P&T News: February 1996, Vol. 16, No. 8

Angiotensin Converting Enzyme Inhibitor Use in Chronic Heart Failure

Timothy G. Burke, Pharm.D.
Peer Review Status: Internally Reviewed by Ron M. Oren, M.D., Assistant Professor, Division of Cardiovascular Diseases, Department of Internal Medicine

Table 1. New York Heart Association Functional Classification of Heart Failure
Class I	No limitation in physical activity.
Class II	Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain.
Class III	Marked limitation of physical activity. Comfortable at rest, but less than ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain.
Class IV	Unable to carry out any physical activity without discomfort.

Heart failure carries a staggering cost to health care. In excess of $10 billion per year is spent on the treatment of heart failure patients. In 1992 there were 654,000 hospital admissions for patients with the principal diagnosis of heart failure, with hospital charges of $5.6 billion.1

Proper treatment of heart failure incorporates both pharmacologic and nonpharmacologic therapies including proper education of the patient, diet and exercise modifications, and the cessation of smoking.1 Treatment of heart failure must be directed to a number of endpoints including:

1) reduction of symptoms;

2) prevention of disease complications;

3) slowing or arresting the progression of the disease; and

4) decreasing mortality

This article will focus on angiotensin converting enzyme (ACE) inhibitor therapy, the pharmacologic therapy that has been shown to have a positive impact on the above mentioned endpoints.

Pharmacologic Treatment of Heart Failure
The appropriate initial pharmacologic management of heart failure is dependent on the presenting signs and symptoms. ACE inhibitors may be considered as sole therapy in patients with symptoms of heart failure (fatigue, dyspnea on exertion) but who do not have symptoms of volume overload. If symptoms persist after the initiation of ACE inhibitors, diuretics may be added. Patients who remain symptomatic after optimal management with ACE inhibitors and diuretics should have digoxin added to the medical regimen. Digoxin has been shown to prevent clinical deterioration in patients with heart failure although its effect on exercise tolerance and mortality is unclear. 1-3

Diuretics should be started immediately in patients with signs and symptoms of volume overload.' These patients should also be given a trial of angiotensin converting enzyme inhibitor therapy unless the patient has a history of intolerance to these agents, symptomatic hypotension, or a serum potassium greater than 5.5 mEq/L that cannot be reduced. In these patients who have a contraindication (Table 2) or a history of intolerance to ACE inhibition, the combination of hydralazine and isosorbide dinitrate is an appropriate alternative (Figure 1).1

Table 2. Contraindications for the Use of ACE Inhibitor Therapy

History of hypersensitivity to or angioedema from ACE inhibitor therapy Serum potassium greater than 5.5 mEq/L Renal failure (relative - ACE inhibitors may be started at one-half the usual starting dose and titrated up dowry) Symptomatic hypotension (relative - ACE inhibitor may be started at one half the usual starting dose and titrated up slowly )

If patients remain symptomatic on the combination of ACE inhibitors, diuretics and digoxin, a consultation with a practitioner who has expertise in the management of heart failure should be obtained. These patients may require more aggressive administration of pharmacotherapeutic agents; differing combinations of diuretics, vasodilators, and investigational medications; or even heart transplantation. I

While the beneficial effects of ACE inhibitor therapy are well established, some practitioners still advocate initial treatment with diuretics alone.4 However, in view of the evidence in favor of ACE inhibitors, diuretics should not be used as first line therapy. Diuretics can be added to ACE inhibitor therapy if the patient shows symptoms of volume overload.

Angiotensin Converting Enzyme Inhibitors: Efficacy
Studies in patients with congestive heart failure have shown that activation of the renin-angiotensin - aldosterone system plays an important part in its physiology. Low renal blood flow, increased sympathetic activity, and diuretic therapy may contribute to a rise in plasma renin activity.5 Renin is released into the circulation where it acts on a plasma globulin substrate to produce the relatively inactive angiotensin I. Angiotensin converting enzyme (also known as bradykinase) then converts angiotensin I to angiotensin II, a potent vasoconstrictor. Aldosterone secretion from the adrenal cortex is stimulated by angiotensin II causing sodium and water retention.6 The result of the increased angiotensin II and aldosterone secretion is vasoconstriction (which impedes left ventricular outflow) and sodium and water retention. ACE inhibition decreases levels of angiotensin II, thus decreasing vasoconstriction. Aldosterone secretion is decreased secondary to low angiotensin levels causing sodium and fluid excretion and retention of potassium. ACE inhibition may cause increases in bradykinase and prostaglandin E2, both potent vasodilators. In the failing heart, growth factor and proto-oncogene stimulation contribute to hypertrophy, and eventually increased myocardial cell death. ACE inhibition inhibits the formation of growth promoter (angiotensin II) and the breakdown of a growth inhibitor (bradykinin). The resulting effects on the growth response may further contribute to the beneficial effects of ACE inhibitors in patients with heart failure. In addition to activation of the renin-angiotensin system, the sympathetic system is activated early in heart failure. This activation can result in abnormal cardiac remodeling and an increase in cardiac ischemia due, in part, to coronary vasoconstriction and increases in myocardial oxygen demand secondary to increased left ventricular end diastolic volumes.7 ACE inhibitor therapy has also been shown to decrease circulating norepinephrine which may further contribute to the decrease in systemic vascular resistance and venous tone seen with ACE inhibitor therapy.5,6

There is considerable evidence that ACE inhibitor therapy will improve hemodynamics, reduce symptoms, increase exercise performance, and prolong life in heart failure patients. In addition, ACE inhibitor therapy reduces the number of hospitalizations in patients with decreased ejection fractions, even if these patients are asymptomatic.8-12 However, enalapril, ramipril and captopril are the only ACE inhibitors to date to show a statistically significant survival benefit in patients with symptomatic heart failure.1,11,12

Enalapril has been shown to reduce mortality in patients with mild to moderate8 and severe9 heart failure. In the SOLVD treatment trial, enalapril in doses of 2.5mg twice daily titrated to 10mg twice daily decreased the overall mortality by 16% when compared to placebo.8 In addition there was a 26% reduction in the combined endpoint of death or hospitalization for heart failure. SOLVD was a four-year trial that enrolled 2569 patients in NYHA class II and III heart failure with the majority (57 %) of the patients in NYHA class II failure. In this trial the majority of the survival benefit resulted from slowing progression of the congestive heart failure (CHF) as there was little effect on sudden death.

The CONSENSUS I9 trial evaluated the survival benefit of enalapril in 253 patients in Class IV heart failure randomized to either placebo or enalapril 2.5 mg twice daily titrated up to 20mg twice daily if tolerated. This trial was discontinued early by the ethics committee because of the benefit of therapy seen early in the trial. There was a mortality reduction of 40% at 6 months and 27% at 12 months when compared to placebo (absolute mortality 52% for placebo, 36% for enalapril). Hypotension occurred in 12% of the patients that were started on 8mg twice daily dosing. When the initial dose was reduced to 2.5mg twice daily, the incidence of hypotension was reduced to less than 3 % .

The V-HEFT II trial10 enrolled 804 patients in NYHA classes II and III heart failure and compared enalapril titrated to 10mg twice daily with the combination of hydralazine 75mg and isosorbide dinitrate 40mg four times daily used in the V-HEFT I trial. The mortality at two years was 25% in the hydralazine/isosorbide group and 18% in the enalapril group, a mortality reduction of 28 %, favoring enalapril.

The SOLVD prevention trial13 evaluated the effect of enalapril on survival and the secondary endpoints of CHF development or hospitalization in 4228 NYHA Class I patients with ejection fractions of < 35 %. Patients were randomly assigned to receive either placebo or enalapril at doses of 2.5 to 10mg twice a day. Follow up averaged slightly over 37 months. There was an 8 % reduction in mortality over the duration of the trial which was not significant. However, there was a 29 % reduction in the combined endpoints of the development of heart failure or death in the treatment group. In addition the enalapril group had a 36 % reduction in the first hospitalization for the treatment of heart failure (434 in the enalapril group vs. 518 in the placebo group).

Ramipril was compared to placebo in 2006 patients in a trial to evaluate mortality in patients who showed clinical evidence of heart failure after an acute myocardial infarction.12 Clinical evidence of heart failure was defined by radiographic evidence, presence of a third heart sound with persistent tachycardia, or ausculatory evidence of pulmonary edema. Patients received ramipril 2.5mg twice daily titrated to 8mg twice daily. Follow-up averaged 15 months. Mortality in the ramipril group was 17% compared to 23% in the placebo group, a risk reduction of 27% (p=0.002). In addition there was a 19% risk reduction for the initial outcome of either death, severe/resistant heart failure, myocardial infarction, or stroke in the ramipril group.

Captopril has also been shown to reduce mortality when used in the treatment of symptomatic heart failure.11 One hundred seventeen NYHA Class II - IV patients evaluated for cardiac transplantation were randomized to receive either captopril 6.25mg initially and titrated to a maximum of 100mg every 6 hours or hydralazine titrated up to 150mg every 6 hours. Isosorbide dinitrate was given to all patients randomized to hydralazine therapy, but was discontinued if intolerable side effects occurred. Isosorbide dinitrate was added to the captopril group if the patient had a history of coronary artery disease or if the pulmonary capillary wedge pressure remained greater than 20 mm Hg after 24 hours of captopril therapy. Overall, 88% of the hydralazine group and 84% of the captopril group received isosorbide dinitrate. Follow up averaged 8 months. The actuarial one - year survival rate was 81 % in the captopril-treated patients and S1 % in the hydralazine treated patients (p=0.05). The improved survival with captopril primarily resulted from a decrease in sudden death.

The SAVE trial14 evaluated the theory that long-term ACE inhibitor therapy could reduce the mortality and the development of heart failure in patients with asymptomatic left ventricular dysfunction post myocardial infarction. Two thousand two hundred thirty-one patients with ejection fractions of 40% or less were randomized to receive either placebo or captopril 6.25mg three times daily and titrated to a maximum of 50mg three times daily. Therapy was started 3 to 16 days post myocardial infarction; follow-up averaged 42 months. Mortality was 25% for the placebo group and 20% in the captopril group for a 19% reduction in mortality (p=0.019). In addition there was a 25% reduction in the incidence of recurrent myocardial infarction and a 22 % reduction in hospitalizations for heart failure in the captopril group.

A recent placebo-controlled trial evaluated the effect of withdrawal of ACE inhibitor therapy in the treatment of chronic heart failure in NYHA Class II and III patients.15 Two hundred twenty-four patients treated with quinapril 10mg twice daily for 10 weeks or longer were randomized to either continue ACE inhibitor therapy or withdrawal and placebo therapy for 16 weeks. Patients assigned to placebo had a significant deterioration in exercise tolerance (p=0.015), NYHA functional class (p=0.004), and quality of life. Additionally, 18 patients were withdrawn from the placebo group due to worsening failure compared to S patients in the quinapril group (p<0.001). Withdrawal of quinapril resulted in a steadily gradual worsening of heart failure over 4 to 6 weeks rather than abrupt deterioration.

The Consensus II trial16 was noteworthy in that it did not show a positive outcome with ACE inhibitor therapy. However, this trial was not conducted in heart failure patients, but in patients who had an acute myocardial infarction and a presenting blood pressure above 100mm Hg systolic and 60mm Hg diastolic. Baseline left ventricular ejection fraction was not performed prior to randomization into the study. A total of 6090 patients was randomly assigned to receive either placebo or intravenous enalaprilat followed by oral enalapril. Mortality rates at one and six months were not statistically different between the two groups; however, the rate did favor the placebo group at six months. Therapy had to be changed because of worsening heart failure in 30% of the placebo group and 27% of the enalapril group (p=0.006). Early hypotension (systolic < 90mm Hg) occurred in 12% of the enalapril group and 3% of the placebo group (P<0.001). This group of patients represented a low mortality, low event rate population during the six-month study period. The mortality reductions seen with ACE inhibitor therapy may require treatment for longer than six months as seen in the heart failure trials." In addition, early hypotension secondary to intravenous enalaprilat administration may have worsened the acute myocardial infarction resulting in a poor outcome in the enalapril group.

Some experts believe that there may be differences between the individual agents due to non- ACE inhibitor effects including differences in tissue penetration and differing effects on prostaglandins and bradykinase.18,19 Other experts, including the authors of the Health and Human Services Clinical Practice Guidelines for the Treatment of Heart Failure,' and the authors of the American College of Cardiology and American Heart Association Guidelines for the Evaluation and Management of Heart Failure,3 believe that the beneficial effects of ACE inhibitor therapy may be a drug class effect and not specific to any single agent or agents.' This view is also held by the authors of a recent meta-analysis that reviewed mortality and morbidity studies in patients with symptomatic heart failure. This overview of 32 randomized controlled trials in 7105 patients with symptomatic heart failure treated with 8 different ACE inhibitors indicates that treatment with ACE inhibitors reduce the risk of death and hospitalization for CHF.20 It would appear that any of the ACE inhibitors studied in heart failure could be used as initial treatment with enalapril being the agent with the strongest body of evidence to support its use.8-10

Complications of Angiotensin Converting Enzyme Inhibitor Therapy
Despite the proven importance of ACE inhibitor therapy, several important clinical issues remain. These include use in patients with borderline hypotension, renal dysfunction, and the importance of the ACE inhibitor-induced cough.

In the large-scale heart failure trials, the percent of patients having dose-related symptomatic hypotension was 5.5% or less - even in patients with Class IV heart failure.8,9 Careful dosage titration by starting with lower doses of drug in those patients with pre- existing hypotension, volume depletion, or hyponatremia may be able to further decrease the problem.2,21 Further, patients with borderline hypotension can often tolerate surprisingly large doses of ACE inhibitor and still remain without orthostatic symptoms. Patients should be assessed closely for volume depletion before initiating therapy with ACE inhibitors. Indicators of volume depletion would include orthostatic hypotension, prerenal azotemia, or metabolic alkalosis. If volume depletion is evident, diuretics should be withheld for 24 to 48 hours until the depletion resolves. Patients who are at risk for first dose hypotension are those with severe heart failure, systolic blood pressure < 100 mm Hg, and/or a serum sodium of < 135 mEq/L. In these patients initial small doses of a short acting agent (captopril 6.25 ma) and monitoring for 2 to 3 hours is recommended. If the test dose is tolerated, captopril 12.5 mg every 8 hours or enalapril 2.5 mg every 12 hours may be started.21

Worsening of baseline renal function is a frequent concern when initiating ACE inhibitor therapy. A high serum creatinine may be a reflection of poor renal perfusion secondary to a low cardiac output. In the SOLVD treatment trial the increase in serum creatinine was 0.1 mg/dl.8 The CONSENSUS trial9 (which only enrolled patients with Class IV failure) found an increase in withdrawals secondary to renal dysfunction of only 1.5%. ACE inhibitor increases in serum creatinine are a reversible phenomena and will return to baseline once the drug is discontinued. If the serum creatinine at baseline is 3.0 mg/dl or greater, the current recommendation is to titrate the ACE inhibitor slowly to a maximum of one-half the usual recommended maintenance dose.' 2' ACE inhibitors should not be instituted at a time when the serum potassium is 5.5 mEq/l or greater. Potassium-sparing diuretics should be discontinued before ACE inhibitor initiation regardless of serum potassium concentration. Potassium supplements should also be withheld unless the serum potassium decreases to below 4 mEq/L.

Cough is a common side effect of ACE inhibitor therapy as well as many other conditions including heart failure. The SOLVD trial8 noted a 37 % incidence of cough with ACE inhibitor therapy. The placebo group in this trial noted a 31% incidence of cough.8 The cough, more troublesome and annoying than disabling, can develop within a week, or have a delayed onset of up to six months after the patient starts therapy. It occurs more often in women than men. It usually disappears within a few days after withdrawal of the ACE inhibitor, but may take as long as four weeks to subside. The cough is a class effect and usually recurs upon rechallenge with the same or a different ACE inhibitor.22 The heart failure patient who presents with cough must first be evaluated to determine whether the cough is a result of pulmonary congestion before ACE inhibitor therapy is discontinued.1,21 If the cough is believed to be due to ACE inhibitor therapy, the patient may be switched to a hydralazine/isosorbide dinitrate combination while evaluating the cough. Subsequent rechallenge with an ACE inhibitor after a two to three week washout period may be helpful.22

Cost Implications
Cost is an important factor for patients on multiple medications often costing hundreds of dollars per month. While the ACE inhibitors are fairly expensive, their cost may be offset by a decrease in hospital admissions. However, the major cost differences between agents should be a consideration when selecting a particular agent for long-term maintenance therapy. Table 3 provides a list of the ACE inhibitors and a comparison of their yearly cost of therapy. Only those ACE inhibitors that have FDA approval for use in heart failure patients are listed in the table. The optimal dose of other ACE inhibitors in the treatment of heart failure is, at this point, unknown.

Table 3. Comparative Dosages and Yearly Costs of ACE Inhibitor Therapy for the Treatment of Heart Failure
DRUG	FORMULARY STATUS	INITIAL DOSE[c]	TARGET DOSE	ACQUISITION COST/YEAR OF THERAPY[d,e]
Captopril (Capoten[R])	F	6.25 mg TID	50 mg TID	$1310
Enalapril (Vasotec[R])	F	2.5 mg BID	10 mg BID	$699
Fosinopril (Monopril[R])	F	10 mg QD	20 mg QD	$277
Lisinopril (Privinil[R], Zestril[R])	NF	5 mg QD	20 mg QD	$305
Ramipril (Altace[R])	NF	2.5 mg BID	5 mg BID	$544
Quinapril (Accupril[R])	NF	5 mg BID	20 mg BID	$664
[a] Dosages listed for these agents are the currently recommended doses for use in the treatment of heart failure. [b] Benzepril (Lotensin[R]) and moexipril (Univasc[R]) are additional currently marketed ACE inhibitors, but they do not currently carry an FDA-labeled indication for heat failure. [c] For patients with significant renal dysfunction (SCr more than 3.0 mg/dl) or symtomatic hypotension, the usual initial dose may be decreased by one-half and titrated slowly upward. [d] Acquisition cost is based on the target dose. [e] Cost listed in the Redbook average wholesale price cost to the patient will vary. [f] Formulary Drug NF = Not stocked at UIHC

Summary
Based on available evidence, the best initial pharmacologic approach to the management of heart failure without fluid overload would be to use ACE inhibitor therapy initially in doses shown to improve survival. Adverse effects associated with ACE inhibitor therapy include hypotension and increases in serum creatinine; however, these effects are usually not clinically significant. Cough is a concern and may be due to either the ACE inhibitor or worsening of the heart failure. During the next six months, the Pharmacy and Therapeutics Subcommittee will be re-evaluating the ACE inhibitors, utilizing current efficacy, adverse effect, and cost data in order to update the UIHC formulary.

References

1. Heart Failure: Evaluation and Care of Patients with Left-Ventricular Systolic Dysfunction. Clinical Practice Guideline number 11. AHCPR Publication No. 94-0612. June 1994.

2. Circulation 1994; 88:2941-52.

3 Circulation 1995; 92:2764-84.

4. Scot Med J 1989; 34:425-7.

5. Am J Med 1984; 77:690-8.

6. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 8tb Edition New York: Pergamon Press; 1990.

7. Ann Intern Med 1994; 121 :363-71.

8. N Engl J Med 1991;325:293-302.

9. N Engl J Med 1987; 316: 1429-35.

10. N Engl J Med 1991; 325:303-10.

11. J Am Coll Cardiol 1992; 19:842-50.

12. Lancet 1993; 342:821-8.

13. N Engl J Med 1992; 327:685-91.

14. N Engl J Med 1992;327:669-77.

15. J Am Coll Cardiol .1993; 22:1557-63.

16. N Engl J Med 1992; 327:678-84.

17. ACC Learning Center Highlights 1993; 8:1-6.

18. Am J Card 1991; 68:106-8.

19. Am Hypertens 1988; 1:214S-6S.

20. JAMA 1995; 273:1450-6.

21. JAMA 1994; 272:1361-6.

22. Ann Intern Med 1992; 117:23442.

Pharmacy and Therapeutics Subcommittee Actions

Drugs Added to Stock

LAMIVUDINE Tablets: 150 mg Oral Solution: 10 mg per ml Lamivudine (Epivir R - GlaxoWellcome) is an antiretrovial agent indicated for use in combination with zidovudine for the treatment of HIV infection.

PANCRELIPASE Tablets: Lipase 8800 units, protease 30,000 units and amylase 30,000 units Non-enteric-coated pancrelipase (Viokase R - A.H.Robins) i8 indicated for the treatment of exocrine pancreatic insufficiency. It is useful for the management of pain associated with chronic pancreatitis.

SAQUINAVIR Capsules: 200 mg Saquinavir (Invirase R - Roche) is an antiretroviral agent that inhibits the activity of HIV protease; it is indicated as combination therapy with nucleoside analogues (e.g., zidovudine, zalcitabine) for the treatment of advanced HIV infection. Cost: Sl.77 per 200 mg capsule.

TALC, STERILE Powder: 5 grams Sterile talc is used as an insulation or slurry for sclerosis of malignant pleural effusions.

TESTOSTERONE Transdermal Patches: 2.5 mg Testosterone transdermal patches (Androderm (R) - SKB) are indicated as replacement therapy in men with a deficiency or absence of endogenous testosterone.

Additional Actions

The following additional strengths of products already stocked have been added:

Desipramine 10 mg Tablets

Estrogens, Conjugated 0.9 mg Tablets

Levothyroxine 0.088 mg Tablets

Drugs Deleted From Stock

DESIPRAMINE 150 mg TABLETS This strength was discontinued due to low use. Two 75 mg tablets may be prescribed as an alternative.

LINDANE SHAMPOO AND LOTION Lindane was deleted because of safety concerns and because it is no longer considered by The Medical Letter to be the "drug of choice" or an alternative agent for the treatment of lice or scabies. Permethrin (Nix (R) Creme Rinse for lice and Elimite (R) 5 % Cream for scabies is available. [NOTE: The May 1995 issue of the P&TNews provides a review of the management of lice and scabies.

MINERAL OIL, STERILE 180 ml BOTTLES Discontinued due to low use. Sterile mineral oil is available in 30 ml bottles.

TESTOSTERONE 4 mg AND C mg TRANSDERMAL PATCHES The Testaderm R brand of testosterone transdermal patches has been deleted due to low use; the Androderm R brand is available.

THYROID TABLETS Discontinued due to low use. Levothyroxine and liothyronine tablets are available.

Vaccine	Birth	1 mo	2 mos	4 mos	6 mos	12 mos	15 mos	18 mos	4-6 yrs	11-12 yrs	14-16 yrs
Hepatitis B[1,2]	Hep B-1 Hep B-2 Hep B-3 Hep B[2]*
Diphtheria, Tetanus, Pertussis[3]			DTP	DTP	DTP	DTP[3] (DTaP at 15= m)			DTP or DTaP	Td
H. influenzae type b[4]			Hib	Hib	Hib[4]	Hib[4]
Polio[5]			OPV[5]	OPV	OPV				OPV
Measles, Mumps, Rubella[6]						MMR			MMR[6] here or	MMR[6] here
Varicella Zoster Virus Vaccine[7]						Var				Var[7]*
Approved by the Advisory Committee on Immunization Practices (ACIP), the American Academy of Pediatrics (AAP), and the American Academy of Family Physicians (AAFP). * Indicates catch-up vaccination: at 11-12 years of age, hepatitis B vaccine should be administered to children not previously vaccinated, and Varicella Zoster Virus vaccine should be administered to children not previously vaccinated who lack a reliable hisotyr of chickenpox. [1] Infants born to HBsAg-negative mothers should receive 2.5 ug of Merck vaccine (Recombivax HB) or 10 ug of SmithKline Beecham (SB) vaccine (Engerix-B). The 2nd dose should be administered 1 or more months after the first dose. Infants born to HVsAg-positive mothers should receive 0.5 mL Hepatitis B Immune Globulin (HBIG) within 12 hr of birth, and either 5 ug of Merck vaccine (Recombivax HB) or 10 ug of SB vaccine (Enerix-B) at a separate site. The 2nd dose is recommended at 1-2 mos of age and the 3rd dose at 6 mos of age. Infants born to mothers who HBsAg status is unknown should receive either 5 ug of Merck vaccine (Recombivax HB) or 10 ug of SB vaccine (Engerix-B) within 12 hr of birth. These 2nd dose of vaccine is recommended at 1 mo of age and the 3rd dose at 6mos of age. [2]Adolescents who have not previously received 3 doses of hepatitis B vaccine should initiate or complete the series at the 11-12 year-old visit. The 2nd dose should be administered at least 1 mo after the 1st dose, and the 3rd dose should be administered at least 4 mos after the 1st dose and at least 2 mos after the 2nd dose. [3]DTP4 may be administered at 12 mos of age, if at least 6 mos have elapsed since DTP3. DTaP (diphtheria and tetanus toxoids and acellular pertussis vaccine) is licensed for the 4th and/or 5th vaccine dose(s) for children aged 15 months or older and may be prefered for these doses in this age group. Td (tetanus and diphtheria toxoids, adsorbed, for adult use) is recommended at 11-12 years of age if at least 5 years have elapsed since the last dose of DTP, DTaP, or DT. [4]Three H. influenzae type b (Hib) conjugate vaccines are licensed for infant use. If PRP-OMP (PedvaxHIB [Merck]) is administered at 2 and 4 mos of age, a dose at 6 mos is not required. After completing the primary series, any Hib conjugate vaccine may be used as a booster. [5]Oral poliovirus vaccine (OPV) is recommended for routine infant vaccination. Inactivated poliovirus vaccine (IPV) is recommended for persons with a congenital or acquired immune deficiency disease or an altered immune status as a result of disease or immunosuppressive therapy, as well as their household contacts, and is an acceptable alternative for other persons. The primary 3-dose series for PIV should be given with a minimum interval of 4 wks between the 1st and 2nd doses and 6 mos between the 2nd and 3rd doses. [6]The 2nd dose of MMR is routinely recommended at 4-6 yes of age or at 11-12 yrs of age, but may be administered at any visit, provided at least 1 mo has elapsed since receipt of the 1st dose. [7]Varicella zoster virus vaccine (Var) can be administered to susceptible children any time after 12 months of age. Unvaccinated children who lack a reliable history of chickenpox should be vaccinated at the 11-12 year-old visit.

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