GLG News by Joseph Franciosa, MD

Implications: Implications: • The clinical trial experience with combination Altace plus hydrochlorothiazide (HCT) indicates safety and efficacy satisfactory for FDA approval. • The combination of ACE inhibitor and thiazide is old and ho-hum, and not as novel as newer combinations like Exforge (Novartis). • The long track record and presumed lower cost of Altace plus HCT could enable this product from King to compete satisfactorily against the more novel combinations of big Pharma. • Given that combination products may be more acceptable by current hypertension treatment guidelines, look for more such products to appear, with the novel ones from big Pharma and the traditional ones from smaller companies. • The hypertension market is still huge, growing, and in need of new treatment options.

Analysis: This article reports the results of a rather conventional clinical trial that compared the effects of a combination of the ACE inhibitor ramipril (Altace, King Pharmaceuticals) plus a low dose (25 mg) of hydrochlorothiazide (HCT) to either component alone as treatment for hypertension. The combination was more effective than either component alone, and a single dose was effective for 24 hrs. The results easily satisfy FDA requirements for approval of a combination antihypertensive agent.

The combination of ACE inhibitor with HCT is not new and almost always produces effects superior to either agent alone. Thus, the present results are not surprising and should obtain FDA approval for the drug. Virtually every old ACE inhibitor has been used effectively with HCT, so there’s nothing new here. Unlike Exforge (Novartis), which is a novel combination that combines an ARB with a calcium blocker, Altace plus HCT is “same old, same old”, just ho-hum. It is difficult to see this combination competing very successfully against the more novel combinations supported by the marketing clout of big Pharma. On the other hand, for a company of King’s size, this may be a modestly successful product. It appears that we are seeing more combination products come to market for hypertension, probably reflecting recent guideline suggestions that the majority of patients with hypertension require more than one drug for adequate control. The option of using lower dose drug combinations has become more acceptable than using single drugs in higher doses which may increase the incidence of side effects. Thus, we may see more combinations, with big Pharma introducing the more esoteric and novel ones, while smaller companies use the more traditional, established, and cheaper combinations. The marketplace for hypertension is big enough for all, and will grow given the large number of undetected and/or inadequately treated hypertensive patients.

Implications: Implications: Clinical trial results indicate that Nebivolol is a safe and effective antihypertensive agent.As a vasodilating beta-1 selective beta blocker, Nebivolol could compete successfully against long-acting carvedilol and metoprolol.To compete successfully, Nebivolol will have to gain approval for use in heart failure, for which it is approved outside the U.S. Nebivolol presents both marketing and developmental challenges to Forest, and if they can meet these satisfactorily, Nebivolol also offers a good opportunity in a large market.

Analysis:  

The present article indicates that Nebivolol (Forest Laboratories) is an effective agent for treating hypertension. It appears to work well alone or in combination with other antihypertensive agents and in different subsets of patients. The development program as presented represents a fairly standard one for an antihypertensive agent and appears to demonstrate efficacy without safety concerns. Nebivolol is not really a new concept as it is a beta-blocker with some ancillary properties. Like carvedilol (Coreg, GlaxoSmithKline), it also has vasodilating properties, and, like metoprolol (Toprol, Astra-Zeneca) it is a beta-1 selective agent.

Nebivolol is somewhat unique in that it combines the characteristics of carvedilol and metoprolol into a single long-acting agent. It is really not “new”, being marketed extensively outside the U.S. In the U.S. it should be positioned well to compete with carvedilol and metoprolol. Since it is a once daily drug, it will not be at a disadvantage against long-acting carvedilol and metoprolol in this respect. However, because these other agents are also approved for use in heart failure, it behooves Forest to pursue heart failure as a new indication. Nebivolol is approved for use in heart failure outside the U.S. With the eventual addition of a heart failure indication, Nebivolol should be able to compete well against long-acting carvedilol, which is not beta-1-selective, and against metoprolol, which is not a vasodilator. The opportunity is there for Forest to achieve success with Nebivolol, depending on their marketing initiatives and future development of the drug.

[Note: This author is currently or recently has been a consultant to Forest Laboratories, GlaxoSmithKline, and AstraZeneca in the areas of hypertension and/or heart failure relative to all of the products discussed here]

Implications:  

Implications:

• Evidence suggests that statins produce potentially beneficial actions in heart failure, independent of lipid lowering.
• Clinical trials of statins in heart failure (independent of cholesterol levels) have been called for.
• Rosuvastatin (Crestor, AstraZeneca) failed to show any beneficial effects on cardiac remodeling, i.e., cardiac structure, function, or size.
• These results are discouraging as without favorably affecting cardiac remodeling, beneficial effects on clinical outcomes are less likely.
• Further large trials focusing on clinical outcomes are needed, but initial optimism is diminished.

Analysis:

Henry Krum MBBS, PhD, FRACP, Emma Ashton BSc, PhD, Christopher Reid BA, MSc, PhD, Victor Kalff MBBS, FRACP, Jim Rogers MBBS, FRACP, John Amarena MBBS, FRACP, Bhuwan Singh MBBS, FRACP and Andrew Tonkin MBBS, MD, FRACP . Double-Blind, Randomized, Placebo-Controlled Study of High-Dose HMG CoA Reductase Inhibitor Therapy on Ventricular Remodeling, Pro-Inflammatory Cytokines and Neurohormonal Parameters in Patients With Chronic Systolic Heart Failure. J Card Fail. 2007 Feb;13(1):1-7

http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WHG-4N5TM58-5&_user=10&_coverDate=02%2F28%2F2007&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=b5ebb421b7f9a8896ea64e2777d47928

Statins reduce mortality in patients with coronary artery disease, but patients with overt heart failure (HF) are often excluded from trials. Because statins possess pharmacologic properties, other than lipid lowering, that may be beneficial on ventricular remodeling in HF, a study of rosuvastatin (ROS - Crestor, AstraZeneca) was carried out in patients with HF and left ventricular ejection fraction (LVEF) <40%.Compared to 46 patients on placebo, 40 patients on ROS experienced a decrease in LDL cholesterol, but there was no significant change in LVEF, cardiac contractility, or heart volume on either treatment, indicating no effect on cardiac remodeling, an important correlate of clinical improvement in HF trials. There were also no effects on symptoms, hospitalizations for HF, or death. The authors concluded that, “despite being safe and effective at decreasing plasma cholesterol, high-dose ROS did not beneficially alter parameters of LV remodeling. Reasons for absence of benefit are uncertain, but may include patient population studied…”

I have been writing in these pages about the potential benefits of statins in heart failure (HF) independent of their cholesterol lowering effect. Most of the supportive data derives from trials of statins in patients with hyperlipidemia and a past history of HF or with risk factors for HF, but usually not with overt HF. Other support comes from animal studies or observational studies. Based on this evidence large randomized clinical trials have been called for. This is the first report of such a trial conducted in patients with symptomatic HF and cardiac dysfunction, and no requirement for hypercholesterolemia. The results are discouraging as the primary endpoint of cardiac remodeling was not altered. Cardiac remodeling indicates adverse changes in cardiac structure, size, and function. Most successful clinical trials (such as beta-blockers or ACE-inhibitors) have shown arrest or reversal of remodeling, which has been associated with improved symptoms and reduced hospitalizations and deaths. Thus, the present results raise concern about the potential for statins to favorably impact clinical outcomes in HF. Further large trials focused on clinical outcomes are needed, but in the meantime, the present results dampen one’s enthusiasm, even mine!

Implications:

• Ximelagatran is the first orally active direct acting thrombin inhibitor.
• It is clearly easier to use and as effective as warfarin, the only other oral antithrombotic agent.
• Because of safety concerns, ximelagatran was not approved and was taken out of development.
• Many patients at risk of thromboses who should receive warfarin do not because of difficulty and risks associated with its use.
• Has this failure to use otherwise indicated warfarin been adequately taken into account in trials comparing it to newer agents?
• Hopefully, lessons were learned in the ximelagatran experience that will make it easier for newer similar agents in the future.

Analysis:

This article confirms what is well known, i.e., that ximelagatran (AstraZeneca), the first orally active direct thrombin inhibitor, is a very effective and good drug. Unfortunately, it was not approved by FDA because of its side effect profile, especially liver toxicity in a small number of patients, and was taken out of development by AstraZeneca. Other direct thrombin inhibitors remain in development, and, hopefully, one of these will eventually be approved. The major advantages of this class of drugs are (1) some can be given orally (unlike heparin or low-molecular weight heparins, e.g. enoxaparin), and (2), they do not require monitoring of blood coagulation (unlike other oral antithrombotic drugs, e.g. warfarin). They do, however, pose a small risk of bleeding complications, as do all antithrombotic agents.

Several clinical trials demonstrated that ximelagatran can be given easily and effectively in a variety of situations associated with risks of thrombotic events like strokes and deep vein thrombosis. Warfarin remains the only antithrombotic agent available for long-term oral use. It is the agent that all new antithrombotic agents are compared to in clinical trials, and such trials confirm the same risks of bleeding with warfarin and the newer agents. What seems to be frequently overlooked in evaluating the relative safety and efficacy of new antithrombotic agents is the difficulty in using warfarin. Patients need to have blood tests regularly to monitor blood coagulation and adjust the dose of warfarin. If under-dosed, there may be lack of efficacy and risk of thrombosis; if overdosed, there is increased risk of bleeding. In addition, many foods and/or drugs interact with warfarin to raise or lower its anticoagulant effect. For these reasons warfarin is difficult to use and many patients who have a clear indication for warfarin do not receive it because of the patient’s unwillingness to take it and/or the physician’s reluctance to prescribe it. Thus, such patients remain at risk for otherwise preventable thrombotic events, and one wonders if this is adequately taken into account when analyzing the results of trials comparing warfarin to direct thrombin inhibitors, like ximelagatran. Hopefully, this will not be the case for new direct thrombin inhibitors that come along, as ximelagatran may have been the “sacrificial lamb.”

NOTE: THIS AUTHOR WAS A CONSULTANT TO ASTRAZENECA IN THE DEVELOPMENT OF XIMELAGATRAN.

Implications:

• Tekturna (Novartis) is the first direct renin inhibitor to be approved by FDA.
• It is unlikely to differ much from angiotensin-converting enzyme inhibitors and angiotensin receptor blockers.
• Thus, Tekturna is not really “new” in terms of its broader class as renin-angiotensin inhibitor.
• Nevertheless, depending on how well it is marketed, Tekturna could be very successful and pose a challenge to other direct renin inhibitors to follow.

 

Analysis:

The first direct renin inhibitor (Tekturna, Novartis) was recently approved for treating hypertension. Blockade of the renin-angiotensin system is accomplished now by angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARBs), both of which act at different points in the system to interfere with renin, a potent vasoconstrictor that raises blood pressure. Direct renin inhibitors block renin earlier in the cascade of events leading to its vasoconstrictor action. Thus, theoretically it might provide a higher degree of blockade of the renin-angiotensin system, just as ARBs theoretically produce more blockade than ACE-I. Although many drugs are available to treat hypertension, there is still an unmet medical need as many hypertensive patients remain undiagnosed and/or inadequately treated. Most patients require multiple drugs to control blood pressure, and it is desirable to use drugs that act through different mechanisms. Thus any agent that involves a new mechanism of action is a welcome addition to the armamentarium. The issue is: what does “new” mean?

This announcement was accompanied by considerable ballyhoo about “first in class”. The key breakthrough involving the renin-angiotensin system was the development of ACE-I, a major advance in treating both hypertension and heart failure. The introduction of ARBs was also accompanied by much ballyhoo since they acted differently from ACE-I. However, that difference has never turned out to be very important in trials comparing the two classes, and ARBs remain just a more expensive alternative to ACE-I. Thus, is Tekturna “déjà vu all over again”? The differences between renin inhibitors and ACE-I or ARBs are also seemingly minor and there is a great likelihood that this “new class” will turn out to be just a minor variant in the broad class of inhibitors of the renin angiotensin system. That is not necessarily bad for the marketers of these newer agents or for patients. Some ARBs have been very successful, depending on the supporting clinical development programs and marketing efforts on their behalf. Similarly, introduction of a new drug for hypertension also helps patients indirectly as the accompanying publicity increases awareness of both patients and physicians about the remaining unmet medical needs in hypertension. Given the past efforts of Novartis, who has successfully marketed both ACE-I and ARB previously, the outlook for Tekturna is promising. It could be impacted, however, by pricing and acceptability by managed care, given the cheaper ACE-I and ARBs. As “first in class”, Tekturna could present a major challenge to other direct renin inhibitors that will surely follow.

Implications:

Implications:

• Statins produce a number of potentially beneficial actions other than lipid lowering that may be important in heart failure.
• There is now evidence suggestive of a survival benefit of statins in patients with HF.
• Clinical trials of statins in heart failure, a large unmet medical need, are apparently underway.
• It appears the pharmaceutical industry is “stepping up to the plate” to explore this major opportunity.

Analysis:

Kiran K. Khush, MD; David D. Waters, MD; Vera Bittner, MD; Prakash C. Deedwania, MD; John J.P. Kastelein, MD; Sandra J. Lewis, MD; Nanette K. Wenger, MD. Effect of High-Dose Atorvastatin on Hospitalizations for Heart Failure. Subgroup Analysis of the Treating to New Targets (TNT) Study. Circulation. 2007;115:576-583

http://circ.ahajournals.org/cgi/reprint/115/5/576

I have been writing in these pages about the multiple potential benefits of statins in conditions other than hyperlipidemia, including heart failure (HF). This study is a subanalysis from the 10,000 patient Treating to New Targets Study (TNT) which compared high dose, 80 mg daily, vs 10 mg daily of atorvastatin (Lipitor, Pfizer) in patients with coronary artery disease. A secondary endpoint of the study was to assess the effects of treatment on hospitalizations for HF, which are relatively common in these patients. Those results are presented in this paper. Overall, hospitalizations for HF occurred in 2.4% of the high dose group vs 3.3% in the low dose group (P=0.116). In patients with a prior history of HF, the results were even more striking, 10.6 vs 17.3%, p=0.009, in favor of the 80mg daily dose group. Blood pressure was not different between the groups and most patients did not experience any coronary events, so the mechanisms of the beneficial effects of high dose atorvastatin are probably not simply due to lipid reduction and an antithrombotic effect. As the authors point out, these results are consistent with numerous earlier reports of potential benefits of statins in HF and prior calls for proper clinical trials to study the role of statins in treating HF. Apparently, such trials are now underway.

As I have pointed out in previous articles, there is ample evidence that statins exert multiple potentially beneficial effects in HF through various mechanisms unrelated to lipid lowering. The potentially large market for HF offers a new opportunity for the statins and the results of the present study provide the first bit of evidence of a potential survival benefit of statins in HF. It appears that the manufacturers of statins have begun to develop this possible new big indication.

Implications:

- 90% of hospitalizations for acutely decompensated heart failure (ADHF) are due to fluid overload.
- Intravenous diuretics and occasionally other agents (e.g. Natrecor) are effective in most patients.
- However, many patients are unresponsive to these other therapies.
- Diuretics and other agents (e.g., Natrecor) may cause renal deterioration and even death.
- Alternative treatments are needed.
- Ultrafiltration appears as safe and effective as diuretics in ADHF.
- Ultrafiltration may even be cost-effective by reducing subsequent rehospitalizations.
- Ultrafiltration offers a promising new alternative to diuretics, but further studies are needed.

Analysis: This study compared ultrafiltration (using the Aquadex System 100, from CHF Solutions of Minneapolis, MN) to standard intravenous (IV) diuretic treatment in 200 patients hospitalized for acutely decompensated heart failure (ADHF) with volume overload. The primary endpoints were change in symptoms and weight loss. After 48 hours, patients on ultrafiltration lost significantly more weight (5.0 vs. 3.1 kg) and more fluids (4.6 vs. 3.1 liters) than those on IV diuretics (both p<0.001). Though symptoms were not different after 48 hours, after 90 days fewer patients treated with ultrafiltration were rehospitalized for HF (18% vs. 32%, p<0.037). There were no significant differences in renal function or number of deaths. The authors conclude that ultrafiltration can safely remove fluids and prevent costly hospital readmissions, and that this offers an alternative approach for patients with ADHF.

It is estimated that there are 1 million hospitalizations annually for HF in the US, and 90% of these are due to ADHF with fluid overload. These patients are almost always treated with IV diuretics and often receive other parenteral agents. Although the majority of these patients respond well with prompt loss of fluids and improvement in symptoms, many are refractory to these treatments. In addition, diuretics may cause renal deterioration, serious electrolyte imbalance, and even death, which the other therapies may also do (e.g., Natrecor). Also, there is no conclusive evidence that they impact outcomes after hospital discharge. Thus, the present results are encouraging as they suggest that ultrafiltration may be a safe and effective alternative to IV diuretics. It is also possible that ultrafiltration may reduce readmissions, the major contributor to healthcare costs in HF. This latter observation, however, requires confirmation by larger clinical trials.

Implications:

CK-1827452 is a novel inotropic drug being developed for heart failure.

Inotropic drugs have “failed” in long-term treatment of heart failure because they increase mortality.

Virtually all prior similar agents looked “promising” when at the same stage as CK-1827452 is now.

The mechanism of inotropic effect is probably not as important as the effect itself, which is harmful.

All potent inotropic drugs, like CK-1827452, are suspect for long-term treatment of heart failure.

There is little reason to be optimistic about the chances for success of CK-1827452.

Analysis:

Amgen has recently allied with Cytokinetics in the development of a new drug for heart failure (HF). The drug involved, CK-1827452, is an inotropic agent that acts through a novel mechanism to make the heart contract more forcefully. So far the drug has been given only to animals and normal human volunteers, and has performed as expected, i.e., improved cardiac contractility in both. The drug is about to enter the next stage (Phase II) in humans with HF, i.e., small trials as “proof of concept”, to be followed by Phase III, or large clinical trials in HF to assess general efficacy and safety if Phase II is successful.

There are many inotropic drugs and all have “failed” in large long-term clinical trials in HF because of their propensity to cause cardiac arrhythmias and an excess of deaths in patients with HF. The list includes amrinone, milrinone, flosequinon, beta-blockers with intrinsic agonist activity (xamoterol, bucindolol), etc. Each of these (and others) acts through different mechanisms, all thought to be unique early on and unlikely to produce harmful effects. They all looked very promising early in development, i.e., at the stage where CK-1827452 is now. So far there is nothing “unique” about CK-1827452.

Having a novel inotropic mechanism may not be important. What seems important is that making the failing heart muscle contract more forcefully, regardless of how this is done, may actually harm the heart muscle, analogous to “beating a dying horse.” The only inotropic drug used for long-term treatment of HF is digitalis (digoxin), and it has not been shown to reduce mortality, but has also not increased mortality, probably because it is a relatively weak inotropic agent compared to the others mentioned. Many HF experts would question the logic of anyone developing a new inotropic agent in this day and age. Such agents are limited to very short-term use in acutely decompensated HF, for which many agents already exist.

Implications: ·  Exforge is a “new” combination of old drugs and resembles existing combinations.

·  The combination is unusual by including components with similar mechanisms of action.

·  The somewhat unusual combination may produce more side effects outside the clinical
   trials setting.

·  Since it does not include a diuretic, Exforge does not conform to current hypertension 
   guidelines.

·  The unusual combination, lack of guideline support, and similarity of Exforge to other products,
   like Lotrel (Novartis), may limit the impact of this “new” old combination.

Analysis: Exforge (Novartis) is a combination of valsartan and amlodipine, neither of which is really “new”. In clinical trials this combination was found “highly effective” and safe, as are virtually all combination products in hypertension. This is a bit of an unusual combination in that both components act through a common pathway, i.e., vasodilation (or relaxation of arterial tone).

There are other older combination products like this, benazepril plus amlodipine, which also combined the calcium channel blocker with a renin-angiotensin system antagonist. Hence, there’s really not much new in Exforge.

Most combinations for hypertension involve drugs that act through somewhat different mechanisms, and frequently include a diuretic as one of the agents. The combination of 2 vasodilators carries a risk of hypotension and does raise some safety concern. Clinical trials often underestimate side effects because patients are followed closely by experts who are often guided closely by the Sponsor. In routine clinical practice, where the drug is given to relatively unselected patients by physicians not necessarily experts and not “supervised” by the Sponsor, side effects are often more frequent. With this unusual combination, careful dosing and close follow-up at the initiation of treatment will be needed.

The drug does not conform to current guidelines that recommend diuretics and/or beta-blockers as first line therapy, with addition of other agents to these as needed. Thus, the marketing success of this “new” combination of old drugs may be limited by potential side effect and lack of endorsement by the “guideline makers”.

Implications:  

Implications:

• Acute decompensated heart failure remains an important medical challenge.

• Inotropic drugs which stimulate the heart to contract more strongly and work harder are commonly used to treat this condition.

• While these drugs do improve cardiac function and symptoms over the very short-term, they also produce serious cardiac arrhythmias and have been associated with increased mortality.

• Levosimendan is a new inotropic agent that acts through a unique mechanism postulated to be safer than other similar drugs.

• The present results suggest that levosimendan is not really different from these other drugs.

• Thus, levosimendan, which has also not been clinically effective in large trials, may be domed to “failure” along with the other inotropic drugs.

Analysis:  

Flevari P, Parissis JT, Leftheriotis D, Panou F, Kourea K, Kremastinos DT. Effect of levosimendan on ventricular arrhythmias and prognostic autonomic indexes in patients with decompensated advanced heart failure secondary to ischemic or dilated cardiomyopathy. Am J Cardiol. 2006 Dec 15;98:1641-5. Epub 2006 Oct 25

http://www.ajconline.org/article/PIIS000291490601719X/abstract

Levosimendan (Simdax®, Abbott)is a novel inotropic-vasodilator drug that acts as a calcium sensitizer and might be safer than prior similar drugs that act through different mechanisms and have been harmful in heart failure (HF). In this study levosimendan or placebo was given intravenously for 24 hours to patients with advanced refractory HF and cardiac function and electrocardiograms were monitored. As expected, measures of cardiac function improved more on levosimendan than placebo. However, the incidence and severity of ventricular arrhythmias were greater in the levosimendan group. Four patients ultimately died, and 3 of these had received levosimendan and experienced ventricular arrhythmias. Thus, despite the claimed different mechanism of action and potential safety advantage of levosimendan, this experience suggests that this agent has the same adverse event profile of other similar agents that have been associated with increased mortality in HF.

Treatment of decompensated HF remains a clinical challenge. Numerous inotropic-vasodilator drugs, e.g., amrinone and milrinone, have been used to treat this condition and these agents have improved cardiac function and symptoms over the short term, but these agents have also produced cardiac arrhythmias and excess deaths in these patients such that inotropic drugs are a last resort intended only for very short-term use in HF. Levosimendan is a new member of this group and its novel mechanism of action was thought to be unlikely to produce the arrhythmias and undesirable outcomes associated with other drugs of this class. Unfortunately, the present study suggests that levosimendan may be as bad as the other drugs in this class. This finding along with its failure to show clinical benefits in large clinical trials, i.e. SURVIVE, raise considerable doubts about the future of levosimendan in particular and the whole class of inotropic drugs in general, regardless of their specific mechanisms of action.

Implications: Pacemakers provide very effective resynchronization therapy in selected patients with heart failure.

Current guidelines limit the use of resynchronization therapy to a small percentage of patients who meet the current electrocardiographic requirements for receiving a pacemaker.

These 2 preliminary studies both show improvements in cardiac function and heart failure symptoms in patients with heart failure and cardiac dyssynchrony without the currently required electrocardiographic abnormalities.

If large clinical trials confirm these results, many more heart failure patients will be candidates for pacemakers and resynchronization therapy.

Analysis: Gabe B. Bleeker, MD, Eduard R. Holman, MD, PhD, Paul Steendijk, PhD, Eric Boersma, PhD, Ernst E. van der Wall, MD, PhD, Martin J. Schalij, MD, PhD and Jeroen J. Bax, MD, PhD_. Cardiac Resynchronization Therapy in Patients With a Narrow QRS Complex. J Am Coll Cardiol, 2006; 48:2243-2250.

http://content.onlinejacc.org/cgi/content/abstract/48/11/2243

Cheuk-Man Yu, MD, FRCP, Yat-Sun Chan, FHKAM, Qing Zhang, MM, Gabriel W.K. Yip, MRCP, Chi-Kin Chan, FHKAM, Leo C.C. Kum, MRCP, LiWen Wu, BM, Alex Pui-Wai Lee, MRCP, Yat-Yin Lam, MRCP and Jeffrey Wing-Hong Fung, FHKAM. Benefits of Cardiac Resynchronization Therapy for Heart Failure Patients With Narrow QRS Complexes and Coexisting Systolic Asynchrony by Echocardiography. J Am Coll Cardiol, 2006; 48:2251-2257

http://content.onlinejacc.org/cgi/content/abstract/48/11/2251

These 2 papers both show that pacemaker insertion for resynchronization therapy in patients with heart failure who do not have usual electrocardiographic evidence of cardiac dyssynchrony can be improved in terms of cardiac function and heart failure symptoms over the short term. Patients in the present studies had dyssynchrony by readily available imaging techniques, but without prolonged QRS complexes on their electrocardiograms, the usual criteria for dyssynchrony as recommended in current management guidelines. Hence, these studies suggest that more patients may be candidates for resynchronization therapy than indicated by present guidelines. Both studies conclude that large, long-term clinical trials are now needed to confirm these results and expand the use of pacemakers for resynchronization therapy to more patients with heart failure.

Pacemakers are highly effective in selected patients with heart failure who have cardiac dyssynchrony, i.e., their hearts don’t contract in an orderly fashion. In such patients insertion of certain types of pacemakers can stimulate the heart in proper sequence and “resynchronize” its contractions. Resychronization therapy has been shown to improve cardiac function and symptoms, and to reduce mortality in patients with heart failure and dyssynchrony. According to current guidelines, only patients with moderately severe heart failure symptoms despite maximal drug therapy and with electrocardiographic evidence of dyssynchrony, i.e., a wide QRS complex, are candidates for resynchronization therapy. By most estimates, only 15-30% of patients with heart failure currently satisfy these requirements. These 2 preliminary studies showing benefits of resynchronization therapy in patients with heart failure and normal QRS complexes suggest that many more patients, up to 70% of those with heart failure, may be candidates for pacemakers if criteria for dyssynchrony other than wide QRS are used. If large clinical trials confirm these preliminary observations, pacemaker implantations for heart failure should increase markedly.

 

Implications:

Implications:

• We can learn from the failure of torcetrapib in clinical trials.
• Drug development is risky and unpredictable, and we need to temper our enthusiasm over news that emerges during this process.
• Hypertension remains an important risk factor for heart disease and requires a renewed commitment by all to detect and treat it properly.
• Torcetrapib-like drugs in development could also run into similar problems.
• We need to know more about mechanisms of diseases and not confuse association with causality.

Analysis: Pfizer’s decision to terminate a clinical trial and development of torcetrapib because of excess deaths occurring during the trial is obviously tragic for the victims and disheartening for many. Nevertheless, we can all learn some lessons from this experience. Bad things can happen anytime during the drug development process and we must remember to cautiously interpret and react to all news, good and bad, during this process. Because it appears the deaths in this trial may have been related to the surprising development of hypertension in patients treated with torcetrapib, we need to remember that hypertension is a significantly more ominous risk factor for atherosclerosis than lipids and we need to renew the commitment to detect and adequately treat hypertension. Pharmaceutical companies have, and should, play a key role in this process. Since the mechanism of the torcetrapib-related deaths is unknown, there has to be concern over other similar drugs in development for the treatment of low levels of so-called “good cholesterol” (HDL-cholesterol). Finally, just because low levels of HDL-cholesterol are associated with increased risk of heart disease, it doesn’t necessarily follow that raising HDL is good, as HDL may just be a “marker” and not a cause of the increased risk.

Implications:

• Statins are an important mature class of drugs with limited or no patent life remaining as treatment for hyperlipidemia.
• Statins produce a number of potentially beneficial actions other than lipid lowering.
• There is ample evidence that statins produce effects that may be important in heart failure.
• Preliminary evidence is sufficient to justify large randomized clinical trials of statins in heart failure, a large unmet medical need.
• It is now up to the pharmaceutical industry to “step up to the plate” and explore this major opportunity.

Analysis:

Khush KK, Waters DD. Effects of statin therapy on the development and progression of heart failure: mechanisms and clinical trials. J Card Fail. 2006;12:664-74


http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WHG-4M34RMR-K&_coverDate=10%2F31%2F2006&_alid=475686039&_rdoc=1&_fmt=&_orig=search&_qd=1&_cdi=6850&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=c95741e90f5a6fd65d0fc3c4f7398bfb

It has been well documented that statins exert many other effects, besides lipid lowering, that may be beneficial in disorders other than hyperlipidemia. Because of these other actions we have previously referred to statins, in these pages, as the “next panacea”. The present article reviews the literature on statins and how their “other” effects might benefit heart failure. Statins have been shown to favorably affect a number of mechanisms that play a role in heart failure, e.g., improving endothelial function, anti-inflammatory activity, neurohumoral inhibition, and reversal of left ventricular remodeling. Furthermore, small preliminary clinical trials in patients at risk of or with heart failure suggest that statins can prevent development of heart failure, prolong survival, and improve cardiac function. The authors conclude that large randomized clinical trials are needed.

Statins are an important class of drugs and many of them are now mature agents already off patent or about to go off patent. There is ample evidence that statins exert their effects through multiple mechanisms unrelated to lipid lowering. Some of these effects may be of particular value in heart failure, which still represents a large unmet medical need as mortality and morbidity rates remain high despite major advances in treatment. Furthermore, heart failure remains epidemic and growing as the population ages. It appears that this potentially large market and the potential efficacy of statins offer a new opportunity for the statins. There is now ample evidence to justify and support the design and conduct of large randomized clinical trials of statins in heart failure. It remains for the manufacturers and marketers of statins to step up and take action.

Implications:

Implications:

• Disease management guidelines have been commonplace.
• Their implementation appears limited in hypertension, as has been noted for other diseases.
• Multiple factors impact guideline implementation, including marketing practices of pharmaceutical companies and individual physician preferences.
• It is unknown whether the limited application of guidelines is a significant result of aggressive pharmaceutical marketing or if such aggressive marketing is really not warranted.

Analysis: Weiss R, Buckley K, Clifford T. Changing patterns of initial drug therapy for the treatment of hypertension in a Medicaid population, 2001-2005. J Clin Hypertens. 2006 8:706-12

Disease management guidelines have become very common and are important because of their potential influence on clinical practice, managed care organizations, and marketing of pharmaceuticals. While guidelines are not binding in any regulatory sense, their proponents advocate them because they are evidence-based and promote state-of-the-art medical practice. The latest guidelines for managing hypertension recommend diuretics as the drug of choice for initiating treatment of hypertension. This article reviews the experience of physicians in the state of Maine in prescribing single drug therapy of newly diagnosed hypertension between 2001 and 2005. Among 5373 patients, in 2001 diuretics were prescribed for 17.5% of patients, with beta-blockers and ACE inhibitors prescribed for 23.5% and 37.5%, respectively. Although use of diuretics increased initially to as much as 30%, it fell again to only 25.5% by 2005, and remained lower than that of beta-blockers (27.8%) and ACE inhibitors ((30.9%). The authors concluded that “There appears to have been limited impact from the guidelines on initial drug choice and even less so on ongoing drug therapy.”

Despite the widespread dissemination of management guidelines for various diseases in recent years, this report supports other similar observations that implementation of these guidelines is very slow in clinical practice. The impact of management guidelines appears limited and may be influenced by numerous factors, including managed care acceptance of them, individual physician practices or preferences, and marketing practices of pharmaceutical companies, who often react to the issuance of guidelines. Based on these results, one wonders how much that reaction, whether favorable or not, impacts the implementation of guidelines.

Implications:

Implications:

• Beta-blockers are key drugs for treating heart failure.
• Carvedilol is the market leader in this area.
• Carvedilol’s position is limited by inconvenient dosing schedules and generics.
• Availability of a new long-acting formulation of carvedilol should enhance its dominance of the marketplace.
• A new formulation with patent protection could also stimulate development of new indications.

Analysis: Packer M. Controlled-release carvedilol: a concluding perspective. Am J Cardiol. 2006 Oct 2;98(7A):67-9.

Beta-blockers are firmly established and routinely recommended for all appropriate patients with heart failure. Carvedilol (CoregÒ, GlaxoSmithKline) dominates the marketplace for beta-blockers in heart failure, but the current product requires twice daily dosing and is readily available generically. This article is the concluding one in a series of articles recently published as a supplement to the American Journal of Cardiology (cited above). This supplement contains several publications describing a new long-acting formulation of carvedilol. As summarized in this article, the new formulation is bioequivalent to the currently marked immediate release short-acting formulation, meaning patients should be able to switch easily to the newer one, which has to be taken only once a day instead of twice daily. Preliminary results of clinical trials suggest that the long-acting formulation is as safe and effective as the short-acting one for its currently approved indications of hypertension, heart failure, and post-myocardial infarction with cardiac dysfunction.

Carvedilol’s commanding position in the marketplace for heart failure is limited only by its inconvenience of thrice daily dosing and its generic availability. Having a new once-daily formulation should significantly solidify carvedilol’s position as the market leader and provide a stimulus for further development of new indications, e.g., metabolic syndrome.

NOTE: This analyst is a paid consultant to GlaxoSmithKline, marketers of carvedilol.