7/27/2017 DISCLOSURES OUTPATIENT MANAGEMENT QUESTION #1 FEATURES OF THIS TALK OF CAD- A PRIMARY CARE PERSPECTIVE

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1 DISCLOSURES OUTPATIENT MANAGEMENT OF CAD- A PRIMARY CARE PERSPECTIVE I am on the Scientific Advisory Boards with stock option compensation for the following companies: TAI Diagnostics Cricket Health, Inc. Michael G. Shlipak, MD, MPH Professor of Medicine, UCSF Chief, Division of General Internal Medicine, SFVA Medical Center Scientific Director, Kidney Health Research Collaborative, UCSF FEATURES OF THIS TALK Covers a broad array of topics Greatest attention to common challenges in decision making All recommendations supported by the following Guideline: AHA Guideline for the Diagnosis and Management of Patients with Stable Ischemic Heart Disease (Circulation, 2012) Class 1 indication: we should do this Class 2 indication: it s reasonable to do this QUESTION #1 Your patient is a 62yo man with history of controlled hypertension, mild overweight (BMI 29), and untreated LDL of 137mg/dL. He reports to you that for about 2 months he has experienced left-sided chest tightness after working up 2 flights of stairs. It is relieved by rest and is not progressing noticeably. The symptoms have not occurred at any other times. What is the probability that the patient s symptoms are caused by CAD? a) <50% b) 60% c) 80% d) >90% 1

2 PRETEST PROBABILITY OF CORONARY HEART DISEASE IN PATIENTS WITH CHEST PAIN ACCORDING TO AGE, GENDER, AND SYMPTOMS Age Nonanginal Chest Pain Atypical angina Typical angina Men Women Men Women Men Women QUESTION #2: YOUR PATIENT IS CAPABLE OF WALKING AND HAS A NORMAL RESTING ECG. WHICH OF THE FOLLOWING TESTS SHOULD YOU ORDER NEXT? a) Exercise only stress test b) Exercise with perfusion imaging c) Exercise echo d) Coronary angiography e) None of the above AHA definitions: low risk ~10% or less high risk ~90% or higher intermediate risk- anything in between Diamond GA et al., N Engl J Med 1979 Weiner DA et al., N Engl J Med 1979 NON INVASIVE TESTING FOR DIAGNOSIS OF ISCHEMIC HEART DISEASE AHA recommendation is to limit testing to intermediate risk patients If patient can exercise and has normal resting ECG, then exercise only stress test If abnormal ECG, then exercise/imaging or exercise echo If patient cannot exercise, then pharmacologic stress with imaging/echo WHY DO WE ONLY TEST PATIENTS WITH INTERMEDIATE PROBABILITY OF CAD? Exercise only: LR+ = 3.0 LR- = 0.42 (Gianrossi R. et al. Circulation, 1989) Exercise echo: LR+ = 3.7 LR- = 0.19 (Fleischmann KE. et al. JAMA 1998) Exercise imaging: LR+ = 2.4 LR- = 0.20 (Fleischmann KE. et al. JAMA 1998) - (0.02) + (0.28) - (0.25) + (0.77) - (0.65) + (0.97)

3 PROMISE TRIAL Is coronary CT angio the best tests for evaluation of intermediate risk patients with chest pain? Douglas P.S. et al N Engl J Med, 2015 TRIAL DESIGN 10,000 participants in North America 193 sites NIH-funded Randomization: CTA- coronary computed tomographic angiography Functional Testing- (one of the 3 options) Exercise EGG Nuclear stress Stress echo Composite: death, MI, UA hospital procedure complication Median follow-up 25 months PATIENT CHARACTERISTICS Age: 60±8 Women: 53% Mean: 2.4 risk factors Typical angina: 17% Atypical angina: 78% Non-anginal symptoms: 10% Individual predicted CAD risk: mean 0.53 QUESTION 3 Among these intermediate risk patients, what percentage would you guess had the primary outcome (death or MI) within 2 years? a) <5% b) 5-10% c) 10-20% d) >20% 3

4 CT ANGIO IS NO BETTER THAN FUNCTIONAL TESTING SUMMARY A lot of testing with very low yield Intermediate risk is actually low risk reflects an excellent prognosis for patients with similar, new-onset, stable chest pain in realworld settings. Incidence of death or MI was only 1%/year in each group QUESTION #4 Based on his symptoms of typical angina, you inform your patient that he has CAD. You explain the proven value of optimal medical therapy Which of the following is not considered part of optimal medical therapy for a patient with anginal symptoms? a) ACE inhibitors (ARBs) b) Aspirin c) Beta blockers d) Statins ASPIRIN All patients with CAD should use mg of aspirin (class 1) Clopidigrel (plavix) should be offered to patients who cannot tolerate aspirin (class 1) Aspirin + clopidigrel for severe patients is reasonable (class 2B) 4

5 BETA BLOCKERS Improved survival in patients with prior MI If patient has prior MI, BB is class 1 If MI >3 years ago, BB is class 2A Best choice for angina symptoms STATINS (MORE ON THIS TOPIC LATER) LDL target <100 mg/dl - class 1 LDL target <70 mg/dl - class 2A No evidence to suggest LDL targets of 70 vs. 100mg/dL in patients with ASCVD ACE INHIBITORS Not clearly indicated in patients with angina because no effect on symptoms Considered a reasonable choice (2A) ACE inhibitors (Class I) must be used for patients with: Reduced ejection fraction CKD with albuminuria CASE CONTINUED Your patient worries that something bad might happen with his heart. He asks you to assess the likelihood of him having a heart attack or dying from his heart disease. How do you determine risk in the secondary prevention setting? 5

6 RISK PREDICTION IN CAD Primary prevention: Patients without CAD or CVD CVD risk calculator Secondary prevention: Patients who have CAD No risk score for ambulatory patients with established CAD CVD risk calculators do not work RISK FACTORS FOR ADVERSE OUTCOMES IN PATIENTS WITH CAD Feared adverse outcomes in CAD patients: Recurrent MI Heart failure Sudden death Traditional CVD risk factors are still important: Blood pressure control Smoking cessation Weight loss Diabetes control Lipid management Encourage exercise Although important, cardiac status matters more for prognosis than metabolic risk factors CARDIAC-SPECIFIC RISK FACTORS IN PATIENTS WITH CAD 1. Exercise capacity 2. Number and size of MIs 3. Reduced ejection fraction 4. HF symptoms 5. BNP/NT-pro-BNP 6. High sensitivity troponins TREATMENT OF ANGINAL SYMPTOMS RANKING ANTI-ISCHEMIC AGENTS (PER AHA GUIDELINES) 1. BBs- top choice 2. CCBs or long acting nitrites (if BB intolerant) 3. Use combinations if necessary 4. NTG (sl or spray) for immediate relief 5. Ranolozine as lesser alternative (class 2A) 6

7 FOLLOW UP IN CAD PATIENTS Routine Assess anginal symptoms and physical function Assess signs of heart failure or arrythmia Risk factor management Lifestyle CASE STUDY FOLLOW UP Your patient is still frustrated by the concept of medical management and concerned that his symptoms indicate an impending heart attack. He asks you why can t I just get a stent and fix this problem? This seems logical- why not proceed to PCI? Situational If heart failure signs or repeat MI echo If new or worsening angina exercise testing or coronary angiography INTERVENTIONS IN STABLE ANGINA Interventions should be limited to patients who fail optimal medical therapy Currently, 85% of all percutaneous coronary intervention (PCI) procedures are elective in patients with stable angina The COURAGE trial demonstrated that PCI does not improve outcomes COURAGE TRIAL Conducted to compare OMT with and without PCI in 2,287 patients with stable angina Funded by the US VA R&D/Canadian Institutes of Health Research Outcome: All-cause mortality Non-fatal MI Initial trial: mean of 4.6 years Boden et al. NEJM 2007 Extended follow-up: 12 years Sedlis et al. NEJM

8 COURAGE OUTCOMES CASE STUDY FOLLOW UP Your patient insists on talking with a specialist You refer to a cardiologist The patient returns to your office 8 weeks later for a follow-up visit Sedlis et al. NEJM 2015 after having received a stent. What happened? CARDIOLOGISTS USE OF PCI FOR STABLE CAD What are cardiologists thinking? Design: focus groups of cardiologists in N. Cal Research Question: Why do cardiologists ignore COURAGE results? Reasons given for performing PCI in stable angina: Belief in the benefits of treating ischemia and in the open artery hypothesis Potential regret (psychological and legal) for not intervening if a cardiac event could be averted Alleviation of patient anxiety Belief that referring PCP expects a procedure Lin et al. Arch Intern Med

9 WHY STATINS ARE BETTER THAN STENTS Severity of stenosis MI risk Stents are small (1-2 cm) relative to length of 3 major coronary arteries (~30cm) and their branches (>30cm) Statins stabilize all the plaques CONCLUSIONS We need to fully implement OMT (β-blocker, statin, aspirin) first, before referring to cardiologists We need to resist the urge to fix patients angina by stenting We need to educate patients that stents do not prevent adverse outcomes We need to be clear about our expectations prior to referring patients to cardiologists QUESTION 5 Your patient returns for follow up. He has been taking 20mg simvastatin. LDL is 110mg, HDL 25mg. Which is the best next step? a) simvastatin b) Change to pravastatin c) Change to atorvastatin d) Add gemfibrozil e) Add niacin NEW RECOMMENDATIONS FOR LIPID MANAGEMENT IN PERSONS WITH CVD 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines High intensity statin therapy should be first line in persons with clinical ASCVD, aged 75, unless contraindicated High- atorvastatin 40-80, rosuvastatin Moderate- simvastatin 20-40, pravastatin 40, lovastatin 40 Low- simvastatin 10, pravastatin 10-20, lovastatin 20 Our patient should be on atorvastatin or rosuvastatin 9

10 SHOULD WE STILL USE SIMVASTATIN? June 8, 2011: FDA restricts use of 80mg simvastatin because of increased risk of myopathy FDA recommends: No new patients on simvastatin 80mg Okay to maintain patients on 80mg if >1 year without symptoms of muscle toxicity Beware of drug interactions Based on the SEARCH Trial (Lancet, 2010) Simvastatin 80mg vs. 20mg in RCT of 12,000 with CAD SEARCH TRIAL RESULTS Difference in myopathy risk: Myopathy (muscle weakness + CK >10x ULN) 80 mg: 52 patients (0.9%) 20 mg: 1 patient (0.02%) Rhabdomyolysis (muscle weakness + CK>40x ULN) 80 mg: 22 patients (0.4%) 20 mg: 0 patients Risk 5-fold higher in year 1 compared with subsequent years Key drug interactions noted Calcium channel blockers, Amiodarone, Ranolazine, and others SEARCH Study Group The Lancet, 2010 QUESTION 6 You decide your patient should switch to atorvastatin. However, he has now stopped his statin due to adverse publicity and will not restart. He tells you that he is now taking niacin because it is a natural option. You recheck his lipids; his HDL is 50mg/dL and his LDL is 140 mg/dl. Your best management option is: a) Reinforce to the patient that statins are by far the best treatment for lipid disorders. b) Congratulate him on his choice because niacin has made his HDL go up beautifully c) Offer a fibrate (e.g. gemfibrozil), as it is an evidencebased treatment for patients like him d) Any of the above approaches is fine. WHY IS NIACIN IN DISFAVOR? AIM-HIGH trial (NEJM 2011) AIM-HIGH Investigators, NEJM 2011 HPS2-THRIVE trial (NEJM, July 17, 2014) HPS2-THRIVE Investigators, NEJM

11 AIM-HIGH TRIAL (NIH, ABBVIE) Participants: N=3,414 in US and Canada Inclusion criteria: Prior CVD On a statin Low HDL and high TG Design: Placebo-controlled RCT Intervention: Niaspan 2 g/day or placebo Outcomes: CVD death, MI, CVA, ACS, revascularization Follow-up: 3 years AIM-HIGH Investigators, NEJM 2011 AIM-HIGH FINDINGS Trial stopped early Event rate was same in both groups AIM-HIGH Investigators, NEJM 2011 HPS2-THRIVE TRIAL (MERCK) Participants: N=25,673 in UK, Scandinavia, and China Inclusion criteria: Prior CVD On a statin Design: Placebo-controlled RCT Intervention: 2g ext-release niacin + 40mg laropiprant vs. placebo Outcomes: CVD death, MI, CVA, and revascularization Follow-up: 4 years HPS2-THRIVE Investigators, NEJM 2014 HPS2-THRIVE FINDINGS But, there is more to the story Primary outcome RR= 0.96 ( ) All-cause mortality RR= 1.09 (0.99 to 1.21) HPS2-THRIVE Investigators, NEJM

12 NIACIN INCREASES RISK FOR SERIOUS ADVERSE EVENTS AND DIABETES Event Rate Ratio (95% CI) Extra Events/100 Users Serious adverse event GI Event 1.28 ( ) 1.0 Musculoskeletal event 1.26 ( ) 0.7 Skin-related event 1.67 ( ) 0.3 Infection event 1.22 ( ) 1.4 Bleeding events 1.38 ( ) 0.7 Diabetes mellitus New-onset 1.32 ( ) 1.3 Worsened condition 1.55 ( ) HPS2-THRIVE Investigators, NEJM 2014 On the basis of the weight of available evidence showing net clinical harm, niacin must be considered to have an unacceptable toxicity profile for the majority of patients, and it should not be used routinely. [the study] lends further evidence to the notion that HDL cholesterol is unlikely to be causal. EFFECTS OF FIBRATES ON CARDIOVASCULAR OUTCOMES Do fibrates improve clinical outcomes? Design: systematic review and meta-analysis Analysis: 18 RCTs from Participants: N=45,058 Jun et al. The Lancet

13 FIBRATE VS. PLACEBO AND CVD RISK Outcome Non-fatal coronary events Relative Risk 95% CI P Value < Total stroke Cardiovascular death All-cause mortality DATA SUMMARY For patients with low HDL: Statins are treatment of choice to decrease CVD risk, regardless of LDL Do not add either niacin or fibrates to statin treatment For patients who cannot tolerate statins: Fibrates appear to lower MI risk, but no other CVD endpoints Niacin has clear harmful effects and uncertain benefits among statin non-users. AHA guidelines state that for statin untreated patients fibrates are a reasonable choice (2A) Jun et al. The Lancet 2010 CASE STUDY FOLLOW UP Now that your patient with stable CAD is on OMT, he has increased exercise, as you recommended. However, he has developed persistent knee pain and wants to take prescription-strength ibuprofen. The label says to ask a doctor before use if you have heart disease. Is the risk real? NSAIDS IN CAD PATIENTS Meta-analysis demonstrated increased risk for incident CAD (Trelle et al. BMJ 2011) Are they clinically harmful in patients with established CAD? No RCT evidence in CAD patients 13

14 BEST EVIDENCE FROM DENMARK National registry of MI patients and pharmacy data Patients with first MI ( ); N= 61,971 34% received NSAIDS; average age = 68, 63% men Follow-up for MI/CHD death Follow-up for bleeding risk Olsen AM et al. JAMA 2015 NSAID ASSOCIATION WITH CVD RISK Outcome: CVD death, MI, stroke No NSAID: 8.3%/year NSAID: 11.2% Adjusted HR: 1.40 ( ) Risks similar across NSAIDS; naproxen rarely used Olsen AM et al. JAMA 2015 NSAID ASSOCIATION WITH BLEEDING RISK Outcome: Intra-cranial, GI, respiratory, or urinary bleeding No NSAID: 2.2%/year NSAID: 4.2% Adjusted HR: 2.0 ( ) Risks similar across NSAIDS Olsen AM et al. JAMA 2015 NSAID CONCLUSIONS MI risk from NSAIDs appears real NSAIDs should be used at most for short-term in CAD patients Evidence supports FDA s Black Box warning (FDA update ): NSAIDs cause MI and stroke, even in first weeks Increased risk with higher dose and duration Uncertain whether risk varies by particular NSAID NSAIDs also cause HF 14

15 THANK YOU! ANY QUESTIONS? 15