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Articel from 'Arzneimittelbrief'

Author Dr. Jochen Schuler, cardiac catheterization laboratory Salzburg

Dr. Schuler regularly writes articles on cardiology topics in independent media ' Arzneimittelbrief'.


The drug Letter 2010 , 44, 17 Perioperative drug management : inhibition of platelet function in cardiovascular diseases

Many patients who need surgery , have heart disease, and therefore obtain inhibitors of platelet function. Specifically, patients in whom vascular operations are planned , and diabetics often have a coronary heart disease (CHD ; prevalence 30-50 % , 1) . Most received acetylsalicylic acid (ASA) for secondary prevention , some even a dual inhibition of platelet function with aspirin plus clopidogrel ( Iscover ® , Plavix ®) , such as the majority of patients with coronary stents. It is mentioned here only clopidogrel. The statements , however, are transferable to the second approved ADP blockers prasugrel ( Effient ®). Approximately 5% of stent patients to be operated on within one year after implantation ( at heart , 2) . With them each the question arises whether the existing inhibition of platelet function without large cardiac risks can be paused in order to minimize the perioperative bleeding risk .
The discussion on this topic reveals conflicts between surgeons , internists and neurologists because of their very different perspective on the problem .
Operations under ASA increase blood loss by about 20-30 % and dual inhibition of platelet function ( aspirin plus clopidogrel ) to 50 % (3) . The latter also results in an increased need for transfusion . Most surgeons fear the intra-and postoperative bleeding and its consequences and therefore want a timely aspirin or clopidogrel break. The summons for operation is therefore associated in most cases with the Note to sell any anticoagulant or aspirin and clopidogrel.
However, this automated approach is dangerous in certain situations and sometimes even negligent. On the one hand , because the discontinuation of antiplatelet drugs may lead to enhanced platelet activation in terms of rebounds ( 4) , on the other hand , because patients can suffer serious complications if their cardiovascular baseline risk is underestimated perioperatively .
In order to decide whether in cardiovascular diseased patients perioperatively drug inhibition of platelet function may be paused , three questions must be answered:

1 How urgent is the planned operation?
2 How important is the inhibition of platelet function for the patient ?
3 How great is the risk of bleeding in the planned operation ?

These questions can not be answered and decided by one discipline alone usually . The communication between surgeons , internists , neurologists, and anesthesiologists is essential.
Question 1 (precedence) : When scheduled, non -cardiac surgery three priority levels can be distinguished: emergency interventions , urgent surgery and elective procedures ( Fig. 1) . If you require emergency interventions ( vital indication ) is required , the question of the cessation of platelet inhibition . In general, it has renewed five days until the platelet pool halfway with functional platelet lasts . Since there is no possibility to antagonize , must be used in these patients with bleeding complications in platelet concentrates .
Elective surgery in patients with high cardiovascular risk within certain critical time intervals after stent implantation or myocardial infarction (see below) must be avoided. You must be postponed to a later date. Only at low cardiovascular risk may elective surgery and antiplatelet be paused .
In urgent intervention is naturally the discussion needs are greatest . This is mostly like to unforeseen interventions, such as resection of newly discovered tumors , surgical treatment of fractures, polypectomy , larger gear meshing These operations should be as late as possible after the cardiovascular event (stroke, myocardial infarction, stent implantation), and at least in the ASA - protection. In some patients, even a bridging treatment ( " bridging" ) with reversible GP-IIb/IIIa-Blockern ( tirofiban = Aggrastat ® , eptifibatide = Integrilin ®) can be attempted. Such interventions should generally be carried out in the vicinity of a catheter center with 24-hour standby .
Heparins are not substitutes for antiplatelet ! A " bridging" with low molecular weight heparin after discontinuation of aspirin and / or clopidogrel is
Although many places common , but ineffective as a substitute and therefore risky (4, 5).

Question 2 (individual importance of platelet inhibition) : The second question is to ask after each individual underlying cardiovascular risk , since it offers derives the need for inhibition of platelet function.
Surgical candidates with low cardiovascular baseline risk are those who have never had a cardiac or neurological event had (primary prevention) or after a cardiac event a long time ( at least a year , even longer is better) were clinically stable . With this constellation of antiplatelet agents can be paused with reasonable risk . An exception are patients with a drug-eluting stent ( drug-eluting stent = DES ) , as this also can close thrombotic years later. These patients should be operated always under ASA protection.
Surgical candidates with high cardiovascular baseline risk are those who have an acute coronary syndrome (ACS ) experienced within the past year or received a coronary stent. Please note: the closer back is the event , the higher the risk . For example, if Patients within the first four weeks after stent implantation surgery (not heart) must be , the cardiac complication (myocardial infarction , re- PTCA , stent thrombosis , death) extremely high (30-50 %), even if the OP under dual inhibition of platelet function is (3). During this time , therefore, only emergency interventions with vital indication shall be permitted. The cardiac risk decreases with uncoated stents ( bare metal stents = BMS) after three months to <5 % in DES there remains at least one year in> 10% . During this time, urgent operations must be carried out according to strict indications , but only under continuous inhibition of platelet function ( at least ASA) . The only exceptions are OP with very high risk of bleeding (see below) .

The most feared complication of aspirin / clopidogrel - break is the stent thrombosis . This is associated with a mortality rate of 20-45 % and very high morbidity (heart failure , ventricular arrhythmias ) (1 , 2). Risk factors for stent thrombosis are complex coronary interventions and complex anatomical vascular conditions , advanced age , diabetes, renal failure , low left ventricular ejection fraction ( LVEF) , hypotension during surgery and - by far the most important - the early exit of platelet inhibition ( 90 -fold increase in the risk , 6) . Therefore: a patient has less than three months earlier, a BMS or less than 12 months before received a DES,
he should , if at all feasible, do not have surgery. This also applies to patients who have had a myocardial infarction, a coronary intervention (PCI) , or stent without a stroke less than six weeks earlier .
The consequences of bleeding in the surgical field are clinically classified as a stent thrombosis or reinfarction as less important. Beyond the stated times (ie > six weeks after myocardial infarction, > three months after BMS or > twelve months following DES) the operation should be absolutely under ASA protection.
After perioperative aspirin and / or clopidogrel break this therapy is the earliest possible date resume (depending on wound conditions ) . Probably it is even advantageous to start with a " loading dose " .

Question 3 (bleeding risk) : This depends on several factors , not only by the concomitant medication ( antiplatelet drugs , SSRI , gingko preparations , etc.). Surgical field , surgical tactics and luck, clarity and compressibility in the circulation area are also important factors. Therefore, ( above), only experienced surgeons and gentle techniques are used in high-risk patients. In an uncompromising hemostasis is ensured. Platelet concentrates and coagulation factors may be indicated for severe bleeding .
There is no agreement as to which operations are to be regarded as particularly risky circulation and which less. In many publications, the following classification is made:
A low risk of bleeding or bleeding com-pressible with very rare transfusion requirements have minor orthopedic , ENT , dermatology , plastic , vascular and general surgical procedures as well as endoscopy with biopsy , surgery of the anterior chamber of the eye (cataract ) and dental surgery. These interventions can quite safely executed under antiplatelet drugs .
An average bleeding risk ( occasional to regular transfusion requirements ; usually insatiable bleeding ) can be found in interventions in visceral surgery ( thyroid , liver, pancreas) , heart surgery, major orthopedic surgery, ENT and reconstructive surgery , endoscopic urology and endoscopic polypectomy . In these operations, a dual antiplatelet therapy is very risky and should not be moved until they
more is required .

A very high risk of bleeding is found in interventions of intracranial neurosurgery, spinal surgery and surgery on the sensory organs , particularly the posterior chamber of the eye ( glaucoma) . These interventions should generally be performed because of the high risk of permanent damage caused by bleeding without platelet inhibitors. Such " unprotected " interventions , however, should only be performed at centers with 24 -hour catheter willingness to intervene in a postoperative acute coronary syndrome right away.
A decision algorithm for patients with high and intermediate cardiovascular risk is proposed in Figure 1.

1 ACC / AHA 2007 Guidelines on Perioperative Cardiovascular Evaluation and Care for noncardiac surgery : Circulation 2007 , 116, E418 . Erratum : Circulation 2008 , 117, E154 and 2008.118 , E143 .
2 Vicenzi , M.N. , et al.: Br J Anaesth . 2006 , 96, 686
3 van Kuijk , J. P. , et al.: Am. J. Cardiol . 2009 , 104, 1229.
4 Möllmann , H., et al . Clin. Res Cardiol . 2009 , 98, 8
5 Chou , S., et al . Rev. Cardiovasc . Med 2009 , 10, 209 6 Iacovou , I., et al . JAMA 2005 , 293, 2126th

The drug Letter 2012 , 46, 62a Early surgery versus conventional therapy for complicated left heart endocarditis
We have reported several times about the value of the operating valve replacement in infective endocarditis ( 1 , 2). Especially with Staph aureus endocarditis , valve replacement is usually necessary . Controversially , however, is the indication and the timing of surgery in left heart endocarditis. It applies in particular to prevent embolic events , which contribute significantly to morbidity and mortality in this disease. The American guidelines (American College of Cardiology - American Heart Association) recommends an early surgical valve replacement only in recurrent emboli and persistent vegetation on the heart valve ( 3). In the guidelines of the European Society of Cardiology however, a valve surgery is recommended when the vegetation is greater than 15 mm in diameter (4). A clinical study was conducted on this issue for the first time presented (5).
Patients from South Korea with left heart endocarditis and large vegetations (diameter of the vegetation on the aortic or mitral valve > 10 mm) were randomized into two groups. Group 1: operation ( n = 37 ) within 48 h after the diagnosis and start of antibiotic therapy. Group 2: These patients (n = 39) were guidelines -compliant and in accordance with the pathogens initially treated only with antibiotics (conventional group). The primary endpoint of the study was defined from death and / or embolic events in the first six weeks after randomization.
Because predefined acute complications or persistent symptoms ( embolism , persistent fever, valvular insufficiency , persistent vegetations in size ) were obtained from the conventional group 30 (77%) patients underwent surgery , 27 yet . During hospitalization and three in the follow-up The primary endpoint was in one patient ( 3%) of group 1 and in nine ( 23%) of group 2 reached ( hazard ratio HR: 0.1 , 95% CI: 0.01-0.82 , p = 0.03). In group 1, one patient died during hospitalization and none had an embolic event. In Group 2, also one patient died during hospitalization and eight had embolic events. A composite endpoint of death and / or embolic event and / or recurrence of endocarditis after six months occurred in 3% of patients in group 1 and in 28% of Group 2 (HR : 0.08 ; CI: 0.01 to 0 , 65 , p = 0.02). Overall, the mortality rate was lower than expected according to the results of other studies in this study. This may be due to the surgical procedure are a total aggressive (there were still operates 77 % of patients in the conventional group ) or to the low proportion ( approximately 10%) of Staph aureus endocarditis in this study.

Conclusion: According to this study is superior to left heart endocarditis with large vegetations , an early surgical valve replacement of conventional therapy.

1 AMB 2007 , 41, 78b.
2 AMB 2012 , 46, 04b .
3 Bonow , RO, et al . Circulation 2006 , 114, e84 16,880,336th Errata : Circulation 2007 , 115, and 2010 E409 , 121, E443 .
4 Habib , G., et al . Eur.Heart J. 2009, 30 , 2369th
5 Kang, D.H , et . al. ( EASE = Early Surgery versus Conventional treatment in infective endocarditis ) : N.
Engl J Med 2012 , 366, 2466th

The drug Letter 2012 , 46 , 33 Renal Sympathikusdenervierung in refractory arterial hypertension
In some patients with hypertension , the blood pressure can not be satisfactorily reduced despite medical polytherapy . For these refractory patients for two years, a catheter interventional procedures are available , the kidney breaks the connection of the sympathetic nerves at least partially . The method and the special catheter was originally developed by a U.S. company called Ardian and sold last year for 800 million U.S. $ in the industry giants Medtronic. Medtronic expects to have great gains from this investment , and the media can be harnessed to the carts marketing . In several major print media and on television has been repeatedly and openly campaigned for the young process . According to the manufacturer already over 2,000 patients were treated until February 2012 worldwide . Presumably, the numbers in the coming months will explode , should no significant complications are known. This dynamic is medically not rational, because so far only four small clinical trials have been completed with a total of fewer than 300 patients and published ( 1) , including only a single randomized controlled .
With the RSD , the kidneys are at least partially decoupled from the sympathetic nervous system. About efferent sympathetic nerve fibers different functions of the kidneys are also controlled , eg Renin , sodium and volume retention and reduction of renal blood flow , and thus the glomerular filtration rate. About afferent sympathetic renal able to increase central sympathetic tone . Already in the 50 years it has recognized the link between the renal nerves and hypertension and tries to denervieren the kidneys with a scalpel . The perioperative complications were so frequent that the method was abandoned . Using electrophysiological materials, it is now possible to perform such denervation much gentler . About the femoral artery is a (4000 € more expensive) advanced ablation catheter in the renal arteries , where the running in the adventitia transmural nerve fibers are laid waste by means of radio frequency energy. With the currently approved system an energy of up to 8 watts each for two minutes released into the arterial wall in the renal artery at 4-6 spiral offset points. The procedure is painful and requires a good sedation . Approximately 10% of patients suffer periprozedural passager sinus bradycardia . In the future, the RSD may run faster and more convenient by multipolar catheters and lower energy output , so that many already speak of a " One Stop " therapy . However, there are anatomical contraindications, eg Renal artery stenosis or very small renal arteries.
After denervation , the systolic blood pressure falls by about 30 mm Hg and the diastolic by about 10 mm Hg He falls off rapidly in some patients , in others only after a few weeks. About 15% are " non-responders " . The success of the measure can ultimately only be judged after six months.
The first 45 patients were treated in 2007-2008 ( 2) and the two-year results of these and other 108 patients published in 2011 (3). The mean age of this first 153 treated patients was 57 years , 39 % were women , 31 % diabetics. The baseline blood pressure was an average of 176/98 mm Hg on average five different antihypertensive agents. The blood pressure reduction was after 1, 6, 12 and 24 months 20/10 , 25/ 11, 23/11 and 32/ 14 mm Hg Four procedural complications occurred : three pseudoaneurysms of the femoral artery and dissection of the renal artery , in each case without permanent damage . Orthostatic blood pressure drops , electrolyte imbalance or significant changes in GFR did not play a role in these two years . In 81 patients after six months, the renal arteries were depicted . There were no consistent changes in the ablation showed . In a patient in a pre-existing renal increased, so that a stent was implanted.
In the only previous randomized, controlled trial of RSD , the Symplicity HTN - 2 study ( 4) , were in 2009 multicenter 106 patients with a systolic BP ≥ 160 mm Hg ( ≥ 150 mm Hg in diabetes mellitus type 2) despite medical polytherapy ( an average of five antihypertensive drugs ) included. The age could be from 18 to 85 years . The calculated GFR had to be > 45 mL / min. Patients received either a RSD (n = 52) or have been further treated in conventional (control group , n = 54). In the RSD group of high blood pressure decreased significantly from (32/ 12 mm Hg , p < 0.0001 ) in the control group it remained almost the same. However, the number of antihypertensive drugs was reduced in the RSD group only 20% of patients in the control group at 6 %.
After RSD a pseudoaneurysm and one patient developed was hypotensive after the procedure. One patient had to be treated for one month analgesic because of prolonged back pain. In 43 patients after six months, the renal arteries were controlled. There were no permanent damage in the area of ​​ablation showed .
Currently running several clinical studies that deal with specific aspects or the effects of RSD , such as hypertensive heart failure ( HF SYMPLICITY ) , metabolic syndrome ( DREAMS ) , obstructive sleep apnea or ESRD. In one study, a decrease of left ventricular hypertrophy and improvement of diastolic heart function was measured (8 ) to RSD . In addition, most patients are recognized in international and regional registers. A total of 27 studies and register for RSD are currently logged in ( 1) at the National Institutes of Health.
The RSD should not be performed before an experienced Hypertensiologe , which does not perform the method itself , has attempted blood pressure lege artis normalize with drugs .

Conclusion : Renal Sympathikusdenervierung (RSD ) is a new , interesting, expensive and painful interventional method in so-called resistant hypertension . A reduction in blood pressure of about 30 mm Hg systolic and 10 mm Hg diastolic is to be expected , however, remains engaged in 15% of patients without the desired effect . The current euphoria that accompanied the RSD seems to us more from marketing as influenced by science. In view of the few studies with small numbers of patients and lack of data on long-term clinical
Effects (reduction of stroke or mortality ? ) Should be limited interventions to a few centers , and all patients in a register ( eg GREAT = German Renal denervation Registry , 6, 7) are recorded . No drug would be approved on the basis of such a thin data layer. But apply to medical devices , unfortunately, another, much too lax requirements (see 5).

1 ( last access : 5.4.2012 ) .
2 Krum , H., et al . Lancet2009 , 373 , 1275th
3 Krum , H., et al ( Symplicity HTN -1 Investigators ) . Hypertension 2011 , 57, 911
4 Esler , MD, et al ( Symplicity HTN -2 Investigators ) . Lancet 2010 , 376, 1903.
5 AMB 2010 , 44, 09th AMB 2012 , 46, 15b.
6 Mahfoud , F., et al . Dtsch . Arztebl . Int. 2011 , 108.725 .
7 Mahfoud , F., et al . Dtsch . Med Wochenschr . 2011 136.2418 .
8 Brandt, M. C. , et al.: J. Am. Coll . Cardiol . 2012 , 59, 901

The drug Letter 2012 , 46 , 29 treatment of peripartum cardiomyopathy
A sudden onset heart failure during the last weeks of pregnancy to six months after birth is called Peripartum cardiomyopathy ( PPCM ) . In about one in 3,000. to 4000. Pregnancy occurs such PPCM . Since this disease has not been systematically collected, one has to rely on information on the incidence of smaller register and expert estimates. The European Society of Cardiology ( ESC) has established in 2010 a working group PPCM (1). The diseases to be collected in Heart Failure Registry (2). A genetic predisposition is most likely because black Africans and Haitians (1:100) significantly more frequent in PPCM cancer than Europeans .
PPCM is highly variable in their clinical course. Sometimes it opens very quickly in a terminal heart failure. In a first manifestation must be assumed that a maternal mortality rate of 10 % and a complete remission at <30 %. Women who ever had a PPCM and get pregnant again , usually fall ill again and violent about it. They must therefore be discouraged from getting pregnant again urgently .
The PPCM arises echocardiography as dilated cardiomyopathy with enlargement of the left ventricle and low ejection fraction (LVEF <45 %). In addition to the clinical signs of heart failure (leg edema, cough , fatigue ) and thromboembolism may occur in more pronounced reduction in LVEF . With appropriate symptoms of PPCM should rapidly cardiological diagnostics done ( echocardiography, proBNP ) in order to start early with the therapy. A late start of treatment is prognostically unfavorable. Unfortunately, the previously healthy women is often too late thought of PPCM and eg the cough misinterpreted as bronchopulmonary infection .
Treatment of PPCM is difficult because the causes are not entirely clear and also the health of mother and child are taken into account. Therapy for congestive heart failure is as ACE inhibitors or angiotensin II receptor antagonist , aldosterone antagonist ( these are all not in pregnancy) , diuretic, beta-1 - selective beta blocker and additionally anticoagulant ( heparin ) in an LVEF < 35%. rapidly
progressive heart failure , the patient should be laid early in a center that has the possibility for mechanical cardiac support . In maternity cases as possible should be used all of the above ingredients , and also they should stop breast-feeding . By weaning the child is not exposed to the drugs and possibly eliminated one cause of PPCM . During pregnancy to ACE inhibitors , angiotensin II receptor antagonist and aldosterone must be avoided because of the risk of fetal damage. As a replacement stand ( the afterload ) hydralazine and / or nitrates available. At great danger to the mother's life , the pregnancy must be terminated. How this is best done is described in detail in the position paper of the ESC ( 1).
A more specific therapeutic approach may dopaminergic inhibitor of prolactin secretion (eg bromocriptine, cabergoline ) . In addition to an inflammatory etiology a genetic defect in prolactin degradation is discussed in PPCM over again. Prolactin during pregnancy and lactation is secreted in large quantities by the anterior pituitary gland to control the growth of the mammary glands, lactation and involution of the uterus after birth. Pathological prolactin degradation products may be responsible for apoptotic and anti- angiogenic effects in the myocardium. The inhibition of prolactin secretion with bromocriptine in mice resulted in a PPCM model ( STAT3 knockout mice ) to a significant improvement or complete prevention of myocardial damage ( 3). These observations have led to several observational studies and smaller studies . In a randomized, "open label proof of concept" study received ten South African pregnant women with newly diagnosed PPCM standard therapy of heart failure and ten women in addition bromocriptine for eight weeks (4). The clinical course during six months was evaluated in a blinded . In the bromocriptine group died one of the ten women in the group without bromocriptine died four . In addition, the LVEF (27% from 27% to 58 % vs 36% . , P = 0.012 ) improved in women with bromocriptine stronger than in the controls. The results of this pilot study have a larger phase II study initiated , coordinated in Hanover. The objective is to include 60 women and to randomize (5).
Unfortunately, many side effects, bromocriptine (hypotension , mental disorders ) and is only very reluctantly used in obstetrics . Alternate substances such as tolerated Cabergoline was also tested for the indication PPCM (6).

Conclusion: Postpartum cardiomyopathy is rare in Europe , of course , but often very unfavorable. It is important to recognize symptoms of heart failure at a high pregnant or have recently given birth early and treated quickly with medication is . Immediate cessation of breastfeeding seems to be pathogenic or therapeutically beneficial. The therapeutic effect of Abstillmedikamenten such as bromocriptine is currently being investigated by the first favorable outcomes in randomized trials. Appropriate therapy trials should be documented necessarily in registers.

1 Sliwa , K., et al . Eur Heart Failure J. 2010 , 12, 767
3 Hilfiker -Kleiner , D., et al.: Cell 2007 , 128, 589
4 Sliwa , K., et al . Circulation 2010 , 121, 1465th
5 ...
6 de Jong , J. S. , et al.: Eur Heart Failure J. 2009 , 11, 220

The drug Letter 2012 , 46, 17 Antithrombotic triple therapy in cardiovascular risk patients
After a myocardial infarction ( STEMI , NSTEMI ) or stent implantation , there is a great risk of recurrence in the first few months . Therefore, after infarcts recommended a 12-month and after implantation of a DES is a 6- 12-month dual inhibition of platelet aggregation ( 1-3).
Problematic because fraught with greater risk of bleeding is the situation when patients additionally oral anticoagulation ( OAC ; phenprocoumon or warfarin) need , eg for atrial fibrillation . This situation is to be expected at least 6-8 % of the patients after the ACS (1) and will become even more common because of the increasing age of the population .
An assumed situation as an example of the complicated considerations for the indication of OAK : A 76 year old female patient with chronic atrial fibrillation and multiple comorbidities with a serum creatinine of 2 mg / dl has einenCHA2DS2 - VASc score ( 4, 5; see Figure 1) of 5 , which corresponds to a very high annual risk of stroke of 6.7 % (6) . According to current guidelines on the procedure for atrial fibrillation , the patient should therefore be anticoagulated orally ( 6). If they must now additionally a year get a dual platelet inhibition due to an intercurrent ACS , the dilemma is perfect because is impossible to assess whether, in view of the very high risk of bleeding , the risk-benefit ratio of such antithrombotic triple therapy is favorable. The HAS- BLED score ( 8) helps to estimate this risk ( see Figure 2). A value> 2 is considered high-risk situation (6). If the described patient under OAK has fluctuating INR values ​​, they must as a risk patient for a non- fatal haemorrhage apply (HAS - BLED score 3). Thus, the potential benefits of triple therapy as stroke and ACS prophylaxis would be offset by a significantly increased risk of bleeding .
According to a large Danish registry that included > 118 000 patients with atrial fibrillation, is under antithrombotic triple therapy, a 4- 5-fold higher risk of non- fatal bleeding compared with OAC alone (7, see Table 1). The risk of bleeding of the described patient is therefore at> 15% / year. Probably , it is even higher, because the trapped in the Register patients had been previously selected by their physicians and had received triple therapy only at relatively low eingeschätztem risk of bleeding.