Chest Pain in a Pregnant Woman

A 36-year-old woman in her 34th week of pregnancy presented to the emergency department after the onset of severe substernal chest pain. The chest pain was sudden in onset and had awoken her from sleep in the early morning. She also noted diaphoresis and nausea. She did not have dyspnea, dizziness, syncope, hemoptysis, cough, or fever.
The fetal heart rate was approximately 150 beats per minute.

Hypotension and tachycardia may suggest a cardiovascular
condition as the cause of her chest pain,although these findings may also occur during normal pregnancy. Obtaining symmetric blood pressures from both arms would be important, since aortic dissection is possible. The absence of a rub during the examination of the heart sounds makes pericarditis less likely than other possible causes,
but it cannot be completely ruled out. The normal lung examination and oxygen saturation make pneumothorax and pneumonia improbable choices. Pulmonary thromboembolism remains a possibility, despite the normal oxygen saturation.

Electrocardiography showed sinus tachycardia with ST-segment elevation of 1 mm in leads II,III, and aVF

Chest radiography revealed a normal cardiac silhouette with no evidence of pneumothorax, consolidation, or effusion.

Initial laboratory studies revealed the following: hemoglobin, 9.0 g per deciliter; hematocrit, 27 percent; platelet count, 126,000 per cubic millimeter; whitecell count, 7000 per cubic millimeter; sodium,
134 mmol per liter; potassium, 3.6 mmol per liter; chloride, 104 mmol per liter; bicarbonate, 17 mmol per liter; blood urea nitrogen, 5 mg per deciliter (1.8 mmol per liter); and serum creatinine, 0.4 mg per deciliter (35.4 μmol per liter). The coagulation studies, including an activated partial-thromboplastin time (aPTT), were normal.

The results of electrocardiography are consistent with acute myocardial injury in the inferior wall, probably due to occlusion of the right coronary artery.Lateral changes and the ST-segment elevation of 1 mm in lead V1 suggest that the infarction involves the inferolateral wall and right ventricle, respectively. A right-sided electrocardiogram should be obtained.

Although rare, myocardial infarction is a well-described complication of pregnancy and is estimated to occur in 1 in 10,000 women during the peripartum period. Coronary atherosclerosis is
a frequent cause, but this patient has no risk factors for atherosclerosis. Other causes include thromboembolism, a spontaneous coronary-artery dissection, and severe coronary-artery vasospasm.
The normal chest radiograph essentially rules out pneumothorax and pneumonia. Pulmonary thromboembolism also appears less likely than other possibilities Chest pain in a pregnant woman may be the result of various conditions, ranging from benign to life-threatening diseases. Cardiovascular causes include a hypertensive crisis, an acute coronary syndrome, pericarditis, myocarditis, and aortic dissection. Possible
pulmonary disorders are pulmonary thromboembolism, spontaneous pneumothorax, and pneumonia. Peptic ulcer disease, gastroesophageal reflux disease, esophageal spasm, costochondritis, and even herpes zoster should also be considered.
The patient’s previous pregnancies had been complicated by preterm labor and a miscarriage. She had had an ectopic pregnancy two years earlier. Her current pregnancy was complicated by hyperemesis gravidarum, and she had required total parenteral nutrition support through a peripherally inserted central catheter for the past 12 weeks. Her only medication was famotidine. She did not smoke cigarettes or use alcohol. She said she did not use illicit drugs.
This woman’s history of preterm labor and spontaneous abortion suggests the possibility of the antiphospholipid-antibody syndrome. The antiphospholipid-antibody syndrome results in a hypercoaguable state and has been associated with myocardial infarction and pulmonary thromboembolism. It may also be associated with systemic
lupus erythematosus, rheumatoid arthritis, and Sjögren’s syndrome — all of which may cause pericarditis or pleuritis. An additional concern is the peripherally inserted central catheter, which might cause thromboembolism, although this is a rare occurrence.
Differential diagnosis remains broad and includes pulmonary thromboembolism, an acute coronary syndrome, aortic dissection, and pericarditis.
In the emergency department, the patient was alert and in distress from her chest pain. She was afebrile, with a blood pressure of 88/60 mm Hg, a pulse of 108 beats per minute, and a respiratory rate of 20 breaths per minute. Oxygen saturation as determined by pulse oximetry was 98 percent, with the patient breathing room air. An examination of the neck showed no jugular venous distention or carotid bruits, and auscultation of the chest revealed no wheezes or crackles. The heart sounds were normal, and there was no murmur, rub, or gallop. An abdominal examination revealed a gravid abdomen without tenderness. There was no cyanosis, clubbing, or edema of the arms or legs. A peripherally inserted central catheter in her left arm was functioning well. The fetal heart rate was approximately 150 beats per minute.

Hypotension and tachycardia may suggest a cardiovascular condition as the cause of her chest pain, although these findings may also occur during normal pregnancy. Obtaining symmetric blood pressures from both arms would be important, since aortic dissection is possible. The absence of a rub during the examination of the heart sounds makes pericarditis less likely than other possible causes, but it cannot be completely ruled out. The normal lung examination and oxygen saturation make pneumothorax and pneumonia improbable choices. Pulmonary thromboembolism remains a possibility, despite the normal oxygen saturation.

Electrocardiography showed sinus tachycardia with ST-segment elevation of 1 mm in leads II, III, and aVF .
Chest radiography revealed a normal cardiac silhouette with no evidence of pneumothorax, consolidation, or effusion.
Initial laboratory studies revealed the following: hemoglobin, 9.0 g per deciliter; hematocrit, 27 percent; platelet count, 126,000 per cubic millimeter; whitecell count, 7000 per cubic millimeter; sodium, 134 mmol per liter; potassium, 3.6 mmol per liter; chloride, 104 mmol per liter; bicarbonate, 17 mmolper liter; blood urea nitrogen, 5 mg per deciliter (1.8 mmol per liter); and serum creatinine, 0.4 mg per deciliter (35.4 μmol per liter). The coagulation studies, including an activated partial-thromboplastin time (aPTT), were normal.
The results of electrocardiography are consistent with acute myocardial injury in the inferior wall, probably due to occlusion of the right coronary artery. Lateral changes and the ST-segment elevation of 1 mm in lead V1 suggest that the infarction involves the inferolateral wall and right ventricle, respectively.

A right-sided electrocardiogram should be obtained. Although rare, myocardial infarction is a well-described complication of pregnancy and
is estimated to occur in 1 in 10,000 women during the peripartum period. Coronary atherosclerosis is a frequent cause, but this patient has no risk factors for atherosclerosis. Other causes include thromboembolism, a spontaneous coronary-artery dissection,
and severe coronary-artery vasospasm. The normal chest radiograph essentially rules out pneumothorax and pneumonia. Pulmonary thromboembolism also appears less likely than other possibilities
given the clinical presentation and the electrocardiogram, but it is not completely ruled out. Although a widened mediastinum would suggest
aortic dissection, chest radiography is insensitive for this condition. For a dissection to explain the electrocardiographic changes, the dissection
would have to extend into the right coronary artery.
Initial routine laboratory studies show anemia and a mild decrease in the platelet count, and coagulation studies were normal. These findings suggest that a diagnosis of the antiphospholipid-antibody syndrome is not as likely as some other choices. A transthoracic echocardiogram may be helpful at this point, because it can be obtained rapidly with no harm to the fetus and would confirm wallmotion abnormalities due to myocardial infarction. In addition, it might detect dilatation of the pulmonary artery, right ventricle, and right atrium or hypokinesis of the right ventricle, as may be seen with pulmonary thromboembolism. Although such an echocardiogram cannot be used to definitively rule out acute aortic dissection, it may detect an intimal flap in the proximal aorta. However, because “time is muscle,” additional studies should not
markedly delay decisions regarding immediate reperfusion therapy.

Owing to the lack of an on-site cardiac catheterization laboratory, the patient was transferred on an emergency basis to a nearby facility for cardiac catheterization with possible percutaneous coronary
intervention. Before she was transported, an aspirin was given, intravenous heparin and nitroglycerin were started, and a single 5-mg dose of intravenous metoprolol was given. A transient decrease
in blood pressure during transport responded to intravenous fluids and discontinuation of nitroglycerin. Although there is some debate about the relative benefits of transfer for emergency cardiac catheterization
and percutaneous coronary intervention in patients presenting with myocardial infarction with ST-segment elevation, in this case the decision is easier. The cause of this patient’s condition has not been established, and both the mother and fetus remain in jeopardy. Cardiac catheterization would help establish the diagnosis as well as offer
the possibility of definitive treatment. The risk to a third-trimester fetus associated with radiation from the procedure is considered negligible if proper shielding of the abdomen is used. Intravenous
fibrinolysis is an alternative for reperfusion and could be given immediately. However, it is rarely used in pregnancy because of limited data and the potential for bleeding. The precipitous drop in blood pressure with intravenous nitroglycerin suggests right ventricular
involvement, and further use of nitroglycerin should be avoided. Aggressive resuscitation with intravenous fluids is appropriate. Intravenous heparin probably has limited value in this setting and
may be detrimental, because acute aortic dissection with right coronary involvement has not been ruled out.
Transthoracic echocardiography, performed at the second hospital, revealed hypokinesis of the inferior wall and posterior wall, with an overall ejection fraction estimated at 50 percent. The right ventricle appeared to be normal in size and function. There were no other valvular abnormalities noted. The electrocardiogram shows a pattern of myocardial injury that involves the inferior and inferolateral walls with ST-segment elevation and Q waves present. There is also mild ST-segment elevation in V1, suggesting right ventricular involvement.

Electrocardiogram.
The electrocardiogram shows a pattern of myocardial injury that involves the inferior and inferolateral walls with ST-segment elevation
and Q waves present. There is also mild ST-segment elevation in V1, suggesting right ventricular involvement.

Cardiac catheterization on an emergency basis is needed. At this point, the potential benefits of the procedure in guiding management and allowing definitive therapy outweigh its risks, which include
bleeding complications, cardiac arrest, and prolonged arrhythmias
Cardiac catheterization was performed after shielding the patient’s abdomen with a lead apron. Coronary angiography showed a normal left main coronary artery, left anterior descending coronary artery, and left circumflex coronary artery. An injection of contrast medium into the right coronary artery revealed a total occlusion of the proximal
vessel, with contrast-medium staining suggestive of a dissection flap

The cause of a spontaneous dissection of a coronary artery during pregnancy is not well understood. The hormonal and hemodynamic alterations that take place during pregnancy may lead to morphologic
changes in the collagen of coronary arteries and weaken the media layer. Spontaneous coronary-artery dissection may also occur in patients with underlying atherosclerotic plaque, connective tissue
diseases, immunological diseases or Kawasaki’s disease. Regardless, the goal now should be immediate restoration of flow with percutaneous
coronary intervention. A temporary pacemaker was placed in the right
ventricle. Eptifibatide, an intravenous glycoprotein IIb/IIIa receptor blocker, and clopidogrel were given. The right coronary-artery occlusion was crossed and then dilated with balloon angioplasty
several times. Multiple intracoronary paclitaxel coated stents were deployed to tack up the dissection flap. The final angiography revealed no stenosis and normal intracoronary blood flow(The patient’s chest pain resolved, and repeated electrocardiography showed improvements
in ST-segment elevations. The fetal heart rate remained in the normal range throughout the procedure It would be ideal to have a full obstetrical team available if any hemodynamic compromise occurs in
such a case. The interventions performed were reasonable on the basis of clinical-trial evidence from patients who were not pregnant, although data are lacking in pregnancy.
Adjunctive therapy with a glycoprotein IIb/IIIa receptor blocker has been associated with improved clinical outcomes after percutaneous coronary intervention, but it may increase risk of bleeding as a result of inhibition of platelet aggregation; this is a particular concern if an emergency delivery is required. Dual antiplatelet therapy with aspirin and clopidogrel is recommended to prevent subacute stent thrombosis. Stenting —as opposed to traditional balloon angioplasty — is theoretically preferable when coronary-artery dissection occurs, in order to adequately tack down the dissection flap. The role of drug-eluting stents has not been established in this setting.

The patient’s hospital course was complicated by an episode of ventricular fibrillation one day after the percutaneous coronary intervention. She was treated with immediate cardioversion and did not
require cardiopulmonary resuscitation. Three days after this episode, still in her 34th week of gestation,labor was induced, and she delivered a healthy baby girl. After delivery, treatment with an angiotensin-
converting–enzyme inhibitor was begun,in addition to the aspirin, clopidogrel, and metoprolol she was taking already.
An implantable cardioverter–defibrillator was also placed before discharge. An angiotensin-converting–enzyme inhibitor may be beneficial for ventricular remodeling during theearly postinfarction period, but it may not be needed in the long term in the absence of coronary atherosclerosis.
Early use of statins is valuable in most patients with myocardial infarction, but their rolehere is uncertain. The use of an implantable cardioverter–defibrillator is highly controversial in this patient, especially as the episode occurred within 24 hours of her myocardial infarction and her ejectionfraction remained relatively preserved.
The optimal timing for delivery of the fetus after the mother has had a myocardial infarction is unknown. If possible, waiting for up to two to three weeks has been recommended in order to allow for
adequate myocardial healing. Earlier delivery may have been reasonable in this case, given the successful revascularization and the episode of ventricular fibrillation. Data are limited to guide the mode of delivery (vaginal or cesarean). Although an episode of spontaneous coronary-artery dissection is not considered an absolute contraindication
to future pregnancies, it may be best for the patientto avoid them. Of course, this decision requires an individualized approach, because data on the potential for recurrence are limited.Evaluating chest pain in pregnant women can bechallenging. Physicians need not only to distinguish between life-threatening and benign conditions,but also to quickly determine the best and safest treatment options for both the patient and the fetus.With the advent of fetal heart-rate monitoring
and improved antenatal testing, potential jeopardy to the fetus has emerged as both a medical and a legal consideration.However, it is important that maternal health remains the primary determining
factor in obstetrical treatment decisions. During emergency medical conditions, the tendency often is to “order first and think later.” This
is especially true when it comes to diagnostic imaging studies. Even though there is considered to be little risk to the fetus from radiation during the final trimester,the desire to avoid unnecessary exposure underscores the importance of the history,physical examination, and simple tests such as electrocardiography in assessing chest pain in
pregnant women. Fetal heart tones also should be quickly determined in any viable pregnancy, because a fetal status that was not reassuring might alter how the situation is managed. During normal pregnancy, left-axis deviation, ST-segment and T-wave abnormalities, and onsignificant
Q waves in leads III and avF may occur,but they are readily distinguishable in most casesfrom the more pronounced changes observed with acute coronary syndromes.Whereas other conditions
that were considered in this case (such as pulmonarythromboembolism) may produce ST-segment changes, the findings were highly suggestive
of myocardial infarction with ST-segment elevation.Furthermore, the echocardiogram confirmed the suspicion of myocardial infarction and justified the emergency cardiac catheterization. Spontaneous coronary-artery dissection is a rare but well-described cause of acute coronary syndromes. Its true incidence is unknown, since cases are often diagnosed post mortem. Most reported cases have been in young women during the peripartum period or in patients with coronary atherosclerosis.The clinical presentation of a patient with this condition is highly variable and depends primarily on the vessel involved and the rate and magnitude of the dissection. Patients may present with
chronic stable angina, acute coronary syndromes,cardiogenic shock, or sudden death from cardiac causes. Although the exact cause of spontaneous coronary dissection in pregnancy is unknown, it is
believed to relate to structural changes within the blood-vessel wall in response to hormonal changes associated with pregnancy, as well as to hemodynamic stress caused by increased coronary blood
flow during pregnancy. Autoimmune conditions, such as systemic lupus erythematosus and the antiphospholipid-antibody syndrome, have also been linked to coronary-artery dissections. Treatment includes medical therapies to reduce ischemia and revascularization performed on an
emergency basis when indicated. Aspirin, anticoagulantagents, and beta-blockers are safe and immediate options in most patients.
In this case, a decision was made to transfer the patient quickly to a
specialized center with the capability of performing emergency cardiac catheterization and percutaneous coronary intervention for reperfusion. As the discussant stated, fibrinolytic agents in this setting are relatively contraindicated because of the potential risk of maternal hemorrhage. Propagation of spontaneous coronary-artery dissection has
also been described with fibrinolysis. Although surgical revascularization has been used, it is typically reserved for cases that involve
multiple vessels or the left main coronary artery. Percutaneous
coronary intervention — and in particular, coronary stenting — has otherwise been successful at reestablishing flow and tacking down the
dissection flap. The role of drug-eluting stents is unknown in this setting. Drug-eluting stents dramatically reduce the rate of restenosis after deployment in patients with coronary-artery disease. However,
they have not been evaluated in patients with coronary-artery dissection or pregnancy. Paclitaxel has been used only rarely in pregnant women with advanced cancer as a systemic agent.
In this limited instance, the agent caused no apparent side effects in the fetus. The early delivery that occurred three days after treatment with this agent also minimized exposure of the fetus. Ventricular tachyarrrhythmias that occur soon after myocardial infarction are thought to be due primarily to electrical instability and increased sympathetic tone.
As mentioned by the discussant, the use of an implantable cardioverter–defibrillator is controversial in this setting, because in-hospital
ventricular tachyarrhythmias within 48 hours after myocardial infarction have not been consistently associated with long-term survival after discharge.

Lidocaine can be safely used during pregnancy to prevent recurrences of ventricular tachyarrhythmias; however, amiodarone should
not be given because of the potential association with neonatal thyroid dysfunction.

Chest Pain and SOB

Distended Abdomen, Chest Pain, Yellow-Tinged Eyes
By LISA SANDERS, M.D.

1. Symptoms
”I thought it was my smoking, and so I quit,” the patient said flatly. His bright blue eyes peered out of his thin, tanned face. ”But, you know, it didn’t make any difference.” He ran his hand through his graying hair. ”I felt like I was going to drop dead just walking to the TV.”
It started a while ago, he told the young resident in the E.R. He would be out of breath when he walked to the store or climbed the stairs. He had to take everything ”real slow.” Then, a couple of months ago he noticed that his abdomen and legs were swollen — that’s when he went to the emergency room the first time. He was in the hospital for a week and was sent home with diuretics but no answers. He was supposed to follow up with a cardiologist, for further evaluation, but he didn’t. He also stopped taking the medicines. He didn’t really like doctors. Until this started a couple of years ago, he hadn’t been sick since he had rheumatic fever as a child. He came back to the hospital this time only because he was scared and he was too winded to work. ”Hell, I can’t even walk.”
He’d worked as a painter, at least until recently. ”Houses or pictures?” the young physician asked. ”Both,” he answered with an unexpected smile. ”I paint murals.” He laughed at his own well-worn joke then stopped as he gasped for air. He quit smoking a year ago and quit drinking after his last hospital stay. On physical examination, he had an enormous abdomen that contrasted significantly with his well-muscled but slender upper body. His eyes, lively and attentive, made him appear younger than his 59 years. The whites, though, had a pale yellow tinge, and his skin was slightly jaundiced beneath his tan. His left lung sounded normal, but on the right, the resident couldn’t hear his breathing at all. His abdomen was tense and filled with fluid — a condition known as ascites. His liver, too, was large and seemed to throb in rhythm with his heart. His legs were swollen and ruddy. A chest X-ray revealed why the right lung was so quiet. The sack containing the lung was filled with fluid.

2. Investigation

The resident, Dr. Jaideep Talwalkar, carefully reviewed the patient’s chart from his first hospitalization. Though the patient had many tests done, the doctors who cared for him then had not been able to make a diagnosis. They thought that the cause of both the ascites and the shortness of breath would probably be found in either the heart or the lungs. The resident thought this was reasonable. Normally blood is pumped from the right side of the heart through the lungs into the left side of the heart, then out into the circulation. When something gets in the way of the smooth flow of blood, you get a backup. It’s like a construction site on a highway: cars have to slow to get past the workers, and that causes traffic to back up for miles before the obstruction. Same with the heart and lungs: if something blocks the forward flow of blood, it gets backed up and you get fluid accumulating in the heart, the lungs, the liver.
So where was the obstruction? Could it be in the lungs? The patient smoked two packs a day for more than 40 years, so severe emphysema was a real possibility. Just about any disease affecting the fragile lung tissue might produce these symptoms — if the damage was extensive enough. Pulmonary emboli — small clots blocking the flow of blood through the lungs — might give the same picture. Or could it be his heart? This patient did have rheumatic fever as a child. Doctors don’t see this much anymore, but before the widespread use of antibiotics, children who had untreated strep throat could develop heart-valve problems decades after the infection. Most commonly the valves became stiff and narrow, hampering blood flow. The resident thought that this was the most likely cause. So did the first set of doctors. They ordered an echocardiogram — a sonogram that looks at the heart in motion — to seek the suspected narrowed valve. They didn’t find it. The test did show that the heart wasn’t normal — the right side of the heart was stretched with backed-up blood to almost twice its normal size, but no blocked valve was found. Instead they saw a valve that was stuck open. Each beat of the heart sent only half the blood forward to the body, and the other half flowed back into the lungs.
Could this valve defect — known as mitral regurgitation — be the cause of his symptoms? The resident didn’t think so, and neither had the first team of doctors. Usually in mitral regurgitation, the squeezing part of the heart is stretched out and weakened by the constant forward and backward flow of blood. In this patient, both the echocardiogram and physical exam suggested that the heart’s ability to squeeze was unimpaired. Talwalkar ordered a CT scan of the lungs to look for either a clot or evidence of severe lung disease and restarted the diuretics to help the patient get rid of excess fluid.
The CT shed little light. There was no sign of a clot, and while the scan showed some lung destruction from his years of smoking, it wasn’t extensive enough to be the cause of the patient’s symptoms.
”I just don’t get it,” the resident said after outlining the case to the cardiologist he had called for help. Could all this be from the mitral regurgitation seen on the echocardiogram? But the patient’s symptoms didn’t fit the results of the echo. The cardiologist reviewed the fuzzy images from the last hospital stay. ”Get another echo,” he suggested. ”They didn’t get a good look at the valve.” A second echo was done. The reading was the same — mitral regurgitation.

3. Resolution

Despite the diuretics, the patient did not improve. The day after his echo he developed a rapid, irregular heart rhythm and chest pain. Blood tests showed that he hadn’t had a heart attack. Still, he couldn’t get out of bed without feeling the pain or the arrhythmia that left him dizzy and out of breath. Whatever he had, it was getting worse, and the resident was no closer to a diagnosis than the earlier doctors had been.
The cardiologist was undeterred by the second negative test. Everything about this case pointed to a blocked valve. The pumping part of the heart was working fine, and if this condition was a result of mitral regurgitation, that wouldn’t be the case. ”I still think the test is wrong,” the cardiologist told the resident. ”I’ve seen mitral stenosis, and I think that’s what he has. We should do it one more time.” The team decided to order a third echo. This time the resident made sure the technician knew what they were looking for. Finally, the test revealed what they had suspected all along. He had severe mitral valve stenosis — his valve was so blocked that the opening was a quarter of its normal size.
How could this happen? How could a test be wrong not once but twice? The cardiologist paused when I asked him this and then said briskly: ”Mistakes happen, but the bottom line was this: Everything pointed to mitral stenosis except for this test. Given that, most likely it was the test that was wrong.”
The patient listened eagerly as the resident relayed that surgery would be needed to repair his narrowed valve, though, he confessed later, he wasn’t sure he really understood what they were talking about. ”Whatever it takes,” he said gamely. ”Let’s just get this done.”
The next day, he was sent to a university hospital nearby for valve replacement. He got a new valve and was back home two weeks later. I called him recently to find out how he felt. ”I’ve never felt better,” he said. ”I went back to see my doctor not too long ago, and you know what he said? He told me to get the hell out of his office. I was too damn healthy to be there.”
Lisa Sanders is an internist and is on the faculty at the Yale University School of Medicine.

The Jupiter Study

Crestor, Guidelines, Rationing and Other CRP
November 13th, 2008 by DrRich

The JUPITER trial, reported this week at the American Heart Association Scientific Sessions and simultaneously published in the New England Journal of Medicine, has created quite a stir in the mass media and in the blogosphere. DrRich would like to do his bit in flaming the controversy.

On its surface the study and its results are pretty straightforward. Nearly 18,000 men and women from 26 countries who had “normal” cholesterol levels but elevated C-reactive protein (CRP) levels were randomized to receive either the statin drug Crestor, or a placebo. CRP is a non-specific marker of inflammation, and an increased CRP blood level is thought to represent inflammation within the blood vessels, and is a known risk factor for heart attack and stroke. Patients randomized to Crestor, after an average treatment period of 1.9 years, had a highly significant 44% reduction in a composite endpoint that included heart attack, stroke, the need for stenting or bypass surgery, and cardiovascular death. Both CRP and cholesterol levels were also significantly reduced in patients taking Crestor.

This study is noteworthy because it is the first large randomized trial to show that Crestor (or any statin) can markedly reduce the incidence of some very nasty cardiovascular outcomes in people who are considered to have “normal” cholesterol levels. (Notably, typical LDL cholesterol levels among primitive hunting/gathering cultures is around 50 mg/dL, instead of the 100 – 120 mg/dL we consider to be normal. These people have an extremely low incidence of cardiovascular disease, so maybe humans’ optimal cholesterol level is much lower than we now think. On the other hand, the low risk of cardiovascular disease among hunters/gatherers may instead be related to the fact that many of them are consumed by bears before they’re 30.)

So here’s what we know from the JUPITER trial: giving Crestor to patients similar to the ones enrolled in this study can be expected to significantly and substantially improve their cardiovascular outcomes, and in a relatively short period of time.

But, as with any clinical trial, this one does not answer all the questions that we would like to have answered.

This trial, for instance, does not tell us whether the beneficial outcome is specific to Crestor, or is a class effect of all statins. (DrRich believes it is very likely to be a class effect, since the statins all tend to behave similarly in virtually every other way.) This trial does not tell us whether reducing CRP levels is beneficial – it only tells us that giving Crestor to people with high CRP levels is beneficial. (As Dr. Centor points out, it is time to begin thinking of statins as plaque-stabilizing drugs instead of cholesterol-lowering drugs; their benefit may not rely on lowering either CRP or cholesterol.) It does not tell us whether using CRP as a screening tool is actually helpful. (Only patients whose CRP was elevated were enrolled in this study. Similar patients – that is, patients who tend to be overweight and have a fairly high incidence of metabolic syndrome and a relatively high incidence of smoking – but with normal CRP levels, might have had the same outcome.) And this trial does not tell us the risks of lifelong Crestor therapy. (DrRich notes, however, that statins have been in widespread clinical use for nearly 20 years, and seem unlikely to hold very many surprises at this point.)

So there’s a lot we still don’t know, and much of what we don’t know would be important to any doctor counseling a patient who wants to reduce their risk of cardiovascular disease.

But still, there should be no controversy here. If medicine were practiced the way it ought to be – where the doctor takes the available evidence, as imperfect as it always is, and applies it to each of her individual patients – then the JUPITER trial would present no special problems. After all, doctors never have all the answers when they help patients make decisions. So, in this case the doctor would discuss the pros and cons of statin therapy – the risks, the potential benefits, and all the quite important unknowns – and place the decision in the perspective of what might be gained if the patient instead took pains to control their weight, exercise, diet, smoking, etc. At the end of the day, some patients would insist on avoiding drug therapy at all costs; others would insist on Crestor and nothing else; yet others would choose to try a much cheaper generic statin; and some would even opt for a trial of lifestyle changes before deciding on statin therapy. In other words, there is a range of reasonable options given the limitations of our knowledge, as there often is in clinical medicine. As time goes by, more scientific evidence is often brought to bear and clinical decisions (hopefully) become more and more effective. But whatever the state of the evidence, doctors and patients can generally get by without violating too severely any ethical or medical precepts that would cause objective and neutral observers to complain very much.

But we don’t practice medicine the way it ought to be. We practice it according to guidelines.

And this makes the stakes very high when it comes to a clinical trial like JUPITER. For guidelines do not generally permit a range of actions tailored to fit individual patients – they generally present a binary answer. In this case, the binary answer yields either no change in clinical practice (and no change in spending), or a change in clinical practice (and an increase in spending, on Crestor, amounting to several billion dollars a year).

So as one might predict, a controversy has broken out.

On one hand, many point out that JUPITER is an important clinical trial which has demonstrated a vital clinical benefit (prevention of heart attack, stroke and death) with a high degree of statistical significance, which meets the high standards demanded by evidence-based medicine, and which therefore obviously demands a change in the clinical guidelines. But on the other hand, many others insist that the JUPITER trial simply does not demonstrate enough of a benefit with Crestor to justify changing the guidelines.

DrRich’s position – that the results of the JUPITER trial are striking and important but incomplete, and ought to change the conversation between, but not dictate the actions of, doctors and patients – does not obtain in the modern era.

So, unable to side with either party, DrRich observes with great interest the debate between those who want to change the guidelines, and those who believe that changing the guidelines would be the greatest of travesties.

Those who want to change the guidelines have, in their favor, the virtue of consistency. For, if one insists that every action by physicians must be supported by evidence-based medicine, then one is pretty much obligated to fully embrace clinical trials like this one that give clear-cut and statistically significant results. Unfortunately, the evidence-based strict-constructionists have painted themselves into a corner when it comes to JUPITER. They will not be able to say, for instance, “Statins are pretty much alike, so we’ll make the guidelines say ’statins’ instead of ‘Crestor.’” For JUPITER did not study “statins,” it studied only Crestor, the most expensive statin on the planet. Expanding the results to all statins (despite a large body of experience that suggests this would be just fine) does violence to the whole concept of evidence-based medicine. It’s just not possible. The strict constructionists have therefore boxed themselves in to advocating a new, multi-billion dollar annual expenditure.

It is even more amusing to observe those who do not want to change the guidelines.

These people fall into two general camps. First, and easier to dismiss, are those who believe that drug companies are the embodiment of evil, and that any clinical trial sponsored by a drug company must be dismissed out of hand. There is furthermore a subset of this group who believe that statins, in particular, are the devil’s work, and represent some sort of effort on the part of the pharmaceutical companies (all of which seem to market a statin of one variety or another) to enslave every American. These people, one can only surmise, would object to statins even if they were proven to cure heart disease, cancer, baldness, obesity AND to produce fine and durable erections upon demand.

DrRich simply points out that the advancement of clinically useful medical science – in America and in the world – is almost entirely dependent on drug companies and other corporate dens of iniquity. That companies must pay for our medical research is the system we’ve invented. Furthermore, our total capitulation to the dictates of evidence-based medicine means that companies must fund large, expensive clinical trials before they are allowed to sell a new product, or create a new indication for an old product. This evidence-based paradigm is inherently a double-edged sword. Sure, it creates a huge barrier to the development and adoption of expensive new therapies (which is the covert rationing dividend of evidence-based medicine), but it also creates opportunities, for companies who manage to successfully complete such trials, to create iron-clad indications for their products. For, once a product has been “proven” in a randomized clinical trial, there is no easy way to legitimately keep that product out of the guidelines and off the shelves. The makers of Crestor have simply figured out the rules. One can whip up anti-corporate emotions by criticizing AstraZeneca for playing the game well, but the fact that the sponsor stands to gain does not negate in any way the results of a well-designed study.

That the anti-pharmaceutical and anti-statin crowds vociferously object to the results of the JUPITER trial is, of course, entirely expected and cheerfully acknowledged. DrRich will merely observe that their position is one of default. It is not dependent on the scientific merit of JUPITER (or any company-sponsored study), and thus it adds no useful information to the debate. We can only note their objections and move on.

The second group of people who object to changing the guidelines are less dogmatic and more open to reason, and indeed (and very interestingly so) claim to be proponents of evidence-based medicine, and thus claim to be willing to follow the data to where it will lead. It seems pretty clear (to DrRich, anyway), that the chief concern of these individuals is cost. That is, this group feels strongly that the implications of the JUPITER trial are simply too costly to follow to their logical conclusion. This, indeed, is a very reasonable position to take.

Unfortunately, the only legitimate way to turn aside the results of a costly but statistically definitive, evidence-based study is by rationing healthcare. (To ration, remember, is to withhold at least some useful medical services from at least some people who would be likely to benefit from those services.) But we can’t do that, because, well, it would be rationing. Because members of this second group are unable to invoke the “r” word, they are therefore forced to find other “reasons” for keeping the guidelines unchanged. This unfortunate situation leaves them little choice but to discover ways in which to impugn the legitimacy of the JUPITER trial.

In short, they find themselves forced to engage in statistical legerdemain in order to diminish the significance of the JUPITER trial. From what DrRich has seen, most of the statistics that have been ginned up to this end have not come directly from the JUPITER trial itself, but instead from an editorial accompanying this study, written by Dr. Mark A. Hlatky.

Most of Dr. Hlatky’s editorial is measured and reasonable. But he has thrown in a key summary sentence that has been greedily grasped by the antialterguidelinetarians, to wit: “The proportion of participants with hard cardiac events in JUPITER was reduced from 1.8% (157 of 8901 subjects) in the placebo group to 0.9% (83 of the 8901 subjects) in the rosuvastatin group; thus, 120 participants were treated for 1.9 years to prevent one event.”

This statement, at least taken at its face value as a stand-alone analysis, is statistically naive and wrong. DrRich will not make anyone wade through the reasons why, because he realizes that one or two of his readers might not enjoy statistical arguments. (Instead he will provide those reasons in this footnote.*) Suffice to say here that Hlatky’s summary statement apparently ignores the appropriately analyzed data which is clearly presented in the JUPITER paper itself, and which documents that the clinical benefit of Crestor was substantially more impressive than this widely-quoted summary statement by Hlatky suggests.

As illegitimate as this summary statement may be, let us accept it for a moment just for the sake of discussion, since that’s the data the antialterguidelinetarians have latched on to. Taking these numbers, the “antis” make the following argument: While the relative reduction in “hard cardiac events” is 50% (1.8 to 0.9), the absolute reduction is only 0.9%, which, anyone would agree, is a pretty small number. So, they conclude, the actual benefit imparted by Crestor is actually quite small.

That’s a very interesting argument. Let’s look at it in a couple of ways.

So we’ve got a population of patients whose risk of heart attack, stroke, bypass surgery/stenting, or death is about 2% at about 2 years, and by giving them a pill we can reduce that risk to about 1%, and we’re arguing that the absolute drop of 1% is not very much to crow about. Well, OK. But what if we found a pill that reduced their risk to zero at 2 years? That is, it completely wiped out the risk of cardiovascular catastrophes. Would that be a good thing? Or would we say, “It’s just a 2% drop, really not much greater than the 1% drop we had with Crestor, so it’s no big deal?” DrRich thinks not. DrRich supposes we would think it’s a very big deal.

When you’re starting at a 2% risk, then any drop in risk is going to be an “absolutely” small number. And if we’re not going to pursue improvements in outcome of such a small magnitude, then why the heck are we worrying about preventative medicine in the first place? Once you get past the big things (drain the swamps, don’t drink the water downhill from the outhouse, etc.) then all preventative medicine tends to consist of small, incremental improvements in outcome. Popular pronouncements to the contrary notwithstanding, preventative medicine is largely the art of spending a lot of money for this kind of incremental improvement. If we decide we shouldn’t do this anymore, then DrRich would find it unfortunate but understandable. But it hardly seems reasonable to arbitrarily focus on this one, particular improvement in preventative cardiology, and (within a healthcare system that insists it is not rationing care) pronounce that this is the one we’re not paying for.

Another way of looking at this “the benefit is too small” argument is by considering that 7.4 million Americans fit the entrance criteria for JUPITER. By giving all these people a statin, we would be preventing about 66,600 major cardiovascular events over a 2 year period. If you’re going to say that 1% is a small number, DrRich will counter that 66,600 is a big number. So do statins offer a substantial benefit or not? It depends on whether you choose to focus arbitrarily on the 1% or the 66,600.

(DrRich understands that many of his readers are not focusing at this moment on the 66,600 cardiovascular catastrophes that could be prevented, but on the 7.4 million people who will be taking a drug that costs $120 per month. But we’re not talking about cost yet, we’re only talking about whether the drug does some good. If we decide it does, then we’ll need to link that “good” to a procedure that measures whether the “good” is worth the money we would need to spend to achieve it. The “antis” try to avoid talking about cost – since that would admit they’re rationing – by insisting that there’s just not enough “good” to bother. DrRich is simply pointing out that such an argument – that preventing 66,600 very bad outcomes is not enough to bother with – is on its face absurd.)

Another argument invoked by the antialterguidelinetarians is based on the “number needed to treat” (NNT) analysis. Again they rely on Hlatky’s unfortunate summary of the data: “120 participants were treated for 1.9 years to prevent one event.” This number – which the “antis” insist is just too high – is misleading for the reasons outlined in the footnote.* The real NNT, based on more legitimate statistical analysis, is plainly laid out in the JUPITER paper itself. It turns out that the longer patients in this trial were treated with Crestor, the lower the NNT became. So: At 2 years, the NNT was 95; at 4 years, it was 31; and at 5 years, it was projected to be only 25. Whether you think it is reasonable to treat 25 people with a pill for 5 years to prevent one of them from having a heart attack, stroke, or death is, DrRich supposes, a matter of opinion. But based on NNT analyses for many widely-accepted therapies in medicine today, it looks pretty good.

All these arguments, of course, are merely distractions. The fact is that JUPITER showed a pretty striking reduction in nasty cardiovascular events, and the only real reason there’s any controversy is because of the cost of Crestor.

That cost is what makes us want to withhold Crestor, even though it is imparting at least some (and, DrRich, argues, quite a bit of) clinical benefit. In other words, the high cost makes us want to ration Crestor. The fact that we can only ration covertly, instead of openly, is what makes us want to bastardize the science and do a Kabuki dance with the statistics.

If we were rationing healthcare openly, then we could do an objective, full-bore cost-benefit analysis on the use of Crestor in JUPITER patients, using legitimate and not ginned-up statistical analysis, and taking into account not only the cost of the drug, but also the cost that would be incurred by failing to stop preventable heart attacks, strokes, etc., and then determining where the overall cost-benefit result fell within our coverage criteria. If it met the criteria we would cover it, if not, not. This decision would not be arbitrary. It would be a fully transparent process, so that if AstraZeneca did not like the results, they would try diligently to find a way to reduce the cost of Crestor (DrRich thinks they would succeed) to a value that would be compatible with their staying in business. (And for the first time, the price of medical products would be determined by a Laffer-like curve, where a price that was too high – like taxes that are too high – would reduce revenue, instead of increase revenue. Companies, being fairly rational, would ratchet their prices down to the optimal price point.)

But since we insist on doing our rationing covertly, DrRich is sorry to say that we’re destined to keep making spurious arguments, and using dumbed down statistical analysis to back them up. The JUPITER trial, while it is imperfect and while it does not answer every question, really is pretty straightforward. That we get so wrapped around the axle trying to fold such clinical trials into our covert rationing paradigm is simply another demonstration of Corollary Four of the Grand Unification Theory of Healthcare: Covert rationing corrupts everything it touches.

*In a long-term clinical study in which the endpoints are events that can occur at any time (such as heart attack, stroke or death), then the probability that an enrolled patient will reach an endpoint in the trial increases the longer he/she has been enrolled in the trial. But in virtually all clinical trials, the length of time different people are enrolled varies greatly. This is because it often takes years to enroll people in clinical trials, so that when the trial ends, some will have been in the trial for many years, others for only a little while. This means that the risk exposure of each research subject is different, and is proportional to the total time they were enrolled. Not uncommonly, the enrollment process is not smooth – there are periods of more rapid enrollment, and periods of slower enrollment – so if all you do is average the enrollment time (as was done here – 1.9 years) you are likely to get skewed results. So it is simply not statistically legitimate to do so.

There is a legitimate way of analysing such longitudinal outcome statistics, and it’s called the Kaplan-Meier method. And indeed, the authors of the JUPITER trial presented in their paper a complete Kaplan-Meier analysis of their data (see Figure 1), and the results look quite a bit different from Hlatky’s summary statement. The Kaplan-Meier analysis reveals that the risk of heart attack, stroke, and death all increase steadily through at least 4 years (5 years was the longest time anyone was enrolled in this study), so that at 4 years, the risk of reaching one of the “cardiovascular event” endpoints was about 8% (not 1.8%). Further, the Kaplan-Meier analysis shows that the protection imparted by Crestor persists through at least 4 years, and that indeed the magnitude of protection (i.e., the difference in outcomes between the treated group and the placebo group) increases for that entire duration. So, at 4 years, the placebo group had roughly an 8% event rate, compared to roughly a 3% event rate for the Crestor group – an absolute difference of about 5% (not 0.9%). This is a far greater benefit than is suggested by Hlatky’s shorthand summary.

JUPITER Crestor CRP clinical guidelines rationing healthcare covert rationing
Posted in General Rationing Issues, Cardiology Topics, Guidelines, Abuse of, Evil Drug Companies

Syncope Evaluation and Management

http://www.mayoclinicproceedings.com/inside.asp?AID=4827&UID=