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Author Dr. Jochen Schuler, cardiac catheterization laboratory Salzburg

Dr. Schuler regularly writes articles on cardiology topics in independent media ' The pharmaceutical letter ' .

 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.
Therefore, the European Society of Cardiology (ESC ) recommends in patients with atrial fibrillation and indication for OAC at ACS a triple antithrombotic therapy for a maximum of six months, and even then only if there is no increased risk of bleeding (HAS - BLED score ≤ 3). The INR should be set at a triple therapy as accurately as possible between 2 and 2.5 and closely monitored. Other drugs that interfere with blood clotting (SSRI = selective serotonin reuptake inhibitors, NSAID = nonsteroidal anti-inflammatory drugs , ginkgo biloba) , should be avoided . For the period of triple therapy ulcer prophylaxis with a proton pump inhibitor should be considered individually , because the gastrointestinal tract is the most common source of bleeding (1).
In a HAS- BLED score ≥ 3, the time should be limited to the triple therapy to only four weeks ( see Table 2). From this recommendation follows that display the implantation of a DES in patients at high risk of bleeding and atrial fibrillation contraindicated
is . In ACS with implantation of a BMS and high risk of bleeding after the triple therapy , dual therapy with OAC plus 75 mg / d clopidogrel (alternatively, low-dose aspirin ) to the end of the 12th Month recommended ( see Table 2). The combination with ASA is according to data from the Danish register potentially safer (see Table 1). After 12 months should be with OAC alone (INR 2-3 ) can be further treated . This is sufficient , because OAK are also in the secondary prevention of CHD effective ( 9).
These recommendations from the ESC , however, to say that it is based on rather weak evidence , because they mostly have only the grade of recommendation 2b ( benefit is not well documented ) and only one level of evidence C ( expert consensus , 2) .
This difficult situation has recently been even more complicated , because in addition to aspirin and clopidogrel in the meantime two other ADP receptor blockers are available ( prasugrel = Effient ® , see 10; ticagrelor = Brilique ® , see 11 ), and in addition to the classical vitamin K antagonists at least one other alternative is for oral anticoagulation ( dabigatran = Pradaxa ® , see 12). Probably soon followed by two other agents ( apixaban = Eliquis ® , Rivaroxaban = Xarelto ® , see 13). Thus, mathematically exist soon at least 12 ways triple therapy .
The new oral anticoagulants have no escape from the security dilemma of triple therapy according to current knowledge . In three Phase II trials , respectively , the risk-benefit relation of a combination of aspirin plus clopidogrel with one of the new drug was compared. The ATLAS ACS -TIMI 46 study evaluated rivaroxaban ( 14) , the APPRAISE trial apixaban ( 15) and the RE- DEEM study dabigatran (16 ) in triple combination . The intention of this study was to improve the prognosis of any one ACS by a triple therapy on. None of these studies was able to demonstrate a significant reduction in second events at ACS . However, for this many patients had been recruited not sufficient. Primary endpoints were each bleeding complications after 180 days. For all three compounds bleeding complications increased in a dose -dependent up to > 20% within half a year . The APPRAISE study was therefore even canceled. This is remarkable , because patients with high bleeding risk or an indication for OAC of the study may not be awarded in each case . Elderly patients with acute coronary syndrome , atrial fibrillation and not stable renal function may have no advantage of the new anticoagulants , because the anticoagulant effect is not measured in renal function, they accumulate and Antidote does not yet exist .

Summary : Antithrombotic triple therapy consisting of an oral anticoagulant (eg phenprocoumon, warfarin) plus dual inhibition of platelet aggregation , should be avoided because of the high risk of bleeding . Patients with chronic atrial fibrillation and indication for oral anticoagulation should therefore at an acute myocardial infarction or acute coronary syndrome (ACS ) only in exceptional cases a coated coronary stent (drug eluting stent = DES ) receive , because it necessarily the indication would be added to a triple therapy and Although only if no increased risk of bleeding . The risk of bleeding can be estimated with different scores. Currently, the HAS- BLED score is predominantly used ( see Figure 2) . In a HAS- BLED score> 2 OF are contraindicated. According to ACS in atrial fibrillation duration of triple therapy should be as short as possible while keeping the individual bleeding risk are taken into account. The INR should be not > 2.5 at a triple therapy and be monitored closely. Are unclear indication for
Triple therapy and a general procedure in patients after mechanical valve replacement or with a history of thromboembolism , in which the INR should be > 3 .

1 Hamm, C. W. , et al. :
2 STEMI Guidelines derESC : Eur Heart J. 2008 , 29, 2909th
3 ESC Guidelines onmyocardial revascularization : Eur Heart J. 2010 , 31, 2501.
4 Lip , G.Y.H. , et al.: Chest 2010 , 137, 263
5 Olesen, J. B. , et al . BMJ2011 , 342, d124 .
6 ESC Guidelines for topic management of atrial fibrillation : Eur Heart J. 2010 , 31, 2369th
7 Hansen, M. L. , et al : Arch. Intern. Med 2010 , 170, 1433.
8 Pisters , R., et al.: Chest 2010 , 138, 1093rd
9 Hurlen , M., et al. ( WARIS II = warfarin , aspirin, reinfarction Study II ) : N. Engl J Med 2002 , 347.969 .
10 AMB 2009 , 43,31 a; AMB 2011 , 45, 01; AMB 2011.45 , 84
11 AMB 2010 , 44.19 ; AMB 2011 , 45, 84
12 AMB 2010 , 44,06 b , AMB 2011 , 45, 07a ; AMB2011 , 45, 88
13 AMB 2011 , 45, 73
14 Mega, J. L. , et al. ( ATLAS ACS -TIMI 46 = rivaroxaban in combination with aspirin alone orwith aspirin and thienopyridine in patients with a AcuteCoronarySyndromes ) : Lancet2009 , 374 , 29
15 Alexander , J. H. , et al. ( APPRAISE = Apixaban for Acute Ischemic and Safety Events PReventionof ) : Circulation2009 , 119, 2877th Oldgren , J., et al (RE- DEEM = dabigatran etexilate dose finding study randomized multi -center , prospective , placebo- controlled , cohortdose escalation study . ) : . Eur. Heart J. 2011 , 32, 2781st

The drug Letter 2012 , 46, 13 When and how should a very elderly patient should be treated antihypertensive ?
Funded by the British Heart Foundation and Servier multicenter HYVET study from 2008 showed that antihypertensive therapy in elderly hypertensive cardiovascular morbidity , particularly strokes , and mortality significantly reduced ( 1). Reminder: in HYVET were 3,845 hypertensive patients > 80 years (mean 83.6 years ) with systolic blood pressure over 160 mm Hg, and very few comorbidities double- blind treatment with 1.5 mg / d sustained-release indapamide ( Natrilix ® , generics) or randomized placebo ( Step 1). Was with the follow-up visits , the blood pressure remains above the systolic target of 150 mm Hg, was the ACE inhibitor perindopril ( Coversum ® , generics) 2 mg / d ( Step 2 ) or 4 mg / d ( Step 3) or placebo will be added .
After two years, the RR target of 48% in the active treatment and of 19.9 % was achieved in the placebo group . The blood pressure was verum average by 15/ 6 mm Hg lower than with placebo. HYVET ended prematurely after a median treatment duration of 1.8 years , as in the placebo group , significantly more patients had died (196 vs . 235) . Overall, the mortality rate in this study was about 5% / year for this age group is very low , which might be due to the small number of comorbidities ( heart failure, 3% , 7% diabetes).
According to the intention-to -treat analysis , there was to study discontinuation under active treatment to 30% less non-fatal strokes and 39% fewer stroke - related deaths in the placebo group . The overall mortality was reduced by antihypertensive therapy by 21% and the incidence of heart failure by 64 %.
The " number needed to treat " ( NNT ) to prevent a stroke within two years was calculated by the authors with 94 and one death at 40. There was no evidence that the antihypertensive therapy of the old hypertensive patients was less well tolerated than placebo . It was at that time concluded that antihypertensive treatment with indapamide and possibly ACE inhibitors for hypertension patients > 80 years is useful (1). Restrictive must be pointed out again that the patients were otherwise quite healthy. Thus, whether the results are transferable to polymorbide elderly patients is not clear. In general, one should also take here : the larger the baseline risk , the greater the potential benefit of therapy.
Now was published by the HYVET authors an "Extension Study " , in which a portion of patients who were treated at the time of study termination or double blind (n = 1,882 ) , for another year - now open and all with the study medication - were further treated (2). It should be clarified by this extended follow-up , whether the early use of antihypertensive therapy for patients is sustained beneficial. For a longer follow-up the funds (public funds ) unfortunately no longer sufficient .
Overall, 1,712 patients agreed to namely 924 for the extension of the study of the original with verum and 788 of those treated with placebo. The therapy was started in all patients anew ( open label ) only with indapamide alone. Thereafter, if the goal of therapy (systolic RR < 150 mm Hg) was not achieved , it was perindopril ( only
2 mg / d is then added to 4 mg / d) and , if necessary , also other antihypertensive agents.
1,559 patients completed this one-year extension phase , 822 previously treated with active treatment and 737 to placebo. At the end of the extension year, the two cohorts were treated in a similar antihypertensive : 24% with indapamide, 21% additionally with 2 mg / d and 54 % at 4 mg / d perindopril . Less than 2% of patients required in addition to the study medication in addition, other antihypertensive agents. After this year, open antihypertensive treatment, no significant difference between the blood pressure values ​​(144/76 143/76 vs . MmHg) found in the former active treatment and the placebo group .
The clinical events are shown in Table 1 . It turned out despite the same antihypertensive treatment now also in the following year a significant reduction in mortality in the active treatment cohort. So it appears that the earliest possible start of antihypertensive treatment has a lasting effect . The incidence of stroke and the development of heart failure were found , however, no significant differences between the two cohorts . These events seem more likely to depend on the control of blood pressure per se , ie, to be a direct drug effect .

Conclusion: The study randomized placebo HYVET - controlled double- blind evidence that antihypertensive therapy in elderly hypertensive patients ( systolic target values ​​< 150 mm Hg) , the incidence of stroke and heart failure significantly lowers and reduces mortality by 20%. The HYVET extension study now shows that as early as possible should treat antihypertensive these patients because the survival benefit in the active treatment group, continues to increase at least one year , even if the patients in the placebo group are now treated equally effective .

1 Beckett, N.S. , et al. ( HYVET = hypertension in the VeryElderly Trial) : N. Engl J Med 2008 , 358, 1887. AMB 2008 , 42, 52
. Beckett , N., et al ( Hypertension in the Very HYVET = Elderly Trial) : BMJ 2011.344 , d7541 .

The drug Letter 2011 , 45, 54b Let's go to the medicine too easily to the radiation exposure ?
The relationship between exposure to high doses of ionizing radiation and the development of cancer is well known. However, even low doses of radiation appear to increase the risk of malignancies , as was shown in a cohort of workers in nuclear power plants (1). Estimates based on studies on the relationship between radiation exposure following the atomic bombing on Japan and the incidence of malignancies among the parties concerned , assume that today up to 2 % of all malignancies in the United States on radiation exposure from diagnostic radiology (especially computed tomography) could be due to (2). Possibly , this risk is still underestimated in medicine. However, so far lacking conclusive evidence from epidemiologic studies .
A recent original work in the Canadian Medical Association Journal found that the radiation exposure is associated in the following years by cardiac interventions after myocardial infarction associated with an increased risk of cancer (3). The authors identified in an administrative hospital discharge database all patients . Between 1.4.1996 and 31.3.2006 had been , hospitalized because of acute myocardial infarction in a hospital in Quebec , Canada On the basis of the social security number of hospital data were linked with the insurance information health insurance of Quebec. The time of follow-up was five years on average. The cohort of 82 861 patients were stratified into five groups: patients without radiation exposure ( n = 19 039 ), patients with a radiation dose of> 0 - ≤ 10 mSv ( millisievert , n = 12,331 ) , > 10 - ≤ 20 mSv (n = 25,310 ) , > 20 - ≤ 30 mSv (n = 11,091 ) and > 30 mSv (n = 15,090 ) .
Overall diseased 12,020 (14.5% ) of these patients with malignant tumor , with tumor diseases during the first year were not considered by the radiation exposure because of an association with radiation exposure is very unlikely. In the multivariate comparative analysis of groups with different radiation exposure , taking into account age, gender and other radiation exposure showed that the risk of developing within an observation period of five years after a conditional by cardiac diagnosis or intervention radiation exposure from cancer per mSv by a factor 1.003 increase (95 % confidence interval : 1.002 to 1.004 ) . This corresponds to a risk increase of 4.5 % , for example, after percutaneous coronary intervention with an assumed average radiation dose of 15 mSv. When applied to the malignancy of 14.5 % in the total cohort can be an absolute risk increase of 0.65 % calculate (4.5% of 14.5 %), which corresponds to a number needed to harm of 154 . This risk must of course be compared with the risk to which is exposed to omission of an indexed coronary intervention the patient . In the study, only patients were studied after acute myocardial infarction , for the benefit of rapid coronary intervention is indisputable. Moreover, during the study, only the disease incidence , but does not capture the lethality. Since it is in patients with coronary
Heart disease ( CHD) has more to older patients , it could be that many of them have died of a cardiovascular event or of other causes before induced by radiation exposure cancer could be diagnosed. Nevertheless, we should encourage the study results, do not trifle with the indication for cardiovascular diagnostics and interventions and the associated radiation exposure. We know from various statistics show that up to 50 % of coronary angiographies in the initial diagnosis of CHD pathological findings revealed that pectoris and the percutaneous interventions in patients with stable angina are rarely life-prolonging (4). In these patients probably outweighs the harmful effects of radiation exposure the potential benefits of the measure.

Conclusion: From a large retrospective cohort study results in a signal that the radiation exposure under cardiological diagnostics and intervention , the risk of developing cancer increase . This risk should be considered when determining the indication for all radiation- intensive investigations and interventions.

1 Cardis , E., et al . BMJ2005 , 331, 77
2 Brenner, D. J. , and Hall, E. J. : N.Engl . J. Med , 2007 , 357, 2277th
3 Eisenberg, M. J. , et al . CMAJ2011 , 183, 430
4 Trikalinos , T.A. , et al . Lancet 2009 , 373 , 911th Erratum : Lancet 2009,374,378 .

The drug Letter 2011 , 45, 33 Dual antiplatelet therapy : is the time ripe for therapy monitoring?
Some patients who receive coronary stents after conditioning a dual antiplatelet therapy with aspirin plus an ADP receptor blockers ( clopidogrel, prasugrel , ticlopidine ) , are against one or even both drug classes "resistant" . Resistant means that a platelet function test with continuous therapy for more than 50 % of the platelets are still functional and aggregate (1). These patients are referred to as "low or" non-responders " .
A decreased in vitro response to platelet inhibition is associated with a poorer prognosis of patients with stent or acute coronary syndrome. According to a meta-analysis of published studies " aspirin resistance " is an odds ratio of 3.78 calculated (95% CI: 2.34 to 6.11 ) for a worse cardiovascular prognosis (2). In a substudy of the TRITON -TIMI 38 trial, the sera of 1744 patients were studied on a genetic condition minder response to clopidogrel ( 3 ) ( comparison of clopidogrel plus aspirin in acute coronary syndrome and stent vs . Prasugrel plus ASA ) . This analysis showed that the carriers of the trait ( clopidogrel "low- responders " ) sections are also significantly worse , both in terms of the combined cardiovascular endpoint (12.1% vs . 8%) as well as the risk of suffering a stent thrombosis (2 , 6% vs . 0.8%). Against this background , the question arises as to whether any patient receiving dual antiplatelet therapy , not only to a " low-or no -response " to ASS , but also on the ADP- receptor blocker has to be examined to the therapy to measure to
tailor . So far, this was for two reasons make sense : on the one hand , because there is no accepted gold standard for platelet function tests and partly because it is unclear how to deal with a " low- responders " .
Among the platelet function tests should be noted that many are offered and used, but the rate of " low- responders " depending on the test used varies greatly (see 4). As was found in the same sera were tested with six different tests , a " aspirin resistance " between 6 % and 60% (5). The validity of the test is therefore to provide much in question. How about now with the process to "low- responders" , would be a good test available?
A prospective single-center intervention study from Bochum leads the way (6). In these so-called BOCLA plan study , a fixed algorithm in pathological test results was examined. 504 patients (mean age 64.3 years , 30.5 % women ) received after coronary stent implantation , as is customary , a loading dose (500 mg of ASA , clopidogrel 600 mg ) , followed by a maintenance therapy with 100 mg daily aspirin and 75 mg of clopidogrel . After 48 but within 72 hours , there was a platelet function testing with the so-called Whole Blood Aggregometry that is cheap , according to the authors and only takes ten minutes. Here, the platelets of patients with ADP for the "Clopidogrel -response " and with arachidonic acid for the "ASS - Response" were stimulated .
In 19.4 % of patients a decreased response was found at 100 mg of ASA and 30.8 % on 75 mg clopidogrel. 8.5% of patients responded poorly to both antiplatelets ( "double low- Response" ) . Risk factors for a "low -response " were among other things an acute coronary syndrome (OR : 1.94 ; CI: 1.08 to 3.48 , p = 0.03 ), diabetes mellitus ( OR: 1.78 ; CI: 1 from 0.08 to 2 , 94 , p = 0.03) , an increased concentration of CRP and increased platelet counts (p = 0.02).
In the case of "low -response " was responding on a fixed schedule : Clopidogrel was washed again with 600 mg " geloadet " and / doubling the maintenance dose to 150 mg d . Inventory of control measurements remains a low response , was changed to another ADP receptor blockers: either ticlopidine ( Loading 500 mg, duration of therapy 250 mg / d), or - after approval - on prasugrel ( loading 60 mg, 10 mg or 20 mg / d maintenance dose ) . Hand remained inadequate "response" , the diagnosis was " non-responders " . These should be pragmatic further treated with 150 mg / d clopidogrel. All patients with elevated doses of ADP- receptor blockers were given , were feared because of the higher risk of bleeding , the dual platelet inhibition only four weeks ( bare metal stent ) or six months ( drug eluting stent ) are taking.
All "ASS -low- responders " were geloadet again with 500 mg of ASA and then received 300 mg / d aspirin and further existing inadequate response 500 mg / d Stock then continue to insufficient inhibition , the diagnosis of " ASA non-responders " was made.
Results: A decreased response to aspirin could be overcome by increasing the dose for all patients , ie there were therefore by definition not found " ASA non-responders " . Clopidogrel resistance was , however, 9.5% of all patients with a doubling of the dose can not be overcome. Due to a change of clopidogrel to ticlopidine succeeded , however , once in 3.9% of patients
To inhibit platelet sufficient so that only 5.6% of the patients the diagnosis of " non-responders " was made. Was prescribed as once approved prasugrel instead of ticlopidine, the platelets were all patients who did not respond to clopidogrel , be adequately inhibited. In this cohort , there were no " non-responders " to a more ADP- receptor blockade .
Critical should be noted that the drug-drug interactions in this study, too little attention has been paid . So had at least 40 % of the "Clopidogrel low- responders " proton pump inhibitors as long-term medication , which could have hindered the activation of clopidogrel . It would have been before a dose increase must first issue the problematic co-medication . Why should we now do not treat all patients with the same higher dose aspirin and prasugrel and waive the testing ? First, because not every patient requires such high doses and secondly, because the risk of bleeding increases with higher doses . A tailored therapy for safety and economic considerations, appears to us as the right way. Whether from the proposed by the authors strategy "test and treat" with dual platelet inhibition at the end also results in a clinical benefit to patients , ongoing randomized , prospective studies are needed to (7). As long as should be tested in our view, only when necessary , such as clinical treatment failure or a high risk of stent thrombosis ( Fig. 1) .

Summary : Results show a single-center study ( 5) that after installation of a coronary stent in 41.7 % of patients , the aggregation of platelets with standard therapy (100 mg / d plus aspirin 75 mg / d clopidogrel ) is insufficiently inhibited. Each party has a platelet function test decreased clopidogrel and every fifth decreased ASS "Response" . By increasing the daily doses of aspirin or clopidogrel can be these " resistance " overcome to some extent. Alternatively, comes a change to a anderenAdenosindiphosphat (ADP ) receptor blocker into consideration. Since very likely to increase the dosage also increases the UAW risk , we advise currently means , as long as no corresponding studies , platelet function tests, only in case of clinical treatment failure ( stent thrombosis , reinfarction , "Target lesion revascularization " ) or a high risk of stent thrombosis ( multiple adjacent Drug eluting stents , complex interventions ) to carry out and align with antiplatelet therapy after these test results ( see Figure 1).

1 Smith, S. C. , et al . Circulation2006 , 113, 156
2 Snoep , J.D , et al . Arch.Intern . Med 2007 , 167, 1593rd
3 Mega, J. L. , et al. ( TRITON -TIMI 38 = Trial to ASSESS ImprovementinTherapeutic Outcomes by optimizing platelet InhibitioNwith prasugrel Thrombolysis In Myocardial 38 - Infarction38 ) : N. Engl J Med 2009 , 360 , 354
4 AMB 2002 , 36, 62 and AMB2006 , 40, 16
5 Lordkipanidze , M., et al . Eur.Heart J. 2007 , 28, 1702nd
6 Neubauer , H., et al. ( BOCLA Plan = Bochum CLopidogreland aspirin Plan) : BMS Med 2011 , 9, 3
7 GRAVITAS = Gauging Responsiveness with AVerifynow assay - Impact onThrombosis And Safety .
8 Mani , H., et al . Hemostasis 2010 , 30, 217