under investigation. In this paper data and examples from clinical trials examining cardiovascular diseases are used as the basis for a review of various adherence principles. Issues reviewed include: the importance of adherence in clinical trials, an overall program /or adherence in clinical trials, and specific issues in adherence from arthritis clinical trials. Special attention is given to a program for the prevention of reduced adherence for participants of a clinical trial as well as acute and chronic intervention plans for those with good adherence and those with reduced adherence in a clinical trial.
The American Journal of Cardiology, 2003
Diabetologia, 2011
Aims/objective Conflicting data regarding cardiovascular effects of thiazolidinediones (TZDs) and... more Aims/objective Conflicting data regarding cardiovascular effects of thiazolidinediones (TZDs) and extra-skeletal effects of vitamin D supported the need for a definitive trial. The Thiazolidinedione Intervention with vitamin D Evaluation (TIDE) trial aimed to assess the effects of TZDs (rosiglitazone and pioglitazone) on cardiovascular outcomes and the effects of vitamin D (cholecalciferol) on cancers and mortality. Methods A large multicentre 3×2 factorial double-blind placebo-controlled randomised trial recruited from outpatient primary care and specialty clinics in 33 countries. From June 2009 to July 2010, 1,332 people with type 2 diabetes and other cardiovascular risk factors aged ≥50 years whose HbA 1c was 6.5-9.5% (48-80 mmol/mol) when using two or fewer glucose-lowering drugs were randomised by a central computer system to placebo (n=541), rosiglitazone 4-8 mg/day (n=399) or pioglitazone 30-45 mg/day (n=392); 1,221 participants were randomised to placebo (n=614) or vitamin D 1,000 IU/day (n=607). Participants and all study personnel were blind to treatment allocation. The primary outcome for the TZD arm was the composite of myocardial infarction, stroke or cardiovascular death, and for the vitamin D arm it was cancer or all-cause death. All randomised participants were included in the primary analysis. Results From the study design, 16,000 people were to be followed for approximately 5.5 years. However, the trial was stopped prematurely because of regulatory concerns after a mean of 162 days without consideration of the accrued data. In the TZD arm, the cardiovascular outcome occurred in five participants (0.9%) in the placebo groups and three participants (0.4%) in the TZD groups (two allocated to pioglitazone, one to rosiglitazone). In the vitamin D arm, the primary outcome occurred in three participants (0.5%) in the placebo group and in two participants (0.3%) receiving vitamin D. Adverse events were comparable in all groups. Conclusions/interpretation Uncertainty persists regarding the clinically relevant risks and benefits of TZDs and vitamin D because of the early cancellation of this comprehensive trial. Trial registration: ClinicalTrials.gov NCT00879970 Funding: The study was funded by GlaxoSmithKline.
European Journal of Clinical Pharmacology, 1991
Summary The Coronary Primary Prevention Tiral (CPPT) was the major clinical investigation conduct... more Summary The Coronary Primary Prevention Tiral (CPPT) was the major clinical investigation conducted in the Lipid Research Clinics (LRC) Program. There were 12 North American clinics involved in this joint double-blind protocol. The hypothesis tested was: lowering plasma cholesterol in middle-aged men with primary hypercholesterolemia [plasma total cholesterol greater than or equal to 265 mg/dl (6.88 mm/1)] who are otherwise healthy leads to a reduction in coronary heart disease (CHD) as manifest by a reduction in definite myocardial infarction (fatal and nonfatal) over a 7-year follow-up of all participants. The trial was conducted in 3806 male volunteers between the ages of 35 and 59, who were randomly assigned to two equal groups. The treatment group received a moderate cholesterol-lowering diet plus cholestyramine; the placebo group received an identical diet plus a placebo. The study medication was administered at 24 g daily in divided doses. The participants were followed up bimonthly for an average of 7.4 years. The diet (daily cholesterol intake of about 400 mg and a polyunsaturated fat/saturated fat ratio of 0.8) lowered plasma cholesterol by an average of 4%, as designed. The cholestyramine group experienced average plasma total cholesterol (TC) lowering and plasma low-density lipoprotein cholesterol (LDC-C) lowering 8.5% and 12.6% greater than the placebo group, respectively. This resulted in a 19% reduction in definite myocardial infarction (P P P P < 0.06) were consistent with and supportive of the main findings of the study. Total mortality also showed a slight decrease in the active treatment group, but the magnitude of the effect was reduced by a greater number of deaths from accidents and violence in the placebo group. The main findings of the study show that the reduction of plasma TC by lowering plasma LDL-C levels can diminish the incidence of CHD morbidity and mortality in men at high risk of CHD. A causal role for these lipids and lipoproteins in the pathogenesis of CHD is strongly suggested. The findings from this and other trials and epidemiologic studies suggest that for every 1 % reduction in TC there is a 2% reduction in risk of CHD. The study cohort remains in long-term follow-up.
Current Cardiovascular Risk Reports, 2009
... Enzymes such as chy-mostatin-sensitive angiotensin IIgenerating enzyme and cathepsin G conve... more ... Enzymes such as chy-mostatin-sensitive angiotensin IIgenerating enzyme and cathepsin G convert angiotensinogen directly to angio-tensin II, whereas ... 5. ONTARGET Investigators, Yusuf S, Teo KK, et al.: Telmis-artan, ramipril, or both in patients at high risk for vascular ...
Evidence-based Cardiovascular Medicine, 1998
Journal of Cardiac Surgery, 2006
Background and Aim: Cardioprotective strategies implemented to prevent ischemic events in patient... more Background and Aim: Cardioprotective strategies implemented to prevent ischemic events in patients at risk for cardiovascular disease have decreased morbidity and prolonged survival. In this review, we have used evidence-based medicine and number-needed-to-treat (NNT) analyses to determine which interventions are most beneficial in minimizing ischemic events and prolonging survival following coronary artery bypass graft (CABG) surgery. Methods: Therapeutic interventions available to minimize ischemic events in the post-CABG patient were analyzed using ACC/AHA Classifications and Level of Evidence Criteria. Based on these recommendations, NNT analyses were performed to determine the effectiveness of each intervention compared to the number of patients needed to be treated before a benefit was apparent. Results: The most beneficial intervention to improve mortality following CABG was the use of high tissue angiotensin-converting enzyme inhibitors, followed by statins and smoking cessation. Conclusions: NNT analyses and evidence-based medicine recommendations provide surgeons with cardioprotective strategies to improve long-term outcomes following CABG surgery.
Controlled Clinical Trials, 1994
Controlled Clinical Trials, 1998
The Women's Health Initiative (WHI) is a large and complex clinical investigation of strategies f... more The Women's Health Initiative (WHI) is a large and complex clinical investigation of strategies for the prevention and control of some of the most common causes of morbidity and mortality among postmenopausal women, including cancer, cardiovascular disease, and osteoporotic fractures. The WHI was initiated in 1992, with a planned completion date of 2007. Postmenopausal women ranging in age from 50 to 79 are enrolled at one of 40 WHI clinical centers nationwide into either a clinical trial (CT) that will include about 64,500 women or an observational study (OS) that will include about 100,000 women. The CT is designed to allow randomized controlled evaluation of three distinct interventions: a low-fat eating pattern, hypothesized to prevent breast cancer and colorectal cancer and, secondarily, coronary heart disease; hormone replacement therapy, hypothesized to reduce the risk of coronary heart disease and other cardiovascular diseases and, secondarily, to reduce the risk of hip and other fractures, with increased breast cancer risk as a possible adverse outcome; and calcium and vitamin D supplementation, hypothesized to prevent hip fractures and, secondarily, other fractures and colorectal cancer. Overall benefit-versus-risk assessment is a central focus in each of the three CT components. Women are screened for participation in one or both of the componentsdietary modification (DM) or hormone replacement therapy (HRT)-of the CT, which will randomize 48,000 and 27,500 women, respectively. Women who prove to be ineligible for, or who are unwilling to enroll in, these CT components are invited to enroll in the OS. At their 1-year anniversary of randomization, CT women are invited to be further randomized into the calcium and vitamin D (CaD) trial component, which is projected to include 45,000 women. The average follow-up for women in either CT or OS is approximately 9 years. Concerted efforts are made to enroll women of racial and ethnic minority groups, with a target of 20% of overall enrollment in both the CT and OS. This article gives a brief description of the rationale for the interventions being studied in each of the CT components and for the inclusion of the OS component. Some detail is provided on specific study design choices, including eligibility criteria, recruitment strategy, and sample size, with attention to the partial factorial design of the CT. Some aspects of the CT monitoring approach are also outlined. The scientific and logistic complexity of the WHI implies particular leadership and management challenges. The WHI organization and committee structure employed to respond to these challenges is also briefly described.
Annals of Clinical Biochemistry, 2009
Journal of Hypertension, Apr 1, 2011
Effects of telmisartan, irbesartan, valsartan, candesartan, and losartan on cancers in 15 trials ... more Effects of telmisartan, irbesartan, valsartan, candesartan, and losartan on cancers in 15 trials enrolling 138 769 individuals The ARB Trialists Collaboration Background Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARBs) reduce cardiovascular disease (CVD) events, but a recent metaanalysis of selected studies suggested that ARBs may increase cancer risks. Objective Candesartan, irbesartan, telmisartan, valsartan, and losartan were assessed for incident cancers in 15 large parallel long-term multicenter double-blind clinical trials of these agents involving 138 769 participants. Patients and methods Individuals at high CVD risk were randomized to telmisartan (three trials, n U 51 878), irbesartan (three trials, n U 14 859), valsartan (four trials, n U 44 264), candesartan (four trials, n U 18 566), and losartan (one trial, n U 9193) and followed for 23-60 months. Incident cancer cases were compared in patients randomized to ARBs versus controls. In five trials (n U 42 403), the ARBs were compared to ACEi and in 11 trials (n U 63 313) to controls without ACEi. In addition, in seven trials (n U 47 020), the effect of ARBs with ACEi was compared to ACEi alone and in two trials ARBs with ACEi versus ARB alone (n U 25 712). Results Overall, there was no excess of cancer incidence with ARB therapy compared to controls in the 15 trials [4549 (6.16%) cases of 73 808 allocated to ARB versus 3856 (6.31%) of 61 106 assigned to non-ARB controls; odds ratio (OR) 1.00, 95% confidence interval (CI) 0.95-1.04] overall or when individual ARBs were examined. ORs comparing combination therapy with ARB along with ACEi versus ACEi was 1.01 (95% CI 0.94-1.10), combination versus ARB alone 1.02 (95% CI 0.91-1.13), ARB alone versus ACEi alone 1.06 (95% CI 0.97-1.16) and ARB versus placebo/control without ACEi 0.97 (95% CI 0.91-1.04). There was no excess of lung, prostate or breast cancer, or overall cancer deaths associated with ARB treatment. Conclusion There was no significant increase in the overall or site-specific cancer risk from ARBs compared to controls.
Journal of Investigative Medicine, Apr 1, 2004
Background Angiotensin-converting enzyme (ACE) inhibitor use is presumed to be contraindicated in... more Background Angiotensin-converting enzyme (ACE) inhibitor use is presumed to be contraindicated in patients with aortic stenosis (AS). We determined the hemodynamic effects of ACE inhibitors in patients with mild to moderate aortic stenosis (AS) and preserved left ventricular function. Methods Thirteen elderly patients (mean [SD] age = 65 [17] years), with mild to moderate AS (aortic jet velocity 2.5–4.0 m/s), normal left ventricular and renal function, and no clinical coronary artery disease, were enrolled in a single-center, open-label trial comparing the hemodynamic effects at baseline and following titration of ramipril to a maximum dose of 7.5 mg twice daily. Patients were identified from echocardiography laboratory logs. Despite a presumed contraindication to ACE inhibitor use in AS patients, 30% (71 of 235) of patients otherwise meeting inclusion or exclusion criteria were excluded owing to current ACE inhibitor use. Patients were monitored with weekly clinic visits, biweekly laboratory tests, and monthly echocardiograms. Results There were no significant changes from baseline to week 8 in echocardiographic parameters, including mean (SD) aortic jet velocity [2.9 (0.4) vs 2.9 (0.4) m/s], calculated aortic transvalvular gradient [18 (6) vs 18 (6) mm Hg], or cardiac output [5.5 (1.2) vs 6.0 (2.1) L/min], or significant changes in blood pressure or heart rate. Early discontinuations were for asymptomatic low blood pressure (one patient) or a reversible creatinine increase of 0.3 mg/dL (one patient). Conclusions Short-term treatment with up to 7.5 mg twice daily of ramipril was well tolerated in patients with mild to moderate AS and preserved left ventricular function. A surprisingly high proportion of patients with documented AS were already receiving ACE inhibitors.
Current Hypertension Reports, 2003
The American Journal of Cardiology, 1990
Social Science Research Network, 2023
Journal of Investigative Medicine, Apr 1, 2004
Evidence-based Cardiovascular Medicine, 1998
The Journal of family practice, 2009
American Journal of Hypertension, 1995
TOMHS is an NHLBl supported \ ' Udy whichexamlned lifestyle and Iifesty~e ph,J.j active dmg thera... more TOMHS is an NHLBl supported \ ' Udy whichexamlned lifestyle and Iifesty~e ph,J.j active dmg therapieJ for rreatiPr, Stage I diastolic hypertenslion (DDP 9O-S'~ml,~,gi. The trial was carried Ol't over ,1••6 years in9U2 1 ,''len and women, Poges;J5•69, initially free ofevidence ofclinical CHD. Particlpents were randomized tooneof six groups: 1) placebo; 2) beta blocker (acebutolol): 3) calcium blocker (amlodipine); 4) diuretic (chlorthalidoneh5f alpha blocker (doxazosln); or6) ACIi inhibitor (enalapril), All groups received lifestyle intervention. Measureawe.re carried outon BP, side effects. quality ofijf~;')lochemistries. llpoproteins, resting and ambulatory BCGs, m-rnode echocardiograms and cardiovascular events. Follow-up ranged from 4 to5.5 years, average follow-up was 4.4 years. Thestcdy group was 38% female (0-34.5), 62% male (n-55.1), 20% were AmtanAmerican. Significant l.ifestyle changes were achieved in all groups. Greater weight loss was associated Wli'iJ favorable changes in BP. lipids, and qualhy oflife. Updeted results will bepresented onside effects, fasting. serum insulin. quality of life. and other study endpoints.
Arthritis & Rheumatism, 1989
Adherence in clinical trials is a consistent problem regardless of the disease process or organ s... more Adherence in clinical trials is a consistent problem regardless of the disease process or organ system under investigation. In this paper data and examples from clinical trials examining cardiovascular diseases are used as the basis for a review of various adherence principles. Issues reviewed include: the importance of adherence in clinical trials, an overall program /or adherence in clinical trials, and specific issues in adherence from arthritis clinical trials. Special attention is given to a program for the prevention of reduced adherence for participants of a clinical trial as well as acute and chronic intervention plans for those with good adherence and those with reduced adherence in a clinical trial.
The American Journal of Cardiology, 2003
Diabetologia, 2011
Aims/objective Conflicting data regarding cardiovascular effects of thiazolidinediones (TZDs) and... more Aims/objective Conflicting data regarding cardiovascular effects of thiazolidinediones (TZDs) and extra-skeletal effects of vitamin D supported the need for a definitive trial. The Thiazolidinedione Intervention with vitamin D Evaluation (TIDE) trial aimed to assess the effects of TZDs (rosiglitazone and pioglitazone) on cardiovascular outcomes and the effects of vitamin D (cholecalciferol) on cancers and mortality. Methods A large multicentre 3×2 factorial double-blind placebo-controlled randomised trial recruited from outpatient primary care and specialty clinics in 33 countries. From June 2009 to July 2010, 1,332 people with type 2 diabetes and other cardiovascular risk factors aged ≥50 years whose HbA 1c was 6.5-9.5% (48-80 mmol/mol) when using two or fewer glucose-lowering drugs were randomised by a central computer system to placebo (n=541), rosiglitazone 4-8 mg/day (n=399) or pioglitazone 30-45 mg/day (n=392); 1,221 participants were randomised to placebo (n=614) or vitamin D 1,000 IU/day (n=607). Participants and all study personnel were blind to treatment allocation. The primary outcome for the TZD arm was the composite of myocardial infarction, stroke or cardiovascular death, and for the vitamin D arm it was cancer or all-cause death. All randomised participants were included in the primary analysis. Results From the study design, 16,000 people were to be followed for approximately 5.5 years. However, the trial was stopped prematurely because of regulatory concerns after a mean of 162 days without consideration of the accrued data. In the TZD arm, the cardiovascular outcome occurred in five participants (0.9%) in the placebo groups and three participants (0.4%) in the TZD groups (two allocated to pioglitazone, one to rosiglitazone). In the vitamin D arm, the primary outcome occurred in three participants (0.5%) in the placebo group and in two participants (0.3%) receiving vitamin D. Adverse events were comparable in all groups. Conclusions/interpretation Uncertainty persists regarding the clinically relevant risks and benefits of TZDs and vitamin D because of the early cancellation of this comprehensive trial. Trial registration: ClinicalTrials.gov NCT00879970 Funding: The study was funded by GlaxoSmithKline.
European Journal of Clinical Pharmacology, 1991
Summary The Coronary Primary Prevention Tiral (CPPT) was the major clinical investigation conduct... more Summary The Coronary Primary Prevention Tiral (CPPT) was the major clinical investigation conducted in the Lipid Research Clinics (LRC) Program. There were 12 North American clinics involved in this joint double-blind protocol. The hypothesis tested was: lowering plasma cholesterol in middle-aged men with primary hypercholesterolemia [plasma total cholesterol greater than or equal to 265 mg/dl (6.88 mm/1)] who are otherwise healthy leads to a reduction in coronary heart disease (CHD) as manifest by a reduction in definite myocardial infarction (fatal and nonfatal) over a 7-year follow-up of all participants. The trial was conducted in 3806 male volunteers between the ages of 35 and 59, who were randomly assigned to two equal groups. The treatment group received a moderate cholesterol-lowering diet plus cholestyramine; the placebo group received an identical diet plus a placebo. The study medication was administered at 24 g daily in divided doses. The participants were followed up bimonthly for an average of 7.4 years. The diet (daily cholesterol intake of about 400 mg and a polyunsaturated fat/saturated fat ratio of 0.8) lowered plasma cholesterol by an average of 4%, as designed. The cholestyramine group experienced average plasma total cholesterol (TC) lowering and plasma low-density lipoprotein cholesterol (LDC-C) lowering 8.5% and 12.6% greater than the placebo group, respectively. This resulted in a 19% reduction in definite myocardial infarction (P P P P < 0.06) were consistent with and supportive of the main findings of the study. Total mortality also showed a slight decrease in the active treatment group, but the magnitude of the effect was reduced by a greater number of deaths from accidents and violence in the placebo group. The main findings of the study show that the reduction of plasma TC by lowering plasma LDL-C levels can diminish the incidence of CHD morbidity and mortality in men at high risk of CHD. A causal role for these lipids and lipoproteins in the pathogenesis of CHD is strongly suggested. The findings from this and other trials and epidemiologic studies suggest that for every 1 % reduction in TC there is a 2% reduction in risk of CHD. The study cohort remains in long-term follow-up.
Current Cardiovascular Risk Reports, 2009
... Enzymes such as chy-mostatin-sensitive angiotensin IIgenerating enzyme and cathepsin G conve... more ... Enzymes such as chy-mostatin-sensitive angiotensin IIgenerating enzyme and cathepsin G convert angiotensinogen directly to angio-tensin II, whereas ... 5. ONTARGET Investigators, Yusuf S, Teo KK, et al.: Telmis-artan, ramipril, or both in patients at high risk for vascular ...
Evidence-based Cardiovascular Medicine, 1998
Journal of Cardiac Surgery, 2006
Background and Aim: Cardioprotective strategies implemented to prevent ischemic events in patient... more Background and Aim: Cardioprotective strategies implemented to prevent ischemic events in patients at risk for cardiovascular disease have decreased morbidity and prolonged survival. In this review, we have used evidence-based medicine and number-needed-to-treat (NNT) analyses to determine which interventions are most beneficial in minimizing ischemic events and prolonging survival following coronary artery bypass graft (CABG) surgery. Methods: Therapeutic interventions available to minimize ischemic events in the post-CABG patient were analyzed using ACC/AHA Classifications and Level of Evidence Criteria. Based on these recommendations, NNT analyses were performed to determine the effectiveness of each intervention compared to the number of patients needed to be treated before a benefit was apparent. Results: The most beneficial intervention to improve mortality following CABG was the use of high tissue angiotensin-converting enzyme inhibitors, followed by statins and smoking cessation. Conclusions: NNT analyses and evidence-based medicine recommendations provide surgeons with cardioprotective strategies to improve long-term outcomes following CABG surgery.
Controlled Clinical Trials, 1994
Controlled Clinical Trials, 1998
The Women's Health Initiative (WHI) is a large and complex clinical investigation of strategies f... more The Women's Health Initiative (WHI) is a large and complex clinical investigation of strategies for the prevention and control of some of the most common causes of morbidity and mortality among postmenopausal women, including cancer, cardiovascular disease, and osteoporotic fractures. The WHI was initiated in 1992, with a planned completion date of 2007. Postmenopausal women ranging in age from 50 to 79 are enrolled at one of 40 WHI clinical centers nationwide into either a clinical trial (CT) that will include about 64,500 women or an observational study (OS) that will include about 100,000 women. The CT is designed to allow randomized controlled evaluation of three distinct interventions: a low-fat eating pattern, hypothesized to prevent breast cancer and colorectal cancer and, secondarily, coronary heart disease; hormone replacement therapy, hypothesized to reduce the risk of coronary heart disease and other cardiovascular diseases and, secondarily, to reduce the risk of hip and other fractures, with increased breast cancer risk as a possible adverse outcome; and calcium and vitamin D supplementation, hypothesized to prevent hip fractures and, secondarily, other fractures and colorectal cancer. Overall benefit-versus-risk assessment is a central focus in each of the three CT components. Women are screened for participation in one or both of the componentsdietary modification (DM) or hormone replacement therapy (HRT)-of the CT, which will randomize 48,000 and 27,500 women, respectively. Women who prove to be ineligible for, or who are unwilling to enroll in, these CT components are invited to enroll in the OS. At their 1-year anniversary of randomization, CT women are invited to be further randomized into the calcium and vitamin D (CaD) trial component, which is projected to include 45,000 women. The average follow-up for women in either CT or OS is approximately 9 years. Concerted efforts are made to enroll women of racial and ethnic minority groups, with a target of 20% of overall enrollment in both the CT and OS. This article gives a brief description of the rationale for the interventions being studied in each of the CT components and for the inclusion of the OS component. Some detail is provided on specific study design choices, including eligibility criteria, recruitment strategy, and sample size, with attention to the partial factorial design of the CT. Some aspects of the CT monitoring approach are also outlined. The scientific and logistic complexity of the WHI implies particular leadership and management challenges. The WHI organization and committee structure employed to respond to these challenges is also briefly described.
Annals of Clinical Biochemistry, 2009
Journal of Hypertension, Apr 1, 2011
Effects of telmisartan, irbesartan, valsartan, candesartan, and losartan on cancers in 15 trials ... more Effects of telmisartan, irbesartan, valsartan, candesartan, and losartan on cancers in 15 trials enrolling 138 769 individuals The ARB Trialists Collaboration Background Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARBs) reduce cardiovascular disease (CVD) events, but a recent metaanalysis of selected studies suggested that ARBs may increase cancer risks. Objective Candesartan, irbesartan, telmisartan, valsartan, and losartan were assessed for incident cancers in 15 large parallel long-term multicenter double-blind clinical trials of these agents involving 138 769 participants. Patients and methods Individuals at high CVD risk were randomized to telmisartan (three trials, n U 51 878), irbesartan (three trials, n U 14 859), valsartan (four trials, n U 44 264), candesartan (four trials, n U 18 566), and losartan (one trial, n U 9193) and followed for 23-60 months. Incident cancer cases were compared in patients randomized to ARBs versus controls. In five trials (n U 42 403), the ARBs were compared to ACEi and in 11 trials (n U 63 313) to controls without ACEi. In addition, in seven trials (n U 47 020), the effect of ARBs with ACEi was compared to ACEi alone and in two trials ARBs with ACEi versus ARB alone (n U 25 712). Results Overall, there was no excess of cancer incidence with ARB therapy compared to controls in the 15 trials [4549 (6.16%) cases of 73 808 allocated to ARB versus 3856 (6.31%) of 61 106 assigned to non-ARB controls; odds ratio (OR) 1.00, 95% confidence interval (CI) 0.95-1.04] overall or when individual ARBs were examined. ORs comparing combination therapy with ARB along with ACEi versus ACEi was 1.01 (95% CI 0.94-1.10), combination versus ARB alone 1.02 (95% CI 0.91-1.13), ARB alone versus ACEi alone 1.06 (95% CI 0.97-1.16) and ARB versus placebo/control without ACEi 0.97 (95% CI 0.91-1.04). There was no excess of lung, prostate or breast cancer, or overall cancer deaths associated with ARB treatment. Conclusion There was no significant increase in the overall or site-specific cancer risk from ARBs compared to controls.