Statins in Low Risk Patients

Although data supporting the use of statins to reduce cardiovascular risk are extensive, questions remain.  Currently experts in cardiovascular health are in disagreement over the use of statins in low-risk patients, particularly patients with high cholesterol but no other cardiovascular risk factors.

While statin benefits are well established, real-world cohort studies have shown higher risks of complications and side-effects than seen in randomized-controlled trials.  For every 100 otherwise healthy men men who take a statin for five years, one or two myocardial infarctions will be prevented but at least one patient will develop diabetes, and 20% or more will experience significant side effects.  

One side of the argument states that in low-risk patients, clinicians should focus on lifestyle changes such as diet, exercise and smoking cessation.  The use of statins in primary prevention is not a standard of care and the decision to initiate therapy should be based off a careful assessment of risk versus benefit.

Although previous meta-analyses have stressed that there is no mortality benefit with statins for primary prevention, a recent meta-analysis published in The Lancet showed that proportional reduction in major vascular events was as great in low risk patients as in high risk patients.  Despite the author’s conclusion that statins are beneficial in low risk patients, clinicians remain divided over this issue.

References: 

Redberg RF, Katz MH.  Healthy men should not take statins.  Journal of the American Medical Association 2012; 307(14):1491-3.

Mihaylova B, Emberson J, Blackwell L et al.  The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: a meta-analysis of individual data from 27 randomised trials.  The Lancet 2012; DOI:10.1016/S0140-6736(12)60367-5

Renin, angiotensin, aldosterone and you

There’s no escaping the kidneys in pharmacy.  Their significance in drug elimination, blood pressure and salt and fluid balance is undeniable.  

Renin is produced by juxtaglomerular cells in the afferent arteriole in response to decreased pressure in the kidney.  Renin is also responsible for the initial rate limiting step in the production of angiotensin.  Angiotensin-converting enzyme (ACE) facilitates the final step in the production of the active angiotensin II and is also responsible for the metabolism of certain peptides, such as bradykinin.

ACE-inhibitors (ACE-i) and angiotensin receptor blockers (ARB) reduce the effects of angiotensin II, which is responsible for vasoconstriction and aldosterone and sodium retention, to decrease the blood pressure and pressure within the kidney through different mechanisms.  ACE-i block ACE; however there are other pathways for the production of angiotensin leading to “ACE escape”.  ARBs would block angiotensin at its site of action, thereby bypassing the risk of “ACE escape”.  Both classes of medications can lead to increases in renin due to sustained lower pressures within the glomerulus.

Though increased bradykinin is the cause of the notorious ACE-i induced dry cough, it also provides added vasodilation.  A recent meta-analysis looking at mortality data from 20 trials utilizing an ACE-i or an ARB compared with a control showed that ACE-i offered a 10% mortality decrease compared with ARBs and the control drug or placebo.  The meta-analysis excluded patients who had heart disease or kidney disease, where RAAS inhibition has already been shown to have significant added benefits.  

The analysis shows that there is a clear mortality benefit to using an ACE-i in patients with hypertension without other comorbidities that would indicate RAAS inhibition.  If a patient is unable to take an ACE-i, there is no added mortality benefit to using an ARB over another antihypertensive.

Aliskiren, or Tekturna, is a direct renin inhibitor, the newest class of RAAS inhibitors.   Researchers hypothesized that using aliskiren in combination with an ACE-i or an ARB would improve outcomes by targeting RAAS through two mechanisms.  The “Aliskiren trial in type 2 diabetes using cardio-renal endpoints” studying aliskiren with an ACE-i or and ARB in diabetics was stopped early in December due to futility as well as increased risk of renal impairment, hypotension, and hypokalemia.  Prior to this in 2008, the TARGET study had also shown lack of benefit with combining an ACE-i and an ARB in patients with vascular disease or diabetes with organ damage.

The Food and Drug Administration, FDA, has recently placed a warning on aliskiren against its use in combination with an ACE-i or an ARB in patients with diabetes or moderate to severe renal impairment. 

While both an ACE-i or an ARB has clear benefit in patients with kidney disease or heart failure, ACE-i are superior to ARBs in mortality benefit in patients with hypertension alone.  Combining an ACE-i with an ARB or aliskiren should be avoided.

References:

Atlas SA.  The renin-angiotensin aldosterone system: pathophysiological role and pharmacologic inhibition.  Journal of Managed Care Pharmacy 2007; 13(8): S9-S20.

van Vark LC, Bertrand M, Akkerhuis KM et al.  Angiotensin-converting enzyme inhibitors reduce mortality in hypertension: a meta-analysis of randomized clinical trials of renin-angiotensin-aldosterone system inhibitors involving 158 998 patients.  European Heart Journal 2012; DOI:10.1093/eurheartj/ehs075. Available at: http://eurheartj.oxfordjournals.org

Lowes R. No aliskiren with ACE inhibitors, ARBs in some patients: FDA.  theheart.org April 20, 2012.  Available at http://www.theheart.org/article/1388139.do

CHEST 2012 is blowing my mind.

After committing the 2008 guidelines to heart and four years of reverence as my holy book, the time has come to toss out the old and move onto the new; CHEST 2012 is here.

Its absolutely amazing how much additional evidence has become available in four years and to see just how much has changed.  Although my work cut out for me, in reviewing the guidelines, it makes it easier to review what the experts recommend, rather than trying to go through all the trials and piece together recommendations myself.  When guidelines wait too long to provide updates, in the end, they end up discrediting themselves *cough* JNC7 *cough*

Less than a year out a pharmacy school, I still have trouble wrapping my head around some of these recommendations.  Have I become this set in my ways?

Let's look at CHEST.

Warfarin:
Warfarin can be initiated the same day that LMWH/fondaparinux/UFH is started for the treatment of VTE .  Pharmacy school hammered into my head the mantra "no loading dose, no loading dose, no loading dose" however new recommendations suggest that patients should be given 10mg of warfarin for the first two days, then dosing after that should be based off the change seen in the INR.  This recommendation seems to apply for any indication for warfarin start.  This will push the patient into range faster, examples given showed patients more likely to get to range a day ahead of patients dosed conventionally.

Rebuttal: First and foremost, I would have to review the individual trials to see if patients were dichotomized by age, but it is unclear if the guidelines are recommending 10mg for two days across the board, including our 80 year old grandmas.  I would like to see data specific to the elderly before following along.
Secondly, irregular dosing makes it more difficult to establish a starting weekly dose outpatient.  From my brief experiences in managing patients in an outpatient warfarin clinic, I have had the most difficulty dosing patients who received highly variable dosing in the hospital, which can end up meaning overshooting or undershooting their INR.

Despite this recommendation by the consensus guideline, I doubt that many of the anticoagulation pharmacists at my facility will buy into it.  The Navajo tend to be slower to respond to warfarin but much more sensitive.  For anticoagulation pharmacists across the Navajo Nation, it is hypothesized that there may be a gene that contributes to this, but we have no way of knowing which patients will be more likely to respond in certain ways.  Despite how slowly the INR budges in the first few days, some of the patients end up shooting up to incredibly high INRs in the second week.  Very little medical research is done on Native Americans (it doesn't take a rocket scientist to figure out why they may be adverse to the idea considering the history with white America) so again, I have no data to support this, but using a loading dose in this population may be more dangerous than using it in other populations.

Dabigatran.
Dabigatran 150mg twice daily is recommended over warfarin for patients with atrial fibrillation with a CHADS score of one or higher.

Dabigatran was approved for atrial fibrillation based off the results from the RE-LY trial, which only looked at 110mg twice daily or 150mg twice daily and excluded patients with a creatinine clearance less than 30mL/min.

I am so excited about the new anticoagulants, and if you understand warfarin, its not difficult to understand why.  Warfarin is a difficult drug.  But the fact of the matter is, these new drugs are relatively unknown.  It is difficult for me to consider recommending an expensive, new drug that has been studied limitedly over the gold standard of anti-coagulation that has been proven effective time and again in clinical trials.  Am I afraid of the unknown? To be honest, yes.  I know what to expect from warfarin, but I'm not entirely sure of all the risks I bestow on a patient by recommending dabigatran.

Furthermore, it is interesting that the guidelines specifically recommend only the 150mg twice daily dosing for patients with "good" renal function.  The 75mg twice daily dose was never studied in clinical trials and many of the new precautions with bleeding are specific to patients with impaired renal function, despite being on the lower dose.  A New Zealand study published in the New England Journal examined a series of case reports regarding bleeding with dabigatran showed that patients with low body weight, low renal function, and older age were at greater risk.  Furthermore, the makers of dabigatran recommend that the INR fall below 2.0 for patients previously on warfarin before starting, which may not always be adhered to.

"But dabigatran did not have that caveat; I think the government wanted it be used. They saw it as a good replacement forwarfarin and wanted as many people as possible to switch. The uptake was very quick—too quick. Doctors were very keen to prescribe it, and everyone got carried away."  Dr. Harper, the primary investigator, tells HeartWire (www.theheart.org).

To my knowledge, only two patients are taking dabigatran at my facility but are taking the 75mg twice daily dose (not according to my recommendation).  One of the patients was switched as a result of variable INR due to non-compliance.  This patient is not going to be anti-coagulated if she is non-compliant with her dabigatran, the difference is that we may not know the difference until she strokes out.

To summarize, I disagree with CHEST's "blanket-statement" recommendation and think that dabigatran should be recommended on a case-to-case basis and the greatest folly I see in the recommendation of the switch to dabigatran is to recommend it in patients who are non-compliant with warfarin.  Patients that refuse to take their anticoagulants will not be anti-coagulated.

Aspirin.
I have a couple of beefs with recommendations regarding aspirin in the new guidelines.

For patients that have undergone hip fracture surgery, there is a strong recommendation for clot prevention therapy for at least 10-14 days, out to 30 days.  Patients can use LMWH, UFH, fondaparinux, warfarin or... aspirin? really? aspirin?  It almost seems hypocritical especially because aspirin has not been recommended as sufficient clot prophylaxis in other scenarios.  LMWH is still recommended first line, and honestly I would need to see the full length VTE prophylaxis guideline to fully file my complaint on this one, but... really? aspirin?

Aspirin is recommended for anyone over the age of 50 WITHOUT symptomatic cardiovascular disease.  Aspirin is cheap and prevents clots.  In the early years of pharmacy school, I was told to give aspirin to anyone over the age of 50 AND to anyone with diabetes, regardless of age.  However, after presenting on the ADA/AHA/ACCF 2010 and U.S. Preventive Service Task Force 2009 guidelines, I began to change my mind.

The majority of trials looking at aspirin for primary prevention did not reach statistical significance additionally, practitioners are beginning to think twice about using aspirin because there absolutely is an increased risk of bleed associated with its use.  Both guidelines focus on weighing the risk of bleed against the risk of having an event.  The Task Forces break down the recommendation by age, and recommend aspirin for age cohorts based on the man's risk of CHD and the woman's risk of stroke. Check the document for the specific recommendation, but to ball-park it, use aspirin in patients ages 60-79 when man's risk of CHD is greater or equal to 10% or woman's risk of stroke is greater of equal to 10% (recommendation for use in patients ages 50-59 starts at a lower risk level ~5%).  The Task Forces do not make a specific recommendation for ages of either gender above the age of 80 due to significantly increased risk of bleed.

ADA is easier to follow but can only apply to patients with diabetes.  For men over 50 and women over 60 with an additional risk factor (smoking, hypertension, hyperlipidemia, family history premature CVD, or albuminuria) low dose aspirin is recommended.   Controlled risk factors are not counted.

The CHEST 2012 recommendation to use aspirin in any patient over 50 almost seems archaic in light of recommendations made recently by other major medical organizations.  The ADA and Task Force guidelines are fairly similar; the CHEST recommendation creates a major discrepancy among other major guidelines.

So

I may not agree with everything in the new guidelines, I may be wary to change my ways, but the great thing about the medical field is that is always changing.  A professor told me that she had been taught NEVER to use a beta-blocker in any patient with heart failure, now it is the standard of care.  These discoveries that completely change clinical practice occur on a year to year basis.  I think the best we can do is educate ourselves, read the literature, and keep an open mind.  Despite my complaints/rebuttals, I love my new CHEST which if filled with a plethora of fabulous recommendations and will help us to guide therapy to improve patient care.

References:
pending (please excuse my unprofessionalism), CHEST exec summary, Chest Anticoagulants, CHEST therapy for VTE disease, USPSTF 2009, ADA/AHA/ACCF 2010, http://www.theheart.org/article/1363757.do

The girl and the peach

I wrote this some time ago, back in September, a lot has been going on.  I feel much more settled in my new home and work environment, but I still need to set aside time to collect my thoughts.

The girl and the peach.

I was also talking to the ER pharmacist today.  We went out to breakfast at Denny’s then tried on boots.  She had worked there during her residency for three months.  The docs and nurses didn’t always like having a pharmacist there.  The ER is small and cramped.  It is often overflowing and beds are set up in the walk ways as needed.  Less critical patients are often moved out of beds and into chairs.  Space is limited.

Besides the trial of becoming accepted as a useful resource in an already crowded area came the emotional toll of seeing good people or children coming in hurt and sometimes permanently damaged from preventable circumstances.  The story that has been told to me repeatedly by ER pharmacist is the story of the girl and the peach.

A young girl (2 years old? 6 years old?) was being watched by her grandmother.  Her parents had gone out for the day.  She was eating a peach.  A slice of the peach slid down her throat.  She was choking.  Grandma called the parents.  They were still in town shopping.  They would be home later.   Grandma knew no first aid.   She didn’t even know enough to try to hit the girl on the back to help her to get it back up.  As the little girl slowly lost oxygen, she became tired.  Grandma told her to go lie down and get some sleep.

When the parents came home hours later, the girl was still sleeping and now, unresponsive.  They moved her into the truck and drove the the ER.  By the time she had gotten there, she had had the peach lodged in her throat for hours already.  She was blue and unresponsive.  As the doctors pounded on her tiny chest and struggled to get breathing tubes down into her throat, they saw a tiny heart rate come back.

A child’s heart is very resilient, the pharmacist told me.  It will keep beating even after they’re gone.

The little girl was probably already gone long before she came into the ER, but they continued to struggle to save her life.

Eventually, the heart monitor showed only a flat line.  She was gone.  She died because she had choked on the soft flesh of a peach and her family was so uneducated about basic first aid that the only recommendation her grandmother had given her was to go lie down in her room.

We all cried that day, she told me.

Emerging vaccines & Latent TB

Human Immunodeficiency Virus (HIV)

In the past 20 years since the development of the first antiretroviral medication, science has made great progress in combating the human immunodeficiency virus, or HIV.  Research on vaccines has not been promising as of yet, but starting this month, a new vaccine made from killed virus will begin its phase 1 trials.  Stay up to date with the Vaccine Trials Network: www.hvtn.org

Malaria

Plasmodium falciparum, the parasitic cause of severe malaria, relies on the anopheles mosquito and the human for its lifecycle.  Eradication of this disease is potentially feasible, if this cycle can be broken.  Interim results for a vaccine showed a 55% protection in infants given the vaccine.  Hope seems to be on the horizon, despite major setbacks in the development of multi-drug resistant strains.

Ebola

This hemorrhagic virus kills 90% of patients it infects.  Currently the only treatment available is supportive care.  Great strides were made in creation of a vaccine when a recent trial showed disease prevention in 80% of mice vaccinated.  The vaccine was created through genetically engineering bacteria to grow the viral surface proteins.

New Treatment Option for Latent Tuberculosis 

In 2010, nine million people around the world were diagnosed with tuberculosis, TB.  Over 11,000 cases were reported in the United States, where prevalence among Native Americans and Pacific Islanders was three times that of caucasian Americans.

Previous options for the treatment of latent TB consisted of either six to nine months of isoniazid or four months of rifampin therapy.  Long treatment durations are difficult for patients to adhere to until completion.

A multicenter randomized trial compared three months of rifapentine with isoniazid to nine months of isoniazid treatment for latent TB.  A total of 7731 patients were followed for 30 months.   

Combination therapy was found to be non-inferior with a trend toward superiority.  Patients taking combination therapy were significantly more likely to finish the treatment regimen, though were more likely to discontinue therapy due to an adverse event.  However, there was significantly less hepatotoxicity with combination therapy.

References:

HIV. CBC News: HIV vaccine trial approved by FDA: Canadian-developed vaccine to start human clinical trials in January 2012.  CBC News 12/20/11.  Available at http://www.cbc.ca/news/health/story/2011/12/20/hiv-vaccine-western.html 

Johnston MI.  HIV vaccine development- improving on natural immunity. The New England Journal of Medicine 2011;365(10):873-875. 

Malaria.    Schweitzer A, Todagbe S, Lell B, Soulanoudjingar SS,  Fernandes J, Abossolo BP, et al. Results of phase 3 trial of RTS,S/AS01 malaria vaccine in African children.  The New England Journal of Medicine 2011;365(20):1863-75. 

White NM. A vaccine for malaria.  The New England Journal of Medicine 2011;365:1926-1927.  

Ebola. Carpenter J. Vaccine developed against ebola.  BBC 12/6/11. Available at http://www.bbc.co.uk/news/science-environment-16011748

New treatment option for latent tuberculosis. Morbidity and Mortality Weekly Report (MMWR). Decrease in reported tuberculosis cases --- United States, 2009.  Centers for Disease Control and Prevention 2010;59(10):289-294.  

Sterling TR, Villarino ME, Borisov AS, Shang N, Gordin F, Bilven-Sizemore E et al.  Three months of rifapentine and isoniazid for latent tuberculosis infection.  The New England Journal of Medicine 2011; 365(23):2155-66.

Bleeding & Dabigatran

Bleeding with Dabigatran 

I could not be more thrilled to see all the new oral anticoagulation options emerge.  Warfarin can be difficult to manage due to its many drug interactions and need for frequent monitoring.  One of the questions that seems to have arisen with some of the new oral anticoagulants if our patients are being placed in additional risk of a thromboembolic event or a bleed due to our inability to monitor levels and predict drug effect in certain patient populations.

Dabigatran is a direct thrombin inhibitor marketed in 2010 for prevention of stroke in atrial fibrillation.  While no difference in bleeding was seen with the 150mg twice daily dose compared to warfarin, the medication is not risk free.

The Food and Drug Administration (FDA) is currently reviewing case reports of bleeding with the manufacturer, Boehringer Ingelheim, to develop better monitoring and risk assessment strategies.

Unlike warfarin, there is currently no reversal method for the effects of dabigatran save for emergency dialysis.  The author of an editorial published in The New England Journal of Medicine expresses concern over the poor outcomes of patients taking dabigatran admitted for trauma.  While warfarin is far from perfect, we are able to reverse some of its effects with the administration of vitamin K.

Patients are at a greater risk of bleeding if they are 75 years old or greater, have kidney problems, or have a history of stomach bleeding.  In patients with renal dysfunction, the risk of bleeding is greater even with the reduced dose.  Renal function should be monitored frequently in these patients.

References:

Bleeding with dabigatran. Cotton BA, McCarthy JJ, Holcomb JB.  Acutely injured patients on dabigatran.  The New England Journal of Medicine 2011;365(21):2039-40.

The American Heart: 2011 in review

Despite increasing health care costs and American waist-lines, the mortality rate for cardiovascular disease declined in the past year, according to a recent report from the American Heart Association, AHA.  

From 1998 to 2008, cardiovascular mortality fell 30% but the AHA document illustrates we have a long ways to go.  Data from 2008 showed that an average of one American will die of cardiovascular disease every 39 seconds, coronary heart disease is responsible for one of every six deaths in the United States, and that one of nine death certificates mentioned heart failure.

The trends are looking good, but cardiovascular disease continues to be the cause of significant morbidity and mortality in the United States.

children & cardiovascular disease

In the past 30 years, the incidence of childhood obesity has risen from 4% to 20% and over half of children 12 to 19 have multiple risk factors for developing cardiovascular disease.  

Among children aged 12 to 19, the prevalence of dyslipidemia is a shocking 20%.  Currently, screening this age group for dyslipidemia has not been universally recommended, though statins can be used in children as young as 8 years of age.

American Indian youths had the third highest prevalence of childhood diabetes, with 2.28 cases per 1000 patients.  

While mortality data decreases, let’s continue to encourage patients to eat healthy and exercise; come on Gallup, let’s move!

References:

The American heart. Roger VL, Go AS, Lloyd-Jones DM, Benjamin EJ, Berry JD, Borden WB et al.  Heart disease and stroke statistics-- 1012 update: a report from the American Heart Association.  Circulation 2012; 125:e2-e220.  

Let’s Move Campaign, accessed at www.letsmove.gov on 01/04/12.

Cholesterol Conundrum

Statins have time and again proven their worth in prevention of cardiovascular events.  To add to the evidence is the “Effect of two intensive statin regimens on progression of coronary disease” (SATURN) trial which looked at atorvastatin and rosuvastatin therapy in patients with at least 20% occlusion in one or more vessels.  

Patients who’s cholesterol reached less than 116mg/dL with either atorvastatin 40mg or rosuvastatin 20mg were again randomized 1:1 to maintain the dosage or to increase.  

There was a statistically significant reduction  in percent atheroma volume in patients taking rosuvastatin, but the clinical benefit remains unknown.

Treat the patient, not the number

“Treat the patient, not the numbers” is one of the many mantras of medicine, yet clinical decisions regarding lipid management are far from simplistic.

Undisputed, dyslipidemia is a major risk factor for cardiovascular events, and while statins continue to show benefit, there is a dearth of evidence supporting clinical benefit with other antilipid therapies.

The AIM-HIGH trial was stopped early due to lack of benefit seen in adding niacin to simvastatin in patients with low HDL and high triglycerides.  The 2008 ENHANCE trial failed to show clinical benefit to adding ezetimibe to simvastatin, although the SHARP trial published earlier this year showed that ezetimibe with simvastatin in patients with chronic kidney injury decreased stroke and re-vascularization compared with a non-study statin.  The ACCORD-lipid trial failed to show clinical benefit to adding fenofibrate to simvastatin.

What these trials all have in common is that they examine non-statin anti-lipid therapy in addition to a statin.  Currently there is a lack of evidence of the benefits of these therapies in patients whom are unable to tolerate a statin.  

Patients who are not at goal but tolerating a statin may receive more benefit being switched to a more potent statin than to add a medication.  Fibrates, niacin, and ezetimbe should still be recommended for patients unable to tolerate a statin.

References:

Nicholls SJ, Ballantyne CM, Barter PJ, Chapman MJ, Erbel RM, Libby P et al.  Effect of two intensive statin regimens on progression of cornoary disease.  The New England Journal of Medicine 2011;365:2078-87.

Boden WE, Probstfield JL, Anderson T, Chaitman BR, Koprowicz K, McBride R et al.  Niacin in patients with low HDL cholesterol levles receiving intensive statin therapy.  The New England Journal of Medicine 2011;365:2255-67.

Kastelein JJP, Akdim F, Stroes ESG, Zwinderman AH, Bots ML, Stalenhoef AFH et al.  Simvastatin with or without ezetimibe in familial hypercholesterolesmia.  The New England Journal of Medicine 2008;358:1431-43.

Baigent C, Landray MJ, Reith C, Emberson J, Wheeler DC, Tomson C et al.  The effects of lowering LDL cholesterol with simvastin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial  The Lancet 2011;377:2181-92.

Ginsberg HN, Elam MB, Lovato LC, Crouse JR, Leiter LA, Linz P et al.  Effects of combination lipid therapy in type 2 diabetes mellitus.  The New England Journal of Medicine 2010;362(17): 1563-74.

Statins and Diabetes

Baby I'm afraid of a lot of things but I ain't scared of loving you.
- Karen O

Diabetes scares me probably more than any other disease state.  Diabetes puts patients at risk of slow healing wounds, peripheral neuropathy, increased infections, kidney failure, cardiovascular events, and is the number one cause of blindness.

My roommate has the best definition of diabetes that I've ever heard:

If you eat too much candy, your foot is going to fall off.

She has a point.

There is no way to prevent type 1 diabetes, but research into preventing type 2 diabetes is endless.  Most recently there has been evidence showing that statins increase the risk of developing diabetes.  An inquisitive NP at my rotation was asking me about a Huffington Post article in regards to the topic, so in the past few days I have attempted to dissect the evidence and assess the risk.

Attention was first called to incident diabetes with statin use when the JUPITER trial was published in NEJM in 2008.  Despite screening for cardiovascular risk factors, an estimated half of all myocardial infarctions occur in patients that are at their target LDL goal.  C-reactive protein, a marker of vascular inflammation, has been shown to be a risk factor for CV events independent of cholesterol levels.  Statins have been shown to reduce C-reactive protein levels in addition to reducing LDL.

The JUPITER trial looked at patients at a LOW risk of CV events but high C-reactive protein levels: men over 50 and women over 60 who had no history of cardiovascular disease, and LDL less than 130mg/dL, and a C-reactive protein level greater than 2.0mg/L.  Patients with diabetes, blood pressure above 190/100, low renal function, or use of anti-lipid therapy were excluded.  17,802 patients randomized to 20mg rosuvastatin or placebo were followed for a median of 1.9 years to the occurrence of the first event: MI, nonfatal stroke, hospitalization for unstable angina, arterial revascularization, or cardiovascular death.

Patients taking rosuvastatin 20mg had a decreased risk of cardiovascular events; one event prevented for every 95 patients treated over two years or 31 patients treated over four years.  However, the study also showed a statistically significant increase in the onset of diabetes in patients taking rosuvastatin.

The Buttery

The PROSPER study published in 2002 also showed a significant increase in diabetes in patients taking pravastatin.

In response, Sattar et al. conducted a meta-analysis of trials containing over 1000 patients treated with a statin for at least a year.  The analysis included 13 trials and 91,140 patients.  The statins used were atorvastatin, lovastatin, rosuvastatin, simvastatin, and pravastatin; where six of 13 trials utilized pravastatin.

Sattar et al. found a 9% increase in new onset diabetes in patients taking a statin, or one more new case of diabetes in a patient on a statin for every 225 patients treated for four years.  Increase in diabetes was seen even without the inclusion of the JUPITER trial.  The only other correlation to the development of diabetes was increasing age.

The analysis by Sattar et al. only included one trial, ASCOT-LLA, that utilized atorvastatin.  The stir in the medical community lately has been over an analysis by Waters et al. published in 2011 looking at the incidence of diabetes in IDEAL, TNT, and SPARCL which all utilized atorvastatin.

New York

I am disappointed that Waters et al. did not conduct a meta-analysis, but they found a trend to new-onset diabetes in the TNT and IDEAL trials and an increase in new-onset diabetes in SPARCL.  Patients that developed diabetes were more likely at baseline to have higher fasting glucose, BMI, white blood cell count, blood pressure total cholesterol/HDL ratio, and triglycerides.  80mg of atorvastatin was more likely to worsen glycemic control than 10 or 20mg atorvastatin.  Age differences, sex, and smoking were not associated with incident diabetes.

The real question is how this will change the way we treat patients.  Despite a slight increase in diabetes, statins have been shown to decrease the risk of cardiovascular events and mortality.  Waters tells heartwire, "Compared with their risk of a cardiovascular event, their risk of developing diabetes is paltry" and advises patients not to stop taking their statins.  Dr. Blumenthal of John Hopkins Medical Institute also comments to theheart.org that this analysis will not change his use of statins.  ALLHAT similarly showed an increase in diabetes in patients taking chlorthalidone, but these patients had improved mortality outcomes.

The available evidence shows that the benefit that patients receive from statins outweighs the risk of diabetes.  To me, these analyses show that no medication comes without risk.  Its a reminder to those that believe or believed that statins should be in our drinking water that this is a prescription medication.  There is a risk of liver dysfunction, rhabdomyolysis, and now, a risk of diabetes associated with their use.   Patients should be monitored accordingly.

I would attempt to make lame parallels between the JUPITER trial and the planet, but I know that I cannot do the planet justice.  I think I have failed my parents.  My mother builds satellites and my dad builds video servers by day, and charts the sky by night.  Check out his amazing nebula photos at:
http://astrospotter.zenfolio.com/

Hyannis 2008

References:
Ridker PM et al.  Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein.  The New England Journal of Medicine 2008;359(21):2195-207.

Shepherd J et al. Pravastatin in elderly individuals at risk of vascular disease: a randomised controlled trial.  Lancet 2002;360:1623-30.

Sattar N et al.  Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials.  Lancet 2010;375:735-42.

Waters DD et al.  Predictors of new-onset diabetes in patients treated with atorvastatin.  Journal of the American College of Cardiology 2011;57(14):1535-45.

Hughes S.  More data on diabetes risk with statins.  March 30, 2011; http://www.theheart.org/article/1203383.do 

Nitrate use in Heart Failure

Isosorbide dinitrate can be used with hydralazine in heart failure as an alternative to ACE-inhibitors or ARBs.  The medications act complementary to dilate the blood vessels.  Hydralazine reduces afterload by decreasing both pulmonary and systemic vascular resistance.  Its effects on vasodilation are not completely understood.  It also has some moderate inotropic effects.  It reduces renal vascular resistance, though not by as much as ACE-inhibitors.¹ 

Nitrates like isosorbide dinitrate relax blood vessels by releasing NO.  Isosorbide dinitrate improves exercise capacity in patients with heart failure^1,2.  Nitrates can inhibit vascular and myocardial remodeling³.  Nitrates must be dosed so that there is a six to eight hour period of negligible drug levels or tolerance may develop.  Hydralazine may decrease nitrate tolerance. ^1,3

The V-HeFT trial in 1986 showed decreased mortality with the use of hydralazine and isosorbide dinitrate compared to prazosin ².  The V-HeFT II trial compared isosorbide dinitrate to enalapril in patients with moderate heart failure and found decreased survival due to a higher incidence of sudden death in the isosorbide dinitrate-hydralazine arm.  There was no difference in mortality rate in African Americans taking isosorbide dinitrate-hydralazine compared to enalapril. ²   

The A-HeFT trail in 2004 compared the addition of isosorbide dinitrate with hydralazine or placebo to standard heart failure treatment in patients of African descent in NYHA stage III or IV heart failure.  The trial was terminated early due to increased survival in patients taking hydralazine with isosorbide dinitrate.  The target dosing used in this trial was 75mg hydralazine and 40mg isosorbide dinitrate three times daily for a total daily dose of 225mg hydralazine and 120mg isosorbide dinitrate.⁴

Compliance is more difficult with a regimen containing isosorbide dinitrate and hydralazine because these medications are dosed three to four times a day.  The new product, BiDil, contains both medications but is about twice as expensive and must also be taken multiple times per day.  There is also a high discontinuation rate due to incidence of headache and GI upset.³

There is a lack of trials evaluating the use of isosorbide dinitrate without hydralazine in heart failure; these medications should be used together³.   The ACC/AHA guidelines recommend to consider the addition of hydralazine with isosorbide dinitrate in African Americans.  However, hydralazine with isosorbide should not be considered before an ACE-inhibitor if the patient has no history or ACE-inhibitor intolerance or if they are tolerating ACE-inhibitor therapy.³  The HFSA guidelines recommend to consider the use of hydralazine and isosorbide dinitrate in African Americans in standard therapy, as they do not respond as well to ACE-inhibitors as white patients.  The HFSA also recommends to consider the addition of hydralazine with isosorbide dinitrate in African Americans with stage II or III heart failure and LV dysfunction even if their regimen includes an ACE-inhibitor or beta-blocker.⁵

*Note: images are not of heart failure but are of the beach

References:

1. Brunton LL, Lazo JS, Parker KL, editors.  Goodman & Gilman’s: the pharmacological basis of therapeutics.  11th ed.  New York: McGraw-Hill Companies, Inc.; 2006.
2. Elkayam U, Bitar F.  Effects of nitrates and hydralazine in heart failure: clinical evidence before the African American heart failure trial.  American Journal of Cardiology 2005;96(suppl):37i-43i.
3. Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG et al.  ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult.  Circulation 2005;112:e154-e235.
4. Taylor AL, Ziesche S, Yancy C, Carson P,  D’Agostino R, Ferdinand K et al.  Combination of isosorbide dinitrate and hydralazine in blacks with heart failure.  The New England Journal of Medicine 2004;351(20):2049-2057.
5. Adams KF, Lindenfeld J, Arnold JMO, Baker DW, Barnard DH, Baughman KL et al.  Executive summary: HFSA 2006 comprehensive heart failure practice guideline.  Journal of Cardiac Failure 2006; 12(1):10-38.

Insulin u-500

Although insulin u-500 has been available since the 1950s, the use has sharply increased in only the past five years as a result of increasing rates of obesity and insulin resistance.

Insulin u-500 is a concentrated form of regular insulin, containing five times the units of insulin per mL as u-100.  Although it is a regular insulin, its pharmacokinetic profile may more resemble that of NPH;  a dose of u-500 may last up to 8 or even 24 hours. and there is a delay associated with the peak of action.¹  Although the total dose of u-500 may be more completely absorbed than large doses of u-100, there is a delay in absorption. ² 

There have been limited pharmacokinetic studies done.  Despite the availability of algorithms for the initiation of insulin u-500, much of the conversion may be trial and error. ¹  Pharmacokinetic reports have shown that a sharp rise in insulin concentration occurs 30 minutes after the dose is injected and peaks at 5 hours.  Insulin level will remain high even at 7 hours.  Insulin u-500 should be given 30 minutes before eating. ^2,3

Initiation of insulin u-500 is recommended for patients that are taking greater than 200 units of insulin daily and have not reached or have difficulty maintaining their goal A1c.  The total daily dose (TDD) of insulin should be added up.  If the patient’s A1c is less than 8%, 10-20% of the TDD should be subtracted. ^1,3

Insulin u-500 has both basal and prandial insulin properties.  On initiation, the TDD can be divided into three doses to be taken with breakfast, lunch and dinner although adequate glycemic control has also been achieved with the use of insulin u-500 in two divided doses.¹  If the TDD is 200-300 units, initiate a BID dosing regimen; 300-750, a TID regimen, and for doses 750-2000 consider dosing four times daily⁴.

Dividing the total daily dose²:  

BID dosing: Give 60% TDD qAM, 40% qPM

TID dosing:  Give 40-45% qAM, 30-40% at noon, and 20-30% qPM

no greater than 10% should be given at bedtime

Insulin u-500 acts more as prandial insulin in some patients, others more as basal; it is unclear if this is due to patient weight, insulin resistance, or the dose given^2,3.  The extent of peaking in insulin concentration has varied between studies.³

The patient should be followed every 2 weeks.  If over half of the blood sugar levels are 70-130, no dose change is needed.  If patient is experiencing hypoglycemic episodes, the dose can be decreased 25 units daily.  For fasting glucose levels of 130-200, the dose can be increased 25 units daily and for fasting glucose levels greater than 200, the daily dose may be increased 50 units. ¹

Insulin u-500 is associated with more weight gain than regular insulin.  For every 1% decrease in A1c, a 2kg increase in body weight can be expected³.  Despite the weight gain, patients will be a decreased risk of diabetic complications later on because of more tightly controlled blood sugar.  Weight loss should continue to be emphasized in patients taking insulin u-500.  Decreased weight will improve insulin sensitivity and may allow the patient to eventually step back down to using insulin u-100.  Weight gain with the switch to this insulin should be something assessed as part of the risks and benefits to starting insulin u-500. ^2,3

References:

1.  Ballani P et al.  Clinical experience with u-500 regular insulin in obese, markedly insulin-resistant type 2 diabetic patients.  Diabetes Care 2006; 29(11):2504-5.

2.  Daily AM et al.  Extreme insulin resistance: indications and approaches to the use of u-500 insulin in type 2 diabetes mellitus.  Curr Diabetes Rep 2011; 11:77-82.

3.  Segal AR et al.  Use of concentrated insulin human regular (u-500) for patients with diabetes.  American Journal of Health System Pharmacists 2010; 67:1526-35.

4.  Cochran E et al.  The use of u-500 in patients with extreme insulin resistance.  Diabetes Care 2005; 28(5): 1240-4.