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  • 1. 1 Your Heart & ValvesCardiac valves are structures that are designed to work like one-way doors. They let bloodflow in from one chamber or vessel to another, and then close to prevent the blood fromregurgitating backward. There are four valves within your heart. They are the mitral, tricuspid,aortic and pulmonic valve.The mitral valve and tricuspid valve lie between the atria (upper heart chambers) and theventricles (lower heart chambers). The aortic valve and pulmonic valve lie between theventricles and the major blood vessels leaving the heart.As blood leaves each chamber of the heart, it passes through a valve. Your heart valvesmake sure that blood flows in only one direction through your heart. 1 of 19 06/12/2010 at 13:16
  • 2. 1.1 A closer looks at what valves look like.Mitral Valve Closed Aortic Valve OpenThe valve is made of strong, thin pieces or flaps of tissue called leaflets.Mitral Valve Open Aortic Valve ClosedThe leaflets are attached to and supported by a ring of tough fibrous tissue called theannulus. The annulus helps to provide support and maintain the proper shape of the valve.The valve leaflets can be compared to doors opening and closing. While the annulusfunctions as the door frame.The leaflets of the mitral and tricuspid valve are also supported by tough, fibrous stringscalled chordae tendineae. These are similar to the strings supporting a parachute. Thechordae tendineae extend from the valve leaflets to small muscles, called papillary muscles,which are part of the inside walls of the ventricles. The chordae tendineae and papillarymuscles keep the leaflets stable against any backward flow of blood.1.2 Structure and Function of the Aortic ValveThe aortic valve consists of 3 half-moon-shaped pocket-like flaps of delicate tissue, referred toas cusps. When the aortic valve is closed, the cusps are perfectly aligned and separate thelarge pumping chamber of the heart (the left ventricle) from the large artery (aorta) thatsupplies blood to the body. During the period when the left ventricle contracts and pumps theblood (systole), the aortic valve opens widely and blood flows freely from the left ventricle tothe aorta. When the left ventricle then relaxes (diastole), the aortic valve closes completely sothat the blood remains in the aorta. During diastole, blood flows into the left ventricle from thelungs through the left atrium across the mitral valve, thus refilling the ventricle for the nextcontraction.2 Congenital Valve DiseaseCongenital Valve Disease is an abnormality that develops before birth. It may be related toimproper valve size, malformed leaflets, or an irregularity in the way the leaflets are attached.This most often affects the aortic or pulmonic valve. • Bicuspid aortic valve disease is a congenital valve disease that affects the aortic valve. Instead of the normal three leaflets or cusps, the bicuspid aortic valve has only two. Without the third leaflet, the valve may be: Bicuspid aortic valve disease affects about 2 percent of the population. 2 of 19 06/12/2010 at 13:16
  • 3. Clinical diagnosis of a bicuspid aortic valve condition was unsatisfactory before the widespread use of cross sectional echocardiography approximately 15 years ago. Because bicuspid aortas have familial clustering (37% of which males are affected in a ration of 4:1) it might also be appropriate to screen first-degree relatives, especially brothers and sons. A bicuspid aortic valve is detected in only about 35% of patients using echocardiograms. BAV is associated with accelerated degeneration of the aortic media (dilatation, aneurysm formation, degradion of elasticity, and dissection), indicating that BAV disease is an ongoing pathological process, not a discrete developmental event. If a bicuspid aortic valve is left untreated, once symptoms start death occurs within 2 to 4 years.• Stenotic - stiff valve leaflets that can not open or close properly• Leaky - not able to close tightly This occurs more frequently in some family members. About 1/4 of patients may have some enlargement of the aorta above the valve. 3 of 19 06/12/2010 at 13:16
  • 4. 3 Diagnosis of valve diseaseOnce onset of symptoms occurs they will increase at the rate of 6% per year or progressiveleft ventricular dilation of 3% to 4% per yearPerforming diagnostic tests help your cardiologist evaluate the extent of your valve disease,its effect on the function of your heart, and the best form of treatment for you. Tests mayinclude:3.1 Echocardiogram (echo)An "echo" is a graphic outline of the hearts movement. A sound-wave transducer wand isplaced on the surface of the chest. High frequency sound-waves are used to provide picturesof the hearts valves and chambers and to look at the pumping action of the heart. Echo isoften combined with Doppler ultrasound and color Doppler to detect changes in the blood flowacross the heart valves and pressures within the chambers. An echocardiogram can beperformed at rest or during exercise, down the throat (more accurate) or externally.3.2 Electrocardiography (ECG)Electrocardiography (ECG) is a quick, simple, painless procedure in which electrical impulsesflowing through the heart are amplified and recorded on a moving strip of paper. This record,the electrocardiogram (the ECG), provides information about the part of the heart that triggerseach heartbeat (the pacemaker), the nerve conduction pathways of the heart, and the rateand rhythm of the heart.An electrocardiogram (ECG) represents the electrical current moving through the heart duringa heartbeat. The currents movement is divided into parts, and each part is given analphabetic designation in the ECG.Each heartbeat begins with an impulse from the hearts pacemaker (sinus or sinoatrial node).This impulse activates the upper chambers of the heart (atria). The P wave representsactivation of the atria.Next, the electrical current flows down to the lower chambers of the heart (ventricles). TheQRS complex represents activation of the ventricles. 4 of 19 06/12/2010 at 13:16
  • 5. The electrical current then spreads back over the ventricles in the opposite direction. Thisactivity is called the recovery wave, which is represented by the T wave.Many kinds of abnormalities can be seen on an ECG. For example, the heart rhythm may beabnormal: too fast, too slow, or irregular. By reading an ECG, doctors can usually determinewhere in the heart the abnormal rhythm starts and can begin to determine its cause.3.3 Multiple-gated acquisition (MUGA) scanThe MUGA scan measures the hearts function and the flow of blood through it. The strongestchamber in the heart is the left ventricle, which serves as the main pump of blood through thebody. The MUGA scan is the most accurate, non-invasive test available to assess the heartsventricles.MUGA is a nuclear heart scan, which means that it involves the use of a radioactive isotopethat targets the heart and a radionuclide detector that traces the absorption of the radioactiveisotope. The isotope is injected into a vein and absorbed by healthy tissue at a known rateduring a certain time period. The radionuclide detector, in this case a gamma scintillationcamera, picks up the gamma rays emitted by the isotope.The MUGA scan is not dangerous. The technetium is completely gone from the body within afew days of the test. The scan itself exposes the patient to about the same amount ofradiation as a chest x ray. The patient can resume normal activities immediately after the test.Normal resultsIf the patients heart is normal, the technetium will appear to be evenly distributed in thescans. In a stress MUGA, patients with normal hearts will exhibit an increase in ejectionfraction or no change.Abnormal resultsAn uneven distribution of technetium in the heart indicates that the patient has coronary arterydisease, a cardiomyopathy, or blood shunting within the heart. Abnormalities in a restingMUGA usually indicate a heart attack, while those that occur during exercise usually indicateischemia. In a stress MUGA, patients with coronary artery disease may exhibit a decrease inejection fraction.3.4 Cardiac Catheterization (Cardiac Cath or Angiogram)A catheter (inserted into your arm or leg) is guided to your heart, contrast dye is injected andx-rays of your coronary arteries, heart chambers, and heart valves are taken.Additional tests, such as the exercise stress echocardiogram, radionuclide scans, andmagnetic resonance imaging (MRI) may also be used. 5 of 19 06/12/2010 at 13:16
  • 6. 4 Valve Replacement and Repair4.1 Mechanical Valve ReplacementAortic MitralMechanical valves are made totally of mechanical parts, which are non-reactive and toleratedwell by the body. The bileaflet valve is used most often. It consists of two pyrolite (qualitiessimilar to a diamond) carbon leaflets in a ring covered with polyester knit fabric.Advantages:Mechanical valves are very sturdy. They are designed to last a lifetime. Re-operations formechanical failures or tissue in-growth are uncommon.Drawbacks:Due to the artificial material involved, patients who receive these valves will need to take ablood-thinner (anticoagulant) medication for the rest of their lives. Blood thinners aremedications (such as warfarin or Coumadin) that delay the clotting action of the blood. Theyhelp prevent clots from forming on the valve prosthesis; such clots can cause a heart attackor stroke and disturb the valve function.Bi Technology valve prosthesis. After the examination of 33 mechanical prostheses over 264months (mean, 72 months), the overall causes of failure modes included paravalvular leak15%, thrombosis 7%, tissue overgrowth 8%, degeneration or mechanical failure 43%, andendocarditis 19%.No clear failure mode predominates with mechanical valve prostheses, although somedesigns have specific inherent limitations.Tri Technology valve prosthesis has a high risk of structural failure; leaflet escape caused bya leaflet’s pivoting system fracture is usually fatal. 6 of 19 06/12/2010 at 13:16
  • 7. 4.2 Mitral valve repairMitral valve repair is the procedure of choice for most patients with mitral regurgitation (aleaky valve). When the leak is caused by mitral valve prolapse (degenerative mitral valvedisease), a variety of repair techniques may be employed. Quadrangular resection is thetechnique used most frequently for posterior leaflet prolapse. Mitral valve repair is superior toreplacement. If repair is not feasible, the subvalvular apparatus should be preserved. Earlysurgery before the development of severe symptoms and demonstrable left ventricularimpairment is also needed to optimize outcomeChordal transfer to correct anterior leaflet prolapse. Posterior leaflet chordae are transferredto the unsupported free edge of the anterior leaflet. The posterior leaflet is repaired as after aquadrangular resection.Gor-Tex chord for correction of anterior leaflet prolapse.Chordae may be constructed from Gore-Tex sutures. A premeasured loop of Gore-Tex isaffixed to the head of the papillary muscle with a pledgetted suture. The loop is then attachedto the free edge of the unsupported anterior leaflet, providing support.Long-term durability is excellent. The new chordae do not rupture or elongate.4.3 Aortic Wrapping and AortoplastyAortic Wrapping of the ascending aorta is a procedure that is carried out to prevent dissectionoccurring with or without Valve replacement.Aortic wrapping with or without aortoplasty may have a beneficial effect not only in dilatedascending aorta but also in all non-dilated BAV patients. Ascending aorta wrapping in BAVpatients may preserve the endothelial lining and prevent further dilatation, aneurysmformation, and dissection. Less elastic tissue in the aortas of BAV patients may explain theanecdotal increase in aortic fragility and propensity for aortic dissection, but at this time thesuspected portion of the aorta will generally be replaced with a dacron graft, a moreestablished procedure with good data on long term durability. Wrap procedures have met withvariable success. 7 of 19 06/12/2010 at 13:16
  • 8. AortaplastyThe wrapping of the supracoronary-ascending aorta during AVR should not increase thesurgical risk. Fixing the Dacron wrap to the aorta with decreasing diameter preventsdislocation of the wrap and therefore erosion of the aorta.It is very important for anticipatory surgery for dilatation of the ascending aorta inpatients with bicuspid aortic valves compared with patients with tricuspid aorticvalves.5 Risk Factors for Patients5.1 Bicuspid Aortic ValveBAV itself is reported as a risk factor for aortic dissection after AVR. Studies have confirmedthe higher risk of late ascending aorta aneurysm or dissection (a tear of the aorta causingblood to flow between the layers of the wall of the aorta and dissects the layers) in patientswith BAV, and reinforce the importance of appropriate timing of ascending aorta replacementin cases of AVR or other cardiac procedures in these patients.Dissection of the ascending aorta is likely in 50% of patients where there is a coexistingbicuspid aortic valve. Research has shown a greater incidence of sudden death andaortic events in the BAV patients (5 times more likely).Regardless of a seemingly normal ascending aorta at surgery the occurrence ofascending aortic alterations during follow-up could not be predicted at the time of the firstoperation and was independent of the ascending aorta diameter. In post mortems thedissection entrance tear was always in the ascending aorta, which usually had severeloss of elastic fibres in its mediaPatients with BAV seem to have a severe alteration of the aortic wall, which ispotentially capable of evolving into acute aortic pathology or progressive dilation ofthe ascending aorta, independent of valve surgery. Currently there are no diagnostic teststhat enable a prediction of which patients with BAV will develop ascending aorta pathology.Most patients who experience acute aortic syndrome die. Operations for acute aorticdissection or ascending aorta aneurysm after AVR have very high perioperative mortality andmorbidity.5.2 Aortic Left Ventricular Ejection Fraction (LVEF)The left ventricular ejection fraction (LVEF) is an important clinical indicator of the cardiacfunction and long-term outcome for patients with coronary artery disease.The left ventricular is assessed by measuring the amount of blood pumped with eachheartbeat (the ejection fraction), ventricle filling, and the blood flow into the pumping chamber.A normal ejection fraction is 50% or more. The hearts ejection fraction is one of the most 8 of 19 06/12/2010 at 13:16
  • 9. important measures of its performance. Although a marker of survival, ejection fraction loosesits prognostic value when it dips under 25% and is above 40-45%.5.3 Aortic Insufficiency (AI, Regurgitation)Aortic Insufficiency (regurgitation) occurs when there is a leakage of the valve backward intothe left ventricle during diastole. This can be caused by structural abnormalities of the valve,similar to those seen in aortic stenosis. Enlargement of the aorta can stretch the valve cuspsand produce aortic regurgitation. The acute onset of aortic regurgitation can occur when thereis an infection of the aortic valve (called infective endocarditis) or a tear in the aorta.Chronic aortic regurgitation may be present for decades before any symptoms occur. The leftventricle is able to compensate for the large volume of blood that flows backward by enlargingthe cavity and increasing the thickness of the muscle. This mechanism allows the heart topump out both the amount of blood required by the body and the blood that has gonebackward into the left ventricle. When symptoms do occur, patients usually experienceshortness of breath or chest discomfort. Long-standing aortic regurgitation may result inirreversible damage to the muscle of the left ventricle, even in the absence ofsymptoms.An aortic valve replacement operation should be performed whenever there is severe aorticregurgitation and the patient develops symptoms. Even in the absence of symptoms, aorticvalve replacement may be necessary in some patients to prevent the irreversible damage tothe heart muscle caused by the extra volume load. If surgery is performed before damage tothe heart muscle becomes irreversible, the outlook is excellent, and most patients can returnto a normal lifestyle.5.4 Atrial Fibrillation (AF)Atrial Fibrillation (AF) decreases relative survival substantially. The liability of leftventricular dysfunction with regard to diminished long-term survival is not completely reversedby valve operation. If operation is not performed before left ventricular dysfunction develops,postoperative medical treatment of these dilated, remodelled ventricles should be considered.The presence of moderate or severe valvular calcification, together with a rapid increase inaortic-jet velocity, identifies patients with a very poor prognosis.Long term follow up studies consistently report better survival rates in patients undergoingaortic rather than mitral valve replacement. Atrial Fibrillation usually results in the fitting of apacemaker as the condition worsens.6 Prognosis after Valve Replacement SurgeryAVR should be considered palliative because the valve prosthesis introduces the patient to anew disease process in which complications include thromboembolism, anticoagulant-relatedbleeding, infection, and structural deterioration. Significant refinements in valve prostheseshave reduced but not eliminated these problems. Furthermore, improvements in surgicaltechnique and myocardial preservation continue to decrease the risks.AVR is generally performed with low hospital mortality and complication rates, and significantsymptomatic improvement can be expected. Aortic valve recipients have a favourableprognostic outcome.Risk factors that determine long-term survival can be identified pre-operatively;Bicuspid Aortic Valve Vs. Tricuspid, exercise capacity, peak heart rate, peak systolic bloodpressure and peak early diastolic velocity (reflecting both systolic and diastolic function) areall better in survivors than in non-survivors. Non-survivors have considerably larger hearts.Post operatively, small increases in exercise capacity are expected and ejection fractionincreases among survivors. No such changes are seen in non-survivors. 9 of 19 06/12/2010 at 13:16
  • 10. After valve replacement The Post Operative survivals are: Control Gradient Double Aortic & M itral Valve 35 to 65 Years survival Prognosis after Surgery 100% Control Gradient Applied to AVR <35 90% 80% 70% AVR <35 Years With congenital Heart Dicease 60% % survived 50% 40% All With Normal (? 50%) Ejection Fraction 30% 20% All With Servere Stenosis 10% 0% 0 5 10 15 20 25 30 Years Survived All With Lo Ejection FractionLong-Term Survival Factors for Bicuspid Aortic Valve: • “Patient self calculated Euro Score” 4.63%. (Surgery mortality). BAV AVR patients due to • Atrial fibrillation disscetion w ithout • Aortic Insufficiency (AI, Regurgitation) Mod/Severe Ascending Aorta Wrap • Ejection Fraction (EF force of muscle) 53% Normal (100% morbidity 10 - • BAV - Dissection of the Ascending Aorta 14years) • Blood pressure at the first postoperative visit. • Post Operative survival 98+/-2%, valve related complications include thromboembolism, bleeding, deterioration of the prosthetic valve requiring re- operation and infective endocarditisis 1% per year. • In-hospital survivability (first 6 – 10 days) was 94-98%. • Major complication 21.7% of patients have one or more. • One month survival including the operative survivability is approximately 92 to 95%, • One year survival was 90-93%, • 5 year survival, see graph above.The prognosis for postoperative valve-related events; life expectancy and event-free lifeexpectancy were 22 and 16 years in males aged 35 years respectively,The presence of a bicuspid aortic valve increases the risk of postoperative dissection nine foldand occurs in patients with BAV at about 54 Vs 62 years in TAV. In a study of Aorticcomplications, dissection of the ascending aorta in patients with BAV replacements alwaysoccurred within 10 to 14 years of initial surgery and was usually fatal. 10 of 19 06/12/2010 at 13:16
  • 11. Actuarially Determined Complication Rates of Mechanical Valves for all patient types,% March 2000: Aortic Mitral 10 y 20 y 30 y 10 y 20 y 30 y Mortality 25-55 40-78 52-100 25-55 40-77 52-100 Thrombo embolism 26 41 47 39 52 54 Bleeding 13 24 26 15 25 26 Endocarditis 4 7 11 4 7 9 Reoperation (explant) 10 15 19 9 21 246.1 Papworth ScoresThe dot is actual death rate. The horizontal line shows the 95% confidence interval aroundthe actual death rate. The cross shows the predicted death rate for patients.This 1st chart shows that Papworth has performed better than predicted in all cardiac surgery,coronary artery bypass grafting and valve surgery.Cardiac Mortality by procedure 1st April 2004 - 31st March 2005The 2nd chart shows no single surgeon in Papworth performs less well than that predicted byEuroSCORE.All Cardiac Surgery by Surgeon 1st April 2004– 31st March 2005 11 of 19 06/12/2010 at 13:16
  • 12. 7 Recovery after heart surgery7.1 Care of your incisionYou will be told how to care for your incision(s) before you leave the hospital. It is importantto:o Keep your incision(s) clean and dry.o Use only soap and water to cleanse the area.o Bathing:  When showers and baths are permitted, they should be limited to 10 minutes. The water temperature should be warm - not too hot or cold. Extreme water temperatures can cause faintness.o Do not apply ointments, oils, salves or dressings to your incision unless specifically told to do so.o Eat a healthy diet to help healing.o Call your doctor if signs of infection appear:  Increased drainage or oozing from incision Increased opening of the incision line  Redness or warmth around the incision  Increased opening of the incision line  Increased body temperature (greater than 101 degrees Fahrenheit or 38 degrees Celsius)7.2 Relief of painSome muscle or incision discomfort, itching, tightness and/or numbness along your incisionare normal after surgery. You should not have pain in your chest similar to what you hadbefore surgery. You will be given a prescription for a pain medication before you leave thehospital.If you had bypass surgery, you may have more pain in your legs than around your chestincision if saphenous vein grafts were used. Walking, daily activities, and time will help tolessen leg discomfort and stiffness.Call your doctor if your sternum feels like it moves, or it pops or cracks withmovement.7.3 Swelling - for those with vein grafts taken from their legsYou may return home with some swelling in your legs and feet, especially if you had veingraphs taken from your legs. If you notice swelling:Place your feet up higher than your heart level when resting. One way to do this is to lieon your bed or couch and put several pillows under your legs. Or, you may lie on the floor andplace your feet on the couch. Try this three times a day for one hour to relieve swelling. (Note-recliners do not adequately elevate your feet).o Do not cross your legso Walk daily even if your legs are swolleno Hospital support hose may be suggestedo Call your doctor if swelling in your leg(s) become worse or painful and/or associated with increased fatigue and/or shortness of breath.7.4 MedicationsYou may need medications after surgery. Your doctor will tell you if you need thesemedications until you recover from heart surgery or lifelong. Make sure you understand thenames of your medications, what they are for, and what times to take them. Only take themedications that are prescribed when you are discharged from the hospital. If you want totake medications you were previously on for other conditions, discuss this with your doctorfirst.7.5 DrivingYour doctor will tell you when you may resume driving. This usually occurs about six to eightweeks after surgery, however, time may be shorter if you had minimally invasive surgery.During this time, you may be a passenger as often as you like.7.6 ActivityFor the first six to eight weeks: 12 of 19 06/12/2010 at 13:16
  • 13. Gradually increase your activity. You may do light household chores, but do not stand in oneplace longer than 15 minutes.Do not lift objects greater than 20 pounds (your doctor may give you a different number ifappropriate). Also, do not push or pull heavy objects.It is OK to perform activities above shoulder level, such as reaching for an object or brushingyour hair. But, do not hold your arms above shoulder level for a longer period of time.You may climb steps unless they have been restricted by your doctor. You may need to restpart of the way if you become tired. Do not climb up and down stairs several times during theday, especially when you first arrive home. It is better to plan activities to go downstairs in themorning and back upstairs when it is time for bed.Pace yourself - spread your activities throughout the day. If you become tired, rest andschedule unfinished activities for another time.Walk daily. Your doctor or cardiac rehabilitation specialist will give you guidelines for walkingwhen you return home.Check with your doctor to confirm activity guidelines.7.7 DietYou should eat a healthy diet to help you heal. Your doctor will tell you if you should followany special diet instructions. It is common after surgery to have a poor appetite at first. If thisis the case, try to eat smaller, more frequent meals. Your appetite should return within the firstfew weeks. If it does not, contact your doctor.7.8 SleepIt is important to get enough rest or you may feel overtired and irritable. Unfortunately, manypeople complain of having trouble sleeping for some time after surgery. Normal sleeppattern`s should return within a few months. Call your doctor if lack of sleep begins causingchanges in behavior or if normal sleep patterns do not return.7.9 WorkYou will need to take time to recover; usually about six to eight weeks (may be earlier withminimally invasive surgery). Your doctor will tell you when you can return to work. If you havethe flexibility at your job, ease back to your work schedule. If possible, start back at half-timeand gradually increase back to your normal routine.8 Drug TherapyImprovements in long-term survival after valve surgery will most likely be achieved through theearlier recognition and correction of significant valve lesions, pacemaker implantation andcontrolled multiple drug therapy.8.1 Anticoagulation Therapy - Warfarin8.1.1 Drugs Potentiating the Effect of WarfarinAntibiotics drugs:There is highly probable evidence for; cotrimoxazole, erythromycin, isoniazid, fluconazole,miconazole, and metronidazole. There is some evidence for; ciprofloxacin, itraconazole, andtetracycline.Cardiac drugs:There is highly probable evidence for; amiodarone, clofibrate, propafenone, propranolol, andsulfinpyrazone. Sulfinpyrazones effect was biphasic, which means that an initial potentiationof effect was noted, followed by inhibition of the effect. There is some evidence for; Quinidine,simvastatin, fluvastatin, and acetylsalicylic acid.Anti-inflammatory or analgesic drugs:There is highly probable evidence for; phenylbutazone, piroxicam, acetylsalicylic acid,acetaminophen, and dextropropoxyphene.Other medications with highly probable or probable evidence were cimetidine, omeprazole,alcohol (only if concomitant liver disease was present), chloral hydrate, disulfiram, phenytoin(late effect of inhibition), tamoxifen, anabolic steroids, and influenza vaccines.It is possible that diltiazem, tobacco, and vancomycin do interact with warfarin because theevidence for no interaction was doubtful. 13 of 19 06/12/2010 at 13:16
  • 14. 8.1.2 Drugs Inhibiting the Effect of WarfarinFew drugs inhibited the effect of warfarin, but there are a proportion with good evidence.There is highly probable evidence for nafcillin, rifampin, griseofulvin, cholestyramine,barbiturates, carbamazepine, chlordiazepoxide, sucralfate, high vitamin K content in enteralfeeds or in the diet, and large amounts of avocado. There is probable evidence fordicloxacillin. Reported interactions for four other drugs in addition to the consumption of largeamounts of broccoli were considered possible evidence.8.1.3 Drugs with No Effect on WarfarinIt is highly probable that several cardiac and gastrointestinal drugs do not interact withwarfarin. These drugs included atenolol, bumetanide, felodipine, metoprolol, moricizine,antacids, famotidine, nizatidine, psyllium, and ranitidine. Seven other drugs also have highlyprobable evidence: enoxacin, diflunisal, ketorolac, naproxen, alcohol (when not taken to levelsinhibiting normal liver function), nitrazepam, and fluoxetine. In addition there is probableevidence for ketoconazole, ibuprofen, and ketoprofen.8.2 HMG CoA Reductase Inhibitors Therapy – StatinsHMG CoA reductase inhibitors (statins) retard the progression of both coronary disease andof aortic stenosis. In some studies, this retardation is related to a fall in low density lipoprotein(LDL), cholesterol, but in others, retardation has occurred without a consistent relationship tocholesterol, suggesting that statin agents may have effects other than simple cholesterollowering to account for their effects on the aortic valve. Although aortic valve replacement andits timing have been the major foci of the therapy of aortic stenosis, it is possible that in thefuture, aggressive therapy with statins and other agents might block or slow the progressionof the valve lesion, forestalling or even preventing the need for aortic valve replacement.8.2.1 Statin - Effects on CholesterolStatins lower total cholesterol 18% to 26%, lower undesirable Low Density Lipoprotein-Cholesterol (LDL-C) 20% to 60%, raised desirable High-Density Lipoprotein-Cholesterol(HDL-C) 5% to 7%, and lowered triglycerides 11% to 17%.8.2.1.1 FDA-Approved Drug Daily Dosage and Usual Decrease in LDL CholesterolAtorvastatin Initial: 10 mg 35%-40% Maximum: 80 mg 50%-60%Fluvastatin Initial: 20 mg 20%-25% Maximum: 40 mg 30%-35%Lovastatin Initial: 20 mg 25%-30% Maximum: 80 mg 35%-40%Mevacor Initial: 20 mg 25%-30% Maximum: 80 mg 35%-40%Pravastatin Initial: 40 mg 30%-35% Maximum: 80 mg 35%-40%Rosuvastatin Initial: 10 mg 40%-45% Maximum: 40 mg 50%-60%Simvastatin Initial: 20 mg 35%-40% Maximum: 80 mg 45%-50%8.2.2 NONLIPID EFFECTS OF STATINSSome pathophysiologic data suggest that statins are also beneficial in the acute setting. Forexample, in the short term (weeks to months) statins have been shown to: • Decrease thrombus formation • Increase fibrinolysis • Inhibit platelet reactivity and aggregation • Reduce thromboxane A production • Improve endothelial function in patients with coronary artery disease • Possibly stabilize plaques and make atheromas less susceptible to rupture by reducing cholesterol synthesis by macrophages, decreasing inflammatory cells, reducing matrix metalloproteinase activation, and promoting collagen accumulation in the fibrous cap • Reduce levels of C-reactive protein, an inflammatory marker and predictor of adverse cardiovascular outcomes.8.2.3 Adverse Events when taking Statins with Multiple Drugs –Avoiding the concomitant use of drugs with the potential to inhibit CYP-dependent metabolismmay decrease the risk of statin-associated myopathy. Alternatively, if drug therapy with a 14 of 19 06/12/2010 at 13:16
  • 15. potent CYP inhibitor is inevitable, choosing a statin without relevant CYP metabolism (eg,pravastatin) should be considered.8.2.3.1 General Statin interactions with drug regimes.Simvastatin, (35.8%); cerivastatin, (31.9%); atorvastatin, (12.2%); pravastatin, (11.8%);lovastatin, (6.7%); and fluvastatin, (1.7%). Statins are the primary cause of 72% of FDAreported cases and suspected secondary cause in 28% of cases. In clinical trials and postmarketing surveillance, there are three statins that are not metabolised by the cytochromeP450 3A4 system (fluvastatin, rosuvastatin and pravastatin) and have exhibited very lowpropensities to elicit myopathy when combined with other agents. These agents should beconsidered initially when contemplating combination lipid-lowering regimens for coronaryprevention.FDA reports of rhabdomyolysis/Myopathy, the breakdown of muscle fibers resulting in therelease of muscle fiber contents into the circulation, that may be manifested by muscle painand in extreme cases dark or cola coloured urine without significant elevations in serumcreatine phosphokinase (CPK) levels, thus pointing out the inadequacy of CK testing forstatin-associated myopathy. Rhabdomyolysis/Myopathy is generally observed between 1-2weeks and 4 months after initiation of therapy. Myalgias and weakness resolve within days to4 weeks after discontinuation.8.2.3.2 Drugs Increasing Risk of Myopathy/RhabdomyolysisCYP3A4 Inhibitors/Substrates OthersCyclosporine, tacrolimus DigoxinMacrolides (azithromycin, clarithromycin, erythromycin) Fibrates (gemfibrozil)Azole antifungals (itraconazole, ketoconazole) NiacinCalcium antagonists (mibefradil, diltiazem, verapamil)NefazodoneProtease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir,saquinavir)SildenafilWarfarin 15 of 19 06/12/2010 at 13:16
  • 16. 8.2.3.3 Statin Associated FDA Reports of Rhabdomyolysis Frequency of No. of Cases Associated With PotentiallyStatin Reports/Unique Cases Interacting Drugs* (n)Simvastatin 321/215 Mibefradil (48) Azole antifungals (4) Fibrates (33) Chlorzoxazone (2) Cyclosporine (31) Nefazodone (2) Warfarin (12) Niacin (2) Macrolide antibiotics (10) Tacrolimus (1) Digoxin (9) Fusidic acid (1)Cerivastatin 231/192 Fibrates (22) Digoxin (7) Warfarin (6) Macrolide antibiotics (2) Cyclosporine (1) Mibefradil (1)Atorvastatin 105/73 Mibefradil (45) Fibrates (10) Macrolide antibiotics (13) Warfarin (7) Cyclosporine (5) Digoxin (5) Azole antifungals (2)Pravastatin 98/71 Fibrates (6) Macrolide antibiotics (6) Warfarin (5) Cyclosporine (2) Digoxin (2) Mibefradil (1) Niacin (1)Lovastatin 51/40 Cyclosporine (12) Digoxin (2) Macrolide antibiotics (11) Nefazodone (2) Azole antifungals (6) Niacin (1) Fibrates (5) Warfarin (1) Mibefradil (3)Fluvastatin 11/10 Fibrates (4) Warfarin (2) Digoxin (1) Mibefradil (1)Rosuvastatin No Data N/A*Each case may be associated with 1 or more potentially interacting drugs.Adapted from Omar MA, Wilson JP. Ann Pharmacother. 2002;36:288–295.8.2.3.4 Statin interactions with warfarinThe interactions between statins and warfarin are complex. Warfarin goes through severaldifferent CYP450 pathways, any of which might serve as a source of interactions with statins.However, whereas most of the interactions previously described result in inhibited statinmetabolism, interactions with warfarin tend to work in the opposite direction and inhibitwarfarin metabolism. The clinical result is an increase in the international normalized ratio(INR), a standardized measure of prothrombin time. The CYP3A4-dependent statins(simvastatin, lovastatin, and atorvastatin) all have the potential to raise the INR in patientstaking warfarin; the effect is variable, and monitoring INR is important to determine whetherthe warfarin dosage must be adjusted. Fluvastatin, metabolized through the CYP2C9pathway, can also interfere with warfarin metabolism and raise the INR. Rosuvastatin canraise the INR without raising warfarin concentrations, which implies that its effect is notmediated through the CYP450 system but is more likely caused by a partial displacement ofwarfarin from its protein-bound state in circulation. For patients taking multiple medications, itis especially important to select agents that are least likely to incur an additional risk of 16 of 19 06/12/2010 at 13:16
  • 17. interaction; for patients who require the addition of lipid-lowering pharmacotherapy to a drugregimen that is already complex, the preferred agents would be the statins that are leastdependent on the CYP450 system in general and on CYP3A4 in particular. Pravastatin isunique among the statins in that it produces no change in the INR in patients taking warfarin,which demonstrates its lack of involvement in the CYP450 pathways and an absence ofeffects on warfarin protein binding, but it has caused an increased INR when combined withthe anticoagulant fluindione. Clinicians should monitor the INR closely after starting statintherapy in any patient receiving anticoagulation therapy; rabdomyolysis and renal failure canoccrred within days8.2.4 Statin Clinical Pharmacokinetics FluvastatinParameter Atorvastatin Fluvastatin XL Lovastatin Pravastatin Rosuvastatin SimvastatinTmax (h) 2–3 0.5–1 4 2–4 0.9–1.6 3 1.3–2.4Cmax (ng/mL) 27–66 448 55 10–20 45–55 37 10–34Bioavailability 12 19–29 6 5 18 20 5(%)Lipophilicity Yes Yes Yes Yes No No YesProtein binding 80–90 >99 >99 >95 43–55 88 94–98(%)Metabolism CYP3A4 CYP2C9 CYP2C9 CYP3A4 Sulfation CYP2C9, CYP3A4 2C19 (minor)Metabolites Active Inactive Inactive Active Inactive Active (minor)ActiveTransporter Yes No No Yes Yes/No Yes YesproteinsubstratesT1/2(h) 15–30 0.5–2.3 4.7 2.9 1.3–2.8 20.8 2–3Urinary 2 6 6 10 20 10 13excretion (%)Fecal excretion 70 90 90 83 71 90 58(%)Based on a 40-mg oral dose, with the exception of fluvastatin XL (80 mg).Adapted from data in Corsini A,et al. Pharmacol Ther. 1999;84:413–428, and White CM. J Clin Pharmacol.2002;42:963–970. 17 of 19 06/12/2010 at 13:16
  • 18. 8.2.5 Human Cytochrome P450 Isoenzymes that Oxidize DrugsCYP1A2 CYP2C9 CYP2C19 CYP2D6 CYP2E1 CYP3A4Acetaminophen Alprenolol Diazepam Amitriptyline Acetaminophen AmiodaroneCaffeine Diclofenac Ibuprofen Codeine Etanol AtorvastatinTheophylline Fluvastatin Mephenytoin Debrisoquine Halothane Clarithromycin Hexobarbital Methylphenobarbital Flecainide Cyclosporine Phenytoin Omeprazole Imipramine Diltiazem Rosuvastatin Phenytoin Metoprolol Erythromycin Tolbutamide Proguanyl Mibefradil Itraconazole Warfarin Rosuvastatin Nortriptyline Ketoconazole Pherexiline Lacidipine Propafenone Lovastatin Propranolol Mibefradil Sparteine Midazolam Thioridazine Nefazodone Timolol Nifedipine Protease inhibitors Quinidine Sildenafil Simvastatin Terbinafine Verapamil Warfarin8.2.6 Inhibitors/Inducers of Cytochrome P450 Enzymatic PathwayCYP Substrates(Statins) Inducers InhibitorsCYP3A4Atorvastatin, Phenytoin, phenobarbital, Ketoconazole, itraconazole, fluconazole,Lovastatin, barbiturates, rifampin, erythromycin, clarithromycin, tricyclicSimvastatin dexamethasone, antidepressants, nefazodone, venlafaxine, cyclophosphamide, fluvoxamine, fluoxetine, sertraline, carbamazepine, troglitazone, cyclosporine A, tacrolimus, mibefradil, omeprazole diltiazem, verapamil, protease inhibitors, midazolam, corticosteroids, grapefruit juice, tamoxifen, amiodaroneCYP2C9Fluvastatin, Rifampin, phenobarbital, Ketoconazole, fluconazole, sulfaphenazoleRosuvastatin phenytoin, troglitazone(2C19-minor)8.3 Angiotensin Converting Enzyme (ACE) Inhibitors TherapyThe narrowing of the vessels increases the pressure within the vessels and can cause highblood pressure (hypertension). Angiotensin II is formed from angiotensin I in the blood by theenzyme, angiotensin converting enzyme (ACE). ACE inhibitors are medications that slow(inhibit) the activity of the enzyme, which decreases the production of angiotensin II. As aresult, the blood vessels enlarge or dilate, and the blood pressure is reduced. This lowerblood pressure makes it easier for the heart to pump blood and can improve the function of afailing heart. In addition, the progression of kidney disease due to high blood 18 of 19 06/12/2010 at 13:16
  • 19. 8.4 Alcohol TherapyThere is compelling epidemiological evidence suggesting that regular light-to-moderatealcohol intake is associated with reduced atheromatous morbidity and mortality. It isinteresting to note that while atherogenesis takes many decades, the beneficial effects ofalcohol accrue only in later life. The reasons for this are uncertain but the effects may be acombination of plaque stabilisation, analogous to the effects of some cholesterol loweringdrugs which affect coronary endpoints relatively quickly, and an antithrombotic effect.To prove causation requires the correct temporal sequence, an ability to control forconfounders, plausible biological explanations, and a consistent and specific effect (ischaemicheart disease appears to be one of the few diseases alcohol benefits). It is only the relativelysmall apparent benefit that precludes definitive statements on causation; it is possible that anas yet unrecognised confounding variable could explain the findings. In addition, over 30 yearsof research has not revealed a definite alternative explanation.Alcohol, especially in excess, does have detrimental effects, which in many groups outweighits benefits. Indeed, other interventions, including dietary modification, are far more effectiveat reducing cardiovascular endpoints. The vast majority of those who abstain do so for areason, which would preclude advising them to take up alcohol, for example, dislike of thetaste/effects, past/family history of alcohol abuse, medical contraindication, ormoral/ethical/religious objections. However, one can reassure our patients that regular light-to-moderate alcohol intake, especially in those at risk, whose diet is steadfastly Western will, atthe very least, do no harm and almost certainly lead to benefit.Is there evidence to enable us to advise what to drink? Although the epidemiological evidencesuggests not, there are at least theoretical reasons why red wines rich in flavonoids andresveratrol may hold extra benefit.Flavonoids, being found particularly in grape skins, occur in the highest concentrations ingrape varieties with thick skins grown in hot climates. Cabernet sauvignon based wines fromAustralia, South America, and the southern Mediterranean are particularly rich sources. Syrah(shiraz) and merlot are good too.Wines from this grape form Burgundy, Sancerre, New Zealand, and the north west UnitedStates are particularly rich in resveratrol. Merlot, gammay, syrah, zinfandel, and pinotagewines may also be too. 19 of 19 06/12/2010 at 13:16