Elevated pulse pressure and white coat effect

Can we differentiate white coat effect from true hypertension in the office?
Difficult(we usually need either a 24 hr ambulatory BP monitoring or frequent home BP measurements.....both of which are cumbersome, and cant be done regularly).....but may be possible.....says Dr.Ahn from Korea, when he presented his study in the American College of Cardiology Scientific sessions earlier this month. Lets see what they found out..

They took 1087 outpatients with chronically treated hypertension, and checked home BP twice daily for 2 week, and then checked it in the office. White coat effect was defined as a difference between the physician's BP and the home BP of above 20 mm Hg systolic or 10 mm Hg diastolic BP. White-coat hypertension was found in 31% of patients. Pulse pressure of 60 mm Hg and above positively correlated with WCE by multivariate analysis. So the author concluded that... if a patient has an elevated BP reading in the clinic along with elevated pulse pressure, we can consider WCE before recommending antihypertensive agents. 


Some other interesting associations from the study : 
1. White-coat hypertension was not associated with age or gender in the study, 
2. Those with a family history of premature coronary disease were more likely to display WCE.
3. Those with diabetes or organ damage including the heart, as well as smokers, were less likely to show WCE.


The positive relationship with family history might be the result from the effects of anxiety and emotional stress, and the negative relationship with diabetes or smoking means that the WCE was relatively benign in these patients. Also pts with diabetes and organ damage may not be able to mount a stress response due to autonomic imbalance, LV dysfuction etc.


Is this important? Well.... it is...as we all know that white coat hypertension is a predecessor for chronic hypertension, as based on the findings from Italy(Hypertension 2009) ...in which thy followed nearly 1400 pts with white coat or masked hypertension , and found that 40% of patients with white coat effect progressed to develop Hypertension over a period of 10 years. So..YES...WHITE COAT HYPERTENSION needs to be identified and monitored closely. We usually dont treat WCH due to risk of hypotension...but they need to be monitored closely for development of hypertension. 

Antihypertensives - a little pharmacology helps

I came across this article recently about some interesting facts about antihypertensive medications and their pharmacology, which I though will be useful for practising clinicians like us!
The article describes about all 4 major types of antihypertensives. But the one which stands out is the angiotension converting enzyme inhibitors----WHY?     due to their difference in pharcological actions compared  to others.Let me start with a question..
If Mr.X tolerates(no hypotension) 5mg of Lisinopril, can we increase the dose to 40mg straightaway?

Most of us would say "NO". But the author says yes....and the explanation is pretty simple, interesting and true!
Unlike the other antihypertensives(beta blockers,CCB,diuretics), ace-i do not have a linear dose-response relationship....meaning that their BP lowering effect is not proportional to the dose. In other words....the efficacy of ace-i is the same irrespective of their dosage. Again...to make it more simple...a dose of 5mg of Lisinopril will lower the BP to the same extent as 40mg of Lisinopril. So why give 40mg in place of 2.5 mg? Well...the dose correlates with the duration of action.the higher the dose...the longer the duration of action!(Brit J Pharm 1984!)
It looks like...we have the low doses of ace-i in the market mainly to be used in patients with heart failure (who might have a low BP due to their other meds) to see if they can tolerate any hypotension induced by addition of ace-i. Also, the common side effect of ace-i...COUGH ..is not dose related.So here again..the dose doesnt matter.

So the article concludes that..ace-i don't have a linear dose-response curve, and so their dose can be increased to the maximal dose without any major concerns for hypotension. But ...one aspect of ace-i that the article doesn't discuss...is hyperkalemia. Well..the risk of hyperkalemia with ace-i is dose related, and whether it would be a good idea to go for a maximal dose straightaway or to increase it gradually, in this aspect.So..bottom line-----beacuse of the risk of hyperkalemia..we may not be able to go to a maximal dose directly, and not because of risk of hypotension.
A quick word abt hyperkalemia with ace-i : the risk is quite low on its own. The risk is high in CKD(4 fold risk), hepatic disease(almost 5 fold risk), taking>15 tablets(5 to 9 fold risk), advanced age(twice likely)...
(Pharm W Sci 2009)

Finally..the above article was published in American J of Cardio vasc Drugs 2011. The graph(above) is a modified graph from the same study. 

Calcium gluconate in a digitalised heart with hyperkalemia! OK...or..NOT OK???

Today's morning report was about a young guy who was admitted with rhabdomyolysis, renal failure and hyperkalemia(K- 12mEq/dl) with sine wave pattern on his EKG. All this was due to a electrocution injury.So ...going through the management of hyperkalemia, someone pitched in the problem of giving Calcium gluconate in patients on Digoxin. Well....we had a couple of explanations for the interaction.So lets review the problem with these two drugs together.
First.....the mechanism of action of Digoxin- Digoxin inhibits the Na⁺/K⁺-ATPase(exchanges 2 K for 3Na) in the cardiac myocyte by competing with potassium,and causes intracellular sodium concentration to increase. This then leads to an accumulation of intracellular calcium by blocking the Na⁺-Ca⁺⁺ exchange system. In the heart, increased intracellular calcium causes more calcium to be released by the sarcoplasmic reticulum, thereby making more calcium available to bind to troponin-C, which increases contractility (inotropy).


Second.....the mechanism of action of Calcium gluconate- a litlte more cellular pathology! . Normally the cardiac myocyte has a resting membrane potential(RMP is -90mV) and a threshold potential at which it is excited(TP is-75mV).So a 15mV depolarisation is needed to excite the myocyte. In hyperkalemia, the RMP becomes less negative (-80mV) , but the TP remains at -75mV. This means that ..now..only a 5mV depolarisation is enough to excite the myocyte. This is the cause of hyperexcitability leading to arrhythmia.Calcium gluconate...by increasing Ca transport across the membrane reduces the TP from -75mV to around -65mV ...restoring the 15mV depolarisation needed to excite the myocyte. (the numbers in mV are just an example)  ...... Annals of Emer Med 2011


Sooo...in patients on Digoxin(which causes positive inotropy through calcium)...if more calcium is given....it can lead to more intracellular calcium in mycocyte leading to what has been described as cardiac tetany due to prolonged depolarisation. So ,does hyperkalemia make this process worse?? Well, probably not. ------Since K+ and digoxin compete for Na/KATPase, the binding depends on the concentration of the two. In hyperkalemic state...K+ binds preferentially than digoxin, on Na/K ATPase, and thus resulting in diminished digoxin action. (to better understand...think about hypokalemic states...where digoxin will bind preferentially to the receptor, and hence result in digoxin toxicity!--which is well known)
A slightly different scenario would be...when some one(with no K+ problems) takes too much digoxin...which will also result in digoxin binding preferentially than K+,  to Na/KATP ase resulting in Dig toxicity. In this setting....pt may go hyperkalemia..as more K+ ends up extracellularly (due to not binding with Na/K ATPase), and if this patient gets Ca gluconate..then again..it can causes arrhythmias.


Bottom line is...if Calcium is given(and pt made hypercalcemic) to any pt on Digoxin ..there is a increased possibility for cardiac arrhythmias(PG Med J 1999) ...irrespective of whether they have hyperkalemia or not. 
Whether these pathophysiologies!! are clinically relevant is not clear, as these interactions are based on few case reports only. Have a look at this animal study (J clin Tox 2004) and this retrospective study on pts ..over 18 years from a hospital in Arizona(J Emer Med 2011).Both of them show no clinically relevant interaction of Calcium administration even in Digoxin toxicity.     !!!!!!!

Some key aspects of Surviving sepsis

The key recommendations covering all aspects of sepsis treatment were outlined in the 2008 update on Surviving sepsis campaign. This is a tribute to my 2 month CU rotation which I completed this week.....


Early goal-directed resuscitation of the septic patient during the first 6 hrs after recognition (1C)
Blood cultures before antibiotic therapy (1C);
 Imaging studies performed promptly to confirm potential source of infection (1C); 
Administration of broad-spectrum antibiotic therapy within 1 hr of diagnosis of septic shock (1B) and severe sepsis without septic shock (1D);
 Reassessment of antibiotic therapy with microbiology and clinical data to narrow coverage, when appropriate (1C); a usual 7–10 days of antibiotic therapy guided by clinical response (1D);
 Source control with attention to the balance of risks and benefits of the chosen method (1C);
 Administration of either crystalloid or colloid fluid resuscitation (1B);
 Fluid challenge to restore mean circulating filling pressure (1C); reduction in rate of fluid administration with rising filing pressures and no improvement in tissue perfusion (1D); Vasopressor preference for norepinephrine or dopamine to maintain an initial target of mean arterial pressure ≥65 mm Hg (1C); dobutamine inotropic therapy when cardiac output remains low despite fluid resuscitation and combined inotropic/vasopressor therapy (1C);
 Stress-dose steroid therapy given only in septic shock after blood pressure is identified to be poorly responsive to fluid and vasopressor therapy (2C); 
Recombinant activated protein C in patients with severe sepsis and clinical assessment of high risk for death (2B except 2C for postoperative patients).
 In the absence of tissue hypoperfusion, coronary artery disease, or acute hemorrhage, target a hemoglobin of 7–9 g/dL (1B);
 A low tidal volume (1B) and limitation of inspiratory plateau pressure strategy (1C) for acute lung injury (ALI)/acute respiratory distress syndrome (ARDS); 
Application of at least a minimal amount of positive end-expiratory pressure in acute lung injury (1C); head of bed elevation in mechanically ventilated patients unless contraindicated (1B); avoiding routine use of pulmonary artery catheters in ALI/ARDS (1A);
 To decrease days of mechanical ventilation and ICU length of stay, a conservative fluid strategy for patients with established ALI/ARDS who are not in shock (1C);
 Protocols for weaning and sedation/analgesia (1B); using either intermittent bolus sedation or continuous infusion sedation with daily interruptions or lightening (1B); avoidance of neuromuscular blockers, if at all possible (1B);
Institution of glycemic control , targeting a blood glucose <150 mg/dL after initial stabilization (2C);
 Equivalency of continuous veno-veno hemofiltration or intermittent hemodialysis (2B); 
prophylaxis for deep vein thrombosis (1A); 
Use of stress ulcer prophylaxis to prevent upper gastrointestinal bleeding using H2 blockers (1A) or proton pump inhibitors (1B); and consideration of limitation of support where appropriate (1D).


Our hospital has a Sepsis alert system whereby anyone getting into ER with tachycardia and fever will be eligible for a STAT call to the ICU resident (which was unfortunately 'I' for the last 2 months!!). http://www.survivingsepsis.org/About_the_Campaign/Documents/Final%2008%20SSC%20Guidelines.pdf

angioedema risk with ace-inhibitors

We recently had an african american male presenting with swollen tongue, lips and a stridor. was intubated for airway compromise..given epinephrine im, benadryl, ranitidine, hydrocortisone. Was extubated the next day after resolution of edema. This gentleman was started on Lisinopril 2 weeks ago for hypertension. This is likely...to be Angioedema due to ace-i!!


The pathophysiologic mechanism of angioedema with regard to ACE inhibitor therapy is believed to relate to the kallikrein-kinin plasma effector system. Bradykinin, which is normally degraded by kininase II/ACE, accumulates in tissues pts on ace-i.  Plasma bradykinin has been shown to increase up to 12-fold during acute angioedema attacks in patients with hereditary or acquired forms of angioedema. A case control study from 1997 showed consistently decreased levels of carboxypeptidase N(kininase1) and C1 esterase inhibitor in pts with angioedema secondary to ace-i Vs pts without angioedema on ace-i.

Another interesting theory has been the association of low levels of dipeptidyl peptidase 4( known to catabolise bradykinin) in pts with ace-i associated angioedema. (Hypertension 2002). The reason this is interesting is because ..... the recent DPP-4 inhibitors(Sitagliptin, Saxagliptin) that we use for diabetes work by inhibiting DPP-4. So if the above theory is true..then we might see an increased risk of angioedema in patients on these medications along with ace-i(as most diabetics need ace-i). Lets wait and see!!!!


Several risk factors for development of angioedema with ace-i have been proposed.The most important predisposing risk factor, evidenced by case-control studies, appears to be ethnic differences.The risk of angioedema with ACE inhibitors is higher in blacks and appears not to be related to dose, specific ACE inhibitors, or concomitant medications...as shown in this nice case control study(Clin Pharm & Ther 1996). Other risk factors are a history of idiopathic angioedema, head and neck surgery, and seafood allergy. 


This study from 1988 ...which looked at 3 studies...each with 12,0000 patients.....showed that the incidence of angioedema is high in the first week of starting Enalapril...and then declined. But previous tolerance to an ACE inhibitor does not exclude the risk for angioedema when therapy is modified to a different ACE inhibitor. Finally...the oberall incidence of angioedema with ace-i is around 0.1 - 0.6% over a period of 6 months (a rough estimate based on studies like OCTAVE  (again showing a higher incidence among African americans than other races)

Red flags in evaluation of syncope

Syncope is one of the commonest presentation to the ERs....and would require substantial spending if everyone gets a complete work up to diagnose or rule out the causes. It would be reasonable to risk stratify patients and investigate. The first step would be to get the definition of syncope right! ----- It is a transient loss of consciousness due to transient global hypoperfusion of brain. 


Not everyone needs admission or specialist referral. Urgent referral or hospital admission for investigation is needed for patients who have chest pain, breathlessness, a history of cardiac disease, family history of sudden death, signs of heart failure, or abnormalities on electrocardiography. The electrocardiography features that suggest cardiac arrhythmias include ventricular tachycardia, a widened QRS complex (>120 ms), sinus bradycardia (<50 beats/min), prolonged or excessively shortened corrected QT interval (>450 ms and < 300 ms, respectively), T wave inversion leads V1–V3, epsilon waves or ventricular late potentials (arrhythmogenic right ventricular dysplasia), and right bundle branch block with ST elevation and T wave inversion in V1–V3 (Brugada syndrome). Patients who report a history of syncope with no warning symptoms (Stokes-Adams attack), syncope during exercise, palpitations preceding syncope, and syncope in the supine position should be investigated by a specialist. People with frequent or injurious syncope or implications for driving also warrant specialist input. Prolonged unconsciousness, confusion after the event, or neurological signs and lateral tongue biting suggest a non-syncopal event, and this should prompt neurological evaluation


To simplify the above, San Fransisco Syncope Rule was developed .SFSR  uses the presence of an abnormal electrocardiogram(any new rythm changes or presence of an abnormal rythm), heart failure(or a c/o shortness of breath), anaemia (haematocrit < 30%), or systolic hypotension (< 90 mm Hg) to identify patients who require urgent action. In the original derivation study, the SFSR had 96% (92% to 100%) sensitivity and 62% (58% to 6%) specificity in identifying patients with short term adverse outcomes. In the study where the SFSR score was validated, it showed a 98% sensitivity and 58% specificity in identifying patients with short term (1 month) mortality. And it had the ability to decrease overall admissions by 7%. A thing to remember in this study..was that the rule was applied after the ER physician has evaluated the patient. So would be optimal for an Internal medicine resident seeing a ER consult.


The reason behind paying special attention to cardiac causes are...cardiac syncope carries a high mortality in all age groups. The Framingham study cohort's age and sex adjusted hazard ratios for death over a mean follow-up of 8.6 years was 2.4 (95% confidence interval 1.78 to 3.26) for cardiac syncope compared with 1.17 (0.95 to 1.44) in the "vasovagal group," which included orthostatic hypotension. 
Have a look at the American College of Cardiology recommendations on evaluation of syncope.

Another nail in the coffin for warfarin --- Rivaroxaban

The oral factor Xa inhibitor , RIVAROXABAN is posing more threat to the existence of warfarin for management of symptomatic deep venous thrombosis and foe stroke prevention in patients with non-valvular Afib. It is a oral tablet and has excellent bioavailability...has a structure somewhat similar to Linezolid.....and has predictable anticoagulant effect across wide variations in age, weight and gender.This drug has been in use in Canada and UK since last year for DVT prophylaxis following hip and knee replacement....as it was shown to be non inferior to enoxaparin, for those indications(RECORD trials)

Rats In Peace

The latest trial on Rivaroxaban ,presented at the European Cardiology Congress ........and published in NEJM Dec 2010 is the EINSTEIN-DVT study. This is a non inferiority study involving 2449 pts with DVT randomizing them to either 15mg twice daily for 3 weeks, followed by 20mg daily of rivaroxaban Vs sc enoxaparin followed by warfarin for upto 12 months. The primary efficacy outcome was the first symptomatic VTE event, which occurred in 2.1% of those on rivaroxaban (n=1731) compared with 3% of those on usual care (n=1718), with a hazard ratio of 0.68 (95% CI 0.44-1.04).The two regimens had comparable safety profiles, with the principal safety outcome—a composite of major and nonmajor clinically relevant bleeding events—being 8.1% in both treatment groups (p=0.77). 


Its probably time for a change in the way patients are anticoagulated! and warfarin has managed to hold the fort for more than 50 years. With these new agents(rivaroxaban & dabigatran) it will be easier for patients and physicians.....as no monitoring is needed. 
But few questions still linger.......Can we reverse the bleeding due to rivaroxaban? when do we stop and restart for any surgical procedures? what are its interactions with other commonly used drugs? .....Im sure FDA will be looking into these facts before giving the final nod.

Clopidogrel- with or without PPI ??

Recently, concerns have been raised about the potential for PPIs to blunt the efficacy of clopidogrel.
Mechanism -  the interaction between the two is most likely due to competitive inhibition of the CYP2C19 isoenzyme trough which clopidogrel is metabolised to its active form.


A 2008 publication in JACC involving 124 pts. showed that omeprazole significantly reduced Clopidogrel's inhibitory effect on platelet P2Y12 measured by a method called Vasodilator stimulated vasoprotein(VASP) phosphorylation testing. A retrospective observational study(JAMA 2009) on 8000 patients on clopidogrel showed that concomitant use of clopidogrel and PPI after hospital discharge for ACS was associated with an increased risk of adverse outcomes than use of clopidogrel without PPI (adjusted odds ratio [AOR], 1.25; 95%confidence interval [CI],1.11-1.41)


This issue was addressed in the recent prospective randomized trial - COGENT ...published in NEJM . around 3700 patients taking clopidogrel and aspirin for cardiovascular reasons were randomly assigned to receive either omeprazole or placebo. The group on PPI showed a significant reduction in the number of GI bleed in 6 months ((1.1% with omeprazole and 2.9% with placebo (hazard ratio with omeprazole, 0.34, 95% confidence interval [CI], 0.18 to 0.63; P<0.001)). Both the groups had similar rates of adverse cardiovascular events. Also....subgroup analysis of trials like CREDO, TRITON  did not show any increase in cardiovascular event with PPI and clopidogrel. 
In spite of these data...FDA put a black box warning on the Clopidogrel-PPI interaction in Nov 2009.


The AHA/ ACC and American College of Cardiology jointly published a consensus statement 2 weeks ago based on the COGENT trial ---
 1.In patients with histories of upper GI bleeding and those at high risk for this complication (e.g., advanced age; concomitant use of warfarin, steroids, or nonsteroidal anti-inflammatory drugs; Helicobacter pylori infection), the benefits of PPI therapy probably outweigh the very small risk that PPI therapy will interfere with clopidogrel's efficacy. 
2.Patients at low risk for GI bleeding who require clopidogrel therapy should not receive concomitant PPIs.


There is some evidence that this interaction(if at all clinically significant) may not be a class effect. The authors of this study in Annals of Pharmacotherapy 2009 suggest that Omeprazole seems to interact more with clopidogrel's action in vitro..than Pantoprazole. May be ..until we get a solid answer from further trials......if PPI need to be used....lets use pantoprazole with clopidogrel (provided the insurance covers!!!!)

Start a statin..worry less about the liver

Adverse effects from some statins on muscle, such as myopathy and rhabdomyolysis, are rare at standard doses, and on the liver, in increasing levels of transaminases, are unusual.Stopping statin use reverses these side-effects, usually leading to a full recovery. Asymptomatic increases in concentrations of liver transaminases are recorded with all statins, but are not clearly associated with an increased risk of liver disease.

With the epidemic of obesity / metabolic syndrome.....we are (and will) see obese patients with high LDL and a slightly abnormal liver function test due to ?NASH....who is in need for a statin. How safe would it be to prescribe a statin to these people?
The recently published post hoc analysis of GREACE study has some evidence to help us. In short...GREACE study is a randomised trial of 1600 pts with CHD treated with Statin to NCEP goals(i.e LDL < 100, Chol <200) Vs regular treatment. It showed a significant reduction in cardiovascular mortality if treated to NCEP targets..over a period of upto 4 years.

In the post hoc analysis in Lancet Nov 2010 ...they took 437 patients from the initial cohort..who had abnormal liver tests( AST /ALT < 3 times normal). Of them 227 were treated with a statin and 210 without a statin. All of the 227 patients on statin had improvements in their liver function whereas the 210 not on a statin showed further increase in LFTs. Also, the pts with abnormal LFTs and on a statin showed a significant decrease in CVS mortality compared to pts with abnormal LFTs and not on statin(a 68% relative risk reduction). Surprisingly...this patient group had a significant reduction in CV mortality compared to pts with normal LFTs and on a statin!
Of the 880 patients(in the whole study) who were on a statin ....< 1% stopped it due to elevation in transaminases(>3 times normal). One caution in interpreting the results of the GREACE study is that ..the average dose of Atorvastatin used was 24 mg. This may not be adequate for some ....but given the clear benefits......they can be started on a statin with monitoring LFTs. So dont hesitate to start a statin in someone with a moderate elevation in LFTs.

The risk of stopping antiplatelet therapy

Antiplatelets , especially Aspirin and Clopidogrel have established their importance in management of coronary artery diseases. But they also pose a bleeding risk. This risk is high if a procedure needing tissue sample is done. We had a 66 yo male ..4 months after a STEMI for which he received a drug eluting stent , and was started on Aspirin and clopidogrel. This clinic visit he is complaining of 6 month h/o early satiety, loss of apetite..and our records show a weight loss of 15lb in last 3 months.He needed a upper GI endoscopy ..with a possible biopsy. What do we do with his antiplatelets? ....Lets look at some facts from AHA

· Cessation of all antiplatelet therapies after PCI, at any time, for any stent, is associated with an increased risk of thrombotic events, including late stent thrombosis. These events are likely to occur within 7 to 30 days of drug discontinuation. 

·Cessation of clopidogrel (alone) during the early period after PCI (within 30 days of either DES or BMS placement) is associated with an increased risk of events. 

·Cessation of clopidogrel (alone) beyond 30 days from the time of BMS placement is common in clinical practice and does not confer increased risk of thrombosis over a brief period of time. 

·Cessation of clopidogrel (alone) upon completion of 6 months of treatment after DES placement is controversial (in terms of long-term risk) but does not seem to confer a significant short-term risk(within the subsequent 30 days) in a majority of patients if aspirin is continued. 

 The importance of continuing aspirin in the above scenarios was shown by a review in JACC 2005, where the median duration of stent thrombosis when both drugs were stopped, was 7 days...compared to 122 days when only clopidogrel was stopped and aspirin was continued.In addition, many retrospective studies have shown safety of continuing aspirin during GI procedures. The GI prcedures have been classified into high & low risk based on the risk of bleeding.

Considering the urgent need for endoscopy, the fact that UGI endoscopy is a low risk for bleeding, and the STEMI 4 months ago....we had our patient continue Aspirin, but stop Clopidogrel 5 days before procedure. He will continue his dual antiplatelet therapy the day after his procedure. As always.....the befits & risks were, and have to be discussed with the patient!

Plumbing paradigm might work!

I recently presented a morning report in my Clinic about preventive Cardiology...and I had mentioned about 'plumbing paradigm' ( relieving coronary blockage whenever we find one) does not make things better compared to a medical & lifestyle approach. I based this on two studies done on patients with stable coronary artery disease -

1.COURAGE trial - 2200 patients with stable CAD(ST depression or T wave inversion on resting ECG, inducible ischemia with exercise, or at least one coronary artery stenosis of at least 80% and angina. EF <30were excluded ). 2/3rds of pts had multivessel disease. Pts were randomised to PCI with bare metal stent Vs medical therapy. Over a period of nearly 5 years..there was no difference in primary outcome of all cause mortality, non fatal MI between 2 groups. Angina relief , stroke, hospitalisation for MI did not differ as well. But..a subgroup(n=314) were further enrolled to undergo nuclear study at baseline and after 1 year. PCI did show a significant reduction in ischemic myocardium compared to medical therapy.
2. BARI 2 trial - 2300 patients with type 2 diabetes and CAD(>50% stenosis of major coronary artery with +ve stress test or >70% stenosis with classic angina. Class 3 & 4 heart failure, creatinine>2 were excluded).Over a period of 5 years there was no significant difference between PCI/CABG  Vs medical therapy alone ...in terms of survival, MI, and angina. 


But ..recently ..the MASS 2 trial was published in Circulation -  a randomised controlled trial of 611 patients with CAD ( with proximal multivessel stenosis .70%, stable class 2 or 3 CHF, HTN or diabetes). Pts were randomised to either CABG or PCI with BMS or medical therapy alone. Follow up for 10 years showed a significant improvement in cardiovascular mortality, recurrent MI, angina ...compared to medical therapy.PCI was associated with an increased need for further revascularization, a higher incidence of myocardial infarction, and a 1.46-fold increased risk of combined events compared with CABG. A thing to note..is that majority of patients in this study had aither triple vessel disease or proximal LAD disease....and this is likely why CABG showed a great benefit. 


So.....based on these studies.....PCI /CABG may be superior to medical therapy in patients with stable multivessel disease( and the plumbing paradigm seems to work). But this cannot be generalized for others with stable and mild CAD ..where medical therapy has equal mortality and antianginal benefit as intervention...provided the disease is stable.

Is hyperbilirubinemia protective ?

Well..a mild increase in unconjugated bilirubin may be a good thing to have!. Iam talking about patients with Gilbert's syndrome(GS) and patients with a mild elevation in their indirect bilirubin in the absence of liver disease. GS is a benign syndrome cause by reduced activity of enzyme UDP Glucronyl Transferase. In one of the famous prospective cohort studies- The British Regional Heat Study(BRHS) there was a U shaped relationship between bilirubin level and heart disease. Men with low bilirubin levels were found to have low concentrations of HDL cholesterol, low FEV1, and low serum albumin. This led to a small study in Univ of Utah...which showed a similar inverse relationship between bilirubin & heart disease.Another prospective study from Europe called PRIME study involving 10,000 men also showed that a slightly elevated bilirubin is a marker of protection against Coronary Heart Disease. Another strong pointer towards this trend is the lesser incidence of heart disease in patients with Gilbert's syndrome compared to general population (Atherosclerosis 2002)


This benefit has been explained on the basis of the antioxidant property of Bilirubin. It might prevent oxygen radicals from damaging the endothelium, and it also prevents oxidation of LDL particles. Bot these effects can explain a lower incidence of Ischemic heart disease in this population. Well....if this idea is true....then it should protect against stoke as well. 


Stroke & bilirubin - A 30% risk reduction in incidence of carotid plaques was found in patients with their bilirubin the highest quartile compared to bilirubin in lowest quartile (Stoke 2001).  recent study published in Stroke 2009 ...studying nearly 80,000 healthy patients showed a 20% risk reduction in ISCHEMIC stroke in patients with high bilirubin levels.
Aaand...it doesnt stop here! Another study from Annals of Hepatology published in 2008 showed that a 0.1 mg/dL increase in bilirubin level was associated with a 6% reduction in the odds of peripheral vascular disease (PAD). The benefit was noticed more in men than women. Another article in JAMA 2007 comparing diabetic pts with Gilbert's syndrome to normal people...showed a a significantly lower prevalence of hypertension, HbA1c, LDLl, total cholesterol, and triglyceride,CRP and higher levels of HDL. They also had a lower incidence of proteinuria as well (have a look at the table). Very recently ,an article in Kidney International (Oct 2010) shows that in rats who had hereditary hyperbilirubnemia had lower incidence of diabetic nephropathy.


It may be difficult to prove whether high bilirubin is an effect of body's need for an antioxidant...or it does genuinely protect against atherosclerosis. But bilirubin seems to offer a definite protection, and could be used as a reasonably good marker of vascular events. The main hindrance to bilirubin's use is that we cannot modify its level...to attain any of these benefits. A level just around upper limit of normal( upto 2.5 x normal in GS) would be the level talked about in the studies.

Success!!! got my patient's LDL to 50mg/dl

First question.......What's the benefit of doing the above? We all know that lower the cholesterol..lower the cardiovascular risk. Latest evidence supports lowering it to < 70 mg/dl for the high risk patients. Well...is there a downside to overdoing this? Yes there is... at least theoretically ..for now.
The normal LDL level is 40 - 70 mg/dl. Cholesterol (mainly LDL particles) play a major role..and are the corner stone for synthesis of many steroid hormones including cortisol, tetosterone, androstenidione, Vitamin D etc. So by looking at this...obviously driving LDL to a much lower level can affect these important physiological processes.
There were a few studies done to see if reduction in LDL with statins affect endogenous steroidogenesis. In a cross sectional study of 350 type 2 diabetic patients on a statin (Diabetes care 2009) showed a significant reduction in total testosterone level with atorvastatin compared with no treatment. But the free bio available testosterone levels were normal. A pharmacology study from Holland shows the same above possibility with Statins.(British J of Clin Pharmacology )

A subgroup analysis of reproductive age group women from WISE trial showed no significant decrease in levels of estrogen or progesterone in pts with LDL < 70 Vs pts with LDL >70. (AJM 2002).
An earlier study from 1994 showed no decrease in levels of adrenal and gonadal steroids in patients with a low LDL on a statin. Most of the above studies...didnt drive down the LDL levels to < 70mg/dl.
A recent study published in 2009 comparing gonadal hormones in pts with LDL <70 with LDL <100...in pts on a statin..showed no significant difference in the sex hormone levels..over a period of 12 weeks. This may be a short duration to assess a reasonable outcome.

On the whole...driving the LDL levels to < 70 may have little or no negative effect on sex &/or adrenal hormone levels. But this possibility can be considered if a pt..with a LDL of <70 complains of decreasing libido.(these pts may also be on Spironolactone..which can make this worse).
Statins have shown some benefit in treating prostate cancer( again..may be due to their effect on lowering levels of testosterone!). Another theoretical concern with excessive lowering of cholesterol will be the possibility of a lack of adrenergic response needed during stress (especially in sepsis, ICU admissions etc) due to low cortisol production. Whether this is true remains to be answered !!

Chlorthalidone.......what a miss!

Chlorthalidone is a diuretic acting on the distal convoluted tubule...same as Hydrochlorthiazide. It is a 'thiazide like diuretic'....as it has a different structure than thiazide diuretics, but acts on the same Na-Cl symporter in the DCT. Chlorthalidone first came to light ..when used in the MRFIT trial in the 1970s. Since then chlorthalidone has been the diuretic of choice in the major hypertension trials - ALLHAT, Hypertension Detection and Follow-up Program (HDFP), Systolic Hypertension in the Elderly Program (SHEP). And chlorthalidone was the only antihypertensive showing some mortality benefit in the ALLHAT trial. 
Inspite of these data, im surprised that we still chose HCTZ on top of chlorthalidone. I cant figure out a valid reason for this swap.(If anyone knows ...let me know)

Studies done to compare Chlorthalidone with HCTZ in the past(1976)..were very small..but they all showed that  chlorthalidone once a day is equally efficacious to HCTZ twice a day....in fact with a trend towards even better blood pressure control and a slightly lesser incidence of hypokalemia. A recent study from Iowa showed a superior antihypertensive effect of chlorthalidone than HCTZ. (again ...small study- 30 pts....short duration-8wks.....no hard outcomes.....but hard to discard!)


So......Chlorthalidone seems to have a definite edge over HCTZ both in reducing BP and in preventing adverse cardiac events..with a similar or may be a better side effect profile.
Why is this difference between the two ? Well...we know the answer to some extent. 
1. Chlorthalidone has a longer elimination half life (50 hrs Vs 10 hrs for HCTZ) -- this means more sustained antihypertensive effects. This has been nicely shown in the above study from Iowa.
2. Bioavailability is the same as HCTZ, but it is 99% protein bound..which helps limit glomerular filtration and excellent delivery to action sites thru secretion. HCTZ is 40% protein bound.
3. Chlorthalidone is 99% bound to RBC carbonic anhydrase ...which forms a reservoir for continued action. 
4.Chlorthalidone is a stronger inhibitor of Carbonic anhydrase than HCTZ.....adding to its diuretic effect.
5. Recently..it has been found that Chlorthalidone decreases platelet aggregation and promotes angiogenesis. 
(Hypertension .July 2010)
6. Finally ..COST . 30 tabs of 50mg Chlorthalidone - $20.00 (12.5 mg starting dose....once a day)
                              100 tabs of 50 mg HCTZ          - $ 16.00 (12.5 starting dose......twice a day)


So..if some one is on HCTZ and doing well...it will be reasonable to leave it. Other wise Im changing to Chlorthalidone. And this is easily the first choice thiazide for me!!
Anyone has an argument?!

combination of Aspirin,Plavix & Warfarin - how bad or how good?

I am sure you had come across those patients who had been on aspirin & warfarin ..or...plavix & warfarin...or rarely all three (either intentionally or by mistake!!). Well...a patient with CAD might benefit more from a antiplatelet...but may need warfarin for A.fib ....will he benefit from both? A recent article from Arch of Int Medicine tried to address these issues by calculating the risk of bleeding associated with each combination.
Lets look at the risk of stoke with A fib at 1 year...so the numbers from the above study would make more sense.

Risk of stroke with A fib - commonly assessed with CHADS2 score
CHADS score of 0,1,2,3,4,5 & 6 carries a 1 year stroke risk of ..roughly 2%,3%, 4%, 6%, 8%, 12% & 18% respectively.So we usually start treatment to prevent this thromboembolic risk by starting them on either antiplatelets or warfarin. This question about warfarin or no warfarin always pops up when we see a patient with A fib.

Now lets see the numbers from the above study where they looked at a cohort of 82,000 patients discharged with a diagnosis of Atrial fibrillation. During a follow up period of 3 years ..11%(13,000 pts) had a fatal or non-fatal bleeding.Having warfarin as the standard ..the hazard ratio for the above end point is as follows
For Aspirin alone - 0.93
for plavix alone - 1.06
for aspirin + plavix - 1.66
for aspirin + warfarin - 1.83
for plavix + warfarin - 3.08
for aspirin +plavix+warfarin - 3.70

Clearly this was something that was expected ..based on previous studies. The crude incidence rate of bleeding was 13% for plavix +warfarin, and 15% for triple therapy. So having these numbers ...gives a better idea for making a risk-benefit decision !! ...So ..whoever your pt is....aspirin+plavix+warfarin seems to be a bad combination!

Not everyone likes it...but has a lot to offer!

As one of the most commonly spoken/advised diet in the clinics...lets have a peek into it.
Dietary Approach to Stop Hypertension(DASH) - Initiated by the NIH, studies were done on specific dietary patterns on the influence of Hypertension. The first study was published in NEJM 1995 ..done on 459 pts with BP <160 systolic ,& diastolic between 80-95. Three type of diets were studied- a control diet (typical american diet), control diet with fruits & vegetables(F/V), and DASH diet. Hypertensives showed a significant 11 & 5 mm Hg drop in their sys & dias BP resp,while on DASH diet. Improvements were noticed as early as in 2 weeks. All 3dietary patterns were taking 3g /day of Sodium.


The next study,DASH-sodium study was done on DASH  Vs the Control diet,each with three levels of Sodium intake(3gm/day, 2.4gm/day, 1.5gm/day of Na) .About 400 pts with BP between 120 - 160 systolic & 80-95 diastolic with 50% blacks were included. The DASH diet, as compared with the control diet,resulted in a significantly lower systolic blood pressure at every sodium level. The combination of DASH +low sodium showed a greater reduction than either agents alone.
So....nowadays you can see ads about DASH diet in many places. This has been taken as a serious issue by the US government recently...given the spreading epidemic of Obesity which is most often associated with Hypertension. 
What does DASH diet consist of - lots of fruits & vegetables,low-fat dairy products, whole grains, poultry, fish, and nuts, while reducing intake of fats, red meat, sweets, and sugar-containing beverages. 

Total fat 27% of calories ,Sodium 2,300 mg (1.5gm is even better), Saturated fat 6% of calories ,Protein 18% of calories,  Carbohydrate 55% of calories, Cholesterol 150 mg,Potassium 4,700 mg, Magnesium 500 mg,  Fiber 30 g.
.Also see this......u can print and give this to your patient for a sample menu.


Latest on DASH trials - A study of Framingham CHD risk score among participants from the DASH trial published in Circulation Aug 2010, showed that..... Compared with control  and F/V diet, the DASH diet reduced estimated 10yr CHD risk by 18% & 11% respectively.There was a significant improvement in LDL veles with DASH, but not with glucose levels. DASH has also shown a 37% reduction in incidence of heart failure in women (Arch of Int Med 2009) 48 - 83 yrs age without a h/o diabetes or heart failure. Only 20% of women had hypertension. What this shows..is that the diet can be of benefit even in people without hypertension, diabetes or CAD.


A common question patients have asked is...If the diet reduces weight? Well...it is not designed to make you loose weight. Added with exercise..then it might(thats another topic !!)

Intra-aortic baloon pump - some useful tips

IABP  was first tried in humans in 1968 by Dr. Kantrowitz (also did the first Cardiac transplant in USA).
Basic principle - Counterpulsation -It is balloon inflation in diastole and deflation in early systole. Balloon inflation causes 'volume displacement' of blood within the aorta, both proximally and distally. This leads to a potential increase in coronary blood flow and potential improvements in systemic perfusion.


Physiological effects -  The primary aim is to improve the LV function by augmenting the coronary blood flow.  IABP inflates at the onset of diastole, thereby increasing diastolic pressure and deflates just before systole, thus reducing LV afterload. The magnitude of these effects depends upon:
        1.Balloon volume: the amount of blood displaced is proportional to the volume of the balloon.
        2.Heart rate: LV and aortic diastolic filling times are inversely proportional to heart rate; shorter diastolic time produces lesser balloon augmentation per unit time.
        3.Aortic compliance: as aortic compliance increases (or SVR decreases), the magnitude of diastolic augmentation decreases.( so beneficial in elderly with stiff arteries than a young elastic aorta)


Indications are... where you need an increase in coronary flow to augment LV function. Its more important to know the absolute contraindications -  Aortic regurgitation, aortic dissection, aortic or popliteal stents, very poor prognosis. Also be careful in pts with peripheral vascular disease.


 Waveform -  The balloon is inflated with Helium so that it quickly travels from pump to balloon...and also gets absorbed in blood incase of balloon rupture. The console uses the EKG waveform &/or systemic arterial waveform as a trigger for inflating the balloon. The balloon inflates with the onset of diastole, which corresponds with the middle of the T-wave(dicrotic notch on arterial wave). The balloon deflates at the onset of LV systole and this corresponds to the peak of the R-wave. Since the distal aortic pressure drops with inflation, you can see a slight dip at the dicrotic notch followed by a second peak due to augmentation of the diastolic pressure ( which should be more than the pts systolic pressure denoted by the peak before the dip @ dicrotic notch). Have a look at the figure.


Monitoring - Depending on hemodynamic status..the inflation can happen with each beat (1:1) or every other beat(1:2) & so on. Keep all these patients on heparin anticoagulation. And importantly monitor their Urine output. If it drops suddenly...confirm the position of the tip of balloon (2cm above carina) with an Xray..as the balloon may be adjacent to the renal artery. Once patient's pressor needs have gone down..start weaning them from IABP by reducing the rate of augmentation 1:2 to 1:3 and so on. 
Hope this helps!!

Isosorbide mononitrate Vs dinitrate - what to use?

This post is due to the question asked by one of my clever interns. What is the difference between the nitrates, and how can we apply that in practice based on the evidence we have.
We use three intrates- nitroglycerine, isosorbide mononitrate(ISMN), isosorbidedinitrate(ISDN). They are used widely for stable & unstable angine , heartfailure, and acute MI.  ISMN & ISDN both have to be denitrified to nitric oxide and cause vasodilation of venules and arteioles.

ISDN - has extensive first pass metabolism in the liver, and its half life is 40 min. Its major metabolites are isosorbide 2 mononitrate & isosorbide 5 mononitrate with half lives of 2 & 4 hrs respectively.
In a study done on pts with tid dose of ISDN with a 14 hr drug free interval, the excercise capacity improved after the first dose. Another study with same dose showed antianginal effects decreased progressively after the 2nd & 3rd dose likely due to tolerance. There is a sustained release ISDN when used at the max dose of 80mg bid ..causes tolerence,but when administered less than 12 hrs apart with a long drug free period...the antianginal effect was ok. One of the major studies of black pts with heart failure A-HEFT trial showed mortality benefit in adding ISDN with hydralazine.This made ACC to include ISDN in their 2009 guidelines for heart failure.

ISMN - doesn't undergo first pass hepatic metabolism.half life is around 4-6 hrs.It is primarily used in the management of chronic stable angina. It is not FDA-approved for treating heart failure. Standard formulations are 20 & 40 mg ..and again when given in an eccentric fashion(less than 12 hrs between daytime doses)...tolerance seems to be less.There is an extended release ISMN given once a day which also gives antianginal efect.

Soooo...... ISMN is preferred for angina as its once daily administration, and does better with compliance. Its better to give the drug in the morning during the time pts are active..and leave them drug free during sleep.
ISDN is recommended for heart failure (especially useful in black people..along with hydralazine), and has to be given in n eccentric fashion ( 8 hrs apart i.e- at 9am & 5pm...and so a 16hr drug free interval) to prevent tolerance. If adherence is an issue..then ISMN can be used in an off label fashion.
Also its safe to taper slowly ..when stopping nitrates..to prevent rebound.