September 5th, 2014
Perspectives on PARADIGM-HF
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!