ADVANCES IN PRIMARY CARE: PRACTICE-CHANGING PAPERS FROM THE PAST YEAR Michael G. Shlipak, MD MPH Chief, Division of General Internal Medicine San Francisco VA Medical Center Professor In-Residence Departments of Medicine, Epidemiology & Biostatistics University of California, San Francisco STRATEGY Topics: Relevant to primary care Slanted towards cardiology/metabolism Goal: practice-modifying studies Mini-topics: Single papers in isolation often cannot tell a story I grouped paper from past year with other recent studies 2 TOPICS Lipids: simvastatin, fibrates, niacin, and HDL Treatment of stable angina: PCI, OMT, and cardiologists NSAIDs: do they all cause CAD? Hypertension: Diuretic choice, age, race CT scans: Is the radiation safe? LIPIDS Simvastatin, Fibrates, Niacin, and HDL 3 1
CASE STUDY An 80-year old white man with prior CAD and an LDL of 95 mg/dl is on 40 mg of simvastatin, but continues to have a low HDL of 24 mg/dl. Should you add niacin to his treatment regimen to raise his HDL? Should you raise his simvastatin or change treatment? TREATMENTS TO INCREASE HDL Niacin Raises HDL by 20% Fibrates (Gemfibrozil, Bezafibrate) Raises HDL by 15-30% CETP inhibitors (Torcetratib) Raises HDL by 72% Unfortunately, it increases mortality (NEJM, 2007) Do any improve outcomes? 5 6 AIM-HIGH STUDY: ATHEROTHROMBOSIS INTERVENTION IN METABOLICSYNDROME WITH LOW HDL/HIGH TRIGLYCERIDES: IMPACT ON GLOBAL HEALTH 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 7 Follow-up: 36 months http://www.aimhigh-heart.com/ AIM-HIGH Investigators, NEJM 2011 AIM-HIGH STUDY Participants: Average age: 64 Hypertension: 71% Diabetes Mellitus: 34% Prior Myocardial Infarction: ~50% Coronary Artery Disease: 92% 8 http://www.aimhigh-heart.com/ AIM-HIGH Investigators, NEJM 2011 2
AIM-HIGH FINDINGS CASE STUDY CONTINUED Trial stopped early Event rate was same in both groups Small increase in stroke risk on niacin reported in press 27 strokes (1.6%) with niacin versus 15 (0.9%) with placebo HR 1.61, 95% CI 0.89-2.90 Not statistically significant (p=0.11) Answer: no benefit to adding niacin for statintreated patients 9 An 80-year old white man with prior CAD and an LDL of 95 mg/dl is on 40 mg of simvastatin, but continues to have a low HDL of 24 mg/dl. Should you add niacin to his treatment regimen to raise his HDL? Should you raise his simvastatin or change treatment? 10 http://www.aimhigh-heart.com/ AIM-HIGH Investigators, NEJM 2011 FDA RESTRICTS USE OF 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 Was this an over-reaction? Is simvastatin different from other statins? 11 SEARCH TRIAL: STUDY OF THE EFFECTIVENESS OF ADDITIONAL REDUCTIONS IN CHOLESTEROL AND HOMOCYSTEINE Funded by Merck 7-year RCT comparing: Simvastatin 80mg vs. 20mg Subjects: 12,064 patients with prior MI Outcome: major vascular events (coronary death, MI, stroke, arterial revascularization) Results: no difference (RR 0.94, 95%CI 0.88-1.01) 12 SEARCH Study Group The Lancet, 2010 3
SEARCH TRIAL RESULTS NEW LABEL ON SIMVASTATIN 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 13 Simvastatin contraindicated in users of: Antifungals Macrolide antibiotics Antiretrovirals Gemfibrozil Do not exceed 10mg simvastatin if using: Verapamil Diltiazem Calcium channel blockers are very common in primary care Do not exceed 20mg simvastatin with: Amlodipine Ranolazine Amiodarone 14 SEARCH Study Group The Lancet, 2010 FDA Safety Announcement, 6/8/2011 LDL-LOWERING EFFECTS OF SIMVASTATIN Simvastatin % Lowered LDL-C 10 mg 30% 20 mg 38% 40 mg 41% 80 mg 47% 15 WHAT SHOULD WE DO? Myopathy risks appear higher with simvastatin compared with other statins Don t go beyond 20 mg, unless you have a good pharmacy or great memory Simvastatin 20 mg equivalent to: Prava 40 mg Lova 40-80 mg If simvastatin 20 mg gives inadequate LDL, use atorvastatin or rosuvastatin 16 FDA Safety Announcement, 6/8/2011 4
CASE STUDY FOLLOW-UP You decide your patient should switch to atorvastatin. However, he has now stopped his statin due to adverse publicity and will not restart. You recheck his lipids; his HDL is 24 mg/dl and his LDL is 130 mg/dl. For non-statin-treated patients, should you treat HDL? If so, which of the following would be appropriate? Fibrate What if the patient cannot or will not take a statin? Niacin 17 18 NIACIN META-ANALYSIS OF PLACEBO- CONTROLLED RCTS SUMMARY OF RESULTS FOR CARDIOVASCULAR EVENTS Summary of 11 RCTs Coronary Drug Project (from the 1970s): only large-scale RCT Other studies very small 27% lower risk of CVD events Publication bias?? 19 20 Bruckert et al. Atherosclerosis 2010 Bruckert et al. Atherosclerosis 2010 5
FIBRATE META-ANALYSES Do fibrates improve clinical outcomes? 4 fibrate meta-analyses in past year Lee et al. Atherosclerosis 2011 Bruckert et al. J Cardiovasc Pharmacol 2011 Loomba and Arora Am J Ther 2010 Jun et al. The Lancet 2010 21 22 EFFECTS OF FIBRATES ON CARDIOVASCULAR OUTCOMES Design: systematic review and meta-analysis Analysis: 18 RCTs from 1950-2010 Participants: N=45,058 FIBRATE VS. PLACEBO AND CVD RISK Outcome Relative Risk 95% CI P Value Non-fatal coronary events 0.81 0.75-0.89 <0.0001 Total stroke 1.03 0.91-1.16 0.69 Cardiovascular death 0.97 0.88-1.07 0.59 All-cause mortality 1.00 0.98-1.08 0.92 23 24 Jun et al. The Lancet 2010 Jun et al. The Lancet 2010 6
DATA SUMMARY For patients with low HDL: Statins are treatment of choice to decrease CVD risk, regardless of LDL No data to add either niacin or fibrates to statin treatment (AIM-HIGH, ACCORD trials) If statin-intolerant, niacin may reduce CVD risk (weak evidence) Fibrates appear to lower MI risk, but no other CVD endpoints TREATMENT OF STABLE ANGINA PCI, OMT, and Cardiologists 25 26 CASE STUDY Your patient returns. He has chest pain that he describes as similar to the angina he had in the past. Onset after 2 blocks of walking, and resolves quickly with rest. As his primary care provider, you counsel him that optimal medical therapy (OMT) is the standard of care for chronic, stable angina. The patient is skeptical and requests a specialist, so you refer him to a cardiologist. CASE STUDY FOLLOW-UP The patient returns to your office 8 weeks later for a follow-up visit after having received a stent. What happened? Will the stent help the patient? 27 28 7
CAD AND INTERVENTIONS COURAGE TRIAL Optimal medical therapy (OMT) Antiplatelet agent, β-blocker, Statin Unless contraindicated Prior to stent era, in chronic stable angina, statins had better outcomes than angioplasty (Pitt et al. NEJM 1999) Currently, 85% of all percutaneous coronary intervention (PCI) procedures are elective in patients with stable angina 29 Conducted to compare OMT with and without PCI N=2,287 patients with stable angina and ischemia, 1999-2004 1,149 had PCI + OMT 1,138 had OMT alone Funded by the US VA R&D/Canadian Institutes of Health Research Outcome: All-cause mortality Non-fatal MI Average follow-up: 4.6 years 30 Boden et al. NEJM 2007 COURAGE OUTCOMES COURAGE RESULTS Adverse event rates: 19.0% in PCI group 18.5% in OMT group HR PCI vs. no PCI: RR 1.05 31 Composite death/mi/stroke: 1.05, 0.87-1.27 Hospitalization for ACS: 1.07, 0.84-1.37 Myocardial Infarction: 1.13, 0.89-1.43 PCI doesn t reduce risk of death, MI, or other CV events when added to OMT in patients with stable angina 32 Boden et al. NEJM 2007 Boden et al. NEJM 2007 8
COURAGE AFTERMATH Huge amount of news coverage Lots of controversy This should have changed practice, right? OMT USE IN PATIENTS UNDERGOING PCI Examined use of OMT in pts. with stable angina undergoing PCI before and after COURAGE trial publication Design: Observational Setting: National Cardiovascular Data Registry, 2005-2009 33 34 Borden et al. JAMA 2011 OMT USE BEFORE AND AFTER PCI, BY ERA OMT USE BEFORE AND AFTER PCI, BY ERA Number (%) of Patients Before PCI After PCI Individual Medications Before COURAGE (n=173,416) After COURAGE (n=293,795) Antiplatelet Agent 89 88 β-blocker 62 63 Statin 62 63 OMT Pre- PCI 44 45 35 OMT Post-PCI 64 66 36 Borden et al. JAMA 2011 Borden et al. JAMA 2011 9
CONCLUSIONS The responsibility of administering the full complement of medical therapy, however, ought not to be placed solely on the interventional cardiologist, but rather be a shared responsibility with the primary physicians caring for the patient. Borden et al. JAMA 2011 What are cardiologists thinking? 37 38 Borden et al. JAMA 2011 CARDIOLOGISTS USE OF PCI FOR STABLE CAD 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 Belief in the open artery hypothesis Potential regret (psychological and legal) for not intervening if a cardiac event could be averted Alleviation of patient anxiety Oculostenotic reflex Belief that referring PCP expects a procedure 39 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 help in the long run We need to be clear about our expectations prior to referring patients to cardiologists 40 Lin et al. Arch Intern Med. 2007 10
CASE STUDY NSAIDS Do they all cause CAD? 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? 42 NSAIDS AND CV RISK Non-steroidal anti-inflammatory drugs (NSAIDs) among most commonly used drugs 2004: rofecoxib (Vioxx) withdrawn from market after RCT showed very strong evidence promoting MI risk Since then, concern and debate over safety of NSAIDs Several standard meta-analyses unable to resolve debate failed to integrate all evidence in one analysis Do non-selective NSAIDS promote CV risk? 43 CV SAFETY OF NSAIDS Meta-analysis: 31 RCTs in 116,429 patients with >115,000 patient years of follow-up Subjects: mostly low CAD risk Analysis: network meta-analysis Primary outcome: Myocardial Infarctions Secondary outcomes: stroke, CV death, allcause mortality 44 Trelle et al. BMJ 2011 11
NETWORK ANALYSES RATE RATIOS FOR NSAIDS COMPARED WITH PLACEBO 676 deaths 1,091 CVD events Average 22 deaths, 35 CVD events per study 45 46 Trelle et al. BMJ 2011 Trelle et al. BMJ 2011 CONCLUSIONS Study confirms that NSAIDs are associated with increased CVD event risk Naproxen seems to be safest Most subjects had low CV risk What about patients with high CAD risk? DURATION OF NSAID TREATMENT AND RISK OF MI Design: Observational Location: Denmark Participants: N=83,677 with first MI from 1997-2006 42% used NSAIDs during F/U Outcomes: death, recurrent MI N = 35,257 47 48 Trelle et al. BMJ 2011 Schjerning Olsen et al. Circulation 2011 12
RISK OF DEATH/RE-MIS WITH NSAID TREATMENT CONCLUSIONS MI risk from NSAIDS appears real NSAIDS should be used only short-term in CAD patients American Geriatric Society recommended therapies include: Tylenol, exercise, topical NSAIDs, opiates NSAID CV risk RR of 1.5; in context: 4% 3% Statins 30% 49 2% 1% NSAIDs 50% 50 Schjerning Olsen et al. Circulation 2011 0% CV Risk Schjerning Olsen et al. Circulation 2011 CASE STUDY HYPERTENSION Diuretic Choice, Age, Race The wife of your patient is an 80 year old African American woman with hypertension. Her SBP is consistently 140-145. According to JNC-VII (2003), HCTZ is an ideal first-line treatment. However: Is HCTZ the best diuretic to choose? Should BP targets be different for the elderly? Should BP targets be different for blacks? 52 13
HYPERTENSION GUIDELINES BP treatment guidelines haven t been updated, but lots of new data in last 8 years 3 recent guidelines/expert opinions: European Hypertension Guidelines (2011) ACC/AHA Elderly (2011) International Society on Hypertension in Blacks (2010) JNC-VIII expected in Spring 2012 IS HCTZ AN INFERIOR DIURETIC? Hydrochlorothiazide (HCTZ): most commonly prescribed thiazide in US Meta-analysis compared HCTZ with nondiuretics using office and 24-hr BP N=1,463 patients in 19 studies 53 54 Messerli et al. JACC 2011 HCTZ WEAKER EFFECTS BY 24-HR BP MONITORING HCTZ equivalent with other agents by office BP IS CHLORTHALIDONE BETTER THAN HCTZ? Design: Meta-analysis of 108 HCTZ clinical trials and 29 Clorthalidone (CLD) clinical trials Objective: Compared dose-response curves of HCTZ and CLD with changes in SBP and potassium 55 56 Messerli et al. JACC 2011 Ernst et al. Am J of Hypertension 2010 14
CLORTHALIDONE IS MORE POTENT THAN HCTZ Drug Mean SBP, mmhg Mean Potassium, meq/l CLD -27.6-0.40 DIURETIC CONCLUSIONS CLD is the more potent diuretic, probably because of its longer half-life Most RCTs that found diuretics to decrease CV risk have used CLD 2011 European guidelines advise using CLD or indapamide, not HCTZ HCTZ -19.0-0.24 57 58 Ernst et al. Am J of Hypertension 2010 SHOULD SBP TARGET DIFFER IN ELDERLY (>80)? Current JNC-VII treatment target <140/90 in all age groups is based on expert opinion rather than RCTs Ideal target in elderly (>80) unclear HYVET Trial showed target <150 had better outcomes than >160 (NEJM 2008) 2011 AHA recs in elderly: 140-145 is acceptable, if tolerated 2011 European recs for >80: <150/90 is acceptable Both documents recommend caution in treating elderly to balance QoL with prevention goals 59 MANAGEMENT OF HTN IN BLACKS Expert panel recommends more aggressive BP treatment targets Primary prevention: <135/85 Broad list of high risk groups should have <130/80 target Best 2-drug combos: Ca channel blocker + ACE-ARB ACE-ARB + diuretic Recommend using ambulatory BP measures for decision-making 60 Flack et al. Hypertension 2010 15
CASE STUDY CT SCANS Is the Radiation Safe? Your patient and his wife return for a visit. Both are doing well, and are interested in cancer screening. They read a news report about using CT scans to determine lung cancer. As former smokers, they ask your opinion on CT scans as screening tests. Should you be concerned about radiation risks? 62 ARE CT SCANS SAFE Topic receiving lots of attention Especially relevant for strategies using CT to screen for CAD or lung cancer Number of CTs performed annually in US went from 3 to 70 million from 1980-2007 RADIATION AND CANCER Biological Effects of Ionizing Radiation (BEIR) VII Phase 2 Report (2006): Described survivors from atomic bombs and nuclear plant accidents Hiroshima/Nagasaki bomb survivors who received 10-100 msv exposures have increased risk of cancer A single modern CT scan can have equivalent radiation exposure 63 64 Smith-Bindman NEJM 2010; Miglioretti and Smith-Bindman Am Fam Phys 2011 16
VARIABILITY IN RADIATION DOSE AND CANCER RISK Setting: 4 N. Cal hospitals Participants: 1,119 consecutive adult patients, Jan-May 2008 Exposure: effective radiation dose to relevant organs Outcome: projected impact on cancer risk DISTRIBUTION OF ESTIMATED EFFECTIVE DOSE BY CT TYPE Minimum thresholds for specific cancers in atomic bomb studies 65 Smith-Bindman et al. Arch Intern Med 2009 Smith-Bindman et al. Arch Intern Med 2009 PROJECTED NUMBER OF CTS TO CAUSE 1 CANCER Type of CT Study Patients (Age 40y), Median (IQ Range), No. Female Male Routine chest, no contrast 720 (540-1160) 1566 (1170-2520) Coronary angiogram 270 (250-420) 595 (540-920) 67 Smith-Bindman et al. Arch Intern Med 2009 IMPLICATIONS IN CURRENT PRACTICE CT-machine manufacturers compete on basis of image quality directly associated with radiation dose Increased imaging speed also leads to higher doses No professional/governmental oversight Radiologists/medical specialists determine how CT tests performed Physicians know little about radiation doses/cancer risks from CTs CT techs don t receive consistent education 68 many not certified Smith-Bindman NEJM 2010; Miglioretti and Smith-Bindman Am Fam Phys 2011 17
HOPE FOR FUTURE FDA launched radiation initiative in Feb. 2010 Encourages professional organizations to take the lead in setting reference levels Safety experts recommend following goals: 50% lower doses for scans Standardized to low radiation default dosing Reduce number of CT scans performed THANK YOU! 69 ANY QUESTIONS? 70 18