September 11th, 2014
FDA Approves New Weight Loss Drug
Larry Husten, PHD
The FDA announced today that it had approved Contrave, the long-awaited and much-disputed weight loss drug. Contrave is a combination of two drugs already approved for other indications: naltrexone hydrochloride, which is used to combat alcohol and opioid dependence, and bupropion, which is used to treat depression and seasonal affective disorder and as an aid to smoking cessation treatment. Contrave is manufactured by Orexigen and will be distributed by Takeda.
The FDA said that Contrave had been approved for use in obese adults (BMI of 30 or over) or overweight adults (BMI of 27 or over) with at least one weight-related condition such as high blood pressure, type 2 diabetes, or elevated cholesterol.
The approval comes several years after the approval in 2012 of two competing weight loss drugs, Arena’s Belviq and Vivus’s Qsymia. Neither drug has achieved much success in the marketplace. Orexigen had originally hoped for an even earlier approval but its hopes were dashed in 2011 when the FDA demanded that the company perform a safety study.
In one clinical trial, significant weight loss — defined as the loss of at least 5% of body weight — was achieved by 42% of people who received Contrave and 17% of people who received placebo. In a trial of people with type 2 diabetes, 36% of patients taking Contrave and 18% of patients taking placebo had a significant weight loss.
The FDA said that people taking Contrave should be evaluated after 12 weeks of treatment. Patients who have failed to lose at least 5% of their body weight should discontinue the drug.
Because Contrave contains buproprion, the label will include a boxed warning alerting physicians and patients to the increased risk of of suicidal thoughts and behaviors associated with antidepressant drugs.
The drug can also cause seizures and is contraindicated in people with seizure disorders. Contrave has also been found to increase blood pressure and should not be used in people with uncontrolled hypertension.
The FDA is requiring Orexigen to perform a cardiovascular outcomes trial and two safety and efficacy trials in pediatric populations.
September 10th, 2014
FDA Advisory Panel Offers Cautious Support for Polypill
Larry Husten, PHD
The controversial polypill took one step closer to reaching the U.S. market after receiving a mostly positive reception from the FDA’s Cardiovascular and Renal Drugs Advisory Committee on Wednesday. The idea for the polypill– which in this case would be composed of aspirin, a statin, and one or more blood pressure drugs– has been kicking around for more than a decade and has attracted considerable doses of support as well as skepticism.
An all-star group of cardiology leaders– including Sir Nicholas Wald, Salim Yusuf, Suzanne Oparil, Sidney Smith, and Clyde Yancy– helped provide the spoonful of sugar that helped the committee swallow the polypill. The FDA also eased the way by limiting the discussion to the use of the polypill for secondary prevention in people who have already had an MI or a stroke.
The more difficult discussion about the polypill for primary prevention use was put off for another day, though panel members and even FDA leaders couldn’t help occasionally commenting on the primary prevention question. Most panelists seemed to agree that the argument for secondary prevention was more straightforward than the argument for primary prevention. Panelist Philip Sager said that the main problem in secondary prevention is that the drugs that would be contained in a polypill are now being underutilized, not overutilized.
The committee generally agreed with the FDA’s proposed indication for use in patients who need the drugs to prevent recurrent events but are unlikely to be closely and carefully monitored by a physician. “We believe there are patients in the USA for whom cardiovascular prevention therapy is appropriate but who cannot get the follow-up necessary for titration, for reasons that include geography, finances, and patient preference,” the FDA wrote in its briefing documents for the committee. “We are asking then whether people who are not, for whatever reason, going to receive regular follow-up are better off on some reasonable doses of drugs for secondary prevention of cardiovascular disease, rather than none, even if they are not getting what is believed to be optimal care.”
The prevailing view was that the polypill was not better than standard care or was not intended to replace standard care but that it could be used where adherence is a problem and when physicians are able to treat a patient but are unable to monitor their care. The FDA’s Robert Temple said that the FDA hopes that fixed-dose combination drugs, including the polypill, can improve adherence, but that the FDA has previously not insisted that improved adherence be demonstrated.
In general the panel was not impressed by research specifically examining the polypill, but this was not a source of major concern since all the individual components of the polypill have been studied in considerable detail. The panelists did not see a strong need for phase 3 or outcome trials with the polypill, but they expressed lots of interest in trials that could look at the effect of the polypill on adherence or that would monitor or assess possible safety issues related to the polypill.
Panel member James De Lemos provided the following comment on the meeting:
The tenor of the discussion was generally quite positive with caveats that some members wanted to see more safety and real world effectiveness data. Others, including myself felt like the FDA’s stated path to approval limited to pharmacokinetic and dynamic studies would be sufficient for regulatory approval, given how much we already know about the individual components that are already used in combination routinely. There would remain lots to learn about in whom and how these fixed dose combinations should be used, but this may best be handled via health services research after market approval. We did not go into much detail about which drugs and doses would make up the ideal polypill.
Salim Yusuf viewed the panel as a positive development:
It is a positive move that the FDA has taken the initiative to discuss possible regulatory pathways for the availability and approval of polypills in the USA. Even in the USA, there are major gaps in treatments of proven, inexpensive and safe drugs in high risk individuals and the polypill can help bridge this gap.
And Sanjay Kaul offered his perspective:
While the current evidence is not strongly supportive of the polypill hypothesis in the setting of secondary prevention, it is sufficient enough to get a favorable consideration from the FDA. It will, however, have to fulfill the regulatory requirement of demonstrating bioequivalence and therapeutic equivalence to exclude the possibility of a pharmacokinetic or pharmacodynamic interaction. The safety issues can be addressed in a phase IV study post approval. In my opinion, the high expectations generated by rosy predictions derived from modeling exercises more than a decade ago will have to be recalibrated.
September 9th, 2014
Lower Rate of Microvascular Complications in Statin Users Who Develop Diabetes
Larry Husten, PHD
In recent years, the medical community has become increasingly aware that taking statins can result in slightly higher glucose levels, and this can lead to a diagnosis of diabetes in a small but statistically significant number of people. But it has been unclear whether the diagnosis of diabetes in people taking statins also places them at increased risk for the microvascular complications linked to diabetes. Now, an observational study published in the Lancet Diabetes & Endocrinology finds that among people newly diagnosed with diabetes, statin users are less likely than nonusers to develop most of these complications. (The beneficial effects of statins in reducing macrovascular complications — cardiovascular disease — in diabetics and others is well established in people at high risk for these events.)
Danish researchers examined the rate of microvascular outcomes in more than 15,000 statin users who developed diabetes and 47,000 nonusers of statins who developed diabetes. Over a median follow-up of 2.7 years, statin users had a 40% reduction in the risk for developing retinopathy (hazard ratio 0.60, CI 0.54–0.66, p<0.0001), a 34% reduction in the risk for diabetic neuropathy (HR 0.66, 0.57–0.75, p<0.0001), and a 12% reduction in gangrene of the foot (HR 0.88, 0.80–0.97, p=0.010). There was no significant difference in the rate of diabetic nephropathy (HR 0.97, 0.85–1.10, p=0·62). The overall results were similar after adjusting for differences between the groups. In rough accord with previous research, the Danish researchers observed that statin users had a 17% increase in the risk for developing diabetes.
The authors conclude: “Whether or not statins are protective against some forms of microvascular disease, a possibility raised by these data, and by which mechanism, will need to be addressed in studies similar to ours, or in mendelian randomization studies…. Ideally, however, this question should be addressed in the setting of a randomized controlled trial.”
Commenting on the study, Darrel Francis offered an overview of the risks and benefits of statins: “For every 1000 primary prevention patients randomized to statin, 5 patients gain a diagnosis of diabetes, while 5 patients are saved from death, 10 from nonfatal myocardial infarction, and 6 from stroke. Some people find this a good deal, but others are cautious because of the justified fear of diabetes.”
September 8th, 2014
Anteroseptal MI and Left-Main Dissection in a Pregnant Woman
Harsh Golwala, MD and James Fang, MD
A 25-year-old woman who is gravida 4, para 2 and is 32 weeks pregnant presents to the emergency department with sudden-onset chest pain that started while she was preparing her kids for school in the morning. An electrocardiogram reveals anteroseptal MI with ST-segment elevations in leads V1–V4 and reciprocal depressions in leads II, III, and aVF.
The patient is immediately taken to the cath lab, where she has a finding of spontaneous distal left-main dissection extending into the left anterior descending artery with TIMI 3 flow.
After transfer to the hospital’s tertiary care center, the patient becomes free of chest pain on a 10-μg/minute nitroglycerin drip, from which she is then weaned in a few hours. ECG shows a >50% reduction in ST-segment changes. The patient is monitored in the CCU. Echocardiography reveals a normal LV ejection fraction with no wall-motion abnormalities.
1. What management approach would you choose for this pregnant woman?
2. Which antiplatelet/anticoagulation strategies should be used?
3. What is the most appropriate revascularization strategy? When should it be initiated?
4. How should delivery of the child be conducted?
September 22, 2014
1. Coronary dissections are generally best managed conservatively. They generally heal with anticoagulation strategies. PCI is often complicated by trying to identify and wire the true lumen; complications are common (see the ACCF/AHA PCI guidelines).
2. I would consider using heparin and a short-acting glycoprotein IIb/IIIa antagonist in order to facilitate delivery.
3. As noted, coronary dissections are best managed conservatively, given the difficulties in identifying the true lumen with either by PCI or surgery.
4. I would consider a cesarean delivery to control the hemodynamic situation of the mother. Direct surgical management of the wound allows for careful use of anticoagulants and antiplatelet agents.
It is also important to screen this woman for fibromuscular dysplasia. Other conditions in the differential diagnosis include Ehlers–Danlos syndrome, giant-cell arteritis, Takayasu’s arteritis, and other true connective-tissue disorders.
September 8th, 2014
Selections from Richard Lehman’s Literature Review: September 8th
Richard Lehman, BM, BCh, MRCGP
CardioExchange is pleased to reprint this selection from Dr. Richard Lehman’s weekly journal review blog at BMJ.com. Selected summaries are relevant to our audience, but we encourage members to engage with the entire blog.
NEJM 4 Sep 2014 Vol 371
Sham Controls in Medical Device Trials (pg. 892): A terrific piece by Rita Redberg discusses sham controls in medical device trials. Whenever sham procedures are used in the control arms of such trials (or in surgical trials generally) they reveal a huge placebo effect. For example, renal denervation therapy produced huge sustained falls in recorded blood pressure in unblinded, uncontrolled trials in people with “resistant hypertension”. But when it was tested in a properly blinded trial using a sham control, it failed to detect enough difference to satisfy its primary end-point. She goes on to point out that percutaneous coronary intervention has never been tested against sham PCI. I’ve just learnt to my amazement that Darrel Francis at Imperial College is planning a trial to do just this in people with angina and single-vessel disease, and it’s still open to extra UK investigators on http://clinicaltrials.gov/ct2/show/NCT02062593.
Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure (OL): And now, alas, to the much-vaunted PARADIGM-HF trial. This has been hyped as the biggest breakthrough in heart failure for at least 20 years. A fixed dose of enalapril was compared with a substance called LCZ696. This turns out to have been a mixture of valsartan and sacubitril, a neutral endopeptidase inhibitor, and most participants ended up receiving a daily dose of 320mg of valsartan, versus 20mg of enalapril. A total of 711 patients (17.0%) receiving LCZ696 and 835 patients (19.8%) receiving enalapril died after a median follow-up of 27 months, at which point the trial was stopped prematurely. So just what are we looking at here? How can we distinguish the effect of the sacubitril from the effect of the high dose of valsartan? Well, we can’t. And this trial is a perfect example of everything that is wrong with heart failure trials. The mean age of the 8442 patients was 63.8, nearly 80% were male, and they were selected by reduced ejection fraction in 1043 centres across 47 countries. A logistic nightmare, but a great way for Novartis to spread influence. And Novartis then collected, managed and analyzed all the data itself. As I have said, a submaximal dose of one drug was compared with a maximal dose of another plus an extra ingredient. There was a run-in period, in which patients who were intolerant to the new treatment (12%) dropped out. Adding bias to bias, the trial was terminated prematurely. One of the primary end-points was hospitalization, which was ably demolished in a JAMA article I pointed out last week. And yes, there was a mortality benefit, but the number-needed-to-treat was about 35 to prevent one death in 2 and half years, in a population far removed from the elderly co-morbid patients we see in real life. As I draw to the end of a clinical career in which I’ve tried to help people with heart failure, I stand bemused. This is just how things have been done for the last 30 years, and it’s not good enough. At the very least, Novartis must make its full data set available for independent analysis. And before sacubitril is licensed, we need a properly designed trial, say between valsartan 160mg b.d. alone and valsartan plus sacubitril, in a typical population with heart failure. It will be very interesting to see what the FDA, the EMA and NICE decide.
JAMA 3 Sep 2014 Vol 312
Comparison of Weight Loss Among Named Diet Programs in Overweight and Obese Adults (pg. 923): Never mind the diet: just consume less. Boring as this is, it’s always the message where weight loss is concerned. The best diet for you is the one you can stick to, says this meta-analysis of named diet programmes for overweight and obese adults. For most people, this seems to be a low-carbohydrate diet. It usually carries the name of Atkins, though plenty of others got there before him.
JAMA Intern Med Sep 2014
Hypoglycemia After Antimicrobial Drug Prescription for Older Patients Using Sulfonylureas (OL): Hypoglycaemia has overtaken hyperglycaemia as a cause for admission in people with diabetes, and sulfonylureas are the commonest oral agents responsible. What we often forget in the hurly-burly of clinical practice is that certain antibiotics are known to potentiate the glucose-lowering effect of sulfonylureas. According to this survey of Medicare claims in Texas, the antibiotic most likely to do this is clarithromycin, with a number needed to harm of 71, followed by levofloxacin, sulfamethoxazole-trimethoprim, metronidazole and ciprofloxacin. Not particularly common then, especially as the first three antibiotics are not usually first-line choices in the UK. There is an excellent commentary by Kasia Lipska on the wider issues.
Lancet 6 Sep 2014 Vol 384
Efficacy of β Blockers in Patients with HF plus AF (OL): The trials which established the role of beta-blockers in systolic heart failure came up with some surprising subgroup results, one of which was that the mortality benefit of ß-blockade did not seem to extend to patients with atrial fibrillation and reduced systolic ejection fraction. On the face of it, you would expect them to benefit most. I have already hinted at the deficiencies of these trials, which were dominated by younger male patients without major comorbidity, but we’ll let that go and congratulate the authors of this paper for coming together and performing an individual patient data meta-analysis based on the randomized trials. A clear message emerges: people with AF do not experience the benefits which people in sinus rhythm derive from taking ß-blockers for heart failure. I hope this message filters out to heart failure nurses as well as cardiologists.
BMJ 6 Sep 2014 Vol 349
Perioperative β Blockade: Guidelines Do Not Reflect the Problems with the Evidence from the DECREASE Trials: In a superb analysis by Graham Cole and Darrel Francis, we’re taken through the sorry story of how perioperative beta-blockade for high risk patients became accepted practice due to the DECREASE trials, which have since been shown to contain internal inconsistencies and unverifiable data. If you meta-analyze all the other trials they show convincing evidence of harm. Now the specialist cardiology societies of Europe and the USA have come up with a shared August 2014 guideline in which they claim to have excluded the DECREASE data, but still come up with a positive recommendation. In fact they have been misled by including meta-analyses which still included the DECREASE results. It’s a story that certainly decreases one’s confidence in the credibility of specialist society guidelines. As Larry Husten has said, guidelines should follow the same rules as declarations of war: only to be issued when there is absolute agreement and an urgent need.
September 5th, 2014
Perspectives on PARADIGM-HF
CardioExchange Editors, Staff
The post titled “Let’s Take a Close Look at PARADIGM-HF” generated a lot of discussion. We present that discussion here in a separate post (edited to better showcase the substantive points of members who offered their insightful comments).
Felix Valencia, MD, PhD Almeria, Spain
A key issue in PARADIGM-HF is blood pressure control as a determinant of outcomes. Treatment with LCZ696 was associated with lower blood pressure and more symptomatic hypotension. Patients who were less sick seem to derive greater benefit in the trial, as suggested by the subgroup analyses by age, NYHA class, prior hospitalization for heart failure, and prior treatment with aldosterone antagonists. These HF patients would have better BP at randomization and greater potential benefit of lowering BP from LCZ696. The significant interaction between treatment effect and NYHA class was in the primary outcome but not in death, so the main interaction was in hospitalization, an endpoint very sensitive to appropriate BP control. We hope that we have a new drug that may help our HF patients to live better and longer. But before accepting that, I think that the role of BP difference in outcomes should be completely clarified.
Milton Packer, MD Dallas, TX
1. Drug Dosing
Dr. Prasad proposes that the dose of enalapril was too low, and we should have used 40 mg daily of enalapril as a comparator. However, when 40 mg of enalapril daily has been used in a clinical trial (CONSENSUS), these extremely high doses were poorly tolerated due to hypotension and renal insufficiency. As a result, even though the target dose may have been 40 mg daily, the actual dose achieved in the CONSENSUS trial was 18.4 mg. However, in the PARADIGM-HF trial, the average dose of enalapril achieved was 18.9 mg. Therefore, the dose of enalapril used as the comparator in the PARADIGM-HF trial was the highest dose of the drug ever used in a clinical trial of heart failure.
There is no evidence that valsaratan 160 mg BID produces more blockade of the renin-angiotensin system than enalapril 10 mg BID. In fact, valsartan 160 mg BID does not even have a mortality effect when compared with placebo, whereas enalapril 10 mg BID does have a survival benefit.
Dr. Prasad contends that the neprilysin inhibitor could have been a placebo, and the difference between treatments was due to more blockade of the renin-angiotensin system in the LCZ696 group. However, more angiotensin blockade would have led to more renal dysfunction and more hyperkalemia, but the LCZ696 had less renal dysfunction and less hyperkalemia.
2. Drug Run-In Periods
Drug run-in periods are not a controversial study-design choice. In fact, this type of design is strongly preferred because it closely mimics clinical practice. In clinical practice, patients who do not tolerate a drug are not maintained on it, and that is the intent of the run-in period. Indeed, the FDA strongly supported our decision to have a double-drug run-in period because it would enhance the credibility of the trial.
3. Stopping What Already Works
As to the claim that it makes little sense to stop a drug that is working to enter a trial, I would ask “How does one conclude that the patients’ prior use of an ACE inhibitor or ARB was “working”? And how effective could ACE inhibitors have been if — when patients were given enalapril 10 mg BID (a dose higher than what most were receiving before entering the trial) — the patients in the PARADIGM-HF trial died earlier, were hospitalized more frequently, and had a worse quality of life?
The real lesson of PARADIGM-HF is that combined angiotensin receptor neprilsyin inhibition is superior to inhibition of the renin-angiotensin system alone in patients with chronic heart failure. That is the conclusion of our paper, which passes stringent peer review in The New England Journal of Medicine.
Vinay Prasad, MD MPH Rockville, MD
The VAL-HeFT trial — where valsartan 160 BID was no better than placebo — occurred in a setting where 92% of patients were already on an ACE inhibitor. As such, it cannot be used to say what the effect of valsartan is among patients not taking an ACE inhibitor, as was the case in PARADIGM-HF.
CONSENSUS shows a benefit for enalapril when doctors attempt to titrate the dose up to 40 mg. The protocol for PARADIGM does not ask providers to replicate this drug goal, settling for 20 mg.
I believe the persistent difference in BP makes the case that the dose matters, particularly as neprilysin inhibition is thought not to confer much BP effect by itself. I think it is dangerous to draw too many conclusions from the rates of hyperkalemia and renal dysfunction, particularly because there is a drug run-in period that may mitigate some of these adverse events. I wonder why the run-in period was twice as long for the study drug than enalapril. The role of drug run-in periods has a vast literature. In this case, it was not necessary, and I am not convinced it was a good design simply because the FDA has said they will accept it.
The bottom line: If sacubutil really adds something to ARB therapy, why not conduct a clean trial of randomizing patients already on an ARB to sacubutil or placebo?
Dismissing the evidence from Val-HeFT eliminates all of the evidence that supports the use of valsartan in heart failure. With Val-HeFT set aside, what evidence is there that valsartan 160 mg BID does anything for patients with heart failure? Second, it is not the dose you plan to achieve that matters; it is the dose you actually achieve. One can design a trial with enalapril with a target dose of even 80 or 200 mg daily, but it would mean very little, because few patients would ever be able to take it. Even if a trial allowed patients to receive 40, 80 or 200 mg daily, it would not provide any useful information about these doses. Third, should we really ignore the differences in the rates of hyperkalemia and renal dysfunction between the two treatments over a period of 27 months, simply because patients had to be able to tolerate both drugs for a few weeks?
My argument about VAL-HeFT, valsartan, and dosing is that it is very possible that the difference observed in PARADIGM-HF was because valsartan was given at 320 mg and enalapril was given at 20 mg. There is no study where these two drugs were compared at these doses to say for sure that they perform similarly.
Pointing out that enalapril had a mortality benefit over placebo in RCT, but that valsartan did not — and, therefore, enalapril by itself is better — is a misleading argument. Enalapril is surely better than not taking an ACE inhibitor, but I disagree that valsartan has no effect by itself. The trial in which it did the same as placebo was one in which most patients were already on an ACE inhibitor. As we know from the ONTARGET trial, the combination of ARB and ACE adds toxicity, but no benefit. I think most doctors believe that taking valsartan is better than not taking either an ACE inhibitor or an ARB, as made clear by the fact that 397 patients were taking valsartan at the screening visit (see PARADIGM-HF’s supplementary appendix).
Now the question becomes: Do we know, with any degree of certainty, who would win in a head-to-head comparison of valsartan 320 mg and enalapril 20 mg? I, and many others, think we don’t know for sure. PARADIGM-HF’s protocol does not attempt to push the dose of enalapril to 40 mg. This is unbalanced.
There is a common misunderstanding that drug run-in periods better reflect the “real” world of clinical practice. They do not. Here is why: Let’s say 4 drugs (A. B, C, and D) are used fairly interchangeably for a medical condition. Let’s also say that Drug A and B are used more often than C and D. A clinician wants to know – maybe she suspects – that Drug B is better than Drug A. How do you test this question to mirror real-world practice? You randomize patients to start with Drug B or Drug A, and allow patients in both arms to switch to other drugs in the class, per investigator discretion, if they are intolerant. Then you look at the intention-to-treat analysis to see which arm does better. This tests the relevant clinical question: If I start with Drug B, do I save lives?
Instead, here is how a run-in period trial would test the question: All patients take Drug A for a couple weeks. Intolerant patients withdraw from the trial. All patients then take Drug B for a few weeks. More patients withdraw. Whoever remains is randomized to Drug A or Drug B, and then you do more or less the same from that point.
One might think that the second scenario (drug run-in) is the same as the first, but more efficient. Unfortunately, it isn’t. It is testing this clinical question: Is it better to stick with Drug B, if you have taken and tolerated A and B, or switch back to A? For many reasons, this is not the same clinical question — and a clinical question that does not mimic real-world practice. Moreover, we have no way to advise (or identify) the people who dropped out.
It’s still not clear why the PARADIGM-HF run-in period was twice as long for LCZ696. More important, why not randomize patients with HF who are already on an ARB to sacubutil or placebo? A good HF trial is not necessarily one that is positive, but one that picks a single clinical question and answers it. PARADIGM-HF may be positive, but it does not answer the clinical question of whether sacubutil does anything.
If the claim that valsartan 320 mg daily may be more effective than enalapril 20 mg daily in preventing cardiovascular death in patients with heart failure were true, the results from PARADIGM-HF could be entirely due to valsartan’s superiority over enalapril rather than an incremental contribution of neprilysin inhibition. Such a proposal is at best quite imaginative; it is shared by no one in the cardiovascular field. Adequately powered head-to-head comparator studies have shown a variety of ARBs at a variety of doses (including valsartan 320 mg daily) to be no better than an ACE inhibitor and generally somewhat inferior to an ACE inhibitor. Therefore, the suggestion that the results of PARADIGM-HF are explicable by the superiority of valsartan alone is at odds with the totality of available evidence.
We have used run-in periods in many heart failure trials, and it was used in the SOLVD Treatment Trial, which originally showed the survival effects of enalapril. If trials with run-in periods were inherently flawed, no trials would use them.
As to the idea that we should have designed the trial as a comparison of valsartan in one arm and valsartan plus a neprilyin inhibitor in the other arm, most patients with heart failure are not taking an ARB, and those receiving valsartan are generally taking a dose less than 320 mg daily. Such a trial would apply to fewer than 10% of patients with chronic heart failure and therefore would have little practical value.
As a general rule, when you develop a new drug, it is a good idea to conduct a trial that keeps everything else the same, except for the addition of the novel drug. PARADIGM-HF does not follow this model and, as such, will always be open to interpretation and hard questions.
The facts are: Valsartan was escalated to 320 mg, whereas enalapril was given at 20 mg (and not pushed to 40 mg). Blood pressure was different between arms, favoring the ARB. These were predominately patients with NYHA class I and II HF, so the enalapril dose could likely have been pushed to 40 mg to make the comparison fair. In any case, the protocol could have called for it. Unfortunately, the protocol did not ask providers to do this, while using the maximum HF dose of valsartan.
Readers can decide if 320 mg of valsartan versus 20 mg of enalapril is fair. Consider this trial on the safety and efficacy of valsartan versus enalapril in heart failure.
CONSENSUS enrolled only NYHA class IV patients, while these were fewer than 1% of patients in PARADIGM-HF. Many patients in PARADIGM-HF might well have been able to tolerate and benefit from enalapril 40 mg. Perhaps that would have resulted in similar BP between arms.
I want to see a study of whether sacubutil does anything by itself. This is typically the sort of study done when a novel agent seeks regulatory approval.
The fact that many (and often industry sponsored) studies use drug run-in periods is not a justification for their use.
I would not approve a drug lacking a fundamental demonstration of efficacy with a legitimate control arm. But I can be convinced that sacubutil is a good drug. In fact, I hope it is, for the sake of our patients. However, PARADIGM-HF is not the trial that should convince the regulators.
It appears that Dr. Prasad and I agree that the PARADIGM-HF trial demonstrates that LCZ696 is superior to enalapril 10 mg BID. The major point of our disagreement is why this was so. My coauthors and I attribute the superiority to neprilysin inhibition. If the superiority were due solely to the dose of valsartan that we used, we would have seen more adverse effects related to inhibition of the renin-angiotensin system in the LCZ696 group than in the enalapril group, not fewer.
David Powell, MD, FACC Springfield, NJ
Valsartan alone (without ACEI) to my knowledge has a minimal evidence base for chronic CHF (as opposed to post-MI). A small subgroup of ValHeFT is all we have (and this was limited to ACEI-intolerant patients). Combined ACEI/ARB has more side effects and negative data from ONTARGET. And spironolactone has an excellent evidence base, excluding my use of ACEI/ARB combination.
The run-in mimics real life with one exception: Patients needed to tolerate ACEI to be enrolled. But is there any reason to think that ACEI intolerance would negate the benefit of ARB/neprilysin inhibitor? Certainly not the ARB benefit. Do patients with ACEI intolerance (mostly cough) have higher levels of bradykinin or other neurohormones that offset the benefit of neprilysin inhibition? I don’t know, but unless convincingly shown, it wouldn’t affect my usage of the new drug. So the tolerance of the new drug tips the scale even further in favor.
I have a reservation about African Americans with respect to angioedema risk. Is this an issue? Is there a way to predict angioedema risk (bradykinin levels)? Is the African American subgroup large enough for safety?
Sure, we should have had a good ACEI vs. ARB trial. I am not certain why we didn’t. But now we have one thing that is better than enalapril with fewer side effects. I think an ARB vs. ARB/neprilysin inhibitor trial would have to be confined to ACEI-intolerant patients.
Harsh Golwala, MD Louisville, OK
I am wondering is there any reason to compare ARB+sacubutil vs. ACE inhibitor — instead of ARB+ sacubutil vs. ARB (with ARB in equivalent doses in both the groups) or ACE inhibitor + sacubutil vs. ACE inhibitor alone (again with ACE inhibitor in equivalent doses). In the end, we all know that enalapril trumps everything, as it has been studied and has shown a mortality benefit in HFrEF patients. So if LCZ696 trumps enalapril (either due to higher dose of valsartan in itself or due to addition of newer drug or combination of both), LCZ696 will be the frontline treatment in the near future.
Enrique Guadiana, MD Monterrey, Mexico
There is no such thing as a perfect trial. Every answer raises new questions. Only for the investor the True is absolute. We are physicians, and we don’t work with absolutes. The results of this study are very interesting — it could be a new door. Why the hurry? Respond to the new inquiries and advance medicine. Remember we are physicians, not investors. I echo all the questions my colleagues have and will wait for the answers.
Westby G Fisher, MD Evanston, IL
Drs. Prasad and Packer both make excellent points. Dr. Prasad’s concerns (which I share) have been made more relevant by our experience with Zetia (another combination drug) that was marketed with much fanfare, only to be later shown to have little benefit over simvastatin alone.
By the way, I’m an EP, not a CHF specialist — but I know enough to understand the incredible influence of media on perceptions of a trial, and the gushingly positive spin this trial has received without critical challenge to stock market and drug pricing. (Cynical, I know, but when every cardiovascular news organization is in bed with pharma these days to assure their survival, we are appropriately cautious.) Time will tell who’s right here, but one thing social media has provided is an educational forum to get these real concerns of this trials design aired and rebutted quickly.
I applaud both Dr. Prasad and Packer’s bravery to discuss their respective perspectives openly and I hope they each understand the value of their discussion to those of us on the (real) front lines of heart failure care.
Larry Husten, PhD New York, NY
Wes, I don’t understand the comparison with Zetia. First of all, this was a drug that got on the market (and was indeed heavily marketed) with absolutely no outcomes data. It was approved on the basis of a surrogate endpoint. LCZ696 isn’t on the market yet, and there has been zero marketing so far — yet it already has more outcomes data than 99% of all the approved drugs.
While I am not a CHF trial expert, neprilysin inhibitors are a new class of drug for the treatment of CHF (and it would seem a fairly narrow CHF population at that). While the PARADIGM-HF results are impressive, the question remains: How much of the CHF improvement was due to the new class of drug vs. its co-drug? While the number of patients studied was impressive, it is unfortunate that we really can’t see how much effect this new class of drug has on HF treatment. Instead, the investigators chose to study the med against an entirely different class of drug (albeit one that’s effective in CHF rx) for the reasons Dr. Packer explains. I think more skeptical types (like me) would like to know what additional value a drug like this adds to our HF treatment options, since this drug is likely to be very expensive.
Increasingly, the cost of any new drug must be weighed against its clinical benefit since our patients are absorbing more and more drug costs themselves. Gone are the days where we can freely jump from one drug to the other without directly determining a drug’s benefits to our patients. It would seem to me that the “value” of such a new drug should be demonstrated before we abandon old therapies that have stood the test of time (like enalapril) for new ones.
Please add your comments to this discussion!
September 3rd, 2014
FAME 2 at 2 Years: Better with Time?
CardioExchange Editors, Staff
Two years ago at the ESC meeting in Munich, initial findings from the FAME 2 randomized trial, which was stopped early for apparent benefit, were presented and simultaneously published in the New England Journal of Medicine. In a blog for CardioExchange, Rick Lange and David Hillis posed 7 concerns about the trial and asked, “Should we be performing PCI in all stable CAD patients who have abnormal FFR?”
Now, the FAME 2 investigators have presented and published their 2-year findings:
PCI + Medical Therapy
Medical Therapy Alone
|Composite of death, MI, or urgent revascularization||
The numbers have changed, but the between-group differences are largely the same.
Asked to comment, Hillis responded:
It is interesting that FFR-driven PCI reduced only the need for urgent revascularization, not the other components of the combined primary end-point. One could argue that this is not terribly surprising, since these flow-limiting stenoses will probably be more likely than less severe ones to cause limiting symptoms that do not respond adequately to medical therapy, thereby requiring revascularization.
What do you think? Are the 2-year findings more convincing than the 7-month findings?
To view all of our coverage from the ESC meeting, go to our ESC.14 Headquarters page.
September 2nd, 2014
Low-Carb Diet Linked to Greater Weight Loss Than Low-Fat Diet
A low-carbohydrate diet is associated with greater weight reduction than a low-fat diet among obese adults, according to an Annals of Internal Medicine study.
Roughly 150 obese adults who were otherwise healthy were randomized to eat either a low-fat (<30% fat) or low-carbohydrate (<40 g/day of digestible carbohydrates) diet. Participants were provided diet-specific handbooks with recipes and meal-planning tips in addition to a daily meal-replacement shake or bar.
At 12 months, the low-carb group had lost 3.5 kilograms more than the low-fat group, even though caloric intakes were similar. The low-carb group also saw greater improvements in body composition, CRP levels, HDL cholesterol, and triglycerides.
NEJM Journal Watch Cardiology editor-in-chief Harlan Krumholz comments: “This study, a welcome trial in an area where we need them, supports the new conventional wisdom that low carb is better than low fat for losing weight — what we do not yet know is which diet is better for lowering risk. That information will require larger trials with much longer follow-up — but we desperately need that information.”
Background: NEJM Journal Watch Cardiology summary on long-term consequences of low-carb diet
September 2nd, 2014
Fractional Flow Reserve Gains Support in Stable CAD and NSTEMI
Larry Husten, PHD
Two studies presented at the European Society of Cardiology meeting in Barcelona offered fresh support for fractional flow reserve (FFR), which has been slowly but surely gaining traction in the interventional cardiology community.
FFR in Patients with Stable CAD
Bernard De Bruyne presented 2-year results from the FAME 2 (Fractional flow reserve versus Angiography for Multivessel Evaluation 2) study (simultaneously published in the New England Journal of Medicine). FAME 2 was designed to find out whether PCI, with the help of FFR, can reduce the rate of hard endpoints in stable coronary artery disease (CAD) compared to medical therapy.
A total of 1220 patients with stable CAD underwent angiography with FFR. Of the group, 27% had no ischemic lesions on FFR (>0.80 pressure gradient) and were entered in a separate registry. Seventy-three percent had at least one stenosis with a pressure gradient of 0.80 or under and were randomized to PCI and medical therapy or medical therapy alone.
At two years the rate of the composite of death, nonfatal MI, or urgent revascularization was 8.1% in the PCI group compared with 19.5% in the medical therapy group (HR 0.39, CI 0.26-0.57, p<0.001). There were no significant differences in the rates of death and MI but the difference in urgent revascularization was large and highly significant (4% versus 16.3%, HR 0.23, CI 0.14-0.38, p<0.001).
After the first week, according to a landmark analysis, the rate of death and MI was significantly lower in the PCI group: 4.6% versus 8% (p=0.04). The investigators said that most MIs in the first week were likely related to procedures and were clinically unimportant, while events later on were more likely to be clinically significant.
FFR in Patients with NSTEMI
Although FFR has been gradually creating a role for itself in the catheterization lab, its use in acute coronary syndromes has not been previously studied. Results of FAMOUS NSTEMI (presented by Colin Berry and published simultaneously in the European Heart Journal) offer the first evidence in support of its use in this population.
A total of 350 NSTEMI patients referred for coronary angiography with at least one stenosis amenable to revascularization were randomized to receive treatment based on FFR or standard care with conventional visual assessment of stenosis severity. Twenty-two percent of patients in the FFR group changed treatment as a result of the FFR results. A total of 22.7% of FFR-guided patients and 13.2% of standard care patients received medical therapy alone. At one year 79% of patients in the FFR group and 86.8% of patients in the standard care group had been revascularized (p=0.054). There were two cases of coronary artery dissection that were attributed to the pressure wire.
Overall hospitals costs were about the same in each group. There was a trend toward more procedural MIs in the standard care group while other major adverse cardiac events that were not related to procedures appeared to occur more frequently in the FFR group. “Compared with the angiography-guided group, the increased adoption of medical therapy at the expense of revascularization in the FFR disclosure group was associated with similar overall health outcomes and quality of life at 1 year. Representing a balance of competing risks, the reduction in procedure-related MI events in the FFR group should be considered against the increase in spontaneous cardiac events during the follow-up.”
In an accompanying editorial, Bernard De Bruyne and Julien Adjedj write that “the message of the FAMOUS trial goes beyond the simple ‘less is more’. The data suggest a pivotal role of the cath lab in ACS, provided the procedure is comprehensive and of good quality… This approach provides all the elements for a complete diagnosis, optimal treatment, and thorough risk stratification. Moreover, this one-stop-shop renders the non-invasive diagnostic work-up largely obsolete.”
Commenting on the studies, Mark Creager, a cardiologist at the Brigham and Women’s Hospital and the president-elect oaf the American Heart Association, said that the studies help move the dial toward increased use of FFR in the cath lab, but they don’t provide an endorsement for universal usage of the technology. He emphasized the importance of clinical judgement in deciding whether patients with stable angina need to go to the cath lab. “Just as COURAGE doesn’t mean that no one with stable angina should get cathed, FAME doesn’t mean that everyone with stable angina should be cathed,” he said. “We’ve been doing FFR in selective cases in order to help decision analysis when we’re not sure.”
September 1st, 2014
Let’s Take a Close Look at PARADIGM-HF
Vinay Prasad, MD MPH
Many have hailed the novel compound LCZ696 as the next great advance in heart failure (HF) treatment, on the heels of findings from the newly published PARADIGM-HF trial. I think this is too generous an interpretation.
LCZ696 is itself a combination of two drugs: valsartan (an angiotensin-receptor blocker) and sacubutil (an inhibitor of neprilysin). During a median follow-up of 27 months, LCZ696 showed superiority to enalapril with respect to the primary composite endpoint (death from cardiovascular causes and hospitalization for HF) and all-cause mortality — with a number needed to treat of 35. (These findings are likely exaggerated, given that the trial was stopped early, but that is not my primary concern with this study.)
Here are three reasons to doubt that PARADIGM-HF sets a new standard both for treatment of HF and for randomized comparative-effectiveness studies:
1. Drug Dosing
In PARADIGM-HF, oral enalapril was dosed up to 10 mg twice daily, whereas LCZ696 was dosed up to 200 mg twice daily (which includes a cumulative 320 mg of valsartan). The problem is that 320 mg is the maximum HF dose of valsartan per drug labeling, but enalapril can be dosed up to 40 mg daily (20 mg twice daily) — double the maximum dose proscribed per protocol.
The actual administered mean dose of the two drugs was 375±71 mg for LCZ696 and 18.9±3.4 mg for enalapril. Not surprisingly, given that the LCZ696 group received more angiotensin-pathway blockade, mean systolic blood pressure was lower in that group (3.2±0.4 mm Hg lower than in the enalapril group).
In effect, drug dosing in PARADIGM-HF was a “straw man” comparison. The reported outcomes may be entirely a consequence of more ARB versus less ACE inhibitor. That is reason enough to doubt the findings. Sacubutil, the novel drug, could have been a sugar pill, and the results may well have turned out the same. But there are two more good reasons to be skeptical.
2. Drug Run-In Periods
Drug run-in periods are a controversial study-design choice — one that I believe must unequivocally be abandoned. In PARADIGM HF, patients with systolic HF were asked to stop the ACE inhibitor or ARB they were already on and take oral enalapril 10 mg twice daily for 2 weeks. Of the 10,513 patients who entered the run-in phase, 1102 (10.5%) discontinued treatment at this point. Then the remaining 9412 patients took LCZ696 for more than twice as long (4 to 6 weeks), during which 977 (10.4%) patients discontinued treatment and 8442 underwent randomization.
The reason why drug run-in periods are problematic is discussed at length in the literature. In short, run-in periods exclude intolerant and nonadherent patients, foster spuriously large treatment effects, and (most troubling) create inclusion criteria that are irreproducible — i.e., that apply to no population we can clearly describe, as reasons for dropout are multifaceted and unique.
Even more concerning is that drug run-in periods test a different question than the one we think we are testing. In PARADIGM-HF, the run-in tested whether sticking with LCZ696 or switching to enalapril is better for HF patients who have taken and tolerated enalapril followed by LCZ696. It effectively turns the trial into a withdrawal study. If stopping LCZ696 is harmful, that counts against enalapril.
3. Stopping What Already Works
All PARADIGM-HF participants were already on an ACE inhibitor and an ARB, the standard of care for systolic dysfunction supported by several randomized trials — and they were asked to stop. Those of us who care for HF patients know quite well that there often is a very good reason why patients end up taking the ACE or ARB they are currently using. It makes little sense to stop what is working to enter this trial.
Here are some better options for how PARADIGM-HF could have been conducted:
- Option A: Compare the novel combo drug with valsartan alone (same dose of valsartan) among patients with newly diagnosed HF.
- Option B: Test sacubutil (the novel drug) against placebo as add-on therapy for patients with HF who are already on an ARB. This is the cleanest option.
- Option C: Randomize patients with HF to either continue their current therapy (and ramp up the dose to the maximal drug-label dose) or switch to the combination drug.
The Real Lesson of PARADIGM-HF
The response to PARADIGM-HF has been positive partly because it has been a long time any new drug has been shown to improve mortality in patients with HF. But our desire to find better options for these patients does not mean we should lower the standards for what counts as a good trial. Few providers would consider a randomized trial comparing valsartan at 320 mg with enalapril at 20 mg to be fair — and adding a novel drug to the valsartan does not make this comparison more palatable. Instead, PARADIGM HF shows that with a large number of patients and the “right” trial design, you can get any conclusion you want. As William Randolph Hearst said, “You furnish the pictures, and I’ll furnish the war.”
PARADIGM-HF does convince me that more angiotensin-pathway blockade is better, but it does not prove the benefit of a novel drug. A history of negative HF trials should teach us that the pretest probability that a novel drug works is very low in HF. The data from PARADIGM-HF do not greatly alter the probability that the drug works.
The concerns I have highlighted cannot be remedied, even with full access to the study data (which should nevertheless be made available) — instead, they are hard-wired into the trial design. For that reason, we must ask for another randomized trial — one that is truly done right. Heart failure patients deserve no less.
From the editors:
This post generated a lot of discussion. To facilitate reader navigation of the many issues addressed, we are presenting that discussion in a separate post (edited to better showcase the substantive points of members who offered their insightful comments). We hope you will help to continue this important conversation.
To view all of our coverage from the ESC meeting, go to our ESC.14 Headquarters page.