JUPITER hits New Orleans: Landmark study shows statins benefit healthy individuals with high CRP levels
New Orleans, LA - The
Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) started the
American Heart Association (AHA)
2008 Scientific Sessions here today with a bang, shaking up the field of primary prevention with new data showing that the treatment of apparently healthy patients with a statin cuts their risk of cardiovascular disease morbidity and mortality by almost half [
1].
In a study of individuals with low LDL cholesterol but elevated C-reactive-protein (CRP) levels, investigators showed that rosuvastatin (Crestor, AstraZeneca) 20 mg significantly reduced the primary end point—a composite of nonfatal MI, nonfatal stroke, hospitalization for unstable angina, revascularization, and confirmed death from cardiovascular causes—by 44% compared with individuals treated with placebo.
Presented by Dr Paul Ridker (Brigham and Women's Hospital, Boston, MA) during the late-breaking clinical-trials session and published online in the New England Journal of Medicine to coincide with the AHA presentation, investigators showed that the benefits extended to all subgroups, including "robust reductions in cardiovascular events with statin therapy in women and black and Hispanic populations, for which data on primary prevention are limited," write the JUPITER investigators.
Calling JUPITER "one of the most important clinical trials in the long history of statin studies," Dr Steven Nissen (Cleveland Clinic, OH) told heartwire that such large reductions in clinical events in less than two years among patients considered healthy by conventional definitions is likely to change the guidelines.
"Ideally, if a patient comes to me with normal LDL-cholesterol levels—in JUPITER, the median LDL-cholesterol level was 108 mg/dL—I tell him to keep doing what he's doing and to go about his business," said Nissen. "Now, what happens when that same patient arrives in my office and I know his CRP is elevated? I know that treating him with intensive statin therapy, despite what the guidelines state, is going to cut his risk of cardiovascular morbidity and mortality in half."
Dr James Stein (University of Wisconsin Medical School, Madison) echoed the sentiments of others when he said that the findings are going to pose challenges, particularly as clinicians grapple with changing how they think about and treat seemingly low-risk patients.
"It is a true landmark in preventive cardiology, not only for its findings, but even more so for the challenges it raises to our current strategies for use of cholesterol-lowering medications and to our risk-assessment paradigms," said Stein.
| Stopped after 1.9 years of study |
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JUPITER was designed as a four-year study but was stopped by AstraZeneca after just 1.9 years based on recommendations from an independent data monitoring board and the JUPITER steering committee. When the study was stopped on March 29, 2008, as reported by heartwire at that time, the company reported unequivocal evidence of a reduction in cardiovascular morbidity and mortality among patients treated with rosuvastatin compared with those treated with placebo. Despite the benefits, Dr Sanjay Kaul (Cedars Sinai Medical Center, Los Angeles, CA) questioned why it was stopped so early, "especially when we have no idea about the long-term safety of very low LDL levels as achieved in this trial."
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Reductions in cardiovascular events line up in JUPITER
JUPITER is a large, multinational, long-term, double-blind, placebo-controlled, randomized clinical trial that included 17 802 healthy men and women assigned to rosuvastatin 20 mg or placebo. The study was designed to assess whether statin therapy should be given to apparently healthy individuals with normal LDL cholesterols but elevated C-reactive protein levels (CRP >2.0 mg/L).
Among patients treated with rosuvastatin, LDL-cholesterol levels were cut in half, decreasing from a median 108 mg/dL at baseline to 55 mg/dL at 12 months. CRP levels were also significantly reduced, declining from 4.2 mg/L at baseline to 2.2 mg/L at 12 months. Triglyceride levels were reduced 17% from baseline among those treated with statin therapy. These effects persisted over the course of the study.
Baseline and change in LDL cholesterol and CRP levels during study period
Measure
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Baseline
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12 mo
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24 mo
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36 mo
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48 mo
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LDL cholesterol (mg/dL)
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Rosuvastatin 20 mg
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108
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55
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54
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53
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55
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Placebo
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108
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110
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108
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106
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109
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High-sensitivity CRP (mg/L)
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Rosuvastatin 20 mg
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4.2
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2.2
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2.2
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2.0
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1.8
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Placebo
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4.3
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3.5
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3.5
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3.5
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3.3
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p<0.001 for all between-group comparisons
After 1.9 years of follow-up, treatment with rosuvastatin significantly reduced the primary composite end point 44% compared with placebo. This reduction was observed among nearly all of the individual end points, including a 55% reduction in nonfatal MI, a 48% reduction in the risk of nonfatal stroke, and a 47% reduction in the risk of hard cardiac events (a composite of MI, stroke, and death from cardiovascular causes).
In terms of absolute benefits, the proportion of patients who had an MI, stroke, revascularization, or hospitalization for unstable angina or died from cardiovascular causes was 1.6% in the rosuvastatin arm and 2.8% in the placebo arm, an absolute risk reduction of 1.2%. Similarly, the proportion of patients with hard cardiac events—cardiovascular death, MI, and stroke—was reduced from 1.8% in the placebo arm to 0.9% in the rosuvastatin arm, an absolute reduction of 0.9%.
JUPITER: Outcomes according to study group
End point
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Patients with event, rosuvastatin (n=8901), n
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Patients with event, placebo (n=8901), n
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Hazard ratio (95% CI)
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Primary end point*
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142
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251
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0.56 (0.46-0.69)
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Nonfatal MI
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22
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62
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0.35 (0.22-0.58)
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Any MI
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31
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68
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0.46 (0.30-0.70)
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Nonfatal stroke
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30
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58
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0.52 (0.33-0.80)
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Any stroke
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33
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64
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0.52 (0.34-0.79)
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Revascularization
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71
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131
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0.54 (0.41-0.72)
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Hospitalization for unstable angina
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16
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27
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0.59 (0.32-1.10)
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Revascularization or hospitalization for unstable angina
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76
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143
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0.53 (0.40-0.70)
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MI, stroke, or death from cardiovascular causes
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83
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157
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0.53 (0.40-0.69)
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Death on any known date
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190
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235
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0.81 (0.67-0.98)
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Any death
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198
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247
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0.80 (0.67-0.97)
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*Primary end point: composite of nonfatal MI, nonfatal stroke, hospitalization for unstable angina, revascularization, and confirmed death from cardiovascular causes
To download tables as slides, click on slide logo above
A subgroup analysis revealed no heterogeneity in any of the results, including an analysis of subgroups based on age, race, or ethnic group, as well as baseline LDL-cholesterol and CRP levels. The investigators report that even patients considered to be at very low risk—those who did not smoke, were not overweight, did not have metabolic syndrome, or had a Framingham risk score of 10% or less—benefited from statin therapy.
Of note, among the 6801 women included in JUPITER, rosuvastatin significantly reduced the primary composite end point by 46%. "These are our most impressive data in women in the primary-prevention setting," Dr Roger Blumenthal (Johns Hopkins Medical Institute, Baltimore, MD) told heartwire.
In terms of side effects, significantly more patients in the rosuvastatin arm developed new diabetes, and they also had significantly higher glycated hemoglobin levels, report investigators. Any reported serious adverse events were similar between the placebo and statin-therapy arms.
Lulled into a false sense of security with "normal" LDL cholesterol levels
To heartwire, Stein said the results, despite the significant risk reduction in apparently healthy individuals, are not surprising. He praised the JUPITER investigators and the study sponsor for exposing the current LDL-cholesterol thresholds for lipid-lowering therapy as arbitrary, but more important, as a poor indicator of cardiovascular risk.
"Many patients with heart attacks have normal LDL-cholesterol values," said Stein. "Thus, doctors and patients are lulled into a false sense of security when their LDL cholesterol is 'normal' and then are surprised when they have a heart attack. JUPITER illustrates this point perfectly. If you look at the median values—age 66 years, body-mass index 28.3 kg/m2, systolic blood pressure 134 mm Hg, and 41% with metabolic syndrome—you know these people are going to have heart attacks and strokes and die. Indeed, in the placebo arm, the event rate was 1.36% per year. But current guidelines say not to treat them."
Nissen pointed out that there has been a lot of recent pushback against the cholesterol hypothesis, with many speculating that lowering LDL-cholesterol levels had no impact on the reduction of cardiovascular risk. Patients in the JUPITER study, he pointed out to heartwire, had a significant 50% reduction in LDL-cholesterol levels, coupled with the significant 37% reduction in CRP levels, and this suggests that LDL cholesterol remains an important end point clinicians should treat.
"Reducing LDL cholesterol while at the same time treating inflammation is one of the reasons why this treatment was so successful," said Nissen. Two other studies, analyses of the PROVE-IT and REVERSAL trials, by Ridker and Nissen, respectively, previously showed that lower CRP levels are associated with fewer cardiovascular events independent of LDL-cholesterol levels [2,3]. Stein said he thinks LDL-cholesterol levels of 100 mg/dL are still too high if the patient has other markers of risk, such as increased age, obesity, and hypertension.
Should every patient undergo CRP testing?
In an editorial accompanying the published study, Dr Mark Hlatky (Stanford University School of Medicine, CA) agreed that guidelines are likely to be revisited, although he is cautious on just how big an impact the findings will have on clinical practice [4].
JUPITER provides yet more evidence about the effectiveness of statin therapy in reducing cardiovascular risk, even among persons who would not currently be considered for pharmacotherapy.
"JUPITER provides yet more evidence about the effectiveness of statin therapy in reducing cardiovascular risk, even among persons who would not currently be considered for pharmacotherapy," writes Hlatky. "Guidelines for primary prevention will surely be reassessed on the basis of the JUPITER results, but the appropriate size of the orbit of statin therapy depends on the balance between the benefits of treatment and its long-term safety and cost."
To heartwire, Kaul said he is not quite as bullish on the findings as others, noting that nearly one out of every five patients screened was enrolled, which has implications about the generalizability for clinical practice, as very few patients have elevated CRP without traditional risk factors. Moreover, clinicians and health-policy experts should focus on the absolute risk reductions, he said.
"The absolute risk differences are less impressive than the relative differences and, together with cost and long-term safety considerations, will serve to temper the conclusions of the study," said Kaul.
In his editorial, Hlatky calculated that 120 patients need to be treated for 1.9 years to prevent one death from cardiovascular causes, MI, or stroke, and this benefit needs to be balanced against concerns about significantly higher glycated hemoglobin levels and increased diabetes incidence observed in the rosuvastatin arm. The JUPITER investigators, on the other hand, calculated the number needed to treat (NNT) based on the primary-end-point event and report that the NNT with rosuvastatin for two years to prevent one primary end point is 95 and just 31 need to be treated for four years to prevent one primary-end-point event.
In his editorial, Hlatky said the design of JUPITER provides only limited information about the role of CRP testing in clinical practice, since investigators did not compare subjects with and without CRP measurements and did not compare the use of CRP with the use of other markers of cardiovascular risk.
"At this point, the current guidelines for measurement of high-sensitivity CRP remain reasonable," writes Hlatky. Measurements of CRP may be obtained in asymptomatic individuals who have an intermediate level of risk, based on standard clinical risk markers, and in whom treatment might change depending on the high-sensitivity CRP level. Blumenthal said most doctors use CRP as a "tie-breaker" to make a decision about which men >50 years and women >60 years would benefit from statins.
Stein told heartwire that the use of more widespread screening of CRP values needs more investigation. The test has high variability and is elevated with infections and injuries, so abnormally high CRP levels do not always reflect arterial injury or cardiovascular-disease risk.
"However, I suspect we should start using it more often," he said. "For starters, it makes communication easier. It summarizes a myriad of metabolic problems that individually are not bad enough to treat but collectively indicate increased risk. Increased CRP tells you that. It is one number, and explaining and implementing it may be easier for physicians and patients than trying to explain why 'borderline' high blood pressure and being 'a little overweight' are bad. They damage and inflame blood vessels, and high CRP shows it."
AstraZeneca sponsored the JUPITER study.
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Sources
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Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. New Engl J Med 2008; DOI: 10.1056/NEJMoa0807646. Available at: http://www.nejm.org.
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Ridker PM, Cannon CP, Morrow D et al. C-reactive protein levels and outcomes after statin therapy. New Engl J Med 2005; 352:20-8.
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Nissen SE, Tuzcu EM, Schoenhagen P et al. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med 2005l 352: 29-38.
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Hlatky M. Expanding the orbit of primary prevention—moving beyond JUPITER. New Engl J Med 2008; 359: published online before print November 9, 2008. DOI: 10.1056/NEJMe0806320. Available at: http://www.nejm.org.
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November 9, 2008 12:18 (EST)
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Tough times for healthcare insurance in SE Michigan
The JUPITER trial is very intriguing data in low risk patients with low LDL's. As everyone knows these are not good times for patients to even have health insurance that will cover rosuvastatin, let alone any healthcare insurance at all. The patients I see in the CCU are higher risk patients with multiple risk factors. I want to see outcome data for rosuvastatin in this patient population. My healthcare insurance at a community hospital in Dearborn, MI will not cover Crestor. The cost alone for patients in the JUPITER population in my area would not be affordable. There is data for CRP lowering for simvastatin and pravastain so I would recommend those two statins over rosuvastatin.
Larry M. Diamond, PharmD. |
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November 9, 2008 12:55 (EST)
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PROVE-IT
The PROVE-IT study showed that atorvastatin 80 mg/d was better than pravastatin 40 mg/d in a typical CCU population of acute infarcts. I would therefore think that using pravastatin or simvastatin (note A-to-Z trial and IDEAL trial) would be inferior to the standard of care (which at the very least in such a high risk population would call for a more potent statin like atorvastatin or rosuvastatin). Economic issues aside, using pravastatin or simvastatin would not be done where I am practicing. |
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November 9, 2008 02:50 (EST)
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Statins
Pretty impressive to see 'all' of the statins now showing benefits in multiple populations of patients. If a generic statin will get your patient to LDL goals (simva 40, lova 80, prava 80) LDL under 70 in ACS setting or very high risk setting. Sounds great for risk reduction. Now we have evidence in MEN and WOMEN who are 'low' risk by FRS definition that we can lower MACE nearly 50% in 2 years. Revolutionary really with this particular agent. (of course I think most clinicians would consider this population with elevated hscrp to be moderate or higher risk - at least we do). Great results. |
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November 9, 2008 03:09 (EST)
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What Jupiter proves and what it does not prove
Jupiter proves that treating individuals with statin reduces the risk for coronary events despite a normal cholesterol. This was already demonstrated with ASCOT-LLA using 10 mg of Lipitor.
It did not prove that using HS-CRP as the tool to screen for risk added value. To prove this, there would need to be a risk factor matched control group with a normal HS-CRP at baseline and followed without treatment for event rates. Considering that in MESA, there was no difference in baseline HS-CRP between those subjects who subsequently had heart attacks and those who didn't, the utility of HS-CRP for screening needs to be seriously questioned.
It also did not prove that Crestor was any better than simvastatin in the subset of individuals with normal LDL and HS-CRP. In ASCOT-LLA, 10 mg lipitor was better at reducing events in individuals with normal lipids than lipitor has ever shown before or since in individuals with elevated cholesterol.
By the way, did anyone notice that there was an increase in fatal MIs; 9 in the treatment arm compared to 6 in the placebo arm? Before I jump on a "better drug" I like to see a reduction in the body count.
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November 9, 2008 03:46 (EST)
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body count was reduce
You shouldn't get excited by 3 extra events. Total mortality was reduced in line with cardiovascular mortality, and both were statistically significant. |
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November 9, 2008 04:42 (EST)
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LDL-P needs to be looked at
In this population - high BMI, HTN, metabolic syndrome - it is very common to have a disconnect between LDL-C and LDL-P. These patients often have undetected (and therefore untreated) elevations in LDL-P with normal levels of LDL-C. By using statins, the LDL-P would be treated to goal in these individuals and would thus diminish their risk. Jupiter is yet another example of why we need to look beyond LDL-C - but mostly at LDL-P - even before we examine CRP. |
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November 9, 2008 05:50 (EST)
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statins
I agree with Dr. Diamond, we will be using simvastatin here ... resources are limited ... there are no data that one statin better than another in "equipotent" doses |
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November 9, 2008 06:59 (EST)
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| FRANCISCO ROBERTO RIZO MORÁN |
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hs-CRP new evidence
The magnitude of risk reduction associated with statins is greater than that predicted on the basis of LDL cholesterol lowering alone. There is accumulating evidence that statins lower plasma levels of hs-CRP in a manner largely independent of LDL cholesterol lowering. In contrast, little benefit has been demonstrated for statin therapy in the absence of both hyperlipidemia and inflammation. |
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November 9, 2008 10:54 (EST)
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BUT is CRP better than Framingham score?
The placebo group showed that .85 pts/100 pt year had a MI, stroke or CV death. If low Framingham risk score is < 10% at 10 years, then it seems that the elevated CRP group didn't seem to have markedly increased events, if one extrapolates from the event rates in the first few years. Is this correct? The event rates in the placebo group still do not seem that high. |
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November 9, 2008 10:55 (EST)
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NNT looks expensive with HS-CRP but not with EBT-CAC
The NNT is 31 subjects for 4 years to prevent one event. Do the math: 31 subjects X 4 years X 12 months X $100 pr month Crestor cost =148,000 dollars for Crestor to prevent one event. In addition you will add 2 office visits with blood work pr year to monitor therapy: $130 a visit X 2 visit a year X 4 years X 31 subject = 32,240 dollars. Therefore: 148,000 + 32,240 = 180,240 dollars pr event prevented over 4 years.
Let’s use a better marker for coronary risk such as EBT calcium imaging using the top quartile of CAC as the threshold for treatment. Do the math: 31 subjects X $400 for each heart scan = 12,400 dollars. The EBT identifies the 25% who are truly at risk therefore you need to put only 7.75 subjects on Crestor instead of 31. Therefore 7.75 subjects X 4 years X 12 months X $100 monthly Crestor cost = 37,000 dollars for Crestor + 12,400 dollars for heart scans = 49,400. In addition you need to monitor therapy on only 7.75 subjects instead of 31. 7.75 subjects X 2 visits a year X 4 years X 130 dollars a visit = 8,060 dollars for therapy monitoring. Therefore: 37,000 dollars for Crestor + 12,400 dollars for EBT CAC + 8,060 dollars for therapy monitoring = 57,460 dollars pr event prevented over 4 years.
If you want to set the bar lower, we could treat the top 50% of EBT scores in order to miss no-one at risk. The costs will go up but EBT still wins. Crestor costs would double at $74,000, clinical follow up would also double at $16,120. Therefore: 74,000 Crestor cost + 12,400 EBT cost + 16,120 follow up costs = 102,520 dollars pr event prevented or roughly 56% of the cost of using HS-CRP alone.
Conclusion: HS-CRP to determine the use of Crestor therapy results in a cost of $180,240 dollars pr event prevented over 4 years. EBT-CAC using the top quartile of EBT as the threshold for treatment with Crestor results in a cost of $57,460 dollars pr event prevented over 4 years or less than 1/3rd the cost of the HS-CRP model. Where I work, a heart attack can easily cost $100,000 with acute plus follow up treatment. Therefore screening with EBT is not only 3 times more cost effective than screening with HS-CRP but it can actually save money compared to not screening. Screening with HS-CRP may save lives but does not also save money.
Take this in the context of the dramatic superiority of EBT-CAC to predict events compared to HS-CRP and the conclusion is inescapable. Using EBT-CAC to determine who needs treatment will result in a cost effective reduction of coronary morbidity and mortality. Use serial EBT to determine adequacy of treatment and the numbers are even better.
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November 9, 2008 10:56 (EST)
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Diabetes
Although the results is impressive but should we take care regarding diabetics as we have a significantly more new diabetes & higher glycated hemoglobin levels |
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November 9, 2008 11:26 (EST)
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CRP vs waist line
I vote for waist line measure as a more reliable and less costly approach for treatment target and decisions. We can nail down the risk or extent of vascular disease with high resolution cimt (a bargain for the past decade at $155 at 2 of our hospitals and without the radiation of ct). I assume chronic disease patients with very high CRP were excluded from Jupiter, but I look forward to seeing details on the enrolled patients.
Re statin choice I would be concerned about rhabdo with 80 of simva and the 25% increased incidence of diabetes with rosuva. If we can afford it, I think we can do better than prava, (atorva goes generic in 3 years). |
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November 9, 2008 11:32 (EST)
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Crestor can be inexpensive
Crestor 40 mg tabs can be quartered, thereby giving us a 50% drop in LDL for about 20 dollars per month. Less than it costs to buy red yeast rice. Pretty cost effective considering a 50% drop in hard events for pts with CRP above 2.0. |
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November 9, 2008 11:33 (EST)
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CIMT vs CAC
Considering the dramatic increased predictive value of CAC over CIMT, I think the 0.7 msv radiation is a price worth paying. |
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November 10, 2008 12:13 (EST)
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LDL Goals
While the focus is on "healthy" individuals...where does this study leave the more typical patient with let's say a baseline LDL of 160 mg/dl. Correct me if I am wrong, there seems to be no data to suggest that reducing one's LDL from 160 to < 70 is more beneficial than reducing the LDL about 30-40%. I find it odd that we are extrapolating lower LDL goals (70mg/dl) from studies whose patient's baseline LDL was near "normal". Does this mean we will be looking for an LDL of 55mg/dl? Still odd to me that we have set these LDL goals when LDL was never a primary endpoint.
My biggest concern is the possible unecessary bombardment of multiple medications to achieve a "number". Side-effects occur; medications are stopped; patients are unwilling to restart meds. This to me would lead to more failure than anything.
We know that statins are beneficial. How do we use them to our patient's best interest? |
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November 10, 2008 12:19 (EST)
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CAC trumps CIMT in the studies......but
William, we don't use common carotid measures which is used by most of the studies. We have found it to be a less reliable than internal carotid and bulb, where we see most of the disease. I try to look at the plaque characteristics and volume to gage response to therapy. Calcification generally progresses despite treatment, as opposed to the lipid content of plaque.
Clearly we need more data on a decade time scale, but the studies in cimt have greatly improved in resolution the last 5 years, essentially giving us a new baseline on our followup studies.
The progress in cimt science has been painfully slow. |
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November 10, 2008 02:53 (EST)
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Calcium probably more reliable
Lipid content of plaque comes and goes regardless of treatment. Stability of calcified plaque burden correlates with a dramatic reduction in coronary events. Calcification generally progresses despite treatment because statins alone usually prevent about 30% of events (Jupiter and ASCOT-LLA being notable exceptions). Treat to stability of calcified plaque and event reduction is over 90%!
Regression of coronary plaque by IVIS in the pioglitazone study correlated with a reduction of events by 18% which did not reach statistical significance. Stability of calcified plaque by EBT was associated in a 17 fold reduction in events in a study by Raggi et al. |
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November 10, 2008 09:18 (EST)
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exciting data
1) This validates the use of Crestor and many EBM types have been waiting for that.
2) The % reduction in events was far greater than expected based on %LDL lowering (see the Supplementary Figure in NEJM with meta-analysis by CTT and other high vs low statin trials). This suggests there may be something unique about Crestor, which will now become my statin of first choice.
3) The reduction in mortality in primary prevention is pretty amazing to these jaded eyes.
4) I agree with Roger Blumenthal that we will now be using CRP much more often as a "tie breaker" to decide on who to treat.
5) Finally a methodologic point - for any primary prevention trial (note the two recent negative diabetes studies with ASA), you need a very large sample size to demonstrate statistical benefit (>17k in JUPITER). Thus we should start to be more suspicious of trials in primary prevention that are less than 10k or do not allow sufficient accrual of events to be adequately powered.
6) The diabetes finding has been seen before with pravastatin, simvastatin and atorvastatin, was not adjudicated centrally, and did not result in large increases in either fasting glucose or HbA1c. Ultimately it's a surrogate marker and the hard outcome (even death) -- what 75% of diabetics will die from (ie CVD) -- was reduced.
Just my 2c worth. |
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November 10, 2008 10:12 (EST)
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Dan,
Thanks again, great comments. Yes, there is no doubt with multiple published trials that rosuva is the most efficacious statin compared to other statins. Only a few head to head statin trials to date in ACS, FH or High Risk CAd and the statin which lowered LDL the most was the winner. This statin is very inexpensive in our area, cheapest branded product and inexpensive if one cuts pills. Most importantly we see clinicians refuse to reach LDL goals and only use generics even though the pt LDL isn't under 100 or 70, they continue to not achieve goal. I was shocked by JUPITER, I expected morbidity. BUT NOT morbidity and mortality in 2 years in a primary prevention group. Astonishing.
Many points can be made from this study.
frustrating to see JPAD and POPADAD both negative. |
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November 10, 2008 10:47 (EST)
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Great new insight and Great trial for AZ and rosuvastatin
JUPITER helps us with the problem of defining a ‘normal LDL’; what is ‘normal’ for one individual, may not be normal for another. JUPITER validates the concept that it is the ‘environment’ of LDL that predicts atherosclerotic events and that, if the environment is a poor one [in JUPITER the inclusion was age (male age >50, female age>60) and elevated CRP], lowering LDL to ‘more normal’ levels (in JUPITER to 55 mg/dL from 108 mg/dL) is of great benefit.
CRP will certainly be utilized much more frequently to determine who needs LDL lowered to 55 mg/dL (or even lower, if the environment is worse [elevated TG, low HDL, (high LDL-P)].
I would like to see an analysis of LpPLA2 levels in JUPITER, since my impression is that LpPLA2 is more specific for identifying plaque inflammation and rupture vulnerability. Perhaps the combination of the two “markers” (a worse environment), would even be more valuable in identifying those with the appearance of “low-risk”, who fail to be identified until after their ACS event.
Great day for rosuvastatin (Crestor) and AZ; a true triumph over critics.
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November 10, 2008 11:24 (EST)
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POPADAD AND JPAD
Mike, I am waiting for ASCEND for the final word on ASA. Neither of these two trials will likely change my practice - both were highly underpowered for their primary outcome analysis and 95% confidence intervals are consistent with clinically important reductions in cardiovascular events for both trial primaries. I do note in JPAD a 90% reduction in fatal CAD/CVD events which was statistically significant and based on only 10 to 11 events. I will still be using ASA in primary prevention diabetics both under and over 65 until I see something much more definitive than these two trials. |
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November 10, 2008 12:10 (EST)
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asa
Dan, we will also, although ADA states all people with diabetes over 40 years old. I may be less aggressive avoiding asa in those with pud or gerd sx etc... unless on ppi. And using ASA only in those with secondary prevention or those over 45-55 men and over 65 in women. Interesting to see an agent everyone feels pretty comfortable with in studies of over 1000 pts each not showing benefit. I don't have 2000 diabetic pts in my practice to statistically seperate. I still believe in asa in higher risk patients. |
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November 10, 2008 12:12 (EST)
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Questions
What is the définition of "apparently healthy persons" when
41.4% had the metabolic syndrome (with normal triglycerides and glucose ?)
Median BMI is 28.3
Why 16.6 % use aspirin without history of CV disease ? |
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November 10, 2008 12:36 (EST)
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questions
Silvestre, you bring up a very good point. apparently healthy meant men over 50 and women over 60 without a history of CVDz or diabetes or uncontrolled HTN and LDL under 130 (normal for a low or mod risk person).
As you know nearly 90K pts were screened fo find 18K low risk pts that met the LDL and hsCRP values required. median age 66, 40% female, bp 134/80, met syn 41% (pretty avg for this age, glucose 94 yet A1c high at 5.7% and HsCRP high over 4 (reflecting met syn and abnl pp glucose) |
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November 10, 2008 01:00 (EST)
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power was 56%
According to my calculations, JPAD had a power of only 56% to detect a statistically significant benefit given the number of patients they enrolled and the number of events they experienced (alpha=0.05, 2539 patients, 86 events in the control group, estimated RRR of 30%, which was how big a risk reduction they reckoned on).
This tells me that you have a slightly better chance than just flipping a coin (50:50) of showing a difference. So again I ask - why should I change my practice based on this trial (or the even smaller POPADAD)?? |
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November 10, 2008 05:54 (EST)
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Incomplete follow-up
How is it that the primary endpoint is being reported at AHA of all places with just 300 of 17,000 patients reaching the 4.5 year follow up interval?? |
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November 10, 2008 05:57 (EST)
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Omega-3
In view of the Italian study published in Lancet showing at a minimum comparable results between Omega-3 fish oils and Crestor would it not be more economical and safer and less expensive to recommend the use of fish oils, omega-3, EPA/DHA?
Thank you. |
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November 10, 2008 11:50 (EST)
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N-3 and Rosuv studies
Fred, so GISSI HF was a different study with older CHF pts (nearly a majority in that study had nonischemic CHF which was unusual). 1 g N-3 costs about $40/mos in our area for pharma grade. Over 4 years NNT was 44 to prevent primary and showed 9% RRR mort reduction.
Apples and oranges with this study. This study discusses a patient population that is considered 'low' risk by guidelines (no cad, cvd, dm and FRS low) with LDL of 108, HDL 49 and TG's normal, bp normal. Yes Met syn was common and HScrp need be high, but many people have argued Met Syn doesn't contribute to risk (its the other factors but in this case the other factors were WNL).
Point of this study is that rosuva now has outcomes and did so in median 1.9 months with this study of people. They not only reduced morbidity but also mortality and the RRR's were nearly 50% very much like the LDL reduction and the hscrp reduction. people can now debate if it was the LDL or the hscrp or both that provided this benefit.
I've heard the competition now saying that rosuva causes DM - are they kidding? Just like atorva did in TNT or PROVEIT? People are so funny to justify their behavior.
We have said it many times:
1. People don't stratify risk well, many are much higher risk than we think as in this case. I think people would have been shocked by the CIMT and EBCT measures in these people.
2. 'All' statins reduce risk.
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November 11, 2008 11:21 (EST)
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Comment on event rates in placebo arm
The event rates in the placebo arm did not seem that elevated beyond what Framingham would predict. THe article says that some of the pts were > 10% risk, but the overall event rates were still low. This dampens my enthusiasm as a risk predictor, and several other papers have noted the ROC of CRP does not appear superior to FRS.
Also, I've found that many pt referrals for "high CRP" are transiently elevated to URI, viral illness, etc. Also, note how they carefully screened out pts with any significant inflammatory diseases. Will PCPs and cardiologists do this in an era of 15 minute visits? |
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November 11, 2008 06:38 (EST)
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Misinformation
I have been told by doctors in 3 different states that the pfizer reps are promoting a message that crestor causes diabetes!!!
Jupiter pts had baseline A1c's of 5.7% with 41% of the total group having Met Syn. FPG was 94 mg/dl in both groups.
Primary and Secondary endpoints for which the study was designed showed in 1.9 years statistical reductions in MACE Primary of 44%, nonfatal MI 65% reduction, any MI 54% reduction, nonfatal stroke 48% reduction, any stroke 48% reduction, MI/Stroke/CVdeath 47% reduction and any death 20% reduction. Also 50% LDL reduction and 37% hscrp reduction.
As with all studies monitoring for adverse events was undertaken and any serious adverse event was the same in both groups 15.2R and 15.5 on placebo, muscle issues same in both groups, death from cancer 0.4%R (35 people) and 0.7% (58 people on placebo) CI 0.02. A1c end of study 5.9% rosuva and 5.8% on placebo, FPG 98 mg/dl both groups, GFR 66.8 ml/min on rosuva and 66.6 ml/min on placebo with CI 0.02 and finaly newly diagnosed diabetes physician reported 270 cases on rosuva (3%) and 216 on placebo (2.4%) with CI 0.01.
With this being said one can summarize in this 'low risk' population without DM, CAD, CVD and normal lipoporotein values, using crestor 20 mg for 1.9 year the risk for MACE etc. is indicated above 65-20% reductions with NNT 85-110 people over a very short time period. Tolerability was the same. Monitered adverse events which one cannot make conclusions from above - because if one did state that crestor 20 mg over this time period raised the risk of new onset diabetes 0.6% NNH of 166 one would also have to say that it also reduced the risk of cancer deaths 0.03% NNT 333 and also was better for GFR values. THIS IS NOT correct to conclude based on this study design.
LIPITOR/PFE reps have no business commenting on this study nor promoting misinformation to their clinicians. Statins have been observed in studies to be associated with higher rates and lower rates of diabetes developing in their treatment arms. If I recall correctly Lipitor in a large outcome trial had higher statistical rates of developing diabetes, so it is interesting to see their company and their reps promoting their current message. |
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November 11, 2008 06:45 (EST)
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Event rates
Primary end point event rates: 0.77 per 100 person year vs. 1.36 per 100 person year would equate to 7.7% on rosuva over 10 years and 13.6% on placebo over 10 years with an NNT of 16.
Any death 1 per 100 person year on rosuv and 1.25 per 100 person year thus 10% and 12.5% with NNT of 40 during that time.
That is assuming the event rates don't increase dramtically with time, which they most likely would. This is however from a primary and secondary prevention a 'low to very low' risk group with low events. 4S had events of over 20% on treatment in 5 years and nearly 30% on placebo and those with diabetes had event rates on treatment over 30% and nearly 40% on placebo over 5 years to put this into perspective.
cheers. |
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November 12, 2008 12:14 (EST)
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Event rates: is CRP really useful
Thanks Michael, so you agree that the event rate is extrapolated to be 13% or so in the placebo group. "Low risk" according to FRS is <=10%. The study had both <10 and > 10% risk patients according to FRS, so it seems that CRP does not add much to risk prediction.
We've known for a long time that many "low risk" FRS pts have CAD and deserve treatment. In my mind Jupiter shows that rosuvastatin has the efficacy to lower events in this group. I'm not sure the study shows that CRP should tell us who is at risk. Any thoughts? |
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November 12, 2008 10:11 (EST)
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CRP
In our practice and based on published evidence we find that hscrp is most predictive of met syn, prediabetes, fatty liver, central adiposity, risk of developing diabetes. Having elevated hscrp increases one's risk for CV events, etc.. That being said we don't do a lot of hscrp simply because we can tell who has met syn with a simple lipid, bp, cmp and tape measure. Perhaps we will increase this, uncertain at this time. We use CIMT for patients over 45 with risk factors and determine risk based on the imaging technique and target lipids etc. based on this.
I agree with aha/acc that in mod risk scores, hscrp increases risk profiles if elevated and think hscrp adds to clinical decision making.
I have met syn but am not overweight and younger without fatty liver/central adiposity and a low starch diet (my hscrp is normal, yet I have a fhx for cad and have multivessel athero with an LDL under 130 and an ApoB between 80 and 110 depending on the day).
I think in this pt population if hscrp elevations would encourage a clinician to be more agressive with lipid, lifestyle and risk mgmt that has been confirmed now to show benefit. In this setting rosuva prevents events and saves lives and does so in a dramatic fashion.
I do think hscrp if elevated and confirmed and other causes of inflammation are ruled out - shows people who have elevated levels of cytokines, adipokines and are higher vascular risk and higher death risk.
good luck |
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November 12, 2008 11:07 (EST)
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No to CRP, yes to tape
Michael-- thanks for the detailed and thoughtful reply. I think you are on the right track -- a tape measure may be as useful in risk stratification as CRP and I will be incorporating that. Also, it's an easy way to assess progress.
It is very telling that Ridker, the man who has been trying to bring CRP to every primary care physician's lab slip -- is not trumpeting the elevated risk of those in the placebo group -- because there was none. There's not said much about the few events in the placebo arm: the hard event rate -- MI/death -- was a modest .8 per year. This is no different from Framingham.
I was initially interested in CRP as a risk stratifier, but now that I have been referred many patients with transiently elevated CRP because of URI or some minor scrape, and the need to repeat it for initial elevation, and now with this prospective study showing little if no increase in events, I don't think I will be adding it. The tape measure is probably as good or better -- and serial measurements are easy to do.
However, it is a great day for Crestor. The drug is so potent it essentially crushed whatever CAD was scattered in the active arm.
I use CAC selectively as a risk stratifier. I hoped that CRP would be an easier and cheaper way for patients to get similar info, but I don't think that's the case. At least it's a "good news" study in that treating with rosuva cuts risk in the "low risk" Framingham group. |
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November 12, 2008 12:05 (EST)
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RCTs underestimate NNT benefit
Because of the multiple exclusion criteria, the patients we see in clinic are often much higher risk than in the trial - and therefore have much more to gain in terms of absolute risk reduction and NNT. A good rule of thumb is to halve or even multiple by 1/3rd the NNT for the trial. A good example of this was the >70 y.o. subgroup in HPS -- NNT=10 in this group in the trial versus about 20-25 overall. I therefore would look to JUPITER as providing a very decent relative risk reduction, which, when applied to the average primary prevention population in clinical practice, will produce excellent NNTs and absolute risk reductions. |
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November 13, 2008 11:14 (EST)
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problem is not with efficacy
The study centered on use of CRP as a screening tool, and the results showed that walking around with an elevated CRP for several years, without statin treatment, lead to little or no increased risk over that predicted by FRS. Despite this, crestor still showed benefit in this group of FRS pts of around 10-15%. So this is the wrinkle: Crestor is so potent, it reduced risk in those with CAD, and the signal was present despite the number of patients without CAD. But as an overall risk marker, CRP did miserably.
So my point is not that Crestor will not reduce events, especially in your typical office practice where you have many higher risk patients. The exclusion criteria in Jupiter were there to establish a traditional low to intermediate risk FRS cohort -- and to enhance the specificity of CRP. So actually, for this study, the exclusion criteria to disallow "spurious" CRP elevation enhance NNT. Think of all the unnecessary troponins that are ordered by the ER and if any pt with an elevated troponin were included in NSTEMI PCI trials. This would dilute the efficacy of intervention. Think if they included patients who had any elevated CRP without repeat CRP testing -- the event rate would have been lower because these people would've had transient viral illness or something similar. Unfortunately, I think that many PCPs will order CRP and treat any elevation without confirming it, as guidelines state.
Jupiter needs to be repeated with CIMT, tape measure or CAC as the screening criterion in a low/mid FRS group. We all know that FRS misses many people who will have an event -- the question is which of these tests is best. They all seem to have validity, and we all appear to use one or the other -- the question is cost and predictive power.
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November 13, 2008 12:01 (EST)
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not necessarily true
Look at the New England Journal analyses of AFCAPS/TexCAPS (lovastatin) and Physician Health Study (aspirin) both by P. Ridker. Both showed that there was only benefit in the strata with high CRP - for statins this was irrespective of lipids. These analyses, coupled with JUPITER, support the notion of stratifying patient risk on the basis of biomarkers for direct treatment benefit. |
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November 13, 2008 09:04 (EST)
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correct
you are correct Dan. Wrote a couple of hsCRP orders today!
Melissa |
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November 13, 2008 11:23 (EST)
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not to take anything
AWAY......
Melissa, I'm a firm believer in statin therapy, does hscrp add value in this setting? These people had A1c 5.7% baseline over 40% had met syn, median age 66 where nearly 1/2 are borderline DM anyway and they have hscrp values that suggest 3-4/5 met syn features.
If your pt has met syn don't you expect high hscrp and higher risk anyway, ie doubling of risk which is what this study confirmed. Rather than 7-8% risk they were really 13-14% risk.
I'm not intending to be the devils advocate as JUPITER has many firsts and some amazing numbers with MI, Stroke and Death reductions all independent. (and confirms why I take it with and LDL similar to this study and why my father is on it post bypass for efficacy and risk reduction)
At AHA are cardiologists really talking about doing more Hscrp measures?
AHA and ACC already rec using hscrp in mod risk pts, will guidelines now rec using hscrp for low risk pts over ages 50-60 yrs of age.
Just curious? And if that is the case why not do lppla2 or ebct or cimt which have been discussed at great length on these forums for more than a year. |
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November 14, 2008 07:22 (EST)
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here goes
Mike,
that answer is yes. HsCRP has kind of been kicked around by most of us thinking it might be helpful in a very select group of patients but not really convinced. Studies have been less than provocative vs just slapping everyone on a meds. With the public becoming more and more anti pharmacy and less compliant, this is kind of a surrogate of the kind of motivation that can be generated for treatment for IMT,CAC etc. It's a motivator and paid for by third party payors without batting an eye, convenient to do , no scheduling, etc. etc. It's a good first step toward motivating a normal LDL patient toward therapy.
Melissa |
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November 14, 2008 12:21 (EST)
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about metabolic syndrome
Yes it's helpful but with 30% of the adult population having metabolic syndrome by NCEP/ATP criteria, I feel that we need to go beyond MetSyn, since we can't have a third of the population ended up on drug therapy. Perhaps a combination of MetSyn and CRP+ is the way to go? |
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November 15, 2008 10:39 (EST)
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Dan, I beg to differ
"we can't have a third of the population ended up on drug therapy"... I disagree
Considering that 1/3rd of the population will die from heart disease and about 1/2 of the population is slated to die from some form of vascular disease, I think that having a significant percentage of the population on cholesterol lowering drugs is a good idea. Too bad this study did not use a reliable technology to predict risk.
The question this study begs is whether HS-CRP finds the correct patients or is it simply a random number generator in the primary prevention population.
Considering the poor performance of HS-CRP in both the St. Francis Heart study and the MESA heart study, my position is that HS-CRP in the primary prevention population is indeed a random number generator. The sad truth is that a random number generator for stratifying risk in subjects with normal LDL cholesterol is better than what we are currently doing with Framingham.
Unfortunately since Crestor is the only statin with reasonable time left on patten, and major teaching institutions rely on big pharma for significant funding, it is necessary for otherwise respectable researchers to froth over this study as though it was real science. But clearly, the Emperor has no clothes. |
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November 15, 2008 11:52 (EST)
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CRP does reclassify risk
C-Reactive Protein and Parental History Improve Global Cardiovascular Risk Prediction. The Reynolds Risk Score for Men
Paul M Ridker MD*, Nina P. Paynter PhD, Nader Rifai PhD, J. Michael Gaziano MD, and Nancy R. Cook ScD
From the Donald W. Reynolds Center for Cardiovascular Research and the Center for Cardiovascular Disease Prevention, Divisions of Preventive Medicine and Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, and MAVERIC, VA Boston Health Care System, all in Boston, Mass.
* To whom correspondence should be addressed. E-mail: pridker@partners.org.
Background—High-sensitivity C-reactive protein and family history are independently associated with future cardiovascular events and have been incorporated into risk prediction models for women (the Reynolds Risk Score for women); however, no cardiovascular risk prediction algorithm incorporating these variables currently exists for men.
Methods and Results—Among 10 724 initially healthy American nondiabetic men who were followed up prospectively over a median period of 10.8 years, we compared the test characteristics of global model fit, discrimination, calibration, and reclassification in 2 prediction models for incident cardiovascular events, one based on age, blood pressure, smoking status, total cholesterol, and high-density lipoprotein cholesterol (traditional model) and the other based on these risk factors plus high-sensitivity C-reactive protein and parental history of myocardial infarction before age 60 years (Reynolds Risk Score for men). A total of 1294 cardiovascular events accrued during study follow-up. Compared with the traditional model, the Reynolds Risk Score had better global fit (likelihood ratio test P<0.001), a superior (lower) Bayes information criterion, and a larger C-index (P<0.001). For the end point of all cardiovascular events, the Reynolds Risk Score for men reclassified 17.8% (1904/10 724) of the study population (and 20.2% [1392/6884] of those at 5% to 20% 10-year risk) into higher- or lower-risk categories, with markedly improved accuracy among those reclassified. For this model comparison, the net reclassification index was 5.3%, and the clinical net reclassification index was 14.2% (both P<0.001). In models based on the Adult Treatment Panel III preferred end point of coronary heart disease and limited to men not taking lipid-lowering therapy, 16.7% of the study population (and 20.1% of those at 5% to 20% 10-year risk) were reclassified to higher- or lower-risk groups, again with significantly improved global fit, larger C-index (P<0.001), and markedly improved accuracy among those reclassified. For this model, the net reclassification index was 8.4% and the clinical net reclassification index was 15.8% (both P<0.001).
Conclusions—As previously shown in women, a prediction model in men that incorporates high-sensitivity C-reactive protein and parental history significantly improves global cardiovascular risk prediction.
Key words: epidemiology • prevention • inflammation • genetics • risk factors |
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November 15, 2008 11:53 (EST)
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CRP does reclassify risk II
Original Article
C-Reactive Protein and Reclassification of Cardiovascular Risk in the Framingham Heart Study
Peter W.F. Wilson, MD; Michael Pencina, PhD; Paul Jacques, DS; Jacob Selhub, PhD; Ralph D'Agostino, PhD and Christopher J. O'Donnell, MD, MPH
From EPICORE (P.W.F.W.), Emory University School of Medicine, and the Atlanta VAMC Epidemiology and Genetics Section, Atlanta, Ga; National Heart, Lung, and Blood Institute (C.J.O.D.); National Heart, Lung and Blood Institute\'s Framingham Heart Study (M.P., R.D.A., C.J.O.D.), Framingham Mass; Department of Mathematics (M.P., R.D.A.), Boston University, Boston, Mass; Tufts USDA Nutrition Center (P.J., J.S.), Boston, Mass.
Correspondence to Peter W. F. Wilson, MD, Suite 1 North, Emory University School of Medicine, 1256 Briarcliff Rd, and the Atlanta VAMC Epidemiology and Genetics Section, Atlanta, GA 30306. E-mail peter.wf.wilson@emory.edu
Background–The relationship of circulating levels of high-sensitivity C-reactive protein (CRP) with cardiovascular disease (CVD) risk, particularly with consideration of effects at intermediate levels of risk, has not been fully assessed.
Methods and Results–Among 3006 offspring participants in the Framingham Heart Study free of CVD (mean age, 46 years at baseline), there were 129 hard coronary heart disease (CHD) events and 286 total CVD events during 12 years of follow-up. Cox regression, discrimination with area under the receiver operating characteristic curve, and net reclassification improvement were used to assess the role of CRP on vascular risk. In an age-adjusted model that included both sexes, the hazard ratios for new hard CHD and total CVD were significantly associated with higher CRP levels. Similar analyses according to increasing homocysteine level showed significant protective associations for hard CHD but not for total CVD. In multivariable analyses that included age, sex, systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, diabetes mellitus, current smoking, hypertension treatment, and homocysteine, the log CRP level remained significantly related to development of hard CHD and total CVD and provided moderate improvement in the discrimination of events. The net reclassification improvement when CRP was added to traditional factors was 5.6% for total CVD (P=0.014) and 11.8% for hard CHD (P=0.009).
Conclusions–Circulating levels of CRP help to estimate risk for initial cardiovascular events and may be used most effectively in persons at intermediate risk for vascular events, offering moderate improvement in reclassification of risk.
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November 15, 2008 02:54 (EST)
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Damned by faint praise
If this is the best HS-CRP can do in a study designed to prove its value, while the largest, longest prospective study on heart disease looking at novel markers, MESA, demonstrates that the average HS-CRP was actually slightly lower in those having a heart attack compared to those without, cased closed! HS-CRP is not the answer in primary prevention. It may have a role in monitoring treatment however there are probably better markers for this. |
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November 17, 2008 12:40 (EST)
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Ridker: of course he likes CRP, he designed the test
Quoting Ridker is like quoting Stone on stents. Several independent groups have questioned its value and the issue has thrashed around in Circ and other journals.
It seems people want to ignore the low event rate in the placebo arm in Jupiter, but it seems pretty clear to me. I had hopes for CRP, but that confirmed it. There are plenty of non-Ridker, non-CRP supportive papers out there. I'm surprised how JUPITER has somehow appeared to revive CRP as a test, when it seems like it has done nothing of the sort.
Critical appraisal of CRP measurement for the prediction of coronary heart disease events: new data and systematic review of 31 prospective cohorts
Tina Shah et al
Background Non-uniform reporting of relevant relationships and metrics hampers critical appraisal of the clinical utility of C-reactive protein (CRP) measurement for prediction of later coronary events.
Methods We evaluated the predictive performance of CRP in the Northwick Park Heart Study (NPHS-II) and the Edinburgh Artery Study (EAS) comparing discrimination by area under the ROC curve (AUC), calibration and reclassification. We set the findings in the context of a systematic review of published studies comparing different available and imputed measures of prediction. Risk estimates per-quantile of CRP were pooled using a random effects model to infer the shape of the CRP-coronary event relationship.
Results NPHS-II and EAS (3441 individuals, 309 coronary events): CRP alone provided modest discrimination for coronary heart disease (AUC 0.61 and 0.62 in NPHS-II and EAS, respectively) and only modest improvement in the discrimination of a Framingham-based risk score (FRS) (increment in AUC 0.04 and –0.01, respectively). Risk models based on FRS alone and FRS + CRP were both well calibrated and the net reclassification improvement (NRI) was 8.5% in NPHS-II and 8.8% in EAS with four risk categories, falling to 4.9% and 3.0% for 10-year coronary disease risk threshold of 15%. Systematic review (31 prospective studies 84 063 individuals, 11 252 coronary events): pooled inferred values for the AUC for CRP alone were 0.59 (0.57, 0.61), 0.59 (0.57, 0.61) and 0.57 (0.54, 0.61) for studies of <5, 5–10 and >10 years follow up, respectively. Evidence from 13 studies (7201 cases) indicated that CRP did not consistently improve performance of the Framingham risk score when assessed by discrimination, with AUC increments in the range 0–0.15. Evidence from six studies (2430 cases) showed that CRP provided statistically significant but quantitatively small improvement in calibration of models based on established risk factors in some but not all studies. The wide overlap of CRP values among people who later suffered events and those who did not appeared to be explained by the consistently log-normal distribution of CRP and a graded continuous increment in coronary risk across the whole range of values without a threshold, such that a large proportion of events occurred among the many individuals with near average levels of CRP.
Conclusions CRP does not perform better than the Framingham risk equation for discrimination. The improvement in risk stratification or reclassification from addition of CRP to models based on established risk factors is small and inconsistent.
And also see:
Assessment of Incremental Coronary Risk Prediction Using C-Reactive Protein and Other Novel Risk Markers
The Atherosclerosis Risk in Communities Study
C-Reactive Protein and Cardiovascular Disease Risk: Still an Unknown Quantity?
right arrow George Davey Smith, MD, DSc; Nic Timpson, MSc; and Debbie A. Lawlor, MB, PhD
4 July 2006 | Volume 145 Issue 1
Interesting how many have already decided CRP should be on everyone's lab slip. |
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November 17, 2008 09:41 (EST)
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Jim F
I agree in some regard. I think this is another study that shows lowering LDL in a 'low risk' population with this age and these demographics shows profound benefit.
Still uncertain how much the hscrp added to the risk prediction or risk reduction. I do however believe that elevated hscrp is bad and having met syn is bad. I have the latter but not the former and have multivessel athero in my 40's. Regret, didn't image myself sooner or believe the results or start lipid mgmt earlier in my life (with 'normal' lipoproteines)
I'm glad to see this study making people think about risk and risk identification and risk stratification and ultimately risk reduction. mc |
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November 20, 2008 04:18 (EST)
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Jupiter
The results of Jupiter are certainly causing a discussion. Since Miller and Miller showed in 1975 that people who developed cardiovascular events with normal or low LDL levels generally had low HDL levels and since Stammler described a low risk population with low LDL and normal HDL, I submit that the high hs-CRP in Jupiter simply reflects a low HDL, though in those with normal HDL, it could also reflect cigarette smoking, obesity, and/or diabetic hypertension. I believe that it might be useful to substitute a LDL:HDL ratio and determine if the results are the same. That would put to rest much of the controversy since hs-CRP should rise and fall with a rise or fall in the ratio. Ridker has already acknowledged that the inflammatory changes in the artery wall are related to cardiovascular risk factors and that more potent statins like rosuva ( which lowers LDL AND raises HDL, and maximally reduces the ratio ) are moreeffective at lowering hs-CRP. I personally do not measure hs-CRP, but rather treat all lipid disorders to plaque stabilizastion/regression levels, with the result that my treated patients have sustained only two fatal AMI's this century--and one was in a cigarette smoker, while the other was in a not well-controlled insulin-dependent diabetic who had been on insulin for over 40 years--and average only one CVA per year, usually in patients aged 75 years or older. |
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November 21, 2008 07:12 (EST)
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might be more than just a lab exam-
William,
What about the thought that the hsCRP might a great motivator, perhaps a less expensive calcium score, to get folks to take medications, adjust their diets, etc.?
Melissa |
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November 22, 2008 10:44 (EST)
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My approach
Melissa,
I don't see that my response to you made it onto the comment page, so I will repeat myself. If you got the original response, please ignore this,
My approach is to show my patients their actual risk, on average. You can find that approach in the August issue of Amer J Cardiol in the Readers' Comments section. Another useful sourse is Advances Studies in Medicine in the February,2004, issue--use the online version because it has the risk table. If you can't find these sources, I will be happy to send you copies,. if you will send me your email address.
In brief, I use a ratio between LDL and HDL ( specifically the Cholesterol Retention Fraction, or CRF, defined as [ LDL-HDL]/ LDL ), on the ordinant of the graph and the systolic blood pressure ( SBP ) on the abcissa. If one plots the CRF-SBP plots of patients who have sustained some clinical atherpthrombotic event on the graph, stratified by cigarette smoking status, one sees most plots are bunched up into a mainstream flow. One can then draw a threshold line, based on the fewest false negatives, above which lie the majority of plots. In patients who have never smoked cigarettes, the area below the threshold line is virtually devoid of plots, and those that do occur belong to patients mainly in their late 70's and older. I tell patients that if their plot lies above the threshold line, then they are at risk of an atherothrombotic event and that the higher the CRF, the younger that event occurs.
In any event, if you look at the letters, let me know what you think. This approach works well for me.
Bill
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November 23, 2008 01:44 (EST)
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Motivate honestly
If we are going to motivate patients, do we want to use a technology that adds nothing to Framingham such as HS-CRP or do we want something that is >7 times more predictive than Framingham such as a calcium score >100?
The inaccuracy of HS_CRP cuts both ways, it can tell people they have risk when they don't but it can also tell people they don't have risk when they do (as was the case with my former partner a few years ago). I think we have a fundamental responsibility to be honest with our patients. |
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November 23, 2008 11:04 (EST)
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?Motivate Honestly
William...From my recollection in MESA, scores of 1-100 had hazard ratios of about 4 with scores>100 about 6-7. This is certainly very helpful in my mind but we still don't have data treating these patients (with "normal" lipid panels and otherwise LDL goals of 130) is beneficial. Like you, I'm not waiting for the study.
It would be great to have an imaging study with JUPITER but I think we would find much of the same...we are simply picking out higher risk patients. I'm not sure it matters exactly how you do it. CIMT, calcium scoring, etc, etc. We can argue about the best methods but there are not head to head comparisons with outcome data (and may never be).
It will be interesting when the hsCRP specifics from this study come out...did patients with higher crp's benefit more. Did those that benefit have greater reduction in crp with treatment? I agree with Melissa it may be a cheaper mode of testing than calciums scoring in some people though obviously will not catch all. |
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November 23, 2008 09:56 (EST)
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hs-CRP
Drs Blanchet and Davidson,
May I offer a comment on hs-CRP? I don't use the test for reasons outlined in my previous comments. If a patient has a lipid disorder on the basis of what I have written--see articles--would I not treat him/her regardless of hs-CRP? Would I want to wait until his/her artery is ahterosclerotic and inflammed? I can get a reasonable idea of when the patient's atherosclerotic event is due on the basis of lipid ratios and cigarette smoking status. ( See tables in Advanced Studies in Medicine, Feb, 2004, on-line version.) I have not yet had any unpleasant surprises. Perhaps you missed my exhibition at the NLA symposium in Seattle last May; if so, I hope to be exhibiting my research at the ISA symposium in Boston, next June.
I suppose that what I am saying is that use of lipid ratios gives one such a good idea of risk all along the LDL spectrum, that I would never not treat a dangerous ratio just because a surrogate marker was not abnormal. Moreover, if I elect to treat a patient's dyslipidemia, I always treat to plaque stabilization/regression levels. This may be why my trated patients have suffered only two fatal AMI's this century so far and average only one CVA per year, mainly in patients in their late 70's and older ages.
Anyway, I thought that I's offer my experience for your consideration.
Bill |
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November 25, 2008 07:55 (EST)
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I still think it will be immensely helpful in some patients
William,
the entire point is that these patients have a NORMAL LDL which lulls some folks, both patient and practitioner, into a false sense of security.
Certainly, when I think the patient has little worry, I'll consider allowing the hsCRP to guide me.
Even though, the population studied here was men age 50 and women age 60 or greater, I might consider allowing it to guide me in those who are "too young" for an accurate calcium score prediction as well.
Melissa |
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November 25, 2008 10:29 (EST)
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I agree
This trial should also help convince primary care docs about the typical late middle aged patient with borderline abnormalities that they are sitting on with lifestyle advice. The risk reduction in patients with pos. family history in JUPITER looks like it convincingly approached 70% (with test of statistical interaction nearly positive). These patients may have normal lipids with systemic inflammation and we know that normal lipids in western societies are not normal in the primordial hunter-gatherer sense. Cord blood in neonates contains 50% of adult LDL levels and yet babies develop just fine with such low LDL cholesterols. Humans are about the only species that develops atherosclerosis and has LDL concentrations 2-10X that of animal species that don't develop atheromata. |
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November 25, 2008 04:34 (EST)
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hs-CRP
Melissa and D
I define normal lipids as those levels that do not lead to atherosclerotic disease, not statistical but functional and practical. Something I picked up from Bill Connor, who was then at Iowa. Hence, how much LDL can be tolerated ( without de4veloping signioficant atherosclerosis ) depends on how much HDL is avaliable--and requires a ratio betweeen LDL and HDL as I noted earlier. Thus, even and LDL of 120 mg/dl can be atherogenic if the HDL is, say 20 mg/dl, but not, as Miller and Miller showed, if the HDL is, say, 50 mg/dl. In other words, as Framingham has pointed out over the years, ratios are where it's at, though I agree that LDL levels influence the interpretation of ratios. My age-sex database includes a number of 80-plus year olds, free-living in the community, only a few of whom have LDL levels below 100 mg/dl. ( What they do have is normal to high HDL levels. )
The predictive graph to which I referred earlier not only tells the physician who is at risk, but also ( combined with the ratio tables and cigarette smoking status ) when they will sustain their clinical events. Of course, one must remember that not all atherothrombotic events are lipid-driven; cigarette smoking, hypertension, and diabetes can play critical roles--especially, cigarettte smoking, which can produce clinical events even in patients with good ratios. ( I know that I am preachhing to the choir. )
I would not treat a terrible ratio just because the hs-CRP is not elevated or the CAC is zero. On this basis, if the patient already has ahterosclerosis, I am trreating it before it becomes symptomatic, and if the patient does not yet have atherosclerosis, I am preventing it.
What do you think?
Bill |
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November 25, 2008 09:06 (EST)
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Keep on keeping on Bill
Bill,
I'm all for prevention. I too treat "normal" lipid profiles with established disease, though I tend to use more niacin in those "normal" total serum cholesterol folks.
Agree that nothing interefers more with our ability to predict long term prognosis than cigarette smoking and obesity.
Melissa |
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November 26, 2008 11:03 (EST)
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HDL MEASUREMENTS
Melissa,
Nice talking to you. Something you might find useful. A number of labs now use direct-measure HDL determinations unstead of the older indirect-measure HDL determinations. At least in my hospital lab, the direct-measure HDL is about 10 mg/dl higher than the indirect-measure; hence, calculated LDL using the direct-measure HDL will be 10 mg/dl lower than the calculated LDL using the indirect-measure determination. If you don't take this into account, your treatment indications and goals will be off. This is not trivial--see my letter in this month's issue of the Journal of Clinical Lipidology.
Bill |
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November 27, 2008 09:26 (EST)
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I'm THANKS-GIVING for my HDL!!
Bill,
Though Dan and others know my HDL story, I will pass it along again, in case others need a little encouragement and motivation.
My HDL started at 25 , 15 years ago. Over time, it rose with exercise to the 40's, and the absolute max I could achieve unmedicated was low to mid 50's. Then, with rosuvastatin it rose to mid to upper 60's. I think my max is 67. I've been off drug since February due to gut surgery and a failed attempt to restart it with muscle pain.(I'm wierd like that). I'm determined to start again but for three weeks have been trying to get a fasting Berkely done without success (early morning patient ST shifts, etc. !!!).
So, if I can go from 25-55 without medication with lifestyle change only , ANYONE CAN DO IT!
Thanks for sharing you insights.
And by the way, Happy thanksgiving to all you folks who celebrated it! Just started my Thanksgiving morning by doing the cardio-x CD of Tony Horton's P90X program with my husband (no disclosures). It will kick your butt!!! (It certainly does mine!). I Highly Highly recommend it. I'm THANKFUL for my husband's dedication to it because his abs look better than they did in college!
Melissa |
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November 27, 2008 10:47 (EST)
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maybe qweekly crestor is the way to go for you Melissa?
Once-a-Week Rosuvastatin (2.5 to 20 mg) in Patients With a Previous Statin Intolerance
References and further reading may be available for this article. To view references and further reading you must purchase this article.
Janelle F. Ruisinger PharmD, a, , James M. Backes PharmDa, Cheryl A. Gibson PhDa and Patrick M. Moriarty MDa
aKansas University Medical Center, Kansas City, Kansas
Received 5 August 2008; revised 25 September 2008; accepted 25 September 2008. Available online 19 November 2008.
The purpose of this study was to determine the efficacy of rosuvastatin dosed once a week in patients with a previous statin adverse event. Rosuvastatin once a week was tolerated by 37 (74%) of the 50 study participants, with doses ranging from 2.5 mg to 20 mg a week (mean 10 ± 4 mg). Patients tolerating the once-a-week regimen experienced a 17% reduction in total cholesterol, 23% reduction in low-density lipoprotein cholesterol, 12% reduction in triglycerides, and a 5% increase in high-density lipoprotein cholesterol (all p <0.001), during a mean follow-up of 4 months ± 2. Although this alternative dosing regimen has not been proven to reduce cardiovascular events, it may provide a therapeutic option for patients who may otherwise go without the proven benefits of statin therapy. In conclusion, this dosing strategy was well tolerated in patients with a history of an adverse event to 1 or more statins and led to significant lipoprotein changes.
Article Outline
References
Figure 1. All p values <0.001. TC = total cholesterol; TG = triglycerides.
View Within Article
--------------------------------------------------------------------------------
Table 1.
Baseline characteristics of patients with previous statin intolerance (n = 50)
Family history of premature coronary heart disease in male first-degree relative <55 yrs of age or female first-degree relative <65 yrs of age.
† n = 37.
View Within Article
--------------------------------------------------------------------------------
Table 2.
Change in serum lipids from baseline of patients tolerating once-a-week rosuvastatin
View Within Article
Corresponding author: Tel: 913-588-2608; fax: 913-588-2355
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November 27, 2008 08:02 (EST)
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Interesting!!!
Dan,
Thanks so very much for posting this information. I've prescribed MWF lipid therapy for years.
For two years, I took Rosuvastatin 5 mg Monday, Wednesday and Friday. About every 6 weeks, I'd have to skip Friday due to that same old muscle ache that always starts in my anterior thigh muscle and deltoids. It would be gone by Monday and I'd start all over. My cholesterol dropped to 169 total (my non medicated total has been as high as 299 and my LDL went to 70, previously 199. My Tgs'are always around 40)
I'd really like to post my Berkely before and after information, just for fun.
Maybe I can get the time to draw it next week?!
I'll probably start bi weekly first, then see how I do.
Melissa |
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November 29, 2008 02:43 (EST)
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"normal LDL"
Interesting when you break down the Framingham offspring study data by percentiles, LDL, non-HDL, Apo B and LDL-P.
We are all familiar with ATP III which recommends goal LDL of <100 in high risk. This is the 20th percentile (i.e. 80% have higher values). Would be non-HDL of 119 (not 130), LDL-P of 1100 and ApoB of 78.
For those "very high risk" goal LDL of <70 mg/dL correlates with percentile of 2%. Would be non-HDL goal 83, LDL-P of 720 and ApoB of 54.
Maybe the magic is not in the CRP, but in the ApoB particle number that is abnormal in a group in JUPITER with metabolic syndrome.
Simple and easy to do. Just check an ApoB particle number or LDL-P and treat appropriately. Especially since MESA data showed how poor LDL reflects ApoB particle number goal in metabolic syndrome (40% in JUPITER)
Just a thought. Comments? Still no data, but I think we all agree we are unwilling to wait for randomized trials while patients and people around us are dropping dead of MIs.
Daniel |
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November 29, 2008 09:31 (EST)
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normal LDL
Dan,
LDL particle number and size both track with HDL and TG, both of which track with the LDL:HDL ratio. I think that in Jupiter, the high hs-CRP is a surrogate for a low HDL sinc people with lower LDL's who develop CVD events tend to have low HDL's ( Miller and Miller, 1975 ). In my experience, those people who develop CVD with lower levels of LDL but normal levels of HDL are virtually always cigarrette smokers ( younger patients ) or have hypertension with or without diabetes ( older patients ). So why not just go with the ratio--it works for me.
Bill |
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November 30, 2008 10:27 (EST)
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Dan...
Believe LDL particle size and apolipoprotein levels were measured in Jupiter...Not published but suspect will see them in several publications to come. I think you are right and will predict events better than CRP |
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December 1, 2008 10:38 (EST)
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many points
Yet the ratios were all great:
TC 186, TG 118, LDL 108, HDL 49
TC/HDL 3.8
TG/HDL 2.4
LDL/HDL 2.2
It would not surprise me if we saw mixed to low density in all of the LDL of this group studied. With LDL of 108 this would equate to LDLp's of 1300-1600 (very much like mine, not the expected under 1100). I have a normal crp however at my age and with my exercise and waist (no steatosis).
hscrp is a simple test to consider if one wishes to stratify risk further, we now know that treating this 'normal' ldl with abnormal crp did prevent events.
Dan, as far as off label we use rosuva 1.25 qd or 2.5 qod or 5-10 qwk for LDL reductions 25-35% on average.
Melissa, I presume your thyroid, esr, b12 and vit d levels are all normal?? If so, have you tried all the other statins. We have the occ pt with the same problem and normal labs and finally find they can tolerate lovastatin 40 mg/day when atorva, rosuva, simva, fluva, prava weren't tolerated... very interesting..
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December 1, 2008 08:14 (EST)
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fine point
Great points again, as usual. Just remember that it is the particle number, not size that truly predicts increased risk. Your example, Michael, of an elevated LDL-P is a great example of how we are UNDER estimating risk in our patients. I suspect if we can reduce the cost, more advanced lipid testing will take a greater part of the ATP IV or V guidelines in management of our CV patients.
Rob, I look forward to seeing that data. Hopefully they will release it in a timely fashion to the public. Unfortunate that they don't include it in the initial publication.
Daniel |
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December 1, 2008 09:52 (EST)
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LDL particle size and/or number
Dan,
I wonder if you might tell me which RCT was done and published that demonstrates the superiority of LDL particle size/number over the LDL:HDL ratio or even LDL/HDL levels. Further, what goals of particle number/size did this RCT designate to stabilize/regress atherosclerotic plaque angiographically or by IVUS. I am unaware of any RCT designed specifically to look at these questions. In the absence of any RCT, comments about LDL particle size/number are simply post-hoc speculation. So please enlighten me.
Bill |
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December 2, 2008 12:26 (EST)
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Bill
Does the data from VAHIT published in Circulation 2006 or the MESA data in Atherosclerosis June 9 2006 or the Framingham Heart study data answer this? AHA scientific sessions 2003 found people in Framingham with met syn and LDL-C under 100, more than 75% had LDL-P over 1000 (quite a surprise). AJC 2006 article found over 2000 people with DM2 and LDL avg 73 mg/dl had avg LDLp of 1100 (quite disparate). Carotid IMT in MESA and quintile for LDLp is very impressive. You can find this data on the fda web pages or each article.
I'm not sure if this is the data you asked for, maybe Dan can be more detailed. I don't intend for this information to direct changes in anyones care and I have no relationship with liposciences. I do however think the published data thus far are very strong for LDL density patterns and LDLp and risk. My TC/HDL ratio and TG/HDL ratio and LDL/HDL ratio and VLDL and NHDL and ApoB didn't predict my multivessel athero in my early 40's. My LDL density testing and/or LDLp did suggest very high risk as seen in MESA and Framingham and VAHIT.
mike
ps. Womens Health Study found LDL-P had higher HR than LDL-C but no better than TC/HDL ratio. Cardiovascular Health study found LDL-P better predictor than LDL-C. VAHIT LDL-P and HDL-P predictors where LDL-C was not. PLAC-I predictive. EPIC LDL-P statistical after adjusting for FRS and LDL-C. LDL-C not statistical after adjusting for FRS (if one corrected for hdl and tg's LDL-P lost value). However in my case (adjusting for tg's and hdl or apob or nhdl or vldl etc.. didn't attenuate the prediction of LDL density or LDL-P). This again doesn't suggest that all people need advanced lipid testing, however I think without it - we still miss people at risk even when tg's and hdl are normal and lpa is normal.
AND i feel the same about noninvasive imaging. Invasive imaging has great value as well, with that being said, we had another new pt in his 50's last week with exertional fatigue and sob -and performed invasive imaging and were able to fix his symptomatic athero dz 95% occlusion with a xience stent.
Prevention and Intervention (both have great applications) He's a new patient and I don't know his lipid levels or fractions or subfractions but that will be part of his follow up care.
Happy Holidays |
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December 2, 2008 07:15 (EST)
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Thanks Mike
Mike,
Being a sun=a-phobe, I have had documented Vit D deficiency, but corrected it, then never rechecked it, so I'll be rechecking that Wednesday (YES, hopefully and finally will be able to get some blood drawn then fasting!!!).
I've utilized Lipitor, Zocor,Pravachol, Crestor, Zetia, and Baycol. My best tolerated : Baycol. I miss it. I loved it. At low dose, it was safe and well tolerated. I've not tried Mevacor.
I appreciate your comments and they are well taken. I only post my personal experience as a reminder that these intolerances are legitimate ongoing problems in our population. I am so happy to see that information on pulse dosing posted by Dan because I believe that discussions like this over the past five years have yielded a desire to study such crazy regimens as bi weekly or weekly therapy. Now if only they would prove a decrease in events!
Congratulations on your patient scenario you described above. Hope he continues to do well!
thanks for the info/advice.
Melissa |
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December 2, 2008 09:28 (EST)
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Your welcome
Yes if your labs are normal, we have found some people the only statin they tolerated was lovastatin 40 hs or of course lescol xl 80 hs is quite well tolerated as well. good luck with those labs, you've teased us about drawing them for 'months' now. :o) |
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December 2, 2008 09:52 (EST)
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I know!
Mike,
You are completely correct. It's like Gilda Radner's Rosanna RosannaDanna always said, "It just goes to show you, it's always something".
A GI bug is rampant in our office, I'm cross covering everyone under the sun, my dad is having a lower GI bleed and I'm waiting for him to arrive at the hospital tonight so I can tuck him in.
So, I'm going to try to go in the morning!
Thanks for the nudge!
Melissa |
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December 2, 2008 10:50 (EST)
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LDL particle number/size
Mike,
I thank you for your response, The VAHIT study used gemfibrozil to treat patients with low HDL and high TG--the VAP study was an add-on study. Since VAHIT was not set up to compare particle size/number versus LDL, HDL, or ratios, it does not tell me that the former is better than the latter. Framingham Heart Study is not an intervention study and likewise can not tell which is the better approach. Both studies are hypothesis-generating until tested by a RCT.
I did not know that Mesa had been finished and that the results had been published. Was Mesa set up to do the comparison? Can you give me the reference?
I'm sorry that you had a coronary event. The ratios approach that I use is described in comments #48,50, and 53. I invite you to plot your initial lipid values combined with systolic blood pressure, stratifying by cigarette smoking status, on the graph. 93% of all people ( 98% of all males ) who develop an atherothrombotic event will either be cigarette smokers, current or past, or will have an ( LDL - HDL )/ LDL --SBP plot above the threshold line. Those few males that I miss predicting tend to be quite old at time of event onset. I understand that some people have artery walls that leak in cholesterol, but such folk are rare. Anyway, if you try my graph, please let me know your results.
Bill |
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December 3, 2008 08:09 (EST)
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thanks!
FYI Mike,
I made it. The blood is actually in a tube and onto the Berkely lab!!!
Thanks for the encouragement!
Melissa |
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