4.15.16 Gluckman Update in Outpatient Medicine/media/GrandRounds...good and life expectancy ≥10 yrs. ¾Strong recommendation • Screen annually between ages 45-54 ¾Qualified recommendation

© 2015 Private & Confidential

Update in Outpatient Medicine

Robert A Gluckman, MD, MACPChief Medical Officer Providence Health Plans

© 2015 Private & Confidential2

Disclosures

• Stock Holdings– Abbott Labs– Abbvie– Bristol Myers Squibb– GE– Proctor and Gamble– Walgreens


Topics• Breast cancer screening• Treatment of low risk DCIS• BP targets revisited• Medication choice in resistant hypertension• Personalized treatment of chronic disease• Treatment of hyperlipidemia in intermediate risk patients• Vitamin D and statin myopathy• Restarting anticoagulants after GI Bleeding in a. fibrillation


ACS Breast Cancer Screening Guidelines• Recommendations limited to average risk women

Assess previous PMH, FH using risk tool

• Performed a systematic evidence review and graded the evidence

• Made strong vs. qualified recommendationsStrong recommendation- Most individuals would want the recommended course of actionQualified recommendation- Majority of individuals would want the recommended course of action but many would not- shared decision making

JAMA 2015;314:1599-1614


ACS BCS Guidelines Key points

• Begin screening at age 45 and continue as long as overall health is good and life expectancy ≥ 10 yrs.

Strong recommendation• Screen annually between ages 45-54

Qualified recommendation• Women ≥ 55 should transition to biennial screening

Qualified recommendation• Women should have the opportunity to start screening at age 40• Women should have the opportunity to undergo annual screening• Clinical breast exam not recommended


USPTF Breast Cancer Screening Guidelines• Recommends biennial screening for women age 50-74

(Grade B)

• Recommends the decision to start screening before age 50 is an individual one (Grade C)

Women placing more emphasis on benefit over harm may choose to begin biennial screening at age 40

• Evidence insufficient for screening age 75 and over, digital breast tomosynthesis (DBT) as primary screening or DBT, ultrasound or MRI as adjunctive screening for women with dense breasts and otherwise negative exam

Ann Intern Med published online Jan 12, 2016


Areas of ControversyAge to start screening

5 year risk for BC dx is similar from 45‐49 (0.9%) than 50‐54 (1.1%).

Incidence age 40‐44 0.6%

Similar distribution of BC deaths by age at diagnosis for women age 45‐49 (10%) and 50‐54 (12%)

Age to stop screeningIncrease in BC incidence increases to age 7926% BC deaths occur after age 74No benefit for screening women in poor health

(i.e. Charlson Co-Morbidity Index ≥ 2)


Areas of Controversy

Screening intervalPremenopausal women undergoing biennial mammography have a 28% increase in advanced stage disease compared with shorter screening intervals

Tumor characteristics similar in women > 50 undergoing annual vs. biennial screening

False positive recalls and biopsies decrease over 30% with biennial vs. annual screening

© 2015 Private & Confidential9 JAMA Surg. 2015; 150(8):739-745 © 2015 Private & Confidential10

Survival Benefit for Low Grade DCIS

• Retrospective longitudinal cohort of SEER database

• 57,222 cases identified, only 2% were untreated – 14% treated with radiation alone

• Approximately 20% of DCIS are Grade 1

JAMA Surg. 2015; 150(8):739-745


10 year survival No surgery 98.8%Surgery 98.6%

10 year survivalNo surgery 90.5%Surgery 98.4%


Estimating Prognosis for Elderswww.eprognosis.ucsf.edu

Charlson Co-Morbidity Index Calculatorhttp://farmacologiaclinica.info/scales/Charlson_Comorbidity/


SPRINT Trial

• 9361 patients with SBP 130-180 mm Hg at high risk for CVD disease

Clinical or subclinical CVD other than CVACKD (excluding PCKD), eGFR 20-59 ml/minFramingham 10 year risk ≥ 15%Age ≥ 75Excluded patients with DM, CVA, LEF or symptomatic CHF, ESRD, poor adherence

• Trial stopped early due to benefitMedian follow up 3.26 years

N Engl J Med 2015; 373:2103-2116 © 2015 Private & Confidential14

SPRINT• Randomized to SBP target of SBP < 120 mm Hg or SBP

< 140 mm Hg

• Treatment algorithm similar to ACCORDDiuretics, ACEI/ARB, CCB preferredCondition warranted med (i.e. BB in CAD)56% of intensive group on 3 or more meds

ACE/ARB > diuretic > CCB > BB

• Follow up monthly x 3 months, then every 3 monthsLabs drawn every 3 months


Intensive treatment group mean SBP 121, 2.8 medsApproximately 50% did not reach treatment goal


Primary outcome: MI, ACS, CVA, decompensated CHF, CV deathNNT 61 ARR 1.6%

Overall mortalityARR 1.2% NNT 83

© 2015 Private & Confidential17 © 2015 Private & Confidential18

SPRINT Trial- Adverse events

Intensive Treatment Standard Treatment Hypotension 2.4% 1.4%

Syncope 2.3% 1.7%

Electrolyte Abnormality

3.1% 2.3%

Injurious Fall 2.2% 2.3%

Acute kidney injury 4.1% 2.5%


HOPE Trial- BP Lowering in Intermediate Risk Patients

•12,705 with intermediate risk for CVD; 2X2 factorial design trial to assess the impact of cholesterol and BP lowering

Men >55 with 1 CV risk factor; women > 60 with 2 CV risk factors, women >65 with 1 CV risk factorRisk factors- elevated waist to hip ratioCurrent or recent smoker (quit within 5 years)Early renal dysfunctionDysglycemia (impaired fasting glucose, glucose tolerance or diet treated DMLow HDLFH premature CAD

•Randomized to candesartan 16 mg plus HCTZ 12.5

•Median follow up 5.6 years

NEJM published online Apr 2, 2016 © 2015 Private & Confidential20

HOPE Trial- BP Lowering in Intermediate Risk Patients

Treatment was not associated with a reduction in CV events in patients with baseline BP <143.5


Effect of Anti-Hypertensive Treatment at Different BP Levels in DM

• Meta-analysis of 49 trials included 73,738 participants, mostly with Type 2 DM

• Prespecified outcomesTotal mortalityCV and non CV mortalityCVA, MI, CHF, AmputationESRD, BlindnessQuality of Life, Adverse Events

BMJ 2016;352:i717 © 2015 Private & Confidential22

Effect of Anti-Hypertensive Treatment at Different Pre-treatment BP Levels in DM

Effect of Anti-Hypertensive Treatment at Different Pre-treatment BP Levels in DM

Increased all cause and CV mortality in patients treat for HTN when Baseline BP <140


Effect of Anti-Hypertensive Treatment at Different Post-treatment BP Levels in DM

All cause and CV mortality increased when post treatment BP <130 mg


Hypertension Update

• Patients with or at high risk for CVD benefit from more intensive BP control

Adverse events more commonTighter control requires more medication and intense monitoring

• Diabetic patients have higher total and CV mortality with more intense treatment


Spironolactone vs. Placebo, Bisoprolol or Doxazosin in Resistant Hypertension- PATHWAY-2 Trial

• 12 month, double blind, placebo controlled, cross over trial

• Patients age 18-79, seated SBP >140 mm Hg135 mmHg in diabetics130 mmHg for home SBP readings

18 readings over 4 days

• All patients treated with maximally tolerated doses of ACE/ARB, CCB, and diuretic

Addressed adherence by home BP measure 6 hours after directly observed therapy, pill count, serum ACE

Lancet 2015; Volume 386: 2059-2068 © 2015 Private & Confidential26

Spironolactone vs. Placebo, Bisoprolol or Doxazosin in Resistant Hypertension- PATHWAY-2 Trial•Excluded patients with eGFR < 45 mL/min

•Patients rotated through 4 cycles of once daily treatmentSpironolactone 25-50 mgBisoprolol 5-10 mgDoxazosin 4-8 mg

•Treatment cycle for 6 weeks, then dose doubled as tolerated, no washout period between cycles

•Primary endpoint home BP readings


Spironolactone Adverse Events• Must monitor potassium carefully in the first weeks of

initiation and with dose escalation2% incidence of hyperkalemia

• 6% of men develop gynecomastia


Deintensification of BP and Glucose Medication Treatment in Older Patients• Retrospective cohort study of 211,667 VA patients > 70

years old with DM and treated for hypertension

• Cohort stratified for BP and Glucose controlVery low

SBP < 120 mm Hg, HgBA1c < 6.0%Moderately low

SBP 120-129 or DBP < 65 mm Hg, HgBA1C 6.0-6.4%Not low

SBP > 130 or DBP >65 mm HG, HgBA1c ≥ 6.5%High

SBP > 140, DBP >90, HgBA1c ≥ 7.5%

JAMA IM Published online October 26, 2015 © 2015 Private & Confidential30

Deintensification of BP and Glucose Medication Treatment in Older Patients• 50% had very or moderately low BP

• 20% had very low or moderately low HgBA1c

• Most patients had life expectancy < 10 years

• Deintensification was uncommon and unrelated to life expectancy

• Most patients with low BP or HgBA1c did not have repeat measurements within 6 months

Implies that clinicians do not identify risk of overtreatment


Treatment with Multiple BP Medications, Achieved BP and Mortality

• 1127 patients over age 80, residing in nursing homes

• Measured BP over 3 consecutive days

• Compared mortality in patients with SBP < 130 who received ≥ 2 anti-hypertensives with other participants.

JAMA Intern Med. 2015; 175(6):989-995


Effects of Low BP in Cognitively Impaired Elderly Patients Treated with Anti-Hypertensive Medications

• Cohort study of 172 patients age ≥ 65 with dementia or MCI with 9 month follow-up

• Risk stratified cohortLow BP ≤ 128 mm HgIntermediate BP 129-144 mm HgHigh BP ≥ 145 mm Hg

• Mean MMSE score 2268% dementia, 32% MCI

JAMA Intern Med. 2015;175(4):578-585


HYVET Trial

•3845 patients ≥ 80,SBP ≥ 160

•Randomized to indapimide or placebo

•Target BP < 150/80

•Low risk patients11.5% CVD6.8% DM

N Engl J Med 2008; 358:1887-1898


Hypertension-Conclusions

• SPRINT trial indicates more aggressive BP targets warranted for some high risk patients, including elderly

• 3 or more drugs often neededACE/ARB, diuretic, CCB initial choicesSpironolactone 4th drug in absence of specific indication for another drug

• Patients with intermediate CV risk without HTN do not benefit from anti-hypertensives

• Diabetics have increased mortality with aggressive BP control

• Personalized treatment goals are necessary with active deintensification for frail patients or those with adverse events


HOPE Trial- Effect of Cholesterol Lowering in Intermediate Risk Patients

• 12,705 participants of intermediate risk who did not have CVD randomized to 10 mg rosuvastatin vs placebo

• First co-primary outcomeDeath from CVD, nonfatal MI, non-fatal CVA

• Second co-primary outcomeAdded CHF, cardiac arrest, revascularization

• Median follow up 5.6 years.

NEJM published online April 2.2016


NNT 111 at 5.6 years


NNT 77 at 5.6 years


HOPE Trial- Effect of Cholesterol Lowering in Intermediate Risk Patients

• Patients at intermediate risk for CV disease have modest benefit from statin use

• Rosuvastatin will be available as a generic later this year


Statin Intolerance Due to Myalgias Can Be Resolved with Vitamin D Therapy• Some evidence that statin intolerance due to MSK symptoms

is associated with lower Vitamin D levels.

• Cohort of 146 patients with statin intolerance and Vitamin D levels < 32 ng/ml (mean 22ng/dl)

• Patients received Vitamin D 50,000-100,000 U/wk.

• 3 weeks after supplementation challenged with a statin (generally Rosuvastatin)

• Follow-up at 6,12 and 24 months-significant drop out• 88-95% of patients were myalgia free

International Journal of Cardiology Published online Oct 22, 2014


Association Between Guideline Recommended Drugs and Death in Older Adults

• Population based cohort study of 8578 Medicare beneficiaries with at least 2 chronic conditions

• Patients completed baseline and 3 annual in home interviews

• Selected conditions with 10% prevalence in cohort

• Ascertained prescription drugs by direct observation drug containers

http://dx.doi.org/10.1136/bmj.h4984Published 02 October 2015) © 2015 Private & Confidential44


Association Between Guideline Recommended Drugs and Death in Older Adults

• Guideline based therapy is effective in the elderly, especially for CVD drugs

• In this cohort, Clopidogrel, Metformin and SSRI’s did not impact mortality


Stroke and recurrent hemorrhage associated with antithrombotic treatment after GI bleeding in patients with atrial fibrillation

• Danish cohort study of 3409 patients with non-valvular atrial fibrillation who experienced GI bleeding while on anti-coagulant treatment

• Assessed all cause mortality, thromboembolism, major bleeding, recurrent GI bleed

• Stratified outcomes by single therapy, dual therapy, and triple therapy

• 27.1% of patients did not resume any anti-thrombotic therapy

BMJ 2015;351:h5876 © 2015 Private & Confidential48

Benefits greatest with single antithrombotic agent HR 0.39


Summary

In patients with non-valvular atrial fibrillation, resuming anti-coagulation after GI bleed is associated with lower mortality


Questions?

Documents

4.15.16 Gluckman Update in Outpatient Medicine/media/GrandRounds...good and life expectancy ≥10 yrs. ¾Strong recommendation • Screen annually between ages 45-54 ¾Qualified recommendation