News You Can Use: Recent Studies that Changed My Practice

Transcription

1 News You Can Use: Recent Studies that Changed My Practice Melissa McNeil, MD, MPH Chief, Section of Women s Health Division of General Internal Medicine University of Pittsburgh Sarah Tilstra, MD, MSc University of Pittsburgh

2 Objectives To identify practice changing studies that have the potential to change our management of women immediately To review the merits of these studies and to evaluate their significance To articulate how we might incorporate the results of these studies in the management of our women patients

3 Case 1 Elinor is a 55 year old woman you are seeing in the office for a well woman visit. She asks you if she should be taking either calcium supplements or increasing calcium in her diet. What do you tell her?

4 The News Calcium intake and risk of fracture: systematic review. Bolland et al. BMJ September 29; 351 Calcium intake and bone mineral density: a systematic review and meta-analysis. Tai et al. BMJ 2015 September 29; 351

5 Background: Recommended Intake A calcium intake of mg/day has been recommended for older individuals to both treat and prevent osteoporosis Average intake in the diet of older people in Western countries around mg/dl day Therefore in order to achieve the recommended calcium intake either an increase in dietary consumption or calcium supplements are required

6 Background: Adverse Effects Recently concerns about the safety of increasing calcium intake have been raised: Increase in cardiovascular events Kidney stones Constipation Admission to the hospital for GE side effects The minor benefit in fracture risk attributed to calcium supplementation coupled with an increasing awareness of these risks have called into question the risk/benefit profile of calcium supplements

7 Objectives of the Two Studies Bolland et al: To examine the evidence underpinning recommendations to increase calcium intake through dietary sources or calcium supplements to prevent fractures Tai et al: To determine whether increasing calcium intake from dietary sources affects bone mineral density (BMD) and if so, whether effects are similar to those of calcium supplements

8 Study 1: Relationship of Calcium Intake and Fracture Calcium intake and risk of fracture: systematic review. Bolland et al. BMJ September 29; 351

9 Methods: Calcium and Fracture Risk Authors undertook a systematic review of RCTs and observational studies of calcium intake and fracture risk to examine the evidence underpinning recommendations to increase calcium intake as a means of preventing fractures Included trials: RCTs or cohort studies of dietary calcium, milk or dairy intake, or calcium supplements (with or without D) Fracture is the endpoint Participants >age 45

10 Results: Dietary Sources of Calcium RCTs: Only 2 studies with limited data No conclusions could be drawn Cohort Studies: 50 publications, 44 studies 14/22 studies reported no relation between calcium intake and total fracture risk 17/21 studies reported no relation between calcium intake and hip fracture 7/8 studies reported no relation between calcium intake and vertebral fracture Thus 43 of the 58 (74%) reported no association between dietary calcium intake and fracture outcome

11 Results: Calcium Supplements Randomized Controlled Trials 26 RCTs (n=69, 107) of calcium supplements that reported fracture outcomes 14 calcium monotherapy 8 CaD 4 were multi-arm or factorial Study details 20 trials used a calcium dose of > 1000 mg/day 21 were in individuals living in the community 15 had a duration of three or more years In 16 studies the mean age of participants was > 70 years In 10/19 studies that reported baseline intake the level was <800

12 Fig 1 Random effects models of effect of calcium supplements on risk of total fracture. Mark J Bolland et al. BMJ 2015;351:bmj.h by British Medical Journal Publishing Group

13 Fig 2 Random effects models of effect of calcium supplements on risk of hip fracture. Mark J Bolland et al. BMJ 2015;351:bmj.h by British Medical Journal Publishing Group

14 Fig 3 Random effects models of effect of calcium supplements on risk of vertebral fracture. Mark J Bolland et al. BMJ 2015;351:bmj.h by British Medical Journal Publishing Group

15 Summary: Impact of Increasing Dietary Calcium on Fracture Risk There is insufficient evidence to assess the effect of increasing dietary calcium on fracture risk 42 cohort studies assessed the relationship between dietary calcium and fracture risk Greater than 75% of analyses found no benefit Most studies did not report reduced risk of fracture in individuals with the recommended 1200 mg/d of calcium intake Thus observational trials do not support a hypothesis of dietary calcium deficiency

16 Summary: Impact of Increasing Calcium Supplementation on Fracture Risk In 26 RCTs, calcium supplementation reduced the risk of total fx by 11% and vertebral fx by 14% The results, however, were not consistent In particular, the largest trials with the lowest risk of bias showed no reduction Only one trial in frail elderly women in residential care with low dietary calcium intake/ low vitamin D showed significant reductions in fracture risk

17 Study 2: Impact of Dietary Calcium Supplementation on BMD Calcium intake and bone mineral density: a systematic review and meta-analysis. Tai et al. BMJ 2015 September 29; 351

18 Methods: Calcium and BMD Authors undertook a systematic review and metaanalysis of randomized controlled trials with BMD as an endpoint to determine if the recommendations to increase calcium intake to prevent osteoporosis are supported Included trials of dietary calcium or calcium supplementation in older adults (>50) to determine : If increasing intake from the diet has effects on BMD And if it is similar to the effects of calcium supplement

19 Eligible Trials of Calcium Supplementation Trial Characteristics Dietary Ca Source (n=15) Ca Supplements (n=51) Agent Studied: Number (%) Number (%) Ca Monotherapy 11 (73) 36 (71) Ca with vitamin D 4 (27) 13 (25) Multi arm with both 0 2 (4) Calcium dose > 1000mg/d 6 (40) 34 (67) Calcium dose < 500 mg/d 2 (13) 7 (14) Duration < 2 years 15(100) 37 (73) Duration > 3 years 0 13 (25) Community living 15 (100) 45 (88) Mostly women 13 (87) 48 (94) Mean age > 70 years 2 (13) 18 (35) Baseline Ca < 800mg/d 9/13 (69) 26/39 (67)

20 Analysis of RCTs of Dietary Calcium Time Point Studies Number BMD Change P Value Lumbar ( ) ( ) Femoral ( ) ( ) <0.001 Total Hip ( ) ( ) <0.001 Total Body ( ) ( ) <0.001

21 Analysis of RCTs of Supplemental Calcium Time Point Studies Number BMD Change P Value Lumbar ( ) < ( ),0.001 Femoral ( ) < ( ) <0.001 Total Hip ( ) ( ) <0.001 Total Body ( ) < ( ) <0.001

22 Summary of Results on BMD Increasing calcium intake from the diet slightly increased BMD by % over two years except at the forearm Calcium supplements increased BMD by % at all sites and at all time points In the RCTs of both dietary calcium and calcium supplements, the increase was present by one year but there were no further increases over time There was no difference in increase in BMD if: Vitamin D was added Calcium supplementation > or < 1000 mg/d Calcium supplemention < or > 500 mg/d Baseline dietary supplementation < or > 800 mg/d

23 Impact These results suggest that widespread untargeted use of either dietary calcium or calcium supplements in older individuals is unlikely to result in meaningful reduction in the incidence of fractures or improvement in bone mineral density

24 Case 2 She says, OK, no real benefit to increasing my calcium. But what about vitamin D? What do you tell her?

25 The News Hansen KE et al. Treatment of vitamin D insufficiency in postmenopausal women; A randomized clinical trial. JAMA Internal Medicine 2015; 176(10):

26 Objective The goal of this study was to evaluate the effects of high dose and low dose cholecalciferol on 1 year changes in Total Fractional Calcium Absorption(TFCA), bone mineral density (BMD), and muscle fitness in postmenopausal women with Vitamin D insufficiency (VDI)

27 Background Low vitamin D levels reduce the TFCA leading to secondary hyperparathyroidism and decreased BMD VDI is currently defined as a serum 25(OH)D level less than 30 ng/ml Approximately 75% of postmenopausal US women have levels below that target

28 Methods This was a double-blind placebo-controlled RCT of postmenopausal women < 75 years with 25(OH)D levels of ng/ml Women were randomized to either: High dose cholecalciferol (loading dose of 50,000 IU/d for 15 days and then 50,000 every 15 days) 800 IU capsule of cholecalciferol every day Outcomes were assessed at one year and included laboratory testing, functional assessment, and clinical outcomes

29 Results Calcium absorption increased 1% (10 g/dl) in the high dose arm but decreased 2% in the low dose arm No difference between the high dose and low dose supplementation groups in BMD scores at any site, muscle mass, functional assessments such as the timed Up and Go or five sit-to stand test scores There were also no differences in falls, physical activity, or other functional status

30 Summary Neither low dose or high dose vitamin D supplementation had any impact on clinical outcomes in women less than 75 years of age

31 Impact This study does not support current recommendations to maintain serum 25(OH)D levels above 30 ng/ml. The IOM recommendations of 25(OH)D levels 20 ng/ml appear to be appropriate and the widespread testing for and supplementation of 25(OH)D levels below 30 ng/ml should be reconsidered.

32 Case 3 Marianne is a 60 year old woman who comes to you for advice. She received a letter from her radiologist telling her that she has increased breast density and that she should talk to her primary care physician to determine if any more testing is needed. What will you tell her?

33 The News Kerlikowske K et al. Identifying women with dense breasts at high risk for interval cancer. 2015: Annals of Internal Medicine. 163(10)

34 Background Breast cancer advocates in many states have lobbied for patient notification about increased breast density because It is a marker of increased risk The sensitivity of mammograms is decreased false negative rate varies up to 10 fold across the categories of breast density 40% of women aged 40 to 74 years have dense breasts (defined as heterogeneously or extremely dense)

35 Background Different professional organizations have differing recommendations: ACOG: recommends against supplemental screening USPSTF and the ACS: state that there is insufficient information to recommend for or against supplemental screening American College of Radiology: suggests that supplemental ultrasound evaluation could be considered. Despite the lack of data and absence of consensus, 24 states have now required that patients with increased breast density be notified of their increased risk and suggest that they discuss additional screening with their providers.

36 Objective The goal of this study was to determine which patients with increased breast density are associated with high interval cancer rates and thus would benefit from supplemental screening

37 Methods Data from the Breast Cancer Surveillance Consortium (BCSC) mammography registries were analyzed Women aged aged 40 to 74 years Who underwent digital screening mammography Between 2002 and 2011 An interval cancer rate greater than 1 case per 1000 mammograms was considered to be unacceptable performance Interval cancer rates were analyzed with different predictive scenarios including: breast density alone, breast density modified by age, and breast density modified by 5 year calculated BCSC breast cancer risk

38 Methods

39 Results

40 Results

41 Summary About half of women with heterogeneously dense breasts or extremely dense breasts were at low to average 5 year breast cancer risks (0% to 1.66%). Interval cancer rates greater than 1 case per 1000 mammography examinations were observed in women: With extremely dense breasts and a 5 year cancer rate of >1.67% With heterogeneously dense breasts and a 5 year cancer rate of >2.5% These two groups represented only 24% of women with dense breasts suggesting that the majority of women with dense breasts are not at risk for increased interval cancer detection

42 Impact Increased breast density alone should not prompt additional supplemental imaging. The most important prognostic factor identified to date to help determine which patients with increased breast density are at risk for interval cancers is the 5 year BCSC breast cancer risk. Physicians should calculate individual breast cancer risks for all patients and use this information in counseling patients about decision making about alternative breast cancer screening strategies.

43 Case 4 Karen presents to you for a well woman visit. She is 42 years old. She asks you if she should begin breast cancer screening. She has no family history of breast cancer and no prior history of breast biopsies. She is an average risk patient for breast cancer. What do you tell her?

44 The News Oeffinger KC et al. Breast cancer screening for women at average risk 2015 guideline update from the American Cancer Society. JAMA. 2015; 314(15):

45 Background Currently the guidelines for breast cancer screening vary among professional organizations causing women and providers much uncertainty about what to recommend In response to new evidence from long-term followup data of screening trials, the American Cancer Society (ACS) commissioned a systematic review of the breast cancer screening literature taking into account the quality of the evidence about the balance of benefits and harms

46 Methods The ACS assembled an interdisciplinary group of experts and tasked them with developing guidelines for average risk women Guidelines were developed and graded: A strong recommendation is meant to convey that benefits > harms Qualified recommendations suggest that there is clear evidence of benefit but less certainty about either the balance of benefits and harms or about patients values and preferences (which, when considered, could lead to different decisions by different patients). Critical outcomes were considered to be prevention of breast cancer deaths, quality of life years gained by screening, life expectancy, false positives, overdiagnosis, and overtreatment Breast cancer characteristics at diagnosis and short and long term emotional effects such as anxiety and depression were considered important but not critical outcomes. A total of 10 RCTs, 22 cohort studies, and 13 case control studies were considered

47 Recommendation 1: Screening Mammography Should Begin at Age 45 (Strong) This recommendation was based on analyzing breast cancer incidence and mortality in 5 year intervals for women between 40 and 50; previous screening trials had clustered outcomes in 10 year age increment The five year risk of breast cancer among women 40 to 44 (0.6%) is less than that in women aged 45 to 49 (0.9%) and women aged 50 to 54 (1.1%) The risk of breast cancer mortality reduction is similarly different with a reduction of 18% in women 40 to 44 and 32% in women 45 to 49 They further qualify this recommendation by stating that all women should have the opportunity to begin screening at age 40 if they so desire

48 Results: Breast Cancer Burden by Age at Diagnosis

49 Recommendation 2: Women aged 45 to 54 should be screened annually (Qualified) Screening interval is important to reduce the diagnosis of interval cancers that appear clinically between screening examinations Data reviewed suggested that in women greater than age 50 few interval cancers were detected; in contrast, in women in their 40s the rate of interval cancers was 40% of the control group incidence rate in the first 12 months after a normal screening examination. It is unclear if this difference is age related or influenced by menopausal state and several studies have suggested that menopausal state is the more important factor.

50 Recommendation 3: After age 55 Biannual Mammography is Recommended (Qualified) The benefits of annual screening are reduced after the menopausal transition; most women will be post menopausal by age 55 More frequent screening over a lifetime carries an increased risk of false positives Balancing risks and benefits 55 is the recommended age at which to transition to biannual screening

51 Recommendation 4: Women should continue screening mammography as long as they have a life expectancy of 10 years (Qualified) Breast cancer incidence continues to increase until age 80, and 26% of breast cancer deaths are attributed to a diagnosis after age 74 For women who are healthy and have a life expectancy greater than 10 years, decisions should be individualized

52 Recommendation 5: The ACS does not recommend clinical breast examinations (CBE) for breast cancer screening (Qualified). The ACS based this recommendation on the fact that there were no studies demonstrating a benefit of CBE in addition to mammography They also cited moderate quality evidence that CBE increases false positive examinations

53 Limitations and Cautions Most of the screening trials began before 2000 and Used only film mammography and Had different breast cancer treatment regimens Thus the long term follow up information may not represent the impact of screening and breast cancer treatment today The ACS also included observational cohorts in its data analysis which the USPSTF does not include because of the inherent risk of bias in cohort studies Patient preferences may vary from individual to individual and the ACS recognizes that different patients may have a different weighing of risks and benefits.

54 Impact The new guidelines are helpful in offering an evidenced based review of newer literature and framing the benefits of screening in the context of harms. It must be remembered that these guidelines refer to women of average breast cancer risk and offer a rational approach to screening in this population of women.

55 Case 5 Karen is still not convinced. She asks you if there is any data to support that less is more and that the reduction in frequency of screening will be safe? What do you tell her?

56 The News Harding C et al. Breast cancer screening, incidence, and mortality across US counties. JAMA Internal Medicine. 2015; 175(9):

57 Background The goal of breast cancer screening is to reduce breast cancer mortality presumably by detecting breast cancers earlier in their course of disease If this is the case, there should be both an increase in the detection of smaller cancers and because of this a decrease in the detection of larger, poor prognosis cancers Since mammography rates vary widely across the United States, associations can be drawn between screening and breast cancer size, incidence, and mortality.

58 Objective Local data on rates of mammography screening and breast cancer diagnosis are available for approximately one-fourth of the US population. These data were used to examine the associations between rates of modern screening mammography and the incidence of breast cancer, mortality from breast cancer, and tumor size

59 Methods US counties reporting breast cancer screening and mortality to the Surveillance, Epidemiology and End Results (SEER) Cancer Registries were analyzed Initial screening took place from January 1 to December 21, 2000 Women over 40 were included in the analysis and no upper age limit was imposed Over 95% of the cancer diagnoses (n=53,207) had 10 years of follow up at the time of final analysis Screening rates varied from 39.1% to 77.8%; breast cancer incidence and breast cancer mortality by county were correlated to the baseline mammography use

60 Results An increase of 10% in the rate of screening was associated with an increase in breast cancer diagnosis (RR 1.16: 95% CI ) Despite an increase in breast cancer diagnosis with increased screening rates, there was no decrease in breast cancer mortality (RR 1.01: 95% CI )

61 Results Screening was associated with an increase in tumors <2 cm in size but not in larger breast cancers

62 Limitations These results are correlations and thus are subject to inherent biases. It is possible that different regions have different breast cancer incidences and that areas with higher breast cancer rates have higher screening rates. It is also possible that women with higher risks of breast cancer request more screening.

63 Summary The most straightforward explanation for this finding of more small tumors but no mortality difference is over-diagnosis of clinically irrelevant tumors which would increase incidence but not impact mortality.

64 Impact Increased breast cancer screening is not necessarily associated with better outcomes. Data such as these are informative in considering current recommendations for the frequency of mammography and the importance of individualized recommendations based on breast cancer risk assessment.

65 Case 6 Janet is a 65 year old woman who presents for her annual wellness exam. She has been post-menopausal on HT for 12 years. Previous attempts to wean her off have failed. She received a letter in the mail from her insurance company telling her that her hormones would no longer be covered as they are very dangerous, and asks you about stopping them. She has no PMH except for wellcontrolled HTN

66 The News The North American Menopause Society statement on continuing use of systemic hormone therapy after age 65. Menopause 2015 Jul; 22:693

67 Background Oral and transdermal estrogens were placed on the Beers list of potentially inappropriate medications (PIMs) in 2003 Physicians have been reluctant to continue hormone therapy (HT) for women who are affected by vasomotor symptoms past age 65 strictly because of age

68 Background Many quality accrediting and reporting programs are using the list of PIMs as an outcome measure for physicians and health plans THUS physicians are withholding these medications insurance companies are not paying for them and patient access is further compromised Two studies in 2015 confirm that the duration of vasomotor symptoms has previously been underestimated and is now thought to last well into the 6 th and 7 th decade for some women

69 Objective To update the 2012 North American Menopause Society position statement, specifically regarding the use of hormone therapy in healthy women with moderate to severe vasomotor symptoms

70 Methods Expert consensus statement from the North American Menopause Society; no further details provided

71 Recommendations It is acceptable for a healthy woman to continue HT with the lowest effective dose after the age of 60 if she is being treated for persistent moderate to severe vasomotor symptoms or osteoporosis and has no other adequate treatment options The benefits of vasomotor symptom management must outweigh the risks of HT for the patient, and that this decision must be made jointly between the patient and her physician

72 Recommendations Women should be counseled about the risks of HT including increased VTE, stroke, breast cancer risk The risks of continuing HT should be evaluated annually as women age and risk factors change HT should not be stopped on the basis of age alone

73 Cautions The risks of HT over age 60 remain real and there is limited data in women on HT above age 70 to guide further recommendations While HT was placed on the Beers list 13 years ago in the midst of the WHI controversy, it remains there even after review in 2012 Despite the wiliness of physicians to prescribe HT to patients, more and more health plans are limiting financial coverage of these medications to patients, especially > age 65

74 Impact The continuation of use of HT in women over 60 for vasomotor symptoms or severe osteoporosis seems acceptable but remains an ongoing conversation between patient and physician and should prompt an annual reassessment of the risks and benefits.

75 Take Home Messages Widespread untargeted use of either dietary calcium or calcium supplements in older individuals is unlikely to result in meaningful reduction in the incidence of fractures Widespread testing for and supplementation of 25(OH)D levels below 30 ng/ml should be reconsidered Increased breast density alone should not prompt additional supplemental imaging; the most important prognostic factor identified to date to help determine which patients with increased breast density are at risk for interval cancers is the 5 year BCSC breast cancer risk

76 Take Home Messages The new ACS guidelines are helpful in offering an evidenced based review of newer literature and framing the benefits of screening in the context of harms Increased breast cancer screening is not necessarily associated with better outcomes and emphasize the importance of individualized recommendations based on breast cancer risk assessment The continuation of use of HT in women over 60 for vasomotor symptoms or severe osteoporosis seems acceptable but remains an ongoing conversation between patient and physician and should prompt an annual reassessment of the risks and benefits

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