Journal of Informed Pharmacotherapy 2004;15 (Jan – Mar)

Editorial

Canadian ePharmacies and the American Public: Mutualistic, Parasitic or Commensal Symbiosis?

Things are heating up on the cross-border prescription front.  Hardly a day goes by without hearing from the opponents and proponents of those Canadian online pharmacies that sell prescription drugs to American consumers at lower prices than their United States (US) pharmacy counterparts.  Unfortunately, its hard to get past the rhetoric when investigating this issue.  The very vehicle that has fueled the latest explosion of prescription business is now bloated with information (and misinformation) on this topic.  Conduct a Google search using the keywords “online pharmacy” and you’ll get no less than 4.5 million hits.  That’s about one hit for every $100 US in Canadian pharmaceutical sales to American consumers in 2002.  Or one hit for every 15 Americans who live without health insurance to support prescription drug costs.  Staggering numbers that reflect the true magnitude of health care system issues to the south.

In this issue, I join four PharmD students from the University of British Columbia as we attempt to capture some of the arguments for and against Canadian online pharmacies. During our investigation of this topic, it became apparent that things just aren’t as simple as they first appeared.  Opinions differ widely about the legality of this practice, an issue partially obscured by the presence of unscrupulous unlicensed pharmacies capitalizing on the public demand for less expensive drugs.  Claims of Canadian drug shortages resulting from the redirection of drugs to American customers have been made, although direct evidence appears to be lacking.   Fears have been voiced about the safety of drugs entering the United States from Canada, including claims of unapproved products, medications that are not stored properly and medicines that may be dispensed in the wrong amounts or without proper labeling.  While certainly valid concerns, these potential problems are not exclusive to the cross-border prescription business.  Concern has also been expressed about the impact of online pharmacies catering to US citizens in an era of Canadian pharmacist shortages, although lucrative business opportunities such as these can have positive spin off benefits to the profession.  And the list goes on.

Underlying the debate on this topic is the significant loss of profits to the pharmaceutical industry resulting from increased product sales at lower Canadian prices.  While Canada comprises only 2.6% of world pharmaceutical sales, the US has a voracious appetite for medications and accounts for 53.4% of the global market. (2)  A 20-fold difference in sales for a 9-fold difference in population.  Theoretically, the industry should be supportive of any activity that increases the likelihood that a prescription will actually be filled and their product will be purchased.  After all, more prescriptions translates into more profit.  However, when those are US prescriptions that will be filled at lower Canadian prices, profits will suffer and that’s contrary to the primary objective of these huge corporations and the shareholders they represent. There is one aspect of this issue for which there is absolutely no debate.  It’s all about money.

Symbiosis is an intimate association between two entities.  When both partners benefit, we have mutualism.  When there is a negative effect on one, we have a parasitic symbiosis and if no beneficial or negative effect exists, we have a commensal relationship.  I invite you to read the review  and decide for yourself what type of association this situation represents.

P. Jewesson, Ph.D. FCSHP – Publishing Editor

Email to the Editors

Why is There No Value in Clinical Practice Guidelines?

With the proliferation of clinical trials and emphasis on evidence-based practice in health professions, clinicians have become increasingly reliant on clinical practice guidelines (CPGs) to guide them in the management of their patients. At best, these guidelines represent a thorough analysis of the available evidence combined with the clinical acumen of the developers and can provide sound practical advice. At worst, they can perpetuate medical myths and disseminate tenuously-founded beliefs of the developers and the interests of their sponsors.

Evidence-based medicine (EBM) has been defined as “the integration of best research evidence with clinical expertise and patient values.”  Patient values are defined as “the unique preferences, concerns and expectations each patient brings to a clinical encounter and which must be integrated into clinical decisions if they are to serve the patient”. The integration of these three critical elements ensures that clinicians and patients can form a diagnostic and therapeutic alliance that will optimize clinical outcomes and quality of life.

To determine whether or not the “third element” of EBM, namely integration of patients’ values, was embodied in the creation of clinical practice guidelines, we decided to review three recently published, widely distributed and influential guidelines pertaining to the treatment of three different chronic medical conditions. These documents were:

  1. The Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) from 2001;
  2. The 2002 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada; (4) and
  3. The Seventh Report of the Joint National Committee (JNC) on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure from 2003.

Our specific goal was to identify the extent to which integration of patient values in therapeutic decision making was discussed. The results were surprising.

The 12-page (~7,500 word) 2001 NCEP guidelines designed to optimize the detection, evaluation, and treatment of elevated lipids in adult patients contained no mention of patient values, nor did the guidelines promote the involvement of patients in the therapeutic decision-making process. There was, however, a discussion of the procedures that can be followed to determine absolute risk based on an assessment of risk factors, and we presumed that the authors intended this information to be shared with the patient.

The 35-page (~19,000 word) 2002 Canadian guidelines for the diagnosis and management of osteoporosis contains only two statements that are suggestive of incorporating patient values. The first statement says that ” when a patient is identified as having a high risk for fracture, a discussion regarding treatment is recommended…”The second states that” it seems prudent to begin the identification of people at high risk for osteoporosis in their 50s, if they are willing to accept a treatment”

Finally, the 13-page (~5,000 word) 2003 JNC report contains only two statements that might be interpreted as attempts at encouraging integration of patient values. The first statement reads, “physicians should provide to patients, verbally and in writing, their specific BP numbers and goals” and the second states, “the patient and physician must agree on BP goals”. Interestingly, these statements refer to the surrogate marker of blood pressure rather than the more clinically relevant cardiovascular endpoints.

While these three recent and important guideline documents contained clear and specific recommendations about whom to treat and how to treat them, only 0.2% of the ~60 pages (~31,500 words) was devoted to integration of patient values into the therapeutic decision-making process.

In 1999, the National Health and Medical Research Council of Australia produced a document entitled “A guide to the development, implementation and evaluation of clinical practice guidelines”.  In this extensive publication, the authors state that one of the key principles for developing guidelines is that “guidelines should make provision for accommodating the different values and preferences of patients” and that guidelines should be developed using a “multidisciplinary approach that includes consumers”  It is not apparent that any of the guidelines we examined involved patients or consumers in their development, nor was much attention paid to the incorporation of patient values and preferences.

There are several potential reasons why the guidelines we reviewed neglected to adequately address patient values. It is conceivable that the developers were not aware of the “third element” of the EBM definition at the time of their construction. It is also possible that no consensus could be reached on what processes should be employed to incorporate patient values into therapeutic decision making. These processes would probably vary depending on the condition involved. Alternatively, the developers may have been unfamiliar with the actual magnitudes of risk and risk reduction associated with the conditions and therapies they are discussing, which relegates discussion with patients about these parameters to an implicit, qualitative exchange. The developers may have assumed that their readers were well aware of the magnitudes of benefit and risk associated with the treatments that they recommend and were already actively incorporating patients values into therapeutic decision making. Finally, it is possible that the authors of the guidelines concluded that patients would not understand the concept or wish to have their values incorporated into therapeutic decision-making. We can only speculate as to the etiology of these omissions.

Recently, one of us (JM) encouraged an author of a review article on the treatment and prevention of osteoporosis to present absolute risk and risk reduction in addition to relative risk and risk reduction data and suggested that this information should be used in the discussion of treatment options with patients. With this information, patients can be informed about what their risk for fractures is, the degree to which this risk may be reduced by taking a medication, the chance that they would experience a benefit from doing so, the potential of developing side effects and even how much money they could expect to spend on drugs in order to “buy” this chance of benefit. The author, who is one of the foremost experts on osteoporosis and bone density monitoring in the USA, President of the International Society of Clinical Densitometry and Vice President of the American College of Endocrinology, responded that “physicians don’t talk to their patients with these conditions in the terms proposed. We tell our patients, ‘Your blood pressure is too high; you should be on medication to reduce it;’ or ‘Your cholesterol level remains elevated despite diet and exercise; we need to add medication to bring it down.’ If [one] takes the approach he (JM) advocates for patients who have osteoporosis, I doubt that many of his patients opt for therapy. I agree with the request for including more complete information about the results of clinical trials. I strongly disagree with his proposal for using this information in clinical practice. I tell patients who have low bone density or a fragility fracture that they have osteoporosis. I tell them that patients who have osteoporosis should be treated. Most patients want my advice, not a lesson in data analysis.”

We find this response troubling. If these comments represent the views of opinion leaders in other areas of clinical practice, it seems unlikely that patient values will be incorporated into consensus guidelines anytime soon. In the absence of these values, practice guidelines will never truly reflect the fundamental principles of evidence-based practice.

P. Loewen, Pharm.D. – Publishing Editor

J. McCormack, Pharm.D. – Associate Editor

P. Jewesson, Ph.D. FCSHP – Publishing Editor

Issues in Pharmacotherapy Practice

contemporary issues by clinical practitioners

Canadian Online Pharmacies Serving U.S. Citizens: Patient Care or Profits?

Abstract

Background: American consumers have turned to Canadian online pharmacies (COPs) as a less expensive source of medications than those purchased in their own country.

Objectives:  In this article we examine some of the positive and negative aspects of Canadian pharmacists providing this service to American customers.

Results: Several arguments for and against COPs dispensing medications to U.S. Citizens are presented.  Issues of international price disparities and controls, pharmaceutical industry motives and profits, pharmacist ethics, best practices and patient rights and needs are just some of the factors that need to be considered when judging the relative benefits and risks of COPs.

Conclusion: Considering the substantial cost savings to American consumers, the profits being made in Canada and the substantial revenue loss that the pharmaceutical industry suffers as this practice expands, it is no surprise that COPs are receiving so much media attention.  When forming your own opinion about COPs, consider what would likely happen if the current medication price conditions were reversed.

Introduction

In an attempt to improve access to affordable medications, American consumers have turned to Canadian online pharmacies (COPs) as a less expensive source of medications than those purchased in their own country.  In the United States (U.S.), virtual pharmacies (otherwise known as internet pharmacies, cyberpharmacies or e-pharmacies) first surfaced in 1999. Since then, many online pharmacies have sprung up in the U.S. and this form of community pharmacy business has also become popular in Canada.  In 2002, there were at least 70 COPs (over one-half are based in Manitoba) and these were reportedly shipping in excess of $500 million U.S. of pharmaceuticals to American consumers during that calendar year.

While the presence of COPs is relatively new, the concept of cross-border shopping for medications is not.  American citizens have been purchasing drugs in Canada for many years.  Prices are cheaper and in some cases, drugs are easier to access than those in the U.S.  The advent of the Internet has simply served to broaden the reach of this practice.

Let’s examine some of the positive and negative aspects of Canadian pharmacists providing this service to American customers.

Some Arguments In Support for COPs Dispensing Medications to U.S. Citizens

1. COPs are simply filling a market niche and provide support for uninsured American consumers.

The U.S. market for international drug supplies is driven by high U.S. drug costs (including the prices of patented drugs) and the high incidence of Americans without health insurance. Some specific examples of disparate drug prices include celecoxib which sells at $78.50 U.S. for one hundred 100mg capsules from a COP versus $144.98 U.S – $178.63 U.S. at two American online pharmacies, and tamoxifen which Walgreens sells at $380.97 U.S. for 180 tablets while this product retails for $102.90 U.S. at a Manitoba-based web pharmacy.  Many other examples (both brand and generic) can be found on the COPs websites themselves.  The price of many drugs in the U.S. is also rising at an average rate that is several fold greater than that of inflation. This is in marked contrast to the lower drug prices and annual patented drug price increases in Canada.

These price pressures are especially difficult for the 65 million Americans (nearly 20% of the U.S. population) who do not have outpatient prescription insurance. To make matters worse, these uninsured persons are reportedly charged higher prices for drugs than HMOs, insurance companies and federal agencies. Together, these factors have created a group of consumers for whom prescriptions are a luxury that they cannot afford.  This reality is evident in the observation that uninsured persons fill 30% less of prescriptions received than those with insurance.

2. COPs allow American consumers to pay for the cost of pharmaceutical innovation instead of advertising  and lobbying.

The primary goal of the pharmaceutical industry is to make a profit. Industry representatives claim that their business is one that involves high risk.  While it is true that the cost of bringing a drug to market is significant, pharmaceutical companies are among the most profitable businesses on the Fortune 500 list and these profits have been consistently high for at least a decade.

Unfortunately, the high prices for pharmaceuticals do not simply reflect the research and development costs of bringing a drug to market, they also encompass the high costs of marketing and lobbying.

In 2000, the pharmaceutical industry spent $2.5 billion U.S. for advertising in the U.S. alone.  To put this into context, more money is spent on the advertising of Vioxx® than advertising of Pepsi or Budweiser beer.  In fact, eight of the top nine pharmaceutical companies reportedly spent at least two-fold more on marketing, advertising, and administration than they devoted to research and development in 2001.  According to Public Citizen research, the pharmaceutical industry  also spent $91.4 million U.S. on federal lobbying in 2002, a 12% increase over the previous year.  These expenses are simply rolled into the prices charged for drug products.  It’s clear that U.S. citizens are paying heavily for advertising and lobbying, and not necessarily for innovation.

3. COPs serve to alert American consumers about drug price conditions outside of their own country and the lack of price controls within.

The high cost of drugs in the U.S. is largely due to a lack of price controls.  This has been described as “America’s other drug problem”.  In fact, the U.S. is the only industrialized nation that does not employ price control mechanisms.  For more than a decade, U.S. congress has failed to provide increased drug coverage by expanding their medicare plan, a plan that would moderate the price of prescription drugs.

In Canada, the Patented Medicines Price Review Board (PMPRB) is responsible for regulating the prices that patentees charge for patented drugs sold in Canada. The manufacturers’ prices of patented drugs, as measured by the Patented Medicine Price Index (PMPI) fell by 1.2% in 2002 and mirrors the price declines and near-negligible increases in the PMPI commencing in 1993. Since the mid-1990’s and up until 2001, Canadian prices for patented drugs have remained 5-12% below the median of foreign prices.

Despite these price controls, the pharmaceutical industry in Canada continues to prosper. Total sales by manufacturers of pharmaceuticals for human use in Canada were estimated to be $13.1 billion CAN in 2002.  This represents an increase of 13.9% over 2001 sales. The share of patented drugs within total drug sales rose from 45% in 1996 to 67.4% in 2002. Total sales of patented drugs, as reported by patentees, reached $8.8 billion CAN in 2002, an increase of 17.3% over the previous year. In fact, in 2002 the median prices of patented medicines in the Canadian market have crept up to a value that is about 1% higher than the median of foreign prices in the seven countries.

4. COPs have been welcomed by American consumers and have received U.S. governmental support.

The presence of COPs has increased American consumer awareness as to how much lower prescription prices are outside the U.S. and a revolt is in the making.  Seniors groups and other organizations are now working with reputable COPs to bridge the gap between U.S. and Canadian drug costs. There is also evidence that municipal, state, and federal governmental support for COPs is mounting. For example, at the municipal level, the local government of Springfield Massachusetts has a plan in place to buy drugs from Canadian Internet pharmacies for its employees. At the state level, the Governor of Illinois is considering a plan to have state employees obtain medications from Canada  At the federal level, after a long and heated American Congress debate in July 2003, the house voted in favour of allowing American citizens to buy prescription medicines abroad. This was a defeat for the pharmaceutical industry and appears to be heralding even further changes  to Medicare and prescription price controls in the U.S..

5. COPs promote more efficient American spending on health care at time when public consumption of  prescription drugs has reached an all time high.

American prescription drug consumption is higher than ever, putting the U.S. health care system under significant economic pressure.  COPs sales to the U.S. results in direct savings to American consumers and should also indirectly help to reduce system pressures.   However, these sales will also negatively impact on North American profits for the pharmaceutical industry.

The American drug market accounts for the largest portion of sales and revenue for the global pharmaceutical industry. According to IMS Health, in 2002 the U.S. accounted for 53.4% of the world’s pharmaceutical sales and significant financial losses could be incurred if American drug prices were regulated.  The industry is  attempting to curtail sales of their products through COPs and is misinforming government officials about the safety of drugs provided by legitimate Canadian outlets. It is apparent, however, that their efforts so far have been insufficient to quell the building momentum.  Undoubtedly industry will step up its campaign against COPs over the next several months.

6. COPs likely represent one of the safest sources of international drug supplies for American consumers.

While counterfeit drugs are a legitimate concern, the distribution of counterfeit drug products is an activity that existed long before the advent of the Internet and the potential for this unscrupulous practice is not limited to COPs alone. American citizens are in fact receiving prescription drugs from numerous countries including Canada. This includes countries with a high prevalence of counterfeit drugs (e.g. Mexico, Argentina, China) where reports suggest that up to 50% of drug products may not meet stated claims.

Drug products produced in Canada are regulated by the Food and Drugs Act. Canadian laws and standards regarding drug purity and quality are at least as stringent as those of the U.S. Food and Drug Administration.  Licensed pharmacists from legitimate COPs dispense these drugs to American consumers in accordance with Canadian regulations and with proper labeling in English.  Product quality should not be an issue when dealing with legitimate COPs who obtain their drug supplies from the same manufacturers and wholesaler sources as traditional brick and mortar pharmacies.  In fact, most drug products dispensed to Canadian consumers originate in the U.S. and are produced by American subsidiaries of the parent conglomerate pharmaceutical companies.  These products are simply purchased from the U.S. through pharmaceutical wholesalers and dispensed back to American customers (“reimportation”).  Ironically, the pharmaceutical industry is claiming potential safety concerns associated with drugs that they themselves are manufacturing.  What the industry is really objecting to is the sale of products at prices that are less than those in the U.S..

7. COPs are able to apply the same standards of practice to American citizens as those that apply to Canadians.

COPS that dispense prescriptions to U.S. citizens must comply with standards of practice pertaining to patient care and drug delivery, as well as the code of ethics of Canadian licensing bodies and prescription regulations of American state board regulators. (35-38)  Unlicensed pharmacies have been fined.  Examples of some COPs that are in operation and adhere to these regulations are Canada Discount Pharmacy (www.canadadiscountpharmacy.com), Canada Meds (www.canadameds.com), and Cross Border Pharmacy (www.crossborderpharmacy.com).  In contrast, there are unlicensed pharmacies in Mexico (e.g. www.pillvalue.com, www.safemeds.com) that do not have this type of regulation.

In response to public concern over the safety of pharmacy practices on the Internet, the National Association of Pharmacy Regulatory Authorities (NAPRA) and the U.S. National Association of Boards of Pharmacy (NABP) have developed a certification system denoted Verified Internet Pharmacy Practice Sites (VIPPS) to allow legitimate businesses to operate.  Although this program does not set standards for cross-border Internet pharmacy, it represents an acknowledgment by American and Canadian regulatory authorities that Internet pharmacy can be a legitimate alternative to traditional brick and mortar pharmacies.

In addition, there are independent organizations such as the North American Pharmacy Accreditation Commission (NAPAC) and the Canadian International Pharmacy Association (CIPA) that have been formed  for the specific purpose of ensuring the quality of cross-border internet pharmacies. Accreditation by one of these organizations provides some degree of protection for the patient through the setting of minimum quality standards.  While NPAC or CIPA accreditation is not mandatory, the consumer can easily identify accredited sites by prominently displayed accreditation seals on the COPs homepage.  A review of 13 sites (accessible via www.canadadrugstores.com) revealed two sites accredited by CIPA only, one by NPAC only, six by both CIPA and NPAC, while four sites did not list a specific accreditation.

8. COPs permit adequate patient-pharmacist interaction to ensure safe therapy.

The patient-pharmacist relationship is a critical part of the pharmaceutical care process.  This is recognized by Canadian pharmacy licensing bodies and organizations setting quality standards for Internet pharmacies. Without face-to-face communication, COPs must find other ways to ensure this relationship is maintained. COPs typically provide a toll-free telephone number and invite patients to call or e-mail questions to a pharmacist.  Others actually incorporate a telephone consultation into the process.

One Alberta-based COPs reports success with such consultations even claiming that many American customers feel they received better information through the telephone consultation than they did in face-to-face interactions with their local pharmacist in the U.S. In addition, most COPs claim to focus their services toward meeting patients’ chronic medication needs.  While this does not negate the potential for drug misadventure, it could be expected to reduce the likelihood of complications associated with the initiation of new drug therapy.  This should, in turn, limit the complexity of their professional interactions, since patients are likely to already be stabilized and familiar with the medication(s) in question. Finally, the convenience and anonymity of the Internet may allow patients the opportunity to ask questions in a less intimidating environment, at a time suitable to them.  In this way the Internet may actually facilitate better communication. Thus, while there is the potential for the patient-pharmacist interaction to suffer as a result of the absence of direct contact, good communication between the patient and pharmacist is still possible and in some ways, it may actually be enhanced.

9. COPs are not the perfect solution, but they represent a reasonable interim solution for some American consumers.

COPs are not the ideal solution for American consumers who require medications.  Ideally, patients would be expected to form a patient-professional relationship with a local community pharmacist.  However, COPs do not preclude such a relationship from forming and being maintained.  In the context of purchasing costly chronic medications, however, they currently represent a reasonable lower cost alternative to American pharmacies.

If a drug is medically necessary but not affordable, the prescription won’t be filled.  COPs make drugs more affordable for the U.S. citizens who  might otherwise go without.  Consequently, one could argue that COPs have an ethical obligation to continue to support these customers.

Some Arguments In Opposition to COPS Dispensing Prescriptions to U.S. Citizens

1. COPs dispensing prescriptions to American consumers is at best controversial, probably unethical and possibly illegal. 

Canada and the U.S. have well-established authorities whose mandate is to regulate pharmacy practice within their jurisdiction.  It is unclear under which jurisdiction U.S. patients who are receiving Canadian pharmacy services should fall.  Canadian provincial pharmacy regulatory authorities recognize that the exportation of prescription drugs from Canada raises legal, ethical, and public policy issues for Canadians, in the context of health care, pharmacy services and availability of prescription drugs.  Several of these authorities have published guidelines that state it is unethical to provide services against the law of other countries.

Provincial pharmacy regulatory authorities in Canada and U.S. state pharmacy regulatory authorities agree that the international movement of prescription drugs between Canada and the United States undermines the regulatory systems established in each country to protect consumers. These organizations identify that failure to regulate (as evidenced by the continued cross-border sale of drugs) provides opportunities for illegitimate groups and medication “facilitators” to establish themselves. This regulation would require significant manpower to achieve and the negative fallout from patient groups would be politically charged.  No one wants to arrest seniors attempting to purchase life-supporting medications from COPs.

Most provinces have guidelines stating that pharmacists should follow the laws in the provinces and countries to which they provide a service. Present U.S. law does not permit U.S. citizens to import prescription drug products that are otherwise commercially available in the U.S. and COPs violate the intent of this law. Alberta pharmacists have been informed that they should not participate in any scheme or service to provide such activity.  Pharmacies and/or pharmacists that accommodate such services may be considered to be practicing unethically, and may be charged with professional and/or proprietary misconduct. In Manitoba, pharmacists have been advised that they must not contravene rules or regulations in effect in the jurisdiction where the patient resides.

2. COPs are unlikely to substantially improve prescription fill rates and these outlets are simply being used as a political tool to gain votes.

Ethically, pharmacists are obliged to undertake reasonable steps to ensure patient compliance with their medication and this would include ensuring its affordability.  While some would argue that cost is a major contributor to poor medication adherence, others question whether inability to pay is truly a major factor contributing to non-compliance in the senior population. U.S. studies have shown that affordability can be linked to prescription non-compliance in 1.5-14% of U.S. seniors. Data from the Medicare Current Beneficiary Survey for 1996 through 1999 suggest that while economic barriers were the most commonly stated reason for not filling a prescription, more than 97% of all seniors obtained the medications prescribed for them by their physicians. Thus, it would appear that the problem of poor prescription filling by seniors may not be as widespread as is often believed.

For years, politicians have been rallying votes by organizing bus trips to Canada in search of affordable drugs. Recently, Illinois Governor Rod Blagojevich has advocated using Canadian pharmacies to manage his drug budget for the state health insurance plan including employees, dependents and retirees. This is a population that is already insured, without issues of accessibility.  These are both attempts to band-aid the situation in the U.S. rather than to find a long-term sustainable plan for all  Americans.

3. COPs will result in drug shortages in Canada.

Canada pharmaceutical sales represents less than 3% of the total world drug sales market, while the U.S. represents over 53% of the global market. Considering the large number of American citizens (including about 7.6 million seniors) without health insurance, the potential American consumer demand for drug supplies from COPs could be overwhelming.

Cross-border sales of prescription drugs are beginning to concern officials at Health Canada. While there may be no direct evidence that COPs are resulting in Canadian drug shortages, their continued presence or expansion could aggravate a pre-existing drug supply problem that exists in both countries.  Although difficult to predict, it is possible that total North American medication consumption could increase by a factor at least as great as the proportion of previously unfilled U.S. prescriptions that would now be honoured by COPs.  Canadian consumers  would be most vulnerable to this situation since most drugs originate in the U.S. and shortages in that country could reduce exports to all others.

In response to increasing COPs sales, manufacturers have begun to limit drug supplies to Canadian outlets that are, or appear to be, engaged in cross-border medication shipping. (27,28,56) Should industry be unwilling to increase the exportation  of drugs to Canada to meet the growing demand related to COPs, drug shortages for Canadian consumers could become a reality.

4. COPs exacerbate a pre-existing shortage of Canadian pharmacists needed to support Canadian patient needs.

There is a pharmacist shortage in Canada, the U.S. and elsewhere.  A survey conducted in 2001 by the Canadian Association of Chain Drug Store identified a vacancy rate of 10% for pharmacist positions across the country and that this shortage has existed for at least the 2 years prior to the survey.  COPs are now attracting new Canadian graduates with salaries that cannot be matched in the balance of the community and hospital sectors.  It is estimated that 15-20% of pharmacists in Manitoba alone are involved with the Internet pharmacy industry. Continued growth of these COPs can be expected to further drain pharmacists away from the pool of those who are available to meet the needs of Canadian consumers.  This can only lead to a decline in the quality of pharmaceutical care provided to our citizens.

5. COPs put patient safety at risk by shipping drugs under uncontrolled conditions to American consumers.

There are potential safety risks associated with the cross-border transport of drugs. COPs that ship medications to the U.S. may be compromising good drug distribution practices through improper drug labeling, storage, handling and non-use of safety caps.  In a recent U.S. Pharmacopeia-sponsored study, over 90% of mail packages were exposed to temperatures outside the recommended range.  Over 25% of these supplies were exposed to temperatures in excess of 40°C. Although, the investigators did not report the number of packages shipped cross-border, the study nevertheless demonstrates that the integrity of packages shipped to the U.S. may be compromised.  Concerns regarding humidity and radiation have also been expressed. For example, the FDA has recently reported the interception of insulin supplies that were shipped across the border unrefrigerated.  As a consequence of these concerns, the Food and Drug Administration, whose mandate is to ensure the safety of Americans, has declared that it cannot guarantee the quality of drugs that are not made and sold in the U.S., and it believes the importation of drugs from Canada represents a potentially dangerous situation.

6. COPs fail to develop adequate patient-health care professional relationships leading to unsafe provision of pharmaceutical care. 

The Canadian Pharmacist Association has recently published a position statement on international prescription services and distance provisions of pharmaceuticals.  This organization emphasizes the need to place the health and safety of patients above all other concerns and declares that a relationship between the patient and pharmacist is essential for the safe and effective use of medications.  The Association explicitly advocates face-to-face communication between patients and pharmacists to build a relationship crucial to optimal management of drug therapy.  These standards are mandated provincially and territorially.  Finally, the Association endorses that all pharmacies in Canada (including COPs) meet these established standards of practice.  Needless to say, face-to-face communication is not possible with COPs.

The College of Pharmacists of British Columbia has recently developed a comprehensive framework of professional practice that defines the role and functions of a pharmacist. This organization states  that the primary role of the pharmacist is to provide pharmaceutical care which involves assessment of the client’s health status and needs, developing a care plan, supporting and monitoring client progress with the plan and then documenting findings, follow-ups, recommendations, information provided and client outcomes.  Again, these professional practice standards cannot be met with COPs. Some on-line pharmacies request only that the client fill out a questionnaire that is reviewed by a doctor after which time the pharmacist fills the prescription. Completing a written questionnaire is deemed all that is required to establish a patient-physician relationship.  Such a superficial exchange puts the patient at risk for drug misadventure.

To illustrate this concern, there have been several widely published problems with online pharmacies based in the U.S..  The FDA recently cited a case of a 52-year old man with episodes of chest pain and a family history of heart disease who died of a heart attack after taking sildenafil (Viagra®) that was purchased from an online source that only required completion of a questionnaire to get the prescription filled. While there was no definitive way to prove that sildenafil caused or contributed to patient’s death, the FDA concluded that a face-to-face interaction with the doctor and/or pharmacist along with a physical exam may have better ensured the appropriateness of the drug.  In another published case report involving a U.S. 20-year old female who required ICU admission after an unintentional overdose of phentermine, it was revealed that the patient with a history of anorexia nervosa had ingested 15 tablets over the course of 8 hours to curb her appetite. The prescription had been filled over the Internet with no direct patient-physician contact and the pharmacy from which the prescription was obtained was from another state.  While this was a U.S. Internet pharmacy-related incident and did not involve cross-border prescriptions, it nevertheless reflects the potential dangers associated with a lack of adequate patient assessment before the prescribing of a medication.   In another published report, a person of normal weight was able to obtain a weight loss drug. Another woman who said she had asthma received a prescription for celecoxib, and a reporter was able to order sildenafil for her 6-month old son using his actual height, weight and birth date.  Yet another individual was able to obtain sildenafil using vital data from his cat. And finally, two additional studies have been published that assessed the quality of service provided by Internet consulting physicians. The investigators posed as patients with known contraindications to sildenafil (i.e. females with coronary artery disease for one and a male with a history of heart attack currently taking nitrates).  Three of 10 physicians prescribed and the Internet pharmacies provided the drug to the women, while 1 of 5 pharmacies dispensed the medication to the male patient despite these contraindications. These are just some of the published examples of potential dangers associated with online pharmacies.  Extending this practice across an international border can only be expected to heighten the potential for misadventure.

In Summary

Cross-border shopping and transportation of goods has been popular as far back as the days of U.S. alcohol prohibition and earlier.  Americans have also purchased medications from Canada on a smaller scale for many years; the extent of this phenomenon has been just “under the radar” until the advent of the internet pharmacy.  Considering the substantial cost savings to American consumers, the profits that are being made by Canadian pharmacies (and Canada in general), and the even greater revenue loss that the pharmaceutical industry suffers as this practice expands, it is no wonder that COPs are now the focus of much public attention.

Issues of international price disparities and controls, pharmaceutical industry motives and profits, pharmacist ethics, best practices and patient rights and needs are just some of the factors that need to be carefully considered when judging the relative benefits and risks of COPs. While COPs may be an interim solution for Americans, we must also contemplate the net cost of this practice to Canadians.

When forming your own opinion about COPs, consider what would happen if the current conditions were reversed. Do you think that U.S. pharmacists would be willing to provide pharmaceuticals to Canadian citizens if drug prices were lower to the south?  Do you think that drug supplies dispensed from U.S. pharmacies would be safe enough for Canadians to consume?  Do you think U.S. pharmacists are professionally and ethically capable enough to provide services to our citizens?  Or do you believe that pharmacists participating in COPs have simply lost sight of their pledge to help people achieve their desired health outcomes in the interest of profits? We would welcome your opinions on this complex issue.

Authors Competing Interests

None declared.

Acknowledgment

This paper was based upon a Pharmacy 554 debate conducted by members of the 2005 graduating class of the UBC Doctor of Pharmacy Program in October 2003.  All authors collaborated towards the creation of the drafts and final editing of this paper.

Evidence-Based Snapshots

with emphasis on rapid review of results

Clinical Efficacy of Three Common Treatments in Acute Otitis Externa in Primary Care: Randomised Controlled Trial

Original Citation

Clinical efficacy of three common treatments in acute otitis externa in primary care: randomised controlled trial. van Balen FA, Smit WM, Zuithoff NP, Verhe TJ.  BMJ 2003;327:1201-5 PubMed Citation

Overall Study Question

These investigators compared acetic acid, to steroid plus acetic acid, to steroid plus antibiotics in the treatment of acute otitis externa.

Patients

213 patients with acute otitis externa. The average age of the patients was 45 years and 50% were female.

Treatment

Patients were randomized in a blinded fashion to receive either acetic acid, acetic acid plus triamcinolone or dexamethasone plus neomycin/polymyxin B all given three times daily until the patient had recovered.

Duration

The study duration was 21 days.

How does this study contribute to the drug therapy of patients with acute otitis externa?

This study suggests that eardrops containing corticosteroids plus acetic acid or corticosteroids plus antibiotics are more effective than acetic acid drops on their own in the treatment of otitis externa. There is no difference in efficacy between eardrops containing a combination of ingredients.

Valsartan, Captopril, or Both in Myocardial Infarction Complicated by Heart Failure, Left Ventricular Dysfunction, or Both?

Original Citation

Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. Pfeffer MA, McMurray JJ, Velazquez EJ, Rouleau JL, Kober L, Maggioni AP, Solomon SD, Swedberg K, Van de Werf F, White H, Leimberger JD, Henis M, Edwards S, Zelenkofske S, Sellers MA, Califf RM; Valsartan in Acute Myocardial Infarction Trial Investigators. N Engl J Med 2003;349 PubMed Citation

Overall Study Question

These investigators compared valsartan, captopril or both in patients with heart failure following an acute myocardial infarction.

Patients

14,703 patients with an acute myocardial infarction complicated by heart failure (Class 1 – 28%, Class 2 – 48%, Class 3 – 18%, Class 4 – 6%).  The average age of the patients was 65 years and  31% were female.

Treatment

Patients were randomized in a blinded fashion to receive either valsartan (20mg PO daily increased to 160 mg PO BID), captopril (6.25mg PO daily increased up to 50 mg PO TID) or both valsartan (20mg PO daily increased to 80 mg PO BID) and captopril (6.25mg PO daily increased up to 50 mg PO TID).

Duration

The median study duration was 25 months.

Results

There was no difference between groups in any end point. End points included death from cardiovascular causes, myocardial infarction, heart failure, resuscitation after cardiac arrest and stroke.

Overall adverse events were 5-6% higher in the combination group.

How does this study contribute to the drug therapy of patients with an acute myocardial infarction complicated by heart failure?

This study suggests that valsartan and captopril are equally effective in the treatment of an acute myocardial infarction complicated with heart failure and the combination of these agents is no more effective than the single agents alone.

Azithromycin for the Secondary Prevention of Coronary Heart Disease Events: The WIZARD Study

Original Citation

Azithromycin for the secondary prevention of coronary heart disease events: the WIZARD study: a randomized controlled trial. O’Connor CM, Dunne MW, Pfeffer MA, Muhlestein JB, Yao L, Gupta S, Benner RJ, Fisher MR, Cook TD; Investigators in the WIZARD Study.  JAMA 2003;290

Overall Study Question

These investigators compared a 12-week course of azithromycin to placebo in patients with stable coronary artery disease.

Patients

7747 patients with a history of myocardial infarction and a C pneumoniae IgG titer of 1:16 or more. Fifty-one percent had angina and 17% were smokers. Post-MI therapy prior to study enrollment included aspirin (87%), ACE inhibitors (42%), beta-blockers (60%), and statins (60%). The average age of the patients was 62 years and 18% were female.

Treatment

Patients were randomized in a blinded fashion to receive either azithromycin (600 mg PO daily for three days then weekly) or placebo for 12 weeks.

Duration

The median study duration follow-up was 14 months.

Results

There was no difference between groups in the primary end point or any of its components; death, recurrent MI, revascularizations, or hospitalizations for angina. Azithromycin did produce a 9% absolute increase in the chance of diarrhea.

How does this study contribute to the drug therapy of patients with coronary artery disease?

This study suggests that in patients with stable coronary artery disease, a 12 week course of azithromycin did not have an impact on coronary heart disease-related events.

Evidence-Based Reviews of the Pharmacotherapeutic Literature

with emphasis on interpretation of the findings, designed to help practitioners put the findings into proper perspective

Serum Digoxin Concentrations and Outcomes in Patients with Heart Failure: Is There Any Association?

Original Citation

Rathore SS, Curtis JP, Wang Y, Bristow MR, Krumholz HM.  Association of serum digoxin concentration and outcomes in patients with heart failure. JAMA 2003;289

Overall Study Question

This study was a post-hoc analysis of data from the 1997 Digitalis Investigation Group (DIG) trial. The DIG trial was a 3-year randomized, double-blind, placebo-controlled trial of the effect of digoxin on mortality and hospitalization rates in adult patients with heart failure, a left ventricular ejection fraction of 45% or less and a normal sinus rhythm.  The DIG investigators reported that digoxin afforded no overall mortality benefit and only a modest reduction in hospitalizations among patients with heart failure and depressed left ventricular systolic function.  The main objective of the current study was to assess the association of variations in serum digoxin concentration (SDC) with mortality and hospitalizations in a subgroup of male patients (mean age 63 years) enrolled in the DIG study.

Of the 6800 male and female patients originally enrolled in the DIG trial, 3,782 men were included in the current analysis.  Of these patients, 1171 were randomly assigned to digoxin and 2611 were randomly assigned to placebo.  Those patients allocated to the digoxin group who had valid SDCs assessed at 1 month following randomization were identified and subsequently divided into 3 subgroups based on SDC thresholds (0.5-0.8 ng/mL, 0.9-1.1 ng/mL and > 1.2 ng/mL) determined from previous studies.

What was the declared relationship between authors and sponsors for this study?

This was an unfunded analysis of data obtained from a public use copy of the DIG study and was conducted independently from the original DIG investigators.

Are the Results of the Study Valid?

1. Was assignment of patients randomized?

Yes.  This study was a post-hoc analysis of a cohort of males who participated in the original randomized, double-blind placebo-controlled DIG trial.  Patients were originally randomly assigned to digoxin or placebo based on a published algorithm based on age, sex, weight and renal function. Adjustments to the initial dose were allowed depending on prior digoxin dosages and concomitant pharmacotherapy.

2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?

Yes.  Among the men assigned to placebo, 28 were excluded from analysis because they died in the month following randomization.  This was done to replicate the same process undertaken for the digoxin-assigned patients.

3. Were patients, their clinicians, and study personnel ‘blind’ to treatment?

Yes. Patients and data investigators were blinded with respect to treatment, and cause of death was determined without knowledge of assigned treatment group.

4. Were the groups similar at the start of the trial?

The baseline characteristics of the digoxin and placebo groups in the main DIG trial appeared to be similar.  However, there were significant differences in baseline characteristics when comparing SDC subgroups.  Patients with a SDC of 0.5 to 0.8 ng/mL tended to have a lower incidence of NYHA class III/IV heart failure as compared to those with higher SDC ranges.  This subgroup was also younger, had a lower occurrence of four or more heart failure signs or symptoms, had better renal function (higher GFR and lower serum creatinine) and had used less nitrates and diuretics than the higher SDC groups.  This would suggest that these patients were less sick and this may have contributed to the higher survival in this patient group.

5. Aside from the experimental intervention, were the groups treated equally?

Yes.  There appeared to be no differences in the additional treatment received by the study patients.

What were the Results?

1. How large was the treatment effect?

Of the 1171 men with SDCs assessed at 1 month, 572 (49%) had an SDC between 0.5 and 0.8 ng/mL, 322 (27%) had an SDC of 0.9 to 1.1% and 277 (24%) had an SDC of 1.2 ng/mL or higher.  There was no overall difference in the primary endpoint (all-cause mortality) among men assigned to placebo or those digoxin recipients who had SDCs assessed (36.2% vs. 36.6%, 95% confidence interval [CI] 9 to 3.8, p = 0.80).

When stratified by serum digoxin concentration, men with lower SDCs of 0.5 to 0.8 ng/mL had a 6.3% lower all-cause mortality rate (p = 0.005; number needed to treat [NNT] = 15) and 5.9% lower rate of hospitalizations (61.9% vs. 67.8%; 95% CI -1.5 to .2; NNT = 17) as compared to the placebo group.  Compared to this subgroup, there was no associated reduction in mortality in the subgroup of men with SDCs of 0.9 to 1.1 ng/mL (absolute difference 2.6%, p = 0.36).  In contrast, men with SDCs > 1.2 ng/mL had an 11.8% increased all-cause mortality rate compared with men in the placebo group (95% CI, 5.7 to 18.0, p < 0.001).

2. How precise was the estimate of the treatment effect?

The 95% CI around the absolute mortality benefit of 6.3% (SDC 0.5 to 0.8 ng/mL subgroup vs. placebo) was .5 to 1. The 95% CI around the non-significant reduction in mortality between this subgroup and the SDC 0.9 to 1.1 ng/mL subgroup was 0 to 8.3, p = 0.36).  Finally, the 95% CI around the absolute all-cause mortality benefit of 11.8% (SDC > 1.2 ng/mL vs. placebo) was 5.7 to 18.0.

Will the Results Help Me in Caring for My Patients?

1. Can the results be applied to my patient care?

Because this was a post-hoc analysis of non-randomized treatment subgroups, the possibility of confounding influences cannot be excluded and it should be considered hypothesis generating only. Additionally, since it only evaluated men with heart failure in sinus rhythm and an LVF EF <45%, generalizability to the general population is limited.

2. Were all clinically important outcomes considered?

Yes. The primary outcome was all-cause mortality at follow-up (mean 37 months). Secondary endpoints were death due to cardiovascular causes, death due to worsening heart failure and hospitalization for worsening heart failure.

3. Are the likely treatment benefits worth the potential harms and costs?

Digoxin is an effective and inexpensive agent for symptom relief, despite its inability to reduce overall mortality rates in heart failure. This analysis suggests that the effectiveness and safety of digoxin in men with heart failure may be optimized by monitoring and maintaining SDC between 0.5 and 0.8 ng/mL. This may require an increase in the number of serum digoxin determinations, with an associated increase in monitoring costs. It is yet to be determined if the benefits outweigh the additional costs.

Commentary

Since the publication of the DIG trial, concerns have been raised regarding the relative efficacy and safety of a SDC greater than 1.0 ng/mL. Recent data have suggested that the maintenance of a low (< 0.09 ng/mL) SDC is as effective in heart failure as higher levels and is associated with a lower incidence of toxicity. What the present analysis does is provide further support for the suggestion that a SDC that has traditionally been considered as normal, may in fact be harmful and that the target therapeutic range for digoxin should be lowered to 0.5-0.8 ng/mL.

How the results of this analysis are translated into everyday clinical practice is difficult to determine. The question of where digoxin fits in the in the treatment of heart failure is probably more important than the issue of the appropriate SDC. Because of the well-established mortality benefits of ACE Inhibitors, beta blockers, and spironolactone, therapy with these agents should be optimized first.  Clinicians must then decide, before any concerns about appropriate SDCs, whether the benefits of using digoxin outweigh its risks. For those who do not believe in the benefits of digoxin, these results will probably have little impact on their current practice. Those who believe that digoxin has a role in alleviating symptoms of heart failure, prolonging exercise tolerance, improving quality of life and reducing hospitalizations, it may now be clinically prudent to attempt to achieve a SDC of 0.5-0.8 ng/mL. Whether it is practical or possible to maintain SDCs in this narrow range is debatable.  It would certainly necessitate more routine use of digoxin level determinations. Whether the benefits of maintaining SDCs within the lower, narrower therapeutic range offset the added cost and workload remains to be determined.  A randomized, controlled trial (including the routine use of beta-blockers) is needed to confirm these findings.

Reviewer Competing Interests

None declared.

Blood Pressure Lowering or Just Candesartan in Acute Ischemic Stroke? The ACCESS Trial

Original Citation

Schrader J, Luders S, Kulschewski A, et al.  The ACCESS Study: evaluation of Acute Candesartan Cilexetil Therapy in Stroke Survivors. Stroke 2003;34:1699-1703.

Overall Study Question

The objective of this study was to assess the safety of modest blood pressure reduction using candesartan in acute ischemic stroke.  Patients with acute ischemic stroke (hemorrhage ruled out by CT) and hypertension such that blood pressure (BP) reduction was indicated, based on current (German) guidelines (SBP >200 mmHg and/or DBP >110 mmHg 6-12 hours after onset or SBP >180 mmHg and/or DBP >105 mmHg 24-36 hours after admission).

This study was conducted in two phases.  PHASE 1: In the experimental arm, the intent was to produce a 10-15% BP reduction within 24 hours using candesartan started on within 24h of admission. In reality, the treatment was started about 30 hours after symptom onset. The dose was titrated from 4 mg daily to 16 mg over the first 48h, according to need. If BP remained very high (SBP >230 mmHg or DBP >115 mmHg on day 1 or SBP >200 mmHg or DBP >110 mmHg on following days) despite candesartan, urapidil (an alpha/beta receptor blocker used commonly in Europe) could be electively added. This portion of the study lasted 7 days, and the control group received placebo during this time. PHASE 2: At 7 days post-stroke, candesartan patients whose BP was still >135/85 mmHg had their dose increased or additional antihypertensives added (hydrochlorothiazide, metoprolol or felodipine). In placebo-treated patients with BP >140/90 mmHg, candesartan was started. This was required in 164/166 patients in the placebo arm. Phase 2 continued for one year. Note that the BP levels justifying intervention used here, based apparently on German guidelines, are slightly lower than the thresholds in the ACLS guidelines used in North America (SBP >220 mmHg, DBP >120 mmHg).

The primary outcomes were mortality or disability (using Barthel Index) at 30 days post-stroke. Secondary outcomes included mortality plus cerebrovascular or cardiovascular events at one year.

What was the declared relationship between authors and sponsors for this study?

Although the study was “supported” by AstraZeneca Germany (makers of candesartan), the authors report that this was an investigator-initiated study. None of the authors were employees of the sponsor. No conflict of interest declarations are included in the manuscript.

Are the Results of the Study Valid?

1. Was assignment of patients randomized?

Yes, during Phase 1, which applied to the primary endpoint. Phase 2 treatment was dictated based on presence or absence of hypertension at 7 days post-stroke and thus was not randomized.

2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?

The plan was to enroll 500 patients. The data safety monitoring board recommended stopping the study when 342 subjects had been enrolled. Only 339 subjects were included in the analysis, although reasons for exclusion of the 3 patients are given (carotid stenosis, brain metastasis). Thus, the analysis was not performed using intention-to-treat methods. The exclusion of 3 subjects is not likely to influence the results meaningfully.

3. Were patients, their clinicians, and study personnel ‘blind’ to treatment?

Yes, in Phase 1. Though the authors do not differentiate between Phases 1 and 2 in this regard, it is difficult to imagine how blinding could have been maintained in phase 2. It is somewhat irrelevant, however, since all patients except two were on candesartan during this phase. 

4. Were the groups similar at the start of the trial?

For the baseline characteristics described, they appeared to be similar.

5. Aside from the experimental intervention, were the groups treated equally?

Yes, during Phase 1. In Phase 2, however, not much detail is provided. It is reported that use of concomitant antihypertensives and aspirin was similar between the two groups. 

What were the Results?

1. How large was the treatment effect? 

Primary endpoint (30 days): No mortality results are provided, aside from what can be observed from the 12-month survival curves, which does show divergence in favour of the experimental group. The Barthel Index scores showed no difference at this point, although the authors report that during the analysis phase they decided that it was invalid to use the Barthel Index based on some new data which had become available. The amount of urapidil required was not reported.

Secondary Endpoint (12 months): Death plus cerebrovascular or cardiovascular events occurred in 9.8% of experimental arm and 18.7% in control arm (p=0.026). Mortality alone occurred in 2.9% of patients in experimental compared to 7.2% in control arm (p=0.07). Cerebrovascular events occurred in 7.5% in experimental compared to 11.5% in control arm while cardiovascular events occurred in 1.2% of the experimental group compared to 6.0% in control arm. The survival curves for the composite secondary endpoint were significantly different (p=0.026), favouring the experimental arm. The odds ratio for the secondary endpoint was 0.475 (95% CI 0.252-0.895).

It is critical to note that despite the use of candesartan, there was no difference blood pressure lowering between the experimental and control groups over the first 7 days. During the 1 year follow-up, the two groups were on roughly the same treatment, so as expected, there were no overall differences in blood pressure here either.

2. How precise was the estimate of the treatment effect?

Unfortunately, no evaluable results for the primary endpoint were provided.  The 95% confidence interval around the absolute risk reduction (ARR) for the secondary endpoint (8.9%) was 1.44-16.25%. Thus, this result is consistent with a fairly large and clinically meaningful treatment effect as well as a small and possibly marginally important one.

Will the Results Help Me in Caring for My Patients?

1. Can the results be applied to my patient care?

Because of the preliminary nature of this data (a Phase II trial with incomplete reporting of primary outcome results) and its failure to test the blood pressure-lowering hypothesis, it would be premature to conclude that candesartan in the preferred agent for pharmacologically lowering BP in the acute stroke phase. It was not effective for lowering blood pressure. However, its use could be considered as an adjunct to standard acute BP-lowering therapy in hopes of replicating the results show in this trial.

2. Were all clinically important outcomes considered?

The outcomes considered were appropriate, however more rigorous endpoint evaluations would have included other measures of function (e.g. Modified Rankin scale) and neurologic outome (e.g. NIH Stroke Scale) as is typically done in acute stroke trials. Curiously, an earlier publication by the authors states that they planned to use exactly these measures.(2)  Using these could have helped the primary endpoint analysis since the Barthel Index had to be abandoned.

3. Are the likely treatment benefits worth the potential harms and costs?

The limitations in reporting of the primary endpoint make it difficult to determine whether the benefits outweigh the harms overall. From a vascular events viewpoint, they certainly appeared to at the 1 year endpoint. Unfortunately, insufficient data is provided to judge whether patients were any better off from a functional or neurological viewpoint at 3 months or 1 year.

Commentary

This trial is the first systematic evaluation of blood pressure lowering in patients with very high BP in the immediate post-stroke period. Current guidelines state that no attempts to lower blood pressure should be made in this phase unless the pressure is very high or there is concomitant myocardial ischemia, heart failure, or arterial dissection. Even then, however, the effects of doing so have not been formally evaluated. The main concern about lowering blood pressure is that it may interfere with a compensatory response to cerebral hypoperfusion and thereby cause harm.

What is remarkable about this trial is that a relatively large effect on vascular events was achieved by starting candesartan immediately, even though blood pressure was not lowered any more than it was in the placebo group. This strongly suggests another mechanism for candesartan’s efficacy in acute stroke. Furthermore, even though both groups were on similar BP-lowering regimens over the next year with similar BP, vascular events continued to accrue at a much higher rate in the group which received placebo during the first 7 days than in the initial candesartan recipients. Looking at the survival curves, it appears that the divergence occurred after the first 7 days.

The authors hypothesize that early vascular remodeling is favourably influenced by angiotensin blockade and the effects of this are manifest over the subsequent months.

While it is clear is that a larger more rigorously reported trial is justified and probably required to confirm the promising hypotheses raised in this trial, in the meantime clinicians are left in a difficult position. For patients who require blood pressure lowering according to ACLS guidelines, should they use candesartan in hopes of replicating the outcome benefits shown in this trial even though it may be inefficacious in meeting blood pressure goals? Or, should they use nitroprusside or labetalol and titrate upward until the BP drops by 10-20%, as the ACLS guidelines currently recommend, despite no clinical trials to suggest benefit? A third option would be to start candesartan in hopes of gleaning its remodeling benefits and use standard BP-lowering drugs as per ACLS to do the “heavy lifting” of BP reduction. I suspect that the third option is justified, particularly in patients with a history of hypertension requiring chronic drug therapy anyway.

Unfortunately this trial did not test its primary hypothesis of whether it is safe to lower blood pressure in the acute stages of ischemic stroke. Nonetheless candesartan appeared to confer significant benefits when initiated early.

Reviewer Competing Interests

None declared.

Prevention of Coronary and Stroke Events with Atorvastatin in Hypertensive Patients:  Impact for Future Clinical Practice Guidelines?

Original Citation

Sever PS, Dahlöf B, Poulter NR, Wedel H, Beevers G, Caulfield M, Collins R, Kjeldsen SE, Kritinsson A, McInnes GT, Mehlsen J, Nieminen M, O’Brien E, Östergren J, for the ASCOT Investigators. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial – Lipid Lowering Arm (ASCOT-LLA): a multicentre randomized controlled trial. Lancet 2003;361:1149-58.

Overall Study Question

The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) was a large multicentre, international trial, which involved two treatment comparisons in a two-by-two factorial design. The first was a prospective, randomized, open, blinded endpoint (PROBE) design comparing two antihypertensive regimens (anticipated to be completed in early 2005).  The second was a prospective, double-blind randomized comparison of the cardiovascular effects of the lipid-lowering agent atorvastatin 10 mg daily compared to placebo among patients who had non-fasting total cholesterol concentrations of ≤6.5 mmol/L. It is the lipid-lowering arm of this trial (ASCOT-LLA) that is the focus of this publication.

Men and women between the ages of 40 and 79 years at the time of randomization were eligible if they were hypertensive according to the study definitions and had at least three pre-specified cardiovascular risk factors. Subjects with untreated hypertension (not already receiving antihypertensive medication) were eligible if they had either a systolic blood pressure (SBP) ≥160 mmHg and/or a diastolic blood pressure (DBP) ≥100 mmHg, while those with treated hypertension (already receiving antihypertensive medication) were eligible if they had SBP ≥140 mmHg and/or DBP ≥90 mmHg. In addition, the study population was required to have at least three of the following risk factors for cardiovascular disease: non-insulin dependent diabetes mellitus (NIDDM), peripheral arterial disease (PAD), previous stroke or transient ischemic attack (TIA), left-ventricular hypertrophy (LVH), other specified abnormalities on electrocardiogram (ECG), microalbuminuria or proteinuria, plasma total cholesterol to HDL-cholesterol ratio ≥6, male gender, age ≥55 years, smoking, or premature history of coronary heart disease in a first degree relative. Patients were excluded if they had any of the following: previous myocardial infarction (MI), currently treated angina, a cerebrovascular event within the previous 3 months, fasting triglycerides >4.5 mmol/L, heart failure, uncontrolled arrhythmias, or any clinically important hematological or biochemical abnormality on routine screening.

Patients fulfilling the criteria for the blood pressure lowering arm of ASCOT, were subsequently eligible for the lipid-lowering arm if they had a non-fasting total cholesterol concentration ≤6.5 mmol/L and were not currently taking a statin or a fibrate. Following an initial study-screening visit, all patients completed a 4-week run-in period in order to allow sufficient time to confirm the patient’s eligibility and obtain informed consent prior to randomization. Also during this time, each patient’s family physician or local investigator had the opportunity to review the non-fasting screening lipid values and consider the need for lipid-lowering treatment.  Only patients whose physicians did not intend to treat them with a statin or a fibrate were randomized to treatment with atorvastatin 10 mg daily or matching placebo.  In this arm of the study, the investigators set out to determine whether lipid-lowering with a statin provided additional beneficial effects to antihypertensive treatment in hypertensive patients with average or below average levels of serum total cholesterol.

The primary endpoint was the combination of nonfatal MI (symptomatic and the so-called silent MI) plus fatal CHD.  The secondary endpoints of interest included each of the following: the primary outcome (non-fatal MI plus fatal CHD) without silent events, all-cause mortality, total CV mortality, fatal and non-fatal stroke, fatal and non-fatal heart failure, total coronary endpoints, and total CV events and procedures. The pre-specified tertiary endpoints included: silent MI, unstable angina, chronic stable angina, PAD, life-threatening arrhythmias (VF or sustained VT or complete heart block), the development of diabetes mellitus or renal impairment, and the primary endpoint among several subgroups. In addition, the investigators planned for an assessment of the effects of treatment on health care costs and on all the major study endpoints among 18 different subgroups of patients (e.g. diabetics, males/females, and previous vascular disease).

What was the declared relationship between authors and sponsors for this study?

The principal funding source for ASCOT was Pfizer (New York, NY; USA). In addition, the Servier Research Group (Paris, France) and Leo Laboratories (Copenhagen, Denmark) provided support in the form of study medications.  However, the authors indicate that ASCOT was conceived, designed, and coordinated by an investigator-led independent steering committee with members representing all of the countries where the trial was being conducted.  While the principal funding source had two members on the steering committee, both had non-voting privileges.  In addition, the data analysis and manuscript preparation were conducted independent of the principal funding source.  The publication also explicitly outlines the potential conflict of interest for the fourteen authors listed.

Are the Results of the Study Valid?

1. Was assignment of patients randomized?

Yes. Patients were recruited from February 1998 to May 2000 out of 686 general practices in Denmark, Norway, and Sweden and 32 regional centres to which patients were referred by their family physicians in the United Kingdom and Ireland. From these practices 19,342 patients were randomized to one of the two antihypertensive regimens (10,244 from the Nordic general practices and 9,098 from the UK/Ireland regional centres) with 10,305 of these subjects eligible for ASCOT-LLA and further randomized to receive atorvastatin 10 mg daily or placebo. Randomization to one of the two groups was assigned by computer, with the use of minimization procedures at one of the two coordinating centres in London and Gothenberg. While this article and the previous publication2 describing the rationale and design of the trial do not specifically address the issues of the total number of patients screened for the study, more than 90% of the patients eligible for the lipid-lowering arm were randomized.

2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?

Yes. A total of 10,305 subjects randomized in the lipid-lowering arm, 5,137 to placebo and 5,168 to atorvastatin 10 mg daily. At the close of follow-up for the lipid-lowering arm, complete information was available for 98.8% (10,186) of the patients randomized. For the remainder of subjects with incomplete data, vital status was obtained for all but 17 of them (10 placebo-assigned subjects (0.19%) and 7 atorvastatin-assigned subjects (0.14%) lost to follow-up). Analysis was conducted in accordance with the intention-to-treat principle. All analyses excluded endpoints deemed invalid by the endpoint committee and statistical censoring was enforced at the end of the study (October 1, 2002) or death before that date.

3. Were patients, their clinicians, and study personnel ‘blind’ to treatment?

Yes, in part. Both the patients and the study personnel were blinded to the lipid-lowering treatment, as they received either atorvastatin 10 mg daily or a matching placebo. The blood pressure lowering arm of the study was conducted according to the prospective randomized open blinded endpoints (PROBE) design, which aims to create conditions more similar to clinical practice than the classical double-blind design. (1)  While two central laboratories (one for the Nordic countries and one for the UK/Ireland) analyzed all blood samples, including serum lipids, it is unclear whether or not the physicians caring for these patients were asked not to perform serum lipid studies at their local laboratory during the trial. All of the study endpoints were adjudicated according to standardized study criteria, definitions and algorithms by at least two members of the independent endpoints committee who were blinded to the study treatments.

4. Were the groups similar at the start of the trial?

Yes. Both the atorvastatin and placebo treated patients had similar baseline demographics, including serum lipid levels and cardiovascular risk factors. They were also similar in terms of their prior use of antihypertensive treatments and their use of aspirin and lipid-lowering treatment (excluding statins and fibrates) at baseline.

5. Aside from the experimental intervention, were the groups treated equally?

Yes. All patients adhered to the same follow-up visit schedule during the study. The study protocol permitted physicians to prescribe additional lipid-lowering therapy for patients in an open-label fashion, if they judged it to be necessary for the patient. Consequently, it was reported that 9% of the placebo-treated patients were prescribed an open-label statin by the end of follow-up. However, it is unclear whether or not there were any differences between the treatment groups in the use of other lipid-lowering medications at the end of follow-up.

What were the Results?

1. How large was the treatment effect? 

The study was stopped prematurely upon the recommendation of the data safety monitoring board (DSMB), on the grounds that atorvastatin had resulted in a significant reduction in the primary endpoint and a significant reduction in the incidence of stroke. While the study was designed to follow-up patients for an average of 5 years, the DSMB recommended this arm of the study be discontinued after a median follow-up of only 3.3 years (33,041 patient-years). The intention-to-treat analysis revealed that the primary endpoint of non-fatal MI (including silent MI’s) plus fatal CHD occurred in 1.9% of the atorvastatin group and 3.0% of the placebo group. The unadjusted hazard ratio (HR) for the primary endpoint was 64% (95% CI 50% to 83%; p=0.0005), resulting in a relative risk reduction (RRR) of 36% (95% CI 17% to 50%), an absolute risk reduction (ARR) of 1.1% (95% CI 0.5% to 1.7%), and a number needed to treat (NNT) of 91 patients (95% CI 59 to 200). Statistically significant reductions also occurred in the atorvastatin-treated patients for the following secondary endpoints: fatal and non-fatal stroke (p=0.0236, ARR = 0.7%, NNT = 143), non-fatal MI’s (excluding silent MI) plus fatal CHD (p=0.0005, ARR =1.0%, NNT = 100), total coronary events (p=0.0005, ARR = 1.4%, NNT = 71), as well as total cardiovascular events and procedures (p=0.0005, ARR = 2.0%, NNT = 50). There was no difference in the incidence of all-cause mortality, cardiovascular mortality, or fatal and non-fatal heart failure. Only one of the seven tertiary endpoints was statistically significant between the groups; chronic stable angina occurred in 0.6% of the atorvastatin-treated patients and 1.1% of the placebo patients resulting in an unadjusted HR = 59% (95% CI 38% to 90%; p=0.0135), RRR = 41%, ARR = 0.5%, and a NNT = 200.

It is important to note that blood pressure was similar in both groups (mean values of ~138/80 mmHg) and that an average blood pressure reduction of 25/14 mmHg was achieved in this trial. At the end of the study follow-up, patients treated with atorvastatin experienced relative reductions of 23% in total cholesterol (TC), 33% in LDL-cholesterol, and 22% in triglycerides (TG), compared to the placebo-treated patients who experienced relative reductions of only 5% in TC, 5% in LDL, and 10% in TG. No significant change in HDL-cholesterol occurred in either group.

The proportional effect of atorvastatin on the combined primary endpoint was not significantly different in any of the 18 prespecified subgroups analyzed. However, there was no significant benefit observed in seven of the subgroups, including patients with diabetes and women.

2. How precise was the estimate of the treatment effect?

The confidence interval for the unadjusted HR for combined primary endpoint of non-fatal MI (including silent MI’s) plus fatal CHD [HR=64%; 95% CI 50% to 83%; p=0.0005], as well as the secondary endpoint of fatal and non-fatal stroke [HR=73%; 95% CI 56% to 96%; p=0.0236] are narrow, indicating precision of point estimates of the treatment effect.

Will the Results Help Me in Caring for My Patients?

1. Can the results be applied to my patient care?

Yes. The results of this study can be generalized to moderately hypertensive patients, who are at moderate risk for cardiovascular events. While the participants in this study were mainly white (95%), males (81%), with mean age of 63 years old, this is consistent with the populations studied in other large prevention trials of the effect of statin treatment on cardiovascular events. Since the inclusion and exclusion criteria were clearly defined and not exceedingly restrictive, they could be easily applied to the majority of patients with moderate hypertension seen in any practice area.

As previously indicated, we do not know the number of patients who were actually screened and failed to meet the entry criteria for the blood pressure arm of the study. However, given that more than 90% of those eligible were randomized in the lipid-lowering arm, we can assume that the study results can be broadly applied to hypertensive patients. For the less than 10% of patients who were eligible but not randomized, no details concerning the reasons are provided. The 4-week run-in period for this study permitted the investigators not to randomize subjects who were deemed unlikely to comply with the treatment protocol for several years. Even if non-compliance was the primary reason for not enrolling these patients, this number is very reasonable given the poor rates of medication adherence usually attributed to the statins in clinical practice.

2. Were all clinically important outcomes considered?

Yes. All of the outcomes were clearly defined and are clinically important.

3. Are the likely treatment benefits worth the potential harms and costs?

Yes. The reductions observed in the in the primary combined endpoint (non-fatal MI plus fatal CHD), as well as the secondary endpoints are both statistically and clinically significant. Atorvastatin was well tolerated in this population, with 87% of patients originally assigned to the active treatment group still taking a statin after 3 years of follow-up. The number of serious adverse events and rates of liver enzyme abnormalities did not differ between the atorvastatin and placebo treated patients. While there was one non-fatal case of rhabdomyolysis in a patient receiving atorvastatin, it was noted that his concurrent high alcohol intake and recent febrile illness might have been a confounding contributor.

Clearly long-term lipid-lowering treatment with a statin is expensive, but the cost savings over time in terms of reduced cardiovascular morbidity and mortality have already been proven. Nevertheless, the cost-effectiveness of long-term use of atorvastatin 10 mg daily for primary prevention among hypertensive patients with a cardiovascular risk profile as low as most of those included in this study remains to be clarified.

Commentary

The current study assessed the impact of atorvastatin specifically in hypertensive patients with reasonably controlled blood pressures and normal or mild-to-moderately elevated levels of serum cholesterol. While patients with hypertension have been included in the previous lipid-lowering trials, this study evaluated the benefits of lipid lowering with a statin in this specific population of patients with a lower range of lipids levels (total cholesterol ≤6.5 mmol/L) than the prior trials. Consequently, the results of the ASCOT-LLA both confirm and extend the results of the two previously published primary prevention trials (WOSCOPS and AFCAPS/TexCAPS ) documenting the benefits of a statin for the prevention of major fatal and non-fatal events coronary and cerebrovascular events. While the magnitude of the benefits observed is consistent with those seen in the earlier primary prevention trials, the present trial had a significantly shorter duration of follow-up (mean 3.3 years) due to its early termination. If the study had been continued for the 5 years of follow-up that was originally planned, we might expect to have observed a further reduction in events. It should also be noted that the study evaluated a fixed starting dose of atorvastatin (10 mg daily). Therefore, whether or not titration of the dose to achieve greater reductions in serum cholesterol may have resulted in any further reduction of events is matter of speculation.

ASCOT is not the only lipid-lowering trial that has been conducted specifically among patients with hypertension. The recently published antihypertensive drug trial ALLHAT also included a randomized lipid-lowering arm. Among a subgroup of 10,355 patients in ALLHAT, the effects of pravastatin 40 mg daily were compared to usual care. Unlike the present trial, there were no significant benefits in terms of cardiovascular and cerebrovascular events were apparent with statin use in ALLHAT. There are numerous reasons why the ASCOT and ALLHAT results are so different. First of all, the baseline demographics of the patients included in the two trials differ substantially; the ALLHAT patient population was slightly older and included patients with a history of CHD (14%), as well as a greater proportion of women and non-white patients. More importantly, there was a substantial use of statins among the patients in the usual care group of ALLHAT, which resulted in a LDL-cholesterol difference of only 17% between the two groups (compared to 29% in ASCOT). Consequently, the most conceivable explanation to account for this discrepancy between the results of ASCOT and ALLHAT is the dose-response effect on cardiovascular events that we expect to be associated with the degree of LDL-cholesterol reduction achieved.

The observation in ASCOT that there was no significant benefit of atorvastatin among women and patients with diabetes contradicts the findings of sub-group analyses of prior lipid-lowering outcome studies. While this observation is surprising, it is likely just a reflection of the fact that there were relatively few events experienced among these patient subgroups. A primary endpoint occurred in only 36 women and 84 diabetics during the study follow-up. Since the study was discontinued prematurely, the apparent lack of benefit of atorvastatin is probably a chance observation due to lack of power to detect a true difference among in these subgroups.

While the current study assessed the benefits of cholesterol lowering in the primary prevention of CHD in hypertensive patients who might not conventionally be considered dyslipidemic, the average number of cardiovascular risk factors (in addition to hypertension) of the population included in the trial was 3.7. The authors report that the placebo group experienced the equivalent of a 9.4% 10-year coronary event rate (non-fatal MI and fatal CHD), which represents a low risk population. However without the average blood pressure reduction of 25/14 mmHg that was achieved in this trial over the follow-up period, the true 10-year coronary risk in the placebo population would have been closer to 15%, indicating that this was at least moderate risk population. Consequently, the data from ASCOT provide support for the adoption of lower lipid treatment thresholds and targets in the clinical practice guidelines, which are currently being revised in Canada. The post-hoc analysis that revealed similar hazard ratios (HR) for the primary endpoint across a range of baseline total cholesterol values (<5.0 mmol/L: HR = 0.63; p=0.098; 5.0-5.99 mmol/L: HR = 0.62; p=0.011; ≥6.0 mmol/L: HR = 0.69; p=0.084) also lends support for lowering the recommended lipid targets.

One important methodological issue that should be highlighted is that nearly 40% of the patients enrolled in this trial would have been classified as being at very high risk for CAD (10-year risk of CAD >30%), based on North American guidelines. (7,8)  From their medical histories, many of these patients had what is considered to be a coronary heart disease (CHD) equivalent: ~25% had diabetes, ~10% had a prior stroke or TIA, and the ~5% of had peripheral vascular disease. In accordance with the current Canadian guidelines7 and usual contemporary practice, these patients would be usually be treated with a statin to achieve a target LDL-cholesterol of <2.5 mmol/L.

ASCOT is the first study to prospectively demonstrate the significant benefits of a statin in patients with hypertension for the primary prevention of both coronary and cerebrovascular events. However, these results confirm the expected benefits of statin therapy observed in subgroup analyses from earlier trials. In addition, by enrolling patients with total cholesterol ≤6.5 mmol/L, this trial extends the range of serum cholesterol across which statins have a proven benefit. Consequently, the importance of this trial will not come from its influence on individual patient pharmacotherapeutic decisions but from its potential to impact the treatment thresholds and lipid targets recommended in future clinical practice guidelines. With the new Canadian guidelines for the management and treatment of dyslipidemia looming on the horizon, we shall soon see whether or not ASCOT has had an impact.

Reviewer Competing Interests

Dr. Pearson has served as a consultant to and received payment for speaking at meetings or funding for clinical research from pharmaceutical companies marketing lipid-lowering medications, including Astra-Zeneca Canada Inc., Bristol-Myers Squibb Canada Inc., Merck Frosst Canada Inc, Merck-Frosst/Schering Pharmaceuticals and Pfizer Canada Inc.

Technology in Practice

helping pharmacotherapy practitioners use technology to enhance their practice

Securing Confidential Data On Your Personal Digital Assistant (PDA):

Part 1. Using The Security Options Built Into The Palm Operating System

Introduction

Do you feel you can’t live without your PDA? Do you rely on the device to help you get through your workday? Perhaps much of your clinical practice and research data resides on this portable device. Imagine the anxiety surrounding the theft or loss of this information repository. Losing a PDA is undoubtedly inconvenient, but for health care professionals the consequences may be more significant than merely inconvenience. Loss of a PDA that contains patient information places patient confidentiality at risk. It behooves healthcare providers to take measures to protect PDA based confidential data.

Some authors suggest that, at a minimum, health care providers should use four basic strategies to safeguard the PDA at all times:

1) activate password protection to control access to information on the device;

2) ensure proper user and device authentication before transmitting information during synchronization;

3) avoid wireless data transmission in public areas, and;

4) employ data encryption technology.

Encryption refers to the translation of data into a secret code that is not readable without first “decrypting” it. Unencrypted data is known as plain text while encrypted data is called ciphertext. This is the first of a two-part article that outlines some PDA security options relevant to health care providers.

The purpose of Part I of the article is to describe how to use the built-in security features of the Palm Operating System (OS) to password protect and lock the device from unauthorized access. Part II of this series will outline some strategies for enhancing PDA security with data encryption and more rigorous access control.

Password Protecting PDA Access Using Security Features Of The Palm OS

The Palm OS includes security features that can be enabled to lock access to the device. A very basic way to protect data is to enable the auto lock security feature on the PDA. This provides a minimal level of data protection whereby a security screen prompts the user to enter a password upon turning on the device. Several steps are required in order to activate the auto lock feature on Palm OS PDAs. These steps are described below.

Procedures For Activating The Palm OS “auto lock” Security Feature
Step 1. Tap the security icon on the main application launcher screen (Figure 1). Figure 1. Application launcher screen

 

Step 2. Click on the password “Unassigned” area on the security screen (Figure 2). Figure 2. Security Screen
Step 3. Enter a password on the password screen (Figure 3). A “hint” can be entered to help users remember a forgotten password. Users will be prompted to re-enter the password on a subsequent screen for verification before the assigned password takes effect. Click “OK” and this will return you to the security screen (Figure 2). Figure 3. Password entry screen
Step 4. After entering and verifying a password, click on the “Auto Lock Handheld” on the security screen (Figure 2). This will bring up the “Lock Handheld” screen where users can specify when the PDA should be locked (Figure 4). Choosing the “On power off” option will require password entry whenever the PDA is turned on. Figure 4. Lock Handheld Screen

Locking Your PDA With A Pen Stroke

A quick method of powering off and locking access to the PDA requires taking advantage of the pen stroke customization features built into the Palm OS. These customization options can be set to enable the PDA user to power off and lock the PDA by sliding the stylus from the bottom to the top of the PDA screen. This option can be set by tapping on the “Prefs” button on the application launcher screen (Figure 1) and selecting the “pen” option from the bottom of the “Preferences” screen (Figure 5). The subsequent screen (Figure 6) provides a list of options or functions that the PDA will perform when the user slides the stylus from the bottom of the writing area to the top of the PDA screen. The pen stroke locking feature is a convenient way for healthcare professionals to seamlessly lock their devices after inputting or reviewing information on the PDA.

Figure 5. Preferences screen.The Pen button on the bottom of the screen provides a list of controls that can be executed by subsequent pen (stylus) strokes. Figure 6. Pen options screen.Selecting “Turn Off & Lock” will enable the user to turn off and lock the PDA by sliding the pen (stylus) from the bottom to the top of the PDA screen.

Limitations Of Palm OS Built-in Security Features

Although the security features built into the Palm OS are easy to activate and convenient to use, they provide only a low level of protection that a knowledgeable programmer can bypass. Version 5 of the OS includes more robust protection than the preceding versions, but some limitations still remain. There are no lower limits on password lengths and thus users can choose inappropriately short or simple passwords. Also, the password obfuscation is weak. Short passwords that consist of only alpha characters are not as secure as passwords that exceed four characters in length and include both alpha and numeric characters. Security experts indicate that the password storage methods on the palm PDA are not well encrypted and are vulnerable to decoding. Other security vulnerabilities that are related to the HotSync procedure, data ownership, network and wireless data transmission and programming code also exist.

Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule

In the United States, the Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule requires both improved efficiency in healthcare delivery by standardizing electronic data interchange, and better protection of confidentiality and security of health data through setting and enforcing standards. While the HIPAA Privacy Rule is specific to the US, all health care professionals have an ethical obligation to protect the confidentiality of patient information. HIPAA dictates that there must be a reasonable assurance that the PDA will not be accessible to unauthorized users. While HIPAA does not mandate that PDA-based records be secured with data encryption technology, some authors suggest that health care professionals who store patient information on a PDA should employ strategies that include data encryption, as well as both user and device authentication.

Summary

Health care providers who store confidential data on PDAs need to take steps to ensure information confidentiality. The Palm OS includes some convenient security features that prevent unauthorized access to the PDA. Some experts recommend that enhanced security, above what the built-in OS features can offer, is prudent in the health care setting. Part II of this series will outline some strategies for enhancing PDA security by including data encryption and more rigorous data access control.

Authors Competing Interests

None declared. The authors have not received any research funding, speaker honoraria, complementary hardware or software from any company for any product pertaining to this manuscript.

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