1. Journal Club Mallory McClester, PGY-4 August 16, 2013

2. Objectives  Review the article contents  Discussion of article critically  Feedback from the group  Final conclusions

3. Background  More than 50% of all adults >65 have hypertension.  Likelihood of developing htn during the average lifespan is >90%.  Hypertension, antihypertensive drugs, and fall injury form a complicated triad.

4. Background  Hypothesis: Initiating antihypertensive agents in the elderly has been associated with an increased risk of falls, and therefore increased risk of hip fracture.

5. Methods  Population based, self-controlled case series  Prescription Drug Database used to identify all Ontario residents aged 66+, initiating anti- hypertensive  All patients with other conditions for which an anti-hypertensive drug may be used were excluded

6. Methods  Cases: First occurrence of hip fx from 4/1/2000-3/31/2009  Linked to: Cohort of newly treated hypertensive elderly patients  To clarify, first patients over the age of 66 starting an antihypertensive were identified. From that, cases of hip fractures were studied specifically.

7. Methods  High risk period  45 days immediately following antihypertensive initiation, observe closely for orthostatic hypotension  Control period (low risk, unexposed)  3 consecutive 45 day periods in preexposure and postexposure  Total observation period was 450 days

8. Date of download: 8/14/2013 Copyright © 2012 American Medical Association. All rights reserved. From: The Risk of Hip Fracture After Initiating Antihypertensive Drugs in the Elderly Arch Intern Med. 2012;172(22):1739-1744. doi:10.1001/2013.jamainternmed.469 Figure 1. Antihypertensive drug use and hip fracture risk: self-controlled case series design. Time division for each patient is included to assess incidence of first acute hip fracture in relation to antihypertensive prescription. All patients in the analysis had at least 1 prescription for an antihypertensive drug and a single incident hip fracture. Figure Legend :

9. Results  301,591 newly treated Ontario hypertensive elderly pts identified  Mean age (SD): 81 (7.3)  Gender: Females (80.7%)

10. Results  Hypertensive Elderly patients with hip fx:  Most exposed to ACE inhibitors (30.1%)  Least exposed to ARBs (4.4%)  This study shows that patients starting treatment had a 43% increased risk of hip fracture during the first 45 days of treatment.

11. Date of download: 8/14/2013 Copyright © 2012 American Medical Association. All rights reserved. From: The Risk of Hip Fracture After Initiating Antihypertensive Drugs in the Elderly Arch Intern Med. 2012;172(22):1739-1744. doi:10.1001/2013.jamainternmed.469 Figure Legend :

12. Results  Incident Rate Ratio consistent among the 5 different classes of antihypertensive drugs  Only ACE-I and Beta-blockers were statistically significant

13. Date of download: 8/14/2013 Copyright © 2012 American Medical Association. All rights reserved. From: The Risk of Hip Fracture After Initiating Antihypertensive Drugs in the Elderly Arch Intern Med. 2012;172(22):1739-1744. doi:10.1001/2013.jamainternmed.469 Figure 2. Forest plot of antihypertensive drugs and hip fracture risk using incidence rate ratios with 95% CIs. Each data point and 95% CI (error bars) represent results from the conditional Poisson regression analysis. The line at 1.0 represents no association; estimates to the right of the line represent an increased risk of hip fracture. ACE indicates angiotensin II converting–enzyme; ARB, angiotensin II receptor antagonist/blocker; BB, β-adrenergic blocker; and CCB, calcium channel blocker. Figure Legend :

14. Date of download: 8/14/2013 Copyright © 2012 American Medical Association. All rights reserved. From: The Risk of Hip Fracture After Initiating Antihypertensive Drugs in the Elderly Arch Intern Med. 2012;172(22):1739-1744. doi:10.1001/2013.jamainternmed.469 Figure Legend :

15. Date of download: 8/14/2013 Copyright © 2012 American Medical Association. All rights reserved. From: The Risk of Hip Fracture After Initiating Antihypertensive Drugs in the Elderly Arch Intern Med. 2012;172(22):1739-1744. doi:10.1001/2013.jamainternmed.469 Figure 1. Antihypertensive drug use and hip fracture risk: self-controlled case series design. Time division for each patient is included to assess incidence of first acute hip fracture in relation to antihypertensive prescription. All patients in the analysis had at least 1 prescription for an antihypertensive drug and a single incident hip fracture. Figure Legend :

16. Discussion  Demonstrates immediate increased risk of hip fracture on initiation of antihypertensive tx in community dwelling hypertensive elderly patients.  Main mechanism supported is orthostatic hypotension leading to falls.

17. Discussion  Thiazide diuretics:  No statistical difference  ACE inhibitors  First dose hypotension? related to venodilation  Beta blockers  Likely Less effective in controlling hypertension in elderly

18. Discussion  Identified Strengths of Study  Large population based study (301,591)  10 year period  Self controlled case series allowed for study of this association  Selection bias avoided (only used cases)  Removed fixed covariates  Identified Limitations  Patients may have been exposed to antihypertensives before age 65  Drug Samples?  No investigation of specific subclasses of medications

19. Critically Speaking  Why is this relevant?  Using these medications is beneficial long term even if short term risk may be increased

20. Relevance: How Common is Systolic Hypertension?  Prevalence of HTN increases with age  67% over age 60 and ¾ of those over the age of 70 have HTN (National Health and Nutrition Examination Survey: NHANES)  SH accounts for 75% of HTN in those over 65  Lifetime Risk Statistic:  Normotensive 65 year old adult who lives to age 85: 90% lifetime probability of developing stage 1 HTN (140-159/90- 99) and 40% risk of stage 2 HTN (>160/100)

21. Meta-analysis  8 trials, over 15,000 patients with SH  Median follow up 3.8 years  Treatment decreased mortality by 13%, stroke by 30%

22. NNT for 5 years to prevent one major CV event….

23. HYVET: Hypertension in the Very Elderly Trial  RCT of nearly 4000 patients from Europe, China, Australia, Tunisia  Age over 80  SBP > 160  Indapamide vs placebo  ACE inhibitor (perindopril) or placebo added as second agent when needed  Primary endpoint: stroke

24. HYVET…  Mean age : 83  Mean standing BP: 173/90  12% had hx of CV disease  1.8 year follow up  Treatment group: 15/6 lower BP

25. HYVET: results EndpointTreatment (rate per 1000 patient-year/# events) Placebo Stroke12.4 (51)17.7 (69) Death from stroke6.5 (27)10.7 (42) Mortality47.2 (196)59.6 (235) Death from CV cause23.9 (99)30.7 (121) Any MI2.2 (9)3.1 (12) p=.45 Any heart failure5.3 (22)14.8 (57) Any CV event33.7 (138)50.6 (193) Any CV event:Death from CV cause, stroke, MI, CHF

26. HYVET results…  30% decrease in rate of fatal or nonfatal stroke  39% decrease in rate of death from stroke  21 % decrease in all cause mortality  23% decrease in CV death  64% decrease in heart failure  Fewer adverse events in treatment group  7.9% in treatment group vs 8.8% in placebo group had orthostatic hypotension

27. HYVET: Take Home points  Overall number of events small (healthy population of elderly)  Stroke: ARR of almost 1% (NNT near 100 over 2 years to prevent one stroke)  Older patients more likely to die from stroke  All cause mortality (secondary outcome): ARR 1.2 % (NNT about 80)

28. Discussion  So looking more closely at the study data and applying this information:  Roughly 300,000 patients  1436 have hip fractures  143 occurred during “risk period”  104 occurred during washout period  Therefore, of 300,000 patients, it seems that the risk of antihypertensive agents may have contributed to 39 more hip fractures.

29. Any thoughts from the audience?

30. Conclusions  This study supports that there is atleast to some degree an increased risk of hip fracture after patients initiate anti-hypertensive agents, most likely secondary to orthostatic hypotension.  No data to support that the risk actually outweighs the benefit of these medications  Use caution when beginning anti-hypertensive agents and warn your patients of side effects.  May be beneficial to actually check all of our patient’s blood pressures while they are standing.

31. References  Butt D, Muhammad M et al. The Risk of Hip Fracture After Initiating Antihypertensive Drugs in the Elderly. JAMA Internal Medicine. 2012; 172(22): 1739-1744.  Hemmelgarn BR, Chen G, Walker R, et al. Trends in antihypertensive drug prescriptions and physician visits in Canada between 1996 and 2006. Can J Cardiol. 2008;24(6):507-512.  Wolf-Maier K, Cooper RS, Banegas JR, et al. Hypertension prevalence and blood pressure levels in 6 European countries, Canada, and the United States. JAMA. 2003;289(18):2363-2369.  Beckett N, Peters R, et al. Treatment of Hypertension in Patients 80 Years of Age and Older. New England Journal of Medicine. 2008; 358(18): 1887-1898.  Woolcott JC, Richardson KJ, Wiens MO, et al. Meta-analysis of the impact of 9 medication classes on falls in elderly persons. Arch Intern Med. 2009;169(21):1952-1960.  Tinetti ME, Williams CS. Falls, injuries due to falls, and the risk of admission to a nursing home. N Engl J Med. 1997;337(18):1279-1284