1. Compare the action of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in the management of patients with heart failure or post-myocardial infarction.

2. Describe the differences in outcomes with β-blockers, digoxin, loop diuretics, aldosterone antagonists, aspirin, and statins used for heart failure.

3. Explain why the American Diabetes Association does not yet include sitagliptin in its algorithm for blood glucose management in type 2 diabetes.

4. Discuss the indications for HPV and herpes zoster vaccination.

5. Present the evidence for use of intravenous zoledronic acid.

Drug Therapies for Heart Failure

Guiding principles: based on patient-oriented evidence that matters (POEMs), rather than disease-oriented evidence surrogate markers (DOES); prescribe correct drug in right dose for appropriate indication; monitor for drug-drug interactions and desired outcomes; balance benefits and risks

Factors to consider: route of administration; frequency of dosing (lower frequency enhances patient compliance); potential for drug-drug, drug-disease interactions; monitoring; cost

Treatment guidelines and algorithms: standardize treatment based on evidence; associated with improved outcomes, although outcomes should improve even more as individual genome data become more accessible

Sample patient: 60-yr-old man post-myocardial infarction (MI), with systolic dysfunction heart failure (HF; ejection fraction [EF] 30%; New York Heart Association [NYHA] Class III)

Medications recommended in various guidelines: angiotensin-converting enzyme inhibitors (ACEIs); angiotensin receptor blockers (ARBs); β-blockers; loop diuretics; digoxin; aldosterone antagonists; aspirin; statins

ACEI or ARB?

Evidence supporting use of ACEIs: reduce morbidity and mortality from heart failure; reduce risk for sudden death and need for hospitalization related to heart failure; diminish symptoms; improve quality of life (all are POEMs); Assessment of Treatment with Lisinopril and Survival (ATLAS) trial—showed superiority of high-dose lisinopril over lower doses at reducing mortality, hospitalization, and enhancing survival among patients with systolic dysfunction

Evidence supporting use of ARBs: candesartan (Atacand), valsartan (Diovan) only ARBs approved by Food and Drug Administration (FDA) for treating heart failure; evidence comes from Candesartan in Heart Failure– Assessment of Mortality (CHARM) trial, Valsartan Heart Failure Trial (Val-HeFT4); CHARM used full candesartan dose of 32 mg/day; Val-HeFT4 used valsartan dose of 160 mg bid; however, ARB should be first-line therapy only if patient ACEI-intolerant (both trials had only ACEI-intolerant subjects); otherwise, ARB should be second-line therapy; combination of ACEI plus ARB not as good as combining ACEI or ARB with β-blocker and aldosterone antagonist

Treatment after MI: full-dose ACEIs reduce morbidity and mortality; among ARBs, only valsartan studied in outcomes trial (Valsartan in Acute Myocardial Infarction Trial [VALIANT]); dose of 160 mg bid reduced morbidity and mortality; compared to captopril, outcomes no different

Precautions: serum potassium must be <5.6 mEq/L at baseline to start ACEI or ARB; if potassium level higher, guidelines recommend checking patient’s use of salt substitutes (contain 50-60 mEq potassium/teaspoon; “like eating a 5-ft banana”); renal function—if impaired, ACEIs and ARBs reduce progression to end-stage renal disease; data stronger for ACEIs and also show associated reduction in morbidity and mortality; expect slight rise in serum creatinine when starting patient on ACEI or ARB; 10% to 20% rise transient, “nothing to worry about;” rise >30% over baseline is “red flag;” usually occurs because patient dehydrated; National Kidney Foundation guidelines suggest stopping ACEI or ARB, correcting patient’s hydration status, then resuming drug; conclusion—ACEI first-line drug for heart failure, post-MI patients

β-blockers: 3 shown to reduce morbidity and mortality in patients with systolic dysfunction heart failure and reduced EF; sustained-release metoprolol (eg, Toprol XL; titrate to target dose 200 mg/day); carvedilol (Coreg; titrate to target dose 25-50 mg bid, if tolerated); both approved by FDA for this indication; bisoprolol (Zebeta) not FDA-approved for this indication, but included in American College of Cardiology-American Heart Association (ACC-AHA) guidelines as off-label recommendation; Cardiac Insufficiency Bisoprolol Study (CIBIS II) established target dose of 10 mg/day; no good comparative data yet; new evidence suggests carvedilol stimulates cardiovascular-protective proteins produced in myocardial cell, as well as protects myocardium from effects of sympathetic nervous system

After MI: do not use intrinsic sympathomimetic activity (ISA) β-blocker (eg, acebutolol [Sectral], pindolol [Visken]; may raise resting heart rate [HR]); other β- blockers acceptable

Precautions: contraindicated if patient has greater than first-degree heart block; monitor HR, electrocardiography, and blood pressure (BP); monitor for orthostatic changes if using α- or β-blocker (patient may experience syncope and fall, possibly breaking hip); may affect glucose and insulin metabolism (monitor patient for hypoglycemia)

Loop diuretics: evidence shows they improve symptoms, not outcomes; dose as needed, based on weight and symptoms; monitor patient’s renal function, potassium and other electrolytes, glucose, and BP

Digoxin: in Digoxin Intervention Group Trial, associated with reduced hospitalization and improved symptoms, but no major effect on mortality; however, as serum digoxin levels increased, so did mortality (men only); “they felt better but died sooner”; new guidelines recommend daily dose <0.125 mg; serum level should be <1 ng/mL (higher levels associated with greater mortality); monitor electrolytes and HR; watch for signs and symptoms of toxicity

Aldosterone antagonists: shown in 2 trials to reduce morbidity and mortality when combined with ACEI or ARB and β -blocker; precautions—baseline potassium must be <5.0 mEq/L; renal function must be normal; serum creatinine must be <2.0 to 2.5 mg/dL, or clearance >30 mL/min; both trials used target doses of 25 mg/day; post-MI, may also prevent cardiac remodeling; compared to spironolactone, eplerenone associated with less risk for gynecomastia in men and menstrual irregularities in women; usually, spironolactone still drug of choice, due to lower cost

Aspirin: good evidence of post-MI reduction in morbidity and mortality; recommended doses 75 to 162 mg/day (post-MI); 75 to 81 mg/day (HF), if patient not candidate for anticoagulation; precautions—control systolic BP before using even baby aspirin, due to increased risk for hemorrhagic stroke; study (British Medical Journal, 2000)— 5499 men; 75 mg baby aspirin associated with 50% to 60% reduction in risk for hemorrhagic stroke and MI, compared to placebo, if systolic BP <130 mm Hg; systolic BP >145 mm Hg associated with no decrease in MI and 42% increase in relative risk for stroke; Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7)—recommends controlling BP before placing patient on aspirin; also monitor for potential interaction with nonsteroidal anti-inflammatory drugs ([NSAIDs]; may blunt effects of aspirin; take aspirin ≥8 hr after last dose of, eg, ibuprofen; can take next dose of ibuprofen 15 to 30 min after taking aspirin; do not use enteric-coated aspirin); sulindac may not interfere with aspirin; cyclooxygenase (COX)-2 inhibitors and acetaminophen do not interfere with aspirin; naproxen may interfere with aspirin for ≤36 hr after last dose (not recommended for people who take aspirin daily)

Statins: good evidence of reduced cardiovascular events post-MI; effect on HF outcomes less clear; precautions— monitor lipids and liver function (guidelines recommends measuring transaminases at baseline and repeating every 12 wk; stop drug if persistently >3 times upper limit of normal); monitor muscle function; limited evidence that coenzyme Q10 (100 mg/day) may reduce statin-related muscle aches in patients with normal creatine kinase levels; watch for drug-drug interactions

What You Need to Know About New Drugs

Sitagliptin (Januvia): incretin; inhibits degradation of endogenous glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP), which affect pancreatic cell function; increases insulin release only while patient eats; does not increase risk for hypoglycemia between meals; acts like metformin by suppressing secretion of glucagon and inhibiting hepatic glucose production; often combined with metformin; no data on morbidity and mortality; no effect on weight; lowers postprandial blood glucose (BG) more than fasting; lowers hemoglobin (Hb)A1c levels to similar extent as metformin, sulfonylureas, and thiazolidinediones (TZDs); higher the baseline HbA1c , the more it drops with sitagliptin (0.5%-1.2%); mostly eliminated unchanged by kidney; usual dose 100 mg/day (50 mg/day if renal function impaired); sitagliptin alone dosed once daily; in combination with metformin (Janumet), dose bid; in algorithm, American Diabetes Association recommends metformin, diet, and exercise as first-line therapy for type 2 diabetes; major contraindication to metformin—diminished renal function (metformin will accumulate and compete with lactic acid for elimination, resulting lactic acidosis); if patient has not attained goal HbA1c level of <7%, add basal insulin to metformin (best evidence-based recommendation); second-tier approach (less evidence )—add TZD (pioglitazone) or incretin (exenatide [Byetta; associated with lower risk for cardiovascular events in one study]); may also add second-generation sulfonylurea; final step in algorithm—add intensive insulin therapy to metformin regimen; sitagliptin “shows some promise” but not included in algorithm due to lack of morbidity and mortality data

Adult immunizations

Quadrivalent human papillomavirus (HPV) recombinant vaccine (Gardasil): indicated for reducing risk for not only cervical cancer, but also vulvar, and vaginal cancer (new labeling); also reduces risk for dysplastic precancerous lesions; currently recommended for females aged 9-26 yr; FDA approval pending for higher age limit (27-45 yr); now being tested in adolescent males and HIV-positive males; warning from Centers for Disease Control and Prevention (CDC)—observe patient for syncopal reactions for 15 min after administering vaccine

Herpes zoster vaccine live (Zostavax): overall efficacy of 51% in Shingles Prevention Study (SPS); efficacy was 64% to 65% among subjects aged 60 to 69 yr, dropping to 41% among those aged 70 to 79 yr, and to 18% among subjects aged >80 yr; recommended by CDC for all patients aged >60 yr; currently being studied in people aged 50 to 59 yr; patients with history of shingles excluded from study; vaccine thought to confer immunity similar to that acquired from disease episode; need for booster, if any, still unknown; must administer within 30 min of removing from storage in freezer (not recommended after that)

Zoledronic acid injection (Reclast): annual intravenous (IV) bisphosphonate infusion to treat osteoporosis; 5 mg administered over >15 min; in Health Outcomes and Reduced Incidence with Zoledronic acid Once yearly (HORIZON) trial, associated with 70% reduction in relative risk for new nonvertebral fractures, compared to placebo; trial included >700 women with osteoporosis; age range 55 to 89 yr; 3-yr fracture rates were 10.9% (placebo), and 3.3% (zoledronic acid); number needed to treat (NNT) 14; also associated with 41% reduction in relative risk (RR) for hip fractures (NNT 91); 1.1% reduction in absolute risk; new indication—in HORIZON Recurrent Fracture Trial of osteoporotic women with history of low-trauma hip fracture (falling from no more than standing height), zoledronic acid associated with 35% reduction in RR for new fractures, compared to placebo; fracture rate in placebo group, 13.9%, compared to 8.6% among women receiving zoledronic acid (NNT 19); currently, only drug with postfracture data; also associated with 28% reduction in total mortality

FRAX: fracture risk assessment tool developed by World Health Organization (WHO); calculates hip fracture risk over next 10 yr based on 11 variables, including weight, smoking status, bone mineral density, and glucocorticoid use; if risk >3%, WHO and National Osteoporosis Foundation believe bisphosphonate treatment cost-effective; bioavailability—oral bisphosphonates have bioavailability of 0.6% when taken correctly; monthly oral dose of ibandronate (Boniva), 150 mg; IV dose 3 mg every 3 mo (bioavailability 100%); if using oral bisphosphonate, patient must take after overnight fast on empty stomach, with full glass of water; patient must remain upright for 30 to 60 min after taking; cannot eat or drink anything for 30 to 60 min (food reduces bioavailability); all bisphosphonates shown to reduce fracture risk, but patients must also take adequate calcium and vitamin D; patients who use gastrointestinal acid suppressors (eg, proton pump inhibitors, H2 blockers) should take calcium citrate (calcium carbonate requires acid for absorption); bisphosphonates associated with slightly increased risk for atrial fibrillation in large retrospective studies