Halten Sie sich fr die Dauer der Messung ruhig. Legen Sie die Man schette sorgfltig an. Halten Sie den Arm mit dem Gert auf Hhe des Herzens
Halten Sie sich fr die Dauer der Messung ruhig (nicht bewegen und nicht sprechen). Ersetzen Sie die Bat terien durch neue Al kalibatterien des Typs AAA.

TECHNISCHE DATEN

Modell: Messprinzip: Anzeige: Messbereich: Messgenauigkeit: Luftablass: Stromversorgung: Speicher: Betriebstemperatur: Lagertemperatur: Manschette: Gre (Messeinheit): Gewicht: K350 MD42780 Oszillometrisch LCD mmHg (Blutdruck) Puls/min. (Pulsfrequenz) 3 mmHg (Druckanzeige) 5 % (Pulsfrequenz) Automatisches Ablassventil Hochleistungs oder Alkalibatterien: 2 x 1,5V = Typ AAA/LRMessergebnisse 5 C bis 45 C max. 40 bis 85 % relat. Luftfeuchtigk. 10 C bis 60 C max. 10 bis 95 % relat. Luftfeuchtigk. fr Handgelenkumfang mm Umfang ca. (79 x 72 x 71) mm ca. 120 g (ohne Batterien)
Hergestellt im Jahre 2004

TABLE OF CONTENTS

Safety instructions. 2 Information about blood pressure and measuring blood pressure. 5 GB
What is blood pressure?. 5 Measuring blood pressure. 6

General view. 10

The unit. 10 Accessories. 10 The display.11

Before use. 12

Inserting batteries. 12 Setting the date and time.13
Measuring blood pressure. 14
Attaching the wrist sleeve. Preparing for the measurement. Measuring. Memory function. 15 17
An error display appears. 19 Technical data. 20

SAFETY INSTRUCTIONS

for using this unit correctly
The unit is suitable for healthy persons above 14 years of age. Use the unit for comparative measurements, particularly during sporting activities. Do NOT use the unit for medical diagnosis. The unit is intended solely for private use and is not a replacement for medical proce dures. Read these instructions carefully and only use the unit as described here. If you give the unit away, please also pass on these instructions.
Keep battery operated units away from children
The unit is battery operated. If swallowed, batteries may endanger life. For these reasons, keep the unit out of reach of children. If a battery is swallowed, please obtain immediate medical assistance.

Using the product correctly
Leaking batteries may damage the unit. You should therefore remove the batteries if the unit will be out of use for a longer period of time. Only start the air supply once the unit is attached correctly to the arm. Only start the air supply once the sleeve is attached correctly to the wrist. Never press the START but ton if the sleeve is not attached. Never try to open and/or repair the appliance yourself. Do not make any changes to settings insi de the unit using your own tools. Contact our Ser vice Centre if the unit is defective.
This unit consists of precision parts and must the refore not be exposed to extreme changes in temperature damp (including dripping water and splashes) direct sunlight shock dust. Never immerse the unit in water. Do not bend the fixed part of the sleeve. Do not drop the unit and do not load objects on top of it. If the unit is stored near to freezing point, leave it to warm up to room temperature before use.
Dispose of batteries carefully
Do not dispose of used batteries in the household rubbish! Batteries should be deposited at a collection point for used batteries.

Notes on maintenance

It is recommended that you check the usability of the unit every three years at least.
Signs used in the operating instructions and on the unit:
Caution! Please take note of the accompanying do cuments (operating instructions). Application part of type BF

Cleaning

You can clean the casing of the blood pressure computer and the sleeve carefully using a soft, slightly damp cloth. Do not apply any pressure du ring cleaning. Do not bend the preshaped sleeve outwards. The sleeve must be neither washed nor dry cleaned. Never use thinners, alcohol or petrol as cleaning materials.
INFORMATION ABOUT BLOOD PRESSURE
AND MEASURING BLOOD PRESSURE
The consequences of too high blood pressure are one of the main causes of death today. Many peop le are unaware that their blood pressure is too high. This blood pressure measuring unit helps you to take regular, comparative measurements. (Indivi dual, irregular measurements are not very me aningful; see below.)

What is blood pressure?

Blood pressure is a measurement of the force that the heart has to exert to pump the blood through the circulatory system and vital organs in the body. The higher the pressure, the harder the heart has to work. Blood pressure can be higher than usual if parts of the circulatory system are restricted, diseased or abnormal in other ways. High blood pressure can cause damage to vital organs including the brain and heart.

Normal and high blood pressure
The guidelines for normal and high blood pressure (diastolic and systolic value) have been defined by the World Health Organization "WHO" as shown in the following table.

Measuring blood pressure

Everybody's blood pressure changes constantly. Fluctuations may be caused by mental and physical factors (such as fear, exertion, smoking, caffeine and stress). Blood pressure can also be affected by the time of day, time of year and temperature.
The following diagram shows typical blood pressu re fluctuations in the course of a working day:
As this figure shows, you should not become de pressed or too pleased about individual, selective measurements.
Important notes on correct measurement
With the help of your unit, you can create a clear overview of your blood pressure by measuring it re gularly. Note the following points so that the values give a realistic image of your blood pressure: Measure your blood pressure several times a day, but always at the same time of day. Measure your pressure when you are relaxed. Try to rest for fifteen minutes before measuring your blood pressure.
You should wait an hour after a large meal before measuring your blood pressure. Do not smoke or drink alcohol before measuring your blood pressure. Do not undertake any physical activity an hour before measuring your blood pressure. Do not measure your blood pressure if you are under stress or are tense. Measure your blood pressure at normal body temperature, but not if you are too hot or cold. Wait for approx. 5 minutes if you want to mea sure your blood pressure again.
Have a doctor diagnose your measurements
After you take your measurements, a doctor should interpret the values and diagnose them. The doctor will tell you which blood pressure level is normal for you, and which peculiarities you should report if they occur.
Do not implement any therapeutic measures without having spoken to a doctor first. NEVER take medicine in particular as a result of the measured values without asking a doctor for advice!
Attention is advised for the following persons: Persons with high blood pressure, diabetes, liver disease, hardened arteries, poor circulation and so on.
The unit's measuring technology
Your blood measuring unit contains high quality technical components and materials for measuring pressure, processing the signals and displaying the values on a liquid crystal display. It also measures and displays your pulse frequency.
The unit measures blood pressure indirectly using a sleeve around the wrist. Inflating the sleeve pres ses the arteries together so that no more blood can flow through them. If the pressure in the sleeve is then reduced, this creates a relation between the sleeve pressure and the blood pressure. The unit has electronic step valves that can detect even slight changes during the measurement, which can be evened out using the sleeve pressure. By reducing the pressure step by step, fluctuati ons in the sleeve are recorded by the unit and inclu ded in the assessment. If no fluctuations are recorded for a step, the air pressure is reduced. Existing fluctuations are assessed at the corre sponding step level until they can be determined precisely.

Arm and wrist measurement
Blood pressure measured at the wrist can differ from the pressure measured at the upper arm, for example because the strength of the arteries in the wrist and upper arm may differ. In many cases, the difference for healthy persons can be 10 mmHg of the systolic and diastolic blood pressure.

GENERAL VIEW

The unit

Accessories

2 alkali batteries, 1.5 V type "AAA" LR03 Storage case

The display

Signs:
The change battery sign appears if the batteries need to be changed. The pulse sign appears when the pulse is display ed. The memory sign indicates the number of the me mory space. You can save up to 90 measurements including the date and time in the unit's memory. The error sign appears if there is an operation or unit error.

BEFORE USE

Inserting batteries
The battery compartment is located at the back of the unit. Push the cover upwards. Insert the two 1.5 V alkali type "AAA" batteries supplied as shown. Pay at tention to the polari ty (the negative terminal faces the spring). Replace the cover on the battery compartment.

Changing batteries

Change the batteries when the battery change sign is displayed. You should also change the batteries if nothing ap pears on the display when you turn the unit on. Always change both batteries together as a pair. As the supplied batteries are intended for checking, they may expire sooner than commerci ally available batteries.

Notes on disposal

Batteries are special waste. Do not dispose of them in the household rubbish!
Setting the date and time
You can adjust the time by pressing the time adjust but ton. The month flashes on the display. Change the month by pres sing the + button. Each time you press the button the month moves on one. After number 12 (December), 1 (January) appears again. Press the time adjust button (or wait approx. 10 seconds) to access the next setting. The day flashes. Set the date using the + but ton. Press the time adjust button (or wait approx. 10 seconds) to access the next set ting. The hour display flashes. AM: If "AM" is displayed in front of the time, then you are in the morning hours (0:00 to 11:59). PM: If "PM" is displayed in front of the time, then you are in the afternoon/evening hours (12:00:00 PM to 23:59). Set the hours using the + button. Press the time adjust button (or wait approx. 10 se conds) to access the next setting. The minute dis play flashes. Set the minutes using the + button. Press the time adjust button (or wait approx. 10 se conds) to confirm the setting. After running through all settings, the unit returns to normal mode.

MEASURING BLOOD PRESSURE

Attaching the wrist sleeve
Remove your watch, jewellery etc. and roll up your sleeve. The unit has to be placed directly on your skin to provide a correct measurement. Attach the wrist sleeve in such a way that it is approx. 1cm away from the palm of your left hand (see fig. B). Ensure that no articles of clothing are trap ped in the sleeve. Hold the lower part of the sleeve as shown in fig. C. Pull down and wrap it around and upwards, so that there is no gap between the sleeve and your wrist. Your thumb holds the sleeve cover as you wrap it around and upwards. Wrap the sleeve according to the shape of your wrist. The result of the measurement is not affected if the sleeve is not straight.
If the sleeve cannot be atta ched to your left arm and if it is not possible to measure your left arm, use your right one. Attach the sleeve as shown in the figure on the right hand side.
Preparing for the measurement
Refer to section Important notes on correct mea surement auf Seite 7.

Posture

Place your elbow on the table or something to lean on and hold your arm so that the wrist sleeve is at heart height. In doing so, support your lo wer arm on the storage box or on a folded towel or similar. To measure your blood pres sure, sit comfortably on a chair, take 5 or 6 deep breaths and relax.

Measuring

Press the on/off button. All lights on the display light up when you press the on/off button. You can use this test to check that the display is complete. This process takes ap prox. 2 seconds.
The image opposite appears after this display test. The unit is ready for measuring. The "0" flashes and the unit automatically starts to in flate the sleeve.
Do not move the sleeve, or your arm or hand muscles while your blood pressure is being measu red, and do not speak. The unit first infla tes the sleeve to approx. 180 mm Hg. The measuring process begins once the correct sleeve pressure has been reached; the value falls. If you want to can cel the measure ment, switch the unit off. The sleeve deflates.

Ending the mea surement

The sleeve deflates when the measure ment is complete. The systolic and diastolic blood pressure and the pulse with the pulse sign appear in the
display. The "mem" memory sign flashes and the memory number appears. The measurement values are transferred automati cally to the memory. You do not need to press the M button.
Errors inflating the sleeve?
If the sleeve pressure is too low, the unit interrupts the measuring process and inflates the sleeve again until sufficient sleeve pressure is reached for the measurement. If the sleeve remains permanently inflated, remove the sleeve from the wrist and contact the Service Centre. The sleeve cannot be inflated if the USB cable is plugged in.

Switching off the unit

Press the on/off button to switch off the unit. The display will go out. If you forget to switch off the unit, it switches off au tomatically approx. 1 minute after the last button was pressed.

Memory function

Measurement values (blood pressure and pulse) are stored automatically in the memory together with the date and time once the measurement is complete.

Displaying memory values

To display the saved measurement values press the memory button M (= "Memory"). It does not matter whether the unit is on or off. The first value displayed is the one that was last measured (such as me mory space 60).
Press the M button again to display the previous memory va lues (59, 58, 57 etc.). The time and date change every 2 se conds during the dis play.
Deleting the memory contents
If you press the M memory button for 5 seconds, you delete all recordings in the memory. The data is also deleted if you remove the batteries. The saved data remains stored if you press the on/ off button.

AN ERROR DISPLAY APPEARS

Display Error/cause Troubleshooting
Check that the batteries have the correct polarity. If necessary, replace the batteries. Remain quiet for the du ration of the measure ment. Attach the sleeve care fully. Keep your arm and the unit at heart height Remain quiet for the du ration of the measure ment (do not move or speak). Replace the batteries with new alkali type AAA batteries. The display The unit is not on. remains The batteries are too dark weak. The batteries were not inserted correctly. Display You spoke or moved whi "EE" le measuring your blood pressure. The sleeve is not atta ched correctly. You did not hold the unit up to heart height. Display You moved while you "E2" were measuring your blood pressure. The batteries are dead.

TECHNICAL DATA

Model: K350 MD42780 Principles of measurement: oscillometric Display: LCD Measuring range: mmHg (blood pressure) pulse/min. (pulse frequency) Measuring accuracy: 3 mmHg (pressure display) 5 % (pulse frequency) Ventilation: automatic escape valve Power supply: high capacity or alkali batteries: 2 x 1.5V = type AAA/LR03 Memory: 90 measurement results Operating temperature: 5 C to 45 C max. 40 to 85 % relat. humidity. Storage temperature: 10C to 60C max. 10 to 95% relat. humidity. Sleeve: for wrist circumference 135 220mm circumference Size (unit of measure): approx. (79 x 72 x 71)mm Weight: approx. 120g (excluding batteries)

Manufactured in 2004

TABLE DE MATIERES
Consignes de scurit. 2 propos de la tension artrielle et de la mesure de la tension artrielle. 5
Qu'est ce que la tension artrielle ?. 5 Mesure de la tension artrielle. 6

ARBs are more selective than ACEIs in that they selectively antagonize AT1 receptors. A theoretic advantage of ARBs is that non-ACE sources of ang II are unable to activate AT1. Blockade of AT1 interrupts the negative feedback loop and increases circulating ang II levels. The result is unopposed AT2 stimulation because of heightened ang II levels resulting in vasodilatation and other beneficial effects. Despite these favorable effects of ARBs, an absolute effectiveness of benefits from this class of medication compared with the ACEIs is yet to be established, particularly in high-risk individuals.22,27 ARBs, like ACEIs, have an effect on the regulation of endothelial function. Ang II plays a significant role in endothelial dysfunction in general and in patients who have diabetes in particular. Insulin binds to tyrosine kinase, which leads to autophosphorylation of tyrosine residue turning on the insulin-signaling pathways, which enhances uptake of glucose by skeletal muscle. The second activated pathway is the mitogen-activated protein kinase, which promotes vascular smooth muscle cell proliferation and migration induced by insulin, thrombin, and platelet-derived growth factors. A third pathway is triggered that leads to activation of P70 S6 kinase, a regulator of protein synthesis.45,46 In animal models, valsartan has shown a reduction in the expression of proinflammatory markers, such as MCP-1, TNF, IL-6, and IL-1, and it inhibits migration of inflammatory cells into the injured arteries. Losartan has shown a decrease in reactive oxidants, increased NO production, and improved flow-mediated vasodilatation.4749 In humans, ARB treatment in patients who have essential hypertension decreases peripheral vascular resistance and radial arterial thickness and reduces left ventricular muscle mass.50 These beneficial effects of ARBs have the potential to
ANGIOTENSIN RECEPTOR BLOCKERS IN HIGH-RISK HYPERTENSIVES
LIFE was one of the initial clinical trials that compared the efficacy of an ARB in a high-risk
population with evidence of target organ damage (left ventricular hypertrophy).52 In patients who had advanced hypertension and left ventricular hypertrophy, losartan in comparison with atenolol showed reduction in composite cardiovascular mortality, MI, and stroke (11% losartan versus 13% atenolol, relative risk [RR] 5 0.13; P 5.021). The benefit was largely derived from the reduction in stroke (losartan 5% versus atenolol 7%). In the subgroup analysis of patients who did not have vascular disease, losartan reduced the primary composite endpoint of cardiovascular morbidity and mortality along with stroke (HR 0.18, P 5.008). These beneficial effects of losartan were most evident in the diabetic subgroup. In the analysis of patients who had diabetes, losartan did reduce primary composite endpoint, cardiovascular mortality, and HF hospitalizations compared with atenolol (hazard ratio [HR] 0.77, P 5.031), and mortality (HR 0.62, P 5.002). In patients who had isolated systolic hypertension in the LIFE study, losartan reduced all-cause mortality (HR 0.72, P 5.05) but failed to show a significant reduction in the primary composite endpoint of cardiovascular mortality and stroke compared with atenolol. In another subgroup analysis of the LIFE trial, losartan versus atenolol revealed that there was actually an increased risk for stroke, 8.9% versus 4.6% for African American patients (adjusted HR 2.18, P 5.03). African American women derive similar benefit from ARBs as men. The subgroup of African American patients who had DM on losartan had a reduction in cardiovascular mortality but not a significant decrease in stroke. Various other studies have evaluated the effects of ARBs on all-cause or cardiovascular mortality and morbidity in patients who have high cardiovascular risk (Table 1). The Morbidity and Mortality after Stroke, Eprosartan Compared with Nitrendipine for Secondary Prevention (MOSES) trial compared morbidity and mortality in treatment with eprosartan or nitrendipine.55 The combined primary endpoint of all-cause mortality, and cardiovascular and cerebrovascular events in patients who had hypertension and history of stroke was compared with nitrendipine. The combined primary endpoint was significantly reduced with eprosartan compared with nitrendipine, with an incidence density of 13.25% versus 16.71%, respectively, and an incidence ratio (IDR) of 0.79 (95% CI 0.660.96; P 5.014). The incidence was also significantly reduced with eprosartan for fatal and nonfatal stroke (IDR 0.75, 95% CI 0.550.97; P 5.025). This difference in the primary outcome is seen despite similar reduction in blood pressure in the two treatment groups. This trial also revealed that patients treated with eprosartan had significantly fewer cerebrovascular events compared with patients treated with nitrendipine. The Valsartan Antihypertensive Long-term Use Evaluation (VALUE) study compared valsartan to the amlodipine in patients who had hypertension and high cardiovascular risk.56 This large, multicenter, randomized trial enrolled 15,245 patients who had treated or untreated hypertension who were at high risk for cardiac events. During the mean follow-up of 4.2 years, there was no difference in all-cause mortality between the two groups (11.0% for valsartan, 10.8% for amlodipine; HR 1.04, 95% CI 0.941.14; P 5.45%). Overall cardiac mortality was similar but fatal and nonfatal MI reached significance (4.8% versus 4.1%, adjusted HR 1.19, 95% CI 1.021.38, P 5.02). ARBs have also been shown to be beneficial in improving chronic cerebral ischemia. Administration of candesartan has been shown to improve cerebral artery media thickness, improve cerebral blood flow, and reduce the expression of c-Fos and c-Jun proteins in the brain that are associated with chronic neurodegenerative diseases.57 Recent studies suggest that RAAS blockade may also reduce the incidence of cerebrovascular events in high-risk groups; for example, the risk for stroke was reduced with ramipril in the HOPE trial, which also included patients who had prior transient ischemic attack (TIA) or stroke.43

FUTURE DIRECTIONS

Given the essential contribution of angiotensin II in regulating blood pressure and endothelial function and vascular and cardiac remodeling, RAAS blockade has been inculcated as inevitable part of cardiovascular therapeutics in various conditions. Studies are under way to determine whether doses greater than those used in the previous trials
Fig. 3. Kaplan-Meier curves for the primary outcome in the three study groups. The composite primary outcome was death from cardiovascular causes, MI, stroke, or hospitalization for HF. (From ONTARGET Investigators, Yusuf S, Teo KK, Pogue J, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008;358:1553; with permission. Copyright 2008, Massachusetts Medical Society.)
or combination of ARB and ACEI therapy will provide more extensive RAAS inhibition and greater protection from end-organ damage in various high-risk groups. The Telmisartan Randomized Assessment Study in ACE-Intolerant Subjects with Cardiovascular Disease (TRANSCEND) trial87 is evaluating telmisartan in reducing cardiovascular risk independent of blood pressure reduction. The Irbesartan in Heart Failure with Preserved Systolic Function (I-PRESERVE)88 trial will evaluate irbesartan therapy in elderly patients (>60 years of age) who have a clinical diagnosis of HF with preserved systolic function. The largest secondary stroke prevention trial undertaken to date, Prevention Regimen for Effectively Avoiding Second Strokes (PROFESS),89 is currently comparing the efficacy and safety of aspirin plus extendedrelease dipyridamole with clopidogrel, and of telmisartan with placebo, in preventing recurrent strokes. Finally, ROADMAP90 is a large-scale trial to assess renoprotective effects of olmesartan. This study will assess the onset of microalbuminuria in patients who have type 2 diabetes. treatment by using ARBs that have proven efficacy for specific disease states will be the key to this approach.
1. Kannel WB. Hazards, risks, and threats of heart disease from the early stages to symptomatic coronary heart disease and cardiac failure. Cardiovasc Drugs Ther 1997;11(Suppl 1):199212. 2. Wild S, Roglic G, Green A, et al. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 2004;27:104753. 3. Narayan KM, Boyle JP, Thompson TJ, et al. Lifetime risk for diabetes mellitus in the United States. JAMA 2003;290:188490. 4. Lewington S, Clarke R, Qizilbash N, et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002;360:190313. 5. Steinberger J, Daniels SR. Obesity, insulin resistance, diabetes, and cardiovascular risk in children: an American Heart Association scientific statement from the Atherosclerosis, Hypertension, and Obesity in the Young Committee (Council on Cardiovascular Disease in the Young) and the Diabetes Committee (Council on Nutrition, Physical Activity, and Metabolism). Circulation 2003;107:144853. 6. Hedley A, Ogden C, Johnson C, et al. Prevalence of overweight and obesity among US children, adolescents, and adults, 19992002. JAMA 2004;291: 284750. 7. Third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation and treatment of high blood cholesterol in adults (adult treatment panel III). National cholesterol education program, National Heart, Lung, and Blood Institute, National Institutes of Health. Circulation 2002; 106:3143421. 8. Sowers JR. Obesity as a cardiovascular risk factor. Am J Med 2003;115(Suppl 8A):37S41S. 9. McFarlane SI, Jacober SJ, Winer N, et al. Control of cardiovascular risk factors in patients with diabetes and hypertension at urban academic medical centers. Diabetes Care 2002;25:71823. 10. Williams B, Poulter N, Brown M, et al. British hypertension society guidelines for hypertension management (BHS-IV): summary. BMJ 2004;328:63440. 11. Neal B, Macmahon S, Chapman N. Effects of ACE inhibitors, calcium antagonists, and other bloodpressure lowering drugs: results of prospectively designed overviews of randomized trials. Blood Pressure Lowering Treatment Trialists Collaboration. Lancet 2000;356:195564. 12. Effects of different regimens to lower blood pressure on major cardiovascular events in older and younger

Aliskiren monotherapy has been compared with representatives of several different classes of antihypertensive medications and has been shown to produce comparable or greater reductions in BP. For example, in a double-blind study, 842 patients with hypertension (mean sitting DBP 95 to 109 mm Hg) were randomized to aliskiren 150 mg or the ACE inhibitor ramipril 5 mg.47 Dose titration (to aliskiren 300 mg/ramipril 10 mg) and subsequent addition of hydrochlorothiazide (12.5 mg, titrated to 25 mg if required) were permitted at weeks 6, 12, 18, and 21 for inadequate BP control. The active treatment period was completed by 81.6% of patients. At week 26, aliskiren-based therapy produced greater mean reductions in SBP (17.9 versus 15.2 mm Hg, P 5.0036) and DBP (13.2 versus 12.0 mm Hg, P 5.025) and higher rates of SBP control (<140 mmHg; 72.5% versus 64.1%, P 5.0075) compared with ramipril-based therapy. During withdrawal, BP increased more rapidly after stopping ramipril-based than aliskiren-based therapy.
When used in combination with a thiazide diuretic, aliskiren is more effective than either monotherapy in reducing BP. In an 8-week, double-blind, placebo-controlled trial, 2776 patients with mean sitting DBP 95 to 109 mm Hg were randomized to receive once-daily treatment with aliskiren (75, 150, or 300 mg), hydrochlorothiazide (HCTZ) (6.25, 12.5, or 25 mg), the combination of aliskiren and HCTZ, or placebo, in a factorial design.48 Combination treatment was superior to both component monotherapies in reducing BP (maximum SBP/DBP reduction of 21.2/14.3 mm Hg from baseline with aliskiren/HCTZ 300/25 mg), and resulted in a higher responder rate (patients with DBP < 90 mm Hg and/or R10 mm Hg reduction) and a better control rate (patients achieving SBP/DBP < 140/90 mm Hg) than either monotherapy. Aliskiren monotherapy reduced PRA by up to 65% from baseline and when HCTZ was combined with aliskiren, decreases in PRA of 46.1% to 63.5% were observed. Dual RAAS inhibition with maximum recommended doses of the DRI aliskiren and the ARB valsartan has shown greater antihypertensive efficacy than monotherapy with either agent. In a doubleblind study, 1797 patients with hypertension (mean sitting DBP 95 to 109 mm Hg and 8-hour daytime ambulatory DBP R 90 mm Hg) were randomly assigned to receive once-daily aliskiren 150 mg, valsartan 160 mg, a combination of aliskiren 150 mg and valsartan 160 mg, or placebo for 4 weeks, followed by forced titration to maximum recommended doses for another 4 weeks.49 At week 8, the mean sitting SBP was lowered from baseline by 17.2, 12.8, 13.0, and 4.6 mm Hg, respectively, and mean sitting DBP was lowered from baseline by 12.2, 9.7, 9.0, and 4.1 mm Hg, respectively, with the combination of aliskiren 300 mg and valsartan 320 mg, valsartan 320 mg monotherapy, aliskiren 300 mg monotherapy, and placebo (P <.0001 combination compared with placebo or either monotherapy) (Fig. 5). The proportion of patients achieving a successful response to treatment at week 8 was significantly higher with the combination of aliskiren and valsartan (66%) than with aliskiren alone (53%; P 5.0003) or valsartan alone (55%; P 5.001). Valsartan monotherapy produced significantly greater increases in PRA from baseline than did placebo (160% versus 18%; P 5.0003). By contrast, aliskiren alone significantly reduced PRA by 73% (P <.0001 versus placebo), while the combination of aliskiren and valsartan led to a 44% reduction in PRA (P <.0001 versus placebo). The combination of aliskiren and valsartan provided significantly greater reductions in plasma aldosterone concentration from baseline at week 8 than did placebo (31% versus 17%; P <.0001). Valsartan alone also reduced aldosterone concentration (25%; P 5.0007 versus placebo), while aliskiren monotherapy had no significant effect on aldosterone concentration. The rates of adverse events and laboratory abnormalities were similar in all groups. Some have hypothesized that reactive renin secretion may limit the effectiveness of DRIs.50 Although aliskiren suppresses PRA, it causes major reactive increases in plasma renin concentration. If the system is at all leaky, allowing even a small percentage of the excess prorenin generated during DRI treatment to be activated, the antihypertensive effect of the DRI may be offset, limiting its utility as an antihypertensive agent. Further study and additional clinical experience with aliskiren and other DRIs, as they become available, are needed to validate or refute this hypothesis.

CLINICAL EXPERIENCE WITH THE CETP INHIBITOR TORCETRAPIB
Torcetrapib, the most extensively studied CETP inhibitor to-date, selectively inhibits plasma CETP by causing a nonproductive complex between CETP and HDL.56 Several early clinical trials were conducted to define the dose and change in lipid parameters, the kinetics of the drug and dynamics of HDL metabolism. Torcetrapib at 120 mg twice daily increased HDL cholesterol by 91% and decreased LDL cholesterol by 42% in healthy subjects.57 In subjects with low HDL-c levels, torcetrapib increased HDL-c and decreased LDL-c levels, either when administered as monotherapy or combined with a statin.58 Torcetrapib was shown to increase apoA-I concentrations modestly by decreasing the catabolism of apoA-I.59 In a phase 2 trial, 162 subjects with below average HDL-c were randomized to torcetrapib 10, 30, 60, or 90 mg/day or placebo.60 There was a dose-dependent increase in HDL-c from 9% to 55%. In another phase 2 multicenter, randomized, double-blinded trial, 174 patients who have low HDL-c either on statins or with LDL-c > 130 mg/dL who would be eligible for statins according to NCEP ATP III guidelines were randomized to varying doses of torcetrapib or placebo for 8 weeks after a run-in period with atorvastatin.61 There was a dose-dependent increase in HDL-c from 8% to 40%, with additional decrease in LDL-c beyond that achieved with atorvastatin alone. In the same trial, torcetrapib/atorvastatin combination was shown to increase the large HDL2 subfractions and decrease the small LDL subfractions while increasing both HDL and LDL particle size.62 In patients who have heterozygous familial hypercholesterolemia (HeFH) who lack LDL receptor, torcetrapib/atorvastatin combination not only raised HDL-c but also decreased LDL-c significantly when compared to atorvastatin alone.63 In patients who have hypertriglyceridemia, torcetrapib/atorvastatin combination had an enhanced LDL lowering effect.63 When fenofibrate and ezetimibe were administered with torcetrapib and atorvastatin in healthy subjects, there was
no change in the pharmacokinetics of torcetrapib.64,65 Torcetrapib at the 60 mg dose was studied in three phase III atherosclerosis imaging trials. The Rating Atherosclerotic Disease Change by Imaging with a New CETP Inhibitor (RADIANCE) 1 and 2 trials were designed to determine the effect of torcetrapib on atherosclerosis progression in patients with HeFH and mixed dyslipidemia respectively.66,67 After an initial run-in phase with atorvastatin, 850 patients were randomized to receive atorvastatin/torcetrapib combination or atorvastatin monotherapy. At the end of 2 years, despite significant rise in HDL-c and reduction in LDL-c levels, there was no difference in the progression of carotid IMT among the intervention and control groups in both RADIANCE 1 and 2. The Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction of Atherosclerosis by CETP Inhibition and HDL Elevation (ILLUSTRATE) trial studied the effect of torcetrapib on coronary atherosclerosis progression. Patients who have CHD were pretreated with atorvastatin to reach an LDL goal of %of 100 mg/dL and then randomized to torcetrapib/ atorvastatin or atorvastatin monotherapy.63 All patients underwent intravascular ultrasonography (IVUS) at baseline and 77% of them had a repeat IVUS after 2 years. At the end of 2 years, there was no significant difference in the percent atheroma volume between the two groups. Posthoc analysis showed an inverse relationship between change in HDL-c level and both total atheroma volume and percent atheroma volume.68 Torcetrapib was also studied in a large phase III clinical outcome trial, the Investigation of Lipid Level Management to understand its Impact in Atherosclerotic Events (ILLUMINATE) trial.69 ILLUMINATE randomized 15,067 patients who have CHD or CHD equivalents to torcetrapib/atorvastatin or atorvastatin after a run-in period with atorvastatin to reach an LDL goal of %100 mg/ dL. The trial was terminated on December 2, 2006 because of increased mortality in the torcetrapib arm and the clinical development of torcetrapib was terminated. Interim analysis at 12 months showed a 72% increase in HDL-c and 25% decrease in LDL-c in due to torcetrapib. There were more cardiovascular (49 versus 35) and noncardiovascular (40 versus 20) deaths in the torcetrapib group than the atorvastain group. Cancer (24 versus 14) and infections (9 versus 0) were the most common cause of noncardiovascular death. There were significant increases in systolic blood pressure of 5.4 mm Hg, increases in serum sodium and bicarbonate levels, and decreases in serum potassium in the torcetrapib group. Posthoc analysis showed that the aldosterone levels in the torcetrapib arm were significantly elevated at 3 months when compared to the atorvastatin-only group despite being similar at the beginning of the trial. Cardiovascular events were inversely proportional to the increase in HDL-c above the median. It is likely that off-target effects of torcetrapib contributed to the adverse outcome in ILLUMINATE.70 All phase III imaging trials of torcetrapib also showed a significant increase in systolic blood pressure in the torcetrapib arm (2.8 mm Hg, 5.1 mm Hg, 4.6 mm Hg increase in RADIANCE 1, 2 and ILLUSTRATE respectively). In rats (both normotensive and spontaneously hypertensive models), which naturally lack CETP, torcetrapib increased blood pressure dose-dependently with a concomitant increase in gene expression of renin angiotensin system (RAS) and endothelin-1 from the adrenal glands as well as aorta (Fig. 1).71 Torcetrapib caused an acute elevation in blood

Fig. 2. Maximum Global Flushing Severity Score (GFSS) in week 1 in study 011, presented as percent of patients. Abbreviations: ERN, extended-release niacin; GFSS, Global Flushing Severity Score; LRPT, laropiprant. (From Paolini JF, Mitchel YB, Reyes R, et al. Effects of laropiprant on nicotinic acid-induced flushing in dyslipidemic patients. Am J Cardiol 2008;101:626; with permission.)
initiation of therapy, an important advance considering that 500 mg NIASPAN is a titration dose with nonsignificant LDL-C-lowering and that approximately one third of patients never titrate upward beyond 500 mg.31 combination therapy with statins (18.9%). These similarities in LDL-C lowering with or without previous statin therapy were observed despite the large differences in baseline LDL-C levels in these two subgroups (approximately 95 vs. approximately 150 mg/dL; this difference was expected due to disparity in enrollment criteria based on statin use and risk category). Similarly, baseline HDL-C and TG levels did not influence the LDL-C lowering efficacy of ER niacin/laropiprant. Finally, the lipid effects of ER niacin/laropiprant and ER niacin were nearly identical, confirming earlier observations that laropiprant alone does not affect lipid levels. The results of Study 020 generally were corroborated in a factorial study designed to evaluate the lipid-modifying efficacy of ER niacin/laropiprant plus simvastatin, compared with the monotherapy of each (Study 022). After a 6- to 8-week washout and a 4-week diet/placebo run-in, 1398 patients were randomized equally to ER niacin/ laropiprant 1 g/20 mg, simvastatin (10, 20, or 40 mg), or ER niacin/laropiprant 1 g/20 mg plus simvastatin (10, 20, or 40 mg) once daily for 4 weeks. At week 5, treatment doses were doubled in all groups except simvastatin 40 mg (unchanged) and ER niacin/laropiprant 1 g/20 mg plus simvastatin 40 mg (switched to ER niacin/laropiprant 2 g/ 40 mg plus simvastatin 40 mg). Significantly larger reductions in LDL-C levels were evident with the coadministration of ER niacin/laropiprant 2 g/40 mg plus simvastatin (pooled across simvastatin doses of 20 mg and 40 mg) compared with ER niacin/laropiprant or simvastatin (pooled across simvastatin doses of 20 mg and 40 mg) (Table 3). In addition, when evaluating the lipid effects of ER niacin/laropiprant 2 g/40 mg plus simvastatin, all individual dose comparisons were significantly different from the respective monotherapy doses.

MECHANICAL INTERVENTIONS AND DEVICES Ultrafiltration
Diuretics have been used to treat HF since the 1950s. However, diuretic refractoriness can occur in patients with acute HF, despite large doses of loop diuretics and metolazone. The Ultrafiltration versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Congestive Heart Failure (UNLOAD) trial55 is the first randomized comparison of intravenous loop diuretic therapy versus ultrafiltration in hypervolemic patients hospitalized with acute HF. It was designed as a prospective, randomized, multicenter trial. There was no ejection fraction inclusion criterion. All patients received conventional HF therapy. The duration and rate of acute fluid removal was at the discretion of the treating physician. The primary endpoint was weight loss and patients dyspnea assessment 48 hours after randomization to ultrafiltration or medical therapy. The trial also included several secondary endpoints. One hundred patients were enrolled in each arm and followed for 90 days or until death. At 48 hours following randomization, ultrafiltration produced more weight loss than conventional medical therapy (5.0 3.1 Kg versus 3.1 3.5 Kg; P 5.001), but dyspnea assessment
Cardiac Resynchronization Therapy
Another example of device innovation is biventricular pacing. Dyssynchrony in myocardial contraction commonly occurs in patients with HF and left bundle branch block, leading to impaired LV function and worsening mitral regurgitation. CRT restores more normal contraction to the LV wall while improving overall heart function. Longitudinal follow-up data suggest that CRT induces reverse remodeling as early as 3 months after
implantation. Experimental data show that restoration of more normal contraction is accompanied by improvement in local loading conditions leading to changes in myocyte protein synthesis.56 CRT should be considered only after conventional pharmacologic treatment has been optimized. Published data suggest that about 70% of patients receiving a biventricular pacemaker improve clinically.57 Proper patient selection is perhaps the most important issue key to success with this therapeutic modality, and is a subject of ongoing discussion, but is still under intense study.58 Indications for CRT include: EF <35%, NYHA class III; QRS-interval of more than 130 msec; medically refractory, LV end diastolic diameter of 55 mm or more; and dyssynchrony on echocardiogram. Studies performed the last few years have demonstrated that CRT in addition to an ICD can lower the composite endpoint of death and hospitalization (Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure [COMPANION] trial59). The European Cardiac Resynchronization Heart Failure (CARE-HF) trial was a multicenter, randomized, controlled mortality trial that compared a population of patients who had systolic dysfunction (LVEF <35%), HF symptoms (NYHA class III-IV), and dyssynchrony by echocardiography with two different treatment strategies: 1) conventional drug therapy and 2) conventional drug therapy plus cardiac resynchronization. Patients were required to have a QRS-duration of more than 120 msec on the electrocardiogram. Those randomized to a device received a Medtronic InSync or InSync III device (Bi-ventricular pacemaker). Patients were followed for a mean of 29.4 months. The primary endpoint was a composite of all-cause mortality or an unplanned hospitalization for a major cardiovascular event. All patients received optimal medical therapy and 409 were additionally randomized to receive a biventricular pacer. Nearly 85% of the study population was on b-blockers. By the end of the study, 224 medically treated patients reached the primary endpoint compared with 159 in the resynchronization group (P <.001). Mortality was strikingly reduced. Unplanned hospitalization was also less in the device group than in the medically treated group (P <.002). CRT significantly reduced death, hospitalization for worsening HF, and symptoms/NYHA classification, while improving quality of life and echocardiographic parameters. The data suggest that for every nine devices implanted, one can prevent one death and three hospitalizations for major cardiovascular events. Biventricular pacing has proved to be a powerful tool in the management of HF. In the United States, it is usually performed in conjunction with implantation of an ICD, but in Europe this is not the case. Patients with class IV HF make up a small subset of these CRT studies, and to date, CRT cannot be considered a form of rescue therapy for the critically ill class IV patient. However, more stable class IV patients may occasionally benefit from CRT.

Patients with HF are clearly receiving better treatment today than was the case 20 years ago. However, the mortality, morbidity, and costs of caring for patients with HF remain substantial. Four new trends are emerging in the development of new therapies: (1) pharmacogenomics is beginning to identify more clearly who the responders and nonresponders might be; (2) designer drugs, including new natriuretic peptides, that include the most effective moieties of several molecules are being hybridized to create highly creative new drugs that may favorably alter specific pathophysiologic components of HF; (3) in the future, small interference ribonucleotides (si RNAs) may be used to silence or activate specific genes that regulate the synthesis of proteins known to alter the clinical course of HF; and (4) stem cell therapy may emerge to stabilize or even reverse the failing heart and some of its associated signs and symptoms. Clinicians may look back some day at how primitive our current armamentarium of drugs and devices, such as intra-aortic balloon pumps, LV assist devices, defibrillators and CRT, might appear. Many challenges remain, but as long as HF is a major public health problem, medical practitioners can expect even more highly creative and innovative therapeutic approaches to the problem.
1. Packer M. The impossible task of developing a new treatment for heart failure. J Card Fail 2002;8:1936. 2. Cohn JN, Ferrari R, Sharpe N, et al. Cardiac remodelingconcepts and clinical implications: a consensus paper from an international forum on cardiac remodeling. J Am Coll Cardiol 2000;35:56982. 3. Hill JA, Olson EN. Mechanisms of disease: cardiac plasticity. N Eng J Med 2008;358:137080. 4. The CONSENSUS trial study group. Effects of enalapril on mortality in severe congestive heart failure. Results of the cooperative north scandinavian enalapril survival study (CONSENSUS). N Eng J Med 1987;316:142935. 5. The SOLVD investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Eng J Med 1991;325:293302.

31. Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with hydralazine-isosrbide dinitrate in the treatment of congestive heart failure. N Eng J Med 1991;325:30310. 32. Thackray S, Witte K, Clark AL, et al. Clinical trials update: OPTIME-CHF, PRAISE-2, ALL-HAT. Eur J Heart Fail 2000;2:20912. 33. VMAC Investigators. Intravenous nesiritide vs nitroglycerine for treatment of decomependated congestive heart failure. A randomized controlled trial. JAMA 2002;287:153140. 34. Taylor AL, Ziesche S, Yancy C, et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Eng J Med 2004;351:204957. 35. The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Eng J Med 1997;336:52533. 36. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Eng J Med 1999;341: 70917. 37. Coletta AP, Clark AL, Nikitin N, et al. Clinical trials update from the European Society of Cardiology: CARMEN, EARTH, OPTIMAAL, ACE, TEN-HMS, MAGIC, SOLVD-X and PATH-CHF II. Eur J Heart Fail 2002;4:6616. 38. Teerlink JR. Recent heart failure trials of neurohormonal modulation (OVERTURE and ENABLE): approaching the asymptote of efficacy? J Card Fail 2002;8:1247. 39. Pitt B, Remme W, Zannad F, et al. Eplerenone, a Selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003;348:130921. 40. Cohn JN, Pfeffer MA, Rouleau J, et al. Adverse mortality effect of central sympathetic inhibition with sustained-release oxonidine in patients with heart failure (MOXCON). Eur J Heart Fail 2003;5:65967. 41. Mann DL, McMurray JJV, Packer M, et al. Targeted anticytokine therapy in patients with chronic heart failure. Results of the randomized etanercept worldwide evaluation (RENEWAL). Circulation 2004;109: 1594602. 42. McMurray JJV, Teerlink JR, Cotter G, et al. Effects of tezosentan on symptoms and clinical outcomes in patients with acute heart failure. JAMA 2007;298: 200919. 43. Cuffe MS, Califf RM, Adams KF Jr, et al. Short-term intravenous milrinone for acute exacerbations of chronic heart failure. A randomized controlled trial. JAMA 2002;287:15417. 44. Lehtonen L, Poder P. The ultility of levosimendan in the treatment of heart failure. Ann Med 2007;39: 217. 45. Mebazaa A, Nieminen MS, Packer M, et al. Levosimendan vs dobutamine for patients with acute decompensated heart failure. JAMA 2007;297: 188391. Cleland JGF, Freemantle N, Coletta AP, et al. Clinical trials update from the american heart association: REPAIR-AMI, ASTAMI, JELIS, MEGA, REVIVE-II, SURVIVE and PROACTIVE. Eur J Heart Fail 2006; 8:10510. Sackner-Bernstein JD, Skopicki HA, Aaronson KD. Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure. Circulation 2005;111(12):148791. Circulation CHF, in press. Yancy CW, Krum H, Massie BM, et al. The second follow-up serial infusions of nesiritide (FUSION II) trial for advanced heart failure: Study rationale and design. Am Heart J 2007;153:47884. Cleland JGF, Coletta AP, Clark AL. Clinical trials update from the American College of Cardiology 2007: ALPHA, EVEREST, FUSION II, VALIDD, PARR-2, REMODEL, SPICE, COURAGE, COACH, REMADHE, pro-BNP for the evaluation of dyspnoea and THIS-diet. Eur J Heart Fail 2007;9:7405. Goldsmith SR, Gheorghiade M. Vasopressin antagonism in heart failure. J Am Coll Cardiol 2005;46: 178591. Konstam MA, Gheorghiade M, Burnet JC Jr, et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure. The EVEREST outcome trial. JAMA 2007;297:131931. Gheorghiade M, Konstam MA, Burnett JC Jr, et al. Short-term clinical effects of Tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure. JAMA 2007;297:133243. Udelson JE, McGrew FA, Flores E, et al. Multicenter, randomized, double-blind, placebo-controlled study on the effect of oral tolvaptan on left ventricular dilation and function in patients with heart failure and systolic dysfunction. J Am Coll Cardiol 2007;49: 21519. Costanzo MR, Guglin ME, Saltzberg MT, et al. Ultrafiltration versus intravenous diuretics for patients hospitalized for acute decompensated heart failure. J Am Coll Cardiol 2007;49:67583. Kass DA. An epidemic of dyssynchrony: but what does it mean? J Am Coll Cardiol 2008;51:127. Cleland JGF, Daubert JC, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005; 352:153949. Beshai JF, Grimm RA, Nagueh SF, et al. Cardiacresynchronization therapy in heart failure with narrow QRS complexes. N Engl J Med 2007;357:246171. Bristow MR, Saxon LA, Boehmer J, et al. Cardiacresynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004;350:214050.

Neurohormonal and Cytokine Effects of Statins in Heart Failure
Progression of HF leads to an activation of the neurohormonal system promoting an overexpression of cytokine as described previously. Monocyte adherence to endothelium in HF is overexpressed and leads to further production of cytokines by endothelium. Reduction of these inflammatory mediators by statin therapy in patients who have HF has been validated in small pilot studies, but this had not been confirmed in randomized clinical trials.14,15 The effects of statins on anti-inflammatory markers appear to be independent of their effects on cholesterol levels. Tousoulis and colleagues9,10 have demonstrated reduction in antithrombin III, protein C, IL-6, factor V, tPA, vascular cell adhesion molecule, P-selectin, and TNF-a involving patients who have NYHA class II through IV HF in two different trials. Whether the anti-inflammatory activities of statins directly translate to clinical benefits has yet to be shown in randomized clinical trials.

Myocardial Effects

In several studies of patients with acute MI ST segment Elevation Myocardial Infarction (STEMI) or Non ST segment Elevation Myocardial Infarction (NSTEMI), new or continued use of statins within the first 24 hours of the acute event has been shown to reduce 24-hour morbidity and mortality. In animal models of experimental MI, statins also have been shown to improve endothelial function, increase endogenous production of NO, inhibit platelet activation, and attenuate ventricular remodeling during the postinfarction period. This is postulated to be linked to the effects of statin on protein kinase called Akt, which has been
DOES LIPID PARADOX EXIST IN HEART FAILURE?
There are limited clinical data supporting the fact that statins may harm patients who have HF. Small observational studies have shown that lower cholesterol concentrations are associated with a poor prognosis and increased mortality in HF. This phenomenon is postulated to be multifactorial and may reflect the onset of cardiac cachexia, liver dysfunction, and impaired nutrition. In theory, statin use in HF remains controversial. This essentially has been based upon the so- called endotoxin hypothesis, which requires the presence of lipoproteins to eliminate bacterial lipopolysacharides

Statins in Heart Failure

and inhibit cytokine release.22 On the contrary, lowering of lipoproteins by statins would increase the lipopolysaccharides and promote infection in patients who have HF.23 Statins are known to cause a decrease in coenzyme Q10, thus worsening oxidative stress and decreasing mitochondrial and myocardial function.24 In patients who have HF, cholesterol modulates inflammatory immune activity, in particular endotoxin levels. Therefore, it is conceivable that lowering cholesterol levels with the use of statins may prove detrimental in some patients who have HF.25 Further studies are needed to elucidate on these aspects of statin therapy in patients who have HF.

clinicians: a scientific statement from the American Heart Association. Circulation 2007;115(12):163442. 59. Recommendations for the medical management of osteoarthritis of the hip and knee: 2000 update. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines. Arthritis Rheum 2000; 43(9):190515. 60. Catella-Lawson F, Reilly MP, Kapoor SC, et al. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med 2001;345(25):180917.
Ranolazine : New Paradigm for Management of Myocardial Ischemia, Myocardial Dysfunction, and Arrhy thmias

Peter H. Stone, MD

Myocardial ischemia Angina Ranolazine Heart failure Diastolic dysfunction
Cardiovascular Division, Brigham and Womens Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115-6110, USA E-mail address: pstone@partners.org Cardiol Clin 26 (2008) 603614 doi:10.1016/j.ccl.2008.06.002 0733-8651/08/$ see front matter 2008 Elsevier Inc. All rights reserved.
Anti-ischemia medications have traditionally focused on optimizing the determinants of the myocardial O2 supply: demand balance. Because myocardial oxygen extraction is maximal at rest, the only way to improve the balance pharmacologically has been to reduce myocardial O2 demand (ie, heart rate, blood pressure or afterload, myocardial contractility, or preload). The approved antianginal medications in the United States are effective by reducing one or more of these O2 demand determinants (Table 1). There are many patients, however, who have chronic coronary disease in whom this pharmacologic approach is inadequate. Many patients either cannot tolerate these conventional agents or have continuing symptoms of ischemia and angina despite their use.1 Ranolazine, which was approved by the US Food and Drug Administration in January 2006, provides a mechanism of action to treat ischemia that has not hitherto been available. Ranolazine is effective to reduce manifestations of ischemia and angina, and it also holds potential promise to be effective in the management of left ventricular dysfunction, particularly diastolic dysfunction, and arrhythmias. This article provides an update on the available studies concerning the value of ranolazine across the spectrum of cardiovascular disease.

MECHANISM OF ACTION

Ranolazine was first believed to be effective by inhibiting free fatty acid metabolism,2 but it was later appreciated that ranolazine exerted this effect only at serum levels that are much higher than those observed in therapeutic usage.3 The mechanism of action now seems to be related to inhibition of the late inward sodium channel (late INa),4 which pathologically remains open in a wide variety of adverse stimuli to the myocardium. Electrical activation of the cardiomyocytes leads to brief opening of the membrane sodium channel, through which sodium ions rapidly enter the cell, generating the rapid depolarization or upstroke of the action potential (Fig. 1A).4 In the normal setting, the inward sodium channels then inactivate rapidly and remain closed during the plateau phase of the action potential. Other ion channels open following electrical activation, including calcium channels, and the calcium ions that enter the cell during the plateau phase of the action potential then trigger the release of the large stores of calcium ions from the sarcoplasmic reticulum. This increased concentration of cytoplasmic calcium initiates the interaction between actin and myosin and enables the contraction process to occur (see Fig. 1A). Following the myocardial

WARFARIN: LONG-TERM ANTICOAGULATION AND ORAL ANTICOAGULANTS
Although there have been attempts to find a substitute for warfarin as an oral anticoagulant, warfarin remains the only approved option for cardiac use. Warfarin is composed of S and R enantiomers and when strongly bound to protein, chiefly albumin, is inactive. If warfarin is displaced from the proteins that bind it activity is increased. The S form, more physiologically active, is metabolized in the liver by the CYP2C9 enzyme system, which is inducible by medications. Warfarin inhibits the vitamin Kdependent coagulation factors II, VII, IX, and X, and inhibitor proteins C and S increasing factors VIII and V activity. The effect of warfarin does not reach full potency until 36 to 72 hours after the first dose is given and factor II levels are reduced. Typically a higher dose of warfarin is given the first 2 days of therapy (25 mg at bedtime).8082 Higher doses have been found to lead to a hypercoagulable state from initial effects on protein C and a falsely elevated international normalized ratio (INR) through isolated effects on the extrinsic pathway and factor VII without complete inhibition of intrinsic pathways. As a result heparin therapy is typically recommended to overlap for 4 to 5 days when initiating therapy to prevent protein Crelated effects and allow for complete inhibition of the intrinsic pathway. A black box warning has been added to labeling by the FDA because of
Table 1 Summary of 2007 anticoagulant for therapy of ST segment elevation myocardial infarction, American College of Cardiology/American Heart Association guideline update Reperfusion/PCI/Supportive Reperfusion with fibrinolytic IV anticoagulation R48 h UFH dosing for maximum 48 h Dosing IV anticoagulant R48 h (max 8 d) Avoid UFH, reduce HIT 60 U IVB per kg (maximum 4000 U) followed by IV infusion of 12 U/kg/h (maximum 1000 U/h) adjust to aPTT of 1.52.0 times control (approximately 5070 s) <75 y old IVB 30 mg and SC 1.0 mg/kg q 12 h start 15 min after IVB R75 y old No IVB, SC 0.75 mg/kg q 12 h CrCl<30 mL/min SC 1.0 mg/kg q 24 h First dose 2.5 mg IV then 2.5 mg SC once daily Dosing to adjust if GPIIb/IIIa receptor inhibitor given for UFH and enoxaparin Bolus with UFH to support procedure Bolus with bivalirudin to support procedure Within 8 h: no additional enoxaparin Within 812 h: 0.3 mg/kg enoxaparin IV Anti-IIa anticoagulant adjusting if GPIIb/IIIa receptor inhibitor given Not to be used alone as anticoagulant because of increase in catheter thrombosis IV or SC UFH or SC LMWH for R48 h or ambulatory For more than 48 h and up to 8 d to reduce HIT as dosed above for patients treated with fibrinolytics Evidence Class I, Level C Class I, Level A Class I, Level C

Vildagliptin

Vildagliptin is a selective DPP-4 inhibitor that enhances islet cell function by increasing a- and b-cell responsiveness to glucose, resulting in meal-stimulated increase in biologically active GLP-1. Additionally, it improves glucose tolerance. Vildagliptin was studied in 279 patients who had type 2 diabetes over 12 weeks, in which vildagliptin was used from 25 to 100 mg daily doses; 50 mg and 100 mg daily doses resulted in a reduction in HgA1c by 0.56% and 0.53%, respectively.42 The
vildagliptin at 50 mg daily dose.51 Vildagliptin showed statistically significant increase in fasting insulin, glucose sensitivity, and rate sensitivity, but the total insulin secretion excursion during meals were unchanged. These changes caused reduction in glucose and an improvement in HgA1c by 0.3 0.1% (p 5 <0.001). Vildagliptin also has been studied in a 12-week, double blind and randomized study on 179 patients with impaired glucose tolerance (IGT) with average HgA1c 5.9%.52 This unique study on pre-diabetic patients showed that vildagliptin 50 mg twice daily decreased HgA1c by 0.15% and glucagon by 3.3 pmol/L/h, and increased insulin by 37 pmol/ L/h, GLP-1 by 8.8 pmol/L/h, and GIP by 51.3 pmol/L/h. Postprandial hyperglycemia was decreased. The decrease in HgA1c occurred despite normal baseline HgA1c, and contrary to previous studies on patients who had type 2 diabetes, there was no change in FPG. It is evident that vildagliptin is effective in improving glycemic control and the b-cell function in patients who have mild hyperglycemia, as in patients who have severe hyperglycemia. A study was conducted to evaluate the efficacy and risks of vildagliptin as monotherapy in elderly patients.53 Vildagliptin as monotherapy in 100 mg daily doses (50 mg twice daily or 100 mg once a day) were studied over 24 weeks in younger (less than 65 years; n 5 1,231) and older (R65 years; n 5 338) patients and the data from five double-blind, randomized, placebo-controlled trials were pooled. The study also included active groups who were treated with either metformin (1,000 mg twice daily) or one of the TZDs (pioglitazone 30 mg daily or rosiglitazone 8 mg daily). The baseline HgA1c in older patients was 8.3 0.1%, which dropped by 1.2 0.1% whereas the baseline HgA1c in younger patients was 8.7 0.0%, which dropped by 1.0 0.0%. Vildagliptin did not increase the adverse side effects in 62% of the older patient population with mild renal impairment and hypoglycemia was rare (0.8%). These results showed that vildagliptin is effective and tolerated well in elderly patients. Vildagliptin (50 mg twice daily) was compared with metformin (1000 mg twice daily) on 780 type 2 drug-nave patients with baseline HgA1c between 7.5% and 11.0%.54 In this 52-week double-blind, randomized, multicenter, parallel group study HgA1c was measured over the study period. At the end of the study, both vildagliptin and metformin reduced HgA1c by 1.0% 0.1% (p 5 <0.001) and 1.4% 0.1% (p % 0.001), respectively. The number of patients who experienced adverse effects was almost similar in the vildagliptin (70.1%) and metformin (75.4%) groups. However, metformin was associated with three- to fourfold greater incidence of diarrhea, nausea and abdominal pain. The incidence of hypoglycemia was equally low with both drugs. Vildagliptin (50 mg twice daily) also has been compared with rosiglitazone (8 mg once a day) as monotherapy in a 24-week study on 786 patients who had type 2 diabetes.55 In this doubleblind, randomized study, monotherapy with vildagliptin and rosiglitazone decreased HgA1c to a similar extent during the 24-week period. At the end of the study, vildagliptin caused a reduction in HgA1c by 1.1 0.1% (p 5 <0.001), whereas rosiglitazone decreased HgA1c by 1.3 0.1% (p 5 <0.001). FPG decreased more with rosiglitazone (-2.3 mmol/L) compared with vildagliptin (1.3 mmol/L). Rosiglitazone, but not vildagliptin, caused an increase in body weight (11.6 0.3 kg; p%0.001). Incidence of edema was greater with rosiglitazone (4.1%) compared with vildagliptin (2.1%), but the incidence of other adverse effects was similar between the two drugs. Vildagliptin has been shown to be efficacious in treating type 2 diabetes as an add-on therapy with metformin.56,57 Vildagliptin in 50 and 100 mg daily doses was evaluated for its antihyperglycemic effect on 544 type 2 diabetic patients who were controlled inadequately (HgA1c 7.5% to 11.0%) on metformin (R1500 mg daily) therapy.57 At the end of 24-week study period, the between-treatment difference (vildagliptin placebo) was 0.7% 0.1% (p < 0.001) and 1.1% 0.1% (p < 0.001) with 50 and 100 mg daily doses of vildagliptin, respectively. The between-treatment difference in FPG was 1.8 0.3 mmol/L (P 5 0.003) and 1.7 0.3 mmol/L (p < 0.001) in patients receiving 50 or 100 mg vildagliptin daily, respectively. Two doses of vildagliptin and placebo had similar incidence of adverse effect; however, GI adverse effects were higher in the placebo group than groups receiving either of the two doses. This study shows that vildagliptin at both doses is effective in improving glycemic control in patients who are not optimally controlled with metformin monotherapy. Hypoglycemia was rare and weight gain was insignificant. Similar results were observed in another study by Ahren and colleagues.56 Vildagliptin also has been demonstrated to be effective in improving glycemic control when added to the on-going treatment with pioglitazone.58 In this 24-week multicenter, double-blind, randomized, parallel group study, vildagliptin at 50 and 100 mg daily doses was compared with placebo as an add-on therapy to maximumdose pioglitazone (45 mg daily) treatment in 463 type 2 diabetic patients who were controlled

inadequately with prior TZD monotherapy. Vildagliptin showed a dose-dependent decrease in HgA1c; 50 and 100 mg daily doses reduced HgA1c by 0.8% 0.1% (p 5 0.001 versus placebo) and 1.0% 0.1% (p < 0.001 versus placebo), respectively. With a similar aim as in the previous study but a different study design, vildagliptin was compared with pioglitazone as monotherapy, and the two drugs were tested as a combination therapy.59 In this 24-week randomized, double-blind, multicenter study 607 type 2 diabetic patients had baseline HgA1c of approximately 8.7%. Pioglitazone (30 mg daily), vildagliptin:pioglitazone (50/15 mg daily) combination, vildagliptin:pioglitazone (100/30 mg daily) combination, and vildagliptin (100 mg daily) showed an adjusted mean change in HgA1c of 1.4% 0.1%, 1.7% 0.1%, 1.9 0.1%, and 1.1% 0.1% from baseline, respectively. These results indicate that both combinations were more potent in reducing HgA1c compared with pioglitazone alone (p 5 0.039 and p < 0.001, respectively). In the high-dose combination therapy, 65% patients achieved HgA1c of 7%, with a tolerability profile similar to pioglitazone 30 mg daily monotherapy. Furthermore, the low-dose combination (50/15 mg daily) had better efficacy and tolerability benefit over pioglitazone 30 mg daily monotherapy. The adverse events ranged from 45.8% in the low-dose combination group to 51.6% in the pioglitazone monotherapy group. Pioglitazone monotherapy was associated with dose-dependent peripheral edema (up to 9.3%). Hypoglycemic events were minimal. These results indicate that vildagliptin/pioglitazone combination may be a more effective initial oral pharmacotherapy than either drug alone for managing type 2 diabetes. Often type 2 diabetes remains uncontrolled on both oral medications and insulin. Vildagliptin was studied as an add-on therapy to insulin in a 24-week multicenter, double-blind, randomized, placebo-controlled, parallel-group study on 296 type 2 diabetic patients who were controlled inadequately (HgA1c 57.5% to 11%) on insulin.60 While on insulin therapy, 144 patients received vildagliptin (50 mg twice daily), and 152 patients received placebo. Patients had a baseline HgA1c of 8.4% 0.1%. The adjusted mean change in HgA1c from baseline (AMD) was 0.5% 0.1% for vildagliptin group and 0.2% 0.1% for the placebo group, with a significant difference between the interventions (p 5 0.01). In patients older than 65 years, the AMD HgA1c was 0.7% 0.1% in the vildagliptin group versus 0.1% 0.1% in the placebo group (p % 0.001). Vildagliptin treatment and placebo were associated with equal number of adverse events (81.3% and 82.9%, respectively). Hypoglycemic events with vildagliptin, however, were less common (p < 0.001) and less severe (p < 0.05) compared with the placebo group. This study demonstrated that vildagliptin improves glycemic control in patients who are not at goal with insulin. Furthermore, the drug is associated with fewer incidents of hypoglycemia.