Medical Discussions

Frishman, William, “Carvedilol,” New England Journal of Medicine, V 339, No 24, December 10, 1998, p. 1759-1765 

BACKGROUND 

• Beta antagonist with alpha 1 antagonist activity
• Approved for HTN in Sept 1995
• Patent will expire in 2006
• Currently, GlaxoSmithKline is developing an extended release version that is in Phase III clinical trials
• The first adrenoreceptor locking drug to receive approval specifically for heart failure 

PHARMACODYNAMIC PROPERTIES                                       

• Racemic lipophilic aryloxypropanolamine                                                                                         
• Causes precapillary vasodilation by means of alpha 1 blockade and nonselective beta blockade
• No sympathomimetic activity
• Carvedilol has two to four times beta antagonist activity when compared to propanolol
• The ratio of alpha:beta activity is 1:10compared to 1:4 for labetolol
• In vitro, the drug has antioxidant activity the significance of is unknown

Kinetics

• Rapidly absorbed after oral administration

• On an empty stomach peak plasma concentrations are achieved in one to two hours

• Absorption can be delayed in additional 60 to 135 minutes if the drug is administered with food.

• Goes through stereoselective first pass hepatic metabolism

• Ninety eight percent of the drug is bound to albumin

• Cleared by the liver Conjugated to glucuronide and excreted in the bile

• Only 16% is excreted by the urine

• Metabolism is affected by the P450 system

• Drugs that inhibit the system may lead to increase concentration such as quinidine, paroxetine, fluoxetene, propefenone

• Interestingly, the S racemere is only slightly affected by the P450 system

• Clearance is delayed in pats over 50 yo

• Pt’s with liver disease have high plasma levels, but the half life remains unchanged

• Pharmacokinetics are not altered in pts undergoing hemodialysis

• HCTZ does not influence the kinetics of carvedilol

• Pt’s with class IV HF may have higher plasma concentrations, but there is considerable overlap between the two.

CLINICAL EFFECTIVENESS 

• The US Carvedilol Heart Failure Program was made up four coordinated studies of a total of 1094 pts with aLVEF < 35 %NYHA class II,III,IV sx
• Must be able to walk for six minutes
• On conventional therapy, pt ’s needed to be able to tolerate carvedilol therapy
• No hospitalization or change in HF failure medications the month previous to enrolling in the study
• The studies lasted 6 to 12 months
• The study tested the ability of subjects to complete a six minute walk test
• At baseline the pts needed a HR 68 SBP of 85
• And needed to be able to complete the six minute walk test
• Pt’s were enrolled in one of the four studies based on how far they could walk
• Results – There was a 48 percent reduction in the progression of HF, defined as death or hospitalization or as sustained increase in HF medication
• Exercise tolerance was unchanged
• Quality of life was also unchanged
• Mortality was initially not a preplanned primary end pt., but the study was terminated 65 percent reduction in mortality (3.2 vs 7.8)
• 68 percent reduction in mortality in pts with Class II HF
• 65 percent reduction in pts with Class III HF
• Reduction in mortality was similar in pts with ischemic vs nonischemic HF
• Based on these results the study was terminated in February 95 based on the recommendation of the data and safety board
• Caveats – reductions in total mortality included some trials which did not show a significant benefit in treatment
• No known benefit on pts with diastolic dysfunction
• Unknown if the drugs effects can be generalized to other alpha1, beta antagonists
• Based on this study and others including one in Australia and New Zealand, the FDA approved the use of carvedilol in HF
• Use for treatment for HTN
• Comparable to other antihypertensives including other beta blockers, diuretics, ACEi, CCB
• Reduced symptoms of chronic stable angina similar to other beta blockers 

CLINICAL USE IN HEART FAILURE 

• Before initiating therapy the dose of ACEi and diuretics should be stabilized
• The recommended starting dose 3.125 BID for two weeks
• If this dose is tolerated then the dose can be doubled at a minimum of every two weeks to the maximal dose 25 bid for pts that <85 kg and 50 bid for pts>85 kg
• Usually costs about $130/month at Walgreens
• Before increasing the dose pt should be evaluated for sx of worsening HF
• Fluid retention or increased dyspnea can be treated with increased diuretics
• Dizziness or hypotension responds to a reduction in the dose of the ACEi

Contraindications

• Decompensated HF
• Bradycardia
• Sick sinus syndrome
• Partial or complete AV block
• Relative contraindication to asthmatics
• Should be used cautiously in pt’s with DM, because it can mask symptoms of hypoglycemia 

SIDE EFFECTS 

• Five percent discontinued the use of the drug because of worsening HF, dizziness, bradycardia
• Decreased renal fxn is a rare side efx
• One percent of pt’s had mild hepatocellular injury, the drug should be discontinued in pt’s with abn LFTs as a result of starting the drug

by Vandana Khungur

Background

Sudden cardiac death (SCD) can occur in patients with CHF despite optimal medical therapy.

Patients with NYHA Class IV heart failure who are not candidates for cardiac transplantation are often excluded from studies such as SCD HeFT due to their high mortality from progressive pump failure.

There have been many more trials looking at primary prevention of SCD in ischemic than in nonischemic cardiomyopathy.

The national coverage determination (NCD) by the Center for Medicare and Medicaid Services for reimbursement of ICD therapy impacts patient selection in the US.

Briefly, and relevant to the article at hand, Medicare covers ICDs for pts with ischemic and non-ischemic dilated cardiomyopathy (if non-ischemic, >9 mos), NYHA Class II or III heart failure, and measured LVEF

1. Pts must not have cardiogenic shock or symptomatic hypotension while in a stable baseline rhythm
2. Pt must not have had a CABG or PTCA within the past 3 months
3. Pt cannot have had an MI within 40 days prior to ICD insertion
4. Pts may not have clinical symptoms or findings that would make them a candidate for coronary revascularization
5. Pts may not have any disease, other than cardiac disease (e.g., cancer, uremia, liver failure), associated with a likelihood of survival less than 1 year.

Ischemic cardiomyopathy trials

Pts who have had an acute MI are at increased risk for SCD, usually due to a tachyarrhythmia.

MADIT I – Multicenter Automatic Defibrillator Implantation Trial

1st trial to demonstrate that ICDs can be used for primary prevention of SCD in high risk, asymptomatic pts
196 pts with prior MI, NSVT on monitoring, LVEF
At 27 month follow-up, findings were significant reductions in the incidence of overall mortality, cardiac mortality, and arrhythmic deaths in pts treated with ICDs. Subset analysis showed benefit only in high-risk pts with more severe heart disease (EF 0.12 sec). Benefit increased progressively with more risk factors.
ICD was compared to amiodarone without a control of no antiarrhythmic.
Based upon the results of MADIT I, the FDA approved the prophylactic use of the ICD in pts with the following:

1. Sustained VT induced by EPS and not prevented with IV procainamide
2. Ischemic heart disease
3. Prior MI
4. NSVT
5. Reduced LVEF (

MADIT II Trial
1232 pts with MI more than 30 days prior to enrollment (and more than 3 months if bypass surgery was performed) and LVEF

Pts were randomly assigned to a prophylactic ICD or conventional medical therapy.
The study was prematurely terminated at an average f/u of 20 months because the ICD reduced all-cause mortality (14.2 vs 19.8 % for conventional therapy, HR 0.65 (0.51-0.93). This survival benefit was entirely due to a reduction in sudden death and was present in all subgroups analyzed.
An unexpected finding was a higher rate of hospitalization for HF in the ICD group (20 vs 15%), possibly due to longer life spans in the ICD group due to prevention of SCD.

Another possible explanation for the increased hospitalization for HF is the development of myocardial injury and decreased LVEF after multiple ICD shocks.

CABG Patch Trial
This trial evaluated the efficacy of an epicardial ICD implanted at the time of CABG for reducing mortality in pts undergoing surgical revascularization for severe CHD who had LVEF

900 pts, no history of sustained VT or syncope. Average f/u of 32 months. 101 deaths in the ICD group (71 cardiac) and 95 in the control group (72 cardiac). HR of 1.07 was not statistically significant.

Prophylactic therapy with ICD did reduce arrhythmic death by 45%, but 71% of the deaths in the trial were nonarrhythmic, so this reduction in arrhythmic death did not impact upon total mortality.

ICD therapy potentially did not reduce mortality because coronary revascularization itself has a beneficial effect in preventing sudden death.

This trial is the main reason why current guidelines recommend against ICD implantation for pts who have recently undergone coronary revascularization.

MUSTT trial

704 pts with a prior MI (
2 year and 5 year rates for the primary end point were significantly lower for EPS guided therapy compared to no therapy, largely attributable to ICD therapy.

DINAMIT trial

Evaluated the role of prophylactic ICD implantation compared to no ICD in 674 pts with an MI within the preceding 6 to 40 days (unlike MADIT and MUSTT, which enrolled pts at least 3 weeks post MI).

LVEF 80 beats/min).

Exclusion criteria included sustained VT >48 hrs post-MI, NYHA class IV HF, or CABG or three vessel PCI post-MI.

No difference in annual all-cause mortality between ICD and control.

Arrhythmic deaths were more frequent in the control arm, nonarrhythmic deaths were more freqent in the ICD arm.

Potential reasons for less of an effect in this trial than in MADIT and MUSTT include that some SCDs in the early postinfarction period are due to recurrent ischemia, which is not completely treated by ICD discharge or ICD implantation may be riskier in pt immediately post MI.

This trial is the main reason that current guidelines recommend that ICD implantation should be deferred until at least 40 days post MI.

Nonischemic cardiomyopathy trials
Ventricular arrhythmias are common in HF pts with a nonischemic cardiomyopathy.

CAT and AMIOVIRT
Neither trial showed survival benefit of prophylactic ICD insertion compared to placebo or amiodarone.

CAT or Cardiomyopathy Trial, randomly assigned 104 pts with recent onset (

AMIOVIRT trial compared an ICD, sometimes with amiodarone, to amiodarone alone in 103 pts with moderate to severe nonischemic dilated cardiomyopathy with class I to III heart failure, LVEF

There was no significant difference in overall survival between the amiodarone and ICD groups at one year or three years.

Both trials were very small, AMIOVIRT did not have a placebo group and both had unexpectedly low mortality rates.

DEFINITE
458 pts enrolled, all received standard medical therapy, including an ACE and beta blocker in most instances.
Almost significant trend toward a reduction in the primary end point of all-cause mortality with an ICD (7.9 vs 14.1%, HR 0.65 (0.4-1.06). In the subset of NYHA Class III pts the difference was significant.

The trial was underpowered and may have shown a significant difference with more study subjects.

Cost-effectiveness of ICD implantation

Cost-effectiveness of ICD implantation for primary prevention of SCD is difficult to determine because there are several variables that enter the equation. The cost of device implantation, cost of generator change, projected life expectancy, and mortality rate, as well as efficacy of ICD therapy all matter. Quality of life adjustments are also factored in. A study entitled “ Cost-effectiveness of implantable cardioverter-defibrillators” Sanders et al., NEJM 20005; 353:1471, estimated cost-effectiveness of prophylactic ICD implantation. Use of an ICD was projected to add one to three quality adjusted life-years (QALYs), with a cost per quality-adjusted year of life saved from $34,900 in MADIT to $70,200 in SCD-HeFT. These costs all fall within the range of $50,000 to $100,000 per QALY gained that is considered to be acceptable in the US.