Global7 the new Millennial Renaissance Vision for the Globe
To Print: Click your browser's PRINT button.
NOTE: To view the article with Web enhancements, go to:
Assessing Guidelines, Strategies, and New Drugs to Get Patients to Target
Linda Brookes, MSc
Medscape Cardiology. 2007; ©2007 Medscape
New data highlighted this month reveal that hypertension control appears to be better in the United States than in Western Europe -- but unfortunately the latest US hypertension guidelines fail to substantially affect blood pressure control in diabetic patients, whereas the new Canadian hypertension guidelines highlight for the first time the dangers of "high normal" blood pressure.
Two new reports further confirm that there is a higher rate of incident diabetes with diuretics and beta-blockers, and beta-blockers are less effective than diuretics, calcium channel blockers, or angiotensin blockers as first-line therapy for elevated blood pressure control.
Finally, the first clinical trials with new second-generation renin inhibitors and a small catalog of new combination antihypertensive pills coming soon in Europe, the United States, and, as a polypill, in India are reported.
Hypertension Control Appears Better in the United States Than in Western Europe
An analysis of survey data appears to confirm previous population-based studies showing that patients with diagnosed hypertension in the United States have lower blood pressure levels and better hypertension control than patients in Western European countries.
The results of the analysis are published in the January 22 issue of Archives of Internal Medicine. The US investigators attribute the difference to lower treatment thresholds and more intensive treatment set out in the most recent US hypertension management guidelines.
However, in their analysis, almost half the US patients did not achieve their goal blood pressure as recommended in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), so "better blood pressure control in the United States should not be too quickly praised," they caution.
The study, which was supported by the MacLean Center for Clinical Medical Ethics, the National Institute of Aging, and the Agency for Healthcare Research and Quality, used patient data collected from surveys conducted in 2004 in France, Germany, Italy, Spain, and the United Kingdom, as well as the United States.
The surveys were part of Cardiomonitor, an ongoing survey of physician visits by ambulatory adult patients with cardiovascular diseases in selected countries carried out since 1980 by an international market research company (Taylor Nelson Sofres Healthcare, London).
In 2004, the physicians in the survey were randomly selected, and those who agreed to participate completed 2-page diaries for 15 cardiovascular patients. Information collected included patient characteristics, initial blood pressure level before treatment, any co-occurring diseases, and the use of 7 types of antihypertensive drugs.
Investigators led by Y. Richard Wang, MD, PhD, of Temple University Hospital and University of Pennsylvania, Philadelphia, identified a total of 21,053 patients with a primary or secondary diagnosis of hypertension in all 6 countries.
These patients had visited a total of 291 cardiologists and 1284 primary care physicians. The patients were 53% male, mean age was 65 years, and 23% had diabetes mellitus.
At least 92% of patients with hypertension in each country were receiving antihypertensive drug therapy.
Use of thiazide-type diuretics was similar across all countries (29% to 13%), but use of other antihypertensive drug classes -- beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs) -- varied considerably. Use of combination therapy (≥ 2 drugs) was highest in the United States (64% vs 44% to 59% in European countries).
Initial blood pressure measurements before treatment were available for 61% to 80% of patients per country and were lowest in the United States (average of 161/94 mm Hg, vs an average of 167-173/96-99 mm Hg in Europe).
The most recent blood pressure reading was also lower in the United States than in any other country (average of 134/79 mm Hg, vs an average of 139-144/80-84 mm Hg in Europe).
Only 65% of US patients had an initial pretreatment blood pressure level ≥ 160/100 mm Hg, compared with 81% to 90% of patients in the European countries.
The rate of hypertension control was found to be highest among the US patients, whether control was defined as < 140/90 mm Hg for all patients or as < 130/80 mm Hg in patients with diabetes and < 140/90 mm Hg in all others. By the later definition, 53% of US patients achieved hypertension control compared with 27% to 40% of European patients.
Multivariate analyses controlling for age, sex, current smoking, and physician specialty showed that, compared with US patients, European patients had higher latest systolic blood pressure (SBP) levels (by 5.3-10.2 mm Hg across countries examined) and diastolic blood pressure (DBP) levels (by 1.9-5.3 mm Hg; all P < .001).
These differences remained significant (P < .01) after controlling for comorbidities and concurrent drug treatment.
European patients were less likely than US patients to have hypertension control or a medication increase for inadequately controlled hypertension (P < .001).
The researchers found that initial pretreatment blood pressure levels accounted for most of the cross-national differences in latest SBP and DBP levels and the likelihood of hypertension control.
Dr. Yang and his colleagues suggest that aggressive treatment in the United States means that some patients may be receiving drug treatment they do not need, involving extra cost. However, these costs are small compared with those that would result from a future cardiovascular event that occurred due to inadequate blood pressure control.
US Hypertension Guidelines Fail to Substantially Affect Blood Pressure Control in Diabetic Patients
Despite the publication of increasingly aggressive guidelines for lowering blood pressure and the superior rate of hypertension control in the United States compared with Europe, another study by Y. Richard Wang, MD, PhD, suggests that the guidelines have had little effect on hypertension control in diabetic patients.
The study is published in the January issue of Diabetes Care. The findings appear to be consistent with previous studies that reported a lack of hypertension control in diabetic patients, despite the higher risk of cardiovascular disease that they have and despite recommendations by diabetes and family physician organizations, as well as those of the JNC.
Dr. Yang compared the effects of the JNC 7 guidelines on blood pressure control in patients with diabetes vs that in nondiabetic patients between 1995 and 2005.
The JNC VI guidelines, published in 1997, lowered blood pressure goals for diabetic patients to < 130/85 mm Hg. This goal was subsequently lowered in 2003, in the JNC 7 guidelines, to 130/80 mm Hg. Goal blood pressure for nondiabetic patients was < 140/90 mm Hg in both JNC VI and JNC 7.
Dr. Yang used data from the National Disease and Therapeutic Index, a nationally representative survey of outpatient visits in the United States carried out by IMS Health (Plymouth Meeting, Pennsylvania). Data were available for 19,616 diabetic and 162,672 nondiabetic adult patients diagnosed with hypertension, representing about 76 million diabetic and 638 million nondiabetic physician visits in the United States.
Defining blood pressure control as blood pressure < 140/90 mm Hg, an improvement in control was seen during the entire period in all diabetic and nondiabetic patients, but percent control was greater in the nondiabetic patients compared with the diabetic patients.
The rate of hypertension control improved for both diabetic and nondiabetic patients by between 1.5% and 2.5% between 1995 and 2005.
"However, the more aggressive goal blood pressure set in the JNC VI and JNC 7 guidelines for patients did not lead to substantially better hypertension control for diabetic subjects compared with nondiabetic subjects, for whom the goal blood pressure remained the same,"
Dr. Yang reports. After publication of JNC VI, there was no immediate change in rate of control (blood pressure < 130/85 mm Hg) in diabetic patients and only a nonsignificant 1.7% increase after 3 years.
A widening gap in blood pressure control was apparent after 2001 that continued after 2003, when JNC 7 was published. By 2005, the rate of blood pressure control in nondiabetic patients (< 140/90 mm Hg) was 20% higher than control (< 130/85 mm Hg) in diabetic patients.
Dr. Yang comments that the findings of his study are "somewhat surprising considering the recognition of JNC guidelines as the gold standard for hypertension treatment, similar recommendations from other organizations such as American Diabetes Association, American College of Physicians, and American Academy of Family Physicians, and public health efforts to promote comprehensive diabetes care.
" He suggests that the reasons for this lack of improvement in blood pressure control in hypertensive patients with diabetes may be due to patient noncompliance with lifestyle recommendations and drug treatment, physician inertia to initiate and intensify treatment, and inadequate access to medical care.
"The continued lack of hypertension control for patients with diabetes in the US despite the publication of more aggressive guidelines has significant long-term cost implications for the health care system," he writes. Identifying effective interventions to deal with the challenge of lowering blood pressure in people with diabetes should be a top priority for future research, he concludes.
New Canadian Hypertension Guidelines Highlight Dangers of High Normal Blood Pressure
New guidelines for hypertension management were released to the public in Canada in January.
The Hypertension: 2007 Public Recommendations, the second public version of the guidelines, has been adapted from the latest professional recommendations by Blood Pressure Canada, the Heart and Stroke Foundation of Canada, the Canadian Hypertension Education Program (CHEP), and the Canadian Hypertension Society.
For the first time, the Canadian guidelines focus on prevention of hypertension and the importance of recognizing "high normal" blood pressure (ie, 130-139/85-89 mm Hg). "More than one half of people with high normal blood pressure develop hypertension within 4 years unless they make lifestyle changes," the guidelines caution.
They also warn that > 9 in 10 Canadians will develop hypertension unless they follow a healthy lifestyle. Recommended ways to lower blood pressure include:
Physical activity for 30-60 minutes most days of the week;
More vegetables, fruit, low-fat dairy products, foods low in saturated and trans fat and salt, whole grains, lean meat, fish, and poultry in the diet; less fat food and canned or prepared foods;
Reducing salt intake;
Drinking less alcohol (≤ 1-2 drinks per day);
No smoking; and
Weight loss (at least 10 lb/5 kg) if overweight.
Advice is given on how to cut down salt intake by reading food labels and restaurant menus more carefully.
The need for regular blood pressure checks is emphasized. Target blood pressures (< 140/90 mm Hg in most people and < 130/80 mm Hg in people with diabetes or kidney disease) are explained and ways of measuring blood pressure at a physician's office or at home are described, along with the possibilities of white coat or masked hypertension when blood pressure is measured by a doctor.
Patients with diabetes or with cholesterol as well as high blood pressure are urged to ask their doctors to do kidney function tests.
As to treating hypertension, the guidelines explain that in most people at least 2 medications (probably taken in a single tablet) will be necessary in addition to the lifestyle changes.
They stress the importance of adherence to treatment and the problems that can arise if patients are not honest with their doctors about forgetting to take medications (unnecessarily increased doses, etc.).
Diuretics, beta-blockers (in patients aged < 60 years), ACE inhibitors, ARBs, and calcium channel blockers (CCBs) "all reduce blood pressure by the same amount on average," say the guidelines.
They say that some patients are more likely to need specific classes of antihypertensive drugs (eg, a diuretic and an ACE inhibitor/ARB in patients with diabetes or kidney disease, and a beta-blocker and an ACE inhibitor in patients with heart disease). They stress that the full effects of antihypertensive medication may not be apparent for up to 6 weeks.
Almost one quarter of Canadian adults -- about 5 million -- are estimated to have hypertension and 2.5 million to have high normal blood pressure. Hypertension is the leading reason for visits to primary care physicians.
Speaking on behalf of the Heart and Stroke Foundation of Canada, Sheldon W. Tobe, MD, (Sunnybrook and Women's College Health Science Centre and University of Toronto) stressed the significance of high-normal blood pressure in the new guidelines.
"We believe family doctors now understand the thresholds for diagnosing high blood pressure. Now we're saying, let's prevent hypertension from occurring. It is a big step forward," he said. "It is time for doctors to take the next step: to recognize the risks of high-normal blood pressure and treat it before it develops into high blood pressure.
" People with blood pressure in the high-normal range have double the risk of heart disease and stroke compared with those with normal blood pressure, he noted. Dr. Tobe believes that lifestyle changes can be as effective in lowering blood pressure as drug therapies.
Patients are more likely to succeed in making lifestyle changes and maintaining them if a physician emphasizes the importance of prevention by arranging a follow-up visit, and the patient is more likely to agree to make lifestyle changes and comply, he says.
Patients with high-normal blood pressure should monitor their blood pressure at home and keep track of their progress and setbacks, he recommends.
Higher Rate of Incident Diabetes With Diuretics and Beta-blockers Confirmed in Analysis of Clinical Trials
An analysis of data from major trials of antihypertensive drugs, published in The Lancet, has confirmed that ARBs and ACE inhibitors have the lowest association with incident diabetes and diuretics and beta-blockers the highest.
William J. Elliott, MD, and Peter M. Meyer, PhD, (Rush University Medical Center, Chicago, Illinois) conducted their analysis using a new statistical technique known as network meta-analysis.
This type of analysis allows the relative effectiveness of 2 treatments to be estimated when they have not been compared with each other directly in a randomized trial, but have each been compared with other treatments.
In this way, Drs. Elliott and Meyer were able to make comparisons of antihypertensive drug classes, including ARBs and ACE inhibitors, that had never been directly compared in a randomized clinical trial. Their study was supported in part by the US National Institutes of Health.
Long-term randomized clinical trials of antihypertensive drugs that reported new cases of diabetes from 1966 to September 15, 2006, were identified from searches of MEDLINE and other medical publication databases and reference lists from all meta-analyses and all other potential sources.
A total of 22 clinical trials comprising 143,153 enrolled participants who did not have diabetes at randomization were found to be eligible for inclusion in the analysis. Seventeen trials enrolled patients with hypertension, 3 enrolled high-risk patients, and 1 enrolled those with heart failure. The trials involved a total of 48 groups of patients randomized to initial treatment with a(n):
ARB (5 groups, 14,185 patients);
ACE inhibitor (8 groups, 22,941 patients);
CCB; (9 groups, 38,607 patients);
Placebo (9 groups, 24,767 patients);
Beta-blocker (9 groups, 35,745 patients); or
Diuretic (8 groups, 18,699 patients).
Using an initial diuretic as the standard of comparison, initial treatment with an ARB, ACE inhibitor, CCB, or placebo was in all cases associated with significantly fewer cases of incident diabetes. The odds ratios were:
ARB 0.57 (95% confidence interval [CI] 0.46-0.72, P < .0001);
ACE inhibitor 0.67 (95% CI 0.56-0.80, P < .0001);
CCB 0.75 (95% CI 0.62-0.90, P = .002);
Placebo 0.77 (95% CI 0.63-0.94, P = .009); and
Beta-blocker 0.90 (95% CI 0.75-1.09, P = .30).
When placebo was used as referent agent, only the initial ARB and the initial diuretic retained significance, with the diuretic associated with a 30% increase in risk of incident diabetes. These results changed little when subjected to sensitivity analyses.
Drs. Elliot and Meyer point out that their results are consistent with those of previous meta-analyses.
The reasons for the different effects of these antihypertensive drug classes may be due to their effects on circulating kinins, pancreatic insulin release, and the peripheral effects of insulin, they suggest, noting that animal studies have also implicated the peroxisome proliferator-activated receptor gamma (PPAR-gamma) receptor. "Which of these is mort important in human beings remains a topic for future research," they say.
They add that the implications of their findings for clinical practice are uncertain, given the approaches of different national hypertension guidelines to diuretics and beta-blockers and the lack of data about the increased cardiovascular risk associated with incident diabetes over the long term.
More high quality data can be expected from current clinical trials such as the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial, the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET), and the Telmisartan Randomized Assessment Study in ACE-Intolerant Subjects With Cardiovascular Disease (TRANSCEND), each of which includes incident diabetes as a primary or secondary end point.
They may also help to determine whether ARBs and ACE inhibitors have significantly different effects on incident diabetes.
First-line Beta-blockers Less Effective Than Diuretics, CCBs, or Angiotensin Blockers for Elevated Blood Pressure
An analysis of clinical trials of beta-blockers by a group of researchers based in South Africa confirm previous reports that beta-blockers are "inferior first-line choices" for the treatment of hypertension compared with diuretics, ACE inhibitors/ARBs, or CCBs.
The analysis, which was funded by the Medical Research Council of South Africa, first appeared in the Journal of Hypertension and has now been published by the Cochrane Collaboration. Its conclusion, which was the same in both publications, was based on the relatively weak effect of beta-blockers in preventing stroke and the absence of an effect on coronary heart disease (CHD) compared with placebo or no treatment.
More importantly, say the authors, they based it on the trend toward worse outcomes compared with CCBs, angiotensin blockers, and thiazide-type diuretics.
The analysis was undertaken because previous meta-analyses compared beta-blockers with all other antihypertensive drugs taken together, whereas the South African group points out that they might be better or worse than a specific class of drugs for a particular outcome measure.
In addition, previous reviews did not examine the tolerability of beta-blockers relative to other antihypertensive medications.
Lead authors Charles Shey Wiysonge, MD, (University of Cape Town, Groote Schuur Hospital) and Hazel A Bradley, MPH, (University of the Western Cape, Bellville) described how they identified eligible clinical trials published through June 2006 by searching the Cochrane Controlled Trials Register, MEDLINE, EMBASE, reference lists of previous reviews, and by contacting researchers.
They were looking for randomized, controlled trials that assessed the effectiveness of beta-blockers compared with placebo, no therapy, or other drug classes, as monotherapy or first-line therapy for hypertension, on mortality and morbidity end points in men and nonpregnant women aged ≥ 18 years.
Thirteen trials, involving 91,561 participants, that met the inclusion criteria were identified. These trials compared beta-blockers with placebo or no treatment (4 trials with 23,613 participants), diuretics (5 trials with 18,241 participants), CCBs (4 trials with 44,825 participants), or ACE inhibitors or ARBs, which were grouped together as renin-angiotensin system (RAS) inhibitors because of small numbers (3 trials with 10,828 participants).
Trial participants were analyzed according to the groups to which they were randomized, regardless of subsequent treatment they actually received.
The researchers found that the effect of beta-blockers on all-cause mortality did not differ from that of placebo, diuretics, or RAS inhibitors, but was significantly higher for beta-blockers compared with CCBs (relative risk [RR] 1.07, 95% CI 1.00-1.14, P = .04), corresponding to an absolute increase of 0.5%. Patients on beta-blockers had a markedly reduced risk of total cardiovascular disease (fatal and nonfatal CHD and stroke, plus congestive heart failure and transient ischemic attack, when reported) compared with placebo (RR 0.88, 95% CI 0.79-0.97).
This was primarily a reflection of the significantly lower risk of stroke with beta-blockers (RR 0.80, 95% CI 0.66-0.96), calculated as an absolute risk reduction of 0.5% compared with placebo.
The effect of beta-blockers on cardiovascular disease was significantly worse than that of CCBs (RR 1.18, 95% CI 1.08-1.29) but did not differ from that of diuretics or RAS inhibitors. Increased total cardiovascular disease was due to an increase in stroke compared with CCBs (RR 1.24, 95% CI 1.11-1.40), an increase in absolute risk of 0.5%.
There was also an increase in stroke with beta-blockers compared with RAS inhibitors (RR 1.30, 95% CI 1.11-1.53), an increase in absolute risk of 1.5%. The effect of beta-blockers on CHD was not significantly different from that of placebo, diuretics, CCBs, or RAS inhibitors.
Patients on beta-blockers were more likely than those on diuretics or RAS inhibitors to discontinue treatment due to side effects, but there was no difference compared with placebo or CCBs.
There were no differences in depressive symptoms among the different treatment groups, but patients on beta-blockers appeared more likely than those on diuretics, CCBs, or RAS inhibitors to develop fatigue.
The risk of sexual dysfunction appeared lower than with diuretics, but higher than with CCBs or RAS inhibitors. Blood pressures (SBP and DBP) in the beta-blocker arms of the trials were 0-2 mm Hg higher than on the other treatment arms.
This study was able to confirm the finding of a previous meta-analysis carried out by Swedish researchers, which found beta-blockers are less effective than other antihypertensive drugs at preventing strokes. However, because of lack of data, Dr. Wiysonge and colleagues were unable to confirm whether the disadvantages of beta-blockers as first-line antihypertensive therapy are limited to elderly patients, as suggested by Canadian researchers Nadia Khan, MD, and Finlay A McAlister, MD, in a previous review.
They also could not draw any conclusions about whether cardioselective and nonselective beta-blockers have different effects, since most of the beta-blocker trials in the analysis used atenolol (75% of participants on beta-blockers). These questions should be addressed in new randomized clinical trials, the researchers recommend.
Clinical Trials Begun With New Second-Generation Renin Inhibitor
Another second-generation oral renin inhibitor has entered clinical trials in development for the treatment of hypertension. Speedel (Basel, Switzerland), the company that licensed and originally developed the first oral renin inhibitor likely to receive regulatory approval, announced in January that a phase 1 trial of SPP1148 had begun to test the safety and tolerability of single and multiple oral doses in healthy volunteers. First results are expected in during the last quarter of 2007.
SPP1148 was selected for clinical trials following the preclinical evaluation of 2 potential candidates from the SPP1100 series on the basis of its superior animal bioavailability, positive effects on renal failure models in animals, and its suitability for manufacturing, Speedel says.
The SPP1100 series is one of several new series of renin inhibitors in development by Speedel Experimenta, the company's late-stage research unit, and is based on a new chemical entity. Speedel is developing a number of series of second-generation renin inhibitors, including the SPP600 series (under license from Roche), the SPP800 series (developed with Locus Pharmaceuticals), and the SPP1100 series.
A member of the SPP600 series, SPP635, progressed to a phase 2a proof-of-concept trial in October 2006. This trial is treating 35 hypertensive patients with SPP635 and is expected to finish during the third quarter of 2007.
Aliskiren (SPP100), the first-in-class renin inhibitor, expected to be on the market in the United States and Europe this year, is partnered with Novartis (Basel) for development and commercialization in hypertension.
Novartis filed for regulatory approval for aliskiren in the United States and Europe in 2006, and the US regulatory review process, which was extended in December by up to 3 months, is expected to be completed during the first quarter of 2007. Novartis predicts that it will launch aliskiren for the treatment of hypertension during the first half of 2007 in the United States and during the first half of 2007 in Europe.
The company presented extensive phase 3 clinical data at cardiology and hypertension conferences, including the World Congress of Cardiology, throughout 2006, and has an ongoing cardiovascular outcome program investigating aliskiren in primary and secondary prevention as well as in heart failure.
Speedel believes that "renin inhibition may be the new gold standard for the treatment of hypertension and related disorders in the next decade." Although renin inhibitors have been described as "a breakthrough," and it has been suggested that renin inhibitors would be expected to have fewer side effects than ACE inhibitors, they might be less powerful in reducing blood pressure because they do not block the degradation of bradykinin.
Other companies reported to be developing renin inhibitors, some of which have moved into early clinical trials, include Actelion, Merck, GlaxoSmithKline/Vita, and Pfizer.
New Combination Antihypertensive Pills Coming Soon in Europe, the United States, and, as a Polypill, in India
Three new pills containing fixed doses of 2 antihypertensive drugs are expected to come on the market within the next 2 years. Two of these pills will contain only blood pressure lowering drugs, but 1 is being touted as the first commercially available "polypill" developed especially with less affluent countries in mind.
The 2-drug pills comprise a CCB and ACE inhibitor or ARB. This combination is becoming increasingly popular as antihypertensive treatment, with or without a thiazide-type diuretic, as demonstrated recently in the blood pressure-lowering arm of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT-BPLA), and as recommended in the latest UK hypertension guidelines.
Fixed Combination of a CCB and a RAS Blocker
Exforge. A combination of the CCB, amlodipine, and the ARB, valsartan, 2 of the world's most prescribed antihypertensive drugs, was approved for the treatment of hypertension by the Food and Drug Administration (FDA) in the United States (December 2006) and the European Union (EU; January 2007).
Novartis, the company that will market the combination pill worldwide as Exforge, announced that it will become commercially available in both regions this year. Both approvals were based on clinical trials in > 5000 patients.
In the EU, Exforge is indicated for the treatment of hypertension in patients whose blood pressure is not adequately controlled by amlodipine or valsartan alone.
It will be launched shortly in Germany followed by launches in most other EU countries throughout the year, pending expiration of the patent protection for amlodipine (held by Pfizer).
The EU decision applies in all 27 EU member states plus Iceland and Norway; Exforge has also been approved in Switzerland. In the United States the FDA issued a tentative approval, pending expiration of market exclusivity and patent protection for amlodipine besylate in September 2007.
Exforge was deemed to have met all the required standards for safety, efficacy, and manufacturing quality and is expected to become available to patients in the US in late September 2007.
Novartis says that clinical trials with Exforge have demonstrated that it helps up to 9 out of 10 patients to reach their blood pressure goal (ie, DBP < 90 mm Hg or a > 10 mm Hg reduction from baseline).[18,19] The combination pill has been shown in trials to deliver reductions in blood pressure of 36 mm Hg and up to 43 mm Hg in some patient populations.
Overall, the pill is well tolerated, with an improved side effect profile over amlodipine alone. In particular, it is associated with a lower incidence of peripheral edema compared with amlodipine monotherapy.
Zaneril. Another new fixed combination of a CCB and a RAS blocker due to be marketed for the first time in 2007 is lercanidipine plus the ACE inhibitor enalapril, which will be launched as Zaneril in Germany in April by Meda (Solna, Sweden) under license from Recordati (Milan, Italy).
The new fixed combination was first approved in Germany in July 2007. Germany will act as Reference Member State in the mutual recognition process for the rest of Europe, which is expected to be completed during 2007. Recordati has licensed Zaneril to Sigma Tau (Rome) for its next launch, in Italy, expected to take place at the beginning of 2008.
Other agreements have been made to market Zaneril in Europe, Korea, Australia, Taiwan, the Middle East, and South Africa.
The second half of 2007 may also see the launch of a combination pill including 2 antihypertensive drugs (lisinopril and atenolol) in India, but this pill will also contain a statin (simvastatin) and aspirin, and will be launched as the first "polypill" by Indian pharmaceutical company Dr. Reddy's Laboratories (Hyderabad).
The polypill will become available after the completion of clinical trials carried out at 10 Indian medical centers. This polypill is meant only for individuals at high risk of heart disease and stroke and not as a mass prescription for everyone over age 55 years, which was the polypill originally proposed by UK researchers Prof Nicholas Wald, DSc, and Prof Malcolm Law, MBBS, (University of London) in 2003. Future launches of the Indian polypill are being planned for 2008-2009 in Russia, Brazil, and Australia.
The pill has been developed in partnership with researchers at the University of Auckland, New Zealand. The formulation is expected to comprise 75 mg of aspirin; 10, 20, or 40 mg of simvastatin; 5-10 mg of lisinopril; and 25 mg of atenolol.
The once-daily pill will be available in 3 strengths, according to the company. Commenting on the constituents of the polypill, Prof Anthony Rodgers, MBChB, PhD (University of Auckland), who has led research into the polypill in New Zealand, said that 2 antihypertensive agents should "be adequate in many cases to treat to goal and also adhere to guidelines.
It may also be easier to find acceptance of a 2-antihypertensive combination by doctors, rather than 3, particularly in cases of mild to moderate hypertension." All the drugs contained in the pill are off patent, making it especially cheap to produce.
A global trial of the polypill will begin in 2007. The Health Research Council of New Zealand has invested NZ$350,000 to support the overall coordination of the trial and recruitment in New Zealand, and Dr. Reddy's will invest NZ$7.5 million in developing the polypill and providing supplies for global clinical trials.
The trial investigators, led by Prof. Rodgers, will recruit about 600 people at high risk of myocardial infarction or stroke in Australia, Brazil, China, South Africa, the United States, and the United Kingdom, as well as India and New Zealand.
If this is successful, a larger trial will be carried out in up to 5000 people at moderate risk of heart disease. A separate trial in New Zealand, funded by the Health Care Research Council, will compare the benefits of the polypill with those of existing medication in 300 Maori and 300 non-Maori participants.
A 3- or 4-drug polypill for developing countries has long been supported by the World Health Organization.
Recently researchers calculated that a 4-drug polypill, like the one being tested by Dr. Reddy's, could halve the risk of death from cardiovascular disease in high-risk patients. However, writing in the January 18 issue of The New England Journal of Medicine, Prof. K. Srinath Reddy, MD, DM (All India Institute of Medical Sciences, New Delhi), a long-time proponent of the polypill for prevention of cardiovascular disease, cautions that the value of such a pill must be "clearly demonstrated, rather then simply assumed."
According to Prof. Reddy, a second Indian pharmaceutical company also has a 4-drug polypill about to enter clinical trials.
Another plan to develop a polypill was revealed at last year's World Congress of Cardiology in Barcelona.
Valentin Fuster, MD, Chairman of the Scientific Advisory and External Evaluation Committee of the Centro Nacional de Investigaciones Cardiovasculares and current president of the World Heart Federation, announced an intended collaboration with the Spanish pharmaceutical industry to develop a polypill for secondary prevention in low- and middle-income countries.
The pill would likely contain an ACE inhibitor, a statin, and aspirin, and first be tested in Spain and larger countries such as China. It should become available by 2010, according to Dr. Fuster.
Wang YR, Alexander GC, Stafford RS. Outpatient hypertension treatment, treatment intensification, and control in Western Europe and the United States. Arch Intern Med. 2007;167:141-147.
Chobanian AV, Bakris GL, Black HR, et al; Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. National Heart, Lung, and Blood Institute; National High Blood Pressure Education Program Coordinating Committee. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42:1206-1252.
Wang YR. Lack of effect of guideline changes on hypertension control for patients with diabetes in the U.S., 1995-2005. Diabetes Care. 2007;30:49-52. Abstract
Joint National Committee on Prevention, Detection, and Treatment of High Blood Pressure. The sixth report of the Joint National Committee on Prevention, Detection, and Treatment of High Blood Pressure (JNC VI). Arch Intern Med. 1997;157:2413-2446.
Blood Pressure Canada, Heart and Stroke Foundation of Canada, Canadian Hypertension Education Program (CHEP), Canadian Hypertension Society. Hypertension: 2007 public recommendations. Available at: http://www.hypertension.ca/chep/docs/chep2007-recommendations-english.pdf and http://ww2.heartandstroke.ca/images/english/CHEP-EN-2007.pdf. Accessed February 21, 2007.
Elliott WJ, Meyer PM. Incident diabetes in clinical trials of antihypertensive drugs: a network meta-analysis. Lancet. 2007;369:201-207. Abstract
Lumley T. Network meta-analysis for indirect treatment comparisons. Stat Med. 2002;21:2313-2324.
Bradley HA, Wiysonge CS, Volmink JA, et al. How strong is the evidence for use of beta-blockers as first-line therapy for hypertension? Systematic review and meta-analysis. J Hypertens. 2006;24:2131-2141. Abstract
Wiysonge CS, Bradley H, Mayosi BM, et al. Beta-blockers for hypertension. Cochrane Database Syst Rev. 2007;(1):CD002003.
Lindholm LH, Carlberg B, Samuelsson O. Should beta blockers remain first choice in the treatment of primary hypertension? A metaanalysis. Lancet. 2005;366:1545-1553. [See Related Links]
Khan N, McAlister FA. Re-examining the efficacy of beta-blockers for the treatment of hypertension: a meta-analysis. CMAJ. 2006;174:1737-1742. [See Related Links]
Speedel (Basel, Switzerland and Bridgewater, New Jersey). Speedel initiates Phase I safety and tolerability testing of SPP1148 in healthy volunteers: Second new series of renin inhibitors for treatment of hypertension to enter clinical trials. January 12, 2007. Available at: http://www.speedel.com. Accessed February 21, 2007.
Staessen JA, Li Y, Richart R. Oral renin inhibitors. Lancet. 2006;368:1449-1456. Abstract
Dahlof B, Sever PS, Poulter NR; for the ASCOT investigators. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet. 2005;366:895-506. Abstract
The National Collaborating Centre for Chronic Conditions. Hypertension: Management of Hypertension in Adults in Primary Care: Partial Update. London, UK: Royal College of Physicians; 2006.
Novartis Pharmaceuticals Corporation. Exforge(R) receives US regulatory approval as a new and highly effective treatment option for patients with high blood pressure. December 22, 2006. Available at: http://www.novartis.com. Accessed February 21, 2007.
Novartis. Exforge(R) approved in Europe as powerful new blood pressure therapy combining two leading medications in a single pill. January 18, 2007. Available at: http://www.novartis.com. Accessed February 21, 2007.
Data on file (Study VAA489A2201 and Study VAA489A2307). Novartis Pharmaceuticals Corporation. East Hanover, New Jersey. 07936. Available at: http://www.novartis.com. Accessed February 21, 2007.
Data on file (Exforge Summary Clinical Efficacy). Novartis Pharmaceuticals Corporation. East Hanover, New Jersey. 07936. Available at: http://www.novartis.com. Accessed February 21, 2007.
Poldermans D, Gamboa R, Fomina I, et al. Comparative safety and blood pressure (BP)-lowering efficacy of a combination of amlodipine + valsartan and lisinopril + hydrochlorothiazide in patients with stage 2 hypertension. Program and abstracts of ASH 2006: 21st Annual Scientific Meeting; May 16-20, 2006; New York, NY. Abstract P217.
Recordati. Recordati signs agreement with Meda for the co-marketing of its new antihypertension product in Germany. February 7, 2007. Available at: http://www.recordati.com. Accessed February 21, 2007.
Recordati. Recordati signs co-marketing agreement with Sigma-Tau in Italy for its new antihypertension product. December 21, 2006. Available at: http://www.recordati.com. Accessed February 21, 2007.
Dr Reddy's. World's first polypill trial. December 7, 2006. Available at: http://www.drreddys.com. Accessed February 21, 2007.
Wald, NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ. 2003;326:1419.
Gaziano TA, Opie LH, Weinstein MC. Cardiovascular disease prevention with a multidrug regimen in the developing world: a cost-effectiveness analysis. Lancet. 2006;368:679-686. Abstract
Reddy KS. The preventive polypill--much promise, insufficient evidence. N Engl J Med. 2007;356:212.
Supported by an independent educational grant from Pfizer.
Linda Brookes, MSc, freelance medical writer based in London and New York
Disclosure: Linda Brookes, MSc, has disclosed no relevant financial relationships.