Are Statins a Pain?

Statins are wonderful drugs which have almost single handedly reduced the global burden of heart disease.  Statins are a class of medications that lower cholesterol, including the “bad cholesterol” (LDL, low density lipoprotein) and raise the “good cholesterol” (HDL, high density lipoprotein). In addition, statins have other properties, such as anti-inflammatory effects, that also contribute to their ability to lower heart disease. For every 40 points that statins lower LDL, the risk of a heart attack is reduced by 20-25% and the risk of dying from heart disease is lowered by 10%. As with all medications, with the good comes the bad; all medications can have side effects. Statins can raise liver enzymes, increase the risk for diabetes and, most significantly, can cause muscle pains.

Muscle pain is the most common side effect of statins. It is also the most common reason that patients stop taking their statin, despite the benefits. The symptoms include muscle pain, aching, cramping or weakness.  Usually both sides of the body are affected and usually large muscle groups (thigh, buttock, back, shoulder) are involved.  A typical example would be muscle cramping in both thighs. Risk factors for statin associated muscle pains include older age, female sex, and lower body mass index (BMI).  Other medications and substances (such as alcohol) that have toxic effects on muscles also increase the risk.  Symptoms usually occur right after starting a statin or after an increase in statin dose. The most extreme side effect of statins is called rhabdomyolysis, a life-threatening condition where the muscles not only are painful they actually break down, releasing a protein that can damage the body.  Symptoms of rhabdomyolysis include weakness, vomiting, confusion, tea colored urine, kidney failure and death.  Fortunately, it is a rare condition, occurring in less than 1 in 1000 patients taking statins.

The true extent of statin associated muscle pain is very hard to determine, even within clinical trials.  In trials, muscle pain from statins is reported in 10-25% of patients, but any seasoned clinician will tell you that, in practice, the number of patients who have muscle pains on statins seems much higher.  The reason may due to a powerful factor called the nocebo effect.  Many are familiar with the placebo effect, the idea that a patient can be given a fake treatment, a “sugar” pill with no real medication, and still derive a benefit from taking that treatment. It is the power of positive thinking; simply because a patient believes a pill with be helpful can cause it to have true physical benefit.   For example, in a hypertension trial a patient given placebo can actually have a lower blood pressure.  In trials, placebos are given to set a baseline. Researchers can see if an active medication provides benefit above and beyond the placebo.  The opposite effect, the nocebo effect, occurs when a patient is given a fake treatment or a sugar pill but still has harm. Just knowing the potential side effect of a medication is enough to bring on real symptoms. The nocebo effect can be triggered by reading package inserts, watching or reading about a medication in the media or by listening to a doctor describe side effects.  The placebo effect is the expectation of benefit from a medication while the nocebo effect is the expectation of harm from a medication.

Statins are especially prone to the nocebo effect, which was nicely documented in a recent trial.  In the first phase of the trial, patients did not know if they were on statin or placebo. The percentage with muscle pain was the same in both groups.  In the next phase, patients could continue on a statin or placebo, but they knew which they were taking. Once patients knew they were on a statin, muscle pains were much more likely among patients taking a statin versus those who were on placebo.  Patients on placebo were twice as likely to have side effects when they did not know which drug they were on. The researchers concluded that the expectation of harm was causing the increased muscle pain rather than the medications themselves.

How should statin associated muscle pain be treated? The first step is to stop the statin. If muscle pains persist after two months, there is likely another cause for the pain.  Once the symptoms resolve, the patient can be challenged with another statin. Patients often tolerate one statin better than another.  Longer acting statins can also be given once or twice per week, to achieve the benefit with fewer side effects. Patients should also be evaluated for other conditions know to cause muscle pains such as an underactive thyroid or low levels of Vitamin D. These conditions should be corrected. Coenzyme Q10 is purported to counteract muscle pains, but it was not shown to be effective in clinical trials. Lastly, if patients cannot tolerate two or three different statins, other cholesterol lowering medications should be used.

PARIS: Polluted Arteries R not In Style

The Great Smog gripped the city of London for four days in 1952.  Smog was not an unusual occurrence in London, but this one was different. It started after a prolonged cold front caused coal fireplaces to work overtime to heat homes. Next, a high-pressure system caused warm air to lie over the cooler ground air. These events prevented the smoke generated from burning coal from rising and escaping.  The smog crippled London, paralyzing transportation. Londoners could not see their feet as they walked and their faces were black with soot if they ventured outside. The Great Smog was deadly as well with approximately 4000 deaths directly attributed to the smog. About half of the deaths were attributed to respiratory disease, but about 25% were due to heart disease.  Due to the Great Smog, Parliament passed the Clean Air Act of 1956, restricting coal use in cities and switching to gas, oil and electricity for heating. In the US in the 1940’s and 1950’s, Pittsburgh symbolized the evils of air pollution. The smog from the steel mills was so thick that street lights had to be turned on during the day. In 1948, Donora Pennsylvania, a town near Pittsburgh, was hit with thick yellow smog that resulted in 20 sudden deaths, 400 hospitalizations and caused 7000 of the 14000 residents to become ill.  As a result, Congress passed the Clean Air Act of 1963 and the Air Quality Act of 1967, both of which helped limit the unhealthy effect of air pollution on the US population.  Air pollution has been associated with heart disease for many years. How and why does air pollution affect the heart?

The unhealthy effects of air pollution are caused by inhaling fine particles in the air. These fine particles can be produced by natural sources, such as dust and wildfires. They are also caused by industrial activity and burning fuel in homes. In addition, a major contributor is emissions from cars and airplanes.  Inhaling these fine particles from the air can stimulate localized and more widespread reactions in the body. These fine particles provoke inflammation in the lungs and the inflammatory cells and proteins produced are released into the body, causing a systemic inflammatory response. Levels of C Reactive Protein, a measure of inflammation, are elevated in the blood after exposure to air pollution.  Local inflammation can trigger asthma and emphysema in the lungs. Exposure to the particles in air pollution has been shown to increase the risk for heart artery disease and increase blood pressure. Since plaque within the heart arteries is an inflammatory process, anything that increases inflammation can increase the severity of blockage in the coronary arteries. This was shown in a ten-year study of calcium in the heart arteries (a marker for plaque in the arteries).  Patients exposed to high levels of traffic-related air pollution in cities had progressive worsening of the calcium in their arteries.  In other words, constant exposure to air pollution accelerates atherosclerosis in the heart arteries. Lastly, air pollutants can increase the risk of blood clotting within the body. All of these factors, elevated blood pressure, the systemic inflammatory response and the increased the risk for blood clotting are mechanisms whereby air pollution can destabilize plaque and trigger a heart attack.  The association between long term exposure to air pollution and heart attacks has been corroborated in many studies worldwide. In addition, exposure to air pollutants has been shown to increase admissions for congestive heart failure and to increase the risk for atrial fibrillation.  Those at higher risk for air pollution related heart disease include people with pre-existing heart disease, those with diabetes and the elderly.

Given the global burden of disease caused by air pollution and the fact that it is a leading modifiable risk factor for heart disease, how can the effects of air pollution be reduced? On an individual level, those at risk should: 1) travel by walking or public transportation rather than by car; 2) avoid being outside in rush hour traffic; 3) exercise in parks and avoid major traffic roads; 4) limit time outdoors during highly polluted periods and 5) use a ventilation system with filtration for homes in high pollution areas.  On the global level, countries should work together to reduce industrial pollution, stop the rise in the global average temperature, reduce emissions and switch from fossil fuels to greener sources of energy.  Signing on to the Paris climate agreement would be a good first step.

Painting a Portrait of Women with Heart Disease

The Mona Lisa by Leonardo da Vinci is perhaps the best-known and most famous work of art in the world.  It was painted in 1503 and still draws huge crowds to its home in the Louvre in Paris.  The Mona Lisa’s beauty stems from her eyes (which appear to follow the observer), her stately posture and her smile, about which many books have been written.  Most importantly, the Mona Lisa depicts the Renaissance ideal of womanhood. While the artist has been successful at portraying the ideal woman, cardiologists are less than ideal in diagnosing and treating heart disease in women. 

Cardiovascular disease is still the leading cause of death in women in the western world. Despite this, women are under-represented in cardiovascular research and women are less likely than men to be tested for heart disease and to receive appropriate heart treatments.

Women are built differently from men, especially when it comes to matters of the heart. Women usually present with heart disease, specifically blockages in the heart arteries, about ten years later than men. This is due to the fact that women are protected by their hormones until menopause and develop high blood pressure, diabetes, obesity and high cholesterol later in life than men. Men with blockages in the heart arteries present with classic, exertional chest pain.  Women, especially those older than 65, are less likely to have chest pain, but may have jaw pain, neck pain, shoulder pain, left arm pain, ear pain or tooth pain. Women will have shortness of breath with exertion or fatigue with exertion. Therefore, symptoms must be evaluated very carefully when a woman sees her cardiologist. In addition, cardiac testing is better suited for men than women. The exercise stress test is able to identify heart artery disease in men about 70% of the time, while in women it decreases to about 60%.  Even combining the stress test with nuclear images of the blood flow to the heart is less accurate in women compared to men.  In addition, women are much more likely than men to have false positive tests (an abnormal test but without blockages on the gold standard test for heart artery disease, the cardiac catherization) for both stress and nuclear stress testing. Overall, the lower ability of stress testing to pick out disease coupled with the higher false positive rate, makes noninvasive cardiac testing in women less accurate.

Even when women have chest pain the characteristics are different than men. In women who have chest pain, many (approximately 50%) will have no significant blockage after heart catheterization. Women with exertional chest pain, but without blockages in the major heart arteries, are felt to have microvascular angina. Microvascular angina is due to abnormal reactions of the small heart arteries to various stimuli (for example, anxiety). Much less is known about treating this entity, despite years of research. What is known is that microvascular angina is very disabling and women continue to have chest pain, continue to have heart testing and continue to be admitted to the hospital because of it. So, women with chest pain despite a normal heart catheterization should not be ignored and medications should continue to be adjusted to relieve symptoms.

Heart disease clearly is not a “man’s disease” as cardiac disease causes the death of one woman per minute in the US.  Risk factors, such as obesity and high blood pressure, are increasing for women, especially as they become older.  Women have a higher risk of dying from a heart attack than men, due to the fact that they are older, have other complicating diseases (for example diabetes) and they present with their heart disease later in its course due to vague symptoms.  Despite this, the picture has become rosier in recent years.  Cardiac disease in women has decreased significantly since 1980 due to improved risk factor treatment, major trials such as the Women’s Health Initiative and public heath campaigns by the American Heart Association (and others) raising awareness of heart disease in women. Hopefully this trend continues, the portrait becomes more ideal and we can all smile a bit more about the positive gains in women’s heart disease.

Blood Pressure Negotiations

The American Heart Association (AHA) encourages everyone to “know his or her numbers”. One of the numbers that the AHA wants us to know is the blood pressure. The AHA recommends that the blood pressure be kept under 120/80. Is that the right number? Is that the right level for blood pressure for everyone? If not, what is the “right” number for the blood pressure?

For those without established high blood pressure (hypertension), yearly blood pressure checks are recommended.  If the blood pressure is over 140/90 on three separate occasions, weeks apart, in a person who is not currently ill, then hypertension is diagnosed and treatment for high blood pressure is started.  It is very important to measure the blood pressure correctly. Often, the blood pressure is elevated in the doctor’s office (called “white coat hypertension”) and checking the blood pressure at home is advised.  To do this properly, one must sit quietly for 15 minutes, with the arm in a relaxed state, propped on a table or armchair and at the level of the heart.  It is recommended that two to three blood pressure measurements be obtained and averaged to determine a true number.

For those with established hypertension, two trials and some recent expert opinions are important to know.  The SPRINT trial split 9000 hypertensive patients into two groups; one group was treated to a blood pressure under 120, the other to under 140. The under 120 group had less heart failure and deaths due to heart disease. The trial concluded that hypertensive patients be treated to a blood pressure under 120. However this conclusion has not yet been universally accepted due to several factors. The under 120 group was taking more medications (an average of 3 meds versus 2 for the 140 group) and had more side effects from medications (falling, low blood pressure and kidney problems).  In addition, the method used to measure blood pressure was very vigorous and may not be representative of blood pressure measurements in the real world. Lastly, SPRINT did not include diabetic patients.

The ACCORD trial was designed for the diabetic hypertensive patient. This trial split 4000 patients into two groups as well: one group’s blood pressure was treated to under 120, the other to under 140.  The theory was that diabetic patients are at high risk for heart disease and that treating aggressively (to under 120) would be better. In fact, the trial found no difference between the groups. It concluded that diabetic patients should be treated to under 140, as the more aggressive target didn’t add any benefit.

What is the blood pressure target for the older hypertensive patient? In 2014, the Joint National Commission changed the blood pressure goal from under 140 to under 150 for those over 60 years old.  In January 2017, the American College of Physicians published an expert opinion document agreeing with treating patients older than 60 to under 150.  However, an analysis of patients in the SPRINT trial who were over 60 years old showed that they too had less cardiac problems when treated to under 120 compared those treated to under 140.  Lastly, in February 2017, a trial following 10,000 older hypertensive patients showed that treating to a blood pressure less than 140 decreased the risk for major cardiac events and deaths.

So, what is the right blood pressure number for the hypertensive patient? Clearly there is no single best number for all patients. There is a lot of disagreement on the blood pressure target between trials and between experts. For now, the best guidelines are the following. Diabetic hypertensive patients should be treated to a blood pressure under 140. Nondiabetic hypertensive patients under age 60 should be under 140 and those who are younger (around 50 years old) or with other significant risk factors for heart disease should be treated to a blood pressure under 120.  Nondiabetic patients older than 60 years old, definitely should be treated to under 150 and possibly under 140.  As all blood pressure medications work and all have their side effects, the best way to manage high blood pressure is for the doctor and the patient to work together. The doctor should try to get the patient’s blood pressure to a proper goal while simplifying the medication regimen (taking meds once or twice per day) and minimizing the side effects. The patient should faithfully take medications, check the blood pressure at home, report side effects and follow agreed upon life style modifications.  The best blood pressure treatment requires constant collaboration and negotiation between the doctor and the patient.

Can an Aspirin a Day Keep the Cardiologist Away?

In the 1890’s, scientists at Bayer developed a new medication they called aspirin. In 1899 Bayer began selling aspirin.  For many decades, aspirin was used to treat pain, fever and inflammation. However, in the 1970’s, aspirin was found to have properties as a blood thinner. It is the blood thinning properties which makes it beneficial for heart disease.  Despite being in existence for more than 100 years, there are still questions about aspirin, such as the optimal dose and who should take it for the prevention of heart disease.

Aspirin’s ability to thin the blood centers around its effect on platelets.  Platelets are cells which circulate in the bloodstream. If there is a tear in the wall of a blood vessel (a cut) or if a cholesterol-laden plaque in an artery breaks open, the platelets rush to the site of the injury and initiate the blood-clotting cascade.  The resulting clot prevents bleeding from a cut or produces a clot within a heart artery, stopping the flow of blood and causing a heart attack.  Aspirin inhibits the platelet’s ability to form a blood clot. This puts the person taking aspirin at risk for bleeding (since the platelets cannot trigger a blood clot) and the “blood is thinned”. Aspirin inhibits platelets for the life of the platelet, about 7 to 10 days. The most serious side effect of aspirin is bleeding. Aspirin may cause bleeding in the stomach (from an ulcer), the colon (from polyps) or the brain.

Aspirin is the mainstay of treatment for heart disease.  In patients having an acute heart attack, aspirin is given immediately (in fact the patient is asked to chew it so it may be absorbed more quickly than if it was swallowed) to counteract the acute blood clot forming in the heart artery.  After a heart attack, an “adult” aspirin (325 mg) is given daily to prevent another heart attack.  This is termed secondary prevention. In this setting, aspirin has been shown to reduce the risk of heart attack, stroke or death by 33%. Similarly, aspirin is given to patents with chest pain due to heart artery disease, stroke patients, patients after heart bypass surgery and patients with a heart stent.  In all of these scenarios, aspirin effectively reduces the risk of a second event balanced by a small increase in the risk for bleeding.

The optimal dose of aspirin is still not known. Doses below 75 mg are not effective, so the lowest dose in use now is “baby” aspirin (81 mg).  Aspirin doses between 75 and 1500 mg are all felt to be equally effective. Low dose aspirin (81 mg) is associated with less risk for bleeding and less gastrointestinal intolerance.  For patients with an acute heart attack, a fresh stent, a recent stroke or after bypass surgery, the initial dose of aspirin should be 325 mg daily for one month, followed by aspirin 81 mg daily indefinitely.

Can aspirin be used to prevent heart disease in people who have not yet had a heart attack (primary prevention)?  The US Preventive Services Task Force recommends a low dose (81 mg) aspirin for adults aged 50 to 69 years old, who have a 10% or greater risk for cardiovascular disease (based on the American College of Cardiology cardiovascular risk calculator-  http://tools.acc.org/ascvd-risk-estimator/), are not at increased risk for bleeding, and have a life expectancy of at least 10 years.

So, shouldn’t everyone be on an aspirin? Probably not. For those who are at low risk for heart disease, the risk of gastrointestinal bleeding and bleeding into the brain outweighs the benefit of even a low dose of aspirin.  For those who have heart disease or a stroke or for those who are at high risk for heart disease, an aspirin a day can save a life and keep you away from your local heart hospital.