Cardiology 101:

Why we do what we do

1)Statintherapy- goals

  1. Take home: High dose better than low dose statin in preventing CV events

Cannon, C, et. al. Intensive vs. Moderate Lipid Lowering with Statins after ACS. NEJM April 8, 2004. Vol 350. No 15. Pg 1495-1504.

Trial compared Pravastatin 40 mg (goal LDL 100) to Atorvastatin 80 mg (goal LDL 70) in patients who were hospitalized in the last 10 days for ACS/USA.

-Pts were on no other lipid lowering drug.

-Study drugs could be increased if goal LDL not obtained

-Baseline: Age 60, 90% white, 80% male, avg LDL 106

-Primary End Point – (composite) death, MI, USA required hospitalization, revascularization/CABG and CVA

-Followed for 2.5 years

-Results – Composite endpoint significant

  • Driven by decrease in revascularization and USA requiring hospitalization
  • Death from any cause (P value 0.07) not statistically significant, but showed a trend towards longer life

2)Statin therapy – CRP

  1. Take home: Healthy (LDL < 130) people on statins may do better, but large NNT

JUPITER Study Group. Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated CRP. NEJM November 20, 2008. Vol. 359. No. 21. Pg 2195-2207.

Trial compared people with LDL < 130 and CRP > 2.0 to rosuvastatin 20 mg qd to placebo and they were followed for the occurrence of composite endpoint of CV events.

-Inclusion criteria: Men > 50, Women > 60, no hx CAD, LDL < 130, CRP > 2.0, Trig < 500

-Exclusion criteria: current/previous statin use, elevated LFTs/CK, chronic inflammatory disease, immunosuppressant use

-Baseline: Age 66, 71% white, 62% male, CRP 4.2, LDL 108

-17,802 patients

-Intention to treat, trial stopped early

-Primary Outcome: (composite) 1st MI, CVA, hospitalization for USA, revascularization, or death from CV cause

  • Primary End Point statistically significant
  • NNT 95 (rosuvastatin for 2 years to prevent 1 primary end point)
  • Rosuvastatin group LDL 55, CRP 2.2
  • Secondary end point of death (any cause) was statistically significant
  • Similar adverse reactions

3) ACE Inhibitors - HTN

  1. Take home: CV events in diabetics with normal EFs may be reduced with ACEi

HOPE Trial – Effects of Angiotensin-Converting Enzyme Inhibitor, Ramipril, on CV Events in High-Risk Patients. NEJM January 20, 2000. Vol 342. No 3. Pg 145-151.

Trial compared patients with vascular disease or DM plus another CAD risk factor (HTN, HLD, tobacco, microalbumuria) without low EF or CHF Sx got either Ramipril 10 mg qd or placebo

-Hypothesis: increased rennin-aldo levels lead to progression of arthrosclerosis

-ACEi known to reduce risk of CAD events in patients with low EFs

-Baseline: Age 66, 80% CAD, 40% PAD, 40% DM, 139/80 Avg BP

-Primary End Point – (composite) MI, CVA or death from CV cause

-Followed for 5 years

-80% still taking Ramipril at end of study (analyzed by ITT)

-12% on placebo had received an ACEi by end of study

-Results – Composite endpoint significant

  • Decrease across the board in death from CV cause, CVA, and MI
  • Secondary endpoint of death from any cause significant
  • However study not powered to show this
  • No real change in BP at end of study 136/77 Avg BP
  • Results thought to be due to effects on Renin-Aldo level
  • Treating 1000 pts with ACEi for 4 years prevents 150 CV events in 70 pts

4)ACE Inhibitors – Post MI

  1. Take home: Acute MI + EF <35% = ACEi

TRACE Study Group. A Clinical Trial of the ACEi Trandolapril in patients with Lt Ventricular Dysfunction after Myocardial Infarction. NEJM December 21, 1995. Vol. 333. No. 25. Pg 1670-1676.

Pts with cardiac biomarker positive myocardial infarction and EF<35% were randomized to receive trandolapril or placebo 3 – 7 days after infarction.

-Inclusion: myocardial infarction defined as positive biomarkers and either EKG changes or chest pain, EF <35% based on 2 cardiologists

-Exclusion: Other need for ACEi, contraindication to ACEi, Cr > 2.3

-Baseline: age 68, 72% male, Killip 2 21%, SBP 120/75

-Intention to treat, followed for 2 years (originally only planned for 1 year, but had not met endpoint)

-Primary End Point: death from any cause

  • Primary end point statistically significant at 2 years
  • Secondary end points of progression to severe CHF significant
  • Significant increase in cough and hypotension in Trandolapril group

5)ACE Inhibitors – CHF NHYA Class II-III

  1. Take home: NHYA Class II-III with EF 35% = ACEi

SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fraction and congestive heart failure. NEJM August 1, 1991. Vol. 325. No. 5. Pg 293-302.

Trial of patients with NYHA Class II or III CHF and EF 35% to receive enalapril vs. placebo to access for possible mortality benefit.

-Followed for 3 years

-Dose of enalapril 2.5 to 20 mg, target dose 10 mg bid

-Primary Outcome: Mortality

  • Statistically significant decrease in mortality
  • Subgroup analysis shows mortality decrease due to decrease in CHF deaths
  • Also decrease in hospitalization and readmissions

6)ACE Inhibitors – CHF NYHA Class IV

  1. Take home: NHYA Class IV with large heart = ACEi

CONSENSUS Trial. The effects of enalapril on mortality in severe congestive heart failure. NEJM June 4, 1987. Vol 316. Pg 1429-1435.

Trial of patients with NYHA Class IV congestive heart failure on diuretic and digoxin to receive placebo or enalapril to access for morality benefit.

-Inclusion: NHYA Class IV CHF and increased heart size based on TTE

-Exclusion: Recent MI

-Enalapril started at 5 mg bid and titrated to 20 mg bid

-Followed for 6 months

-Primary Outcome: Mortality (trial stopped early)

  • Statistically significant (p .003) difference in mortality in treatment arm
  • Appeared to be due to halting of CHF progression
  • Improvement in NYHA Class compared to placebo
  • Withdrawal due to hypotension higher in enalapril group

7)ARBs

  1. Take home: NHYA Class IV with large heart = ACEi

CHARM Investigators. Effects of candesartan in patients with chronic heart failure and reduced left-ventrciular systolic function intolerant to angiotensis-converting-enzyme inhibitors. Lancet September 6, 2003. Vol. 362. Pg. 772-776

Trial of patients with symptomatic heart failure (EF <40%) not on ACE inhibitors secondary to intolerance were prescribed candesartan or placebo and followed.

-Target dose – 32 mg Candesartan

-ACEi intolerance – cough (72%), hypotension (13%), renal dysfunction (12%)

-Inclusion: symptomatic heart failure (NYHA Classs II – IV), EF > 40%, intolerance to ACEi

-Baseline: Age 66, 89% white, EF 30%, 2000 patients

-Intention to treat, followed for 2.5 years

-Primary End Point: Cardiovascular death or unplanned admission to the hospital for worsening CHF

  • Primary outcome statistically significant (p <.0001)
  • Placebo event rate 18.2%, Candesartan event rate 13.8%
  • No difference in mortality

8)Spironolactone

  1. Take home: EF<35% with NYHA Class III or IV symptoms = spirnolactone

RALES Study. The Effect of Spironolactone on Morbidity and Mortality in patients with Severe Heart Failure. NEJM September 2, 1999. Vol. 341. No. 10. Pg 709-717.

Trial compared patients with severe heart failure (EF<35%) to optimal medical management with and without spirnolactone 25 mg.

-Inclusion: NHYA class III or IV

-Exclusion: Cr > 2.5, K > 5.0

-Spironolactone 25 mg qd (could be increased to 50 mg if Sx or 25 mg qod if hyperkalemia)

-Baseline: Age 65, 86% white, 73% male, EF 25%, ischemic/nonischemic 54/46%, similar meds

-Intention to treat analysis

-Stopped early after 2 years of follow up

-Primary End Point: death from any cause

  • 30% reduction in the risk of death in the spirnolactone group
  • 30% reduction in hospitalization, improvement in NYHA class symptoms
  • No significant hyperkalemia differences, spirnolactone group did have more gynecomastia

9)Beta blockers

  1. Take home: EF <35% = beta blocker

Carvedilol Heart Failure Study Group. The Effect of Carvedilol on Morbidity and Mortality in patients with Chronic Heart Failure. NEJM May 23, 1996. Vol 334. No 21. Pg 1349-1355.

Trial of patients with chronic heart failure (EF < 35%) were given either carvedilol or placebo. Other medical therapy remained constant.

-1100 patients

-Baseline: Age 58, 75% male, 85% NYHA Class II or III

-Pts with EF < 35% already on medical therapy

-Excluded HR < 68 or on CCB

-Goal of 25 to 50 mg bid if tolerated

-Followed for 1 year, ITT analysis

-Primary End Point: Death at 60 days

  • Statistically significant mortality benefit
  • Stopped early due to benefit
  • HR decreased by 12 beats/min in carvedilol group, no change in BP
  • Adverse Rxn
  • Increased dizziness, hypotension and diarrhea

10)Isosorbide dinitrate/hydralazine

  1. Take home: Consider isosorbide/hydralazine in african-americans with severe CHF

A-HEFT Investigators. Combination of Isosorbide Dinitrate and Hydralazine in Blacks with Heart Failure. NEJM November 11, 2004. Vol. 351. No. 20. Pg 2049-2057.

Trial of black patients with NHYA Class III or IV heart failure to receive optimal medical therapy +/- hydralazine and isosorbide dinitrate.

-Theory that blacks have less rennin-angiotensin than Caucasians

-Inclusion: at least 3 month history of heart failure, EF < 35% or EF <45% with dilated ventricle

-Exclusion: Acute MI, hypotension, hypertrophic or restrictive cardiomyopathy

-Initially hydralazine 37.5/isosorbide 20 mg tid titrated to 75/40 tid

-Baseline: Age 56, 56% male, NHYA III 96%, DM 40%, BP 125/77

-Intention to treat, stopped early

-Primary End Point: composite (weighted) of death from any cause, 1st hospitalization for CHF, and QOL score

  • Composite endpoint significant
  • Subgroup analysis showed significant difference in death from any cause prompting trial to be stopped early

11)Digoxin

  1. Take home: only use digoxin for symptoms and watch out for toxicity

The Digitalis Investigation Group. The Effect of Digoxin on Mortality and Morbidity in Pts with heart failure. NEJM February 20, 1997. Vol 336. No. 8. Pg 525-533.

Trial compared Pts with EF < 45%, already on ACEi, diuretics on digoxin to those on placebo.

-Baseline: Age 60, EF 28%, 78% male, 86% white, 53% class II, 33% class III/IV

-Followed for 4 years

-Primary End Point – mortality

-Results

  • No difference in mortality b/w digoxin and placebo
  • Fewer hospitalizations for worsening CHF
  • Less deaths from worsening CHF in Digoxin arm
  • More deaths from “other cardiac” in Digoxin arm (arrhythmias?)
  • Dig level achieved ~1

12)Biventricular Pacing

  1. Take home: Wide QRS, low EF, bad CHF then highly consider BiV (morbidity and likely mortality benefit)

COMPANION Investigators. Cardiac-Resynchronization Therapy with or without Implantable Defibrillator in Advanced Chronic Heart Failure. NEJM, May 20, 2004. Vol 350. No. 21. Pg 2140-2150.

Trial comparing Pts with NYHA Class III/IV heart failure (ischemic or nonischemic), EF <35%, QRS > 120 ms were assigned to optimal medical therapy (diuretic, ACEi, beta-blocker, spironolactone) or optimal medical therapy plus cardiac-resynchronization therapy with or without defibrillator.

-Baseline: Age 68, 69% male, 82% NYHA Class III, EF 20%, QRS 158

-Followed for 3 years, ITT

-Primary End Point – death or hospitalization from any cause

-Secondary End Point – death from any cause

-Results

  • BiV and BiV-ICD both achieved statistically significant decrease in death or hospitalization from any cause
  • Death from any cause (secondary end point) for BiV was nearly significant HR .76 with CI .58-1.01, p = .06, for BiV-ICD was significant
  • Subgroup analysis showed increasing mortality benefit with increasing QRS 120-150 < 150-170 < 170+ and Class IV > III
  • Significant crossover in medical management group to receiving BiV-ICD
  • Quality of life and 6 minute walk both improve

13)ICD Implantation

  1. Take home: CAD + EF <30% = ICD

MADIT II Investigators. Prophylactic Implantation of a Defibrillator in Patients with Myocardial Infarction and Reduced Ejection Fraction. NEJM. March 21, 2002. Vol 346. No 12. Pg 677-883.

Trial of patients with prior MI and EF 30% or less to receive an implantable defibrillator or optimal medical therapy. No EP testing required prior for risk stratification.

-Prior MI defined by: q waves on EKG, positive biomarkers in hospitalization for suspected MI, wall motion abnormalities with evidence of CAD on angiography, fixed defect on nuclear stress

-Excluded: NYHA Class IV

-1200 patients

-Baseline: Age 64, 84% male, 70% NYHA class I or II, 50% QRS > .12

-Followed for 4 years, ITT analysis

-Primary end point: death from any cause

  • Statistically significant in HR .69 (.51-.93) number of deaths (p .016)
  • Survival appears as early as 9 months
  • Lower EF (< 25%) had a bigger benefit
  • 31% reduction in risk of death

14)ICD vs. Antiarrythmic

  1. Take home: EF < 35% (ischemic or nonischemic) ICD superior to amiodarone

SCD-HeFT Investigators. Amiodarone or an Implantable Cardioverter-Defibrillator for Congestive Heart Failure. NEJM. January 20, 2005. Vol. 352. No. 3. Pg 225-238.

Trial compared patients with NYHA Class II and III heart failure and EF 35% to optimal medical management, amiodarone, or ICD implantation.

-Inclusion: NYHA Class II or III, stable CHF due to ischemia or nonischemic causes, EF 35%

  • Ischemia defined as >75% stenosis in 1 of 3 major coronary arteries or h/o MI

-ICD’s were single lead placed, amiodarone load weigh based

-Baseline: Age 60, Male 76%, , 76% white, EF 25%, DM 29%, NSVT 23%

-Followed for 2 – 5 years

-Primary end point: Mortality

  • Statistically significant (p = .007) mortality benefit for ICD vs. placebo
  • Averaged 5% annual rate of shocks
  • RR reduction 23%, absolute risk reduction 7.2%
  • No benefit for amiodarone vs. placebo

15)Aspirin

  1. Take home: History of CAD = ASA

Berger, JS, Brown, DL, Becker, RC. Low-dose aspirin in patients with stable cardiovascular disease: a meta-analysis. Am J Med 2008; 121:43.

-Low dose ASA in secondary prevention of CVD

-Pts had either history of MI, stable angina or CVA/TIA

-6 studies with 10,000 patients.

-Results

  • 21% reduction in risk of CV events (nonfatal MI, nonfatal CVA and CV death)
  • 13% reduction in all cause mortality
  • Pts treated with ASA had statisticallysignificant more bleeding

16)Risk Stratification – TIMI Risk Score

  1. Take home: TIMI Risk Score is a useful prognostic tool in the evaluation of USA/NSTEMI

Antman, E. et. al. The TIMI Risk Score for Unstable Anginia/Non-ST Elevation MI: A method for Prognostication and Therapeutic Decision Making. JAMA. August 16, 2000. Vol. 284. No. 7. Pg 835-842.

Cohort Study were prognostic variables were applied to a patient population who was then followed for 14 days to determine their likelihood of developing the primary end point (mortality, new/recurrent MI or revascularization). Used data from ESSENCE and TIMI IIb trials.

-Criteria: based on analysis these 7 showed statistical significance (p < .05) related to primary outcome

  • Age 65
  • At least 3 risk factors for CAD (FMHx, HTN, HLD, DM, + tob)
  • Known prior coronary stenosis of 50%
  • ST deviation
  • 2 anginal symptoms in the last 24 hours
  • ASA use in the last 7 days
  • Elevated cardiac biomarkers

-Results (primary outcome)

  • TIMI 0/1  4.7%
  • TIMI 4  20%
  • TIMI 6/7  41%

17)Heparin/LMWH

  1. Take home: Enoxaparin as good, maybe better than heparin

ESSENCE Investigators. A Comparison of LMWH with unfractionated heparin for unstable CAD. NEJM. August 14, 1997. Vol 337. No 7. Pg 447-452.

Trial of patients with USA or NSTEMI to receive either 1 mg/kg enoxaparin SQ bid or continuous IV heparin gtt therapy for 48 hrs to 8 days.

-Patients had angina at rest and at least 1 of the following

  • ST depression, transient ST elevation, T wave changes, h/o MI or PCI/CABG

-Baseline: Age 64, 66% male, 42% FMHx, 55% HTN, 44% HLD, 22% DM, 24% tobacco

-Primary End Point: (composite) death, MI, or recurrent angina at 14 days

-Recurrent angina - - angina at rest + EKG changes

-Results

  • Primary end point statistically significant
  • Driven by decrease in MI and recurrent angina (310 events) vs. death (36 events)
  • Secondary end point of 30 days also significant
  • Again driven by MI and recurrent angina
  • Subgroup analysis of death alone showed no improved survival at any time
  • Increased risk of minor, but not major hemorrhage with enoxaparin

18)Thrombolytics

  1. Take home: STEMI + no cath lab = t-PA. The sooner the better.

The GUSTO Investigators. An International Randomized Trial Comparing Four Thrombolytics Strategies for Acute Myocardial Infarction. NEJM September 2, 1993. Vol 329. No 10. Pg 673-682.

Trial compared the use of streptokinase and SQ heparin, streptokinase and IV heparin, t-PA and IV heparin, and streptokinase, t-PA and IV heparin.

-40,000 patients in trial, multicenter, multinational

-Pts with 6 hours or less of symptoms plus at least 1 mm ST elevation

-Pts with h/o CVA, heavy bleeding, severe uncontrolled HTN (SBP >180) contraindicated

-All patients received ASA and beta blocker (unless contraindication)

-Baseline: Age 62, 75% male, 15% DM, BP 130/73, Time to treatment 160 minutes

-Primary End Point: death at 30 days

  • t-PA with IV heparin had statistically significant impact on mortality at 24 hr and 30 days without an increase nonfatal ischemic/hemm CVA
  • Patency of artery 85% post t-PA
  • Secondary outcomes showed lower CHF, arrhythmia, cardiogenic shock with t-PA

19)GIIb/IIIa Inhibitors - STEMI

  1. Take home: STEMI  consider GIIb/IIIa inhibitors

ADMIRAL Investigators. Platelets Glycoprotein IIb/IIIa inhibition with Coronary Stenting for Acute Myocardial Infarction. NEJM June 21, 2001. Vol. 344. No. 25. Pg 1895-1903.

Trial compared patients with acute myocardial infarctions to receiving abciximab plus stenting vs. stenting alone plus optimal medical therapy.

-Inclusion: Sx of MI within 12 hours, ST elevation 1 mm

-Exclusion: bleeding disorder, thrombolytic administration, uncontrolled HTN

-Heparin continued for 24 hours (aPTT 1.5-2.0 x control)

-Baseline: Age 60, 80% male, prev PCI/CABG 15%

-Followed for 6 months, intention to treat

-Primary End Point: (composite) death, reinfarction, or target-vessel revascularization

  • Composite end point significant at 30 days and 6 months
  • Driven by reduction in target vessel revascularization
  • Not significant reductions in death or reinfarction
  • Trend towards survival benefit noted, but numbers small (300 total pts in study
  • Increased risk of minor bleeding

20)Early Invasive vs. Conservative Management of USA/NSTEMI

  1. Take home: Elevated troponin, ST changes  consider earlier PCI

TACTICS Investigators. Comparison of Early Invasive and Conservative Strategies in patients with Unstable Coronary Syndromes treated with the GIIb/IIIa Inhibitor Tirofiban. NEJM June 21, 2001. Vol. 344. No. 25. Pg 1879-1887.

Trial compared patients with USA/NSTEMI (elevated cardiac markers, ST/T wave changes) who were treated with heparin, ASA, GIIb/IIIa inhibitors to early invasive strategy (catheterization and revascularization within 48 hrs) to conservative (catheterization only with positive stress test or recurrent ischemia).

-Inclusion: Angina > 20 min within 24 hr and 1 of the following (ST dep/elev, T wave inv, elevated cardiac markers or h/o coronary artery disease).

-Exclusion: Persistent ST elavation, h/o PIC or CABG, Cr > 2.5

-Baseline: Age 62, 65% male, 77% white, ST or T wave changes 50%

-All patients encouraged to receive beta blocker, statins, nitrates as appropriate

-60% of experimental arm underwent PCI/CABG (22 hr after randomization)

-36% of control arm underwent PCI/CABG 2/2 + stress/recurrent ischemia (79 hours after randomization)

-Primary End Point: (composite) death, nonfatal myocardial infarction, and rehospitalization for ACS at 6 months

  • Composite outcome significant – however, driven by nonfatal MI and rehospitalization
  • Mortality benefit not apparent
  • Subgroup analysis showed trend towards improved outcomes in DM, TIMI >5, elevated troponins, ST changes

21)Coronary Angioplasty

  1. Take home: STEMI + cath lab = angioplasty.

The GUSTO IIb Investigators. A clinical trial comparing primary coronary angioplasty with t-PA for acute myocardial infarction. NEJM June 5, 1997. Vol 336. No. 23. Pg 1621-1628.

Trial compared patients within 12 hours of acute myocardial infarction and evidence of ST elevation to primary angioplasty vs. t-PA.