Clinical Pearls Cardiology American College of Physicians

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Clinical Pearls Cardiology American College of Physicians Powered By Docstoc
					                                       ACP Colorado Chapter

                                       2009 Scientific Meeting

                                                Notes

 Case 1: ACS: Early Invasive (anatomy driven revascularization) versus conservative (ischemia
driven revascularization) and choice of Initial antithrombotic Rx

       A 77 yo hispanic female with a remote IWMI and RCA PCI in 1995 is admitted to hospital with 3
       days of moderate intensity, non-radiating, episodic non-exertional and exertional chest tightness
       lasting up to 15 min. The last episode of CP occurred earlier today. The patient is comfortable
       and symptom free.

       Cardiac risk factor profile includes longstanding DM-2 and HTN, obesity, dyslipidemia controlled
       on Rx, and remote smoking (stopped 1995). There is no history of bleeding. There is a Hx of
       GERD.

       Chronic medical Rx includes ASA 81 mg, atorvastatin 20 mg, metoprolol 50 mg bid, lisinopril 10
       mg each day, HCTZ 25 mg, glyburide 10 mg bid, metformin 1000 mg bid, and omeprazole 20 mg
       bid.

       On exam she is 5’3” and weight 190 pounds, BMI 33.7. BP is 136/80, HR 68, normal
       cardiopulmonary exam except for a 3/6 Systolic murmur heard at the RUSB and also the LSB
       with normal carotid upstrokes.

       ECG shows small (old) inferior Q waves, early precordial QRS transition, possible LVH by voltage
       criteria, and new T wave inversions in the anterior precordial leads. Tn is 1.2 (positive > 0.6).

       Creatinine is 0.9, BUN is 26, albumin is 3.8. The chemistry lab reports renal function (GFR):
                                2                                       2
       MDRD 59 ml/min/1.73m , Abbreviated MDRD 65 mL/min/1.73m , Cockcroft Gault with lean
       weight estimated 120 pounds: 45 ml/min.



       Questions:

       What management strategy would produce the best short term clinical outcome in terms of
       avoiding a major adverse cardiac event and likelihood of readmission with UA or MI?

               a. Early invasive with angiographic driven culprit lesion or complete revascularization
                  with PCI or CABG
               b. Conservative management with ischemia driven cath and revascularization
               c. Either early invasive or conservative management is likely to produce a similar
                  outcome
Summary: 77 yo with known CAD now with clinical illness likely to be threatened MI (NSTEMI,
high likelihood ACS, “high-risk” UA). The identifying features of NSTEMI/(high risk UA) are: 1.
Patient is likely to have CAD, 2. illness pattern suggests threatened MI (brief or accelerating
illness, typical location and quality of Sx), either abnormal ECG (new ST shift or T abnormality or
positive Tn.

Answer: A

Notes:

There is compelling (recent) RCT evidence (with possible exception of ICTUS) supporting an
early invasive approach with angiographic driven revascularization. (IA recommendation in
ACC/AHA 2007 Guideline). In aggregate there is around a 20-30% expected reduction in D,
D/nonfatal MI, and readmit for UA.. And, an early invasive approach is likely to be more efficient
since this patient is likely to have concerning findings on non-invasive testing.

The most important qualification is that catheterization and revascularization are feasible and
sensible. Features that make cath and revascularization feasible include no active bleeding or
high risk for bleeding, reasonable renal function, and no major co-morbid condition that would
preclude early invasive approach and revascularization, patient understands and is willing). Also
do not make that mistake of inferring that all mild Tn elevations equate with NSTEMI or “high risk
UA”.

Contrast the strong evidence for improved clinical outcomes in UA/NSTEMI with cath and
revascularization to limited benefits of revascularization in chronic angina COURAGE trial.




After discussing management with the patient you plan to consult cardiology for early invasive
evaluation (which will likely occur tomorrow morning). Which initial anti-thrombotic drug regimen
would produce the best clinical outcome (RCT proven best)? And, should there be dosing
adjustment for impaired renal function?

         a.   ASA, UFH
         b.   ASA, UFH, Plavix
         c.   ASA, UFH, Eptifibatide
         d.   ASA, UFH, Eptifibatide, Plavix
         e.   ASA, Enoxaparin
         f.   ASA, Enoxaparin, Plavix
         g.   ASA, Enoxaparin, Eptifibatide, Plavix
         h.   ASA, Bivalirudin
         i.   ASA, Bivalirudin, Plavix
         j.   ASA, Bivalirudin, Eptifibatide, Plavix
         k.   Other:


Renal adjustment in dosing?

         a. Yes
         b. No
Summary: 77 yo with known CAD now with clinical illness likely to be threatened MI (NSTEMI,
high likelihood ACS, “high-risk” UA).

Answer: Regimen: B, C, or I. Dosage adjustment: No

Notes:

The RCT data set regarding best initial antithrombotic regimen and its application in clinical
practice is complex. The recommended regimen is influenced by timing of cath (immediate, < 12
hours, next day), ischemic risk (death if MI occurs, coronary anatomy), bleeding risk (advanced
age, small stature, renal dysfunction), pre cath estimate of the likelihood patient will require
CABG (where one would wish to avoid plavix load), and operator or institutional preference for a
specific regimen.

There are several reasonable, evidence based options for initial antithrombotic (ie upstream of
the cath lab). All patients with NSTEMI/High Risk UA should be treated with ASA and an
antithrombin. A second antiplatelet agent (plavix or GpIIb/IIIA inhibitor is recommended in the
ACC/AHA 2007 guideline. And the option to treat with 4 agents (asprin, antithrombin, GpIIb/IIIa
inhibitor, and plavix is discussed despite the lack of RCT to support using 4 agents.

For this specific patient reasonable regimens with an early invasive approach would include:
ASA, UFH, Integrilin, ASA, Plavix, UFH until cath with plan to switch to bivalirudin for
revascularization, or ASA , bivalirudin, Plavix.

Although there is a lack of widespread consensus a few “pearls” apply::

         If CABG is very likely avoid plavix

         Those at highest risk of adverse ischemia related events (high risk UA in patient with
         poor LV function) Rx with ASA, UFH and GpIIb/IIIA inhibitor

         If the patient is at increased risk of bleeding avoid exposure to 4 agents, for any
         substantial duration of time.

         If patient is at increased risk of bleeding favor ASA, Bivalirudin, Plavix regimen.

         With immediate cath, keep the the antitthombotic strategy simple (ASA and antithrombin),
         and use the angiographic anatomy to further adjust Rx

With regards adjustment in dosing for renal function, there are several options for estimating GFR
and the may give conflicting estimates particularly in small stature, elderly females. The standard
approach is to adjust integrilin dose for CrClr < 50 ml/min and bivalirudin dosing for CrClr < 30 ml
per min by the Cockroft Gault approach. Most interventional cardiologists would not recommend
dosage adjustment for this patient.
       If the patient declined invasive evaluation and was to be managed with an ischemia driven
       approach, what antithrombotic regimen would you advise

       Initial:

                  a.   ASA, UFH 48h
                  b.   ASA, UFH and Eptifibatide for 48h
                  c.   ASA, Enoxaparin until discharge
                  d.   ASA, Fondaparinux until discharge
                  e.   Other:


       At discharge (assuming no recurrent spontaneous or provocable ischemia) with a conservative
       approach:

                  a.   ASA
                  b.   ASA and Plavix one month
                  c.   ASA and Plavix one year
                  d.   ASA and Plavix indefinitely


       Summary: 77 yo with known CAD now with clinical illness likely to be threatened MI (NSTEMI,
       high likelihood ACS, “high-risk” UA).

       Answer: In patient: C or D. At discharge B or C.

       Notes:

       Enoxaparin or Fondaparinux is favored versus unfractionated heparin (UFH) in patients whose
       high risk UA is managed conservatively with an ischemia driven approach. The benefits of more
       aggressive antithrombotic Rx (GpIIb/IIIa inhibitors) are realized with an early invasive catheter
       based revascularization approach. If this patient declined an early invasive approach, reasonable
       options would be ASA and either enoxaparin or fondaparinux until discharge.

       In patients with high risk UA treated with a conservative, ischemia driven approach, there is RCT
       evidence in support of Plavix for at least one month and up to one year. If this patient were
       treated medically, ASA would be continued indefinitely and plavix for up to one year.




References:

   1. Anderson JL, et al. ACC/AHA 2007 Guidelines for the Management of Patients with Unstable
      Angina / Non-ST-Elevation Myocardial Infarction: Executive Summary. JACC 2007; 50:652-76
   2. Stone GW, et al. Antithrombotic Strategies in patients with Acute Coronary Syndromes
      Undergoing Early Invasive Management: On Year Results from the Acuity Trial. JAMA
      2007;298:2497-2506
   3. Stone GW, et al. Bivalirudin during Primary PCI in Acute Myocardial Infarction. NEJM
      2008;358:2218-2230
   4. Kastrati A, et al. Bivalirudin versus Unfractionated Heparin during Percutaneous Coronary
      Intervention. NEJM 2008;359:688-96
Case 2: Rate vs Rhythm Control in AFIB

      A 63 yo female with a chronic Stage C LV systolic HF is hospitalized with anasarca and found to
      be in atrial fibrillation (new in last 3 months, no Sx of palpitations). She has chronic LVDF due
      extensive AWMI 5 yrs prior. She was hospitalized earlier this year with decompensated HF and
      was in sinus rhythm. She has no palpitations. She has gained 25 pounds and has diffuse,
      extensive edema, NHYA III+ DOE, orthopnea and PND. She does not sense her heart racing or
      beating irregularly.

      PMHx includes AWMI with LAD PCI and stent, DM-2, remote Lt breast cancer with 4/13 positive
      nodes Rx with lumpectomy and adjuvant TAC chemo Rx and radiation, HTN, obesity.

      Medical therapy at admission includes furosemide 40 mg bid, digoxin 0.125 mg each day,
      metoprolol 25 mg bid, lisinopril 10 mg each day, Insulin, ASA 81 mg, etc

      On physical exam she is 5’1” and weighs 202 pounds. HR is 95 bpm and irregular. BP is 95/70.
      Oxygen sat on 2 lpm is 92%. Dry weight is estimated from prior visits to be around 175. There
      are basilar crackles. On cardiac exam there is a soft S3 at the apex, a Grade III/VI murmur of
      MR or TR at the LLSB, neck veins are distended to the angle of the Jaw at 45 degrees. There is
      sacral edema and 4+ edema to the hips.

      ECG shows atrial fibrillation, prior AWMI.

      Echocardiogram shows LVEF < 20% with very severe generalized hypokinesis, moderate biatrial
      enlargement, RVE with at least moderate if not severe RV systolic dysfunction, moderate MR,
      moderate TR with PA systolic pressure around 65 mm Hg.

      Cr is 1.3

      The patient looses 20 pounds with diuresis and is symptomatically improved. BP remains low
      (around 90 systolic) and the patient remains in atrial fibrillation with a ventricular rate of 80-90
      beats per minute (with no sensation of palpitations). Creatinine is now 1.5 mg/dl. The patient has
      been anticoagulated since admission.



      Questions:

      Would the subsequent clinical outcome be better in this patient with a rhythm control versus rate
      control strategy? Yes or No

      What is the most effective rhythm control strategy for this patient?

          a. With HF resolved perform TEE and if no LAA thrombus, perform cardioversion and treat
             with warfarin. Then follow for recurrent AFIB
          b. Begin warfarin and after 3-4 weeks of therapeutic INR’s, perform cardioversion. Then
             follow for recurrent AFIB
          c. Begin warfarin and amiodarone (with anticipated increased warfarin effect) and after 3-4
             weeks of therapeutic INR’s, perform cardioversion. Continue amiodarone indefinitely if
             effective in maintaining NSR and no substantial toxicity.
          d. Refer for AV node ablation and placement of a biventricular pacemaker
          e. Begin warfarin and refer to an electrophysiologist for cutting edge AFIB Rx with either
             dofetilide, dronedarone (when approved) or RF ablation with pulmonary vein isolation
For each option except “d” listed above, give an estimate that the patient will be in sinus rhythm
one year from now.



    a.   ________%
    b.   ________%
    c.   ________%
    d.   NA
    e.   ________%


Summary: 63 yo with Stage C progressing to Stage D LV systolic heart failure (very severe LV
systolic dysfunction as well as moderate to severe RV systolic dysfunction, and moderate biatrial
enlargement. Severe HF decompensation associated with new AFIB. The issue is whether to
recommend a rhythm control strategy or rate control strategy. (The other management issue in
AFIB is anticoagulation. For this patient with CHADS2 score of 3 and no bleeding issues,
warfarin is advised)

Answer: Strategy C. Estimates of NSR at one year: < 25% for A and B, 50% for strategy C, as
high as 70-80% for strategy E.

Notes:

There is no RCT evidence to suggest improved clinical outcome for AFIB in LV systolic HF with a
“routine” rhythm control versus rate control strategy (No to first question).

If a rhythm control strategy was chosen (for instance because either AFIB symptoms persist),
simple cardioversion without antiarrhythmic drug therapy would be associated with a high AFIB
recurrence risk (unless a “reversible cause” was corrected). The usual clinical strategy would be
strategy C: treat with warfarin to therapeutic INR for 3-4 wks while loading with warfarin and then
perform cardioversion. Dofetilide is used with extreme caution due potential proarrhythmia (QT
prolongation, renal dysfunction, drug interactions). There is RCT data to suggest that
dronedarone increases mortality in (severe NYHA III-IV) LV systolic HF so it will not be an option
when approved (ANDROMEDA). There is a small (N =80) rct of AFIB ablation vs AV node
ablation with biventricular pacing in symptomatic drug resistant AFIB in LV HF suggesting
improved functional outcome with AFIB ablation.

With stragegies A and B, the likelihood that the patient will maintain NSR is likely to be in the
range of 25% or less. With amiodarone the likelihood the patient will maintain NSR is likely to
approach 50%. With RF ablation of AFIB, the likelihood the patient will maintain NSR is likely to
be 70-80%. These estimates may be generous given this patient’s advanced HF.

Rhythm control involves cardioversion, antiarrhythmic drug therapy, and in selected cases
catheter ablation. Warfarin is recommended indefinitely even with clinically successful (NSR)
rhythm control. Choice of drug therapy is tailored based on potential risk of antiarrhythmic drug
toxicity with the following options in specific subgroups: HF (amiodarone or dofetilide), CAD
(sotalol, amiodarone, dofetilide), LVH (amiodarone), none of the proceeding (propafenone,
flecainide, sotalol, amiodarone).
       Rate control involves Rx to make ventricular rate at rest < 80, VR with light activity such as 6 min
       walk < 110 (and average HR on Holter < 100 with no HR > 100% age predicted max). In
       selected cases AV nodal ablation with pacemaker is required.

       In the average AFIB patient (without systolic HF), multiple RCT’s with intention to treat analysis
       suggest that the rate and rhythm control strategies produce similar clinical outcomes. Many
       interpret the RCT’s as showing that a rhythm control strategy with current drug Rx (limited
       efficacy, measurable toxicity) is on average no better than a rate control strategy. This is not to
       say that sinus rhythm is not desirable; a highly effective, non toxic therapy to produce sinus
       rhythm would likely be better than what can be achieved with current rhythm control strategies.
       The decision regarding rate vs rhythm control is always carefully tailored for the individual patient
       (and often requires substantial discussion of the complex pros and cons of the alternatives).

       AF-CHF is a recently reported RCT of rhythm vs rate control in AFIB (mostly persistent, some
       paroxysmal) and Stage C LV systolic HF (LVEF ≤ 35%). Amiodarone and cardioversion were
       used to achieve rhythm control. N = 1376. Median duration f/u 37 mo. Average age 67. Average
       LVEF 27%. Findings: virtually identical CV mortality as well as composite of CV mortality, stroke,
       and worsening HF. Higher hospitalization rate for rhythm control (borderline p value).
       Conclusion: Rate control (assuming control of symptoms achieved) should be considered a
       primary approach for patients with AFIB and LV systolic HF.

       ATHENA is a large RCT of Dronedarone vs placebo in paroxysmal afib in the elderly and has not
       yet been published. N = 4628. Entry: age > 75 or age > 70 and risk factor (HTN, DM, CVAA/TIA,
       LA > 50 mm, LVEF < 40). Duration 21 months. Median age 73. Only 12% had LVEF < 45%
       Dronedarone therapy reduced the composite endpoint of death or first CV hospitalization by 24%.
       Stroke, CV death, and death due to arrhythmia were also significantly reduced. Total mortality
       was 5% in the dronedarone group and 6% in the placebo group (p = .18). In ANDROMEDA,
       dronedarone Rx in severe HF was associated with increased mortality resulting in early
       termination of the study.




References:

   1. Roy D, et al. Rhythm Control versus Rate Control for Atrial Fibrillation and Heart Failure. NEJM
      2008;358:2667-77.
   2. Cain ME Curtis AB. Rhythm Control in Atrial Fibrillation – One Setback after Another. NEJM
      2008;358: 2725-2727.
   3. Khan MN, et al. Pulmonary-Vein Isolation for Atrial Fibrillation in Patients with Heart Failure.
      NEJM 2008;359:1778-85
   4. Reifel, JA. A contemporary look at classic trials in atrial fibrillation: What do they really show and
      how might they apply to future therapies. Am J Cardiol 2008;102(Suppl)3H-11H
   5. Coletta AP, et al. Clinical trials update from Heart Rhythm 2008 and Heart Failure 2008:
      ATHENA (and others). Eur J Heart Failure 2008 10(9)917-20
CASE 3: New Guidelines for SBE Prophylaxis

      A 77yo retired computer engineer sees for a routine annual exam. 3 years ago you identified a
      murmur of MR and an echocardiogram demonstrated myxomatous mitral valve disease with MR
      (see below). Antibiotic prophyaxis with Amoxicillin and effort to maintain favorable dental hygiene
      was advised.

      He describes himself as physically active but does not specifically exercise. He denies rest or
      exertional dyspnea or symptoms to suggest HF, cardiac ischemia, or arrhythmia.

      PMHx includes recurrent DVT with permanent warfarin recommended and prior prostatectomy.

      Medications: Warfarin and Amoxicillin antibiotic prophylaxis.

      Physical exam shows him to be a thin, healthy appearing, elderly male. BO is 138/76 and HR is
      52 beats per minute. O2 sat on RA is 96%. Lungs are unremarkable. Cardiac exam shows
      normal PMI position, a mid to late III-IV/VI systolic murmur typical for MR at the LLSB and cardiac
      apex. There is no click. There is no S3. Venous pressure is normal. There are mild venous
      varicosities and trace ankle edema.

      ECG shows sinus bradycardia, normal cardiac axis and intervals. No evidence for chamber
      enlargement or hypertrophy.

      Echocardiogram is reported to show mild LA enlargement, mild to moderate mitral valve leaflet
      thickening and redundancy with moderate posterior leaflet prolapse and moderate or moderate to
      severe MR. LV size and function are normal. PA pressure was estimated to be upper normal.

      The patient reports that at his last dental visit, the dentist told him he no longer needs to take an
      antibiotic. He wants to know if this is correct and what you advise.



      Questions:

      The most recent AHA practice guideline recommendation for this patient is:

          a. Antibiotic prophylaxis is never recommended for mitral valve prolapse
          b. Antibiotic prophylaxis is recommended for mitral valve prolapse if there is moderate or
             worse MR or leaflet thickening
          c. Antibiotic prophylaxis is recommended for mitral valve prolapse if there is advanced gum
             disease
          d. Antibiotic prophylaxis is recommended for mitral valve prolapse if there has been prior
             endocarditis
The primary reasons cited by the AHA Guideline writing committee for recommending more
conservative use of antibiotic prophylaxis include all of the following except:

    a. Endocarditis is more likely to result from (common random) bacteremia from chewing
       food or tooth brushing than with dental manipulation
    b. Daily brushing and flossing, and periodic dental cleaning is more important than
       prophylactic antibiotic therapy in reducing the risk of endocarditis
    c. In a large randomized trial, antibiotic prophylaxis risk exceeded its benefits
    d. Antibiotic prophylaxis prevents few if any cases of endocarditis in individuals who
       undergo a dental procedure.


Summary: 77 yo with myxomatous mitral valve degeneration, posterior leaflet prolapse and
moderate or moderate to severe MR. NYHA I. Issue of antibiotic prophylaxis for dental
procedure.

Answer: D. Reason: C

Notes:

Practice guidelines for prevention of IE with antibiotics prior to dental procedures are largely
opinion-based. A RCT to assess the efficacy of antibiotic prophylaxis is not feasible. The most
recent AHA guideline takes a much more conservative approach to IE prevention than prior
guidelines and “may violate long-standing expectations and practice patterns by patients and
health care providers”. The principal argument in favor of the new guideline may be its simplicity
and applicability rather than the limited hard science supporting it.

The more conservative approach to IE prevention in the current guideline is based on several
suppositions and the goal of simplifying the approach. Important elements of the guideline
include:

1. Antibiotic prophylaxis is unlikely to prevent more than a small number (percentage) of cases
   of IE even if 100% effective because most IE may be due random bacteremia from routine
   daily events (chewing, brushing, etc). The evidence linking IE with a recent dental procedure
   (particularly if the IE developed more than 30d from the procedure is largely circumstantial.
   (contrast with the concept that the frequency and duration of bacteremia is related to the
   magnitude of tissue trauma, density of microbial flora, and degree of inflammation or infection
   at the site of trauma…but “there may not be a clinically significant difference in the frequency,
   nature, magnitude, and duration of bacteremia associated with a dental procedure compared
   with that resulting from routine daily activities”….”it is likely that the frequency and cumulative
   duration of exposure to bacteremia from routine daily events over 1 year are much higher
   than those that result from dental procedures.”)
2. Antibiotic prophylaxis efficacy in preventing IE is not well documented. There has been
   overemphasis on antibiotic prophylaxis and under emphasis on maintenance of good oral
   hygiene and regular dental care “which are likely more important in reducing lifetime IE risk
   than antibiotic prophylaxis for dental procedures”.
3. The risk of antibiotic associated adverse events may exceed its benefit (in average risk
   individuals) (“…the committee is unaware of any cases of fatal anaphylaxis resulting from the
   administration of a penicillin recommended in the AHA guidelines for IE prophylaxis.”
4. IE antibiotic prophylaxis is recommended for dental procedures only with the highest risk of
   adverse outcome from IE: prosthetic cardiac valve, previous IE, congenital heart disease
          (shunts, conduits, unrepaired, prosthetic material or device), and cardiac transplant patients
          with cardiac valvulopathy. IE antibiotic prophylaxis is no longer recommended based solely
          on the lifetime risk of IE (myxomatous mitral valve disease with MR, bicuspid and
          dysfunctional aortic valve, rheumatic valve disease…”but the risk of IE would likely be
          influenced by the severity of valvular disease”)
       5. Antibiotic prophylaxis is recommended for procedures on respiratory tract or infected skin or
          musculoskeletal structures for patients with the same cardiac conditions above. Antibiotic
          prophylaxis is not recommended for GU or GI tract procedures
       6. Antibiotic prophylaxis for those at highest risk if the dental procedure involves manipulation of
          gingival tissue, periapical tissue, or perforation of the oral mucosa.
       7. “Studies are necessary to monitor the effects, if any, of these recommended changes in IE
          prophylaxis..small changes in IE incidence will be hard to detect…Subsequent AHA
          guidelines will be based on the results of such studies.”



        After a close reading of the guideline, some practitioners may wish to make more individualized
       recommendations for antibiotic prophylaxis based on the severity of the cardiac problem, the
       status of dental hygiene, and the patient’s wishes in the context of uncertainty re benefits and risk
       for antibiotic prophylaxis.



References:

   1. Wilson W, et al. Prevention of Infective Endocarditis. Guidelines from the AHA. Circulation
      2007; 116:1736-54. (Guideline reprint can be requested by calling 800-242-8721; Reprint No: 71-
      0407)
   2. Bonow, RO, et al. 2008 Focused Update Incorporated Into the ACC/AHA 2006 Guideines for the
      Management of Patients with Valvular Heart Disease. JACC 2008;52:e1-e142. (available at
      www.acc.org)
CASE 4: Long-term Dual Antiplatelet Therapy with Aspirin and Clopidogrel in chronic CAD

       A gastroenterologist phones to ask if aspirin and plavix may be withdrawn for colonscopy and
       possible polypectomy in a patient of yours. (The patient had one small adenoma at screening
       colonoscopy 8 years ago and a repeat exam was advised). There has been no GI bleeding or Sx
       to suggest colonic problem.

       The patient is a 75 yo who presented in 2005 with AWMI. Primary PCI of the LAD was performed
       with a single bare metal stent. The patient was demonstrated to have multivessel coronary
       obstruction and following the MI a 16mm long Taxus drug coated stent was placed in the proximal
       circumflex and a 20mm Taxus drug coated stent was placed in the mid RCA. Subsequent echo
       showed normal LV function. The patient was advised permanent dual antiplatelet therapy and is
       considered completely revascularized.

       Other medical problems include longstanding HTN, mild RAD, dyslipidemia, and chornic fatigue.

       Medications chronically include ASA 81 mg qd, Plavix 75 mg qd, Metoprolol 12.5 mg bid,
       Simvastatin 40 mg each evening, Lisinopril 5 mg each day, Qvar inhaler, Albuterol inhaler prn,
       MVI and 3 fish oil capsules each day.

       On last exam a few months ago he was healthy, mildly overweight (5’8” 178), BP 122/78, HR 48
       bpm, with oxygen sat of 96%. Cardiac exam was normal.

       Recent labs include Creatinine 1.2 mg/dl, LDL 69 mg/dl, nonHDL 102.

       Questions:

       What would you advise with regards interruption of antiplatelet therapy for elective colonoscopy?

           a. There is very low cardiac risk at this point. Stop ASA and Plavix 7 days prior to
              colonoscopy and resume both the day after a diagnostic only procedure or 7-10 days
              after polypecotmy.
           b. There is some cardiac risk but it is likely to be low. Do not interrupt aspirin, stop Plavix 7
              days prior to colonoscopy. If polypectomy is required do not resume plavix for at least 2
              weeks.
           c. Cardiac risk is intermediate. Stop Plavix 5 days prior to the procedure and plan to
              resume with a 300 mg load the day after the procedure even if polypectomy is required.
           d. There is high cardiac risk. Do not interrupt either aspirin or plavix. Inform the patient that
              if colonoscopy reveals a polyp, a second procedure will be required with special effort
              based on the input of the cardiologist and gastroenterologist to balance cardiac risks from
              interruption of antiplatelet therapy and the risk of bleeding.


       Which of the following is not a risk factor for very late (> 1 year from placement) drug coated stent
       thrombosis?

           a.   Stent length
           b.   Bifurcation stent
           c.   Stent placed at time of MI
           d.   Specific drug coated stent (Taxus ≥Cypher > Exience > Endeavor)
           e.   Diabetes
Summary: 75 yo, with prior MI and multivessel angioplasty with DES in Cx as well as RCA. Total
stent length 36 mm. Normal LV function. Issue of interruption of antiplatelet Rx 3 years after PCI
for colonoscopy with possible need for polypectomy.

Answer: B for regimen, D for risk factor (with qualification).

Notes:

There is a persistent risk of very late stent thrombosis (> 1 year) after placement of a drug eluting
stent in the range of .5% per year. This risk persists out to 4 years or longer after stent
placement. The pathogenesis of late drug coated stent thrombosis may involve impaired
endothelialization, acquired stent malaposition, reaction to stent polymer, stent strut fracture,
and/or interruption of antiplatelet therapy. There is a hazard of late stent thrombosis when
antiplatelet therapy is interrupted for an elective surgical or endoscopic procedure but a precise
numerical estimate of risk is problematic. Factors that increase the risk of stent thrombosis
include partial or complete withdrawal of antiplatelet therapy within the first year of stent
placement, increasing stent length or lesion complexity (bifurcation disease), stent placement
during acute MI or in thrombus laden lesion, DM, and renal insufficiency. At present there is
clinical uncertainty regarding the “best” duration of dual antiplatelet therapy in a patient such as
this and a large RCT comparing 12 vs 30 mo of Rx has been initiated.

This patient’s risk of late stent thrombosis with complete interruption of antiplatelet therapy might
be in the range of 1%. In general, it seems unwise to completely interrupt antiplatelet therapy for
elective surgery in individuals who are on chronic dual antiplatelet therapy after DES and who
have one or more risk factors for stent thrombosis. Although there is little hard clinical evidence
to guide your recommendation, it would be reasonable to recommend strategy B after discussing
the pros and cons of alternative management strategies with the patient and the
gastroenterologist.

The indications for long term dual antiplatelet therapy with ASA and Clopidogrel best supported
by clinical evidence include: PCI with DES (dual antiplatelet therapy for minimum of one year),
ACS managed conservatively by an ischemia driven approach, and perhaps high risk ASCVD
secondary prevention (post-hoc subset analysis in Charisma). Secondary prevention of stroke is
not an indication for dual antiplatelet therapy. Chronic dual antiplatelet therapy is associated with
an increased risk of major bleeding (.5-1%) and is associated with significant (out of pocket) drug
expense. The clinical challenge is to focus dual antiplatelet therapy where the benefits in
preventing adverse ischemic events substantially outweigh the bleeding risk.

In those in whom there is an indication for dual antiplatelet therapy with ASA and clopidogrel,
there has been increased focus on the issue of genetic polymorphisms in the cytochrome P450
isoforms involved in clopidogrel activation. As many as 30% whites, 40% blacks, and 55% east
Asians are carriers of loss of function alleles for CYP2C19 and have less platelet inhibition on
clopidogrel and substantially higher ischemic event rates. If a change in therapy can be
demonstrated to improve outcome in those with loss of function alleles, genetic testing might
influence the specifics of dual antiplatelet therapy in those with indications. Finally, there is
observational data to suggest that PPI’s (omeprazole and perhaps pantroprazole) may interfere
with clopidogrel activation by competing for CYP2C19 metabolism. Based on limited evidence, it
is rational to avoid PPI’s in patients on dual antiplatelet therapy if possible.
References:

1. Grines CL, et al. Prevention of Premature Discontinuation of Dual Antiplatelet Therapy in Patients with
Coronary Artery Stents. JACC 2007;49:734-9

2. Brilakis ES, et al. Perioperative Management of Patients with Coronary Stents. JACC 2007;49:2145-
50

3. Ho PM, et al. Incidence of Death and Acute Myocardial Infarction Associated with Stopping
Clopidogrel after Acute Coronary Syndrome. JAMA 2008;299:532-9

4. Gilard M, et al. Influence of omeprazole on the antiplatelet action of clopidogrel assocatiated with
aspirin: the randomized double blind OCLA (Omeprazole Clopidogrel Aspirin) Study. JACC
2008;51:3256-60.

5. Windecker S, Meier B. Late Coronary Stent Thrombosis. Circulation 2007;116:1952-65

6. Freedman JE, Hylek EM. Clopidogrel, genetics, and drug responsiveness. NEJM 2009;360:411-413.

7. Gilard M, et al. Influence of omeprazole on the antiplatelet action of clopidogrel associated with
aspirin. JACC 2008;51:256-60.
CASE 5: CAD Screening

      A 54 yo male diagnosed with DM-2 at age 46 and with other risk factors for CAD including
      dyslipidemia, HTN, and overweight requests screening for CAD and an hsCRP level. His father
      died suddenly presumably of MI in his mid 50’s. Other primary family members are well. He
      exercises regularly with a stable pattern of minmal exertional dyspnea that has not changed in
      years. There is no angina.

      CAD risk factor profile:

              Age 54, male
              DM-2 (8 yrs in duration) on combination Metformin and Glipizide (HgbA1c 7.8, range 6.6-
              7.8)
              Obesity (5’10” and 228, BMI 32.7)
              Never smoked
              HTN (on lisinopril)
              Positive family history (father)
              Dyslipidemia on simvastatin:
                      TG 231 (highest 382)
                      HDL 35 (lowest 32)
                      LDL 53 (highest 116)


      His current medical therapy is

              ASA 81 mg each day
              Glipizide 10 mg bid
              Metformin 850 mg tid
              Lisionpril 10 mg each day
              Allopurinol 300 mg each day
              Simvastain 40 mg each day


      Exam shows no evidence ASCVD. BP is 130/84. HR is 66. ECG is normal. Cr is 1.1.

      Questions:

      How would you respond to his request for CAD screening?

          a. No testing is warranted, there is no hard data to show a benefit beyond the usual
             secondary prevention approach from testing asymptomatic individuals. DM-2 is a “CAD”
             equivalent suggesting a “high” CAD risk. Continue current Rx. Report Symptoms.
          b. His Framingham risk is intermediate at 16% when calculated from the risk profile above.
             Testing for ischemia with a standard treadmill test is warranted and his risk can be
             estimated from the Duke score, Heart Rate Recovery, chronotropic incompetence, etc. If
             his prognosis is worrisome or if there is significant ischemia, further action will be
             required.
          c. His Framingham risk is intermediate at 16% when calculated from the risk profile above.
             The exertional dyspnea could be subtle indicator of CAD. Treadmill gSPECT imaging is
             warranted. If there is significant ischemia, further action will be required.
          d. The strong family history is worrisome. An EBCT coronary calcium score should be
             obtained and further action based on scoring (for instance if the score is > 400, testing for
             ischemia is warranted)
          e. A coronary CT angiogram should be performed. If there is no significant stenosis, testing
             should be repeated in 5 years.
Summary: 54 yo with DM-2, obesity, HTN, positive family history premature CAD, low HDL and
elevated TG without overt Sx of ischemia requests CAD screening and hsCRP testing.

Answer: A

Notes:

Because there is neither compelling RCT evidence to prove a benefit of screening with any non-
invasive test modality (treadmill testing, EBCT Coronary Calcium Score, Coronary CT
angiography, Carotid Intimal Medial Thickness, ABI, etc) nor evidence for cost-effectiveness,
routine CAD screening in asymptomatic adults is not advocated by any major professional
organization (ACP, AHA, ACC, USPHSTF) particularly in those at low risk for CHD events (with
the definition of low risk open to interpretation). For those at increased or high CAD risk (for
instance DM, intermediate Framingham risk, or multiple risk factors and male > 45 or female >
55), although routine screening is not advocated, some latitude to screen is given in guidelines
(asymptomatic middle aged diabetics who plan a vigorous exercise program should undergo
exercise testing, EBCT Calcium Score in intermediate Framingham Risk “may be reasonable”).
The AAFP recommends exercise testing for pilots, air traffic controllers and those with high
physical stress jobs such as fire fighters. Without RCT and cost-effectiveness data, an evidence
based approach to CAD screening asymptomatic individuals (even those in higher risk groups)
has not been firmly established.

 On the other hand, the public may hear a much different message with substantial direct to
consumer advertising for CAD screening, headline news focusing on premature sudden coronary
death (Tim Russert), and cardiovascular expert opinion advocating routine imaging for
atherosclerosis (SHAPE). Patients often request CAD screening, and medical-legal
considerations may lead physicians to test simply to avoid litigation should an adverse event
occur in an individual denied testing.

This case illustrates the “muddy waters” commonly confronted by clinicians. If the symptoms are
interpreted as insignificant, the practice guideline recommendation in 2009 remains strategy A:
focus on primary prevention with therapeutic lifestyle change including LDL-C < 100 mg/dl (NCEP
III update 2004, NCEP Guideline currently being revised). If you concluded this patient is
(significantly) symptomatic then testing for ischemia would be sensible (B or C). If this patient
were not diabetic and his Framingham risk were estimated to be “intermediate (10 yr risk 10-
20%)”, EBCT scoring to further refine risk might impact recommended treatment and is
considered a “reasonable” strategy (ACC/AHA practice guideline) (D). At this point the role of
MDCT Coronary Angiography remains uncertain in 2009 but would undoubtedly be advocated by
some cardiologists if this patient was thought to be symptomatic (E)!

The ACC/AHA Expert Consensus on Coronary Artery Calcium Scoring for CAD screening
concluded:

         It may be reasonable to consider CAC measurement in patients at intermediate CHD risk
         (Framingham 10-20% 10 yr risk) (with the idea that it will influence the intensity of primary
         prevention). If the CAC score is 0 in an intermediate risk patient, primary prevention
         treatment intensity should not be reduced. If the CAC score is > 400, there is no strong
         evidence in favor of additional non-invasive testing (treadmill test)

         CAC measurement is not recommend in patients at low CHD risk (<10% 10 yr risk)
        CAC measurement is not recommended for those at high CHD risk (> 20% 10 yr risk)
        (with the idea that “secondary” prevention is already advocated)

Clinicians discussing CAD screening with patients are forced to struggle with multiple complex
dimensions including:

        The target and outcome of screening (identify plaque and intensify of LDL lowering vs
        identify high risk anatomy and revascularize)

        Choice of Test (hsCRP, EBCT Coronary Calcium Score, MDCT Coronary Angiography,
        other)

        Incremental value of testing beyond Framingham Risk (increase in discriminant accuracy)

        Test risks, costs, and inconveniences (including radiation and iodinated contrast
        exposure, labeling as diseased, and downstream testing if screen positive)

        Target population (too young? too old?, definition of low risk, intermediate risk, high
        risk?)

        Proven safety and declining expense of statin to lower LDL reduces the impetus for
        complex testing.

        LDL level to be achieved and uncertain interaction between duration of treatment and
        benefit (can treatment be deferred and still achieve most of its potential vs treatment
        earlier in the disease for longer duration and higher benefit)

        Patient wishes and expectations, personal lifestyle decisions, values

        Who pays (in context of lack of hard evidence for benefit or cost-effectiveness)



How would you respond to his request for hsCRP testing?

    a. No testing is needed, secondary prevention approach is warranted, LDL should be kept <
       100 with statin prn
    b. Testing is needed, if hsCRP is > 2, LDL should be kept < 70
    c. Testing is needed, if hsCRP is > 2, additional risk stratification testing with treadmill or
       coronary CTA is sensible.


Summary: 54 yo with DM-2, obesity, HTN, positive family history premature CAD, low HDL and
elevated TG without overt Sx of ischemia requests CAD screening and hsCRP testing. On
simvastatin 40 mg (Heart Protection Study) LDL is 53 mg/dl.

Answer: A

 No testing is needed. LDL is < 70 mg/dl and there is no evidence even for secondary prevention
that hsCRP testing should further influence Rx. If LDL were > 70 mg/dl, and there was a dilemma
about whether to further intensify statin therapy, hsCRP > 2 would support more aggressive Rx.
On the other hand, for secondary prevention, if LDL remains > 70 and hsCRP is < 2, risk is higher
than it would be with LDL < 70.
Notes:

hs-CRP is a predictor of incident CAD in those with no known CAD and recurrent events in those
with CAD. hs-CRP levels are deemed favorable when < 1 mg/L, intermediate at 1-3, and
elevated when > 3 mg/L. Testing is should be done in metabolically stable patients free of active
inflammation or medical illness and ideally, two determinations obtained 2 or more weeks apart
averaged since there is some fluctuation in levels over time.

Prior to the publication of JUPITER, the AHA/CDC Scientific Statement indicated hsCRP
measurement “may be used at the discretion of the physician as part of global coronary risk
assessment in individuals free of CAD particularly among those at intermediate Framingham
Risk”.

JUPITER is a large (N=17,802) double blind, placebo controlled RCT in asymptomatic mean > 50
and women > 60 free of CHD with LDL < 130, TG < 500, and no current or prior lipid lowering
therapy. Diabetics were excluded. Individuals with hs-CRP ≥ 2.0 mg/L were randomized to
rosuvastatin 20 mg per day vs placebo. (89,890 were screened, 37,611 excluded for LDL ≥ 130
mg/dl, and of the 52,279 remaining 25,883 had hs-CRP < 2 mg/L. Ultimately of the 26,286
remaining 17,802 were enrolled.)

The median age of participants was 66 with 62% men and 38% women. The median entry LDL-
C level was 108 md/dl. About 15% were current smokers and 41% had metabolic syndrome. If
the median levels of TC, LDL, HDL, and BP reported for study participants are used to estimate
Framingham risk an estimate of 8(female)-13%(male) is calculated. Thus the participants are of
older age and their 10 yr CHD risk is likely to be in the range of 10-20%.

Rosuvastatin 20 mg/d lowered LDL-C to around 55 mg/dl and hs-CRP from 4.2 to 2.2. The study
was stopped prematurely due apparent benefit after 1.9 years of follow-up.

The primary endpoint of CV death, non-fatal MI, stroke, unstable angina, or arterial
revascularization was reduced from 2.8% in the placebo group to 1.6% in the rosuvastatin group
(p highly significant). A harder endpoint, CV death, MI, CVA was reduced from 1.8% in the
placebo group to .9% in the rosuvastatin group. The survival curves free of adverse outcomes
diverged with increasing study duration so that in those followed up to 4 years the absolute risk
reduction in CV Death/MI/CA was 2%. The NNT for 2 years to prevent a hard endpoint is 120
and with an estimated cost for rosuvastatin at $3.45 per day, the cost to prevent one major hard
event was $302,220 ($251,850 for 4 years of Rx and an absolute risk reduction of 2%). It is likely
that a generic high dose simvastatin would produce similar results at much less cost and would
be cost effective. JUPITER provides support for using hs-CRP testing in intermediate risk older
adults to extend statin drug therapy to group in whom Rx would not previously been
recommended. Those who view long term generic statin therapy as safe and inexpensive are
likely to apply the results of JUPITER in regular clinical practice.

In a post-hoc analysis of PROVE IT-TIMI 22, a RCT of Prava 40 vs Atorva 80 in secondary
prevention of CAD after ACS, CHD event rates were as follows:
        The observational evidence regarding hs-CRP in secondary prevention from one high intensity
        statin trial:

        LDL > 70 mg/dl          hs-CRP > 2              CHD Risk 4.6 events per 100 patient yrs

        LDL > 70 mg/dl          hs-CRP < 2              CHD Risk 3.2 events per 100 pt yrs

        LDL < 70 mg/dl          hs-CRP > 2              CHD risk 3.1 events per 100 pt yrs

        LDL < 70 mg/dl          hs-CRP < 2              CHD risk 2.4% events per 100 pt yrs




References:

1. USPSTF: Screening for Coronary Heart Disease. Ann Intern Med 2004;140:569-72

2. Stern S. Are we getting nearer to screening for atherosclerosis? Circulation 2008;117:122-6

3. Greenland P., et al. ACCF/AHA 2007 Clinical Expert Consensus Document on Coronary Artery
Calcium Scoring by Computed Tomography in Global Cardiovascular Risk Assessment and in Evaluation
of Patients with Chest Pain. JACC 2007;49:378-402

4. Naghavit M, Falk E, Hecht HS, et all. From Vulnerable Plaque to Vulnerable Patient – Part III:
Executive Summary of the Screening for Heart Attack Prevention and Education (SHAPE) Task Force
Report. Am J Cardiol 2006;98:2H-15H

5. Brindis R, et al. ACCF/ASNC Appropriateness Criteria for SPECT Myocardial Perfusion Imaging.
JACC 2005;46:1587

6. Gottlieb I, Lima JAC and Kramer CM. Should all high-risk patients be screened with computed
tomography angiography? Circulation 2008; 117:1318-1332, 1333-1339.

7. de Feyter PJ, Schultz CJ. Computed tomography coronary angiography for screening asymptomatic
subjects. JACC 2008;366-68.

8. Redberg RF, Walsh J. Pay Now, Benefits May Follow – The Case of Cardiac Computed Tomographic
Angiography. NEJM 2008;359:2309-11

9. Ridker PM, et al. Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-
Reactive Protein. NEJM 2008;359:2195-207

10. Pearson T, et al. Markers of inflammation and cardiovascular disease. AHA/CDC Scientific
Statement. Circulation 2003;107:499-511.

11. Ridker PM, et al. C-Reactive Protein levels and Outcomes after Statin Therapy. NEJM 2005;352:20-
8.
CASE 6: LDL target for secondary prevention in CAD



      The same 54 yo as in CASE 5 with DM-2, HTN, Obesity, and dyslipidemia undergoes EBCT and
      is found to have a calcium score of 408 with most of the calcium in the RCA. His Calcium score
                  Th
      is 408 is 90 PCT for age and sex. There has been no change in clinical status.

      CAD risk factor profile:

      Age 54, male
      DM-2 (8 yrs in duration) on combination Metformin and Glipizide (HgbA1c 7.8, range 6.6-7.8)
      Obesity (5’10” and 228, BMI 32.7)
      Never smoked
      HTN (on lisinopril)
      Positive family history (father)
      Dyslipidemia on simvastatin:
              TG 231 (highest 382)
              HDL 35 (lowest 32)
              LDL 53 (highest 116)


      His current medical therapy is

              ASA 81 mg each day
              Glipizide 10 mg bid
              Metformin 850 mg tid
              Lisionpril 10 mg each day
              Allopurinol 300 mg each day
              Simvastain 40 mg each day


      Question:

      If his LDL on high dose (max dose) statin were 86 rather than 53, what would you advise?

      a.   Continue current Rx as long as LDL remains < 100 mg/dl
      b.   Add ezetimibe to max dose statin (or switch to Vytorin) to make LDL < 70
      c.   Add low dose sustained relaease niacin to max dose statin to make LDL < 70
      d.   Add colesevelam (Welchol) to max dose statin to make LDL < 70




      Summary: 54 yo with DM-2, HTN, Obesity, Dyslipidemia with EBCT 408 with most of the calcium
                                                Th
      in the RCA. His Calcium score is 408 is 90 PCT for age and sex.

      Answer: A with qualification

      The option to intensify the max dose statin should be discussed with the patient in the context of
      little hard science. The patient’s preferences should be given increased weight given the lack of
      data from which to choose a “best” or “proven” strategy.
Notes:

The NCEP III Guideline was updated in 2004 to incorporate newer clinical trial data (angiographic
and clinical studies) regarding intensive statin therapy (high potency, high dose statins to produce
low LDL levels < 70 mg/dl for CAD secondary prevention:

NCEP III Revision                                     LDL Target
2004
0-1 Risk Factor or                                    < 160
Low Framingham Risk
(< 10% at 10 years)
> 2 risk factors                                      < 130
Intermediate Framingham Risk
(10-20% at 10 years)
CHD or CHD Risk equivalent                            < 100
(> 20% 10 year risk)
Very High Risk: CHD plus                              < 70
multiple risk factors (especially DM) or
poorly controlled risk factors (continued smoking) or
multiple metabolic syndrome risk factors or
recent ACS
Risk Factors: cigarette smoking, BP > 140/90 or HTN Med Rx,HDL < 40, Family Hx, age > 45
male or 55 female. HDL > 60 counts as negative one risk factor

Since 2004 additional clinical and angiographic trial data on intensive statin therapy (high
potency, high dose, LDL < 70) for secondary prevention has been published and some is
included in the table below. Although, the clinical trial data base is complex and expert
interpretation varies, intensive statin therapy seems safe in the short to intermediate term and
well supported by evidence for improved outcomes. The NCEP recommendations for CAD
secondary prevention are currently being revised with new recommendations expected in 2009.

Areas of controversy include the magnitude of benefit from more intensive statin therapy, the cost
of intensive therapy if a trade name drug is used (both out of pocket expense to patient and cost
to insurers), cost-effectiveness, side-effects such as myalgias, and uncertain long-term safety. In
addition there is little science to guide practice when the LDL target is not met on max dose high
potency statin.

At present some experts recommend a LDL goal of < 70 mg/dl in all patients with established
CAD. Others suggest using the specific statin regimens from the intensive statin therapy trials
without regard to achieved LDL level (for instance simply prescribe Atorva 80 for all with ACS
based on PROVE IT findings). Others recommend treating most CAD or CAD equivalent with the
lowest dose of statin that produces a LDL level of < 100 and reserve more aggressive therapy for
those at highest risk. Some suggest use of nonstatin LDL lowering medications (ezetimibe,
niacin, bile acid sequestrant) in combination with statins when patients are not at LDL goal while
                                                                            nd
others urge caution in combining drugs. The threshold LDL for adding a 2 drug to max dose
statin is also controversial (> 70-100).

There has been quite a bit of controversy regarding the role of ezetimibe (Zetia) as LDL lowering
agent in CAD prevention. The ENHANCE Trial of Simva 80 vs Simva 80 plus Ezetimibe 10 to
slow atherosclerosis progression (carotid intimal medial thickening) in heterozygous familial
hypercholesterolemia showed no benefit in a study of 720 individuals followed for 24 months
despite lower LDL levels 193 vs 141. Multiple potential explanations for this result are tenable
including the possibility that additional LDL lowering achieved with this agent does not fit with the
large data base demonstrating a strong correlation between LDL reduction and ASCVD outcomes
with statin Rx. There has been intense scrutiny of this trial as well as the study drug
        manufacturer’s handling of the analysis and release of the trial data in a timely fashion. At this
        point, there is inadequate evidence to determine with certainty whether additional LDL lowering
        produced with ezetimibe is clinically beneficial or not.

        Ezetimibe was again in the news with the publication of SEAS (Simva 40 vs Simva 40 plus
        Ezetimibe 10 in 1873 individuals with asymptomatic mild to moderate aortic stenosis to reduce
        the composite of CAD events and AVR. Although there were no effects on the rate of AVR over
        52 months, the risk of ischemic cardiovascular events was lower in the combination therapy
        group. However, cancer (several sites) occurred more frequently in the simva-ezetimibe group.
        When cancer risk on simva-ezetimibe was analyzed in two additional large onging trials using this
        combination (SHARP and IMPROVE-IT) there was no compelling evidence to suggest an
        increase cancer risk. At this point there is inadequate evidence to demonstrate that simva-
        ezetimibe increases the risk of cancer vs simvastatin alone.

        Data has recently been published to suggest that Ezetimibe 5 produces virtually identical LDL
        lowering as Ezetimibe 10 when combined with statin. Thus lower doses achieve similar LDL
        lowering effects and might improve cost effectiveness.

        When niacin or ezetimibe are added to a statin the risk of myalgia/myositis increases. Patient
        education is required.




References:

1. Grundy SM, et al. Implications of recent clinical trials for the National Cholesterol Education Program
Adult Treatment Panel III Guidelines. JACC 2004;44:720-32.

2. Kastelein JJP. Simvastatin with or without Ezetimibe in Familial Hypercholesterolemia. (ENHANCE)
NEJM 2008;358:1431-43

3. Brown RG, Taylor AJ. Does Enhance Diminish Confidence in Lowering LDL or in Ezetimibe? NEJM
2008;358:1504-1507.

4. Rossebo AB, et al. Intensive Lipid Lowering with Simvastatin and Ezetemibe in Aortic Stenosis
(SEAS). NEJM 2008;359:1343-56

5. Peto R, et al. Analysis of Cancer Data from Three Ezetimibe Trials. NEJM 2008;359:1357-66
Clinical Trials of Intensive LDL lowering (excluding smaller angiographic studies)

            HPS        REVERSAL       A to Z        PROVE       TNT         IDEAL        SAGE
                                                    IT
Study       2002       2004           2004          2004        2005        2005         2007
Date
Entry       CAD,       Angio CAD      ACS           ACS         CAD         CAD          CAD
Criteria    PAD,       > 20%                                                with prior   age 65-
            DM                                                              MI           85 with
                                                                                         ischemia
                                                                                         on AECG
Size,     20,536       654            4497          4162      10,001        8888         893
duration  5 years      1.5 years      2.0 years     2 years   4.9 years     4.4years     1 year
Lipid     TC >         LDL > 125      TC < 250      TC < 240  LDL 130-      NA           LDL 100-
          135                                                 250                        250
Age       40-80        56             61            58        61            62           72
Treatment Simva        Atorva 80      Simva 80      Atorva 80 Atorva        Atorva       Atorva 80
          40                                                  80            80
Control   Placebo      Prava 40       Simva 20      Prava 40 Atorva         Simva        Prava 40
                                                              10            20
LDL base    131        150            111           106       152           122          145
LDL t       NA         79             66            62        77            81           65
LDL c       NA         110            81            95        101           104          79
Delta LDL   39         31             15            33        24            23           14
Mort        12.9 vs    .3 vs          5.5 vs        2.2 vs    5.7 vs        8.2 vs       1.3% vs
            14.7       .3             6.7           3.2       5.6           8.4          4.0%
CV Mort     5.7 vs     NA             4.1 vs        1.1 vs    2.0 vs        5.0 vs       .9 vs
            6.9                       5.4           1.4       2.5           4.9          2.2
Nonfatal    3.5 vs     1.2 vs         7.1 vs        6.6 vs    4.9 vs        6.0 vs       3.6% vs
M (first)   5.6        2.1            7.4           7.4       6.2           7.2          3.6%
CV Mort     8.7 vs     NA             NA            7.2 vs    6.7 vs        9.3 vs       NA
or          11.8                                    8.3       8.3           10.4
nonfatal
MI
Comment     Control    IVUS study     Dose                      Run in      Stable       Ischemia
            group                     escalation                phase       CAD          study
            statin                    over                      Atorva
            17%                       several                   10 and
                                      months                    enter if
                                                                LDL <
                                                                130
Primary     Yes        NA             Maybe         Yes         Yes         Maybe        Yes
endpoint
curves
diverge
with time
Case 7: Revascularization vs Medical Therapy in Stable Chronic CAD

      The same 54 yo with DM-2, HTN, Obesity, and dyslipidemia undergoes EBCT and is found to
                                                                                                    Th
      have a calcium score of 408 with most of the calcium in the RCA. His Calcium score is 408 (90
      PCT for age and sex). There has been no change in clinical status. He has minimal stable
      dyspnea with exercise that is unchanged over the past several years.

      Questions:

      Based on extrapolation from the COURAGE Trial, what would you advise next?

               a. Continue Current Rx, educate about Sx of ischemia and system access for Sx MI,
                  prescribe prn NTG and follow clinically
               b. Continue Current Rx, educate about Sx of ischemia and system access for Sx MI,
                  prescribe beta blocker and prn NTG and follow clinically
               c. Order a standard treadmill test. If abnormal proceed to cath.
               d. Order a treadmill testing with myocardial perfusion imaging. Reserve cardiac
                  catheterization for more substantial cardiac ischemia
               e. Proceed directly to coronary angiography


      Summary: 54 yo with DM-2, HTN, Obesity, Dyslipidemia with EBCT 408 with most of the calcium
                                                Th
      in the RCA. His Calcium score is 408 is 90 PCT for age and sex.

      Answer: C

      Notes:

      COURAGE was a RCT of PCI vs Medical therapy in 2287 patients with stable CAD with at least
      one proximal coronary stenosis of 70% and objective evidence of ischemia. Individuals with CCS
      IV angina, markedly positive stress test, LVEF < 30%, and refractory HF were excluded. In
      COURAGE 12% of patients were asymptomatic and 30% mildly symptomatic with CCS I angina.
      There was no difference in the risk of D or non fatal MI over 4.6 years of follow up in the two
      study arms. COURAGE suggests that if there is not severe ischemia on a stress test or LVSD,
      that an aggressive approach to performing revascularization with PCI is unnecessary in patients
      with stable CAD.

      Answer: Assuming that the mild stable dyspnea might be a symptom of CAD, order either a
      standard treadmill test or a treadmill test with myocardial perfusion imaging and reserve cardiac
      catheterization for marked test positivity or LV dysfunction.



      The Patient undergoes treadmill testing with gSPECT imaging. The findings are:

      Bruce protocol, total duration 9:21 stopping due fatigue
      No Sx of cardiac ischemia
      Max HR 178
      Max SBP 208
      Pressure Rate Product 37K
      ECG at max exercise shows 1.5-2 mm of flat to mildly up-sloping ST depression infero-laterally
      that resolves in < 1 minute into recovery
      At max exercise there are several salvos of nonsustained VT resolving within a minute of
      stopping exercise
        The Nuclear Perfusion images are negative for reversible myocardial hypoperfusion


        You refer the patient to cardiology. The cardiologist recommends adding a betablocker and
        following clinically. The patient calls you and asks for a second opinion

        You respond by stating:

              a. A second opinion is sensible, a coronary angiogram should be performed with coronary
                 revascularization for any stenosis > 70%
              b. A coronary CT angiogram is sensible, if it shows a stenosis > 70%, coronary angiography
                 can be performed with revascularization
              c. No further testing is warranted at this point. Continue Current Rx, educate about Sx of
                 ischemia and system access for Sx MI, prescribe beta blocker and prn NTG and follow
                 clinically.


        Summary: 54 yo with DM-2, HTN, Obesity, Dyslipidemia with EBCT 408 with most of the calcium
                                                  Th
        in the RCA. His Calcium score is 408 is 90 PCT for age and sex. Treadmill data abnormal but
        perfusion imaging negative.

        The correct answer is C.

        He then asks about when he should be retested…



References:

1. Boden WE, et al. Optimal Medical Therapy with or without PCI for Stable Coronary Disease. NEJM
2007;356:1503-16.

2. Weintraub WS, et al. Effect of PCI on Quality of Life in Paients with Stable Coronary Disease. NEJM
2008;359:677-87

3. Lin GA, et al. Frequency of Stress Testing to Document Ischemia Prior to Elective Percutaneous
Coronary Intervention. JAMA 2008;300:1765-1773.

4. ACCF/AHA 2009 Appropriateness Criteria for Coronary Revasculariztion. JACC 2009;53 (e pub
online)

				
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